ANTIBACTERIAL.ANTIMYCOPLASMAL COMPOUNDS RELATED TO MUPIROCIN

This invention relates to a novel class of compounds having antibacterial and antimycoplasmal activity, to processes for their preparation and to their use in human and veterinary medicine, and also to intermediates for use in the preparation of such compounds.

Mupirocin, the compound of formula (A):

(A) ^' exhibits good activity against Gram positive bacteria, H.influenzae. Legionella and mycoplasma. It is marketed as a. topical formulation by Beecham Group p .c. under the trade mark BACTROBAN. Mupirocin (formerly known as pseudomonic acid) is rapidly hydrolysed in yjv& to monic acid A, the compound of formula (B):

(B)

which is inactive.

Various proposals have been made to improve the metabolic stability of mupirocin with respect to enzymatic hydrolysis by varying the nature of the C-1 to C-3 fragment, for instance, by modification ofthe C-1 ester functional group. Examples of this strategy include C-1 heterocyclic derivatives (EP-A-O 087 953 and EP-A-O 123 578, Beecham Group p.l.c), C-1 amides (US 4 312 764, Beecham Group Ltd), and C-1 ketones, including nigr alia aryl and heterocyclic ketones (US 4 312 874, Beecham Group Ltd, Klein ei al, poster presented at the Third Annual Chemical Congress of North America, Toronto, June 1988, and si. Med. Chem. 1989, __2, 151). In addition, various modifications elsewhere in the C-1 to C-3 fragment, other than at C-1, have also been made, including β-ketoesters (Klein ≤£ al, ibid.), C-2 alkyl and C-2 halo derivatives (Crimmin M. J. ≤£ al; sE. Chem. Soc. Perkin Trans.1. 1985, 549), and reduction of the C-2 C-3 double bond (Chain E.B. __t al, _L Chem. Soc. Perkin Trans.1. 1977, 294). No improvement in the overall biological profile, compared with mupirocin, was, however, observed. Indeed, the β-ketoester is reported to have shown little if any antibacterial activity.

It has now been surprisingly found that alternative modification ofthe C- 1 to C-3 fragment leads to compounds with an enhanced biological profile.

Accordingly, the present invention provides a compound of formula (IA), (IB) or (IC):

(IA)

(IB)

(IC) wherein R° denotes a substituted or unsubstituted hydrocarbyl or heterocyclyl group. More specifically R° denotes the term (A) _n - (B) _m ; wherein n and m are integers having a value of 0 or 1; A is a (Cι _β) alkyl, (C2-6) alkenyl, or (C2-6) alkynyl group; B is a (C3.7) cycloalkyl, (C4.7) cycloalkenyl, aryl, heterocyclyl or heteroaryl group. Both A and B may be optionally substituted as herein below defined. In the R° moiety when n is 0 then A represents a bond, and when m is 0 then B represents hydrogen; m and n may not both represent 0 at the same time.

Suitably when n is 0 and m is 1, B is a substituted or unsubstituted (C4.7) cycloalkenyl, aryl, heterocyclyl or heteroaryl group. B is preferably an aryl or heteroaryl moiety. More specifically, B is a cyclohexenyl, phenyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl, or thiazolyl group.

Suitably, when n is 1, is 0, and B is hydrogen, then A is a (Cχ.g)alkyl moiety. A is preferably a substituted or unsubstituted butyl group.

Suitably, when n is 1, and m is 1, then A is a (C2-β)alkenyl, (C2-6) lkynyl group. Preferably, when n is 1, and m is 1, then B is a substituted or unsubstituted aryl or heteroaryl group, such as a furanyl or phenyl. More preferably A is an ethenyl or acetylenyl (ethynyl) group.

Suitably B is a substituted or un-substituted aryl or heteroaryl group. As used herein the term "(un)substituted" refers to both the substituted and unsubstituted derviative. Preferably B is a (un)substituted phenyl, (un)substituted pyrimidinyl, (un)substituted thiazolyl, (un)substituted oxazolyl, or (un)substituted pyridyl. More preferably B is an (un)substituted phenyl, (un)substituted pyridyl, or (un)substituted pyrimidinyl.

As defined herein both A or B may be optionally substituted, independently, with up to five, preferably up to three substituent groups, hereinafter referred to as X and Xx respectively.

Examples of suitable X groups for A, when n is 1, include, cyano, amino, (Cι_6)alkanoyIamino, mono- or di- (Cχ_g)alkylamino, hydroxy,

(Cχ_g)alkoxy, substituted (Cχ.g)alkoxy [also referred to as -0-Rχ], (Cχ.g)_dkylthio, (un)substituted heterocyclylthio, arylthio, (un)substituted sulphamoyl, (un)substituted carbamoyl, amidino, guanidino, nitro, halogen, carboxy and salts and esters thereof, (Cχ.g)alkanoyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, and acyl groups.

Suitably optional substituents Q_χ), for B when m is 1, include, for example, (Cχ.g)alkyl, (po-y)halo(Cχ.g)alkyl, cyano, (un)substituted heterocyclyl, amino, (C .g)alkanoylamino, mono- or c_-(Cχ_g)alkylamino, substituted mono- or di-(Cχ_g)alkylamino, [also referred to as -NR2R3], hydroxy, (Cχ_g)alkoxy, substituted (Cχ_g)alkoxy [also referred to as -O-R1], (Cχ_g)alkenoxy, hydroxy substituted (Cχ.g)alkoxy, (un)substituted heterocyclylthio, arylthio, arylsulphinyl, arylsulphonyl, (Cχ.g)alkylthio, (Cχ.g)alkylsulphinyl, (Cχ.g)alkylsulphonyl, (un)substituted sulphamoyl,

(un)substituted carbamoyl, amidino, guanidino, nitro, halogen, carboxy

and salts and esters thereof, (Ci .g) alkylcarbonyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, and acyl groups.

When X or Xx is a substituted alkoxy [ -O-R^], as hereinbefore defined, the Rx group may be a (C2- ) alkenyl, (Cχ.g) alkoxy alkyl, (poly)hydroxy (Cχ.g) alkyl, (poly)halo(Cχ.g) alkyl, substituted or unsubstituted heteroaryl (Cχ.g) alkyl, substituted mono- or di- amino (Cχ.g) alkyl, substituted or unsubstituted heterocyclyl (Cχ.g) alkyl, or N-(C;χ.g alkyl )- N- heteroaryl-(Cχ.g)alkyl.

As used herein, the term "(poly)" refers to the optional substitution of more than one, such as (poly)haloalkyl would allow for more than one halogen, independently on the alkyl moiety, i.e., -CF3.

Preferably the x group is a C2-3 alkenyl, hydroxy Cχ.g alkyl,

(Cχ.g)alkoxy(Cχ.g)alkyl, (poly)halo(Cχ.g) alkyl, (un)substituted (Cχ.g) alkyl heteroaryl, (un)substituted (Cχ.g) alkyl heterocyclyl, or N-(Cχ.g alkyl)-N- pyridyl-(Cχ.g)alkyl. Preferably the heteroaryl is a pyridyl, or furanyl moiety. Preferably the heterocyclyl is a piperidine group.

More preferably Rx is ethenyl, 2-ethanol, 3-propanol, -CH2-O-CH3,

CH2-furanyl, CH2-furan-2-yl-5-nitro; CF3, N-methyl-N-2- pyridylaminoethyl, N-piperidinylethyl, or 4-pyridylmethyl.

When Xx is NR2R3, the R2 and R3 moieties are independently a (Cχ.g) alkyl group or one of 2 or R3 may be a hydroxy (Cχ.g) alkyl group. Preferably, both R2 and R3 are (Cχ.g) alkyl, more preferably methyl; or one of R2 R3 is methyl and the other 2-ethanol.

Preferably the Xx substitutents are selected from hydroxy, substituted and unsubstituted (Cχ.g)alkoxy, (Cχ.g)alkyl, oxy(Cχ.g)alkyl, cyano, chloro, fluoro, bromo, nitro, hydroxy(Cχ.g)alkyl, (Cχ.g)alkylthio, (Cχ.g)alkylsulphinyl, (C^.g) alkylsulphonyl, NR2R3, or (un)substituted heterocyclyl, or gem di(Cχ.g)alkoxy(Cι.g)alkyl.

More preferably Xx is methoxy, C(0)CI_3, methyl, cyano, chloro, fluoro, bromo, -CH(OCH ₂ CH ₃ )2, nitro, -CH(O), N(CH ₃ ) ₂ , SCH3, S(0)CH ₃ , S(0)2CH3, -CH2OH, piperidine, O-CF3, hydroxy, ethenyloxy, 2-

hydroxyethoxy, N-(2-hydroxyethyl)-N-methylamino, 3-hydroxypropyloxy, azidoethoxy, N-methyl-N-pyridylaminoethoxy, piperidinylethoxy, pyridylmethyloxy, nitrofuranyl methyloxy, or furanylmethyloxy.

For the optional substituent groups X and Xx wherein their respective members are also referred to as (un)substituted group, the optional substituents for said groups are independently substituted up to five times, preferably up to three times, from the same group listed herein under the Xx term. For example, (unsubstituted carbamoyl would allow the nitrogen atom to be mono- or di-substituted with a (C .g)alkyl moiety; the (un)substitued heterocyclic would allow, for example, a piperidine ring to be substituted by a (Cχ.g)alkyl, or hydroxy moiety; an (un)substituted heteroaryl would allow for a furanyl ring to be substituted by a nitro group.

Preferred substituent groups Q£χ) when B is an aryl group include, for example, halogen, cyano, (Cχ.g)alkyl, hydroxy(Cχ.g)-alkyl, oxo(Cχ.g)alkyl, gem di(Cχ.g)alkoxy(Cχ.g)alkyl, (Cχ.g)alkoxy, (C2-g)alkenoxy, hydroxy(Cχ_g)alkoxy, (Cχ.g)alkoxy(Cχ.g)alkoxy, halo(Cχ_g)al__yl, hydroxy, __o_ino, mono- or di-(Cχ.g)alkylamino, acylamino, nitro, carboxy,

(Cχ.g)alkoxycarbonyl, (Cχ.g)alkoxycarbonyl(Cχ.g)alkyl,

(Cχ.g)alkylcarbonyloxy, (Cχ.g)alkylthio, (Cχ.g)alkylsulphinyl,

(Cχ.g)-alkylsulphonyl, sulphamoyl, mono- or di-(Cχ.g)alkylsulphamoyI, carbamoyl, mono- or di-(Cχ.g)alkylcarbamoyl and heterocyclyl.

Preferred substituents (Xx) when B is a heteroaryl group include, for example, halogen, (Cχ.g)alkyl, (Cχ.g)cycloalkyl, (Cχ.g)alkoxy, hydroxy(Cχ_g)alkoxy, halo(Cχ_g)alkyl, hydroxy, amino, mono- or di-(Cχ.g)alkylamino, N-hydroxy(Cχ_g)alkyl N-(Cχ_g)alkyl amino, carboxy, (Cχ.g)alkoxycarbonyl, (Cχ_g)alkoxycarbonyl(Cχ_g)alkyl, aryl, oxo, non-aromatic heterocyclyl, (Cχ.g)alkylthio, (Cχ.g)alkylsulphinyl and

(C χ.g)alkylsulphonyl .

Preferred substituent G_χ) when B is a heterocyclyl group include, for example, halogen, (Cχ.g)alkyl, hydroxy(Cχ.g)alkyl, (Cχ.g)alkoxy, hydroxy(Cχ.g)alkoxy, halo(Cχ.g)alkyl, hydroxy, amino, mono- or di-(Cχ.g)_d__yl_unino, carboxy, (Cχ.g)alkoxycarbonyl, (Cχ.g)alkoxycarbonyl(Cχ.g)alkyl, aryl and oxo.

When a substituent group, preferably in the (B) _m term, has an acidic hydrogen arising from the presence in a heteroaryl ring of an NH moiety, for instance, when R° is pyrazolyl, the hydrogen may be replaced by a (X or Xx) substituent as hereinbefore defined. Preferably the substitutent is a (Cχ.g) alkyl group.

As used herein, the term "alkyl" group or moiety referred to herein may be a straight or branched hydrocarbon chain, and may contain, for example, up to 12 carbon atoms, suitably up to 6 carbon atoms. The alkyl chain may be unsubstituted or substituted. In particular, the alkyl group or moiety may be an unsubstituted or substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl or tert-butyl group. Examples of suitable optional substituents for any such alkyl group or moiety include the above-listed substituents for the (A) _n term.

When used herein, the term 'aryl' includes, unless otherwise defined, phenyl or naphthyl.

When used herein, the term 'heterocyclyl' and 'heterocyclic' includes non-aromatic single or fused rings comprising up to four heteroatoms in each ring selected from oxygen, nitrogen and sulphur. Suitably, the heterocyclic ring comprises from 4 to 7, preferably from 5 to 6 ring atoms. A fused heterocyclic ring system may include aromatic carbocyclic and heteroaryl rings. Suitably the heterocyclic group is piperidinyl.

When used herein, the term 'heteroaryl' includes aromatic hetrocyclic containing rings and ring systems as is commonly defined in the art, such as by Katritzky et al.. Handbook of Heterocyclic Chemistry, Pergamon Press, Oxford, England (1985). As defined therein, a heteroaromatic structure is based on the 6 π-electron system. These structure are related to and formally derived from benzene by successive replacement of one or two annular CH groups by trivalent or divalent heteroatom groups respectively. The overall patttern of filled bonding molecular orbitals is retained. Thus replacement of one CH group by 0 ⁺ , S ⁺ , or N gives the six-membered pyrylium, thiinium or pyridine systems, and replacement of two CH groups by O, S, or NH gives the five-membered furan, thiophene, or pyrrole. Multiple replacements are also possible with up to four

heteroatoms in five- and six-membered rings. Suitably the heteroaryl ring has 5 to 6 ring atoms in each ring. Prefered heteroaryl groups herein include, pyridyl, pyriinicLinyl, furanyl, thienyl, thiazolyl, isoxazolyl, oxazolyl and pyrazolyl.

When used herein, the term "hydrocarbyl" may include groups having up to 18 carbon atoms, suitably up to 10 carbon atoms, conveniently up to 6 carbon atoms. Suitable groups include those listed under the (A) _n term and the (B) _m term groups which do not contain a heteroatom, i.e. cycloalkyl, cycloalkenyl and aryl.

It will be appreciated that another aspect of the present invention is in the many variations which can result from the point of attachment ofthe respective heteroaryl rings, such as in the 2-pyridyl, 3-pyridyl or 4-pyridyI moieties. Further where isomers of a heteroaryl exist, such as in a 1,3- pyrazolyl or 1,2- pyrazolyl, said isomers are also another aspect ofthe present invention.

When used herein, the term 'halogen' refers to fluorine, chlorine, bromine or iodine. Preferably, the halogen is fluoro, chloro or bromo.

It will be further appreciated that in compounds of formula (I), the moiety:

will have the same relative and absolute stereochemistry at each ofthe chiral centres (indicated by *) as that of corresponding moiety in mupirocin i.e. [2S, 3R, 4R, 5S] about the tetrahydropyran ring and [2S, 3S, 4S, 5S] in the 5-(2,3-epoxy-5-hydroxy-4-methylhexyl) sidechain ofthe tetrahydropyran ring.

The compounds of the present invention may exist in the forms shown in formulae (IA), (IB) or (IC), the three forms being in equilibrium. It will be appreciated that the compounds of formulae (IA), (IB), and (IC) are interrelated by keto-enol tautomerism, with formula (IA) representing the keto tautomer and formula (IB) and (IC) representing the two possible

enol tautomers. References hereinafter to 'formula (I)' encompass all three forms unless the context requires otherwise.

It will be appreciated that in compounds of formula (I), the group R° may contain one or more chiral centres. The present invention encompasses all such resultant isomeric possibilities.

Since the compounds of formula (I) of the present invention are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt wt basis). Impure preparations ofthe compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I). Preferably, whenever possible, the compounds ofthe present invention are obtained in crystalline form.

When some of the compounds of this invention are allowed to crystallise, or are recrystallised, from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.

Examples of compounds within the scope of this invention include the following:

3R,4R-Dihydroxy-2S-[2,4-Dioxo-4-(4-methoxyphenyl)-but-l-y l]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-(2,4-dioxo-4-phenyl-but-l-yl)-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxypyrid-5-yl)-but-l- yl]-5S-(2S,3S,epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyra n;

2S-[4-(4-Acetylphenyl)-2,4-dioxobut-l-yI]-3R,4R-dihydroxy - 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[4-(4-dimethylaminophenyl)-2,4-dioxobu t-l-ylJ- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-(2,4-dioxo-4-(furan-3-yl)but-l-y.]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(l-methylpyrazol-4-yl)- but-l-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(furan-2-yl)but-l-yl]5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(pyrid-4-yl)but-l-yl]5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(pyrid-3-yl)but-l-yl]5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(pyrid-2-yl)but-l-yl]5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-methylisoxazol-5-yl)- but-l-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetra- hydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-methoxyphenyl)but-l-yl ]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[4-(4-cyanophenyl)-2,4-dioxobut-l-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

- ii -

3R,4R-Dihydroxy-2S-[4-(4-chlorophenyl)-2,4-dioxo-but-l-yl ]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[4-(4-diethoxymethylphenyl)-2,4-dioxob ut-l-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[4-(4-dioxo-4-(4-formylphenyl)-but-l-y l]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-nitrophenyl)-but- 1-yl]-

5S-(2S,3S-epoxy-5S-hydroxy-4S-methy_hexyl)tetrahydropyran .

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(thien-2-yl)but-l-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(thien-3-yl)but- l-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[4-(2-dimethylaminopyrid-5-yl)-2,4- dioxobut-l-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methyl- hexyDtetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methylthiopyrid-5-yl)b ut-l-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methylsulphinylpyrid-5 -yl)but-l-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; ^'

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methylsulphonylpyrid-5 -yl)but-l-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)-tetrahydropyran;

3R,4R-Dihydroxy-2S-[4-(2-chloropyrid-5-yl)-2,4-dioxobut-l -yl]-5S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(5-hydroxymethylfuran-2-y l)but-l-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-nitrothien-4-yl)but-l- yl]-5S-(2S,3S-

epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[4-(2-bromopyrid-5-yl)-2,4-dioxobut-l- yl]-5S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(5-methoxyfuran-2-yl)but- l-yl]-5S-

(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-(piperidin-l-yl)-pyrim idin-5-yl)but-l- yIl-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyra n;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(l-methyl-2-methylthioimi dazol-4-yl)- but-l-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahyd ropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxyphenyl)but-l-yl ]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methylthiophenyl)but-l - yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyra n;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methylsulphinyl-phenyl )- but-l-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methyl-hexyl)tetrahy dropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methylsulphonyl-phenyD - but-l-yl)-5S-(2S,3S-epoxy-5S-hydroxy-4S-methyl-hexyl)tetrahy dropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-cyanophenyl)but-l-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-trifluoromethoxy-pheny l)- but-l-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahyd ropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-fluorophenyl)but-l-yl] - 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-hydroxyphenyl)but-l-yl ]-5S-(2S,3S- epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R Dihydroxy-2S-[4-(4-allyloxyphenyl)-2,4-dioxobut-l-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-bihydroxy-2S-[2,4-dioxo-4-(4-methoxymethyloxophenyl )but-l-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[4-(but-l-yl)-2,4-dioxobut-l-yl]-5S-(2 S,3S-epoxy- 5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-hydroxyethoxy}pheny l)but-l-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(3-fluorophenyl)but-l-yl] -5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-fluorophenyl)but-l-yl] -5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[4-(3,4-difluorophenyl)-2,4-dioxobut-l -yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyraιi;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-N-(2-hydroxyethyl)-N- methylaminopyrid-5-yl)but-l-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4 S- methylhexyDtetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-(4-hydroxypiperidin-l- yl)pyrid-5-yl)- but-l-yl]-5S-[2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)-tetrahy dropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-(3-hydroxyprop-l-oxy)p yrid-5-yl)but- l-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropy ran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxythiazol-5-yl)bu t-l-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[4-(cyclohexen-l-yl)-2,4-dioxobut-l-yl ]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[3,5-dioxo-l-(furan-2-yl)hex-l(E)-en-6 -yl]-5S-

(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetra-hydropyran;

3R,4R-Dihydroxy-2S-[3,5-dioxo-l-(4-methoxyphenyl)hex-l(E) -en-6-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-(3 ,5-dioxo- l-phenyIhex-l-yn-6-yl)-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[4-(2-dimethylaminopyrimidin-5-yl)-2,4 -dioxobut- l-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropy ran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methoxypyrimidin-5-yl) but-l-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-azidoethoxy}phenyl) but-l-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dmydroxy-2S-[2,4-dioxo-4-(4-{2-N-methyl-N-2-pyridyl amino- ethoxy}phenyl)but-l-yl-5S-(2S,3S-epoxy-5S-hydroxy-4S- methylhexyDtetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-piperidinylethoxy}p henyl)but-l-yl- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{4-pyridylmethyloxy}ph enyl)but-l-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{5-nitrofuran-2-ylmeth yloxy}phenyl) but-l-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahyd ropyran; and

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{furan-2-ylmethyloxy}p henyl)but-l- yl]-5S-(2S,3S-epoxy-6S-hydroxy-4S-methylhexyl)tetrahydropyra n.

Preferred compounds of the instant invention are:

3R,4R-Dihydroxy-2S-[2,4-Dioxo-4-(4-methoxyphenyl)but-l-yl ]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dmydroxy-2S-[2,4-dioxo-4-(2-methoxypyrid-5-yl)- but-l-yl]-5S-(2S,3S,epoxy-5S-hydroxy-4S-methylhexyl)tetrahyd ropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-nitrophenyl)-but-l-yl] - 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)-tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(2-methylthiopyrid-5-yl)- but-l-yl]-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahyd ropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methylthiophenyl)but-l -yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[4-(2-chloropyrid-5-yl)-2,4-dioxobut-l -yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-_luorophenyl}but-l-yl] - 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R Dihydroxy-2S-[4-(4-allyloxyphenyl)-2,4-dioxobut-l-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-methoxymethyloxophenyl )but-l-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran;

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-hydroxyethoxy}pheny l)but-l-yl]- 5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran; and

3R,4R-Dihydroxy-2S-[2,4-dioxo-4-(4-{2-azidoethoxy}phenyl) but-l-yl]-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropyran.

Compounds of the present invention may be prepared by methods known for the preparation of β-diketones. Some of these processes will be more

appropriate than others.

Suitably, compounds of formula (I) may be prepared by a process which comprises treating a compound of formula (II):

(ID

in which Z^, Z^ and Z^ are the same or different and each is hydrogen or a hydroxyl-protecting group, and R° is as hereinbefore defined;

with an oxidising agent which converts a β-hydroxyketone into a β-diketone;

and thereafter, and if necessary, removing any hydroxyl-protecting groups.

Suitably such oxidising agents include, for example, activated manganese dioxide, 2,3-dichloro-5,6- dicyano-l,4-benzoquinone (DDQ), chromium trioxide, pyridinium dichromate, pyridinium chlorochromate, dimethylsulphoxide/trifluoroacetic anhydride, dimethylsulphoxide/oxalyl chloride, ruthenium tetroxide, and tetra-n-propylammonium perruthenate.

Suitably, the oxidation reaction is effected in a organic solvent such as, for example, dioxan, acetonitrile, tetrahydrofuran, ether, carbon tetrachloride, chloroform, dichloromethane, benzene or toluene and at a temperature which is preferably in the range from -20° to 100°C.

Preferably, the compounds of Formula (I) wherein (A) _n is an alkenyl or alkenyl moiety in which the double or triple bond is in a conjugated or non-conjugated system with the rest ofthe molecule are made according to

the process of Formula (II) as noted above. Alternatively, under carefully controlled conditions the process of Formula (VI) as hereinbelow defined, may also be used.

Compounds of formula (II) are novel and useful intermediates for the preparation of compounds of formula (I).

Accordingly, a further aspect of the invention also provides a compound of formula (II) as hereinbefore defined.

Compounds of formula (II) may be prepared by a process which comprises treating a compound of formula (III):

(III)

in which Z*, Z^ and Z^ are as hereinbefore defined and M ⁺ is a metal such as lithium, with an aldehyde of formula (IV):

R ^O CHO (IV)

in which R° is as hereinbefore defined and thereafter, and if necessary, removing any hydroxyl-protecting groups.

A compound of formula (III) may be obtained by treating a ketone compound of formula (V):

OZ

(V)

in which Z , Z^ and 7? are as hereinbefore defined, with a suitable enolising agent such as, for example, lithium diisopropylamide.

It will be appreciated that in practice, the compound of formula (III) may be generated in situ, prior to the treatment thereof with a compound of formula (IV).

The preparation of a compound of formula (V) is described in GB 1 587 58 (to Beecham Group pic).

In a further aspect, the present invention provides a second process for preparing a compound of formula (I) as hereinbefore defined, which process comprises treating a compound of formula (VI):

(VI)

in which i , Z , Z^ and R° are as hereinbefore defined, with a reagent capable of converting a terminal methylene-substituent to an oxo- substituent and thereafter, and if necessary, removing any hydroxyl-protecting groups.

Suitable reagents for effecting such a conversion include ozone and osmium tetroxide, each of which forms an intermediate which may then be converted to the compound of formula (I). Alternative reagents useful in the conversion herein may be found in Harrison et al. Compendium of Organic Synthetic Methods, Wiley-Interscience (1971).

Ozonolysis may be effected under conditions conventionally used for such a reaction. Thus the reaction may be effected at a low temperature, for instance about -70°, in the presence of a suitable solvent such as dichloromethane. The intermediate ozonide thus formed may be

conveniently decomposed by an agent conventionally used for such a task, of which triphenyl phosphine is especially preferred.

Alternatively, the compound of formula (VI) may be treated with osmium tetroxide, according to the procedure described by V. Van Rheenen, R.C. Kelly and D.Y. Cha, Tetrahedron Lett. 1976, 1973. Preferably a catalytic quantity of osmium tetroxide is employed, in the presence of a tertiaryamine oxide catalyst such N-methylmorpholine N-oxide, in a solvent such as aqueous tetrahydrofuran, to give an intermediate 1,2-diol which may then be treated with an oxidising agent such as sodium periodate to give the compound of formula (VI).

Compounds of formula (VI) are novel and useful intermediates for preparing of compounds of formula (I).

Accordingly, a further aspect of the invention also provides a compound of formula (VI) as hereinbefore defined.

Suitably, compounds of formula (VI) may be prepared by a process which comprises treating the acid of formula (VII) or an activated derivative thereof:

(VII) in which Z^, Z^ and Z^ are the same or different and each is hydrogen or a hydroxyl-protecting group,

with an organometallic reagent;

and thereafter, and if necessary, removing any hydroxyl-protecting groups.

Suitable organometallic reagents include:

(i) a Grignard reagent ofthe formula R°MgX in which R° is as defined with respect to formula (I) and X represents chlorine, bromine or iodine, which reaction may optionally be carried out in the presence of copperd) iodide as catalyst;

(ii) an organolithium reagent of formula R°Li in which R° is as defined with respect to formula (I);

(iii) an organomanganous reagent ofthe formula R°MnCl in which R° is as defined with respect to formula (I); and

(iv) an organocerium reagent R°Li-CeX3, in which R° is as defined with respect to formula (I) and X represents chlorine, bromine or iodine.

The reaction with the organometallic reagent may be conveniently carried out in an ethereal or hydrocarbon solvent, the choice of which is dependent upon the specific requirements ofthe organometallic reagent. Preferably, the Grignard reagent is generated and used in diethyl ether or tetrahydrofuran.

The reaction is generally carried out in an inert atmosphere such as argon or nitrogen and at ambient temperature or below. The period for which the reaction is allowed to proceed depends upon the particular starting materials employed. The course ofthe reaction may be followed by conventional methods such as thin layer chromatography and the reaction may be terminated when an optimum quantity of product is present in the reaction mixture.

Suitable activated derivatives ofthe acid of formula (VII) include thio-esters of formula (VIII):

(VIII) in which l , Z^ and 7? are as hereinbefore defined and the moiety:

represents a 5- or 6-membered heterocyclic ring which may contain in addition to the nitrogen atom, one or two further heteroatoms selected from oxygen, nitrogen and sulphur and which may be substituted or fused to a benzene ring which may itself be substituted.

Preferred thio-esters are of formula (Villa):

(Villa) in which 7 , Z^ and 7? are as hereinbefore defined.

Other suitable activated derivatives of the acid of formula (VII) include mixed anhydrides of the formula (IX):

(IX) in which Zl, 7? ¹ , and ? are as hereinbefore defined, and R is (Cχ.g)alkyl;

and ofthe formula (X):

(X)

in which TX, Z , and Z^ are as hereinbefore defined, and R^ and Bβ are the same or different and each denotes an aryl group, for instance phenyl, or a (Cχ.g)alkoxy group, for instance ethoxy.

Further suitable activated derivatives ofthe acid of formula (VII) include amides ofthe formula (XI):

(XI)

in which Z. Z^ and 7? are as hereinbefore defined, R^ and R^ are the

same or different, and each is (C] _g)alkyl, preferably methyl, or the substituents R ⁴ and R^ form a (C2"7)alkylene chain and;

amides of the formula (XII):

(XII)

in which Z , Z^, and 7? are as hereinbefore defined and R^ and R?, together with the nitrogen atom to which they are bonded, form an imidazolyl or triazolyl ring.

The reaction of an N-methoxy-N-methylamide compound with an organolithium or a Grignard reagent to form a ketone is described by

Nahm and Weinreb in Tetrahedron Lett. 1981, 3815. The reaction of an α,β-unsaturated acid or its imidazolyl derivative with a Grignard reagent is described in Chem. Ber., 1965, 9__> 1284.

Suitably a thio-ester of formula (VIII) is treated with an organomanganous reagent of formula R°MnCl, as hereinbefore defined.

Suitably an amide of formula (XI) or (XII) is treated with an organolithium reagent of formula R°Li as hereinbefore defined:

Suitable organometallic reagents may be prepared according to conventional procedures.

Suitable organomanganous reagents of the formula R°MnCl may be conveniently prepared by addition of an organolithium reagent R°Li to a solution of manganous chloride and lithium chloride in dry THF, or a suspension of anhydrous manganous chloride in dry THF. An excess of R°MnCl is preferably employed. Alternatively, a Grignard reagent may

be used in place ofthe organolithium reagent, to generate the organomanganous reagent R°MnCl.

Other organomanganous reagents which may be used instead of R°MnCl include:

(i) (R°)3MnLi or (R°)3MnM X in which X is as hereinbefore defined, as described in Synthetic Communications. 1979, 9_, 639;

(ii) R°MnI in ether; as described in Synthetic Communi cati ons . 1979, 1, 639; and

(iii) R°MnBr in ether, as described in Tetrahedron Lett.. 1976, 3155.

As in the case of R°MnCl, the above organomanganous reagents may be prepared in situ when required.

Organocerium reagents may be generated in situ by treatment of an organolithium compound ofthe formula R°Li, in which R° is as hereinbefore defined, with cerium (III) halide, by analogy with the procedure described by Imamoto el al; J.Chem. Soc. Chem. Commun. 1982, 1042.

The activated derivatives of compounds of formula (VI) may be prepared from the compounds of formula (VI) by standard methodology.

Compounds of formula {VII) may be obtained by treating the protected methylester of monic acid with a base such as lithium diisopropylamide, as described by Crimmin et at, J. Chem. Soc. Perkin Trans 1. 1985, 549, followed by ester hydrolysis.

Advantageously, a compound of formula (VI) may be prepared by treating a compound of formula (XI) in which R ⁴ and R^ each is methyl with an organometallic reagent which is preferably an organolithium reagent of the formula R°Li.

Compounds of formula (XI) are novel and useful intermediates in the preparation of compounds of formula (VI).

Accordingly, a further aspect ofthe invention provides compounds of formula (XI) as hereinbefore defined.

Compounds of formula (XI) may also be obtained by a process which comprises treating a compound of formula (XIII):

(XIII)

in which Z*, Z^, Z^, 4 and R are as hereinbefore defined, with a strong non-nucleophilic base such as, for example, lithium diisopropylamide, followed by quenching with a mild proton source such as ammonium chloride.

Compounds of formula (XIII) are novel and useful intermediates for the preparation of compounds of formula (XI).

Accordingly, a further aspect ofthe invention provides a compound of formula (XIII) as hereinbefore defined.

Compounds of formula (XIII) may be prepared from monic acid by initial conversion thereof to an activated derivative, for instance a mixed anhydride such as that formed with iso-butylchloroformate, followed by subsequent treatment with an amine HN(OR4)R5 in which R ⁴ and R^ are as hereinbefore defined, or a salt thereof; under standard conditions, for instance, with dichloromethane as the reaction solvent, at about 0°C for 2h; and thereafter and if required, introducing any hydroxyl-protecting groups that may be subsequently required.

In a further aspect, the present invention provides a third process for preparing a compound of formula (I) which process comprises treating a

(xrv) in which Z , Z^, β, R ⁴ and R^ are as hereinbefore defined, with a compound of formula (XV):

R°COCH ₂ -

(XV)

in which R° is as hereinbefore defined and thereafter, and if necessary, removing any hydroxyl-protecting groups.

Compounds of formula (XEV) are novel and useful intermediates for the preparation of compounds of formula (I).

Accordingly, a further aspect ofthe invention provides a compound of formula (XEV) as hereinbefore defined.

Compounds of formula (XIV) may be prepared from the corresponding acids of formula (XVI):

(XVI)

in which Z Z and Z^ are as hereinbefore defined, by initial conversion thereof to an activated derivative, for instance a mixed anhydride such as that formed with iso-butylchloroformate, followed by subsequent

treatment with an amine HN(OR ⁴ )R ⁵ , in which R ⁴ and R ^δ are as herein¬ before defined, or a salt thereof, under standard conditions, for instance, with dichloromethane as the reaction solvent, at about 0°C for 2h.

Compounds of formula (XVI) are novel and useful intermediates for the preparation of compounds of formula (I).

Accordingly, a further aspect of the invention provides a compound of formula (XVI), as hereinbefore defined.

Compounds of formula (XVI) may be prepared from compounds of formula (V), as hereinbefore defined, and in which the hydroxyl groups are protected, preferably as a silylether, by initial conversion thereof to the enol form followed by ozonoloysis and subsequent decomposition of the intermediate ozonide using, for instance, dimethyl sulphide.

Compounds of formula (I) may be obtained from other compounds of formula (I) by suitable manipulation ofthe substituents present in the group R° according to conventional methodology. For instance, an alkylthio substituent may be converted to an alkyl sulphinyl or an alkylsulphonyl substitutent by treatment thereof with a conventional oxidising agent such as m-chloroperbenzoic acid.

When used herein, the term 'hydroxyl-protecting group' refers to any such group known in the art which may be removed without disruption of the remainder ofthe molecule. Suitable hydroxyl-protecting groups include those described in 'Protective Groups in Organic Synthesis', T.W. Greene, Wiley-Interscience, New York 1981.

The hydroxyl groups of the compounds of formulae (II), (III), (V) to (XIV) and (XVI) may be protected at any stage of the above processes, using conventional methods. The hydroxyl-protecting group may be removed by methods known in the art, including enzymatic methods.

Particularly suitable hydroxyl-protecting groups are silyl groups since these are readily removed under mild conditions. Such groups are introduced using conventional silylating agents, including halosilanes and silazanes, ofthe formulae below:

wherein Me denotes methyl and ^Bu denotes t-butyl, Y is halogen and each group L is independently selected from hydrogen, (Cχ.g)alkyl, (Cχ.g)alkoxy, aryl or aryl(Cχ-4)alkyl. A preferred silyating agent is trimethylsilyl chloride. Particularly suitable protecting groups are trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups. Preferred protecting groups are trimethylsilyl groups because of their ease of removal.

The glycol function ofthe compounds of formulae (II), (III), (V) to (XIV) and (XVI)may be protected by forming a cyclic derivative using a compound of formula (XVII):

OR

8 1 1 0

R -C-OR

1 1

OR

(XVII)

wherein Bβ is hydrogen or (Cχ.g)alkyl and each of R^, RlO-and RH is (Cχ_g)alkyl. In the cyclic derivative Z and Z^ together are a moiety:

a 1

R OR

\ /

in which R^ is as hereinbefore defined and R ^ is (Cχ.g)alkyl.

Suitably ^ is hydrogen, methyl, ethyl, n- or iso-propyl; most suitably it is hydrogen. The groups ^, R O and RH are suitably methyl, ethyl, n- or iso-propyl, or n-, iso-, sec- or t-butyl; most suitably methyl.

Similarly the hydroxyl groups of a compound of formula (I) may be protected prior to conversion to a further compound of formula (I) as described above.

In each case the hydroxyl-protecting groups described above may be removed by mild acid hydrolysis followed by alkaline hydrolysis, for instance, as described by J.P. Clayton, K. Luk and N.H. Rogers, in 'Chemistry of Pseudomonic Acid, Part II', J.C.S. Perkin Trans. I. 1979, 308.

The compounds of this invention are useful in therapy, in particular for the treatment of bacterial and mycoplasma-induced infections in non-human and human animals, such as the treatment of respiratory tract infections, otitis, meningitis, skin and soft tissue infections in human animals, mastitis in cattle, and respiratory infections in non-human animals such as pigs and cattle.

The compounds of this invention are active against both Gram negative and Gram positive organisms, including Haemophilus. for instance H.influenzae QI; Branhamella.for instance B.Catarrhalis 1502; Streptococci, for instance S.pyogrenes CN10 and S.pneumonia PU7; and Staphylococci. for instance S.aureus Oxford, Legrionella. for instance Lj_ pneumophila: and against mycoplasma. In addition, compounds of the present invention are active against Staphylococci organisms such as aureus and S. epidermis which are resistant, including multiply resistant, to other anti-bacterial agents, for instance macrolides; aminoglycosides; lincosamides; and β-lactams, such as, for example methicillin.

The compoi ds of this invention are also active against mycoplasma-induced infection, in particular Mycoplasma fermentans. which has been implicated as a co-factor in the pathogenesis of AIDS.

Accordingly in a further aspect, the present invention provides a method of treating humans infected with M. fermentans. in particular humans also infected with HIV, which method comprises treating humans in need of such therapy with an anti-mycoplasmal effective amount of a compound of formula (II).

This invention also provides a pharmaceutical or veterinary composition which comprises a compound of formula (I) (hereinafter referred to as the 'drug') together with a pharmaceutically or veterinarily acceptable carrier or excipient.

The compositions may be formulated for administration by any route, for instance, by topical, parenteral or oral administration and would depend on the disease being treated. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical or sterile parenteral suspensions.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous

vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p.-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

For topical application to the skin the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics and cosmetics, such as 'Harry's Cosmeticology' published by Longman, and the British Pharmacopoeia.

Suppositories will contain conventional suppository bases, e.g. cocoa-butters or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilizing the drug and a sterile vehicle. The drug, depending on the vehicle and concentration used, can be suspended in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability thereof the composition may be frozen after filling into the vial and water removed under vacuum. The dry lypophilized powder is then sealed in the vial. The drug can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the drug.

For topical application to the ear, the drug may be made up into a suspension in a suitable liquid carrier, such as water, glycerol, diluted ethanol, propylene glycol, polyethylene glycol or fixed oils.

For topical application to the eye, the drug is formulated as a suspension in a suitable, sterile aqueous or non-aqueous vehicle. Additives, for instance buffers such as sodium metabisulphite or disodium edetate; preservatives including bactericidal and fungicidal agents, such as phenylmercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.

The dosage employed for compositions administered topically will, of course, depend on the size of the area being treated. For the ears and eyes each dose will typically be in the range from 10 to 100 mg ofthe drug.

Veterinary compositions for intramammary treatment of mammary disorders in animals, especially bovine mastitis, will generally contain a suspension ofthe drug in an oily vehicle.

The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, ofthe drug.depending on the method of administration. Where the compositions are in unit dose form, each dosage unit will preferably contain from 50-500 mg ofthe drug. The dosage as employed for adult human treatment will preferably range from 100 mg to 3 g, per day, for instance 250 mg to 2 g of the drug per day, depending on the route and frequency of administration.

Alternatively, the drug may be administered to non-human animals as part ofthe total dietary intake. In this case the amount of drug employed may be less than 1% by weight of the diet and in preferably no more than 0.5% by weight. The diet for animals may consist- of normal foodstuffs to which the drug may be added or the drug may be included in a premix for adimxture with the foodstuff. A suitable method of administration of the drug to a non-human animal is to add it to the non-human animal's drinking water. In this case a concentration of the drug in the drinking water of about 5-500 μg/ml, for example 5-200 μg/ml, is suitable.

The present invention further provides a method for treating the human or non-human animal which method comprises administering a compound of formula (I) as hereinbefore defined, to a human or non-human animal in need of such therapy.

Alternatively, a pharmaceutical composition as hereinbefore described may be employed in the treatment.

In particular aspects ofthe treatment, there are provided methods for treating bacterial infections and mycoplasma-induced infections of human or non-human animals, especially respiratory infections in human or

non-human animals.

The present invention also provides a compound of formula (I) as hereinbefore defined for use in therapy.

The present invention also provides a compound of formula (I) as hereinbefore defined for use in the manufacture of a medicament for anti-bacterial therapy or mycoplasma-induced infections.

The following Examples illustrate the invention, but are not intended to limit the scope in any way.

The Examples hereinafter are named according to the IUPAC convention. For the H nmr data, however, the numbering system is derived, from monic acid viz:

Preparation of N-methoxy-N-methyl 6.7.13-tris-trimethylsilyl monamide

M,__.-d-πιethyl hydroxylamine hydrochloride (1.95grams (hereinafter g.), 20milimoles (hereinafter mmoles)) was dissolved in dichloromethane/aqueous sodium hydroxide (20milliters (hereinafter ml: 10ml, 2.5Molar (hereinafter M)). The aqueous layer was re- extracted with dichloromethane (10ml) and the combined organic layers washed with saturated brine (5ml). The organic layer was dried (MgS04) and added to monic acid isobutyl carbonic anhydride (lOmmoD*. After stirring at 20°C for 1 hour (hereinafter h) the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen chloride and brine. The combined aqueous solutions were extracted with ethyl acetate, and the combined organic solutions dried (MgS04) and concentrated to give the amide, 3.0g.

This was taken up in tetrahydrofuran (50ml) and treated with triethylamine (8.4ml, 60mmol) and chlorotrimethyl silane (6.3ml, δOmmol). After 10 minutes a catalytic amount of 4-DMAP was added.

After 2h at room temperature the reaction was diluted with diethyl ether, filtered, and the filtrate evaporated. The residue was taken up in hexane, refiltered, and washed with water and brine. After drying and

evaporation the residue was taken up in hexane (20ml) and allowed to crystallise at 0 to -20°C, to give the required product as a colourless crystalline solid, 34.0g, 50%, mp 78-79°C.

*Monic acid isobutyl carbonic anhydride was obtained by treating monic acid with iso-butylchloroformate and triethylamine in tetrahydrofuran at from -5 to 20°C for about 30 min.

Example 1

3R.4R-Dihvdroxy-2S-r2.4-Dioxo-4-(4-methoxyphenyl)- but-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahvdropyran

a) Deconfugation of

N-Methoxy-N-methyl-6.7.13-tristrimethylsilylmonamide

A solution of N-methoxy-N-methyl-6,7,13-tristrimethylsilylmonamide (1.2g, 2mmol) in dry THF (20ml) under argon at -70°C was sequentially treated with diisopropylamine (0.03ml, 0.2mmol) and a solution of i-butyllithium (1.7M, 1.4ml, 2.4mmol) in hexane. After 30min the reaction mixture was quenched with saturated ammonium chloride. Ethyl acetate was added and the organic phase was washed with water, brine, then dried and evaporated to give a 4:1 mixture ofthe deconjugated ⁺ and conjugated* monamides in quantitative yield, δg (CDCI3) inter alia 4.93 (4/5H, s, 15-H+), 5.03 (4/5H, s, 15-H+) 6.18 (1/5H, s, 2-H*).

b) 2-r3R.4R-BistrimethvIsilyloxy-5S-(2S.3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahvdropyran-2S- yllmethylprop-2-ene-l-yl 4-methoxyphenyl ketone

A solution of p.-bromoanisole (0.75ml, 6mmol) in THF (20ml) at -70°C under argon was treated with a solution of n-butyllithium (1.5M, 4ml, 6mmol) in hexane. After 30min the mixture was treated with a solution of the mixture from la (1.2g, 2mmol) in THF (5ml). After a further 30min saturated ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSθ4),evaporated and chromatographed on silica eluting with ethyl

acetate/hexane mixtures to give material containing the title compound (543mg); δg (CDCI3) inter alia 0.93 (3H, d, si 6.9Hz, 17-H ₃ ), 1.19 (3H, d, si 6.3Hz, I4-H3), 3.87 (3H, s, Ar-OMe), 4.89 (IH, s, 15-H), 5.06 (IH, s, 15-H), 6.92 (2H, d, si 8.4Hz, 3',5'-H ₂ ), 7.97 (2H, d, si 8.7Hz, 2',6'-H ₂ ).

c) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-Dioxo-4- (4-methoxyphenyl)-but-l-yl1-5S-(2S.3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahvdrofuran

A solution ofthe ketone from lb (630mg, 0.8mmol) in dichloromethane (25ml) at -70°C was ozonolysed until a blue colour persisted. Argon was then passed through the mixture. Triphenylphosphine (124gmg 0.47mmol) was added and the mixture warmed to room temperature. The mixture was evaporated to low volume and chromatographed on silica eluting with ethyl acetate/hexane mixtures to give the title compound (370mg, 70%); δ _H (CDCI3) inter alia 0.89 (3H, d, si 7.0Hz, 17-H ₃ ), 1.20 (3H, d, si 6.3Hz, 14-H ₃ ), 3.86 (3H, s, OMe), 6.20 (IH, s, 2-H), 6.93 (2H, d, si 8.7Hz, 3',5'-H ₂ ), 7.95 (2H, d, si 8.7Hz, 2',6'-Hz). The !H spectrum indicated that the title compound was essentially in the enolic form.

d) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-methoxy_henyl)- but-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl) tetrahydropyran

A solution ofthe ketone from lc (360mg, 0.54mmol) in methanol (10ml) was treated with dimethylaminopyridine dihydrochloride (3mg). After 30min the reaction mixture was diluted with dichloromethane, washed with sodium hydrogen carbonate solution, dried and evaporated. Chromatography on silica eluting with dichloromethane/methanol mixtures gave the title compound (175mg, 74%); v _max (KBr) 3435,

1603cm- ¹ ; λ _max (EtOH) 324nm (ε _m 18,430); δg (CDCI3) inter alia 0.93 (3H, d, si 7.0Hz, I7-H3), 1.20 (3H, d, si 6.1Hz, 14-H ₃ ), 3.86 (3H, s, Ar-OMe), 6.20 (IH, s, 2-H), 6.92 (2H, d, si 9.8Hz, 3',5 ^* -H ₂ ), 7.87 (2H, d, si 9.8Hz, 2',6'-H ₂ ). δc (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.7 (C-9), 39.7 (C-8), 42.5 (C-4), 42.8 (C-12), 55.5 (OMe), 55.7 (C-10), 61.3 (C-11), 65.6 (C-16), 69.1 (C-6), 70.3 (C-13), 71.3 (C-7), 73.9 (C-5), 96.5 (C-2), 114.0 (C-3'5'), 126.9 (C-1'), 129.3 (C-2',6'), 163.3 (C-4'), 183.0 (C-3), 193.1 (C-1). M/Z (FAB) MH± 437. The H nmr spectrum indicatd that the title compound

was essentially in the enolic form.

Example 2

3R.4R-Dihvdroxy-2S-(2.4-dioxo-4-phenyl-but-l-ylV5S-

(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetrahydropyran

^' a) 2-r3R.4R-Bistrimethylsilyloxy-5S-(2S.3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahvdropyran-2S- vnmethylprop-2-en-l-yl phenyl ketone

A solution ofthe products from la (600mg, lmmol) in THF (20ml) under argon at -70°C was treated with a solution of phenyllithium in ether (2M, 1.5ml, 3mmol). After 30min the reaction was worked up as in lb to give material containing the title compound (300mg); δjj (CDCI3) inter alia

0.89 (3H, d, si 7.1Hz), 1.19 (3H, d, si 6.3Hz, 14-H ₃ ), 4.91 (IH, s, 15-H), 5.08 (IH, s, 15-H), 7.40-7.60 (3H, m), 7.44-8.05 (2H, m).

b) 3R.4R-BistrimethvIsilyloxy-2S-(2.4-dioxo-4-phenyl- but-l-vD-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyDtetrhydropyran

The material from 2a (300mg, 0.47mmol) was converted to the title compund (182mg, 61%) using the method described in lc δjj (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17-H ₃ ), 1.20 (3H, d, J 6.3Hz, 14-H ₃ ), 6.27 (IH, s, 2-H), 7.43-7.60 (3H, m), 7.82-7.95 (2H, m). The lH spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-(2.4-dioxo-4-phenyl-but-l-yl)- 5S-(2S.3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahvdropyran

Using the method described in Id, the ketone from 2b (180mg, 0.28mmol) was deprotected to give the title compound (53mg, 47%); υ _max (KBr) 3422, 1609, 1570cm- ¹ ; λ _max (EtOH) 312nm (ε _m 13,620), 248 (5140); δg (CDCI3), inter alia 1.06 (3H, d, si 6.9Hz, 17-H ₃ ), 1.29 (3H, d, si 6.2Hz, -H3), 6.28 (IH, s, 2-H), 7.36-7.64 (3H, m), 7.83-7.98 (2h, m); δø (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.6 (C-9), 39.6 (C-8), 42.8 (C-4), 42.8 (C-12), 55.7 (C-10), 61.3 (C-11), 65.7 (C-16), 69.0 (C-13), 71.3 (C-7), 73.8 (C-5), 97.5

(C-2), 127.1 (C-3'5'), 128.7 (C-2',6'), 132.6 (C-4'), 134.3 (C-1'), 182.3 ⁽ C-3), 196.0 (C-1); (Found: M ⁺ 406.1991. C22H30O7 requires M 406.1992). The ^Η. spectrum indicated that the title compound was essentially in the enolic form.

Example 3

3R.4R-Dιhvdroxy-2S-r2.4-dioxo-4-(2-methoxypyrid-5-yl)- but-l-vn-5S-(2S.3S.epoxy-5S-hvdroxy-4S-methylhexyl)tetrahvdr opyran

a) 2-r3R.4R-Bistrimethylsilyloxy-5S-(2S.3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahvdropyran-2S- yrimethylprop-2-ene-l-vI 2-methoxy pyrid-5-yl ketone

Using the method described in lb and on the same scale,

2-methoxy-5-bromopyridine (1.13g, 6mmol) was reacted to give material containing the title compound (470mg); δfj (CDCI3) inter alia 0.89 (3H, d, si 7.0Hz, I7-H3), 1.20 (3H, d, si 6.3Hz, 14-H ₃ ), 4.00 (3H, s, OMe), 4.90 (IH, s, 15-H), 15.08 (IH, s, 15-H), 6.77 (IH, d, si 8.8Hz, 3'-H), 8.16 (IH, dd, si 2.3, 8.6Hz, 4'-H), 8.82 (IH, d, si 2.2Hz, 6'-H).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4- (2-methoxypyrid-5-yl)but-l-yll-5S-(2S.3S-epoxy-5S- trimethylsiIyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in lc, the material from 3a (470mg, 0.71mmol) was converted to the title compound (330mg, 70%); δπ (CDCI3) inter alia 0.90 (3H, d, si 7.0Hz, 17-H ₃ ), 1.19 (3H, d, si 6.3Hz, 14-H ₃ ), 4.00 (3H, s, OMe), k6.18 (IH, s, 2-H), 6.79 (IH, d, si 8.7Hz, 3'-H), 8.06 (IH, dd, si 2.3, 8.7Hz, 4'-H), 8.72 (IH, d, 2.7Hz, 6'-H). The ^B. spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-methoxypyrid-5- yl but-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahydropyran

Using the method described in Id, the material from 3b was deprotected to give the title compound (lOOmg, 46%); v _max (KBr) 3503, 3428, 1603,

1494cm- ¹ ; λ _max (EtOH) 315.5nm (ε _m 17,120); δ _H (CDCI3) inter alia 0.93 (3H, d, _17.0Hz, 17-H3), 1.22 (3H, d, _16.3Hz, 14-H ₃ ), 4.00 (3H, s, OMe), 6.19 (IH, s, 2-H), 6.80 (IH, d, 19.8Hz, 3 ^* -H), 8.05 (IH, dd, si 2.4, 9.8Hz, 4'-H), 8.72 (IH, d, s! 2.4Hz, 6'-H); δc (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.7 (C-9), 39.7 (C-8), 42.2 (C-4), 42.9 (C-12), 54.3 (C-10), 55.7 (C-11), 61.3 (OMe), 65.7 (C-16), 69.0 (C-6), 70.3 (C-13), 71.4 (C-7), 73.9 (C-5), 96.8 (C-2), 111.0 (C-3'), 124.0 (C-5'), 137.2 (C-4'), 147.6 (C-6'), 166.7 (C-2'), 181.9 (C-3), 194.0 (C-1); (Found: M ⁺ 437.2048. C ₂ 2H3χNOs requires M ⁺ 437.2050).

Example 4

2S-r4-(4-Acetylphenyl)-2.4-dioxobut-l-vn-3R.4R- dihvdroxy-5S-(2S.3S-epoxy-5S-hydroxy-4S-methylhexyl)- tetrahydropyran

To a solution ofthe trimethylsilylenol ether of p_- bromoacetophenone (1.63g, 6mmol) in THF (20ml) under argon at -70°C was added dropwise a solution of n- butyllithium (1.5M, 4ml, 6mmol) in hexane. After 30min a solution ofthe mixture from la (1.2g, 2mmol) in THF (5ml) was added. After 30min saturated ammonium chloride was added and the mixture extracted with ethyl acetate. The organic phase was washed with brine, dried and evaporated. The residue was filtered through silica eluting with 20% (v/v) ethyl acetate/hexane. The filtrate was evaporated then dissolved in methanol (20ml) and treated with dimethylaminopyridine dihydrochloride (3mg). After 20min the mixture was diluted with ethyl acetate washed with sodium hydrogen carbonate, brine then dried and evaporated. Chromatography on silica eluting with dichloromethane/methanol mixtures gave material (330mg) which was a 2:1 mixture of deconjugated* and conjugate+ ketones [δg (CDCI3) 5.00 (2/3H, s, 15-H*), 5.18 (2/3H, s, 15-H*), 6.83 (1/3H, s, 2-H+)].

This material was dissolved in dichloromethane (30ml) and ozonolysed at -70°C until a green/blue colour was obtained. Argon was then passed through the solution. Triphenylphosphine (194mg, 0.74mmol) was added and the mixture warmed to room temperature. Evaporation to low volume followed by chromatography on silica eluting with

dichloromethane/methanol mixtures gave the title compound (106mg); ^v max (KBr) 3436, 1684, 1603cm- ¹ ; λ _max (EtOH) 256nm (E _m 8,550), 324.5 (11,750); δg (CDCI3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H ₃ ), 1.22 (3H, d, si 6.3Hz, -H3), 2.65 (3H, s, COMe), 6.31 (IH, s, 2-H), 7.96 and 8.02 (4H, ABq, si 8.5Hz); δc (CDCI3) 12.7 (C-17), 20.8 (C-14), 26.8 (COMe), 31.6 (C-9), 39.7 (C-8), 42.8 (C-12), 43.0 (C-4), 55.6 (C-10), 61.2 (C-11), 65.5 (C-16), 69.0 (C-6), 70.3 (C-13), 71.3 (C-7), 73.9 (C-5), 98.3 (C-2), 127.2 (C-3'5'), 128.6 (C-2',6'), 138.3 (C-1'), 139.6 (C-4'), 179.8 (C-3), 197.5 (C-1), 197.6 (C_QMe); (Found: M ⁺ 448.2106. C24H ₃₂ 0 ₈ requires M 448.2097). The ¹ H spectrum indicated that the title compound was essentially in the enolic form.

Example 5

3R.4R-Dihvdroxy-2S-r4-(4-dimethylaminophenyl)-2.4- dioxobut-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahvdropvran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(4-dimethylamino- phenyl)-4-hvdroxy-2-oxobut-l-yll-5S-(2S.3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahvdropyran

A solution of diisopropylamine (0.48ml, 3.36mmol) in dry THF (25ml) under argon at -30°C was treated dropwise with a solution of n-butyllithium (1.5M, 2.24ml, 3.36mmol) in hexane. After 15min the mixture was cooled to -70°C and treated dropwise over 5min with a solution of tristrimethylsilylmonone (1.45g, 2.8mmol) in THf (7ml). After 1 hour the mixture was treated with a solution of E-dimethylaminobenzaldehyde (447mg, 3.2mmol) in THF (2ml). After a further hour saturated ammonium chloride was added. The mixture was extracted with ethyl acetate and the organic phase washed with brine, then dried and evaported. Chromatography on silica eluting with ethyl acetate/hexane mixtures gave the title compound (300mg); δg (CDCI3) inter alia 0.89 (3H, d, _[ 7.0Hz, 17-H ₃ ), 1.22 (3H, d, si 6.3Hz, 14-H ₃ ), 2.94 (6H, s, NMe ₂ ), 4.06-4.19 (IH, m, 5-H), 5.05-5.14 (IH, m, 1-H), 6.65-6.86 (2H, m, 2',6'-H ₂ ), 7.25 (2H, d, J 6.5Hz, 3'5'-H ₂ ).

b) 3R.4R-Bistrimethylsilyloxy-2S-r4-(4-dimethylamino-

phenylV2.4-dioxobut-l-vI1-5S-(2S.3S-epoxy-5S-tri- methylsilyloxy-4S-methylhexyI)tetrahvdropyran

A solution ofthe product from 5a (300mg, 0.45mmol) in dioxan (15ml) was treated with 2,3-dichloro-5,6- dicyanobenzoquinone (102mg, 0.45mmol). After 5min the mixture was diluted with dichloromethane, filtered through Kieselguhr, washing with dichloromethane, and the filtrate evaporated. Chromatography on silica eluting with ethyl acetate/hexane mixtures gave the title compound (250mg, 83%); δg (CDCI3) inter alia 0.89 (3H, d, si 7.0Hz, I7-H3), 1.19

(3H, d, si 6.3Hz, M-H3), 3.06 (6H, s, -NMe ₂ ), 6.17 (IH, s, 2-H), 6.68 (2H, d, si 9.0Hz, 3'5'-Η.2), 7.82 (2H, d, 9.0Hz, 2',6'-H ₂ ). The 41 spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-r4-(4-dimethylaminophenyl)-2.4- dioxobut-l-vn-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahvdropvran

A solution ofthe product of 5b (lOOmg, O.lδmmol) in THF (5ml) was treated with 0.4M HCl (1ml). After 2min saturated sodium hydrogen carbonate solution (1ml) was added. The mixture was then extracted with ethyl acetate and the organic phase washed with brine, dried and evaporated. Chromatography on silica eluting dichloromethane/methanol mixtures gave the title compound (64mg, 95%); v _max (KBr) 3424, 1715, 1597, 1524cm- ¹ ; λ _max (EtOH) 370nm (E _m 29,750); δg (CDCI3) inter alia 0.94 (3H, d, si 7.0Hz, 17-H ₃ ), 1.20 (3H, d, si 6.3Hz, 14-H ₃ ), 3.07 (6H, s, -NMe ₂ ), 6.16 (IH, s, 2-H), 6.64 (2H, d, 19.0Hz, 3',5'-H ₂ ), 7.82 (2H, d, si 9.0Hz, 2',6'-H ₂ ); δc (CDCI3) 12.7 (C-17), 20.7 (C-14), 31.7 (C-9), 39.6 (C-8), 39.7 (NMe ₂ ), 42.5 (C-4), 42.6 (C-12), 55.6 (C-10), 61.3 (C-11), 65.6 (C-16), 69.3 (C-6), 70.3 (C-13), 71.3 (C-7), 74.0 (C-5), 95.6 (C-2), 111.1 (C-3',5"), 121.1 (C-1"), 129.3 (C-2',6), 153.4 (C-4'), 183.8 (C-3), 192.1 (C-1); (Found: M ⁺ » 449.2423. C24H35NO7 requires M 449.2414).

Example 6

3R.4R-Dihvdroxy-2S-(2.4-dioxo- ^' 4-(furan-3-yl)but-l-yl1- 5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetrahydropyran

a) 3R.4R-Bistri-nethylsilyloxy-2S-r4-(furan-3-yl)-4- hvdroxy-2-oxobut-l-yll-5S-(2S.3S-epoxy-5S-trimethyl- siIyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 5a and on the same scale, furan-3-carboxaldehyde (0.28ml, 3.2mmol) was reacted to give the title compound (1.3g, 75%); δg (CDCI3) inier alia 0.90 (3H, d, si 7.1Hz, 17-H ₃ ), 1.20 (3H, d, si 6.3Hz, 14-H ₃ ), 4.07-4.18 (IH, m, 5-H), 5.05-5.18 (IH, m, 1-H), 6.38-6.42 (IH, m, 4'-H), 7.35-7.44 (2H, m, 2',5'-H ₂ ).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(furan- 3-yl)but-l-yl1-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyPtetrahydropyran

The product from 6a (650mg) in benzene (30ml) was treated with manganese dioxide (1.76g) and refluxed with provision for azeotropic removal of water (Dean and Stark apparatus containing molecular sieves 4A) for 4 hours. The mixture was diluted with dioxan filtered through Kieselguhr, washing pad well with dioxan and evaporated. Chromatography on silica eluting ethyl acetate/hexane mixtures gave the title compound (267mg, 41%); δg (CDCI3) inter alia 0.89 (3H, d, _[ 7.1Hz, I7-H3), 1.19 (3H, d, si 6.4Hz, 14-H ₃ ), 5.92 (IH, s, 2-H), k6.70 (IH, d, si 1.2Hz, 4'-H), 17.45 (IH, m, 5'-H), and 7.99 (IH, s, 2'-H). The ^l ΕL spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(furan-3-yl)but- l-vI1-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahydropyran

Using the method described in 5c, the product from 6b (200mg, 0.33mmol) was deprotected to give the title compound (120mg, 93%); v _max (KBr) 3427, 1718, 1620, 1509cm- ¹ ; λ _max (EtOH) 303.5nm (E _m 11,075); δg (CDCI3) inter alia 0.93 (3H, d, J 7.0Hz, 17-H ₃ ), 1.21 (3H, d, J 6.3Hz, -H3), 5.93 (IH, s, 2-H), 6.69 (IH, d, si 1.6Hz, 4'-H), 7.46 (IH, s, with further fine coupling, 5'-H), 8.02 (IH, bs, 2'-H); δc (CDCI3) 12.5 (C-17), 20.6 (C-14), 31.4 (C-9), 39.4 (C-8), 41.9 (C-4), 42.6 (C-12), 55.5 (C-10), 61.1 (C-11), 65.4 (C-16), 68.5 (C-6), 70.1 (C-13), 71.1 (C-7), 73.6 (C-5), 98.1 (C-2), 107.8 (C-2"), 123.8 (C-3'), 144.1 (C-4"), 145.6 (C-3'), 178.3 (C-3), 188.1

(C-1); M/Z 396 (M+, 100%) and 95 (100). (Found M+ 396.1788; C20H28O8 requires M 396.1784). The ^K nmr spectrum indicated that the material was essentially in enolic form.

Example 7

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-( l-methylpyrazol-4-vl )- but-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methvIhexyl)- tetrahvdropvran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-4-(l- methvIpyrazol-4-yl)-2-oxobut-l-yl1-5S-(2S.3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 5a, and on the same scale, l-methylpyrazole-4-carboxaldehyde (352mg, 3.2mmol) was reacted to give the title compound (1.25g, 71%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.1Hz, I7-H3), 1.20 (3H, d, si 6.3Hz, 14-H ₃ ), 3.87 (3H, s, l'-Me), 4.07-4.17 (IH, m 5-H), 5.12-5.22 (IH, m 1-H), 7.36 (IH, s, 5'-H), 7.43 (IH, s, 3 ^* -H).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(l- methylpyrazol-4-yl)-but-l-vn5S-(2S.3S-epoxy-5S- trimethylsilyIoxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 6b, the product from 7a (450mg, 0.7mmol) in benzene (15ml) was reacted with manganese dioxide (1.25g) for 1 1/2 hours to give the title compound (260mg, 58%); δjj (CDCI3) inter alia 0.90 (3H, d, s 7.0Hz, I7-H3), 1.20 (3H, d, _[ 6.4Hz, 14-H ₃ ), 3.94 (3H, s, NMe), 5.92 (IH, s, 2-H), 7.86 (2H, bs, 3',5'-H ₂ ). The ^X H nmr spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(l-methylpyrazol- 4-yl)but-l-vn-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahvdropyran

Using the method described in 5c, the product from 7b (250mg, 0.4mmol) was deprotected to give the title compound (125mg, 76%); v _max (KBr) 3424, 1718, 1617, 1546cm- ¹ ; λ _max (EtOH) 308nm (ε _m 10,030); δg

(CDC1 ₃ ) inter alia 0.94 (3H, d, si 7.1Hz, 17-H ₃ ), 1.22 (3H, d, si 6.3Hz, ^' -H3), 3.94 (3H, s, NMe), 5.94 (IH, s, 2-H), 7.87 (2H, s, 3',5'-H ₂ ); δc (CDCI3); 12.7 (C-17), 20.7 (C-14), 31.6 (C-9), 39.3 (C-8), 39.6 (l'-Me), 41.5 (C-4), 42.8 (C-12), 55.6 (C-10), 61.1 (C-11), 65.5 (C-16), 68.9 (C-6), 70.3 (C-13), 71.2 (C-7), 73.9 (C-5), 97.6 (C-2), 120.3 (C-4'), 131.7 (C-3'), 139.3 (C-5"), 179.6 (C-3), 191.5 (C-1); MZ (FAB) MNa± 433, MH± 411. The ^lη Α spectrum indicated that the title compound was essentially in the enolic form. Extra signals were observed in the l^C nmr spectrum which were identified as being from the presence of a small amount of the diketone form.

Example 8

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(furan-2-yl)but-l-yll- 5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetrahvdropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(furan-2-yl)- 4-hvdroxy-2-oxobut-l-yll-5S-(2S.3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 5a, and on the same scale, furan-2-carboxaldehyde (0.28ml, 3.36mmol) was reacted to give the title compound (1.196g, 69%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.1HZ, I7-H3), 1.20 (3H, d, si 6.4Hz, 14-H ₃ ), 4.10-4.22 (IH, m, 5-H), 5.15-5.22 (IH, m, 1-H), 6.27 (IH, m, 3'-H), 6.33-6.35 (IH, m, 4'-H), and 7.37 (IH, m, 5'-H); m/z 614 (M ⁺ , 1%) and 117 (100). (Found: M ⁺ , 614.3136. ^c 29 ^H 54θ8Si3 requires M, 614.3127).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(furan- 2-yl)but-l-yl1-5S-(2S.3S-epoxy-5S-trimethvIsilyloxy-4S- methylhexy tetrahvdropyran

Using the method described in 6b, the product from 8a (1.176g, 1.9mmol) in benzene (40ml) was reacted with manganese dioxide (4.3g) for 1 1/2 hours to give the title compound (0.601g, 51%); δjj (CDCI3) inter alia 0.90 (3H, d, sϊ 7.1Hz, 17-H3), 1.20 (3H, d, si 6.4Hz, 14-H ₃ ), 6.17 (IH, s, 2-H), 6.54 (IH, dd, 3.6 and 1.7Hz, 4'-H), 7.15 (IH, d, 3.7Hz, 3'-H), and 7.57 (IH, m, 5'-H); m z 612 (M+, 1%), 597 (1), 117 (90), and 73 (100). (Found: M+,

612.2979. C29H52θsSi3 requires M, 612.2970). The ^X H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(fαran-2-yl)but-l- yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyI)tetra- hvdropyran

Using the method described in 5c, the product from 8b (0.6g, 0.98mmol) was deprotected to give the title compound (0.289g, 74%); v _max (KBr) 3472, 1627, 1467, 1087, and 1046cm- ¹ ; λ _max (EtOH) 321.5nm

(ε _m 20,440); δg (CDC1 ₃ ) inter alia 0.93 (3H, d, _[ 7.0Hz, 17-H ₃ ), 1.22 (3H, d, si 6.3Hz, I4-H3), 6.17 (IH, s, 2-H), 6.55 (IH, dd, si 3.5 and 1.7Hz, 4'-H), 7.16 (IH, d, si 3.5Hz, 3'-H), and 7.58 (IH, s, with fine coupling, 5 _. '-H); δc (CDCI3/CD3OD); 12.5 (C-17), 20.6 (C-14), 31.6 (C-9), 39.6 (C-8), 41.2 (C-4), 42.6 (C-12), 55.6 (C-10), 61.1 (C-11), 65.6 (C-16), 68.7 (C-6), 70.1 (C-7), 71.0 (C-13), 74.0 (C-5), 96.8 (C-2), 112.5 (C-4'), 116.0 (C-3"), 146.2 (C-5"), 150.1 (C-2"), 175.1 (C-3), and 191.1 (C-1); w/z 396 (M ⁺ , 1%) and 137 (100). (Found: M ⁺ , 396.1784. C20H28O8 requires M, 396.1784). The ^X H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 9

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(pyrid-4-yl)but-l-yll- 5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetrahydropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(pyrid-4-yl)-

4-hvdroxy-2-oxobut-l-vIl-5S-(2S.3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetτahvdropyran

Using the method described in 5a, and on the same scale, pyridine-4-carboxaldehyde (0.32ml, 3.36mmol) was reacted to give the title compound (1.20g, 68%); δjj

(CDCI3) inter alia 0.90 (3H, d, si 7.1Hz, 17-H ₃ ), 1.19 (3H, d, si 6.3Hz, I4-H3), 5.14-5.22 (IH, m, 1-H), 7.34-7.38 (2H, m, 3' and 5'-H), and

8.56-8.60 (2H, m, 2' and 6'-H); m/z 625 (M ⁺ , 3%) and 117 (100). (Found:

M ⁺ , 625.3288. C30H55NO7S13 requires M, 625.3286).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(pyrid- 4-yl)but-l-yll-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyDtetrahvdropyran

Using the method described in 6b, the product from 9a(1.18g, 1.88mmol) in benzene (60ml) was reacted with manganese dioxide (3.3g) for 2 hours to give the title compound (0.556g, 47%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.0Hz, I7-H3), 1.20 (3H, d, si 6.4Hz, 14-H ₃ ), 6.33 (IH, s, 2-H), 7.75-7.79 (2H-, m, 3' and 5'-H), and 8.76 (2H, br, 2' and 6'-H); m/z 623 (M+, 4%), 117 (99), and 73 (100). (Found: M ⁺ , 623.3131. C3oH ₅ 3N0 ₇ Si3 requires M, 623.3130). The 1-H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(pyrid-4-yl)but-l- yl1-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetra- hvdropyran

Using the method described in 5c, the product from 9b (0.535g, 0.86mmol) was deprotected to give the title compound (0.32 lg, 92%); v _max (KBr) 3421, 1595, 1550, 1455, 1111, and 1062cm- ¹ ; λ _max (EtOH) 316.5nm

(ε _m 10,786); δ _H (CDCI3/CD3OD) inter alia 0.93 (3H, d, _s i 7.1Hz, 17-H ₃ ), 1.22 (3H, d, si 6.3Hz, 14-H ₃ ), 2.63 (IH, dd, si 15.1 and 8.5Hz, 4-H), 2.73 (IH, dd, si 7.6 and 2.1Hz, 11-H), 2.82 (IH, td, si 5.7 and 2.1Hz, 10-H), 2.98 (IH, dd, si 15.1 and 3.3Hz, 4-H), 6.33 (IH, s, 2-H), 7.69-7.73 (2H, m, 3' and 5'-H), and 8.70-8.75 (2H, m, 2' and 6'-H); δ _C (CDCI3/CD3OD); 12.5 (C-17), 20.6 (C-14), 31.6 (C-9), 39.8 (C-8), 42.6 (C-12), 43.2 (C-4), 55.6 (C-10), 61.0 (C-11), 65.6 (C-16), 68.5(C-6), 70.1 (C-7), 70.9 (C-13), 73.9 (C-5), 98.6 (C-2), 120.6 (C-3' and 5'), 141.9 (C-4'), 150.2 (C-2' and 6'), 177.1 (C-3), and 198.6 (C-1); m z 407 (M ⁺ , 6%) and 148 (100). (Found: M+, 407.1954. C2 H29NO7 requires M, 407.1944). The ^Η. n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 10

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(pyrid-3-yl)but-l-yl l-

5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetrahvdropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(pyrid-3-vD-

4-hvdroxy-2-oxobut-l-vIl-5S-(2S.3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 5a, tristrimethylsilylmonone (1.34g, 2.58mmol) and pyridine-3-carboxaldehyde (0.29ml, 3.1mmol) were reacted to give the title compound (1.154g, 71%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.0Hz, 17-H3), 1.19 (3H, d, si 6.3Hz, 14-H ₃ ), 5.19-5.27 (IH, m, 1-H), 7.33 (IH, dd, si 7.8 and 4.9Hz 5'-H), 7.77-7.82 (IH, m, 4'-H), 8.54 (IH, dd, si 4.7 and 1.1Hz, 6'-H), and 8.62 (IH, d, si 1.6Hz, 2'-H) (contains approximately 4% pyridine-3-carboxaldehyde).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(pyrid- 3-yl but-l-yl1-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyDtetrahvdropyran

Using the method described in 6b, the product from 10a(1.10g, 1.76mmol) in benzene (70ml) was reacted with manganese dioxide (4.0g) for 2 1/2 hours to give the title compound (0.513g, 47%); δjj (CDCI3) inter alia 0.90 (3H, d, si 7.1Hz, I7-H3), 1.19 (3H, d, si 6.4Hz, 14-H ₃ ), 6.29 (IH, s, 2-H), 7.43 (IH, dd, si 7.9 and 4.9Hz, 5 ^r -H), 8.20 (IH, dt, si 7.9 and 1.7Hz, 4'-H), 8.73 (IH, m, 6 -H), and 9.09 (IH, s with fine coupling, 2'-H); m/z 623 (M ⁺ , 75%), and 331 (100). (Found: M+, 623.3118. C3oH ₅₃ N07Si3 requires M, 623.3130). The ^H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(pyrid-3-yl)but-l- yl1-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetra- hydropyran

Using the method described in 5c, the product from 10b (0.50g, 0.80mmol) was deprotected to give the title compound (0.262g, 81%); v _max (KBr) 3411, 1597, 1452, 1111, and 1043cm- ¹ ; λ _max (EtOH) 312nm (ε _m 12,785); δ _H (CDCI3) 0.93 (3H, d, si 7.0Hz, 17-H ₃ ), 1.22 (3H, d, 6.4Hz, 14-H ₃ ), 6.34 (IH, s, 2-H), 7.42 (IH, dd, 8.0 and 4.9Hz, 5'-H), 8.18 (IH, dt, si 8.0 and 1.7Hz, 4'-H), 8.72 (IH, dd, si 4.9 and 1.4Hz, 6'-H), and 9.07 (IH, d, si 1.8Hz, 2 -H); δc (CDCI3) 12.8 (C-17), 20.8 (C-14), 31.6 (C-9), 39.8 (C-8), 42.5 (C-4), 42.8 (C-12), 55.5 (C-10), 61.0 (C-11), 65.5 (C-16), 68.6 (C-6), 70.3 (C-7), 71.2 (C-13), 73.6 (C-5), 97.9 (C-2), 123.6 (C-5'), 130.4 (C-3 ^* ),

134.7 (C-4 ¹ ), 148.1 (C-6'), 152.4 (C-2 ¹ ), 179.4 (C-3), and 196.4 (C-1); m/z 407 (M+, i7%) and 106 (100). (Found: M ⁺ , 407.1946. C2XH29NO7 requires M, 407.1944). The ¹ H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 11

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(pyrid-2-yl)but-l-vnbut- l-yl15S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahvdropvran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(pyrid-2-yl)- 4-hvdroxy-2-oxobut-l-vn-5S-(2S.3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 5a, tristrimethylsilylmonone (1.04g, 2mmol) and pyridine-2-carboxaldehyde (0.23ml, 2.4mmol) were reacted to give the title compound (0.804g, 64%); δg (CDCI3) inter alia 0.89 (3H, d, si 7.0Hz, I7-H3), Ϊ.19 (3H, d, 6.3Hz, 14-H ₃ ), 5.21-5.27 (IH, m, 1-H), 7.22 (IH, m, 5'-H), 7.51 (IH, d, si 7.8Hz, 3'-H), 7.73 (IH, t with further fine coupling, si 7.7Hz, 4 ^* -H), and 8.54 (IH, d, J 4.7Hz, 6'-H); m z 625 (M ⁺ , 3%), 129 (100), 117 (100), and 73 (100). (Found: M ⁺ , 625.3281. C ₃₀ H55NO7Si3 requires M, 625.3286).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(pyrid- 2-yl)but-l-yl1-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyPtetrahvdropyran

Using the method described in 6b, the product from lla(0.790g,

1.26mmol) in benzene (35ml) was reacted with manganese dioxide (2.5g) for 2 hours to give the title compound (0.275g, 35%); δjj (CDCI3) inter alia 0.89 (3H, d, si 7.1Hz, 17-H ₃ ), 1.19 (3H, d, si 6.3Hz, 14-H ₃ ), 6.89 (IH, s, 2-H), 7.37-7.44 (IH, m, 5'-H), 7.83 (IH, dt, si 1.7 and 7.8Hz, 4'-H), 8.08 (IH, d, si 7.8Hz, 3'-H), 8.67 (IH, d, si 4.2Hz, 6'-H); m/z 623 (M ⁺ , 14%), 148 (75), 117 (82), and 73 (100). (Found: M ⁺ , 623.3143. C3θH53Nθ7Si3 requires M, 623.3130). The ^B. n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(pyrid-2-yl but-l- yl1-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahvdropvran

Using the method described in 5c, the product from lib (0.260g, 0.42mmol) was deprotected to give the title compound (0.042g, 25%); v _max (KBr) 3399, 1607, 1587, 1516, 1449, and 1045cm- ¹ ; λ _max (EtOH) 314nm (ε _m 11,010); δg KCD ₃ ) ₂ CO] inter alia 0.92 (3H, d, _ϊ 7.0Hz, 17-H ₃ ), 1.16 (3H, d, si 6.4Hz, 14-H ₃ ), 6.98 (IH, s, 2-H), 7.57 (IH, ddd, si 7.4, 4.8, and 1.4Hz, 5'-H), 8.00 (IH, dt, si 7.7 and 1.7Hz, 4'-H), 8.10 (IH, d, si 7.8Hz, 3'-H), and 8.71 (IH, d, with further fine coupling, si 4.8Hz, 6'-H); m/z (TSP) 408 (MH+, 65%) and 99 (100); /z 407 (M+, 40%) and 122 (100). (Found: M ⁺ , 407.1950. C2XH29NO7 requires M, 407.1944).

Example 12

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(3-methylisoxazol-5-yl) but-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahydropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(3-methyl- isoxazbl-5-yl)-4-hvdroxy-2-oxobut-l-yll-5S-(2S.3S- epoxy-5S-trimethylsiIyloxy-4S-methylhexyl)tetrahydropyran

Using the method described in 5a, tristrimethylsilylmonone (1.04g, 2mmol) and 3-methylisoxazole-5-carboxaldehyde (0.267g, 2.4mmol) were reacted to give the title compound (0.834g, 66%); δjj (CDCI3) inter alia 0.90 (3H, d, si 7.0Hz, 17-H ₃ ), 1.19 (3H, d, si 6.4Hz, 14-H ₃ ), 2.29 (3H, s, 3'-CH ₃ ), 5.18-5.27 (IH, m, 1-H), and 6.10 (IH, s, 4'-H); m/z 629 (M ⁺ , 8%), 129 (100), 117 (100), and 73 (100). (Found: M ⁺ , 629.3260. C29H55NO8S13 requires M, 629.3236).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-f3- methylisoxazol-5-yl)but-l-vn-5S-(2S.3S-epoxy-5S-tri- methylsilyloxy-4S-methylhexyl)tetrahydropyran

Using the method described in 6b, the product from 12a(0.815g,

1.29mmol) in benzene (35ml) was reacted with manganese dioxide (2.04g) for 2 hours to give the title compound (0.360g, 42%); δχι (CDCI3) inter alia 0.89 (3H, d, si 7.0Hz, 17-H ₃ ), 1.19 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 2.37 (3H, s, 3'-CH ₃ ), 6.32 (IH, s, 2-H), and 6.69 (IH, s, 4'-H); m z (TSP) 645 (MNH4+, 100%) and 628 (MH+, 65); m/z 627 (M ⁺ , 10%), 612 (12), 117 (100), and 73 (100). (Found: M+, 627.3104. C29H5 ₃ N0 ₈ Si3 requires M, 627.3079). The 4l n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(3-methylisoxazol-

5-vDbut-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahvdropvran

Using the method described in 5c, the product from 12b (0.380g, O.βmmol) was deprotected to give the title compound (0.167g, 68%); v _max (KBr) 3395, 1617, 1584, 1512, 1457, 1412, and 1055cm- ¹ ; λ _max (EtOH) 330nm (ε _m 13,500); δ _H [(CD ₃ ) ₂ SO] inter alia 0.83 (3H, d, si 7.1Hz, 17-H ₃ ), 1.07 (3H, d, J 6.4Hz, 14-H ₃ ), 2.25 (3H, s, 3'-CH ₃ ), 5.83 (IH, s, 2-H), and 6.64 (IH, s, 4'-H); δc (CD3OD) 11.3 (isox-CH ₃ ), 12.3 (C-17), 20.4 (C-14), 32.9 (C-9), 41.5 (C-8), 43.7 (C-12), 45.1 (br, C-4), 56.9 (C-10), 61.3 (C-11), 66.5 (C-16), 70.1 (C-6), 70.8 (C-13), 71.6 (C-7), 76.0 (br, C-5), 99.0 (br, C-2), 106.6 (br, C-4'), 161.9 (C-3 ^* ), 170.5 (br, C-5 ^* ), 171.4 (br, C-3), and 197.0 (br, C-1); m z (FAB, thioglycerol) 450 (MK+) and 434 (MNa+); m/z 411 (M+, 0.1%), 125 (80), and 43 (100). (Found: M ⁺ , 411.1892. C20H29NO8 requires M, 411.1893). The ¹ H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 13

SR^R-Dihvdroxy-ΣS-re^-dioxo^-fS-methoxyphenvPbut- l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahvdropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(3-methoxy- phenyl)-4-hvdroxy-2-oxobut-l-yll-5S-(2S.3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 5a, and on the same scale,

3-methoxybenzaldehyde (0.39ml, 3.2mmol) was reacted to give the title compound (1.06g, 56%); δg (CDC1 ₃ ) inter alia 0.89 (3H, d, 17.1Hz, 17-H ₃ ), 1.19 (3H, d, si 6.3Hz, -H3), 3.82 (3H, s, OMe), 4.07-4.20 (IH, m, 5-H), 5.09-5.21 (IH, m, 1-H), 6.78-6.85 (IH, m, 6'-H), 6.90-6.99 (2H, m, 2', 4'-H ₂ ), 7.23-7.32 (IH, m, 5'-H); m/Α 654 (M ⁺ , 0.5%) and 117 (100). (Found: M+, 654.3456. ^c 32 ^H 58°8 ^Si 3 requires M, 654.3440 ⁾ .

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(3- methoxyphenyl but-l-yll-5S-r2S.3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 6b, the product from 13a(1.0g, 1.49mmol) in benzene (50ml) was reacted with manganese dioxide (3.0g) for 3 hours to give the title compound (0.610g, 61%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.1Hz, I7-H3), 1.19 (3H, d, si 6.4Hz, 14-H ₃ ), 3.86(3H, s, OMe), 6.25 (IH, s, 2-H), 7.06 (IH, dd, si 1.6, 8.0Hz, 6'-H), 7.35 (IH, dd, si 7.8, 8.0Hz, 5'-H), 7.40-7.51 (2H, m, 2 ^* . 4'-H ₂ ); m z 652 (M 1%) and 41 (100). (Found: M ⁺ , 652.3280. C35H ₅ g0 ₈ Si3 requires M, 652.3280).

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(3-methoxyphenyl but-l-yl1-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl - tetrahydropyran

Using the method described in 5c, the product from 13b (250mg,

0.37mmol) was deprotected to give the title compound (140mg, 87%); v _max (KBr) 3430, 1718, 1576, 1457cm- ¹ ; λ _max (EtOH) 309nm (ε _m 15,360); δg (CDCI3) inter alia 0.94 (3H, d, si 7.0Hz, 17-H ₃ ), 1.21 (3H, d, si 6.4Hz, I4-H3), 3.86 (3H, s, OMe), 6.26 (IH, s, 2-H), 7.08 (IH, d with further fine coupling, I £a.8.0Hz, 6'-H), 7.30-7.52 (3H, m, 2", 4\

5'-H ₃ ); δc (d -MeOH), 12.0 (C-17), 20.0 (C-14), 32.6 (C-9), 41.3 (C-8), 42.6 (C-4), 43.4 (C-12), 55.6 (C-10), 56.5 (OMe). 60.9 (C-11), 66.1 (C-16), 69.5 (C-6), 70.4 (C-13), 71.2 (C-7), 75.1 (C-5), 98.1 (C-2), 113.8 (C-5'), 119.0 (C-4'), 120.1 (C-6'), 130.5 (C-3), 137.KC-1'), 161.0 (C-3'), 183.1 (C-3), 196.3 (C-1); m/z 436 (M ⁺ , 0.2%) and 135 (100). (Found: M ⁺ , 436.2105.

C27H32O8 requires M, 436.2097). The 1-H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 14

3R.4R-Dihvdroxy-2S-r4-(4-cvanophenyl)-2.4-dioxobut-l- yl1-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahydropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(4-cvanophenyl)- 4-hvdroxy-2-oxobut-l-yll-5S-(2S.3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 5a, and on the same scale, 4-cyanobenzaldehyde (419mg, 3.2mmol) was reacted to give the title compound (1.25g, 68%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.0Hz, I7-H3), 1.20 (3H, d, si 6.3Hz, 14-H ₃ ), 4.08-4.19 (IH, m, 5-H), 5.16-5.28 (IH, m, 1-H), 7.49 (2H, d, _T 8.2Hz, 2", 6'-H ₂ ), 7.62 (2H, d, si 8.2Hz, 3', 5'-H ₂ ).

b) 3R.4R-Bistrimethylsilyloxy-2S-r4-(4-cvanophenyl)- 2.4-dioxobut-l-vn-5S-(2S.3S-epoxy-5S-trimethylsilyl- oxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 6b, the product from 14a(1.25g) in benzene (65ml) was reacted with manganese dioxide (3.5g) for 1 hour to give the title compound (625mg, 50%); δg (CDCI3) 0.90 (3H, d, si 7.0Hz, 17-H ₃ ), 1.20 (3H, d, si 6.3Hz, 14-H ₃ ), 1.31-1.45 (IH, m, 8-H), 1.50-1.66 (2H, m,

9-H), 1.80-1.90 (IH, m, 12-H), 2.39 (IH, dd, si 10.2, 14.8Hz, 4-H), 2.62-2.75 (2H, m, 10, 11-H ₂ ), 2.86 (IH, dd, J 2.6, 14.7Hz, 4-H), 3.46 (IH, dd, J 2.4, 9.2Hz, 6-H), 3.57 (IH, d, si 11.3Hz, 16-H), 3.77-3.92 (2H, m, 7, 13-H ₂ ), 3.96 (IH, d, si 11.3Hz, 16-H), 4.07-4.20 (IH, m, 5-H), 6.28 (IH, s, 2-H), 7.74 (2H, d, si 8.5Hz, 3', 5'-H ₂ ), 7.97 (2H, d, si 8.5Hz, 2', 6'-H ₂ ). The IH spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-r4-(4-cvanophenyl)-2.4-dioxo- but-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahvdropyran

Using the method described in 5c, the product from 14b (200mg,

0.31_Q_nol) was deprotected to give the title compound (95mg, 71%); v _max (KBr) 3431, 2230, 1597, 1558cm- ¹ ; λ _max (EtOH) 321.5nm (ε _m 16,280); δg (CDCI3) inter alia 0.94 (3H, d, si 7.0Hz, 17-H ₃ ), 1.22 (3H, d, si 6.3Hz, U-H3), 6.29 (IH, s, 2-H), 7.75 (2H, d, si 8.4Hz, 3', 5'-H ₂ ), 7.97 (2H, d, si 8.4Hz, 2', 6'-H ₂ ); δ _C (CDCI3) 13.1 (C-17), 21.2 (C-14), 31.9 (C-9), 40.1 (C-8), 43.2 (C-12), 43.3 (C-4), 56.0 (C-10), 61.6 (C-11), 66.0 (C-16), 69.2 (C-6), 70.6 (C-13), 71.7 (C-7), 74.2 (C-5), 98.8 (C-2), 115.8 (C-1"), 118.4 ^■ (C-4'), 127.8 (C-2", 6'), 132.8 (C-3', 5'), 138.7(CN),179.1 (C-3), 198.1 (C-1); m/z (FAB) 454 __-Na+). The 1-H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 15

3R.4R-Dihvdroxy-2S-r4-(4-chlorophenyl)-2.4-dioxo-but-l- yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahydropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(4-chlorophenyl)- 4-hvdroxy-2-oxobut-l-yll-5S-(2S.3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 5a, and on the same scale, 4-chlorobenzaldehyde (450mg, 3.2mmol) was reacted to give the title compound (1.4g, 76%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.0Hz, 17-H ₃ ), 1.18 (3H, d, si 6.4Hz, 14-H ₃ ), 4.07-4.18 (IH, m, 5-H), 5.08-5.20 (IH, m, 1-H), 7.28-7.32 (4H, m, Ar); m/z 658 (M ⁺ , 0.01%) and 117 (100). (Found: M ⁺ , 658.2947. C3XH55O7CIS-3 requires M, 658.2944).

b) 3R.4R-Bistrimethylsilyloxy-2S-r4-(4-chlorophenyl)- 2.4-dioxobut-l-yll-5S-(2S.3S-epoxy-5S-trimethylsilyl- oxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 6b, the product from 15a(700mg, 1.06mmol) in benzene (30ml) was reacted with manganese dioxide (1.75g) for 2 hours to give the title compound (296mg, 42%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.0Hz, 17-H ₃ ), 1.10 (3H, d, si 6.3Hz, 14-H ₃ ), 3.94-4.08 (IH, m, 5-H), 6.23 (IH, s, 2-H), 7.41 (2H, d, si 8.6Hz, 3', 5'-H ₂ ), 7.82 (2H, d, si 8.6Hz, 2', 6'-H ₂ ); m/z, 656 (M ⁺ , 5%) and 117 (100). (Found: M ⁺ , 656.2803.

C31 ^H 53°7 ^lSi 3 requires M, 656.2788).

c) 3R.4R-Dihvdroxy-2S-r4-(4-chlorophenyl)-2.4-dioxo- but-l-vll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)= tetrahydropyran

Using the method described in 5c, the product from 15b (296mg, 0.45mmol) was deprotected to give the title compound (160mg, 80%); v _max (KBr) 3424, 1718, 1595, 1486, 1451, 1380cm- ¹ ; λ _max (EtOH) 313nm (ε _m 17,760) and 255 (7,460); _H (CDCI3) inter alia 0.93 (3H, d, si 7.0Hz, I7-H3), 1.22 (3H, d, si 6.3Hz, 14-H ₃ ), 6.20 (IH, s, 2-H), 7.43 (2H, d, si 8.6Hz, 3", 5'-H ₂ ), 7.82 (2H, d, si 8.6Hz, 2', 6'-H ₂ ); δ _C (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.6 (C-9), 39.7 (C-8), 42.7 (C-4), 42.8 (C-12), 55.7 (C-10), 61.3 (C-11), 65.6 (C-16), 69.0 (C-6), 70.3 (C-13), 71.3 (C-7), 73.9 (C-5), 97.4 (C-2), 128.4 (C-3', C-5'), 129.0 (C-2", C-6"), 134.6 (C-1'), 140.4 (C-4'), 181.1 (C-3), 196.0 (C-1); m/z 441 (MH+, 2%) and 139 (100). (Found: M ⁺ , 441.1680. C22H30O CI requires M, 441.1680). The ¹ H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 16

3R.4R-Dihvdroxy-2S-r4-(4-diethoxymethylphenyl)-2.4- dioxobut-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahvdropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(4-diethoxy- methv-phenyl)-4-hvdroxy-2-oxobut-l-yl1-5S-(2S.3S-epoxy- 5S-trimethylsilyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 5a, and on the same scale, terephthalaldehyde-mono, diethyl acetal (666mg, 3.2mmol) was reacted to give the title compound (1.52g, 75%); δg (d4-MeOH) inter alia 0.90 (3H, d, si 7.0Hz, I7-H3), 1.20 (3H, d, si 6.3Hz, 14-H ₃ ), 4.02-4.16 (IH, m, 5-H), 5.10-5.19 (IH, m, 1-H), 5.47 (IH, s, ArCH-(OEt) ₂ ), 7.36 and 7.42 (4H, ABq, si 8.4Hz); m/z (FAB) 749 (MNa+).

b) 3R.4R-Bistrimethylsilyloxy-2S-r4-(4-diethoxy methylphenyl)-2.4-dioxobut-l-vn-5S-(2S.3S-epoxy-5S-

trimethylsilyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 6b, the product from 16a(1.0g, 1.38mmol) in benzene (50ml) was reacted with manganese dioxide (2.5g) for 2 hours to give the title compound (535mg, 53%); δg (d4-MeOH) inter alia 0.89 (3H, d, si 7.0Hz, 17-H ₃ ), 1.19 (3H, d, i 6.3Hz, 14-H ₃ ), 1.22 (6H, t, si 7.1Hz, -(OEt) ₂ ), 4.07-4.17 (IH, m, 5-H), 5.55 (IH, s, Ar-C_H-(OEt) ₂ ), 6.41 (IH, s, ^" 2-H), 7.56 (2H, d, 18.3Hz, 3', 5'-H ₂ ), 7.92 (2H, d, si 8.3Hz, 2', 6'-H ₂ ); m/z 724 (M ⁺ , 0.1%) and 432 (100). (Found: M ⁺ , 724.3860. C ₃ gHg θ9Si ₃ requires M, 724.3858). The l-H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-r4-(4-diethoxymethylphenyl)- 2.4-dioxobut-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S- methvIhexyDtetrahvdropyran

Using the method described in Id, the product from 16b (150mg, 0.21mmol) in ethanol (5ml) was deprotected to give the title compound (60mg, 57%); λ-n _nγ (EtOH) 315nm (ε _m 18,870) and 252 (7,350); δg (dg-acetone) inter alia 0.92 (3H, d, si 7.0Hz, I7-H3), 1.10-1.30 (9H, m,

I7-H3, 2 x OEt), 5.58 (IH, s, -C_H-(OEt) ₂ ), 6.52 (IH, s, 2-H), 7.59 (2H, d, si 8.4Hz, 3", 5 ^* -H2), 7.99 (2H, d, s∑ 8.4Hz, 2', 6'-H ₂ ); δc (dg-acetone) 12.3 (C-17), 15.5 (-CH2_v___), 20.8 (C-14), 32.7 (C-9), 41.3 (C-8), 43.0 (C-4), 43.3 (C-12), 55.8 (C-10), 60.4 (C-11), 61.6 (-CH ₂ Me). 66.0 (C-16), 69.4 (C-6), 70.1 (C-7), 71.1 (C-13), 75.1 (C-5), 98.0 (C-2), 101.6 (C_H(-OEt) ₂ ), 1- 7.6 and 127.7 (C-2", 6', 3", 5'), 135.5 (C-4"), 144.9 (C-1'), 183.0 (C-1), 197.2 (C-3). The ! l n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 17

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-f4-formylphenv -but-l- yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahvdropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(4- formylphenvDbut-l-yl1-5S-(2S.3S-epoxy-5S-trimethyl- sOyyloxy-4S-methylhexyI)tetrahvdropyran

The product from 16b (llOmg) was dissolved in acidic chloroform (10ml) [standard solution: chloroform (100ml):concentrated hydrochloric acid (1 drop)]. After 1 1/2 hours the mixture was evaporated and chromatographed on silica eluting with ethyl acetate/ hexane mixtures to give the title compound (60mg, 60%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.1Hz, 17-H ₃ ), 1.20 (3H, d, si 6.2Hz, 14-H ₃ ), 4.08-4.22 (IH, m, 5-H), 6.33 (IH, s, 2-H), 7.95 and 8.04 (4H, ABq, si 8.4Hz, Ar), 10.09 (IH, s, -CHO); m/z. (FAB) 673 (MNa+).

b) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-formylphenyl)- but-l-yl1-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahvdropvran

Using the method described in 5c, the product from 17a (50mg, O.Oδmmol) was deprotected to give the title compound (33mg, 100%); v _max (KBr) 3427, 1701, 1602, 1564cm- ¹ ; λ _max (EtOH) 322.5nm (ε _m 16,240) and 258 (9,430); δπ (CDCI3) inter alia 0.93 (3H, d, si 7.0Hz, 17-H ₃ ), 1.21 (3H, d, si 6.3Hz, U-H3), 6.33 (IH, s, 2-H), 7.94 and 8.01 (4H, ABq, si 8.3Hz, Ar), 10.06 (IH, s, -CHO); δc (CDCI3) 12.8 (C-17), 20.9 (C-14), 31.6 (C-9), 39.8 (C-8), 42.9 (C-12), 43.2 (C-4), 55.7 (C-10), 61.3 (C-11), 65.7 (C-16), 69.0 (C-6), 70.3 (C-7), 71.4 (C-13), 73.9 (C-5), 98.2 (C-2), 127.6 (C-3', 5 ^* ), 129.8 (C-2', 6"), 138.6 (C-4'), 139.5 (C-1'), 179.3 (C-1), 191.6 (CHO), 197.9 (C-3); /z 434 (M ⁺ , 2%) and 133 (100); (Found: M ⁺ , 434.1944. C23H30O8 requires M, 434.1941). The ¹ H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 18

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-nitrophenyl)-but-l-yll -

5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)-tetrahvdropyra n

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-4-(4- nitrophenyl)-2-oxobut-l-yll-5S-(2S.3S-epoxy-5S-tri- methylsilyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 5a, and on the same scale, 4-nitrobenzaldehyde (483mg, 3.2mmol) was reacted to give the title

compqund (1.42g, 76%); δg (CDC1 ₃ ) inter alia 0.90 (3H, d, si 7.0Hz, ^■ 17-H3), 1.19 (3H, d, _s i 6.3Hz, 14-H ₃ ), 4.08-4.17 (IH, m, 5-H), 5.22-5.33 (IH, m, l-H), 7.55 (2H, dd, si 1.5, 8.7Hz, 2', 6'-H ₂ ), 8.21 (2H, d, si 8.7Hz, 3', 5'-H ₂ ); m z 669 (M ⁺ , 5%) and 117 (100). (Found: M+, 669.3198. 5 C3XH55NO9S-3 requires M, 669.3185).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(4- nitrophenyl)but-l-vIl-5S-(2S.3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyl)tetτahydropyran 0

Using the method described in 6b, the product from 18a(1.0g, 1.49mmol) in benzene (50ml) was reacted with manganese dioxide (2.5g) for 45 minutes to give the title compound (618mg, 68%); δjj (CDCI3) inter alia

0.90 (3H, d, si 7.0Hz, 17-H ₃ ), 1.20 (3H, d, _s i 6.3Hz, 14-H ₃ ), 4.08-4.22 (IH, 5 m, 5-H), 6.32 (IH, s, 2-H), 8.04 (2H, d, 8.8Hz, 2", 6'-H ₂ ), 8.30 (2H, d, si

8.8Hz, 3', 5'-H ₂ ); m/z 667 (M+, 5%) and 117 (100). (Found: M ⁺ , 667:3043. ^c 31 ^H 53 ^N0 9 ^Si 3 requires M, 667.3043). The ^X H spectrum indicated that the title compound was essentially in the enolic form.

0 c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-nitrophenyl)- but-l-yl1-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)- tetrahydrppyrqn

Using the method described in 5c, the product from 18b (200mg, 0.3mmol) 5 was deprotected to give the title compound (83mg, 61%); v _max (KBr)

3112, 1588, 1488, 1451, 1346cm- ¹ ; λ _max (EtOH) 331.5nm (ε _m 13,490) and 253.5 (9,430); δ _H (CDCI3) inter alia 0.94 (3H, d, si 7.0Hz, 17-H ₃ ), 1.22 (3H, d, si 6.2Hz, I4-H3), 6.32 (IH, s, 2-H), 8.03 (2H, d, si 8.9Hz, 2", 6'-H ₂ ), 8.30 (2H, d, si 8.9Hz, 3", 5'-H ₂ ); δ _C (CDCI3) 12.8 (C-17), 20.9 (C-14), 31.6 d (C-9), 39.8 (C-8), 42.9 (C-12), 43.1 (C-4), 55.7 (C-10), 61.3 (C-11), 65.6 (C-16), 68.9 (C-7), 70.4 (C-6), 71.4 (C-13), 73.9 (C-5), 98.8 (C-2), 123.8 (C-2", 6"), 128.0 (C-3", 5'), 140.0 (C-1 ^* ), 149.9 (C-4'), 178.2 (C-1), 198.1 (C-3); m/z (FAB) 469 (MNH ₄ +) and 452 (MH+). The iH n.m.r. spectrum indicated that the title compound was essentially in the enolic form. 5

Example 19

e R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(thien-2-yl)but-l-vn-5S-

(2S.3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahvdropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(thien-2-yl)-4- hvdroxy-2-oxobut-l-yll-5S-(2S.3S-epoxy-5S-trimethylsilyl- oxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 5a, tristrimethylsilylmonone (1.15g, 2.22mmol) and thiophene-2-carboxaldehyde (0.24ml, 2.6mmol) were reacted to give the title compound (1.086g, 78%); δχι (CDCI3) inter alia 0.90 (3H, d, si 7.1Hz, 17-H ₃ ), 1.20 (3H, d, si 6.4Hz, 14-H ₃ ), 5.36-5.46 (IH, m, l-H), 6.94-7.00 (2H, m, 3' and 4'-H), and 7.22-7.28 (IH, m, 5'-H); m/z 630 (M ⁺ , 4%) and 117 (100). (Found: M+, 630.2909. C29H ₅₄ θ7SSi3 requires M, 630.2898).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(thien-2- yl)but-l-yl1-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- methvlhexvDtetrahvdropyran

Using the method described in 6b, the product from 19a (1.05g, 1.66mmol) in benzene (40ml) was reacted with manganese dioxide (2.6g) for 1 3/4h to give the title compound (0.684g, 66%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.0Hz, I7-H3), 1.20 (3H, d, si 6.3Hz, 14-H ₃ ), 6.13 (IH, s, 2-H), 7.12 (IH, dd, si 3.9 and 4.9Hz, 4'-H), 7.59 (IH, dd, si 0.9 and 4.9Hz, 3'-H), and 7.70 (IH, dd, si 0.9 and 3.9Hz, 5'-H); m/z 628 (M ⁺ , 2%), 336 (90), 117 (100), and 73 (99). (Found: M ⁺ , 628.2759. C29H ₅₂ θ7SSi3 requires M, 628.2742). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(thien-2-yl)but-l- yn-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 5c, the product from 19b (0.670g, l.Oβmmol) was deprotected to give the title compound (0.367g, 84%); υ _max (KBr) 3421, 1611, 1412, 1272, 1110, and 1043cm" ¹ ; λ _max (EtOH) 325nm (ε _m 15,308); δg (CDCI3) inter alia 0.94 (3H, d, si 7.0Hz, 17-H ₃ ), 1.21 (3H, d, si 6.3Hz, I4-H3), 6.13 (IH, s, 2-H), 7.14 (IH, dd, si 3.9 and 4.9Hz, 4'-H), 7.62 (IH, dd, si 4.9 and 0.9Hz, 3'-H), and 7.72 (IH, dd, s∑ 3.9 and 0.9Hz, 5'- H); δ _C (CDCI3) 12.7 (C-17), 20.7 (C-14), 31.6 (C-9), 39.6 (C-8), 40.8 (C-4),

42.8 (C-12), 55.6 (C-10), 61.2 (C-11), 65.6 (C-16), 68.8 (C-6), 70.3 (C-7), 71.3 (C-13), 74.0 (C-5), 97.3 (C-2), 128.3, 130.6 and 132.6 (C-3', 4', 5'), 140.9 (C-2"), 180.7 (C-3), and 189.3 (C-1); m/z 412 (M+, 1%) and 111 (100). (Found: M ⁺ , 412.1559. C20H28O7S requires M, 412.1556). The Η n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 20

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(thien-3-yl)but-l-yl1-5S- (2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetrahvdropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-4-(thien- 3-ylV2-oxobut-l-yl1-5S-(2S.3S-epoxy-5S-trimethylsilyloxy- 4S-meth ylhexyl tetrah vdrop yran

Using the method described in 5a, tristrimethylsilylmonone (1.15g, 2.22mmol) and thiophene-3-carboxaldehyde (0.23ml, 2.6mmol) were reacted to give the title compound (0.953g, 68%); δjj (CDCI3) inter alia 0.90 (3H, d, si 7.1Hz, 17-H ₃ ), 1.19 (3H, d, si 6.3Hz, 14-H ₃ ), 5.21-5.29 (IH, m, l-H), 7.04-7.09 (IH, m, 4'-H), 7.22-7.24 (IH, m, 2'-H), and 7.28-7.32 (IH, m, 5'-H); m/z 630 (M ⁺ , O.^o), 226 (65), 129 (92), 117 (88), and 73 (100). (Found: M ⁺ , 630.2897. C29H54O7SS-3 requires M, 630.2898).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(thien- 3-vDbut-l-yl)-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl )tetrahydropyran

Using the method described in 6b, the product from 20a (0.93g, 1.47mmol) in benzene (40ml) was reacted with manganese dioxide (2.5g) for 1 3/4h to give the title compound (0.537g, 58%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.1Hz, I7-H3), 1.20 (3H, d, 6.3Hz, 14-H ₃ ), 6.10 (IH, s, 2-H), 7.34 (IH, dd, si 3.0 and 5.1Hz, 4 ^* -H), 7.46 (IH, dd, si 1.1 and 5.1Hz, 5'-H), and 8.01 (IH, dd, si 1.1 and 3.0Hz, 2'-H); m/z 628 (M ⁺ , 2%), 336 (78), 117 (85), and 73 (100). (Found: M ⁺ , 628.2753. C29H 2θ7SSi3 requires M, 628.2742). The Η n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(thien-3-yl)but-l- vn-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetrahvdro pvran

Using the method described in 6c, the product from 20b (0.53g, 0.84mmol) was deprotected to give the title compound (0.309g, 89%); υ _max (KBr) 3417, 1609, 1508, 1258, 1109, and 1054cm- ¹ ; λ _max (EtOH) 313nm (ε _m 16,375); δg (CDCI3) inter alia 0.94 (3H, d, si 7.0Hz, 17-H ₃ ), 1.21 (3H, d, si 6.2Hz, I4-H3), 7.36 (IH, dd, s∑ 2.9 and 5.1Hz, 4'-H), 7.45 (IH, dd, s∑ 1.2 and 5.1Hz, 5'-H), and 8.04 (IH, dd, s∑ 1.2 and 2.9Hz, 2'-H); δg (CDCI3)

12.6 (C-17), 20.7 (C-14), 31.6 (C-9), 39.6 (C-8), 42.3 (C-4), 42.7 (C-12), 55.6 (C-10), 61.2 (C-11), 65.6 (C-16), 68.9 (C-6), 70.2 (C-7), 71.2 (C-13), 73.8 (C-5), 98.0 (C-2), 125.8, 126.6 and 129.9 (C-2', 4' and 5'), 138.1 (C-3'), 177.9 (C-3), and 194.9 (C-1); m z 412 (M+, 2%), 394 (7), 153 (70), and 111 (100). (Found: M+, 412.1563. C20H28O7S requires M, 412.1556). The Η n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 21

3R.4R-Dihvdroxy-2S-r4-(2-dimethylaminopyrid-5-yl)-2.4- dioxobut-l-vn-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methyl- hexyPtetrahydropyran

a) 2-Dimethylaminopyridine-5-carboxaldehvde

5-Bromo-2-dimethylaminopyridine (1.005g, δ.Ommol) was dissolved in dry THF (25ml), cooled to -70°C, and treated dropwise with nbutyllithium (1.5M, 3.67ml, 5.5mmol). The mixture was stirred at -70°c for lh, then N,N-dimethyl-formamide (1.16ml, lδmmol) added. Stirring was continued for a further hour, then the reaction quenched with saturated ammonium chloride. Water was added, and the mixture extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried and evaporated. The crude product was purified by column chromatography, on silica (36g), eluting with 20, 40 and 60% ethyl acetate in hexane, to give the title compound as white crystals (0.617g, 82%); m.p.5δ-δδ.δ°C; δjj (CDCI3) 3.22 (6H, s, N(CH ₃ ) ₂ ), 6.56 (IH, d, s∑ 9.0Hz, 3'-H), 7.92 (IH, dd, s∑ 9.0 and 2.3Hz, 4'-H), 8.δ6 (IH, d, J 2.3Hz, 6'-H), and 9.77 (IH, s, CHO);

m z lδO (M ⁺ , 100%), 13δ (83), 121 (88), and 44 (86). (Found: M ⁺ , ^' 150.0795. C ₈ HχoN ₂ 0 requires M, 150.0793).

b) 3R.4R-Bistrimethylsilyloxy-2S-r4-(2-dimethylamino- 5 pyrid-5-vP-4-hvdroxy-2-oxobut-l-yl1-5S-(2S.3S-epoxy-δS- trimethylsilyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in δa, tristrimethylsilylmonone (1.038g, 2mmol) and 2-diιnethylaminopyridine-δ-carboxaldehyde (0.330g, 0 2.2mmol) were reacted to give the title compound (1.04g, 78%); δg

(CDC1 ₃ ) inter alia 0.90 (3H, d, si 7.1Hz, 17-H ₃ ), 1.19 (3H, d, si 6.3Hz, 14- H3), 3.09 (6H, s, N(CH ₃ ) ₂ ), δ.04-δ.ll (IH, m, l-H), 6.δ2 (IH, d, si 8.8Hz, 3 ^* -H), 7.52 (IH, dt, 8.8 and 2.8Hz, 4'-H), and 8.13 (IH, d, si 2.3Hz, 6'-H); m/z 668 (M ⁺ , 3%), 226 (100), 129 (90), 117 (80), and 73 (70). (Found: M+, 5 668.3724. C22HgoN ₂ θ7Si3 requires M, 668.3708).

c) 3R.4R-Bistrimethylsilyloxy-2S-r4-(2-dimethylamino- pyrid-5-yl)-2.4-dioxobut-l-vn-5S-(2S.3S-epoxy-δS-trimethyl silyloxy-4S-methylhexyl)tetrahvdropyran 0

Using the method described in 6b, the product from 21b (l.Olg, l.δlmmol) in benzene (3δml) was reacted with manganese dioxide (2.6g) for 3h to give the title compoimd (0.440g, 44%); δjj (CDCI3) inter alia 0.89 (3H, d, s∑ 7.1Hz, I7-H3), 1.19 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 3.18 (6H, s, N(CH ₃ ) ₂ ), 6.13 δ (IH, s, 2-H), 6.δl (IH, d, si 9.1Hz, 3'-H), 7.96 (IH, dd, si 9.1 and 2.4Hz, 4'- H), and 8.72 (IH, d, s∑ 2.4Hz, 6'-H); m/z 666 (M ⁺ , ¹¹ %), 6δl (3), and 149 (100). (Found: M ⁺ _> 666.3δδl. C32H ₅ 8N2θ7Si3 requires M, 666.3δ52). The Η n.m.r. spectrum indicated that the title compound was essentially in the enolic form. 0 d) 3R.4R-Dihvdroxy-2S-r4-(2-dimethvIaminopyrid-5-yl)- 2.4-dioxobut-l-yll-δS-(2S.3S-epoxy-δS-hvdroxy-4S-methyl- hexyPtetrahydropyran

Using the method described in 5c, the product from 21c (0.420g,

0.63mmol) was deprotected to give the title compound (0.238g, 84%); υ _{m x} (KBr) 3371, 1624, 15δ4, 1401, HOδ, 10δ9, and 785cm- ¹ ; λ _m (EtOH) 355nm (ε _m 35,913);. δπ (CDCI3/CD3OD) inter alia 0.93 (3H, d, si 7.0Hz,

17-H ₃ ), 1.21 (3H, d, si 6.3Hz, 14-H ₃ ), 3.19 (6H, s, N(CH ₃ ) ₂ ), 6.13 (IH, ^' s, 2- H), 6.δ3 (IH, d, si 9.1Hz, 3'-H), 7.94 (IH, dd, si 2.3 and 9.1Hz, 4'-H), and 8.71 (IH, d, J 2.3Hz, 6'-H); δc (CDCI3/CD3OD) 12.6 (C-17), 20.6 (C-14), 31.7 (C-9), 38.1 (N(CH ₃ ) ₂ ), 39.6 (C-8), 41.8 (C-4), 42.7 (C-12), δδ.7 (C-10), δ 61.2 (C-11), 65.6 (C-16), 68.9 (C-6), 70.2 (C-7), 71.1 (C-13), 74.0 (C-δ), 9δ.6 (C-2), lθδ.1 (C-4'), 118.0 (C-δ'), 13δ.9 (C-3'), 149.1 (C-6'), 160.6 (C-2'), 183.3 (C-3), and 191.5 (C-1); m/z 450 (M ⁺ , 5%) and 149 (100). (Found: M ⁺ , 450.2372. C23H34N2O7 requires M, 450.2366). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. 0

Example 22

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-methylthiopyrid-5-vP- but-l-yll-δS-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyPtetrahv dropyran 5 a) 2-Methylthiopyridine-δ-carboxaldehvde

Using the method described in 21a, δ-bromo-2-methylthio-pyridine (1.020g, δmmol) was converted to the title compound (0.6δ0g, 8δ%); 0 m.p.43-4δ ^θ C; δg (CDCI3) 2.64 (3H, s, SCH3), 7.31 (IH, d, si 8.δHz, 3'-H), . 7.94 (IH, dd, si 2.1 and 8.δHz, 4'-H), 8.84 (IH, d, si 2.1Hz, 6'-H), and 10.00 (IH, s, CHO); m/z lδ3 QΛ+, 100%), lδ2 (60), 124 (10), and 107 (48). (Found: M ⁺ , lδ3.0247. C7H7NOS requires M, lδ3.0248).

δ b) 3R.4R-Bistrimethylsilyloxy-2S-r4-(2-methylthiopyrid- 5- _y l).4-hvdroxy-2-oxobut-l-yll-δS-(2S.3S-epoxy-δS-tri methylsilvIoxy-4S-methylhexyl)tetrahvdropyran

Using the method described in δa, tristrimethylsilylmonone (2.7δ0g, 0 δ.3mmol) and 2-methylthiopyridine-δ-carboxaldehyde (0.890g, δ.δmmol) were reacted to give the title compound (2.840g, 80%); δjj (CDCI3) inter alia 0.90 (3H, d, si 7.1Hz, 17-H ₃ ), 1.19 (3H, d, si 6.4Hz, 14-H ₃ ), 2.δ9 (3H, s, SCH3), δ.ll-δ.19 (IH, m, l-H), 7.20 (IH, d, j∑ 8.3Hz, 3'-H), 7.δ8 (IH, dt, si 8.3 and 2.8Hz, 4'-H), and 8.43 (IH, d, J 2.0Hz, 6'-H); m/z 671 (M ⁺ , 2%), δ 129 (6δ), 117 (8δ), and 73 (100). (Found: M ⁺ , 671.3187. C3χH57Nθ7SSi3 requires M, 671.3164).

c) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(2-

methylthioPyrid-δ-vPbut-l-yl1-δS-f2S.3S-epoxy-δS- trimethyl-silyloxy-4S-methvIhexyl)tetrahvdropyran

Using the method described in 6b, the product from 22b (2.09g, 3.11mmol) δ in benzene (lδOml) was reacted with manganese dioxide (2.8g) for 24h to give the title compoimd (1.340g, 64%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.1Hz, I7-H3), 1.20 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 2.61 (3H, s, SCH3), 6.23 (IH, s, 2-H), 7.24 (IH, d, s∑ 8.δHz, 3'-H), 7.9δ (IH, dd, s∑ 2.2 and 8.δHz, 4'-H), and 8.91 (IH, d, s∑ 2.2Hz, 6'-H); m/z 669 (M+, 3%), lδ2 (4δ), 117 (9δ), 7δ 10 (δ6), and 73 (100). (Found: M ⁺ , 669.3018. C3χH ₅₅ Nθ7SSi3 requires M, 669.3007). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

d) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-methylthiopyrid- Iδ 5-vPbut-l-yll-δS-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyP- tetrahvdropyran

Using the method described in δc, the product from 22c (0.648g, 0.97mmol) was deprotected to give the title compound (0.341g, 78%); 0 m.p.l35.5-136°C; found C, δ7.91; H, 6.88; N, 3.09; S, 7.10%. C22H3XNO7S requires C, δ8.26; H, 6.89; N, 3.09; S, 7.07%; υ _max (KBr) 3483, 3392, 1583, 1298, 1120, 1106, and 1061cm" ¹ ; λ _max (EtOH) 336nm (ε _m 29,695); δπ (CDCI3/CD3OD) inter alia 0.93 (3H, d, 1 .0Hz, 17-H ₃ ), 1.22 (3H, d, si 6.4Hz, I4-H3), 2.61 (3H, s, SCH3), 6.26 (IH, s, 2-H), 7.27 (IH, d, si 8.5Hz, δ 3'-H), 7.98 (IH, dd, si 8.5 and 2.3Hz, 4'-H), and 8.89 (IH, d, si 2.3Hz, 6 -H); δc (CDCI3/CD3OD) 12.3 (C-17), 13.2 (SCH3), 20.3 (C-14), 31.6 (C-9), 39.7 (C-8), 42.0 (C-4), 42.5 (C-12), δδ.6 (C-10), 60.9 (C-11), 6δ.6 (C-16), 68.4 (C- 6), 70.0 (C-7), 70.6 (C-13), 73.9 (C-δ), 97.0 (C-2), 120.8 (C-4"), 12δ.9 (C-δ'), 133.9 (C-3'), 148.1 (C-6'), 16δ.2 (C-2'), 180.δ (C-3), and 194.6 (C-1); m/z 4δ3 0 (M ⁺ , TO, 3-67 (100) and lδ2 (6δ). (Found: M ⁺ , 4δ3.182δ. C22H3XNO7S requires M, 4δ3.1821). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 23 δ

3R.4R-Dihvdroxy-2S-[2.4-dioxo-4-(2-methylsulphinylpyrid-

5-vPbut-l-yll-5S-r2S.3S-epoxy-5S-hvdroxy-4S-methylhexyP- tetrahvdropyran

The product from 22c (0.21δg, 0.32mmol) was dissolved in dichloromethane (9ml), cooled in an ice bath, saturated sodium hydrogen carbonate (O.δml) and water (l.δml) were then added, followed by 3- δ chloroperbenzoic acid (ca.9δ%, 0.064g, 0.3δmmol). The mixture was stirred for 3/4h, then separated, and the aqueous extracted with dichloromethane (x2). The combined organic phases were washed with brine, dried and evaporated. The product was purified by column chromatography, on silica (lOg), eluting with 30-40% ethyl acetate in 10 hexane, to give the pure product (0.1δ2g, 69%).

This material was dissolved in THF (7ml), water (0.7ml) added, followed by glacial acetic acid (0.7ml). Further portions of glacial acetic acid

(δ x 0.4ml) were added over the following 28h. After this the solution was lδ evaporated to dryness, and purified by column chromatography to give the title compound (0.064g, 62%); υ _max (KBr) 340δ, 1602, 14δl, 1109, 1084, and 1042cm" ¹ ; λ _max (EtOH) 322nm (ε _m lδ,δδ0); δg (CDCI3) inter alia 0.94 (3H, d, si 7.0Hz, 17-H ₃ ), 1.23 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 2.90 (3H, s, SOCH3), 6.33 and 6.3δ (IH, 2s, 2-H), 8.13 (IH, d, s∑ 8.2Hz, 3'-H), 8.39 (IH,

20 br d, 4'-H), and 9.06 (IH, s, 6'-H); δc (CDCI3) 12.8 (C-17), 20.9 (C-14), 31.7 (C-9), 39.9 (C-8), 41.1, 42.7 and 42.8 (C-4, C-12 and SOCH3), δδ.6 (C-10), 61.1 (C-11), 6δ.6 (C-16), 68.8 (C-6), 70.4 (C-7), 71.3 (C-13), 73.9 (C-δ), 98.δ (C-2), 119.4 (C-4'), 131.5 (C-5'), 136.5 (C-3 ^* ), 148.3 (C-6'), 169.0 (C-2'), 178.3 (C-3), and 197.2 (C-1); m/z (FAB, thioglycerol) 491 (MNa+) and 470

2δ (MH ⁺ ). The spectra indicated that the compound was a mixture of sulphoxide isomers, and essentially in the enolic form.

Example 24

30 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-methylsulphonylpyrid- δ-vPbut-l-vn-δS-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyP- tetrahvdropyran

The product from 22c (0.23δg, 0.3δmmol) was dissolved in 3δ dichloromethane (lδml), saturated sodium hydrogen carbonate (l.δml) and water (3ml) added, and the mixture stirred while 3-chloroperbenzoic acid (ca.9δ%, 0.140g, 0.77mmol) was added. Stirring was continued for seven hours, then water added and the mixture extracted with

dichloromethane (x3). The combined organic extracts were dried and evaporated. The crude material was purified by column chromatography, on silica (lOg), eluting with 2δ-40% ethyl acetate in hexane, to give the pure product (0.097g, 40%). δ

This material was deprotected using the method described in δc, to give the title compound (0.037g, δ7%); υ _max (KBr) 3490, 1623, 1307, 1163, 1103, 1060, and 778cm- ¹ ; λ _max (EtOH) 320nm (ε _m 14,012); δg (CDCI3/CD3OD) inter alia 0.94 (3H, d, 7.1Hz, 17-H ₃ ), 1.22 (3H, d, s∑ 10 6.4Hz, U-H3), 3.29 (3H, S, S0 ₂ CH ₃ ), 6.38 (IH, S, 2-H), 8.18 (IH, d, s∑

8.2Hz, 3'-H), 8.4δ (IH, dd, si 8.2 and 2.0Hz, 4'-H), and 9.16 (IH, d, si 2.0Hz, 6'-H); /z48δ (M ⁺ , 0.1%), 13δ (70), and 122 (100); m/z (FAB, thioglycerol) 498 (MNa ⁺ ) and 486 (MH ⁺ ). The Η n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Iδ

Example 2δ

3R.4R-Dihvdroxy-2S-r4-(2-chloropyrid-δ-vP-2.4-dioxobut-l -yll- δS-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyPtetrahydropyran 0 a) N-Methoxy.N-methyl-2-chloropyridine-δ-carboxamide

2-Chloropyridine-δ-carboxylic acid (l.δ76g, lOmmol) was dissolved in dry THF (100ml), cooled in an ice-bath, then triethylamine (l.δml, llmmol) δ added, followed by iso-butylchloroformate (1.3ml, lOmmol). The mixture was stirred for 3/4h, then N,0-dimethylhydroxylamine (≤x hydrochloride salt, lδmmol) in dichloromethane (70ml) was added. After stirring for 13/4h, the mixture was diluted with dichloromethane, washed with water, aqueous sodium hydrogen carbonate, and brine, dried and 0 evaporated. The crude product was purified by column chromatography, on silica (2δg), eluting with 40% ethyl acetate in hexane, to give the title compound (1.280g, 64%); δg (CDCI3) 3.3δ and 3.δδ (6H, 2s, 2 x CH3), 7.3δ (IH, d, si 8Hz, 3'-H), 8.0 (IH, dd, J 8 and 2Hz, 4'-H), and 8.7 (IH, d, si 2Hz, 6'-H). δ b) 2-Chloropyridine-δ-carboxa dehvde

The product from 2δa (1.25g, 6.23mmol) was dissolved in dry

dichloromethane (25ml), cooled to -70°C, and treated dropwise with diisobutyl_d__ninium hydride (1.0M in toluene, 9.3ml, 9.3mmol). After stirring for lh at -70°C, the reaction was quenched with methanol and saturated sodium sulphate solution. The mixture was filtered, the phases 5 separated, the organic washed with brine, dried and evaporated. The crude product was purified by column chromatography, on silica (18g), eluting with 20% ethyl acetate in hexane, to give the title compound (0.743g, 84%); m.p.80-81°C; found C, δθ.86; H, 2.60; N, 9.8δ; Cl, 24.83%. CgH4C.NO requires C, δθ.91; H, 2.8δ; N, 9.89; Cl, 2δ.0δ%; υ _max 0 (CH2CI2) 1713, 1584, 1560, 1349, 1102, and 837cm" ¹ ; δg (CDCI3) 7.52 (IH, d, s∑ 8.3Hz, 3'-H), 8.15 (IH, dd, s∑ 2.3 and 8.3Hz, 4'-H), 8.87 (IH, d, s∑ 2.3Hz, 6'-H), and 10.11 (IH, s, CHO); m/z 141/143 (M ⁺ , 75 and 25%), 140/142 (100 and 37), and 112/114 (54 and 18). (Found: M ⁺ , 140.9981. CgH ₄ ClNO requires M, 140.9981). 5 c) 3R.4R-Bistrimethylsilyloxy-2S-r4-(2-chloropyrid- 5-vP-4-hvdroxy-2-oxobut-l-yll-5S-(2S.3S-epoxy-δS-tri- methyl-silyloxy-4S-methylhexyl)tetrahvdropyran

0 Using the method described in δa, tristrimethylsilylmonone (1.038g, 2mmol) and 2-chloropyridine-δ-carboxaldehyde (0.3 llg, 2.2mmol) were reacted to give the title compound (0.910g, 69%); δjx (CDCI3) inter alia 0.90 (3H, d, s∑ 7.1Hz, 17-H ₃ ), 1.19 (3H, d, J 6.3Hz, 14-H ₃ ), δ.l6-δ.24 (IH, m, l-H), 7.32 (IH, d, s∑ 8.3Hz, 3'-H), 7.71 (IH, dt, s∑ 8.3 and 2.3Hz, 4'-H), δ and 8.37 (IH, d, s∑ 2.3Hz, 6'-H); m/z 660 (MH+, 3%), 129 (4δ), 117 (77), and 73 (100); m/z (FAB, 3-NOBA/Na) 682 (MNa+) and 660 (MH+). (Found: MH+, 660.2967. C3oH55ClN0 ₇ Si3 requires M, 660.2978).

d) 3R.4R-Bistrimethylsilyloxy-2S-r4-(2-chloropyrid- 0 δ-vP-2.4-dioxobut-l-yl1-δS-(2S.3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyPtetrahvdropyran

Using the method described in 6b, the product from 25c (0.880g, 1.33mmol) in benzene (40ml) was reacted with manganese dioxide (1.5g) 5 for 3h, to give the title compound (0.442g, δ0%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.1Hz, 17-H ₃ ), 1.20 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 6.24 (IH, s, 2- H), 7.42 (IH, d, s∑ 8.4Hz, 3'-H), 8.13 (IH, d, s∑ 8.4 and 2.4Hz, 4'-H), and 8.8δ (IH, d, s∑ 2.4Hz, 6'-H); m/z 6δ7 (M ⁺ , 0.3%), 117 (70), and 73 (100).

(Found: M ⁺ , 6δ7.2747. C3θH ₅ 2ClNθ7Si3 requires M, 6δ7.2740). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

δ e) 3R.4R-Dihvdroxy-2S-r4-(2-chloropyrid-δ-vP-2.4- dioxobut-l-yl1-5S-(2S.3S-ePoxy-5S-hvdroxy-4S-methylhexyP- tetrahvdropyran

Using the method described in δc, the product from 2δd (0.420g, 10 0.64mmol) was deprotected to give the title compound (0.223g, 79%); v _m a (KBr) 3443, lδ89, 14δ2, 1303, 1110, 10δ7, and lOlδcm" ¹ ; λ _max (EtOH) 316nm (ε _m lδ,694); δg (CDCI3/CD3OD) inter alia 0.94 (3H, d, si 7.0Hz, I7-H3), 1.22 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 6.33 (s, 2-H, partly exchanged), 7.δ0 (IH, d, s∑ 8.4Hz, 3'-H), 8.20 (IH, dd, s∑ 8.4 and 2.4Hz, 4'-H), and 8.86 (IH, lδ d, si 2.4Hz, 6'-H); δc (CDCI3/CD3OD) 11.3 (C-17), 19.2 (C-14), 31.0 (C-9), 39.4 (C-8), 41.5 (C-4), 41.8 (C-12), 5δ.O (C-10), δ9.9 (C-11), 64.8 (C-16), 67.7 (C-6), 69.4 (C-13), 73.3 (C-7), 76.9 (C-δ), 97.2 (C-2), 123.9 (C-3'), 129.1 (C-5'), 136.8 (C-4'), 147.7 (C-6'), 153.8 (C-2'), 177.8 (C-3), and 195.2 (C-1); m z 441 (M ⁺ , 3%), 140/142 (100/35), and 69 (94). (Found: M ⁺ , 441.15δ9. 0 C21H28CINO7 requires M, 441.1δδ4). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 26

δ 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(δ-hvdroxymethvIfuran-2- vPbut-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyP- tetrahvdropyran

a) δ-Triethyls-Iyloxymethylfuran-2-carboxaldehyde 0 δ-Hydroxymethylfuran-2-carboxaldehyde (0.63 lg, δmmol) was dissolved in dry dichloromethane (10ml), cooled in an ice-bath, and triethylamine (1.0ml, 7mmol) added followed by triethylchlorosilane (1.0ml, 6mmol). After stirring for 3/4h, the mixture was evaporated. The residue was δ purified by column chromatography, on silica (17 ), eluting with 10% ethyl acetate in hexane, to give the title compound (1.194g, 99%); δj£ (CDCI3) O.δδ-0.8 (6H, m, 3 x CH ₂ ), 0.8δ-l.lδ (9H, m, 3 x CH3), 4.6δ (2H, s, CH ₂ 0), 6.4 and 7.1 (2H, 2d, J 4Hz, 3 and 4-H), and 9.δ (IH, s, CHO).

b) 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-2-oxo-4-(5- triethylsiIyloxymethylfuran-2-yPbut-l-yl1-5S-(2S.3S-epoxy- δS-trimethylsilyloxy-4S-methvIhexyl)tetrahvdropyran δ

Using the method described in δa, tristrimethylsilylmonone (1.038g, 2mmol) and δ-triethylsilyloxymethylfuran-2-carboxaldehyde (0.δ29g, 2.2mmol) were reacted to give the title compound (l.OOOg, 66%); δjj (CDC1 ₃ ) inter alia 0.62 (6H, br q, 3 x CH ₂ ), 0.86-1.0 (12H, m, 17-H ₃ and 10 3 x CH3), 1.20 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 4.61 (2H, s, OCH ₂ ), δ.l3-δ.20 (IH, m, l-H), 6.19 and 6.21 (2H, 2d, s∑ 3.2Hz, 3' and 4'-H); m/z (FAB, 3- NOBA Na) 781 (MNa+).

c) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(δ-tri- lδ ethylsilyloxymethylfuran-2-vPbut-l-yl1-δS-(2S.3S-epoxy-δS- trimethylsilyloxy-4S-methylhexyPtetrahvdropyran

Using the method described in 6b, the product from 26b (0.97δg, 1.28mmol) in benzene (70ml) was reacted with manganese dioxide (4.1g) 20. for 3 l/2h to give the title compound (0.39δg, 41%); δπ (CDCI3) inter alia 0.6δ (6H, br q, 3 x CH ₂ ), 0.86-1.01 (12H, m, 17-H ₃ and 3 x CH3), 1.20 (3H, . d, si 6.4Hz, -H3), 4.70 (2H, s, OCH ₂ ), 6.14 (IH, s, 2-H), 6.41 (IH, d, si

3.δHz, 4'-H), and 7.10 (IH, d, s∑ 3.δHz, 3'-H); m z 7δ6 (M+, 2%), 117 (100), . and 73 (98). (Found: M ⁺ , 7δ6.3949. C3gHg8θ9Si ₄ requires M, 7δ6.3940). 2δ The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

d) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(δ-hvdroxymethyl- furan-2-yl)but-l-vn-δS-(2S.3S-epoxy-δS-hvdroxy-4S-methyl-

30 hexyPtetrahvdropyran

Using the method described in δc, the product from 26c (0.386g, O.δmmol) was completely deprotected to give the title compound (0.1δ3g, 72%); υ _max (KBr) 3411, 1618, 1209, 1101, and 1020cm" ¹ ; λ _max (EtOH) 330nm 35 (ε _m 19,562); δg (CDCI3/CD3OD) inter alia 0.94 (3H, d, s∑ 7.0Hz, 17-H ₃ ), 1.22 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 4.62 (2H, s, OCH ₂ ), 6.18 (s, 2-H, partly exchanged), 6.47 (IH, d, s∑ 3.5Hz, 4'-H), and 7.16 (IH, d, s∑ 3.δHz, 3'-H); δc (CDCI3/CD3OD) 12.3 (C-17), 20.4 (C-14), 31.5 (C-9), 39.6 (C-8), 40.7 (C-4),

42.δ (C-12), δδ.6 (C-10), δ6.9 (OCH ₂ ), 60.9 (C-11), 6δ.4 (C-16), 68.4 ⁽ C-6), 70.1 (C-7), 70.7 (C-13), 73.9 (C-δ), 96.7 (C-2), 110.0 (C-4'), 117.1 (C-3'), 149.4 (C-2'), lδ8.9 (C-δ'), 175.4 (C-3), and 190.0 (C-1); m/z 426 (M ⁺ , 1%), 140 (100), 12δ (92), and 69 (90). (Found: M ⁺ , 426.1900. C2χH ₃ o0 ₉ δ requires M, 426.1890). The 'H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 27

0 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-nitrothien-4-vPbut-l- vIl-5S-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyPtetra- hvdropvran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-4-(2-nitro- 5 thien-4-vP-2-oxobut-l-yll-5S-(2S.3S-epoxy-δS-trimethyl- silyloxy-4S-methylhexyPtetrahydropyran

Using the method described in δa, tristrimethylsilylmonone (1.038g, 2mmol) and 2-nitrothiophene-4-carboxaldehyde (0.346g, 2.2mmol) were 0 reacted to give the title compound (0.390g, 69%); δfi (CDCI3) inter alia 0.90 (3H, d, s∑ 7.1Hz, 17-H ₃ ), 1.20 (3H, d, s∑ 6.3Hz, 14-H ₃ ), δ.ll-δ.21 (IH, m, l-H), 7.46-7.δ0 and 7.87-7.91 (2H, m, 3' and δ'-H); m/z (FAB, 3- NOBA/Na) 698 (MNa ⁺ ).

δ b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(2- nitrothien-4-vPbut-l-yll-δS-(2S.3S-epoxy-δS-tri-methyl- silvIoxy-4S-methylhexyPtetrahydropyran

Using the method described in 6b, the product from 27a (O.δOOg, 0 0.74mmol) in benzene (3δml) was reacted with manganese dioxide (l.Og) for 4 l/2h to give the title compound (0.186g, 37%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.0Hz, 17-H ₃ ), 1.20 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 6.08 (IH, s, 2-H), 8.14 and 8.23 (2H, 2d, 1.7Hz, 3' and δ'-H); m/z (FAB, thioglycerol) 674 (MH+); m/z (FAB, 3-NOBA/Na) 718 (M + 2Na-H+). The Η n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-nitrothien-4-yl)

hut-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl) tetrahydropyran

Using the method described in .δc, the product from 27b (0.170g, δ 0.2δmmol) was deprotected to give the title compound (0.09δg, 83%); υ _max (KBr) 3423, 1604, lδ34, 1506, 1336, 1111, and 1052cm ^"1 ; λ _max (EtOH) 311nm (ε _m 20,545); δg (CDCI3) inter alia 0.94 (3H, d, s∑ 7.0Hz, 17-H ₃ ), 1.22 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 6.09 (IH, s, 2-H), 8.16 and 8.22 (2H, 2d, s∑ 1.7Hz, 3" and 5'-H); δc (CDCI3/CD3OD) 12.4 (C-17), 20.4 (C-14), 31.9 (C- 10 9), 40.1 (C-8), 42.1 (C-4), 42.7 (C-12), δδ.9 (C-10), 61.0 (C-11), 6δ.8 (C-16), 68.6 (C-6), 70.2 (C-7), 70.6 (C-13), 74.2 (C-δ), 98.1 (C-2), 126.7 and 134.δ (C-3' and δ'), 137.8 (C-4'), lδ2.7 (C-2'), 17δ.8 (C-3), and 19δ.l (C-1); m/z (FAB, thioglycerol) 47δ (MNH4+) and 4δ8 (MH+); m/z (FAB, 3-NOBA Na) δ02 (M + 2Na-H+) and 480 (MNa+). lδ

Example 28

3R.4R-Dihvdroxy-2S-r4-(2-bromopyrid-5-vP-2.4-dioxobut-l- vn-δS-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyPtetra- 0 hvdropyran

a) N-Methoxy. N-methyl-2-bromopyridine-δ-carboxamide

Using the method described in 2δa, 2-bromopyridine-δ-carboxylic acid 2δ (2.02g, lOmmol) was reacted to give the title compound (1.637g, 67%); δf_ (CDCI3) 3.3δ and 3.55 (6H, 2s, 2 x CH3), 7.5δ (IH, d, J 8Hz, 3'-H), 7.9 (IH, dd, s∑ 8 and 2Hz, 4'-H), and 8.7 (IH, d, s∑ 2Hz, 6'-H).

b) 2-Bromopyridine-δ-carboxaldehvde

30

Using the method described in 2δb, N-methoxy, N-methyl-2- bromopyridine-δ-carboxamide (1.60g, 6.δ3mmol) was reacted to give the title compound (1.042g, 86%); m.p.l03.δ-104°C (chloroform hexane); found C, 38.72; H, 2.09; N, 7.δ3; Br, 42.62%. C H4BrNO requires C, 38.74; H, 3δ 2.17; N, 7.δ3; Br. 42.96%; δg [(CD ₃ ) ₂ CO] 7.8 (IH, d, s∑ 8Hz, 3'-H), 8.1δ (IH, dd, s∑ 8 ana 2Hz, 4'-H), 8.85 (IH, d, s∑ 2Hz, 6'-H), and 10. lδ (IH, s, CHO).

c) 3R.4R-BistrimethylsilvIoxy-2S-r4-(2-bromopyrid-5- vP-4-hvdroxy-2-oxobut-l-yl1-5S-(2S.3S-epoxy-δS-trimethyl- silyloxy-4S-methylhexyl)tetrahvdropyran

5 Using the method described in δa, tristrimethylsilylmonone (1.038g, 2mmol) and 2-bromopyridine-δ-carboxaldehyde (0.409g, 2.2mmol) were reacted to give the title compound (0.729g, δ2%); δjj (CDCI3) inter alia 0.90 (3H, d, si 7.0Hz, 17-H ₃ ), 1.19 (3H, d, si 6.3Hz, 14-H ₃ ), δ.l3-δ.22 (IH, m, l-H), 7.47 (IH, d, si 8.2Hz, 3'-H), 7.δ8-7.64 (IH, m, 4'-H), and 8.3δ (IH, 10 d, si 2.3Hz, 6'-H); m/z (NH3, DCI) 706/704 (MH+, 10%), 186/188 (δO), 108 (δO), and 90 (100).

d) 3R.4R-BistrimethylsiIyloxy-2S-r4-(2-bromopyrid-5- vP-2.4-dioxobut-l-vIl-δS-(2S.3S-epoxy-δS-trimethyl- lδ silyloxy-4S-methylhexyPtetrahvdropyran

Using the method described in 6b, the product from 28c (0.721g, 1.02mmol) in benzene (40ml) was reacted with manganese dioxide (1.44g) ____&_ hours to give the title compound (0.320g, 4δ%); δu (CDCI3) inter 0 alia 0.90 (3H, d, si 7.1Hz, I7-H3), 1.20 (3H, d, si 6.3Hz, 14-H ₃ ), 6.24 (IH, s, 2-H), 7.δ9 (IH, d, si 8.3Hz, 3'-H), 8.01 (IH, dd, si 8.3 and 2.δHz, 4'-H), and 8.82 (IH, d, s∑ 2.δHz, 6'-H); rn/z 701/703 QΛ+, 1%), 409/411 (δ), 117 (100), and 73 (97). (Found: M ⁺ , 701.2232. C3oH5 ₂ BrN0 ₇ Si3 requires M, 701.223δ). The l-H n.m.r. spectrum indicated that the compound was δ essentially in the enolic form.

e) 3R.4R-Dihvdroxy-2S-[4-(2-bromopyrid-δ-vP-2.4-dioxo but-l-yl1-δS-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyP- tetrahvdropyran 0

Using the method described in δc, the product from 28d (0.3 lOg, 0.44mmol) was deprotected to give the title compound (0.090g, 42%); m.p.l33-134°C; found C, δl.δ3; H, δ.8δ; N, 2.94%; C ₂ χH28BrN0 ₇ requires C, δl.86; H, δ.80; N, 2.88%; _ _max (KBr) 343δ, lδ76, 14δ2, 1096, δ 10δ7, and 1013cm" ¹ ; λ _max (EtOH) 313 (ε _m 18,198) and 248nm (8,079); δ _H (CD3OD) inter alia 0.94 (3H, d, 7.1Hz, 17-H ₃ ), 1.19 (3H, d, si 6.4Hz, I4-H3).6.47 (IH, s, 2-H), 7.73 (IH, d, s∑ 8.δHz, 3'-H), 8.16 (IH, dd, s∑ 8.δ and 2.4Hz, 4'-H), and 8.86 (IH, d, si 2.4Hz, 6'-H); δc (CD3OD) 12.3 (C-17),

20.3 (C-14), 33.0 (C-9), 41.8 (C-8), 43.2 (C-4), 43.7 (C-12), δ6.9 (C-10), 61.2 (C-11), 66.4 (C-16), 69.8 (C-6), 70.7 (C-13), 71.5 (C-7), 75.4 (C-δ), 99.1 (C-2), 129.6 (C-3'), 131.5 (C-5'), 138.4 (C-4 ¹ ), 146.4 (C-2'), 149.8 (C-6'), 179.7 (C-1), and 197.8 (C-3); m/z (NH ₃ DCI) 486/488 (MH+, 30%), 200/202 δ (35), and 122 (100); m/z 485/487 (M+, 2%), 226/228 (48), 200/202 (70),

184/186 (80), 71 (85), and 69 (100). (Found: M ⁺ , 485.1022. C2iH ₂ 8BrN0 ₇ requires M, 48δ.l049). The IH n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

10 Example 29

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(δ-methoxyfuran-2-yl)but -l- yll-δS-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyl)tetra- hydropyran lδ a) δ-Methoxyfuran-2-carboxaldehvde

n-Butyllithium (1.5M, 7.3ml, llmmol) was added slowly to dϋsopropylamine (l.δml, lO.δmmol) in THF (20ml) at -30°C. Stirred for

20 10 mins, cooled to -70°C, and 2-methoxyfuran (0.98 lg, lOmmol) in THF . (8ml) added slowly. After stirring for V_h dimethylformamide (2.4ml, 30mmol) was added, and the mixture stirred for a further lh. After quenching with saturated aqueous ammonium chloride, the mixture was extracted with dichloromethane (x2). The combined organic extracts were

2δ washed with brine, dried and carefully evaporated. The residue was purified twice by flash chromatography, eluting with ether/hexane mixtures, to give the title compound (0.463g, 37%); δg (CDCI3) 4.0δ (3H, s, OCH3), δ.δδ (IH, d, si 4Hz, 4-H), 7.3 (IH, d, si 4Hz, 3-H), and 9.3δ (IH, s, CHO).

30 b) 3R.4R-BistrimethylsiIyloxy-2S-r4-hvdroxy-4-(δ- methoxyfuran-2-vP-2-oxobut-l-yll-δS-(2S.3S-epoxy-δS- trimethylsilyloxy-4S-methylhexyl)tetrahvdropyran

35 Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and δ-methoxyfuran-2-carboxaldehyde (0.29g, 2.2mmol) were reacted to give the title compound (l.Oδδg, 82%); δg (CDCI3) inter alia 0.9 (3H, d, s∑ 7Hz, I7-H3), 1.2 (3H, d, 6Hz, 14-H ), 3.8 (OCH3), 4.9-δ.lδ (2H,

m, l-H and 4'-H), and 6.1 (IH, d, si 4Hz, 3'-H). The product was unstable, and readily dehydrated.

c) 3R.4R-Bistrimethylsylyloxy-2S-r2.4-dioxo-4-(methoxy- δ furan-2-vPbut-l-yll-δS-(2S.3S-epoxy-5S-trimethylsilyloxy-

4S-methylhexyl)tetrahvdropyran

Using the method described in 6b, the product from 29b (l.Olg, 1.57mmol) in benzene (40ml) was reacted with manganese dioxide (3.0g) for 4 hours

10 to give the title compound (0.1δ9g, 16%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.1Hz, I7-H3), 1.20 (3H, d, si 6.3Hz, 14-H ₃ ), 3.96 and 3.97 (OCH3), δ.39 (0.8H, d, si 3.6Hz) and δ.41 (0.2H, d, s∑ 3.8Hz, 4'-H), δ.98 (0.8H, s, 2-H), and 7.14 (0.8H, d, s∑ 3.6Hz) and 7.23 (0.2H, d, s∑ 3.8Hz, 3'-H); m/z (NH3 DCI) 643 (MH+, 22%) and 90 (100); m/z 643 (MH+, 3%), 12δ (δO), lδ 117 (100), and 73 (72). (Found: MH+, 643.3140. C30H55O9S13 requires MH+ 643.31δ4).

d) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(δ-methvoxyfuran-2- vPbut-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyP- 0 tetrahydropyran

Using the method described in δc, the product from 29c (0.146g, 0.23mmol) was deprotected to give the title compound (0.080g, 82%); - _max (KBr) 3432, 1718, 1627, lδ23, 1426, and 1042cm-l; λ _max (EtOH) 347nm δ (ε _m 16,692); δg (CD3OD) inter alia 0.94 (3H, d, si 7.1Hz, 17-H ), 1.20 (3H, d, si 6.4Hz, I4-H3), 3.97 (OCH3), δ.δ9 (IH, d, si 3.7Hz, 4'-H), 6.01 (IH, s, 2-H), and 7.29 (IH, d, si 3.7Hz, 3'-H); δc (CD3OD) 12.3 (C-17), 20.4 (C-14), 33.0 (C-9), 40.6 (C-4), 41.7 (C-8), 43.8 (C-12), δ6.9 (C-10), δ8.9 (OCH3), 61.3 (C-11), 66.δ (C-16), 69.7 (C-6), 70.8 (C-13), 71.5 (C-7), 74.4 and 75.δ 0 (C-δ), 8δ.6 (C-4'), 96.7 (C-2), 122.3 (C-3'), 142.2 (C-2'), 166.4 (C-δ'), 178.2 (C-1), and 187.0 (C-3); m/z (NH3 DCI) 427 (MH ⁺ , 100%); rn/z 426 (M ⁺ , 3%), 140 (60), and 12δ (100). (Found: M ⁺ , 426.1892. C2XH30O9 requires M, 426.1890). The n.m.r. spectra indicated that the title compound was mainly in the enolic form, but contained 20-40% ofthe diketone. 5

Example 30

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-(piperidin-l-vP-

pyrimidin-δ-yl)but-l-yll-δS-(2S.3S-epoxy-5S-hvdroxy-4S- methylhexyPtetrahvdropyran

a) 2-(Piperidin-l-vPpyrimidine-5-carboxaldehvde δ δ-Bromo-2-chloropyrimidine was converted to δ-bromo-2-(piperidin-l- yPpyrimidine using the method of Nasielski et al (Tetrahedron 1972, 28., 3767). Using the method described in 21a, δ-bromo-2-(piperidin-l- yPpyrimidine (3.63g, lδmmol) was converted to the title compound (1.23g, 10 43%); δπ (CDCI3) l.δ-1.8 (6H, m, 3',4',δ'-CH ₂ ), 3.8-4.1 (4H, m, 2 x NCH ₂ ), 8.65 (2H, s, 4' and 6'-H), and 9.7 (IH, s, CHO).

b) 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-2-oxo-4-(2- (piperidin-l-vPpyrimidin-δ-yl)but-l-yl1-δS-(2S.3S-epoxy-δ S- lδ trimethylsilyloxy-4S-methylhexyPtetrahvdropyran

Using the method described in δa, tristrimethylsilylmonone (1.038g, 2mmol) and 2-(piperidin-l-yl)pyrimidine-δ-carboxaldehyde (0.421g, 2.2mmol) were reacted to give the title compoimd (1.140g, 80%); δg 0 (CDCI3) inter alia 0.90 (3H, d, si 7.0Hz, 17-H ₃ ), 1.19 (3H, d, s∑ 6.4Hz, I4-H3), 1.48-1.90 (9H, m, 9-H ₂ , 8-H, 3 x CH ₂ ), 3.72-3.98 (7H, m, 16,13,7-H and 2 x NCH ₂ ), 4.98-δ.08 (IH, m, l-H), and 8.30 (2H, s, 4' and 6'-H); m/z (NH3 DCI) 710 (MH+, 20%), 192 (100), and 91 (82); m/z 710 (MH+, 3%), 709 (M ⁺ , 2), 191 (70), 129 (82), and 117 (100). (Found: M ⁺ , δ 709.3981. C34Hg ₃ N3θ ₇ Si3 requires M, 709.3974).

c) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(2- (piperidin-l-yPpyrimidin-δ-vPbut-l-yll-δS-(2S.3S-epoxy-δS - trimethylsilyloxy-4S-methylhexyPtetrahvdropyran

30

Using the method described in 6b, the product from 30b (1.12g, l.δ8mmol) in benzene (70ml) was reacted with manganese dioxide (3.0g) for 4 hours to give the title compound (0.681g, 61%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.0Hz, I7-H3), 1.19 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 1.5-1.9. (9H, m, 9-H ₂ , 8-H,

35 3 x CH ₂ ), 3.7-3.95 (7H, m, 16,13,7-H and 2 x NCH ), 6.06 (IH, s, 2-H), and 8.77 (2H, s, 4' and 6'-H); m/z (NH3 DCI) 708 (MH+, 7%), 147 (97), 91 . (100), and 74 (95); m/z 707 (M+, 1%), 190 (98), and 73 (100). (Found: M+, 707.3820. C34HgχN3θ ₇ Si3 requires M, 707.3817). The xH n.m.r.

spectrum indicated that the title compound was essentially in the enolic form.

d) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-fpiperidin-l-vP- 5 pyrimidine-δ-vPbut-l-yll-δS-(2S.3S-epoxy-δS-hvdroxy-4S- methylhexyPtetrahvdropyran

Using the method described in δc, the product from 30c (O.βδδg, 0.92mmol) was deprotected to give the title compound (0.388g, 8δ%);

10 found C, 60.72; H, 7.7δ; N, 8.49%. C25H37N3O7 requires C, 61.08; H, 7.δ9; N, 8.δδ%; v _m∑LX (KBr) 3466, 1609, 1641, 1269, 12δ4, and 803cm-l; λmax (EtOH) 348nm (ε _m 33,937); δg (CDCI3/CD3OD) inter alia 0.93 (3H, d, s∑ 7.1Hz, I7-H3), 1.22 (3H, d, s∑ 6.3Hz, 14-H ₃ ), l.δ8-1.90 (8H, m, 9-H ₂ and 3 x CH ₂ ), 3.74-4.0 (8H, m, δ,7,13,16-H and 2 x NCH ₂ ), 6.08 (IH, s, lδ 2-H), and 8.77 (2H, s, 4" and 6'-H); δc (CDCI3/CD3OD) 12.4 (C-17), 20.4 (C-14), 24.8 (C-4"), 26.0 (C-3" and δ"), 31.9 (C-9), 40.0 (C-8), 41.3 (C-4), 42.7 (C-12), 45.4 (C-2" and 6"), 5δ.9 (C-10), 61.1 (C-11), 6δ.8 (C-16), 68.7 (C-6), 70.2 (C-7), 70.6 (C-13), 74.3 (C-δ), 9δ.6 (C-2), 116.3 (C-δ'), 168.0 (C-4 ^* and 6'), 161.9 (C-2'), 182.1 (C-1), and 190.8 (C-3); m z 491 (M ⁺ , 7%), 0 232 (36), 206 (54), 204 (56), and 190 (100). (Found: M ⁺ , 491.2602.

C25H37N3O7 requires M, 491.2630). The l-H n.m.r. spectrum indicated ^• that the title compound was essentially in the enolic form.

Example gl 5

3R.4R-Dihvdroxy-2S-[2.4-dioxo-4-(l-methyl-2-methylthio- imidazol-4-vPbut-l-yl1-6S-(2S.3S-epoxy-6S-hvdroxy-4S- methylhexyPtetrahydropyran

0 a) Ethyl l-methvI-2-methylthioimidazole-4-carboxylate

Ethyl 2-mercaptoimidazole-4(5)-carboxylate (lO.Og, 58mmol) was dissolved in dry DMF (200ml), and sodium hydride (80% in oil, 3.5g, llβmmol) added slowly with cooling. The mixture was stirred for lh under 5 argon, cooled in an ice bath, and methyl iodide (14.4ml, 232mmol) added. The reaction was then stirred overnight, diluted with water (200ml) and extracted with ethyl acetate (6 x 100ml). The combined organic extracts were washed with brine, dried and evaporated. The crude product was

separated by flash chromatography eluting with 32-44% ethyl acetate in hexane, to give (a) the 1,2,5-isomer (3.742g, 32%), and (b) the title compound (4.261g, 37%); δ _H (CDCI3) 1.35 (3H, t, s∑ 7Hz, CH3). 2.6 (3H, s, SCH3), 3.6 (3H, s, NCH ₃ ), 4.3 (2H, q, s∑ 7Hz, CH ₂ ), and 7.55 (IH, s, δ-H). δ The assignments of the structures were confirmed by n.O.e. studies.

b) l-Methyl-2-methylthioimidazole-4-carboxaldehvde

Ethyl l-methyl-2-methylthioimidazole-4-carboxylate (1.97g, 9.8mmol) was 10 dissolved in dry THF (80ml) under argon, then diisobutylaluminium hydride (1.0M in toluene, 22ml, 22mmol) was added slowly. The mixture was stirred at room temperature for lV_h, and at reflux for V_h. The reaction was cooled, quenched with methanol (2δml) and saturated sodium sulphate (31ml), and stirred for lδ minutes. The mixture was then lδ filtered, washing well with ethyl acetate, and the filtrate extracted with ethyl acetate (x4). The combined organic extracts were dried and evaporated to give crude 4-hydroxymethyl-l-methyl-2- methylthioimidazole (1.43g, 92%).

20 This material was dissolved in dry chloroform (70ml), activated manganese dioxide (1.5g) added and the mixture stirred for 30 minutes. Only a little reaction had occurred, so 4A sieves (4g) were added, followed portionwise by more manganese dioxide (3.5g). After stirring overnight the reaction was complete. The mixture was filtered, washing the

2δ manganese dioxide thoroughly with chloroform and dichloromethane, and the filtrate evaporated. The residue was purified by column chromatography on silica (38g), eluting with 90-100% ethyl acetate in hexane, to give the title compound as a white solid (1.183g, 84%; 77% overall); υ _max (CH ₂ C1 ₂ ) 1680, 1640, 1320, and 1130cm- ¹ ; δg (CDCI3)

30 2.68 (3H, s, SCH3), 3.66 (3H, s, NCH3), 7.68 (IH, s, δ-H), and 9.7 (IH, s, CHO).

c) 3R.4R-Bistrimethylsilyloxy-2-r4-hvdroxy-4-(l-methyl-2- methylthioimidazol-4-vP-2-oxobut-l-yll-δS-(2S.3S-epoxy-6S-

3δ trimethylsilyloxy-4S-methylhexyPtetrahvdropyran

Using the method described in δa, tristrimethylsilylmonone (1.038g, 2mmol) and l-methyl-2-methylthioimidazole-4-carboxaldehyde were

reacted to give the title compound (l.OδOg, 78%); δπ (CDCI3) inter alia 0.89 (3H, d, s∑ 7.0Hz, 17-H ₃ ), 1.19 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 2.67 (3H, s, SCH3), 3.58 (3H, s, NCH3), 5.10-6.18 (IH, m, l-H), and 6.88 (IH, s, 5'-H); m/z (NH3 DCI) 675 (MH+, 40%) and 157 (100); m/z 674 (M ⁺ , 1%), l-δ6 δ (δO), 129 (62), and 117 (100). (Found: M ⁺ , 674.3267. C30H58N2O7SS-3 requires M, 674.3273).

d) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(l- methyl-2-methvIthioimidazol-4-yl)but-l-vn-5S-(2S.3S- 0 epoxy-5S-trimethylsilyloxy-4S-methylhexyPtetrahvdropyran

Using the method described in 6b, the product from 31c (1.03g, 1.50mmol) in benzene (70ml) was reacted with manganese dioxide (2.0g) for 2 hours to give the title compound (0.656g, 64%); δfi (CDCI3) inter alia 0.89 (3H, d, s∑7.0Hz, I7-H3), 1.19 (3H, d, si 6.3Hz, 14-H ₃ ), 2.66 (3H, s, SCH3), 3.62 (3H, s, NCH3), 6.44 (IH, s, 2-H), and 7.55 (IH, s, 5'-H); m/z (NH3 DCI) 673 (MH+ 100%); m/z 673 (MH+, 2%), 672 (M+, 1%), i97 (30), 155 (53), 117 (50), and 73 (100). (Found: M ⁺ , 672.3125. C3oH ₅ gN2θ7SS_3 requires M, 672.3116).

e) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(l-methyl-2-methyl- thioimidazol-4-vPbut-l-yl1-5S-(2S.3S-epoxy-6S-hvdroxy-4S- methylhexyl )tetrahvdropyran

Using the method described in 5c, the product from 31d (0.240g,

0.36mmol) was deprotected to give the title compound (0.140g, 85%); υ _max (KBr) 3426, 1616, 1451, 1379, 1332, 1135, 1108, and 1055cm- ¹ ; λ _max (EtOH) 328nm (ε _m 17,229); δg (CDCI3) inter alia 0.93 (3H, d, s∑ 7.1Hz, 17-H3), 1.22 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 2.66 (3H, s, SCH3), 3.64 (3H, s, NCH3), 6.44 (IH, s, 2-H), and 7.58 (IH, s, 5'-H); δc (CDCI3) 12.6 (C-17),

16.1 (SCH3), 20.7 (C-14), 31.6 (C-9), 33.6 (NCH3), 39.5 (C-8), 42.2 (C-4), 42.8 (C-12), 55.7 (C-10), 61.3 (C-11), 65.6 (C-16), 69.1 (C-6), 70.3 (C-7),

71.2 (C-13), 73.9 (C-δ), 96.9 (C-2), 126.3 (C-5"), 137.9 (C-4'), 146.7 (C-2"), 178.5 (C-1), and 193.2 (C-3); m/z (NH3 DCI) 457 (MH+, 100%) ^' ; m/z 456 (M ⁺ , 2%), 170 (7δ) and 15δ (100). (Found: M+, 456.1922. C2XH32N2O7S requires M, 656.1930). The ¹ H n.m.r. spectrum indicated that the title compound was mainly in the enolic form (17% ofthe diketone present).

Example 32

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-methoxyphenvPbut-l-yll - δS-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyPtetrahvdropyran δ a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(2-methoxyphenyl)- 4-hvdroxy-2-oxobut-l-yll-5S-(2S.3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyPtetrahvdropyran

10 Using the method described in δa, tristrimethylsilylmonone (0.72δg,

1.4mmol) and 2-methoxybenzaldehyde (218mg, 1.68mmol) were reacted to give the title compound (600mg, 65%); δg (CDCI3) inter alia 0.89 (3H, d, s∑ 7.1Hz, I7-H3), 1.19 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 3.83 (3H, s, OMe), 4.08-4.19 (IH, m, H-5), δ.36-5.60 (IH, m, H-l), 6.85 (IH, d, I 8.1Hz, H-3'), 6.98 (IH, lδ t, J 7.2Hz, H-δ'), 7.24 (IH, dt, s∑ 1.6 and 8.0Hz, H-4'), 7.48 (IH, d, s∑ 7.4Hz, H-6'). (Found: M+, 664.3456. C32H ₅ 8θ ₈ Si3 requires M, 654.3440).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(2- methoxyphenyPbut-l-vIl-5S-(2S.3S-epoxy-5S-trimethyl-

20 silyloxy-4S-methylhexyPtetrahvdropyran

Using the method described in 6b, the product from 32a (600mg, 0.92mmol) in benzene (50ml) was reacted with manganese dioxide (1.5g) for 3 hours to give the title compound (260mg, 43%); δg (CDCI3) inter alia 25 0.89 (3H, d, s∑ 7.0Hz, 17-H ₃ ), 1.19 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 3.92 (3H, s, OMe), 6.53 (IH, s, 2-H), 6.96 (IH, d, s∑ 8.3Hz, 3 ^* -H), 7.02 (IH, t, j∑ 7.7Hz, 5'-H), 7.43 (IH, dt, s∑ 1.8 and 8.3Hz, 4'-H), 7.88 (IH, dd, s∑ 1.8 and 7.8Hz, 6'-H). (Found: M ⁺ , 652.3293. C3 ₂ H5g0 ₈ Si3 requires M, 652.3283).

30 c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-methoxyphenvP- but-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyPtetra- hvdropyran

Using the method described in 5c, the product from 32b (250mg, 35 0.38mmol) was deprotected to give the title compound (142mg, 85%); υ _max (KBr) 3431, 1718, 1603, 1489cm"l; λ _max (EtOH) 326.5nm (ε _m 12,445), 306 (11,456), 253.5 (4,740); δg (CDCI3) inter alia 0.94 (3H, d, s∑ 7.0Hz, I7-H3), 1.20 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 3.92 (3H, s, OMe), 6.58 (IH, s, 2-H),

6.97 (IH, d, s∑ 8.3Hz, 3'-H), 7.04 (IH, t, si 7.7Hz, 5'-H), 7.45 (IH, dt, si 1.8 and 8.3Hz, 4'-H), 7.91 (IH, dd, si 1-8 and 7.8Hz, 6'-H); δc (CDC1 ₃ ) 12.7 (C-17), 20.7 (C-14), 31.6 (C-9), 39.δ (C-8), 42.8 (C-12), 43.3 (C-4), 55.7 (C-10), δδ.7 (ArOMe), 61.3 (C-11), 65.6 (C-16), 69.3 (C-7), 70.3 (C-6), 71.3 (C-13), 73.7 (C-5), 102.4 (C-2), 111.7 (C-5'), 123.4 (C-D, 130.2 (C-3'), 133.2 (C-6"), 168.6 (C-2'), 180.1 (C-1), 196.7 (C-3). (Found: M ⁺ , 437.2164. C23H33O8 requires M, 437.2175). The IH n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 33

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-methylthiophenvPbut-l- yl1-5S- (2S.3S-epoxy-5S-hvdroxy-4S-methylhexyPtetrahvdropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(4-methylthio- phenvP-4-hvdroxy-2-oxobut-l-yll-5S-(2S.3S-epoxy-6S- trimethyl-siIvIoxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 5a, tristrimethylsilylmonone (2.175g, 4.2mmol) and 4-methylthiobenzaldehyde (0.64ml, 4.8mmol) were reacted to give the title compound (2.12g, 7δ%); δg (CDCty inter alia 0.89 (3H, d, si 7.0Hz, I7-H3), 1.19 (3H, d, si 6.3Hz, 14-H ₃ ), 2.48 (3H, s, ArSMe), 4.05- 4.18 (IH, m, 5-H), 5.08-5.20 (IH, m, l-H), 7.20-7.34 (4H, m, Ar); m/z (FAB) 693 (_yTNa ⁺ ).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(4- methvIthiophenvPbut-l-yl1-5S-(2S.3S-epoxy-5S-trimethyl- silyloxy-4S-methylhexyPtetrahvdropyran

Using the method described in 6b, the product from 33a (2.12g, 3.16mmol) in benzene (150ml) was reacted with manganese dioxide (4.2g) for 2 hours to give the title compound (1.3g, 62%); δg (CDCI3) inter alia 0.89 (3H, d, s∑ 7.1Hz, I7-H3), 1.19 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 2.52 (3H, s, ArSMe), 6.23 (IH, s, 2-H), 7.26 (2H, d, 8.6Hz, 3',5'-H ₂ ), 7.80 (2H, d, s∑ 8.6Hz, 2',6'-H ₂ ). (Found: M ⁺ , 668.3060. C32H ₅ g0 ₂ SSi requires M, 668.3055).

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-methylthio- phenvPbut-l-vn-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methyl-

hexvl Hetrah vdrop vran

Using the method described in δc, the product from 33b (2δ0mg, 0.37mmol) was deprotected to give the title compound (144mg, 8δ%); υ _max δ (KBr) 3425, 1591, 1488, 1436, 1267cm- ¹ ; λ _max (EtOH) 337nm

(ε _m 27,090), 239 (5,680); δg (CDC1 ₃ ) inter alia 0.94 (3H, d, si 7.0Hz, I7-H3), 1.21 (3H, d, si 6.3Hz, 14-H ₃ ), 2.35 (3H, s, ArSMe), 6.23 (IH, s, 2-H), 7.26 (2H, d, si 8.6Hz, 3',5'-H ₂ ), 7.80 (2H, d, s∑ 8.6Hz, 2',6'-H ₂ ); δc (CDCI3) 11.9 (C-17), 14.5 (ArSMe), 20.0 (C-14), 31.5 (C-9), 39.6 (C-8), 41.9 0 (C-4), 42.3 (C-12), 5δ.5 (C-10), 60.7 (C-11), 66.4 (C-16), 68.3 (C-7), 69.9 (C-6), 70.3 (C-13), 73.8 (C-5), 96.6 (C-2), 125.1 (C-3',5 ^* ), 127.2 (C-2',6'), 130.5 (C-1'), 144.9 (C-4'), 181.9 (C-1), 194.1 (C-3). (Found: M ⁺ , 452.1867. C23H32O7S requires M 452.1869). The IH n.m.r. spectrum indicated that the title compound was essentially in the enolic form. 5

Example 34

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-methylsulphinyl-phenvP - but-l-yll-δS-(2S.3S-epoxy-5S-hvdroxy-4S-methyl-hexyP- 0 tetrahydropyran

Using the method described in 23, the product from 33c (200mg, 0.3mmol) was reacted to give the pure product (17δmg, 85%). This material was deprotected using the method described in 5c to give the title compound 5 (154mg, 4δ%); υ _max (KBr) 3417, 1600, 1560, 1451, 1292cm-l; λ _max

(EtOH) 317nm (ε _m 17,420), 225 (7,480); δg (CDCI3) inter alia. 0.90 (3H, d, s∑ 7.1Hz, I7-H3), 1.22 (3H, d, J 6.3Hz, 14-H ₃ ), 2.77 (3H, s, ArS(O)Me), 6.30 (IH, s, 2-H), 7.72 (2H, d, si 8.4Hz, 3',5'-H ₂ ), 8.03 (2H, d, si 8.4Hz, 2',6'-H ₂ ); δc (CDCI3) 12.7 (C-17), 20.6 (C-14), 31.6 (C-9), 39.6 (C-8), 42.8 0 (C-12 and C-4), 43.6 (ArS(O)Me), 65.6 (C-10), 61.1 (C-11), 65.6 (C-16), 66.8 (C-7), 70.3 (C-6), 71.2 (C-13), 73.7 (C-5), 98.0 (C-2), 123.9 (C-3',5'), 128.0 (C-2',6'), 137.2 (C-1'), 149.5 (C-4 ^* ), 180.1 (C-1), 196.7 (C-3); m/z (FAB) 491 (MNa+), 469 (MH+). The lH n.m.r. spectrum indicated that the title compound was essentially in the enolic form. 5

Example 35

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-f4-methylsulphonyl-phenyl )-

but-l-vP-6S-(2S.3S-epoxy-5S-hvdroxy-4S-methyl-hexyl)- tetrahvdropyran

Using the method described in 24, the product from 34c (200mg, 0.3mmol) was reacted to give the pure product (lδδmg, 74%). This material was deprotected using the method described in δc to give the title compound (90mg, 92%); υ _max (KBr) 3496, 3438, 1622, 1602cm"l; λ _max (EtOH) 317.5nm (ε _m 14,610), 239 (8,540); δg (CD3OD) inter alia 0.94 (3H, d, s∑ 7.1Hz, I7-H3), 1.21 (3H, d, si 6.3Hz, 14-H ₃ ), 3.13 (3H, s, ArS0 ₂ Me), 6.37 (approx. IH, s, exch, 2-H), 7.92-8.17 (4H, m, Ar); m/z (FAB) 485 (MH+). The H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 36

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(3-cvanophenvPbut-l-vn- 5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetrahvdropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(3-cvanophenvP-4- hvdroxy-2-oxobut-l-yl1-5S-(2S.3S-epoxy-5S-trimethylsilyloxy- 4S-methylhexyl)tetrahvdropyran

Using the method described in 5a, and on the same scale, 3- cyanobenzaldehyde (4.19mg, 3.2mmol) was reacted to give the title compound (1.46g, 80%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.1Hz,

I7-H3), 1.20 (3H, d, si 6.3Hz, 14-H ₃ ), 5.13-5.26 (IH, m, l-H), 7.48-7.62 (3H, m), 7^70 (IH, s, 2'-H); m/z (NH3 DCI), 667 (MNH4+, 50%), 650 (MH+, 10%), 536 (100).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(3- cvanophenvPbut-l-yll-δS-(2S.3S-epoxy-δS-trimethylsilyloxy- 4S-methylhexyPtetrahvdropyran

Using the method described in 6b, the product from 36a (1.4δg, 2.23mmol) in benzene (120ml) was reacted with manganese dioxide (2.18g) for 3V_h to give the title compound (574mg, 40%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.1Hz, I7-H3), 1.20 (3H, d, 6.4Hz, 14-H ₃ ), 6.26 (IH, s, 2-H), 7.68 (IH, t, si 7.8Hz, 5'-H), 7.79 (IH, dd, J 1.2 and 7.7Hz, 4 ^* -H), 8.10 (IH, dd, 1 1.0 and

6.7Hz, 6'-H), 8.16 (IH, d, s∑ 1.4Hz, 2'-H); m/z 648 (MH ⁺ ).

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(3-cvanophenvPbut- l-vn-5S-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyl)tetra- hvdropyran

Using the method decribed in δc, the product from 36b (δδOmg, O.δδmmol) was deprotected to give the title compound (315mg, 86%); υ _max (KBr) 3439, 2232, 1610, 1670, 1452cm"l; λ _max (EtOH) 312.δnm (ε _m 14,620), 239.5 (9,990); δg (CDC1 ₃ ) inter alia 0.94 (3H, d, _s ∑ 7.0Hz, 17-H ₃ ) 1.22 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 6.27 (IH, s, 2-H), 7.60 (IH, t, s∑ 7.8Hz, 5'-H), 7.80 (IH, d, with further fine coupling, s∑ 7.8Hz, 4'-H), 8.10 (IH, d, with further fine coupling, s∑ 8.0Hz, 6'-H), 8.16 (IH, d, s∑ 1.2Hz, 2'-H); δc (CDCI3) 12.9 (C-17), 21.0 (C-14), 31.8 (C-9), 39.9 (C-8), 42.9 (C-4), 43.0 (C-12), 65.8 (C-10), 61.4 (C-11), 65.8 (C-16), 69.0 (C-6), 70.5 (C-13), 71.5 (C-7), 74.1 (C-5), 98.0 (C-2), 113.3 (C-1'), 118.2 (C-3"), 129.8 (C-2'), 130.9 (C-4'), 131.3 (C-6'), 135.4 (C-5'), 136.0 (CN), 179.6 (C-3), 196.9 (C-1). (Found: M+ 431.1949. C23H29NO7 requires M 431.1944). The IH n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 37

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-trifluoromethoxy- phenvPbut-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methyl- hexyP-tetrahvdropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(4-trifluoro- methoxyphenvP-4-hvdroxy-2-oxobut-l-yll-5S-(2S.3S-epoxy-

5S-trimethylsilyloxy-4S-methylhexyPtetrahvdropyran

Using the method described in 5a, tristrimethylsilymonone (1.45mg, 2.8mmol) and 4-trifluoromethoxybenzaldehyde (608mg, 3.2mmol) were reacted to give the title compound (1.52g, 76%); δg (CDCI3) inter alia 0.93 (3H, d, s∑ 7.1Hz, I7-H3), 1.23 (3H, d, J 6.4Hz, 14-H ₃ ), 4.07-4.18 (IH, m, 5-H), 5.10-5.22 (IH, m, l-H), 7.18-7.28 (2H, m, 3',5'-H ₂ ), 7.38-7.49 (2H, m, 2 ^* ,6'-H ₂ ); m/z (NH3 DCI) 726 (MNH4+, 30%), 90 (100%). [Found: MH+. 709.3239. C3χH ₅ 5θ ₈ F ₃ Si3 requires MH, 709.3235.]

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(4- trifluoromethoxyphenyPbut-l-yl1-5S-(2S.3S-epoxy-5S-tri- methylsilvIoxy-4S-methylhexyPtetrahydropyran

Using the method described in 6b, the product from 37a (l.δg, 2.15mmol) in benzene (120ml) was reacted with manganese dioxide (3g) for 1V_ hours to give the title compound (772mg, 51%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.1Hz, I7-H3), 1.20 (3H, d, 16.4Hz, 14-H ₃ ), 4.08-4.20 (IH, m, 5-H), 6.24 (IH, s, 2-H), 7.22-7.34 (2H, m, 3',5'-H ₂ ), 7.93 (2H, d, 8.8Hz, 2\6'-H ₂ ); m/z 707 (MH+, 8%), 73 (100). [Found: ME, 707.3072. C31H59O8F3S-3 requires ME, 707.3079.]

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-trifluoro- methoxyphenvPbut-l-yn-5S-(2S.3S-epoxy-5S-hvdroxy-4S- methylhexyl )tetrahvdropyran

Using the method described in 5c, the product from 37b (750mg, 1.06mmol) was deprotected to give the title compound (350mg, 74%); -max (KBr) 3496, 1624, 1583, 1506, 1441cm" ¹ ; λ _ma χ (EtOH) 311nm (ε _m 16,860), 243.5 (6730); δg (CDCI3) inter alia 0.93 (3H, d, si 7.0Hz,

I7-H3), 1.21 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 6.24 (IH, s, 2-H), 7.24-7.35 (2H, m, 3',5'-B ₂ ), 7.92 (2H, d, s∑ 8.8Hz, 2',6'-H ₂ ); δc (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.6 (C-9), 39.7 (C-8), 42.7 (C-4), 42.9 (C-12), 55.7 (C-10), 65.7 (C-16), 69.0 (C-7), 70.3 (C-6), 71.4 (C-13), 73.9 (C-5), 97.5 (C-2), 120.6 (C-3',5 ^* ), 129.0 (C-2',6 ^* ), 132.9 (C-1 ^* ), 152.2 (C-4 ^* ), 180.9 (C-1), 196.0 (C-3); /z 491 (MH+, 30%), 189 (100). [Found: M2+, 491.1893. C23H30O8F3 requires MH. 491.1893.] The l-H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 38

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-fluorophenvPbut-l-yll- 5S-(2S.3S-epoxy-5S-hydroxy-4S-methylhexyPtetrahvdropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-(4-fluorophenvP-4- hvdroxy-2-oxobut-l-yl1-5S-(2S.3S-epoxy-5S-trimethylsilyloxy- 4S-methylhexyl )tetrah vdropyran

Using the method described in 5a, tristrimethylsilylmonone (1.4δg, 2.8mmol) and 4-fluorobenzaldehyde (0.34ml, 3.2mmol) were reacted to give the title compound (l.δg, 83%); δg (CDCI3) inter alia 0.89 (3H, d, s∑ 7.1Hz, I7-H3), 1.19 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 4.08-4.17 (IH, m, 5-H), 5.11- 5.22 (IH, m, l-H), 7.03 (2H, t, s∑ 8.7Hz, 3',5'-H ₂ ), 7.30-7.41 (2H, m, 2 ^, ,6'-H ₂ ); m/z (NH3 DCI) 660 (MNH4+, 52%), 643 (MH+, lδ), 90 (100). [Found: ME+, 643.3811. C3χH ₅₅ θ7FSi3 requires MH, 643.3318.]

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(4-fluorophenyl)b ut-l- vn-6S-(2S.3S-epoxy-6S-trimethylsilyloxy-4S-methylhexyPtetrah vdropyran

Using the method described in 6b, the product from 38a (l.δg, 2.34mmol) in benzene (70ml) was reacted with manganese dioxide (3.0g) for 13 _ hours to give the title compound (890mg, 69%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.1Hz, I7-H3), 1.20 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 4.06-4.18 (IH, m, 5-H), 6.22 (IH, s, 2-H), 7.13 (2H, t, s∑ 8.7Hz, 3',δ'-H2), 7.91 (2H, dd, s∑ 5.4 and 8.7Hz, 2',6'-H ₂ ); m/z (NH3 DCI) 641 (MH+). [Found: MH+, 641.3167. C3χH ₅₄ θ7FSi3 requires MH, 641.3161.]

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-fluorophenvPbut-l-vn-5S- ⁽ 2S.3S-e ^p oxy-δS-hvdroxy-4S-methylhexyPtetrahvdropyran

Using the method described in 5c, the product from 38b (400mg, 0.625mmol) was deprotected to give the title compound (21δmg, 81%); -max (KB^ ³⁴²⁷ , 1603, 1605, 1452cm ^" l; λ _ma χ (EtOH) 310nm

(ε _m 15,800), 248.5 (5,785); δg (CDCI3) inter alia 0.93 (3H, d, s∑ 7.1Hz, I7-H3), 1.21 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 6.22 (IH, s, 2-H), 7.13 (2H, t, s∑ 8.7Hz, 3 ^* ,5'-H ₂ ), 7.90 (2H, dd, s∑ 5.4 and 8.7Hz, 2',6'-H ₂ ); δc (CDCI3) 12.8 (C-17), 20.8 (C-14), 31.6 (C-9), 39.7 (C-8), 42.6 (C-4), 42.9 (C-12), 55.7 (C-10), 61.3 (C-11), 65.7 (C-16), 69.0 (C-7), 70.3 (C-6), 71.4 (C-13), 73.9 (C-5), 97.2 (C-2), 115.8 (d, J 23Hz, C-3',5'), 129.6 (d, J 9Hz, C-2',6'), 130.7 (d, s∑ 3Hz, C-1'), 165.4 (d, s∑ 252Hz, C-4'), 181.8 (C-1), 195.1 (C-3); m/z (NH3 DCI) 425 (MH+, 15%), 79 (100). [Found: MH+. 425.1968. C22H30O7F requires ME, 425.1976.] The IH n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

EXAMPLE 39

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-hvdroxyphenyl)but-1 -vn-δS-(2S.3S- epoxy-5S-hydroxy-4S-methylhexyPtetrahvdropyran

al 4-Triethylsilyloxybenzaldehvde δ

A suspension of 4-hydroxybenzaldehyde (610mg, δmmol) in dichloromethane (30ml) at 5° under argon was treated with triethylamine (0.84ml, 6mmol) followed by triethylsilyl chloride (1ml, 6mmol). After 30 minutes ether was added and the mixture filtered through Kieselguhr. The filtrate was washed with brine, dried (MgS04) and evaporated to give the title aldehyde (l.lg) as an orange oil; δ(CDC_3) 0.65-1.42 (15H, m), 6.96 (2H, d, s∑ 9Hz), 7.83 (2H, d, si 9Hz), 9.95 (IH, s). This material was sufficiently pure for further synthetic manipulations.

bl 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-2-oxo-4-(4-triethyl - silyloxyphenyPbut-l-yll-5S-(2S.3S-epoxy-5S-trimethylsilyloxy -4S- meth ylhexyl )tetrahydropyran

Using the method described in 5a, 4-triethylsilyloxy-benzaldehyde (520mg, 2mmol) and tris trimethylsilylmonone (1.04g, 2mmol) were reacted to give the title compound (1.2g, 80%); δg (CDCI3) inter alia 0.66- . 0.82 (6H, m, Si(CH ₂ CH ₃ )3), 0.89 (3H, d, si 7.0Hz, 17-H ₃ ), 0.99 (9H, t, si

7.4Hz, Si(CH ₂ CH3) ₃ ), 4.08-4.17 (IH, m, 5-H), 5.05-5.16 (IH, m, l-H), 6.84

(2H, d, si 8.5Hz, 3 ^* ,5 ^* -H2), 7.18-7.27 (2H, m, 2',6'-H ₂ ); m/z (FAB; 3- NOBA/Na) 777 (MNa+, 100%).

__i 3R.4R-Bistrimethylsilyloxy-2S-[2.4-dioxo-4-(4-triethylsilyro xy- phenvPbut-l-yl1-5S-(2S.3S-epoxy-5S-trimethvIsilyloxy-4S- methylhexyl )tetrahy drop yran

Using the method described in 6b, the product from 39b (1.2g) in benzene (70ml) was reacted with manganese dioxide (3.4g) for 3 hours to give the title compoimd (598mg, 50%); δg (CDCI3) inter alia 0.68-0.82 (6H, m, Si(CH ₂ CH3)3), 0.90 (3H, d, si 7.0Hz, 17-H ₃ ), 1.00 (9H, t, si 7.4Hz, Si(CH ₂ CH3) ₃ ), 1.20 (3H, d, si 6.4Hz, 14-H ₃ ), 6.20 (IH, s, 2-H), 6.88 (2H, d, si 8.7Hz, 3',5'-H2), 7.81 (2H, d, 8.7Hz, 2',6'-H ₂ ); m z (FAB; 3-NOBA/Na) 775 (MNa+, 40%), 235 (100%).

d_> 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-hvdro-rvphenvPhut-l-vn-5S - (2S.3S-epoxy-δS-hvdroxy-4S-methylhexyPtetrahvdropyran

Using the method described in 5c the product from 39c (598mg, O.δmmol) δ was deprotected to give the triethylsilylated title compound (264mg). This material was dissolved in tetrahydrofuran (THF) (δml) and treated with acetic acid (30μl, O.δmmol) and a solution of tetrabutylammonium fluoride trihydrate in THF (1M, O.δml, O.δmmol). After 20 minutes the mixture was diluted with ethyl acetate and washed with brine, dried, evaporated 0 and chromatographed on silica eluting with dichloromethane/ methanol mixtures to give the title compound containing 25% tetrabutyl ammonium acetate (234mg). This mixture was treated with ethyl acetate (10ml), water (5ml) and nonafluorobutane sulphonate (76mg). The organic phase was separated, washed with brine, dried and evaporated. 5 Chromatography eluting with dichloromethane/methanol mixtures gave the title compound (168mg) as a solid; v _max (KBr) 3385, 1604, 1508, 1455cm-l; λ _ma χ (EtOH) 326nm (ε _m 21,460); δg (dg-acetone) inter alia .0.92 (3H, d, s∑ 7.1Hz, 17-H ₃ ), 1.16 (3H, d, si 6.4Hz, 14-H ₃ ), 6.39 (IH, s, 2- H), 6.95 (2H, d, si 8.8Hz, 3',5'-H ₂ ), 7.90 (2H, d, si 8.8Hz, 2',6 ^* -H ₂ ); δc (dg- 0 acetone) 12.3 (C-17), 20.8 (C-14), 32.6 (C-9), 41.2 (C-8), 42.3 (C-4), 43.3 (C- 12), 55.6 (C-10), 60.4 (C-11), 66.0 (C-16), 69.4 (C-7), 70.1 (C-6), 71.1 (C-13), .75.1 (C-5), 96.7 (C-2), 116.3 (C-3',5 ^* ), 127.3 (C-1'), 130.2 (C-2',6 ^* ), 162.5 (C- 4'), 184.9 (C-1), 194.1 (C-3); m_z 440 (MNH +, 12%), 423 (MH+, 15%), 181 _. (100%). δ

EXAMPLE 40

3R.4R Dihvdroxy-2S-r4- ⁽ 4-allyloχyphenvP-2.4-dioxobut-l-yl1-δS-(2S.3S- 0 epoxy-5S-hydroxy-4S-methylhexyPtetrahvdropyran

} 4-Allyloxybenzaldehvde

A solution Of 4-allyloxybromobenzene (K. Mino et al. Synthesis. 1979, 688) 5 (l.δg, 7.δmmol) in THF (2δml) at -70° under argon was treated with a solution of n-butyllithium in hexane (1.5M, 5ml, 7.5mmol). After 30 minutes the reaction mixture was treated with dimethylformamide (0.88ml, 11.25mmol). After 10 minutes saturated ammonium chloride was

added and the mixture extracted with ethyl acetate. The organic phase was washed with brine, dried, evaporated and chromatographed on silica eluting with ethyl acetate/hexane mixtures to give the title compound (784mg) contaminated with ethyl acetate (16%); δg (CDCI3) inter alia 4.61 (IH, dd, si 2,6Hz), 4.93 (IH, dd, si 2,14Hz), 6.71 (IH, dd, si 6,14Hz), 7.12 (2H, d, si 9Hz), 7.88 (2H, d, s∑ 9Hz), 9.93 (IH, s). This material was used in further synthetic transformations.

__! 3R.4R-Bistrimethylsilyloxy-2S-r4-(4-allyloxyphenvP-4-hvdroxy -2- oxobut-l-yll-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyPtetrahvdropyran

Using the method described in 5a, and on the same scale, the product from 40a was reacted to give the title compound (815mg, 43%); δg (CDCI3) inter alia 0.89 (3H, d, s∑ 7.0Hz, 17-H ₃ ), 1.19 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 4.08- 4.17 (IH, m, 5-H), 4.42 (IH, d, si 6.0Hz, 2"-H), 4.75 (IH, d, si 13.7Hz, 2"-H), 6.63 (IH, dd, si 6.0, 13.7Hz, 1"-H), 6.98 (2H, d, s∑ 8.6Hz, 3 ^* ,5'-H ₂ ), 7.32 (2H, dd, si 8.6Hz, 2',6'-H ₂ ); m_z (NH3DCI) 684 (MNH4 ⁺ , 10%), 90 (100%).

£_ 3R.4R-Bistrimethylsilyloxy-2S-r4-(4-allyloxyphenyl)-2.4-diox obut-l- yll-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S-methylhexyPtetra hvdropyran

Using the method described in 6b, the product from 40b (800mg, 1.2mmol) in benzene (50ml) was reacted with manganese dioxide (1.2g) for 3 hours to give the title compound (437mg, 55%); δg (CDCI3) inter alia 0.89 (3H, d, si 7.0Hz, I7-H3), 1.19 (3H, d, si 6.2Hz, 14-H ₃ ), 4.08-4.17 (IH, m, 5-H), 4.56 (IH, d, si 6.0Hz, 2 ^* '-H), 4.89 (IH, d, si 13.6Hz, 2"-H), 6.21 (IH, s, 2-H), 6.68 (IH, dd, si 6.0, 13.6Hz, 1"-H), 7.09 (2H, d, 8.7Hz, 3 ^* ,5 ^* -H ₂ ), 7.88 (2H, d, si 8.7Hz, 2',6'-H ₂ ); m/z (FAB; 3-NOBA Na) 687 (M a+, 18%), 117 (100%).

ill 3R.4R-Dihvdroxy-2S-[4-(4-allvIoxyphenvP-2.4-dioxobut-l-yl1-5 S- (2S.3S-epoxy-5S-hvdroxy-4S-methylhexyPtetrahvdropyran

Using the method described in 5c, the product from 40c (370mg,

0.56mmol) was deprotected to give the title compound (218mg, 87%); v _m ax (KBr) 3436, 1600, 1502, 1440cm ^" l; λ _max (EtOH) 323nm (εm 22620); δg (CDCI3) inter alia 0.94 (3H, d, J 7.0Hz, 17-H ₃ ), 1.21 (3H, d, si 6.3Hz, 14-

H ₃ ), 4.59 (IH, dd, si 1.8, 6.1Hz, 2"-H), 4.91 (IH, dd, si 1-8, 13.6Hz, 2"-H), 6.22 (IH, s, 2-H), 6.69 (IH, dd, _s i 6.0, 13.6Hz, 1"-H), 7.05 (2H, d, s∑ 8.8Hz, 3',5'-H ₂ ), 7.88 (2H, d, s∑ 8.8Hz, 2',6'-H ₂ ); δ _C (CDC1 ₃ ) 12.7 (C-17), 20.8 (C- 14), 31.6 (C-9), 39.7 (C-8), 42.5 (C-4), 42.6 (C-12), 55.7 (C-10), 61.3 (C-11), 5 65.7 (C-16), 69.1 (C-7), 70.3 (C-6), 71.3 (C-13), 73.9 (C-5), 96.7 (C-2), 97.4 (C-2"), 116.5 (C-3',5'), 129.0 (C-1'), 129.3 (C-2',6'), 146.7 (C-1"), 160.2 (C-4'), 182.3 (C-1), 194.7 (C-3). [Found: M+ 448.2119. C24H32O8 requires M 448.2097]. The H n.m.r. spectrum indicated that the title compound was essentially in the enolic form. 0

EXAMPLE 41

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-methoxymethyloxophenyP but-l-vn- 5 5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyPtetrahvdropyran

al 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-2-oxo-4-(4- methoxymethyloxyphenvPbut-l-vn-5S-(2S.3S-epoxy-5S-trimethyls ilyloxy- 4S-methylhexyl Hetrahvdrop yran 0

Using the method described in 5a, tristrimethylsilylmonone (1.038g, 2mmol) and 4-methoxymethyloxobenzaldehyde (J.P. Yardley et al. Synthesis, 1976, 244) (365mg, 2.2mmol) was reacted to give the title compound (1.25g, 91%); δg (CDCI3) inter alia 0.89 (3H, d, s∑ 7.0Hz, 17- δ H3), 1.19 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 3.47 (3H, s, OMe), 4.02-4.18 (IH, m, 5- H), 5.03-5.15 (IH, m, l-H), 5.17 (2H, s, OCH ₂ 0), 7.02 (2H, d, s∑ 8.7 Hz, 3',5'-H ₂ ), 7.22-7.32 (2H, m, 2 ^* ,6'-H ₂ ); m_z (NH3, DCI), 702 (MNH4+, 8%), 239 (100%).

0 bj 3R.4R-Bistrimethylsilyloxy-2Sr2.4-dioxo-4-(4-methoxymethyl- oxyphenvPbut-l-yl]-δS-(2S.3S-epoxy-δS-trimethylsilyloxy-4S - methylhexyPtetrahvdropyran

Using the method described in 6b, the product from 41a (1.2g, 1.7δmmol) 5 in benzene (50ml) was reacted with manganese dioxide (l.δg) for 3 2 hours to give the title compound (750mg, 62%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.0Hz, I7-H3), 1.20 (3H, d, 6.3Hz, 14-H ₃ ), 3.49 (3H, s, OMe), δ.23 (2H, s, OCH ₂ 0), 6.21 (IH, s, 2-H), 7.07 (2H, d, J 8.9Hz, 3',5'-H ₂ ), 7.86

(2H, d, si 8.9Hz, 2 ^* ,6'-H ₂ ); m_z (NH ₃ , DCI) 683 (MNH ₄ +, 16%), 90 (100%).

c 3R.4R-Dihydroxy-2S-r2.4-dioxo-4-(4-methoxymethyloxyphenvPbut - l-yll-5S-(2S.3S-epoxy-6S-hydroxy-4S-methylhexyI)tetrahvdropy ran

Using the method described in δc, the product from 41b (7δ0mg) was deprotected to give the title compound (400mg, 78%); v _max (KBr) 3421, 1602, 1507, 1454cm-l; λ _ma χ (EtOH) 321.5nm (εm 20,160); δg (CDC1 ₃ ) inter alia 0.94 (3H, d, si 7.1Hz, 17-H ₃ ), 1.21 (3H, d, si 6.3Hz, M-H3), 3.49 (3H, s, OMe), 5.24 (2H, s, OCH ₂ 0), 6.21 (IH, s, 2-H), 7.08 (2H, d, si 8.9Hz, 3 ^* ,5 ^* -H ₂ ), 7.δ6 (2H, d, si 8.9Hz, 2",6 ^* -H ₂ ); δc (CDCI3) 12.8 (C-17), 20.8 (C- 14), 31.7 (C-9), 39.7 (C-8), 42.7 (C-4), 42.9 (C-12), 55.8 (C-10), 56.3 (OMe), 65.7 (C-11), 69.2 (C-7), 70.3 (C-6), 71.4 (C-13), 73.7 (C-5), 94.2 (OCH ₂ 0), 96.7 (C-2), 116.1 (C-3',5"), 127.9 (C-D, 129.2 (C-2',6'), 160.9 (C-4"), 182.7 (C-1), 194.4 (C-3); (Found: M+ 466.2198. C24H34O9 requires M

466.2203). The iH n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

EXAMPLE 42

3R.4R-Dihvdroxy-2S-r4-(but-l-vP-2.4-dioxobut-l-yl1-5S-(2S .3S-epoxy-5S- hvdroxy-4S-methylhexyPtetrahydropyran

al 2-[3R.4R-Bistrimethylsilyloxy-5S-(2S.3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyPtetrahvdropyran-2S-yl1methyl prop-2- ene-l-yl but-l-yl ketone

A 1.75:1 mixture ofthe product from la (900mg, l.δmmol) in THF (20ml) under argon at -70° was treated dropwise with a solution of n- butyllithium in hexane (l.δM, 2ml, 3mmol). After 30 minutes the mixture was worked-up and purified as in lb to give material containing the title compound (320mg); δg (CDCI3) inter alia 3.16 (2H, s, 2-H2), 4.90 (IH, s, 15-H), 5.03 (IH, s, 15-H).

bl 3R.4R-Bistrimethylsilyloxy-2S-r4-(but-l-vP-2.4-dioxobut-l-yl ]-5S- (2S.3S-epoxy-5S-trimethyl-silvIoxy-4S-methylhexyl1tetrahvdro pyran

The material from 41a (300mg) in dichloromethane (20ml) was ozonolysed and then purified as described in lc to give the title compound (93mg, 50%); δg (CDC1 ₃ ) inter alia 1.20 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 5.59 (IH, s, 2-H).

5 _Ξ1 3R.4R-Dihvdroxy-2Sr4-(but-l-vP-2.4-dioxobut-l-vn-6S-(2S.3S- epoxy-5S-hvdroxy-4S-methylhexyl)tetra-hvdropyran

Using the method described in 5c, the product from 41b (85mg, 0.14mmol) was deprotected to give the title compound (43mg, 78%); v _max (KBr) 3460, 0 1622, 14δ9cm-l; λ _ma χ (EtOH) 276nm (εm 9,295); δg (CDCI3) inter alia 1.20 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 5.60 (IH, s, 2-H); rn z (NH3, DCI) 387 (MH+, 100%). The iH n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

5 EXAMPLE 43

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-(2-hvdroxyethoχy}phen vPbut-l-vn- 5S-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyPtetrahvdropyran

0 al 4-(2-Triethylsilyloxyethoxy)benzaldehvde

A solution of 4-(2-hydroxyethoxy)benzaldehyde (J. Bernstein et al. JACS, 1951, IS, 906) (996mg, 6mmol) in dichloromethane (20ml) under argon at 5° was treated with triethylamine (1.17ml, 8.4mmol) followed by δ triethylsilyl chloride (1.21ml, 7.2mmol). After 30 minutes the mixture warmed to room temperature and after a further 30 minutes ether was added and the mixture was washed with 5% citric acid, saturated sodium bicarbonate and brine then dried and evaporated to give the crude title compound (l.δ3g, 91%); δg (CDCI3) 0.64 (6H, q, s∑ 7.δHz), 0.9δ (9H, t, si 0 7.δHz), 4.00 (2H, t, si 5.1Hz), 4.14 (2H, t, s∑ 5.1Hz), 7.02 (2H, d, s∑ 8.7Hz), 7.83 (2H, d, s∑ δ.7Hz), 9.90 (IH, s).

hi 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-2-oxo-4-(4-{2- triethylsiIyloxyethoxy)phenvPbu_-l-yl1-5S-(2S.3S-epoxy-5S- 6 trimethylsilyloxy-4S-methylhexyPtetrahvdropyran

Using the method described in 5a, tristrimethylsilylmonone (1.04g, 2mmol) and the product from 43a (560mg, 2mmol) were reacted to give the

title compound (1.33g, 83%); δg (CDCI3) 0.64 (6H, q, s∑ 8.0Hz, SiCH ₂ ), 0.90 (3H, d, si 7.0Hz, 17-H ₃ ), 0.98 (9H, t, si 8.0Hz, SiCH2M_.), 1-18 (3H, d, si 6.3Hz, I4-H3), 5.07-5.18 (IH, , l-H), 6.89 (2H, d, si 8.6Hz, 3 ^, ,5'-H ₂ ), 7.28 (2H, d, s∑ δ.6Hz, 2',6 ^* -H ₂ ); m/z (NH3.DCI) 816 (MNH ₄ ⁺ , 5%), 90 5 (100%).

£l 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(4-f2-triethyl- silyloxyethoxylphenvPbut-l-yn-5S-(2S.3S-epoxy-6S-trimethylsi lyloxy-4S- methylhexyPtetrahvdropyran 0

Using the method described in 6b, the product from 43b (1.3g, 1.63mmol) in benzene (70ml) was reacted with manganese dioxide (2.7g) for 3 2 hours to give the title compoimd (713mg, 5δ%); δg (CDCI3) inter alia 0.65 (6H, q, s∑ 7.9Hz, Si(CH ₂ Me) ₃ ), 0.90 (3H, d, s∑ 7.0Hz, 17-H ₃ ), 0.98 (9H, t, s∑ 5 8.0Hz, Si(CH2Me)3), 1.20 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 4.12 (2H, t, 4.9Hz, 1 ^* '- H ₂ ), 6.20 (IH, s, 2-H), 6.95 (2H, d, s∑ 8.7Hz, 3',5'-H ₂ ), 7.δ7 (2H, d, s∑ δ.7Hz, 2 ^* ,6'-H2); m_z (FAB: thioglycerol) 797 (MH- ^* -, 1-0%), 167 (100%).

il 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-(2-hvdroxyethoxy)phenvPbu tv- 0 l-yn-5S-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyPtetrahvdropyr an

Using the method described in 5c, the product from 43c (700mg, O.δδmmol) was deprotected to give the title compound (294mg, 72%); v _m ax (KBr) 3421, 1603, 1506, 1451cm"l; λ _max (EtOH) 324.5nm (εm 20,790); δg δ (CDCl3/d4-MeOH) inter alia 0.93 (3H, d, si 7.1Hz, 17-H ), 1.21 (3H, d, si 6.3Hz, M-H3), 4.14 (2H, t, si 4.δHz, 1"-H ₂ ), 6.23 (approx. IH, s, 2-H), 6.9δ (2H, d, si δ.9Hz, 3 ^* ,5'-H ₂ ), 7.δ6 (2H, d, s∑ δ.9Hz, 2 ^* ,6'-H2); δc (CDCI3ΛI4- MeOH) 12.3 (C-17), 20.3 (C-14), 31.5 (C-9), 39.6 (C-δ), 41.7 (C-4), 42.5 (C- 12), 55.6 (C-10), 60.9 (C-11), 65.4 (C-2"), 6δ.6 (C-7), 69.5 (C-1"), 70.1 (C-6), 70.7 (C-13), 73.9 (C-5), 96.4 (C-2), 114.4 (C-3',5 ^* ), 127.1 (C-1'), 129.1 (C- 2\6 ^* ), 162.3 (C-4 ^* ), lδ2.7 (C-1), 193.5 (C-3); m/z (FAB: Glycerol) 467 (MH+, 30%), lδ5 (100%). The ^X H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

EXAMPLE 44

3R.4R-Dihvdroxy-2S-[2.4-dioxo-4-(3-fluorophenvPbut-l-yll- 5S-r2S.3S- epoxy-δS-hvdroxy-4S-methylhexyPtetrahvdropyran

al 3R.4R-Bistrimethylsilyloxy-2S-r4-(3-fluorophenyl)-4-hvdroxy- 2- oxobut-l-yl1-δS-(2S-3S-epoxy-5S-trimethylsilyloxy-4S-methyl - hexy tetrahvdropyran 5

Using the method described in δa, tristrimethylsilylmonone (1.04g, 2mmol) and 3-fluorobenzaldehyde (0.23ml, 2.2mmol) were reacted to give the title compound (0.998g, 78%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7Hz, I7-H3), 1.19 (3H, d, s∑ 6.4Hz, 14-H ₃ ), δ.08-5.24 (IH, m, l-H), 6.91- 10 7.37 (4H, m, 2',4',δ',6 ^* -H ₄ ); (Found M ⁺ 642.3237. C31H55O3FS13 requires 642.3240).

__1 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(3-fluorophenvPbu t-l- yll-δS-(2S.3S-epoxy-δS-trimethylsilyloxy-4S-methylhexyPtet rahvdropyran lδ

Using the method described in 6b, the product from 44a (0.99g, l.δmmol) in benzene (70ml) was reacted with manganese dioxide (2.0g) for 3 2 hours to give the title compound (439mg, 49%); δg (CDCI3) inter alia 0.91 (3H, d, s∑ 7.0Hz, 17-H3), 1.21 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 6.24 (IH, s, 2-H), 0 7.16-7.26 (IH, m, 3'-H), 7.37-7.48 (IH, m, 4 ^* -H), 7.58-7.71 (2H, m, 2',6'- H ₂ ); m_z (NH3.DCI) 641 (MH+, 30%), 90 (100%).

£l 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(3-fluorophenvPbut-l-yl1-5S- (2S.3S-epoxy-5S-hvdroxy-4S-methvIhexyPtetrahvdropyran δ

Using the method described in 5c, the product from 44b (480mg) was deprotected to give the title compound (229mg, 76%); v _max (KBr) 3423, 1581, 1455, 1380cm" ¹ ; λ _max (EtOH) 312nm (εm 15,735); δg (CDCI3) inter alia 0.94 (3H, d, s∑ 6.9Hz, 17-H ₃ ), 1.22 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 6.24 (IH, s, 0 2-H), 7.17-7.69 (4H, m, 2',4',5 ^* ,6'-H4); δc (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.6 (C-9), 39.6 (C-8), 42.7 (C-4), 42.8 (C-12), 55.6 (C-10), 61.2 (C-11), 65.6 (C-16), 68.9 (C-6), 70.2 (C-7), 71.3 (C-13), 73.8 (C-5), 97.7 (C-2), 113.8 (d, J 43.3Hz, C-4'), 119.3 (d, J 21.2Hz, C-2'), 122.7 (C-6"), 130.2 (d, 7.9Hz, C-5'), 136.6 (d, s∑ 7.1Hz, C-1'), 162.8 (d, J247.3Hz, C-3"), 180:6 (C-1), 191.3 (C-3). 5 (Found: M ⁺ 424.1898. C22H29O7F requires M 424.1897). The !B n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

EXAMPLE 46

3R.4R-Dihvdroxy-2S-[2.4-dioxo-4-(2-fluorophenvPbut-l-vn-5 S-(2S.3S- epoxy-5S-hvdroxy-4S-methylhexyl)tetrahydropyran 5 al 3R.4R-Bistrimethylsilyloxy-2S-r4-(2-fluorophenyl)-4-hvdroxy- 2- oxobut-l-vIl-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyPtetrahvdropyran

10 Using the method described in δa, tristrimethylsilylmonone (1.04g,

2mmol) and 2-fluorobenzaldehyde (0.23ml, 2.2mmol) were reacted to give the title compound (δδOmg, 66%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.0Hz, I7-H3), 1.20 (3H, d, 6.3Hz, 14-H ₃ ), 4.06-4.19 (IH, m, 5-H), δ.40- 5.60 (IH, m, l-H), 6.87-7.06 (IH, m, 5'-H), 7.14-7.32 (2H, m, 4',6'-H ₂ ), lδ 7.62-7.60 (IH, m, 3 ^* -H); m/z (NH3.DCI) 660 (MMH4+ 15%), 90 (100%).

1_1 3R.4R-Bistrimethylsilyloxy-2S-[2.4-dioxo-4-(2-fluorophenvPbu t-l- yll-5S-(2S.3S-epoxy-δS-trimethylsilyloxy-4S-methylhexyPtetr ahvdropyran

0 Using the method described in 6b, the product from 45a (730mg) in benzene (50ml) was reacted with manganese dioxide (1.65g) for 3 2 hours to give the title compound (480mg, 67%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.0Hz, I7-H3), 1.19 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 6.3δ (IH, d, si 1.2Hz, 2- H), 7.07-7.18 (IH, m, Ar-H), 7.20-7.26 (IH, m, Ar-H), 7.42-7.63 (IH, m, Ar- δ H), and 7.90-7.99 (IH, m, Ar-H); m/z 640 (M ⁺ , 0.6%), 62δ(l), 165(63), 117(92), and 73(100). The iH n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

£) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-fluorophenvPbut-l-yl1-5S- 0 (2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 5c, the product from 45b (0.1 lOg, 0.17mmol) was deprotected to give the title compound (0.053g, 67%); v _max (KBr) 1610, 1587, 1459, 1112, 1043, and 771cm"l; λ _ma χ (EtOH) 312nm 5 (εm 15,920); δg (CDCI3) inter alia 0.94 (3H, d, s∑ 7.0Hz, 17-H ₃ ), 1.21 (3H, d, s∑ 6.3Hz, W-H3), 6.39 (IH, s, 2-H), 7.08-7.30 (2H, m, 2Ar-H), 7.42-7.56 (IH, m, Ar-H), and 7.87-7.99 (IH, m, Ar-H); m z (NH3DCI) 442 (MNH4+ 10%), 425 (MH+, lδ), and 156 (100); m/z (FAB, 3-NOBA/Na) 447 (MNa+).

The iH n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

EXAMPLE 46 δ

3R.4R-Dihvdroxy-2S-r4-(3.4-difluorophenyl)-2.4-dioxobut-l -yll-5S-(2S.3S- epoxy-5S-hvdroxy-4S-methylhexyl)tetrahvdropyran

al 3R.4R-Bistrimethylsilyloxy-2S-r4-(3.4-difluorophenvP-4-hvdro xy-2- 10 oxobut-l-yl1-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyPtetrahvdropyran

Using the method described in δa, tristrimethylsilylmonone (1.04g, 2mmol) and 3,4-difluorobenzaldehyde (0.24ml, 2.2mmol) were reacted to lδ give the title compound (O.δδOg, 66%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.1Hz, I7-H3), 1.20 (3H, d, si 6.4Hz, 14-H ₃ ), 5.07-6.17 (IH, m, l-H), and 7.01-7.30 (3H, m, Ar-H); m_z 660 (M ⁺ , 0.5%), 129 (46), 117 (δ5), and 73 (100).

0 bl 3R.4R-Bistrimethylsilyloxy-2S-[4-(3.4-difluorophenvP-2.4-dio xobut- l-vn-6S- ⁽ 2S.3S-epoxy-5S-trimethylsilyloxy-4S- meth ylhexyl )tetrahvdropyran

Using the method described in 6b, the product from 46a (1.39g) in benzene 26 (100ml) was reacted with manganese dioxide (2.5g) for 3 2 hours to give the title compound (7δ0mg, 67%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.1Hz, I7-H3), 1.20 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 6.20 (IH, s, 2-H), 7.17-7.29 (IH, m, Ar-H), and 7.61-7.73 (2H, m, Ar-H); m/z 65δ (M ⁺ , 0.6%), 643(1), 117(73), and 73(100); m/z (FAB 3-NOBA Na) 703 (M-H+2Na+) and 6δl 0 (MNa ⁺ ). The iH n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

£) 3R.4R-Dihvdroxy-2S-r4-(3.4-difluorophenvP-2.4-dioxo-but-l-yl l-5S- (2S.3S-epoxy-δS-hvdroxy-4S-methylhexyPtetrahvdrόpyran 5

Using the method described in δc, the product from 46b (3δ5mg, O.δδmmol) was deprotected to give the title compound (226mg, δ7%); v _max (KBr) 1612, 1594, 1516, 12δ0, 1118, 1090, and 1043cm"l; λ _max (EtOH)

311.δnm (εm 14,940); δg (CDCI3) inter alia 0.94 (3H, d, si 7.0Hz, I7-H3), 1.22 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 6.19 (IH, s, 2-H), 7.19-7.31 (IH, m, Ar-H), and 7.61-7.78 (2H, m, Ar-H); δc (CDCI3) 12.2 (C-17) 20.2 (C-14), 31.6 (C- 9), 39.8 (C-8), 41.9 (C-4), 42.5 (C-12), 5δ.7 (C-10), 60.9 (C-11), 65.6 (C-16), δ 68.6 (C-6), 70.0 (C-7), 70.5 (C-13), 74.0 (C-δ), 97.2 (C-2), 116.3 GI 19Hz) and 117.5 (s∑ 18Hz) (C-2 ^* and 5'), 123.δ (C-6'), 131.3 (C-1'), 149.δ and 153.0 (two overlapping dd, s∑ 253 and 13Hz, C-3' and 4'), 130.4 (C-1), and 194.5 (C-3); _n___ (FAB 3-NOBA/Na) 437 (M-H+2Na+) and 465 (MNa+); m/z (FAB Thioglycerol) 460 (MNH4- ¹ -) and 443 (MH+). The iH n.m.r. spectrum 0 indicated that the title compound was essentially in the enolic form.

EXAMPLE 47

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-N-(2-hvdroxyethvP-N- methvIaminopyrid-5-vPbut-l-yl1-5S-(2S.3S-epoxy-5S-hvdroxv-4S - methylhexyPtetrahydropyran

al 5-Bromo-2-N-(2-hvdroxyethyl)-N-methylaminopyridine

2,5-Dibromopyridine (4.74g, 20mmol) in 2-(methylamino)ethanol (5ml, 62mmol) was heated at 95-110°C for 6h, and stirred at RT for 16h. The viscous oil was then diluted with water (30ml) and extracted with ethyl acetate (3 x 50ml). The combined organic extracts were washed with brine, dried and evaporated to give a pale yellow viscous oil (4.565g, 99%); δg (CDCI3) 3.05 (3H, s, NCH3), 3.70 (2H, t, sl 4.7Hz, CH ₂ ), 3.34 (2H, t, s∑ 4.7Hz, CH ₂ ), 4.27 (IH, br, OH, xch + D ₂ 0), 6.45 (IH, d, s∑ 9.0Hz, 3-H), 7.52 (IH, dd, s∑ 9.0 and 2.5Hz, 4-H), and δ.Oδ (IH, d, s∑ 2.4Hz, 6-H); m/z 232/230 CM ⁺ , lδ%) and 201/199 (100). (Found: M ⁺ , 230.0056. CsHχχBrN2θ requires M, 230.0055).

J2__ 5-Bromo-2-N-methyl-N-(2-triethylsilyloxyethyPamino pyridine

5-Bromo-2-N-(2-hydroxyethyl)-N-methylaminopyridine (4.53g, 19.6mmol) was dissolved in dry dichloromethane (70ml)i cooled in an ice bath, and treated with triethylamine (3.δml, 27mmol) and chlorotrietbylsilane ^' (3.95ml, 23.5mmol). After five minutes the mixture was diluted with ether, filtered and evaporated. The residue was purified by column chromatography on silica (47g), eluting with 3-5% ethyl acetate in hexane,

to give the pure product as a colourless oil (6.510g, 96%); δg (CDCI3) 0.5- 0.62 (6H, m, 3xSiCH ₂ ), O.δδ-0.96 (9H, m, 3xCH ₃ ), 3.08 (3H, s, NCH3), 3.64 (2H, d, si 5.8Hz, CH ₂ ), 3.7δ (2H, d, s∑ δ.7Hz, CH ₂ ), 6.42 (IH, d, si 9.1Hz, 3-H), 7.47 (IH, dd, si 9.1 and 2.5Hz, 4-H), and δ.13 (IH, d, s∑ 2.δHz, 6-H); m/z 347/346 (MH+, 40%), 346/344 (M+, 50), and 201/199(100). (Found: M ⁺ , 344.0919. requires M, 344.0920).

__) 2-N-Methyl-N-(2-triethylsilyloxyethvPaminopyridine-δ- carboxaldehvde

5-Bromo-2-N-methyl-N-(2-triethylsilyloxyethyl)aminopyridi ne (1.727g, δmmol) was dissolved in dry THF (30ml), cooled to -90°C, and treated dropwise with n-butyllithium (1.5M, 3.67ml, δ.δmmol). The mixture was . stirred at -9δ°C for five minutes, then N,N-dimethylformamide (1.16ml, lδmmol) added. Stirring was continued for 3/4h at -90°C, then the reaction was quenched with saturated ammonium chloride. Water was added, and the mixture extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried and evaporated. The crude product was purified by column chromatography, eluting with 10- 15% ethyl acetate in hexane, to give the title compound as a pale yellow oil (1.354g, 92%); δg (CDCI3) 0.56 (6H, q, j∑ 7.9Hz, 3xSiCH ₂ ), 0.92 (9H, t, s∑ 7.9Hz, 3-H), 3.21 (3H, s, NCH3), 3.72-3.3δ (4H, m, 2 x CH ₂ ), 6.58 (IH, d, s∑ 9.0Hz, 3-H), 7.90 (IH, dd, s∑ 9.0 and 2.2Hz, 4-H), 8.53 (IH, d, s∑ 2.2Hz, 6- H), and 9.76 (IH, s, CHO); m/z 29δ (MH+, 60%), 294 (M ⁺ , 55), 163 (70), and 136 (100). (Found: M ⁺ , 294.1767. Cχ5H2gN2θ2Si requires M, 294.1764).

dl 3R.4R-BistrimethylsiIyloxy-2S-r4-hvdroxy-4-(2-N-methyl-N-(2- triethylsilyloxyethvPaminopyrid-5-vP-2-oxobut-l-yl1-δS-(2S. 3S-epoxy-5S- trimethylsilyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in δa, tristrimethylsilylmonone (1.038g, 2mmol) and 2-N-methyl-N-(2-triethylsilyloxyethyl)aminopyridine-5- carboxaldehyde (0.647g, 2.2mmol) were reacted to give the title compound (1.353g, δ3%); δg (CDCI3) inter alia 0.52-0.64 (6H, m, 3xSiCH2), O.δδ- 0.9δ (12H, m, 4xCH ₃ ), 3.11 (3H, s, NCH3), 5.01-5.12 (IH, m, l-H), 6.53 (IH, br d, 3'-H), 7.50 (IH, br d, 4'-H), and δ.09 (IH, d, s∑ 2.2Hz, 6'-H); m z (FAB, 3NOBA/Na) 835 (MNa+) and 813 (MH+).

e_) 3R.4R-Bristrimethylsilyloxy-2S-r2.4-dioxo-4-(2-N-methyl(2- triethylsilyloxyethvPaminopyrid-5-vPbut-l-yl1-δS-(2S.3S-epo xy-δS- trimethylsilyloxy-4S-methylhexyl)tetrahydropyran

Using the method described in 6b, the product from 47d (1.331g, 1.64mmol) in benzene (70ml) was reacted with manganese dioxide (4.1g) for δh to give the title compound (0.631g, 48%); δg (CDCI3) inter alia O.δ- 0.63 (6H, m, 3xSiCH2), 0.87-0.97 (12H, m, 4XCH3), 1.20 (3H, d, s∑ 6.3Hz, M-H3), 3.19 (3H, s, NCH3), 6.13 (IH, s, 2-H), 6.5δ (IH, br d, 3 ^* -H), 7.95 (IH, dd, si 9-1 and 2.1Hz, 4'-H), and 8.70 (IH, d, s∑ 2.2Hz, 6 ^* -H); m z δlO (M+, 1%) 293(40), 135(46), 117(73), and 73(100). (Found: M ⁺ , δlθ.4524. C3gH74N2θ8Si4 requires M, 810.4522). The iH n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

£) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-N-(2-hvdroxyethyl)-N- methvϊaminopyrid-δ-vPbut-l-yll-5S-(2S.3S-epoxy-δS-hvdroxy -4S- methvIhexyPtetrahydropyran

Using the method described in 5c, the product from 47e (0.610g,

0.75mmol) was completely deprotected to give the title compound (0.32δg, 90%); v _max (KBr) 3423, 1603, 1521, 1403, 1279, 1111, and 1054cm" ¹ ; ^λ max (EtOH) 3δ6nm (εm 32,162); δg (CDCI3/CD3OD) inter alia 0.92 (3H, d, s∑ 7.1Hz, 17-H ₃ ), 1.21 (3H, d, si 6.3Hz, 14-H ₃ ), 3.16 (3H, s, NCH3), 6.14 (IH, s, 2-H), 6.58 (IH, d, si 9.1Hz, 3 ^* -H), 7.96 (IH, dd, s∑ 9.1 and 2.4Hz, 4'- H), and 8.63 (IH, d, si 2.4Hz, 6 ^* -H); δc (CDCI3/CD3OD) 12.5 (C-17), 20.5 (C-14), 31.8 (C-9), 37.9 (NCH3), 39.8 (C-3), 41.5 (C-4), 42.7 (C-12), 53.4 (NCH3), δδ.δ (C-10), 61.1 (C-11), 61.2 (OCH ₂ ), 66.7 (C-16), 6δ.7 (C-6), 70.2 (C-7), 70.δ (C-13), 74.2 (C-5), 95.δ (C-2), lθδ.9 (C-4 ^* ), 119.0 (C-5 ^* ), 14δ.7 (C-6 ^* ), 160.3 (C-2 ^* ), lδ3.1 (C-1), and 191.4 (C-3); m z 4δ0 (M ⁺ , 2%) and 163 (100). (Found: M ⁺ , 430.2471. C24H3gN2θs requires M, 4δ0.2472). The n.m.r. spectra indicated that the title compound was mainly in the enolic form.

EXAMPLE 48

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-(4-hvdroxypiperidin-l- yl)pyrid-5- vPbut-l-vn-5S-[2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetrahv dropyran

al 5-Bromo-2-(4-hvdroxypiperidin-l-yPpyridine

2,5-Dibromopyridine (3.554g, lδmmol) and 4-hydroxypiperidine (4.δ52g, δ 45mmol) were heated at 100-110°C for lh. The mixture was diluted with water and extracted with ethyl acetate (3x40ml). The combined organic extracts were dried and evaporated to give a white solid, which was recrystallised from chloroform/ hexane to give the title compound as white crystals (3.0δ8g, 79%); m.p. 98.δ-99.δ°C; found C, 46.66; H, 5.10; N, 0 10.69%. CχoH ₁₃ BrN2θ requires C, 46.71; H, 5.10; N, 10.89%; δg

(CDCI3) 1.48-1.66 (3H, m, 3'-H, 5'-H, OH), 1.90-2.05 (2H, m, 3'-H, 5 ^* -H), 3.10-3.26 (2H, m, 2'-H, 6 ^* -H), 3.87-4.06 (3H, m, 2'-H, 4'-H, 6'-H), 6.58 (IH, d, s∑ 9.1Hz, 3-H), 7.52 (IH, dd, s∑ 9.1 and 2.5Hz, 4-H), and 8.17 (IH, d, s∑ 2.4Hz, 6'-H; m/z 268/256, 213/211 (90), 201/199 (80), 187/185 (85), and 5 157/169 (69). (Found: (M ⁺ , 256.0216. C ₁₀ Hχ3BrN ₂ O requires M, 256.0211).

___ 5-Bromo-2-(4-trimethylsilyloxypiperidin-l-yPpyridine

0 δ-Bromo-2-(4-hydroxypiperidin-l-yl)pyridine (2.985g, ll.βmmol) was dissolved in dry dichloromethane (40ml), coled in an ice bath, and treated with triethylamine (2.1ml, lδmmol) and chlorotrimethylsilane (1.76ml, 14mmol). After ^h the mixture was diluted with ether, filtered and evaporated. The residue was redissolved in ether, filtered and evaporated 5 to give an off-white crystalline solid (3.797g, 99%); δg (CDCI3) 0.14 (9H, s, Si(CH ₃ ) ₃ ), 1.49-1.66 (2H, m, 3'-H, δ'-H), 1.76-1.90 (2H, m, 3'-H, 5'-H), 3.11-3.26 (2H, m, 2 ^* -H, 6 ^* -H), 3.δ2-3.99 (3H, m, 2'-H, 4'-H, 6 ^* -H), 6.57 (IH, d, s∑ 9.1Hz, 3-H), 7.50 (IH, dd, J 9.1 and 2.5Hz, 4-H), and δ.17 (IH, d, si 2.4Hz, 6-H); m/z 330/328 (M ⁺ , 80%), 211/213 (100), and 73(74). (Found: 0 M ⁺ , 328.0606. Cχ3H ₂ ιBrN ₂ OSi requires M, 32δ.0607).

ci 2-(4-Trimethylsilyloxypiperidin-l-yPpyridine-δ-carboxaldehv de

Using the method described in 47c, 5-bromo-2-(4-trimethylsilyloxy- 5 piperidin-l-yl)pyridine (1.647g, δmmol) was reacted to give the title compound as yellow crystals (0.932g, 67%); δg (CDCI3) O.lδ (9H, s, Si(CH ₃ ) ₃ ), 1.51-1.69 (2H, m, 3'-H, δ'-H), 1.77-1.92 (2H, m, 3'-H, δ'-H), 3.44-3.63 (2H, m, 2'-H, 6'-H), 3.92-4.13 (3H, m, 2'-H, 4'-H, 6'-H), 6.6δ (IH,

- 9δ - d, _s ∑ 9.1Hz, 3-H), 7.91 (IH, dd, 9.1 and 2.3Hz, 4-H), 8.54 (IH, d, s∑ 2.3Hz, 6-H), and 9.76 (IH, s, CHO); m_z 278 (M ⁺ , 60%), 263 (38), 209 (78), 161 (100), and 107 (69). (Found: M ⁺ , 278.1454. C H ₂ 2N2θ2Si requires M, 278.1451). 5 dl 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-4-(2-(4-trimethyl- silyloxypiperidin-l-vPpyrid-δ-vP-2-oxobut-l-yll-δS-(2S.3S- epoxy-δS- trimethylsilyloxy-4S-methylhexyPtetrahvdropyran

0 Using the method described in δa, tristrimethylsilylmonone (1.038g,

2mmol) and 2-(4-trimethylsilyloxypiperidin- l-yl)pyridine-δ-carboxaldehye (0.613g, 2.2mmol) were reacted to give the title compound (1.135g, 71%); δg (CDCI3) inter alia 0.90 (3H, d, 7.1Hz, I7-H3), 1.19 (3H, d, s∑ 6.3Hz, I4-H3), δ.02-5.16 (IH, m, l-H), 6.68 (IH, br d, 3'-H), 7.53 (IH, br d, 4'-H), 5 and 8.13 (IH, d, s∑ 2.2Hz, 6 ^* -H); m/z (NH3, DCI) 797 (MH+, 15%) and 279 (100); m/z 796 (M ⁺ , 0.2%), 278(31), 129(74), and 73(100). (Found: M ⁺ , 796.4364. C38H72N2O8S14 requires M, 796.4366).

j_l 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(2-(4-trimethyl- 0 silyloxypiperidin-l-vPpyrid-5-vPbut-l-vIl-6S-(2S.3S-epoxy-5S - trimethyl sil yloxy-4S-methylhexyl )tetrahydrop yran

Using the method described in 6b, the product from 48d (1.120g, 1.4mmol) in benzene (70ml) was reacted with manganese dioxide (2.9g) for 3h to δ give the title compound (0.633g, 57%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.0Hz, I7-H3), 1.20 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 6.13 (IH, s, 2-H), 6.6-6.72 (IH, m, 3 ^* -H), 7.95 (IH, br d, 4"-H), and 3.70 (IH, d, s∑ 2.3Hz, 6 ^* -H); m/z (NH3 DCI) 795 (MH- ¹ -, 15%), 251(32), 92(52), and 90(100); m/z 794 (M ⁺ , 0.5%), 277 (100), 117 (76), and 73 (96). The ^X H n.m.r. spectrum indicated 0 that the title compound was essentially in the enolic form.

f _. 3R.4R-Dihydroxy-2S-r2.4-dioxo-4-(2-(4-hvdroxypiperidin-l-vPp yrid- δ-vPbut-l-yll-5S-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyP- tetrahvdropyran

Using the method described in 5c, the product from 4δe (0.600g, 0.75mmol) was completely deprotected to give the title compound (0.240g, 63%); m.p. 137-133°C (chloroform/ethyl acetate/hexane); v _max (KBr)

3453, 1608, 1500, 1440, 1357, 1250, and 1075cm- ¹ ; λ _max (EtOH) 358 ^" nm (ε _m 33,099); δg (CD ₃ OD) inter alia 0.94 (3H, d, s∑ 7.2Hz, 17-H ₃ ), 1.19 (3H, d, s∑ 6.4Hz, -H3), 1.34-1.68 (3H, m, 12-H, 3"-H, 5"-H), 1.86-2.02 (3H, m, 8-H, 3"-H, 5"-H), 4.16-4.28 (2H, m, 2"-H), 6"-H), 6.26 (IH, s, 2-H), 6.85 5 (IH, d, s∑ 9.2Hz, 3'-H), 7.99 (IH, dd, si 9.2 and 2.4Hz, 4'-H), and δ.67 (IH, d, _s i 2.3Hz, 6'-H); δc (CD3OD) 12.2 (C-17), 20.2 (C-14), 32.9 (C-9), 34.7 (C- 3" and δ"), 41.6 (C-δ), 42.0 (C-4), 43.6 (C-2" and 6"), 43.7 (C-12), 56.δ (C- 10), 61.2 (C-11), 66.3 (C-16), 68.3 (C-4"), 69.8 (C-6), 70.6 (C-13), 71.5 (C-7), 75.6 (C-5), 96.6 (C-2), 107.1 (C-4 ^* ), 120.1 (C-5'), 137.4 (C-3'), 149.9 (C-6'), 0 161.6 (C-2'), 184.4 (C-1), and 192.4 (C-3); m/z 506 (M ⁺ , 5%), 247(20),

220(29), and 206(100). (Found: M ⁺ , 506.2624. C26H38N2O8 requires M, 506.2628). A further quantity of the title compound (0.096g, 2δ%) was obtained after chromatography of the mother liquors. The n.m.r. spectra indicated that the compound was essentially in the enolic form. 5

EXAMPLE 49

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-(3-hvdroxyprop-l-oxy)p yrid-5-vPbut- l-yl1-δS-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyPtetrahvdropy ran 0 al 3-Iodo-l-triethylsilyloxypropane

3-Bromopropan-l-ol (1.81ml, 20mmol) and sodium iodide (6.7δg, 45mmol) in acetone (lδml) were refluxed for l^h. The mixture was cooled, 5 filtered and reduced in volume. Water was added and the mixture extracted with ether. The combined organic extracts were washed with sodium metabisulphite solution and brine, dried and evaporated. The residue was distilled, using a water pump (15mm Hg), to give 3- iodopropan-1-ol (2.8δ5g, 7δ%) b.p. 96-100°C; δg (CDCI3) 2.04 (2H, q, s∑ 0 7Hz, 2-H ₂ ), 3.1δ (IH, s, OH), 3.3 (2H, t, s∑ 7Hz, 1-H ₂ ), and 3.7 (2H, t, s∑ 7Hz, 3-H ₂ ).

3-Iodopropan-l-ol (2.79g, lδmmol) was dissolved in dry dichloromethane (30ml), cooled in an ice bath, and treated with triethylamine (2.3ml, δ 20mmol) and chlorotriethylsilane (3ml, 17.δmmol). After ^h the mixture was diluted with ether, filtered and carefully evaporated to give the title compound, which was used without further purification.

b Ethyl 2-(3-triethylsilyloxyprop-l-oxy)pyridine-5-carboxylate

A suspension of ethyl 2-hydroxypyridine-5-carboxylate (1.170g, 7mmol) and silver carbonate (1.930g, 7mmol) in benzene (30ml) was stirred with δ 3-iodo-l-triethylsilyloxypropane (Iδmmol) for 23h. T.l. showed little or no reaction, so more benzene was added and the mixture gently refluxed for 4δh, then stirred at room temperature for a further 4δh. The mixture was then filtered and evaporated. The crude product was separated by column chromatography, eluting with 0-20% ethyl acetate in hexane, to 0 give: (a) recovered 3-iodo-l-triethylsilyloxypropane (1.33g, 4.4mmol); (b) the title compound (contaminated with a little of (a)) (l.δδg, ca-65%); δg (CDCI3) 0.63-0.69 (6H, m, 3xSiCH ₂ ), 0.39-1.01 (9H, m, 3xCH ₃ ), 1.39 (3H, t, si 7.1Hz, CH3), 2.01 (2H, q, si 6.2Hz, 2'-H ₂ ), 3.79 (2H, t, si 6.2Hz, 3 ^* - CH ₂ ), 4.37 (2H, q, si 7.1Hz, Cθ2CH ₂ ), 4.46 (2H, t, J_ 6.2Hz, l'-H ₂ ), 6.74 5 (IH, d, si δ.9Hz, 3-H), δ.lδ (IH, dd, si δ.δ and 2.4Hz, 4-H), and δ.δ2 (IH, d, s∑ 2.4Hz, 67-H); m z (NH3 DCI) 340 (MH+, 100%); m/z 339 (M ⁺ , 0.δ%), 310(91), 252(100), and 224(4δ). (Found: M+, 339.1δ63. Cχ ₇ H ₂ 4Nθ4Si requires M, 339.1δ66); and (c) the N-alkylated compound (0.56g, 24%).

0 cl 2- ⁽ 3-Triethylsilyloxyprop-l-oxy)pyridine-5-carboxaldehyde

Ethyl 2-(3-triethylsilyloxyprop-l-oxy)pyridine-δ-carboxylate (1.53g, 4.δmmol) was dissolved in dry THF (50ml) under argon, then diisobutyl¬ aluminium hydride (1.0M, 5ml, δmmol) was added slowly. After stirring δ for -/2h, more diisobutylεduminium hydride (δml) was added, and stirring continued for a further lh. Methanol (11ml) and saturated sodium sulphate (14ml) were added, and the mixture stirred for lδminutes. The salts were filtered off through celite, the filtrate dried and evaporated to give the hydroxymethyl compound as a colourless oil (1.36g, 100%). This 0 material was dissolved in dichloromethane (50ml), activated manganese dioxide (2.7g) added, and the mixture stirred for 16h. After filtering, the filtrate was evaporated to give a colourless oil. This residue was purified by column chromatography, eluting with 10% ethyl acetate in hexane, to give the title compound (0.95δg, 72%); δg (CDCI3) 0.64-0.66 (6H, m, 3xSiCH ₂ ), 0.39-1.0 (9H, m, 3xCH ₃ ), 2.02 (2H, q, si 6.2Hz, 2 ^* -H ₂ ), 3.δ0 (2H, t, 16.2Hz, 3 ^* -H ₂ ), 4.51 (2H, t, si 6.3Hz, l'-H ₂ ), 6.δ2 (IH, d, si δ.δHz, 3-H), δ.06 (IH, dd, si δ.7 and 2.4Hz, 4-H), δ.62 (IH, d, si 2.4Hz, 6-H), and 9.95 (IH, s, CHO); m z (NH3 DCI) 296 (MH+, 100%); m z 296 (MH+, 1%), 266

(M-Et+, 68), 208 (100), and 124 (70). (Found: MH+, 296.1681. Cl5H ₂ gN0 ₃ Si requires M, 296.1682. Found M-Et+, 266.1203. ^c 13 ^H 20 ^NO 3 ^Si requires M, 266.1212 ⁾ .

5 d 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-4-(2-(3-triethyl- silyloxyprop-l-oxy)pyrid-5-yl)-2-oxobut-l-yl1-δS-(2S.3S-epo xy-δS- trimethylsilyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in δa, tristrimethylsilylmonone (1.038g, 10 2mmol) and 2-(3-triethylsilyloxyprop-l-oxy)pyridine-5-carboxaldehyde

(O.βδOg, 2.2mmol) were reacted to give the title compound (1.454g, δ9%); δg (CDCl3) inter_alia 0.64-0.65 (6H, m, 3xSiCH ₂ ), 0.86-1.00 (12H, m,

4xCH ₃ ), 1.19 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 1.94-2.05 (2H, m, 2"-H ₂ ), 4.12 (IH, dt, J 9.6 and 2.9Hz, 5-H), 4.33 (2H, t, J 6.2Hz, 1"-H ₂ ), 5.09-5.16 (IH, m, 1- lδ H), 6.73 (IH, d, s∑ 8.δHz, 3'-H), 7.60-7.68 (IH, m, 4'-H), and 8.11 (IH, d, s∑

2.2Hz, 6'-H); m/z 813 (M ⁺ , 0.4%), 266(56), 208(72), 117(61), and 73(100).

(Found: M ⁺ , 813.4509. C ₃ 9H75NO Si requires M, 813.4519).

≤l 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-4-(2-(3-triethyl- 20 silvloxvprop-l-oxy)pyrid-5-vP-2-oxobut-l-yl1-5S-(2S.3S-epoxy -6S- trimethvIsilyloxy-4S-methylhexyPtetrahvdropyran

Using the method described in δa, tristrimethylsilylmonone (1.038g, 2mmol) and 2-(3-triethylsilyloxyprop-l-oxy)pyridine-δ-carboxaldehyde

25 (0.650g, 2.2mmol) were reacted to give the title compound (1.4δ4g, 89%); δg (CDCI3) inter alia 0.54-0.66 (6H, m, 3xSiCH ₂ ), 0.86-1.00 (12H, m, 4xCH ₃ ), 1.19 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 1.94-2.05 (2H, m, 2"-H ₂ ), 4.12 (IH, dt, 9.6 and 2.9Hz, 5-H), 4.38 (2H, t, s∑ 6.2Hz, 1"-H ₂ ), 5.09-5.18 (IH, m, 1- H), 6.73 (IH, d, si 8.5Hz, 3'-H), 7.60-7.68 (IH, m, 4'-H), and 8.11 (IH, d, s∑

30 2.2Hz, 6'-H); m/z δl3 (M ⁺ , 0.4%), 266(66), 203(72), 117(61), and 73(100). (Found: M ⁺ , 813.4509. C ₃ gH75Nθ9Si ₄ requires M, 813.4519).

ej 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(2-(3-triethyl- silyloxyprop-l-oxy)pyrid-5-yPbut-l-yl]-δS-(2S.3S-epoxyrδS- 35 trimethylsilyloxy-4S-methylhexyl)tetrahvdropyran

Using the method described in 6b, the product from 49d (1.426g, 1.75mmol) in benzene (70ml) was reacted with manganese dioxide (3.δg)

for 3h to give the title compound (0.770g, 54%); δg (CDCI3) inter alia 0.55-0.66 (6H, m, 3xSiCH ₂ ), 0.87-1.0 (12H, m, 4xCH ), 1.20 (3H, d, s∑ 6.4Hz, M-H3), 1.95-2.06 (2H, m, 2"-H ₂ ), 4.46 (2H, t, s∑ 6.3Hz, 1"-H ₂ ), 6.19 (IH, s, 2-H), 6.77 (IH, d, s∑ 8.δHz, 3'-H), 3.06 (IH, dd, s∑ δ.7 and 2.5Hz, 4'- H), and δ.70 (IH, d, s∑ 2.3Hz, 6'-H); z δll (M ⁺ , 0.1%), 782(2), 117(68), and 73(100); m z (NH3 DCI) 812 (MH+, 1%), 191(25), 132(45), and 90(100). The l-H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

f_ 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-(3-hvdroxyρrop-l-oxy)pyr id-5- vPbut-l-yll-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyPtetrahv dropyran

Using the method described in 5c, the product from 49e (0.740g, O.θlmmol) was completely deprotected to give the title compound (0.286g, 65%); v _max (KBr) 3437, 1604, 1493, 1313, 1293, and lOδδcm- ¹ ; λ _max (EtOH) 319nm (ε _m 20,731); δg (CD3OD) inter alia 0.94 (3H, d, s∑ 7.2Hz, I7-H3), 1.19 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 1.91-2.03 (3H, m, 8-H, 2"-H ₂ ), 3.73 (2H, t, s∑ 6.3Hz, 3"-H ₂ ), 4.46 (2H, t, s∑ 6.3Hz, 1"-H ₂ ), 6.36 (IH, s, 2-H), 6.86 (IH, d, _I8.8Hz, 3'-H), δ.17 (IH, dd, si δ.δ and 2.δHz, 4'-H), and δ.72 (IH, d, si 2.3Hz, 6'-H); δc (CD3OD) 12.3 (C-17), 20.3 (C-14), 33.0 (C-9 and 2"), 41.7 (C-δ), 42.5 (C-4), 43.7 (C-12), 56.7 (C-10), 59.5 (C-3"), 61.2 (C-11), 64.δ • (C-1"), 66.4 (C-16), 69.δ (C-6), 70.7 (C-13), 71.5 (C-7), 75.5 (C-5), 97.7 (C- 2), 112.0 (C-3 ^* ), 125.6 (C-5 ^* ), 133.7 (C-4 ^* ), 14δ.5 (C-6 ^* ), 167.δ (C-2 ^* ), 163.0 (C-1), and 194.9 (C-3); m/z 481 (M ⁺ , 0.5%), 138(60), and 122(100). (Found: M ⁺ , 481.2313. C2 H35NO requires M, 481.2312). A further quantity of the title compound (0.122g, 28%) was obtained after chromatography of the mother liquors. The n.m.r. spectra indicated that the compound was essentially in the enolic form.

EXAMPLE 50

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-methoxythiazol-5-vPbut -l-yl1-5S- (2S.3S-epoxy-6S-hydroxy-4S-methylhexyPtetrahvdropyran

al 2-Methoxythiazole-5-carboxaldehyde

2-Methoxythiazole (contained 25% 2-bromothiazole, 0.50g, 4.3mmol) was dissolved in THF (20ml), cooled to -70%, and treated dropwise with n-

butyllithium (1.5M, 3.2ml, 4.8mmol). The mixture was stirred for 7δ minutes, then N,N_-dimethylformamide (1.16ml, lδmmol) added. Stirred for a further l-^h, then quenched with saturated ammonium chloride and ether. The phases were separated, the organic washed with water, δ dried and reduced to a small volume. The crude product was purified by flash chromatography, eluting with 60% ether in pentane, to give the title . compound as an orange oil (1.08g); δg (CDCI3) 4.1δ (3H, s, OCH3), 7.86

(IH, s, 4-H), and 9.83 (IH, s, CHO), signals were also observed for solvents and a few minor impurities. 10 hi 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-4-(2-methoxythiazol -5- vP-2-oxobut-l-yll-6S-(2S.3S-epoxy-δS-trimethylsilyloxy-4S- methylhexyPtetrahydropyran

lδ Using the method described in δa, tristrimethylsilylmonone (1.03δg,

2mmol) and the product from δOa (max. 3.2mmol) were reacted to give the title compound (1.032g, 7δ%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.1Hz, I7-H3), 1.20 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 4.05 (3H, s, OCH3), 5.21-5.32 (IH, m, l-H), and 6.93 (IH, s, 4 ^* -H); m/z 661 (M ⁺ , TO, 226 (20), 143 (39), 129 0 (46), 117 (72), and 73 (100). (Found: M ⁺ , 661.296δ. C29H ₅ 5N0 ₈ SSi3 requires M, 661.2956). .

fi) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(2-methoxythiazol -5- vPbut-l-yll-δS-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- δ methylhexyPtetrahvdropyran

Using the method described in 6b, the product from 50b (l.OOOg, l.δlmmol) in benzene (70ml) was reacted with manganese dioxide (3.0g) for 3h to give the title compound (0.43 lg, 43%); δg (CDCI3) inter alia 0.90 0 (3H, d, s∑ 7.1Hz, 17-H ₃ ), 1.20 (3H, d, J 6.3Hz, 14-H ₃ ), 4.13 (3H, s, OCH3), δ.96 (IH, s, 2-H), and 7.75 (IH, s, 4'-H); m z 659 (M ⁺ , 0.1%), 644 (0.2), 164(29), 142(40), 117(δ9), and 73(100); m z (NH3 DCI) 660 (MH+, 22%) and 90(100)., The iH n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

35 dl 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-methoxythiazol-δ-vPbut-l -vn- 5S-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyl)tetτahvdropyran

Using the method described in δc, the product from δOc (0.415g, 0.63mmol) was deprotected to give the title compound (0.243g, 87%); v _max

(KBr) 3424, 1616, 1488, 1401, 1277, 1109, and 1048cm ^" l; λ _max (EtOH) δ 32δnm (ε _m 15,663); δg (CD3OD) 0.94 (3H, d, s∑ 7.2Hz, 17-H ₃ ), 1.20 (3H, d, _s i 6.4Hz, W-H3), 4.13 (3H, s, OCH3), 6.17 (IH, s, 2-H), and 7.93 (IH, s, 4'- H); δc (CD3OD) 12.3 (C-17), 20.3 (C-14), 33.0 (C-9), 40.3 (C-4), 41.8 (C-8),

43.6 (C-12), 56.9 (C-10), 59.9 (OCH3), 61.3 (C-11), 66.4 (C-16), 69.δ (C-6), •

70.7 (C-13), 71.6 (C-7), 7δ.δ (C-5), 97.9 (C-2), 132.0 (C-5"), 143.3 (C-4 ^* ), 0 160.9 (C-2 ^* ), 183.9 (C-1), and 188.1 (C-3); m/z (NH3 DCI) 444 (MH+,

100%), 158(33), 91(79), and 74(36); m/z 443 (M ⁺ , 0.5%), 157(51), and 142(100). (Found: M ⁺ , 443.1665. C ₂ oH29N0 ₈ S requires M, 433.1614).

The n.m.r. spectra indicated that the title compound was mainly in the enolic form.

EXAMPLE 51

3R.4R-Dihvdroxy-2S-[4-(cvclohexen-l-vP-2.4-dioxobut-l-vn- 5S-(2S.3S- epoxy-5S-hydroxy-4S-methylhexyPtetrahvdropyran

al 3R.4R-Bistrimethylsilyloxy-2S-[4-(cvclohexen-l-yP-4-hvdroxy- 2- oxobut-l-yll-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyPtetrahvdropyran

Using the method described in 5a, tristrimethylsilylmonone (1.038g,

2mmol) and cyclohexene-1-carboxaldehyde (2.2mmol) were reacted to give the title compound (0.593g, 47%); δg (CDCI3) inter alia 0.89 (3H, d, si

7.1Hz, I7-H3), 1.19 (3H, d, 16.4Hz, U-H3), 4.13 (IH, td, si 9.5 and 3.0Hz, 5-H), 4.37-4.48 (IH, m, l-H), and 5.72 (IH, br s, 2'-H); m z (NH3 DCI) 646 (MNH+4, 15%), 629 (MH+, 3), 536(50), 519 (18), 128(100), and 90(83).

h) 3R.4R-Bistrimethylsilyloxy-2S-r4-(cyclohexen-l-yl)-2.4-dioxo but-l- yn-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S-meth ^' ylhexyPtetrahvdropyran

^• Using the method described in 6b, the product from δla (0.58g, 0.92mmol) in benzene (70ml) was reacted with manganese dioxide (l.δg) for 3 2I1 to give the title compound (0.224g, 39%); δg (CDCI3) inter alia 0.39 (3H, d, s∑

7.0Hz, I7-H3). 1.19 (3H, d, si 6.3Hz, 14-H ₃ ), 5.76 (IH, s, 2-H), and 6.90

(IH, br s, 2'-H); m/z 626 (M ⁺ , 2%), 611 (0.6), 334 (13), 151 (33)„ 117 (72), and 73 (100). (Fouind: M ⁺ , 626.3492. C3χH5sθ7Si3 requires M,

626.3491). The ^B n.m.r. spectrum indicated that the title compound was 5 essentially in the enolic form.

_1 3R.4R-Dihvdroxy-2S-r4-(cvclohexen-l-vP-2.4-dioxobut-l-yll-δ S- (2S.3S-epoxy-5S-hvdroxy-4S-methylhexyPtetrahvdropyran

0 Using the method described in δc, the product from δlb (0.212g,

0.34mmol) was deprotected to give the title compound (0.134g, 97%); v _m ax

(KBr) 3423, 2927, 1640, 1588, 1450, 1110, and 1080cm- ¹ ; λ _ma χ (EtOH) 307nm (ε _m 12,570); δg (CD3OD) inter alia 0.94 (3H, d, si 7.1Hz, 17-H ₃ ), 1.19 (3H, d, si 6.5Hz, 14-H ₃ ), 1.66-1.73 (6H, m, 9-H ₂ , 4'-H ₂ , 5'-H ₂ ), 2.14- 5 2.33 (4H, m, 3'-H ₂ , 6'-H ₂ ), 5.86 (IH, s, 2-H), and 6.92 (IH, br s, 2'-H); δc (CD3OD) 12.3 (C-17), 20.3 (C-14), 22.7, 23.2, 24.δ and 27.0 (C-3', 4', 5' and

6'), 33.0 (C-9), 41.7 (C-8), 43.3 (C-4), 43.7 (C-12), 66.9 (C-10), 61.2 (C-11), 66.4 (C-16), 69.8 (C-6), 70.7 (C-13), 71.5 (C-7), 75.4 (C-δ), 97.3 (C-2), 134.8 (C-D, 137.7 (C-2'), 182.9 (C-1), 199.2 (C-3); z 410 (M ⁺ , 2%), lδl (52), 0 and 109 (100). (Found: M ⁺ , 410.2307. C22H34O7 requires M, 410.2305).

The n.m.r. spectra indicated that the title compound was essentially in the enolic form.

5 EXAMPLE 52

3R.4R-Dihvdroxy-2S-r3.δ-dioxo-l-(furan-2-vPhex-l(E)-en-6 -yll-δS-(2S.3S- epoxy-5S-hvdroxy-4S-methylhexyPtetra-hvdropyran

0 al 3R.4R-Bistrimethylsilyloxy-2S-ri-(furan-2-vP-3-hvdroxy-δ-ox ohex- l(E)-en-6-yll-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyl )tetrahvdrop yran

Using the method described in δa, tristrimethylsilylmonone (1.038g, δ . 2mmol) and 3-(furan-2-yl)propenal (0.269g, 2.2mmol) were reacted to give the title compound (1.207g, 94%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.0Hz, 17-H3), 1.20 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 4.7-4.8 (IH, m, l-H), 6.14

(1H, dd, si lδ.δ and 5.4Hz, l'-H), 6.23 (IH, d, si 3.3Hz, 3"-H), 6.36 (lH, ^' dd, s∑ 3.3 and 1.8Hz, 4"-H>, 6.49 (IH, dd, 15.8 and 1.0Hz, 2'-H), and 7.34 (IH, d, s∑ 1.4Hz, 5"-H); m z 640 (M ⁺ , 0.4%), 622 (0.4), 129 (54), 117 (100), and 73 (98). (Found: M ⁺ , 640.3267. C3χH ₅ g0 ₈ Si3 requires M, 640.3283).

hi 3R.4R-Bistrimethylsilyloxy-2S-[3.5-dioxo-l-(furan-2-vPhex-l( E)-en-

6-vn-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyPtetrahvdropyran

Using the method described in 6b, the product from 52a (1.187g, l.δδmmol) in benzene (70ml) was reacted with manganese dioxide (3.0g) for 2h to give the title compound (0.320g, 69%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.1Hz, I7-H3), 1.20 (3H, d, s∑ 6.3Hz, 14-H ₃ ), δ.71 (IH, s, 2-H), 6.3δ (IH, d, si lδ.6Hz, l'-H), 6.47 (IH, dd, si 3.4 and 1.9Hz, 4"-H), 6.57 (IH, d, si 3.4Hz, 3"-H), 7.34 (IH, d, si 15.6Hz, 2 ^* -H), and 7.48 (IH, d, si 1.5Hz, 5"- H); m z 638 (M ⁺ , 1%), 623(1), 121(67), 117(89), and 73(100). (Found: M ⁺ , 638.3140. C3XH54O8S-3 requires M, 638.3127). The ^X H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

__} 3R.4R-Dihvdroxy-2S-r3.δ-dioxo-l-(furan-2-vPhex-l(E)-en-6-vn -5S- (2S.3S-epoxy-5S-hydroxy-4S-methylhexyPtetraydropyran

Using the method described in 5c, the product from 52b (0.78 lg, 1.22mmol) was deprotected to give the title compound (0.477g, 93%); m.p. 150-151 ^O C; v _ma χ (KBr) 1632, 1594, 1458, 1115, 1017, and 756cm" ¹ ; λ _max (EtOH) 358nm (ε _m 33,626); δg (CD3OD) inter alia 0.94 (3H, d, si 7.0Hz, I7-H3), 1.20 (3H, d, sI 6.4Hz, 14-H ₃ ), 5.82 (IH, s, 2-H), 6.43 (IH, d, si 15.7Hz, 1 ^* -H), 6.54 (IH, dd, 3.4 and 1.9Hz, 4"-H), 6.71 (IH, d, s∑ 3.4Hz, 3"-H), 7.36 (IH, d, J lδ.7Hz, 2 ^* -H), and 7.62 (IH, d, s∑ 1.4Hz, 5"-H); δ _c (CD3OD) 12.2 (C-17), 20.3 (C-14), 33.0 (C-9), 41.7 (C-8), 43.7 (C-12), 44.1 (C-4), 66.8 (C-10), 61.3 (C-11), 66.4 (C-16), 69.8 (C-6), 70.7 (C-13), 71.5 (C- 7), 75.3 (C-δ), 102.6 (C-2), 113.6, llδ.4, 121.3, 127.2, and 146.2 (C-1 ^* , 2 ^* , 3", 4" and 5"), 163.1 (C-2 ^** ) (C-3 and 1 not visible); m/z 422 (M+, 4%), 163 (40), and 121(100); (Found: M ⁺ , 422.1946. C22H30O8 requires M, 422.1941). The spectra indicated that the title compound was essentially in the enolic form.

EXAMPLE 53

3R.4R-Dihvdroxy-2S-r3.5-dioxo-l-(4-methoxyphenvPhex-l(E)-en- 6-vn-6S- (2S.3S-epoxy-5S-hvdroxy-4S-methylhexyPtetrahvdropyran

δ al 3R.4R-Bistrimethylsilyloxy-2S-r3-hydroxy-l-(4-methoxyphenvP- 5- oxohex-l(E)-en-6-yll-5S-(2S.3S-epoxy-δS-trimethylsilyloxy-4 S- methylhexyPtetrahvdropyran

Using the method described in 5a, tristimethylsilylmonone (1.038g, 0 2mmol) and 4-methoxycinnamaldehyde (0.357g, 2.2mmol) were reacted to give the title compound (1.200g, 88%); δg (CDCI3) inter alia 0.89 (3H, d, s∑ 7.1Hz, I7-H3), 1.19 (3H, d, s∑ 6.3Hz, 14-H ₃ ), 3.81 (3H, s, OCH3), 4.68-4.78 (IH, m, l-H), 6.07 (IH, dd, si 15.9 and 6.1Hz, l'-H), 6.58 (IH, d, si 15.9Hz, 2 ^* -H), 6.85 (2H, d, si 8.7Hz, 2"-H, 6"-H), and 7.31 (2H, d, s∑ 8.7Hz, 3"-H, 5"- 5 H); m/z (NH3 DCI) 698 (MNH ₄ +, 5%), 680 (MH+, 1), 180(38), 163(100), and 90(δ2).

h 3R.4R-Bistrimethylsilyloxy-2S-[3.5-dioxo-l-(4-methoxyphenyl) hex- l ⁽ E ⁾ -en-6-yl1-5S- ⁽ 2S.3S-epoxy-5S-trimethylsilyloxy-4S- 0 methylhexyPtetrahvdropyran

Using the method described in 6b, the product from 53a (1.157g, 1.70mmol) in benzene (70ml) was reacted with manganese dioxide (3.0g) for 2h to give the title compound (0.840g, 73%); δg (CDCI3) inter alia 0.90 δ (3H, d, s∑ 7.0Hz, 17-H ₃ ), 1.20 (3H, d, <Σ 6.3Hz, 14-H ₃ ), 3.84 (3H, s, OCH3), . 5.71 (IH, s, 2-H), 6.36 (IH, d, s∑ 15.9Hz, l'-H), 6.90 (2H, d, s∑ 8.8Hz, 2"-H, 6"-H), 7.47 (2H, d, s∑ 8.8Hz, 3"-H, δ"-H), and 7.56 (IH, d, s∑ 15.9Hz, 2'-H); m/z 678 (M ⁺ , 0.4%), 663 (0.7), 161(82), 117(63), and 73(100). (Found: M ⁺ , 678.3461. C34H5sθ8Si3 requires M, 678.3440). The ^-H n.m.r. spectrum 0 indicated that the title compound was essentially in the enolic form.

£l 3R.4R-Dihvdroxy-2S-r3.5-dioxo-l-(4-methoxyphenyl)hex-l(E)-en -6- yl1-δS-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetrahvdropyr an

δ Using the method described in 5c, the product from 51b (0.815g, 1.2mmol) was deprotected to give the title compound (0.46δg, 84%); m.p. 130-132°C; v _ma χ (KBr) 349δ, 1636, 158δ, 1511, 1251, 1174, and 1114cm" ¹ ; λ _ma χ (EtOH) 3δ9nm (ε _m 35,962); δg (CD3OD) inter alia 0.94 (3H, d, s∑ 7.0Hz,

17-H ₃ ), 1.19 (3H, d, si 6.5Hz, 14-H ₃ ), 3.82 (3H, s, OCH3), δ.82 (IH, s, 2-H), 6.51 (IH, d, si 15.9Hz, 1"-H), 6.95 (2H, d, si δ.δHz, 2"-H, 6"-H), and 7.54 (3H, 2d, si 15.9 and δ.δHz, 2"-H, 3"-H, 5"-H); δc (CD3OD/CDCI3) 12.2 (C- 17), 20.3 (C-14), 32.6 (C-9), 41.1 (C-8), 43.3 (C-12), 43.7 (C-4), 56.8 5 (OCH3), 56.6 (C-10), 61.1 (C-11), 66.2 (C-16), 69.4 (C-6), 70.5 (C-13), 71.1 (C-7), 75.0 (C-5), 101.8 (C-2), 115.1 (C-2" and 6"), 121.0 (C-2 ^* ), 128.7 (C-1"), 130.4 (C-3" and 5"), 140.6 (C-1'), 162.3 (C-4"), 178.1 (C-1), and 199.4 (C-3); ^" m/z 462 (M ⁺ , 0.6%) and 161(100). (Found: M ⁺ , 462.2270. C25H34O8 requires M, 462.2254). The n.m.r. spectra indicated that the title 10 compound was essentially in the enolic form.

EXAMPLE 54

3R.4R-Dihvdroxy-2S-(3.5-dioxo-l-phenylhex-l-vn-6-vP-6S-(2 S.3S-epoxy- lδ 6S-hydroxy-4S-methylhexyl)tetrahvdropyran

al 3R.4R-BistrimethylsilvIoxy-2S-(3-hydroxy-5-oxo-l-phenylhex-l -vn-

6-vP-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- methylhexyPtetrahvdropyran 0

Using the method described in δa, tristrimethylsilylmonone (1.038g, 2mmol) and phenylpropynal (0.27ml, 2.2mmol) were reacted to give the title compound (1.139g, 36%); δg (CDCI3) inter alia 0.90 (3H, d, si 7.0Hz, I7-H3), 1.20 (3H, d, si 6.3Hz, 14-H ₃ ), δ.00-5.10 (IH, m, l-H), and 7.27-7.49 δ (5H, m, Ar-H); m/z 648 (M+, 6%), 117(80), and 73(100). (Found: M ⁺ , 648.3346. C33H5g0 ₇ Si3 rquires M, 648.334).

hi 3R.4R-Bistrimethylsilyloxy-2S-(3.δ-dioxo-l-phenylhex-l-vn-6 -vP- 5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S-methylhexyPtetrahydr opyran 0

The product from 52a (0.660g, lmmol) in dichloromethane (60ml) was stirred with manganese dioxide (active black, 1.38g) at room temperature for 75 minutes. After this time the mixture was filtered and the filtrate evaporated. The crude product was purified by column chromatography, 5 eluting with 3-10% ethyl acetate in hexane, to give the title compound (0.328g, 50%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.1Hz, 17-H ₃ ), 1.20 (3H, d, 16.3Hz, I4-H3), 5.9δ (IH, s, 2-H), and 7.32-7.60 (5H, m, Ar-H); m z 646 (M ⁺ , 0.2%), 631 (0.6), 2δ8(2δ), 186(41), 117(46), and 73(100).

(Found: M ⁺ , 646.3164. C33H ₅ 4θ ₇ Si3 requires M, 646.3177). The n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

_! 3R.4R-Dihvdroxy-2S-(3.5-dioxo-l-phenyl(hex-l-vn-6-vP)-δS-(2 S.3S- epoxy-5S-hvdroxy-4S-methylhexyPtetrahvdropyran

Using the method described in δc, the product from 54b (0.320g, 0.49mmol) was deprotected to give the title compound (0.117mg, 55%); ^v max ( Br) 3419, 2203, 1602, 1443, 1110, 1043, and 758cm- ¹ ; λ _max

(EtOH) 328nm (ε _m 20,521); δg (CD3OD) inter alia 0.94 (3H, d, si 7.1Hz, I7-H3), 1.20 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 5.98 (IH, s, 2-H, exchanging rapidly), and 7.38-7.61 (5H, m, Ar-H); δ _C (CDCI3) 12.7 (C-17), 20.6 (C-14), 31.6 (C-9), 36.4 (C-4), 39.7 (C-8), 42.8 (C-12), 55.7 (C-10), 61.3 (C-11), 65.7 (C-16), 68.7 (C-6), 70.1 (C-7), 71.2 (C-13), 73.7 (C-5), 85.1 and 94.3 (C=C), 105.6 (C-2), 120.3 (C-1'), 126.0-132.6 (C-Ar), C-1 and C-3 assignments uncertain as all forms rapidly interconverting; m/z 430 (M ⁺ , 18%), 412(5), 200(30), 186(100), and 110(66). (Found: M ⁺ , 430.1984. C24H30O7 requires M, 430.1992). The spectra indicated that the title compound was mainly in the enolic form.

EXAMPLE 55

3R.4R-Dihvdroxy-2S-r4-(2-dimethylaminopyrimidin-5-vP-2.4- dioxobut-l- yll-5S-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyPtetrahvdropyra n

al 2-Dimethylaminopyrimidine-5-carboxaldehvde

δ-Bromo-2-chloropyrimidine was converted, using the methods described in 30a, to the title compound (0.495g, 62%); δg (CDCI3) 3.31 (6H, s, N(CH ₃ ) ₂ ), 8.73 (2H, s, 4-H, 6-H), and 9.77 (IH, s, CHO); m/z 151 (M ⁺ , 100%), 136(55), 122(74), and 95(45). (Found: M ⁺ , 151.0747. CgHgN ₃ 0 requires M, 151.0746).

hi 3R.4R-Bistrimethylsilyloxy-2S-r4-(2-dimethylaminopyrimidin-5 -vP- 4-hvdroxy-2-oxobut-l-yl1-5S-(2S.3S-epoxy-δS-trimethylsilylo xy-4S- methylhexyPtetrahvdropyran

- llO - Using the method described in δa, tristrimethylsilylmonone (1.038g, 2mmol) and 2-dimethylaminopyrimidine-δ-carboxaldehyde (0.333g, 2.2mmol) were reacted to give the title compound (0.997g, 74%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.1Hz, 17-H ₃ ), 1.19 (3H, d, s∑ 6.4Hz, 14- δ H3), 3.20 (6H, s, N(CH ₃ ) ₂ ), 4.9δ-5.0δ (IH, m, l-H), and 3.33 (2H, s, 4'-H, 6 ^* -H); m_z 669 (M ⁺ , 1%), 176(46), 151(42), 129(72), 117(93), and 73(100). (Found: M ⁺ , 669.3645. requires M, 669.3661).

s) 3R.4R-BistrimethvIsilyloxy-2S-r4-(2-dimethylaminopyrimidine- 5- 0 vP-2.4-dioxobut-l-vn-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S - methylhexyPtetrahvdropyran

Using the method described in 6b, the product from δ3b (0.949g, 1.42mmol) in benzene (70ml) was reacted with manganese dioxide (3g) for 3h to give the title compound (0.421g, 45%); δg (CDCI3) inter alia 0.90 (3H, d, s∑ 7.1Hz, I7-H3), 1.19 (3H, d, s∑ 6.4Hz, 14-H ₃ ), 3.28 (6H, s, N(CH ₃ ) ₂ ), 6.07 (IH, s, 2-H), and 8.80 (2H, s, 4 ^* -H, 6 ^* -H); m z 667 (M ⁺ , TO, 652(2), 192(50), 150(74), and 73(100). The ¹ H n.m.r. spectrum indicated that the titie compound was essentially in the enolic form.

dl 3R.4R-Dihvdroxy-2S-[4-(2-dimethylaminopyrimidin-5-vP-2.4- dioxobut-l-vn-5S-(2S.3S-epoxy-5S-hvdroxy-4S- methylhexyPtetrahvdropyran

Using the method described in 5c, the product from 53c (0.387g,

0.58mmol) was deprotected to give the title compound (0.253g, 97%); v _max (KBr) 3478, 1604, 1559, 1412, 1326, 1284, 1109, and 1059cm- ¹ ; λ _max (EtOH) 344nm (ε _m 29,85δ); δg (CD3OD) inter alia 0.94 (3H, d, si 7.0Hz, 17-H3), 1.19 (3H, d, 16.4Hz, 14-H ₃ ), 3.26 (6H, s, N(CH ₃ ) ₂ ), 6.26 (IH, s, 2- H), and δ.δl (2H, s, 4 ^* -H, 6 ^* -H); δc (CD3OD/CDCI3) 12.2 (C-17), 20.2 (C- 14), 32.6 (C-9), 37.6 (N(CH ₃ ) ₂ ), 41.2 (C-8), 41.6 (C-4), 43.3 (C-12), 56.6 (C- 10), 61.1 (C-11), 66.2 (C-16), 69.4 (C-6), 70.5 (C-13), 71.1 (C-7), 75.1 (C-5), 96 (C-2), 117.3 (C-5 ^* ), 158.4 (C-4 ¹ and 6'), 163.4 (C-2'), 183.1 (C-1), and 191.6 (C-3); m/z 451 (M+, 2%), 166(30), and 150(100). (Found: M ⁺ , 451.2343. C22H33N3O7 requires M, 451.2319). The n.m.r. spectra indicated that the title compound was essentially in the enolic form.

EXAMPLE 56

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(2-methoxypyrimidin-δ-yl)bu t-l-yll-5S- (2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetrahvdropyran

5 al 2-Methoxypyrimidine-5-carboxaldehvde

Using the method described in 21a, 5-bromo-2-methyoxypyrimidine (O.δδg, 3.07mmol) was converted to the title compound (O.lδδg, 44%); δg (CDC1 ₃ ) 4.14 (3H, s, OCH3), 9.00 (2H, s, 4-H, 6-H), and 10.03 (IH, s, 10 CHO); m z 133 (M ⁺ , 100%), 123(20), and 108(80). (Found: M ⁺ , 138.0433. CgHgN2θ2 requires M, 138.0429).

hi 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-4-(2-methoxypyrimid in- 5-vP-2-oxobut-l-yll-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S- lδ methvIhexyPtetrahvdropyran

Using the method described in δa, tristrimethylsilylmonone (O.δOg, 0.97mmol) and 2-methoxypyrimidine-5-carboxaldehyde (0.134g, 0.97mmol) were reacted to give the title compound (0.384g, 61%); δg 0 (CDCI3) inter alia 0.90 (3H, d, s∑ 7.1Hz, 17-H ₃ ), 1.20 (3H, d, J 6.4Hz, 14- H3), 4.02 (3H, s, OCH3), δ.11-5.21 (IH, m, l-H), and 8.δ3 (2H, s, 4'-H, 6'- H); m_z (NH3 DCI) 657 (MH+, 70%), 536(31), and 139(100).

_! 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(2-methoxypyrimid in-5- 5 vPbut-l-yll-5S-(2S.3S-epoxy-5S-trimethylsilyloxy-4S-methyl- hexyPtetrahvdropyran

Using the method described in 6b, the product from 54b (0.373g, 0.57mmol) in benzene (δOml) was reacted with manganese dioxide (l.Og) 0 for 3h to give the title compound (0.160g, 43%); δg (CDCI3) inter alia 0.89 (3H, d, s∑ 7.0Hz, I7-H3), 1.19 (3H, d, si 6.3Hz, 14-H ₃ ), 4.09 (3H, s, OCH3), 6.17 (IH, s, 2-H), and 8.9δ (2H, s, 4'-H, 6'-H); m/z 654 (M ⁺ , 2%), 639(1), 117(9δ), and 73(100). (Found: M ⁺ , 654.3186. C3oH5 ₄ N2θ ₈ Si3 requires M, 654.3186). 5 dl 3R.4R-Dihydroxy-2S-[2.4-dioxo-4-(2-methyoxypyrimidin-5-yl)bu t-l- yn-5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyPtetrahvdropyran

Using the method described in δc, the product from δ4c (O.lδg, 0.23minol) was deprotected to give the title compound (0.04δg, 45%); δg (CD3OD) 0.94 (3H, d, si 7.0Hz, 17-H ₃ ), 1.19 (3H, d, s∑ β.δHz, 14-H ₃ ), 1.30-1.48 (IH, m, 12-H), 1.64-1.74 (2H, m, 9-H ₂ ), 1.91-2.03 (IH, m, 8-H), 2.52 (IH, dd, si 14.8 and 9.4Hz, 4-H), 2.70 (IH, dd, si 7.δ and 2.2Hz, 11-H), 2.81 (IH, dt, si 5.7 and 2.2Hz, 10-H), 2.92 (IH, dd, _s i 14.8 and 2.9Hz, 4-H), 3.44 (IH, dd, si 9.2 and 3.0Hz, 6-H), 3.57 (IH, d, si 11.3Hz, 16-H), 3.73-3.84 (IH, m, 13-H), 3.δ7-3.95 (2H, m, 7-H, 16-H), 4.03 (IH, dt, si 3.0 and 9.4Hz, 5-H), 4.09 (3H, s, OCH3), 6.42 (IH, s, 2-H), and 9.08 (2H, s, 4'-H, 6'-H); m z 438 (M ⁺ , 3%), 153(71), and 137(100). (Found: M ⁺ , 438.2007. C2XH30N2O8 requires M, 438.2002). The l-H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 57

3R.4R-Dihvdroxy-2S-[2.4-dioxo-4-(4-(2-azidoethoxy)phenvPb ut-l-vIl ^' -5S- (2S.3S-epoxy-5S-hydroxy-4S-methyIhexyPtetrahvdropyran

a) 4-(2-Azidoethoxy)benzaIdehyde

A solution of 4-(2-hydroxyethoxy)benzaldehyde (1.328g, 8mmol) in dichloromethane (30ml) was treated with triethylamine (1.34mmol, 9.6mmol) and methane sulphonyl chloride (0.7ml, 9mmol). After 1 hour the reaction mixture was diluted with dichloromethane, washed with dilute citric acid, saturated sodium hydrogen carbonate and brine then dried and evaporated.

The residue was dissolved in dichloromethane (30ml) and treated with tetramethyl guanidinium azide (1.42g, 9mmol). After 24 hours more tetramethyl guanidinium azide (1.42g, 9mmol) was added and the mixture was heated at 40°C. After 48 hours at 40°C followed by 2 days at room temperature the reaction mixture was washed with water, dilute citric acid, saturated sodium hydrogen carbonate and brine then dried and evaporated. Chromatography on silica eluting with ethyl acetate hexane mixtures gave the title compound (1.17g, 76%); υ _m ax CH2CI2) 2105, 1675, 1600cm" ¹ ; δg (CDCI3) 3.65 (2H, t, J 5.0Hz), 4.24 (2H, t, J 5.0Hz), 7.06 (2H, d, J δ.δHz), 7.δδ (2H, d, J δ.δHz), 9.91 (IH, s).

b) 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-2-oxo-4-(4-(2- azidoethoxy)phenvPbut-l-vn-6S-(2S.3S-epoxy-6S-trimethv1si1yl oxy-4S- methylhexyPtetrahvdropyran

5 Using the method described in 5a, tristrimethylsilylmonone (2.076g,

4mmol) and the product from 57a (764mg, 4mmol) were reacted to give the title compound (2.3 lg, 81%); δg (CDCI3) inter alia 0.88 (3H, d, J 7.0Hz, I7-H3), 1.20 (3H, d, J 6.3Hz, 14-H ₃ ), 3.59 (2H, t, J 5.0Hz, ArOC_H ₂ ), 5.06- 5.1δ (IH, m, 1.H), 6.90 (2H, d, 8.6Hz, 3',δ'-H ₂ ), 7.25-7.38 (2H, m, 2',6'- 10 H ₂ ).

c) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(4-(2- azidoethoxy)phenvPbut-l-yll-δS-(2S.3S-epoxy-5S-trimethylsil yloxy-4S- meth ylhexyl )tetrahydrop yran lδ

Using the method described in 6b, the product from δ7b (2.25g, 3.17mmol) in benzene (140ml) was reacted with manganese dioxide (4.5 lg), for 3 hours to give the title compound (1.35g, 60%); δg (CDCI3) inter alia 0.89 (3H, d, J 7.0Hz, I7-H3), 1.20 (3H, d, J 6.3Hz, 14-H ₃ ), 3.63 (2H, t, J δ.OHz,

20 1"-H ₂ ), 4.22 (2H, t, J δ.OHz, 2"-H ₂ ), 6.22 (IH, s, 2-H), 6.96 (2H, d, J 8.8Hz, 3',5'-H ₂ ), 7÷88 (2H, d, J 8.8Hz, 2',6'-H ₂ ); (Found M ⁺ , 707.3439. _• C33H57N3θsSi3 requires M 707.3454).

d) 3R.4R-Dihydroxy-2S-r2.4-dioxo-2-oxo-4-(4-f2-azidoethoxy)phen yl)but- 5 l-yl1-5S-(2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)tetrahydropy ran

Using the method described in 5c, the product from 57c (120mg, 0.l7mmol) was deprotected to give the title compound (70mg, 90%); -max (KBr) 3424, 2112, 1604, 1507cm" ¹ ; λ _max (EtOH) 324.δnm (ε _m 21,260); δg (CDCI3) 0 inter alia 0.94 (3H, d, J 7.1Hz, 17-H ₃ ), 1.21 (3H, d, J 6.3Hz, -H3), 4.21 (2H, t, J 5.2Hz, 2"-H ₂ ), 6.21 (IH, s, 2-H), 6.93 (2H, d, J 8.9Hz, 3'δ'-H ₂ ), 7.86 (2H, d, 8.9Hz, 2'6'-H ₂ ); δ _C (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.6 (C- 9), 39.6 (C-8), 42.8 (C-4), 42.8 (C-12), 50.0 (C-1"), 56.7 (C-10), 61.3 (C-11), 65.6 (C-16), 67.2 (C-2"), 69.0 (C-7), 70.3 (C-6), 171.3 (C-13), 73.9 (C-5), 96.7 5 (C-2), 114.5 (C-3',5 ^* ), 127.5 (C-1'), 129.3 (C-2'6'), 161.8 (C-4'), lδ2.7 (C-1), 194.3 (C-3); in z (NH3DCI) 492 (MH+, 100%). The *H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 58

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-f2-N-methyl-N-2- pyridylaminoethoxy)phenvPbut-l-yl-5S-(2S.3S-epoxy-5S-hvdroxy -4S- δ methylhexyPtetrahvdropyran

a) 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-2-oxo-4-(4-(2-N-met hyl-

N-2-pyridylaminoethoxylphenyl)but-l-yl1-δS-(2S.3S-epoxy- δS- trimethylsilyloxy-4S-methylhexyPtetrahvdropyran 0

Using the method described in 5a, tristrimethylsilylmonone (518mg, lmmol) and 4-(2-N-methyl-N-2 pyridylaminoethoxy)benzaldehyde (2δ6mg, lmmol) were reacted to give the title compound (580mg, 7δ%); δg (CDC1 ₃ ) inter alia 0.90 (3H, d, 7.0Hz, 17-H ₃ ), 1.20 (3H, d, 6.3Hz, 14-H ₃ ), 5 3.15 (3H, s, N-Me), 5.06-6.16 (IH, m, l-H), 6.48-6.59 (2H, m, Ar-H), 6.88 (2H, d, 8.8Hz, 3",5 ^* -H ₂ ), 7.21-7.30 (2H, m, Ar-H), 7.41-7.62 (IH, m, Ar- H), .δ.03-8.19 (IH, m, Ar-H); m/z (NH ₂ DCI) 775 (MH+, 5%), 2δ7 (100%).

b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(4-f2-N-methvI-N- 2- 0 pyridylaminoethoxy)phenvPbut-l-yl-5S-(2S.3S-epoxy-δS- trimethylsiIyloxy-4S-methylhexyPtetrahvdropyran

Using the method described in 6b, the product from 58a (560mg, 0.72mmol) in benzene (60ml) was reacted with manganese dioxide (1.12g) δ for 4 hours to give the title compound (277mg, 49%); δg (CDCI3) inter alia 0.δ9 (3H, d, J 7.0Hz, 17-H ₃ ), 1.20 (3H, d, J 6.3Hz, 14-H ₃ ), 3.16 (3H, s, N- Me), 4.26 (2H, t, J 5.6Hz, l'-H ₂ ), 6.20 (IH, s, 2-H), 6.48-6.62 (2H, m, 3" ^* ,5 ^m -H ₂ ), 6.94 (2H, d, δ.δHz, 3 ^* ,5 ^* -H ₂ ), 7.47 (IH, dd, J 1.9, 7.1Hz, 5 ^* "- H), 7.δ4 (2H, d, δ.δHz, 3',6 ^* -H ₂ ), δ.lδ (IH, dd, J 1.4, 4.δHz, 6"'-H ₂ ); 0 (Found: M ⁺ , 772.3983. C3gHg ₄ N ₂ θ8Si3 requires M 772.3971).

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-(2-N-methyl-N-2- pyridylaminoethoxyιphenvPbut-l-yl1-5S-(2S,3S-epoxy-5S-hvdro xy-4S- methylhexyPtetrahvdropyran

Using the method described in 5c, the product from 58b (250mg, 0.32mmol) was deprotected to give the title compound (180mg, 94%); υ _m ax (KBr) 3423, 1599, 1558, 1499, 1452cm- ¹ ; λ _max (EtOH) 324.5nm (ε _m

25,150), 248.5 (18,630); δg (CDCI3) inter alia 0.90 (3H, d, J 7.0Hz, 17- H3), 1.20 (3H, d, 6.3Hz, 14-H ₃ ), 3.13 (3H, s, N-Me), 4.27 (2H, t, J 5.6Hz, 1"-H ₂ ), 6.21 (IH, s, 2-H), 6.53 (IH, d, J 8.7Hz, 3"'-H), 6.5δ (IH, dd, J 5.0, 6.8Hz, 5"'-H), 6.9δ (2H, d, J 8.δHz, 3',5'-H ₂ ), 7.48 (IH, dd, J 1.9, 7.1Hz, δ 4"'-H), 7.86 (2H, d, J δ.δHz, 3',6'-H ₂ ), 6.17 (IH, d, J 4.9Hz, with further fine coupling, 6 ^* "-H); δc (CDCI3) 12.7 (C-17), 20.7 (C-14), 31.6 (C-9), 37.6 (N-Me), 39.6 (C-8), 42.7 (C-4), 42.8 (C-12), 49.3 (C-1"), 5δ.7 (C-10), 61.2 (C- 11), 65.6 (C-16), 66.7 (C-2"), 69.2 (C-7), 70.3 (C-6), 71.3 (C-13), 73.8 (C-5), 96.4 (C-2), 105.7 (C-2"'), 111.9 (C-5'"), 114.5 (C-3'5'), 126.7 (C-D, 129.2 (C- 0 2',6"), 137.3 (C-4 ^*** ), 147.8 (C-6 ^* "), lδδ.2 (C-4 ^* ), 162.6 (C-2"'), 182.δ (C-1), 193.9 (C-3); jn/z (NH3 DCI) 5δ6 (M ⁺ , 5δ%), 121 (100%). The ^X H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

5 Example 59

3R.4R-Dihvdroxy-2S-[2.4-dioxo-4-(4-(2-piperidinylethoxy)p henvPbut-l-yl- 5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyl)tetrahvdropyran

0 a) 3R.4R-Bistrimethylsilyloxy-2S-[4-hvdroxy-2-oxo-4-(4-(2- piperidinylethoxy)phenvPbut-l-yll-5S-(2S.3S-epoxy-6S-trimeth ylsilyloxy- 4S-methylhexyPtetrahvdropyran

Using the method described in 5a, tristrimethylsilylmonone (1.0388g, 5 2mmol) and 4(2-piperidinylethoxy)benzaldehyde (466mg, 2mmol) (HD Cossey et al, JCS, 1963, 4322) were reacted to give the title compound (l.Og, 66%); δg (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, 17-H ₃ ), 1.20 (3H, d, 6.3Hz, -H3), 5.08-5.1δ (IH, m, 5-H), 6.δ7 (2H, d, J 8.7Hz, 3',5'-H ₂ ), 7.23-7.34 (2H, m, 2',6'-H ₂ ). 0 b) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(4-f2- piperidinylethoxy)phenvPbut-l-vn-δS-(2S.3S-epoxy-6S-trimeth ylsilyloxy-

4S-methylhexyPtetrahvdropyran

5 Using the method described in 6b, the product from 59a (l.Og, 1.3mmol) in benzene (70ml) was reacted with manganese dioxide (l.δg) for 3 hours to give the title compound (4δ4mg, 45%); δg (CDCI3) inter alia 0.69 (3H, d, J 7.0Hz, 17-H3), 1.21 (3H, d, J 6.4Hz, 14-H ₃ ), 6.20 (IH, s, 2-H), 6.93 (2H, d,

^" 8.8Hz, 3 ^r ,5'-H ₂ ), 7.87 (2H, d, ^" 8.8Hz, 2',6'-H ₂ ); (Found: M ⁺ , 749.4181. C38H 7NOsSi3 requires M 749.4176).

c) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-,2- piperidinylethoxy)phenyPbut-l-vn-δS-(2S.3S-epoxy-5S-hvdroxy -4S- methylhexyPtetrahvdropyran

Using the method described in δc, the product from 59b (450mg, 0.6mmol) was deprotected to give the title compound (180mg, 66%); υ _max (KBr) 3425, 2933, 1602, 1509, 1453cm ^"1 ; λ _max (EtOH) 326nm (ε _m 2000); δg (CDC1 ₃ ) inter alia 0.93 (3H, d, J 7.1Hz, 17-H ₃ ), 1.22 (3H, d, J 6.3Hz, 14- H3), 6.20 (IH, s, 2-H), 6.96 (2H, d, J 8.8Hz, 3 ^* ,δ ^* -H ₂ ), 7.85 (2H, d, J 8.8Hz, 2',6'-H ₂ ); δc (CDCI3) 12.8 (C-17), 20.9 (C-14), 24.2 (C-4 ^*** ), 25.9 (C-3" ^* ,5'"), 31.8 (C-9), 42.7 (C-4), 43.0 (C-12), 65.2 (C-2 ^* ",6'"), 55.8 (C-10), 57.8 (C-2"), 61.3 (C-11), 65.7 (C-16), 66.3 (C-1"), 69.2 (C-7), 70.5 (C-6), 71.9 (C-13), 74.0 (C-5), 96.6 (C-2), 114.7 (C-3',5 ^* ), 127.0 (C-1 ^* ), 129.3 (C-2'6 ^* ), 162.7 (C-4 ^* ), 183.0 (C-1), 194.0 (C-3); (Found: M ⁺ , 533.3001. C29H43NO8 requires M 533.2989). The l-H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 60

3R.4R-Dihvdroxy-2S-[2.4-dioxo-4-(4-f4-pyridylmethyloxy)ph envPbut-l-yrι- 5S-(2S.3S-epoxy-5S-hvdroxy-4S-methylhexyPtetrahydropyran

a) 4-(4-Pyridylmethyloxy)benzaldehyde

A solution of p-hydroxybenzaldehyde (436mg, 4mmol) in THF (50ml) and 0°C under argon was sequentially treated with triphenylphosphine (2.1g, δmmol), 4-hydroxymethylpyridine (976mg, δmmol) and diethylazodicarboxylate (1.26ml, δmmol). After V* hour ice bath removed. After 1 hour reaction mixture evaporated, added ethyl acetate and 5N hydrochloric acid. Acid phase separated, covered with ethyl acetate and basified with saturated sodium hydrogen carbonate. Organic phase separated, dried and evaporated. The residue was chromatographed on silica eluting diochloromethane/ethyl acetate mixtures to give the title compound (440mg, 52%); δg (CD3OD) 5.21 (2H, s, l'-H ₂ ), 7.04 (2H, d, J 8.7Hz, 3.5-H2), 7.51 (2H, d, J 6.1Hz, 3',5'-H ₂ ), 7.89 (2H, d, J 8.7Hz, 2,6-

H ₂ ), 8.60 (2H, d, J 6.1Hz, 2',6'-H ₂ ), 9.92 (IH, s, -CHO).

b) 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-2-oxo-4-(4-(4- pyridylmethyloxy}phenyl)but-l-yll-δS-(2S.3S-epoxy-δS-trime thylsilyloxy- 4S-meth ylhexyl )tetrah vdropyran

Using the method described in δa, tristrimethylsilylmonone (1.038g, 2mmol) and the product from 60a (426mg, 2mmol) were reacted to give the title compound (1.07g, 73%); δg (CDCI3) inter alia 0.92 (3H, d, J 7.1Hz, I7-H3), 1.20 (3H, d, J 6.3Hz, 14-H ₃ ), 4.06-4.18 (IH, m, δ-H), δ.10 (2H, s, 1"-H ₂ ), 5.10-6.18 (IH, m, l-H), 6.93 (2H, d, 8.7Hz, 3',5'-H ₂ ), 7.23-7.39 (4H, m, Ar-H), δ.62 (2H, d, J 5,9Hz, 2"',6'"-H ₂ ); m/z (NH3 DCI) 732 (MH+, 80%) 94 (100%).

c) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(4-(4- pyridylmethyloxy)phenvPbut-l-yl1-5S-(2S.3S-epoxy-δS-trimeth ylsilyloxy- 4S-methylhexyl)tetrahvdropyran

Using the method described in 6b, the product from 60b (l.Og, 1.37mmol) in benzene (70ml) was reacted with manganese dioxide (2.25g) for 3 hours to give the title compound (600mg, 60%);a δg (CDCI3) 0.90 (3H, d, J 7.0Hz, I7-H3), 1.20 (3H, d, J 6.3Hz, 14-H ₃ ), δ.16 (2H, s, 1"-H ₂ ), 6.22 (IH, s, 2-H), 7.02 (2H, d, J 8.6Hz, 3 ^* ,5'-H ₂ ), 7.37 (2H, d, J δ.δHz, 3"",5'"-H ₂ ), 7.39 (2H, d, J 8.6Hz, 2 ^* ,6 ^* -H ₂ ), 8.6δ (2H, d, J 5.8Hz, 2"',6'"-H ₂ ); (Found: M ⁺ , 729.3546. C37H ₅ gN0 ₈ Siθ3 requires M 729.3549.

d) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-f4- pyridylmethyloxy}phenvPbut-l-yl1-5S-(2S.3S-epoxy-5S-hvdroxy- 4S- methylhexyPtetrahvdropyran

Using the method described in 5c, the product from 60c (40mg,

0.055mmol) was deprotected to give the title compound (22mg, 78%); υ _max

(KBr) 3418, 1715, 1602, 1507, 1450cm" ¹ ; λ _max (EtOH) 325nm (ε _m 21140); δg (CDCI3) inter alia 0:92 (3H, d, J 7.0Hz, 17-H ₃ ), 1.23 (3H, d, J 6.3Hz, U-H3), 5.15 (2H, s, 1"-H ₂ ), 6.20 (2H, s, 2-H), 7.00 (2H, d, J 8.8Hz, 3',5'-

H ₂ ), 7.37 (2H, d, 5.8Hz, 3 ^, ",5 ^,,, -H2), 7.88 (2H, d, 8.8Hz, 2',6'-H ₂ ), 8.63

(2H, d, J 5.8Hz, 2",5"-H ₂ ); m/z (NH3 DCI) 514 (MH+, 55%), 94 (100%).

The l-H n.m.r. spectrum indicated that the title compound was essentially

in the enolic form.

Example 61

6 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-fδ-nitrofuran-2-ylmethyl oxy)phenyl) but-l-yl]-δS-(2S.3S-epoxy-δS-hvdroxy-4S-methylhexyl)tetrah ydropyran

a) 4-(5-Nitrofuran-2-ylmethyloxy)benzaIdehyde

10 A solution of 2-hydroxymethyl-5-nitrofuran (S. Brokerman and

T. Globerman, Tet, 1974, 30, 3873) (1.22g, lOmmol) in THF (100ml) under argon at 5°C was sequentially treated with triphenylphosphine (2.62g, lOmmol), p-hydroxybenzaldehyde (1.14g, 8mmol) and dimethylazodicarboxylate (1.46g, lOmmol). After 2 hours reaction mixture 5 diluted with ethyl acetate, washed with water then dried and evaporated. The residue was chromatographed on silica eluting with hexane/dichloromethane mixtures to give the title compound (1.6g, 81%); δg (CDC1 ₃ ) 5.19 (2H, s, 1 ^* -H ₂ ), 6.68 (IH, d, ^" 3.7Hz, 3"-H), 7.08 (2H, d, J 8.7Hz, 3,δ-H ₂ ), 7.34 (IH, d, 3.7Hz, 4"-H), 7.90 (2H, d, 8.7Hz, 2,6-H ₂ ). 0 b) 3R.4R-Bistrimethylsilyloxy-2S-r4-hydroxy-2-oxo-4-(4-(5-nitro furan- 2-ylmethyloxylphenvPbut-l-vn-5S-(2S.3S-epoxy-5S-trimethylsil yloxy-4S- methylhexyPtetrahvdropyran

5 Using the method described in 5a, tristrimethylsilylmonone (1.038g,

2mmol) and the product from 61a (494mg, 2mmol) were reacted to give the title compound (1.16g, 76%); δg (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, I7-H3), 1.20 (3H, d, ^" 6.3Hz, 14-H ₃ ), 5.06 (2H, s, 1"-H ₂ ), 5.07-5.12 (IH, m, l-H), 6.62 (IH, d, J 3.3Hz, 3 ^*** -H), 6.92 (2H, d, J 8.7Hz, 3 ^* ,5'-H ₂ ), 7.26-7.48 0 (3H, m).

c) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(4-(5-nitrofuran- 2- ylmethyloxy ⁾ phenyPbut-l-yl1-6S- ⁽ 2S.3S-epoxy-5S-trimethvIsilyloxy-4S- meth ylhexyl )tetrahvdrop yran δ

Using the method described in 6b, the product from 61b (1.16g, 1.52mmol) in benzene (60ml) was reacted with manganese dioxide (3.02g) for δ hours to give the title compound (270mg, 23%); δg (CDCI3) inter alia 0.89 (3H,

d, J 7.0Hz, 17-H ₃ ), 1.18 (3H, d, J 6.4Hz, 14-H ₃ ), 5.13 (2H, ^* s, 1"-H ₂ ), 6.20 (IH, s, 2-H), 6.63 (IH, d, J 3.6Hz, 3"'-H), 6.96 (2H, d, J 9.0Hz, 3,δ-H ₂ ), 7.32 (IH, d, J 3.6Hz, 4"'-H), 7.90 (2H, d, J 8.9Hz, 2',6'-H ₂ ); m/z (NH3 DCI) 781 (MNH ₄ +, 20%), 764 (MH+, 50%), 112 (100%).

d) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-(δ-nitrofuran-2- ylmethyloxy)phenvPbut-l-yl1-5S-(2S.3S-epoxy-5S-hvdroxy-4S- methylhexyPtetrahvdropyran

Using the method described in 5c, the product from 61c (250mg,

0.33mmol) was deprotected to give the title compound (126mg, 70%); - _ma χ (KBr) 3463, 1604, 1507, 1468cm" ¹ ; λ _max (EtOH) 319.5nm (ε _m 30,504); δg (d -MeOH) inter alia 0.96 (3H, d, J 7.0Hz, 17-H3), 1.20 (3H, d, J 6.3Hz, U-H3), 5.23 (2H, s, 1"-H ₂ ), 6.36 (IH, s, 2-H), 6.85 (IH, d, J 3.6Hz, 3"'-H), 7.11 (2H, d, J 6.8Hz, 3',5'-H ₂ ), 7.44 (IH, d, J 3.6Hz, 4"'-H), 7.93 (2H, d, J δ.δHz, 2',6'-H ₂ ); δc (CD3OD) 12.4(C-17), 20.5 (C-14), 33.1 (C-9), 41.8 (C- 8), 42.7 (C-4), 43.9 (C-12), 57.0 (C-10), 61.4 (C-11), 63.2 (C-16), 66.7 (C-2"), 70.0 (C-7), 70.9 (C-6), 71.1 (C-13), 75.7 (C-5), 97.7 (C-2), 113.4 (C-2"'), 114.3 (C-3'"), 116.0 (C-3',5'), 129.6 (C-1 ^* ), 130.4 (C-2',6 ^* ), 154.9 (C-1"'), 162.9 (C-4 ^* ), 184.1 (C-1), 195.1 (C-3); m/z (NH3 DCI) 565 (MNH4+, 8%), 548 (MH+, 20%), 112 (100%). The l-H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Example 62

3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-[furan-2-ylmethyloxy)p henvPbut-l- yll-5S-(2S.3S-epoxy-6S-hydroxy-4S-methylhexyPtetrahvdropyran

a) 4-(Furan-2-ylmethyloxy)benzaldehvde

Furfurylalcohol (0.86ml, lOmmol) was added dropwise to a cold (5°C) mixture of sodium hydride (δ0%, 300mg, lOmmol) in DMF (40ml). After 1 hour p-fluoro-benzaldehyde (1.07ml, lOmmol) was added. After 3 hours reaction mixture poured into water and extracted with ethyl acetate. Organic phase washed with dilute sodium carbonate and brine then dried and evaporated. Chromatography on silica eluting ethyl acetate/hexane mixtures gave the title compound (700mg, 35%); δg (CDCI3) inter alia 5.10 (2H, s, l'-H ₂ ), 6.38 (IH, dd, J 1.9, 3.2Hz, 4"-H), 6.46 (IH, d, J 3.1Hz,

δ' ^* -H), 7.04 (2H, d, δ.7Hz, 3,5-H ₂ ), 7,41 (IH, bs, 3"-H), 7.86 (2H, d, J δ.7Hz, 2,6-H ₂ ), 9.92 (IH, s, CHO).

b) 3R.4R-Bistrimethylsilyloxy-2S-r4-hvdroxy-2-oxo-4-(4-(furan-2 - δ ylmethyloxy)phenvPbut-l-vI1-δS-(2S.3S-epoxy-5S-trimethylsil yloxy-4S- methylhexyPtetrahydropyran

Using the method described in δa, tristrimethylsilylmonone (1.03δg, 2mmol) and the product from 62a (400mg, 2mmol) were reacted to give the 0 title compound (686mg, 43%); δg (CDCI3) inter alia 0.90 (3H, d, J 7.1Hz, I7-H3), 1.21 (3H, d, 6.3Hz, 14-H ₃ ), 4.98 (2H, s, 1"-H ₂ ), δ.06-5.17 (IH, m, δ-H), 6.39 (IH, dd, J 1.9, 3.2Hz, 4"'-H), 6.41 (IH, d, 3.2Hz, 3'"-H), 6.96 (2H, d, J δ.6Hz, 3 ^* ,5'-H ₂ ), 7.24-7.35 (2H, m, 2',6'-H ₂ ), 7.45 (IH, d, J 1.7Hz, 5 ^* "-H); m/z (NH3 DCI) 738 (MNH4- ¹ -, 2δ%), 203 (100%).

c) 3R.4R-Bistrimethylsilyloxy-2S-r2.4-dioxo-4-(4-ffuran-2- ylmethyloxy)phenyPbut-l-yl1-5S-(2S.3S-epoxy-δS-trimethylsil yloxy-4S- methylhexyPtetrahydropyran

Using the method described in 6b, the product from 62b (650mg, 0.9mmol) in benzene (60ml) was reacted with manganese dioxide (1.3g) for 3 hours to give the title compound (293mg, 43%); δg (CDCI3) 0.89 (3H, d, J 7.1Hz, I7-H3), 1.20 (3H, d, 6.2Hz, 14-H3), 4.07-4.16 (IH, m, δ-H), δ.07 (2H, s, 1 ^* '-H), 6.20 (IH, s, 2-H), 6.41 (IH, dd, J 1.9, 3.2Hz, 4 ^* "-H), 6.47 (IH, d, J 3.4Hz, 3' ^* '-H), 7.02 (2H, d, J 3.9Hz, 3',5'-H ₂ ), 7.4δ (IH, d, J 2.0Hz, 5"'-H), 7.δδ (2H, d, J δ.9Hz, 3',6'-H ₂ ); m/z (NH3 DCI) 719 (MH+, 40%), 90 (100%).

d) 3R.4R-Dihvdroxy-2S-r2.4-dioxo-4-(4-ffuran- 2v]methyloxy)phenvPbut-l-vn-5S-(2S.3S-epoxy-5S-hvdroxy-4S- methylhexyPtetrahvdropyran

Using the method described in 5c, the product from 62c (260mg, 0.36mmol) was deprotected to give the title compound (15δmg, 87%); -max (KBr) 3424, 1716, 1603, 1507, 1452cm" ¹ ; λ _max (EtOH) 324.5nm (ε _m 22,418); δg (CDCI3) inter alia 0.92 (3H, d, 7.1Hz, 17-H ₃ ), 1.22 (3H, d, J 6.3Hz, I4-H3), 5.09 (2H, s, 1"-H), 6.20 (IH, s, 2-H), 6.40 (IH, dd, J 1.9, 3.1Hz, 4"'-H), 6.47 (IH, d, J 3.1Hz, 3" ^* -H), 7.04 (2H, d, J 8.9Hz, 3 ^* ,5'-H2), 7.88 (2H, d, 8.9Hz, 2',6'-H ₂ ); δc (CDCI3) 12.7 (C-17), 20.8 (C-14), 31.6

(C-9), 39.6 (C-8), 42.δ (C-4), 42.8 (C-12), 64.2 (C-10), 61.3 (C-11), 62.4 (C- 16), 6δ.6 (C-1"), 69.1 (C-7), 70.3 (C-6), 71.3 (C-13), 73.9 (C-5), 96.6 (C-2), 110.4 (C-3'"), 110.6 (C-4 ), 127.3 (C-1'), 129.2 (C-2',6'), 143.6 (C-5'"), 149.5 (C-2""), 162.0 (C-4'), 182.7 (C-1), 194.2 (C-3); m/z (NH ₃ DCI) 503 (MH+, 85%), δ3 (100%). The l-H n.m.r. spectrum indicated that the title compound was essentially in the enolic form.

Biological Data

The activity ofthe Examples 1 to 62 against various bacteria* which are important in the diseases of humans was assayed in vitro using serial dilutions in nutrient agar with δ% chocolated horse blood.

The MIC's were determined after incubation for 18h at 37°C and values in the range 0.03 to 128 mg/ml" ¹ were observed.

* H. influenzae QI: B. catarrhalis 1502; S. pyogenes CN10;

S. pneumoniae PU7; and S. aureus Oxford.

The antibacterial activity of compounds of the instant invention against Legionella organisms are assayed in the following manner:

All compounds to be tested are dissolved in distilled water.

Organism: L.pneumophila 1624, serogroup 1. The culture is thawed from frozen skim milk stocks and streaked onto supplemented buffered charcoal yeast extract agar (BCYEα, Oxoid). Three days later, colonies are suspended into tissue culture medium (TCM=Eagle's Minimal Essential Medium + Earles' salts supplemented with 10% foetal calf serum, 2mM L-glutamine and 1% non-essential amino acids) to

MacFarland's barium sulphate opacity standard 0.5. The suspension is further diluted 1:100 in TCM to yield a final inoculum of 4÷δ3 x 106

cfu/ml.

Inoculation of cells: Human foetal lung fibroblast (MRC-δ) cells are grown to 80% confluency in 6-well plates. The medium is removed and the monolayers washed twice with Dulbecco's PBS and the inoculum added.

Dosing: Sixteen hours after infection (time Oh), the medium is removed and the inoculated monolayers washed twice to remove any adherent, non-intracellular, organisms. The compounds are prepared to the required concentrations (0.5, 2 and 8μg/ml) in TCM, and added to the cells. Erythromycin at 0.5 and 2μg/m is used as a control.

Sampling: At 0, 3, 12, 24, 36, 4δ and 72h after the dose, the medium is removed from one well/treatment, and the monolayers washed twice.

Sterile distilled water is added and left for 30 min to lyse the cells. After vigorous trituration, the lysate is serially diluted in Mueller Hinton brother and plated onto BYCEα and 6% horse blood agars. Colonies of L.pneumophila are counted after 72h incubation at 37°C.

Stability tests: The stability ofthe compounds in TCM is also examined over a 72h period. Solutions of 2 μg/ml of each ofthe compounds to prepared in TCM and incubated at 37°C or 4°C and aliquots are removed at intervals. The compounds of formula (I) are assayed against Bacillus subtilis ATCC 6633 and erythromycin lactobinate against Sarcina lutea NCTC 8340, using standards prepared in TCM.