BACKGROUND OF THE INVENTION European Patent 309,477 relates to ecteinascidins 729,743,745,759A, 759B and 770. The ecteinascidin compounds are disclosed to have antibacterial and other useful properties. Ecteinascidin 743 is now undergoing clinical trials as an antitumour agent.

Ecteinascidin 743 has a complex tris (tetrahydroisoquinolinephenol) structure of the following formula (I) : In ecteinascidin 743, the 1,4 bridge has the structure of formula (IV): Other known ecteinascidins include compounds with a different bridged cyclic ring system, such as occurs in ecteinascidin 722 and 736, where the bridge has the structure of formula (V): ecteinascidins 583 and 597, where the bridge has the structure of formula (VI) : and ecteinascidin 594 and 596, where the bridge has the structure of formula (VII) : The complete structure for these and related compounds is given in J. Am. Chem.

Soc. (1996) 118, 9017-9023. This article is incorporated by reference.

The ecteinascidins are currently prepared by isolation from extracts of the marine tunicate Ecteinascidin turbinata. The yield is low, and alternative preparative processes have been sought.

A synthetic process for producing ecteinascidin compounds is described in US Patent 5,721,362, see also WO 9812198. The claimed method is long and complicated. By way of illustration, there are 38 Examples each describing one or more steps in the synthetic sequence to arrive at ecteinascidin 743.

Claim 25 of US 5,721,362 is directed at an intermediate phenol compound of a given formula (11), which we refer to also as Intermediate 11 or Int-11. It has the following bis (tetrahydroisoquinolinephenol) structure (II): where MOM is a methoxymethyl substituent and TBDPS is a tert-butyldiphenylsilyl substituent.

From Intermediate 11 it is possible to synthesise another interesting antitumour agent, phthalascidin, see Proc. Natl. Acad. Sci. USA, 96,3496-3501,1999. Phthalascidin is a bis (tetrahydroisoquinolinephenol) derivative of formula (III): More generally, phthalascidin and related compounds are described in WO 0018233.

Claim 1 is directed at compounds of formula: wherein the substituent groups defined by R,, R2. R3, R. 4, R5, R6, R7, R8 and R9 are each independently selected from the group consisting of H, OH, OR', SH, SR', SOR', SO2R', NO2, NH2, NHR', N (R') 2, NHC (O) R', CN, halogen, =O, C (=O) H, C (=O) R', COSH, CO2R', C1-C12 alkyl, C2-C12 alkenyl, C2-Clr alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic; wherein each of the R'groups is independently selected from the group consisting of H, OH, N02, NH2, SH, CN, halogen, =0, C (=O) H, C (=O) CH3, C02H, CO2CH3, C,-C, 2 alkyl, C2- C12 alkenyl, C2-C12 alkynyl, aryl, aralkyl, and heteroaromatic; wherein each dotted circle represents one, two or three optional double bonds; wherein R7 and R8 may be joined into a carbocyclic or heterocyclic ring system; and wherein X and X2 are each independently defined as above for R)-Rs and further include various permitted definitions.

Further naturally occuring compounds are known which lack a bridged cyclic ring system. They include the bis (tetrahydroisoquinolinequinone) antitumor-antimicrobial antibiotics safracins and saframycins. and the marine natural products renieramicins and xestomycin isolated from cultured microbes or sponges. They all have a common dimeric tetrahydroisoquinoline carbon framework. These compounds can be classified into four types, types I to IV, with respect to the oxidation pattern of the aromatic rings.

Type I, dimeric isoquinolinequinones, is a system of formula (VIII) most commonly occurring in this class of compounds, see the following table I.

Table I Structure of Type I Saframycin Antibiotics.

Substituents <BR> <BR> <BR> <BR> Compound Rl4a Rl4b R21 R25a R25b R2sc<BR> <BR> <BR> <BR> <BR> saframycin A H H CN O O CH3<BR> <BR> <BR> <BR> <BR> <BR> saframycin B H H H O O CH3<BR> <BR> <BR> <BR> <BR> saframycin C H OCH3 H O O CH3<BR> <BR> <BR> <BR> <BR> <BR> saframycinG H OH CN O O CH3 saframycin H H H CN OH CH2COCH3 CH3 <BR> <BR> <BR> saframycin S H H OH O O CH3 saframycin Y3 H H CN NH2 H CH3 saframycin Ydl H H CN NH2, H CH2H5 saframycin HHCN00C2H, <BR> <BR> <BR> <BR> saframycin Yd2 H H CN NH, H H<BR> <BR> <BR> <BR> <BR> <BR> <BR> saframycinY2b H Q CN NH. H CH3 saframycin Y2b-d H Qb CN NH2 H C2H5 saframycin AH2 H H CN Ha OHa CH3 <BR> <BR> <BR> <BR> saframycin AH2Ac H H CN H OAc CH3 saframycin AH1 H H CN OHa Ha CH3 saframycin AHlAc H H CN OAc H CH3 <BR> <BR> <BR> <BR> saframycin AR3 H H H H OH CH3 a assignments are interchangeable. b where the group Q is of formula (IX) : Type I aromatic rings are seen in saframycins A, B and C; G and H ; and S isolated from Streptomyces lavendulae as minor components. A cyano derivative of saframycin A, called cyanoquinonamine, is known from Japanese Kokai JP-A2 59/225189 and 60/084288.

Saframycins Y3, Yd I, Ad I, and Yd2 were produced by S. lavendulae by directed biosynthesis, with appropriate supplementation of the culture medium. Saframycins Y2b and Y2b. d dimers formed by linking the nitrogen on the C-25 of one unit to the C-14 of the other, have also been produced in supplemented culture media of S. lavendulae. Saframycins AR, (=AH2,), a microbial reduction product of saframycin A at C-25 produced by Rhodococcus amidophilus, is also prepared by nonstereoselective chemical reduction of saframycin A by sodium borohydride as a 1: 1 mixture of epimers followed by chromatographic separation [the other isomer AH, is less polar]. The further reduction product saframycin AR3. 21- decyano-25-dihydro-saframycin A. (= 25-dihydrosaframycin B) was produced by the same microbial conversion. Another type of microbial conversion of saframycin A using a Nocardia species produced saframycin B and further reduction by a Mvcobacterium species produced saframycinAH'Ac. The 25-0-acetates of saframycin AH, and AH) have also been prepared chemically for biological studies.

Type I compounds of formula (X) have also been isolated from marines sponges, see Table II.

Table II Structures of Type I Compounds from Marine Sponges.

Substituents R"a R R R renieramycin A OH H H-C (CH3) =CH-CH3 renieramycin B OC2H5 H H-C (CH3) =CH-CH3 renieramycin C OH O O-C (CH3) =CH-CH3 renieramycin D OC2H5 0 0-C (CH3) =CH-CH3 renieramycin E H H OH-C (CH3) =CH-CH3 renieramycin F OCH3 H OH-C (CH3) =CH-CH3 xestomycin OCH3 H H-CH3 Renieramycins A-D were isolated from the antimicrobial extract of a sponge, a Reniera species collected in Mexico, along with the biogenetically related monomeric isoquinolines renierone and related compounds. The structure of renieramycin A was initially assigned with inverted stereochemistry at C-3, C-11, and C-13. However, careful examination of the'H NMR data for new, related compounds renieramycins E and F, isolated from the same sponge collected in Palau, revealed that the ring junction of renieramycins was identical to that of saframycins. This result led to the conclusion that the formerly assigned stereochemistry of renieramycins A to D must be the same as that of saframycins.

Xestomycin was found in a sponge, a Xestospongia species collected from Sri Lancan waters.

Type II compounds of formula (XI) with a reduced hydroquinone ring include saframycins D and F, isolated from S. lavendulae, and saframycins Mx-1 and Mx-2, isolated from Myxococcus xanthus. See table III.

Table III Type II Compounds Substituents Compound R14a R14b R21 R25a R25b R25c saframycin D O O H O O CH3 saframycin F O O CN O O CH3 saframycin Mx-1 H OCH3 OH H CH3 NH2 saframycin Mx-2 H OCH3 H H CH3 NH2 The type III skeleton is found in the antibiotics safracins A and B, isolated from cultured Pseudomonasfluorescens. These antibiotics of formula (XII) consist of a tetrahydroisoquinoline-quinone subunit and a tetrahydroisoquninolinephenol subunit. where R2'is-H in safracin A and is-OH in safracin B.

Saframycin R, the only compound classified as the Type IV skeleton, was also isolated from S. lavendulae. This compound of formula (XIII), consisting of a hydroquinone ring with a glycolic ester sidechain on one of the phenolic oxygens, is conceivably a pro-drug of saframycin A because of its moderate toxicity.

All these known compounds have a fused system of five rings (A) to (E) as shown in the following structure of formula (XIV): The rings A and E are phenolic in the ecteinascidins and some other compounds, while in other compounds, notably the saframycins, the rings A and E are quinolic. In the known compounds, the rings B and D are tetrahydro, while ring C is perhydro.

SUMMARY OF THE INVENTION The present invention provides new compounds with the fused system of five rings (A) to (E). In particular, it provides new compounds which can be made from intermediates described in WO 9812198 or by a new process which is part of this invention. In this latter respect, we refer to our WO 0069862 published 23 November 2000, and which relates to hemisynthetic methods and new compounds. The present application claims priority from that PCT filing, and we incorporate that text by reference to the extent that there is disclosure therein which is not in the present specification.

In WO 0069862, various routes are described for the preparation of ecteinascidin compounds, including ecteinascidin 743, as well as ecteinascidin analogs including phthaliscidin. The present invention is founded partly on the use of intermediates of WO 0069862 to prepare further analogs of the ecteinasacidins.

PREFERRED EMBODIMENTS We have found that compounds of the invention have exceptional activity in the treatment of cancers, such as leukaemias, lung cancer, colon cancer, kidney cancer and melanoma.

Thus, the present invention provides a method of treating any mammal, notably a human, affected by cancer which comprises administering to the affected individual a therapeutically effective amount of a compound of the invention, or a pharmaceutical composition thereof.

The present invention also relates to pharmaceutical preparations. which contain as active ingredient a compound or compounds of the invention, as well as the processes for their preparation.

Examples of pharmaceutical compositions include any solid (tablets, pills. capsules. granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable composition or oral, topical or parenteral administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. These compositions may need to be sterile when administered parenterally.

Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, intraperitoneal and intravenous administration. We prefer that infusion times of up to 24 hours are used, more preferably 2-12 hours, with 2-6 hours most preferred. Short infusion times which allow treatment to be carried out without an overnight stay in hospital are especially desirable.

However, infusion may be 12 to 24 hours or even longer if required. Infusion may be carried out at suitable intervals of say 2 to 4 weeks. Pharmaceutical compositions containing compounds of the invention may be delivered by liposome or nanosphere encapsulation, in sustained release formulations or by other standard delivery means.

The correct dosage of the compounds will vary according to the particular formulation, the mode of application, and the particular situs, host and tumour being treated.

Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.

The compounds and compositions of this invention may be used with other drugs to provide a combination therapy. The other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or a different time.

The identity of the other drug is not particularly limited, and suitable candidates include: a) drugs with antimitotic effects, especially those which target cytoskeletal elements, including microtubule modulators such as taxane drugs (such as taxol, paclitaxel. taxotere. docetaxel), podophylotoxins or vinca alkaloids (vincristine, vinblastine) ; b) antimetabolite drugs such as 5-fluorouracil, cytarabine, gemcitabine, purine analogues such as pentostatin, methotrexate); c) alkylating agents such as nitrogen mustards (such as cyclophosphamide or ifosphamide) ; d) drugs which target DNA such as the antracycline drugs adriamycin. doxorubicin, pharmorubicin or epirubicin; e) drugs which target topoisomerases such as etoposide; f) hormones and hormone agonists or antagonists such as estrogens. antiestrogens (tamoxifen and related compounds) and androgens, flutamide, leuprorelin. goserelin. cyprotrone or octreotide; g) drugs which target signal transduction in tumour cells including antibody derivatives such as herceptin; h) alkylating drugs such as platinum drugs (cis-platin, carbonplatin. oxaliplatin, paraplatin) or nitrosoureas; i) drugs potentially affecting metastasis of tumours such as matrix metalloproteinase inhibitors; j) gene therapy and antisense agents; k) antibody therapeutics; 1) other bioactive compounds of marine origin, notably the didemnins such as aplidine; m) steroid analogues, in particular dexamethasone; n) anti-inflammatory drugs, in particular dexamethasone; o) anti-emetic drugs, in particular dexamethasone; p) skeletal muscle protectors, such as L-carnitine or precursor amino acids.

The present invention also extends to the compounds of the invention for use in a method of treatment, and to the use of the compounds in the preparation of a composition for treatment of cancer.

In one aspect of the invention, we make no claim to the compounds 2. 3. 5. 8-OH-2. and 14 to 21 described in one or more of the GB priority patent applications for our PCT application published as 0069862. In a related aspect, the present invention extends to compounds which differ in respect of one or more of the substituents present at C-1, C-5. C- 7, C-8, or C-18 in the compounds of these GB priority patent applications.

The compounds of this invention include compounds which do not have a hydroxy group at the C-18 position. Furthermore, the compounds of this invention include compounds which do not have a dicarboximidomethyl substituent, such as phthalimidomethyl, at the C-1 position. In particular, we provide active compounds where the subsituent X1 is not as shown in the penultimate line at page 19 of WO0018233.

In one aspect, the analogs of this invention are typically of the formula (XVIIa) : or formula (XVIIb) : where R'is an optionally protected or derivatised aminomethylene group, an optionally protected or derivatised hydroxymethylene group; R4 is-H; R'is-H or-OH; R7 is-OCH3 and R8 is-OH or R7 and R8 together form a group -O-CH2-O-; R14a and Rl4b are both-H or one is-H and the other is-OH,-OCH3 or -OCH2CH3. or R14a and R14b together form a keto group; and Rl5 is-H or-OH; R2'is-H,-OH or-CN; and derivatives including acyl derivatives thereof especially where R is acetyloxy or other acyloxy group of up to 4 carbon atoms.

In the present invention, a key class of products includes phthalascidin and has the general formula (XX): where R'is an amidomethylene group; R is a small oxy-sidechain; and R21 is a cyano group or a hydroxy group. For phthalascidin, R'is a phthalimidomethylene group; R5 an acetoxy group; and R2'is a cyano group. Other groups for R'include mono-and di-N-substituted amidomethylenes as well as other cyclic amidomethylenes, and other groups for Rs include further Cl-C4 acyl groups, as well as Cl-C4 alkyl groups.

In the present invention, a key class of intermediates and analogs includes Intermediate 11 and has the general formula (XXI): where Protl and Prot2 are hydroxy protecting groups, preferably different. For Intermediate 11 itself the group Prot'is a methoxymethyl group, and Prot2 is a t-butyldiphenylsilyl group.

In the light of the preceding explanations, it can be seen that the present invention provides novel analogs and novel intermediate compounds. Depending on ring A, the compounds include those of formula (XXIIa) : or of formula (XXIIb): where: R'is-CH2NH2 or-CH20H, or a protected or derivatised version of such a group and R4 is- H; Rs is-OH or a protected or derivatised version of such a group; R14a and R14b are both-H or one is-H and the other is-OH or a protected or derivatised version of such a group,-OCH3 or-OCH2CH3, or R 14a and Rl4b together form a keto group; R12 is-H-,-CH3-or-CH2CH3- ; Rls is-H,-OH or a protected or derivatised version of such a group; and Rl8 is-OH or a protected or derivatised version of such a group.

In one embodiment, preferably at least of R1, R5, R14a, R14b, R15 or R18 is a protected or derivatised group.

In one variation of this invention, the group R'is not a tert-butyldiphenylsilyl substituent and/or the group Rl8 is not a methoxymethyloxy group.

Preferably R'is-CH2NH2 or-CH20H, or a protected or derivatised version of such a group and R4 is-H.

Preferably Rl4a and Rl4b are both-H.

Preferably Rl2 is-CH3.

One preferred class of intermediates includes the compound which we identify as compound 25, of formula: The preferred class is thus of the general formula where the group MOM is replaced by any other protecting group, and/or the allyl is replaced by any other protecting group.

Other preferred intermediates includes the compounds which we identify as compounds 17,43 and 45.

17 43 45 Other N-acyl derivatives may readily be made from compound 45 and are an important part of this invention. Suitable acyl groups include those previously mentioned. The corresponding 21-hydroxy compounds are also useful and are among the active compounds which we have found.

From the activity data and other considerations, it can be seen that the active compounds of this invention include a preferred class of compounds of the general formula (XXIII): where R'is as previously defined for formula (XVIIb) and is preferably a derivatised aminomethylene group of moderate bulk ; R5 is as previously defined for formula (XVIIb) and is preferably a derivatised hydroxy group of low bulk; R 12 is as previously defined and is preferably-CH3- ; and R21 is a hydroxy or cyano group.

R'is suitably a hydrophobic group and which thus lacks free amino, hydroxy or other hydrophilic function. Typically R'is a group-CH2-NH2-CO-Ra, where Ra is as defined but preferably has a linear chain length of less than 20 atoms, more preferably less than 15 or 10 atoms, where a 1,4-phenyl is counted as a chain length of four atoms and similar considerations apply to other cyclic groups (for example, 1,2-cyclohexyl is chain length of two), and the linear chain of less than 10,15 or 20 atoms can itself be substituted. In particular, the data suggests there is a balance to be achieved between having no such group Ra-CO-and having a large, bulky group.

In one variation, we prefer that R'is free from cyclic groups, especially aromatic groups. In a related variation, the present invention does not prepare the compounds which are described in the article Proc. Natl. Acad. Sci. USA, 96,3496-3501,1999, incorporated by reference. Our preferred groups for R'exclude the corresponding substituents CH2R2 shown in Table 1 of that article, specifically the groups A, B, C and D for R2.

R is preferably an acetyl group.

In particularly preferred compounds, the group R'is acylated on an-NH2 group, and for example N-acyl derivatives can be formed from groups-CH2NH2 and-CH2-NH-aa. The acyl derivatives can be N-acyl or N-thioacyl derivatives thereof. The acyl groups can be of formula-CO-Ra, where Ra is as defined and is chosen to meet the indicated criteria.

Suitable acyl groups include alanyl, arginyl, aspartyl, asparagyl, cystyl, glutamyl, glutaminyl, glycyl, histidyl, hydroxyprolyl., isoleucyl, leucyl, lysyl, methionyl, phenylalanyl, prolyl, seryl, threonyl, thyronyl, tryptophyl, tyrosyl, valyl, as well as other amino acid acyl groups, which may be L-or D-. Such amino acid acyl groups are preferred derivatised on the amino group to give hydrophobicity.

In a variation, the group R'is a derivatised hydroxymethylene group. Similar considerations apply as with the derivatised aminomethylene group.

The invention extends to compounds where the various substituents around the ring are as defined in the WO 0018233, which we incorporate by reference. Thus, as appropriate, substituents in the present compounds can be chosen, among other possibilites from H, OH, OR', SH, SR', SOR', S02R', N02, NH2, NHR', N (R') 2, NHC (O) R', CN, halogen, =O, Cl-C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic; wherein each of the R'groups is independently selected from the group consisting of H, OH, NO2, NH2, SH, CN, halogen, =O, C (=O) H, C (=O) CH3, C02H, C02CH3. C-C6 alkyl, phenyl. benzyl and heteroaromatic.

Suitable halogen substituents in the compounds of the present invention include F, Cl, BrandI.

Alkyl groups preferably have from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, and most prefereably 1,2,3 or 4 carbon atoms. Methyl, ethyl and propyl including isopropyl are particularly preferred alkyl groups in the compounds of the present invention. As used herein, the term alkyl, unless otherwise modified, refers to both cyclic and noncyclic groups, although cyclic groups will comprise at least three carbon ring members.

Preferred alkenyl and alkynyl groups in the compounds of the present invention have one or more unsaturated linkages and from 2 to about 12 carbon atoms, more preferably 2 to about 8 carbon atoms, still more prefereably 2 to about 6 carbon atoms, even more prefereably 1,2,3 or 4 carbon atoms. The terms alkenyl and alkynyl as used herein refere to both cyclic and noncyclic groups, although straight or branched noncyclic groups are generally more preferred.

Preferred alkoxy groups in the compounds of the present invention include groups having one or more oxygem linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms, and most preferably 1,2,3 or 4 carbon atoms.

Preferred alkylthio groups in the compounds of the present invention have one or more thioether linkages and from 1 to about 12 carbon atoms, more prefereably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylthio groups having 1,2,3 or 4 carbon atoms are particularly preferred.

Preferred alkylsulfinyl groups in the compounds of the present invention include those groups having one or more sulfoxide (SO) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfinyl groups having 1,2,3 or 4 carbon atoms are particularly preferred.

Preferred alkylsulfonyl groups in the compounds of the present invention include those groups having one or more sulfonyl (S02) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfonyl groups having 1, 2,3 or 4 carbon atoms are particularly preferred.

Preferred aminoalkyl groups include those groups having one or more primary, secondary and/or tertiary amine groups, and from I to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, even more preferably 1,2,3 or 4 carbon atoms. Secondary and tertiary amine groups are generally more preferred than primary amine moieties.

Suitable heteroaromatic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, e. g., coumarinyl including 8-coumarinyl, quinolinyl including 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl and benzothiazol. Suitable heteroalicyclic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, e. g., tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolindinyl groups.

Suitable carbocyclic aryl groups in the compounds of the present invention include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups. Typical carbocyclic aryl groups contain 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms. Specifically preferred carbocyclic arykl groups include phenyl including substituted phenyl, such as 2-substituted phenyl, 3- substituted phenyl, 2,3-substituted phenyl, 2,5-substituted phenyl, 2.3.5-substituted and 2,4,5-substituted phenyl, including where one or more of the phenyl substituents is an electron-withdrawing group such as halogen. cyano, nitro. alkanoyl, sulfinyl. sulfonyl and the like; naphthyl including 1-naphthyl and 2-naphthyl; biphenyl; phenanthryl: and anthracyl.

Any references herein to substituted groups in the compounds of the present invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups, e. g., halogen such as fluoro, chloro, bromo and iodide; cyano; hydroxyl; nitro; azido; alkanoyl such as a C1-6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about °2 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms ; alkoxy groups having those having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms or from I to about 6 carbo atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms ; alkylsulfinyl groups including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; carbocyclic aryl having 6 or more carbons, particularly phenyl (e. g., R being a substituted or unsubstituted biphenyl moiety); and aralkyl such as benzyl.

Without being exhaustive, in terms of the formula: preferred compounds of this invention have one or more of the following definitions: Rl is-OR, where R is H, acyl, especially acetyl, alkyl-CO- (alkyl being up to about 20 carbon atoms, more preferably from 1 to about 12 carbon atoms, and especially an odd number of carbon atoms such as 3,5,7 and 9), cycloalkyl-alkyl-CO-and especially alkyl groupings with a terminal cyclohexyl group and up to six additional carbon atoms in the sidechain, or a protecting group, especially methoxymethyl. and R, is more especially OH.

R2 is methoxy.

R3 is methyl.

R4 is hydrogen.

R5 is methyl or hydrogen, especially methyl.

R6 is-CN or-OH.

Xl is-NHR',-NH-aa-R'or-OR'where aa is an optionally protected amino acid acyl group, especially alanine, phenylalanine, cysteine, proline, valine, arginine, tryptophan or other amino acid. Other possibilities for X include-N (R') 2,-N (R')-aa-R', and-N- (aa-R') 2. In the case of any group-aa-R', the R'is usually on the amino group of the amino acid, and there may be two such substituents. R'is preferably H; alkyl-CO- (alkyl being up to 25 carbon atoms, such as up to 17,19 or 21 carbon atoms and preferably an odd number of carbon atoms corresponding to a fatty acid carboxylic acid of even number of carbon atoms or else a low number of carbon atoms such as 1 to 6), especially CH3- (CH2) n-CO- where n is for example 1,2,4,12 or 16; alkenyl, especially allyl; haloalkyl-CO-, especially CF3-CO- ; cycloalkyl-alkyl-CO-, preferably alkyl groupings with a terminal cyclohexyl group and up to six additional carbon atoms in the sidechain, especially cyclohexyl- (CH2) n-CO- where n is for example 1 or 2; haloalkyl-O-CO-, especially trichloroethoxycarbonyl; arylalkyl-CO-or arylalkenyl-CO-especially phenyl-methyl/ethyl/vinyl-CO-, where aryl may be substituted as in trifluoromethylcinnamoyl; optionally substituted heteroaryl-CO-, where the substituents and heterocyclic group are as elsewhere discussed, as in 2-chloronicotinoyl; alkenyl-CO- especially crotonyl; opitionally subsituted aminoalkyl-CO-, particularly amino acid acyl, especially alanine, phenylalanine, cysteine, proline, valine, arginine, tryptophan or other amino acid, or a derivative thereof, as in Boc-phenylalanine, valine, proline, arginine or tryptophan, or as in phenethylalanine, trifluoroethylacetylalanine, trifluorodiacetylalanine and isomers thereof, or diacetyl-or dipropionyl-trifluoroacetyl, or as in or as in Cbz-Val-or a group notionally derived from cysteine and being of general formula ProtSH-S-CH2-C (=NOProt°H)-CO-or ProtSH-S-CH=C (-OProt°H)-CO-, where ProtSH and Prot°H are protecting groups for thiol and for hydroxy, especially where ProtSH is Fm and Prot is methoxy for the first formular MOM for the second formula ; or other possibilities such as a protecting group as in an alkoxycarbonyl such as Boc, or PhNR'CS. The various groups may be susbtituted as indicated elsewhere in this specification.

R7 and Rg are-O-CH2-O-or R7 is =O and Rs is OMe, especially R7 and Rg are-O-CH2-O-.

Rg is methyl.

X2 is-OR", where R"is preferably H; alkyl-CO-, especially acetyl; alkenyl especially allyl; alkenyl-O-CO-, especially allyl-O-CO- ; haloalkyl-CO-, especially trifluoromethylcarbonyl or chloromethylcarbonyl or 2-chloroethylcarbonyl or perfluoropropylcarbonyl.

Of special interest are compounds wherein: Ri is-OR, where R is H or acetyl, alkyl-CO-, especially n-propyl-CO-, and Rl is more especially OH.

R2 is methoxy.

R3 is methyl.

R4 is hydrogen.

R5 is methyl.

R6 is-CN or-OH.

XI is-NHR', where R'is preferably alkenyl, especially allyl, alkyl-CO- (alkyl being 1 to 6 carbon atoms, especially CH3- (CH2) n-CO- where n is for example 1 to 6, and more especially 1 to 4); cycloalkyl-alkyl-CO-, especially cyclohexyl- (CH2) n-CO where n is 1 or 2; arylalkyl-CO-or arylalkenyl-CO-especially phenethylcarbonyl, phenylvinylcarbonyl or benzylcarbonyl, alkenyl-CO-especially CH3-CH=CH-CO- ; amino acid acyl, especially Cbz- Val- ; optionally substituted heteroaryl-CO-, especially 2-chloropyridinylcarbonyl ; or X, is-NH-aa-R'where aa is alanine, phenylalanine, tryptophan or valine; R'is an amino subsituent and is arylalkyl-CO-especially phenethylcarbonyl or benzylcarbonyl; alkyl-CO- (alkyl being 1 to 6 carbon atoms, especially CH3- (CH2) n-CO- where n is for example 1 to 6 and more especially 1,2 or 4; alkenyl-CO-especially CH3-CH=CH-CO- ; or protecting group especially alkyloxy-CO as in Boc; or Xi is-OR'where R'is preferably alkyl-CO- (alkyl being 1 to 6 carbon atoms, especially CH3- (CH2) n-CO- where n is for example 1 to 6, and more especially 2; arylalkyl-CO-or arylalkenyl-CO-especially phenethylcarbonyl, phenylvinylcarbonyl or trifluoromethylcinnamoyl.

R7 and R8 are-O-CH2-O-.

Rg is methyl.

X2 is-OR", where R"is H; acetyl, allyloxycarbonyl, chloromethylcarbonyl or perfluoropropylcarbonyl; and R"is more especially H; acetyl or allyloxycarbonyl.

Especially preferred embodiments of the present invention are the novel ecteinascidin-like compounds with the following general structures I, II and III that have been prepared from compounds 17,25,43 and 45 derived from cyanosafracin B.

Compound 25 corresponds to the synthetic intermediate 3 described in US patent No 6,124,292. Wherein R', X2, Ri and R6 are each independently selected from the groups defined below: R' X2 R1 R6 H OH OH CN CH2CH=CH2 OAc OAc OH COCH2CH3 OCH2CH=CH2 OMOM<BR> COCH2CH2CH3 OCOOCH2CH=CH2 OCOCH2C6H" CO (CH2) 4CH3 OCOCF3 OCOCH2CH2C6H CO (CH2) 12CH3 OCOCH2C1 OCOCH2CH2CH3 CO (CH2) 16CH3 OCOCH2CH2CI OCO (CH2) 4CH3 COCH2C6H, OCOCF2CF2CF3 OCO (CH2) 8CH3 <BR> <BR> <BR> COCH2CH2C6H"OCO (CH2), 6CH3<BR> <BR> <BR> <BR> <BR> COOCH2CC13 COCH2Ph COCH2CH2Ph COCH=CHCH3 COCH=CHPh COCH=CHArCF3 COCH (CH3) NHCOCH2CH2Ph CO-(S)-CH (CH3) NHCOCF3 CO- (R)-CH (CH3) NHCOCF3 CO- (S)-CH (NHCbz) CH (CH3) 2 Boc CSNHPh In the formulae (XVIIa) or (XVIIb), Rl is typically aminomethylene, amidomethylene or R1 with R4 forms a group (IV) or (V). Suitable amidomethylene groups include those of formula-CH2-NH-CO-CHCH3-NH2 derived from alanine, and similar groups derived from other amino acids, notably, both D and L, glycine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, methionine, cysteine, aspartate, asparagine, glutamatic acid, glutaminyl lysine, arginine, proline, serine. threonine, histidine and hydroxyproline. A general formula for the group Rl is then-CH2-NH-aa, where aa indicates an acyl amino acid group.

The group RI can be acylated on an-NH2 group, and for example N-acyl derivatives can be formed from groups-CH2NH2 and-CH2-NH-aa. The acyl derivatives can be N-acyl or N-thioacyl derivatives thereof, as well as cyclic amides. The acyl groups can illustratively be alkanoyl, haloalkanoyl, arylalkanoyl, alkenoyl, heterocyclylacyl. aroyl, arylaroyl, haloaroyl, nitroaroyl, or other acyl groups. The acyl groups can be of formula- CO-Ra, where Ra can be various groups such as alkyl, alkoxy, alkylen, arylalkyl. arylalkylene, amino acid acyl, or heterocyclyl, each optionally substituted with halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy, alkyl, amino or substituted amino. Other acylating agents include isothiocyanates, such as aryl isothiocyanates, notably phenyl isocyanate. The alkyl, alkoxy or alkylene groups of Ra suitably have 1 to 6 or 12 carbon atoms, and can be linear, branched or cyclic. Aryl groups are typically phenyl, biphenyl or naphthyl. Heterocyclyl groups can be aromatic or partially or completely unsaturated and suitably have 4 to 8 ring atoms, more preferably 5 or 6 ring atoms, with one or more heteroatoms selected from nitrogen, sulphur and oxygen.

Without being exhaustive, typical Ra groups include alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, arylalkylene, haloalkylarylakylene, acyl, haloacyl, arlyalkyl, alkenyl and amino acid. For example, Ra-CO-can be acetyl, trifluoroacetyl, 2,2,2- trichloroethoxycarbonyl, isovalerylcarbonyl, trans-3- (trifluoromethyl) cinnamoylcarbonyl, heptafluorobutyrylcarbonyl, decanoylcarbonyl, trans-cinnamoylcarbonyl, butyrylcarbonyl, 3- chloropropyonylcarbonyl, cinnamoylcarbonyl, 4-methylcinnamoylcarbonyl, hydrocinnamoylcarbonyl, or trans-hexenoylcarbonyl, or alanyl, arginyl, aspartyl. asparagyl, cystyl, glutamyl, glutaminyl, glycyl, histidyl, hydroxyprolyl., isoleucyl, leucyl, lysyl, methionyl, phenylalanyl, prolyl, seryl, threonyl, thyronyl, tryptophyl, tyrosyl, valyl, as well as other less common amino acid acyl groups, as well as phthalimido and other cyclic amides.

Other examples may be found among the listed protecting groups.

Compounds wherein-CO-Ra is derived from an amino acid and include an amino group can themselves form acyl derivatives. Suitable N-acyl commands include dipeptides which in turn can form N-acyl derivatives.

In an important aspect of this invetnion, there are provided preferred compounds of the formula: wherein: R'is-CH2-N (R') 2 or-CH2-ORa, where Ra is H; alkyl-CO- ; haloalkyl-CO- ; cycloalkylalkyl- CO- ; haloalkyl-O-CO- ; arylalkyl-CO- ; arylalkenyl-CO- ; heteroaryl-CO- ; alkenyl-CO- ; alkenyl ; amino acid acyl ; or a protecting group; R5 is-OR", where R"is H; alkyl-CO- ; cycloalkyl-CO- ; haloalkyl-CO-or a protecting group ; Rl8 is-OR, where R is H, alkyl-CO- ; cycloalkylalkyl-CO- ; or a protecting group; R21 is-CN or-OH.

Typically such a compound is of the formula: wherein Rl, R5, R", and R21 are as defined.

In such preferred compounds of this invention, R1 can be-CH2-NHRa.

Ra can be-aa-Rb where aa is amino acid acyl and Rb is as defined for Ra. The amino acid acyl is optionally further substituted with one or more Ra groups.

In further preferred comopunds, Rl is-CH2-NH-aa-Rb where aa is an amino acid and Rb is hydrogen; protecting group; arylalkenyl-CO-; haloalkyl-CO-; alkyl-CO; arylalkyl-CO-; or amino acid acyl. Such comopunds include those wherein R1 is -CH2-NHaa-Rb where aa is alanine and Rb is hydrogen, Boc, PhNHCS-, CF3CO-, PhNAcCS-, trifluorocinnamoyl, cinnamoyl, C3F7CO-, butyryl, 3-chloroproprionoyl, hydrocinnamoyl, hexanoyl. phenylacetyl, Cbz-val or acetyl ;-CH2-aa-Rb where aa is valine and Rb is Cbz or Boc ;-CH,-aa-Rh where aa is phenylalanine and Rb is Boc ;-CH2-aa-Rb where aa is proline and R6 is Boc; -CH2-aa- Rb where aa is arginine and Rb is Boc; or-CH2-aa-Rb where aa is tryptophan and Rb is Boc.

Rl can be-CH2-NRa-aa-Rb where aa is an amino acid, Ra is alkyl-CO-and Rb is haloalkyl-CO-. Such compounds include those wherein R'is-CH2-NRa-aa-Rb where aa is acetylalanine, Ra is acetyl or butyryl, and Rb is CF3-CO-.

R'can be-CH2-NHRa where Ra is hydrogen, protecting group, alkyl-CO-; alkenyl- CO-; arylalkenyl-CO-; arylalkyl-CO-; heteroaryl-CO-; cycloalkylalkyl-CO-; or alkenyl.

Such compounds include those wherein R1 is -CH2-NHRa where Ra is hydrogen, Troc, acetyl; isovaleroyl, decanoyl, cinnamoyl, hydrocinnamoyl, phenylacetyl, propionyl, myristoyl, stearoyl, hexanoyl, crotonyl, chloronicotinoyl, cyclohexylacetyl, cyclohexylpropionyl or allyl.

R'can be-CH2-ORa where Ra is hydrogen; a protected cysteine; a cysteine derivative of the formula ProtSH-S-CH2-C (NHProtNH)-CO-, where ProtSH and ProtNH are protecting groups for thiol and for amino ; a protecting group; alkyl-CO- ; arylalkyl-CO- ; arylalkenyl- CO- ; a cysteine derivative of the formula ProtSH-S-CH2-C(=NOProtOH)-CO- where ProtSH and ProtOH are protecting groups for thiol and for hydroxy; or a cysteine derivative of formula ProtSH-S-CH=C(-OProtOH)-CO-, where ProtSH and Prot°H are protecting groups for thiol and for hydroxy. Such compounds include those wherein R'is-CH2-ORa where Ra is hydrogen; S-Fm-O-TBDMS-cysteine ; a cysteine derivative of the formula ProtSH-S-CH2-C (NHProtNH)- CO-, where ProtSH is Fm and Prot°H is Troc; TBDPS; butyryl ; trfiluormethylcinnamoyl ; cinnamoyl ; hydrocinnamoyl; a cysteine derivative of the formula ProtSH-S-CH2- C (=NOProt°H)-CO-where ProtSH is Fm and Prot°H is methoxy; or a cysteine derivative of formula ProtSH-S-CH=C (-OProt°H)-CO-, where Prote is Fm and Prot°H is MOM.

In these preferred compounds, Ri is suitably-OR", where R"is H; alkyl-CO where the alkyl has an odd number of carbon atoms, o-cyclohexylalkyl-CO-; or a protecting group.

In these preferred compounds, Rl8 is suitably-OR, where R is H, alkyl-CO- ; or a protecting group; In one variation which relates to intermediate products, the ring A is modified to incorporate the substructure shown as formula (XX) or (XXI), discussed later.

In another variation relating to intermediates, the group R'can be -CH20-CO-CFu-CH2-S-Prot3, derived from a compound of formula (XIX), where Prot3 and Fu have the indicated meanings. In such a case, R and R8 from the oxymethyleneoxy group. The group Rl8 is usually protected. Usually R2'is cyano.

Preferably Rl4a and R14b are hydrogen. Preferably Rl5 is hydrogen. The O-acyl derivatives are suitably aliphatic O-acyl derivatives, especially acyl derivatives of 1 to 4 carbon atoms, and typically an 0-acetyl group, notably at the 5-position.

Suitable protecting groups for phenols and hydroxy groups include ethers and esters, such as alkyl, alkoxyalkyl, aryloxyalkyl, alkoxyalkoxyalkyl, alkylsilylalkoxyalkyl, alkylthioalkyl, arylthioalkyl, azidoalkyl, cyanoalkyl, chloroalkyl, heterocyclic, arylacyl, haloarylacyl, cycloalkylalkyl, alkenyl, cycloalkyl, alyklarylalkyl, alkoxyarylalkyl, nitroarylalkyl, haloarylalkyl, alkylaminocarbonylarylalkyl, alkylsulfinylarylalky, alkylsilyl and other ethers, and arylacyl, aryl alkyl carbonate, aliphatic carbonate, alkylsulfinylarlyalkyl carbonate, alkyl carbonate, aryl haloalkyl carbonate, aryl alkenyl carbonate, aryl carbamate, alkyl phosphinyl, alkylphosphinothioyl, aryl phosphinothioyl, aryl alkyl sulphonate and other esters. Such groups may optionally be substituted with the previously mentioned groups in Rl.

Suitable protecting groups for amines include carbamates, amides, and other protecting groups, such as alkyl, arylalkyl, sulpho-or halo-arylalkyl, haloalkyl, alkylsilylalkyl, arylalkyl, cycloalkylalkyl, alkylarylalkyl, heterocyclylalkyl, nitroarylalkyl, acylaminoalkyl, nitroaryldithioarylalkyl, dicycloalkylcarboxamidoalkyl, cycloalkyl. alkenyl. arylalkenyl, nitroarylalkenyl, heterocyclylalkenyl, heterocyclyl, hydroxyheterocyclyl. alkyldithio, alkoxy-or halo-or alkylsulphinyl arylalkyl, hetercyclylacyl, and other carbamates, and alkanoyl, haloalkanoyl, arylalkanoyl alkenyl, heterocyclylacyl. aroyl, arylaroyl, haloaroyl, nitroaroyl, and other amides, as well as alkyl, alkenyl. alkylsilylalkoxyalkyl, alkoxyalkyl, cyanoalkyl, heterocyclyl, alkoxyarylalkyl. cycloalkyl, nitroaryl, arylalkyl, alkoxy-or hydroxy-arylalkyl, and many other groups. Such groups may optionally be substituted with the previously mentioned groups in Rl.

Examples of such protecting groups are given in the following tables. protection for-OH group ethers abbreviation methyl methoxymethyl MOM benzyloxymethyl BOM methoxyethoxymethyl MEM 2- (trimethylsilyl) ethoxymethyl SEM methylthiomethyl MTM phenylthiomethyl PTM azidomethyl cyanomethyl 2,2-dichloro-l, l-difluoroethyl 2-chloroethyl 2-bromoethyl tetrahydropyranyl THP 1-ethoxyethyl EE phenacyl 4-bromophenacyl cyclopropylmethyl allyl propargyl isopropyl cyclohexyl t-butyl benzyl 2,6-dimethylbenzyl 4-methoxybenzyl MPM or PMB o-nitrobenzyl 2,6-dichlorobenzyl 3,4-dichlorobenzyl 4- (dimethylamino) carbonylbenzyl 4-methylsuflinylbenzyl Msib 9-anthrylmethyl 4-picolyl heptafluoro-p-tolyl tetrafluoro-4-pyridyl trimethylsilyl TMS t-butyldimethylsilyl TBDMS t-butyldiphenylsilyl TBDPS triisopropylsilyl TIPS esters aryl formate aryl acetate aryllevulinate aryl pivaloate ArOPv aryl benzoate aryl 9-fluorocarboxylate aryl methyl carbonate 1-adamantyl carbonate t-butyl carbonate BOC-OAr 4-methylsulfinylbenzyl carbonate Msz-Oar 2,4-dimethylpent-3-yl carbonate Doc-Oar aryl 2,2,2-trichloroethyl carbonate aryl vinyl carbonate aryl benzyl carbonate aryl carbamate dimethylphosphinyl Dmp-OAr dimethylphosphinothioyl Mpt-OAr diphenylphosphinothioyl Dpt-Oar aryl methanesulfonate aryl toluenesulfonate aryl 2-formylbenzenesulfonate protection for the-NH2 group carbamates abbreviation methyl ethyl 9-fluorenylmethyl Fmoc 9- (2-sulfo) fluroenylmethyl 9- (2, 7-dibromo) fluorenylmethyl 17-tetrabenzo [a, c, g, i] fluorenylmethyl Tbfmoc 2-chloro-3-indenylmethyl Climoc benz [flinden-3-ylmethyl Bimoc 2,7-di-t-butyl [9- (10, 10-dioxo-10, 10,10,10- tetrahydrothioxanthyl)] methyl DBD-Tmoc 2,2,2-trichloroethyl Troc 2-trimethylsilylethyl Teoc 2-phenylethyl hZ 1- (1-adamantyl)-1-methylethyl Adpoc 2-chlooethyl 1,1-dimethyl-2-chloroethyl 1,1-dimethyl-2-bromoethyl 1,1-dimethyl-2,2-dibromoethyl DB-t-BOC 1,1-dimethyl-2,2,2-trichloroethyl TCBOC 1-methyl-1- (4-biphenyl) ethyl Bpoc <BR> <BR> <BR> <BR> <BR> 1- (3, 5-di-t-butylphenyl)-1-1-methylethyl t-Burmeoc 2- (2'-and 4'-pyridyl) ethyl Pyoc 2,2-bis (4'-nitrophenyl) ethyl Bnpeoc <BR> <BR> <BR> <BR> <BR> n- (2-pivaloylamino)-1, 1-dimethylethyl<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 2-[(2-nitrophenyl) dithio]-1-phenylethyl NpSSPeoc<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 2- (n, n-dicyclohexylcarboxamido) ethyl t-butyl BOC 1-adamantyl 1-Adoc 2-adamantyl 2-Adoc vinyl Voc allyl Aloc or Alloc 1-isopropylallyl Ipaoc cinnamyl Coc 4-nitrocinnamyl Noc 3- (3'-pyridyl) prop-2-enyl Paloc 8-quinolyl n-hydroxypiperidinyl alkyldithio benzyl Cbz or Z p-methoxybenzyl Moz p-nitrobenzyl PNZ p-bromobenzyl p-chlorobenzyl 2,4-dichlorobenzyl 4-methylsulfinylbenzyl Msz 9-anthrylmethyl diphenylmethyl <BR> <BR> <BR> <BR> phenothiazinyl- (l 0)-carbonyl<BR> <BR> <BR> <BR> <BR> n'-p-toluenesulfonylaminocarbonyl<BR> <BR> <BR> <BR> <BR> <BR> n'-phenylaminothiocarbonyl amides formamide acetamide chloroacetamide trifluoroacetamide TFA phenylacetamide 3-phenylpropanamide pent-4-enamide picolinamide 3-pyridylcarboxamide benzamide p-phenylbenzamide n-phthalimide n-tetrachlorophthalimide TCP 4-nitro-n-phthalimide n-dithiasuccinimide Dts n-2, 3-diphenylmaleimide n-2, 5-dimethylpyrrole n-2, 5-bis (triisopropylsiloxyl) pyrrole BIPSOP n-1, 1,4,4-tetramethyldisiliazacyclopentante adduct STABASE 1, 1, 3,3-tetramethyl-1,3-disilaisoindoline BSB special-NH protective groups n-methylamine n-t-butylamine n-allylamine n- [2-trimethylsilyl) ethoxy] methylamine SEM n-3-acetoxypropylamine n-cyanomethylamine n- (1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl) amine n-2, 4-dimethoxybenzylamine Dmb 2-azanorbornenes n-2, 4-dinitrophenylamine n-benzylamine Bn n-4-methoxybenzylamine MPM n-2, 4-dimethoxybenzylamine DMPM n-2-hydroxybenzylamine Hbn n- (diphenylmethyl) amino DPM n-bis (4-methoxyphenyl) methylamine n-5-dibenzosuberylamine DBS n-triphenylmethylamine Tr n- [ (4-methoxyphenyl) diphenylmethyll amino MMTR n-9-phenylflurenylamine Pf n-ferrocenylmethylamine Fcm n-2-picolylamine n'-oxide n-1, 1-dimethylthiomethyleneamine n-benzylideneamine n-p-methoxybenzylideneamine n-diphenylmethyleneamine n-(5, 5-dimethyl-3-oxo-1-cyclohexenyl) amine n-nitroamine n-nitrosoamine diphenylphosphinamide Dpp dimethylthiophosphinamide Mpt diphenylthiophosphinamide Ppt dibenzyl phosphoramidate 2-nitrobenzenesulfenamide Nps n-1-(2, 2,2-trifluoro-1,1-diphenyl) ethylsufenamide TDE 3-nitro-2-pyridinesulfenamide Npys p-toluenesulfonamide Ts benzenesulfonamide Examples of preferred methods of this invention will firstly be considered with reference to starting compunds 45, 43 and 25. It will be appreicated that the particular substituents, notably at positions C-5 and C-18. can be varied in the light of the present disclosure.

The preferred methods of producing the compounds of formula I, II and III are described below in the following reaction schemes with examples of typical substituent groups.

Scheme 1 As illustrated in Scheme 1 the first step for producing the preferred compounds (I) (where Ri = OH, X2 = OAc and R6 = CN or OH) of the present invention from compound 45 is the high yielding conversion of the amino group to the amide group.

After acylation of the amino group the second step is the transformation of the CN group into an OH group by reaction with silver nitrate in AcCN/H2O.

The preparation of other compounds of the general formula I of the present invention starting from compound 17 is described below (Scheme 4).

Scheme 2 As illustrated in Scheme 2 another group of interesting derivatives with formula II (where R, = OH, X2 = OAc and R6 = CN or OH) can be obtained from compound 43 using the following sequence. Acylation of the amino group to provide the corresponding amide and transformation of the CN group into an OH group by reaction with silver nitrate in AcCN/H20.

The preparation of other compounds of the general formula II of the present invention starting from compound 17 is described below (Scheme 4).

Scheme 3 III The preferred procedure for producing compounds of formula III is the transformation of compound 25 into the corresponding ester derivatives by acylation of the OH group, deprotection of the phenol group followed by acetylation and deprotection of the MOM group to provide the corresponding ester followed by transformation of the CN group to the OH group by reaction with silver nitrate in AcCN/H2O to give the compound of formula III (where R = OH, X2 = OAc and R6 = CN or OH).

Other compounds of the general formulae I and II of the present invention can be prepared from compound 17 via the amine intermediate 120 as described in Scheme 4.

Scheme 4 L'Ho orme Moto MOMO Me \° OMe YO HO ; t3Me OH Me Me \ CHZ=CHCFIpOCOCI M° W N--Me TFA Me N--Me N Me I/N I N J Phenylnsothpcyanate N p O = O CN - CN 0 \-O CN XMe c t -NHBoc Mye o ORME Orme HO/Me j HO Me HO/Me Me p HO OMe Me Ho N Me Me 0 HO OMe Me \ N_ _M Me \ i N I N I i N I Y N 'Me p _/NJ/ O N--MU NHCSNHPH NH2 NHR NHR MYE Me 120 Bu3SnH OMe ORME OMe HO Me OMe HO Me OH HO/Me OR OR R Cl N--Me N-j-Me \ pGNp3 Me N Me /Ny N--Me L 0L i N - Ny 0 Y = O CN 0 \.-O EN \-O N NHR NHR The following additional compounds of the present invention (including for example 140 and 141) have been prepared starting from cyanosafracin B (2) as described in detail in the examples (Scheme 5).

Scheme 5 As the skilled artisan will readily appreciate, the reaction schemes described herein may be modified and/or combined in various ways, and the compounds generated therefore are to be considered as being part of this invention. In particular the starting material and/or reagents and reactions can be varied to suit other combinations of the substituent groups in the formulae I, II and III.

In a related aspect, the present invention is directed at the use of a known compound, safracin B, also referred to as quinonamine, in hemisynthetic synthesis.

More generally, the invention relates to a hemisynthetic process for the formation of intermediates, derivatives and related structures of ecteinascidin or other tetrahydroisoquinolinephenol compounds starting from natural bis (tetrahydroisoquinoline) alkaloids. Suitable starting materials for the hemi-synthetic process include the classes of saframycin and safracin antibiotics available from different culture broths, and also the classes of reineramicin and xestomycin compounds available from marine sponges.

A general formula (XV) for the starting compounds is as follows: where: R'is an amidomethylene group such as -CH2-NH-CO-CR25aR25bR25c where R25a and R25b form a keto group or one is-OH,-NH2 or-OCOCH3 and the other is-CH2COCH3,-H,-OH or-OCOCH3, provided that when R25a is -OH or -NH2 then R25b is not-OH, and R25C is-H,- CH3 or-CH2CH3, or R'is an acyloxymethylene group such as-CH2-0-CO-R. where R is- C (CH3) =CH-CH3 or-CH3; R5 and R8 are independently chosen from-H,-OH or -OCOCH2OH, or R5 and R8 are both keto and the ring A is a p-benzoquinone ring; Rl4a and Rl4b are both-H or one is-H and the other is-OH,-OCH3 or-OCH2CH3, or Rl4a and R'4b together form a keto group; Rl5 and R18 are independently chosen from-H or-OH. or R5 and R8 are both keto and the ring A is a p-benzoquinone ring; and R2'is-OH or-CN.

A more general formula for these class of compounds is provided below: wherein the substituent groups defined by R1, R2, R3, R4, R5, R6, R7, Rs, Rg, Rlo are each independently selected from the group consisting of H, OH, OCH3, CN, =O, CH3; wherein X are the different amide or ester functionalities contained in the mentioned natural products; wherein each dotted circle represents one, two or three optional double bonds.

Thus, according to the present invention, we now provide hemisynthetic routes for the production of intermediates including Intermediate 11 and thus for the production of the ecteinascidin compounds as well as phthalascidin and additional compounds. The hemisynthetic routes of the invention each comprise a number of transformation steps to arrive at the desired product. Each step in itself is a process in accordance with this invention. The invention is not limited to the routes that are exemplified, and alternative routes may be provided by, for example, changing the order of the transformation steps, as appropriate.

In particular, this invention involves the provision of a 21-cyano starting material of general formula (XVI): h e Rl Rs R8 Rl4a Rl4b RlS and Rl8 are as defined.

Other compounds of formula (XVI) with different substituents at the 21-position may also represent possible starting materials. In general, any derivative capable of production by nucleophilic displacement of the 21-hydroxy group of compounds of formula (XV) wherein R21 is a hydroxy group cis a candidate. Examples of suitable 21-substituents include but are not limited to: a mercapto group; an alkylthio group (the alkyl group having from 1 to 6 carbon atoms); an arylthio group (the aryl group having from 6 to 10 carbon atoms and being unsubstituted or substituted by from 1 to 5 substituents selected from, for example, alkyl group having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, halogen atoms, mercapto groups and nitro groups); an amino group; a mono-or dialkylamino (the or each alkyl group having from I to 6 carbon atoms) : a mono-or diarylamino group (the or each aryl group being as defined above in relation to arylthio groups); an a-carbonylalkyl group of formula-C (Ra) (Rb)-C (=O) RC, where Ra and Rb are selected from hydrogen atoms, alkyl groups having from 1 to 20 carbon atoms. aryl groups (as defined above in relation to arylthio groups) and aralkyl groups (in which an alkyl group having from 1 to 4 carbon atoms is substituted by an aryl group a defined above in relation to arylthio groups), with the proviso that one of Ra and Rb is a hydrogen atom; R° is selected from a hydrogen atom, an alkyl group having from 1 to 20 carbon atoms. aryl groups (as defined above in relation to arylthio groups), an aralkyl group (in which an alkyl group having from 1 to 4 carbon atoms is substituted by an aryl group a defined above in relation to arylthio groups), an alkoxy group having from 1 to 6 carbon atoms, an amino group or a mono-or dialkylamino group as defined above.

Thus, in a more general aspect, the present invention relates to processes where the first step is to form a 21-deriviative using a nucleophilic reagent. We refer to such compounds as 21-Nuc compounds.

The presence of the 21-cyano group is required for some of the end-products, notably ecteinascidin 770 and phthalascidin, while for other end-products it acts as a protecting group which can readily be converted to another substituent, such as the 21-hydroxy group of ecteinascidin 743 or of 21-hydroxyphthalascidin. The adoption of the 21-cyano compound as the starting material effectively stabilises the molecule during the ensuing synthetic steps, until it is optionally removed. Other 21-Nuc compounds can offer this and other advantages.

In one important aspect, the present invention consists in the use of a 21-cyano compound of the general formula (XVI) in the preparation of a bis-or tris- (tetrahydroisoquinolinephenol) compounds. Products which may be prepared include intermediates such as Intermediate 11, and the ecteinascidins and phthalascidin, as well as new and known compounds of related structure.

Preferred starting materials include those compounds of formula (XV) or (XVI) where Rl4a and Rib are both hydrogen. Preferred starting materials also include compounds of formula (XV) or (XVI) where RIS is hydrogen. Furthermore, the preferred starting materials include compounds of formula (XV) or (XVI) where ring E is a phenolic ring.

Preferred starting materials further include compounds of formula (XV) or (XVI) where at least one, better at least two or three of R5, R8, Rls and Rl8 is not hydrogen.

Examples of suitable starting materials for this invention include saframycin A, saframycin B, saframycin C, saframycin G, saframycin H, saframycin S, saframycin Y3, saframycin Ydl, saframycin Ad,, saframycin Yd2, saframycin AH2, saframycin AH2Ac, saframycin AHI, saframycin AH, Ac, saframycin AR3, renieramycin A, renieramycin B, renieramycin C, renieramycin D, renieramycin E, renieramycin F, xestomycin, saframycin D, saframycin F, saframycin Mx-1, saframycin Mx-2, safracin A, safracin B and saframycin R.

Preferred starting materials have a cyano group in position 21, for the group R21.

In a particularly preferred aspect, the invention involves a hemisynthetic process wherein the transformation steps are applied to safracin B: SAFRACIN B Safracin B presents a ring system closely related to the ecteinascidins. This compound has the same pentacycle structure and the same substitution pattern in the right- hand aromatic ring, ring E. Also, safracin B presents very close similarities to some of the synthetic intermediates in the total synthesis of ET-743, particularly to the intermediate 11.

Such intermediate can be transformed into Et-743 using a well established method.

Synthetic conversion of safracin B into intermediate 11 will therefore provide an hemi- synthetic method to obtain ET-743.

Thus, we provide Intermediate 11 made from this compound safracin B, and compounds derived from Intermediate 11, particularly ecteinascidin compounds. We further provide phthalascidin made from safracin B. The invention also relates to use of safracin B in the production of Intermediate 11, phthalascidin, ecteinascidin compounds and the other intermediates of the invention. The invention also relates to compounds described herein derived from the other suggested starting materials, and use of those compounds in the production of such compounds.

The more preferred starting materials of this invention have a 21-cyano group. The currently most preferred compound of the present invention is the compound of Formula 2.

This compound is obtained directly from safracin B and is considered a key intermediate in the hemisynthetic process. compound 2 In a related aspect, we provide cyanosafracin B by fermentation of a safracin B- producing strain of Pseudomonasfluorescens, and working up the cultured broth using cyanide ion. The preferred strain of Pseudomonasfluorescens is strain A2-2, FERM BP-14, which is employed in the procedure of EP 055,299. A suitable source of cyanide ion is potassium cyanide. In a typical work-up, the broth is filtered and excess cyanide ion is added. After an appropriate interval of agitation, such as 1 hour, the pH is rendered alkaline, say pH 9.5, and an organic extraction gives a crude extract which can be further purified to give the cyanosafracin B.

Safracin B includes an alanyl sidechain. In one aspect of the invention, we have found that protection of the free amino group with a Boc group can give strong advantages.

In general, the conversion of the 21-cyano starting compound to an ecteinascidin analog of this invention can be carried out in accordance with our copending PCT patent application, attorney reference wpp83894, which also claims priority from the PCT filing published as WO 0069862 published 23 November 2000, and which relates to hemisynthetic methods and new compounds. We incorporate the text of the copending PCT application, attorney reference wpp83894, by reference to the extent that there is disclosure therein which is not in the present specification.

Typically the hemisynthesis of an analog of this invention involves: a) conversion if necessary of a quinone system for the ring E into the phenol system b) conversion if necessary of a quinone system for the ring A into the phenol system; c) conversion of the phenol system for the ring A into the methylenedioxyphenol ring; and d) derivatisation as appropriate, such as acylation.

Step (a), conversion if necessary of a quinone system for the ring E into the phenol system, can be effected by conventional reduction procedures. A suitable reagent system is hydrogen with a palladium-carbon catalyst, though other reducing systems can be employed.

Step (b), conversion if necessary of a quinone system for the ring A into the phenol system is analogous to step (a), and more detail is not needed.

Step (c), conversion of the phenol system for the ring A into the methylenedioxyphenol ring, can be effected in several ways, possibly along with step (b).

For example, a quinone ring A can be demethylated in the methoxy substituent at the 7- position and reduced to a dihydroquinone and trapped with a suitable electrophilic reagent such as CH2Br2, BrCH2CI, or a similar divalent reagent directly yielding the methylenedioxy ring system, or with a divalent reagent such as thiocarbonyldiimidazol which yields a substituted methylenedioxy ring system which can be converted to the desired ring.

Derivatisation in step (d) can include acylation, for instance with a group Ra-CO-as well as conversion of the 12-NCH3 group to 12-NH or 12-NCH2CH3. Such conversion can be effected before or after the other steps, using available methods.

By way of illustration, it is now feasible to transform cyanosafracin B in a shorter and more straightforward way to make new analogs. Cyanosafracin B can be transformed into Intermediate 25; INT-25 and from this derivative it is possible to introduce further analogs of this invention.

One method of this invention transforms cyanosafracin B into intermediate 25 through a sequence of reactions that involves essentially (1) removal of methoxy group placed in ring A, (2) reduction of ring A and formation of methylene-dioxy group in one pot, (3) hydrolysis of amide function placed over carbon 1, (4) transformation of the resulting amine group into hydroxyl group.

The conversion of the 2-cyano compound into Intermediate 25 usually involves the following steps (see scheme II): formation of the protected compound of Formula 14 by reacting 2 with tert-butoxycarbonyl anhydride ; converting of 14 into the di-protected compound of Formula 15 by reacting with bromomethylmethyl ether and diisopropylethylamine in acetonitrile ; selectively elimination of the methoxy group of the quinone system in 15 to obtain the compound of Formula 16 by reacting with a methanolic solution of sodium hydroxide; transforming of 16 into the methylene-dioxy compound of Formula 18 by employing the next preferred sequence: (1) quinone group of compound 16 is reduced with 10% Pd/C under hydrogen atmosphere; (2) the hydroquinone intermediate is converted into the methylenedioxy compound of Formula 17 by reacting with bromochloromethane and caesium carbonate under hydrogen atmosphere; (3) 17 is transformed into the compound of Formula 18 by protecting the free hydroxyl group as a OCH2R group. This reaction is carried out with BrCH2R and caesium carbonate, where R can be aryl, CH=CH2, OR'etc. elimination of the tert-butoxycarbonyl and the methyloxymethyl protecting groups of 18 to afford the compound of Formula 19 by reacting with a solution of HCI in dioxane. Also this reaction is achieved by mixing 18 with a solution of trifluoroacetic acid in dichloromethane; formation of the thiourea compound of Formula 20 by reacting 19 with phenylisothiocyanate; converting compound of Formula 20 into the amine compound of Formula 21 by reacting with a solution of hydrogen chloride in dioxane; transforming compound of Formula 21 into the N-Troc derivative 22 by reacting with trichloroethyl chloroformate and pyridine; formation of the protected hydroxy compound of Formula 23 by reacting 22 with bromomethylmethyl ether and diisopropylethylamine ; transforming compound of Formula 23 into the N-H derivative 24 by reacting with acetic acid and zinc; conversion of compound of Formula 24 into the hydroxy compound of Formula 25 by reaction with sodium nitrite in acetic acid. Alternatively, it can be used nitrogen tetroxide in a mixture of acetic acid and acetonitrile followed by treatment with sodium hydroxide.

Also, it can be used sodium nitrite in a mixture of acetic anhydride-acetic acid, followed by treatment with sodium hydroxide.

Scheme II OMe OMe Me 0 j! f ° J ° HO Me HO Me Me Me YY O Me I I N-'Me Boc20, EtOH I I Mc MOMBr, DIPEA I Me0 N/ hAep N Me ° °"-"\ NH NH M Ny NH2 NHBoc 0 NFN NHB Me 2 14 ° T Me Me O, Me O/Me \ OMe 0 O I OH I /Me OH NAOS 1M e ; 9 5 e Allyl bnomid M N--mu MeOHHo 2) ClBrCH2. C52CO3 Cs2C03 N O- O NHCN NHCN p NHCN NHB NHBoc -Boc 16 17 OMe 18 OMe Ha OCH Ho mye HCVDoxane4. 3M MW Phenylisothiorynnat v HCUDoxane43M ee --- N Me--- N/N, HO N CH2C'2 \-O'EN \-O O-NH NH NH oirNHCSNHPh O of NH2 20 21 19 25 The conversion of the Intermediate 25 compound into other analogs of this invention is then readily achieved, as illustrated for example in Scheme III, which usually involves the followingsteps: transforming compound of formula 24 into the derivative 30 by protecting the primary hydroxyl function with (S)-N-2,2,2-tricloroethoxycarbonyl-S- (9H-fluoren-9- ylmethyl) cysteine 29; converting the protected compound of formula 30 into the phenol derivative 31 by cleavage of the allyl group with tributyltin hydride and dichloropalladium-bis (triphenylphosphine). transforming the phenol compound of Formula 31 into compound of formula 32 by oxidation with benzeneseleninic anhydride at low temperature; The route described above to transform Intermediate 25 can be conveniently modified to form other derivatives.

In more detail, the conversion of the starting 21-cyano compound to a related product of this invention, such as one of formula (XX), usually involves the following steps: a) conversion if necessary of a quinone system for the ring E into the phenol system b) formation of the-R'group at the 5-position in ring A ; c) formation of the R'group at the 1-position in ring B ; and d) conversion if necessary of a quinone system for the ring A into the phenol system; e) conversion of the phenol system for the ring A into the methylenedioxyphenol ring.

These steps have many similarities with the steps given previously. Step (c) typically involves forming a group-CH2NH2 at the I-position and acylating it.

Phthlascidin can be made using Intermediates described in the conversion of cyanosafracin B into Intermediate 25. For example, Intermediates 21 and 17 are suitable starting materials to make Phthlascidin and other analogs of this invention.

As shown in scheme V, the process for the synthetic formation of phthlascidin starting from Intermediate 21 comprises the sequential steps of : transforming of 21 into the compound of Formula 27 by reaction with phthalic anhydride in dichloromethane and carbonyldiimidazole. converting of 27 into phthlascidin by reacting with tributyltin hydride and dichloro palladium-bis (triphenylphosphine) or basic media, followed by reaction with acetyl chloride.

Scheme V PMalascidin As shown in scheme VI, the process for the synthetic formation of phthlascidin starting from Intermediate 17 comprises the sequential steps of : acetylation of the hydroxyl group of compound of formula 17 with acetyl chloride and pyridine to give the acetylated intermediate compound of formula 42; removal of the tert-butoxycarbonyl and the methyloxymethyl protecting groups of 42 to afford the compound of Formula 43 by reacting with a solution of HCI in dioxane. Also this reaction is achieved by mixing 42 with a solution of trifluoroacetic acid in dichloromethane; formation of the thiourea compound of Formula 44 by reacting 43 with phenylisothiocyanate; converting compound of Formula 44 into the amine compound of Formula 45 by reacting with a solution of hydrogen chloride in dioxane; transforming of 45 into phthlascidin by reaction with phthalic anhydride in dichloromethane and carbonyldiimidazole. Other analogs can be made for example from 43 or 45 by a similar manner.

Scheme VI Me OMe OMe Me OMe I HO Me OH OVO I Me OAC v/ OAc Mye -0 .. 6N ° M')'" Me N-Me AcCi. PY _ CFizGz O i N /T l, CN 'NH N NHCN Of NHBoc 0eNH2 NHBoc 43 17 Pnenybsohtlocyanat CH2C'2 t CMe OMe HO/Me OMe HO, Me OAc O HO Me HO/Me OAc Onc mye Me OAc c 3M N,-e Me in D. n. 0 O f V O -0 CN -O oCN CtilGy. CDI -NH O N N N O-NHCSNHPh 45 44 44 PhtalasCdin The conversion of the 21-cyano compound to Intermediate 11 or a related intermediate of formula (XXI) usually involves the following steps: a) conversion if necessary of a quinone system for the ring E into the phenol system b) formation of the-OProtl group at the 18-position, in ring E ; c) formation of the-CH2-OProt2 group at the I-position, in ring B ; and d) conversion if necessary of a quinone system for the ring A into the phenol system; e) conversion of the phenol system for the ring A into the methylenedioxyphenol ring.

Step (b), formation of the-OProt'group at the 18-position in ring E, is a typical protection reaction for a phenol group, and no special comments need to be made.

Appropriate conditions are chosen depending on the nature of the protecting group. The other steps are similar to the other reactions.

Step (b), formation of the-CH2-OProt2 group at the 1-position in ring B, is normally carried out by forming a group-CH2NH2 at the 1-position and then converting the amine function to a hydroxy function and protecting. Thus, where the starting material has a group Rl which is-CH2-NH-CO-CR25aR2sbR2'c then it is matter of removing the N-acyl group.

Where the starting material has a group R'which is-CH2-0-CO-R then no change may be needed for an ecteinascidin product where the substituent R'is the same. For other products, it is matter of removing the O-acyl group. Various procedures are available for such de-acylations. In one variation, the deacylation and conversion to a hydroxy function are performed in one step. Thereafter, the hydroxy group can be acylated or otherwise converted to give the appropriate R'group.

U. S. Patent NA 5, 721,362 describe synthetic methods to make ET-743 through a long multistep synthesis. One of the Intermediates of this synthesis is Intermediate 11. Using cyanosafracin B as starting material it is possible to reach Intermediate 11 providing a much shorter way to make such Intermediate and therefor improving the method to make ET-743 Cyanosafracin B can be converted into Intermediate 25 by the methods described above. From Intermediate 25 is possible to reach Intermediate 11 using the following steps, see scheme VII. formation of the protected hydroxy compound of Formula 26 by reacting 25 with tert- butyldiphenylsilyl chloride in the presence of a base; final cleavage of the allyl group with tributyltin hydride and dichloropalladium-bis (triphenylphosphine) in 26 that leads to the formation of the intermediate 11.

Scheme VII Int-11 One embodiment of the synthetic process of the present invention to transform safracin B into intermediate 11 is a modification and extension of Scheme VIII and comprises the sequential steps of : stereospecifically converting the compound Safracin B to the compound of Formula 2 by selective replacement of OH by CN by reacting with KCN in acid media ; forming the thiourea compound of Formula 3 by reacting compound of Formula 2 with phenyl isothiocyanate; converting the thiourea compound of Formula 3 into the acetamide of Formula 5 by an hydrolysis in acid media followed by addition of acetic anhydride; The intermediate amine compound of Formula 4 can be isolated by quenching the hydrolysis in acid media with sodium bicarbonate, but this intermediate is highly unstable, and is transformed quickly into a five member cyclic imine, named compound 6; forming the protected compound of Formula 7 by reacting with bromomethylmethyl ether and diisopropylethylamine in dichloromethane; selectively de-methylating the methoxy group of the quinone system of compound of Formula 7 into the compound of Formula 8 by reacting with methanolic solution of sodium hydroxide; transforming the compound of Formula 8 into methylenedioxy-compound of Formula 9 by the preferred following sequence: (1) quinone group of compound 8 is reduced with 10% Pd/C under hydrogen atmosphere; (2) the hydroquinone intermediate is converted into the methylene-dioxy compound of Formula 9 by reacting with bromochloromethane and cesium carbonate under hydrogen atmosphere; (3) compound of Formula 9 is transformed into compound of Formula 10 by protecting the free hydroxyl group as a OCH2R group. by reacting with BrCH2R and cesium carbonate, where R can be aryl, CH=CH, OR'etc. ; converting the acetamide group of compound of Formula 10 into the corresponding hydroxyl group of Formula 11 by reaction with nitrogen tetroxide in a mixture of acetic acid and acetic acetate followed by treatment with sodium hydroxide; alternatively can be used sodium nitrite in a mixture of acetic anhydride acetic acid, followed by treatment with sodium hydroxide; alternatively the acetamide group of compound of Formula 10 can be converted into the primary amine group by reacting with hydrazine or with Boc, O DMAP followed by hydrazine; such primary amine can be converted into the corresponding hydroxyl group (compound of Formula 11) by an oxidative conversion of the primary amine into the corresponding aldehyde with 4-formyl-1-methylpyridinium benzenesulphonate or other pyridinium ion, followed by DBU or other base treatment and further hydrolization, and followed by the reduction of the aldehyde to the corresponding hydroxyl group with lithium aluminium hydride or other reducing agent ; forming the protected compound of Formula 26 by reacting with t-butyldiphenylsilyl chloride and dimethylaminopyridine in dichloromethane; transforming the silylated compound of Formula 26 into the intermediate 11 by deprotection of the OCH2R protecting group, by reacting under reductive conditions or acid conditions.

Typical procedures are with palladium black under hydrogen atmosphere, or aqueous TFA, or tributyltin hydride and dichlorobis (triphenylphosphine palladium).

In yet another preferred modification, the cyano compound of Formula 2 can be transformed into Intermediate 11 using an extension of the scheme II, involving the further steps of. formation of the protected hydroxy compound of Formula 26 by reacting 25 with tert- butyldiphenylsilyl chloride in the presence of a base; final cleavage of the allyl group with tributyltin hydride and dichloropalladium-bis (triphenylphosphine) in 26 that leads to the formation of the intermediate 11.

Thus, it is possible to transform cyanosafracin B into a number of intermediates and derivatives with potential antitumor therapeutic activity. These intermediates can be made starting from already described compounds, or using alternative routes.

Intermediates described herein comprise compound 47, and a numbers of amide derivatives made using compounds 45 or 43.

In Scheme VIII is described formation of compound 47 using the following sequence: forming the thiourea compound of Formula 3 by reacting compound of Formula 2 with phenyl isothiocyanate; converting the thiourea compound of Formula 3 into the acetamide of Formula 5 by an hydrolysis in acid media followed by addition of acetic anhydride; The intermediate amine compound of Formula 4 can be isolated by quenching the hydrolysis in acid media with sodium bicarbonate, but this intermediate is highly unstable, and is transformed quickly into a five member cyclic imine, named compound 6; forming the protected compound of Formula 7 by reacting with bromomethylmethyl ether and diisopropylethylamine in dichloromethane; selectively de-methylating the methoxy group of the quinone system of compound of Formula 7 into the compound of Formula 8 by reacting with methanolic solution of sodium hydroxide; transforming the compound of Formula 8 into methylenedioxy-compound of Formula 10 by the preferred following sequence: (1) quinone group of compound 8 is reduced with 10% Pd/C under hydrogen atmosphere; (2) the hydroquinone intermediate is converted into the methylene-dioxy compound of Formula 9 by reacting with bromochloromethane and cesium carbonate under hydrogen atmosphere; (3) compound of Formula 9 is transformed into compound of Formula 10 by protecting the free hydroxyl group as a allyloxy group, by reacting with allyl-bromide and cesium carbonate; transforming the compound of formula 9 into acetyl-derivative 46 by reaction with acetyl chloride in pyridine; transforming compound of formula 46 into de-protected compound 47 by reaction with hydrochloric acid in dioxane.

Scheme VIII o on or. k OMe OMe OMe OMe '1 0 0 0 Me m Me Me N J Me I I N_-Me PnenWmmne MC N_ _t HGVbonw 8 5u MC N 1/ HG 6 SNVDIOXANi Me I I V N =, :) u N CH, C 2) NAHCO3 0 AcOEt/WOHrrEA N EN 0 CN 2 osS9NHz 3 NHCSNHPH 4 6 T 1) HG 6. 5WDIOXANE 2) Ac>O OYE ORME Me & Me N- N--W WWBR. DIPEA kk N. CH N--Me N OMe OMe o 5 0 o e 0 N 0 0 EN aN 7) Garc-H. GzCO ; j/ cc, c /N o = _ o'y NHN NHCN 10 OMe HOHo me / OAc Onc ° "°\ \ 1 AcCI. PV/N p ./ AcCl. py INN 0 CH2r42 0 \-O OUT O Other useful amide intermediate derivatives are made starting from already described intermediate 45 using the next scheme: Scheme IX The second step is optional. This process is an important part of the invention, particularly where the group R is a group Ra as previously defined. Furthermore, the Scheme VIII can be readily broadened to enable preparation of compounds of formula (XXIII), by inclusion in the starting material of a different group at the 5-position, either a group directly intended for the product or a group which can be removed or otherwise modified to give the desired group.

From compound 45 can be made a group of analogs through the following sequence: acylation in the amino group of compound of Formula 45 by a wide range of acyl derivatives to provide the corresponding amides, where preferred acyl groups are acetyl, cinnamoyl chloride, p-trifluorocinnamoyl chloride, isovaleryl chloride phenylisothiocyanate or aminoacids, or the other examples previously given of groups RaCO-. transforming the CN group into an OH group by reaction with silver nitrate in a mixture AcN/H20.

Other useful amide intermediate derivatives are made starting from already described intermediate 43 using the next scheme: Scheme X From Compound 43 can be obtained another group of interesting derivatives using the following sequence: (a) acylation in the amino group of compound of Formula 43 by a wide range of acyl derivatives to provide the corresponding amides, where preferred acyl groups are acetyl, cinnamoyl chloride, p-trifluorocinnamoyl chloride, isovaleryl chloride or aminoacids, or the other examples previously given of groups RaCO-.

(b) transforming the CN group into an OH group by reaction with silver nitrate in a mixture AcN/H20 Reflecting the active compounds, an important process in accordance with this invention is as follows: where Rs for the end product is as defined for the compound (XXII) and may be different in the starting material and converted thereto as part of the process, Rl8 is a hydroxy group in the end product but may be a protected hydroxy group in the starting material and converted thereto as part of the process, R12 for the end product may be the same as in the starting material or may be converted thereto as part of the process, R21 for the end product is as defined and if a hydroxy group may be formed from a cyano group as part of the process, Ra is as defined, and may be further acylated as part of the process to give an end product with an acylated Ra group as discussed.

Rs is preferably oxyacetyl or other small oxyacyl group in the starting material and is not changed in the reaction. R'8 is preferably a hydroxy group in the starting material and is not changed in the reaction. RIZ is preferably-NCH3-in the starting material and is not changed in the reaction. R21 the end product is as defined and if a hydroxy group may be formed from a cyano group as part of the process. Ra is in the final product is preferably as defined in relation to the compound of formula (XXIII).

Another important method of this invention includes the reaction: Another important method of this invention includes the reaction: Another important method of this invention includes the reaction includes the reaction where a group R'is aminomethylene is converted to a hydroxymethylene group.

Another important method of this invention includes the reaction for preparing a 21- cyano compound of formula (XVI) which comprises reacting a compound of formula (XV): where Rl. R5, R8 Rl4a, Rl4b Rl 5 and Rl 8 are as defined and R2 is a hydroxy group, with a source of cyanide ion, to give the desired 21-cyano compound.

In addition, processes using other nucleophile-containing compounds, to produce similar compounds of formula (XVI) wherein the 21-position is protected by another nucleophilic group, a 21-Nuc group, are also envisaged. For example, a 21-Nuc compound of formula (XVI) with an alkylamino substituent at the 21-position can be produced by reacting the compound of formula (XV) wherein R21 is a hydroxy group with a suitable alkylamine. A 21-Nuc compound of formula (XVI) with an alkylthio substituent at the 21- position can also be produced by reacting the compound of formula (XV) wherein R2'is a hydroxy group with a suitable alkanethiol. Alternatively, a 21-Nuc compound of formula (XVI) with an a-carbonylalkyl substituent at the 21-position can be produced by reacting the compound of formula (XV) wherein R21 is a hydroxy group with a suitable carbonyl compound, typically in the presence of a base. Other synthetic routes are available for other 21-Nuc compounds.

Another important reaction of this invention involves treatment of a 21-cyano product of this invention to form a 21-hydroxy compound. Such compounds have interesting in vivo properties.

For the avoidance of doubt, the stereochemistries indicated in this patent specification are based on our understanding of the correct stereochemistry of the natural products. To the extent that an error is discovered in the assigned stereochemistry, then the appropriate correction needs to be made in the formulae given throughout in this patent specification.

Furthermore, to the extent that the syntheses are capable of modification, this invention extends to stereoisomers.

CYTOTOXIC ACTIVITIY ICso OM) Compound P-388 A-549 HT-29 MEL-28 CV-1 DU-145 OMe HOMME O Me N Me0 2 0. 009 0. 018 0. 018 0. 018 0. 023 2 ou. HO Me HOMME N--M, Ma N--Me Me0 met N O NHCN O, O 0.15 >0.15 0.15 >0.15 OY 14 i o _ MMeo/Me 0 Mye meo-IJO 0 aN Mye0 O NHCN O of NH + 1. 44 1.44 1.44 1.44 OMe oye O mye N--mye HA O NHCN O >1. 5 >1.5 >1. 5 >1.5 16 X OMe OMe OH Mye N--Me /N O nu 0+ 1. 4 1.4 1.4 1.4 ° 17 Oye MiMeMt 'o Me N--Me /N o of NH T u O NHCN O t O I G (t O I Cl l 6 0. 01 0.01 0.01 0.01 18 orme- HOMME M. mye I NN--Me /N NHCN \-O aN 0 con NH 0. 08 0. 16 0. 01 0. 16 orme- - O Mye N--Me zon N--M, NHCN 0. 01 0. 01 0. 01 0. 01 QNHCSNHPh CN OMe-_. HOMME HO M. H 21 0. 019 0.019 0.019 0.019 o - Zon \-O N4N 21 Ho O Mye Me N- O NHCN NH 0. 014 0.014 0.014 0.014 0.014 0.014 _ ZU O Mye Me /N NHCN Oko cH2cci 23 0.13 0.13 0.13 0.13 0.13 0.13 om Me O MtÒMe 0. 18 1. 8 1. 8 1 8. 1 8 N= o NH2 24 ou, OMe ' Moto Mye N--mye /N 0 NHCN OH 25 0. 2 0.2 0.2 0.2 0.2 - OMe K2N OMe 35 0 Me U cyme 36 OU, ORME -o'c'N 36 M. OH J J . 0 O CN ° 36 OMe HO/Me OH Me N--Me N O O N 0. 001 0.001 0.001 0.001 0.001 0.001 i oM __- l OMe OC mye N--Me /N NEZ 0. 13 0.13 0.13 0.13 0.13 OMe OM OM. _ HO Me OAC Mua N--Me N O wO-0. 008 0.016 0.008 0.008 0.016 NHz om. Omis HO Me OAC Me HO N--Me /N RAZ onc Gaz N-- OMe HOMME ONC Me I IJ N-Me. V. V1... OMe <Me 0. 01 0. 01 0. 01 0. 01 0. 01 tnNH 45 3 oh HOMME 0 Y-"-" or con NH NU OYE OMe OMe H, M O I T'M 6 2. 171 2. 171 2. 171 2. 171 2. 171 OM. OMe HO Y "'YTV"'0. 005 0. 005 0. 005 0. 005 OMe O NHCN MeO _ Oo Me N Mye e OYE mye0 O NHCN NH 0. 22 0.22 0.22 0.22 0.22 o 7 oM- OMe 0-0 Mye Me N HO ° >9 >18. 1 >18. 1 >18. 1 >18. 1 8 OMe..... _-. Mevl OH Me Yin \ 0 '"nr"' 9 OMIS "o O Mye \ N_ _ /N oJs 10 >1. 65 >1.65 >1.65 >1. 65 >1.65 0 10 oMe. _.-... __ __ O, Onc mye N--Me O \-O-NH ZN 0.016 0.016 0.016 0.016 0.016 Me Me gaz HO-11, onc Mt N--Me O NHN \° NHCN 0. 001 0.001 0.001 0.001 0.001 47 OMe HO ONC Me -mye N O N 0. 0008 0. 001 0. 0008 0. 0008 0. 001 ok 48 OMe homme Oc mye N--mye \-O EN O -O NHCN oye Ho M. OMe- HO Me ONC Me N--Me O NH 0. 007 0. 007 0. 007 0. 007 0. 007 CF oye 50 OMe HO Me OAc Me i N Me 0 0 NH 0. 0001 0.0001 0.0001 0.0001 0.0001 me Nu ! NU "0 Me ONC Me J OAc Mye N Me 0 -0 CN NH Me Om 0. 001 0.001 0.001 0.001 0.001 , oye 2 OMe ; ß Me | OAc Me N Me Me J j) 0 NH 0. 0001 0.0001 0.0001 0.0001 0.0001 DNHCF3 Me 0 53 OMe HO Me PO Me N YMe me N-Me -. e ozon pNHCF Me 054 orme nNHCF, HO Me Ohm Mu i N Me . N, y 0 NHCF NH 0. 01 0. 01 0. 01 0. 01 0. 01 MeT 55 OMe OMe M. Mye N--Me O NHCN . H'. 0. 18 0.9 0.18 0.8 0.9 56 OMe.. __.. _.. __.- OMe OU Mye OH nor o nu 0. 14 0.14 0.14 0.14 0.14 "56 OMe HOJMe Me OC Me ° 57 . N NFIN V. VVI V. VVI V. VV1.. pNHCSNPh Q Ac 58 OMe HO Me OAc Me N mye zany 0 ,-o NH 6N 0. 001 0. 001 0.0001 0. 001 0.0005 N M. 0 tu Go OMe OMe OAc mye me, 0 0 NH NH 0. 001 0.001 0.001 0.001 0.001 -3FI 61 OMe HOME OAc Mye Me . N, y 0 NH H NH CN 0. 001 0.001 0.0005 0.001 M e Orme HO, OYE o Me . N, y 0 N 0. 0001 0. 0001 0. 0001 0. 0001 0. 0001 63 oye HO Me OAc Mu i N Me M. 0 NH N CI 0. 001 0. 001 0. 001 0. 001 "' 64 Oye HO Me Me Mye Memye \-o NAH °'° \H 0. 0001 0.0001 0.0001 0.0001 0.0001 65 orme HO Me OC Me NMR 0 NH"0. 0001 0. 0001 0. 0001 0. 0001 0. 0001 Cbz oye OMe-- ONC Mye Mye N mye 0 NH Me 0. 0001 0.0001 0.0001 0.0001 0.0001 -NHUCF3 Me0 67 OMe HOME Onc Mye OAc ho MYE NN--Me ° 68 0. 0008 0.001 0.0008 0.0008 0.001 OMe OMe Ho Me OAc Me i N Me . N, y o NH wo 0. 001 0.001 0.001 0.001 0.001 me Nu oye OMe OMe OAc Me N Me Q Ny -O OH nu 0. 0001 0.0001 0.0001 0.0001 0.0001 °'070 OMe HOMME OC Me N p. te OMe M ; r k r \< 0 CN 0 0 0 t) 1 0 U l > 0 I 0 U 0 t} i 0 0 0 0 [0 t N_'No-Me °"0. 0008 0. 0008 0. 0001 0. 0008 0. 0001 Q N''/1 OMe Ho mye OC Mye N mye Ny 0 NH 0. 0001 0.0001 0.0001 0.0001 0.0001 ob 74 Oye OMe HO oc Mye N-Me 0 Nu i 0. 0001 0.0001 0.0001 0.0001 0.0001 OMe OMe MO-Me OMe OC Me N Me N_, o 0 °"0. 0001 0.0001 0.0001 0.0001 0.0001 74 OMe Ho mye RAZ mye N mye _o NHN 0. 1 0. 1 0. 1 0. 1 0. 1 Nu oye ho mye OYE HOMME OAC mye N mye . N, y 0 OYE Ho Me OiCHz), e OMe HO, Me OAc Mezzo N mye zizi 0 O H °"0. 0001 0. 0001 0. 0001 0. 0001 0. 0001 0. 0001 oye Oye OAc Mu N mye 0 0 NHN 0. 0001 0. 0008 0. 0001 0. 0001 0. 0008 on OMe HO Me Oc Mu N mye Ny 0 N 0. 001 0. 001 0. 001 0. 001 0. 001 Mxr S Oye OMe OU, Onc N Me/N Me 0 p NH I y 0 NH OH 0. 0001 0.0001 0.0001 0.0001 0.0001 orme OMe OAc MYE N MYE 0 NH i I ''° \H° 0. 0007 0. 0007 0. 0007 0. 0007 0. 0007 tu OMe HO Me OC Me i N Me N_ °"° L°"0. 0001 0.0001 0.0001 0. 0001 0.0001 82 OMe HO Me OC Me NMR 0. 0001 0.0001 0.0001 0.0001 0.0001 0.0001 o- 83 OMe OMe OAc Mye i N Me i N, H NH 0. 0001 0.0008 0.0001 0.0001 0.0008 o 84 OMe HO Me Me J J OAc Me NO-Me Nu 0 0 N 0. 0006 0.001 0.0006 0.001 0.0006 Y- Mu 5 ,, O. 0 01 O. 0 01 (/O O 1 O O O 1 O O O I O O O I OMe OMe OAc \ M 0 Me NH 0. 001 0. 001 0. 001 0. 001 0. 001 0. 001 0- NH 86 OMe HO Me OAc Me zizi 0 NU \O CN 0. 0007 0.0001 0.0001 0.0001 0.0001 087 'M 87 OMe. _ Oye OAc Mye Me 0 Mye 0 cl O"^eN ° OH OMe Oye c MYE Me N nu H 0 NH 8N 0. 001 0.007 0.001 0.001 0.007 OMe Me" OMe 0 89 Oye Mye i N Me Nu mye NH H NHCbz 0 NHNNHCbz 0. 01 0.01 0.01 0.01 0.01 N Me0'90 Me go Oye Mye N mye o. NU H °"0. 001 0. 001 0.001 0. 001 0.001 me 0 91 oye HO Me Onc Me NMR NU o 0. 0001 0.0001 0.0001 0.0001 0.0001 me 0 9 zozo Mye 9 2 VMG H mye OAT Me N IAe zizi 0 NH nu 0. 001 0.001 0.001 0.001 0.001 0.001 <Me NH -)--93 OMe HO Me OC Me N mye N_J. 4Me 0 NH OH 0. 0007 0. 0007 0. 0007 0. 0007 0. 0007 O'ZH 0 MeN-"-C 94 OMe HO Me OAc J.. J) OAc Me, NYMe 0 OH 0 H 0. 0001 0. 0001 0. 0001 0. 0001 0. 0001 Me 0 95 OMe HO Me Me Mu N mye nu 0 H 0. 001 0.007 0.001 0.001 0.007 nu H Me 0 96 ^, 2 96 OMe OMe Me Nu 0 0 97 oye MOM MOM Me Me N AAe me N-Me o °">1 >1 >1 >1 zon OMe MOU Me MeÒMe _ Ny 0 °'099 °o i 99 Oye Me mou Me/N 6Ae 0 -0 \ CN 0 O/I/ 100 0. 1 0. 1 0. 1 0.1 0.1 oMe MOTO OH Me N-mye O. l O. 1 O. 1 O. 1 O. 1 ion Orme OMe Me/NYMe 0 con 0 \0 CN 0. 1 0.1 0.1 0.1 0.1 o4a3e, CF3 102 Oye OMe OH Oh NMR 0 00aN 0. 1 0. 1 0. 1 0. 1 0. 1 103 oye MOTO MYE OH OU -me 0 \0 CN 0. 1 0.1 0.1 0.1 0.1 104 oye OMe OMe OAc Mye N mye 0 oJ~ 105 0. 1 0.1 0.1 0.1 0.1 o- 105 go MOM Me OAc Me N 0 °"0. 6 0.6 0.6 0.6 0.6 O/\ CFs L 106 orme MOMO Me ONC pro, NMR \S0 Oc A 01 01 01 01 °o i oye orme- MOMO Me OAc mye N Me 0 uOO 0. 01 0. 07 0. 07 0. 07 0. 07 108 oye OMe Ou, Mye mye to N °"0. 0001 0.0008 0.0008 0.0008 0.0008 log ome OMe OC Me N Me Nu 0 mur 0. 001 0.001 0.001 0.001 0.001 omit oye ! HO Me HO Me Me J J OAc Mye N Me Nu 0 w 111 0. 0001 0.0001 0.0001 0.0001 0.0001 oye 111 OMe-- OMe OAc Mye N mye 0 °O-0. 0007 0. 0007 0. 0007 0. 0007 0. 0007 112 ome Ho mye OAc Mye N Me 0 °"0. 0001 0. 0001 0.0001 0.0001 0.0001 113 OMe Ho mye OC Me, N Me 0 0 \0 OH 0. 0001 0.0001 0.0001 0.0001 0.0001 O/\ CF3 ome OMe Me Onc Me, N Me . N, y 0 0 0. 0001 0.0001 0.0001 0.0001 0.0001 i5 oye "0 mye Onc onc nez mye 0. 0001 0.0007 0.0007 0.0007 0.0007 116 orme "0 Hz N-Me N-Me 0 NH NU r-NHBoc 0. 06 0. 06 0.06 0.06 0.06 "0 ° HA ° ° JT Me s N-Me Zany oye NH NU r""= i l g 0.001 0.001 0.001 0.001 0.001 OMe L. oye ouzo Me, nome N-. e NH Ne i, o .- OMe 0 H ome Me ouzo Me N-Me 0 06 0. 06 0. 06 0. 06 0. 06 nu, 120 L oye Orme 'o I Mye N--Me -O NHCN 0. 006 0. 006 0. 006 0. 006 0. 006 NI N, z Orme -M. ° JT Moto Me O- \-O CL "122 0.1 0.1 0.1 0.1 0.1 o OMe HO Me I HO Me Nu Mye \ N--Me O --O CN NH 0. 0001 0. 0001 0. 0001 0. 0001 0. 0001 M @ rMe Ho mye MOM O. mye N--Me O -O CN NH O I 125 0. 001 0.001 0.001 0.001 0.001 125 ORME Me Mye N--Me kan NU 0 TU NH 0. 0001 0. 0001 0. 0001 0. 0001 0.0001 Y) Ho 0 OMe Me N-- Mye o nu 0kr_ \-O NHCN 0. 0001 0. 0001 0. 0001 0. 0001 0. 0001 127 127 pue Ho11% zozo Me N--mec NIOLOS O NHH 0. 0001 0. 0001 0. OO00I 0.0001 0.0001 128 Oye MOMO/Mc Mye Me N--mye \-O-dH NU -O OF1 NH o 0. 1 0. 1 0. 1 0. 1 0. 1 Y OMe. _. _.. _ MOMOo7ßr Me OH ( Me Mu N 0 MH nu O 0. 1 0. 1 0. 1 0. 1 0. 1 130 momo Me -0 ? N MW Mye Me /N \-O TN -O CN NSi O "0 0. 5 0. 5 0. 5 0. 5 0. 5 131 "homo momo Me MOM" Mye N--Me -mu nu NH N O 133 0. 05 0.1 0.1 0. 1 0. 1 132 L OMe MOMO/Me QO NH N--mye /N O NNN 133 FI Orme F MOMO Me - Mye N--Me Me N--MU O CN NU 134 0. 5 0.5 0.5 0.5 0.5 0.5 OMe OMe NU FCO mye N--Me /N NH L--O CN NH O "Q 0.01 0.01 0.01 0.01 0. 01 am. '"Y\T" HOMME MYE Mye N--Me O NHN 0. 001 0. 001 0. 001 0. 001 0.001 Hz ci Orme HO O''O mye N--Me NU NU CN NH 137 0. 01 0.01 0.01 0.01 0.01 137 FF F F HO M. 'I F HO/Ms OXO Mye Mye /N N vC N nu 138 0. 006 0.006 0.006 0.006 0.006 c') am, 01. Ac0 Me O O Mye N--mu O NHN 0. 01 0. 01 0. 01 0. 01 0. 01 0 139 L 139 OMe HO MYE Ha mye I I N-'Me --MU Met ° 0. 08 0. 08 0. 08 0. 08 0. 08 'y 140 140 OMe HOMME Mye N--mye N Mye0 /"0. 01 0. 01 0. 01 0. 01 0.01 0. 01 141 (5m-- e HO/Me OAC Me Ho N--Me /N NU -O CN NIi of NHBOC 0. 0013 0.0013 174 OMe Ho OAC Me c mye RAZ Gaz Nu jazz 0 tu OMe HO Me OC Mye Ha OSA. OSA' -0 CN I N--Me N o LJ \-O CN ton OMe- HOMME ONC Mye N--Me HO Me O HAN NU NU NHBoc >1 >1 177 OMe Ho M. IRA. Mye N--mu O NH N o<NHBoc 0. 00012 0. 00012 END 178 OMe OAc H Me 0.012 0. 012 OAc Me e /N M zozos O OH nah UNS H 179 OMe HOMME OC Mye N--Me /N O -O CN NH oCl I N 0. 00015 0.00015 180 ; N Me 0.00015 Me ONC mye N--Me 181 ou oye H- Onc \-o CN 181 OMe HO/Me OAC Me N--Me s N O NHN O 0. 0015 0.0015 182 /j OMe osa. Oc mye N--mye /N N -O CN NH V 0. 013 0.013 183 orme HOMME OAc mye N--Me \-O-CN N. JNHN O/J 0. 0015 0.0015 184 ou. v'OMe OC mye Mye /N O zozo N NU zu wO c 0. 12 0.12 185 S OMe ME Mye Ou. M. NU N--. 1 NH O'/wPh 0. 0014 0.0014 186 0 OMe OMe OAC OAc I Me N--Me /N N5 Me CN \-O-CN Ru Ph 0. 013 0.013 187 0 xI1 OMe Me onc Mye Me N--Me N- r-. e NON N ^ _Ph N, FN 0. 012 0.012 188 0 OMe v O Me OAc 0-1 mye N--M, O O CN NU ON ^ _p zon 0. 06 0. 06 189 orme-- Oye ONC Mye °'NH raz O ZINN N ON'CF 0. 013 0. 013 190 U oye Ou. Oc Mye Nu r"YCF IT 0. 13 0. 13 191 OYE ace C) Ac OMe ru ONC Me 0--Me O O CN NAc Ac O _ N _CF Me Q 0. 12 0. 12 192 ^ OMe ? OMe OAC Me N--Me ) C NN- L O O N CN l'_ N II CFa ""° 0.11 0.11 193 o. ou. Me ONC Me N--mye N--Me o NHN TON IT 0.012 0.012 194 o. __ Me Me J J) ONC mye NU \-O'EN 0 N NHN 0_,, rH IT 0. 012 0. 012 195 0 J OMe /mye onc Mye N--mye N. O NHCN3 NH ON'CF IT 0. 1 0. 1 196 oye HO Me ONC mye zu \-O N N. O CN NH 197 OMe HOMME O Me N--Me I/N O O 0.0015 0.0015 Ooph 198 OMe M<MeMe mye- N mye /N 0 O CN ol >1 zozo 199 OMe MOTO Mesa mye Nu PO O -O CN 0. 056 0.056 MOM 202 202 CYTOTOXIC ACTIVITY (M) OUt HO Ue DUe OUe 1 41 A, OA. OAC I OAe I OAC I OAC OSA ./. O H a O N .-0 OH \ I LO OH LO OH L-O OH SOLID CFn pvHH O CF 66 TUMORS LINE Bladder 5637 6. 02E-10 3. 42E-10 1. 91E-10 2. 04E-11 Breast MX-1 1. 65E-06 NA 2. 38E-09 NA Colon HT-29 7.84E-10 1. 97E-08 2. 12E-09 8. 44E-12 Gastric Hs746t 7.90E-12 2. 18E-09 7. 10E-11 2. 21E-09 Liver SK-HEP-1 1. 79E-12 6. 01E-11 3. 15E-09 9. 91E-I I NSCL A549 3. 25E-09 7. 68E-06 NA NA Ovary SK-OV-3 4.39E-11 1. 02E-07 8. 74E-09 NA Pancreas PANC-1 7. 22E-11 4. 17E-09 1. 29E-10 1. 19E-10 Pharnynx FADU 5.41E-11 1.58E-09 3.71E-10 5.98E-09 Prostate PC3 6.65E-09 2.15E-09 4. 70E-09 1.52E-10 Prostate DU-145 5.73E-10 1.83E-07 $2.22E-09 NA Prostate LNCAP 5. 45E-10 2. 17E-10 3. 94E-11 Renal 786-O 6. 58E-12 1. 59E-09 1. 72E-09 1.03E-10 SCL NCI-H187 7.14E-14 9.57E-10 7.78E-14 Retinoblastoma Y-79 7.14E-14 7.36E-10 8.85E-11 Melanoma Mel-28 2.60E-10 3.17E-09 2, 18E-09 1.23E-10 Fibrosarcoma SW-694 9.91E-10 NA$1.39E-06 NA Chondrosarcoma CHSA 3. 24E-10 6. 77E-09 1. 39E-09 2. 30E-10 Osteosarcoma OSA-FH 1. 94E-09 1. 39E-09 1. 09E-09 1.11 E-10 ou HO . k HO Me H Ih OAC OAC OAC *H 0 Ho o_ once New -O QH \. D DH L-0 OH SOLID or", r^' o" o' I TUMORS LINE 94 Bladder 5637 1. 65E-10 7. 85E-10 3. 18-09 Breast MX-1 NA 2. 85E-06 NA Colon HT-29 7.43E-10 1. 2E-10 NA Gastric Hs746t 9. 35E-10 6. 25E-09 1. 37E-07 Liver SK-HEP-1 1. 40E-09 9. 03E-10 9. 50E-09 NSCL A549 NA NA NA Ovary SK-OV-3 NA NA Pancreas PANC-1 8.93E-10 2. 58E-9 1.03E-08 Pharnynx FADU 8.41E-103. 77E-081. I4E-09 Prostate PC3 8. 13E-10 9. 34E-09 Prostate DU-145 NA NA NA Prostate LNCAP NA Renal 786-0 7. 88E-10 2. 90E-09 1. OOE-08 SCL NCI-H187 2. 07E-12 Retinoblastoma Y-79 1. 31E-11 7. 78E-09 Melanoma Mel-28 1.08E-09 1.13E-09 4.48E-09 $Fibrosarcoma SW-694 NA Chondrosarcoma CHSA 1. 08E-09 2. 25E-09 1.09E-08 OsteosarcomaOSA-FH8. 84E-101. 35-089. 50E-09 _ _ HO tk HOw'W HO HO M-, N, ra. '', N Nu e"I M. ia ijw 0 0 ./0 H _ e nJ -o oH .. o oW.. o on -o oH HN NN HH NH LEUKEMIAS 66 w o v Y% v Y 66" & LINE 67 70 80 LYMPHOMAS ALL Promyelocytic 9. 38E-09 HL60 leukemia ALL Acute Molt 3 6. 13E-10 2.8E-09 5.66E-10 1. 55E-14 lymphoblastic CML Chronic K562 2.33E-07 myelogenous Leukemia Mo-B Hairy B-cell LymphomaT- H9 1.99E-11 cell Lymphoma Hut 78 5. 50E-11 2. 57E-10 4.62E-9 6.21E-1 I Cutaneus T cell Lymphoma MC116 2.15E-10 2.65E-10 3.8E-09 NA undifferentiated Lymphoma RAMOS 7.77E-13 Burkitts B celll Lymphoma U-937 1.77E-10 5.27E-11 3. 28E-11 3. 06E-11 Histiocytic OMt 0* 0 HOs 6H \-o 6H 0 NU NH Ale J J p Ny O ON .-O OH l. p LEUKEMIAS 0-illt" y r & LINE 92 94 81 LYMPHOMAS ALL Promyelocytic 5. 92E-09 1.23E-10 3.97E-10 HL60 leukemia ALL Acute Molt 3 8.85E-10 2.54E-09 7. 53E-12 lymphoblastic CML Chronic K562 1.09E-08 4.45E-08 myelogenous Leukemia Mo-B Hairy B-cell Lymphoma T- H9 4.48E-09 1.14E-08 cell Lymphoma Hut 78 9.9E-10 1.06E-08 7.46E-09 Cutaneus T cell Lymphoma MC 116 NA 1.41E-09 1.13E-08 undifferentiated Lymphoma RAMOS 5.26-11 8.85E-10 7.15E-09 Burkitts B celll Lymphoma ... U-937 5. 15E-10 Histiocytic OMe OMe HO, Me HO, Me Onc onc w W N-Me ole, Me W I Ny W I Ny L-O OH L-O OH SOLID TUMORS LINE 71 93 Bladder 56'7 2. 81 E-09 2. 84E-10 BreastMX-12. 50E-06NA Colon HT-29 NA 8. 97E-09 Gastric Hs746t 2. 97E-08 9. 19E-09 Liver SK-HEP-1 5. 07E-09 1. 08E-09 NSCL A549 NA 9. 41 E-09 Ovary SK-OV-3 2. 21E-07 NA Pancreas PANC-1 2. 90E-09 1. 00E-09 Pharnynx FADU 7. 94E-09 1. 39E-08 ProstatePC31. 46-089. 32E-10 Prostate DU-145 NA NA Prostate LNCAP 5. 39E-09 Renal 786-O 6. 55E-09 1. 72E-09 SCL NCI-H187 3. 98E-11 Retinoblastoma Y-79 3. 14E-09 Melanoma Mel-28 3. OSE-08 1. 15E-09 Fibrosarcoma SW-694 NA NA Chondrosarcoma CHSA 1. 73E-08 2. 1 OE-09 Osteosarcoma OSA-FH 8. 56E-08 1. 30E-09 OMe OMe OMe OM OAc Onc Me N-Me SOLID NH \O ÕH . _p- Nô N TUMORS LINE 82 95 Bladder 5637 9. 91E-10 1. 17E-09 Breast NA 1. 92E-09 Colon HT-29 NA NA Gastric Hs746t 1. 36E-09 8. 15E-09 LiverSK-HEP-11. 17E-096. 21E-09 NSCL A549 NA NA Ovary SK-OV-3 2. 90E-08 NA Pancreas PANC-1 1.37E-09 8.61E-09 PhamynxFADU3. 05E-084. 38E-08 Prostate PC3 Prostate DU-145 NA NA Prostate LNCAP 2. 38E-08 1. 77E-08 Renal 786-O 2. 27E-09 1. 54E-08 SCL NCI-H187 2. 41E-11 9. 89E-11 Retinoblastoma Y-79 3. 08E-10 7. 45E-10 Melanoma Mel-28 2. 85E-09 1. 42E-08 Fibrosarcoma SW-694 Chondrosarcoma CHSA 1.63E-09 2.91-08 Osteosarcoma OSA-FH 4. 37E-09 1. 15E-08 out out N W N Me OAe I OAC I N. nu OH 0 OH NH NH LEUKEMIAS & LYMPHOMAS LINE 71 93 ALL Promyelocytic HL60 1. 50E-08 HL60 leukemia ALL Acute Molt 3 1.62E-09 3.87E-09 lymphoblastic CML K562 6.89E-08 Chronic myelogenous Lymphoma T-cell H9 1.08E-08 Lymphoma Hut 78 7.33E-09 1.97E-09 Cutaneus T cell Lymphoma MC116 1.62E-08 3.81E-09 undifferentiated Lymphoma RAMOS 1.1 E-09 Burkitts B celll Lymphoma U-937 1.92E-09 1.08E-09 Histiocytic oh use 04, 01, OAC I OAC O I N. Me MO/I N-Me J o a -o o" LEUKEMIAS & o**-o Mye LYMPHOMAS LINE 82 95 ALL Promyelocytic 4. 93E-10 7.36E-09 HL60 leukemia ALL 9.86E-10 9.86E-10 Acute Molt 3 lymphoblastic CML Chronic K562 1.87E-08 1.18E-08 myelogenous Lymphoma T-cell H9 1. 20E-08 2. 43-08 Lymphoma Hut 78 Cutaneus T cell Lymphoma MC 116 1.04E-09 1.49E-09 undifferentiated Lymphoma RAMOS 5. 01E-09 Burkitts B celll Lymphoma U-937 Histiocytic OMe OMe Hc \ 4 OAc Ohc J° J. w I Ny w I Ny SOLID N N TUMORS LINE 114 116 Bladder 5637 1. 14E-08 1. 71 E-08 BreastMX-12. 81E-087. 25E-13 Colon HT-29 4. 08E-07 2. 96E-07 Gastric Hs746t 3. 57E-08 1. 24E-09 Liver SK-HEP-1 1. 63-08 1. 94E-09 NSCL A549 2. 81 E-06 1. 56-05 Ovary SK-OV-3 7. 03E-06 7. 78E-08 PancreasPANC-11. 03E-089. 47E-09 Pharnynx FADU 4. 59E-07 2. 46E-08 Prostate PC3 7. 88E-08 Prostate DU-145 7. 03E-08 1. 56E-06 Prostate LNCAP 5. 98E-07 6. 83E-08 Renal 786-O 1. 46E-08 5. 26E-12 SCL NCI-H187 8. 02E-10 7. 78E-14 Retinoblastoma Y-79 8. 85E-10 7. 78E-14 Melanoma Mel-28 1. 76E-08 5. 89E-08 Fibrosarcoma SW-694 3. 38E-06 6. 69E-06 Chondrosarcoma CHSA 2. 53E-08 4. 49E-08 Osteosarcoma OSA-FH 6. 34E-08 5. 26E-07 OMe OMe HCOME H04Me ONC OC Me N. ! p W CTTT ' \ OH"0 on SOLID 0 0 0 0 TUMORS LINE 115 113 Bladder 5637 7. 88E-10 3. 02E-08 Breast MX-1 NA 4. 75E-08 Colon HT-29 8. 99E-09 1. 34E-08 Gastric Hs746t 2. 95E-08 7. 05E-07 Liver SK-HEP-1 1. 29E-09 6. 12E-08 NSCL A549 8. 22E-06 8. 49E-09 Ovary SK-OV-3 3. 55E-08 PancreasPANC-15. 68E-101. 28E-08 Pharnynx FADU 5. 40E-11 2. 47E-08 Prostate PC3 7. 71E-10 6. 18E-10 Prostate DU-145 NA 1. 17E-08 Prostate LNCAP 3. 29E-07 Renal 786-O 9. 23E-10 1. 13E-08 SCL NCI-H 187 2. 33E-10 Retinoblastoma Y-79 1. 03E-08 2. 64E-09 Melanoma Mel-28 2. 23E-08 1. 25E-08 Fibrosarcoma SW-694 8. 53E-06 NA Chondrosarcoma CHSA 1. 55E-05 2. 95E-08 OsteosarcomaOSA-FH1. 29E-095. 01E-08 o L4. H 11, o Ny"" OAc I _Ale O p LEUKEMIAS& LYMPHOMAS LINE 114 116 ALL Promyelocytic HL60 1.34E-08 leukemia ALL Acute Molt 3 2.48E-09 1.44E-08 lymphoblastic CML Chronic 1. 56E-07 6.13E-08 K562 myelogenous Lymphoma T-cell H9 1.56E-07 1. 91E-08 Lymphoma Hut 78 6.47E-08 7.31 E-09 Cutaneus T cell Lymphoma MC116 1.69E-08 6.38E-09 undifferentiated Lymphoma RAMOS 8.86E-09 7.15E-10 Burkitts B celll Lymphoma U-937 7.6E-08 Histiocytic ow C) W Au OAt I Oc Mye -0 Oy -O ON 0 O LEUKEMIAS& LYMPHOMAS LINE 115 113 ALL Promyelocytic HL60 3. 1 E-09 HL60 leukemia ALL Acute Molt 3 8. 69E-11 4.63E-08 lymphoblastic CML Chronic 2.11 E-08 K562 myelogenous Lymphoma T-cell H9 2.17E-08 6.76E-08 Lymphoma Hut 78 4.81E-08 2.06E-08 Cutaneus T cell Lymphoma MC116 5. 27E-11 1.51E-08 undifferentiated Lymphoma RAMOS 1.86E-09 9.09E-09 Burkitts B celll Lymphoma U-937 1.03E-08 Histiocytic EXAMPLES OF THE INVENTION The present invention is illustrated by the following examples.

Example 1 To a solution of 2 (21.53 g, 39.17 ml) in ethanol (200 ml), tert- butoxycarbonyl anhydride (7.7 g, 35.25 ml) was added and the mixture was stirred for 7 h at 23 °C. Then, the reaction was concentrated in vacuo and the residue was purified by flash column chromatography (Si02, hexane: ethyl acetate 6: 4) to give 14 (20.6 g, 81 %) as a yellow solid.

Rf : 0.52 (ethyl acetate: CHCl3 5: 2).

'H NMR (300 MHz, CDC13) : 6 6.49 (s, 1H), 6.32 (bs, 1H), 5.26 (bs, 1H) * 4.60 (bs, 1 H), 4.14 (d, J= 2. 4 Hz, 1H), 4.05 (d, J= 2. 4 Hz, 1 H), 3.94 (s, 3H), 3. 81 (dSJ=4. 8Hz 1H) 3. 7 (s, 3H), 3.34 (br d, J= 7.2 Hz, 1H), 3.18-3.00 (m, 5H), 2.44 (d, J= 18.3 Hz, 1H), 2, 29 (s, 3H), 2.24 (s, 3H), 1.82 (s, 3H), 1.80-1.65 (m, 1H). 1.48 (s, 9H), 0.86 (d, J= 5.7 Hz,') 3H) 13C NMR (75 MHz, CDCl3) : 8 185.5,180.8,172.7.155.9,154.5.147.3.143.3.141.5.135.3.

130.4,129.2,127.5,120.2,117.4,116.9,80.2,60.7,60.3,58.5,5 5.9,55. 8, 54. 9, 54.4,50.0, 41.6,40.3,28.0,25.3,24.0,18.1.15.6,8.5.

ESI-MS m/z : Calcd. for C34H43N5O8; 649.7. Found (M+H) + : 650.3.

Example 2 14 15 To a stirred solution of 14 (20.6 g, 31.75 ml) in CH3CN (159 ml), diisopropylethylamine (82.96 ml, 476.2 ml), methoxymethylene bromide (25.9 ml, 317.5 ml) and dimethylaminopyridine (155 mg, 1.27 ml) were added at 0 °C. The mixture was stirred at 23 °C for 24h. The reaction was quenched at 0 °C with aqueous 0. IN HCI (750 ml) (pH = 5), and extracted with CH2C12 (2 x 400 ml). The organic phase was dried (sodium sulphate) and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, gradient hexane: ethyl acetate 4: 1 to hexane: ethyl acetate 3: 2) to give 15 (17.6 g. 83 %) as a yellow solid.

Rf: 0.38 (hexane: ethyl acetate 3 : 7).

'H NMR (300 MHz, CDC13) : 6 6.73 (s, 1H), 5.35 (bs. 1H), 5.13 (s, 2H), 4.50 (bs, 1 H). 4.25 (d, J= 2.7 Hz, 1H), 4.03 (d, J= 2.7 Hz, 1H), 3. 97 (s, 3H), 3. 84 (bs, 1H) 3. 82-3. 65 (m IH) * 3.69 (s, 3H), 3.56 (s, 3H), 3.39-3.37 (m, 1H), 3.20-3.00 (m, 5H), 2.46 (d, J= 18 Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 1.85 (s, 3H), 1.73-1.63 (m, 1H), 1.29 (s, 9H), 0.93 (d. J= 5.1 Hz, 3H) 13C NMR (75 MHz, CDC13) : 8 185.4,180.9,172.4,155.9,154.5,149.0,148.4* 141.6.135.1, 131.0,129.9,127.6,124.4,123.7,117. 3,99.1,79.3,60.7,59.7,58.4,57.5,56.2.55.9,55.0.

54.2,50.0,41.5,39.9,28.0,25.2,24.0.18.1,15.6,8.5.

ESI-MS m/z : Calcd. for C36H47N509 : 693.8. Found (M+H) + : 694.3.

Example 3 15 16 To a flask containing 15 (8 g, 1.5 ml) in methanol (1. 61) an aqueous solution of 1M sodium hydroxide (3.2 1) was added at 0 °C. The reaction was stirred for 2h at this temperature and then, quenched with 6M HCI to pH = 5. The mixture was extracted with ethyl acetate (3 x 1 1) and the combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, gradient CHC13 to CHCl3 : ethyl acetate 2: 1) to afford 16 (5.3 mg, 68 %).

Rf : 0. 48 (CH3CN: H20 7 : 3, RP-C18) 'H NMR (300 MHz, CDC13) : 8 6.73 (s, 1H), 5.43 (bs, 1H), 5.16 (s, 2H), 4.54 (bs, 1H), 4.26 (d, J= 1.8 Hz, 1H), 4.04 (d, J= 2.7 Hz 1H), 3. 84 (bs, 1H), 3.80-3.64 (m, 1H) * 3. 58 (s, 3H).

3.41-3.39 (m, 1H), 3. 22-3.06 (m, 5H), 2.49 (d, J= 18.6 Hz 1H), 2.35 (s. 3H). 2. 30-2.25 (m, 1H), 2.24 (s, 3H), 1.87 (s, 3H), 1.45-1.33 (m, 1H), 1.19 (s, 9H), 1.00 (brd. J= 6.6 Hz 3H) 13C NMR (75 MHz, CDCl3) : 5 184.9,180.9,172.6,154.7,151.3,149.1,148.6.144.7,132. 9.

131.3,129.8,124.5,123.7,117.3,116.8,99.1,79.4,59.8,58.6,5 7.7,56.2,55.6,54.9.54.5, 50.1,41.6,40.1,28.0,25.3,24.4,18.1,15.7,8.0.

ESI-MS m/z: Calcd. for C35H45N509 : 679. 7. Found (M+H) + : 680. 3.

Example 4 To a degassed solution of compound 16 (1.8 g, 2.64 ml) in DMF (221 ml) 10 % Pd/C (360 mg) was added and stirred under H2 (atmospheric pressure) for 45 min. The reaction was filtered through celite under argon, to a flask containing anhydrous Cs2CO3 (2.58 g, 7.92 ml). Then, bromochloromethane (3.40 ml 52.8 ml), was added and the tube was sealed and stirred at 100 °C for 2h. The reaction was cooled, filtered through a pad of celite and washed with CH2CI2. The organic layer was concentrated and dried (sodium sulphate) to afford 17 as a brown oil that was used in the next step with no further purification.

Rf : 0.36 (hexane: ethyl acetate 1: 5, Si02).

'H NMR (300 MHz, CDC13) : 8 6.68 (s, 1H), 6.05 (bs, 1H), 5.90 (s, 1H), 5.79 (s, 1H), 5.40 (bs, 1H), 5.31-5.24 (m, 2H), 4.67 (d, J= 8.1 Hz, 1H), 4.19 (d, J= 2.7 Hz, 1H), 4.07 (bs, 1H), 4.01 (bs, 1H), 3.70 (s, 3H), 3.67 (s, 3H), 3.64-2.96 (m, 5H), 2.65 (d, J=18. 3 Hz, 1H), 2.33 (s, 3H), 2.21 (s, 3H), 2.04 (s, 3H), 2.01-1.95 (m, 1H), 1.28 (s, 9H), 0.87 (d, J= 6.3 Hz, 3H) 3C NMR (75 MHz, CDC13) : 8 172.1,162.6,154.9,149.1,145.7,135.9,130.8,130.7,125.1, 123.1,117.8,100.8,99.8,76.6,59.8,59.2,57.7,57. 0,56.7,55.8,55.2,49.5,41.6.40.1,36.5.

31.9,31.6,29.7,28.2,26.3,25.0,22.6,18.2,15.8,14.1,8.8.

ESI-MS m/z: Calcd. for C36H47NsOg : 693. 34. Found (M+H) + : 694.3.

Example 5 To a flask containing a solution of 17 (1.83 g. 2.65 ml) in DMF (13 ml). Cs2CO3 (2.6 g, 7.97 ml), and allyl bromide (1.15 ml, 13.28 ml) were added at 0° C. The resulting mixture was stirred at 23 °C for 1 h. The reaction was filtered through a pad of celite and washed with CH2C12. The organic layer was dried and concentrated (sodium sulphate).

The residue was purified by flash column chromatography (Si02, CHCl3 : ethyl acetate 1: 4) to afford 18 (1.08 mg, 56 %) as a white solid.

Rf : 0. 36 (CHCl3 : ethyl acetate 1: 3).

'H NMR (300 MHz, CDC13) : 5 6.70 (s, 1H), 6.27-6.02 (m, 1H), 5.94 (s, 1H), 5.83 (s, 1H), 5.37 (dd, Jl= 1.01 Hz, J2= 16.8 Hz, 1H), 5.40 (bs, 1H), 5, 25 (dd, J, 1. 0 Hz, Jazz 10.5 Hz, 1H), 5.10 (s, 2H), 4.91 (bs, 1H), 4.25-4.22 (m, 1H), 4.21 (d, J= 2.4 Hz, 1H), 4.14-4.10 (m, 1H), 4.08 (d, J=2.4 Hz, 1H), 4.00 (bs, 1H), 3.70 (s, 3H), 3.59 (s, 3H), 3.56-3.35 (m, 2H), 3.26-3.20 (m, 2H), 3.05-2.96 (dd, J1= 8.1 Hz, J2=18 Hz, 1H), 2.63 (d, J=18 Hz, 1H), 2.30 (s, 3H), 2.21 (s, 3H), 2.09 (s, 3H), 1.91-1.80 (m, 1H), 1.24 (s, 9H), 0.94 (d, J= 6.6 Hz, 3H) 13CNMR (75 MHz, CDC13) : 6 172.0,154.8,148.8,148.6,148.4,144.4,138.8,133.7,130.9, 130.3,125.1,124.0,120.9,117.8,117.4,112.8,112.6,101.1,99.2,7 3.9,59.7,59. 3*57. 7 56.9,56.8,56.2,55.2,40.1,34.6,31.5,28.1,26.4,25.1,22.6,18.5, 15.7,14.0,9.2.

ESI-MS m/z: Calcd. for C39H5 IN509 : 733.4. Found (M+H) + : 734.4.

Example 6 i 0 OMe \ OMe %) OMe % OMe O O Me, NYMe Me i N-Me j/4. 3M HCUdioxane N I/ 1. 2h, 23°C O-_ O CN NH NH -NHO/ OY0" Me O Me 18 19 To a solution of 18 (0.1 g, 0.137 ml) in dioxane (2 ml), 4.2M HCI/dioxane (1.46 ml) was added and the mixture was stirred for 1.2h at 23 °C. The reaction was quenched at 0 °C with sat. Aqueous sodium bicarbonate (60 ml) and extracted with ethyl acetate (2x70 ml).

The organic layers were dried (sodium sulphate) and concentrated in vacuo to afford 19 (267 mg, 95 %) as a white solid that was used in subsequent reactions with no further purification.

Rf : 0.17 (ethyl acetate: methanol 10: 1, Si02) 1H NMR (300 MHz, CDC13) : 8 6.49 (s, 1H), 6.12-6.00 (m, 1H), 5.94 (s, 1H), 5.86 (s, 1H), 5.34 (dd, J= 1. 0 Hz, J= 17. 4 Hz, I H), 5.25 (dd, J= 1. 0 Hz, J= 10. 2 Hz, I H), 4.18-3.76 (m, 5H), 3.74 (s, 3H), 3.71-3.59 (m, 1H), 3.36-3.20 (m, 4H), 3.01-2.90 (m, 1H), 2.60 (d, J= 18. 0 Hz, 1H), 2.29 (s, 3H), 2.24 (s, 3H), 2.11 (s, 3H), 1.97-1.86 (m, 1H), 0.93 (d, J= 8. 7 Hz, 3H) 3C NMR (75 MHz, CDC13) : 8 175.5,148.4,146.7,144.4,142.4,138.9,133.7,131.3,128.3, 120.8,117.9,117.4,113.8,112.4,101.1,74.2,60.5,59.1,56.5,56.1 ,56.3,56.0,55.0,50.5, 41.6,39.5,29.5,26.4,24.9,21.1,15.5,9.33.

ESI-MS m/z: Calcd. for C32H39N506 : 589. Found (M+H) + : 590.

Example 7 % OMe % OMe HO, Me HO, Me 0 Me/N-rMe Me/ N'Me 0< ; phenylisothiocyanate $e __ N-Me \0 CN \O CN NH NH oAyNH2 o<NHCSNHPh Me Me 19 20 To a solution of 19 (250 mg, 0.42 ml) in CH2CI2 (1.5 ml), phenyl isothiocyanate (0.3 ml, 2.51 ml) was added and the mixture was stirred at 23° C for 1h. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography (Si02, gradient Hexane to 5: 1 hexane: ethyl acetate) to afford 20 (270 mg, 87 %) as a white solid.

Rf : 0.56 (CHCl3 : ethyl acetate 1: 4).

'H NMR (300 MHz, CDC13) : 8 8.00 (bs, 1H), 7.45-6.97 (m, 4H), 6.10 (s, 1H), 6.08-6.00 (m, 1H), 5.92 (s, 1H), 5.89 (s, 1H), 5.82 (s, 1H), 5.40 (dd, J= 1.5 Hz, J= 17. 1 Hz, 1H), 3.38 (bs, 1H), 5.23 (dd, J= 1.5 Hz, J= 10.5 Hz, 1H), 4.42-4.36 (m, 1H), 4.19-4.03 (m, 5H), 3.71 (s, 3H), 3.68-3.17 (m, 4H), 2.90 (dd, J=7. 8 Hz, J= 18. 3 Hz, 1H), 2.57 (d, J= 18. 3 Hz, 1H), 2.25 (s, 3H), 2.12 (s, 3H), 2.10 (s, 3H), 1.90 (dd, J= 12. 3 Hz, J= 16. 5 Hz, IH), 0.81 (d, J= 6. 9 Hz, 3H).

13C NMR (75 MHz, CDCl3) : 8 178.4,171.6,148.6,146.8,144.3,142.7,138.7,136.2,133.6, 130.7,129.8,126.6,124.2,124.1,120.9,120.5,117.7,117.4,116.7, 112.6,112.5,101. 0, 74.0,60.6,59.0,57.0,56.2,56.1,55.0,53.3,41.4,39.7,26.3,24.8, 18. 3, 15. 5,9.2.

ESI-MS m/z: Calcd. for C39H44N606S : 724. 8 Found (M+H) + : 725.3.

Example 8 OMe % OMe OMe HO Me Me NYMe O I N N-Me 4. 2N HCI in Dioxano Me Nome 0 30 min., 23 oc I NU O -O CN NHCSNHPH NH Me Me 20 21 To a solution of 20 (270 mg, 0.37 ml) in dioxane (1 ml), 4.2N HCI/dioxane (3.5 ml) was added and the reaction was stirred at 23'C for 30 min. Then, ethyl acetate (20 ml) and H20 (20 ml) were added and the organic layer was decanted. The aqueous phase was basified with saturated aqueous sodium bicarbonate (60 ml) (pH = 8) at 0 °C and then. extracted with CH2C12 (2 x 50 ml). The combined organic extracts were dried (sodium sulphate), and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, ethyl acetate: methanol 5: 1) to afford compound 21 (158 mg, 82%) as a white solid.

Rf : 0.3 (ethyl acetate: methanol 1: 1).

1H NMR (300 MHz, CDCl3) : 6 6.45 (s, 1H), 6.12-6.03 (m, 1H), 5.91 (s, IH). 5.85 (s, 1H), 5.38 (dd, Jl= 1.2 Hz, J2= 17. 1 Hz, IH), 5.24 (dd, Zu 1.2 Hz, =10. 5 Hz, 1H), 4.23-4.09 (m, 4H), 3.98 (d, J= 2.1 Hz, 1H), 3.90 (bs, 1H), 3.72 (s, 3H), 3. 36-3. 02 (m. 5H), 2.72-2.71 (m, 2H), 2.48 (d, J= 18.0 Hz, 1 H), 2.33 (s, 3H), 2.22 (s, 3H), 2.11 (s, 3H), 1.85 (dd, Jl= 11.7 Hz, Je= 15.6 Hz, 1H)).

3C NMR (75 MHz, CDC13) : 8 148.4,146.7,144.4,142.8,138.8,133.8,130.5,128.8,121.5, 120.8,118.0,117.5,116.9,113.6,112.2,101.1,74.3,60.7,59.9,58. 8,56.6,56.5,55.3,44.2, 41.8,29.7,26.5,25.7,15.7,9.4.

ESI-MS m/z: Calcd. for C29H34N405 : 518.3. Found (M+H) + : 519.2.

Example 9 To a solution of 21 (0.64 g, 1.22 ml) in CH2Cl2 (6.13 ml), pyridine (0.104 ml, 1.28 ml) and 2,2,2-trichloroethyl chloroformate (0.177 ml, 1.28 ml) were added at-10 °C. The mixture was stirred at this temperature for lh and then, the reaction was quenched by addition of O. 1N HCI (10 ml) and extracted with CH2C12 (2 x 10 ml). The organic layer was dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, (hexane: ethyl acetate 1 : 2) to afford 22 (0.84 g, 98%) as a white foam solid.

Rf : 0.57 (ethyl acetate: methanol 5: 1).

'H NMR (300 MHz, CDC13) : 8 6.50 (s, 1H), 6.10-6.00 (m, 1H), 6.94 (d, J= 1.5 Hz, 1H), 5.87 (d, J= 1.5 Hz, 1H), 5.73 (bs, 1H), 5.37 (dq, J, = 1.5 Hz, J2= 17. 1 Hz, 1H), 5.26 (dq, J1= 1.8 Hz, J= 10.2 Hz, 1H), 4.60 (d, J= 12 Hz, 1H), 4.22-4.10 (m, 4H), 4.19 (d, J= 12 Hz, 1H), 4.02 (m, 2H), 3.75 (s, 3H), 3.37-3.18 (m, 5H), 3.04 (dd, J, = 8.1 Hz, J2 = 18 Hz, 1H), 2.63 (d, J= 18 Hz, 1H), 2.31 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H), 1.85 (dd, Jl= 12. 3 Hz, J2= 15.9 Hz, 1H).

13C NMR (75 MHz, CDCl3) 8 154.3,148.5,146.7,144.5,142.8,139.0,133.8,130.7,128.7, 121.3,120.8,117.8,117.7,116.8,112.7,101.2,77.2,74.3,60.7,59. 9,57.0,56.4,55.3,43.3, 41.7,31.6,26.4,25.3,22.6,15.9,14.1,9.4.

ESI-MS m/z: Calcd. for C32H35CI3N407 : 694.17. Found (M+H) + : 695.2.

Example 10 To a solution of 22 (0.32 g, 0.46 ml) in CH3CN (2.33 ml). diisopropylethslamine (1.62 ml, 9.34 ml), bromomethyl methyl ether (0.57 ml, 7.0 ml) and dimethylaminopyridine (6 mg, 0.046 ml) were added at 0 °C. The mixture was heated at 30 °C for 1 Oh. Then. the reaction was diluted with dichloromethane (30 ml) and poured in an aqueous solution of HCI at pH = 5 (10 ml). The organic layer was dried over sodium sulphate and the solvent was eliminated under reduced pressure to give a residue which was purified by flash column chromatography (Si02, hexane: ethyl acetate 2: 1) to afford 23 (0.304 g, 88%) as a white foam solid.

Rf : 0.62 (hexane: ethyl acetate 1 : 3).

'H NMR (300 MHz, CDC13) : 6 6.73 (s, IH), 6.10 (m, 1H), 5.94 (d, J= 1.5 Hz, 1H), 5.88 (d, J= 1.5 Hz, 1H), 5.39 (dq, Jl= 1. 5 Hz, J2= 17.1 Hz, 1 H), 5.26 (dq, Jl= 1.8 Hz,. J= 10.2 Hz, 1H), 5.12 (s, 2H), 4.61 (d, J= 12 Hz, 1H), 4.55 (t, J= 6.6 Hz, 1H), 4.25 (d, J= 12 Hz, 1H), 4.22-4.11 (m, 4H), 4.03 (m, 2H), 3.72 (s, 3H), 3.58 (s, 3H), 3.38-3.21 (m, 5H), 3.05 (dd, J1= 8. 1 Hz, J2= 18 Hz, 1H), 2.65 (d, J= 18 Hz, 1H), 2.32 (s, 3H), 2.23 (s, 3H), 2.12 (s, 3H), 1.79 (dd, Jl= 12.3 Hz, J2= 15.9 Hz, 1H) ; 13C NMR (75 MHz, CDC13) 8 154.3,148.6,148.4,144.5,139.0,133.6,130. 6, 130.1, 125.07,124.7,124.0,121.1,117.7,112.6,101.2,99.2,77.2,74.4,74 .1, 59.8, 59.8, 57. 7, 57.0,56.8,56.68,55.3,43.2,41.5,26.4,25.2,15.9,9.3.

ESI-MS m/z: Calcd. for C34H39Cl3N408 : 738.20. Found (M+H) + : 739.0.

Example 11 23 24 To a suspension of 23 (0.304 g, 0.41 ml) in 90% aqueous acetic acid (4 ml), powder zinc (0.2 g, 6.17 ml) was added and the reaction was stirred for 7 hour at 23 °C. The mixture was filtered through a pad of celite which was washed with CH2CI2. The organic layer was washed with an aqueous sat. solution of sodium bicarbonate (pH = 9) (15 ml) and dried over sodium sulphate. The solvent was eliminated under reduced pressure to give 24 (0.191 g, 83%) as a white solid.

Rf : 0. 3 (ethyl acetate: methanol 5: 1).

IH NMR (300 MHz, CDC13) : 6 6.68 (s, 1 H), 6.09 (m, 1H), 5.90 (d, J= 1.5 Hz, 1 H), 5.83 (d, J= 1.5 Hz, 1H), 5.39 (dq, JI= 1.5 Hz, J2= 17.1 Hz, 1H), 5.25 (dq, J, = 1.5 Hz. J2= 10.2 Hz, 1H), 5.10 (s, 2H), 4.22-4.09 (m, 3H), 3.98 (d, J= 2.4 Hz, 1H), 3.89 (m, 1H), 3.69 (s, 3H), 3.57 (s, 3H), 3.37-3.17 (m, 3H), 3.07 (dd, J/= 8.1 Hz, Jazz 18 Hz, 1H), 2.71 (m, 2H), 2.48 (d, J= 18 Hz, 1H), 2.33 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H), 1.80 (dd, Jl= 12.3 Hz, Jazz 15.9 Hz, 1H) 3C NMR (75 MHz, CDCl3) : 8 148.5,148.2,144.3,138.7,133.7,130.7,129.9,125.0,123.9, 121.3,117.9,117.5,113.6,112.0,101.0,99.2,74.0,59.8,59.7,58.8 ,57.6,57.0,56.2,55.2, 44.2,41.5,31.5,26.4,25.6,22.5,16.7,14.0,9.2.

ESI-MS m/z: Calcd. for C3tH38N406 : 562. 66. Found (M+H) + : 563.1.

Example 12 To a solution of 24 (20 mg, 0.035 ml), in H20 (0.7 ml) and THF (0.7 ml). NaN02 (12 mg, 0.17 ml) and 90% aqueous. AcOH (0.06 ml) were added at 0 °C and the mixture was stirred at 0 °C for 3h. After dilution with CH2CI2 (5 ml), the organic layer was washed with water (1 ml), dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, hexane: ethyl acetate 2: 1) to afford 25 (9.8 mg, 50%) as a white solid.

Rf : 0. 34 (hexane: ethyl acetate 1: 1).

1H NMR (300 MHz, CDC13) : 6 6.71 (s, 1H), 6.11 (m, 1H), 5.92 (d, J= 1.5 Hz. 1H), 5.87 (d, J= 1. 5 Hz, 1H), 5.42 (dq, J1= 1.5 Hz, J2= 17. 1 Hz, 1H), 5.28 (dq, J1= 1.5 Hz, J2= 10.2 Hz, 1H), 5.12 (s, 2H), 4.26-4.09 (m, 3H), 4.05 (d, J= 2.4 Hz, 1 H), 3.97 (t, J= 3.0 Hz. 1H), 3.70 (s, 3H), 3.67-3.32 (m, 4H), 3.58 (s, 3H), 3.24 (dd, J/= 2. 7 Hz, J2= 15.9 Hz, 1H), 3. 12 (dd, Jl= 8.1 Hz, J2= 18.0 Hz, 1H), 2.51 (d, J= 18 Hz, 1H), 2.36 (s, 3H), 2.21 (s, 3H), 2.12 (s, 3H), 1.83 (dd, J, = 12.3 Hz, J2= 15.9 Hz, 1H) 13C NMR (75 MHz, CDCl3) # 148.7,148.4,138.9,133.7,131.1,129.4,125.1,123.9,120.7, 117.6,117.5,113.2,112.3,101.1,99.2,74.0,63.2,59.8,59.7,57.9, 57.7,57.0,56.5,55.2, 41.6,29.6,26.1,25.6,22.6,15.7,9.2.

ESI-MS m/z: Calcd. for C31H37N307 : 563.64. Found (M+H) + : 564.1.

Example 13 Ho+S41 2, 2,2-Trichioroethyl chloroforrnate HO+SX NH3CI NaH, THF, reflux NHTroc 29 The starting material (2.0 g, 5.90 ml) was added to a suspension of sodium hydride (354 mg, 8. 86 ml) in THF (40 ml) at 23 °C, following the suspension was treated with allyl chloroformate (1.135 ml, 8.25 ml) at 23 °C and then refluxed for 3 hours. The suspension was cooled, filtered off, the solid washed with ethyl acetate (100 ml), and the filtrate was concentrated. The oil crude was ground with hexane (100 ml) and kept at 4°C overnight.

After, the solvent was decanted and the light yellow slurry was treated with CH2CI, (20 ml), and precipitated with hexane (100 ml). After 10 minutes, the solvent was decanted again.

The operation was repeated until appearing a white solid. The white solid was filtered off and dried to afford compound 29 (1.80 g, 65%) as a white solid.

'H-NMR (300 MHz, CDC13) : 6 7.74 (d, J= 7.5 Hz, 2H), 7.62 (d, J= 6.9 Hz, 2H). 7. 33 (t, J= 7.5 Hz, 2H), 7.30 (t, J= 6.3 Hz, 2H), 5.71 (d, J= 7.8 Hz, 1H), 4.73 (d, J= 7.8 Hz, 2H), 4.59 (m, 1H), 4.11 (t, J= 6.0 Hz, 1H), 3.17 (dd, J= 6.0 Hz, J= 2.7 Hz, 2H), 3.20 (dd. J= 5.4 Hz, J= 2. 1 Hz, 2H).

13C-NMR (75 MHz, CDC13) : 8 173.6,152.7,144.0,139.7,137.8,126.0,125.6.123.4,118.3, 73.4,52.4,45.5,35.8,33.7.

ESI-MS m/z: Calcd.. for C20H18Cl3NO4S : 474.8. Found (M+Na) + : 497.8 Example 14 A mixture of compound 25 (585 mg, 1.03 ml) and compound 29 (1.47 mg, 3.11 ml) were azeotrope with anhydrous toluene (3 x 10 ml). To a solution of 25 and 29 in anhydrous CH2Cl2 (40 ml) was added DMAP (633 mg, 5.18 ml) and EDC-HC1 (994 mg, 5.18 ml) at 23 °C. The reaction mixture was stirred at 23 °C for 3 hours. The mixture was partitioned with saturated aqueous solution of sodium bicarbonate (50 ml) and the layers were separated. The aqueous layer was washed with CH2CI2 (50 ml). The combined organic layers were dried over sodium sulphate, filtered and concentrated. The crude was purified by flash column chromatography (ethyl acetate/hexane 1: 3) to obtain 30 (1.00 g. 95%) as a pale cream yellow solid.

1H-NMR (300 MHz, CDC13) : # 7.72 (m, 2H), 7.52 (m, 2H), 7.38 (m, 2H), 7.28 (m, 2H), 6.65 (s, 1H), 6.03 (m, 1H), 5.92 (d, J= 1.5 Hz, 1H), 5.79 (d, J= 1.5 Hz, 1H), 5.39 (m, 1H), 5.29 (dq, J= 10.3 Hz, J= 1.5 Hz, 1H), 5.10 (s, 2H), 4.73 (d, J= 11.9 Hz, 1H), 4.66 (d, J= 11. 9 Hz.

1H), 4.53 (m, 1H), 4.36-3.96 (m, 9H), 3.89 (t, J= 6.4 Hz, 1H), 3.71 (s, 3H), 3.55 (s, 3H), 3.33 (m, 1H), 3.20 (m, 2H), 2.94 (m, 3H), 2.59 (m, 1H), 2.29 (s, 3H), 2.23 (s, 3H), 2.02 (s, 3H), 1.83 (dd, J= 16.0 Hz, J= 11.9 Hz, 1H).

3C-NMR (75 MHz, CDCl3) : 6 169.7.154.0,148.8,148.4,145.7,144.5,140.9.139.0,133.7, 130.9,130.6,127.6,127.0,124.8,124.6,124.1,120.8,119.9,118.2, 117.7,117.3,112.7, 112.1,101.3,99.2,74.7,73.9,64.4,59. 8, 57.7,57. 0, 56.8,55.4,53.3,46.7,41.4,36.5,34.7, 31.5,26.4,24.9,22.6,15.7,14.0,9.1.

ESI-MS m/z : Calcd.. for C51H53Cl3N4O10S : 1020.4. Found (M+H) + : 1021.2 Example 15 To a solution of 30 (845 mg, 0.82 ml), acetic acid (500 mg, 8.28 ml) and (PPh3) 2PdCl2 (29 mg, 0.04 ml) in anhydrous CH2Cl2 20 ml at 23 °C was added, dropwise, Bu3SnH (650 mg, 2.23 ml). The reaction mixture was stirred at this temperature for 15 min., bubbling was. The crude was quenched with water (50ml) and extracted with CH2C1, (3 x 50 ml). The organic layers were dried over sodium sulphate, filtered and concentrated.

The crude was purified by flash column chromatography (ethyl acetate/hexane in gradient from 1: 5 to 1: 3) to obtain compound 31 (730 mg, 90%) as a pale cream yellow solid.

'H-NMR (300 MHz, CDC13) : 6 7.72 (m, 2H), 7.56 (m, 2H), 7.37 (m. 2H), 7. 30 (m. 2H), 6.65 (s, 1H), 5.89 (s, 1H), 5.77 (s, 1H), 5.74 (s, 1H), 5.36 (d, J= 5.9 Hz, 1H), 5.32 (d, J= 5.9 Hz, 1H), 5.20 (d, J= 9.0,1H), 4.75 (d, J= 12.0 Hz, 1H), 4.73 (m, 1H), 4.48 (d. J= 11.9 Hz. 1H), 4.08 (m, 4H), 3.89 (m, 1H), 3.86, (t, J= 6.2 Hz, 1H), 3.70 (s, 3H), 3.69 (s. 3H), 3.38 (m, 1H), 3.25 (m, 1H), 3.02-2.89 (m, 4H), 2.67 (s, 1H), 2.61 (s, 1H), 2.51 (dd, J= 14.3 Hz, J= 4.5 Hz, 1H), 2.29 (s, 3H), 2.23 (s, 3H), 1.95 (s, 3H), 1.83 (m, 1H).

3C-NMR (75 MHz, CDC13) : 8 168.2,152.5,148.1,146.2,144.4,144.3,143. 3,139.6,134.6, 129.7,129.6,126.2,125.6,123.4,123.3,121.6,118.5,116.3,110.7, 110. 2, 105. 1,99.4,98.5, 75.2,73.3,61.7,58.4,57.9,56.3,56.1,55.1,54.7,53.9,51.9,45.2, 40.1,35.6,33.3,24.8, 23.3., 14.5,7.3.

ESI-MS m/z: Calcd.. for C48H49CI3N4Ol0S : 980. 3. Found (M+H) + : 981.2 Example 16 To a solution of 31 (310 mg, 0. 32 ml), in anhydrous CH2CI2 (15 ml) at-10 °C was added a solution of benzeneseleninic anhydride 70 % (165 mg, 0.32 ml), in anhydrous CH2CI2 (7 ml), via cannula, keeping the temperature at-10 °C. The reaction mixture was stirred at-10 °C for 5 min. A saturated solution of sodium bicarbonate (30 ml) was added at this temperature. The aqueous layer was washed with more CH2CI, (40 ml). The organic layers were dried over sodium sulphate, filtered and concentrated. The crude was purified by flash column chromatography (ethyl acetate/hexane in gradient from 1: 5 to 1: 1) to obtain 32 (287 mg, 91%, HPLC: 91.3%) as a pale cream yellow solid and as a mixture of two isomers (65: 35) which were used in the next step.

'H-NMR (300 MHz, CDC13) : 8 (Mixture of isomers) 7.76 (m, 4H), 7.65 (m, 4H). 7.39 (m, 4H), 7.29 (m, 4H), 6.62 (s, 1H), 6.55 (s, 1H), 5.79-5.63 (m, 6H), 5.09 (s, 1H). 5.02 (d, J= 6. 0 Hz, 1H), 4.99 (d, J= 6.0 Hz, 1H), 4.80-4.63 (m, 6H), 4.60 (m, 1H), 4.50 (m, 1H). 4.38 (d, J= 12.8 Hz, J= 7.5 Hz, 1H), 4.27 (dd, J= 12.8 Hz, J= 7.5 Hz, 1H), 4.16-3.90 (m, I OH), 3.84 (s, 3H), 3.62 (s, 3H), 3.50 (s, 3H), 3.49 (s, 3H), 3. 33-2. 83 (m, 14H), 2.45-2.18 (m, 2H), 2.21 (s.

6H), 2.17 (s, 6H), 1.77 (s, 6H), 1.67 (m. 2H).

3C-NMR (75 MHz, CDCI3) : 8 (Mixture of isomers) 168. 6,168.4,158.6,154.8,152.8, 152.5,147.3,147.2,146.8,144.1,144.0,140.8,139.7,137.1,129.8, 129.3,128.4,128.7, 126.5,125.5,123.7,123.6,123.5,123.4,122.2,121.3,118.3,115 : 8,115.5,110.2,106.9, 103.5,103.2,100.1,99.6,97.9,97.7,93.8,73.4,70.9,69.2,64.9,62 .5,59.3,58.9,58.4,56.7, 56.3,56.2,55.4,55.2,55.1,54.9,54.7,54.3,54.1,53.8,52.8,45.5, 40.5,40.0,39.8,35.8, 35.5,33.9,33.7,30.1,28.8,24.2,24.1,21.2,14.5,14.4,12.7,6.0,5 .7.

ESI-MS m/z: Calcd.. for C48H49Cl3N40nS : 996.3. Found (M+H) + : 997.2 Example 17 32 33 The reaction flask was flamed twice, purged vacuum/Argon several times and kept under Argon atmosphere for the reaction. To a solution of DMSO (39.1 ml, 0.55 ml. 5 equivalents.) in anhydrous CH2CI2 (4.5 ml) was dropwise added triflic anhydride (37.3 ml, 0.22 ml, 2 equivalents.) at-78 °C. The reaction mixture was stirred at-78 °C for 20 minutes, then a solution of 32 (110 mg, 0.11 ml, HPLC: 91.3%) in anhydrous CHC12 (1 ml, for the main addition and 0.5 ml for wash) at-78 °C was added, via cannula. During the addition the temperature was kept at-78 °C in both flasks and the colour changed from yellow to brown. The reaction mixture was stirred at-40 °C for 35 minutes. During this period of time the solution was turned from yellow to dark green. After this time,'Pr2NEt (153 ml, 0.88 ml, 8 equivalents.) was dropwise added and the reaction mixture was kept at 0 °C for 45 minutes, the colour of the solution turned to brown during this time. Then t- butanol (41.6 ml, 0.44 ml, 4 equivalents.) and 2-'Butyl-1, 1, 3,3-tetramethylguanidine (132.8 ml, 0.77 ml, 7 equivalents.) were dropwise added and the reaction mixture was stirred at 23 °C for 40 minutes. After this time, acetic anhydride (104.3 ml, 1.10 ml, 10 equivalents.) was dropwise added and the reaction mixture was kept at 23 °C for 1 hour more. Then the reaction mixture was diluted with CH2CI2 (20ml) and washed with aqueous saturated solution ofNH4Cl (50ml), sodium bicarbonate (50ml), and sodium chloride (50ml). The combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue was purified by flash column chromatography (eluent: ethyl acetate/hexane gradient from 1 : 3 to 1: 2) to afford compound 33 (54 mg, 58%) as a pale yellow solid.

'H-NMR (300 MHz, CDC13) : 5 6.85 (s, 1H), 6.09 (s, 1H), 5.99 (s, 1H), 5.20 (d, J= 5.8 Hz, 1H), 5.14 (d, J= 5.3 Hz, 1H), 5.03 (m, 1H), 4.82 (d, J= 12.2,1H), 4.63 (d, J= 12.0 Hz, 1H), 4.52 (m, 1H), 4.35-4.17 (m, 4H), 3.76 (s, 3H), 3.56 (s, 3H), 3. 45 (m, 2H), 2.91 (m. 2H), 2. 32 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.12 (m, 2H), 2.03 (s, 3H).

3C-NMR (75 MHz, CDCl3) : 5 168. 5,167.2,152.7.148.1,147.1,144.5,139.6 139.1.130.5.

129.0,123.7,123.5,123.3,118.8,116.5,112.1,100.6,97.8,73.3 ,60.5,59.4.59. 2. 58. 3.

57.6,57.4,56.1,53.3,53.1,40.6,40.0,31.0,22.2,18.9,14.4,8. 1.

ESI-MS m/z: Calcd.. for C36H39Cl3N4O11S : 842.1. Found (M+H) + : 843. 1 Example 18 33 34 To a solution of 33 (12 mg, 0.014 ml) in dry dichloromethane (1.2 ml) and HPLC grade acetonitrile (1.2 ml) was added at 23 °C sodium iodide (21 mg, 0.14 ml) and freshly distilled (over calcium hydride at atmospheric pressure) trimethylsilyl chloride (15. 4 mg, 0.14 ml). The reaction mixture turned to orange colour. After 15 min the solution was diluted with dichloromethane (10 ml) and was washed with a freshly aqueous saturated solution of Na2S204 (3 x 10 ml). The organic layer was dried over sodium sulphate, filtered and concentrated. It was obtained compound 34 (13 mg, quantitative) as pale yellow solid which was used without further purification.

1H-NMR (300 MHz, CDC13) : 8 6.85 (s, 1H), 6.09 (s, 1H), 5.99 (s, 1 H), 5.27 (d, J= 5.8 Hz, 1H), 5.14 (d, J= 5. 3 Hz, 1H), 5.03 (d, J= 11.9 Hz, 1H), 4.82 (d, J= 12.2,1H), 4.63 (d, J= 13.0 Hz, 1H), 4.52 (m, 1H), 4.34 (m, 1H), 4.27 (bs, 1H), 4.18 (m, 2H), 3.76 (s, 3H), 3.56 (s, 3H), 3.44 (m, 1H), 3.42 (m, 1H), 2.91 (m, 2H), 2.32 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.03 (s, 3H).

ESI-MS m/z : Calcd.. for C34H3sN4O oS : 798.1. Found (M+H) + : 799.1 Example 19 34 35 To a solution of 34 (13 mg, 0.016 ml) in a mixture of acetic acid/H2O (90: 10, 1 ml) was added powder Zinc (5.3 mg, 0.081 ml) at 23 °C. The reaction mixture was heated at 70 °C for 6 h. After this time, was cooled to 23 °C, diluted with CH2CI2 (20 ml) and washed with aqueous saturated solution of sodium bicarbonate (15 ml) and aqueous solution of Et3N (15 ml). The organic layer was dried over sodium sulphate, filtered and concentrated. The residue was purified by flash column chromatography with Silica-NH2 (eluent: ethyl acetate/hexane gradient from 0: 100 to 50: 50) to afford compound 35 (6.8 mg, 77% for two steps) as a pale yellow solid.

'H-NMR (300 MHz, CDC13) : 8 6.51 (s, 1 H), 6.03 (dd, J= 1.3 Hz, J= 26.5 Hz, 2H), 5.75 (bs, 1H), 5.02 (d, J= 11.6 Hz, IH), 4.52 (m, I H), 4.25 (m, 2H), 4.18 (d, J= 2.5 Hz, I H), 4.12 (dd, J= 1.9 Hz, J= 11.5 Hz, 1H), 3.77 (s, 3H), 3.40 (m, 2H), 3.26 (t, J= 6.4 Hz, 1H), 2.88 (m, 2H), 2.30-2.10 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H), 2.02 (s, 3H).

3C-NMR (75 MHz, CDCl3) : 8 174.1,168.4,147.8,145.4,142.9,140.8,140.1,131.7,130.2, 129.1,128.3,120.4,118.3,117.9,113.8,111.7,101.7,61.2,59.8,59 .2,58.9,54.4,53.8, 54.4,41.3,41.5,34.1,23.6,20.3,15.5,9.4.

ESI-MS m/z: Calcd.. for C3lH34N4OsS : 622.7. Found (M+H) + : 623.2.

Example 20 35 36 A solution of N-methyl pyridine-4-carboxaldehyde iodide (378 mg, 1.5 mmol) in anhydrous DMF (5.8 mL) was treated with anhydrous toluene (2 x 10 mL) to eliminate the amount of water by azeotropic removal of the toluene. A solution of 35 (134 mg, 0.21 mmol), previously treated with anhydrous toluene (2 x 10 mL), in anhydrous CH2CI2 (distilled over CaH2,7.2 mL) was added, via cannula, at 23 °C to this orange solution. The reaction mixture was stirred at 23 °C for 4 hours. After this time DBU (32.2 uL, 0.21 mmol) was dropwise added at 23 °C and it was stirred for 15 minutes at 23 °C. A freshly aqueous saturated solution of oxalic acid (5.8 mL) was added to the reaction mixture and was stirred for 30 minutes at 23 °C. Then the reaction mixture was cooled to 0 °C and NaHC03 was portionwise added followed by addittion of aqueous saturated solution of NaHC03. The mixture was extracted with Et20. K2CO3 was added to the aqueous layer and it was extrated with Et20. The combined organic layers were dried over MgS04 and the solvent was removed under reduced pressure. The crude was purified by flash column chromatography (AcOEt/hexane from 1/3 to 1/1) to afford compound 36 (77 mg, 57%) as pale yellow solid.

'H-NMR (300 MHz, CDC13) : 8 6.48 (s, 1H), 6.11 (d, J= 1. 3 Hz, 1H), 6.02 (d, J= 1. 3 Hz, 1H), 5.70 (bs, 1H), 5.09 (d, J= 11. 3 Hz, 1H), 4.66 (bs, 1H), 4.39 (m, 1H), 4.27 (d, J= 5. 6 Hz, 1H), 4.21 (d, J= 10. 5 Hz, 1H), 4.16 (d, J= 2. 6 Hz, 1H), 3.76 (s, 3H), 3.54 (d, J= 5. 1 Hz, 1H), 3.42 (d, J=8. 5Hz, lH), 2.88-2.54 (m, 3H), 2.32 (s, 3H), 2.24 (s, 3H), 2.14 (s, 3H), 2.04 (s, 3H). 13C-NMR (75 MHz, CDC13) : 8 186.7,168.5,160.5,147.1,146.4,142.9,141.6,140.7, 130.4,129.8,121.7 (2C), 120.0,117.8,117.1,113.5,102.2,61.7,61.4,60.3,59.8,58.9,54.6, 41.6,36.9,29.7,24.1,20.3,15.8,14.1,9.6.

ESI-MS m/z: Calcd.. for C3lH3lN309S : 621.7. Found (M+H) + : 622.2.

Example 21 HA I OMe Me0 I NH OMe ot'HO Me HO MeO9\ HO Me Ac0 S I , NH A S I A c 09's I c s Me, NMe Me I N-I-Me Sllicagel, EtOH o, N \-O CN t° CN 36 Et-770 To a solution of 36 (49mg, 0.08 ml) and 2- [3-hydroxy-4-methoxyphenyl] ethylamine (46.2 mg, 0.27 ml) in ethanol (2.5 ml) was added silica gel (105 mg) at 23 °C. The reaction mixture was stirred at 23 °C for 14 h. It was diluted with hexane and poured into a column of chromatography (ethyl acetate/hexane from 1/3 to 1/1) to afford Et-770 (55 mg. 90%) as a pale yellow solid.

1H-NMR (300 MHz, CDC13) : 8 6.60 (s, 1H), 6.47 (s, 1H), 6.45 (s, 1H), 6.05 (s, 1H), 5.98 (s, 1H), 5.02 (d, J=11. 4 Hz, 1H), 4.57 (bs, 1H), 4.32 (bs, 1H), 4.28 (d, J= 5.3 Hz, 1H), 4.18 (d, J= 2. 5 Hz, 1H), 4.12 (dd, J= 2.1 Hz, J= 11.5 Hz, 1H), 3.78 (s, 3H), 3.62 (s, 3H), 3.50 (d, J= 5.0 Hz, 1 H), 3.42 (m, 1 H), 3.10 (ddd, J=4.0 Hz, J= 10.0 Hz, J= 11.0 Hz, 1 H), 2.94 (m, 2H), 2.79 (m, 1H), 2.61 (m, 1H), 2.47 (m, 1H), 2.35 (m, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H), 2.09 (m, 1H), 2.04 (s, 3H).

ESI-MS m/z: Calcd.. for C40H42N4OloS : 770. 7. Found (M+H) + : 771.2 Example 22 To a solution of 21 (22 mg, 0.042 ml) in CH2C12 (0.8 ml) was added phthalic anhydride (6.44 mg, 0.042 ml) and the reaction mixture was stirred for 2h at 23 °C. Then, carbonyldiimidazole (lmg, 0.006 ml) was added and the mixture was stirred at 23 °C for 7h.

Then, carbonyldiimidazole (5.86mg, 0.035 ml) was added and the reaction was stirred at 23 °C for an additional 17h. The solution was diluted with CH2CI2 (15 ml) and washed with 0. 1 N HCI (15 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, hexane: ethyl acetate 2: 1) to afford 27 (26.4 mg, 96%) as a white solid.

Rf : 0. 58 (ethyl acetate).

1H NMR (300 MHz, CDC13) : 7.73-7.64 (m, 4H), 6.40 (s, 1H), 6.12-6.01 (m, 1 H), 5.63 (s, 1H), 5.58 (d, J= 1. 5 Hz, 1H), 5.37 (dd, Jl= 1.8 Hz, J2= 17.4 Hz), 5.23 (dd, J1= 1.8 Hz, J2= 10.5 Hz, 1H), 5.12 (d, J= 1.5 Hz, 1H), 4.22-4.15 (m, 3H), 4.08 (d, J= 1. 8 Hz, 1H), 3.68 (s, 3H), 3.59-3.55 (m 2H), 3.35 (d, J= 8. 1 Hz, 1 H), 3.27-3.16 (m, 2H), 3.05 (dd, J1= 8. 1 Hz, J2= 18.3 Hz, 1H), 2.64 (d, J= 18. OHz, 1H), 2.30 (s, 3H), 2.24 (s, 3H), 2.09 (s, 3H), 1.80 (dd, J/= 11. 4Hz, J2=15Hz, lH) ; 3C NMR (75 MHz, CDC13) : 8 167.7,148.9,146.4,144.2,142.6,139.5,134.0,133.5,132.0, 131.0,128.3,123.0,121.3,120.9,118.1,117.5,116.8,113.6,112.4, 100.8,74.5,60.6,60.5, 57.7,56.6,55.6,55.5,42. 3,41.7,26.6,25.5,15.9,9.46.

ESI-MS m/z: Calcd. for C37H35N407 : 648.79. Found (M+H) + : 649.3.

Example 23 To a solution of 27 (26 mg, 0.041 ml) in CH2CI2 (11 ml), acetic acid (11 ml), (PPh3) 2PdCl2 (2.36 mg) and Bu3SnH (28 ml, 0.10 ml) were added at 23 °C. After stirring at that temperature for 2h the reaction was poured into a pad of flash column (Si02, gradient Hex to hexane: ethyl acetate 2: 1) to afford 28 (24.7 mg, 99 %) as a white solid.

Rf : 0.33 (hexane: ethyl acetate 2: 1).

'H NMR (300 MHz, CDC13) : 6 7.75-7.70 (m, 2H), 7.69-7.65 (m, 2H), 6.39 (s. 1H), 5.82 (bs, 1H), 5.50 (d, J= 1. 5 Hz, 1H), 5.0 (d, J= 1. 5 Hz, 1H), 4.45 (bs, 1H), 4.23-4.19 (m, 2H), 4.10- 4.09 (m, 1H), 3.73 (s, 3H), 3.60-3.48 (m, 2H), 3.36-3.33 (m, 1H), 3.26-3.20 (m, 1H), 3.14- 3.08 (m, 1H), 3.98 (d, J= 14.4 Hz, 1H), 2.61 (d, J= 18. 3 Hz, 1H), 2.30 (s, 3H). 2.23 (s, 3H), 2.06 (s, 3H), 1.85 (dd, J1= 12 Hz, J2= 15.3 Hz); 3C NMR (75 MHz, CDC13) : 5 167.8,146.4,145.1,143.9,142.7,137.1,133.5,131.9,130.8, 128.4,122.9,120.8,118.0,116. 8, 114. 0, 113.4,106.4,100.4,60.6,60.5,57.8,56.6,55.5, 55.2,42.6,41.5,25.6,25.5,15.8,8.9.

ESI-MS m/z: Calcd. for C34H32N407 : 608. 6. Found (M+H) + : 609.2.

Example 24 OMe OMe HO Me HO Me OH I OCOCH3 I Me, N YMe CH3COCI, py, CH2CI2 Me, N-Me N-Me N-Me Onc, lu -O, CN -O, CN N O N O O O 28 phthalascidin To a solution of 28 (357 mg, 0.058 ml) in CH2CI2 (3 ml), acetyl chloride (41.58 ml, 0.58 ml) and pyridine (47.3 ml, 0.58 ml) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH2CI2 (15 ml) and washed with 0.1 N HCI (15 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN : H20 60: 40) to afford phthalascidin (354 mg, 94%) as a white solid.

Rf : 0. 37 (CH3CN: H20 7: 3, RP-18).

'H NMR (300 MHz, CDC13) : 8 7.72-7.68 (m, 2H), 7.67-7.63 (m, 2H), 6.38 (s, 1H), 5.69 (d, J= 1. 2 Hz, IH), 5.64 (d, J= 1. 2Hz, IH), 5.30 (bs, IH), 4.25-4.21 (m, 2H), 4.02 (d, J= 2. 1 Hz, 1H), 3.64-3.62 (m, 5H), 3.33 (d, J= 8. 4 Hz, 1H), 3.21-3.16 (m, 1H), 3.02 (dd, JI= 8. 1 Hz, J2= 18 Hz, 1H), 2.76 (dd, J1= 1.8 Hz, Jazz 15.6 Hz, IH), 2.63 (d, J= 17. 7 Hz, 1H), 2.29 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.0 (s, 3H), 1.73 (dd, J1= 12.0 Hz, J2= 15.3 Hz, 1H)) 3C NMR (75 MHz, CDC13)) : 8 168.5,167.6,146.2,144.2,142.5,141.0,140.5,133.4, 131.8,130.7,128.2,120.9,120.8,117.9,116.4,113.6,101.1,60.4,6 0.0,57.0,56.3,55.6, 55.4,41.6,41.5,26.5,25.2,20.2,15.7,9.4.

ESI-MS m/z: Calcd. for C36H34N408 : 650. Found (M+H) + : 651.2.

Example 25 To a solution of 17 (300 mg, 0.432 ml) in CH2CI2 (2 ml), acetyl chloride (30.7 ml, 0.432 ml) and pyridine (34.9 ml, 0.432 ml) were added at 0 °C. The reaction mixture was stirred for 2h at that temperature and then, the solution was diluted with CHzCI2 (15 ml) and washed with 0. 1 N HCI (15 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to afford 42 (318 mg. 100%) as a white solid that was used in subsequent reactions with no further purification.

Rf : 0.5 (ethyl acetate: methanol 5: 1).

1H NMR (300 MHz, CDCl3). 6 6.66 (s, 1H), 5.93 (d, J= 1. 2 Hz, 1 H), 5.83 (d, J= 1. 2 Hz, 1H), 5.42 (t, J= 6. 6 Hz, 1H), 5.07 (d, J= 5.7 Hz, 1H), 4.98 (d, J=5. 7Hz, lH), 4. 16 (d, J= 1. 8 Hz, 1H), 4.11 (d, J= 2. 7 Hz, 1H), 3.98 (bs, 1H), 3.73-3.61 (m, 2H), 3.64 (s, 3H), 3.52-3.48 (m, 1H), 3.50 (s, 3H), 3.33 (d, J= 9. 6 Hz, 1H), 3.17-3.14 (m, 1H), 2.97-2.87 (m, 1H), 2.75- 2.70 (d, J= 16. 8 Hz, 1H), 2.26 (s, 6H), 2.16 (s, 3H), 1.96 (s, 3H), 1.70 (dd, Jl= 11.7 Hz, Jr 15.6 Hz, 1H), 1.33 (s, 9H), 0.59 (d, J= 6. 0 Hz, 3H).

3C NMR (75 MHz, CDCl3)) : 8 172.0,168.3,162.3,148.2,144.4,140.4,140.2,130.9, 130.5,125.3,123.4,120.8,117.6,112.7,111.7,101.4,99.1,79.2,59 .5,58.8,57.5,57.4, 56.4,55.5,55.0,41.3,39.0,28.2,26.4,24.6,19.9,18.4,15.4,9.1.

ESI-MS m/z: Calcd. for C38H49N5010 : 735.82. Found (M+H) + : 736.3.

Example 26 To a solution of 42 (318 mg, 0.432 ml) in CH2C12 (2.16 ml), trifluoroacetic acid (1.33 ml, 17.30 ml) was added and the reaction mixture was stirred for 3.5h at 23 °C. The reaction was quenched at 0 °C with saturated aqueous sodium bicarbonate (60 ml) and extracted with CH2Cl2 (2 x 70 ml). The combined organic layers were dried (sodium sulphate) and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, ethyl acetate: methanol 20: 1) to afford 43 (154 mg, 60%) as a white solid.

Rf : 0. 22 (ethyl acetate: methanol 5: 1).

1H NMR (300 MHz, CDCl3). # 6. 47 (s, 1H), 6.22 (bs, 1H), 5.95 (d, J= 1. 2 Hz, 1H), 5.88 (d, J= 1.2 Hz, 1H), 4.08-4.06 (m, 2H), 4. 01 (bs, 1H), 3.69 (s, 3H), 3.49 (d, J= 3. 6 Hz, 1H), 3.33 (d, J= 8.1 Hz, 1H), 3.26-3.22 (m, 1H), 2.95 (dd, Jl= 8.1 Hz, J2= 18 Hz, 1 H), 2.80-2.76 (m, 2H), 2.58 (d, J=18Hz, 1H), 2.29 (s, 3H), 2.27 (s, 3H), 2.21 (s, 3H), 1.96 (s, 3H), 1.77 (dd, Jl= 12.3 Hz, J2= 15.6 Hz, 1 H), 0.90 (d, J=6. 9 Hz, 3H).

13C NMR (75 MHz, CDCl3)) : 8 174.8,169.0,146.8,144.4,142.8,140.5,140.2,131.1, 128.8,120.8,120.5,117.1,112.9,111.6,101.5,60.3,59.0,56.5,56. 3,55.6,55.1,50.2,41.6, 39.5,26.8,26.3,24.9,20.2,15.4,9.2.

ESI-MS m/z: Calcd. for C3lH37Nso7 : 591.65. Found (M+H) + : 592.3.

Example 27 To a solution of 43 (154 mg, 0.26 ml) in CH2CI2 (1.3 ml), phenyl isothiocyanate (186 ml, 1.56 ml) was added and the mixture was stirred at 23° C for 2h. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography (Si02, gradient Hexane to hexane: ethyl acetate 1: 1) to afford 44 (120 mg, 63 %) as a white solid.

Rf : 0.41 (ethyl acetate: methanol 5: 1).

1H NMR (300 MHz, CDCl3). # 8. 17 (s, 1H), 7.49-7.44 (m, 3H), 7.31-7.24 (m, 3H), 7.05 (d, J= 6. 9 Hz, 1H), 5.98 (d, J= 1.2 Hz, 1H), 5.87 (d, J= 1.2 Hz, 1H), 5.52 (bs, 1H), 4.54 (t, J= 6.6 Hz, 1H), 4.15 (d, J= 2.1 Hz, 1H), 4.03 (d, J= 2. 7 Hz, 2H), 3.80 (bs, 1H), 3.66 (s, 3H), 3.40 (bs, 1H), 3.32 (d, J= 7. 8 Hz, 1H), 3.16 (d, J= 11. 7 Hz, 1H), 2.82-2.61 (m, 3H), 2. 29 (s, 3H), 2.20 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.80 (dd, J1= 12.0 Hz, J2= 15.9 Hz, 1H), 0.62 (d, J= 6.0 Hz, 3H).

13C NMR (75 MHz, CDCl3) 8 178.5,171.9,168.7,146.7,144.5,142.6,140.6,140.3,136.3, 131.0,129.9,128.9,126.7,124.4,120.9,120.6,117.7,116.6,112.7, 111.9,101.4,60.4,58.7, 57.5,56.1,55.7,55.1,53.3,41.4,38.8,26.3,24.4,20.2,18.1,15.3, 9.2.

ESI-MS m/z: Calcd. for C38H42N607S : 726.3. Found (M+H) + : 727.3.

Example 28 OMe OMe HO Me OMe OAc OAc-I OAc HO I Me Me OAc N Me 5. 3N HCI in Dioxane Me i NYMe I O = 2. 5h, 23 °C w, Ny 0 CN p CN HAN o<NHCSNHPh H2N O Me 44 45 To a solution of 44 (120 mg, 0.165 ml) in dioxane (0.9 ml), 5. 3N HCI/dioxane (1.8 ml) was added and the reaction was stirred at 23 °C for 2.5h. Then, CH2CI2 (10 ml) and H20 (5 ml) were added to this reaction and the organic layer was decanted. The aqueous phase was basified with saturated aq sodium bicarbonate (20 ml) (pH = 8) at 0 °C and then, extracted with CH2CI2 (2x15 ml). The combined organic extracts were dried (sodium sulphate), and concentrated in vacuo to afford 45 (75 mg, 87%) as a white solid that was used in subsequent reactions with no further purification.

Rf : 0.23 (ethyl acetate: methanol 5: 1).

'H NMR (300 MHz, CDCl3) : 8 6.43 (s, 1H), 5.94 (d, J= 1. 2 Hz, 1H), 5.87 (d, J= 1. 2Hz, 1H), 4.10 (d, J= 2. 1 Hz, 1H), 3.98 (d, J= 2. 4 Hz, 1H). 3.91 (bs, 1H), 3.69 (s, 3H), 3.34-3.25 (m, 2H), 3.05 (dd, J1= 1.8 Hz, J2= 8. 1 Hz, 1 H), 2.80-2.73 (m, 3H), 2.46 (d, J= 18 Hz, 1H), 2.30 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 1.98 (s, 3H), 1. 79 (dd, Jl= 12.6 Hz, J2= 16.2 Hz, 1H) ; 13C NMR (75 MHz, CDCl3)) : 6 168.7,146.7,144.4.142.9,140.4,130.4,128.9,121.1, 120.8,117.8,116.8,113.6,111.5,101.4,67.6,60.5,59.8,58.4,56.6 ,55.8,55. 3,43.6,41.8, 31.3,25.6,20.2,15.6,9.2.

ESI-MS m/z : Calcd. for C2gH32N406 : 520.58. Found (M+H) + : 521.3.

Example 29 OMe OMe HO>, Me HO, Me OAc c OAc OAc I Me N-Me Me H NMe Pht Anh., CH2CI2, CDI tf N _ 17h, 23°C p CN O I t _ NHC \ NHz0=\j' 45 Phtalascidin To a solution of 45 (10 mg, 0.02 ml) in CH2CI2 (0.4 ml) was added phthalic anhydride (2.84 mg, 0.02 ml) and the reaction mixture was stirred for 2 h at 23 °C. Then, carbonyldiimidazole (0.5 mg, 0.003 ml) was added and the mixture was stirred at 23 °C for 7h. Then, carbonyldiimidazole (2.61 mg, 0.016 ml) was added and the reaction was stirred at 23 °C for an additional 17h. The solution was diluted with CH2CI2 (10 ml) and washed with 0.1 N HCI (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN : H2O 60: 40) to afford phthalascidin (11.7 mg, 93%) as a white solid.

Rf : 0.37 (CH3CN: H20 7: 3, RP-18).

'H NMR (300 MHz, CDC13) : 8 7.72-7.68 (m, 2 h), 7.67-7.63 (m, 2 h), 6.38 (s, I H), 5.69 (d, J= 1. 2 Hz, 1H), 5.64 (d, J= 1. 2 Hz, 1H), 5.30 (bs, 1H), 4.25-4.21 (m, 2 h), 4.02 (d, J= 2. 1 Hz, 1H), 3.64-3.62 (m, 5H), 3.33 (d, J= 8. 4 Hz, 1H), 3.21-3.16 (m, 1H), 3.02 (dd, J/= 8.1 Hz, J2= 18 Hz, 1H), 2.76 (dd, Jazz 1.8 Hz, = 15.6 Hz, 1H), 2.63 (d, J= 17. 7 Hz, 1H), 2.29 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.0 (s, 3H), 1.73 (dd, Jl= 12.0 Hz, J2= 15. 3 Hz, 1H)) ; i3C NMR (75 MHz, CDC13)) : 8 168.5,167.6,146.2,144.2,142.5,141.0,140.5,133.4, 131.8,130.7,128.2,120.9,120.8,117.9,116.4,113.6,101.1,60.4,6 0.0,57.0,56.3,55.6, 55.4,41.6,41.5,26.5,25.2,20.2,15.7,9.4.

ESI-MS m/z : Calcd. for C36H34N408 : 650. Found (M+H) + : 651.2.

Example 30 To a solution of 25 (18 mg, 0.032 ml) in DMF (0.05 ml), cat. DMAP (0.5 mg, 0.004 ml), imidazole (5 mg, 0.08 ml) and tert-Butyldiphenylsilyl chloride (12.5 ml, 0.048 ml) were added at 0 °C and the reaction mixture was stirred for 6h at 23 °C. Water (10 ml) was added at 0 °C and the aqueous phase was extracted with hexane: ethyl acetate 1: 10 (2 x 10 ml). The organic layer was dried (sodium sulphate), filtered, and the solvent was removed under reduced pressure. The crude was purified by flash column chromatography (SiCh. hexane: ethyl acetate 3: 1) to afford 26 (27 mg, 88 %) as a white solid.

Rf : 0.29 (hexane: ethyl acetate 3: 1).

'H NMR (300 MHz, CDC13) 5 7.61-7.58 (m, 2 h), 7.42-7.28 (m, 8H), 6.71 (s, IH), 6.19-6.02 (m, 1H), 5.78 (d, J= 1.2 Hz, 1H), 5.64 (d, J= 1.2 Hz, IH), 5.40 (dd, J1= 1.2 Hz, J2= 17.1 Hz, IH), 5.27 (dd, Jl= 1. 2 Hz, J2= 10.2 Hz, IH), 5.13 (s, 2 h), 4.45 (d, J= 2.4 Hz, I H), 4.24 (d, J= 2.1 Hz, 1H), 4.17-4.06 (m, 3H), 3.75 (s, 3H), 3.64 (dd, Jl= 2.4 Hz, J= 9.9 Hz, IH), 3.59 (s, 3H), 3.42-3.21 (m, 4H), 3.10 (dd, Jl= 8. 1 Hz, J2= 17.7 Hz, IH), 2.70 (d, J= 17.7 Hz, IH), 2.33 (s, 3H), 2,26 (s, 3H), 2.11 (s, 3H), 2.08-1.89 (m, 1H), 0.87 (s, 9H); 3C NMR (75 MHz, CDCI3) : 6 148.5,148.3,148.1,144.0,139.0,135.6,135.4,133.8,133.1, 132.6,130.5,130.3,129.6,129.4,127.5,127.4,125.1,124.3,121.6, 118.5,117.5,112.9, 111.7,100.8,99. 2,74.0,67.7,61.5,59.6,59.0,57.7,57.1,55.4,41.6,29.6,26.6,25. 5,18.8, 15.8,9.2.

ESI-MS m/z: Calcd. for C47HssN307Si : 801.3. Found (M+H) + : 802.3.

Example 31 26 ET-11 To a solution of 26 (7 mg, 0.0087 ml) in CH2C12 (0.15 ml), acetic acid (2.5 ml, 0.044 ml), (PPh3) 2PdCl2 (0.5 mg, 6.96 x 10 4 mol) and Bu3SnH (3.5 ml, 0.013 ml) were added at 23 °C. The reaction mixture was stirred at that temperature for lh. The solution was diluted with a mixture of hexane : ethyl acetate 5: 1 (0.5 ml) and poured into a pad of flash column (Si02, gradient 5: 1 to 1 : 1 hexane: ethyl acetate) affording ET-11 (5 mg, 75 %) as a white solid.

Rf : 0.36 (hexane: ethyl acetate 1: 5, silica).

'H NMR (300 MHz, CDC13) : 8 7.56 (m, 2 h), 7.41-7.25 (m, 8H), 6.67 (s, 1H), 5.72 (d, J= 1.0 Hz, 1H), 5.58 (d, J= 1.0 Hz, 1H), 5. 51 (s, IH), 5.38 (d, J= 5. 75 Hz, 1H), 5.16 (d, J= 5.7 Hz, 1H), 4.57 (d, J= 2.9 Hz, 1H), 4.21 (m, 1H), 4.09 (m, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.68 (dd, J1= 2. 1 Hz, J2= 10. 4 Hz, 1H), 3.38-3.26 (m, 3H), 3.11 (dd, J1= 2.5 Hz, J2= 15. 7 Hz, 1H), 3.01 (dd, Je= 8.9 Hz, J2= 17.9 Hz, 1H), 2.70 (d, J= 17.9 Hz, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H), 1.89 (dd, J= 12. 1 Hz, J, = 15.7 Hz, 1H), 0.9 (s, 9H).); "C NMR (75 MHz, CDC13) : 8 149.0,147.4,145.3,144.3,136.3,135.7,135.4,133.2,130.9, 130.5,129.6,129.5,127.5,125.0,118.6,112.5,112.1,105.7,100.5, 99.8,68.5,61.5,59.7, 58.8,57.7,56.9,56.5,55.4,41.7,26.6,26.2,25.5,18.9,15.8,14.2, 8.7.

ESI-MS m/z: Calcd. for C44H5lN307Si : 761. Found (M+H) + : 762.

Example 32 A solution of 2 (3.0 g, 5.46 ml) and phenyl isothiocyanate (3.92mL. 32.76 ml) in CH2CI2 (27 ml) was stirred at 23° C for 1.5h. The reaction mixture was partitioned between CH2Cl2 (10 ml) and H20 (5 ml). The organic layer was dried over sodium sulphate, filtered and concentrated. The residue was purified by flash column chromatography (Si02, gradient Hex to 2: 3 hexane: ethyl acetate) to give 3 (3. 29 g, 88%) as a yellow solid.

Rf : 0. 27 (ACN: H20 3: 2, RP-C18) ; 'H NMR (300 MHz, CDCl3) : 8 7.77 (bs, 1H), 7.42-7.11 (m, 5H), 6.65 (d, 1H), 6.29 (s, 1H).

5.6-5.5 (m, 1H), 4.19-4.14 (m, 2 h), 4.08 (d, 1H), 3.92 (s, 3H), 3.87-3.65 (m, 6H), 3.77 (s, 3H), 3.37-2.98 (m, 8H), 2.50 (d, 1H), 2.31 (s, 3H), 2.20 (s, 3H), 1.96 (d, 1H), 1.87 (s, 3H), 1.81-1.75 (m, 1H), 0.96 (d, 3H); 13C NMR (75 MHz, CDC13) : 6 185.7,180.9,178.9,172.0,155.7,147.1,143.2,142.4,136.0,135.1, 130.5,129.9, 129.3,128.5,126.9,124.4,120.2,117.4,116.3,77.1,60.9,58.6,56. 2,55.8,55.0,54.6,53.5, 41.7,40.3,25.1,24.5,18.4,15.8,8.7 ESI-MS m/z: Calcd. for C36H40N6O6S : 684.8. Found (M+H) + : 685.2.

Example 33 OMe H°Ss, Me ho, mye Me HO Me 1) HCI 6. 5M in dioxane01 I'i J Me Me0 N N 1 Me O C CN 2) NaCO3H N NH Mezzo PhHNSCHN CN H N 3 4 A solution of 3 (0.143 g, 0.208 ml) in 6.5 M HCl/dioxane (150 ml) was stirred at 23 °C for 6h. Then, toluene (3 ml) was added to this reaction and the organic layer was decanted. The residue was partitioned between saturated aqueous sodium bicarbonate (3 ml) and CHC13 (3x3 ml) The organic layers were dried and concentrated to afford title compound as a mixture of 4 and 6 (4: 6 90: 10) which slowly cyclizes to 6 on standing.

Rf : 0.4 (ethyl acetate: methanol5 : 1, silica); 'H NMR (300 MHz, CDC3) : 6 6.45 (s, 1H), 4.16 (m, 1H), 4.02 (d, IH), 3.96 (s. 3H), 3.79 (m, 2 h), 3.75 (s, 3H), 3. 35 (m, 1H), 3.20-3.00 (m, 3H), 2.87 (d, 1H), 2.75 (d, I H). 2.43 (d, 1H), 2.34 (s, 3H), 2.30 (s, 3H), 1.93 (s, 3H), 1.72-1.5 (m, 3H); ESI-MS m/z: Calcd. for C26H3oN40s : 478.5. Found (M+H) + : 479.2 Example 34 OMe HO Me OMe ho, mye Me nome I I N E 6. 5M HCI in dioxane Me I MeO i 45 min, 23 OC I I NH N CN PHHNSCHN N N ° T O 3 A solution of 3 (0.143 g, 0.208 ml) in 6.5M HCI/dioxane (150 ml) was stirred at 23 °C for lh. Evaporation of the solvent gave a residue which was purified by flash column chromatography (ethyl acetate/methanol/triethylamine 100: 25: 0.1) to give 6 (80 mg, 83%) as a yellow solid.

Rf : 0. 26 (ACN: H20 3: 2, RP-C18) ; 'H NMR (500 MHz, CDC13) : 8 6.46 (s, 1H), 5.9 (bs, 1H) 4.67 (dd, J=18. 3 Hz, J= 7.8 Hz, 1H), 4.24 (d, 1H), 4.16 (s, 3H), 3.93 (d, J=2. 7 Hz, 1H), 3.8 (m, 2 h), 3. 77 (s. 3H), 3.45 (m, 2 h), 3.08 (dd, J=17. 9 Hz, J=3, 6 Hz, 1H), 2.78 (m, 1H), 2.55 (d, 1H), 2.3 (m, 1H) 2. 3 (s. 3H), 2.28 (s, 3H), 1.90 (s, 3H); 13C NMR (75 MHz, CDCl3) : 8 186.2,162.1,154.9,146.9,145.3,143.0,130.1,129.4,128,1, 125.0,121.4,116.4,116.2,66.6,60.7,60.7,60.1,59.6,58.8,55.6,5 4.9,41.9,25.3,24.7, 15. 7,8.9.

ESI-MS m/z : Calcd. for C26H2gN404 : 460.5. Found (M+H) + : 461. 1 Example 35 OMe OMe OMe OMe O Me N Y Me Me HCI 5. 3 M in dioxane I N T Me O r CN t- NH O s CN NU PHHNSCHN 0 0 T NH i O I 5 3 3 To a solution of 3 (2.38 g, 3.47 ml) in dioxane (5 ml) 5.3M HCI in dioxane (34 ml) was added and the reaction was stirred at 23 °C for 45 minutes. Then Ac20 (51 ml, 539.5 ml) was added and the mixture was stirred for 4h. The reaction was cooled at 0 °C and partitioned between aqueous saturated Na2C03 (300 ml) and ethyl acetate (300 ml) at this temperature. The organic phase was dried over sodium sulphate, filtered and concentrated.

The residue was purified by flash column chromatography (Si02, gradient CH2C12 to CH2Cl2 : ethyl acetate 1: 2) to give 5 (1.75 g, 97%) as a yellow solid.

Rf : 0. 53 (ACN: H20 3: 2, RP-C18) ; 'H NMR (300 MHz, CDC13) : 8 6.51 (s, 1H), 5.98 (bs, 1H), 4.84 (dd, 1H), 4.17 (d, 1H), 4.00 (d, 1H), 3.99 (s, 3H), 3.85 (bs, 1H), 3.81 (m, 1H), 3.74 (s, 3H), 3.70 (d, 1H), 3.23 (m, 1H), 3.11 (dd, 1H), 3.09 (m, 1H), 2.93 (m, 2 h), 2.44 (d, 1H), 3.67 (s, 3H), 2.25 (s, 3H), 1.70 (s, 3H), 1.60-1.50 (m, 2 h), 1.29 (s, 3H); 3C NMR (75 MHz, CDC13) : 8 185.9,180.8,169.9,160.2,156.2,147.0,143.1.140.4.136.1.

130.6,129.6,127.9,120.4,117.2,61.0,60.7,58.6,56.1,55.7,55 .1,54.3.41.8. 41. 1. 25. 7.

23.9,22.2,15.7,8.7.

ESI-MS m/z : Calcd. for C2sH32N406 : 520. 6. Found (M+H) + : 521.1 Example 36 To a solution of 5 (1.75 g, 3.36 ml) in CH2CI2 (17 ml) diisopropylethylamine (11. 71 ml, 67.23 ml), DMAP (20 mg, 0.17 ml) and bromomethyl methyl ether (4.11 ml, 50.42 ml) were added at 0 °C. After 6 h at 23 °C the reaction was partitioned between CH2Cl2 (50 ml) and aqueous saturated sodium bicarbonate (25 ml). The organic layer was dried over sodium sulphate and the solvent was eliminated under reduced pressure. The crude was purified by flash column chromatography (RP-18, CH3CN/H2O 1/1) to give 7 (1.32 g, 70%) as a yellow solid.

Rf : 0. 34 (ACN: H20 2 : 3, RP-C18) ; 'H NMR (300 MHz, CDC13): 8 6.74 (s, 1H), 5.14 (s, 2 h), 4.82 (m, 1H), 4.22 (d, 1H), 4.00 (s, 3H), 4.0 (m, 1H), 3.83 (m, 2 h), 3.7 (s, 3H), 3.58 (s, 3H), 3.4 (m, 1H), 3.2-2.95 (m, 6H), 2.43 (d, 1H), 2.37 (s, 3H), 2.22 (s, 3H), 1.89 (s, 3H), 1.5-1.4 (m, 2 h), 1.31 (s, 3H); 3C NMR (75 MHz, CDC13) : 8 185.9,180.7,169.6,156.2,148.9,148.5,140.3,136.2,131.3, 130.1,127.7,124.6,123.7,117. 3,99.5,99.2,60.9,59.7,58.8,57.7,56.4,55.7,55.0,54.2, 51.0,41.6,41.0,40.5,25.5,23.9,22. 3,19.3,15.6,14.6,8.6. ESI-MS m/z: Calcd. for C3oH36N407 : 564.6. Found (M+H) : 565.3 Example 37 To a solution of 7 (0.37 g, 0. 65 ml) in methanol (74 ml) at 0 °C was added 1 M sodium hydroxide (130 ml). The reaction was stirred for 15 minutes and then, quenched at 0 °C with 6M HC1 to pH = 5. The mixture was extracted with ethyl acetate (3 x 50 ml) and the combined organic layers were dried over sodium sulphate and concentrated in vacuo.

The residue was purified by flash column chromatography (RP-C18 CH3CN: H20 1/ : 1) to afford 8 (232 mg, 65%) as a yellow oil.

Rf : 0.5 (ACN: H20 3: 2, RP-C18) ; 1H NMR (300 MHz, CDC13) : 8 6.75 (s, 1H), 5.15 (s, 2 h), 4.86 (m, 1H), 4.26 (d, 1H),), 4.01 (d, 1H), 3.88-3.81 (m, 2 h), 3.70 (s, 3H), 3.58 (s, 3H), 3.39 (m, 1H), 3.27-3.21 (m, 1H), 3.18- 3.08 (m, 2 h), 3.03-2.97 (m, 1H) 2.47 (d, 1H), 2.37 (s, 3H), 2.22 (s, 3H), 1.90 (s, 3H), 1.57- 1.46 (m, 2 h), 1.33 (s, 3H); 3C NMR (75 MHz, CDC13) : 5 185.3,180.6,175.9,170.1,151.5,148.9,148.6,143.3,133.7, 131.5,129.9,124.7,123.5,117.1,117.0,99.2,59.8,58.7,57.8,56.3 ,55.3,54.9,54.3,41.5, 40.7,29.6,25.5,24.4,22.2,20.7,15.7,8.0.

ESI-MS m/z : Calcd. for C29H34N407 : 550.6. Found (M+H) + : 551.2 Example 38 To a degassed solution of compound 8 (240mg, 0.435 ml) in DMF (30 ml) 10 % Pd/C (48 mg) was added and the reaction was stirred under H2 (atmospheric pressure.) for lh. The reaction was filtered through a pad of celite under Argon to a Schlenk tube, as a colourless solution, containing anhydrous Cs2C03 (240 mg, 0.739 ml). Then, bromochloromethane (0.566 ml, 8. 71 ml) was added. The tube was sealed and stirred at 90 °C for 3h. The reaction was cooled and filtrated through celite and washed with CH2C12.

The organic layer was concentrated and dried (sodium sulphate) to afford 9 as a brown oil that was used in the next step with no further purification.

Rf : 0. 36 (Si02, hexane: ethyl acetate 1: 5) 'H NMR (300 MHz, CDC13) : 8 6.71 (s, 3H), 5.89 (d, 1H), 5.81 (d, 1H), 5.63 (bs. 1H), 5.33 (d, 1H), 5.17 (d, 1H), 4.97 (m, 1H), 4.20 (d, 1H), 4.09 (m, 1H), 3.99 (m, 1H), 3.68 (m, IH), 3.65 (s, 6H), 3.59-3.47 (m, 4H), 3.37-3.27 (m, 2 h), 3.14- 2.97 (m, 2 h), 2.62 (d, I H), 2.32 (s, 3H), 2.20 (s, 3H), 2.08 (s, 3H), 1.72 (m, 1H), 1.36 (s, 3H); 13C NMR (75 MHz, CDC13) : 8 169.8,149.1,147.4,145.5,136.2,130.9,130.8,125.0,122.9, 117.7,112.6,111.8,106.4,100.8,99.8,59.8,58.9,57.7,56.6,56.4, 55.5,55.2,41.6,40.1, 29.6,25.9,25.0,22.6,15.6,8.8.

ESI-MS m/z : Calcd. for C3oH36SiN407 : 564.6. Found (M+H) + : 565.3.

Example 39 9 10 To a flask containing 9 (245 mg, 0.435 ml) in DMF, (4 ml), cesium carbonate (425 mg, 1.30 ml) and allyl bromide (376 ml, 4.35 ml) were added at 0 °C and the mixture was stirred at 23 °C for lh. The reaction was filtered though a pad of celite and partitioned between CH2C12 (25 ml) and H20 (10 ml). The organic phase was dried (sodium sulphate) and concentrated at reduced pressure to afford a residue that was purified by flash column chromatography (Si02, CHCl3 : ethyl acetate 1: 2) to give 10 as a yellow oil. (113 mg. 43 %).

Rf : 0.36 (hexane: ethyl acetate 1: 5) 'H NMR (300 MHz, CDC13) : 5 6.74 (s, 1H), 6.3-6.0 (m, 1H), 5.94 (d, 1H), 5.87 (d, 1H), 5.43-5.36 (m, 2 h), 5.22 (s, 2 h), 5.00 (m, 1H), 4.22 (m, 1H), 4.17-4.01 (m, 1H), 3.98 (m, 2 h), 3.71-3.67 (m, 1H), 3.69 (s, 3H), 3.62-3.51 (m, 3H), 3.58 (s, 3H), 3.39-3.37 (m, 1H), 3.31- 3.26 (m, 3H), 3.09 (dd, 1H), 2.56 (d, 1H), 2.36 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H), 2.24-2.10 (m, 1H), 1.82-1.73 (m, 1H), 1.24 (bs, 3H) 13 C NMR (75 MHz, CDC13) : 8 169.4,148.8,148.3,139.1,133.7,130.9,130.3,125.2,120.2, 117.7,113.1,112.6,101. 3,99.3,74.1,59.7,59.3,57.8,57.0,56.1,56.1,55.2,41.6,41.0, 40.9,29.7,26.3,22.5,15.6,9.3 ESI-MS m/z: Calcd. for C33H40N407 : 604.7. Found (M+H) + : 605.3.

Example 40 To a solution of 9 (22 mg, 0.039 ml) in CH2CI2 (0.2 ml), acetyl chloride (2.79 ml, 0.039 ml) and pyridine (3.2 ml, 0.039 ml) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH2CI2 (10 ml) and washed with 0.1 N HC1 (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to afford 46 (22 mg, 93%) as a white solid.

Rf : 0. 4 (hexane: ethyl acetate 1: 5).

1H NMR (300 MHz, CDCl3). # 6.74 (s, 1H), 5.97 (d, J= 0. 9 Hz, 1H), 5.91 (d, J= 0. 9 Hz, 1H), 5.12 (d, J= 5.7 Hz, 2 h), 5.04 (d, J= 5.7 Hz, 1H) 4.90 (t, J= 6 Hz, 1H), 4.17 (d, J= 2. 7 Hz, 1H), 4.05 (d, J= 2. 7 Hz, 1H), 4.01 (bs, 1H), 3.71 (s, 3H), 3.57 (s, 3H), 3.50-3.44 (m, 2 h), 3.38-3. 36 (m, 1H), 3. 30-3.26 (m, 1H), 3.00 (dd, J1= 7.8 Hz, J2= 18. 0 Hz, 1H), 2.79 (d, J= 12.9 Hz, 1H), 2.60 (d, J=18. 0 Hz, 1H), 2.35 (s, 3H), 2.32 (s, 3H), 2.21 (s, 3H), 2.00 (s, 3H), 1.68 (dd, Jl=11. 7 Hz, J2= 15. 6 Hz, 1H).

ESI-MS m/z: Calcd. for C32 h38N4O8 : 606.67. Found (M+H) + : 607.3.

Example 41 OMe OMe momo Me HO Me Mu Me "YMe Me i I Me Onc Me N--Me HCI 5.3M in dioxane 0 lh, 23 OC 0 -0 \ CN-0 CN NH NH O'\ O'' 46 47 To a solution of 46 (8 mg, 0.013 ml) in dioxane (0.1 ml), 5.3N HCI/dioxane (0.5 ml) was added and the reaction was stirred at 23 °C for 1 h. Then, the solution was diluted with CH2C12 (5 ml) and washed with 0.1 N HCI (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to afford 47 (5 mg.

70%) as a white solid.

Rf : 0.4 (hexane: ethyl acetate 1: 5).

H NMR (300 MHz, CDC13). 6 6. 51 (s, 1H), 5.97 (d, J=1. 2Hz, IH), 5.91 (d, J=1. 2Hz, 1H), 4.97 (bs, 1 H), 4.11 (bs, 1H), 4.04-4.02 (m, 2 h), 3.75 (s, 3H),), 3.65 (d, J= 2. 1 Hz, 2 h), 3.56-3. 30 (m, 2 h), 3.04 (dd, Jazz 7.5 Hz, J2= 18 Hz, 1H), 2.80 (d, J= 14. 4 Hz, 1H), 2.59 (d, J= 18. 3 Hz, IH), 2.33 (s, 3H), 2.24 (s, 3H), 2.00 (s, 3H), 1.76 (dd, J= 12.0 Hz, J= 15.9 Hz, 1H), 1.33 (s, 3H), 1.25 (s, 3H).

ESI-MS m/z : Calcd. for C30H34N407 : 562.61. Found (M+H) + : 563.3.

Example 42 OMe OMe Nn JL M. HOMe OMe OMe OAc OAc I Mye Me, I N Me isovaleryl chloride, py, \ N Me N CH2CI2 0°C, 1h p = zon 0 C NH2 O 45 48 To a solution of 45 (10 mg, 0.0192 ml) in CH2CI2 (0.3 ml), isovaleryl chloride (2.34 ml, 0.0192 ml) and pyridine (1.55 ml, 0.0192 ml) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH2CI2 (5 ml) and washed with 0.1 N HCI (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex : ethyl acetate 1: 2) to afford 48 (11 mg, 95%) as a white solid.

Rf : 0. 12 (Hex: ethyl acetate 1: 2).

1H NMR (300 MHz, CDC13) : 8 6.50 (s, 1H), 5.98 (d, J= 1.5Hz, 1H), 5.91 (d, J= 1.5 Hz, 1H), 5.75 (s, 1H), 5.02 (t, J= 5. 4 Hz, 1H), 4.10 (d, J= 1.5 Hz, 1H), 4.06 (d, J= 2. 7 Hz, 1H), 4.02 (d, J= 2. 7 Hz, 1H), 3.77 (s, 3H), 3.76-3.71 (m, 1H), 3.86-3.28 (m, 3H), 3. 04 (dd, J1= 8.1 Hz, J2= 18.3Hz, 1H), 2.78 (d, J=15. 9 Hz, 1H), 2. 55 (d, J=18 Hz, 1H), 2.32 (s, 6H), 2.26 (s, 3H), 1.98 (s, 3H), 1.84-1.68 (m, 2 h), 1.36 (d, J= 7.2 Hz, 2 h), 0.69 (d, J= 6. 6 Hz, 3H). 0. 62 (d, J=6. 6 Hz, 3H).

ESI-MS m/z : Calcd. for C33H4ON407 : 604.69. Found (M+H) + : 605.3.

Example 43 os OMe OMe HO HO OAc OAc w I Me/ N-Me decanoyl chloride, py, I p<soNJs CH2C12, 0°C, 1h o- zon NH J \ » 0 \ CN NH (CH2) 8 45 49 To a solution of 45 (10 mg, 0.0192 ml) in CH2C12 (0.3 ml), isovaleryl chloride (3.98 ml, 0.0192 ml) and pyridine (1.55 ml, 0.0192 ml) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH2CI2 (5 ml) and washed with 0.1 N HCI (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: ethyl acetate 1: 2) to afford 49 (12.4 mg, 96%) as a white solid.

Rf : 0.7 (ethyl acetate : methanol 10 : 1).

1H NMR (300 MHz, CDC13) : 8 6. 50 (s, 1H), 5.98 (d, J= l. SHz, 1H), 5.91 (d, J= 1. 5 Hz, 1H), 5.73 (s, 1H), 5.08 (t, J= 5. 4 Hz, 1H), 4.10 (d, J= 1. 5 Hz, 1H), 4.05 (m., 1H), 4.01 (m, 1H), 3.76 (s, 3H), 3.65-3.61 (m, 1H), 3.40-3.27 (m, 3H), 3.03 (dd, Jl= 8.1 Hz, J2= 18.6 Hz, 1H), 2.78 (d, J=13. 2 Hz, 1H), 2.57 (d, J=18. 3 Hz, 1H), 2.32 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 1.99 (s, 3H), 1.79 (dd, Jl= 12.0 Hz, J2= 16.5 Hz, 1H), 1.73-1.42 (m, 4H), 1.33-1.18 (m, 10H), 1.03 (m, 2 h), 0.87 (t, J= 6.6 Hz, 3H). ESI-MS m/z: Calcd. for C3gH5oN407 : 674. 83. Found (M+H) + : 675.5.

Example 44 OMe OMe HO, Me OAc OAc mye OAc Mye, N-Me trans-ClOH6CIF30, PY, I I j o ~N N J CH2CI2, 0°, 1 h. 0 -O CN 'C CN NH2 n 3 o 0 45 50 To a solution of 45 (14.5 mg, 0.0278 ml) in CH2C12 (0. 3 ml), trans-3-trifluoromethyl cinnamoyl chloride (4.76 ml, 0.0278 ml) and pyridine (2.25 ml, 0.0278 ml) were added at 0 °C. The reaction mixture was stirred for 1h and then, the solution was diluted with CH2CI, (5 ml) and washed with 0. 1 N HCI (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: ethyl acetate 1: 1) to afford 50 (18.7 mg, 94%) as a white solid.

Rf : 0.64 (ethyl acetate: methanol5: 1) 1H NMR (300 MHz, CH30D). 6 7.74-7.55 (m, 4H), 7.23 (d, J= 16. 0 Hz, 1 H), 6.34 (s, 1 H), 6.12 (d, J= 16. 0 Hz, 1H), 6.07 (d, J= 0. 9 Hz, 1H), 5.96 (d, J= 0. 9 Hz, 1H), 4.39 (d, J= 2. 4 Hz, 1H), 4.07-4.05 (m, 1 H), 3.81 (bs, 1H), 3.46-3.51 (m, 3H), 3.42 (s, 3H), 3.09 (br d, J= 12.0 Hz, 1H), 2.94-2.85 (m, 2 h), 2.74 (d, J=18. 3 Hz, 1H), 2.38 (s, 3H), 2.23 (s, 3H), 2.02 (s, 3H), 1.80 (s, 3H), 1.84-1.75 (m, 1H).

13C NMR (75 MHz, CDCl3)) : 8 168.7,165.3,146.5,144.7,142.6,140.6,138.0,135.9, 131.0,130.9,129.1,128.6,125.8,125.7,124.5,124.4,122.7,121.2, 117.8,116.5,113.0, 112.0,101.7,60.4,59.1,56.5,56.4,55.6,55.3,41.8,40.3,26.6,25. 1,20. 3,15.4,9.3.

ESI-MS m/z : Calcd. for C38H37F3N407 : 718.72. Found (M+H) + : 719.3.

Example 45 OMe OMe HO Onc onc Mye, Meo Me Isovaleryl chloride. Py ve 4 J CH2CI2, 0°C, 1h O- '--O CN \ » 0 t CN NH nu NH Me \ » Me 'NH j Ho N H NH2 0L 43 51 To a solution of 43 (33 mg, 0.0557 ml) in CH2CI2 (0.4 ml), isovaleryl chloride (6.79 ml, 0. 0557 ml) and pyridine (4.5 ml, 0.0557 ml) were added at 0 °C. The reaction mixture was stirred for I h and then, the solution was diluted with CH2CI2 (5 ml) and washed with 0.1 N HC1 (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: ethyl acetate 1: 2) to afford 51 (34 mg, 91%) as a white solid.

Rf : 0.09 (Hex: ethyl acetate 1: 2).

'H NMR (300 MHz, CDCl3) : 8 6.46 (s, lH), 6.10 (bs, IH), 5.99 (d,. J= 0.9Hz, IH), 5.90 (d, J= 0. 9 Hz, 1H), 5.30 (t, J= 6. 0 Hz, 1H), 4.10-4.05 (m, 3H), 3.81 (bs, 1H), 3.74 (s, 3H), 3.54 (bs, lH), 3.38-3.36 (m, 1H), 3.29-3.21 (m, IH), 3.00 (dd, J/= 8.0 Hz, J, = 18.0 Hz, IH), 2.25 (s, 3H), 2.20 (s, 3H), 2.00 (s, 3H), 1. 95-1.90 (m, 3H), 0.87 (d, J=6. 6 Hz, 6H), 0.76 (d, J=6. 0 Hz, 3H).

ESI-MS m/z: Calcd. for C36H45NsOg : 675.77. Found (M+H) + : 676.3.

Example 46 OMe OMe HO Me HO Ho au c N-Me Me OAc I trans-ClOH6CIF30, PY, Me N-Me 1 O CH2CI2, 0°, 1h. ° t ~ O = 0 » 0 \ CN NH NH Me <Me NH 0"NH NH2 O +CF3 43 2 To a solution of 43 (33 mg, 0.0557 ml) in CH2C12 (0.4 ml), trans-3-trifluoromethyl cinnamoyl chloride (9.52 ml, 0.0557 ml) and pyridine (4.5 ml, 0.0557 ml) were added at 0 °C. The reaction mixture was stirred for Ih and then, the solution was diluted with CH2Cl2 (5 ml) andwashed with 0. 1 N HCI (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: ethyl acetate 1: 2) to afford 52 (40 mg, 92%) as a white solid.

Rf : 0. 21 (hexane: ethyl acetate 1: 2).

'H NMR (300 MHz, CD30D). 6 7.74-7.47 (m, 4H), 6.49 (s, 1H), 6.40 (d, J= 15. 6 Hz, 1 H), 6.00 (d, J= 1. 5 Hz, IH), 5.90 (d, J= 1. 5 Hz, 1H), 5.47 (t, J= 6 Hz, 1H), 4.12-4.09 (m, 3H), 3.93 (bs, IH), 3.71 (s, 3H), 3.59-3.58 (m, 1H), 3.38 (d, J=7. 8 Hz, 1H), 3.29 (d, J=12. 0 Hz, 1H), 3.00 (dd, J1= 8.1 Hz, J2= 18.3 Hz, 1H), 2.79-2.78 (m, 1H), 2.65 (d, J=18. 3 Hz, I H) 2.29 (s, 6H), 2.28 (s, 3H), 2.22 (s, 3H), 1.84-1.80 (m, 1H), 0.85-0.84 (m, 3H).

3C NMR (75 MHz, CDC13) 8 171.9,168.8,164.4,146.9,144.6,143.0,140.5,140.5,139.3, 135.7,131.1,131.0,129.4,129.1,126.0,124.1,124.0,122.4,121.1, 120.7,120.6,117.7, 116.9,112.8,112.0,101.6,60.6,59.3,57.1,56.3,55.9,55.2,49.0,4 1.7,49.9,26.5,25.1, 20.2,18.4,15.7,9.3.

ESI-MS m/z : Calcd. for C41H42F3N508 : 789. 8. Found (M+H) + : 790. 3.

Example 47 OMe OMe HO Me HO Me OAc i OAc I Me N-Me Trifluoroacetic anhydride Me N-Me tN CH2CI2, 5h, 23 °C otN \-o N \-O N NH NH o<NH2 oy Y Me Me O 43 53 To a solution of 43 (10 mg, 0.0169 ml) in CH2CI2 (0.2 ml) trifluoroacetic anhydride (2.38p1,0.0169 ml) was added at 23 °C. The reaction mixture was stirred for 5h and then, the solution was diluted with CH2CI2 (5 ml) and washed with 0.1 N HCI (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: ethyl acetate 3: 2) to afford 53 (10.7 mg, 93%) as a white solid.

Rf : 0.57 (ethyl acetate: methanol5: 1). in NMR (300 MHz, CDC13) 8 6.45 (s, 1H), 6.00 (d, J= 1. 2 Hz, 1H), 5.90 (d, J= 1. 2 Hz, 1H), 5.87 (bs, 1H), 5.32 (bs, 1H), 4.12 (d, J= 2. 1 Hz, 1H), 4.08 (d, J= 1.8 Hz. 1H), 3.78-3.56 (m, 3H), 3.72 (s, 3H), 3.40 (d, J= 8. 1 Hz, 1 H), 3.25 (d, J= 9.3 Hz, 1 H), 3.00 (dd, Jl= 8.4 Hz, J2= 18.0 Hz, 1H), 2.77 (dd, J1= 2. 1 Hz, -) = 15. 9 Hz, 1H), 2.68 (d, J= 18.6 Hz, 1H), 2.30 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 2.00 (s, 3H), 1.75 (dd, J= 11. 4 Hz, J2= 15.9 Hz, 1H), 0.69 (d, J= 6. 3 Hz, 3H).

'3C NMR (75 MHz, CDC13) 8 170.1,168.6,156.0,147.0,144.6,143.0,140.6,140.4,131.0, 129.4,120.9,120.7,117.6,116.8,112.4,112.1,101.6,60.5,59.0,57 .1,56.3,55.6,55.2, 48.7,41.6,39.4,26.5,24.9,20.2,17.8,15.4,9.2.

ESI-MS m/z: Calcd. for C33H36F3N5O8: 687. 63. Found (M+H) + : 688.66.

Example 48 OMe OMe HO Me HO Me w. 0 Me, NYMe Trifluoroacetic anhydride Me NYMe 0 CH2C'2, 5h, 23-C0 \-o 0 N NHNH Me Me 0 MeMe 0 19 54 To a solution of 19 (11 mg, 0.0169 ml) in CH2Cl2 (0.2 ml) trifluoroacetic anhydride (2.38 ml, 0.0169 ml) was added at 23 °C. The reaction mixture was stirred for 5h and then, the solution was diluted with CH2C12 (5 ml) and washed with 0.1 N HCI (3 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: ethyl acetate 3: 2) to afford 54 (10.7 mg, 93%) as a white solid.

Rf : 0.6 (ethyl acetate: methanol5: 1).

'H NMR (300 MHz, CDCl3) 6 7.33 (d, J= 6. 3 Hz, 1H), 6.45 (s, 1H), 6.04 (m, 1 H), 5.95 (d, J= 1.5 Hz, 1H), 5.84 (d,. J= 1.5 Hz, 1H), 5.32 (m, 2 h), 5.21 (m, 1H), 4.11 (m, 4H), 3.73 (s, 3H), 3.64 (m, 2 h), 3.51 (m, 1 H), 3.37 (d, J- 7. 8 Hz, 1H), 3.22 (m, 2 h), 3.03 (dd, lH, Jl=8. 1 Hz, J2= 18.3 Hz, 1H), 2.60 (d, J= 18. 3 Hz, 1H), 2.29 (s, 3H), 2.24 (s, 3H), 2.08 (s, 3H), 1.86 (dd, Jazz 12 Hz, J2= 16.2 Hz, 1H), 0.82 (d, J= 7. 2 Hz, 3H).

13C NMR (75 MHz, CDC13) 8 170.0,156.0,148.4,147.1,144.3,143.0,138.7,133.8,130.5, 129.4,120.6,120.4,117.6,117.5,117.0,113.5,112.5,112.4,101.1, 74.1,66.8,60.4,59.3, 56.9,56.6,56.3,55.4,48.7,41.6,40.1,26.2,25.0,17.6,15.4,9.1.

ESI-MS m/z: Calcd. for C35H39F3N507 : 685.69. Found (M+H) + : 686.3.

Example 49 To a solution of 54 (100 mg, 0.415 ml) in CH2Cl2 (4 ml), acetic acid (40 ml).

(PPh3) 2PdCl2 (8.4 mg, 0.012 ml) and Bu3SnH (157 ml, 0.56 ml) were added at 23'C. After stirring at that temperature for 2 h the reaction was poured into a pad of flash column (Si02, gradient Hex to hexane: ethyl acetate 2: 1) to afford 55 (90 mg, 96%) as a white solid.

Rf : 0.6 (hexane: ethyl acetate 1: 2). lH NMR (300 MHz, CDC13) 8 7.55 (d, J= 7. 2 Hz, 1H), 6.45 (s, 1 H), 5.90 (d, J= 1. 2 Hz, 1H), 5.82 (d, J= 1. 2 Hz, 1H), 5.37 (t, J= 6. 0 Hz, 1 H), 4.15 (d, J= 2. 1 Hz, 1H), 4.04 (d, J= 1. 8 Hz, 1H), 3.70 (s, 3H), 3.66-3.53 (m, 2 h), 3.37-3. 31 (m, 2 h), 3.19-3.15 (d, J= 11. 7 Hz, 1H), 3.08- 3.00 (m, 2 h), 2.56 (d, J=18. 3 Hz, 1H), 2.30 (s, 3H), 2.24 (s, 3H), 2.04 (s, 3H), 1.91 (dd, J1= 12.0 Hz, J2= 15.6 Hz, 1H), 0.84 (d, J= 6. 9 Hz, 3H).

13C NMR (75 MHz, CDC13) 8 170.1,156.3,147.3,144.9,144.4,143.3,136.7,130.7,129.3, 120.6,117.6,117.4,114.4,112.1,107.7,101.0,85.8,60.5,59.3,56. 5,56.4,56.2,55.2,48.9, 41.6,40.9,25.7,25.3,18.0,15.6,8.7.

ESI-MS m/z : Calcd. for C32 h35F3N507 : 645.63. Found (M+H) + : 646.2.

Example 50 To a solution of 17 (200 mg, 0.288 ml) in CH2CI2 (1.44 ml), trifluoroacetic acid (888 ml, 11.53 ml) was added and the reaction mixture was stirred for 4h at 23 °C. The reaction was quenched at 0 °C with saturated aqueous sodium bicarbonate (60 ml) and extracted with ethyl acetate (2 x 70 ml). The combined organic layers were dried (sodium sulphate) and concentrated in vacuo to afford 56 (147 mg, 93%) as a white solid that was used in subsequent reactions with no further purification.

Rf : 0.19 (ethyl acetate: methanol5: 1).

H NMR (300 MHz, CD30D). 86. 48 (s, 1 H), 5.88, d, J= 0. 9 Hz, 1H), 5.81 (d, 0. 9 Hz, 1H), 4.35 (d, J= 2. 4 Hz, 1H), 4.15 (d, J= 1. 8 Hz, 1H), 3.99-3.98 (m, 1H), 3.70 (s, 3H), 3.52- 2.96 (m, 7H), 2.68 (d, J= 18. 3 Hz, I H), 2.24 (s, 3H), 2.23 (s, 3H), 2.06 (s, 3H), 1.85 (dd, Zu 11.7 Hz, J2= 15.6 Hz, 1H), 0.91 (d, J= 6. 6 Hz, 3H).

13CNMR (75MHz, CD30D) : 8 173. 2. 149.1,145.6,144.9,138.0,132.2,130.6,121.4, 119.6,117.4,114.3,109.2,102.5,82.3,60.4,58.4,58.3,57.8,56.6, 50.1,42.3,41.6,27.8, 26.2,19.5,15.5,9.8.

ESI-MS m/z: Calcd. for C29H35N506 : 549. 62. Found (M+H) + : 550.3.

Example 51 To a solution of 56 (10 mg, 0.018 ml) in CH2CI2 (0.4 ml), phenyl isothiocyanate (13 ml, 0.109 ml) was added and the reaction was stirred at 23° C for 1.5h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (sitz gradient Hexane to 1 : 1 hexane: ethyl acetate) to afford 57 (8 mg, 65%) as a white solid.

Rf : 0. 57 (ethyl acetate: methanol 10 : 1).

1H NMR (300 MHz, CDCl3) : 5 7.88 (bs, 1H), 7.41-7.36 (m, 2 h), 7.27-7.22 (m, I H), 7.02- 7.00 (d, J= 7.8 Hz, 2 h), 6.71 (d, J= 7. 2 Hz, 1H), 6.31 (s, 1H), 6.17 (bs, 1H), 5.93 (d, J=1. 2 Hz, 1H), 5.83 (d, J= 1.2 Hz, 1H), 5.55 (bs, 1H), 5.20-5.17 (m, 1H), 4.16 (d, J= 1. 8 Hz, 1H), 4.05 (bs, 1H), 4.02 (d, J= 2. 4 Hz, 1H), 3.79 (s, 3H), 3.75-3.71 (m, 1H), 3.35 (d, J= 7. 8 Hz, 1H), 3.28-3.19 (m, 2 h), 3.12-2.97 (m, 2 h), 2.50 (d, J=18. 3 Hz, 1H), 2.32 (s, 3H), 2.21 (s, 3H), 2.15-2.09 (dd, Jl= 11.4 Hz, J= 15.9 Hz, 1H), 1.95 (s, 3H), 0.88 (d, J=6. 9 Hz, 3H).

3C NMR (75 MHz, CDCI3) : 6 178. 5,171.7,147.2,145.0,144.3,143.3,137.0,135.7,130.6, 130.4,129.6,127.5,124.3,120.6,117.7,117.2,115.3,112.1,108.3, 100.9,60.9,59.5,56.7, 56.5,56.2,55.2,54.1,41.7,41.1,26.3,25.4,18.5,15.8,9.0.

ESI-MS m/z : Calcd. for C36H4oN606S : 684.81. Found (M+H) + : 685.3.

Example 52 To a solution of 57 (45 mg, 0.065 ml) in CH2CI2 (0.5 ml), acetyl chloride (4.67 ml, 0.065 ml) and pyridine (5.3 ml, 0.065 ml) were added at 0 °C. The reaction mixture was stirred for 3h and then, the solution was diluted with CH2C12 (10 ml) and washed with 0.1 N HCI (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN : H20 40: 60) to afford 58 (14 mg, 28%) as a white solid.

Rf : 0. 34 (CH3CN: H20 7: 15).

'H NMR (300 MHz, CDCI3). ã 11.90 (d, J= 6. 6 Hz, 1H), 7.45-7.40 (m, 3H). 7.18-7.15 (m, 2 h), 6.58 (s, 1H), 6.00 (d, J= 1. 2 Hz, 1H), 5.89 (d, J= 1. 2 Hz, 1H), 5.70 (s, 1H), 5.37 (t, J= 4.8 Hz, 1H), 4.48 (m, 1H), 4.23 (bs, 1H), 4.07 (bs, 2 h), 3.85-3.75 (m, 1H), 3.70 (s, 3H), 3.46-3.41 (m, 2 h), 3.24-3.20 (m, 1H), 3.00-2.95 (m, 1H), 2.87-2.75 (m, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H), 2.00 (s, 3H), 1.85 (dd, J= 11.4 Hz, J2= 15.6 Hz, 1H), 1.66 (s, 3H), 0.82 (d, J= 6. 0 Hz, 3H).

13 C NMR (75 MHz, CDC13)) : 8 182.6,174. 3,171.0,146.6,144.6,142.7,142.3,140.7, 140.2,131.3,129.8,129.3,128.9,128.8,121.5,120.4,117.3,116.6, 112.8,112.0,111.3, 101.5,60.5,59.0,57.6,56.2,55.9,55.3,55.1,41.6,39.4,27.8,26.5 ,24.8,20.2,17.1,15.5, 9.3.

ESI-MS m/z: Calcd. for C4oH44N608S : 768.88. Found (M+H) + : 769.2.

Example 53 OMe OMe OMe OMe Ho-" Me A 5.3N HCI in Dioxane Me N-Me N 23 °C O w I N y 0 C 0 NH NH2 -NHCSNHPh T Me 57 59 A solution of 57 (130 mg, 0.189 ml) in dioxane (1 ml), 5.3N HCI/dioxane (1.87 ml) was added and the reaction was stirred at 23 °C for 4h. Then, CH2C12 (15 ml) and H20 (10 ml) were added to this reaction and the organic layer was decanted. The aqueous phase was basified with saturated aq sodium bicarbonate (60 ml) (pH = 8) at 0 °C and then, extracted with ethyl acetate (2x50 ml). The combined organic extracts were dried (sodium sulphate), and concentrated in vacuo to afford 59 (63 mg, 70%) as a white solid.

Rf : 0. 15 (ethyl acetate: methanol5: 1).

H NMR (300 MHz, CDCI3). 6 6.67 (s, 1H), 5.99 (d, J= 0. 9 Hz, 1H), 5.91 (d, J= 1. 2 Hz, 1H), 5.10 (bs, 1H), 4.32 (d, J= 7. 2 Hz, 1H), 4.25 (dd, Jazz 3.6 Hz, J2= 9.3 Hz, 1H), 3.7 (s, 3H), 3.71-3.64 (m, 2 h), 3.50 (dd, J1= 2. 4 Hz, = 15.9 Hz, 1H), 3.42-3.37 (m, 2 h), 3.16 (dd, J1=3. 6 Hz, J2= 12.9 Hz, 1H), 2.57 (dd, J1= 9.3 Hz, J2= 12.9 Hz, 1H), 2.27 (s, 3H), 2.11 (s, 3H), 1.91 (dd, Jl= 12.0 Hz, J2= 15.9 Hz, 1H).

ESI-MS m/z: Calcd. for C26H3oN405 : 478.5. Found (M+H) + : 479.3.

Example 54 OMe OMe HO Me HO Me OAc I OAc I c OAC Me I N-Me Trans-C9H6CIO, PY Me I N-Me I N y CHZCI2, 1 h, 0 °C O N C NH NH NH l |1 N \¢H Cw Me Me 43 60 A solution of 43 (20 mg, 0.0338 mmol) in CH2CI2 (0.3 ml), cinnamoyl chloride (5.63 mg, 0.0338 mmol) and pyridine (2.73 ml, 0.0338 mmol) were added at 0 °C. The reaction mixture was stirred for 1h and then, the solution was diluted with CH2CI2 (10 ml) and washed with 0.1 N HCI (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, EtOAc: MeOH 20: 1) to afford 60 (22 mg, 90%) as a white solid.

Rf : 0.56 (EtOAc: MeOH 5: 1).

H NMR (300 MHz, CDCI3). 7.51 (s, IH), 7.50-7.47 (m, 2H), 7.36-7.35 (m, 2H), 6.43 (s, 1 H), 6.36 (brd, J= 15. 9 Hz, 2H), 6.01 (d, J= 1. 5 Hz, 1H), 5.90 (brd, J= 1. 5 Hz, 2H), 5.42 (t, J= 6.0 Hz 1H), 4.12-4.07 (m, 3H), 3.96-3.95 (m, 1H), 3.73 (bs, 3H), 3.58 (bs, 2H), 3.39 (d, J= 8. 7 Hz, 1H), 3.25 (d, J= 11.7 Hz, 1H), 3.0 (dd, Jl= 7.5 Hz, J= 17.7 Hz, I H), 2.78 (d, J= 15.9 Hz, 1H), 2.67 (d, J= 16. 5 Hz, 1H), 2.29 (s, 6H), 2.23 (s, 3H), 1.99 (s, 3H), 1.82 (dd, J/= 11.4 Hz, J2= 15.6 Hz, 1H), 0.83 (d, J= 6. 0 Hz, 3H).

3C NMR (75 MHz, CDC13)) : 8. 172.0,165.0,146.9,144.6,143.1,141.0,140.5,134.8, 131.0,129.7,129.1,128.8,127.8,125.5,123.8,123.0,121.1,120.5, 117.7,116.9,112.8, 112.0,101.9,60.6,59.2,57.1,56.4,55.9,55.3,48.8,41.7,40.0,26. 5,25.1,20.3,18.5,15.7, 9.3.

ESI-MS m/z: Calcd. for C40H43NsO8 : 721. 8. Found (M+H) + : 722.3.

Example 55 A solution of 45 (19 mg, 0.0364 mmol) in CH2CI2 (0.3 ml), heptafluorobutyryl chloride (5.44 ml, 0.0364 mmol) and pyridine (2.95 ml, 0.0364 mmol) were added at 0 °C.

The reaction mixture was stirred for lh and then, the solution was diluted with CH2CI2 (10 ml) and washed with 0.1 N HCI (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, EtOAc: MeOH 20: 1) to afford 61 (11.7 mg, 45%) as a white solid.

Rf : 0. 76 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) 8 6.46 (s, IH), 6.12 (bs, IH), 5.98 (d, J= 1. 2 Hz, 1H), 5.93 (d, J= 1.2 Hz, 1H), 5.72 (bs, 1H), 4.13-4.11 (in, 2H), 4.0 (d, J= 2. 4 Hz, 1H), 3.98-3.96 (m, 1H), 3.73 (s, 3H), 3.39 (d, J= 7. 5 Hz, 1 H), 3.39-3.28 (m, 2H), 3.09 (dd, Jl= 8.1 Hz,. 7= 18.0 Hz, 1H), 2.80 (d, J= 16. 2 Hz, 1H), 2.46 (d, J= 18.3 Hz, 1H), 2.32 (s, 6H), 2.21 (s, 3H), 1.99 (s, 3H), 1.80 (dd, Jl= 12.0 Hz, J2= 16.2 Hz, 1H), ESI-MS m/z: Calcd. for C32H31FN407 : 716.6. Found (M+H) + : 717.2.

Example 56 A solution of 43 (24 mg, 0.04 mmol) in CH2CI2 (0. 3 ml), butyryl chloride (4.15 ml, 0.04 mmol) and pyridine (3.28 ml, 0.04 mmol) were added at 0 °C. The reaction mixture was stirred for I h and then, the solution was diluted with CH2Cl2 (10 ml) and washed with 0. 1 N HC1 (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, EtOAc: MeOH 20: 1) to afford 62 (24 mg, 90%) as a white solid.

Rf : 0.35 (EtOAc: MeOH 5 : 1).

1H NMR (300 MHz, CDC13) 8 6.47 (s, 1H), 6.10 (d, J= 6. 5 Hz, 1H), 6.0 (d, J= 1. 5 Hz, 1H), 5.91 (d, J= 1. 5 Hz, 1H), 5.86 (bs, 1H), 5.31 (d, J= 6. 9 Hz, 1H), 4.11-4.06 (m, 3H), 3.85-3.81 (m, 1H), 3.75 (s, 3H), 3.59-3.53 (m, 2H), 3.38 (d, J= 7. 5 Hz, 1H), 3.27-3.22 (m, 1H), 3.0 (dd, J1= 7.8 Hz, J2= 17.4 Hz, 1H), 2.79 (d, J= 15. 3 Hz, 1H), 2.63 (d, J= 17. 7 Hz, 1H), 2.31 (s, 3H), 2.0 (s, 3H), 1.80 (dd, J1= 12.0 Hz, J2= 15.9 Hz, 1H), 1.58 (q, J= 7. 2 Hz, 2H), 0.89 (t, J= 7.2 Hz, 3H), 0.76 (d, J= 6.6 Hz, 3H).

ESI-MS m/z : Calcd. for C35H43N5O8: 661.64. Found (M+H) + : 662.3 Example 57 A solution of 43 (19 mg, 0.0364 mmol) in CH2CI2 (0.3 ml), cinnamoyl chloride (6.06 mg, 0.0364 mmol) and pyridine (2.95 ml, 0.0364 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH2CI2 (10 ml) and washed with 0. 1 N HCI (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, EtOAc: MeOH 20: 1) to afford 63 (20.1 mg, 85%) as a white solid.

Rf : 0.65 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDCL3) 5 7.39-7.29 (m, 5H), 6.42, (s, 1H), 6.01 (d, J= 1. 5 Hz, 1H), 5.92 (d, J= 1. 5 Hz, 1H), 5.73 (bs, 1H), 5.24 (t, J= 6. 8 Hz, 1H), 4.12-4.08 (m, 3H), 3.66-3.64 (m, 2H), 3.58 (bs, 3H), 3.36 (d, J= 8. 7 Hz, 1H), 3.29 (d, J= 12. 0 Hz, IH), 2.98 (dd, Jazz 8.1 Hz, J2= 18 Hz, 1H), 2. 33 (s, 6H), 2.29 (s, 3H), 2.01 (s, 3H), 1. 84 (dd, J1= 12.0 Hz, J2= 15.9 Hz, 1H).).

ESI-MS m/z: Calcd. for C37H3gN407 : 650.72. Found (M+H) + : 651.2.

Example 58 OMe OMe OMe OMe OAc AMIE OAc OAc Me Me Me Xe 3-chloropropionyl chloride Me<e Py, CH2ClZ, 1h, 0 °C O . Ny \-0 \ CN \O CN NHNH Me Me 0 Me 43 64 A solution of 43 (20 mg, 0.0338 mmol) in CH2CI2 (0.3 ml), 3-chloropropionyl chloride (3.22 ml, 0.0338 mmol) and pyridine (2.73 ml, 0.0338 mmol) were added at 0 °C.

The reaction mixture was stirred for I h and then, the solution was diluted with CH2C12 (10 ml) and washed with 0.1 N HCI (5 ml). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, EtOAc: MeOH 20: 1) to afford 64 (20.5 mg, 89%) as a white solid.

Rf : 0.32 (EtOAc: Hexane 5: 1).

1H NMR (300 MHz, CDC13) 6.48 (s, 3H), 6.28 (m, 1H), 5.99 (d, J= 1. 2 Hz, 1H), 5.91 (d, J= 1.2 Hz, 1H), 5.86 (bs, 1H), 5.31 (m, IH), 4.08-4.07 (m, 3H), 3.75 (s, 3H), 3.72-3.53 (m, 5H), 3.39 (d, J= 8. 1 Hz, IH), 3.24 (d, J= 12. 0 Hz, IH), 3.00 (dd, J, = 8.1 Hz, J2= 18.0 Hz, IH), 2.79 (d, J= 13. 5 Hz, IH), 2.50 (t, J= 6. 3 Hz, 2H), 2.32 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 2.0 (s, 3H), 1.79 (dd, Zu 12.3 Hz, J2= 14.8 Hz, 1H), 0.81 (d, J= 6. 3 Hz, 3H).

Example 59 OMe OMe OMe OMe AXE HO Me Me Me I N-Me butyryl chloride Me N-Me N)/Py, CH2CI2, 1 h, 0 °C/ N N NHz NH NH2 NH 45 65 A solution of 43 (19 mg, 0.0364 mmol) in CH2C12 (0.3 ml), butyryl chloride (3.78 ml , 0. 0364 mmol) and pyridine (2.95 ml, 0.0364 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH2C12 (10 ml) and washed with 0.1 N HC1 (5 ml). The organic layer was dried over sodium sulphate, filtered. and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, EtOAc: MeOH 20: 1) to afford 64 (19 mg, 87%) as a white solid.

Rf : 0.60 (EtOAc: MeOH 5: 1).

1H NMR (300 MHz, CDCI3) 6.50 (s, 1H), 5.98 (d, J= 1. 5 Hz, 1H), 5.91 (d. J= 1. 5 Hz, 1H), 5.75 (s, lH), 5.01 (t, J= 6. 4 Hz, 1H), 4.10-4.09 (m, 1H), 4.06 (d, J= 2. 1 Hz, IH), 4.03-4.02 (m, 1H), 3.76 (s, 3H), 3.67-3.60 (m, 1H), 3.42-3. 35 (m, 2H), 3.29 (d, J= 12.0 Hz, 1H), 3.02 (dd, J/= 7.8 Hz, J2= 17.7 Hz, 1H), 2.79 (d, J= 14. 1 Hz, 1H), 2.56 (d, J= 18. 3 Hz, 1H). 2. 32 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 1.78 (dd, J1= 12.0 Hz, J2= 15.9 Hz, 1 H), 1.63 (s. 3H), 1.53-1.46 (m, 2H), 1.28-1.16 (m, 2H), 0.68 (t, J= 7. 2 Hz, 3H).

ESI-MS m/z : Calcd. for C32H38N407 : 590.67. Found (M+H) + : 591.2.

Example 60 To a solution of 50 (31.7 mg, 0.044 mmol) in CH3CN/H2O (1.5 ml/0.5 ml), AgNO3 (225 mg, 1.32 mmol) was added and the reaction was stirred at 23°C for 17 h. Then brine (10 ml) and Aq sat NaHC03 (10 ml) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH3Cl2 (20 ml). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, EtOAc: MeOH 5: 1) to afford 66 (16 mg, 51 %) as a white solid.

Rf : 0. 26 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) 8 7.66-7.42 (m, 4H), 7.20 (bs, 1H), 6.44 (s. 1H). 5.97 (b. J= 1. 2 Hz, 1H), 5.90 (d, J= 1. 2 Hz, 1H), 5.76 (bs, 1H), 5.28 (bs, 1H), 4.54 (bs, 1 H), 4.43 (bs. 1H), 4.00 (bs, 1H), 3.68-3.57 (m, 4H), 3.47 (d, J= 3. 3 Hz, 1H), 3.40 (d, J= 11. 7 Hz. 1H). 3.17 (d, J= 6. 9 Hz, 1H), 2.92 (dd, Jl= 8.1 Hz, J2= 17.7 Hz, 1H), 2.74 (d, J= 17. 1 Hz, 1 H), 2.48 (d, J= 18.6 Hz, 1H), 2.32 (s, 6H), 2.28 (s, 3H), 1.99 (s, 3H), 1.76 (dd, J1= 12.0 Hz. J, = 16.2 Hz, 1H).

ESI-MS m/z: Calcd. for C37H3gF3N3Os : 709. Found (M+-17) : 692.3.

Example 61 To a solution of 53 (57 mg, 0.0828 mmol) in CH3CN/H20 (1.5 mL/0. 5 ml), AgN03 (650 mg, 3.81 mmol) was added and the reaction was stirred at 23°C for 24 h. Then, brine (10 ml) and Aq sat NaHC03 (10 ml) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI2 (20 ml). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc: MeOH 5: 1) to afford 67 (28 mg, 50%) as a white solid.

Rf : 0.28 (EtOAc: MeOH 10: 1).

'H NMR (300 MHz, CDCl3) d 6.47 (s, 1H), 5.97 (s, 1H), 5.88 (s, 1H), 5.35 (bs, 1H), 4.51 (bs, 1H), 4.41 (bs, 1H), 4.12-4.05 (m, 1H), 4.00 (d, J= 2. 7 Hz, 1H), 3.77 (s, 3H), 3.64 (bs, 1H), 3. 46 (d, J= 3.3 Hz, 1H), 3.34 (d, J= 11. 4 Hz, 1H), 3.18 (d, J= 7.5 Hz, 1H), 2.95 (dd, J1= 8.4 Hz, Jazz 18.3 Hz, 1H), 2.70 (d.

J= 15. 6 Hz, 1H), 2.48 (d, J= 17. 7 Hz, 1H), 2.28 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H). 1.98 (s, 3H), 1.68 (dd, J= 12 Hz, J2= 15.6 Hz, 1H), 0.86 (d, J= 6. 3 Hz, 3H).

ESI-MS m/z: Calcd. for C32H37F3N409 : 678.66. Found (M+-17) : 661.2.

Example 62 48 68 To a solution of 48 (32 mg, 0.0529 mmol) in CH3CN/H20 (1.5 ml/0. 5 ml), AnNO3 (270 mg, 1.58 mmol) was added and the reaction was stirred at 23°C for 24 h. Then, brine (10 ml) and Aq sat NaHC03 (10 ml) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI2 (20 ml). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, EtOAc: MeOH 5: 1) to afford 68 (18 mg, 56%) as a white solid.

Rf : 0.40 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) d 6.50 (s, 1H), 5.95 (d, J= 1. 2 Hz, 1H), 5.88 (d, J= 1. 2 Hz, 1H), 5.23 (d, J= 6.9 Hz, 1H), 4.45 (d, J= 3. 3 Hz, 1H), 4.38 (s, 1H), 4.01 (d, J= 2. 4 Hz, 1H), 3.78 (m, 1H), 3.77 (s, 3H), 3.41-3.37 (m, 1H), 3.17-3.15 (m, 1H), 2.96 (dd, J=7. 8Hz, J 18.0 Hz, 1H), 2.70 (d, J= 15. 3 Hz, 1H), 2.40 (d, J= 18. 0 Hz, 1H), 2.30 (s, 6H), 2.27 (s, 3H), 1.76- 1.65 (m, 1H), 1.35-1.25 (m, 2H), 0.89-0.82 (m, 1H), 0.69 (d, J= 6.6 Hz, 3H), 0. 58 (d, J= 6. 6 Hz, 3H) Example 63 To a solution of 51 (27 mg, 0.04 mmol) in CH3CN/H20 (1.5 ml/0.5 ml). AgN03 (204 mg, 1.19 mmol) was added and the reaction was stirred at 23°C for 24 h. Then, brine (10 ml) and Aq sat NaHC03 (10 ml) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (20 ml). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, EtOAc: MeOH 5: 1) to afford 69 (10 mg, 38%) as a white solid.

Rf : 38 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) d 6.48 s, 1H), 6.16 (bs, 1H), 5.98 (d, J= 1.5 Hz, 1H), 5.89 (d, J= 1.5 Hz, 1H), 5.33 (t, J= 6. 0 Hz, 1H), 4.50 (m, 1H), 4.40 (m, 1H), 4.11-4.09 (m, 1 H), 4.00 (d, J= 2. 6Hz, 1H), 3.78 (s, 3H), 3. 41-3.32 (m, 3H), 3.18 (d, J= 8. 4 Hz, 1 H), 2.94 (dd, J/= 8.4 Hz, J2= 18.3 Hz, 1H), 2.70 (d, J= 14.4 Hz, 1H), 4.45 (d, J= 18. 3 Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H), 2.04 (s, 3H), 2.00-1.86 (m, 3H), 1.73 (m, 1H), 0.87 (d, J= 6. 3 Hz, 6H).

Example 64 63 70 To a solution of 63 (15 mg, 0.023 mmol) in CH3CN/H20 (1.5 ml/0. 5 ml). AgN03 (118 mg, 0.691 mmol) was added and the reaction was stirred at 23°C for 24 h. Then, brine (10 ml) and Aq sat NaHC03 (10 ml) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2C12 (20 ml). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, EtOAc : MeOH 5 : 1) to afford 70 (20.1 mg, 85%) as a white solid.

Rf : 0.43 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) d 7.38-7.28 (m, 5H), 6.48 (s, 1H), 5.98 (d, J=1. 5 Hz, 1H), 5.91 (d, J=1. 5 Hz, 1H), 5.75 (bs, 1H), 5.38 (brd, 1H), 5.30 (bs, 1H), 4.53 (m, 1H), 4.42 (m, 1H), 4.02 (d, J=2. 7 Hz, 1H), 3.78-3.65 (m, 5H), 3.46-3.40 (m, 2H), 3.17 (d, J=7. 8 Hz, 1H), 2.94 (dd, JI=7. 8Hz, J2=17. 7Hz, lH), 2.73 (d,. J=16. 8Hz, lH), 2.45 (d, J=18.0 Hz, 1H), 2.31 (s, 6H), 2.28 (s, 3H), 1.97 (s, 3H), 1.77 (dd, Jl=12. 0 Hz, J2=15. 3 Hz, 1H).

Example 65 To a solution of 65 (25 mg, 0.042 mmol) in CH3CN/H20 (1.5 ml/0.5 ml), AgN03 (215.56 mg, 1.269 mmol) was added and the reaction was stirred at 23°C for 24 h. Then, brine (10 ml) and Aq sat NaHC03 (10 ml) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI2 (20 ml). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, EtOAc: MeOH 5: 2) to afford 71 (16mg, 65%) as a white solid.

Rf : 0.0.5 (EtOAc: MeOH 5: 2).

1H NMR (300 MHz, CDCl3) d 6.50 (s, 1H), 5.95 (d, J=1. 5 Hz, 1H), 5.78 (s, 1H), 5.19 (bs, 1H), 4.45 (d, J=3. 3 Hz, 1H), 4.37 (bs, 1H), 4.11 (brd, J=4. 8 Hz, 1H), 4.01 (d, J=2. 1 Hz, 1H), 3.76 (s, 1H), 3.71-3.69 (m, 1H), 3.49-3.35 (m, 1H), 3.24 (d, J=13. 5 Hz, 1H), 3.15 (d. J=9. 3 Hz, 1H), 2.95 (dd, J1=8. 1 Hz, =17. 7 Hz, 1H), 2.70 (d, J=15. 6 Hz, 1H), 2.40 (d, J=18. 0Hz, 1H), 2.31 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H), 1.96 (s, 3H), 1.75-1.66 (m, lH), 1.52-1.17 (m, 2H), 0.66 (t, J=7. 2 Hz, 3H).

Example 66 To a solution of 45 (35 mg, 0.0672 mmol) in CH2CI2 (0.3 mL), hydrocinnamoyl chloride (11.58 µ1, 0.0672 mmol) and pyridine (5.43 1L, 0.0672 mmol) were added at 0 °C.

The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2CI2 (10 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: ethyl acetate 2: 1 to ethyl acetate) to afford 72 (30 mg, 68%) as a white solid.

Rf : 0.51 (ethyl acetate: MeOH 10: 1).

1H NMR (300 MHz, CDC13) 8 7.23-7.12 (m, 3H), 7.05-7.00 (m, 2H). 5.97 (d. J= 1. 2 Hz, 1H), 5.91 (d, J= 1.2 Hz, 1H), 5.73 (s, 1H), 5.04 (brt, 1H), 4.08 (d, J= 2. 4 Hz. 1H), 4.02 (bs. 1H), 4.00 (d, J= 2.4 Hz, 1H), 3.58 (dd, Je= 4.5 Hz, J2= 13.8 Hz, 1H), 3.47 (bs. 3H). 3.33 (d.

J= 7. 5 Hz, 1H), 3.29 (dt, J= 2.7 Hz, Jazz 11.7 Hz, 1H), 3.00 (dd, J1= 7.8 Hz. J2= 18.3 Hz, 1H), 2.79 (d, J= 14.1 Hz, 1H), 2.58-2.50 (m, 3H), 2.32 (s, 3H), 2.29 (s. 3H), 2.03 (s, 3H), 2.01 (s, 3H), 1.94-1.76 (m, 4H).

ESI-MS m/z: Calcd. for C37H40N407 : 652.7. Found (M+Na) + : 675.3.

Example 67 OMe OMe HO Me HO OMe Me N-Me phenyl acetyl chloride, py N-Me CH2CI2, 0°C, 1h 0 0 CN 45 73 NH2 zu 45 73 45 To a solution of 45 (45 mg, 0.0576 mmol) in CH2CI2 (0.3 mL), phenyl acetyl chloride (7. 61 µl, 0.0576 mmol) and pyridine (4.6 pL, 0.0576 mmol) were added at 0 °C. The reaction mixture was stirred for I h and then, the solution was diluted with CH2CI2 (10 mL) and washed with 0.1 N HCI (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: ethyl acetate 3: 1 to Hex: ethyl acetate 1: 1) to afford 73 (25.8 mg, 70 %) as a white solid.

Rf : 0. 5 (Hex: ethyl acetate: MeOH 5: 10: 2).

1H NMR (300 MHz, CDC13) 8 7.18-7.17 (m, 3H), 6.85 (bs, 2H), 6.54 (s, 1H), 5.89 (d, J= 1.5Hz, 1H), 5.83 (d,. J= 1.5 Hz, 1H), 5.76 (s, 1H), 5.08 (bs, 1H), 4.12 (d, J= 2. 1 Hz, 1H), 4.09 (d, J= 2. 1 Hz, 1H), 3.98 (bs, 1H), 3.73 (s, 3H), 3. 51-3.46 (m, 2H), 3. 35 (d, J= 8. 4 Hz, 1H), 3.25 (dt, Jl= 2.7 Hz, J2= 12.0 Hz, 1H), 3.03 (d, J= 8. 7 Hz, 1H), 3.02-2.94 (m, 2H), 2.75 (d, J= 16.8 Hz, 1H), 2.63 (d, J= 18.0 Hz, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 2.22 (s. 3H9,1.98 (s, 3H), 1.80 (dd, J1= 12.0 Hz, J2= 16. 2 Hz, 1H).

ESI-MS m/z: Calcd. for C36H3gN407 : 638. 7. Found (M+1) + : 639.2.

Example 68 OMe OMe HO Me HA" HO OAc Me propionyl chloride, py N-Me Y Nu CH2CI2, 0°C, 1h O CN 0 CN NH NH O 45 74 To a solution of 45 (30 mg, 0.0576 mmol) in CH2CI2 (0.3 mL), propyonyl chloride ( 5 pLL, 0.0576 mmol) and pyridine (4.6 µL, 0.0576 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH2C12 (10 mL) and washed with 0. 1 N HCI (5 mL). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: ethyl acetate 5 : 1 to Hex: ethyl acetate 1: 1 to ethyl acetate) to afford 74 (23 mg, 70 %) as a white solid.

Rf : 0.59 ( (Hex : ethyl acetate: MeOH 5: 10: 2).

IH NMR (300 MHz, CDC13) 8 6.50 (s, lH), 5.97 (d, J= 1. 2 Hz, 1H), 5.91 (d, J= 1. 2 Hz, 1H), 5.76 (s, 1H), 5.00 (t, 1H), 4.09 (d, J= 1.2 Hz, 1H), 4.04 (bs, 2H), 3.74 (s, 3H), 3.62 (dd, J/= 6.6 Hz, J2= 13.2 Hz, 1H), 3.43 (bs, 1H), 3 37 (d, J= 8. 4 Hz, 1H), 3.29 (d, J= 12. 0 Hz, 1H), 3.02 (dd, J1= 8.1 Hz, J2= 18. 3 Hz, 1 H), 2.80 (d, J= 14. 4 Hz, 1H), 2.55 (d, J= 18. 0 Hz, 1 H), 2.31 (s, 3H), 2.24 (s, 3H), 2.00 (s, 3H), 1.78 (dd, J= 12.0 Hz, J2= 15.6 Hz, 1H), 1.64-1. 50 (m, 2H), 0. 70 (t, J= 7.8 Hz, 3H).

ESI-MS m/z : Calcd. for C3 H36N407 : 576. 6. Found (M+1)+: 577. 2.

Example 69 OMe OMe HO Me HO Me OAc Onc (mye /Y- Me, N Me myristoyl chloride, py \ N N/Me J/CH2CI2, 0°C, 1 h 0 N \-0 \ CN NH NH2 j NHZ O (CHzpz ! 45 75 To a solution of 45 (15 mg, 0.0288 mmol) in CH2CI2 (0.25 mL), myristoyl chloride ( 7.83 µL, 0.0288 mmol) and pyridine (2. 3 L, 0.0288 mmol) were added at 0 °C. The reaction mixture was stirred for Ih and then, the solution was diluted with CH2CI2 (10 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: ethyl acetate 6: 1 to Hex: ethyl acetate 1: 1) to afford 75 (15 mg, 71 %) as a white solid.

Rf : 0.65 (Hex: ethy acetate : MeOH 10: 10: 1).

'H NMR (300 MHz, CDC13) 8 6.49 (s, 1H), 5.97 (d, J= 1. 2 Hz, 1H), 5.91 (d, J= 1. 2 Hz, 1H), 5.72 (s, 1H), 4.99 (t, 1H), 4.09 (d, J= 1. 5 Hz, 1H), 4.05 (d, J= 1. 5 Hz, 1H), 4.02 (bs, 1H), 3.76 (s, 3H), 3.61-3.59 (m, 1H), 3.39 (bs, 1H), 3. 35 (d, J= 7. 8 Hz, 1H), 3.29 (d, J= 12. 3 Hz, 1H), 3.04 (dd, Jl= 8.1 Hz, J2= 18.3 Hz, 1H), 2.78 (d, J= 15. 6 Hz, 1H), 2.55 (d, J= 18. 3 Hz, 1H), 2.32 (s, 6H), 2.25 (s, 3H), 1.99 (s, 3H), 1.78 (dd, J1= 12.3 Hz, 7= 15.0 Hz, 1H), 1.25- 1.24 (m, 12H), 0.87 (d, J= 6. 0 Hz, 3H).

ESI-MS m/z: Calcd. for C42Hs8N407 : 730.9. Found (M+1) + : 731.4.

Example 70 OMe OMe HO Me HO HO OA Me a stearoyl chloride, py Me I N-Me CH2C'2, O-C, 1 h 0 0 i-N NH NU -O CN NH2 O CN NH I 45 76 To a solution of 45 (15 mg, 0.0288 mmol) in CH2Cl2 (0.25 mL), stearoyl chloride ( 9.7 pL, 0.0288 mmol) and pyridine (2.3 pL, 0.0288 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0. 1 N HCI (5 mL). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: ethyl acetate 3: 1 to Hex: ethyl acetate 1 : 1) to afford 76 (16 mg, 70 %) as a white solid.

Rf : 0. 46 (Hex: ethyl acetate: MeOH 10: 10: 1).

1H NMR NMR (300 MHz, CDCI3) 5 6.49 (s, 1H), 5.98 (d, J= 1. 5 Hz, 1H), 5.91 (d, J= 1. 5 Hz, 1H), 5.73 (s, 1H), 4.99 (t, J= 5.7 Hz, 1H), 4.09 (d, J= 1. 8 Hz, 1H), 4.05 (d, J= 2. 4 Hz, 1H), 4.01 (bs, 1H), 3.76 (s, 3H), 3.61-3.59 (m, 1H), 3.38 (bs, 1H), 3.36 (d, J= 7. 2 Hz, 1H), 3.28 (d, J= 12. 0 Hz, 1H), 3.03 (dd, J, = 7.8 Hz, J2= 18.3 Hz, 1H), 2.78 (d, J= 15. 9 Hz, 1H), 2.57 (d, J= 18. 3 Hz, 1 H), 2.32 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H), 1.99 (s, 3H), 1.77 (dd, J= 11. 7 Hz, J2= 15.6 Hz, 1H), 1.25-1.24 (m, 16H), 0.87 (d, J=6. 3Hz, 3H).

ESI-MS m/z: Calcd. for C46H66N407 : 786.4. Found (M+22) + : 809.5.

Example 71 OMe OMe HO MYE HO OMe Me A hexanoylchloride, py X Me Nu CH2C'2, O-C, 1. 5 h --O CN nu 0 0 CN O 45 77 To a solution of 45 (31 mg, 0.0595 mmol) in CH2CI2 (0.3 mL), hexanoyl chloride ( 8.32 pL, 0.0595 mmol) and pyridine (4.8 nul, 0.0595 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0.1 N HCI (5 mL). The organic layer was dried over Na2SO4. filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: ethyl acetate 3: 2 to ethyl acetate) to afford 77 (26 mg, 70 %) as a white solid.

Rf : 0.65 (ethyl acetate MeOH 10 : 1).

1H NMR (300 MHz, CDC13) 8 6.50 (s, 1H), 5.98 (d, J= 1. 5 Hz, 1H), 5.91 (d, J= 1. 5 Hz, 1H), 5.74 (s, 1H), 5.00 (t, J= 5. 4 Hz, 1H), 4.09 (d, J= 2. 7 Hz, 1 H), 4.05 (d, J= 2. 4 Hz, 1 H), 4.01 (bs, 1H), 3.76 (s, 3H), 3.61-3.58 (m, 1H), 3.02 (dd, \J1= 8. 1 Hz, J2= 18. 3 Hz, 1 H), 2.78 (d, J= 14.4 Hz, 1H), 2.56 (d, J= 18.3 Hz, 1H), 2.31 (s, 6H), 2.25 (s, 3H), 2.00 (s, 3H), 1.78 (dd, Jazz 12.0 Hz, J2= 15.9 Hz, 1H), 1.53-1.40 (m, 2H), 1.29-1.12 (m, 4H), 1.07-0.97 (m, 2H), 0.81 (t, J= 7. 5 Hz, 3H).

ESI-MS m/z: Calcd. for C34H42N407 : 618.7. Found (M+1) + : 619.3.

Example 72 OMe OMe HO OAc OAc Me N-Me _ Propionyl chloride, py MeMe j \° CN N 2CI2, O-C, NHCN 0 NU2 CON 45 78 To a solution of 45 (20 mg, 0.0384 mmol) in CH2Cl2 (0.3 mL), trans-crotonyl chloride (3.68 pL, 0.0384 mmol) and pyridine (3.1 µL, 0.0384 mmol) were added at 0 °C.

The reaction mixture was stirred for lh and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0.1 N HCI (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: ethyl acetate 4: 1 to ethyl acetate) to afford 78 (16 mg, 71 %) as a white solid.

Rf : 0. 55 (ethyl acetate: MeOH 5: 1).

1H NMR (300 MHz, CDC13) 8 6.50-6.40 (m, 1H), 6.46 (s, I H), 5.97 (d, J= 1. 5 Hz, 1H), 5.91 (d, J= 1. 5 Hz, I H), 5.77 (s, 1H), 5.08 (bst, 1H), 4.10 (d, J= 1.5 Hz, 1H), 4.05 (m, 2H), 3.78 (s, 3H), 3.67 (bs, 1H), 3.42-3.29 (m, 3H), 3.04 (dd, J/= 8.1 Hz, J= 18.3 Hz, IH), 2.78 (d, J= 15.3 Hz, 1H), 2.53 (d, J= 18. 3 Hz, 1H), 2.32 (s, 3H), 2.26 (s, 3H), 1.98 (s, 3H), 1.79 (dd, J/= 12.0 Hz, J2= 15.6 Hz, 1H), 1.70 (dd, J1= 1.2 Hz, J2= 6.6 Hz, 3H).

ESI-MS m/z: Calcd. for C32H36N407 : 588.6. Found (M+l) + : 589.3.

Example 73 To a solution of 45 (50 mg, 0.096 mmol) in CH2C12 (0.5 mL), Cbz-L-Val-OH (24.12 mg, 0.096 mmol) and carbonyl diimidazole (18.7 mg, 0.115 mmol) were added at 0 °C. The reaction mixture was stirred for 16 h at room temperature and then, the solution was diluted with CH2CI2 (15 mL) and washed with 0.1 N HCI (10 mL). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 4 : 1) to afford 79 (25 mg, 34 %) as a white solid.

Rf : 0. 7 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) 8 7.33-7.28 (m, 5H), 6.45 (s, 1H), 5.96 (s, 1H), 5.90 (bs, 1H), 5.82 (s, 1H), 5.53 (bs, 1H), 5.09 (bs, 1H), 5.05 (d, J= 3. 3 Hz, 2H), 4.16 (bs, 1H), 4.09 (d, J= 2.4 Hz, 1H), 4.02 (bs, 1H), 3.75 (s, 3H), 3.74 (m, 1H), 3.37-3.35 (m, 2H), 3.26-3.21 (m, 3H), 3.00 (dd, J, = 8.1 Hz, J2= 18. 3 Hz, 1H), 2.77 (d, J= 15. 6 Hz, 1H), 2.55 (d, J= 18. 0 Hz, 1H), 2.30 (s, 3H), 2.27 (s, 3H), 2.25 (s, 3H), 1.98 (s, 3H), 1.70-1.66 (m, 1H), 0.65 (d, J= 6. 6 Hz, 3H).

ESI-MS m/z : Calcd. for C41H47NsO9 : 753.8. Found (M+1) + : 754.2.

Example 74 To a solution of 72 (18 mg, 0.0275 mmol) in CH3CN/H20 (1.5 mL/0.5 mL). AgN03 (140.5 mg, 0.827 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI2 (20 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc: MeOH 10: 1) to afford 80 (13 mg, 74 %) as a white solid.

Rf : 0.37 (EtOAc: MeOH 5: 1).

'HNMR (300 MHz, CDC13) 8 7.23-7.11 (m, 3H), 7.06-7.01 (m, 2H), 6.43 (s, 1H), 5.95 (d, J= 1.2 Hz, 1H), 5.88 (d, J= 1. 2 Hz, 1H), 5.71 (bs, 1H), 5.19 (bs, 1H), 4.45 (d, J= 3. 0 Hz, 1H), 4.37 (bs, 1H), 4.02-3.96 (m, 1H), 3.75-3.68 (m, 2H), 3.48 (s, 3H), 3.41-3.36 (m, 2H), 3.28- 3.24 (m, 1H), 3.15 (d, J= 7. 5 Hz, 1 H), 3.01-2.88 (m, 2H), 2.70 (d, J= 15. 9 Hz, 1 H), 2.57-2.51 (m, 2H), 2.31 (s, 3H), 2.27 (s, 3H), 2.00 (s, 6H), 1.77-1.68 (m, 1H).

ESI-MS m/z: Calcd. for C36H4lN308 : 643.3. Found (M-17) + : 626.2.

Example 75 73 81 To a solution of 73 (23 mg, 0.036 mmol) in CH3CN/H2O (1.5 mL/1 mL), AgNO3 (183 mg, 1.08 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI2 (20 mL). The solution was extracted and the organic layer was dried over Na2S04, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (Si02, gradient EtOAc: MeOH 5: 1 to MeOH) to afford 81 (9.3 mg, 41 %) as a white solid.

Rf : 0.3 (EtOAc: MeOH 5: 1).

'HNMR (300 MHz, CDCl3) 8 7.17-7.13 (m, 3H), 6.85 (m, 2H), 6.54 (s, 1H), 5.90 (d, J= 1. 5 Hz, 1H), 5.84 (d, J= 1. 5 Hz, 1H), 5.22 (m, 1H), 4.43 (bs, 1H), 4.39 (d, J= 2. 4 Hz, 1H), 4.00 (d, J= 2. 4 Hz, 1H), 3.71 (s, 3H), 3.64-3.29 (m, 2H), 3.16 (d, J= 8. 7 Hz, 1H), 2.98-2.88 (m, 3H), 2.67 (d, J= 14. 8 Hz, 1H), 2.45 (d, J= 18. 3 Hz, 1H), 2.33 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 1.97 (s, 3H), 1.68 (dd, Jl= 12.8 Hz, J2= 14.7 Hz, 1H), ESI-MS m/z: Calcd. for C35H3gN308 : 629.7. Found (M+-OH) : 612.3.

Example 76 74 82 To a solution of 74 (20 mg, 0.0346 mmol) in CH3CN/H2O (1.5 mL/1 mL), AgN03 (176.6 mg, 1.04 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (20 mL). The solution was extracted and the organic layer was dried over Na2S04, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (SiO2, EtOAc: MeOH 1: 1) to afford 82 (12.9 mg, 66 %) as a white solid.

Rf : 0.3 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) 8 6.50 (s, 1H), 5.95 (d, J= 1. 2 Hz, 1H), 5.89 (d, J= 1. 2 Hz, 1H), 5.19 (d, 1H), 4.46 (d, J= 3. 0 Hz, 1 H), 4.38 (d, J= 1. 8 Hz, 1H), 4.00 (d, J= 2. 1 Hz, 1 H), 3.74 (s, 3H), 3.70-3.66 (m, 1H), 3.38 (dt, Jl= 2.7 Hz, J2= 13.2 Hz, 1H), 3.25 (d, J= 13. 8 Hz, 1H), 3.16 (d, J= 7. 5 Hz, 1H), 2.96 (dd, Jl= 7.2 Hz, J, = 17.7 Hz, 1H), 2.71 (d, J= 15. 6 Hz, 1H), 2.40 (d, J= 18. 0 Hz, 1H), 2.30 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H), 1.97 (s, 3H), 1.71 (dd, Jl= 11.7 Hz, j2= 15. 3 Hz, 1H), 1.60-1.48 (m, 2H), 0.67 (t, J= 7. 5 Hz, 3H).

ESI-MS m/z : Calcd. for C3oH37N30s : 567.6. Found (M-17) + : 550.2.

Example 77 To a solution of 77 (14 mg, 0.0226 mmol) in CH3CN/H20 (1.5 mL/l mL), AgN03 (115.3 mg, 0.68 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (SiO2, EtOAc: MeOH 5: 1) to afford 83 (9 mg, 65 %) as a white solid.

Rf : 0. 25 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) 8 6.50 (s, 1H), 5.96 (d, J= 1. 5 Hz, 1H), 5.89 (d, J= 1.5 Hz, 1H), 5.73 (bs, 1H), 4.44 (d, J= 3.6 Hz, 1H), 4.37 (s, 1H), 4.01 (d, J= 2. 4 Hz, 1H), 3.77 (s, 3H), 3.73-3.64 (m, 1H), 3.39 (dt, Jl= 3.0 Hz, jazz 9.3 Hz, 1 H), 3.22 (d, J= 14. 5 Hz, 1 H), 3.16 (d, J= 7. 5 Hz, 1H), 2.95 (dd, Jl= 8.1 Hz, J2= 17.4 Hz, 1H), 2.70 (d, J= 14. 5 Hz, 1H), 2.41 (d, J= 18. 3 Hz, 1H), 2.30 (s, 3H), 2.29 (s, 3H), 2.25 (s, 3H), 1.96 (s, 3H), 1.71 (dd, Jl= 12.0 Hz, J2= 15.6 Hz, 1H), 1.48-1.46 (m, 2H), 1.24-1.10 (m, 4H), 1. 00-0.95 (m, 2H), 0.80 (t, J= 7. 2 Hz, 3H).

ESI-MS m/z: Calcd. for C33H43N308 : 609.7. Found (M-17) + : 592.3.

Example 78 78 84 To a solution of 78 (15 mg, 0.025 mmol) in CH3CN/H2O (1.5 mL/1 mL), AgNO3 (130 mg, 0.764 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAc: MeOH 1: 1) to afford 84 (10 mg, 71 %) as a white solid.

Rf : 0.19 (EtOAc: MeOH 5: 1).

1H NMR (300 MHz, CDC13) 8 6.49 (s, 1H), 6.47-6.37 (m, 1H), 5.94 (d, J= 1.5 Hz, 1H), 5.88 (d, J= 1. 5 Hz, 1H), 5.77 (bs, 1H), 5.26 (d, J= 5. 7 Hz, 1H), 4.93 (d, J= 14. 7 Hz, 1H), 4.48 (d, J= 11. 1 Hz, 1H), 4.38 (d, J= 2. 7 Hz, 1H), 4.02 ((d, J= 2. 1 Hz, 1H), 3.79 (s, 3 H), 3.76-3.72 (m, 1H), 3.42 (dt, J=2. 7 Hz, J= 12.0 Hz, 1H), 3.28 (d, J= 13. 2 Hz, 1H), 3.15 (d, J= 6. 6 Hz, 1H), 2.96 (dd, Jl= 8.7 Hz, J2= 18. 0 Hz, 1H), 2.70 (d, J= 15. 0 Hz, 1H), 2.38 (d, J= 18. 0 Hz, 1H), 2.30 (s, 3H), 2.28 (s, 3H), 1.95 (s, 3H), 1.72 (dd, (J1= 12.3 Hz, J2= 17.4 Hz, 1H), 1.98 (dd, Jl= 1.5 Hz, J2= 6.9 Hz, 3H).

ESI-MS m/z: Calcd. for C3, H37N308 : 579.6. Found (M-17) + : 562.3.

Example 79 43 85 To a solution of 43 (25 mg, 0.422 mmol) in CH2Cl2 (0. 3 mL), hydrocinnamoyl chloride (6.27 uL, 0.422 mmol) and pyridine (3.41 nul, 0.422 mmol) were added at 0 °C.

The reaction mixture was stirred for lh and then, the solution was diluted with CH2CI2 (10 mL) and washed with 0.1 N HCI (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 4: 1 to EtOAc) to afford 85 (30 mg, 68 %) as a white solid.

Rf : 0. 54 (EtOAcMeOH 10: 1).

'H NMR (300 MHz, CDC13) 8 7.28-7.14 (m, 5H), 6.45 (s, 1H), 6.07 (brd, 1H), 5.99 (d, J= 1.2 Hz, 1H), 5.90 (d, J= 1.2 Hz, 1H), 5.88 (s, 1H), 5.31 (brt, 1H), 4.09-4.06 (m, 3H), 3.80- 3.75 (m, 1H), 3.73 (s, 3H), 3.57-3.51 (m, 2H), 3.38 (d, J= 7. 5 Hz, 1H), 3.24 (m, 1H), 3.00 (dd, J1= 8.4 Hz, J2= 18.0 Hz, 1H), 2.89-2.85 (m, 2H), 2.79 (d, J= 16. 5 Hz, 1H), 2.61 (d, J= 18.0 Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 2.00 (s, 3H), 1.79 (dd, Jl= 12.3 Hz, J2= 16.2 Hz, 1H), 0.72 (d, J= 6. 6 Hz, 3H).

ESI-MS m/z: Calcd. for C4oH4sN508 : 723.8. Found (M+23) + : 746.3.

Example 80 OMe OMe HO Me HO Me OAc EtOAc Me Me, N-Me hexanoyl chloride, py N-Me CH2CI2, O-C, lh0 -O ! CN -O t CN NH NH NHNH Me Me 0 MeMe 0 86 43 To a solution of 43 (20 mg, 0.0338 mmol) in CH2Cl2 (0.25 mL), hexanoyl chloride (4.72 pL, 0.0338 mmol) and pyridine (2.73 p1L, 0.0338 mmol) were added at 0 °C. The reaction mixture was stirred for lh and then, the solution was diluted with CH2CI2 (10 mL) and washed with 0.1 N HCI (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 1: 1 to EtOAc) to afford 86 (10 mg, 43 %) as a white solid.

Rf : 0.74 (EtOAc: MeOH 10: 1).

'H NMR (300 MHz, CDCl3) 6 6.47 (s, 1H), 6.12 (brd, IH), 6.00 (d, J= 1. 2 Hz, 1H), 5.91 (d, J= 1. 2 Hz, 1H), 5.30 (m, 1H), 4.09-3.99 (m, 3H), 3.84-3.82 (m, 1H), 3.75 (s, 3H), 3.57-3.55 (m, 2H), 3.39 (d, J= 6. 9 Hz, 1H), 3.24 (d, J= 12.0 Hz, 1H), 3.04 (dd, J/= 9.0 Hz, J2= 18.3 Hz, 1H), 2.77 (d, J= 115.3Hz, 1H), 2.63 (d, J= 18. 0 Hz, 1H), 2.32 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 2.00 (s, 3H), 1.80 (dd, J1= 11.7 Hz, J= 15.6 Hz, 1H), 1.55-1.50 (m, 2H), 1.30-1.22 (m, 6H), 0.87 (t, J= 6.9 Hz, 3H), 0.75 (d, J= 6.6 Hz, 3H).

ESI-MS m/z: Calcd. for C37H47N508 : 689.8. Found (M+1) + : 690. 3.

Example 81 OMe OMe OMe OMe OAc I OAc I N-Me N- Me N-Me phenyl acetyl chloride, py Me N-Me CH2CI2, 0°C, 1 h \<° t CN \O f CN NH NH H Me O'-SO Même 0-- 43 87 To a solution of 43 (33 mg, 0.0557 mmol) in CH2Cl2 (0.4 mL), phenyl acetyl chloride (7.36 µL, 0.0557 mmol) and pyridine (4.5 pL, 0.0557 mmol) were added at 0 °C. The reaction mixture was stirred for 1h and then, the solution was diluted with CH2CI2 (10 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 2: 1) to afford 87 (13 mg, 32 %) as a white solid.

Rf : 0.63 (Hex: EtOAc: MeOH 5 : 10: 2).

'H NMR (300 MHz, CDC13) 6 7.37-7.20 (m, 5H), 6.26 (s, 1H), 6.14 (d, J= 6. 6 Hz, 1H), 5.98 (d, J= 1. 2 Hz, 1H), 5.83 (s, 1H), 5.27 (t, J= 6. 2 Hz, 1H), 4.11 (d, J= 2.1 Hz, 1H), 4.07 (d, J= 3.0 Hz, 1H), 4.04 (s, IH), 3.86-3.81 (m, 1H), 3.70 (s, 3H), 3.54-3.53 (m, 2H), 3.44 (bs, 2H), 3. 36 (d, J= 8.1 Hz, 1H), 3.22 (dt, J1= 2.7 Hz, J2= 12.0 Hz, 1H), 2.93 (dd, J1= 7. 2 Hz, J2= 18.3 Hz, 1H), 2.77 (d, J= 14. 4 Hz, 1H), 2.59 (d, J= 18. 0 Hz, 1H), 2.31 (s, 3H), 2.26 (s, 3H), 2.17 (s, 3H), 2.01 (s, 3H), 1.78 (dd, J, = 10.8 Hz, J2= 15.6 Hz, 1H), 0.65 (d, J= 6. 3 Hz, 1H).

ESI-MS m/z: Calcd. for C39H43N508 : 709. 8. Found (M+1) + : 710.3.

Example 82 OMe OMe OMe OMe HO OA Mye Me N-Me propionyl chloride, py Me N-Me CH2CI2, 0°C, i h \-o CN \° CN NH NH 0), NH2 OX-- Me Me 43 88 To a solution of 43 (30 mg, 0.05 mmol) in CH2CI2 (0.3 mL), propionyl chloride (4.40 µL, 0.05 mmol) and pyridine (4.04 pL, 0.05 mmol) were added at 0 °C. The reaction mixture was stirred for 1h and then, the solution was diluted with CH2Cl2 (15 mL) and washed with 0. 1 N HCI (10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 1 : 1 to EtOAc) to afford 88 (18 mg, 56 %) as a white solid.

Rf : 0. 49 (Hex: EtOAc: MeOH 1: 10: 2).

1H NMR (300 MHz, CDC13) # 6.46 (s, 1H), 6.16 (brd, 1H), 5.99 (d, J= 1. 2 Hz, 1H), 5.95 (s, 1H), 5.90 (d, J= 1.2 Hz, 1H), 5.34 brt, 1H), 4.12-4.06 (m, 3H), 3.84 (bs, 1H), 3.74 (s, 3H), 3.63 (dd, Jl= 6.3 Hz, J2= 12.9 Hz, 1H), 3.50-3.48 (m, 1H), 3.39 (d, J= 8. 1 Hz, 1 H), 3.23 (d, J= 11. 7 Hz, 1H), 3.00 (dd, J/= 8.4 Hz, J2= 18. 3 Hz, 1H), 2.78 (d, J= 15. 6 Hz, 1H), 2.63 (d, J= 18. 3 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 1.87-1.80 (m, 1H), 1.06 (t, J= 7. 5Hz, 3H), 0.74 (d, J= 6. 9 Hz, 3H).

ESI-MS m/z: Calcd. for C34H41N5O8: 647. 7. Found (M+1) + : 648.2.

Example 83 OMe OMe HO Me HO Me OAc OAc I Ou 'N Me trans-crotonyl chloride, py / CH2CI2, O-C, I h o N \-o N NH NH o<NH2 odeNt Me Me 43 89 To a solution of 43 (20 mg, 0.0338 mmol) in CH2CI2 (0.3 mL), propionyl chloride (3. 238 uL, 0.0338 mmol) and pyridine (2.73 µL, 0.0338 mmol) were added at 0 °C. The reaction mixture was stirred for 1 h and then, the solution was diluted with CH2CI2 (10 mL) and washed with 0.1 N HCI (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 3: 1 to AcOEt) to afford 89 (11. 5 mg, 52 %) as a white solid.

Rf : 0.57 (EtOAc: MeOH 10: 1).

'H NMR (300 MHz, CDCl3) 8 6.82-6.70 (m, 1H), 6.46 (s, IH), 6.11 (d, 1 H), 6.00 (d, J= 1. 5 Hz, 1H), 5.89 (d, J= 1. 5 Hz, 1H), 5.85 (s, 1H), 5.77 (dd, J1= 1. 5 Hz, J2= 15.3 Hz, 1H), 5.37 (bst, 1H), 4.13-4.06 (m, 3H), 3.19 (m, IH), 3.73 (s, 3H), 3.55 (m, 2H), 3.38 (d, J= 1. 5 Hz, 1H), 3.23 (d, J= 11. 4 Hz, 1H), 3.00 (dd, J= 8.4 Hz, J2= 18.3 Hz, 1H), 2.78 (d, J= 15. 0 Hz, 1H), 2.65 (d, J= 18.0 Hz, IH), 2.31 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 2.00 (s, 3H), 1.85-1.82 (m, 4H), 0.77 (d, J= 6. 3 Hz, 3H).

ESI-MS m/z: Calcd. for C35H4lN5Og : 659.7. Found (M+l) + : 660.3.

Example 84 43 90 To a solution of 43 (15 mg, 0.0253 mmol) in CH2CI2 (0.3 mL), Cbz-L-Val-OH (6.39 mg, 0.0253 mmol) and carbonyl diimidazole (4.86 mg, 0.03 mmol) were added at 0 °C. The reaction mixture was stirred for 16 h at room temperature and then, the solution was diluted with CH2CI2 (15 mL) and washed with 0.1 N HCI (10 mL). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 1: 1 to EtOAc) to afford 90 (6.7 mg, 32 %) as a white solid.

Rf : 0. 79 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) 8 7.35 (bs, 5H), 6.46 (s, 1H), 6.28 (d, J= 6. 0 Hz, 1 H), 5.98 (d, J= 1. 2 Hz, 1H), 5.89 (d, J= 1. 2 Hz, 1H), 5.77 (s, 1H), 5.44 (bs, 1H), 5.30 (bs, 1H), 5.08 (s, 2H), 4.09-4.06 (m, 3H), 3.94-3.89 (m, 1H), 3.70-3.66 (m, 5H), 3.38 (d, J= 11. 7 Hz, 1H), 3.01 96 (dd, Jl= 7.8 Hz, Jar 18. 3 Hz, 1H), 2.79 (d, J= 14. 1 Hz, 1H), 2.63 (d, J= 18. 0 Hz, 1H), 2.30 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 1.99 (s, 3H9,1.97-1.81 (m, 2H), 0.83 (d, J= 6. 6 Hz, 3H), 0.80 (d, J= 6. 6 Hz, 3H), 0.75 (d, J= 6.9 Hz, 3H).

ESI-MS m/z: Calcd. for C44H52N60, o : 824.9. Found (M +1) + : 825.4.

Example 85 62 91 To a solution of 62 (20 mg, 0.030 mmol) in CH3CN/H20 (1.5 mL/1 mL), AgNO3 (154 mg, 0.90 mmol) was added and the reaction was stirred at 23'C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAc : MeOH 3: 1) to afford 91 (13 mg, 66 %) as a white solid.

Rf : 0.18 (EtOAc: MeOH 10 : 1).

H NMR (300 MHz, CDCl3) 8 6.49 (s, 1 H), 6.16 (d, 1H), 5.98 (d, J= 1. 5 Hz, 1 H), 5.89 (d, J= 1.5 Hz, 1H), 5.32 (bs, 1H), 4.41 (bs, 1H), 4.00 (bs, 1H), 3.79 (s, 3H), 3.70-3.65 (m, 2H), 3.37-3.32 (m, 2H), 3.19-3.17 (m, 1H), 2.94 (dd, J/= 9.0 Hz, J2= 15.0 Hz, 1H), 2.74 (d,. J= 15.9 Hz, 1H), 2.46 (d, J= 17. 1 Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H), 2.04-2.01 (m, 2H), 1.98 (s, 3H), 1.64-1.62 (m, 1H), 1.54-1.52 (m, 2H), 0.89-0.84 (m, 6H).

ESI-MS m/z: Calcd. for C34H44N409 : 652.7. Found (M-17) + : 635.3.

Example 86 To a solution of 85 (10 mg, 0.0138 mmol) in CH3CN/H2O (1.5 mL/I mL), AgNO3 (70.4 mg, 0.414 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI2 (15 mL). The solution was extracted and the organic layer was dried over Na2S04, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAc: MeOH 4: 1) to afford 92 (7 mg, 71 %) as a white solid.

Rf : 0.20 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDCl3) 8 7.25-7.13 (m, 5H), 6.47 (s, 1H), 6.13 (brd, IH), 5.97 (d, J= 1.2 Hz, 1H), 5.88 (d, J= 1. 2 Hz, 1 H), 5.34 (brt, 1H), 4.50 (bs, 1H), 4.40 (bs, 1 H), 4.00 (bs, 1H), 3.76 (s, 3H), 3.70-3.65 (m, 3H), 3.34 (d, J= 11. 7 Hz, 1H), 3.17 (d, J= 5. 1 Hz, 1H), 2.98- 2.83 (m, 3H), 2.72 (d, J= 14. 4 Hz, 1H), 2.44 (d, J= 19. 2 Hz, 1H), 2.30 (s, 3H), 2.27 (s, 6H), 1.97 (s, 3H), 1.72 (m, 1H), 0.82 (d, J= 6.6 Hz, 3H).

ESI-MS m/z : Calcd. for C39H46N409 : 714. 8. Found (M-17) + : 697.3.

Example 87 93 86 To a solution of 86 (6 mg, 0.0087 mmol) in CH3CN/H20 (1.5 mL/l mL), AgNO3 (44 mg, 0.26 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAc: MeOH 5: 1) to afford 93 (5 mg, 85 %) as a white solid.

Rf : 0.018 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) 8 6.48 (s, 1 H), 6.17 (d, I H), 5.98 (d, J= 1. 5 Hz, 1H), 5.89 (d, J= 1.5 Hz, 1H), 5.33 (bs, 1H), 4.51 (d, 1H), 4.40 (d, 1H), 4.00 (d, 1H), 3.78 (s, 3H), 3.76-3.65 (m, 2H), 3.36-3.32 (m, 2H), 3.18 (d, J= 6. 9 Hz, 1 H), 2.98-2.89 (m, 1H), 2.71 (d, J= 15. 0 Hz, 1H), 2.45 (d, J= 17. 7 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 1.98 (s, 3H), 1.68-1.50 (m, 3H), 1.29-1.19 (m, 6H), 0.88-0.84 (m, 6H).

ESI-MS m/z: Calcd. for C36H4gN4Og : 680.7. Found (M-17) + : 663.3.

Example 88 87 94 To a solution of 87 (12 mg, 0.0169 mmol) in CH3CN/H20 (1.5 mL/1 mL), AgNO3 (86 mg, 0.507 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAc: MeOH 5: 1) to afford 94 (8.8 mg, 74 %) as a white solid.

Rf : 0.28 (EtOAc: MeOH 5: 1).

1H NMR (300 MHz, CDC13) 8 7.34-7.18 (m, 5H), 6.37 (s, 1H), 6.20 (d, 1H), 5.96 (d, J= 1. 5 Hz, 1H), 5.88 (d, J= 1. 5 Hz, 1H), 5.30 (t, 1H), 4.50 (bs, 1H), 4.39 (d, J= 1. 8 Hz, 1H), 3.99 (d, J= 2. 1 Hz, 1H), 3.73 (s, 3H), 3.69-3.60 (m, 3H), 3.37-3.30 (m, 3H), 3.17 (d, J= 18.1 Hz, 1H), 2.89 (dd, Jl= 7.5 Hz, J2= 18. 3 Hz, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H), 1.99 (s, 3H), 1.71 (dd, J, = 11.7 Hz, J2= 15.0 Hz, 1H), 0.77 (d, J= 6. 6 Hz, 1H).

ESI-MS m/z: Calcd. for C38H44N409 : 700.7. Found (M-17) + : 683.2.

Example 89 To a solution of 88 (14 mg, 0.0216 mmol) in CH3CN/H20 (1.5 mL/1 mL), AgN03 (110 mg, 0.648 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2S04, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAc: MeOH 5: 1) to afford 95 (9.7 mg, 70 %) as a white solid.

Rf : 0. 16 (EtOAc: MeOH 5: 1).

1H NMR (300 MHz, CDCl3) 8 6.48 (s, 1H), 6.10 (d, 1H), 5.97 (d, J= 1. 2 Hz, 1H), 5.89 (d, J= 1.2 Hz, 1H), 5.36 (bs, 1H), 4.51 (bs, 1H), 4.40 (d, J= 2.1 Hz, 1H), 4.00 (d, J= 2. 1 Hz, 1H), 3.78 (s, 3H), 3.76-3.62 (m, 3H), 3.33 (d, J= 11. 7Hz, 1 H), 3.18 (d, J= 8. 4 Hz, 1H), 2.94 (dd, Jl= 8.4 Hz, J2= 16.5 Hz, 1H), 2.72 (d, J= 15. 0 Hz, 1H), 2.45 (d, J= 18. 3 Hz, 1 H), 2.31 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H), 1.97 (s, 3H), 1.86 (m, 2H), 1.73 (dd, J, = 12.0 Hz, J2= 15. 0 Hz, 1H), 1.05 (t, J= 7. 8 Hz, 3H), 0.83 (d, J= 6. 9 Hz, 3H).

ESI-MS m/z: Calcd. for C33H42N4O9: 638. 7. Found (M-17) + : 621.2.

Example 90 To a solution of 89 (10 mg, 0.015 mmol) in CH3CN/H20 (1.5 mL/1 mL). AgNO3 (77.2 mg, 0.454 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then. brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI2 (15 mL). The solution was extracted and the organic layer was dried over Na2S04, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAc : MeOH 1: 1) to afford 96 (9 mg, 92 %) as a white solid.

Rf : 0. 016 (EtOAc : MeOH 5: 1).

'H NMR (300 MHz, CDCI3) 5 6.76-6.69 (m, 1H), 6.47 (s, 1H), 6.18 (brd, 1H), 5.97 (d, J= 1.5 Hz, 1H), 5.88 (d, J= 1. 5 Hz, 1H), 5.71 (dd, J, = 1.5 Hz, J2= 16.2 Hz, 3H), 5.32 (bs, 1H), 4.50 (m, 1H), 4.41 (m, 1H), 3.99 (m, 1H), 3.78 (m, 4H), 3.64-3.58 (m, 2H), 3.34 (d, J= 11. 1 Hz, 1H), 3.17 (d, J= 8. 6 Hz, 1H), 2.95 (dd, Jl= 7.5 Hz, J2= 17.4 Hz, 1 H), 2.70 (d, J= 16. 2 Hz, 1H), 2.48 (d, J= 17. 7 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 2.17 (s, 6H), 1.97 (s, 3H), 1.82- 1.74 (m, 4H), 0.88 (t, J= 5.2 Hz, 3H).

ESI-MS m/z: Calcd. for C34H42N409 : 650.7. Found (M-17) + : 633.3.

Example 91 OMe OMe OMe OMe O ( Me+ t butyryl chloride, py Me+, te -' Iy CHZCIz, 0°C, 2 h p -0 ! CN \-0 6N OH 0o 25 97 To a solution of 25 (100 mg, 0.177 mmol) in CH2CI2 (0.5 mL), butyryl chloride (24 pL, 0.23 mmol) and pyridine (17 nul, 0.212 mmol) were added at 0 °C. The reaction mixture was stirred for 2h at room temperature and then, the solution was diluted with CH2CI2 (30 mL) and washed with 0.1 N HCI (20 mL). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 3: 1) to afford 97 (99 mg, 88 %) as a colorless oil.

Rf : 0.64 (Hex: EtOAc 1: 1).

1H NMR (300 MHz, CDC13) 8 6.66 (s, 1H), 6.16-6.05 (m, 1H), 5.93 (d, J= 1. 2 Hz, 1H), 5.87 (d, J= 1. 2 Hz, 1H), 5.40 (dd, J/= 1. 2 Hz, J2= 17.1 Hz, 1H), 5.26 (dd, J1= 1.2 Hz, Jazz 10.2 Hz, 1H), 5.13-5.08 (m, 2H), 4.44 (dd, J1= 3.6 Hz, J= 11. 1 Hz, 1H), 4.21-4.07 (m, 5H), 3.74 (m, 1H), 3.72 (s, 1H), 3.57 (s, 3H), 3.35 (d,. J= 10. 5 Hz, 1H), 3.26-3.21 (m, 2H), 3.98 (dd, J1= 8.7 Hz, J2= 18.0 Hz, 1H), 2.54 (d,. J= 18.0 Hz), 2.30 (s, 3H), 2.21 (s, 3H), 2.13 (s, 3H), 1.92- 1.65 (m, 3H), 1.42-1.34 (m, 2H), 0.80 (t, J= 7. 5 Hz, 3H).

ESI-MS m/z: Calcd. for C35H43N309 : 633.7. Found (M+l) + : 634.3.

Example 92 OMe OMe MOMO, Me MOMO, Me O Me N-Me t-3- (trifluoromethyl) cinnamoyl chloride Me N-Me I,/ s y py, CH2CI2, 0°C, 1 h N 0 0 zon OH CF3 25-- 98 25 98 WJ To a solution of 25 (100 mg, 0.177 mmol) in CH2C12 (0.4 mL), trans-3- (trifluoromethyl) cinnamoyl chloride (35 µL, 0.23 mmol) and pyridine (17 tL. 0.212 mmol) were added at 0 °C. The reaction mixture was stirred for 1 h at room temperature and then, the solution was diluted with CH2CI2 (30 mL) and washed with 0.1 N HCI (20 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex: EtOAc 6: 1 to Hex: EtOAc 1: 1) to afford 98 (122 mg, 90 %) as a white solid. Rf : 0. 478 (Hex: EtOAc 1: 1). lH NMR (300 MHz, CDC13) 8 7.64-7.48 (m, 4H), 7.37 (d, J= 15. 6 Hz, 1 H), 6.62 (s, 1 H), 6.16-6.07 (m, 1H), 6.12 (d, J= 15. 6 Hz, 1H), 5.94 (d, J= 1. 2 Hz, 1H), 5.89 (d, J= 1. 2 Hz, 1H), 5.41 (dd, JI= 1.8 Hz, J2= 17.1 Hz, 1H), 5.28 (dd, Jl= 1.8 Hz, J2= 12.0 Hz, 1H), 5.04 (q, J= 6. 0 Hz, 1H), 4.60 (dd, Jl= 3.3 Hz, J2= 11.1 Hz, 1 H), 4.22-4.15 (m, 5H), 3.90 (dd, Jl= 4.2 Hz, J2= 11.1 Hz, IH), 3.55 (s, 3H), 3.38 (s, 3H), 3.35-3.34 (m, 1H), 3.27-3.25 (m, 1H), 3.22 (bs, 1H), 2.98 (dd, Jl= 7.8 Hz, J2= 18.0 Hz, 1H), 2.61 (d, J= 17. 7 Hz, 1 H), 2.29 (s, 3H), 2. 16 (s, 3H), 2.00 (s, 3H), 1.80 (dd, J1= 11. 7 Hz, J2= 15.6 Hz, IH).

ESI-MS m/z: Calcd. for C4lH42F3N3Os : 761.7. Found (M+l) + : 762.3.

Example 93 OMe %, OMe MOMO, Me MOMO, Me 'o Me, N Me hydrocinnamoyl choride, py meuve CH2CIz, 0°C, 2 h 0/, CN O = OHT 0 zu 25 99 To a solution of 25 (68 mg, 0.12 mmol) in CH2Cl2 (0.4 mL), hydrocynnamoyl chloride (20 µL, 1.12 mmol) and pyridine (10 1L, 1.01 mmol) were added at 0 °C. The reaction mixture was stirred for 2h at room temperature and then, the solution was diluted with CH2CI2 (30 mL) and washed with 0.1 N HCI (20 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 5: 1 to Hex : EtOAc 2: 1) to afford 99 (41 mg, 49 %) as a white solid. Rf : 0.47 (Hex: EtOAc 1: 1).

'H NMR (300 MHz, CDC13) 8 7.29-7.18 (m, 3H), 7.04-7.02 (m, 2H), 6.66 (s, 1H), 6.16-6.07 (m, 1H), 5.93 (d, J= 1. 2 Hz, 1H), 5.87 (d, J= 1.2 Hz, 1H), 5.40 (dd,. J, = 1.7 Hz, J2= 17. 4 Hz, 1H), 5.26 (dd, J, = 1.7 Hz, J2= 10.2 Hz, 1H), 5.09 (dd, J, = 6.0 Hz, J2= 8.7 Hz, 2H), 4.43 (dd, J1= 3.3 Hz, J2= 11.1 Hz, 1H), 4.20-4.14 (m, 3H), 4.06 (t, J= 3. 7 Hz, 1 H), 4.02 (d, J= 2. 4 Hz, 1H), 3.72 (dd, J1= 4.5 Hz, J2= 11. 1 Hz, 1H), 3.56 (s, 3H), 3.55 (s, 3H), 3.32 (brd, J= 8. 7 Hz, 1H), 3.26 (dd, J1= 1.9 Hz, J2= 8. 1 Hz, 1H), 3.23-3.20 (m, 1H), 3.01 (brd, J= 8. 1 Hz, 1H), 3.23-3.20 (m, 1H), 3.26 (dd, J1= 1. 9 Hz, J2= 8.1 Hz, 1 H), 2.95 (d, J= 1. 8 Hz, I H), 2.71-2.64 (m, 3H), 2.53 (d, J= 17. 7 Hz, 1H), 2.26 (s, 3H), 2.14 (s, 6H), 1.83 (dd, J1= 12.3 Hz, J2= 15.9 Hz, 1H).

ESI-MS m/z : Calcd. for C4oH45F3N30s : 695.3. Found (M+1) + : 696.3.

Example 94 OMe OMe OMe OMe Me I N-Me cinnamoyl cho6de, py me te ow N/CH2CI2, 0°C, 2 h Oe N/ -O CN O OU O 25 11 Ono To a solution of 25 (100 mg, 0.177 mmol) in CH2Cl2 (0.4 mL), cynnamoyl chloride (35 mg, 0.21 mmol) and pyridine (17 pL, 0.21 mmol) were added at 0 °C. The reaction mixture was stirred for 2h at room temperature and then, the solution was diluted with CH2C12 (30 mL) and washed with 0.1 N HC1 (20 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 6: 1) to afford 100 (94 mg, 76 %) as a white solid. Rf : 0.49 (Hex: EtOAc 1: 1).

1H NMR (300 MHz, CDC13) 8 7.42-7.33 (m, 6H), 6.62 (s, 1H), 6.16-6.05 (m, 1H), 6.10 (d, J= 15. 9Hz, 1H), 5.94 (d, J= 1.2 Hz, 1H), 5.88 (d, J= 1. 2 Hz, 1H), 5.43 (dd ? J/= 3.0 Hz, J2= 17.1 Hz, 1H), 5.27 (dd, Jl= 3.0 Hz, J2= 12.0 Hz, 1 H), 5.04 (q, J= 6. 0 Hz, 1H), 4.55 (dd, J/= 3.9 Hz, J2= 11.1 Hz, 1H), 4.22-4.15 (m, 5H), 3.87 (dd, J= 4. 5 Hz, jazz 11.1 Hz, 1 H), 3.55 (s, 3H), 3.39 (s, 3H), 3.36-3.33 (m, 1 H), 3.26-3.22 (m, 2H), 2.98 (dd, J1= 8.1 Hz, Jazz 17.7 Hz, 1H), 2.63 (d, J= 17. 7 Hz, 1H), 2.29 (s, 3H), 2.03 (s, 3H), 1.82 (dd, J1= 11.7 Hz, J2= 15.3Hz, 1H).

ESI-MS m/z : Calcd. for C40H43N3O8: 693. 3. Found (M+1) + : 694.3.

Example 95 To a solution of 97 (40 mg, 0.063 mmol) in CH--, C12 (0.7 mL), acetic acid (17.8 gel), Pd (PPh3) 2Cl2 (3.64 mg, 0.0052 mmol) and Bu3SnH (67.9 µL, 0.252 mmol) were added at 23 °C. The reaction mixture was stirred for 2h at that temperature and then, the solution was poured into a pad of flash column (Si02, gradient Hex: EtOAc 5 : 1 to Hex: EtOAc 3: 1) to afford 101 (30 mg, 80 %) as a white solid. Rf : 0.4 (Hex: EtOAc 1: 1).

1H NMR (300 MHz, CDC13) 8 6.65 (s, 1H), 5.90 (d, J= 1. 5 Hz, 1H), 5.82 (d, J= 1. 5 Hz, 1H), 5.54 (s, 1H), 5.33 (d, J= 6. 0 Hz, 1H), 5.13 (d, J= 6. 0 Hz, 1H), 4.54 (dd, Jl= 3.6 Hz, J2= 11.4 Hz, 1H), 4.18 (d, J= 2. 1 Hz, 1H), 4.13 (d, J= 2. 4 Hz, 1H), 4.07 (t, J= 3. 3 Hz, 1H), 3.75 (dd, Jl= 3.9 Hz, J2= 11.1 Hz, 1H), 3.70 (s, 3H), 3.35 (d, J= 8. 4 Hz, 1H), 3.24 (dd, Jl= 2.7 Hz, J2= 8.7 Hz, 1H), 3.10 (dd, J1= 2.4 Hz, J2= 15.0 Hz, 1 H), 3.01 (d, J= 8. 1 Hz, 1H), 2.95 (d, J= 7.8 Hz, 1H), 2.58 (d, J= 18. 3 Hz, 1H), 2.29 (s, 3H), 2.21 (s, 3H), 2.10 (s, 3H), 1.89-1.66 (m, 3H), 1.36-1.25 (m, 2H), 0.77 (t, J= 7. 5 Hz, 3H).

ESI-MS m/z: Calcd. for C32H39N308 : 593.6. Found (M+1) + : 594.8 Example 96 To a solution of 98 (37 mg, 0.0485 mmol) in CH2C12 (0.7 mL), acetic acid (20 µL), Pd (PPh3) 2Cl2 (4 mg, 0.0057 mmol) and Bu3SnH (53 pue, 0.194 mmol) were added at 23 °C. The reaction mixture was stirred for 5h at that temperature and then, the solution was poured into a pad of flash column (Si02, gradient Hex: EtOAc 6: 1 to Hex: EtOAc 2: 1) to afford 102 (25 mg, 71 %) as a white solid. Rf: 0.38 (Hex: EtOAc 1: 1).

1H NMR (300 MHz, CDC13) 8 7.63-7.60 (M, 2H), 7.50-7.49 (M, 2H), 7.24 (d, J= 15. 9 Hz, 1H), 6.59 (s, 1H), 5.98 (d, J= 15. 9 Hz, 1H), 5.92 (d, J= 1. 5 Hz, 1H), 5.84 (d, J= 1. 5 Hz, 1H), 5.66 (s, 1H), 5.20 (d, J= 6. 0 Hz, 1H), 4.87 (d, J= 6. 0 Hz, 1H), 4.71 (dd, J1= 2.7 Hz, J= 10.8 Hz, 1H), 4.16-4.15 (m, 3H), 3.93 (dd, Jl= 3.3 Hz, =ll. l Hz, 1H), 3.66 (s, 3H), 3. 36 (brd, J= 10. 2 Hz, 1H), 3.26 (brd, J= 11. 7 Hz, 1H), 3.10 (brd, J= 15. 0 Hz, 1H), 2.96 (dd, J1= 7.8 Hz, J2= 17.7 Hz, 1H), 2.62 (d, J= 17. 7 Hz, 1H), 2.27 (s, 3H), 2.14 (s, 3H), 1.97 (s, 3H), 1.79 (dd, J1= 12.0 Hz, J2= 15. 8 Hz, 1H).

ESI-MS m/z: Calcd. for C38H38F3N308 : 721.7. Found (M+1) + : 722.2.

Example 97 To a solution of 99 (41 mg, 0.059 mmol) in CH2Cl2 (1 mL), acetic acid (25 µL), Pd (PPh3) 2CI2 (5 mg, 0.0071 mmol) and Bu3SnH (63 µL, 0.235 mmol) were added at 23 °C.

The reaction mixture was stirred for 4.5 h at that temperature and then, the solution was poured into a pad of flash column (Si02, gradient Hex: EtOAc 6 : 1 to Hex : EtOAc 1: 1) to afford 103 (34.2 mg, 89 %) as a white solid. Rf : 0.49 (Hex: EtOAc 1: 1).

OH NMR (300 MHz, CDCl3) 6 7.24-7.15 (m, 3H), 7.03-7.01 (m, 2H), 6.65 (s, 1H), 5.89 (bs, 1H), 5.82 (bs, 1H), 5.49 (s, 1H), 5.31 (d, J= 6. 0 Hz, IH), 5.12 (d, J= 6. 0 Hz IH), 4.53 (dd, J/= 3.3 Hz, J2= 11.1 Hz, 1H), 4.18 (d, J= 2. 7 Hz, 1H), 4.07 (m, 2H), 3.75 (dd, J/= 3.9 Hz, J2= 11.1 Hz, 1H), 3.69 (s, 3H), 3.62 (s, 3H), 3.32 (d, J= 7.8 Hz, 1H), 3.25 (d, J= 10. 8 Hz, 1H), 3.12 (d, J= 14. 7Hz, 1H), 3.00 (d, J= 7. 8 Hz, 1H), 2. 94 (d, J= 8. 1 Hz, 1H), 2.66-2.60 (m, 3H), 2.57 (d, J= 18.0 Hz, 1H), 2.28 (s, 3H), 2.14 (s, 3H), 2.10 (bs, 3H), 1.83-1.74 (m, 1H).

ESI-MS m/z: Calcd. for C37H4lN30s : 655.7. Found (M+1) + : 656.3.

Example 98 To a solution of 100 (40 mg, 0.0576 mmol) in CH2CI2 (1 mL), acetic acid (25 µL), Pd (PPh3) 2Cl2 (4.8 mg, 0.007 mmol) and Bu3SnH (62 aL, 0.23 mmol) were added at 23 °C.

The reaction mixture was stirred for 5 h at that temperature and then, the solution was poured into a pad of flash column (Si02, gradient Hex: EtOAc 4: 1 to Hex: EtOAc 1: 1) to afford 104 (30 mg, 82 %) as a white solid. Rf : 0.41 (Hex: EtOAc 1: 1).

'H NMR (300 MHz, CDC13) 8 7.36 (s, 5H), 7.30 (d, J= 16.2 Hz, 1H), 6.59 (s, 1 H), 5.99 (d, J= 16. 2 Hz, 1H), 5.91 (d, J= 1.2 Hz, 1H), 5.84 (d, J= 1. 2 Hz, 1H), 5.60 (s, 1H), 5.20 (d, J= 5.6 Hz, 1H), 4.94 (d, J= 5. 6 Hz, 1H), 4.63 (dd, JI= 3.3 Hz, J2= 11.4 Hz, 1H), 4.18-4. 15 (m, 3H), 3.91 (dd, J1= 3. 9 Hz, J2= 11. 1 Hz, 1H), 3.66 (s, 3H), 3.49 (s, 3H), 3.35 (brd, J= 15, 0 Hz, 1H), 3.26 (brd, J= 11.4 Hz, 1 H), 3.10 (brd, J= 15.0 Hz, 1H), 2.96 (dd, Jl= 8.4 Hz, J2= 18.0 Hz, 1H), 2.63 (d, J= 18. 0 Hz, 1H), 2.27 (s, 3H), 2.13 (s, 3H), 2.00 (s, 3H), 1.80 (dd, J1= 12.0Hz, J2= 14.4 Hz, 1 H).

ESI-MS m/z: Calcd. for C37H39N3Og : 653.7. Found (M+ 23) + : 676.2.

Example 99 To a solution of 101 (24 mg, 0.041 mmol) in CH2C12 (0.4 mL), acetyl chloride (3 µL, 0.041 mmol), and pyridine (3.3 pL, 0.041 mmol) were added at 0 °C. The reaction mixture was stirred for 2 h and then, the solution was diluted with CH2C12 (15 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 5: 1 to Hex: EtOAc 1: 1) to afford 105 (23 mg. 88 %) as a white solid. Rf : 0. 40 (Hex: EtOAc 1: 1).

'H NMR (300 MHz, CDCl3) 8 6. 66 (s, 1H), 5.97 (d, J= 1.2 Hz, 1H), 5.91 (d, J= 1. 2 Hz. 1 H), 4.58 (d, J= 3. 0 Hz, 1H), 4.54 (d, J= 3. 0 Hz, 1H), 4.07 (t, J= 3.3 Hz, 1H), 3.77 (dd, J1= 3. 9 Hz, J2= 11.4 Hz, 1H), 3.73 (s, 3H), 3.57 (s, 3H), 3.35 (d, J= 10.2 Hz, 1H), 3.22 (dt, J1= 2.7 Hz, J2= 11. 7 Hz, 1H), 2.98 (dd, J1= 8.1 Hz, J2= 18.0 Hz, 1H), 2.80 (d, J= 13. 5 Hz, 1H), 2.58 (d, J= 18. 0 Hz, 1H), 2.33 (s, 3H), 2.30 (s, 3H), 2.21 (s, 3H), 2.02 (s, 3H), 1.89-1.76 (m, 2H), 1.72-1.66 (m, 1H), 1.37-1.25 (m, 2H), 0.78 (t, J= 7. 5 Hz, 3H).

ESI-MS m/z : Calcd. for C34H4lN309 : 635. 7. Found (M+1) + : 636.8.

Example 100 To a solution of 102 (16 mg, 0.022 mmol) in CH2C12 (0.2 mL), acetyl chloride (1.9 pL, 0.0266 mmol), and pyridine (2.15 pL, 0.0266 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2C12 (10 mL) and washed with 0.1 N HC1 (7 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 4: 1 toEtOAc) to afford 106 (12 mg, 71 %) as a white solid. Rf : 0.60 (Hex: EtOAc 1: 1). tH NMR (300 MHz, CDC13) 8 7.83 (bs, 1H), 7.65-7.58 (m, 2H), 7.49-7.44 (m, 1H), 7.14 (d.

J= 16. 2 Hz, 1H), 6.62 (s, 1H), 6.06 (d, J= 16. 2 Hz, 1H), 6.00 (d, J= 1.2 Hz, 1H), 5.95 (d, J= 1.2Hz, lH), 5.02 (d, J=5. 7Hz, IH), 4.96 (bs, 1H), 4.92 (d, J= 5.7 Hz, 1H), 4.15-4. 11 (m, 3H), 3.88 (dd, Jl= 3.3 Hz, = 11.1 Hz, 1H), 3.08 (bs, 3H), 2.93 (dd, J1= 8.1 Hz, 7-18. 3 Hz.

1H), 2.80 (d, J= 13. 2 Hz, 1H), 2.64 (d, J= 18. 0 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 2.08 (s, 3H), 1.91 (s, 3H), 1.69 (dd, J1= 11.7 Hz, J2= 15.9 Hz, 1H).).

ESI-MS m/z: Calcd. for C40H40F3N3O9: 763. 7. Found (M+1) + : 764.2.

Example 101 To a solution of 103 (34 mg, 0.052 mmol) in CH2CI2 (0.2 mL), acetyl chloride (4.4 ßL, 0.062 mmol), and pyridine (5 µL, 0.062 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2CI2 (10 mL) and washed with 0.1 N HC1 (7 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 4: 1 toEtOAc) to afford 107 (25.5 mg, 70 %) as a white solid. Rf : 0. 48 (Hex: EtOAc 1 : 1).

'H NMR (300 MHz, CDC13) 5 7.25-7.14 (m, 3H), 7.06-7.04 (m, 2H), 6.66 (s, 1H), 5.96 (d, J= 1.2 Hz, 1H), 5.91 (d, J= 1. 2 Hz, 1H), 5.11 (d, J= 5. 4 Hz, 1H), 4.14 (d, J= 3.3 Hz, 1H), 4.07 (d, J= 3. 6 Hz, 1H), 4.04 (d, J= 2. 7Hz, 1H), 3.78 (dd, J1= 3.3 Hz, Ja-10. 8 Hz, 1H), 3.55 (s, 3H), 3.51 (s, 3H), 3.33 (brd, J= 8. 1 Hz, 1H), 3.23 (dt, Jl= 2.7 Hz, Jr 11.7 Hz, 1H), 2.97 (dd, J1= 8.1 Hz, J2= lo. O Hz, 1H), Z. Si (d, J= 14. 1 Hz, 1H), 2. 63-2. 52 (m, 3H), 2 (s. 3H), 2.29 (s, 3H), 2.26-202 (m, 2H), 2.09 (s, 3H), 2.04 (s, 3H), 1.74 (dd, J, = 12.0 Hz, = 15. 6 Hz, 1H).

ESI-MS m/z: Calcd. for C39H43N3O9: 697. 7. Found (M+1) + : 698. 3.

Example 102 To a solution of 104 (29 mg, 0.0443 mmol) in CH2CI2 (0.3 mL), acetyl chloride (3.77 I1L, 0.053 mmol), and pyridine (4.3 pL, 0.053 mmol) were added at 0 °C. The reaction mixture was stirred for 2 h and then, the solution was diluted with CH2CI2 (15 mL) and washed with 0.1 N HCI (10 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex: EtOAc 4: 1 toEtOAc) to afford 108 (21.6 mg, 70 %) as a white solid. Rf: 0.58 (Hex: EtOAc 1 : 1).

'H NMR (300 MHz, CDC13) 8 7.47-7.44 (m, 2H), 7. 35-7. 34 (m, 3H), 7.29 (d, J= 15. 9 Hz, 1H), 6.62 (s, 1H), 5.99 (d, J= 1. 2 Hz, 1H), 5.93 (d, J= 1. 2 Hz, 1H), 5.05 (d, J= 5. 7 Hz, 1H), 4.94 (d, J= 5.7Hz, 1H), 4.81 (d, J= 11. 5 Hz, 1H), 4.16-4.11 (m, 3H), 3. 34 (brd, J= 5.4 Hz, 1H), 3.24 (bs, 3H), 3.22-3.20 (m, 2H), 2.94 (dd, J1= 8.1 Hz, J2= 18.0 Hz, 1H), 2.80 (d, J= 14.1 Hz, 1H), 2.64 (d, J= 18. 0 Hz, 1H), 2.32 (s, 3H), 2.28 (s, 3H), 2.09 (s, 3H), 1.94 (s, 3H), 1.71 (dd, J1= 11. 7 Hz, J2= 15.6 Hz, 1H), ESI-MS m/z: Calcd. for C39144IN309 : 695.7. Found (M+1) + : 696.2.

Example 103 To a solution of 105 (16 mg, 0.025 mmol) in CH2C12 (0.2 mL), trifluoroacetic acid (77 µL, 1 mmol) was added at 0 °C and the reaction mixture was stirred for 3.5 h at 23°C.

The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1: 1) to afford 109 (12 mg, 81 %) as a white solid. Rf : 0. 32 (Hex: EtOAc 1: 1).

'H NMR (300 MHz, CDC13) 8 6.43 (s, 1 H), 5.97 (d, J= 1. 5 Hz, 1 H), 5.91 (d, J= 1. 5 Hz, 1H), 5.69 (s, 1H), 4.51 (dd, J1= 3.3 Hz, J2= 11.1 Hz, 1H), 4.10-4.05 (m, 3H), 3.78-3.77 (m, 1H), 3.75 (s, 3H), 3.33 (d, J= 8. 1 Hz, 1H), 3.22 (dt, J/= 2.7 Hz, Jazz 12.0 Hz, 1H), 2.96 (dd, J1= 8.4 Hz, J2= 17.7 Hz, 1H), 2.80 (d, J= 15. 6 Hz, 1H), 2.55 (d, J= 18. 0 Hz, 1 H) * 2.33 (s, 3H), 2.24 (s, 3H), 2.01 (s, 3H), 1.87-1.66 (m, 3H), 1.37-1.27 (m, 2H), 0.77 (t, J= 7. 5 Hz, 3H).

ESI-MS m/z : Calcd. for C32H3lN3Os : 591.6. Found (M+1) + : 592.8.

Example 104 To a solution of 106 (90 mg, 0.1178 mmol) in CH2C12 (0.3 mL). trifluoroacetic acid (750 µL, 4.71 mmol) was added at 0 °C and the reaction mixture was stirred for 7 h at 23°C.

The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1: 1) to afford 110 (71 mg, 84 %) as a white solid. Rf : 0. 6 (Hex: EtOAc 1: 1).

IH NMR (300 MHz, CDCl3) 8 7.76 (bs, 1H), 7.62-7.57 (m, 2H), 7.48-7.45 (m, 1H), 7.12 (d, J= 16. 2 Hz, 1H), 6.37 (s, 1H), 6.00 (d, J= 16. 2 Hz, 1H), 5.98 (d, J= 1.2 Hz, I H), 5.92 (d, J= 1.2 Hz, 1H), 5.60 (bs, 1H), 4.88 (d, J= 10. 2 Hz, 1H), 4.14 (bs, 1H), 4.10 (d, J= 2. 4 Hz, 1H), 4.03 (d, J= 2. 4 Hz, 1H), 3.89 (dd, Je= 2.7 Hz, J-) = 11.4 Hz, 1H), 3.32 (d, J= 8. 4 Hz, 1H), 3.26-3.21 (m, 4H), 2.91 (dd, J1= 8. 1 Hz, J2= 18. 0 Hz, 1H), 2.82 (d, J= 13. 8 Hz, 1 H), 2.58 (d, J= 18.0 Hz, 1H), 2.33 (s, 3H), 2.24 (s, 3H), 2.05 (s, 3H), 1.89 (s, 3H), 1.84 (dd, Jazz 12.0 Hz, J= 15.6 Hz, 1H).

ESI-MS m/z: Calcd. for C3gH36F3N30g : 719.7. Found (M+1) + : 720.3.

Example 105 To a solution of 107 (20 mg, 0.286 mmol) in CH2C12 (0.2 mL), trifluoroacetic acid (88) iL, 1.144 mmol) was added at 0 °C and the reaction mixture was stirred for 4 h at 23°C.

The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1 : 1) to afford 111 (18 mg, 96 %) as a white solid. Rf : 0.39 (Hex: EtOAc 1: 1).

'H NMR (300 MHz, CDC13) 8 7.23-7.16 (m, 3H), 7.06-7.04 (m, 2H), 6.43 (s, 1 H), 5.96 (d, J= 1. 5 Hz, 1H), 5.90 (d, J= 1. 5 Hz, 1H), 6.66 (s, 1H), 4.52 (dd, Jl= 3. 3 Hz, J, = 11.1 Hz, 1H).

4.07 (s, 1H), 4.05 (d, J= 3. 3 Hz, 1H), 4.03 (d, J= 2. 4 Hz, IH), 3.76 (dd, y/=3. 6Hz= 11. 1 Hz, 1H), 3.56 (s, 3H), 3.31 (d, J= 7.5 Hz, 1H), 3.23 (d, J= 12.0 Hz, 1H), 2.95 (dd, J/= 8.1 Hz, J2= 18.0 Hz, 1H), 2.80 (d, J= 15. 3 Hz, 1H), 2.63-2.58 (m, 2H), 2.53 (d, J= 18. 0 Hz, 1H), 2.33 (s, 3H), 2.61 (s, 3H), 2.21-2.09 (m, 2H), 2.13 (s, 3H), 2.02 (s, 3H). 1.85 (dd, J/= 11.7 Hz, J2= 115. 3Hz, 1H). ESI-MS m/z: Calcd. for C37H3gN3Og : 653.7. Found (M+1) + : 654.3.

Example 106 To a solution of 108 (14 mg, 0.02 mmol) in CH2CI2 (0.4 mL), trifluoroacetic acid (61.5 p1L, 0.8 mmol) was added at 0 °C and the reaction mixture was stirred for 6 h at 23°C.

The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 2: 1) to afford 112 (12 mg, 92 %) as a white solid. Rf : 0. 36 (Hex: EtOAc 1: 1).

'H NMR (300 MHz, CDC13) 8 7.46-7.45 (m, 2H), 7.35-7.20 (m, 4H), 6.38 (s, 1H), 6.05 (d, J= 15.9 Hz, 1H), 5.98 (d, J= 1. 2 Hz, 1H), 5.93 (d, J= 1. 2 Hz, 1H), 5.57 (s, 1H), 4.71 (d, J= 9.3 Hz, 1H), 4.17-4.13 (m, 2H), 4.08 (d, J= 1. 9 Hz, 1H), 3.89 (dd, J/= 3.6 Hz, y-11. 4 Hz, 1H), 3.33 (m, 5H), 3.26-3.22 (m, 1H), 2.93 (dd, Jl= 9.0 Hz, J= 17.4 Hz, 1H), 2.34 (s, 3H), 2.25 (s, 3H), 2.05 (s, 3H), 1.97 (s, 3H), 1.81 (dd, J1= 12.0 Hz, J2= 15. 6 Hz, 1H).

ESI-MS m/z: Calcd. for C37H37N3Og : 651. Found (M+1) + : 652.2.

Example 107 109 113 To a solution of 109 (10 mg, 0.017 mmol) in CH3CN/H20 (1.5 mL/1 mL), AgN03 (86 mg, 0.5 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then. brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAc: MeOH 3: 1) to afford 113 (7 mg, 71 %) as a white solid.

Rf : 0. 41 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) 8 6.45 (s, 1H), 5.95 (d, J= 1.5 Hz, 1H), 5.88 (d, J= 1. 5 Hz, 1H), 5.65 (bs, 1H), 4.50-4.48 (m, 2H), 4.44 (d, J=2. 1 Hz, 1H), 3.96 (d, J= 3. 0 Hz, 1H), 3.76 (s, 3H), 3.74-3.70 (m, 1H), 3.30 (d, J= 12. 3 Hz, 1H), 3.13 (d, J= 7. 5 Hz, 1H), 2.86 (dd, Jl= 5.7 Hz, J2= 18.3 Hz, 1H), 2.73 (d, J= 14.7 Hz, 1H), 2.48 (d, J= 17. 7 Hz, 1H), 2.33 (s, 3H), 2.24 (s, 3H), 2.17 (s, 3H), 2.00 (s, 3H), 1.86-1.55 (m, 3H), 1.42-1.23 (m, 2H), 0.75 (t, J= 7. 5 Hz, 3H).

ESI-MS m/z: Calcd. for C31H3gN2O9 : 582. 6. Found (M-17) + : 565. 3.

Example 108 To a solution of 110 (42.8 mg, 0.059 mmol) in CH3CN/H2O (1.5 mL/1 mL). AgN03 (303 mg, 1.78 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI2 (20 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAc: MeOH 5: 1) to afford 114 (30 mg, 71 %) as a white solid.

Rf : 0. 30 (EtOAc: MeOH 5: 1).

1H NMR (300 MHz, CDCl3) 8 7.75 (bs, 1H), 7.61-7.56 (m, 2H), 7.45-7.42 (m, 1H), 7.12 (d, J= 16. 2 Hz, 1H), 6.38 (s, 1H), 6.02 (d, J= 16. 2 Hz, 1H), 5.97 (d, J= 1. 5 Hz, 1H), 5.90 (d, J= 1.5 Hz, 1H), 5.50 (bs, 1H), 4.87 (bs, 1H), 4.56 (m, 1H), 4.45 (bs, 1H), 3.92 (d, J= 2. 4 Hz, 1H), 3.31 (dt, J1= 3.6 Hz, J2= 12.9 Hz, 1H), 3.21 (bs, 3H), 3.13 (d, J= 7. 8 Hz, 1H), 2.82 (dd, J/= 8.1 Hz, J2= 18.0 Hz, 1H), 2.75 (d, J= 14. 7 Hz, 1H), 2.49 (d, J= 18. 0 Hz, 1H), 2.33 (s, 3H), 2.21 (s, 3H), 2.05 (s, 3H), 1.89 (s, 3H), 1.78 (dd, Jazz 12.0 Hz, J2= 15.6 Hz, 1H).

ESI-MS m/z : Calcd. for C37H37F3N2O9 : 710.6. Found (M-17) + : 693.2.

Example 109 To a solution of 111 (12 mg, 0.018 mmol) in CH3CN/H20 (1.5 mL/1 mL), AgNO3 (93.5 mg, 0.55 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAc: MeOH 1: 1) to afford 115 (10 mg. 86 %) as a white solid.

Rf : 0.43 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) 8 7.23-7.14 (m, 3H), 7.05-7.03 (m, 2H), 6.45 (s, I H), 5.93 (d, J= 1. 2 Hz, 1H), 5.88 (d, J= 1. 2 Hz, 1H), 5.63 (brd, 1H), 4.55-4.49 (m, 2H), 4.43 (d, J= 2. 7 Hz, 1H), 3.96 (d, J= 3. 1 Hz, 1H), 3.80-3.73 (m, 1H), 3.56 (bs, 3H), 3.32 (dt, J/= 3.3 Hz, J2= 12.6 Hz, 1H), 3.13 (d, J= 6.0 Hz, 1H), 2.86 (dd, J1= 7.5 Hz, J2= 18. 3 Hz, 1H), 2. 74 (d, J= 14.7 Hz, 1H), 2.61-2.56 (m, 2H), 2.47 (d, J= 18. 0 Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H), 2.01 (s, 3H), 1.99-1.94 (m, 2H), 1.78 (dd, JJ= 11. 7 Hz, J2= 15.0 Hz, 1H).

ESI-MS m/z: Calcd. for C36H4oN209 : 644.7. Found (M-17) + : 627.2.

Example 110 To a solution of 112 (12 mg, 0.018 mmol) in CH3CN/H20 (1.5 mL/1 mL), AgN03 (93 mg, 0.55 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAc: MeOH 1 : 1) to afford 116 (8 mg, 70 %) as a white solid.

Rf : 0. 41 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) 8 7.44-7.43 (m, 2H), 7.34-7.27 (m, 4H), 6.39 (s, 1H), 6.03 (d, J= 15. 9 Hz, 1H), 5.96 (d, J= 1. 5 Hz, 1H), 5.90 (d, J= 1. 5 Hz, IH), 5.55 (m, IH), 4.47 (m, 1H), 4.50 (m, 1H), 3.94 (d, J= 3. 6 Hz, IH), 3.85 (dd, Jazz 3.3 Hz, J= 11. 1 Hz, I H), 3.66 (bs, 3H), 3.34-3.31 (m, 2H), 3.13 (d, J= 5. 1 Hz, 1H), 2.93-2.73 (m, 2H), 2.53 (d. J= 18. 0 Hz, 1H), 2.33 (s, 3H), 2.22 (s, 3H), 2.03 (s, 3H), 1.94-1.82 (m, 1H).

ESI-MS m/z: Calcd. for C36H3gN2O9 : 642.7. Found (M-17) + : 625.2.

Example 111 To a solution of 17 (6.28 g, 9.06 mmol) in CH2CI2 (45.3 mL), allyl chloroformiate ( 3.85 mL, 36.24 mmol) and pyridine (2.93 mL, 36.24 mmol) were added at 0 °C. The reaction mixture was stirred for 16 h at 23°C and then, the solution was diluted with CH2C12 (150 mL) andwashed with 0. 1 N HC1 (2 x 100 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure to give 117 (5.96 g, 84 %) which was used in following steps with no further purification.

Rf : 0. 56 (CH2Cl2 : EtOAc 1: 1).

'H NMR (300 MHz, CDC13) 6 6.72 (s, 1H), 6.05-5.94 (m, 1H), 6.01 (s, 1H), 5.91 (s, 1H), 5.44 (dd, J1 = 1.2 Hz, J2 = 17.1 Hz, 1H), 5.35 (dd, Jl = 1.2 Hz, J2 = 10.5 Hz, 1H), 5.34 (m, 1H), 5.10 (d, J = 5.7 Hz, 1H), 5.05 (d, J = 5.7 Hz, 1H), 4.68 (d, J = 5.7 Hz, IH), 4.65 (dt, Jl = 1.2 Hz, J2 = 6 Hz, 1H), 4.18 (brd, J = 9 Hz, 2H), 4.04 (bs, 1H), 3.70 (s, 3H). 3.67-3.60 (m, 1H), 3.55 (s, 3H), 3.43-3.41 (m, 2H), 3.29-3.25 (m, 2H), 3.00 (dd, Jl = 8.7 Hz, J2 = 18.3 Hz, 1H), 2.90 (dd,J1 = 2.4 Hz, J2 = 16. 2 Hz, 1H), 2.75 (d, J= 18.3 Hz, 1H), 2.35 (s, 3H), 2.22 (s, 3H), 2.06 (s, 3H), 1.83 (dd, J1 = 11.4 Hz, J2 = 15.9 Hz, 1H), 1.39 (s, 9H). 0.73 (d, J = 6. 9 Hz, 3H).

13C NMR (75 MHz, CDC13) 8 172.1,152.8,148.6,148.3,144.6,140.7,140.6,131.5,131.2, 131.1,130.4,125.3,125.0,123.3,120.9,119.1,118.8,117.6,112.9, 112.0,101.6,99.2,71.8, 69.0,68.4,59.7,59.2,57.6,57.3,56.7,55.8,55.2,41.4,39.9,28.2, 26.0,25.0,18.6,15.6, 9.0.

ESI-MS m/z : Calcd. for C40H51N5O11: 777.8. Found (M+1) + : 778.3 Example 112 To a solution of 117 (3.96 g, 5.09 mmol) in MeOH (37.4 mL), trimetylchlorosilane ( 6.5 mL, 50.9 mmol) was added at 0 °C. The reaction mixture was stirred for 4 h at 23°C and then, the solvent was eliminated under reduced pressure. The residue was diluted with EtOAc (70 mL) and washed with a saturated aqueous solution of NaHC02 (2 x 45 mL). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated in vacuo to give 118 (2.77 g, 86 %) which was used in following steps with no further purification.

Rf : 0.61 (Hex: EtOAc 1 : 1).

'H NMR (300 MHz, CDC13) 8 6.50 (s, 1H), 6.45 (m, 1H), 6.10-6.03 (m, 1H), 6.00 (s, 1H), 5.93 (s, 1 H), 5.47 (dd, 77 = 1.2 Hz, J2 = 17.1 Hz, 1 H), 5.3 8 (dd, JI = 1.2 Hz, J2 = 10.5 Hz, 1H), 4.81-4.64 (m, 2H), 4.10-4.03 (m, 3H), 3.75 (s, 3H), 3.70-3.44 (m, 2H), 3.35 (d, J = 8.1 Hz, 1H), 3.28 (dt, Jl = 2.7 Hz, J2 = 9 Hz, 1H), 2.98 (dd, Jl = 7.8 Hz, J2 = 18 Hz, 1H), 2.90 (dd, Jl = 2. 7 Hz, J2 = 16.2 Hz, 1 H), 2.78 (dd, Jl = 6.9 Hz, J2 = 14.1 Hz, 1H), 2.63 (d, J = 18.3 Hz, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 2.04 (s, 3H), 1.88 (dd, Jl = 13.2 Hz, J2 = 15.6 Hz, 1H), 0.95 (d, J = 6.9 Hz, 3H).

13C NMR (75 MHz, CDC13) 8 175.8,152.9,146.6,144.6,142.5,140.8,140.6,131.5,131.3, 128.5,121.1,120.8,118.9,117.8,117.0,113.2,111.9,101.7,68.9,6 0.6,59.1,56.6,56.4, 55.7,55.2,50.5,41.7,39.4,26.1,25.0,21.0,15.6,9.2.

ESI-MS m/z: Calcd. for C33H39N508 : 633. 6. Found (M+1) + : 634.2.

Example 113 OMe p OMe HO Me N-Me I N-Me N TMe Ny Phenylisothiocyanate p Y-0 CNCH2C ! 2, 23°C, 3h NH NH NH NHCSNHPH O' I 118 119 To a solution of 118 (3.52 g, 5.56 mmol) in CH2Cl2 (28 mL), phenylisothiocyanate ( 3.99 mL, 33.36 mmol) was added at 23 °C. The reaction mixture was stirred for 3 and then, the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography to afford 119 (3.5 g, 82 %) as a white solid.

Rf : 0. 52 (CH2Cl2 : EtOAc 1: 5).

'H NMR (300 MHz, CDC13) 8 7.69 (bs, 1H), 7.49-7.46 (m, 2H), 7.34-7.21 (m, 2H), 6.96 (d, J = 6.9 Hz, 1H), 6.06-5.97 (m, 1H), 6.03 (s, 1H), 5.96 (bs, 1H), 5.91 (s, 1 H), 5.66 (s, 1H), 5.47 (dd, JI = 1.5 Hz, J2 = 17. 1 Hz, 1 H), 5.37 (dd, Jl = 1.5 Hz, J2 = 10.5 Hz, 1 H), 5.36 (s, 1H), 4.75-4.70 (m, 2H), 4.54-4-49 (m, 1 H), 4.14 (d, J = 2. 4 Hz, 1H), 4.07-4.06 (m, 2H), 3.70 (s, 3H), 3.44 (m, 1H), 3.35 (d, J = 8.1 Hz, 1H), 3.21 (dt, Jl = 2.7 Hz, J2 = 6.6 Hz, 1H), 2.94-2.82 (m, 2H), 2.63 (d, J = 18 Hz, 1H), 2.24 (s, 3H), 2.06 (s, 3H), 2.06 (s, 3H), 1.90 (dd, J1 = 11.7 Hz, J2 = 15. 9 Hz, 1H), 0.71 (d, J = 6. 9 Hz, 3H).

3C NMR (75 MHz, CDC13) 6 178.6,171.9,152.8,146.7,144.5,142.6,140.8,140.5,136. 3, 131.3,131.0,129.9,129.8,128.9,126.7,125.2,124. 3,121.1,120.6,118.9,117.7,116.5, 112.8,112.1,101.6,68.9,60.5,58.9,57. 3,56.1,55.9,55.1,53. 3,41.5,39.2,25.9,24.6,20.9, 15.4,9.1.

ESI-MS m/z: Calcd. for C40H44N3OsS : 768.8. Found (M+1) + : 769.3.

Example 114 119 To a solution of 119 (3.38 g, 4.4 mmol) in MeOH (22 mL), trimetylchlorosilane (2.3 mL, 22 mmol) was added at 0 °C. The reaction mixture was stirred for 1.5 h at 23°C and then, the solvent was eliminated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with 0.1 N HCI (2 x 75 mL). The aqueous phase was basified with a saturated aqueous solution of NaHC02 and extracted with CH2C12 (2 x 100 mL). The combined organic layers were dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure to afford 120 (2.47 g, 100 %) as a white solid which was used in following steps with no further purification.

Rf : 0.26 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) 6 6.45 (s, 1H), 6.05-5.98 (m, 1H), 5.97 (d, J = 1.2 Hz, 1H), 5.90 (d, J = 1.2 Hz, 1H), 5.44 (dd, Jazz 1.2 Hz, J2 = 17.1 Hz, 1H), 5.35 (dd, J1 = 1.2 Hz, J2 = 10.2 Hz, 1H), 4.75-4.71 (m, 2H), 4.12-4.10 (m, 1H), 3.99 (d, J = 2.4 Hz, 1H), 3.92 (bs, 1H), 3.73 (s, 3H), 3.36-3.26 (m, 2H), 3.06 (dd, Jl = 8.4 Hz, J2 = 18 Hz, 1H), 2.89 (dd, 77 = 2.7 Hz, J2 = 15.9 Hz, 1H), 2.75-2.73 (m, 2H), 2.48 (d, J = 18 Hz, 1H), 2.32 (s, 3H), 2.23 (s, 3H), 2.05 (s, 3H), 1.85 (dd, Xi = 11. 7 Hz, J2 = 15.6 Hz, 1H).

3C NMR (75 MHz, CDC13) 8 153.0,146.6,144.5,142.8,140.7,131.5,130.5,128.9,121.3, 120.9,119. 1,117.9,116.7,113.8.111.6,101.5,69.0,60.6,59.8,58.7,56.5,56. 0,55.3,44.2, 41.8,31.6,26.1,25.7,15.7,9.2.

ESI-MS m/z: Calcd. for C30H34N407 : 562.6. Found (M+1) + : 563.2.

Example 115 To a solution of 120 (2.57 g, 4.4 mmol) in CH2C12 (44 mL), TrocCl (0.91 mL, 6.6 mmol) and pyridine (0.53 mL, 6.6 mmol) were added at-20 °C. The reaction mixture was stirred for 30 min at 0°C and then, the solution was diluted with CH2CI2 (50 mL) and washed with 0. 1 N HC1 (2 x 25 mL). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure to give 121 (3.24 g, 100 %) which was used in following steps with no further purification.

Rf : 0.62 (EtOAc: MeOH 5 : 1).

1H NMR (300 MHz, CDCl3) # 6.50 (s, 1H), 6.07-6.01 (m, 1H), 5.99 (d, J = 1.2 Hz, 1H), 5.93 (d, J= 1.2 Hz, 1H), 5.68 (s, 1H), 5.46 (dd, JI = 1.2 Hz, J2 = 17.1 Hz, 1H), 5.37 (dd, J1 = 1.2 Hz, J2 = 10.5 Hz, 1H), 4.74 (t, J = 5.7 Hz, 2H), 4.63-4.62 (m, 1 H), 4.54 (d, J = 12 Hz, 1H), 4.30 (d, J = 12 Hz, 1H), 4.14-4.11 (m, 2H), 4.02-4.01 (m, 2H), 3.75 (s, 3H), 3.36- 3.26 (m, 3H), 3.04 (dd, Jl = 8.1 Hz, J2 = 17.7 Hz, 1 H), 2.91 (dd, Jl = 2.4 Hz, J2 = 15.6 Hz, 1H), 2.60 (d, J = 17.7Hz, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 2.04 (s, 3H), 1.84 (dd, Jl = 12 Hz, J2 = 15. 9 Hz, 1H).

ESI-MS m/z: Calcd. for C33H35Cl3N4O9: 738. 0. Found (M+1) + : 737.2.

Example 116 To a solution of 121 (0.45 g, 0.60 mmol) in CH3CN (4 mL), diisopropylethylamine (2.17 mL, 12.46 mmol), bromomethyl methyl ether (0.76 mL, 9.34 mmol) and dimethylaminopyridine (8 mg, 0.062 mmol) were added at 0 °C. The reaction mixture was heated at 40°C for 5 h. Then, the reaction was diluted with CH2CI2 (50 mL) and washed with 0. 1 N HCl (2 x 25 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure to give 122 (0.453 g, 95 %) which was used in following steps with no further purification.

Rf : 0.31 (RP-18 CH3CN-H20 8: 2).

1H NMR (300 MHz, CDCl3) 8 6.70 (s, 1H), 6.05-5.99 (m, 1H), 5.97 (s, 1 H), 5.92 (s, 1H), 5.43 (dd, JI = 1.2 Hz, J2 = 17.1 Hz, 1H), 5.34 (dd, JI = 1.2 Hz, J2 = 10.5 Hz, 1H), 5.10- 5.04 (m, 2H), 4.72-4.68 (m, 2H), 4.60 (t, J = 5.7 Hz, 1H), 4.49 (d, J = 12.3 Hz, 1H), 4.38 (d, J = 12. 3 Hz, 1H), 4.18 (d, J = 2.7 Hz, 1H), 4.03-4.00 (m, 2H), 3.71 (s, 3H), 3.54 (s, 3H), 3.38-3.22 (m, 4H), 3.04 (dd, Jl = 7.8 Hz, J2 = 18.3 Hz, 1H), 2.91 (dd, Jl = 2.4 Hz, J2 = 15.9 Hz, 1H), 2.61 (d, J = 18 Hz, 1H), 2.31 (s, 3H), 2.20 (s, 3H), 2.03 (s, 3H), 1.76 (dd, J1 = 11.7 Hz, J2 = 15. 6 Hz, 1H).

ESI-MS m/z: Calcd. for C33H39Cl3N401o : 782. 0. Found (M+l) + : 783. 2.

Example 117 To a suspension of 122 (0.45 g, 0.579 mmol) in 90 % aqueous acetic acid (6 mL), powder zinc (0.283 g, 4.34 mmol) was added and the reaction was stirred for 6 h at 23 °C.

Then, the mixture was filtered through a pad of celite which was washed with CH2CI2 (25 mL). The organic layer was washed with an aqueous sat. solution of sodium bicarbonate (pH= 9) (2 x 15 mL), dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure to give 123 (0.351 g, 100 %) which was used in following steps with no further purification.

Rf : 0.38 (Si02, EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDCl3) 8 6.68 (s, 1H), 6.06-5.99 (m, 1H), 5.97 (d, J = 1.5 Hz, 1H), 5.91 (d, J = 1.25 Hz, 1H), 5.44 (dd, JI = 1. 5Hz, J2= 17. 4Hz, IH), 5.36 (dd, Jl = 1. 5Hz, J2 = 10.2 Hz, 1H), 5.08 (q+J = 5.7 Hz, 2H), 5.74-4.70 (m, 2H), 4.02 (d, J = 3 Hz, 1H), 4.00 (d, J= 2. 4 Hz, 1H), 3.91 (m, 1H), 3.71 (s, 3H), 3.56 (s, 3H), 3.37-3.35 (m, 1H), 3.29 (t, J= 2.7 Hz, 1H), 3.08 (dd, J1 = 7. 5 Hz, J2 = 18 Hz, 1H), 2.90 (dd, Jl = 2.7 Hz, J2 = 15.9 Hz, 1H), 2.74 (dd, Jl = 2.4 Hz, J2 = 5.1 Hz, 2H), 2.48 (d, J = 18 Hz, 1H), 2.35 (s, 3H), 2.20 (s, 3H), 2.05 (s, 3H), 1.80 (dd, V7 = 12 Hz, J2 = 15.9 Hz, 2H).

ESI-MS m/z: Calcd. for C32H3gN408 : 606.6. Found (M+1) + : 607.3.

Example 118 1 OMe OMe 0 OMe 0 HO OMe Me HO Me 0 Mye Me H-Me cinnamoyl chlodde, py Me N--Me /N p O -CH2CI2, 0°C, 1.5 h L _ NH2 NH nu2 O 1 20 t3 zu To a solution of 120 (100 mg, 0.177 mmol) in CH2C12 (0.7 mL), cinnamoyl chloride ( 29.5 mg, 0.177 mmol) and pyridine (14.37 pL, 0.177 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CHoCI2 (15 mL) and washed with 0.1 N HC1 (10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 2: 1 to Hex: EtOAc 1: 3) to afford 124 (86 mg, 70 %) as a white solid.

Rf : 0.77 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDCI3) 6 7.39-7.26 (m, 5H), 7.25 (d, J = 15.6 Hz, 1H), 6.44 (s, 1H), 6.01 (d, J = 1.2 Hz, 1H), 5.94 (d, J = 1.2 Hz, 1H), 5.68 (s, 1H), 5.65 (d, J = 15.6 Hz, 1H), 5.44 (dd, J 1 = 1.2 Hz, J2 = 17. 1 Hz, 1H), 5.35 (dd, Jl= 1.2 Hz, J2 = 10.5 Hz, I H), 5.18 (t, J = 6 Hz, 1H), 4.73-4.69 (m, 2H), 4.11-4.09 (m, 3H), 3.66-3.58 (m, 2H), 3.65 (s, 3H), 3.38- 3.31 (m, 3H), 3.02 (dd, Jl = 8.4 Hz, J2 = 18.3 Hz, 1H), 2.92 (dd, J I = 2.7 Hz, J2 = 15.6 Hz, 1H), 2.59 (d, J = 18.3 Hz, 1H), 2.31 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1.89 (dd, Jl = 12.3 Hz, J2 = 16.2 Hz, 1H).

3C NMR (75 MHz, CDC13) 8 165.5,152.7,146.6,144.4,142.6,140.7,140.5,140.1,134.7, 131.2,130.6,129.3,128.7,128.4,127.6,120.8,120.5,120.3,118.9, 117.6,116.5,113.2, 111.8,101.6,68.8,60.4,59.0,56.2,56.1,55.7,55.0,41.5,40.6,25. 9,25.1,15.5,9.0.

ESI-MS m/z : Calcd. for C39H40N4O8 : 692.7. Found (M+1) + : 693.2.

Example 119 To a solution of 124 (495 mg, 0.713 mmol) in CH2Cl2 (28 mL), acetic acid (163 µL), Pd (PPh3) 2C12 (50 mg, 0.0713 mmol) and Bu3SnH (384 pL, 1.42 mmol) were added at 0 °C.

The reaction mixture was stirred for 2 h at 23°C and then, the solution was poured into a pad of flash column (Si02, gradient Hex: EtOAc 1 : 1 to EtOAc) to afford 125 (435 mg, 100 %) as a white solid. Rf : 0.22 (Hex: EtOAc 1: 2).

'H NMR (300 MHz, CDC13) 8 7.36-7.33 (m, 5H), 7.28 (d, J = 15.9 Hz, 1 H), 6.45 (s, 1H), 5.90 (s, 1H), 5.83 (s, 1H), 5.55 (d, J = 15. 6 Hz, 1H), 5.24 (t, J = 12. 9 Hz, 1H), 4.17 (d, J = 1.8 Hz, 1H), 4.10-4.07 (m, 2H), 3.72 (s, 3H), 3.46-3.32 (m, 3H), 3.14-3.00 (m, 2H), 2.54 (d, J= 18 Hz, 1H), 2.32 (s, 3H), 2.05 (s, 6H), 1.89 (dd, J, = 12 Hz, J2 = 15.3 Hz, 1H).

13C NMR (75 MHz, CDC13) 8 165.7,146.9,145.1,144.2,143.0,140.8,136.5,134.5,130.6, 129.4,128.9,127.9,127.7,120.8,119.8,117.8,114.1,112.9,107.1, 100.8,60.5,59.2,56.4, 56.0,55.1,41.4,30.7,25.5,25.3,15.5,8.9.

ESI-MS m/z: Calcd. for C35H36N406 : 608.6. Found (M+1) + : 609.2.

Example 120 To a solution of 125 (86 mg, 0. 124 mmol) in CH3CN/H20 (1.5 mL/1 mL), AgN03 (632 mg, 3.72 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI2 (20 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAc: MeOH 2: 1) to afford 126 (70 mg, 83 %) as a white solid.

Rf : 0.07 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) 8 7.40-7.28 (m, 5H), 7.25 (d, J = 15.6 Hz, 1H), 6.48 (s, 1H), 6.00-5.94 (m, 1H), 5.96 (s, 1H), 5.92 (s, 1H), 5.89 (s, 1H), 5.53 (d, J= 15.6 Hz, 1H), 5.42- 5.36 (m, 2H), 5.31 (dd, J, = 1.2 Hz, J2 = 10.8 Hz, 1H), 4.71-4.65 (m, 2H), 4.51 (d, J = 3 Hz, 1H), 4.42 (bs, 1H), 4.07 (bs, 1H), 3.79 (dd, J, = 6. 9 Hz, J2 = 12. 9 Hz, 1H), 3.68 (s, 3H), 3.62-3. 59 (m, 1H), 3.41-3. 37 (m, 1H), 3.16 (d, J = 7. 8 Hz, 1H), 2.95 (dd, J, = 7. 5 Hz, J2 = 17.4 Hz, 1H), 2.88-2.83 (m, 1H), 2.43 (d, J= 18 Hz, 1H), 2.28 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H), 1.81 (dd, J, = 11.7 Hz, J2 = 15. 3 Hz, 1H).

13 C NMR (75 MHz, CDC13) 8 165.5,152.9,146.7,144.5,144.4,142.7,141.0,140.0,134.6, 131.4,130.7,129.2,128.8,128.5,127.8,127.7,124.6,121.2,120.9, 118.9,116.5,114.9, 114.7,111.3,101.6,93.3,92.3,83.2,68.9,60.6,57.8,56.8,56.6,56 .3,52.5,52.2,41.6,26.1, 24.6,15.6,9.1. ESI-MS m/z: Calcd. for C38H4lN309 : 683. 7. Found (M-17) + : 666. 3 Example 121 \ OMe \ OMe 0 OMe 0 HO OMe Me ho Me Me N--Me hidrocinnamoyl chloride, py N N Me I o CH2CI2, OOC, 1-5 h tO ZC N NH NHz j NH2 0 zu 127 To a solution of 120 (1.61 g, 2.85 mmol) in CH2CI2 (4 mL), hydrocinnamoyl chloride (423 µL, 2.85 mmol) and pyridine (230 pL, 2.85 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2CIr (50 mL) and washed with 0. 1 N HC1 (30 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 2: 1 to EtOAc) to afford 127 (1.64 g, 83 %) as a white solid.

Rf : 0.63 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) 8 7.26-7-14 (m, 3H), 7.04-7.01 (m, 2H), 6.44 (s, 1H), 6.07-5.99 (m, 1H), 5.97 (d, J = 1.5 Hz, 1H), 5.91 (d, J = 1.5 Hz, 1H), 5.75 (bs, 1H), 5.45 (dd, Y = 1.5 Hz, J2 = 17.4 Hz, 1H), 5.36 (dd, J, = 1.5 Hz, J2 = 10.2 Hz, IH), 5.03 (t, J = 5. 7 Hz, 1H), 5.74-5.66 (m, 2H), 4.09 (d, J = 2.4 Hz, 1H), 4.01 (bs, 1H), 3.97 (d, J = 2.7 Hz, 1H), 3.62 (dd, Jazz 8.4 Hz, J2 = 13.5 Hz, 1H), 3.42 (s, 3H), 3.37-3.28 (m, 3H), 3.04-2.87 (m, 3H), 2.67-2.46 (m, 4H), 2.29 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 1.83-1.79 (m, 1H).

3C NMR (75 MHz, CDC13) 8 171.8,152.8,146.7,144.5,144.4,142.7,140.9,140.8,140.6, 131.4,130.7,128.9,128.4,128.2,128.1,126.0,120.8,120.4,118.9, 117.6,116.6,113.0, 111.9,101.6,68.9,60.3,59.0,56.3,56.2,55.6,55.1,41.6,40.3,37. 7,31.0,25.9,25.2,15.5, 9.1. ESI-MS m/z : Calcd. for C39H42N408 : 694.3. Found (M+1) + : 695. 3.

Example 122 To a solution of 127 (50 mg, 0.072 mmol) in CH3CN/H20 (1.5 mL/1 mL), AgNo3 (444 mg, 2.16 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2C12 (15 mL). The solution was extracted and the organic layer was dried over Na2S04, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAc: MeOH 3: 1) to afford 128 (30 mg, 61 %) as a white solid.

Rf : 0.65 (EtOAc: MeOH 5: 1).

1H NMR (300 MHz, CDCl3) 8 7.22-7.11 (m, 3H), 7.06-7.03 (m, 2H), 6.43 (s, 1 H), 6.08-5.98 (m, 1H), 5.96 (d, J = 1.5 Hz, 1H), 5.90 (d, J = 1.5 Hz, 1H), 5.66 (bs, 1H), 5.44 (dd, J, = 1.5 Hz, J2 = 17. 4 Hz, 1H), 5.36 (dd, J, = 1.5 Hz, J2 = 10.5 Hz, 1H), 4.78-4.65 (m, 2H), 4.44 (d, J = 3 Hz, 1H), 4.36 (bs, 1H), 3.99 (td, J1 = 2.1 Hz, J2 = 9.9 Hz, 1H), 3.78-3.67 (m, 1H), 3.56 (dt, Jl = 1.5 Hz, J2 = 11.1 Hz, 1H), 3.43 (s, 3H), 3.30-3.12 (m, 2H), 3.02-2.89 (m, 1H), 2.83 (dd, JI = 2.7 Hz, J2 = 15.9 Hz, 1H), 2.62-2.51 (m, 2H), 2.36 (d, J = 18.6 Hz, 1H), 2.27 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.86-1.66 (m, 3H).

13 NMR (75 MHz, CDC13) 8 171.6,146.7,141.2,141.1,131.5,130.5,128.9,128.3,128.2, 128.2,125.9,124.7,121.1,121.0,118.8,111.3,101.6,94.0,83.2,68 .8,60.3,57.9,56.6, 56.3,52.3,52.0,41.7,41.6,41.1,37.9,31.1,31.0,26.1,24.6,15.5, 9.2.. ESI-MS m/z: Calcd. for C38H43N309 : 685.7. Found (M-17) + : 668.3.

Example 123 To a solution of 127 (1.64 g, 2.36 mmol) in CH3CN (12 mL), diisopropylethylamine (8.22 mL, 47.2 mmol), bromomethyl methyl ether (2.89 mL, 35.4 mmol) and dimethylaminopyridine (29 mg, 0.236 mmol) were added at 0 °C. The reaction mixture was heated at 40°C for 5 h. Then, the reaction was diluted with CH2CI2 (80 mL) and washed with 0. 1 N HCI (3 x 25 mL). The organic layer was dried over Na2SO4. filtered, and the solvent was eliminated under reduced pressure to give 129 (1.46 g, 84 %) which was used in following steps with no further purification.

Rf : 0.24 (RP-18 CH3CN-H20 8: 2).

'H NMR (300 MHz, CDC13) 6 7.27-7.11 (m, 3H), 7.05-7.02 (m, 2H), 6.67 (s, 1H), 6.08-5.98 (m, I H), 5.96 (d, J = 1.2 Hz, 1H), 5.90 (d, J = 1.2 Hz, 1H), 5.44 (dd, Jl = 1.2 Hz, J2 = 17.1Hz, 1H), 5.34 (dd, J7 = 1.2 Hz, J2 = 10.5 Hz, 1H), 5.05 (d, J = 6 Hz, 1H), 5.00 (d, J = 6 Hz, IH), 4.97 (t, J= 5. 1 Hz, IH), 4.75-4.68 (m, 2H), 4.16 (d, J = 2.7 Hz, IH), 3.98-3.97 (m, 1H), 3.68-3.67 (m, 1H), 3.65-3.61 (m, 1H), 3.52 (s, 3H), 3.35 (s, 3H), 3.32-3.26 (m, 3H), 3.05-2.86 (m, 3H), 2.59-2.48 (m, 2H), 2.30 (s, 3H), 2.02 (s, 3H), 1.94 (s, 3H), 1.91-1.67 (m, 3H).

3c NMR (75 MHz, CDC13) 6 171.4,152.7,148.5,148.3,144.5,140.9,140.8,140.4,131.1, 130.9,130.4,130.1,128.4,128.2,126.0,124.6,123.7,120. 3,119.0,112.9,111.8,101.6, 99.1,68.9,59.4,59.1,57.5,56.7,56.3,55.4,55.1,41.5,40.2,37.7, 30.9,25.8,25.2,15.5, 9.0.

ESI-MS m/z : Calcd. for C4iH46N409 : 738. 8. Found (M+ 23) + : 761.2.

Example 124 To a solution of 129 (1.46 g, 1.97 mmol) in CH2Cl2 (40 mL), acetic acid (450 µL), Pd (PPh3) 2Cl2 (138 mg, 0.197 mmol) and Bu3SnH (1.06 mL, 3.95 mmol) were added at 0 °C. The reaction mixture was stirred for 5 h at 23°C and then, the solution was poured into a pad of flash column (Si02, gradient Hex: EtOAc 1: 1 to EtOAc) to afford 130 (1.1 g, 85 %) as a white solid. Rf : 0. 22 (Hex: EtOAc 1: 2).

1H NMR (300 MHz, CDC13) 8 7.21-7.12 (m, 3H), 6.98-6.95 (m, 2H), 5.86 (s, 1H), 5.84 (s, 1H), 5.79 (bs, 1H), 5.26 (d, J = 6 Hz, 1H), 5.11 (d, J = 6 Hz, 1H), 5.05 (t, J = 5.7 Hz, 1H), 4.19 (d, J = 2. 4 Hz, 1H), 4.03 (d, J = 2.4 Hz, 1H), 3.99 (bs, 1H), 3.65 (s, 3H), 3.56 (s, 3H), 3.53-3.42 (m, 2H), 3. 34 (d, J = 8.7 Hz, 1H), 3.27 (brd, J = 11.7 Hz, 1H), 3.11 (d, J = 15 Hz, 1H), 2.99 (dd, Jl = 8.4 Hz, J2 = 18.3 Hz, 1H), 2.64-2.52 (m, 3H), 2.29 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 1.84 (t, J = 7.8 Hz, 2H), 1.71 (dd, J1 = 12. 9 Hz, J2 = 13.5 Hz, 1H).

'3C NMR (75 MHz, CDC13) 6 171.7,149.0,147.6,140.6,132.1,131.9,130.9,130.5,128.5, 128.4,128.3,128.0,126.0,124.9,124.6,123.1,117.6,100.8,99.6,5 9.6,58.9,57.6,56.6, 56.5,55.6,55.1,41.5,37.8,31.5,31.1,25.9,25.1,22.6,15.5,8.8.

ESI-MS m/z: Calcd. for C37H42N407 : 654.7. Found (M++ Na): 655.1 Example 125 To a solution of 130 (130 mg, 0.198 mmol) in CH2Cl2 (1 mL), trifluoroacetyl anhydride (41. 9 µL, 0.297 mmol) and pyridine (24 pL, 0.297 mmol) were added at 0 °C.

The reaction mixture was stirred for 2.5 h and then, the solution was diluted with CH2CI2 (10 mL) and washed with 0.1 N HC1 (7 mL). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 4: 1 to Hex: EtOAc 1: 4) to afford 131 (93 mg, 62 %) as a white solid.

Rf : 0.30 (Hex: EtOAc 1: 2).

'H NMR (300 MHz, CDC13) 5 7.25-7.16 (m, 3H), 7.04-7.02 (m, 2H), 6.78 (s, IH), 6.02 (d, J = 1.2 Hz, 1H), 5.95 (d, J=1. 2Hz, 1H), 5.11 (d, J = 6. 6 Hz, 1 H), 4.98 (d, J = 6.6 Hz, 1H), 4.95 (t, J = 6. 3 Hz, 1H), 4.61 (bs, 1H), 4.30 (s, 1H), 4.08 (s, 1H), 3.96 (d, J = 7.2 Hz, 1H), 3.66-3.54 (m, 1H), 3.50 (s, 3H), 3.39 (s, 3H), 3.19 (dd, Jl = 7.8 Hz, J2 = 18. 3 Hz, 1H), 2.88 (d, J = 18.6 Hz, 1H), 2.79 (dd, J 1 = 2. 7 Hz, J2 = 15.9 Hz, 1H), 2.66-2.62 (m, 1H), 2.57 (s, 3H), 2.06 (s, 6H), 1.94-1.87 (m, 1H), 1.77-1.68 (m, 2H).

ESI-MS m/z: Calcd. for C39H41F3N408 : 750.7. Found (M+ Na) + : 751.2.

Example 126 To a solution of 130 (130 mg, 0.198 mmol) in CH2C12 (2 mL), chloroacetyl chloride ( 23.65 pL, 0.297 mmol) and pyridine (24 aL, 0.297 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2CI, (10 mL) and washed with 0. 1 N HC1 (7 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 2: 1 to Hex: EtOAc 1: 1) to afford 132 (130 mg, 90 %) as a white solid.

Rf : 0. 31 (Hex: EtOAc 1 : 2).

'H NMR (300 MHz, CDC13) 6 7.24-7.15 (m, 3H), 7.07-7.05 (m, 2H), 6.69 (s, 1H). 6. 00 (d, J = 1. 5 Hz, 1H), 5.94 (d, J = 1. 5 Hz, 1H), 5.11 (d, J = 5.7 Hz, 1H), 5.04 (d, J = 5. 7 Hz, 1H), 4.93 (m, 1H), 4.36 (s, 2H), 4.16 (d, J = 2.7 Hz, 1H), 4.01 (m, 2H), 3.64 (dd, 77 = 6.9 Hz, J2 = 12.3 Hz, 1H), 3.54 (s, 3H), 3.40 (s, 3H), 3.38-3.35 (m, 2H), 2.29 (dt, Jl = 3 Hz, J2 = 12 Hz, 1H), 3.03 (dd, Jl = 7.8 Hz, J2 = 18 Hz, 1H), 2.77 (dd, J7 = 2.4 Hz, J2 = 16.2 Hz, 1H), 2.58-2.52 (m, 3H), 2.32 (s, 3H), 2.02 (s, 3H), 1.92-1.85 (m, 1H), 1.76-1.65 (m, 2H).

13C NMR (75 MHz, CDC13) 8 171.6,164.9,148.3,144.6,140.9,140.8,139.8,132.1,131.9, 131.1,130.0,128.2,126.0,125.0,124.6,123.5,120.1,117.5,113.0, 111.5,101.7,99.1,64.9, 59.7,58.9,57.7,56.6,56.4,55.2,55.1,41.5,40.2,39.9,37.7,30.9, 26.3,25.1,15.4,9.1.

ESI-MS m/z : Calcd. for C39H43ClN4O8: 730. 2. Found (M+1) + : 731. 1.

Example 127 To a solution of 130 (130 mg, 0.198 mmol) in CH2Cl2 (2 mL), chloropropionyl chloride (28. 35 µL, 0.297 mmol) and pyridine (24 pL, 0.297 mmol) were added at 0 °C.

The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2CI2 (10 mL) and washed with 0.1 N HC1 (7 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1: 1) to afford 133 (94 mg, 64 %) as a white solid.

Rf : 0.43 (Hex: EtOAc 1: 2).

'H NMR (300 MHz, CDC13) 8 7.23-7. 12 (m, 3H), 7.06-7.04 (m, 2H), 6.69 (s, 1H), 5.97 (s, 1H), 5.92 (s, 1H), 5.08 (d, Y= 6 Hz. 1H), 5. 00 (d, J= 6 Hz, 1H), 4.97 (m, 1 H), 4.16 (bs, 1H), 4.00 (m, 1H), 3.88 (t, J = 6. 9 Hz, 2H), 3.75 (t, J = 6.9 Hz, 2H), 3.59 (dd, Ji = 6.3 Hz, J2 = 12. 3 Hz, 1H), 3.53 (s, 3H), 3.37 (s, 3H), 3.03-3.26 (m, 1H), 3.17-2.97 (m, 3H), 2.83- 2.73 (m, 2H), 2.58-2.52 (m, 3H), 2.31 (s, 3H), 2.03 (s, 6H), 1.93-1.86 (m, 1H), 1.79-1.64 (m, 2H).

3C NMR (75 MHz, CDC13) 8 171.9,167.8,148.3,144.7,140.8,132.1,132.0,131.1,130.2, 128.2,126.1,125.2,124.6,123.7,122.2,120.2,117.6,114.7,112.9, 111.8,101.7,99.3,74.9, 65.0,59.6,59.0,57.7,56.7,56.4,55.4,55.1,41.5,38.5,37.8,37.2, 31.0,26.4,25.2,15.5, 9.3.

ESI-MS m/z: Calcd. for C40H4sClN408 : 744.2. Found (M+1) + : 745.0.

Example 128 To a solution of 130 (160 mg, 0.244 mmol) in CH2C12 (2 mL), heptafluorobutyryl chloride (54.5 L, 0.366 mmol) and pyridine (40 pL, 0.49 mmol) were added at 0 °C. The reaction mixture was stirred for 2 h and then, the solution was diluted with CH2CI2 (15 mL) and washed with 0.1 N HC1 (10 mL). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 2: 1 to Hex: EtOAc 1: 4) to afford 134 (120 mg, 63 %) as a white solid.

Rf : 0.40 (Hex: EtOAc 1: 2).

'H NMR (300 MHz, CDC13) 8 7.25-7.16 (m, 3H), 7.04-7.02 (m, 2H), 6.77 (s, 1H), 6.02 (d, J = 1. 5 Hz, 1H), 5.96 (d, J = 1.5 Hz, 1H), 5.11 (d, J = 6. 6 Hz, 1H), 4.95 (d, J = 6. 6 Hz, 1H), 4.94 (m, 1H), 4.58 (m, 1H), 4.25 (bs, 1H), 4.06 (bs, 1H), 3.88 (d, J = 6.9 Hz, 1H), 3.64 (dd, Jl = 7.5 Hz, J2 = 12.9 Hz, 1H), 3.55-3.53 (m, 1H), 3.49 (s, 3H), 3.38 (s, 3H), 3.17 (dd, J1 = 8. 1 Hz, J2 = 18. 9 Hz, 1H), 2.85 (d, J = 18.3 Hz, 1H), 2.77 (dd, Jl = 2. 7 Hz, J2 = 16.2 Hz, 1H), 2.60-2.57 (m, 3H), 2.56 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H), 1.96-1.88 (m, 1H), 1.79- 1.69 (m, 2H).

ESI-MS m/z : Calcd. for C4iH4tF7N40g : 850.7. Found (M+1) + : 851.3.

Example 129 To a solution of 131 (93 mg, 0.123 mmol) in CH2C12 (1 mL), trifluoroacetic acid (381 pL, 4.95 mmol) was added at 0 °C and the reaction mixture was stirred for 6 h at 23°C.

The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to give 135 (65 mg, 75 %) as a white solid which was used in following steps with no further purification. Rf : 0.26 (Hex: EtOAc 1: 1).

1H NMR (300 MHz, CDCl3) # 7.24-7.15 (m, 3H), 7.04-7.01 (m, 2H), 6.45 (s, 1 H), 6.03 (d, J= 1. 5 Hz, 1H), 5.97 (d, J = 1. 5 Hz, 1H), 5.62 (s, 1H), 4.97 (m, 1H), 4.09 (d, J = 1. 8 Hz, 1H), 4.03 (bs, 1H), 3.99 (d, J = 2.4 Hz, 1H), 3.73 (dd, Jl-7. 5 Hz, J2 = 12 Hz, 1H), 3.38 (s, 3H), 3.34-3.28 (m, 3H), 3.05 (dd, J1 = 8.4 Hz, J2 = 18.3 Hz, IH), 2.75 (dd, J1 = 3.3 Hz, J2 = 16.5 Hz, 1H), 2.60-2.47 (m, 3H), 2.30 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1.91-1.65 (m, 3H).

ESI-MS m/z : Calcd. for C37H37F3N407 : 706.2. Found (M+1) + : 707.2.

Example 130 To a solution of 132 (130 mg, 0.177 mmol) in CH2C12 (1 mL), trifluoroacetic acid (545 pL, 7.08 mmol) was added at 0 °C and the reaction mixture was stirred for 3.5 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to give 136 (118 mg, 97 %) as a white solid which was used in following steps with no further purification. Rf : 0.27 (Hex: EtOAc 1: 1).

'H NMR (300 MHz, CDC13) 8 7.23-7.13 (m, 3H), 7.06-7.03 (m, 2H), 6.45 (s, 1H), 5.98 (d, J = 1. 2 Hz, 1 H), 5.91 (d, J = 1.2 Hz, 1H), 5.04 (t, J= 4. 5 Hz, 1H), 4. 37 (bs, 2H), 4.13 (d, J = 2.1 Hz, 1H), 4.03 (bs, 2H), 3.68-3.61 (dd, J1= 7.2 Hz, J2 = 12.3 Hz 1H), 3.40 (s 3H), 3.37-3.28 (m, 3H), 3.02 (dd, J1 = 8.4 Hz, J2 = 18.6 Hz 1H), 2.75 (dd, Jl= 2. 7 Hz, J2= 15.9 Hz 1H), 2.58-2.50 (m, 3H), 2.32 (s, 3H), 2.01 (s, 6H), 1.94-1.67 (m, 3H). i3C NMR (75 MHz, CDCl3) 5 171.8,165.0,146.8,144.6,142.9,141.0,140.9,139.8,132.0, 130.3,129.4,128.5,128.3,126.0,120.8,120.1,117.4,116.1,113.0, 111.5,101.7,60.5,58.7, 56.3,56.2,55.2,55.0,41.5,40.4,39.5,37.7,31.0,29.6,26.4,25.3, 15.5,9.2.

ESI-MS m/z: Calcd. for C37H39C1N407 : 686.2. Found (M+1) + : 687.2.

Example 131 To a solution of 133 (94 mg, 0.126 mmol) in CH2C12 (1 mL), trifluoroacetic acid (385 pL, 5.0 mmol) was added at 0 °C and the reaction mixture was stirred for 2.5 h at 23°C.

The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to give 137 (118 mg, 97 %) as a white solid which was used in following steps with no further purification. Rf : 0.24 (Hex: EtOAc 1: 1).

'H NMR (300 MHz, CDC13) 6 7.25-7.14 (m, 3H), 7.05-7.03 (m, 2H), 6.44 (s, 1H), 5.98 (d, J= 1.5 Hz, 1H), 5.92 (d, J = 1.5 Hz, 1H), 5.82 (s, 1H), 5.20 (t, J= 4.8 Hz, 1H), 4.07 (d, J = 2.1 Hz, 1H), 5.82 (s, 1H), 5.20 (t, J = 4.8 Hz, 1H), 4.07 (d, J = 2. 1 Hz, 1H), 4.01 (bs, 1H), 3.98 (d, J = 2.4 Hz, 1H), 3.93-3.84 (m, 2H), 3.63 (ddd, Jl = 1. 5 Hz, J2 = 6.9 Hz, J3 = 12 Hz, 1H), 3.44 (bs, 3H), 3.37-3.26 (m, 3H), 3.11-3.06 (m, 2H), 3.01 (dd, J1 = 8. 4 Hz, J2 = 18.3 Hz, 1H), 2.80 (brd, J = 13.8 Hz, 1H), 2.58-2.47 (m, 3H), 2.29 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H), 1.93-1.68 (m, 3H).

3C NMR (75 MHz, CDC13) 6 171.7,168.0,146.7,144.6,142.8,142.1,141.0,140.8,140.1, 130. 7,129.0,128.2,126.0,122.2,120.9,116.7,114.7,113.1,111.7,102. 3,101.7,72.0,60.4, 59. 1,56.4,56.3,55.7,55.2,41.7,40.3,38.8,37.8,37.1,31.0,26.4,25. 2,15.5,9.4.

ESI-MS m/z: Calcd. for C38H41ClN4O7: 700.2. Found (M+23) + : 723.1.

Example 132 To a solution of 134 (46 mg, 0.054 mmol) in CH2C12 (1 mL), trifluoroacetic acid (166 pL, 2.16 mmol) was added at 0 °C and the reaction mixture was stirred for 10 h at 23°C.

The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to give 138 (35 mg, 80 %) as a white solid which was used in following steps with no further purification. Rf : 0. 26 (Hex: EtOAc 1 : 1).

'H NMR (300 MHz, CDC13) 8 7.23-7.12 (m, 3H), 7.04-7.01 (m, 2H), 6.45 (s, 1H), 6.03 (d, J = 1.5 Hz, 1H), 5.97 (d, J= 1.5 Hz, 1H), 5.64 (s, 1H), 4.98 (m, 1H), 4.09 (d, J = 2.1 Hz, 1H), 4.03 (bs, 1H), 3.98 (d, J = 2.4 Hz, 1H), 3.75 (dd, Jl-9. 6 Hz, J2 = 14. 1 Hz, 1H), 3.35 (s, 3H), 3.29-3.24 (m, 3H), 3.04 (dd, Jl= 7.8 Hz, J2 = 18.0 Hz, 1H), 2.74 (dd, Jl= 3.0 Hz, J2 = 16.8 Hz, 1H), 2.57-2.45 (m, 3H), 2.30 (s, 3H), 2.03 (s, 6H), 1.92-1.64 (m, 3H). ESI- MS m/z: Calcd. for C39H37F7N407 : 806.7. Found (M+1) + : 807.3.

Example 133 139 136 To a solution of 136 (45 mg, 0.065 mmol) in CH2C12 (0.3 mL), acetyl chloride (4.65 , uE, 0.065 mmol), and pyridine (5.2 ßL, 0.065 mmol) were added at 0 °C. The reaction mixture was stirred for 4 h and then, the solution was diluted with CH2CI2 (15 mL) and washed with 0. 1 N HC1 (7 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex: EtOAc 5: 1 to EtOAc) to afford 139 (27 mg, 57 %) as a white solid.

Rf : 0.36 (Hex: EtOAc 1: 2).

'H NMR (300 MHz, CDCl3) 8 7.26-7.14 (m, 3H), 7.07-7.04 (m, 2H), 6.84 (s, 1H), 6.00 (d, J= 1.2 Hz, 1H), 5.94 (d, J= 1.2 Hz, 1H), 4.94 (t, J= 5.1 Hz, 1H), 4.39-4. 38 (m, 2H), 4.02 (bs, 2H), 3.67 (d, J= 3 Hz, 1H), 3.60-3.54 (m, 1H), 3.47-3.35 (m, 3H), 3.42 (s, 3H), 3.26 (dt, J, = 4.8 Hz, J2 = 8. 7 Hz 1H), 3.02 (dd, J, = 8. 1 Hz, b = 18. 3 Hz, 1H), 2.64-2. 38 (m, 3H), 2.35 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H), 1. 95-1.69 (m, 3H).

ESI-MS m/z : Calcd. for C39H41ClN4O8 : 729.2. Found (M+23) + : 752.3.

Example 134 To a solution of 2 (15 mg, 0.0273 mmol) in CH2Cl2 (0.2 mL), acetyl chloride (1.94 pL, 0.0273 mmol), and pyridine (2.20 pL, 0.0273 mmol) were added at 0 °C. The reaction mixture was stirred for 20 minutes and then, the solution was diluted with CH2Cl2 (15 mL) and washed with 0. 1 N HC1 (5 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAcMeOH 5 : 1) to afford 140 (9 mg, 56 %) as a light yellow solid. Rf : 0. 56 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDCl3) # 6.52 (s, 1H), 6.40 (s, 1H), 5.73 (d, J= 7. 5 Hz, IH), 4.95 (d, J= 6.9 Hz, 1H), 4.20 (d, J= 1. 5 Hz, 1H), 4.00 (s, 3H), 3.86 (d, J= 4. 5 Hz, 1H), 3.79 (s, 3H), 3.78-3.77 (m, 1H), 3.40-3.35 (m, 2H), 3.24 (dt,, J, = 3.6 Hz, J2= 11. 4 Hz, 1H), 3.17 (d, J= 7.8 Hz, 1H), 3.11 (d, J= 7.5 Hz, 1H), 3.04 (dd, J, = 3.6 Hz, J2= 18.6 Hz, 1H), 2.92 (dt,, J, = 3.3 Hz, J2= 14. 1 Hz, 1H), 2.43 (d, J= 18. 0 Hz, 1H), 2.37 (s, 3H), 2.29 (s, 3H), 1.89 (s, 3H), 1.79 (s, 3H), 1.75 (dd, J1= 2.7 Hz, J2= 6.9 Hz, 1H), 0.99 (d, J= 7. 5 Hz, 3H).

ESI-MS m/z: Calcd. for C31H37NsO7 : 591.6. Found (M+1) + : 592.3.

Example 135 To a solution of 2 (15 mg, 0.0273 mmol) in CH2CI2 (0.2 mL), trifluoroacetyl anhydride (3.85 pL, 0.0273 mmol was added at 23 °C. The reaction mixture was stirred for 30 minutes and then, the solution was diluted with CH2CI2 (15 mL) and washed with 0.1 N HCI (5 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient EtOAc to EtOAcMeOH 4: 1) to afford 141 (12.1 mg, 69 %) as a light yellow solid. Rf : 0.73 (EtOAc: MeOH 5: 1).

'H NMR (300 MHz, CDC13) 5 6.90 (d, J= 6.6 Hz, 1 H), 6.56 (s, 1 H), 5.11 (d, J= 6. 6 Hz, 1 H), 4.47 (bs, 1H), 4.23 (bs, 1H), 3.97 (s, 3H), 3.93 (bs, 1H), 3.85-3.81 (m, 1H), 3.77 (s, 3H), 3.40-3-36 (m, 2H), 3.23 (dd, J, = 7.2 Hz, J2= 18.6 Hz, 1H), 3.13-3.08 (m, 3H), 1.86 (s, 3H), 1.74 (dd, Jazz 10.8 Hz, J2= 16.8 Hz, 1H), 1.07 (d, J= 6. 9 Hz, 3H).

ESI-MS m/z: Calcd. for C3lH34F3NsO7 : 645.6. Found (M+1) + : 646. 3.

Example 136 UMe OMe HO Me AcO Ac0 Me Me N-Boc-Phenylalanine N--Me Mye N N--Me DIPEA, DMAP 0 N Z- \-O C -O CN EDC. HCI, CH2CI2 NH2 N, Boc 45 Ph 174 To a solution of 45 (30 mg, 0.058 mmol) in CH2Cl2 (0.87 mL), DIPEA (15.0 mL, 0.086 mmol), EDC-HC1 (27.6 mg, 0.145 mmol), N-Boc-Phenylalanine (22.9 mg, 0.086mmol) and DMAP (0.7 mg, 0.006 mmol) were added at room temperature and the reaction mixture was stirred for 4h. Then, the solution was diluted with CH2CI2 (10 mL) and washed successively with 0.1 N HCI (5 mL) and a solution of 10% NaHC03 (5 ml).

The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1: 2) to afford 174 (17 mg, 38%) as a white solid.

Rf = 0.35 Hex : AcOEt 1: 2.

'H NMR (300 MHz, CDC13) 7.24-7.15 (m, 3H), 7.05-7.02 (m, 2H), 6.43 (s, 1H), 5.88 (s, 1H), 5.78 (s, 1H), 5.64 (s, 1H), 5.63 (bs, 1H), 4.80 (bs, 1H), 3.98 (s, 1H), 3.85 (bs, 2H), 3.75 (bs, 1H), 3.58 (bs, 1H), 3.53 (bs, 3H), 3.38 (m, 1H), 3.17-3.10 (m, 3H) 2.90 (dd, J, = 8.7 Hz, J2 = 17-7 HZ, 1H), 2.73 (d, J= 14.4 Hz, 1H), 2.57 (m, 1H), 2.43-2.37 (m, 1H), 2.25 (s, 3H), 2.24 (s, 3H), 2.10 (s, 3H), 1.94 (s, 3H), 1.76 (dd, J, = 12.3 Hz, J2 = 15.6 Hz, 1H), 1.19 (bs, 9H). 13C NMR (75 MHz, CDCl3) 171.2,168.8,146.6,144.6,142.8,140.6,137.0,130.7, 129.5,129.0,128.4,126.8,121.1,121.0,117.8,116.7,113.3,111.8, 101.5,60.5,59.7,57.0, 56.4,55.3,41.9,41.6,38.7,31.6,29.7,28.2,26.5,25.2,22.6,20.3, 15.7,14.1,9.3.

ESI-MS m/z: Calcd. for C42H49N509 : 767.87. Found (M+1) + : 768.3.

Example 137 OMe OMe HO sAt Me Ace Me AcO I Me N--Me I N--Me N-Boc-Valine o N I /N DIPEA, DMAP NH 0 nu 0 < CN EDC. HCI, CH2CI2 H NH2 OY'Boc 45 175 To a solution of 45 (30 mg, 0.058 mmol) in CH2CI2 (0.87 mL), DIPEA (15.0 mL, 0.086 mmol), EDC#HCl (27.6 mg, 0.145 mmol), N-Boc-Valine (18.8 mg, 0.086 mmol) and DMAP (0.7 mg, 0.006 mmol) were added at room temperature and the reaction mixture was stirred for 4 h. Then, the solution was diluted with CH2C12 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1: 2) to afford 175 (18 mg, 43%) as a white solid.

Rf = 0.25 Hex: EtOAc 1: 1.

'H NMR (300 MHz, CDCl3) 8 6.42 (s, 1H), 5.97 (s, 1H), 5.82 (s, 1H), 5.73 (bs, 1H), 5.50 (bs, 1H), 4.82 (bs, 1H), 4.15 (bs, 1H), 4.03 (bs, 1H), 3.96 (bs, 1H), 3.72 (s, 3H), 3.61 (m, 1H), 3.41-3.15 (m, 3H), 2.96 (dd, J, = 8.4 Hz, J2 = 18.3 Hz, 1H), 2.72 (d, J = 16. 5 Hz, 1H), 2.53 (d, J= 18 Hz, 1H), 2.25 (s, 3H), 2.21 (s, 3H), 1.93 (s, 3H), 1.81 (dd, J, = 14.1 Hz, J2 = 14.7 Hz, 1H), 1.34 (s, 9H), 0.83-0.76 (m, 2H), 0.61 (d, J= 6. 3 Hz, 3H), 0.54 (d, J= 6.3 Hz, 3H).

3C NMR (75 MHz, CDCI3) 8 171.6,168.7,155.4,146.8,144.5,142.9,140.7,130.7,128.8, 121.0,120.6,117.7,116.8,113.3,111.9,101.4,60.6,60.0,59.3,57. 2,56.3,55.2,41.7,29.7, 29.3,28.2,26.2,25.2,22.6,20.3,18.9,17.7,15.7,14.1,9.3.

ESI-MS m/z: Calcd. for C38H49N509 : 719.82. Found (M+1) + : 720.3.

Example 138 45 176 To a solution of 45 (38 mg, 0.073 mmol) in CH2Cl2 (1.09 mL), DIPEA (19.0 mL, 0.109 mmol), EDC-HCI (34.9 mg, 0.182 mmol), N-Boc-Proline (23.5 mg, 0.109 mmol) and DMAP (0.8 mg, 0.007 mmol) were added at 23 °C and the reaction mixture was stirred for 4. 5 h. Then, the solution was diluted with CH2CI2 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1: 1) to afford 176 (33 mg, 63%) as a white solid.

Rf = 0. 14 Hex : EtOAc 1 : 2.

'H NMR (300 MHz, CDC13) 8 6.49 (s, 1H), 6.02 (bs, 1H), 5.90 (s, 1H), 5.74 (s, 1H), 4.19 (bs, 1H), 4.09 (bs, 1H), 3.98 (bs, 1 H), 3.76 (s, 3H), 3. 38 (d, J = 6 Hz, 2H), 3.22 (d, J = 11. 7 Hz, 1H), 3.15-2.99 (m, 2H), 2.80 (d, J= 15.3 Hz, 1H), 2.63-2.58 (m, 1H), 2.32 (s. 3H), 2.26 (s, 6H), 1.99 (s, 3H), 1.78-1.62 (m, 1H), 1.50-0.83 (m, 7H), 1. 21 (s, 9H).

ESI-MS m/z: Calcd. forC3gH47N50g : 717.81. Found (Mi 718.3.

Example 139 To a solution of 45 (50 mg, 0.144 mmol) in CH2CI2 (0.96 mL), DIPEA (41.8 mL, 0.240 mmol), EDC-HCI (46.0 mg, 0.240 mmol), N-Boc-Arginine hidrochloride hydrate (47.2 mg, 0.144 mmol) and DMAP (1. 1 mg, 0.01 mmol) were added at 23 °C and the reaction mixture was stirred for 4 h. Then, the solvent was removed under vacuum and the residue was purified by flash column chromatography (Si02, Hex: EtOAc 1: 2) to afford 177 (58 mg, 78%) as a white solid.

Rf = 0.40 MeOH: EtOAc 1: 5.

'H NMR (300 MHz, CDC13) 8 7.53 (bs, 1H), 6.95 (bs, 3H), 6.54 (bs, 1H), 6.48 (s, 1H), 6.07 (s, 1H), 6.00 (bs, 1H), 5.88 (s, 1H), 5.11 (bs, 1H), 4.23 (s, 1H), 4.08 (s, 1H), 4.02 (s, 1H), 3.76 (s, 3H), 3.70 (bs, 1H), 3.48 (bs, 1H), 3.37 (d, J = 6.9 Hz, 1H), 3.18 (d, J= 10.2 Hz, 1H), 3.00-2.94 (m, 3H), 2.82-2.70 (m, 2H), 2. 34 (s, 3H), 2.25 (s, 6H), 1.99 (s, 3H), 1.73 (brt, J= 14.1 Hz, 1H), 1.40 (s, 9H), 1.25 (bs, 3H), 0.95-0.85 (m, 2H).

ESI-MS m/z: Calcd. for C39H52N8O9: 776. 88. Found (M+1) + : 777.3.

Example 140 To a solution of 45 (50 mg, 0.096 mmol) in CH2Cl2 (1.44 mL), DIPEA (25.8 mL, 0.144 mmol), EDC-HC1 (46.0 mg, 0.240 mmol), N-Boc-Tryptophan (43.8 mg, 0.144 mmol) and DMAP (1.2 mg, 0.009 mmol) were added at 23 °C and the reaction mixture was stirred for 4 h. Then, the solution was diluted with CH2CI2 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1 : 2) to afford 178 (57 mg, 74%) as a white solid.

Rf = 0. 12 Hex : EtOAc 1: 1.

'H NMR (300 MHz, CDCl3) 5 8.50 (bs, 1H), 7.73-7.71 (m, 1H), 7.13-7.12 (m, 3H), 6.51 (s, 1H), 5.72 (s, 1H), 5. 36 (bs, 1H), 5.28 (bs, 1H), 4.95 (bs, 1H), 4.41 (bs, 1H), 4.05 (s, 1H), 3.70 (s, 3H), 3.50 (bs, 2H), 3.30-3.17 (m, 4H), 2.89-2.82 (m, 3H), 2.40 (s, 3H), 2.29 (s, 3H), 2.19 (s, 3H), 2.03 (s, 3H), 1.49 (s, 9H), 1.26-1.25 (m, 2H).

ESI-MS m/z: Calcd. for C44H5oN609 : 806. 90. Found (M+1) + : 807.3.

Example 141 To a solution of 178 (43 mg, 0.053 mmol) in CH3CN/H20 (3 mL/2 mL), AgN03 (271 mg, 1.60 mmol) was added and the reaction was stirred at 23°C for 17 h. Then, Aq sat NaCl (10 mL) and Aq sat NaHC03 (10 mL) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (20 mL). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (SiOz, EtOAc : MeOH 5 : 1) to afford 179 (24 mg, 56%) as a white solid.

Rf= 0.38 EtOAc: MeOH 5: 1.

IHNMR (300MHz, CDCl3) o 8.40 (s, 1 H), 7.66 (bs, IH), 7.25-7.21 (m, 1H), 7. 16-7.09 (m, 2H), 6.45 (s, 1H), 5.75 (bs, 1H), 5.55 (bs, 1H), 5.45 (s, 1H), 5.25 (bs, 1H), 4.36 (bs, 1H), 4.16 (bs, 1H), 4.05 (bs, 1H), 3.95 (s, 1H), 3.69 (s, 3H), 3.35-3.02 (m, 6H), 2.83-2.73 (m, 3H), 2.35 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.99 (s, 3H), 1.77 (dd, J = 12 Hz, J) = 15.3 Hz 1H).

ESI-MS m/z: Calcd. for C43H5lN5010 : 797.89. Found (M-17) + : 780.

Example 142 To a solution of 45 (50 mg, 0.0960 mmol) in CH2CI2 (0. 7 mL), 2-Chloronicotinoyl chloride (17.7 mg, 0.101 mmol) and pyridine (8. lmL, 0.101 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2CI2 (5 mL) and washed with 0. 1 N HC1 (3 mL). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1: 1) to afford 180 (45 mg, 71%) as a white solid.

Rf = 0. 18 Hex : EtOAc 1 : 2.

'H NMR (300 MHz, CDC13) 8 8.32-8.29 (m, 1H), 7.38-7.34 (m, 1H), 7.14-7.09 (m, 1H), 6.14 (s, 1H), 5.97 (d, J= 1.2 Hz, 1H), 5.92-5.91 (m, 2H), 5.75 (d, J = 2. 1 Hz, 1H), 4.18 (d, J = 2.1 Hz, 1H), 4.15 (s, 1H), 4.07 (s, 1H), 3.91-3.73 (m, 2H), 3.68 (s, 3H), 3.36 (d, J= 7.5 Hz, 1H), 3.31 (dt, JI=2. 4Hz, J2= 11.7 Hz, 1H), 2.92 (dd, J1 = 8. 1 Hz, J2= 18Hz, lH), 2.80 (d, J= 16.2 Hz, 1H), 2.58 (d, J= 18 Hz, 1H), 2. 31 (s, 3H), 2.27 (s, 3H), 1.99 (s, 3H), 1.91 (s, 3H) 1.97-1.83 (m, 1H).

13 NMR (75 MHz, CDC13) 6 168.6,164.8,150.3,147.2,146.5,144.6,142.5,140.6,139.0, 130.9,130.5,128.8,122.3,120.8,120.3,117.6,116.3,112.7,112.1, 101.6,60.6,58.8,56.5, 56.3,55.6,55.1,41.6,39.8,31.5,26.2,24.9,20.3,15.5,9.3.

ESI-MS m/z: Calcd. for C34H34ClNsO7 : 659.2. Found (M+1) + : 660.1.

Example 143 To a solution of 180 (39 mg, 0.059 mmol) in CH3CN/H20 (3 mL/2 mL), AgN03 (301mg, 1.77 mmol) was added and the reaction was stirred at 23°C for 17 h. Then, Aq sat NaCl (10 mL) and Aq sat NaHC03 (10 mL) solutions were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2CI2 (20 mL).

The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, EtOAc: MeOH 5: 1) to afford 181 (28 mg, 73%) as a white solid.

Rf= 0.24, EtOAc: MeOH 5: 1.

'H NMR (300 MHz, CDC) 5 8.33-8.31 (m, 1H), 7.40-7.35 (m, 1H), 7.16-7.09 (m, 2H), 6.20 (s, 1H), 5.98 (d, J = 1.2 Hz, 1H), 5.96 (s, I H), 5.92 (d, J = 1.2 Hz, IH), 5.63 (bs, 1H), 4.60 (bs, 1H), 4.47 (bs, 1H), 4.02-3.95 (m, 2H), 3.69 (s, 3H), 3.65-3.56 (m, 1H), 3.48 (s, 3H), 3.43-3.38 (m, 1H), 3.17 (brd, J= 7.2 Hz, 1H), 2.88 (dd, J, = 8.7 Hz, J2 = 18.3 Hz, 1H), 2.74 (d, J= 15.3 Hz, 1H), 2.40 (d, J= 18. 3 Hz, 1H), 2.32 (s, 3H), 2.26 (s, 3H), 2.00, (s, 3H), 1.99 (s, 3H), 1.77 (dd, JI = 12 Hz, J2 = 15 Hz, 1H).

'3C NMR (75 MHz, CDC13) õ 168.1,165.0,150.0,147.2,146.5,144.4,142.5,140.9,138.7, 131.5,130.2,128.9,122.3,121.1,120.7,116.1,114.4,111.4,101.5, 82.6,60.6,57.8,56.2, 52.1,41.6,31.5,26.4,24.5,22.6,20.3,15.6,14.1,9.3.

ESI-MS m/z: Calcd. for C33H35ClN408 : 650.2 Found (M-17) + : 633.3.

Example 144 To a solution of 45 (30 mg, 0.058 mmol) in CH2Cl2 (0.87 mL), DIPEA (15.0 mL, 0.086 mmol), EDC-HCI (27.6 mg, 0.145 mmol), cyclohexylacetic acid (12.2 mg, 0.086 mmol) and DMAP (0.7 mg, 0.006 mmol) were added at 0°C and the reaction mixture was stirred for 5 h. Then, the solution was diluted with CH2C12 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1: 2) to afford 182 (10 mg, 27%) as a white solid.

Rf = 0. 11 Hex : EtOAc 1 : l.

'H NMR (300 MHz, CDC13) 8 6.50 (s, 1H), 5.98 (d, J= 1.2 Hz, 1H), 5.91 (d, J= 1.2 Hz, 1H), 5.75 (s, 1H), 5.02-4.91 (m, 1H), 4.11 (bs, 1H), 4.04 (d, J= 2.1 Hz, 1H), 4.01 (bs, 1H), 3.78 (s, 3H), 3.72-3.69 (m, 1H), 3.38-3.29 (m, 3H), 3.05 (dd, JI=7. 8Hz, J2-18. 0Hz, IH), 2.77 (d, J= 15.6 Hz, 1H), 2.54 (d, J= 18. 6 Hz, 1H), 2.33 (s, 3H), 2.32 (s, 3H), 2.27 (s, 3H), 1.98 (s, 3H), 1.79 (dd, J1 = 11.7 Hz, J2 = 15.6 Hz, I H), 1. 59-0.61 (m, 13H).

ESI-MS m/z: Calcd. for C36H44N407 : 644.76. Found (M+1) + : 645.3.

Example 145 To a solution of 45 (30 mg, 0.058 mmol) in CH2C12 (0.87 mL), DIPEA (15.0 mL, 0.086 mmol), EDC-HC1 (27.6 mg, 0.145 mmol), cyclohexylacetic acid (12.2 mg, 0.086 mmol) and DMAP (0.7 mg, 0.006 mmol) were added at 0°C and the reaction mixture was stirred for 5 h. Then, the solution was diluted with CH2C12 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1: 2) to afford 183 (17 mg, 38%) as a white solid.

Rf = 0. 13 Hex : EtOAc 1: 1.

H NMR (300 MHz, CDC13) 8 6.87 (s, 1H), 5.99 (d, J = 1.2 Hz, I H), 5.92 (d, J= 1.2 Hz, 1H), 4.95 (t, J= 5.7 Hz, 1H), 4.08 (bs, 1H), 4.00 (bs, 1H), 3.71 (s, 3H), 3. 64 (d, J= 1.8 Hz, 2H), 3.38 (d, J= 6.6 Hz, 1H), 3.33-3.32 (m, 1H), 3.27 (d, J= 11. 7 Hz, 1H), 3.06 (dd, J, = 7.8 Hz, J2 = 18.0 Hz, 1H), 2.65-2.59 (m, 1H), 2.50-2.47 (m, 1H), 2.35 (s, 3H), 2.27 (s, 6H), 1.99 (s, 3H), 1.78-1.74 (m, 1H) 1.60-0.62 (m, 26H).

ESI-MS m/z : Calcd. for C44H56N408 : 768.94. Found (M+1) + : 769.3.

Example 146 To a solution of 45 (30 mg, 0.058 mmol) in CH2C12 (0.87 mL), DIPEA (15.0 mL, 0.086 mmol), EDC#HCl (27.6 mg, 0.145 mmol), cyclohexylpropionic acid (13.5 mg, 0.086 mmol) and DMAP (0.7 mg, 0.006 mmol) were added at 0°C and the reaction mixture was stirred at 23 °C for 6 h. Then, the solution was diluted with CH2CI2 (10 mL) and washed successively with 0.1 N HCI (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1: 2) to afford 184 (15 mg, 39%) as a white solid.

Rf = 0.15 Hex: EtOAc 1: 1.

'H NMR (300 MHz, CDC13) 8 6.50 (s, 1H), 5.98 (s, 1H), 5.91 (s, 1H), 5.74 (s, 1H), 5.01 (t, J= 5.1 Hz, 1H), 4.09 (bs, 1H), 4.06 (s, 1H), 4.02 (bs, 1H), 3.76 (s, 3H), 3.64-3.58 (m, 1H), 3.42-3.41 (m, 1H), 3.36 (d, J= 7.5 Hz, 1H), 3.28 (d, J= 12.3 Hz, 1H), 3.05 (dd, J, = 8.6 Hz, J2 = 18 Hz, 1H), 2.79 (d, J= 14.7 Hz, 1H), 2.57 (d, J= 18 Hz, 1H), 2.32 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H), 1.99 (s, 3H), 1.77 (dd, J1 = 12. 0 Hz, J2 = 15. 9 Hz, IH), 1. 62-0. 71 (m, 15H). ESI-MS m/z : Calcd. for C37H46N407 : 658.78. Found (M+1) + : 659.3.

Example 147 To a solution of 45 (30 mg, 0.058 mmol) in CH2C12 (0.87 mL), DIPEA (15.0 mL, 0.086 mmol), EDC-HCI (27.6 mg, 0.145 mmol), cyclohexylpropionic acid (13.5 mg, 0.086 mmol) and DMAP (0.7 mg, 0.006 mmol) were added at 0°C and the reaction mixture was stirred for 6 h. Then, the solution was diluted with CH2C12 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1: 2) to afford 185 (21 mg, 46%) as a white solid.

Rf = 0. 17 Hex : EtOAc 1 : 1.

1H NMR (300 MHz, CDC13) 8 6.86 (s, 1H), 5.99 (s, 1H), 5.92 (s, 1H), 4.97 (t, J= 5. 4 Hz, 1H), 4.10 (d, J= 2. 4 Hz, 1H), 4.01 (bs, 1H), 3.70 (s, 3H), 3.64 (d, J= 2. 4 Hz, 1 H), 3.51 (bs, 1H), 3.37 (d, J= 8. 1 Hz, 1H), 3.23 (d, J = 11. 1 Hz, 1H), 3.02 (dd, J/=7. 8Hz, =I8Hz, 1H), 2.69-2.59 (m, 4H), 2.35 (s, 3H), 2.26 (s, 6H), 2.00 (s, 3H), 1.76-0.72 (m, 30H). t3C NMR (75 MHz, CDC13) 8 173.1,171.5,168.2,147.9,144.7,142.5,140.7,140.3,130.9, 130.6,127.7,123.3,120.0,117.5,113.1,111.9,101.6,60.5,59.0,57 .3,56.7,55.2,55.0, 41.6,39.9,37.2,33.5,33.0,32.9,32.9,32.8,32.5,32.4,31.9,31.7, 29.7,29.3,26.6,26.5, 26.2,24.9,20.3,15.8,14.1,9.4.

ESI-MS m/z: Calcd. for C46H60N4O8 : 796.4. Found (M+1) + : 797.5.

Example 148 To a solution of 72 (111 mg, 0.162 mmol) in CH2CI2 (0.81 mL), DIPEA (56.3 mL, 0.324 mmol), butyryl chloride (33.6 mL, 0.324 mmol) and DMAP (1. 96 mg. 0.016 mmol) were added at 0 °C and the reaction mixture was stirred for 5 h at this temperature. Then, the solution was diluted with CH2CI2 (10 mL) and washed successively with 0.1 N HCI (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN : H20 1: 1) to afford 186 (65.4 mg. 54%) as a white solid.

Rf = 0. 21 Hex: EtOAc 1 : 2.

1H NMR (300 MHz, CDC13) 8 7.24-7.15 (m, 3H), 7.12-7.04 (m, 2H), 6.84 (s, 1H), 5.98 (d, J = 1.2 Hz, 1H), 5.92 (d, J= 1.2 Hz, 1H), 4.97 (t, J= 5.7 Hz, 1H), 4.03 (m, 3H), 3.63 (d, J = 2.7 Hz, 1H), 3.50 (m, 2H), 3.44 (s, 3H), 3.37 (d, J= 8. 4 Hz, 1H), 3. 24 (dt, J, =27HZ, J2= 11.7 Hz, 1H), 3.02 (dd, J, = 8.1 Hz, J2 = 18.3 Hz, 1H), 2. 65-2.54 (m, 7H), 2.35 (s, 3H), 2.25 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 1.87-1.75 (m, 3H), 1.08 (t, J= 7.5 Hz, 3H).

3c NMR (75 MHz, CDC13) 6 171.7,170.8,168.2,147.8,144.7,142.5,140.8,140.6,140. 3, 131.1,130.5, 128.3, 128.2,127.6,126.0,123.2,117.5,112.9,111.8,101.6,60.2,59.0,57 .3, 56.6,55.1,54.9,41.5,39.9,37.8,36.0,31.0,26.5,24.8,22.6,20.2, 18.5,15.6,13.7,9.3.

ESI-MS m/z: Calcd. for C4lH46N408 : 722.83. Found (M+1) + : 723.2.

Example 149 To a solution of 72 (80 mg, 0.122 mmol) in CH2Cl2 (0.61 mL), DIPEA (64.0 mL, 0.367 mmol), hexanoyl chloride (49.5 mL, 0. 367mmol) and DMAP (1.50 mg, 0.012 mmol) were added at 0 °C and the reaction mixture was stirred at this temperature for 5h.

Then, the solution was diluted with CH2C12 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN : H20 6: 4) to afford 187 (86.1 mg, 94%) as a white solid.

Rf = 0.25 Hex: EtOAc 1: 2 'H NMR (300 MHz, CDC13) 5 7.20-7.06 (m, 3H), 6.99-6.97 (m, 2H), 6.77 (s, IH), 5.91 (s, 1H), 5.85 (s, 1H), 4.90 (m, 1H), 3.96 (d, J = 3 Hz, 2H), 3.57-3.55 (m, 1H), 3.43 (bs, 2H), 3.36 (bs, 3H), 3.29 (brd, J= 10.5 Hz, I H), 3.18 (d, J = 11.7 Hz, I H), 2.97 (dd, J, = 4.8 Hz, J2 = 12 Hz, 1H), 2.58-2.46 (m, 6H), 2.28 (s, 3H), 2.18 (s, 3H), 2.00 (s, 3H), 1.95 (s, 3H), 1.86- 1.66 (m, 7H), 1.41-1.38 (m, 2H), 0.86-0.81 (m, 3H).

3C NMR (75 MHz, CDC13) 6 171.7,171.0,168.2,147.8,144.7,142.5,140.8,140.6,140. 3, 131.1,130.5,128.3,128.2,127.6,126.0,117.5,112.9,111.8,101.6, 60.2,59.0,57.3,56.6, 55.1,55.0,41.5,39.9,37.8,34.1,31.3,31.1,29.6,24.8,24.7,22.3, 20.2,15.6,13.8.

ESI-MS m/z: Calcd. for C43HsoN408 : 750.88. Found (M+1) + : 751.3.

Example 150 To a solution of 85 (80 mg, 0. 110 mmol) in CH2Cl2 (0.55 mL), DIPEA (57.7 mL, 0.331 mmol), butyryl chloride (34.4 mL, 0.331mmol) and DMAP (1.30 mg, 0. 011 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 5 h. Then, the solution was diluted with CH2C12 (10 mL) and washed successively with 0.1 N Hic1 (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN : H20 1: 1) to afford 188 (70.1 mg, 80%) as a white solid.

Rf= 0.54 MeOH: EtOAc 1: 5.

'H NMR (300 MHz, CDC13) 8 7.28-7.14 (m, 5H), 6.80 (s, 1H), 6.07 (d, J= 6.6 Hz, 1H), 6.00 (d, J= 1. 5 Hz, 1H), 5.90 (d, J= 1. 5 Hz, 1H), 5.35 (t, J = 5. 4 Hz, 1H), 4.12 (d, J = 2. 4 Hz, 1H), 4.05 (bs, 1H), 3.89 (brt, J= 6.9 Hz, 1H), 3.66 (s, 3H), 3.64-3.63 (m, 1H), 3.59-3.45 (m, 2H), 3.40 (brd, J= 7.8 Hz, 1H), 3.20 (dt, J, = 2.7 Hz, J2 = 12 Hz, 1H), 3.00 (dd, J, = 8.1 Hz, J2 = 18 Hz, 1H), 2.87 (t, J = 8. 1 Hz, 2H), 2.71 (d, J = 18. 6 Hz, 1H), 2.66-2.61 (m, 1H), 2.58 (t, J= 7.2 Hz, 2H), 2.41-2.35 (m, 2H), 2.33 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 2.00 (s, 3H), 1.90-1.77 (m, 3H), 1.08 (t, J= 7.2 Hz, 3H), 0.69 (d, J= 6.9 Hz, 3H).

13C NMR (75 MHz, CDCl3) 8 172.0,171.3,170.8,168.5,147.7,144.7,142.5,140.6,140.5, 140.3,131.0,130.7,128.4,128.2,127.7,126.1,123.1,120. 3,117.5,112.7,111.8,101.6, 60.3,59.1,57.3,57.2,55.4,54.9,48.2,41.5,39.5,38.0,36.0,31.4, 26.8,26.6,24.6,20.1, 18. 5,18.1,15.7,13.7,9.2.

ESI-MS m/z: Calcd. for C « HslNsO9 : 793.9. Found (M+1) + : 794.3.

Example 151 85 189 To a solution of 85 (80 mg, 0.110 mmol) in CH2C12 (0.55 mL), DIPEA (57.7 mL, 0.331 mmol), hexanoyl chloride (46.3 mL, 0. 331mmol) and DMAP (1.30 mg, 0. 011 mmol) were added at 0 °C and the reaction mixture was stirred at 23°C for 5 h. Then. the solution was diluted with CH2Cl2 (10 mL) and washed succesively with 0.1 N HCl (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by column chromatography (RP-18, CH3CN: H20 1: 1) to afford 189 (80 mg, 88%) as a white solid.

Rf = 0.23 Hex: EtOAc 1 : 3.

'H NMR (300 MHz, CDC13) 8 7.21-7.08 (m, 5H), 6.74 (s, 1H), 6.00 (d, J = 6.9 Hz, 1H), 5.94 (d, J= 1.5 Hz, 1H), 5.84 (d, J= 1.5 Hz, 1H), 5.24 (t, J = 5.4 Hz, 1H), 4.06 (bs, 1H), 4.00 (bs, 1H), 3.83 (t, J= 6 Hz, 1H), 3.59 (s, 3H), 3.57 (m, 1H), 3.53-3.40 (m, 2H), 3.33 (d, J = 7.8 Hz, 1H), 3.14 (d, J= 11. 7 Hz, 1H), 2.94 (dd, J, = 8.4 Hz, J2 = 18 Hz, 1H), 2.81 (t, J= 7.5 Hz, 2H), 2.65 (d, J= 18 Hz, 1H), 2.60-2.54 (m, 1H), 2.52 (t, J= 7.2 Hz, 2H), 2.35-2.29 (m, 2H), 2.27 (s, 3H), 2.17 (s, 3H), 2.15 (s, 3H), 1.95 (s, 3H), 1.76-1.60 (m, 3H), 1. 35-1.29 (m, 2H), 1.84 (m, 2H), 0.85-0.78 (m, 3H), 0.62 (t, J= 6.6 Hz, 3H).

13C NMR (75 MHz, CDCl3) # 172.0,171.3,171.1,168.4,147.8,144.8,142.6,140.7,140.5, 131.2,130.6,128.4,128.3,127.7,126.2,123.1,120. 3,117.5,112.6,112.0,101.7,60.4,59.1, 57.4,57.2,55.4,54.9,48.3,41.5,39.6,38.1,34.1,33.6,31.5,31.3, 26.7,24.7,22.3,20.2, 18. 2,15.7,13.9,9.3.

ESI-MS m/z: Calcd. for C46Hs5Ns09 : 821.96. Found (M+1) + : 822.3.

Example 152 53 190 To a solution of 53 (100 mg, 0.145 mmol) in CH2C12 (0.72 mL), DIPEA (50.6 mL, 0.291 mmol) and acetyl chloride (20.7 mL, 0.291 mmol) were added at 0 °C and the reaction mixture was stirred for 4 h at 23 °C. Then, the solution was diluted with CH2C12 (10 mL), and washed successively with 0.1 N HCI (5 mL), and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1: 2) to afford 190 (27 mg, 25%) as a white solid.

Rf = 0.24 Hex: EtOAc 1: 1.

'H NMR (300MHz, CDCl3) 8 6.82 (s, 1H), 6.02 (d, J= 0.9 Hz, 1H), 5.92 (d, J= 0.9 Hz, 1H), 5.30 (bs, 1H), 4.14 (d, J= 2. 7 Hz, 1H), 4.10 (s, 1H), 3.90-3.73 (m, 2H), 3.68 (s, 3H), 3.67 (bs, 1H), 3.49 (bs, 1H), 3.42 (brd, J= 8.1 Hz, 1H), 3.24-3.20 (m, 1H), 3.01 (dd, J1 = 8.4 Hz, J2 = 18.3 Hz, 1H), 2.78 (d, J= 18 Hz, 1H), 2.64 (brd, J= 15.6Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 2.02 (s, 3H), 1. 77 (dd, J, = 11.7 Hz, J2 = 15.6 Hz, 1H), 0.65 (d, J= 6. 6 Hz, 3H).

13 NMR (75 MHz, CDC13) 8 170.2,168.6,168.1,167.6,147.9,144.9,142.8,140.5,131.5, 131.0,127.7,123.2,120.3,117.5,112. 3,112.2,101.7,60.4,59.0,57.4,57.2,55.2,54.9, 48.6,41.5,39.1,36.6,29.7,26.7,24.6,20.7,20.2,17.6,15.5,9.2.

ESI-MS m/z: Calcd. for C3sH3sF3NsOg : 729.70. Found (M+l) + : 730.3.

Example 153 To a solution of 53 (150 mg, 0.218 mmol) in CH2CI2 (1.09 mL). DIPEA (151.9 mL, 0.87 mmol), butyryl chloride (90.6 mL, 0.87 mmol) and DMAP (2.70 mg, 0.02 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h.. Then, the solution was diluted with CH2C12 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN: H20 4: 1) to afford 191 (20.2 mg, 12%) as a white solid.

Rf = 0. 3 Hex : EtOAc 1 : 1.

1H NMR (300 MHz, CDC13) 8 6.81 (s, 1H), 6.03 (d, J= 1.2 Hz, 1H), 5.92 (d, J= 1.2 Hz, 1H), 5. 16 (t, J= 5.4 Hz, 1H), 4.13 (d, J= 2.1 Hz, 1H), 4.10 (bs, 1H), 3.87-3.82 (m, 1H), 3.80-3.74 (m, 1), 3.68 (s, 3H), 3.64 (d, J = 3 Hz, 1H), 3.52-3.47 (m, 1H), 3.42 (brd, J = 7.2 Hz, 1H), 3.24-3.20 (m, 1H), 3.02 (dd, J1 = 8.1 Hz, J2 = 18.3 Hz, 1H), 2.77 (d, J = 17. 7 Hz, 1H), 2.64 (brd, J= 16.2 Hz, 1H), 2.58 (t, J= 7.2 Hz, 2H), 2.33 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H), 2.02 (s, 3H), 1.87-1. 73 (m, 3H), 1.08 (t, J= 7.2 Hz, 3H), 0.68 (d, J= 6.6 Hz, 3H).

13C NMR (75 MHz, CDC13) 8 172.8,172.1,170.4,157. 8, 150.0,146.9,144.8,142.6,142.5, 133. 3,132.8,129.6,125.3,122.3,119.5,118.4,115.7,114.3,114.2,103. 8,62.4,61.0,59.4, 59. 2,57.2,57.0,50.6,43.6,41.2,38.1,31.7,28.7,26.6,22.2,20.6,19. 7,17.5,15.7,11.2.

ESI-MS m/z: Calcd. for C37H42F3N509 : 757. 75. Found: 758.5 (M+1) +, 780.5 (M+23) +.

Example 154 53 192 To a solution of 53 (150 mg, 0.218 mmol) in CH2C12 (1. 09 mL), DIPEA (151.9 mL, 0.87 mmol), acetyl chloride (62.0 mL, 0.87 mmol) and DMAP (2.70 mg, 0.02 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 5 h. Then, the solution was diluted with CH2C12 (10 mL) and washed successively with 0.1 N HCI (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2SO4^ filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN: H20 1: 1) to afford 192 (111 mg, 62%) as a white solid.

Rf = 0.25 Hex: EtOAc 1: 1.

'H NMR (300 MHz, CDC13) 8 6.80 (s, 1H), 5.87 (s, 1H), 5.81 (s, 1H), 4.70 (dd, J, = 2.4 Hz, J2 = 9.9 Hz, 1H), 4.20 (d, J= 6.3 Hz, 1H), 4.09 (s, 1H), 3.74 (s, 3H), 3.60 (s, 1H), 3.28 (d, J = 7.5 Hz, 1H), 3.17 (d, J= 12 Hz, 1H), 3.07 (dd, J, = 7.2 Hz, J2 = 18.3 Hz, 1H), 2.93 (d, J= 13.2 Hz, 1H), 2.66 (d, J= 15. 3 Hz, 1H), 2.53 (d, J= 17.7 Hz, 1H), 2.47-2.20 (m, 1H), 2.37 (s, 1H), 2.33 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 1.96 (s, 3H), 1.72 (t, J= 14.4 Hz, 1H), 1.53 (d, J= 6.9 Hz, 3H).

13C NMR (75 MHz, CDC13) 6 174.1,168.6,168.4,167.5,147.7,144.8,142.2,140.4,131.1, 130.5,126.9,123.3,120.4,117.5,112.4,111.8,101.1,60.7,60.6,57 .6,57.2,56.6,55.3, 52.7,48.3,41.5,31.6,29.7,26.4,25.5,23.0,22.6,20.7,20.5,20.2, 17.8,15.9,14.1,9.5. ESI-MS m/z : Calcd. for C39H42F3Nsoll : 813.7. Found (M+1) + : 814.3.

Example 155 53 193 To a solution of 53 (150 mg, 0.218 mmol) in CH2CI2 (1.09 mL), DIPEA (151.9 mL, 0.87 mmol), butyryl chloride (90.6 mL, 0.87 mmol) and DMAP (2. 70 mg, 0.02 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h. Then, the solution was diluted with CH2CI2 (10 mL) and washed successively with 0. 1 N HCI (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN: H20 4: 1) to afford 193 (58 mg, 30%) as a white solid.

Rf = 0. 38 Hex : EtOAc 1 : 1.

'H NMR (300 MHz, CDC13) 8 6.85 (s, 1 H), 5.99 (d, J= 1.2 Hz, 1H), 5.90 (d, J = 1.2 Hz, 1H), 5.47-5.42 (m, 2H), 4.09-4.08 (m, 2H), 3.69 (s, 3H), 3.66 (m, 1H), 3.41 (d, J= 7.5 Hz, 1H), 3.28-3.18 (m, 2H), 3.07 (dd, J, = 8.1 Hz, J2 = 18 Hz, 1H), 2.66 (d, J = 18. 6 Hz, 1H), 2.61-2.39 (m, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.01 (s, 3H), 1.95-1.79 (m, 6H), 1.72-1.59 (m, 6H) 1.09 (t, J= 7.5 Hz, 3H), 0.99-0. 94 (m, 6H), 0.85 (d, J= 6. 9 Hz, 3H).

3c NMR (75 MHz, CDC13) 6 171. 2,170.7,169.1,168.4,148.1,145.0,142.7,140.9,140.6, 131.2,130.5,128.4,123.4,119.9,117.6,113.0,112.1,101.9,60.7,5 9.5,57.6,56.5,55.7, 55.2,41.8,41.4,36.3,35.8,29.9,27.0,25.3,20.5,20.0,18.8,18.3, 15.8,14.0,13.8,13.4, 12. 7,9.6.

ESI-MS m/z: Calcd. for C45H54F3N5011 : 897.93. Found (M+1) + : 898. 3.

Example 156 To a solution of 53 (150 mg, 0.218 mmol) in CH2CI2 (1.09 mL). DIPEA (151.9 mL, 0.87 mmol), hexanoyl chloride (121.9 mL, 0.87 mmol) and DMAP (2.70 mg, 0.02 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h. Then, the solution was diluted with CH2CI2 (10 mL) and washed successively with 0. 1 N HCI (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN : H20 4: 1) to afford 194 (37. 5 mg, 22%) as a white solid.

Rf= 0.32 Hex: EtOAc 1: 1.

1H NMR (300 MHz, CDC13) # 6.80 (s, 1H), 6.02 (d, J= 1.2 Hz, 1H), 5.92 (d, J= 1.2 Hz, 1H), 5.22 (t, J= 5.7 Hz, 1H), 4.13 (d, J = 2. 4 Hz, 1H), 4.09 (s, 1H), 3.88-3.81 (m, 1H), 3.80- 3.71 (m, 1H), 3.67 (s, 3H), 3.64 (d, J= 3 Hz, 1H), 3.52-3.43 (m, 1H), 3.41 (brd, J = 6.6 Hz, 1H), 3.23-3.19 (m, 1H), 3.00 (dd, J, = 8.7 Hz, J2 = 18.6 Hz, 1H), 2.77 (d, J = 18Hz, 1 H), 2.67-2.56 (m, 3H), 2.33 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 2.01 (s, 3H), 1.82-1.74 (m, 4H), 1.43-1.38 (m, 3H), 0.97-0.88 (m, 3H), 0.67 (d, J= 6.9Hz, 3H).

13C NMR (75 MHz, CDC13) 8 171.2,170.3,168.6,148.2,145.1,143.0,140.8,140.7,131.7, 131.1,127.8,123.5,120.6,117.7,112.5,102.0,60.7,59.2,57.6,57. 4,55.4,55.2,48.9,41.8, 34.4,31.8,31.6,29.9,26.9,25.0,24.8,22.9,22.5,20.4,17.9,15.8, 14.3,14.1,9.5.

ESI-MS m/z: Calcd. for C39H46F3N509 : 785.81. Found: 786 (M+I) +, 805.5 (M+23) +.

Example 157 53 195 To a solution of 53 (150 mg, 0.218 mmol) in CH2Cl2 (1.09 mL), DIPEA (75.9 mL, 0.436 mmol), and decanoyl chloride (92.7mL, 0.436 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h. Then, the solution was diluted with CH2CI2 (10 mL) and washed successively with 0.1 N HCI (5 mL), and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN: H20 1: 1) to afford 195 (75 mg, 41%) as a white solid.

Rf= 0.32 Hex: EtOAc 1: 1.

'H NMR (300 Hz, CDCI3) 8 6.82 (s, 1H), 6.03 (d, J= 1.5 Hz, 1H), 5.93 (d, J= 1.5 Hz, 1H), 5.26 (bs, 1H), 4.15 (s, 1H), 4.11 (s, 1H), 3.89-3.75 (m, 2H), 3.68 (s, 3H), 3.65 (bs, 1H), 3.52- 3.44 (m, 1H), 3.43 (d, J= 8.1 Hz, 1H), 3.22 (brd, J= 11. 4 Hz, 1H), 3.03 (dd, J, = 7. 8 Hz, J2 = 17. 4 Hz, 1H), 2.78 (d, J= 17.7 Hz, 1H), 2.69-2.56 (m, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 2.23 (s, 3H), 2.03 (s, 3H), 1.83-1.74 (m, 3H), 1.83-1.74 (m, 12H), 0.90-8.88 (m, 3H), 0.68 (d, J= 6 Hz, 3H).

3c NMR (75 Hz, CDC13) 8 171.0,170.1,168.4,148.0,144.8,142.8,140.5,131.5,130.8, 127.5,123.3,120.3,117.5,112. 3,112.2,101.7,60.4,59.0,57.4,57.2,55.1,55.0,48.6,41.5, 39.1,34.2,31.8,29.4,29.2,26.7,25.0,24.6,22.6,20.2,17.6,15.5, 14.0,9.2.

ESI-MS m/z: Calcd. for C43H54F3NsOg : 841.91. Found (M+1) + : 842.3.

Example 158 To a solution of 53 (150 mg, 0.218 mmol) in CH2C12 (1.09 mL). DIPEA (75.9 mL, 0.436 mmol), and stearoyl chloride (147.3 mL, 0.436 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h. Then, the solution was diluted with CH2CI2 (10 mL) and washed successively with 0.1 N HCI (5 mL) and a solution of 10% NaHC03 (5 ml).

The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN : H20 1: 1) to afford 196 (86 mg, 41%) as a white solid.

Rf = 0.42 Hex: EtOAc 1: 1.

1H NMR (300 MHz, CDCl3) # 6.81 (s, 1H), 6.03 (s, 1H), 5.92 (s, IH), 5.21 (bs, 1H), 4.14 (s, 1H), 4. 10 (s, 1H), 3.88-3.74 (m, 2H), 3.67 (s, 3H), 3.64 (d, J= 3 Hz, 1H), 3.49 (brd, J= 14.7 Hz, 1H), 3.42 (d, J= 8.1 Hz, 1H), 3.22 (brd, J = 11.4 Hz, 1H), 3.02 (dd, J, = 8.7 Hz, = 18.6 Hz, 1H), 2.78 (d, J= 18Hz, 1H), 2.68-2.56 (m, 3H), 2.33 (s, 3H), 2.25 (s, 3H), 2.02 (s, 3H), 1.82-1.73 (m, 3H), 1.42-1.19 (m, 28H), 0.87 (t, J= 7.2 Hz, 3H), 0.67 (d, J= 6.6 Hz, 3H).

3c NMR (75 MHz, CDC13) 6 171.0,170.2,168.5,147.9,144.8,142.8,140.4,131.4,130.9, 127.5,123.3,120.4,117.5,112.4,112.1,101.7,60.4,58.9,57.4,57. 2,55.2,55.0,48.6,41.5, 39.0,34.2,31.9,29.7,29.6,29.4,29. 3,29.2,26.7,25.1,24.6,22.7,20.2,17.6,15.5,14.1, 9.2. ESI-MS m/z : Calcd. for C51H70F3N5O9 : 953.5. Found (M+1) + : 954.4.

Example 159 To a solution of 45 (10 mg, 0.019 mmol) in CH2CI2 (0.095 mL), triethylamine (2.94 mL, 0.021 mmol) and allyl bromide (2.0 mL, 0.023 mmol) were added at 23 °C. The reaction mixture was stirred for 6 h and then, the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (SiO2, MeOH : EtOAc 1: 5) to afford 197 (3.8 mg, 35%) as a white solid.

Rf= 0.19 EtOAc: MeOH 5: 1.

1H NMR (300 MHz, CDC13) 8 6.43 (s, 1H), 5.95 (s, 1H), 5.89 (s, 1H), 5.62-5.59 (m, 1H), 4.94-4.84 (m"2H), 4.19 (s, 1H), 4.08 (s, 1H), 3.98 (t, J = 4. 5 Hz, 1H), 3.76 (s, 3H), 3.32- 3.26 (m, 2H), 3.07 (dd, J, = 7.5 Hz, J2 = 17. 4 Hz, 1 H), 2.89 (d, J = 6 Hz, 2H), 2.80 (d, J = 3.9 Hz, 1H), 2.76 (d, J= 3.3 Hz, 1H), 2.57-2.52 (m, 2H), 2.33 (s, 6H), 2.24 (s, 3H), 1.99 (s, 3H), 1.88-1.79 (dd, J1 = 12.9Hz, = 15. 9 Hz, 1H).

ESI-MS m/z: Calcd. for C31H36N4O6 : 560.64. Found (M+1) + : 561.3.

Example 160 To a solution of 146 (50 mg, 0.096 mmol) in CH2C12 (0.96 mL), pyridine (11.7 mL, 0.144 mmol), and cinnamoyl chloride (24.0 mg, 0.144 mmol) were added at 23 °C and the reaction mixture was stirred for 18 h at that temperature. Then, the solution was diluted with CH2Cl2 (10 mL) and washed successively with 0.1 N HCI (5 mL) and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex: EtOAc 1: 2) to afford 198 (54 mg, 86%) as a white solid.

Rf = 0. 45 Hex : EtOAc 1: 1.

1H NMR (300 MHz, CDC13) 6 7.41-7.37 (m, 6H), 6.38 (s, 1H), 6.19-6.03 (m, 1 H), 6.08 (d, J = 15.9 Hz, 1H), 5.93 (d, J= 1.5 Hz, 1H), 5.88 (d, J= 1.5 Hz, 1H), 5.62 (s, 1H), 5.38 (dd, Jazz 1.5 Hz, Jz = 17.1 Hz, 1H), 5.26 (dd, J, = 1.5 Hz, k., = 10.5 Hz, 1H), 4.47 (dd, J, = 3.6 Hz, J2 = 10.8 Hz, 1H), 4.23-4.11 (m, 5H), 3.89 (dd, J = 4. 8 Hz, J2 = 11. 1 Hz, 1H), 3.51 (s, 3H), 3.34 (brd, J=8. 4Hz, 1H), 3.27-3.21 (m, 2H), 2.97 (dd, J1 = 7.8 Hz, J2 = 17. 7 Hz, 1H), 2.28 (s, 3H), 2.15 (s, 3H), 2.04 (s, 3H), 1.91 (dd, J, = 12 Hz, Ja = 15. 6 Hz, 1H).

13C NMR (75 MHz, CDCl3) # 166.5,148.8,146.7,144.7,144.5,142.7,139.5,134.4,134.1, 131.1,130.6,129.1,128.7,128.2,121.9,121.2,118.5,117.8,116.8, 112.9,112.7,101.5, 74.7,65.2,60.7,60.6,57.4,56.8,56.6,55.7,41.9,31.8,26.7,25.5, 22.9,15.9,14.4,9.7.

ESI-MS m/z: Calcd. for C38H39N3O7 : 649.7. Found (M+1) + : 650.3.

Example 161 To a solution of 161 (78. 5 mg, 0.146 mmol) and the cysteine derivative (81. 1 mg, 0.247 mmol) in anhydrous CH2C12 (7.3 mL), DMAP (50 mg, 0.41 mmol) and EDC. HCI (78.1 mg, 0.41 mmol) were added at 23 oC. The reaction mixture was stirred at 23 oC under Argon atmosphere for 1.5 h. The mixture was diluted with CH2C12 (20 mL) and extracted with an aqueous saturated solution of sodium bicarbonate (25 mL). The aqueous phase was extracted with additional CH2C12 (20 mL) and the combined organic extracts were dried over Na2S04, filtered and the solvent was eliminated under reduced pressure. The crude of the reaction was purified by flash column chromatography (inner diameter of the column 2 cm, height of silica 10 cm) with mixtures of ethyl acetate/hexane in a gradient manner, from 1: 4 to 3: 1 as eluent. Compound 199 (113 mg, 88%) was obtained as a pale yellow solid.

Rf = 0. 36 Hex : EtOAc 1 : 1.

'H NMR (300 MHz, CDC13) 8 : 7.76 (d, J = 7.8 Hz, 2H), 7.63 (d, J = 7.8 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.29 (t, J = 7.6 Hz, 2H), 6.54 (s, 1H), 5.80 (s, 1H), 5.74 (s, 1H), 5.10 (d, J = 5.7 Hz, 1H), 5.08 (d, J = 5.7 Hz, 1H), 4.50 (dd, J = 4.9 Hz, J = 11.8 Hz, 1H), 4.20-4.05 (m, 4H), 4.02 (s, 3H), 3.81 (s, 3H), 3.61 (d, J = 13.8 Hz, 1H), 3.55 (d, J= 13.8 Hz, 1H), 3.50 (s, 3H), 3.21 (m, 1H), 3.06 (m, 1H), 3.00 (d, J = 6.0 Hz, 2H), 2.90 (dd, J = 8.9 Hz, J = 17.4 Hz, 1H), 2.79 (s, 1H), 2.56 (m, 1H), 2.50 (dd, J = 4.8 Hz, J = 14.9 Hz, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 1.80 (s, 3H), 1.75 (m, 2H).

ESI-MS m/z: Calcd. for C46H48N4010S : 848. 3. Found: 849.3 (M+1) +, 871.3 (M+23) +. HPLC: Conditions: Column: Simmetry C18, Mobile phase: CH3CN/H20 in gradient from 50 to 100% in 25 minutes. 0 = 1 mL/min, t= 40 °C. Retention time: 16.04 minutes. HPLC purity in area: 89.29%.

Example 162 To a solution of 161 (80 mg, 0.148 mmol) and the cysteine derivative (76 mg, 0.223 mmol) in anhydrous CH2C12 (6.8 mL), DMAP (45 mg, 0.37 mmol) and EDC. HCI (71 mg, 0.37 mmol) were added at 23 °C. The reaction mixture was stirred at 23 °C under Argon atmosphere for 2.5 h Then, the mixture was diluted with CH2C12 (20 mL) and extracted with an aqueous saturated solution of sodium bicarbonate (25 mL). The aqueous phase was extracted with additional CH2CI2 (20 mL) and the combined organic extracts were dried over Na2S04, filtered and the solvent was eliminated under reduced pressure. The crude of the reaction was purified by flash column chromatography (inner diameter of the column 2 cm, height of silica 10 cm) with mixtures of ethyl acetate/hexane in gradient from 1: 4 to 3: 1 as eluent. Compound 200 (83 mg, 65%) was obtained as a pale yellow solid.

Rf = 0. 5 Hex : EtOAc 1 : 1.

'H NMR (300 MHz, CDC13) 8 : 7.71 (m, 3H), 7.49 (d, J = 7.3 Hz, 1H), 7.36 (t, J = 7.3 Hz, 2H), 7.32- 7.23 (m, 2H), 6.65 (s, 1H), 5.80 (s, 1H), 5.79 (s, 1H), 5.13 (d, J = 6. 1 Hz, 1H), 5.11 (d, J = 6. 1 Hz, 1H), 5.05 (d, J = 6.1 Hz, 1H), 5.01 (d, J = 6.3 Hz, 1H), 4.76 (dd, J = 3.9 Hz, J = 11. 9 Hz, 1H), 4.15- 4.03 (m, 4H), 3.96 (t, J = 4.0 Hz, 1H), 3.87 (s, 3H), 3.55 (s, 3H), 3.51 (s, 3H), 3.34-3.29 (m, 2H), 3.24 (dd, J = 5. 5 Hz, J = 13.5 Hz, 1H), 3.03 (m, 1H), 2.97 (t, J = 7.5 Hz, IH), 2.44-2.35 (m, 3H), 2.29 (s, 3H), 2.14 (s, 3H), 1.98 (dd, J = 8. 06, J = 15. 1 Hz, 2H), 1.75 (s, 3H).

13C NMR (75 MHz, CDC13) 8 196.98,161.13,158.21,149.01,148.78,145.05,144.91, 141.01,140.69,140.07,137.53,132.76,131.15,129.41,127.70,127. 67,127.21,126.83, 125.28,125.05,124.94,122.51,119.84,119.73,116.61,110.26,104, 57,101.40,99.23, 96.70,70.25,63.15,60.40,58.89,57.52,56.98,56.72,56.15,55.06, 47.22,41.37,38.26, 35.22,29.57,25.34,15.62,7.26.

ESI-MS m/z : Calcd. for C47H49N30nS : 863.97. Found: 865.0 (M+1) +, 887. 1 (M+23) +. HPLC: Conditions: Column : Simmetry C18, Mobile phase: CH3CN/H20 in gradient from 50 to 100% in 25 minutes. = I mL/min, t= 40 °C. Retention time: 15. 36 minutes. HPLC purity in area: 91.56%.

Example 163 To a solution of 161 (418 mg, 0.77 mmol) and the cysteine derivative (321 mg, 0.77 mmol) in anhydrous CH2C12 (35 mL), DMAP (235 mg, 1.92 mmol) and EDC. HC1 (369 mg, 1.92 mmol) were added at 23 °C and the reaction was stirred under Argon atmosphere for 2 h. The mixture was diluted with CH2C12 (20 mL) and extracted with an aqueous saturated solution of sodium bicarbonate (25 mL). The aqueous phase was extracted with additional CH2C12 (20 mL) and the combined organic extracts were dried over Na2S04, filtered and the solvent was eliminated under reduced pressure. The crude of the reaction was purified by flash column chromatography (inner diameter of the column 3 cm, height of silica 11 cm) with mixtures of ethyl acetate/hexane in a gradient manner, from 1: 3 to 3: 1 as eluent. Compound 201 (372 mg, 52%) was obtained as a pale yellow solid.

Rf = 0.41 Hex: EtOAc 1: 1.

'H-RMN (CDC13, 300 MHz) 8 7.76-7.64 (m, 4H), 7.41-7.30 (m, 4H), 6.54 (s, IH major isomer), 6.51 (s, 1H, minor isomer), 5.69 (s, 1H, minor isomer), 5.67 (s, 1H, major isomer), 5.60 (s, 1H minor isomer), 5.57 (s, 1H major isomer), 5.08 (s, 2H), 4.26 (t, J= 5.1 Hz, IH minor isomer), 4.23 (t, J= 4.9 Hz, 1H major isomer), 4.07-4.03 (m, 3H), 3.98- 3.88 (m, 3H), 3.84 (s, 3H), 3.71 (dt, J, = 5.6 Hz, J2 = 10.0 Hz, 1H), 3. 49 (s, 3H, major isomer), 3. 49 (s, 3H, minor isomer), 3.40 (dt, J1 = 5.6 Hz, = 9.5 Hz, 1H), 3. 18 (m, 3H), 3.11 (m, I H). 2.91-2.82 (m, 1H), 2.48-2.28 (m, 2H), 2.24 (s, 3H), 2.16 (s, 3H, major isomer), 2.14 (s. 3H. minor isomer), 2.03 (s, 3H), 1.91 (dt, J1 = 8. 8 Hz, J2 = 14.4 Hz, 1H), 1.76 (s, 3H, minor isomer).

1.76 (s, 3H major isomer), 0.85 (s, 9H minor isomer), 0.85 (s, 9H major isomer). 0.04 and 0.01 (s, 6H both isomers).

ESI-MS m/z: Calcd. for C5lH6lN301OSSi : 935.4. Found: 936.4 (M+1) +, 958. 3 (M+23) +.

Example 164 To a solution of 25 (2 mg, 0.0035 mmol) and an excess amount of the cysteine derivative in anhydrous CH2CI2 (0.2mL), an excess amounts of DMAP and EDC. HC1 were added at 23 °C. The reaction mixture was stirred at 23 °C under Argon atmosphere for 14 h. Then, the mixture was diluted with CH2C12 (10 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL). The aqueous phase was extracted with additional CH2CI2 (10 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was eliminated under reduced pressure. The crude of the reaction was purified by flash column chromatography (Si02, Hex: EtOAc 4: 1) to afford 202 as a pale yellow solid.

IH NMR (300 MHz, CDC13) (poor resolution) 8 7.78.7,62 (m, 4H), 7.41-7.26 (m, 4H), 6.73 (s, 1H), 6.10 (m, 1H), 5.92 (d, J = 1. 3 Hz, 1H), 5.88 (d, J = 1. 3 Hz, 1H), 5.40-5.22 (m, 2H), 5.11 (s, 3H), 5.02 (d, J = 13. 8 Hz. 1H). 4.29-4.02 (m, 6H), 3.97 (m, 1H), 3. 72 (d. J = 12.5 Hz, 2H), 3.70 (s, 3H), 3.58 (s, 3H), 3.51 (d, J = 12.3 Hz, 2H), 3.50 (s, 3H), 3.49-3.20 (m.

4H), 2.54-2.28 (m, 4H), 2.40 (s, 3H), 2.21 (s, 3H), 2.16 (s, 3H).

Fermentation Procedures Example A Seed medium YMP3 containing 1% glucose; 0.25% beef extract; 0.5% bacto- peptone; 0.25% Nazi ; 0.8% CaC03 was inoculated with 0.1% of a frozen vegetative stock of the microorganism, strain A2-2 of Pseudomonasfluorescens, and incubated on a rotary shaker (250 rpm) at 27°C. After 30 h of incubation, the seed culture was added to a agitated-vessel fermentor with a production medium composed of 2% dextrose; 4% mannitol, 2% dried brewer's yeast (Vitalevor Biolux, Belgium) ; 1% (NH4) 2SO4 ; 0.04% K2HP04 ; 0.8 KC1 ; 0.001% FeCl3; 0.1% L-Tyr; 0.8% C03Ca; 0.05% PPG-2000; 0.2% anti- foam silicone (ASSAF-100, RHODIA UK). The sterilisation was carried out at 122°C 30 minutes. The volume inoculated was a 2% (v/v). The temperature was 27°C (0 to 16h) and 24°C from 16h to final process (41 hours). The dissolve oxygen-pressure was upper to 25%.

The pH was controlled at 6.0 with diluted sulphuric acid since 28 hours till final process.

The overpressure was 0.5 bar. A 1% mannitol or sorbitol was added from 16 h to final process (for two days running) and 2% for three days fermentation-process.

After 41 or 64 hours, the fermentation broth must be extracted for recovery safracin B or KCN treatment in the clarified broth for recovery safracin B-cyano.

Example B Obtention of safracin B cyano from the crude extract.

A clarification or filtration from the fermentation broth at pH 6 removes the solids. The clarified broth was adjusted a pH 9.5 with diluted sodium hydroxide and extracted twice with 2: 1 (v/v) ethyl acetate, methylene chloride or butyl acetate. The extraction was carried out into an agitated-vessel during 20', the temperature of the mixture was maintained at 8 to 10°C. The two phases were separated by a liquid-liquid centrifuge. The organic phase was dried with sodium sulphate anhydrous or frozen and then filtered for removing ice. This organic phase (ethyl acetate layer) was evaporated until obtention of an oil-crude extract.

Example C Obtention of safracin B cyano from the clarified broth.

A clarification or filtration from the fermentation broth at pH 6 removes the solids. The clarified broth was adjusted at pH 3.9 with concentrated acetic acid. 0.5 grams per litre of KCN are added to the clarified broth an incubated at 20°C during 1 hour with agitation.

Then, the temperature was decreased at 15°C and the pH was adjusted at 9.5 with diluted sodium hydroxide and extracted with 2: 1.5 (v/v) ethyl acetate. The extraction was carried out into an agitated-vessel during 20 minutes, the temperature of the mixture was maintained at 8 to 10°C. The two phases were separated by a liquid-liquid centrifuge. The organic phase was dried with sodium sulphate anhydrous. This organic phase (ethyl acetate layer) was evaporated until obtention of an oil-crude extract. This extract was purified by flash column chromatography (SiO2, gradient 20: 1 to 10 : to 5: 1 ethyl acetate: methanol) to afford quantitatively compound 2 as a light yellow solid.

Rf : 0.55 (ethyl acetate: methanol5 : 1) ;. tR= 19.9 min [HPLC, Delta Pack C4,5um, 300 A, 150x3 mm, k=215 =, flow 0. 7 ml/min, temp= 50°C, grad. : CH3CN-aq. NaOAc (lOmM) 85%-70% (20')] ; 'H NMR (300 Mhz, CDC13) : 8 6.54 (dd, J, = 4. 4Hz, J2= 8.4 Hz, I H), 6.44 (s, I H), 4.12 (d, J = 2.4 Hz, 1H), 4.04 (d, J= 2.4 Hz, IH), 4. 00 (s, 3H), 3.87 (bs, 1H), 3.65 (ddd, J, = 1.5 Hz, J2 = 8.7 Hz, J3 = 9.9 Hz, 1H), 3.35 (br. D, J= 8.4 Hz, 1H), 3.15-2.96 (m, 4H), 2.92 (q, J= 7.2 Hz, 1H), 2.47 (d, J= 18. 3 Hz, 1H), 2.29 (s, 3H), 2.18 (s, 3H) 1.83 (s, 3H), 1.64 (ddd, J, = 2.7 Hz, J2 = 11.1 Hz, J3 = 14.1 Hz, 1H), 0.79 (d, J= 7.2 Hz, 3H); 13C NMR (75 Mhz, CDC13) : 5 186.0 (q), 175.9 (q), 156.2 (q), 146.8 (q), 142.8 (q), 140.7 (q), 136.6 (q), 130. 5 (q), 128.8 (q), 127.0 (q), 120.5 (s), 117.4 (q), 116.5 (q), 60.8 (t), 60.4 (s), 58.7 (t), 56.2 (s), 55.7 (s), 54.8 (s), 54.8 (s), 54.4 (s), 50.0 (s), 41. 6 (t), 39.8 (d), 25.2 (d), 24.4 (d), 21.2 (t), 15.5 (t), 8.4 (t).

ESI-MS m/z: Calcd for C29H35N506 : 549. 6. Found (M+Na) + : 572.3.

Example D A medium (50 1) composed of dextrose (2%), mannitol (4%), dry brewer's yeast (2%), ammonium sulphate (1%), potassium secondary phosphate (0.04%), potassium chloride (0.8%), iron (III) chloride 6-hydrate (0.001%), L-tyrosine (0.1%), calcium carbonate (0.8%), poly- (propylene glycol) 2000 (0.05%) and antifoam ASSAF 1000 (0.2%) was poured into a jar-fermentor with 75 1 total capacity and, after sterilisation, inoculated with seed culture (2%) of A2-2 strain (FERM BP-14) and aerated cultivation under agitation was carried out at 27°C to 24°C for 64 hours (aeration of 75 1 per minute and agitation from 350 to 500 rpm). The pH was controlled by automatic feeding of diluted sulphuric acid from 27 hours to final process. A 2% mannitol was added from 16 hours to final process. The cultured medium (45 1) thus obtained was, after removal of cells by centrifugation, adjusted to pH 9.5 with diluted sodium hydroxide, extracted with 25 litres of ethyl acetate twice. The mixture was carried out into an agitated-vessel at 8°C for 20 minutes. The two phases were separated by a liquid-liquid centrifuge. The organic phases were frozen at-20°C and filtered for removing ice and evaporated ice and evaporated until obtention of a 40 g oil-dark-crude extract. After introduction of the cyanide group and purification, 3.0 grams of safracin B cyano were obtained.

Example E A medium (501) composed of dextrose (2%), mannitol (4%), dry brewer's yeast (2%), ammonium sulphate (1%), potassium secondary phosphate (0.02%, potassium chloride (0.2%), Iron (III) chloride 6-hydrate (0.001%, L-tyrosine (0.1%), calcium carbonate (0.8%, poly- (propylene glycol) 2000 (0.05%) and antifoam ASSAF 1000 (0.2%) was poured into a jar-fermentor with 75 1 total capacity and, after sterilisation, inoculated with seed culture (2%) of A2-2 strain (FERM BP-14) and aerated cultivation under agitation was carried out at 27°C to 24°C for 41 hours (aeration of 75 1 per minute and agitation from 350 to 500 rpm).

The pH was controlled by automatic feeding of diluted sulphuric acid from 28 hours to final process. A 1% mannitol was added from 16 hours to final process. The cultured medium (45 1) thus obtained was, after removal of cells by centrifugation, adjusted to pH 3.9 with 200 ml of conc. acetic acid. 25 grams of potassium cyanide 97% were added and after 1 hour of agitation at 20°C, the pH was adjusted to 9.5 with 1500 ml of a solution 10% sodium hydroxide. Then, extracted with 35 litres of ethyl acetate. The mixture was carried out into an agitated-vessel at 8°C for 20 minutes. The two phases were separated by a liquid-liquid centrifuge. The organic phase was dried by sodium sulphate anhydrous and evaporated until obtention of a 60 g oil-dark-crude extract.

After chromatography, 4.9 grams of safracin B cyano were obtained.

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