Field of Invention

This invention relates to compounds that have antibiotic activity including but not limited to anticancer and antimicrobial activity. More particularly, the invention relates to calicheamicinone, related compounds and processes for preparing the same.

Background of the Invention

Calicheamicin y^ (referred to herein as calicheamicin) contains a complex bicyclic enediyne allylic core structure and oligosaccharide chain connected through a glycosyl bond to the core structure. Removal of the carbohydrate chain releases the aglycone, calicheamicinone. The oligosaccharide chain binds at the 5' side of a TCCT DNA sequence through interactions in the minor groove of the DNA strand. The enediyne core can introduce single- or double- stranded cuts in the DNA. Calicheamicin has antibiotic activity, particularly antitumor activity. (Smith et al . 1993; Haseltine et al. 1991; Aiyer et al 1994; Lee et al . 1992) .

The synthesis of calicheamicin and calicheamicinone has been achieved. Calicheamicin is extremely potent but lacks the specificity desired for an effective antitumor drug. There is a continuing need to identify new calicheamicinone-related compound intermediates and

conjugates that overcome _t t- _V h _te e. _s see oprro ^u b ^u lems. Moreover, there is continuing need for improved methods of synthesizing these ompounds and analogs or derivatives thereof .

Summary of the Invention

This invention relates to the aglycone of calicheamicinone and processes for the preparation of this compound and derivatives or analogs thereof. In one embodiment, the invention involves the chemical synthesis of racemic calicheamicinone and analogs or derivatives thereof. Many of the products that can be synthesized according to the invention have antibiotic activity including, but not limited to, anticancer, antifungal or antimicrobial activity. See, e.g., U.S. Patent Nos ^: 5,264,586 and 5,550,246, incorporated herein by reference. For example, the processes disclosed herein can be used to synthesize 1, 2, 3, 82,83, 84, 32, 33 and related analogs and derivatives.

In another embodiment, a process according to the invention results in optically pure enantiomers of calicheamicinone 1, and comprises formal routes for the synthesis of structure 1, 2, 3, 32, 33, 82 or 83 and their enantiomers. It will be appreciated that certain individual steps in the formal routes may be interchanged ^; the invention includes combinations of the formal routes disclosed herein and includes but is not limited to the use 5 of individual steps or combinations of such steps.

The invention involves, for example, compounds that follow. The compounds can be prepared by the methods described in the examples below of straightforward variations on these methods.

A compound represented by the following formula with syn or anti stereochemistry about carbon 5 with respect to the substituent at carbon 2:

wherein

V is a cyclic ketal;

W is nitro, amino, or protected amino,

X is ester, alkyloxycarbonyl, -CHO, hydroxymethyl or protected hydroxymethyl;

Y,U are =0, or Y is a protected hydroxyl and U is hydrogen, or Y is hydroxyl and U is hydrogen;

Zl, Z2 are =0, or Zl is hydroxyl and Z2 is hydrogen, or Zl is protected hydroxyl and Z2 is hydrogen.

In the compound described immediately above, the cyclic ketal can be, for example, a cyclic ethylene ketal, and the protected amino group can be, for example, a allyloxycarbonylamino group. In the compound, the protected hydroxymethyl group can be, for example, a pivaloyloxymethyl group, and the protected hydroxyl of substituent Y can be, for example, a p-methoxyphenoxymethyloxy group. The protected hydroxyl of substituent Zl can be, for example, a trialkylsilyloxy group. A compound represented by the following formula:

wherein

VI and V2 are a cyclic ketal; W is nitro, amino, or protected amino; X is ester, alkyloxycarbonyl, -CHO, hydroxymethyl or protected hydroxymethyl;

Y,U are =0, or Y is a protected hydroxyl and U is hydrogen, or Y is hydroxyl and U is hydrogen;

Zl is protected hydroxyl; and

Z2 is protected acetylide. In this compound, the cyclic ketal can be, for example, a cyclic ethylene ketal. The protected amino group can be, for example, a allyloxycarbonylamino group, and the protected hydroxymethyl group can be, for example, a pivaloyloxymethyl group. Also, the protected hydroxyl of substituent Y can be, for example, a p- methoxyphenoxymethyloxy group. The protected hydroxyl of substituent Zl can be, for example, a trialkylsilyloxy group, while the protected acetylide can be, for example, trialkylsilylacetylide, where said alkyl contains from 1 to 4 carbon atoms.

A compound represented by the following formula:

wherein

VI, V2 are a cyclic ketal;

W is independently nitro, amino, or protected amino;

Y is a hydroxyl or protected hydroxyl,

W

Zl, Z2 are =0, or Zl is hydroxyl and Z2 is H, or Zl is a protected hydroxyl and Z2 is H. The cyclic ketal can be, for example, a cyclic ethylene ketal. The protected amino group can be, for example, a allyloxycarbonylamino group. The hydroxyl group of substituent Y can be, for example, a tert-butylcarbonyloxy group, and the protected hydroxyl group of substituent Zl can be, for example, a trialkylsilyloxyl group.

A compound represented by the following formula:

wherein

VI, V2 are a cyclic Ketal, W is a protected amino,

Yl, Y2 are =0, or Yl is a hydroxyl and Y2 is H, or Yl is a protected hydroxyl and Y2 is H, Z2 is hydroxyl or a protected hydroxyl,

Zl is a protected acetylide. The cyclic ketal can be, for example, a cyclic ethylene ketal. The protected amino can be, for example, a

allyloxycarbonylamino. The protected hydroxyl of substituent Yl can be, for example, a tert-butylcarbonyloxy group, and the protected hydroxyl of substituent Z2 can be for example, a trialkylsilyloxy group. The protected acetylide can be, for example, a trialkylsilylacetylide. A compound represented by the following formula:

wherein

Tl, T2 are =0, or Tl is a hydroxyl and T2 is H, or

Tl is a protected hydroxyl and T2 is H, U is a hydroxyl, or a protected hydroxyl,

VI, V2 are a cyclic ketal,

W is a protected amino,

X is a trialkyl silyl,

Y is a trialkyl silyl, Z is protected hydroxyl.

The protected hydroxyl of substituent Tl can be, for example, p-methoxyphenoxymethyloxy or dimethoxyphenoxymethyloxy. The protected hydroxyl of

substituent U can be, for example, a chloroacylated hydroxyl group. The cyclic ketal can be, for example, a cyclic ethylene ketal. The protected amino group can be, for example, an allyloxycarbonylamino group. The trialkyl silyl group can be, for example, trimethyl silyl. The protected hydroxyl group of substituent Z can be, for example, a trialkyl silyloxy group.

A compound represented by the following formula:

wherein VI, V2 are cyclic ketal,

W is an amino, protected amino, or amino substituted with a DNA recognition group,

X is a trialkyl silyl group, H, or a halogen, Y is a trialkyl silyl group, H, or a halogen, Z is hydroxyl or a protected hydroxyl group.

The cyclic ketal can be, for example, a cyclic ethylene ketal. The protected amino group can be, for example, a allyloxycarbonylamino group. The trialkyl silyl can be, for

example, a trimethyl silyl group. The protected hydroxyl group of substituent Z can be, for example, a trialkylsilyloxy group. The DNA recognition group can be, for example, an oligosaccharide or a lexitropsin.

A compound selected from the group consisting of 82, 83 or 84,

and wherein

R ² is carboxymethyl, carboxyallyl, hydrogen, a monosaccharide, a disaccharide, a trisaccharide, an allyl, an alkyl, an alkenyl, an alkynyl, a

W 7

hydroxyalkyl, an oxoalkyl, or a DNA recognizing group;

R ¹ is hydrogen, an amino acid moiety, a peptide, a • monosaccharide, a disaccharide, a trisaccharide, an alkyl, an alkenyl, an alkynyl, an hydroxyalkyl, an oxoalkyl, or a DNA recognizing group; R* is hydrogen, an amino acid moiety, a peptide, a monosaccharide, a disaccharide, a trisaccharide, an alkyl, an alkenyl , an alkynyl, an hydroxyalkyl , an oxoalkyl, or a DNA recognizing group;

R ⁷ is hydrogen and R ⁸ is selected from the group consisting of C _x -C ₆ acyl, benzoyl, C^Cg alkoxy carbonyl and benzyloxy carbonyl, or R7 and R8 together form a moiety selected from the group consisting of:

R ⁹ is a hydroxyl, or OR ¹² , R ¹² is a DNA recognizing group; R ⁵ is selected from S _n R ⁶ (wherein n = 1 , 2 or 3) ,

OR ⁶ or -NHR ⁶ , and R ^s is hydrogen, an amino acid moiety, a peptide, a monosaccharide, a disaccharide, a trisaccharide, a heparin polymer, a heparin polymer-containing group, an alkyl, an alkenyl, an

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SUBST1TUTE SHEET (RULE 26)

alkynyl, a hydroxyalkyl, an oxoalkyl, or a DNA recognizing group;

R ¹⁰ , R ¹⁰ ' are a =0 or a cyclic ketal; and R ¹¹ is an alkyl, functionalized alkyl, polyether or a DNA recognizing group.

The DNA recognizing group can be, for example, an oligosaccharide or a lexitropsin. The functionalized alkyl can be, for example, functionalized with an ester, keto, hydroxy, oxo, amino, or acylamino group. The invention also involves methods such as the following methods.

A method comprising the step of: a) combining in a suitable solvent under suitable conditions for stereo-selective reaction at carbon 5, at least partially dehydrated CeCl ₃ , lithium

(trialkylsilyl) acetylide and

where R _x is an alkyl group, R ₂ is a hydroxyl protecting group, R _{i t} R ₃ ' are a cyclic ketal, to form a reaction product of the following formula

The Rj _. group can be, for example, a t-butyl group. The R ₂ group can be, for example, a p-methoxyphenoxymethyl group or dimethoxyphenoxymethyl group. The R ₃ , R ₃ ' can be, for example, a cyclic ethylene ketal.

A method comprising the step of: a) combining in a suitable solvent under suitable conditions for stereo-selective reaction at carbon

5, at least partially dehydrated CeCl ₃ , lithium (trialkylsilyl) acetylide and

where R _x is an alkyl group and R ₃ , R ₃ ' are a cyclic ketal, to form a reaction product stereo-selectively of the following formula:

Cofoy

with the indicated stereochemical relationship between the acetylene at carbon 5 and the nitrogen at carbon 2. The Rj group can be, for example, an alkoxycarbonylamino group. The R ₂ group can be, for example, a tert-butyl dimethylsilyloxyl group.

A method comprising the step of: refluxing a suitable solvent containing a mixture of a free radical brominating agent combined with

where Rj is a protected amino group, R ₂ is a

» trialkylsilyloxyl group, and R ₃ , R ₃ ' are a cyclic ketal, to form the following reaction products

The Ri group can be, for example, an alkoxycarbonylamino group. The R ₂ group can be, for example, a tert-butyl dimethylsilyloxyl group.

A method comprising the step of: combining in a suitable solvent under suitable conditions for stereo-selective reaction at carbon

9, at least partially dehydrated CeCl ₃ , lithium

(trialkylsilyl) acetylide and

where R _x is a protecting group, R ₂ is a protecting group, and R ₃ , R ₃ ' are a cyclic ketal, to form a reaction product of the following formula

The R _x group can be, for example, a p-methoxyphenoxymethyl group or a dimethoxyphenoxymethyl. The R ₂ can be, for example, a tert-butyl dimethylsilyl group. The cyclic ketal can be, for example, a cyclic ethylene ketal.

The method comprising the step of: treating with a suitable hydride reducing agent, the compound

where R _x is a nitro group, R ₂ is a protecting group, R ₃ , R ₃ ' are a cyclic ketal and R ₄ is a suitable chiral auxiliary, under conditions to remove the chiral auxiliary to produce the reaction products

The R ₂ group can be, for example, a tert-butyl dimethylsilyl group. The chiral auxiliary can be, for example, (-)-8- phenylmenthol.

The invention involves numerous advantages that follow from the description below as well as the summary above.

Brief Description of the Drawings

Figure 1: Compounds 1-3 are targets of the synthesis (1- (±) calicheamicinone, 2-triol, 3-lactone) . Scheme 1 is the formation of ketone 7, the first key intermediate. Figure 2. Scheme 2 presents the formation of compound 22, an advanced intermediate. ^a AOM ^■ = p- methoxyphenoxymethyl; yields in brackets refer to the 5α series. The reactions for the 5α series were done under similar conditions to those used for the 5β series shown. Figure 3. Alternative key intermediate 32 was synthesized in scheme 3. ^a Yields in brackets refer to the 5α series (the reactions were done under similar conditions to those used for the 5β series shown) .

Figure 4: Scheme 4 presents the synthesis of 46. ^a AOM = p-methoxyphenoxymethyl. ^b Both 44 and 45 are inseparable mixtures of C(9) epimers (8:1 in favor of 44 and 45) . ^c The C(9) epimer of 46, isolated in 39% yield, can be converted into 46 (see text) .

Figure 5 : A pathway to increase the yield of compound 46 is shown in scheme 5. ^a The C(9) epimer of 46, isolated in 42% yield, can be converted into 46 (see text) ; after one equilibration the total yield of 46 is 71%.

Figure 6 : Final steps in the synthesis of (±) - calicheamicinone are shown in scheme 6. Figure 7: Ketone 7 is synthesized in scheme 7 in a Diels-Alder reaction. Scheme 8 shows the conversion of

ketone 7 into racemic calicheamicinone 1 by two related routes. Compounds 69-72 represent compounds that allow the Diels-Alder reaction to proceed in an asymmetric manner.

Figure 8: Scheme 9 shows the synthesis of 72, a reagent for use in an asymmetric Diels-Alder reaction. Scheme 9 Reagents and condi tions : I, acryloyl chloride, Et ₃ N, DMAP, CH ₂ C1 ₂ , 0°C, 5 min, 93%; ii, NaI0 ₄ , Os0 ₄ , 1:3 water-dioxane, 2 h, ca . 100%; iii, MeN0 ₂ , neutral alumina, 0°C, 0.5 h, room temperature, ca.3 h, 91%; iv, MsCl, Et ₃ N, 0°C, 7 min, 90%. Scheme 10 shows the formal synthesis of (-)- calicheamicinone. Scheme 10 Reagen ts and condi tions : I, 72, THF, -78°C, 35 min; aqueous NH ₄ C1, room temperature, 2 h, 64%; ii, NaBH ₄ , MeOH, 0°C, 15 min, ca . 100%; iii, t- BuMe ₂ SiOTf, 2,6-lutidine, ca . 100%; iv, 2 equiv. DIBAL, - 78°C, 4 h, -30°C, 20 h; 2 equiv. DIBAL, -30°C, 24 h, 80%; v, separate by silica flash chromatography, 9:1 hexane-EtOAc and then 4:1 hexane-EtOAc; 53% yield of 81a and 27% yield of 81b (from 77) .

Figure 9: Structures of targets and key intermediates are shown.

Detailed Description of Invention

This invention relates to an improved process for the synthesis of (±) -calicheamicinone (1) and the (+) and (-) enantiomers. Targets for synthesis in this invention also

include triol 2, the synthetically equivalent lactone 3 and derivatives 82, 83 and 84.

Intermediate compounds disclosed herein are useful for the preparation of, e.g., 1, 2, 3 and 81, as well as for the preparation of other novel compounds, including but not limited to compounds described in U.S. patents 5,474,765 or 5,264,586. New chemical intermediates disclosed herein include, for example, structures 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, or 81. Structure 22 is also referred to herein as 33. Synthesis of the desired intermediate or target compound can be carried out using the steps described herein. Reaction conditions for some of the disclosed steps are described, for example, in U.S. Patent No. 5,550,246, incorporated herein by reference. The novel processes or portions thereof can be used to synthesize 82, 83 or 84 wherein R ² , R ³ , R\ R ⁵ , R ⁷ , R ^a , R ⁹ , R ¹⁰ and R ¹¹ preferably are chemical groups described herein. Herein, the term "alkyl group" refers to a radical containing only carbon and hydrogen, and lacking double or triple bonds. In this invention alkyl radicals generally contain from 1 to 15 carbon atoms, e.g., 1 to 4 carbon atoms.

Herein, the term "alkenyl group" refers to radicals containing only carbon and hydrogen, and having at least one double bond but no triple bonds. In this invention alkenyl radicals generally contain from 1 to 15 carbon atoms, e.g., 1 to 4 carbon atoms.

Herein, the term "alkynyl group" refers to radicals containing only carbon and hydrogen and having at least one triple bond. An alkenyl radical may have zero, one, or more double bonds. In this invention alkynyl radicals generally contain from 1 to 15 carbon atoms, e.g., 1 to 4 carbon atoms .

Herein, an "hydroxyalkyl group" has from 1 to 15 carbon atoms, e.g., 1 to 4 carbon atoms and may have single, double or triple bonds as in alkyl, alkynyl or alkenyl radicals. However, one or more hydrogens is replaced with a hydroxyl group.

Herein, a "oxoalkyl group" has from 1 to 15 carbon atoms, e.g., 1 to 4 carbon atoms and may have single, double or triple bonds as in alkyl, alkynyl or alkenyl radicals. However, two hydrogens on one carbon atom have been replaced with an oxygen atom.

In structures 82, 83 or 84, R ^s is independently selected from S _n R ⁶ (wherein n = 1 , 2 or 3) , wherein, R ^fi is independently hydrogen; an amino acid moiety or a peptide; a monosaccharide, a disaccharide or trisaccharide; a heparin polymer or heparin polymer-containing group; an alkyl; alkenyl; alkynyl; alcohol or ketone group. Alternatively,

R ⁵ can be a protected hydroxyl or protected amino group, e.g., -OR, or -NHR ⁶ . Alternatively, R ⁵ can be a heparin polymer or heparin polymer-containing group, as described in U.S. patent application 5,474,765, incorporated herein by reference. Those with ordinary skill can readily ascertain or determine the appropriate step for the insertion of these groups, appropriate solvents, and reagents and appropriate reaction conditions.

In structures 82, 83 or 84, R ² is independently hydrogen; a monosaccharide, a disaccharide or trisaccharide; an allyl; an alkyl; alkenyl; alkynyl; alcohol or ketone group. Those with ordinary skill can readily ascertain or determine the appropriate step for the insertion of these groups, appropriate solvents and reagents and appropriate reaction conditions.

In structures 82, 83 or 84, R ³ is independently hydrogen; an amino acid or an amino acid chain; a monosaccharide, a disaccharide or trisaccharide; an alkyl; alkene; alkyne; alcohol or ketone group. Those with ordinary skill can readily ascertain or determine the appropriate step for the insertion of these groups, appropriate solvents and reagents and appropriate reaction conditions.

In structures 82, 83 or 84, R ⁴ is independently hydrogen; an amino acid or an amino acid chain; a monosaccharide, a disaccharide or trisaccharide; an alkyl; alkene; alkyne; alcohol or ketone group. Those with ordinary skill can readily ascertain or determine the appropriate

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SUBST1TUTE SHEET (RULE 26)

step for the insertion of these groups, appropriate solvents and reagents and appropriate reaction conditions.

In structure 83, R ⁷ and R ⁸ together can form a moiety selected from the R ¹ and R ² groups described in U.S. application 5,264,586, incorporated herein by reference.

In structures 82, 83 or 84, R ⁹ is independently a hydroxyl group or a recognition unit for DNA such as a carbohydrate or a lexitropsin.

In structure 84, R ¹¹ is independently an alkyl, functionalized alkyl, polyether or a DNA recognizing group. A polyether group can serve to alter solubility.

In structure 82, 83 or 84, R ¹⁰ is independently an oxoalkyl or a cyclic ketal.

A DNA recognition group typically confers specificity by its binding preference for particular DNA sequences. For example, a lexitropsin such as netropsin, which preferentially binds to A-T rich sequences, can be used as a nucleic acid recognizing group. Another suitable DNA recognition group is the monosaccharide and trisaccharide groups of esperamicin A _: . See, e.g., U.S. Patent No. 5,384,412, incorporated herein by reference.

The novel process can be used to synthesize related compounds with metal complexes such as those described in U.S. patent 5,412,082, incorporated herein by reference. Other related enediyne compounds can be made after suitable modification of the processes disclosed herein. For example, a hydroxyl group can be included at carbon 6,

as in enediyne aglyone antitumor moieties such as esperamicin A _1# during the synthetic pathways disclosed herein. See, e.g., U.S. Patent No. 5,504,206, incorporated herein by reference. The C(6) hydroxyl preferably is incorporated at or before formation of compound 7.

In one embodiment, ketene acetal 5 is converted into silyl enol ether 6, which undergoes a Diels-Alder reaction with methyl (E) -2-nitropropenoate 66 to produce ketone 7. Modification of the nitro, ester, and allyl substituents then result in ketone 18.

Compound 18 has been discovered to undergo a stereoselective reaction with cerium trimethylsilylacetylide to place the acetylene unit syn to the nitrogen function. More basic acetylide reactants such as the lithium analog are less preferred. Further elaboration takes the synthesis as far as aldehyde 22 (also termed Compound 33) .

Similarly, ketone 7 can be converted into tricyclic ketone 28, which also reacts with cerium trimethylsilylacetylide but in the opposite stereochemical sense to 18, so as to place the acetylene unit anti to the nitrogen function (28 - 29) . Further elaboration results in lactone 32. Both 22 and 32 can be used as intermediates for the synthesis of (±) -calicheamicinone.

In the first pathway to calicheamicinone (Route B, Figure 7, Figure 4) , monoacetylenic aldehyde 33 which reacts with cerium trimethylsilylacetylide to stereoselectively form the bis (acetylene) 36 as the major product. This is

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SUBST1TUTESHEET(RULE26)

elaborated into lactone 40 which was desaturated (40-44) and acylated on nitrogen. The acetylenic silyl groups are then removed, so as to generate bis (acetylene) 46, and the terminal acetylenic hydrogens are replace by iodine. The resulting diidodide 56 forms the cyclic enediyne 57 on reaction with (Z) -1,2-bis (tributylstannyl)ethene in the presence of a (Ph3P)3Pd, and the enediyne is elaborated into {+) -calicheamicinone.

In the second pathway, bis (acetylene) 46 is synthesized from lactone 47, using, as a key step, free radical bromination of the derived lactone 51. See Figure 5. Compound 47 is the same as Compound 32. The resulting bromo lactone 52 is converted into aldehyde ester 54, and this is reacted with cerium trimethylsilylacetylide to stereoselectively give 55, convertible by the action of TBAF into 46.

The previous embodiments involved a Diels-Alder reaction between ketene acetal 6 and methyl 3- nitropropenoate (66) , to give ketone 7 (Scheme 7 of Figure 7) . As shown in Scheme 8 (Figure 7) , ketone 7 is converted into racemic calicheamicinone by two related methods, via 67 and 67' (in a first route, termed route A) and 68 and 68' (in a second route, termed Route B) . Transformations 7-67- 67'-(±)-l and 7-68-68'- (±) -1 were done using racemic compounds, but only one enantiomer is shown in Scheme 8 of Figure 7. Diagrams emphasize that in one route the acetylene at C(5) is introduced syn to the nitrogen, while

in the other route the relationship is anti. Further elaboration of 67' and 68' involves converting C(2), C(3), and C(4) to sp ² hybridization, so that the only stereogenic center retained in 67' and 68' is C(5) . In an alternative process, ketone 7 is used as the starting material to synthesize either enantiomer of calicheamicinone 1. This aspect of the present invention involves the discovery of an asymmetric Diels-Alder reaction between the ketene acetal 6 and a chiral auxiliary, e.g., the 3-nitropropenoate 72, resulting in the optically pure adduct 77. Compound 77 can subsequently be converted into either enantiomer of calicheamicinone (1) via one of two alternative pathways. Compound 72 can be derived, for example, from (-) -8-phenylmenthol (71) . Alternatively, the enantiomer (+) -8-phenylmenthol can be used. Either enantiomer of 7 can serve equally well for the preparation of (-)-l. The enantiomer of 7 with 2S absolute configuration is processed by route A, while the 2R isomer would also give (-)-l, but by route B. To carry out the initial Diels-Alder reaction in an asymmetric manner and form optically pure material, a nitroalkene 69 is used in which group X is a chiral auxiliary. One group of candidates are oxazolidinones, e.g. compound 70. Alternatively, (-) -8-phenylmenthol 71 can be used. Compound 71 is readily available from .R-pulegone as described in Ort, 1987. Compound 71 can be converted to

ketone 72 by reaction with 6, as shown in Scheme 9 of Figure 8.

Ketone 77 is reduced with NaBH4 to obtain a mixture of alcohols epimeric at C(5) , which are then silylated (78- 79; t-BuMe2SiOTf, 2,6-lutidine, ca . 100% over two steps) . Other trialkylsilyl moieties may also be used, e.g., a triethylsilyl moiety. The chiral auxiliary is disengaged by treatment with DIBAL-H (Diisobutyl aluminum hydride, also referred to as DIBAL) to afford 80 and 71. The t-BuMe2Si group at C(5) is removed if the reaction is carried out at room temperature. On the other hand, the reaction with DIBAL is very slow at -78°C. Therefore, it is preferable to add about 2 equivalents (equiv.) of DIBAL-H and carry out the reaction at -78°C for 4 hours (h) , transfer the reaction flask to a bath at -3,0°C for 24 h, add about 2 equiv. of DIBAL-H and stir at -30°C for about 24 h. At this point, the C(5) epimeric silyl ethers 80 can be isolated in 80% yield, and the auxiliary can be recovered in 92% yield. Epimers 80 are easily separated by flash chromatography over silica gel to obtain 81a (53% from 77) and 81b (27% from 77) .

The preparation of optically pure 81a and 81b as described above constitutes a formal synthesis of (-)- calicheamicinone. Application of Route B results in the formation of (+) -calicheamicinone the unnatural stereoisomer.

A pharmaceutical composition is contemplated that comprises a novel compound described herein as active agent dissolved or dispersed in a pharmaceutically acceptable carrier. A pharmaceutical composition is prepared by any of the methods known in the art of pharmacy all of which involve bringing into association the active compound and the carrier therefor. For therapeutic use, a novel compound can be administered in the form of conventional pharmaceutical compositions. Such compositions can be formulated so as to be suitable for oral or parenteral administration, or as suppositories. In these compositions, the agent is typically dissolved or dispersed in a physiologically tolerable carrier.

A carrier or diluent is a material useful for administering the active compound and must be

"pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. As used herein, the phrase "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce an untoward reaction, such as gastric upset, dizziness and the like, when administered to a mammal. The physiologically tolerable carrier can take a wide variety of forms depending upon the preparation desired for administration and the intended route of administration.

As an example of a useful composition, a compound of the invention (active agent) can be utilized, dissolved or

dispersed in a liquid composition such as a sterile suspension or solution, or as isotonic preparation containing suitable preservatives. Particularly well-suited for the present purposes are injectable media constituted by aqueous injectable buffered or unbuffered isotonic and sterile saline or glucose solutions, as well as water alone, or an aqueous ethanol solution. Additional liquid forms in which these compounds can be incorporated for administration include flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil, and the like, as well as elixirs and similar pharmaceutical vehicles. Exemplary further liquid diluents can be found in Remmington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA (1980) . An active agent can also be used in compositions such as tablets or pills, preferably containing a unit dose of the compound. To this end, the agent (active ingredient) is mixed with conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums, or similar materials as non-toxic, physiologically tolerable carriers. It should be understood that in addition to the aforementioned carrier ingredients the pharmaceutical formulation described herein can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, preservatives (including

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^' SUBSTΪTUTESHEET(RULE26)

antioxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.

The term "unit dose", as used herein, refers physically discrete units suitable as unitary dosages for administration to warm blooded animals, each such unit containing predetermined quantity of the agent calculated to produce the desired therapeutic effect in association with the pharmaceutically acceptable diluent. Examples of suitable unit dosage forms in accord with this invention are tablets, capsules, pills, powder packets, granules, wafers, cachets, teaspoonfuls, dropperfuls, ampules, vials, segregated multiples of any of the foregoing, and the like. An exemplary compound of the invention is present in such a pharmaceutical composition in an amount effective to achieve the desired result. For example, where in vi tro DNA cleavage is the desired result, a compound of the invention can be utilized in an amount sufficient to provide a concentration of about 1.0 to about 5000 micromolar (μM) with a DNA concentration of about 0.02 μg/μL. The non- naturally occurring isomer of calicheamicimone, when linked to the natural carbohydrate unit, appears to be more efficient in causing double strand cleavage of DNA than the natural compound. Compounds of the present invention provide potent DNA-cleaving activity.

As a cytotoxic (antitumor) agent, an effective amount of a compound is about 0.1 to about 15 mg per kilogram of

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SUBSTTTUTESHEET(RULE26)

body weight or an amount sufficient to provide a concentration of about 0.01 to about 50 μg/mL to the bloodstream. A compound of the invention exhibits antimicrobial activity in a concentration range of about 0.01 ng to about 50 μg/mL. The above concentrations and dosages vary with the particular compound of the invention utilized as well as with the target, e.g., DNA, tumor, microbe, as is known.

The invention will be further understood with reference to the following illustrative embodiments, which are purely exemplary and should not be taken as limiting the true scope of the present invention as described in the claims.

Abbreviations

AOM, p-methoxyphenoxymethyl; DMAP, p- dimethylaminopyridine; TBAF, tetrabutylammonium fluoride;

LDA, lithium diisopropylamide; NBS, N-bromosuccinimide ; THF, tetrahydrofuran. DMAP, p(dimethylamino)pyridine; Tf, S0 ₂ CF ₃ . Wedge-shaped lines are used for bonds projecting upwardly and dashed lines are used for bonds projecting downwardly.

Example 1

Two intermediates, compounds 22 and 32, useful for the synthesis of (±) - calicheamicinone are synthesized in this example. A key step in the formation of these intermediates is the stereoselective addition of an acetylene unit.

An ester exchange reaction with β-keto ester 4, C1CH ₂ CH ₂ 0H and Ti(0Pr-J) ₄ followed by K ₂ C0 ₃ treatment generated ketene acetal 5. Triene 6 was formed by deprotonating 5 to the z-enolate using (Ph ₂ MeSi) ₂ NLi and trapping with Me ₃ SiCl . A Diels-Alder reaction with triene 6 and methyl- (E) -2-nitropropenoate 66 was used to form ketone 7, a key intermediate in the synthesis. Its structure was confirmed by x-ray analysis. Ketone 7 contains all necessary carbons of the target compounds, except for the enediyne and carbamate. See Figure 1.

As shown in Figure 2, reduction of 7 with NaBH ₄ produced a 2:1 mixture of C(5) epimeric alcohols 8, of which the major epimer (5-β) is shown. The alcohols were separated after silylation with t-BuMeSiOTF and 2,6-lutidine to form 9. Both isomers were independently converted into ketone 18 by identical routes, but only the procedure for the major β isomer is described. Yields for the corresponding α isomer are given in Scheme 2 in parentheses. DIBAL-H reduction of the ester group of alcohol 9 generated primary alcohol 10. A pivoloate protective moiety was added to alcohol 10 using t-BuCOCl and DMAP, forming compound 11. Cleavage of the double bond in 11 with Os0 ₄ and NaI0 ₄ , resulted in aldehyde 12. Reduction of 12 with NaBH ₄ to the corresponding alcohol 13 and protection with p- methoxyphenoxymethyl chloride and I-Pr ₂ NEt resulted in compound 14. The nitro group of 14 was reduced with NiCl ₂ and NaBH ₄ to form 15, then protected with allyloxycarbonyl

-30-

SUBST1TUTESHEET(RULE26)

chloride and pyridine to generate carbamate 16. Desilylation of carbamate 16 with TBAF resulted in 17; subsequent Collins oxidation gave ketone 18.

Introduction of the enediyne system into ketone 18 was initiated with cerium trimethylsilyl-acetylide . This reaction had high stereoselectivity and an excellent yield. The cerium salt was prepared as follows. Cerium chloride heptahydrate was dehydrated by stirring for 3-12 hours at 130°C under 0.05 mmHg. After cooling the anhydrous salt, it was covered with tetrahydrofuran (THF) and sonicated overnight to obtain a fine suspension. The suspension was cooled to -78°C and a precooled (-78°C) , freshly made solution of lithium salt of trimethylsilylacetylene in THF was rapidly added and stirred at -78°C for 40 minutes. An acetylene unit was introduced at C5 of ketone 18, syn to the nitrogen substituent, by cerium trimethylsilylacetylide treatment, resulting in tertiary alcohol 19. Compound 19 was protected with t-BuMe ₂ SiOTf and 2,6-lutidine to form 20, then reduced with DIBAL-H to remove the pivaloyl group, forming alcohol 21. Oxidation of 21 resulted in aldehyde 22, an advanced key intermediate that serves as the starting point for attachment of an acetylenic unit at C(9) in a stereocontrolled manner, introduction of a double bond at C(2)-C(3), and geometrically controlled introduction of a double bond at C(4) - C(7) .

An alternative advanced intermediate 32 was synthesized as shown in Scheme 3 of Figure 3. Compounds 22 (also

referred to herein as 33) and 32 are both suitable for conversion into 1 and related compounds. The second approach was also initiated from racemic 10. Both the C(5- β) isomer and the corresponding C(5-α) isomer can be used. As described above, only the route from 5-β is shown, but yields for the same reactions in the 5-α series are given in Scheme 3 of Figure 3.

As shown in Figure 3, the double bond of 10 was first cleaved with Os0 ₄ and NaI0 ₄ and the resulting equilibrium mixture of lactols 23 produced a single pivaloate 24 in the presence of t-BuCOCl and pyridine. The nitro group of 24 was reduced with NiCl ₂ and NaBH ₄ to form 25, then protected with allyloxycarbonyl chloride and pyridine to afford 26. Compound 26 was desilylated with TBAF to generate 27 then PCC oxidized, forming compound 28. The first acetylene unit was introduced into 28 by reaction with cerium trimethylsilylacetylide, forming tertiary alcohol 29. The cerium salt was prepared as described for scheme 2. In this alternative route, the acetylene was introduced anti to the nitrogen, opposite to that observed in the first route.

Protection of the hydroxyl of 29 with t-BuMe ₂ SiOTf and 2,6- lutidine resulted in 30. DIBAL-H reduction of 30 removed the pivaloyl group to form 31; Collins oxidation then produced compound 32. Addition of double bonds at C(4) - C(7) and C(2) - C(3) and an acetylene unit at C(9) are described below.

-32-

SUBSTITIJTE SHEET (RULE 26)

In both 22 and 32, the only stereogenic center that is preserved after elaboration to (±) - calicheamicinone is C(5) . Consequently, when synthesizing (-) - calicheamicinone of natural stereochemistry as depicted in 1, intermediates corresponding to 7 with (2R) absolute configuration must be processed by the route of Figure 2. The reactions of Figure 3 would be used to prepare the (2S) isomer.

O 7

SPECTRAL DATA Compound 4

FTIR (CHC1 ₃ cast) 1749, 1718 cm" ¹ ;

^X H NMR (CDC1 ₃ , 200 MHZ) δ 5.81 (dd t, J = 16.8, 10.4, 6.4 Hz, 1 H) , 5.09-5.03 (m, 1 H) , 5.09-4.98 (m, 1 H) , 4.40 (t, J = 6.4 Hz, 2 H) , 3.60 (t, J = 6.4 Hz, 2 H) , 3.52 (s, 2 H) , 2.68 (t, J ^" = 7.2 Hz, 2 H) , 2.32-2.40 (m, 2 H) ; ¹³ C NMR (CDCI3, 50.3 MHZ) δ 201.15, 166.33, 136.22, 115.00, 64.23, 48.42, 41.46, 41.09, 26.87; exact mass m/z calculated for C ₉ H13CIO ₃ 204.05531, found 204.0553.

Compound 5

FTIR (CHCI ₃ cast) 1715, 1674, 1621, 1586 cπrr ¹ ;

^X H NMR (CDCI ₃ , 200 MHZ) δ 2.25-2.37 (m, 2 H) , 2.42-2.52 (m, 2 H) , 4.33-4.41 (m, 2. H) , 4.51-4.62 (m, 2 H) , 4.88- 5.05 (m, including s at δ 4.93, 3 H) , 5.77 (ddt, J = 17.2, 10.1, 6.5

Hz, 1 H) ;

¹³ C NMR (CDCI3, 100.6 MHZ) δ 28.83, 41.45, 65.40, 68.16,

78.38, 114.41, 137.76, 168.32, 196.40; exact mass m/z calculated for CgH^Os 168.0787, found

168.0785.

Compound 7

X-Ray structure determined.

FTIR (CHCI3 cast) 1733, 1560 cm ^"1 ; ^X H NMR (CDCI ₃ , 400 MHZ) δ 2.12-2.20 (m, 1 H) (, 2.33-2.42 (m, 1 H) , 2.56 (α, J = 8.0 Hz, 1 H) , 2.78 (d, J = 8.0 Hz, 1 H) ,

2.96-3.05 (m, 1 H) , 3.70 (s, 3 H) , 3.83 (dd, J = 10.0, 5.0 Hz, 1 H) , 3.86-4.03 (m, 4 H) , 5.00-5.05 (dm, J = 8.0 Hz, 2 H) , 5.33 (d, J = 10.0 Hz, 1 H) , 5.52-5.63 (m, 1 H) ; ¹³ C NMR (CDC1 ₃ , 100.6 MHZ) δ 32.02, 44.46, 47.99, 48.66, 52.68, 65.76, 65.83, 85.04, 107.11, 118.11, 133.25, 169.60, 202.38; exact mass m/z calculated for Cχ ₃ Hι7N0 ₇ 299.1005, found 299.1001.

Anal. Calculated for Cι ₃ Hι7N0 ₇ : C 52.17, H 5.73, N 4.68. Found: C 52.25, H 5.78, N 4.68.

Compounds 8α &β ["α" refers to C- (5) , the substituent being below the plane of the paper; the β isomer has the C- (5) substituent above the plane of the paper.]

FTIR (CH ₂ C1 ₂ cast) 3530, 1736 cm" ¹ ; ^X H NMR (CDCI ₃ , 400 MHZ) δ 5.77-5.58 (m, 1 H) , 5.08-4.90 (m,

3 H) , 4.15 (dt, J = 12.0, 4.5 Hz, 0.67 H) , 4.08-3.82 (m,

4.66 H) , 3.70 (s) and 3.64 (s) (3 H) , 3.54 (dd, J = 8.4, 4.4

Hz, 0.67 H) , 2.67-2.44 (m) and 2.10-1.75 (m) (6 H) ;

¹³ C NMR (CDCI ₃ , 100.6 MHZ) δ (major) 170.8, 136.8, 116.2, 107.3, 84.6, 68.3, 65.4, 65.2, 52.0, 43.0, 41.5, 39.3, 27.3,

(minor) 171.6, 134.6, 117.5, 108.1, 84.4, 67.9, 65.8, 65.1,

52.3, 45.1, 42.8, 35.6, 32.2; exact mass m/z calculated for 301.11615, found

301.11637. Compound 9α (minor isomer) X-Ray structure determined.

FTIR (CH ₂ CI2 cast) 1738 cm ^-1 ; ⁱ H NMR (CDC1 ₃ , 400 MHZ) δ 5.70-5.57 (m, 1 H) , 5.10-4.90 (m,

3 H) , 4.05-3.79 (m, 6 H) , 3.70 (s, 3 H) , 2.34-2.21 (m, 1 H) ,

2.13-2.02 (m, 1 H) , 1.98-1.75 (m, 3 H) , 0.91 (s, 9 H) , 0.07 (s, 3 H) , 0.04 (s, 3 H) ;

¹³ C NMR (CDCI3, 100.6 MHZ) δ 172.0, 135.0, 117.4, 107.6,

85.0, 67.2, 65.3, 64.7, 52.1, 43.6, 42.9, 37.4, 31.9, 25.5,

17.8, -4.8, -4.9; exact mass m/z calculated for Cι ₅ H24N0 ₇ Si (M-t-Bu) 358.13220, found 358.13268 (M-t-Bu) .

Compound 9β (Major isomer)

FTIR (CH ₂ CI ₂ cast) 1741 cm ^"1 ; ^α H NMR (CDCI ₃ , 400 MHz) δ 5.65-5.50 (m, 1 H) , 5.03-4.87 (m,

3 H) , 4.10-4.03 (m, 1 H) , 4.03-3.84 (m, 4 H) , 3.61 (s, 3 H) , 3.52 (dd, J = 12.3, 4.4 Hz, 1 H) , 2.62-2.50 (m, 1 H) , 2.48-

2.36 (m, 1 H) , 1.85 (dt, J = 14.8, 8.6 Hz, 1 H) , 1.77 (d, J

= 8.5 HZ, 2 H) , 0.88 (s, 9 H) , 0.08 (s, 3 H) , 0.07 (s, 3 H) ;

¹³ C NMR (CDCI ₃ , 100.6 MHz) δ 170.7, 137.0, 115.9, 107.5,

84.8, 68.7, 65.5, 65.3, 51.9, 44.9, 42.6, 40.4, 27.0, 25.7, 18.0, -4.7; exact mass m/z calculated for Ci ₉ H ₃ 3N0 ₇ Si 415.20261, found

415.20252.

Anal. Calculated for C ₁₉ H ₃ 3N0 ₇ Si : C 54.92, H 8.00, N 3.37, O

26.95. Found: C 55.039, N 8.110, N 3.236. Compound 10a

FTIR (CH ₂ CI ₂ cast) 3550 cm ^"1 ;

-36-

SUBSTTTUTE SHEET (RULE 26)

ⁱ H NMR (CDCI ₃ , 400 MHz) δ 5.90-5.62 (m, 1 H) , 5.14-4.98 (m, 2 H) , 4.91 (d, J = 1.3 Hz, 1 H) , 4.13-3.98 (m, 4 H) , 3.85- 3.68 (m, 3 H) , 2.69-2.50 (m, 2 H) , 2.40-2.23 (m, 2 H) , 1.97- 1.78 (m, 3 H) , 0.90 (s, 9 H) , 0.07 (s, 3 H) , 0.06 (s, 3 H) ; ¹³ C NMR (CDCI ₃ , 100.6 MHz) δ 136.3, 116.6, 106.6, 86.0,

68.4, 65.1, 64.9, 59.0, 41.2, 40.7, 40.4, 31.7, 25.7, 17.9, -4.3, -4.8; exact mass m/z calculated for Cι ₄ H ₂ 4NOgSi (M-t-Bu) 330.13730, found 330.13706. Anal. Calculated for Cι ₈ H ₃ 3N0 ₆ Si : C 55.79, H 8.58, N 3.61. Found: C 55.48, H 8.60, N 3.44.

Compound 10 β

FTIR (CH ₂ C1 ₂ cast) 3544, 3442 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHz) δ 5.96-5.77 (m, 1 H) , 5.18-4.97 (m, 2 H) , 4.58 (d, J = 9:3 Hz, 1 H) , 4.10-4.01 (m, 1 H) , 4.01-

3.87 (m, 4 H) , 3.80-3.63 (m, 2 H) , 2.70-2.57 (m, 1 H) , 2.54-

2.40 (m, 1 H) , 2.37-2.25 (m, 1 H) , 2.12-1.88 (m, 2 H) , 1.88-

1.70 (m, 2 H) , 0.89 (s, 9 H) , 0.07 (s, 3 H) , 0.06 (s, 3 H) ;

¹³ C NMR (CDCI3, 100.6 MHz) δ 138.5, 115.7, 106.9, 86.6, 69.0, 65.0, 60.0, 42.0, 40.4, 40.2, 25.6, 17.9, -4.6, -4.9; exact mass m/z calculated for C ₁₄ H ₂ 4.N0 ₆ Si (M-t-Bu) 330.13730, found 330.13697; exact mass m/z calculated for C ₁₈ H ₃ 3N0 ₆ Si

^' 387.2077, found 387.2074.

Anal. Calculated for Cι ₈ H ₃ 3N0 ₆ Si : C 55.78, H 8.58, N 3.61. Found: C 56.12, H 8.76, N 3.79.

Compound llα

FTIR (CH ₂ C1 ₂ cast) 1733 cm ^"1 ; ⁱ H NMR (CDC1 ₃ , 400 MHz) δ 5.80-5.64 (m, 1 H) , 5.15-5.02 (m, 2 H) , 4.76 (α, J ^" = 3.7 Hz, 1 H) , 4.30 (dd, J = 11.0, 5.8 Hz, 1 H) , 4.12-3.85 (m, 5 H) , 3.80-3.68 (m, 1 H) , 2.90-2.78 (m,

1 H) , 2.56-2.41 (m, 1 H) , 2.35-2.20 (m, 2 H) , 1.98-1.82 (m,

2 H) , 1.21 (s, 9 H) , 0.90 (s, 9 H) , 0.06 (s, 3 H) , 0.05 (s,

3 H) ;

¹³ C NMR (CDCI ₃ , 100.6 MHz) δ 177.6, 135.4, 117.1, 106.7, 85.3, 68.0, 64.9, 60.6, 41.1, 40.0, 37.7, 31.6, 27.0, 25.6, 17.8, -4.4, -4.9; exact mass m/z calculated for Ci ₉ H ₃ 2N0 ₇ Ξi (M-t-Bu) 414.19479, found 414.19321.

Compound llβ FTIR (CH ₂ Cl ₂ cast) 1733 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHz) δ 5.85-5.70 (m, 1 H) , 5.12-4.91 (m, 2 H) , 4.75 (d, J = 8.2 Hz, 1 H) , 4.29-4.14 (m, 2 H) , 4.14- 3.88 (m, 5 H) , 2.84-2.68 (m, 1 H) , 2.49-2.35 (m, 1 H) , 2.35- 2.23 (m, 1 H) , 2.15-1.96 (m, 2 H) , 1.83 (dd, J = 13.8, 8.3 Hz, 1 H) , 1.19 (s, 9 H) , 0.90 (s, 9 H) , 0.07 (s, 3 H) , 0.05 (s, 3 H) ;

¹³ C NMR (CDCI ₃ , 100.6 MHz) δ 177.8, 137.5, 116.1, 106.7, 86.7, 69.0, 65.2, 65.0, 62.6, 41.1, 40.0, 39.8, 38.7, 27.1, 25.7, 18.0, -4.5, -4.8; exact mass m/z calculated for C ₁₉ H ₃ 2N0 ₇ Si (M-t-Bu) 414.19479, found 414.19495.

Compound 12α

FTIR (CH ₂ C1 ₂ cast) 1729 cm ^"1 ;

^X H NMR (CDC1 ₃ , 400 MHz) δ 9.72 (dd, J = 2.2, 1.1 Hz, 1 H) , 4.71 (dd, J = 2.9, 1.2 Hz, IH) , 4.19 (dd, J = 11.3, 5.6 Hz, 1 H) , 4.15-3.85 (m, 5 H) , 3.78-3.67 (m, 1 H) , 3.07-2.93 (m,

1 H) , 2.90-2.78 (m, 1 H) , 2.68-2.55 (m, 1 H) , 2.44-2.32 (m,

2 H) , 2.02-1.90 (m, 1 H) , 1.20 (s, 9 H) , 0.87 (s, 9 H) , 0.07 (s, 3 H) , 0.05 (s, 3 H) ;

¹³ C NMR (CDC1 ₃ , 100.6 MHz) δ 200.5, 177.8, 106.6, 85.4, 68.6, 65.2, 65.1, 61.2, 43.0, 40.5, 39.8, 38.8, 36.3, 27.1, 25.7, 17.9, -4.2, -4.6; exact mass m/z calculated for CιeH ₃ θN0 ₈ Si (M-t-Bu) 416.17407, found 416.17344.

Compound 12 β FTIR (CH ₂ C1 ₂ cast) 1731 cm ^"1 ; ⁱ H NMR (CDC1 _3/ 400 MHz) δ 9.72 (d, J = 1.1 Hz, 1 H) , 4.66 (d, J = 11.2 Hz, 1 H) , 4.20-4.07 (m, 2 H) , 4.07-3.86 (m, 5 H) , 3.01-2.87 (m, 2 H) , 2.78-2.65 (m, 1 H) , 2.41 (dd, J = 17.1, 4.5 Hz, 1 H) , 1.90 (dd, J = 13.5, 4.0 Hz, 1 H) , 1.75 (dd, J = 13.5, 11.2 Hz, 1 H) , 1.18 (s, 9 H) , 0.85 (s, 9 H) , 0.07 (s, 3 H) , 0.04 (s, 3 H) ;

¹³ C NMR (CDCI ₃ , 100.6 MHz) δ 199.5, 177.3, 107.2, 86.0, 68.4, 65.5, 65.2, 62.6, 40.2, 38.7, 37.8, 37.6, 36.8, 26.9, 25.6, 17.9, -4.9, -5.0; exact mass m/z calculated for Cι ₈ H ₃ 0NO ₈ Si (M-t-Bu) 416.17407, found 416.17398.

Anal. Calculated for C ₂ 2H39N0 ₈ Si : C 55.79, H 8.30, N 2.96. Found: C 56.00, H 8.34, N 2.84.

Compound 13α

FTIR (CH ₂ C1 ₂ cast) 3500, 1732 cm ^"1 ; ^X H NMR (CDC1 ₃ , 400 MHz) δ 4.72 (d, J = 3.5 Hz, 1 H) , 4.36 (dd, J ^" = 11.2, 5.5 Hz, 1 H) , 4.17-3.83 (m, 5 H) , 4.82-3.65 (m, 3 H) , 2.93-2.80 (m, 1 H) , 2.43-2.22 (m, 2 H) , 1.99-1.80 (m, 2 H) , 1.66-1.45 (m, 1 H) , 1.60 (s, 1 H, OH), 1.22 (s, 9

H) , 0.90 (s, 9 H) , 0.08 (s, 3 H) , 0.07 (s, 3 H) ; ¹³ C NMR (CDCI ₃ , 100.6 MHz) δ 178.0, 106.7, 85.5, 68.6, 65.0,

61.2, 61.1, 40.3, 39.0, 38.8, 30.4, 27.1, 25.7, 17.9, -4.4,

-4.7; exact mass m/z calculated for C _1B H ₃ 2N0 ₈ Si (M-t-Bu) 418.18973, found 418.18841. Compound 13 β

FTIR (CH ₂ C1 ₂ cast) 3500, 1731 cm ^"1 ; ⁱ H NMR (CDC1 ₃ , 400 MHz) δ 4.69 (d, J = 10.9 Hz, 1 H) , 4.26- 4.07 (m,3 H) , 4.07-3.87 (m, 3 H) , 3.75-3.51 (m, 2 H) , 2.94- 2.78 (m, 1 H) , 2.58 (bs, 1 H, OH) , 2.33-2.20 (m, 1 H) , 2.03- 1.86 (m, 2 H) , 1.85-1.60 (m, 2 H) , 1.19 (s, 9 H) , 0.91 (s, 9 H) , 0.11 (s, 6 H) ; ¹³ C NMR (CDCI ₃ , 100.6 MHz) δ 177.7, 107.2, 86.4, 69.7, 65.3,

65.2, 62.6, 61.9, 39.9, 39.0, 38.7, 26.9, 25.7, 18.0, -4.8,

-5.0; exact mass m/z calculated for Cι ₈ H ₃ 2N0 ₈ Si (M-t-Bu) 418.18973, found 418.18973.

Compound 14α

FTIR (CH2CI2 cast) 1732 cm ^"1 ; iH NMR (CDCI3, 400 MHz) δ 6.97-6.87 (m, 2 H) , 6.85-6.76 (m, 2 H) , 5.12 (ABq, J = 6.9, Δυ = 11.3 Hz, 2 H) , 4.68 (dd, J = 4.0, 0.9 Hz, 1 H) , 4.29 (dd, J = 11.1, 4.4 Hz, 1 H) ,

4.10-3.85 (m, 5 H) , 3.82-3.65 (m, 3 H) , 3.77 (s, 3 H) , 2.82- 2.73 (m, 1 H) , 2.40-2.30 (m, 1 H) , 2.26 (dd, J = 13.5, 9.2 Hz, 1 H) , 2.02-1.86 (m, 2 H) , 1.57-1.46 (m, 1 H) , 1.19 (s, 9 H) , 0.88 (s, 9 H) , 0.06 (s, 3 H) , 0.04 (s, 3 H) ; ¹³ C NMR (CDCI3, 100.6 MHz) δ 177.8, 154.6, 151.2, 117.2, 114.6, 106.7, 93.9, 85.4, 68.7, 66.7, 65.0, 65.0, 61.0, 55.6, 40.3, 38.8, 38.7, 38.5, 27.5, 27.1, 25.7, 17.9, -4.3, -4.7; exact mass m/z calculated for C ₃ oH ₄ 9NOιθSi 611.31256, found 611.31224.

Compound 14 β

FTIR (CH ₂ C1 ₂ cast) 1732 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHz) δ 6.98-6.87 (m, 2 H) , 6.87-6.73 (m,

2 H) , 5.12 (ABq, J = 7.2, Δυ = 4.4 Hz, 2 H) , 4.69 (d, J = 8.5 Hz, 1 H) , 4.19 (d, J = 5.6 Hz, 2 H) , 4.08-3.85 (m, 5 H) , 3.85-3.57 (m, 2 H) , 3.77 (s, 3 H) , 2.64 (bs, 1 H) , 2.22 (bs, 1 H) , 2.05-1.92 (m, 1 H) , 1.92-1.73 (m, 2 H) , 1.73-1.58 (m, 1 H) , 1.17 (s, 9 H) , 0.87 (s, 9 H) , 0.04 (s, 3 H) , 0.03 (s,

3 H) ;

¹³ C NMR (CDC1 ₃ , 75.5 MHZ) δ 177.7, 154.5, 151.1, 117.1, 114.6, 106.6, 93.5, 86.5, 69.0, 67.4, 65.1, 65.0, 62.9, 55.6, 39.7, 39.4, 38.7, 32.7, 27.0, 25.7, 17.9, -4.7, -4.9; exact mass m/z calculated for C ₃ oH ₄ 9NOιθSi 611.31256, found 611.31105.

Compound 15α

FTIR (CH ₂ C1 ₂ Cast) 3449, 3386, 1725 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 7.01-6.90 (m, 2 H) , 6.87-6.75 (m,

2 H) , 5.13 (ABq, J = 6.9, Δυ = 7.3 Hz, 2 H) , 4.31 (dd, J ^" = 11.2, 7.3 Hz, 1 H) , 4.10 (dd, J = 11.3, 7.3 Hz, 1 H) , 4.00- 3.84 (m, 4 H) , 3.80-3.62 (m, 3 H) , 3.76 (s, 3 H) , 2.87 (d, J = 5.7 Hz, 1 H) , 2.27 (bs, 1 H) , 2.07-1.76 (m, 2 H) , 1.90 (dd, J = 13.4, 7.9 Hz, 1 H) , 1.68 (dd, J = 13.4, 3.9 Hz, 1 H) , 1.63-1.49 (m, 1 H) , 1.36 (bs, 2 H, NH ₂ ) , 1.17 (s, 9 H) , 0.87 (S, 9 H) , 0.02 ( s , 3 H) , 0.01 (s, 3 H) ;

¹³ C NMR (CDCI ₃ , 100.6 MHZ) δ 178.2, 154.5, 151.4, 117.3, 114.5, 110.0, 93.9, 69.4, 67.2, 65.0, 64.2, 63.4, 55.6, 52.5, 39.9, 38.6, 38.2, 38.0, 27.1, 27.1, 25.7, 17.9, -4.5, -4.8; exact mass m/z calculated for C ₃₀ H ₅ lNO ₈ Si 581.33838, found 581.33746.

Compound 15 β

FTIR (CH ₂ C1 ₂ cast) 3451, 3385 cm ^"1 ;

^X H NMR (CDCI ₃ , 400 MHZ) δ 7.00-6.88 (m, 2 H) , 6.84-6.72 (m, 2 H) , 5.11 (s, 2 H) , 4.55 (dd, J ^" = 11.4, 4.7 Hz, 1 H) , 4.10- 3.70 (m, 7 H) , 3.76 (s, 3 H) , 3.66-3.54 (m, 1 H) , 2.66 (d, J

= 11.3 Hz, 1 H) , 2.02-1.82 (m, 3 H) , 1.80 (dd, J = 13.4, 4.2 Hz, 1 H) , 1.63 (dd, J = 13.1, 11.5 Hz, 1 H) , 1.68-1.51 (m, 1 H) , 1.18 (s, 11 H) , 0.86 (s, 9 H) , 0.03 (s, 3 H) , 0.01 (s, 3 H) ; ¹³ C NMR (CDC1 ₃ , 100.6 MHZ) δ 178.0, 154.5, 151.3, 117.4, 114.4, 109.3, 93.9, 70.5, 69.1, 65.1, 64.0, 55.5, 52.8, 41.0, 38.6, 38.3, 27.1, 25.7, 18.0, -4.8, -4.9; exact mass m/z calculated for C ₃ oH ₅ lN0 ₈ Si 581.33838, found 481.33639. Compound 16α

FTIR (CH ₂ C1 ₂ cast) 3446, 1729 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 7.00-6.89 (m, 2 H) , 6.89-6.73 (m,

2 H) , 6.00-5.84 (m, 1 H) , 5.33-5.17 (m, 2 H) , 5.12 (s, 2 H) ,

4.87 (d, J = 9.7 Hz, 1 H, NH) , 4.55 (d, J = 5.5 Hz, 2 H) , 4.24 (dd, J = 11.3, 6.3 Hz, 1 H) , 4.13-3.72 (m, 7 H) , 3.76

(s, 3 H) , 3.69 (t, J = 6.4 Hz, 2 H) , 2.63-2.43 (m, 1 H) ,

1.95-1.82 (m, 1 H) , 1.82-1.57 (m, 4 H) , 1.17 (s, 9 H) , 0.86

(s, 9 H) , 0.00 (s, 3 H) , -0.02 (s, 3 H) ;

¹³ C NMR (CDCI ₃ , 75.5 MHZ) δ 178.0, 156.1, 154.6, 151.3, 132.8, 117.5, 117.3, 114.6, 108.4, 94.1, 68.6, 67.3, 65.6,

65.0, 64.7, 62.9, 55.6, 52.1, 39.7, 38.7, 37.8, 37.6, 27.1,

26.3, 25.6, 17.8, -4.7, -5.0; exact mass m/z calculated for C ₃₄ H ₅ 5Nθ _! θSi 665.35950, found

665.36017. Compound 16 β

FTIR (CH ₂ CI ₂ cast) 3347, 1727 cm ^"1 ;

-43-

SUBSTITUTE SWEET (RULE 26)

ⁱ H NMR (CDC1 ₃ , 400 MHZ) δ 7.00-6.90 (m, 2 H) , 6.86-6.75 (m, 2 H) , 6.00-5.81 (m, 1 H) , 5.35-5.17 (m, 2 H) , 5.12 (s, 2 H) , 4.66 (d, J ^** - 10.2 Hz, 1 H, NH) , 4.62-4.48 (m, 2 H) , 4.28

(dd, J = 11.4, 4.4 Hz, 1 H) , 4.12-3.73 (m, 8 H) , 3.77 (s, 3 H) , 3.69-3.54 (m, 1 H) , 2.04-1.88 (m, 3 H) , 1.82-1.70 (m, 2 H) , 1.70-1.53 (m, 1 H) , 1.17 (s, 9 H) , 0.86 (s, 9 H) , 0.04

(s, 3 H) , 0.03 (s, 3 H) ;

¹³ C NMR (CDCI ₃ , 75.5 MHZ) δ 177.9, 156.1, 154.5, 151.3, 132.8, 117.7, 117.4, 114.5, 108.3, 93.8, 70.2, 68.8, 65.6, 65.4, 65.0, 63.5, 55.5, 52.5, 40.6, 38.8, 38.6, 38.5, 27.1, 25.7, 22.6, 18.0, -4.9, -5.0; exact mass m/z calculated for C ₃₄ H55θ _! θNSi 665.35950, found 665.36039.

Compound 17 α FTIR (CH ₂ C1 ₂ cast) 3520, 3352, 1725 cm ^"1 ;

^X H NMR (CDCI ₃ , 400 MHZ) δ 7.00-6.88 (m, 2 H) , 6.86-6.79 (m, 2 H) , 5.97-5.81 (m, 1 H) , 5.36-5.17 (m, 2 H) , 5.12 (s, 2 H) , 4.70 (d, J ^" = 10.2 Hz, 1 H, NH) , 4.65-4.48 (m, 2 H) , 4.25 (dd, J = 11.5, 5.1 Hz, 1 H) , 4.15-3.85 (m, 7 H) , 3.77 (s, 3 H) , 3.69 (t, J = 6.4 Hz, 2 H) , 3.44 (d, J = 8.9 Hz, 1 H,

OH) , 2.48-2.35 (m, 1 H) , 2.18-2.07 (m, 1 H) , 1.96-1.75 (m, 3 H) , 1.50-1.37 (m, 1 H) , 1.17 (s, 9 H) ;

¹³ C NMR (CDCI ₃ , 100.6 MHZ) δ 178.1, 156.1, 154.7, 151.3, 132.7, 117.9, 117.4, 114.6, 109.3, 94.0, 68.8, 67.1, 65.8, 65.5, 63.4, 55.6, 52.8, 40.1, 38.7, 37.3, 34.7, 27.1, 26.2;

exact mass m/z calculated for C ₂₈ H ₄ lNOχθ 551.27307, found 551.27185.

Compound 17 β

FTIR (CH ₂ C1 ₂ cast) 3450, 3354, 1725 cm ^"1 ; ⁱ H NMR (CDC1 ₃ , 400 MHZ) δ 6.98-6.88 (m, 2 H) , 6.88-6.76 (m, 2 H) , 5.99-5.80 (m, 1 H) , 5.35-5.18 (m, 1 H) , 5.16 (ABq, J = 7.0, Δυ = 11.6 Hz, 2 H) , 4.68 (d, J = 9.9 Hz, 1 H, NH) , 4.62-4.45 (m, 2 H) , 4.33-4.18 (m, 1 H) , 4.10-3.70 (m, 8 H) , 3.77 (s, 3 H) , 3.68-3.56 (m, 1 H) , 2.97 (d, J = 5.1 Hz, 1 H, OH) , 2.22-2.13 (m, 1 H) , 2.13-2.00 (m, 1 H) , 2.00-1.83 (m, 2 H) , 1.81-1.62 (m, 2 H) , 1.16 (s, 9 H) ;

¹³ C NMR (CDC1 ₃ , 100.6 MHZ) δ 178.0, 156.2, 154.7, 151.0, 132.7, 117.7, 117.3, 114.6, 108.2, 93.8, 68.9, 68.6, 65.7, 65.4, 65.0, 63.2, 55.5, 52.5, 40.8, 39.1, 38.6, 38.2, 27.1, 22.4; exact mass m/z calculated for C2 _S H ₄ INO1O 551.27307, found 551.27210.

Compound 18

FTIR (CH ₂ C1 ₂ cast) 3351, 1724 cm ^"1 ; iH NMR (CDCI ₃ , 400 MHZ) δ 6.98-6.87 (m, 2 H) , 6.87-6.76 (m,

2 H) , 6.02-5.82 (m, 1 H) , 5.38-5.16 (m, 2 H) , 5.07 (ABq, J = 7.0, Δυ = 11.6 Hz, 2 H) , 4.73 (bs, 1 H) , 4.59 (d, J = 5.4 Hz, 2 H) , 4.28-4.15 (m, 2 H) , 4.15-3.85 (m, 5 H) , 3.77 (s, 3 H) , 3.75-3.56 (m, 2 H) , 2.88-2.69 (m, 2 H) , 2.50 (dd, J = 15.1, 1.2 Hz, 1 H) , 2.36-2.22 (m, 1 H) , 2.11-1.94 (m, 1 H) , 1.88-1.71 (m, 1 H) , 1.16 (s, 9 H) ;

¹³ C NMR (CDC1 ₃ , 100.6 MHZ) δ 206.5, 178.0, 156.1, 154.6, 151.1, 132.6, 117.9, 117.3, 114.6, 108.7, 93.9, 66.1, 65.9, 65.8, 65.2, 55.6, 53.0, 47.3, 40.2, 38.7, 27.0, 26.0; exact mass m/z calculated for C2 _S H39NO ₁ O 549.25739, found 549.25836. Compound 19

FTIR (cκ ₂ Cl ₂ cast) 3446, 1727 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 7.00-6.90 (m, 2 H) , 6.86-6.75 (m, 2 H) , 6.00-5.82 (m, 1 H) , 5.34-5.15 (m, 2 H) , 5.15 (ABq, J = 6.9 Hz, Δυ = 14.6 Hz, 2 H) , 4.84 (d, J = 9.3 Hz, 1 H, NH) ,

4.55 (d, J = 5.3 Hz, 2 H) , 4.44-4.31 (m, 1 H) , 4.09-3.71 (m, 7 H) , 3.77 (s, 3 H) , 3.71-3.61 (m, 1 H) , 3.26 (bs, 1 H, OH) , 2.58-2.44 (m, 1 H) , 2.25-2.14 (m, 1 H) , 2.16 (dd, J = 14.1, 1.5 Hz, 1 H) , 2.07-1.92 (m, 1 H) , 1.86 (d, J = 14.1 Hz, 1 H) , 1.83-1.78 (m, 1 H) , 1.17 (s, 9 H) , 0.16 (s, 9 H) ;

¹³ C NMR (CDC1 ₃ , 100.6 MHZ) δ 177.8, 156.1, 154.6, 151.1, 132.6, 117.6, 117.4, 114.5, 109.0, 107.0, 93.9, 88.3, 68.8, 68.4, 65.6, 65.2, 64.4, 62.5, 55.5, 51.8, 43.5, 41.7, 40.4, 38.6, 27.0, 23.5, -0.26; exact mass m/z calculated for C ₂₆ H ₄ 2NOι0Si (M-CH ₃ 0-C ₆ H ₄ 0) 524.26794, found 524.26726.

Compound 20

FTIR (CH ₂ C1 ₂ cast) 3449, 1729 cm ^"1 ; ⁱ H NMR (CDC1 _3/ 400 MHZ) δ 7.00-6.90 (m, 2 H) , 6.87-6.76 (m, 2 H) , 6.00-5.82 (m, 1 H) , 5.37-5.15 (m, 2 H) , 5.11 (s, 2 H) , 4.83 (d, J = 8.6 Hz, 1 H, NH) , 4.55 (d, J ^" = 5.3 Hz, 2 H) ,

4.46-4.28 (m, 1 H) , 4.10-3.69 (m, 7 H) , 3.77 (s, 3 H) , 3.69- 3.57 (m, 1 H) , 2.55-2.40 (m, 1 H) , 2.11-1.94 (m, 2 H) , 1.84 (ABq, J ^" = 14.0 Hz, Δυ = 74.6 Hz, 2 H) , 1.78-1.57 (m, 1 H) , 1.18 (s, 9 H) , 0.83 (s, 9 H) , 0.18 (s, 3 H) , 0.15 (s, 3 H) , 0.14 (s, 9 H) ;

¹³ C NMR (CDC1 ₃ , 100.6 MHZ) δ 177.9, 156.2, 154.6, 151.5, 132.8, 117.7, 117.5, 114.6, 108.9, 107.2, 94.1, 90.6, 70.7, 68.9, 65.7, 65.2, 64.5, 63.2, 55.6, 52.1, 44.2, 43.2, 40.0, 38.7, 27.2, 25.8, 24.1, 18.2, -0.37, -2.6, -2.8; exact mass m/z calculated for CsgHβSNOiOSi 761.39905, found 761.40023.

Compound 21

FTIR (CH ₂ C1 ₂ cast) 3493, 3445, 2168, 1725 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 7.00-6.89 (m, 2 H) , 6.89-6.75 (m, 2 H) , 5.98-5.80 (m, \ H) , 5.37-5.09 (m, 2 H) , 5.15 (ABq, J = 6.9, Δυ = 11.0 Hz, 2 H) , 4.82 (d, J = 9.8 Hz, 1 H, NH) , 4.66-4.47 (m, 2 H) , 4.14-4.04 (m, 1 H) , 4.04-3.51 (m, 8 H) , 3.77 (s, 3 H) , 3.34-3.20 (m, 1 H) , 2.40-2.11 (m, 2 H) , 2.05 (dd, J = 13.9, 1.6 Hz, 1 H) , 1.91-1.70 (m, 2 H) , 1.78 (d, J = 13.9 Hz, 1 H) , 0.83 (s, 9 H) , 0.19 (s, 3 H) , 0.16 (s, 9 H) , 0.16 (s, 3 H) ;

¹³ C NMR (CDCI3, 100.6 MHZ) δ 156.5, 154.8, 151.0, 132.8, 117.7, 117.6, 114.7, 108.9, 107.5, 94.0, 90.7, 70.8, 69.9, 65.7, 65.1, 64.5, 61.2, 55.6, 52.3, 44.4, 42.8, 42.2, 25.8, 22.9, 18.1, -0.31, -2.6, -2.8;

exact mass m/z calculated for C ₃₃ H52N0 ₉ Si ₂ (M-CH ₃ ) 662.31805, found 662.31612.

Compound 22

FTIR (CH ₂ C1 ₂ cast) 3351, 2165, 1725 cm ^"1 ; ^X H NMR (CDC1 ₃ , 400 MHZ) δ 9.80 (bs, 1 H) , 7.00-6.88 (m, 2

H) , 6.88-6.75 (m, 2 H) , 5.97-5.78 (m, 1 H) , 5.37-5.16 (m, 2 H) , 5.10 (s, 2 H) , 4.82 (bs, 1 H) , 4.57 (d, J = 5.2 Hz, 2 H) , 4.28 (t, J = 8.1 Hz, I H ) , 4.08 -3.83 (m, 4 H) , 3.83- 3.61 (m, 2 H) , 3.76 (s, 3 H) , 2.93-2.76 (m, 1 H) , 2.34-2.05 (m, 2 H) , 2.03 (ABq, J = 14.4, Δυ = 57.9 Hz, 2 H) , 1.88-1.66 (m, 1 H) , 0.83 (s, 9 H) , 0.18 (s, 3 H) , 0.17 (s, 3 H) , 0.16 (s, 9 H) ;

¹³ C NMR (CDCI ₃ , 75.5 MHZ) δ 202.2, 155.9, 154.6, 151.3, 132.6, 117.8, 117.4, 114.5, 108.1, 106.6, 93.8, 91.1, 70.9, 67.5, 65.1, 64.3, 55.'6, 52.7, 50.8, 44.1, 42.9, 25.8, 25.6, 18.2, -0.41, -2.8, -2.9; exact mass m/z calculated for C ₃₄ H ₅ 3N0 ₉ Si 675.32587, found 675.32628.

Compound 23α FTIR (CH ₂ C1 ₂ cast) 3347, 1551 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 5.25-5.15 (m) and 4.90-4.80 (m) [1 H] , 4.10-3.76 (m, 6 H) , 3.53 (dd, -7 = 12.5, 2.9 Hz) and 3.45 (dd, J 12.4, 3.9 Hz) , [1 H] , 3.00 (d, J = 4.9 Hz) and 2.45 (dd, J = 3.7, 1.5 Hz), [1 H] , 2.54-2.42 (m) and 2.20-2.10 (m) [1 H] , 2.04-1.44 (m, 4 H) , 0.91 (s, 9 H) , 0.06 (s, 6 H) ; ¹³ C NMR (CDCI ₃ , 75.5 MHZ) major δ 107.7, 91.3, 86.1, 69.5,

48-

SUBSTTTUTE SHEET (RULE 26)

65.4, 64.7, 60.4, 38.4, 35.7, 34.1, 29.7, 25.7, 17.9, -4.0, -4.8; exact mass m/z calculated for Cι ₇ H ₃ 0NO ₆ Si (M-OH) 372.18423, found 372.18404; exact mass m/z calculated for Ci ₃ H ₂ 2N0 ₇ Si (M-t-Bu) 332.11655, found 332.11652.

Compound 23β

FTIR (CH2CI ₂ cast) cm ^"1 ; 3371, 1550 cm"l; iH NMR (CDCI ₃ , 400 MHZ) δ 5.40 (bs, 0.75 H) , 5.05 (d, J =

12.5) and 5.03 (d, J = 12.5) [1 H] , 4.78-7.67 (m, 0.25 H) , 4.21-3.85 (m, 6 H) , 3.75-3.55 (m, 0.5 H) , 3.30-3.20 (m, 0.75 H) , 2.70-2.40 (m, 2.5 H) , 2.35-2.18 (m, 0.27 H) , 2.05-1.93 (m, 0.25 H) , 1.85-1.72 (m, 2.75 H) , 1.60-1.43 (m, 0.75 H) , 1.38-1.16 (m, 0.25 H) , 0.84 (s, 9 H) , 0.07 (s) and 0.04 (s) [6 H] ; exact mass m/z calculated for Ci3H ₂ 2N0 ₇ Si (M-t-Bu) 332.11655, found 332.11577.

Compound 24α

FTIR (CH ₂ C1 ₂ cast) 1742 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 5.76 (dd, J ^" = 6.6, 3.5 Hz, 1 H) , 4.82 (d, J = 8.8 Hz, 1 H) , 4.08-3.70 (m, 6 H) , 3.59 (dd, J =

12.5, 3.1 Hz, 1 H) , 2.93-2.79 (m, 1 H) , 2.30-2.17 (m, 1 H) , 2.03 (dd, J = 14.2, 5.7 Hz, 1 H) , 1.87 (dd, J = 14.2, 3.7 Hz, 1 H) , 1.82-1.63 (m, 2 H) , 1.23 (s, 9 H) , 0.90 (s, 9 H) , 0.08 (s, 6 H) ;

¹³ C NMR (CDCI ₃ , 75.5 MHZ) δ 176.9, 107.4, 93.3, 85.9, 69.2, 65.3, 64.8, 64.4, 39.1, 38.8, 38.7, 28.7, 27.0, 25.6, 18.0, -4.2, -4.5; exact mass m/z calculated for Cχ ₇ H ₃ θNθ ₆ Si (M-t-Bu) 372.18423, found 372.18496.

Compound 24β

FTIR (CH ₂ C1 ₂ cast) 1746 cm ^"1 ;

^X H NMR (CDCI ₃ , 400 MHZ) δ 5.59 (dd, J = 9.9, 2.6 Hz, 1 H) ,

5.07 (d, J = 12.4 Hz, 1 H) , 4.17-4.09 (m, 1 H) , 4.01-3.87 (m, 4 H) , 3.74-3.65 (m, 2 H) , 2.56-2.48 (m, 1 H) , 2.34-2.27

(m, 1 H) , 1.88-1.78 (m, 3 H) , 1.52-1.38 (m, 1 H) , 1.23 (s, 9

H) , 0.88 (s, 9 H) , 0.074 (s, 6 H) ;

¹³ C NMR (CDCI ₃ , 75.5 MHZ) δ 176.9, 108.0, 94.8, 85.4, 67.9,

66.3, 65.6, 65.1, 39.6, 39.1, 38.7, 34.6, 27.0, 25.7, 24.7, 18.1, -4.8; exact mass m/z calculated for C^HsoNOeSi (M-t-BuCO)

372.18423, found 372.18318.

-50-

SUBSTTTUTE SHEET (RULE 26)

Compound 25α

FTIR (CH ₂ C1 ₂ cast) 1739 cm ^"1 ; ⁱ H NMR (CDC1 ₃ , 400 MHZ) δ 5.79 (dd, J = 8.4, 3.4 Hz, 1 H) , 4.39 (dd, J = 11.8, 5.9 Hz, 1 H) , 4.03-3.85 (m, 5 H) , 3.45 (dd, J = 11.8, 3.3 Hz, 1 H) , 2.93 (d, J = 8.0 Hz, 1 H) ,

2.07-1.86 (m, 3 H) , 1.86-1.73 (m, 1 H) , 1.73-1.64 (m, 2 H) , 1.36 (bs, 2 H, NH ₂ ) , 1.22 (s, 9 H) , 0.86 (s, 9 H) , 0.05 (s, 3 H) , 0.04 (s, 3 H) ;

¹³ C NMR (CDCI ₃ , 100.6 MHZ) δ 177.0, 110.0, 93.7, 70.2, 64.8, 64.7, 64.6, 51.6, 38.8, 38.7, 37.7, 37.3, 29.0, 27.0, 25.7, 17.9, -4.2, -4.5; exact mass m/z calculated for C ₂₂ H ₄ lN0 ₆ Si 443.27030, found 443.27126.

Compound 25β FTIR (CH ₂ C1 ₂ cast) 1744 cm ^"1 ; iH NMR (CDC1 ₃ , 400 MHZ) δ 5.60 (dd, J = 9.9, 2.6 Hz, 1 H) , 4.48 (d, J = 11.4 Hz, 1 H) , 4.09-3.93 (m, 5 H) , 3.56 (dd, J = 11.8, 2.7 Hz, 1 H) , 3.09 (d, J = 11.8 Hz, 1 H) , 2.22-2.12 (m, 1 H) , 1.87-1.76 (m, 2 H) , 1.70-1.52 (m, 2 H) , 1.35 (bs, 2 H, NH ₂ ) , 1.22 (s, 9 H) , 0.87 (s, 9 H) , 0.053 (s, 6 H) ;

¹³ C NMR (CDCI ₃ , 75.5 MHZ) δ 177.0, 109.8, 95.4, 68.9, 66.8, 65.5, 65.1, 50.4, 39.8, 38.7, 38.3, 38.1, 27.0, 25.8, 25.0, 18.1, -4.7, -4.8; exact mass m/z calculated for C ₂₂ H ₄ lNθ ₆ Si 443.27030, found 443.27039.

Compound 26α

FTIR (CH ₂ C1 ₂ cast) 3365, 1735 cm ^"1 ; ⁱ H NMR (CDC1 ₃ , 400 MHZ) δ 5.98-5.82 (m, 1 H) , 5.75-5.60 (m, 1 H) , 5.48-5.10 (m, 2 H) , 4.92-4.5 (m, 3 H) , 4.25-4.00 (m, 3 H) , 4.00-3.73 (ra, 4 H) , 3.60-3.48 (m, 1 H) , 2.10-1.89 (m, 2 H) , 1.89-1.60 (m, 4 H) , 1.22 (s, 9 H) , 0.88 (s, 9 H) , 0.05 (s, 6 H) ;

¹³ C NMR (CDCI ₃ , 100.6 MHZ) δ 177.1, 156.4, 133.0, 117.5, 108.8, 94.2, 70.1, 65.6, 64.9, 51.3, 40.3, 38.7, 37.3, 35.7, 29.4, 27.0, 25.6, 17.9, -4.5, -4.8; exact mass m/z calculated for C2 ₂ H ₃ 6N0 ₈ Si (M-t-Bu) 470.22101, found 470.22222.

Compound 26β

FTIR (CH ₂ C1 ₂ cast) 3317, 1742 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 5.98-5.84 (m, 1 H) , 5.66-5.53 (m, 1 H) , 5.46-5.10 (m, 2 H) , 4.73-4.36 (m, 3 H) , 4.28-4.14 (m, 1 H) , 4.14-3.84 (m, 6 H) , 3.60-3.50 (m, 1 H) , 2.27-2.14 (m, 1 H) , 1.88-1.70 (m, 3 H) , 1.70-1.55 (m, 1 H) , 1.53-1.38 (m, 1 H) , 1.22 (s, 9 H) , 0.89 (s, 9 H) , 0.05 (s, 6 H) ; ¹³ C NMR (CDCI ₃ , 75.5 MHZ) major δ 177.1, 156.3, 133.0,

117.7, 108.9, 95.1, 68.6, 66.2, 65.4, 65.2, 50.9, 39.6, 38.7, 38.3, 37.1, 27.0, 25.8, 24.7, 18.1, -4.8; exact mass m/z calculated for C ₂₂ H ₃ 6N0 ₈ Si (M-t-Bu) 470.22101, found 470.22089. Compound 27α

FTIR (CH ₂ C1 ₂ cast) 3513, 3449, 3332, 1728 cm ^"1 ;

52-

SUBST1TUTE SHEET (RULE 26)

ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 5.98-5.83 (m, 1 H) , 5.67-5.54 (m, 1 H) , 5.44-5.10 (m, 2 H) , 4.73-4.47 (m, 3 H) , 4.30-3.90 (m, 6 H) , 3.84-3.68 (m, 2 H) , 3.64-3.53 (m, 1 H) , 2.36-2.22(m, 1 H) , 2.05-1.72 (m, 3 H) , 1.72-1.47 (m, 2 H) , 1.21 (s, 9 H) ; ¹³ C NMR (CDCI ₃ , 75.5 MHZ) major δ 176.8, 156.2, 132.8, 117.7, 109.8, 94.5, 70.4, 66.0, 65.6, 65.4, 51.0, 40.3, 38.6, 35.0, 34.9, 29.7, 26.9; exact mass m/z calculated for Cι ₅ H ₂ 2NO _e (M-t-BuCOO) 312.14471, found 312.14407. Compound 27β

FTIR <CH ₂ C1 ₂ cast) 3440, 3364, 1725 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 5.96-5.82 (m, 1 H) , 5.65-5.55 (m, 1 H) , 5.46-5.12 (m, 2 H) , 4.73-4.38 (m, 3 H) , 4.30-4.16 (m, 1 H) , 4.16-3.84 (m, 6 H) , 3.65-3.54 (m, 1 H) , 2.43-2.31 (m, 1 H) , 2.02-1.93 (m, 1 H) , 1.93-1.57 (m, 4 H) , 1.54-1.40 (m, 1 H) , 1.23 (S, 9 H) ;

¹³ C NMR (CDCI ₃ , 75.5 MHZ) major δ 177.1, 156.4, 132.9, 117.7, 108.8, 95.2, 67.8, 65.3, 65.6, 65.3, 50.8, 38.8, 38.6, 37.6, 36.9, 26.9, 24.5; exact mass m/z calculated for Cι ₅ H ₂ 2N0 ₇ (M-t-Bu) 328.13962, found 328.13923; low resolution mass m/z calculated for C2 ₀ H ₃ INO8 (M) 413.2, found 413.2.

Compound 28

FTIR (CH ₂ C1 ₂ cast) 3342, 1719 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 5.98-5.83 (m, 1 H) , 5.70-5.60 (m, 1 H) , 5.41-5.15 (m, 2 H) , 4.85-4.52 (m, 3 H) , 4.50-4.39 (m,

-53-

SUBSTmJTE SHEET (RULE 26)

1 H) , 4.18-3.84 (m, 5 H) , 3.70-3.60 (m, 1 H) , 2.89-2.78 (m,

2 H) , 2.66-2.54 (m, 1 H) , 2.11-1.75 (m, 3 H) , 1.22 (s, 9 H) - ¹³ C NMR (CDC1 ₃ , 75.5 MHZ) δ 205.2, 176.7, 156.3, 132.6, 117.9, 108.7, 92.9, 66.0, 65.9, 65.3, 64.7, 51.9, 46.8, 46.4, 38.7, 36.0, 28.4, 26.9; exact mass m/z calculated for C ₂ oH ₂ 9N0 ₈ 411.18930, found 411.18786; m/z calculated for Cι ₆ H ₂ 0NO ₈ (M-t-Bu) 354.11890, found 354.11855.

Compound 29 X-Ray structure obtained.

FTIR (CH ₂ C1 ₂ cast) 3479, 3356, 1732 cm" ¹ ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 6.00-5.84 (m, 1 H) , 5.67-5.54 (m,

1 H) , 5.47-5.11 (m, 2 H) , 4.72-3.91 (m, 10 H) , 3.60-3.50 (m,

1 H) , 2.30-2.20 (m, 1 H) , 2.20-2.01 (m, 3 H) , 1.63-1.47 (m, 1 H) , 1.23 (s, 9 H) , 0.17 (s, 9 H) ;

¹³ C NMR (CDCI3, 75.5 MHZ) major δ 176.9, 156.1, 132.8,

117.8, 108.9, 105.1, 94.6, 90.3, 70.6, 65.9, 65.7, 65.5,

65.4, 50.3, 44.5, 40.1, 38.6, 35.1, 29.6, 26.9, -0.23; exact mass m/z calculated for C ₂ 5H39N0 ₈ Si 509.24451, found 509.24618; m/z calculated for C25H ₃ 7N0 ₇ Si (M-H ₂ 0) 491.23392, found 491.23376.

Compound 30

FTIR (CH2CI2 cast) 3444, 1744 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 6.00-5.82 (m, 1 H) , 5.66-5.56 (m, 1 H) , 5.45-5.10 (m, 2 H) , 4.81-4.51 (m, 3 H) , 4.29-4.10 (m,

2 H) , 4.10-3.97 (m, 1 H) , 3.97-3.74 (m, 3 H) , 3.57-3.45 (m,

1 H) , 2.14-1.98 (m, 3 H) , 1.98-1.84 (m, 2 H) , 1.67-1.57 (m,

1 H) , 1.24 (s, 9 H) , 0.87 (s, 9 H) , 0.17 (s, 15 H) ; ¹³ C NMR (CDC1 ₃ , 75.5 MHZ) major δ 177.0, 156.3, 133.0, 117.6, 108.0, 106.5, 94.8, 92.3, 71.1, 66.5, 65.6, 65.3, 64.7, 50.5, 45.6, 42.6., 38.7, 35.3, 29.3, 27.0, 25.7, 18.2, -0.37, -2.8, -3.0; exact mass ι ^* π/z calculated for C ₂₇ H ₄ 4N0 ₈ Si ₂ (M-t-Bu) 566.26056, found 566.25978; low resolution mass m/z calculated for C ₃₁ H ₅ 3N0 ₈ Si ₂ 623.3, found 623.0. Compound 31

FTIR (CH2CI ₂ cast) 3440, 1720 cm ^"1 ;

^X H NMR (CDCI ₃ , 400 MHZ) δ 6.00-5.85 (m, 1 H) , 5.50-4.54 (m, 5 H) , 4.33-3.32 (m, 7 H) , 2.66-1.15 (m, 8 H) , 0.88 (s, 9 H) , 0.26-0.07 (m, 15 H) ; ¹³ C NMR (CDCI ₃ , 75.5 MHZ) δ 156.4, 133.0, 117.5, 108.0,

106.8, 91.7, 91.1, 71.4, 65.6, 65.5, 65.1, 64.7, 50.0, 42.5, 39.6, 35.8, 28.6, 25.7, 18.2, -0.32, -2.8, -3.0. exact mass m/z calculated for C ₂₆ H ₄ 3Nθ ₆ Si ₂ (M-H ₂ 0) 521.26288, found 521.26210; low resolution mass m/z calculated for C ₂₆ H ₄ 5N0 ₇ Si ₂ 539.27344, found 539.4. Compound 32 FTIR (CH ₂ C1 ₂ cast) 3441, 3340, 1739 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 6.00-5.85 (m, 1 H) , 5.35-5.17 (m,

2 H) , 4.85-4.50 (m, 4 H) , 4.29-3.76 (m, 6 H) , 2.96-2.77 (m, 1 H) , 2.62-2.23 (m, 3 H) , 2.17-1.96 (m, 2 H) , 0.86 (s, 9 H) ,

0.18 (S, 15 H) ;

55-

SUBSηTUTE SHEET (RULE 26)

¹³ C NMR (CDC1 ₃ , 75.5 MHZ) major δ 170.1, 156.2, 132.7, 117.8, 107.4, 105.7, 93.3, 69.8, 69.0, 65.7, 65.1, 64.9, 50.0, 44.7, 42.0, 34.7, 30.3, 25.5, 18.0, -0.51, -3.0, -3.0; exact mass m/z calculated for C ₂ 5H ₄ oN0 ₇ Si ₂ (M-CH ₃ ) 522.23431, found 522.23261; low resolution mass m/z calculated for C ₂₆ H ₄ 3N0 ₇ Si ₂ 537.257, found 537.2.

Example 2

In the preceding Example, key intermediates 32 and 33 were synthesized. These advanced intermediates were elaborated into (±) - calicheamicone 1 as described below. All compounds in this Example are racemic. However, only one enantiomer is drawn in each case except that the other enantiomeric representation of 32 is also drawn (Compound 47) . Both 32 and 33 are represented exactly as shown, in order to emphasize the stereochemistry at C(5) relative to the other stereogenic centers. The stereochemistry at C(5) is preserved while other stereogenic centers are converted to sp ² -hybridization during synthesis. Monoacetylenic aldehyde 33 was reacted with cerium trimethylsilylacetylide, prepared as in Example 1, to achieve stereoselective formation of alcohol 36 as the major product (Figure 4) . Isolated yield of the major product ranged from 71 - 76%. Yield of the C(9) epimer minor product was 18%. Acylation of compound 36 with ClCH ₂ C0Cl and DMAP generated 37. The p-AOM group of 37 was removed

-56-

SUBSTTTUTESHEET(RULE26)

with (NH ₄ ) ₂ Ce (N0 ₃ ) ₆ to form 38. Alcohol 38 was oxidized to aldehyde 39 by the method of Collins. Hydrolysis of chloroacetyl ester 39 in aqueous NH ₃ formed lactols, which were readily convertible to lactone 40 through Collins oxidation.

Double bonds were next introduced at C(4) - C(7) and C(2) - C(3) as follows. Desaturation of C(4) - C(7) of 40 with phenylselenenyl chloride and LDA, and oxidation with demethyldioxirane resulted in compound 41. The allyloxycarbonyl group of 41 was removed with Pd(PPh ₃ ) ₄ and dimedone, forming compound 42. Some selenenylation may also occur on the nitrogen. X-ray analysis confirmed the structure of 42. N-chlorination of 42 with t-BuOCl formed 43. Room temperature treatment of 43 with DABCO afforded 44 as an 8 : 1 mixture of C(9) epimers. The major isomer is shown in Figure 4. N-methoxycarbonylation of 44 with triphosgene and methanol gave 45 (78% from 42) , also an 8:1 mixture of C(9) epimers. Alkynyl silyl groups were removed with TBAF without separation to generate 46, resulting in further epimerization at C(9) . Compound 46 (46% isolated yield from isomer mixture 45) was chromatographically separated from the C(9) - epimer (39% isolated yield) .

The structure of 46 was confirmed by X-ray analysis. A crucial feature of the molecular dimensions of 46 was the distance between the terminal alkynyl carbons, which was

4.154+,.005A. The C(9) epimers of 46 were interconverted to

some extent by TBAF. A method to equilibrate them to raise the yield of 46 to 70% is described below.

Compound 46 was also made from racemic 32, represented by enantiomer 47 in Figure 5. Using methods and reagents described above, 47 was desaturated at C(4)-C(7) to obtain 48, deprotected at nitrogen to form 49, desaturated at C(2)- C(3) to form 50, and methoxycarbonylated to form 51. Next, C(9) of compound 51 was brominated in the following manner. (PhCO) ₂ 0 ₂ was added to 51, covered with dry CC1 ₄ , refluxed under argon, and illuminated with a 100 W tungsten filament bulb. N-bromosuccinimide (ΝBS) was added at intervals. The resulting mixture was filtered through a pad of Celine using CC1 ₄ . Evaporation of the filtrate at room temperature gave the crude product 52. Brominated compound 52 was hydrolyzed with aqueous AgΝ0 ₃ to give 53 then esterified with CH ₂ N ₂ to form aldehyde ester 54. Compounds 52 and 53 exist as two hydroxy lactones, epimeric at C(9) . Compound 54 was reacted stereoselectively with freshly prepared cerium trimethylsilylacetylide, forming 55. Desilylation of 55 with TBAF resulted in 46 (46%) , identical to the material obtained by Figure 4.

During desilylation of 55, some epimerization occurs at C(9) . However, treatment of the anti-isomer acetylenic units at C(5) and C(9) with Bu ₄ N0Ac gives quantitatively a 6:4 mixture in favor of 46. Therefore, by equilibrating the anti-diyne once, it is possible to convert 55 into 46 with a 71% yield.

-58-

SUBSΠTUTE SHEET (RULE 26)

Acetylenic hydrogens in 46 were replaced with iodine, using NIS and AgN0 ₃ resulting in 56. As shown in Figure 6, Pd-mediated condensation of 56 generated the cyclic enediyne

57 using Pd(PPh ₃ ) ₄ and (Z) -1, 2-bis (trirnethylstannyl) ethene at 60°C. After DIBAL-H reduction of 57, the solubility of

58 was improved by desilylation with TBAF to form 59. Reduction of 59 with NaBH ₄ gave triol 60. Silylation of 60 to 61, followed by selective hydrolysis with a 3:6:1 ratio of AcOH, THF and H ₂ 0 generated allylic alcohol 62. Under Mitsunobu conditions with diisopropyl azodicarboxylate, Ph ₃ P and AcSH, 62 was converted to thiol acetate 63, then deacylated with DIBAL-H to generate thiol 64. Compound 64 is stable in the absence of oxygen, but relatively labile in the presence of oxygen. Compound 64 was converted directly to trisulfide 65 with N- (methyldithio)phthalimide (88% yield from 63) . Finally, acid hydrolysis of 65 with TsOH and H ₂ 0 disengaged the two remaining protecting groups, resulting in synthetic (+_) - calicheamicinone 1.

SPECTRAL DATA Compound 33

Same as compound 22 of example 1.

Compound 36

FTIR (CH ₂ C1 ₂ cast) cm ^"1 ; 3435, 3407, 2174, 1696 crrri; ⁱ -H NMR (CDC1 _3/ 400 MHZ) δ 7.03-6.80 (m, 2 H) , 6.80-6.75 (m, 2 H) , 6.00-5.83 (m, 1 H) , 5.43-5.15 (m, 2 H) , 5.15 (ABq, J = 6.7, Δυ = 25.9 Hz, 2 H) , 4.99 (d, J = 9.3 Hz, 1 H, NH) , 4.69

-59-

SUBSTTΓUTE SHEET (RULE 26)

(dd, J = 5.0, 4.3 Hz, 1 H) , 4.66-4.48 (m, 2 H) , 4.20-4.05 (m, 2 H) , 4.05-3.78 (m, 6 H) , 3.76 (s, 3 H) , 2.50-2.33 (m, 1 H) , 2.33-2.18 (m, 1 H) , 2.18-2.05 (m, 1 H) , 2.02 (dd, J = 13.9, 1.9 Hz, 1 H) , 1.98-1.87 (m, 1 H) , 1.81 (d, J = 13.9 Hz, 1 H) , 0.83 (s, 9 H) , 0.19 (s, 3 H) , 0.17 (s, 9 H) , 0.16 (S, 3 H) , 0.15 (s, 9 H) ;

¹³ C NMR (CDC1 ₃ , 100.6 MHZ) δ 157.4, 154.6, 151.6, 132.6, 118.2, 117.7, 114.6, 108.8, 107.7, 105.6, 94.4, 91.0, 90.7, 70.6, 70.2, 66.2, 65.1, 64.6, 62.9, 55.7, 52.3, 45.8, 44.7, 42.7, 25.8, 23.8, 18.1, -0.12, -0.32, -2.6, -2.8; exact mass HRFAB (NOBA) m/z calculated for C ₃₉ H ₆ 3NOgSi ₃ Na 796.3708, found 796.3695.

Minor Isomer from Preparation of Compound 36

FTIR (CH ₂ C1 ₂ cast) 3435, 3407, 2174, 1696 cm ^"1 ; ⁱ H NMR (CDCI3, 400 MHZ) δ 7.03-6.90 (m, 2 H) , 6.87-6.76 (m, 2 H) , 6.00-5.85 (m, 1 H) , 5.40-5.08 (m, 4 H) , 4.90 (d, J = 9.9 Hz, 1 H) , 4.73-4.45 (m, 3 H) , 4.19-3.67 (m, 8 H) , 3.76 (s, 3 H) , 2.58-2.45 (m, 1 H) , 2.42-2.28 (m, 1 H) , 2.14 (bs, 1 H, OH) , 1.91 (ABq, J = 13.8, Δv = 83.9 Hz, 2 H) , 1.90-1.78 (m, 1 H) , 0.82 (s, 9 H) , 0.18 (s, 3 H) , 0.16 (s, 9 H) , 0.15 (S, 3 H) , 0.13 (s, 9 H) ;

¹³ C NMR (CDCI ₃ , 100.6 MHZ) δ 156.7, 154.5, 151.3, 132.8, 117.7, 117.5, 114.5, 108.9, 107.5, 106.9, 93.9, 91.1, 89.0. 70.5, 69.6, 65.9, 65.1, 64.6, 63.5, 55.4, 52.0, 47.4, 45.4, 42.5, 25.7, 22.9, 18.0, -0.48, -0.59, -2.70, -2.90;

Compound 37

-60-

SUBST1TUTE SHEET (RULE 26)

FTIR (CH ₂ C1 ₂ cast) 3386, 1771, 1726 cm ^"1 ; ⁱ H NMR (CDC1 ₃ , 400 MHZ) δ 7.03-6.90 (m, 2 H) , 6.85-6.78 (m, 2 H) , 5.98-5.78 (m, 1 H) , 5.79 (d, J = 4.0 Hz, 1 H) , 5.37- 5.14 (m, 2 H) , 5.14 (ABq, J = 6.9, Δυ = 39.2 Hz, 2 H) , 4.75 (d, J = 10.3 Hz, 1 H, NH) , 4.58-4.40 (m, 2 H) , 4.20-3.85 (m, 5 H) , 3.94 (ABq, J = 15.6, Δυ = 131.2 Hz, 2 H) , 3.85-3.78 (m, 1 H) , 3.77 (s, 3 H) , 3.63-3.53 (m, 1 H) , 2.57-2.43 (m, 1 H) , 2.43-2.31 (m, 1 H) , 2.15-1.92 (m, 2 H) , 2.00 (dd, J =

13.8, 1.8 Hz, 1 H) , 1.80 (d, J = 13.8 Hz, 1 H ) , 0.85 (s, 9 H) , 0.19 (s, 3 H) , 0.18 (s, 12 H) , 0.15 (s, 9 H) ;

¹³ C NMR (CDCI ₃ , 100.6 MHZ) δ 166.7, 156.2, 154.6, 151.5, 132.8, 117.9, 117.4, 114.6, 108.7, 107.5, 100.5, 94.0, 93.9, 91.2, 70.4, 69.3, 66.0, 65.3, 65.0, 64.8, 55.7, 51.5, 44.5,

43.9, 42.9, 41.0, 25.8, 23.6, 18.2, -0.32, -2.7, -2.8; exact mass HRFAB (NOBA) m/z calculated for C ₄ iHg4ClNOιθSi ₃ Na

872.3424, found 872.3391.

Compound 38

FTIR <CH ₂ C1 ₂ cast) 3444, 1771, 1726 cm ^"1 ;

^X H NMR (CDCI3, 400 MHZ) δ 5.96-5.80 (m, 1 H) , 5.82 (d, J = 3.8 Hz, 1 H) , 5.38-5.10 (m, 2 H) , 4.77 (d, J = 10.3 Hz, 1 H, NH) , 4.59-4.35 (m, 2 H) , 4.17 (ABq, J = 15.3, Δυ -= 27.9 Hz, 2 H) , 4.11-3.72 (m, 6 H) , 3.72-3.60 (m, 1 H) , 2.60-2.40 (m, 2 H) , 2.16-1.90 (m, 2 H) , 1.81 (d, J = 13.8 Hz, 1 H) , 1.52 (bs, 1 H, OH) , 0.88 (s, 9 H) , 0.22 (s, 3 H) , 0.20 (s, 3 H) , 0.17 (s, 9 H) , 0.15 (s, 9 H) ;

¹³ C NMR (CDC1 ₃ , 100.6 MHZ) δ 166.5, 156.2, 132.8, 117.9, 108.6, 107.5, 100.4, 94.2, 91.2, 70.5, 65.9, 65.3, 65.1,

64.7, 63.5, 51.5, 44.7, 44.1, 42.9, 41.2, 27.1, 25.8, 18.2, 0.37, -2.7, -2.8; exact mass m/z calculated for C ₃₃ H ₅ 6ClN0 ₈ Si ₃ 713.30023, found 713.29980. Compound 39

FTIR (CH ₂ C1 ₂ cast) 3441, 1773, 1729 cm ^"1 ; ⁱ H NMR (CDC1 _3/ 400 MHZ) δ 9.71 (t, J = 1.5 Hz, 1 H) , 5.98- 5.80 (m, 1 H) , 5.77 (d, J = 4.0 Hz, 1 H) , 5.38-5.13 (m, 2

H) , 4.77 (d, J = 10.2 Hz, 1 H, NH) , 4.58-4.36 (m, 2 H) , 4.13 (ABq, J = 15.6, Δυ = 54.1 Hz, 2 H) , 4.17-3.84 (m, 5 H) , 3.84-3.73 (m, 1 H) , 3.47-3.32 (m, 1 H) , 2.91-2.68 (m, 2 H) , 2.68-2.54 (m, 1 H) , 2.61 (dt, J ^" = 12.4, 3.6 Hz, 1 H) , 2.08 (dd, J - ^* - 14.0, 1.6 HZ, 1 H) , 1.74 (d, J = 14.0 Hz, 1 H) ,

0.83 (s, 9 H) , 0.20 (s, 6 H) , 0.19 (s, 9 H) , 0.16 (s, 9 H) ; ¹³ C NMR (CDCI ₃ , 100.6 MHZ) δ 201.2, 166.3, 156.1, 132.7, 118.0, 107.9, 107.2, 99.7, 94.3, 91.8, 70.1, 66.0, 65.4,

64.8, 64.7, 51.4, 43.5, 43.0, 42.6, 41.1, 38.9, 25.9, 18.2, -0.38, -2.6, -2.8; exact mass m/z calculated for C ₂₉ H ₄ 5ClN0 ₈ Si ₃ (M- t-C ₄ Hg) 654.2141, found 654.21380.

Compound 40

FTIR (CH ₂ C1 ₂ cast) 3344, 1747 cm ^"1 ; ⁱ H NMR (CDCI3, 400 MHZ) δ 6.00-5.80 (m, 1 H) , 5.40-5.19 (m, 3 H ) , 4.80 (bs, 1 H, NH) , 4.58 (d, J - 5.5 Hz, 2 H) , 4.10-

3.80 (m, 5 H) , 3.04-2.85 (ra, 1 H) , 2.85-2.70 (m, 1 H) , 2.55 (dd, J = 18.9, 10.2 Hz, 1 H) , 2.40-2.23 (m, 1 H) , 2.04 (ABq, J = 13.5, Δυ = 72.4 Hz, 2 H) , 0.88 (s, 9 H) , 0.20 (s, 6 H) , 0.18 (s, 18 H) ; ¹³ C NMR (CDC1 ₃ , 100.6 MHZ) δ 169.1, 156.2, 132.6, 117.9,

107.4, 106.9, 101.3, 69.4, 69.3, 66.0, 65.4, 64.7, 50.6, 42.8, 40.7, 40.2, 28.1, 25.8, 18.2, -0.32, -0.37, -2.8, - 2.9; exact mass m/z calculated for C ₂₇ H ₄ 2N0 ₇ Si (M-t-Bu) 576.22693, found 576.22687.

Compound 41

FTIR (CH ₂ C1 ₂ cast) 3440, 1736 cm" ¹ ; ⁱ H NMR (CDC1 ₃ , 400 MHZ, 50_C) δ 6.22 (s, 1 H) , 6.00-5.84 (m, 1 H) , 5.37-5.14 (m, 3 H) , 4.95 (bs, 1 H, NH) , 4.60 (d, J = 5.6 Hz, 2 H) , 4.21-3..80 (m, 5 H) , 2.98 (d, J = 12.0 Hz, 1 H ) , 2.10 (ABq, J = 13.6, Δυ = 258.5 Hz, 2 H) , 0.94 (s, 9 H) , 0.25 (s, 3 H) , 0.24 (s, 3 H) , 0.20 (s, 9 H) , 0.14 (s, 9 H) ; ¹³ C NMR (CDCI ₃ , 100.6 MHZ) major δ 162.4, 158.0, 155.9,

132.5, 118.2, 112.5, 106.9, 103.7, 101.1, 93.5, 91.3, 69.1, 66.9, 66.2, 65.6, 65.0, 56.7, 49.3, 42.7, 25.8, 18.3, -0.32,

-0.42, -2.7, -3.0; exact mass m/z calculated for C ₃ iH49N0 ₇ Si ₃ 631.28168, found

631.28020.

Compound 42 X-Ray structure determined.

FTIR (CH ₂ C1 ₂ cast) 3393, 3325, 1731 cm" ¹ ;

63-

SUBSTΓΓUTE SHEET (RULE 26)

ⁱ H NMR (CDC1 ₃ , 400 MHZ) δ 6.15 (s, 1 H) , 5.80 (s, 1 H) , 4.18-3.92 (m, 4 H) , 2.81 (ABq, J = 12.2, Δυ = 13.3 Hz, 2 H) , 2.04 (ABq, J = 13.3, Δυ = 316.4 Hz, 2 H) , 1.30 (bs, 2 H, NH ₂ ) , 0.92 (s, 9 H) , 0.24 (s, 3 H) , 0.22 (s, 3 H) , 0.18 (s, 9 H) , 0.13 (s, 9 H) ;

¹³ C NMR (CDCI ₃ , 100.6 MHZ) δ 163.0, 160.3, 111.3, 107.6, 103.8, 102.0, 93.2, 90.7, 69.4, 66.9, 65.5, 65.2, 58.2, 49.7, 43.8, 25.8, 18.3, -0.26, -0.39, -2.6, -3.0; exact mass m/z calculated for C2 ₇ H ₄ 5N0 ₅ Si ₃ 547.26056, found 547.26030.

Compound 45

FTIR {CH ₂ C1 ₂ cast) cm" ¹ ; 3401, 1731, 1655 cm ^" l; ⁱ H NMR (CDCI ₃ , 300 MHZ) δ (two isomers in 8:1 ratio) 6.30

(s) and 6.16 (s) , [1 H] , 6.21 (bs) and 6.14 (bs) [1 H] , 5.81 (bs) and 5.24 (bs) [1 ^* H] , 4.20-3.91 (m, 4 H) , 3.74 (s) and

3.68 (s) [3 H] , 2.33 (d, J = 13.3 Hz, 1 H) , 2.16 (d, J =

13.3 Hz) and 2.06 (d, J = 13.3 Hz) [1 H] , 0.88 (s, 9 H) ,

0.30-0.09 (m, 24 H) ;

¹³ C NMR (CDCI ₃ , 75.5 MHZ) δ 163.0, 154.2, 151.5, 132.4, 121.4, 112.3, 104.8, 103.2, 99.5, 93.3, 91.5, 67.5, 65.6,

65.3, 47.1, 25.6, 18.2, -0.20, -0.43, -2.9, -3.0; exact mass iTi/z calculated for C ₂₉ H45N0 ₇ Si ₃ 603.25037, found

603.24997.

Compound 46 X-Ray structure determined.

FTIR (CH ₂ C1 ₂ cast) 3291, 2118, 1732, 1662 cm ^"1 ;

64-

SUBSTTTUTE SHEET (RULE 26)

ⁱ H NMR (CDC1 ₃ , 400 MHZ) δ 6.19 (s, 1 H) , 6.12 (bs, 1 H, NH) ,

5.82 (d, J = 2.2 Hz, 1 H) , 4.22-4.00 (m, 4 H) , 3.77 (s, 3

H) , 2.65 (s, 1 H) , 2.52 (d, J = 2.2 Hz, 1 H) , 2.30 (ABq, J ^" = 13.3, Δυ = 113.1 Hz, 2 H) , 0.91 (s, 9 H) , 0.27 (s, 3 H) , 0.26 (s, 3 H) ;

¹³ C NMR (CDCI3, 75.5 MHZ) δ 162.7, 154.2, 151.6, 132.1, 121.4, 112.2, 104.7, 81.6, 78.5, 76.1, 74.0, 67.2, 66.6, 65.9, 65.7, 53.3, 46.8, 25.6, 18.2, -2.8, -2.9; exact mass m/z calculated for C ₂₃ H ₂ 9N0 ₇ Si 459.17133, found 459.17124.

C- (9) Epimer of 46

FTIR (CH ₂ C1 ₂ cast) 3298, 2120, 1729 cm ^"1 ; ⁱ H NMR (CDC1 ₃ , 400 MHZ) δ 6.37 (s, 1 H) , 6.19 (bs, 1 H, NH) ,

5.83 (d, J = 2.2 Hz, 1 H) , 4.17-4.00 (m, 4 H) , 3.75 (s, 3 H) , 2.79 (s, 1 H) , 2/50 (d, J = 2.2 Hz, 1 H) , 2.33 (ABq, J = 14.1, Δυ = 152.7 Hz, 2 H) , 0.85 (s, 9 H) , 0.23 (s, 3 H) , 0.19 (s, 3 H) . exact mass m/z calculated for C ₂₃ H ₂ 9N0 ₇ Si 459.17133, found 459.17205. Compound 47

Same as compound 32. Compound 48

FTIR (CH ₂ C1 ₂ cast) 3336, 1731 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 6.41 (s) and 6.40 (s) [1 H] , 5.99- 5.03 (m, 1 H) , 5.38-5.17 (m, 2 H) , 5.03 (d, J = 10.1 Hz) and 4.85 (d, J = 10.1 Hz) [1 H] , 4.67-4.34 (m, 4 H) , 4.20-4.07

(m, 1 H) , 4.07-3.72 (m, 4 H) , 3.00-2.82 (m, 1 H) , 2.44 (d, J = 14.9 Hz, 1 H) , 1.91 (d, J = 14.9 Hz) and 1.86 (d, J = 14.9 Hz) [1 H] , 0.86 (S, 9 H) , 0.20 (s, 12 H) , 0.072 (s, 3 H) ; ¹³ C NMR (CDC1 ₃ , 75.5 MHZ) major δ 164.0, 157.4, 156.1, 123.6, 118.0, 116.0, 106.8, 102.9, 94.5, 70.0, 67.0, 65.9,

65.1, 56.1, 47.4, 35.8, 25.5, 18.2, -0.44, -3.1, -3.4; exact mass m/z calculated for C ₂ 6H4iN0 ₇ Si ₂ 535.24219, found 535.24079.

Compound 49 FTIR (CH ₂ C1 ₂ cast) 3389, 3322, 1727 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 6.28 (s, 1 H) , 4.79-4.64 (m, 1 H) , 4.51-4.38 (m, 1 H) , 4.12-3.84 (m, 4 H) , 2.78 (s, 2 H) , 2.12 (ABq, J = 14.6, Δυ = 275.3 Hz, 2 H) , 0.88 (s, 9 H) , 0.21 (s, 12 H) , 0.090 (s, 3 H) ; ¹³ C NMR (CDCI ₃ , 75.5 MHZ) δ 164.6, 159.6, 115.0, 107.8,

103.5, 94.1, 70.3, 67.4, 65.4, 65.1, 57.9, 47.6, 36.3, 25.5,

18.2, -0.38, -3.1, -3.3; exact mass m/z calculated for C2 ₂ H ₃ 7Nθ ₅ Si ₂ 451.22104, found 451.22165. Compound 50

FTIR <CH ₂ C1 ₂ cast) 3465, 3354, 3223, 2169, 1696, 1634, 1601 cm ^"1 ; ⁱ H NMR (CDC1 ₃₍ 400 MHZ) δ 5.87 (s, 1 H) , 4.94 (ABq, J =

13.3, Δυ = 21.2 Hz, 2 H) , 4.20-4.02 (m, 6 H) , 2.27 (ABq, J = 13.5, Δυ = 12.2 Hz, 2 H) , 0.85 (s, 9 H) , 0.21 (s, 3 H) , 0.19

(s, 3 H) , 0.18 (s, 9 H) ;

¹³ C NMR (CDC1 ₃ , 75.5 MHZ) δ 165.6, 154.3, 141.3, 105.8, 105.3, 103.6, 98.0, 91.7, 67.4, 65.3, 65.2, 65.0, 45.7, 25.5, 18.1, -0.38, -3.0, -3.0; exact mass m/z calculated for C ₂₂ H ₃ 5NOsSi ₂ 449.20538, found 449.20485.

Compound 51

FTIR <CH ₂ C1 ₂ cast) 3410, 3301, 1725 cm" ¹ ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 6.30 (bs, 1 H, NH) , 6.23 (s, 1 H) ,

4.92 (ABq, J = 14.7, Δυ = 9.1 Hz, 2 H) , 4.11-3.98 (m, 4 H) , 3.73 (s, 3 H) , 2.28 (ABq, J = 13.7, Δυ = 73.1 Hz, 2 H) , 0.85

(s, 9 H) , 0.23 (s, 3 H) , 0.18 (s, 9 H) , 0.15 (s, 3 H) ;

¹³ C NMR (CDCI ₃ , 75.5 MHZ) δ 163.9, 153.9, 151.8, 131.0,

113.0, 104.3, 103.6, 93.5, 67.9, 67.5, 65.3, 65.2, 53.0,

46.1, 25.4, 18.1, -0.51, -3.1; exact mass m/z calculated for C ₂₃ H ₃ 4N0 ₇ Si ₂ (M-CH ₃ ) 492.18738, found 492.18590; low resolution mass m/z calculated for

C ₂₄ H ₃ 7N0 ₇ Si ₂ 507.21, found 507.4.

Compound 54

FTIR (CH ₂ C1 ₂ cast) 3270, 2114, 1720 cm ^"1 ; ^X H NMR (CDCI3, 400 MHZ) δ 9.58 (s, 1 H) , 7.49 (s, 1 H, NH) ,

6.43 (s, 1 H) , 4.20-4.00 (m, 4 H) , 3.76 (s, 3 H) , 3.69 (s, 3 H) , 2.64 (s, 1 H) , 2.35 (ABq, J = 13.7, Δυ = 23.7 Hz, 2 H) , 0.86 (s, 9 H) , 0.22 (s, 3 H) , 0.17 (s, 3 H) ; ¹³ C NMR (CDCI ₃ , 75.5 MHZ) δ 187.7, 166.9, 154.1, 146.2, 143.5, 123.6, 116.7, 104.4, 82.8, 76.5, 70.0, 65.5, 53.4, 51.7, 49.8, 25.6, 18.2, -3.0, -3.2;

exact mass m/z calculated for C ₂₂ H ₃ lN0 ₈ Si 465.18188, found 465.18268.

Compound 55

FTIR (CH ₂ C1 ₂ cast) 3402, 3274, 2175, 2115, 1732, 1655 cm ^"1 ; ⁱ H NMR (CDC1 ₃ , 400 MHZ) δ 6.34 (s, 1 H) , 6.14 (s, 1 H) , 5.86 (s, 1 H) , 4.12-4.00 (m, 4 H) , 3.74 (s, 3 H) , 2.76 (s, 1 H) , 2.32 (ABq, J = 13.9, Δυ = 135.9 Hz, 2 H) , 0.87 (s, 9 H) , 0.23 (s, 3 H) , 0.20 (s, 3 H) , 0.15 (s, 9 H) ; ¹³ C NMR (CDCI ₃ , 75.5 MHZ) δ 163.0, 154.2, 149.8, 133.3, 120.6, 114.0, 104.2, 99.7, 82.1, 91.8, 77.2, 67.8, 67.7, 65.5, 65.5, 52.9, 46.6, 25.6, 18.2, -0.26, -2.9, -3.1; exact mass m/z calculated for C ₂ gH37N0 ₇ Si ₂ 531.21088, found 531.21006. Compound 56 FTIR (CH ₂ C1 ₂ cast) 3288, 2181, 1723 cm" ¹ ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 6.14 (s, 1 H) , 6.00 (bs, 1 H, NH) , 5.94 (s, 1 H) , 4.17-4.00 (m, 4 H) , 3.78 (s, 3 H) , 2.27 (ABq,

J = 13.3, Δυ = 95.1 Hz, 2 H) , 0.91 (s, 9 H) , 0.26 (s, 3 H) ,

0.25 (s, 3 H) ;

¹³ C NMR (CDC1 _3/ 75.5 MHZ) δ 162.6, 154.4, 151.5, 132.2,

111.9, 104.7, 91.8, 88.7, 68.8, 67.8, 65.9, 65.7, 53.5, 46.9, 25.6, 18.2, 6.7, 4.6, -2.9, -3.1; exact mass m/z calculated for C ₂₃ H ₂ 7l ₂ Nθ ₇ Si 710.96466, found

710.96434.

Compound 57

FTIR (CH ₂ C1 ₂ cast) 3288, 1728 cm ^"1 ; ^X H NMR (CDCI ₃ , 400 MHZ) δ 6.14 (s, 1 H) , 6.12 (bs, 1 H) ,

5.93 (d, J = 9.6 Hz, 1 H) , 5.88 (bs, 1 H, NH) , 5.84 (dd, J =

69-

SUBSTTTUTE SHEET (RULE 26)

9.6, 1.8 Hz, 1 H) , 4.25-3.90 (m, 4 H) , 3.78 (s, 3 H) , 2.36 (ABq, J = 13.2, Δυ = 61.1 Hz, 2 H) , 0.94 (s, 9 H) , 0.26 (s, 6 H) ;

¹³ C NMR (CDC1 ₃ , 75.5 MHZ) δ 162.5, 154.4, 154.0, 128.1, 124.6, 123.4, 110.9, 104.8, 99.2, 96.3, 91.0, 87.9, 69.3, 68.7, 65.9, 65.3, 53.3, 45.5, 25.6, 18.1, -3.0, -3.0; exact mass m/z calculated for C ₂₅ H ₂ 9Nθ7Si 483.17133, found 483.17034.

Compound 58 FTIR (CH ₂ C1 ₂ cast) 3299, 1729 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 6.02 (d, J = 2.2 Hz) and 5.97 (d, J = 2.5 Hz) [1 H] , 5.89 (d, J = 2.9 Hz) and 5.86 (d, J = 2.9 Hz) [1 H] , 5.78 (dd, J = 2.7, 1.6 Hz) and 5.76 (dd, J = 2.7, 1.8 Hz) [1 H] , 5.68 (bs, 1 H, NH) , 5.66-5.59 (m, 1 H) , 5.55- 5.49 (m, 1 H) , 4.20-3-.86 (m, 4 H) , 3.73 (s, 3 H) , 3.21 (d, J = 10.6 Hz) and 2.84 (d, J = 10.2 Hz) [1 H, OH] , 2.40 (d, J = 13.4 Hz) and 2.39 (d, J = 13.4 Hz) [1 H] , 2.26 (d, J = 13.4 Hz) and 2.25 (d, J = 13.4 Hz) [1 H] , 0.92 (s, 9 H) , 0.32- 0.18 (m, 6 H) ; exact mass m/z calculated for C ₂₅ H ₃ iN0 ₇ Si 485.186964, found 485.186945.

Compound 59

FTIR (CH ₂ C1 ₂ cast) 3388, 1717 cm ^'1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 7.06 (bs, 1 H, NH) , 6.05-5.76 (m, 3 H) , 5.65-5.27 (m, 3 H) , 4.18-3.84 (m, 4 H) , 3.63 (s, 3 H) ,

2.44 (H ABX, JAB = 13.4, J _A x = 5.9 Hz, 1 H) , 2.12 C% ABX, JAB = 13.4, J _B χ = 8.2 Hz, 1 H) . exact mass m/z calculated for CigHiδNOg (M-H ₂ 0) 353.08994, found 353.08885. Compound 60

FTIR (CH ₂ C1 ₂ cast) 3384, 1717 cm ^"1 ; ⁱ H NMR (CDC1 ₃ , 400 MHZ) δ 6.72 (bs, 1 H, NH) , 6.43 (dd, J =

8.3, 6.9 Hz, 1 H) , 5.85 (dd, J = 9.5, 1.0 Hz, 1 H) , 5.82 (d, J = 9.5 Hz, 1 H) , 5.60 (s, 1 H) , 4.66 (bs, 1 H, OH) , 4.32 (dd, J = 13.0, 8.3 Hz, 1 H) , 4.21 (dd, J = 13.0, 6.9 Hz, 1 H) , 4.10-3.88 (m, 4 H) , 3.77 (s, 3 H) , 3.12 (bs, 1 H, OH) , 2.57 (bs, 1 H, OH) , 2.45 (ABq, J = 14.4, Δυ = 96.0 Hz, 2 H) ; exact mass HRFAB (NOBA) m/z calculated for C]_ ₉ Hι9Nθ ₇ Na (M+Na) 396.1059, found 396.1043. Compound 61

FTIR (CH2CI ₂ cast) 3404, 1715 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) δ 6.11 (dd, J = 8.0, 5.4 Hz, 1 H) , 5.86 (d, J = 9.4 Hz, 1 H) , 5.81 (bs, 1 H, NH) , 5.80 (dd, J =

9.4, 1.5 Hz, 1 H) , 5.74 (bs, 1 H) , 4.41 (dd, J = 14.5, 8.0 Hz, 1 H) , 4.36 (dd, J = 14.5, 3.3 Hz, 1 H) , 4.16-3.85 (m, 4

H) , 3.74 (s, 3 H) , 2.36 (ABq, J = 13.3, Δυ = 145.8 Hz, 2 H) , 2.35 (s, 1 H, OH), 1.06-0.90 (m, 18 H) , 0.79-0.55 (m, 12 H) ; exact mass m/z calculated for C ₃ iH ₄ 7θ ₇ NSi ₂ 601.28912, found 601.28946. Compound 62

FTIR (CH ₂ C1 ₂ cast) 3378, 1716 cm" ¹ ;

ⁱ H NMR (CDC1 ₃ , 400 MHZ) δ 6.29 (t, J = 6.7 Hz, 1 H) , 5.96 (br, 1 H, NH) , 5.87 (d, J = 9.3 Hz, 1 H) , 5.82 (dd, J = 9.3, 1.4 Hz, 1 H) , 5.79 (bs, 1 H) , 4.28 (t, J = 6.7 Hz, 2 H) , 4.10-3.85 (m, 4 H) , 3.73 (s, 3 H) , 2.46 (t, J = 7.0 Hz, 1 H, OH) , 2.45 (s, 1 H, OH) , 2.38 (ABq, J = 13.6, Δυ = 154.7 Hz, 2 H) , 1.01 (t, J = 8.0 Hz, 9 H) , 0.83-0.69 (m, 6 H) ; exact mass m/z calculated for C ₂ sH3iθ ₇ NSi 487.20264, found 487.20079.

Compound 63 FTIR (CH ₂ C1 ₂ cast) 3404, 1735, 1690 cm ^"1 ; ⁱ H NMR (CDCI ₃ , 400 MHZ) 6 6.03 (dd, J = 8.9, 6.5 Hz, 1 H) , 5.95 (bs, 1 H, NH) , 5.85 (d, J = 9.1 Hz, 1 H) , 5.81 (dd, J = 9.1, 1.3 Hz, 1 H) , 5.80 (br, 1 H) , 4.10-3.85 (m, 6 H) , 3.74 (s, 3 H) , 2.36 (s, 1 H, OH) , 2.34 (ABq, J = 13.5, Δυ = 162.8 Hz, 2 H) , 2.33 (s, 3 H) , 1.00 (t, J = 8.0 Hz, 9 H) , 0.80- 0.69 (m, 6 H) ; exact mass m/z calculated for C ₂₇ H ₃ 5θ ₇ NSIS 545.19037, found 545.19001.

Compound 65 FTIR (CH ₂ C1 ₂ cast) 3403, 1737 cm ^"1 ; ⁱ H NMR (CDC1 ₃ , 400 MHZ) δ 6.29 (dd, J = 9.9, 4.8 Hz, 1 H) , 5.95 (bs, 1 H, NH) , 5.86 (d, J = 9.1 Hz, 1 H) , 5.81 (dd, J = 9.1, 1.4 Hz, 1 H) , 5.80 (bs, 1 H) , 4.11-3.86 (m, 5 H) , 3.73 (dd, J = 11.3, 4.7 Hz, 1 H) , 3.73 (s, 3 H) , 2.55 (s, 3 H) , 3.43 (s, 1 H, OH) , 2.41 (ABq, J = 13.3, Δυ = 135.1 Hz, 2 H) , 1.00 (t, J = 8.0 Hz, 9 H) , 0.86-0.66 (m, 6 H) ;

-72-

SUBST1TUTE SHEET (RULE 26)

exact mass HRFAB (NOBA) m/z calculated for C ₂₆ H ₃ 5Nθ ₆ SiS ₃ Na (M+Na) 604 . 1294 , found 604 . 1290 .

Compound 1

FTIR (CH ₂ C1 ₂ cast) 3358, 1713, 1674 cm" ¹ ; ⁱ H NMR (CDC1 ₃ , 400 MHZ) δ 6.95 (bs, 1 H, NH) , 6.48 (dd, J = 9.3, 6.6 Hz, 1 H) , 6.02 (dd, J = 6.7, 1.2 Hz, 1 H) , 5.91 (dd, J = 9.4, 1.2 Hz, 1 H) , 5.88 (d, J = 9.4 Hz, 1 H) , 4.12 (dd, J = 14.1, 9.3 Hz, 1 H) , 3.86 (dd, J 14.1, 6.6 Hz, 1 H) , 3.78 (s, 3 H) , 3.02 (ABq, J ^" = 16.9, Δυ = 143.9 Hz, 2 H) , 3.21 (br s, 1 H) , 2.68 (s, 1 H) , 2.54 (s, 3 H) . exact mass HRFAB (NOBA) m/z calculated for Cι ₈ Hι7N0 ₅ S ₃ Na (M+Na) 446.0167, found 446.0162.

Example 3

In Example 3, th.e initial Diels-Alder reaction was carried out in an asymmetric manner.

Acylation of 71 with acryloyl chloride, Et ₃ N and DMAP produced ester 73 (Scheme 9 of Figure 8) . The double bond of 73 was cleaved with NaI0 ₄ -Os0 ₄ (ca 100%) to generate a mixture of glyoxylate 74 and the corresponding hydrate 75. Compound 75 underwent a Henry reaction with nitromethane in the presence of neutral alumina to give a mixture of alcohols. Dehydration of the alcohols by mesylation and in si tu elimination resulted in 3-nitropropenoate 72. The vinyl hydrogens of 72 had J = 13.5 Hz.

A Diels-Alder reaction of 72 with ketene acetal 6 was carried out at -78°C and, after mild hydrolysis in aqueous NH ₄ C1 at room temperature for 2 hours (h) , yielded adduct 77, as shown in Figure 8. Compound 77 was purified by flash chromatography and crystallization, with a 64% yield. No other diastereoisomers were detected. However, the mass balance was not quantitative, and other minor constituents may have been formed. X-ray analysis showed that the absolute stereochemistry is as shown. The corresponding reaction with methyl ester 66 proceeded with a 53% yield, indicating that the efficiency of the Diels-Alder reaction is somewhat sensitive to the nature of the O-alkyl group of the ester. From the absolute stereochemistry of the adduct, further elaboration to (-)- calicheamicinone preferably follows path A of Scheme 8 (Figure 7) .

Reduction of ketone 77 with NaBH ₄ gave a mixture of alcohols 78 epimeric at C(5) that were silylated with t- BuMe ₂ SiOTf and 2,6-lutidine to form 79. The chiral auxiliary was removed by DIBAL treatment to afford 80 and 71. DIBAL-H (2 equiv.) was added at -78°C and, after 4 hours, the reaction flask was transferred to a bath at -30°C. Another portion of DIBAL-H (2 equiv.) was added 24 hours after the first batch, and was continuously stirred for 24 hours. At this point, the C(5) epimeric silyl ethers 80 were isolated in 80% yield, and the auxiliary was

recovered in 92% yield. Epimers 80 were separated by flash chromatography over silica gel to afford 81a (53% from 77) and 81b (27% from 77) .

Each of these alcohols and the corresponding racemic compounds were converted into their Mosher esters and examined by ¹⁹ F NMR spectroscopy. Both 81a and 81b were optically pure, the CF ₃ -signals (two in each case) for the corresponding racemic materials being well separated (22 and 57 Hz, respectively) . In Examples 1 and 2, material corresponding to 81a and

81b was converted into (±) -calicheamicinone by route A

(Scheme 8 of Figure 7) . Consequently, preparation of optically pure 81a and 81b as described in this example constituted formal synthesis of (-) - calicheamicinone. Application of route -B (Scheme 8 of Figure 7) would lead to (+) -calicheamicinone, the unnatural stereochemical enantiomer.

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To the extent not already indicated, it will be understood by those of ordinary skill in the art that any one of the various specific embodiments herein described and illustrated may be further modified to incorporate features shown in other of the specific embodiments.

The foregoing de'tailed description has been provided for a better understanding of the invention only and no unnecessary limitation should be understood therefrom as some modifications will be apparent to those skilled in the art without deviating from the spirit and scope of the appended claims.