The silylation of 3(S)-hydroxytetrahydrofuran-2-one (I) with TBDMS-Cl and imidazole gives the silyl ether (II), which is methylated with MeLi in THF yields the 3(S)-(TBDMSO)-5-hydroxy-2-pentanone (IV), through the hemiketal intermediate (III). Simultaneously, the cyclization of 1,3-dichloropropanone (V) with thioacetamide (VI) in refluxing ethanol affords 4-(chloromethyl)-2-methylthiazole (VII), which is treated with tributylphosphine to provide the phosphonium salt (VIII). The condensation of (VIII) with the ketone (IV) gives the unsaturated alcohol (IX), which is oxidized to the corresponding aldehyde (X) by means of oxalyl chloride in DMSO. The condensation of (X) with 2-phosphonopropionic acid triethyl ester (XI) by means of KHMDS gives the dienoic acid ethyl ester (XII), which is reduced with DIBAL in THF yielding the corresponding primary alcohol (XIII). The condensation of (XIII) with the chiral sulfone intermediate (XIV) by means of KHMDS and PPh3 affords the corresponding adduct (XV), which is desulfurized with Na/Hg in THF/methanol giving the silylated diol (XVI). The selective monodesilylation of (XVI) with CSA in methanol/dichloromethane yields the primary alcohol (XVII), which is oxidized with Dess Martin periodinane (DMP) to the aldehyde (XVIII). The condensation of (XVIII) with the intermediate chiral ketone (XIX) by means of LDA in THF affords the hydroxy ketone (XX).

The silylation of the OH group of (XX) with TBDMS-triflate gives the fully silylated ketone (XXI), which is selectively monodesilylated with CSA in methanol/dichloromethane affording the primary alcohol (XXII). Oxidation of (XXII) first with Dess Martin periodinane (DMP) and then with NaClO2 provides the corresponding carboxylic acid (XXIII), which is again selectively desilylated with TBAF in THF to give the 15-hydroxy-5-oxoheptadecadienoic acid (XXIV). The cyclization of (XXIV) by means of DEC and DMAP in chloroform yields fully silylated Epothilon D (XXV), which is desilylated with HF/pyridine in THF to afford Epothilon D (XXVI). Finally, this compound is epoxidized with MCPBA in chloroform to afford the target Epothilon B.

The chiral sulfone intermediate (XIV) has been obtained as follows: The silylation of 3-hydroxy-2(R)-methylpropionic acid methyl ester (XXVII) as usual gives the silylated ester (XXVIII), which is reduced to the chiral propanol (XXIX). The reaction of (XXIX) with TsCl and pyridine yields the tosylate (XXX), which is condensed with methyl phenyl sulfone (XXXI) by means of n-BuLi in THF to afford the chiral sulfone (XXXII). Desilylation of (XXXII) with TBAF in THF provides the 4-hydroxy-3-methylbutylsulfone (XXXIII), which is finally resilylated with TBDMS-Cl and imidazole to furnish the target intermediate (XIV).

The intermediate chiral ketone (XIX) has been obtained as follows: The silylation of 3(S)-hydroxy-2,2-dimethyl-5-(TBDMSO)pentanoic acid methyl ester (XXXIV) with TBDMS-triflate gives the fully silylated ester (XXXV), which is reduced with DIBAL in THF to yield the alcohol (XXXVI). The oxidation of (XXXVI) with Dess Martin periodinane (DMP) affords the aldehyde (XXXVII), which by reaction with ethylmagnesium bromide in ethyl ether provides the expected secondary alcohol (XXXVIII). Finally, this compound is oxidized with Dess Martin periodinane (DMP) to furnish the target chiral ketone (XIX).

The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provide the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of KOtBu in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of TsOH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).

Hydrolysis of the dimethylacetal group of (XXVIII) with Ts-OH in dioxane/water yields the corresponding aldehyde (XXIX), which is submitted to an intramolecular aldolization by means of KHMDS in THF to afford a mixture of diastereomeric macrolactones (XXX) and (XXXI). The undesired isomer (XXX) was recovered, oxidized with DMP to the ketone (XXXII) and reduced again with NaBH4 to provide high yields of the desired isomer (XXXI). Selective desilylation of (XXXI) with HF/pyridine in THF gives the diol (XXXIII), which is selectively monosilylated with Tbdms-OTf and lutidine in dichloromethane, yielding the bis-silylated triol (XXXIV). The oxidation of the free OH group of (XXXIV) with DMP in dichloromethane affords the corresponding ketonic derivative (XXXV), which is deprotected with HF/pyridine in THF, providing the free dihydroxy compound (XXXVI). Finally, this compound is epoxidized by means of dimethyldioxirane (DMDO) in dichloromethane.

The reaction of (R)-glycidol (XLVI) with dihydropyran (DHP) and PPTS in dichloromethane gives the protected glycidol (XLVII), which is treated with the lithium acetylide (XLVIII) and BF3/Et2O in THF to yield the acetylenic alcohol (IL). The protection of the OH group of (IL) with Mem-Cl and DIEA in hot dichloroethane affords compound (L), which is treated with PPTS in methanol to provide the primary alcohol (LI). The oxidation of (LI) with oxalyl chloride in DMSO/dichloromethane gives the corresponding aldehyde (LII), which is treated with Me-MgBr in ethyl ether to yield the secondary alcohol (LIII). The oxidation of (LIII) with TPAP and NMO in dichloromethane affords the methyl ketone (LIV), which is condensed with the phosphine oxide (LV) by means of BuLi in THF, providing the adduct (LVI). The reaction of (LVI) with N-iodosuccinimide (NIS) and Cy2BH in ethyl ether gives the iodovinyl compound (LVII), which is treated with acetic anhydride, yielding the intermediate (IX).

Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) and catalyzed by (S)-(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to gives the desired thiazole intermediate (IX).

Hydrolysis of the dimethylacetal group of (XXVIII) with Ts-OH in dioxane/water yields the corresponding aldehyde (XXIX), which is submitted to an intramolecular aldolization by means of KHMDS in THF to afford a mixture of diastereomeric macrolactones (XXX) and (XXXI). The undesired isomer (XXX) was recovered, oxidized with DMP to the ketone (XXXII) and reduced again with NaBH4 to provide high yields of the desired isomer (XXXI). Selective desilylation of (XXXI) with HF/pyridine in THF gives the diol (XXXIII), which is selectively monosilylated with Tbdms-OTf and lutidine in dichloromethane, yielding the bis-silylated triol (XXXIV). The oxidation of the free OH group of (XXXIV) with DMP in dichloromethane affords the corresponding ketonic derivative (XXXV), which is deprotected with HF/pyridine in THF, providing the free dihydroxy compound (XXXVI). Finally, this compound is epoxidized by means of dimethyldioxirane (DMDO) in dichloromethane to afford the target epothilone B.

The reaction of 4-methyl-4-penten-1-ol (I) with PBr3 gives the corresponding alkyl bromide (II), which is condensed with epoxide (III) and propyne (IV) by means of Mg, CuI and pentynyl lithium to yield, after silylation with Tbdms-Cl, the protected diol (V). The selective deprotection of (V) with DDQ gives the secondary alcohol (VI), which is oxidized by the Swern reagent to afford the ketone (VII). Alternatively, ketone (VII) can also be obtained by direct oxidation of the protected diol (V) with the Jones reagent. The Horner Emmons condensation of ketone (VII) with phosphonate (VIII) provides the unsaturated alkyl thiazole (IX), which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X). The oxidation of (X) with the complex SO3/Pyr yields the carbaldehyde (XI). Alternatively, (XI) can also be obtained by direct oxidation of the terminal double bond of (IX) with (Ipc)2BH and pyridinium chlorochromate (PCC). The condensation of aldehyde (XI) with ketoacid (XII) by means of LDA in THF affords the heptadecadienoic acid (XIII), which is silylated with Tbdms-OTf to provide the protected linear precursor (XIV). The cyclization of (XIV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XV), which is desilylated by means of TBAF in THF to yield the unprotected precursor (XVI). Finally, this compound is epoxidated by means of dimethyldioxirane (DMDO) in acetone to afford the target epothilone B.

The condensation of 3-buten-2-one (I) with the phosphonate (II) by means of LDA gives the alkylated thiazole (III), which is enantioselectively epoxidated to the chiral oxirane (V) by means of oxone and the chiral ketone (IV). Alternatively, the oxidation of the chiral epoxybutanol (VI) with CrO3 or SO3 /pyridine yields the epoxybutanone (VII), which is condensed with phosphorane (II) by means of LDA to afford the already reported chiral oxirane (V). The condensation of (V) with alkyl bromide (VIII) and propyne (IX) by means of Mg, CuBr and pentynyl lithium provides the undecatrienyl thiazole (X), which is treated with Tms-OTf in order to protect its OH group, yielding the silyl ether (XI). The oxidation of the terminal double bond of (XI) by means of (Ipc)2BH and CrO3 affords the carbaldehyde (XII), which is condensed with ketoacid (XIII) by means of LDA in THF to provide the undecadienoic acid (XIV). The cyclization of (XIV) by means of benzenesulfonyl chloride and pyridine gives the macrocyclic intermediate (XV), which is finally epoxidated by means of DMDO in acetone to furnish the target epothilone B.

The condensation of alkyl bromide (I) with epoxide (II) and propyne (III) by means of Mg, CuI and pentynyl lithium gives the secondary alcohol (IV), which is silylated with Sem-Cl to yield the protected diol (V). The selective deprotection of (V) with DDQ gives the secondary alcohol (VI), which is oxidized by means of SO3 /pyridine to afford the ketone (VII). The condensation of ketone (VII) with phosphonate (VIII) by means of BuLi in THF provides the unsaturated alkyl thiazole (IX), which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X). The oxidation of (X) with oxalyl chloride yields the carbaldehyde (XI), which is condensed with ketoacid (XII) by means of LDA in THF to afford the heptadecadienoic acid (XIII). The protection of the free OH group of (XIII) with Troc-Cl and DMAP in dichloromethane provides the protected linear precursor (XIV), which is selectively monodeprotected with TFA in dichloromethane to furnish the linear hydroxyacid (XV). The macrocyclization of (XV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XVI), which is deprotected first with HF and pyridine (desilylation), and then with Zn and HOAc (elimination of the Troc protecting group), to yield the unprotected precursor (XVII). Finally, this compound is epoxidated by means of dimethyldioxirane (DMDO) in acetone to afford the target epothilone B.

The condensation of 3-buten-2-one (I) with the phosphonate (II) by means of LDA gives the alkylated thiazole (III), which is enantioselectively epoxidated to the chiral oxirane (V) by means of oxone and the chiral ketone (IV). Alternatively, the oxidation of the chiral epoxybutanol (VI) with CrO3 or SO3 /pyridine yields the epoxybutanone (VII), which is condensed with phosphorane (II) by means of LDA to afford the already reported chiral oxirane (V). The condensation of (V) with alkyl bromide (VIII) and propyne (IX) by means of Mg, CuBr and pentynyl lithium provides the undecatrienyl thiazole (X), which is treated with Tms-OTf in order to protect its OH group, yielding the silyl ether (XI). The oxidation of the terminal double bond of (XI) by means of (Ipc)2BH and CrO3 affords the carbaldehyde (XII), which is condensed with ketoacid (XIII) by means of LDA in THF to provide the undecadienoic acid (XIV). Finally, the cyclization of (XIV) by means of benzenesulfonyl chloride and pyridine gives the target epothilone D.

The reaction of 4-methyl-4-penten-1-ol (I) with PBr3 gives the corresponding alkyl bromide (II), which is condensed with epoxide (III) and propyne (IV) by means of Mg, CuI and pentynyl lithium to yield, after silylation with Tbdms-Cl, the protected diol (V). The selective deprotection of (V) with DDQ gives the secondary alcohol (VI), which is oxidized by the Swern reagent to afford the ketone (VII). Alternatively, ketone (VII) can also be obtained by direct oxidation of the protected diol (V) with the Jones reagent. The Horner Emmons condensation of ketone (VII) with phosphonate (VIII) provides the unsaturated alkyl thiazole (IX), which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X). The oxidation of (X) with the complex SO3/Pyr yields the carbaldehyde (XI). Alternatively, (XI) can also be obtained by direct oxidation of the terminal double bond of (IX) with (Ipc)2BH and pyridinium chlorochromate (PCC). The condensation of aldehyde (XI) with ketoacid (XII) by means of LDA in THF affords the heptadecadienoic acid (XIII), which is silylated with Tbdms-OTf to provide the protected linear precursor (XIV). The cyclization of (XIV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XV), which is finally desilylated by means of TBAF in THF to yield the target epothilone D.

The condensation of alkyl bromide (I) with epoxide (II) and propyne (III) by means of Mg, CuI and pentynyl lithium gives the secondary alcohol (IV), which is silylated with Sem-Cl to yield the protected diol (V). The selective deprotection of (V) with DDQ gives the secondary alcohol (VI), which is oxidized by means of SO3 /pyridine to afford the ketone (VII). The condensation of ketone (VII) with phosphonate (VIII) by means of BuLi in THF provides the unsaturated alkyl thiazole (IX), which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X). The oxidation of (X) with oxalyl chloride yields the carbaldehyde (XI), which is condensed with ketoacid (XII) by means of LDA in THF to afford the heptadecadienoic acid (XIII). The protection of the free OH group of (XIII) with Troc-Cl and DMAP in dichloromethane provides the protected linear precursor (XIV), which is selectively monodeprotected with TFA in dichloromethane to furnish the linear hydroxyacid (XV). The macrocyclization of (XV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XVI), which is deprotected first with HF and pyridine (desilylation), and then with Zn and HOAc (elimination of the Troc protecting group), to finally yield the target epothilone D.

Butane-1,4-diol (II) is anchored to chloromethyl-RESIN (I) by means of tetrabutylammonium iodide and NaH in DMF, and without isolation is treated with PPh3 I2 and imidazole to yield the phosphonium salt (III), which is treated with NaHMDS in THF/DMSO, affording the phosphorane (IV). The condensation of (IV) with the chiral aldehyde (V) in THF provides the anchored olefin (VI), which is desilylated with HF in pyridine/THF. The resulting alcohol is submitted to a Swern oxidation to give the anchored aldehyde (VII). The condensation of (VII) with the ketoacid (VIII) by means of LDA and ZnCl2 in THF yields the adduct (IX) as a diastereomeric mixture. The esterification of carboxylic acid (IX) with the alcohol (X) by means of DCC and DMAP affords the corresponding ester (XI), which is submitted to a macrocyclic ring-closing metathesis catalyzed by a ruthenium catalyst providing, after chromatographic separation of isomers, the macrocyclic lactone (XII). The desilylation of (XII) by means of TFA in dichloromethane gives the precursor (XIII), which is finally epoxidated with methyl(trifluoromethyl)dioxirane (XI) to yield the target epothilone A.

The condensation of the phosphonium salt (I) with the ketone (II) by means of NaHMDS in THF gives the diene (III), which is selectively monodeprotected with CSA in methanol/dichloromethane to yield the primary alcohol (IV). The oxidation of (IV) with SO3/pyridine affords the corresponding aldehyde (V), which is condensed with the ketoacid (VI) by means of LDA in THF to provide the heptadienoic acid (VII). The protection of the OH group of (VII) y means of Tbdms-OTf and lutidine in dichloromethane gives the fully silylated compound (VIII), which is selectively monodeprotected with TBAF in THF to yield the hydroxyacid (IX). The macrolactonization of (IX) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF affords the macrolactone (X), which is deprotected with TFA in dichloromethane to provide the precursor (XI). Finally, this compound is epoxidized by means of methyl(trifluoromethyl)dioxirane in acetonitrile to furnish the target epothilone B.

Butane-1,4-diol (II) is anchored to chloromethyl-RESIN (I) by means of tetrabutylammonium iodide and NaH in DMF, and without isolation is treated with PPh3 I2 and imidazole to yield the phosphonium salt (III), which is treated with NaHMDS in THF/DMSO, affording the phosphorane (IV). The condensation of (IV) with the chiral aldehyde (V) in THF provides the anchored olefin (VI), which is desilylated with HF in pyridine/THF. The resulting alcohol is submitted to a Swern oxidation to give the anchored aldehyde (VII). The condensation of (VII) with the ketoacid (VIII) by means of LDA and ZnCl2 in THF yields the adduct (IX) as a diastereomeric mixture. The esterification of carboxylic acid (IX) with the alcohol (X) by means of DCC and DMAP affords the corresponding ester (XI), which is submitted to a macrocyclic ring-closing metathesis catalyzed by a ruthenium catalyst providing, after chromatographic separation of isomers, the macrocyclic lactone (XII). Compound (XII) is finally desilylated by means of TFA in dichloromethane to give the target epothilone C.

Synthesis of intermediate triphenylphosphonium salt (VII): The condensation of the chiral oxazolidinone (I) with cinnamyl bromide (II) by means of NaHMDS in THF gives the adduct (III), which is treated with LiBH4 in Et2O/water to yield the alcohol (IV). The protection of (IV) with Tbdms-Cl and imidazole in DMF affords the silyl ether (V), which is treated with ozone and reduced with NaBH4 to provide the alcohol (VI). The reaction of (VI) with I2 and PPh3 gives the desired triphenylphosphonium iodide (VII).

Synthesis of intermediate aldehyde (XV): The oxidation of 4-(benzyloxy)butanol (VIII) with oxalyl chloride gives the aldehyde (IX), which is condensed with 2-(triphenylphosphoranylidene)propionic acid ethyl ester (X) in hot THF to yield the unsaturated ester (XI). The enantioselective dihydroxylation of (XI) by means of AD-mix beta and methanesulfonamide in butanol/water affords the chiral dihydroxyester (XII), which is protected with 2,2-dimethoxypropane and CSA to provide the acetonide (XIII). The reduction of the ester group of (XIII) with DIBAL in THF gives the alcohol (XIV), which is finally oxidized with DMP to yield the desired intermediate aldehyde (XV).

Assembly of the target compound: The condensation of the phosphonium salt (VII) with the aldehyde (XV) by means of NaHMDS in THF gives the adduct (XIX), which is debenzylated and hydrogenated with H2 over Pd/Al2O3 in ethanol and oxidized with NaIO4 and RuCl3 to yield the carboxylic acid (XX). The activation of (XX) with pivaloyl chloride affords the anhydride (XXI), which is condensed with the lithium oxazolidinone (XXII) to provide the cyclic amide (XXIII). The enantioselective hydroxylation of (XXIII) by means of the Davis oxaziridine and NaHMDS gives the alpha-hydroxyamide (XXIV), which is treated with N,O-dimethylhydroxylamine (XXV) to yield the methoxyamide (XXVI). The protection of the OH group of (XXVI) with Tbdms-OTf and lutidine affords the silyl ether (XXVII), which is treated with MeLi in THF, affording the methyl ketone (XXVIII). The condensation of (XXVIII) with tributyl(2-methylthiazol-4-ylmethyl)phosphonium chloride (XXIX) by means of KHMDS in THF provides the adduct (XXX).

The selective deprotection of (XXX) with CSA in dichloromethane gives the primary alcohol (XXXI), which is oxidized with DMP in dichloromethane to yield the aldehyde (XXXII). The condensation of (XXXII) with methyltriphenylphosphonium iodide (XXXIII) by means of BuLi in hexane/THF, followed by treatment with HCl in ethanol, affords the diunsaturated vicinal diol (XXXIV), which is selectively silylated to provide the vicinal diol (XXXV). The monosulfonation of (XXXV) with Ms-Cl and TEA furnishes the mesylate (XXXVI), which is cyclized to the epoxide (XXXVII) by means of K2CO3 in methanol. The oxidation of the terminal double bond of (XXXVII) with OsO4 and NaIO4 gives the aldehyde (XXXVIII), which is condensed with the intermediate ketone (XVIII) by means of LDA in THF to provide the adduct (XXXIX).

The treatment of (XXXIX) with Tbdms-OTf as before gives the silyl ether (XL), which is oxidized at its terminal double bond with OsO4 and NaIO4 to give the aldehyde (XLI).The oxidation of (XLI) with NaClO2 yields the carboxylic acid (XLII), which is selectively deprotected with TBAF in THF affording the hydroxyacid (XLIII). The macrolactonization of (XLIII) by means of 2,3,6-trichlorobenzoyl chloride and TEA in toluene provides the protected macrolactone (XLIV), which is finally desilylated by means of TFA in dichloromethane to yield the target epothilone B.

Synthesis of undecenoic ester intermediate (XXI): The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, TsOH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and Me-Li in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and TsOH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).

The asymmetric catalytic aldol reaction of aldehyde (XVI) with acetophenone by means of a chiral lanthane catalyst yields a diastereomeric mixture of hydroxyketones from which the desired isomer (XVII) is isolated. The Baeyer-Villiger oxidation of (XVII) with trimethylsilyl peroxide and SnCl4 affords the phenyl ester (XVIII), which is deprotected with BCl3 in dichloromethane, giving the trihydroxyester (XIX). The selective protection of (XIX) with Tbdms-OTf and DIEA in dichloromethane yields the bis silylated compound (XX), which is finally oxidized with DMP in dichloromethane to furnish the target undecenoic ester intermediate (XXI).

Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with HF and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in CH2Cl2 to yield the target thiazole intermediate (XXXIV).

Assembly of the target compound: The condensation of intermediates (XXI) and (XXXIV) by means of 9-BBN, a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXV), which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXVI). The macrolactonization of (XXXVI) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF affords the macrolactone (XXXVII), which is desilylated with HF and pyridine in THF, furnishing the dihydroxylactone (XXXVIII). Finally, this compound is epoxidated by means of dimethyldioxirane (XXXIX) in dichloromethane.

The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, Ts-OH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and MeLi in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and Ts-OH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).

The asymmetric catalytic aldol reaction of aldehyde (XVI) with acetophenone by means of a chiral lanthane catalyst yields a diastereomeric mixture of hydroxyketones from which the desired isomer (XVII) is isolated. The Baeyer-Villiger oxidation of (XVII) with trimethylsilyl peroxide and SnCl4 affords the phenyl ester (XVIII), which is deprotected with BCl3 in dichloromethane, giving the trihydroxyester (XIX). The selective protection of (XIX) with Tbdms-OTf and DIEA in dichloromethane yields the bis-silylated compound (XX), which is finally oxidized with DMP in dichloromethane to furnish the target undecenoic ester intermediate (XXI)

Synthesis of the thiazole intermediate (XXXIII): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with phosphonium salt (XXVII), LHMDS, Hg(OAc)2 and tetrabutylammonium iodine (TBAI) in THF provides the olefin (XXX), which is iodinated with I2 and NaHMDS in THF to give the iodinated olefin (XXXI). The desilylation of (XXXI) with HF and pyridine in THF yields the secondary alcohol (XXXII), which is acylated with Ac2O, TEA and DMAP in dichloromethane to afford the target thiazole intermediate (XXXIII).

Assembly of the target compound: The condensation of intermediates (XXI) and (XXXIII) by means of 9-BBN, a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXIV), which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXV). The macrolactonization of (XXXV) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF affords the macrolactone (XXXVI), which is desilylated with HF and pyridine in THF, furnishing the dihydroxylactone (XXXVII). Finally, this compound is epoxidated by means of dimethyldioxirane (XXXVIII) in dichloromethane to give the target epothilone B.

The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, Ts-OH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and MeLi in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and Ts-OH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).

The asymmetric catalytic aldol reaction of aldehyde (XVI) with acetophenone by means of a chiral lanthane catalyst yields a diastereomeric mixture of hydroxyketones from which the desired isomer (XVII) is isolated. The Baeyer-Villiger oxidation of (XVII) with trimethylsilyl peroxide and SnCl4 affords the phenyl ester (XVIII), which is deprotected with BCl3 in dichloromethane, giving the trihydroxyester (XIX). The selective protection of (XIX) with Tbdms-OTf and DIEA in dichloromethane yields the bis-silylated compound (XX), which is finally oxidized with DMP in dichloromethane to furnish the target undecenoic ester intermediate (XXI).

Synthesis of the thiazole intermediate (XXXIII): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with phosphonium salt (XXVII), LHMDS, Hg(OAc)2 and tetrabutylammonium iodine (TBAI) in THF provides the olefin (XXX), which is iodinated with I2 and NaHMDS in THF to give the iodinated olefin (XXXI). The desilylation of (XXXI) with HF and pyridine in THF yields the secondary alcohol (XXXII), which is acylated with Ac2O, TEA and DMAP in dichloromethane to afford the target thiazole intermediate (XXXIII).

Assembly of the target compound : The condensation of intermediates (XXI) and (XXXIII) by means of 9-BBN, a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXIV), which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXV). The macrolactonization of (XXXV) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF affords the macrolactone (XXXVI), which is finally desilylated with HF and pyridine in THF, furnishing the target epothilone D.

Synthesis of undecenoic ester intermediate (XXI): The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, Ts-OH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and Me-Li in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and RaNi in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and Ts-OH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).

The asymmetric catalytic aldol reaction of aldehyde (XVI) with acetophenone by means of a chiral lanthane catalyst yields a diastereomeric mixture of hydroxyketones from which the desired isomer (XVII) is isolated. The Baeyer-Villiger oxidation of (XVII) with trimethylsilyl peroxide and SnCl4 affords the phenyl ester (XVIII), which is deprotected with BCl3 in dichloromethane, giving the trihydroxyester (XIX). The selective protection of (XIX) with Tbdms-OTf and DIEA in dichloromethane yields the bis-silylated compound (XX), which is finally oxidized with DMP in dichloromethane to furnish the target undecenoic ester intermediate (XXI).

Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with FH and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in dichloromethane to yield the target thiazole intermediate (XXXIV).

Assembly of the target compound: The condensation of intermediates (XXI) and (XXXIV) by means of 9-BBN, a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXV), which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXVI). The macrolactonization of (XXXVI) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF affords the macrolactone (XXXVII), which is finally desilylated with HF and pyridine in THF to provide the target epothilone C.

The reaction of (S)-malic acid (I) with dimethoxypropane (II) and Ts-OH gives the carboxymethyldioxolanone (III), which is reduced with BH3/DMS and Ts-OH in toluene, yielding the chiral 2-hydroxybutyrolactone (IV). The silylation of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V), which is methylated to the lactol (Via) by means of methyl lithium in THF. The condensation of the partially silylated dihydroxypentanone (VIb) (tautomer of (VIa)) with thiazolylphosphonium salt (VII) by means of LiHMDS in THF provides the unsaturated primary alcohol (VIII), which by Swern oxidation is converted into the corresponding aldehyde (IX). The condensation of (IX) with phosphonate (X) by means of KHMDS in THF furnishes the heptadienoic ester (XI), which is reduced with DIBAL in THF to give the primary alcohol (XII). The reaction of (XII) with I2 and PPh3 in acetonitrile/Et2O gives the allylic iodide (XIII), which is condensed with sulfone (XIV) by means of KHMDS and Na/Hg in MeOH/THF, yielding the protected diol (XVII). The sulfone (XIV) has been obtained by condensation of the chiral propanol (XV) with methylphenylsulfone (XVI) by means of Ts-Cl and BuLi. The selective deprotection of the primary silyl ether of (XVIII) with CSA in methanol/dichloromethane affords the primary alcohol (XVIII), which is finally oxidized with DMP in dichloromethane to afford the target intermediate carbaldehyde (XIX).

The enantioselective condensation of 3-(tert-butyldimethylsilyloxy)propanal (XX) with ketene acetal (XXI) catalyzed by N-tosyl-D-valine and BH3/THF gives the beta-hydroxyester (XXII), which is silylated with Tbdms-OTf, yielding the bis-silyl ether (XXIII). The reduction of (XXIII) with DIBAL in toluene affords the carbinol (XXIV), which is oxidized to the corresponding aldehyde (XXV) with DMP in dichloromethane. The Grignard condensation of (XXV) with Et-MgBr in ethyl ether gives the secondary alcohol (XXVI), which is oxidized with DMP as before to yield the ketone (XXVII). Alternatively, the silylated ester (XXIII) can be treated with Tms-CH2-Li in pentane/methanol to give the methyl ketone (XXVIII), which is methylated again with MeI and LDA in THF to afford the ketone (XXVII). The condensation of ketone (XXVII) with the intermediate carbaldehyde (XIX) by means of BuLi in THF gives the adduct (XXIX), which is silylated with Tbdms-OTf, yielding the fully silylated compound (XXX). The selective monodesilylation of (XXX) with CSA in MeOH/dichloromethane affords the primary alcohol (XXXI), which is oxidized with DMP and NaClO2 to provide the carboxylic acid (XXXII).

The selective monodesilylation of (XXXII) with TBAF in THF gives the hydroxyacid (XXXIII), which is submitted to a macrolactonization by means of EDC and DMAP in chloroform to yield the macrolactone (XXXIV). The desilylation of (XXXIV) with HF in pyridine/THF affords the dihydroxy macrolactone (XXXV), which is finally epoxidized by means of MCPBA in chloroform to furnish the target epothilone B.

The reaction of (S)-malic acid (I) with dimethoxypropane (II) and Ts-OH gives the carboxymethyldioxolanone (III), which is reduced with BH3/DMS and Ts-OH in toluene, yielding the chiral 2-hydroxybutyrolactone (IV). The silylation of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V), which is methylated to the lactol (VIa) by means of methyl lithium in THF. The condensation of the partially silylated dihydroxypentanone (VIb) (tautomer of (VIa)) with thiazolylphosphonium salt (VII) by means of LiHMDS in THF provides the unsaturated primary alcohol (VIII), which by Swern oxidation is converted into the corresponding aldehyde (IX). The condensation of (IX) with phosphonate (X) by means of KHMDS in THF furnishes the heptadienoic ester (XI), which is reduced with DIBAL in THF to give the primary alcohol (XII). The reaction of (XII) with I2 and PPh3 in acetonitrile/Et2O gives the allylic iodide (XIII), which is condensed with sulfone (XIV) by means of KHMDS and Na/Hg in MeOH/THF, yielding the protected diol (XVII). The sulfone (XIV) has been obtained by condensation of the chiral propanol (XV) with methylphenylsulfone (XVI) by means of Ts-Cl and BuLi . The selective deprotection of the primary silyl ether of (XVIII) with CSA in methanol/dichloromethane affords the primary alcohol (XVIII), which is finally oxidized with DMP in dichloromethane to afford the target intermediate carbaldehyde (XIX).

Assembly of the target compound: The enantioselective condensation of 3-(tert-butyldimethylsilyloxy)propanal (XX) with ketene acetal (XXI) catalyzed by N-tosyl-D-valine and BH3/THF gives the beta-hydroxyester (XXII), which is silylated with Tbdms-OTf, yielding the bis-silyl ether (XXIII). The reduction of (XXIII) with DIBAL in toluene affords the carbinol (XXIV), which is oxidized to the corresponding aldehyde (XXV) with DMP in dichloromethane. The Grignard condensation of (XXV) with Et-MgBr in ethyl ether gives the secondary alcohol (XXVI), which is oxidized with DMP as before to yield the ketone (XXVII). Alternatively, the silylated ester (XXIII) can be treated with Tms-CH2-Li in pentane/methanol to give the methyl ketone (XXVIII), which is methylated again with MeI and LDA in THF to afford the ketone (XXVII). The condensation of ketone (XXVII) with the intermediate carbaldehyde (XIX) by means of BuLi in THF gives the adduct (XXIX), which is silylated with Tbdms-OTf, yielding the fully silylated compound (XXX). The selective monodesilylation of (XXX) with CSA in MeOH/dichloromethane affords the primary alcohol (XXXI), which is oxidized with DMP and NaClO2 to provide the carboxylic acid (XXXII).

The selective monodesilylation of (XXXII) with TBAF in THF gives the hydroxyacid (XXXIII), which is submitted to a macrolactonization by means of EDC and DMAP in chloroform to yield the macrolactone (XXXIV). Finally, the desilylation of (XXXIV) with HF in pyridine/THF affords the target epothilone D

The synthesis of intermediate tridecenoic acid (VIII) has been performed as follows: The reaction of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether gives the chiral beta-hydroxy ketone (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of the double bond of (IV) affords the aldehyde (V), which is oxidized with NaClO2 to the carboxylic acid (VI). Finally, this compound is condensed with 2(S)-methyl-6-heptenal (VII) by means of LDA in THF to provide the intermediate tridecenoic acid (VIII).

The oxoacid intermediate (VI) has been obtained as follows: The condensation of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) gives the chiral 5(S)-hydroxy-4,4-dimethyl-7-octen-3-one (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of (IV) in dichloromethane affords the aldehyde (V), which is finally oxidized with NaClO2 in tert-butanol/water to provide the target oxoacid intermediate (VI).

The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF, providing the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).

Assembly of the final product: The condensation of SAMP hydrazone (XVII) with 4-(benzyloxy)butyl iodide (XVIII) by means of LDA in THF gives the chiral 2-methylhexanal hydrazone (XIX), which is ozonolyzed in dichloromethane, yielding the free aldehyde (XX). The reduction of (XX) with NaBH4 in methanol affords the corresponding alcohol (XXI), which is protected with Tbdms-Cl and TEA in dichloromethane, providing the silyl ether (XXII). The hydrogenolysis of (XXII) with H2 over Pd/C in THF furnishes the alcohol (XXIII), which is oxidized to the aldehyde (XXIV) with oxalyl chloride, DMSO and TEA in dichloromethane. The condensation of aldehyde (XXIV) with the intermediate phosphonium salt (XVI) by means of NaHMDS in THF gives the silylated diol (XXV), which is selectively monodesilylated with CSA in dichloromethane/methanol to yield the primary alcohol (XXVI). The oxidation of (XXVI) with SO3/pyridine, DMSO and TEA in dichloromethane affords the corresponding aldehyde (XXVII), which is condensed with the oxoacid intermediate (VI) by means of LDA in THF to provide the linear heptadecadienoic acid (XXVIII) as a diastereomeric mixture.

Intermediate (XXVIII) separated at the carboxylic acid (XXX) step. The full silylation of (XXVIII) with Tbdms-OTf and lutidine in dichloromethane gives the tetrasilyloxy compound (XXIX), which is stepwise desilylated first with K2CO3 in methanol to yield the carboxylic acid (XXX), and then with TBAF in THF to afford the hydroxyacid (XXXI). The macrolactonization of (XXXI) was carried out with the Yamaguchi method using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF to yield the silylated macrolactone (XXXII), which is deprotected with TFA in dichloromethane to afford the dihydroxymacrolactone (XXXIII). Finally, the double bond of (XXXIII) is epoxidated with methyl(trifluoromethyl)dioxirane (A) in acetonitrile.

The synthesis of the intermediate chiral aldehyde (XVIII) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid methyl ester (I) with DIBAL in dichloromethane gives the aldehyde (II), which by condensation with phosphorane (III) in refluxing benzene yields the unsaturated aldehyde (IV). The condensation of (IV) with the chiral borane (V) in ethyl ether affords the chiral unsaturated alcohol (VI), which is treated with Tbdms-Cl and imidazole to provide the sill ether (VII). The oxidation of the terminal double bond of (VIII) with OsO4 and Pb(OAc)4 in THF/tBuOH/water gives the aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the carboxylic acid (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is reduced by reaction with CCl4 and PPh3, followed by a reductive dechlorination with LiBHEt3, to furnish the dimethylated olefin (XII). Hydroxylation of the terminal double bond of (XII) with 9-BBN in THF gives the primary alcohol (XIII), which is treated with I2 and PPh3 in ethyl ether/CH3CN to yield the iodo derivative (XIV). The condensation of (XIV) with the chiral 1-(propylideneamino)pyrrolidine (XV) by means of LDA in THF affords intermediate (XVI), which is converted into the nitrile (XVII) by reaction with monoperoxyphthalic acid magnesium salt (MMPP) in MeOH. Finally this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).

The condensation of 2,2-dimethyl-3-oxopentanal (XIX) with the chiral borane (V) in ethyl ether gives the chiral hydroxyketone (XX), which is treated with Tbdms-OTf and lutidine in dichloromethane to yield the silyl ether (XXI). Ozonolysis of the terminal double bond of (XXI) affords the aldehyde (XXII), which is oxidized to the carboxylic acid (XXIII) with NaClO2. The condensation of (XXIII) with the reported intermediate aldehyde (XVIII) by means of LDA in THF provides the hydroxyacid (XXIV), which is silylated with Tbdms-OTf and lutidine in dichloromethane to furnish the fully silylated compound (XXV). The hydrolysis of the silyl ester of (XXV) with K2CO3 in methanol gives the carboxylic acid (XXVI), which is selectively desilylated with TBAF in THF to yield the hydroxyacid (XXVII).The macrolactonization of (XXVII) by treatment with 2,4,6-trichlorobenzoyl chloride and TEA in THF, followed by a treatment with DMAP in toluene, affords the silylated macrolactone (XXVIII).

Compound (XXVIII) is deprotected with TFA in CH2Cl2 to provide the dihydroxymacrolactone (XXIX). Finally, this compound is epoxidated with methyl(trifluoromethyl)dioxirane (XXX) or MCPBA to furnish the target epothilone B.

The oxoacid intermediate (VI) has been obtained as follows: The condensation of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) gives the chiral 5(S)-hydroxy-4,4-dimethyl-7-octen-3-one (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of (IV) in dichloromethane affords the aldehyde (V), which is finally oxidized with NaClO2 in tert-butanol/water to provide the target oxoacid intermediate (VI).

The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF, providing the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).

Assembly of the final product: The condensation of SAMP hydrazone (XVII) with 4-(benzyloxy)butyl iodide (XVIII) by means of LDA in THF gives the chiral 2-methylhexanal hydrazone (XIX), which is ozonolyzed in dichloromethane, yielding the free aldehyde (XX). The reduction of (XX) with NaBH4 in methanol affords the corresponding alcohol (XXI), which is protected with Tbdms-Cl and TEA in dichloromethane, providing the silyl ether (XXII). The hydrogenolysis of (XXII) with H2 over Pd/C in THF furnishes the alcohol (XXIII), which is oxidized to the aldehyde (XXIV) with oxalyl chloride, DMSO and TEA in dichloromethane. The methylation of aldehyde (XXIV) with Me-MgBr in THF gives the secondary alcohol (XXV), which is oxidized with tetrapropylammonium perruthenate (TPAP) in dichloromethane, yielding the methyl ketone (XXVI). The condensation of ketone (XXVI) with the intermediate phosphonium salt (XVI) by means of NaHMDS in THF gives the silylated diol (XXVII), which is selectively monodesilylated with CSA in dichloromethane/methanol to yield the primary alcohol (XXVIII). The oxidation of (XXVIII) with SO3/pyridine, DMSO and TEA in dichloromethane affords the corresponding aldehyde (XXIX), which is condensed with the oxoacid intermediate (VI) by means of LDA in THF to provide the linear heptadecadienoic acid (XXX) as a diastereomeric mixture that is separated at the carboxylic acid (XXXII) step.

The fully silylation of (XXX) with Tbdms-OTf and lutidine in dichloromethane gives the tetrasilyloxy compound (XXXI). The stepwise desilylation first with K2CO3 in methanol to yield the carboxylic acid (XXXII), and then with TBAF in THF, affords the hydroxyacid (XXXIII). The macrolactonization of (XXXIII) was carried out with the Yamaguchi method using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF to yield the silylated macrolactone (XXXIV), which is deprotected with TFA in dichloromethane to afford the dihydroxymacrolactone (XXXV). Finally, the double bond of (XXXV) is epoxidated with methyl(trifluoromethyl)dioxirane (XXXVI) in acetonitrile to provide the target epothilone B.

The condensation of the known ketone (XVII) with aldehyde (XVIII) by means of LDA in THF gives the hydroxyketone (XIX), which is silylated with Tbdms-OTf and TEA in dichloromethane, yielding the silyl ether (XX). The terminal vinyl group of (XX) is cleaved oxidatively by means of OsO4 and NaIO4 in THF/water, affording the aldehyde (XXI), which is oxidized to acid (XXII) by means of NaClO2 in t-butanol/water. Acid (XXII) is esterified to methyl ester (XXIII), which is selectively deprotected at the Pmb group by hydrogenation with H2 over Pd/C in ethanol to provide the primary alcohol (XXIV). The oxidation of (XXIV) with tetrapropylammonium perruthenate (TPAP) furnishes the aldehyde (XXV), which is submitted to a Wittig condensation with the intermediate phosphonium salt (XVI) by means of LiHMDS in THF to give the adduct (XXVI). The hydrolysis of the ester group of (XXVI) with NaOH in warm isopropanol yields the carboxylic acid (XXVII), which is selectively deprotected by means of TBAF in THF to afford the hydroxyacid (XXVIII).

Synthesis of intermediate ketone (XVIII): The reaction of 2,2-dimethyl-3-oxopentanal (XVI) with (+)-allyldi(isopinocampheyl)borane in ethyl ether gives the chiral beta-hydroxyketone (XVII), which is silylated with Tbdms-OTf and lutidine in dichloromethane to afford the desired intermediate ketone (XVIII).

The aldol condensation of 2,2-dimethyl-3-oxopentanal (I) with acetylsultam (II) by means of Et3B/OTf and DIEA gives the aldol adduct (III), which is treated with Tbdms-OTf to yield the silyl ether (IV). The TiCl4 catalyzed aldol reaction between ketone (IV) with the intermediate aldehyde (V) affords the aldol adduct (VI), which is treated with Tbdms-OTf to provide the silylated adduct (VII). Finally the cleavage of the sultam group of (VII) by means of LiO2H furnishes the already known carboxylic acid intermediate (VIII)

The synthesis of the intermediate chiral aldehyde (XVIII) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid methyl ester (I) with DIBAL in dichloromethane gives the aldehyde (II), which by condensation with phosphorane (III) in refluxing benzene yields the unsaturated aldehyde (IV). The condensation of (IV) with the chiral borane (V) in ethyl ether affords the chiral unsaturated alcohol (VI), which is treated with Tbdms-Cl and imidazole to provide the sill ether (VII). The oxidation of the terminal double bond of (VIII) with OsO4 and Pb(OAc)4 in THF/tBuOH/water gives the aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the carboxylic acid (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is reduced by reaction with CCl4 and PPh3, followed by a reductive dechlorination with LiBHEt3, to furnish the dimethylated olefin (XII). Hydroxylation of the terminal double bond of (XII) with 9-BBN in THF gives the primary alcohol (XIII), which is treated with I2 and PPh3 in ethyl ether/acetonitrile to yield the iodo derivative (XIV). The condensation of (XIV) with the chiral 1-(propylideneamino)pyrrolidine (XV) by means of LDA in THF affords intermediate (XVI), which is converted into the nitrile (XVII) by reaction with monoperoxyphthalic acid magnesium salt (MMPP) in methanol. Finally, this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).

The condensation of 2,2-dimethyl-3-oxopentanal (XIX) with the chiral borane (V) in ethyl ether gives the chiral hydroxyketone (XX), which is treated with Tbdms-OTf and lutidine in dichloromethane to yield the silyl ether (XXI). Ozonolysis of the terminal double bond of (XXI) affords the aldehyde (XXII), which is oxidized to the carboxylic acid (XXIII) with NaClO2. The condensation of (XXIII) with the reported intermediate aldehyde (XVIII) by means of LDA in THF provides the hydroxyacid (XXIV), which is silylated with Tbdms-OTf and lutidine in dichloromethane to furnish the fully silylated compound (XXV). The hydrolysis of the silyl ester of (XXV) with K2CO3 in methanol gives the carboxylic acid (XXVI), which is selectively desilylated with TBAF in THF to yield the hydroxyacid (XXVII).The macrolactonization of (XXVII) by treatment with 2,4,6-trichlorobenzoyl chloride and TEA in THF, followed by a treatment with DMAP in toluene, affords the silylated macrolactone (XXVIII), which is finally deprotected with TFA in dichloromethane to provide the target epothilone D.

The oxoacid intermediate (VI) has been obtained as follows: The condensation of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) gives the chiral 5(S)-hydroxy-4,4-dimethyl-7-octen-3-one (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of (IV) in dichloromethane affords the aldehyde (V), which is finally oxidized with NaClO2 in tert-butanol/water to provide the target oxoacid intermediate (VI).

The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF to provide the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).

Assembly of the final product: The condensation of SAMP hydrazone (XVII) with 4-(benzyloxy)butyl iodide (XVIII) by means of LDA in THF gives the chiral 2-methylhexanal hydrazone (XIX), which is ozonolyzed in dichloromethane, yielding the free aldehyde (XX). The reduction of (XX) with NaBH4 in methanol affords the corresponding alcohol (XXI), which is protected with Tbdms-Cl and TEA in dichloromethane, providing the silyl ether (XXII). The hydrogenolysis of (XXII) with H2 over Pd/C in THF furnishes the alcohol (XXIII), which is oxidized to the aldehyde (XXIV) with oxalyl chloride, DMSO and TEA in dichloromethane. The condensation of aldehyde (XXIV) with the intermediate phosphonium salt (XVI) by means of NaHMDS in THF gives the silylated diol (XXV), which is selectively monodesilylated with CSA in dichloromethane/methanol to yield the primary alcohol (XXVI). The oxidation of (XXVI) with SO3/pyridine, DMSO and TEA in dichloromethane affords the corresponding aldehyde (XXVII), which is condensed with the oxoacid intermediate (VI) by means of LDA in THF to provide the linear heptadecadienoic acid (XXVIII) as a diastereomeric mixture that is separated at the carboxylic acid (XXX) step. The fully silylation of (XVIII) with Tbdms-OTf and lutidine in dichloromethane gives the tetrasilyloxy compound (XXIX), which is stepwise desilylated first with K2CO3 in methanol to yield the carboxylic acid (XXX).

Compound (XXX) is treated with TBAF in THF to afford the hydroxyacid (XXXI). The macrolactonization of (XXXI) was carried out with the Yamaguchi method using 2,4,6-trichlorobenzoyl chloride , TEA and DMAP in THF to yield the silylated macrolactone (XXXII), which is finally deprotected with TFA in dichloromethane to afford the target epothilone D.

The condensation of the known ketone (XVII) (2) with aldehyde (XVIII) by means of LDA in THF gives the hydroxyketone (XIX), which is silylated with Tbdms-OTf and TEA in dichloromethane, yielding the silyl ether (XX). The terminal vinyl group of (XX) is cleaved oxidatively by means of OsO4 and NaIO4 in THF/water, affording the aldehyde (XXI), which is oxidized to acid (XXII) by means of NaClO2 in t-butanol/water. Acid (XXII) is esterified to methyl ester (XXIII), which is selectively deprotected at the Pmb group by hydrogenation with H2 over Pd/C in ethanol to provide the primary alcohol (XXIV). The oxidation of (XXIV) with tetrapropylammonium perruthenate (TPAP) furnishes the aldehyde (XXV), which is submitted to a Wittig condensation with the intermediate phosphonium salt (XVI) by means of LiHMDS in THF to give the adduct (XXVI). The hydrolysis of the ester group of (XXVI) with NaOH in warm isopropanol yields the carboxylic acid (XXVII), which is selectively deprotected by means of TBAF in THF to afford the hydroxyacid (XXVIII).

The reaction of 2,2-dimethyl-3-oxopentanal (XXXI) with (+)-diisopinocampheyl(allyl)borane (XXXII) in ethyl ether gives the chiral beta-hydroxy ketone (XXXIII), which is protected with Tbdms-OTf to yield the silyl ether (XXXIV). The ozonolysis of the double bond of (XXXIV) affords the aldehyde (XXXV), which is oxidized with NaClO2 to the carboxylic acid (XXXVI). Finally, this compound is condensed with 2(S)-methyl-6-heptenal (VII) by means of LDA in THF to provide the intermediate tridecenoic acid (XII).

The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (I) with DIBAL in dichloromethane gives the corresponding carbaldehyde (II), which is condensed with phosphorane (III) in refluxing benzene to yield the propionaldehyde (IV). The diastereocontrolled condensation of (IV) with (+)-allyl-di(isopinocampheyl)borane (V) in ethyl ether affords the chiral homoallyl alcohol (VI), which is silylated with Tbdms-Cl and imidazole to provide the silyl ether (VII).The oxidation of the terminal double bond of (VII) by means of OsO4, NaIO4 and 4-methylmorpholine N-oxide gives the 4-pentenal derivative (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the methyl heptadienoate (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is protected with trityl chloride and DMAP to provide the trityl ether (XII). The Hydroxylation of the terminal double bond of (XII) with 8-BBN and H2O2 gives the primary alcohol (XIII), which is treated with I2 and PPh3 to yield the iodo compound (XIV). The condensation of (XIV) with the hydrazone (XV) by means of LDA affords the chiral undecadienylhydrazone (XVI), which is treated with monoperoxyphthalic magnesium salt (MMPP) to provide the undecadienenitrile (XVII). The reduction of (XVII) with DIBAL in toluene gives the corresponding aldehyde (XVIII).

The synthesis of intermediate tridecenoic acid (VIII) has been performed as follows: The reaction of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether gives the chiral beta-hydroxy ketone (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of the double bond of (IV) affords the aldehyde (V), which is oxidized with NaClO2 to the carboxylic acid (VI). Finally, this compound is condensed with 2(S)-methyl-6-heptenal (VII) by means of LDA in THF to provide the intermediate tridecenoic acid (VIII).

The oxoacid intermediate (VI) has been obtained as follows: The condensation of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) gives the chiral 5(S)-hydroxy-4,4-dimethyl-7-octen-3-one (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of (IV) in dichloromethane affords the aldehyde (V), which is finally oxidized with NaClO2 in tert-butanol/water to provide the target oxoacid intermediate (VI).

The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF, providing the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).

Assembly of the final product: The condensation of SAMP hydrazone (XVII) with 4-(benzyloxy)butyl iodide (XVIII) by means of LDA in THF gives the chiral 2-methylhexanal hydrazone (XIX), which is ozonolyzed in dichloromethane, yielding the free aldehyde (XX). The reduction of (XX) with NaBH4 in methanol affords the corresponding alcohol (XXI), which is protected with Tbdms-Cl and TEA in dichloromethane, providing the silyl ether (XXII). The hydrogenolysis of (XXII) with H2 over Pd/C in THF furnishes the alcohol (XXIII), which is oxidized to the aldehyde (XXIV) with oxalyl chloride, DMSO and TEA in dichloromethane. The condensation of aldehyde (XXIV) with the intermediate phosphonium salt (XVI) by means of NaHMDS in THF gives the silylated diol (XXV), which is selectively monodesilylated with CSA in dichloromethane/methanol to yield the primary alcohol (XXVI). The oxidation of (XXVI) with SO3/pyridine, DMSO and TEA in dichloromethane affords the corresponding aldehyde (XXVII), which is condensed with the oxoacid intermediate (VI) by means of LDA in THF to provide the linear heptadecadienoic acid (XXVIII) as a diastereomeric mixture.

Intermediate (XXVIII) separated at the carboxylic acid (XXX) step. The full silylation of (XVIII) with Tbdms-OTf and lutidine in dichloromethane gives the tetrasilyloxy compound (XXIX), which is stepwise desilylated first with K2CO3 in methanol to yield the carboxylic acid (XXX), and then with TBAF in THF to afford the hydroxyacid (XXXI). The macrolactonization of (XXXI) was carried out with the Yamaguchi method using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF to yield the silylated macrolactone (XXXII), which is deprotected with TFA in dichloromethane to afford the the target epothilone C.

Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) catalyzed by (S)(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to give the desired thiazole intermediate (IX).

The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provide the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of KOtBu in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of TsOH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).

Hydrolysis of the dimethylacetal group of (XXVIII) with Ts-OH in dioxane/water yields the corresponding aldehyde (XXIX), which is submitted to an intramolecular aldolization by means of KHMDS in THF to afford a mixture of diastereomeric macrolactones (XXX) and (XXXI). The undesired isomer (XXX) was recovered, oxidized with DMP to the ketone (XXXII) and reduced again with NaBH4 to provide high yields of the desired isomer (XXXI). Selective desilylation of (XXXI) with HF/pyridine in THF gives the diol (XXXIII), which is selectively monosilylated with Tbdms-OTf and lutidine in dichloromethane, yielding the bis-silylated triol (XXXIV). The oxidation of the free OH group of (XXXIV) with DMP in dichloromethane affords the corresponding ketonic derivative (XXXV), which is deprotected with HF/pyridine in THF, providing the free dihydroxy compound (XXXVI). Finally, this compound is epoxidized by means of dimethyldioxirane (DMDO) in dichloromethane.

Alternatively, the hydrolysis of the intermediate dimethylacetal (XXVII) with TsOH in dioxane/water gives the aldehyde (XXXVII), which is condensed with tert-butyl acetate (XXXVIII) by means of LDA in THF, yielding the hydroxyester (XXXIX). The desilylation of (XXXIX) with HF/pyridine in THF affords the trihydroxy compound (XL), which is selectively resilylated with Tbdms-OTf and lutidine, providing the bis-silylated compound (XLI). The oxidation of the free OH group of (XLI) with DMP in dichloromethane gives the ketonic compound (XLII), which is treated with Tbdms-OTf and lutidine in dichloromethane to furnish the silyl ester (XLIII). The condensation of (XLIII) with the thiazole intermediate (IX) as before gives the adduct (XLIV), which is hydrolyzed by means of K2CO3 in methanol/water, yielding the hydroxyacid (XLV). The intramolecular lactonization of (XLV) by means of 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in toluene affords the previously reported macrolactone (XXXV), which is desilylated with HF/pyridine to (XXXVI) and finally epoxidated with DMDO in dichloromethane.

Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) and catalyzed by (S)-(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to gives the desired thiazole intermediate (IX).

The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provide the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane to furnish the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of tBu-OK in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of Ts-OH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).

Hydrolysis of the dimethylacetal group of (XXVIII) with Ts-OH in dioxane/water yields the corresponding aldehyde (XXIX), which is submitted to an intramolecular aldolization by means of KHMDS in THF to afford a mixture of diastereomeric macrolactones (XXX) and (XXXI). The undesired isomer (XXX) was recovered, oxidized with DMP to the ketone (XXXII) and reduced again with NaBH4 to provide high yields of the desired isomer (XXXI). Selective desilylation of (XXXI) with HF/pyridine in THF gives the diol (XXXIII), which is selectively monosilylated with Tbdms-OTf and lutidine in dichloromethane, yielding the bis-silylated triol (XXXIV). The oxidation of the free OH group of (XXXIV) with DMP in dichloromethane affords the corresponding ketonic derivative (XXXV), which is deprotected with HF/pyridine in THF, providing the free dihydroxy compound (XXXVI). Finally, this compound is epoxidized by means of dimethyldioxirane (DMDO) in dichloromethane to afford the target epothilone B.

Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) catalyzed by (S)(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to gives the desired thiazole intermediate (IX)

The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provides the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of tBu-OK in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of Ts-OH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).

Hydrolysis of the dimethylacetal group of (XXVIII) with Ts-OH in dioxane/water yields the corresponding aldehyde (XXIX), which is submitted to a intramolecular aldolization by means of KHMDS in THF to afford a mixture of diastereomeric macrolactones (XXX) and (XXXI). The undesired isomer (XXX) was recovered, oxidized with DMP to the ketone (XXXII) and reduced again with NaBH4 to provide high yields of the desired isomer (XXXI). Selective desilylation of (XXXI) with HF/pyridine in THF gives de diol (XXXIII), which is selectively monosilylated with Tbdms-OTf and lutidine in dichloromethane, yielding the bis-silylated triol (XXXIV). The oxidation of the free OH group of (XXXIV) with DMP in dichloromethane affords the corresponding ketonic derivative (XXXV), which is finally deprotected with HF/pyridine in THF, providing the target epothilone D.

The condensation of the phosphonium salt (I) with the ketone (II) by means of NaHMDS in THF gives the diene (III), which is selectively monodeprotected with CSA in methanol/dichloromethane to yield the primary alcohol (IV). The oxidation of (IV) with SO3/pyridine affords the corresponding aldehyde (V), which is condensed with the ketoacid (VI) by means of LDA in THF to provide the heptadienoic acid (VII). The protection of the OH group of (VII) y means of Tbdms-OTf and lutidine in dichloromethane gives the fully silylated compound (VIII), which is selectively monodeprotected with TBAF in THF to yield the hydroxyacid (IX). The macrolactonization of (IX) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF affords the macrolactone (X), which is finally deprotected with TFA in dichloromethane to provide the target epothilone D.

Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) catalyzed by (S)(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to give the desired thiazole intermediate (IX).

The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provides the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of tBu-OK in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of Ts-OH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).

Hydrolysis of the dimethylacetal group of (XXVIII) with Ts-OH in dioxane/water yields the corresponding aldehyde (XXIX), which is submitted to an intramolecular aldolization by means of KHMDS in THF to afford a mixture of diastereomeric macrolactones (XXX) and (XXXI). The undesired isomer (XXX) was recovered, oxidized with DMP to the ketone (XXXII) and reduced again with NaBH4 to provide high yields of the desired isomer (XXXI). Selective desilylation of (XXXI) with HF/pyridine in THF gives the diol (XXXIII), which is selectively monosilylated with Tbdms-OTf and lutidine in dichloromethane, yielding the bis-silylated triol (XXXIV). The oxidation of the free OH group of (XXXIV) with DMP in dichloromethane affords the corresponding ketonic derivative (XXXV), which is finally deprotected with HF/pyridine in THF, providing the target epothilone C.

Alternatively, the hydrolysis of the intermediate dimethylacetal (XXVII) with Ts-OH in dioxane/water gives the aldehyde (XXXVI), which is condensed with tert-butyl acetate (XXXVII) by means of LDA in THF, yielding the hydroxyester (XXXVIII). The desilylation of (XXXVIII) with HF/pyridine in THF affords the trihydroxy compound (XXXIX), which is selectively resilylated with Tbdms-OTf and lutidine, providing the bis-silylated compound (XL). The oxidation of the free OH group of (XL) with DMP in dichloromethane gives the ketonic compound (XLI), which is treated with Tbdms-OTf and lutidine in dichloromethane to furnish the silyl ester (XLII). The condensation of (XLII) with the thiazole intermediate (IX) as before gives the adduct (XLIII), which is hydrolyzed by means of K2CO3 in methanol/water, yielding the hydroxyacid (XLIV). The intramolecular lactonization of (XLIV) by means of 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in toluene affords the already reported macrolactone (XXXV), which is finally desilylated with HF/pyridine to give the target epothilone C.

The protection of the allyl alcohol (I) with dihydropyran and PPTS in dichloromethane gives the tetrahydropyranyl ether (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi and CuCN in THF to yield the adduct (IV). The hydroxylation of (IV) with Davis' oxaziridine, NaHMDS and CSA affords the alcohol (V), which is silylated with Tbdms-OTf and lutidine to provide the silyl ether (VII). The hydrolysis of the oxazolidinone group of (VII) with Et-SH and Et-SK in THF gives the thioester (VIII), which is methylated with Me2CuLi in ethyl ether, yielding the methyl ketone (IX). The condensation of (IX) with phosphonate (X) by means of BuLi in THF affords the diene (XI), which is treated with MgBr2 in ethyl ether in order to eliminate the THP protecting group and obtain the primary alcohol (XII). The sulfonation of (XII) with Ms2O and TEA in dichloromethane gives the mesylate (XIII), which is treated with LiBr in acetone to yield the allyl bromide (XIV). Finally, (XIV) is condensed with methyltriphenylphosphonium bromide (XV) by means of BuLi in THF affording the desired intermediate phosphonium salt (XVI).

The condensation of the known ketone (XVII) with aldehyde (XVIII) by means of LDA in THF gives the hydroxyketone (XIX), which is silylated with Tbdms-OTf and TEA in dichloromethane, yielding the silyl ether (XX). The terminal vinyl group of (XX) is cleaved oxidatively by means of OsO4 and NaIO4 in THF/water, affording the aldehyde (XXI), which is oxidized to acid (XXII) by means of NaClO2 in t-butanol/water. Acid (XXII) is esterified to methyl ester (XXIII), which is selectively deprotected at the Pmb group by hydrogenation with H2 over Pd/C in ethanol to provide the primary alcohol (XXIV). The oxidation of (XXIV) with tetrapropylammonium perruthenate (TPAP) furnishes the aldehyde (XXV), which is submitted to a Wittig condensation with the intermediate phosphonium salt (XVI) by means of LiHMDS in THF to give the adduct (XXVI). The hydrolysis of the ester group of (XXVI) with NaOH in warm isopropanol yields the carboxylic acid (XXVII), which is selectively deprotected by means of TBAF in THF to afford the hydroxyacid (XXVIII).

The macrolactonization of (XXVIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF provides the protected macrolactone (XXIX), which is deprotected with TFA in dichloromethane to give the trienic macrolactone (XXX). Selective hydrogenation of the disubstituted double bond of (XXX) by means of potassium azodicarboxylate (DKAD) and AcOH in dichloromethane yields the precursor (XXXI), which is finally epoxidized with dimethyldioxirane (XXXII) in dichloromethane to afford the target epothilone B.

The reaction of chiral aldehyde (I) with dimethyl diazomethylphosphonate (II) by means of tBu-OK in THF gives the acetylenic ester (III), which is condensed with ally bromide derivative (IV) by means of CuI and TEA in DMF/ethyl ether to yield the dienyne (V). The partial hydrogenation of (V) over a Lindlar catalyst in hexane affords the trienoic ester (VI). The hydrolysis of (VI) with NaOH in warm isopropanol provides the corresponding carboxylic acid (VII), which is selectively desilylated with TBAF in THF to give the hydroxyacid (VIII). The macrolactonization of (VIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in benzene/THF yields the protected macrolactone (IX), which is deprotected with TFA in dichloromethane to afford the trienic macrolactone (X). Selective hydrogenation of the disubstituted double bond of (X) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane provides the precursor (XI), which is finally epoxidated with dimethyldioxirane (XII) in dichloromethane to furnish the target epothilone B.

The protection of the allyl alcohol (I) with dihydropyran and PPTS in dichloromethane gives the tetrahydropyranyl ether (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi and CuCN in THF, yielding the adduct (IV). The hydroxylation of (IV) with Davis' oxaziridine, NaHMDS and CSA affords the alcohol (V), which is silylated with Tbdms-OTf and lutidine, providing the silyl ether (VII). The hydrolysis of the oxazolidinone group of (VII) with Et-SH and Et-SK in THF gives the thioester (VIII), which is methylated with Me2CuLi in ethyl ether, yielding the methyl ketone (IX). The condensation of (IX) with phosphonate (X) by means of BuLi in THF affords the diene (XI), which is treated with MgBr2 in ethyl ether in order to eliminate the THP protecting group and obtain the primary alcohol (XII). The sulfonation of (XII) with Ms2O and TEA in dichloromethane gives the mesylate (XIII), which is treated with LiBr in acetone to yield the allyl bromide (XIV). Finally, (XIV) is condensed with methyltriphenylphosphonium bromide (XV) by means of BuLi in THF affording the desired intermediate phosphonium salt (XVI).

The condensation of the known ketone (XVII) (2) with aldehyde (XVIII) by means of LDA in THF gives the hydroxyketone (XIX), which is silylated with Tbdms-OTf and TEA in dichloromethane, yielding the silyl ether (XX). The terminal vinyl group of (XX) is cleaved oxidatively by means of OsO4 and NaIO4 in THF/water, affording the aldehyde (XXI), which is oxidized to acid (XXII) by means of NaClO2 in t-butanol/water. Acid (XXII) is esterified to methyl ester (XXIII), which is selectively deprotected at the Pmb group by hydrogenation with H2 over Pd/C in ethanol to provide the primary alcohol (XXIV). The oxidation of (XXIV) with tetrapropylammonium perruthenate (TPAP) furnishes the aldehyde (XXV), which is submitted to a Wittig condensation with the intermediate phosphonium salt (XVI) by means of LiHMDS in THF to give the adduct (XXVI). The hydrolysis of the ester group of (XXVI) with NaOH in warm isopropanol yields the carboxylic acid (XXVII), which is selectively deprotected by means of TBAF in THF to afford the hydroxyacid (XXVIII).

The macrolactonization of (XXVIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF provides the protected macrolactone (XXIX), which is deprotected with TFA in dichloromethane to give the trienic macrolactone (XXX). Finally, the selective hydrogenation of the disubstituted double bond of (XXX) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane yields the target epothilone D.

The reaction of chiral aldehyde (I) with dimethyl diazomethylphosphonate (II) by means of tBu-OK in THF gives the acetylenic ester (III), which is condensed with ally bromide derivative (IV) by means of CuI and TEA in DMF/ethyl ether to yield the dienyne (V). The partial hydrogenation of (V) over a Lindlar catalyst in hexane affords the trienoic ester (VI). The hydrolysis of (VI) with NaOH in warm isopropanol provides the corresponding carboxylic acid (VII), which is selectively desilylated with TBAF in THF to give the hydroxyacid (VIII). The macrolactonization of (VIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in benzene/THF yields the protected macrolactone (IX), which is deprotected with TFA in dichloromethane to afford the trienic macrolactone (X) (1). Finally, the selective hydrogenation of the disubstituted double bond of (X) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane provides the target epothilone D.

The reaction of chiral aldehyde (I) with dimethyl diazomethylphosphonate (II) by means of tBu-OK in THF gives the acetylenic ester (III), which is condensed with ally bromide derivative (IV) by means of CuI and TEA in DMF/ethyl ether to yield the dienyne (V). The partial hydrogenation of (V) over a Lindlar catalyst in hexane affords the trienoic ester (VI). The hydrolysis of (VI) with NaOH in warm isopropanol provides the corresponding carboxylic acid (VII), which is selectively desilylated with TBAF in THF to give the hydroxyacid (VIII). The macrolactonization of (VIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in benzene/THF yields the protected macrolactone (IX), which is deprotected with TFA in dichloromethane to afford the trienic macrolactone (X). Selective hydrogenation of the disubstituted double bond of (X) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane provides the precursor (XI), which is finally epoxidated with dimethyldioxirane (XII) in dichloromethane to furnish the target epothilone B.

The reaction of chiral aldehyde (I) with dimethyl diazomethylphosphonate (II) by means of tBu-OK in THF gives the acetylenic ester (III), which is condensed with ally bromide derivative (IV) by means of CuI and TEA in DMF/ethyl ether to yield the dienyne (V). The partial hydrogenation of (V) over a Lindlar catalyst in hexane affords the trienoic ester (VI). The hydrolysis of (VI) with NaOH in warm isopropanol provides the corresponding carboxylic acid (VII), which is selectively desilylated with TBAF in THF to give the hydroxyacid (VIII). The macrolactonization of (VIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in benzene/THF yields the protected macrolactone (IX), which is deprotected with TFA in dichloromethane to afford the trienic macrolactone (X) (1). Finally, the selective hydrogenation of the disubstituted double bond of (X) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane provides the target epothilone D.

The ozonolysis of the terminal double bond of (I) gives the aldehyde (II), which is condensed with the acetylenic alcohol (II) by means of Zn(OTf)2 in the presence of (+)-N-methylephedrine to yield the chiral acetylenic diol (IV). The reaction of (IV) with benzoyl chloride and TEA affords the monobenzoate (V), which is treated with K2CO3 and LiAlH4 to provide the chiral allyl alcohol derivative (VI). The cyclization of (VI) with the phosphonate (VII) by means of Et-MgBr in isopropanol/dichloromethane gives the isooxazoline (VIII), which is treated with Tbdms-OTf to yield the corresponding silyl ether (IX). The condensation of (IX) with 2-methylthiazole-4-carbaldehyde (X) by means of DBU and LiCl affords the isooxazoline derivative (XI), which is treated with SmI2, Et3B and NaBH4 to cleave the isoxazoline ring and yield the diol (XII). The reaction of (XII) with SOCl2, TEA and TBAF affords the chiral epoxide (XIII), which is silylated with Tes-Cl and TEA to provide the silyl ether (XIV). The selective hydrolysis of the primary silyl ether of (XIV) with HOAc in THF/water gives the primary alcohol (XV), which is oxidized with TPAP and NMO in dichloromethane to yield the corresponding aldehyde (XVI).

The condensation of (XVI) with ketone (XVII) by means of LDA affords the open-chain precursor (XVIII), which is protected at the OH group with Troc-Cl and pyridine to afford compound (XIX). The oxidation of (XIX) at the terminal vinyl group by means of OsO4, NMO and Pb(OAc)4 provides the carboxylic acid (XVIII), which by selective cleavage of its Tes- protecting group with HF and pyridine furnishes the hydroxyacid (XIX). The macrolactonization of (XIX) by means of 2,4,6-trichlorobenzoyl chloride gives the protected macrolactone (XX). The reaction of (XX) with Zn and NH4Cl in methanol cleaves the Troc-protecting group, yielding the silylated precursor (XXI), which is finally treated with HF and pyridine to afford the target epothilone A

The cyclization of phosphonate (I) with the chiral alcohol (II) by means of tert-butyl hypochlorite and Et-MgBr gives the isoxazoline (III), which is condensed with 2-methylthiazole-4-carbaldehyde (IV) by means of DBU and LiCl in acetonitrile to yield the secondary alcohol (V). The oxidation of (V) with TPAP and NMO in dichloromethane affords the corresponding ketone (VI), which is treated with the Grignard reagent (VII) in THF to provide the expected secondary alcohol (VIII). The silylation of (VIII) with Tes-OTf in dichloromethane gives the silyl ether (IX), which is treated with SmI2, Et3B and NaBH4 to cleave the isoxazoline ring and yield the diol (X). The reaction of (X) with SOCl2, TEA and TBAF affords the chiral epoxide (XI), which is silylated with Tes-Cl and TEA to provide the silyl ether (XII). The selective hydrolysis of the primary silyl ether of (XII) with HOAc in THF/water gives the primary alcohol (XIII), which is oxidized with TPAP and NMO in dichloromethane to yield the corresponding aldehyde (XIV). The condensation of (XIV) with ketone (XV) by means of LDA affords the open-chain precursor (XVI).

The protection of the OH group of (XVI) with Troc-Cl and pyridine affords compound (XVII), which is oxidized at the terminal vinyl group by means of OsO4, NMO and Pb(OAc)4 to provide the carboxylic acid (XVIII). The selective cleavage of the Tes- protecting group with HF and pyridine furnishes the hydroxyacid (XIX), which is submitted to a macrolactonization by means of 2,4,6-trichlorobenzoyl chloride to give the protected macrolactone (XX). The reaction of (XX) with Zn and NH4Cl in methanol cleaves the Troc-protecting group, yielding the silylated precursor (XXI), which is finally treated with HF and pyridine to afford the target epothilone B.

The reduction of the protected (S)-ethyl lactate (I) with DIBAL in dichloromethane gives the aldehyde (II), which by a Grignard condensation with allylmagnesium bromide (III) in ethyl ether yields the homoallylic alcohol (IV). The reaction of (IV) with Tbdms-Cl and imidazole in DMF affords the silyl ether (V), which is ozonolyzed with O3 in dichloromethane/methanol to provide the aldehyde (VI), which, by a new Grignard condensation with isopropenylmagnesium bromide (VII) in THF, gives the allyl alcohol derivative (VIII). Compound (VIII) is treated with triethyl orthoacetate (refluxing xylene) in a Johnson Claisen rearrangement to yield the (E)-unsaturated ester (IX), which is debenzylated by treatment with DDQ to afford the secondary alcohol (X). The oxidation of (X) with oxalyl chloride provides the ketoester (XI), which is oxidized with AD-mix beta in tert-butanol/water to furnish the diol (XII) as an inseparable mixture of isomers. This mixture, by a Wittig condensation with the phosphonium salt (XIII) and KHMDS in THF, gives a mixture of the hydroxylactones (XIV) and (XV) that are separated by chromatography. Compound (XIV) is mesylated with MsCl and TEA and treated with K2CO3 in methanol to give the desired epoxyester (XVI). The diastereomer (XV) with wrong configuration is recovered by a double inversion: Compound (XV) is mesylated and the resulting derivative is then epoxidated with K2CO3 in methanol to yield the epoxide (XVII), which is treated with K2CO3 in methanol/water to afford the hydroxylactone (XIV) with the adequate configuration.

The reduction of the methyl ester of (XVI) with DIBAL in dichloromethane gives the aldehyde (XVIII), which is condensed with the chiral phosphonate (XIX) by means of BuLi in ethyl ether to yield the enoylsultam (XX). The methylation of (XX) with L-selectride and methyl iodide affords the methylated sultam (XXI), which is desilylated with TBAF and reprotected with Tes-Cl and TEA to provide triethylsilyl ether (XXII) with a more favorable silyl leaving group needed in the remaining synthetic steps. Elimination of the sultam group of (XXII) by means of DIBAL in dichloromethane gives the aldehyde (XXIII), which is condensed with the ketone (XXIV) by means of LDA to yield the aldol (XXV). The protection of the OH group of (XXV) with Troc-Cl ad pyridine affords compound (XXVI), which is oxidized at the terminal vinyl group by means of OsO4 and NaIO4 to provide the aldehyde (XXVII). The selective desilylation of (XXVII) by means of HF and pyridine furnishes the hydroxy aldehyde (XXVIII).

The oxidation of the aldehyde group of (XXVIII) with NaClO2 gives the hydroxyacid (XXIX), which is submitted to a Yamaguchi cyclization by means of 2,4,6-trichlorobenzoyl chloride to yield the macrolactone (XXX). Elimination of the Troc protecting group of (XXX) with Zn and NH4Cl affords the silylated precursor (XXXI), which is finally treated with HF and pyridine to provide the target epothilone B.

The synthesis of the chiral 3-heptanone intermediate has been obtained as follows: The protection of the OH group of the chiral lactone (I) with Tbdms-Cl and imidazole gives the silyl ether (II), which is reduced with DIBAL to yield the lactol (III).The reaction of (III) with the Tebbe reagent affords the pentenol derivative (IV), which is oxidized with Dess-Martin periodinane (DMP), affording the aldehyde (V). The Grignard synthesis of (V) with ethylmagnesium bromide (VI) provides the 3-heptanol derivative (VII), which is hydroxylated at the terminal double bond by means of BH3/THF and H2O2, giving the diol (VIII). The selective protection of the primary OH group of (VIII) with Dmt-Cl, DIEA and DMAP yields the trityl ether (IX), which is finally oxidized with DMP to afford the desired chiral heptanone (X)

Synthesis of the target epothilone: The condensation of the iodinated dioxolane (XI) with the phenylsulfone (XII) by means of BuLi and DMPU gives the adduct (XIII), which is deprotected with Amberlyst 15 to yield the diol (XIV). Regioselective silylation of (XIV) with Tbdms-Cl and imidazole affords the monosilylated diol (XV), which is fully protected with Sem-Cl and DIEA, providing compound (XVI). The reaction of (XVI) with tributyltin hydride gives the stannane (XVII), which is condensed with the chiral aldehyde (XVIII) by means of SnBr4 to yield the 4-decanol derivative (XIX). The elimination of The OH group of (XIX) is performed via its reaction with Cl-C(S)-OPh (XX) to afford the thiocarbonate (XXI), which is then treated with tributyltin hydride to provide the dehydroxylated compound (XXII). Selective deprotection of (XXII) with DDQ gives the primary alcohol (XXIII), which is esterified with pivaloyl chloride, yielding the pivaloyl ester (XXIV). The selective desilylation of the Tbdms group of (XXIV) with TBAF gives the primary alcohol (XXV), which is oxidized to the corresponding aldehyde (XXVI) by means of DMP. The Grignard reaction of aldehyde (XXVI) with methylmagnesium bromide yields the secondary alcohol (XXVII).

The oxidation of the secondary OH group of (XXVII) with DMP gives the methyl ketone (XXVIII), which is condensed with the phosphonate (XXIX) to yield the diene (XXX). Reductive removal of the pivalate group of (XXX) by means of DIBAL affords the primary alcohol (XXXI), which is oxidized with DMP to provide the corresponding aldehyde (XXXII). The aldol condensation between aldehyde (XXXII) and the already reported intermediate, the ketone (X), by means of LDA gives the aldol (XXXIII), which is silylated with Tbdms-OTf and deprotected at the primary dimethoxyltrityl group by means of dichloroacetic acid to give the primary alcohol (XXXIV). The oxidation of (XXXIV) with DMP and NaClO2, followed by elimination of the Sem protecting group with MgBr2 and Bu-SH, yields the hydroxyacid (XXXV), which is submitted to macrocyclization under the modified Yamaguchi conditions (2,4,6-trichlorobenzoyl chloride and DMAP) to afford the silylated epothilone derivative (XXXVI). Finally, this compound is desilylated by means of TFA and epoxidized with DMDO to furnish the target epothilone B.

The synthesis of the chiral 3-heptanone intermediate has been obtained as follows: The protection of the OH group of the chiral lactone (I) with Tbdms-Cl and imidazole gives the silyl ether (II), which is reduced with DIBAL to yield the lactol (III).The reaction of (III) with the Tebbe reagent affords the pentenol derivative (IV), which is oxidized with Dess-Martin periodinane (DMP), affording the aldehyde (V). The Grignard synthesis of (V) with ethylmagnesium bromide (VI) provides the 3-heptanol derivative (VII), which is hydroxylated at the terminal double bond by means of BH3/THF and H2O2, giving the diol (VIII). The selective protection of the primary OH group of (VIII) with Dmt-Cl, DIEA and DMAP yields the trityl ether (IX), which is finally oxidized with DMP to afford the desired chiral heptanone (X).

Synthesis of the target epothilone: The condensation of the iodinated dioxolane (XI) with the phenylsulfone (XII) by means of BuLi and DMPU gives the adduct (XIII), which is deprotected with Amberlyst 15 to yield the diol (XIV). Regioselective silylation of (XIV) with Tbdms-Cl and imidazole affords the monosilylated diol (XV), which is fully protected with Sem-Cl and DIEA, providing compound (XVI). The reaction of (XVI) with tributyltin hydride gives the stannane (XVII), which is condensed with the chiral aldehyde (XVIII) by means of SnBr4 to yield the 4-decanol derivative (XIX). The elimination of The OH group of (XIX) is performed via its reaction with Cl-C(S)-OPh (XX) to afford the thiocarbonate (XXI), which is then treated with tributyltin hydride to provide the dehydroxylated compound (XXII). Selective deprotection of (XXII) with DDQ gives the primary alcohol (XXIII), which is esterified with pivaloyl chloride, yielding the pivaloyl ester (XXIV). The selective desilylation of the Tbdms group of (XXIV) with TBAF gives the primary alcohol (XXV), which is oxidized to the corresponding aldehyde (XXVI) by means of DMP. The Grignard reaction of aldehyde (XXVI) with methylmagnesium bromide yields the secondary alcohol (XXVII).

The oxidation of the secondary OH group of (XXVII) with DMP gives the methyl ketone (XXVIII), which is condensed with the phosphonate (XXIX) to yield the diene (XXX). Reductive removal of the pivalate group of (XXX) by means of DIBAL affords the primary alcohol (XXXI), which is oxidized with DMP to provide the corresponding aldehyde (XXXII). The aldol condensation between aldehyde (XXXII) and the already reported intermediate, the ketone (X), by means of LDA gives the aldol (XXXIII), which is silylated with Tbdms-OTf and deprotected at the primary dimethoxyltrityl group by means of dichloroacetic acid to give the primary alcohol (XXXIV). The oxidation of (XXXIV) with DMP and NaClO2, followed by elimination of the Sem protecting group with MgBr2 and Bu-SH, yields the hydroxyacid (XXXV), which is submitted to macrocyclization under modified Yamaguchi conditions (2,4,6-trichlorobenzoyl chloride and DMAP) to afford the silylated epothilone derivative (XXXVI). Finally, this compound is desilylated by means of TFA to furnish the target epothilone D.

The ketonic intermediate (VI) has been obtained as follows: The condensation of the 3-(tert-butyldimethylsilyloxy)propionaldehyde (I) with the silylated enol ether (II), catalyzed by the chiral boron reagent (III), gives the phenyl hydroxyester (IV), which is protected with Tbdms-Cl to provide the silyl ether (V). Finally, the Grignard reaction of (V) with Et-MgBr affords the target ketonic intermediate (VI).

The chiral iodovinyl derivative (IX) has been obtained as follows: The chiral alkyne (VII) is treated with trimethylsilyl chloride and NaI to give the iodovinyl compound (VIII), which is finally enantioselectively methylated with NaHMDS and methyl iodide to afford the target iodovinyl compound (IX).

The allylation of 2-(2-methylthiazol-4-ylmethylene)propionaldehyde (X) with allyl(diisopinocampheyl)borane gives the chiral secondary alcohol (XI), which is protected with Tbdms-Cl, yielding the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and NaIO4 affords the chiral aldehyde (XIII), which is condensed with the intermediate iodovinyl compound (IX) by means of Ni/Cr to provide the allyl alcohol derivative (XIV). The reaction of (XIV) with SOCl2 gives the rearranged chloromethyl compound (XV), which is treated with LiEt3BH to cleave the oxazolidine chiral auxiliary and dechlorinate the chloromethyl group, yielding the primary alcohol (XVI). The controlled oxidation of the OH group of (XVI) with PCC affords the aldehyde (XVII), which is submitted to an aldol condensation with the intermediate ketone (VI) by means of LDA to provide the aldol (XVIII). The protection of the OH group of (XVIII) with Tbdms-Cl gives the fully silylated compound (XIX), which is regioselectively monodesilylated with camphorsulfonic acid (CSA) to yield the primary alcohol (XX).

The oxidation of alcohol (XX) with PCC and NaClO2 gives the carboxylic acid (XXI), which is regioselectively monodesilylated with TBAF, yielding the hydroxyacid (XXII). The macrolactonization of (XXII) under Yamaguchi conditions (2,4,6-trichlorobenzoyl chloride) affords the macrolactone (XXIII), which is desilylated with HF and pyridine to provide the precursor (XXIV). Finally, this compound is epoxidated with MCPBA to afford the target epothilone B.

The ketonic intermediate (VI) has been obtained as follows: The condensation of the 3-(tert-butyldimethylsilyloxy)propionaldehyde (I) with the silylated enol ether (II), catalyzed by the chiral boron reagent (III), gives the phenyl hydroxyester (IV), which is protected with Tbdms-Cl to provide the silyl ether (V). Finally, the Grignard reaction of (V) with Et-MgBr affords the target ketonic intermediate (VI).

The chiral iodovinyl derivative (IX) has been obtained as follows: The chiral alkyne (VII) is treated with trimethylsilyl chloride and NaI to give the iodovinyl compound (VIII), which is finally enantioselectively methylated with NaHMDS and methyl iodide to afford the target iodovinyl compound (IX).

The allylation of 2-(2-methylthiazol-4-ylmethylene)propionaldehyde (X) with allyl(diisopinocampheyl)borane gives the chiral secondary alcohol (XI), which is protected with Tbdms-Cl, yielding the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and NaIO4 affords the chiral aldehyde (XIII), which is condensed with the intermediate iodovinyl compound (IX) by means of Ni/Cr to provide the allyl alcohol derivative (XIV). The reaction of (XIV) with SOCl2 gives the rearranged chloromethyl compound (XV), which is treated with LiEt3BH to cleave the oxazolidine chiral auxiliary and dechlorinate the chloromethyl group, yielding the primary alcohol (XVI). The controlled oxidation of the OH group of (XVI) with PCC affords the aldehyde (XVII), which is submitted to an aldol condensation with the intermediate ketone (VI) by means of LDA to provide the aldol (XVIII). The protection of the OH group of (XVIII) with Tbdms-Cl gives the fully silylated compound (XIX), which is regioselectively monodesilylated with camphorsulfonic acid (CSA) to yield the primary alcohol (XX).

The oxidation of alcohol (XX) with PCC and NaClO2 gives the carboxylic acid (XXI), which is regioselectively monodesilylated with TBAF, yielding the hydroxyacid (XXII). The macrolactonization of (XXII) under Yamaguchi conditions (2,4,6-trichlorobenzoyl chloride) affords the macrolactone (XXIII), which is finally desilylated with HF and pyridine to provide the target epothilone D.

The intermediate carboxylic acid (V) has been obtained as follows: The reaction of the chiral auxiliary oxazolidinone (I) with the oxoaldehyde (II) by means of Bu2B-OTf, DIEA and Raney Ni in dichloromethane gives the oxazolidide (III), which is treated with Tbdms-OTf, yielding the silyl ether (IV), which is easily purified. Elimination of the auxiliary with LiOH and H2O2 in THF/water affords the target carboxylic acid (V).

The reaction of bromide (V) with Mg and then with CuBr and propyne gives a cuprate complex that is treated with 1-hexyne, yielding the nonisolated copper complex (VII). The reaction of the protected chiral epoxide (IX) (obtained by reaction of the epoxide (VIII) with Pmb-Br, NaH and TBAI in THF) with copper complex (VII) affords the (Z)-alkene (X), which is treated with Sem-Cl and DIEA to protect its OH group, providing (XI). Selective elimination of the Pmb protecting group of (XI) with DDQ furnishes the secondary alcohol (XII), which is oxidized under Swern protocol to the ketone (XIII) with (COCl)2 and TEA in dichloromethane. The Wadsworth-Emmons olefination of (XIII) with the known phosphonate (XIV) by means of BuLi in THF gives pure triene (XV), which is submitted to a diastereoselective hydroboration with bis(diisopinocampheyl)borane and oxidative workup to yield the primary alcohol (XVI). The Swern oxidation of (XVI) with (COCl)2 affords the aldehyde (XVII), which is submitted to an aldol condensation with the intermediate oxoacid (V) by means of LDA in THF to provide the aldol product (XVIII) as a (6R,7S)(6S,7R) diastereomeric mixture.

The treatment of (XVIII) with Troc-Cl and pyridine gives fully protected (XIX) as the same diastereomeric mixture, which is selectively deprotected at the Sem group with TFA in dichloromethane to yield the corresponding mixture of hydroxyacids (XX). The macrolactonization of (XX) by the Yamaguchi method (2,4,6-trichlrobenzoyl chloride, TEA and DMAP in toluene) gives the diastereomeric mixture of lactones (XXI), which are readily separated by flash column chromatography. The desired diastereomer (XXII) is desilylated with HF and pyridine, yielding the hydroxylactone (XXIII), which is treated with Zn and NH4Cl in refluxing aqueous methanol to eliminate the Troc protecting group and provide the unprotected precursor (XXIV). Finally, this compound is epoxidated with methyl(trifluoromethyl)dioxirane (MTFDO) to afford the target epothilone B.

The intermediate phosphonium bromide (XVII) is obtained as follows: The reaction of the glucoside (I) with Me2CuLi in THF gives the methyl derivative (II), which is converted into the unsaturated pyranoside (III). The reductive deoxygenation of (III) with Pd(OAc)2 and NaBH4 affords the acetate (IV), which is treated with NaOMe in methanol to afford the carbinol (V). The oxidation of (V) with oxalyl chloride in DMSO provides the carbaldehyde (VI), which is treated with Me-Mg-Br in THF to give the secondary alcohol (VII). The oxidation of (VII) with oxalyl chloride in DMSO yields the ketone (VIII), which is condensed with the phosphonate (IX) (obtained by reaction of 4-(chloromethyl)-2-methylthiazole (X) with triethyl phosphite (XI) at 165 C) by means of tBu-OK in THF to afford the vinyl-dihydropyran (XII). The opening of the dihydropyran ring of (XII) by means of HOAc in THF/water, followed by reduction of the intermediate aldehyde, provides the unsaturated diol (XIII). The regioselective bromination of (XIII) with CBr4 and PPh3 in acetonitrile gives the bromo derivative (XIV), which is silylated with Tbdms-OTf to yield the silyl ether derivative (XV). Finally, this compound is condensed with methylenetriphenylphosphorane (XVI) in THF to afford the target intermediate, the phosphonium bromide (XVII).

The reaction of the glucoside (I) with Me2CuLi in THF gives the methyl derivative (II), which is oxidized with oxalyl chloride in DMSO to yield the tetrahydropyranone (XVIII). The treatment of (XVIII) with TEA in dichloromethane/methanol causes isomerization of the methyl group of (XVIII) to (XIX), which is reduced with NaBH4 in methanol/DMF to afford the secondary alcohol (XX). The cleavage of the benzylidene protecting group of (XX) with H2 over Pd/C in ethyl acetate provides the trihydroxy compound (XXI), which is regioselectively monosilylated at the primary OH group with Tbdms-Cl and pyridine to gives the silyl ether (XXII). The epoxidation of (XXII) by the orthoester method yields the epoxide (XXIII), which is opened with dimethylmagnesium in ethyl ether to afford the methylated secondary alcohol (XXIV). The desilylation of (XXIV) by means of TBAF in THF provides the dihydroxy compound (XXV), which is regioselectively brominated with CBr4 and PPh3 to give the bromomethyl compound (XXVI). The silylation of the remaining OH group of (XXVI) with Tbdms-Cl and imidazole in DMF yields the silyl ether (XXVII), which is treated with Zn in hot isopropanol/water to open the tetrahydropyran ring to afford, with simultaneous dehydrobromination, the unsaturated aldehyde (XXVIII). The reduction of (XXVIII) with NaBH4 provides the corresponding alcohol (XXIX), which is silylated with Tbdms-Cl as before to give the fully silylated diol (XXX). The oxidation of the terminal double bond of (XXX) first with OsO4 and then with H5IO6 yields the aldehyde (XXXI), which is condensed with the Grignard reagent (XXXII) to afford the secondary alcohol (XXXIII). The oxidation of (XXXIII) with TPAP and NMO in acetonitrile provides the ketone (XXXIV), which is oxidized at its terminal double bond with OsO4 and H5IO6 to give the carbaldehyde (XXXV). The condensation of (XXXV) with the lithium derivative of tert-butyl acetate (XXXVI), followed by silylation of the intermediate alcohol, yields the nonanoic ester (XXXVII), which is regioselectively monodesilylated with PPTS in ethanol to afford the primary alcohol (XXXVIII).

The oxidation of (XXXVIII) with TPAP and NMO in acetonitrile gives the carbaldehyde (XXXIX), which is condensed with the intermediate phosphonium bromide (XVII) by means of LiHMDS in THF to yield the heptadecadienoic ester (XL). The regioselective deprotection of (XL) by means of Tms-OTf in dichloromethane affords the hydroxyacid (XLI), which is submitted to a macrocyclization by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF to provide the protected didehydro precursor (XLII). The desilylation of (XLII) by means of TFA in dichloromethane yields the free didehydro precursor (XLIII), which is hydrogenated by means of 2,4,6-tri-isopropylbenzenesulfonyl hydrazide and TEA in refluxing ethyl ether to afford epothilone D (XLIII). Finally, this compound is epoxidated by means of dimethyldioxirane (DMDO) in dichloromethane.

The intermediate phosphonium bromide (XVII) is obtained as follows: The reaction of the glucoside (I) with Me2CuLi in THF gives the methyl derivative (II), which is converted into the unsaturated pyranoside (III). The reductive deoxygenation of (III) with Pd(OAc)2 and NaBH4 affords the acetate (IV), which is treated with NaOMe in methanol to afford the carbinol (V). The oxidation of (V) with oxalyl chloride in DMSO provides the carbaldehyde (VI), which is treated with Me-Mg-Br in THF to give the secondary alcohol (VII). The oxidation of (VII) with oxalyl chloride in DMSO yields the ketone (VIII), which is condensed with the phosphonate (IX) (obtained by reaction of 4-(chloromethyl)-2-methylthiazole (X) with triethyl phosphite (XI) at 165 C) by means of tBu-OK in THF to afford the vinyl-dihydropyran (XII). The opening of the dihydropyran ring of (XII) by means of AcOH in THF/water, followed by reduction of the intermediate aldehyde, provides the unsaturated diol (XIII). The regioselective bromination of (XIII) with CBr4 and PPh3 in acetonitrile gives the bromo derivative (XIV), which is silylated with Tbdms-OTf to yield the silyl ether derivative (XV). Finally, this compound is condensed with methylenetriphenylphosphorane (XVI) in THF to afford the target intermediate, the phosphonium bromide (XVII).

The reaction of the glucoside (I) with Me2CuLi in THF gives the methyl derivative (II), which is oxidized with oxalyl chloride in DMSO to yield the tetrahydropyranone (XVIII). The treatment of (XVIII) with TEA in dichloromethane/methanol causes isomerization of the methyl group of (XVIII) to (XIX), which is reduced with NaBH4 in methanol/DMF to afford the secondary alcohol (XX). The cleavage of the benzylidene protecting group of (XX) with H2 over Pd/C in ethyl acetate provides the trihydroxy compound (XXI), which is regioselectively monosilylated at the primary OH group with Tbdms-Cl and pyridine to give the silyl ether (XXII). The epoxidation of (XXII) by the orthoester method yields the epoxide (XXIII), which is opened with dimethylmagnesium in ethyl ether to afford the methylated secondary alcohol (XXIV). The desilylation of (XXIV) by means of TBAF in THF provides the dihydroxy compound (XXV), which is regioselectively brominated with CBr4 and PPh3 to give the bromomethyl compound (XXVI). The silylation of the remaining OH group of (XXVI) with Tbdms-Cl and imidazole in DMF yields the silyl ether (XXVII), which is treated with Zn in hot isopropanol/water to open the tetrahydropyran ring to afford, with simultaneous dehydrobromination, the unsaturated aldehyde (XXVIII). The reduction of (XXVIII) with NaBH4 provides the corresponding alcohol (XXIX), which is silylated with Tbdms-Cl as before to give the fully silylated diol (XXX). The oxidation of the terminal double bond of (XXX) first with OsO4 and then with H5IO6 yields the aldehyde (XXXI), which is condensed with the Grignard reagent (XXXII) to afford the secondary alcohol (XXXIII). The oxidation of (XXXIII) with TPAP and NMO in acetonitrile provides the ketone (XXXIV), which is oxidized at its terminal double bond with OsO4 and H5IO6 to give the carbaldehyde (XXXV). The condensation of (XXXV) with the lithium derivative of tert-butyl acetate (XXXVI), followed by silylation of the intermediate alcohol, yields the nonanoic ester (XXXVII), which is regioselectively monodesilylated with PPTS in ethanol to afford the primary alcohol (XXXVIII).

The oxidation of (XXXVIII) with TPAP and NMO in acetonitrile gives the carbaldehyde (XXXIX), which is condensed with the intermediate phosphonium bromide (XVII) by means of LiHMDS in THF to yield the heptadecadienoic ester (XL). The regioselective deprotection of (XL) by means of Tms-OTf in dichloromethane affords the hydroxyacid (XLI), which is submitted to a macrocyclization by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF to provide the protected didehydro precursor (XLII). The desilylation of (XLII) by means of TFA in dichloromethane yields the free didehydro precursor (XLIII), which is finally hydrogenated by means of 2,4,6-tri-isopropylbenzenesulfonyl hydrazide and TEA in refluxing ethyl ether to afford the target epothilone D.

The aldol condensation of 2,2-dimethyl-3-oxopentanal (I) with acetylsultam (II) by means of Et3B/OTf and DIEA gives the aldol adduct (III), which is treated with Tbdms-OTf to yield the silyl ether (IV). The TiCl4 catalyzed aldol reaction between ketone (IV) with the intermediate aldehyde (V) affords the aldol adduct (VI), which is treated with Tbdms-OTf to provide the silylated adduct (VII). Finally the cleavage of the sultam group of (VII) by means of LiO2H furnishes the already known carboxylic acid intermediate (VIII)

The protection of 2(S)-methyl-6-hepten-1-ol (I) with Tes-Cl gives the silyl ether (II), which is oxidized by known methods to yield the aldehyde (III). The condensation of (III) with the acetylenic alcohol (IV) by means of Zn(OTf)2 and TEA to afford the acetylenic diol (V), which is selectively monobenzoylated with benzoyl chloride and TEA, providing the benzoate (VI). Extrusion of acetone from (VI) by means of K2CO3 in refluxing toluene gives the chiral octyne derivative (VII), which is reduced and debenzoylated with LiAlH4 in ethyl ether to yield the unsaturated alcohol (VIII). The condensation of (VIII) with the phosphonate (IX) by means of Et-MgBr affords the isoxazoline (X), which is treated with Tbdms-OTf and DIEA to provide the silyl ether (XI). The condensation of the phosphonate (XI) with 2-methylthiazole-4-carbaldehyde (XII) gives the adduct (XIII), which is treated with SmI2 to open the isoxazoline ring and yield the beta-hydroxy ketone (XIV). The reduction of (XIV) by means of BEt3 and NaBH4 affords the beta-diol (XV), which is treated with SOCl2 and TEA to provide the cyclic sulfite (XVI). The treatment of (XVI) with TBAF in refluxing THF/water gives the chiral epoxide (XVII), which is silylated with Tes-Cl and TEA to yield the bis silyl ether (XVIII). The selective deprotection of the primary silyl ether of (XVIII) by means of Ac-OH in THF/water affords the primary alcohol (XIX).

The oxidation of (XIX) by means of TPAP and NMO gives the aldehyde (XX), which is condensed with the chiral ketone (XXI) by means of LDA in THF to yield the aldol (XXII). The protection of the OH group of (XXII) with Troc-Cl and pyridine affords the Troc-ester (XXIII). The oxidation of the terminal vinyl group of (XXIII) with OsO4, NMO and Pb(OAc)4 provides the aldehyde (XXIV), which is selectively monodesilylated by treatment with HF and pyridine at 0 C to give the alcohol (XXV). The oxidation of the aldehyde group of (XXV) with NaClO2 yields the hydroxyacid (XXVI), which is submitted to macrolactonization by means of 2,4,6-trichlrobenzoyl chloride, TEA and DMAP to afford the protected macrolactone (XXVII). The cleavage of the Troc- protecting group of (XXVII) by means of Zn and NH4Cl in methanol provides the silylated precursor (XXVIII), which is finally treated with HF and pyridine at 40 C to furnish the target Epothilone A.

The reaction of the oxime (I) with the 1-methylallyl alcohol (II) by means of Et-MgBr gives the isoxazoline (III), which is condensed with 2-methylthiazole-4-carbaldehyde (IV) by means of DBU and LiCl in acetonitrile to yield the adduct (V). The oxidation of (V) with TPAP and NMO affords the methyl ketone (VI), which is condensed with the Grignard reagent (VII) in THF to provide the tertiary alcohol (VIII). The protection of (VIII) by means of Tes-OTf gives the silylated compound (IX), which is oxidated with SmI2 in THF to yield the beta-hydroxy ketone (X). The reduction of (X) with Et3B and NaBH4 in THF/methanol affords the beta-diol (XI), which is treated with SOCl2, TEA and TBAF to provide the epoxide derivative (XII). The silylation of both OH groups of (XII) by means of Tes-Cl and TEA in dichloromethane furnishes the bis-silyl ether (XIII), which is selectively monodesilylated by means of AcOH in THF/water to give the primary alcohol (XIV). The oxidation of this alcohol by means of TPAP and NMO yields the carbaldehyde (XV).

The condensation of (XV) with the chiral ketone (XVI) by means of LDA in TH gives the aldol (XVII). The protection of the OH group of (XVII) with Troc-Cl and pyridine yields compound (XVIII), which is oxidized at the vinyl group by means of OsO4, NaIO4, selectively monodesilylated with HF and pyridine, and further oxidated with NaClO2 to afford the hydroxyacid (XIX). The Yamaguchi macrolactonization of (XIX) by means of 2,4,6-trichlorobenzoyl chloride provides the macrocyclic lactone (XX). Elimination of the Troc protecting group of (XX) by means of Zn and NH4Cl gives the silylated precursor (XXI), which is finally deprotected by means of HF and pyridine to yield the target epothilone B.

The aldol condensation of 2,2-dimethyl-3-oxopentanal (I) with acetylsultam (II) by means of Et3B/OTf and DIEA gives the aldol adduct (III), which is treated with Tbdms-OTf to yield the silyl ether (IV). The TiCl4 catalyzed aldol reaction between ketone (IV) with the intermediate aldehyde (V) affords the aldol adduct (VI), which is treated with Tbdms-OTf to provide the silylated adduct (VII). Finally the cleavage of the sultam group of (VII) by means of LiO2H furnishes the already known carboxylic acid intermediate (VIII)

The intermediate chiral epoxide (III) has been obtained as follows. The Sharpless epoxidation of 3-buten-2(R)-ol (I) gives the chiral epoxide (II), which is protected with Pmb-Br and NaH to yield the target epoxide intermediate (III).

The intermediate phosphonate (X) has been obtained as follows. The cyclization of thioacetamide (IV) with ethyl 3-bromopiruvate (V) in ethanol gives 2-methylthiazole-4-carboxylic acid ethyl ester (VI), which is reduced by means of LiAlH4 in ethyl ether to yield the carbinol (VII). The bromination of (VII) with CBr4 and PPh3 in CCl4 affords the 4-bromomethyl-2-methylthiazole (VIII), which is finally condensed with triethyl phosphite (IX) to provide the target phosphonate intermediate (X). Alternatively, the cyclization of thioacetamide (IV) with 1,3-dichloroacetone (XI) gives 4-(chloromethyl)-2-methylthiazole (XII), which is condensed with triethyl phosphite (IX) to also provide the target phosphonate intermediate (X).

Synthesis of the target epothilone D. The condensation of 4-methyl-4-pentenyl bromide (XIII) with propyne (XIV) and 1-hexynyl lithium (XV) by means of CuBr in DMSO/ethyl ether gives the copper complex (XVI), which is condensed with the chiral epoxide (III) to yield the chiral unsaturated alcohol (XVII). The protection of the free OH group of (XVII) with Sem-Cl and DIEA in dichloromethane affords compound (XVIII). The selective cleavage of the Pmb-protecting group of (XVIII) by means of DDQ, followed by oxidation of the resulting alcohol with oxalyl chloride provides the methyl ketone (XIX), which is condensed with the intermediate phosphonate (X) by means of BuLi in THF to give the adduct (XX). The hydroxylation of the terminal vinylene double bond of (XX) by means of (Ipc)2BH and LiOH yields the primary alcohol (XXI), which is oxidized with (COCl)2, PTAP or DMP to afford the corresponding aldehyde (XXII). The condensation of aldehyde (XXII) with the known carboxylic acid (XXIII) by means of LDA in THF provides the linear adduct (XXIV), which is treated with Troc-Cl to protect the free OH group of (XXIV) yielding carboxylic acid (XXV).

The selective cleavage of the Sem protecting group of (XXV) by means of MgBr2, MeNO2 and BuSH gives the hydroxyacid (XXVI), which is submitted to macrolactonization by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF to yield the protected macrolactone (XXVII). The treatment of (XXVII) with Zn and NH4Cl cleaves the Troc protecting group of to yield lactone (XXVIII), which is treated with HF and pyridine to afford epothilone D (XXIX). Finally, this compound is epoxidated by means of MCPBA or DMDO to provide the target epothilone B.

The intermediate chiral epoxide (III) has been obtained as follows. The Sharpless epoxidation of 3-buten-2(R)-ol (I) gives the chiral epoxide (II), which is protected with Pmb-Br and NaH to yield the target epoxide intermediate (III).

The intermediate phosphonate (X) has been obtained as follows. The cyclization of thioacetamide (IV) with ethyl 3-bromopiruvate (V) in ethanol gives 2-methylthiazole-4-carboxylic acid ethyl ester (VI), which is reduced by means of LiAlH4 in ethyl ether to yield the carbinol (VII). The bromination of (VII) with CBr4 and PPh3 in CCl4 affords the 4-bromomethyl-2-methylthiazole (VIII), which is finally condensed with triethyl phosphite (IX) to provide the target phosphonate intermediate (X). Alternatively, the cyclization of thioacetamide (IV) with 1,3-dichloroacetone (XI) gives 4-(chloromethyl)-2-methylthiazole (XII), which is condensed with triethyl phosphite (IX) to also provide the target phosphonate intermediate (X).

Synthesis of the target epothilone D. The condensation of 4-methyl-4-pentenyl bromide (XIII) with propyne (XIV) and 1-hexynyl lithium (XV) by means of CuBr in DMSO/ethyl ether gives the copper complex (XVI), which is condensed with the chiral epoxide (III) to yield the chiral unsaturated alcohol (XVII). The protection of the free OH group of (XVII) with Sem-Cl and DIEA in dichloromethane affords compound (XVIII). The selective cleavage of the Pmb protecting group of (XVIII) by means of DDQ, followed by oxidation of the resulting alcohol with oxalyl chloride provides the methyl ketone (XIX), which is condensed with the intermediate phosphonate (X) by means of BuLi in THF to give the adduct (XX). The hydroxylation of the terminal vinylene double bond of (XX) by means of (Ipc)2BH and LiOH yields the primary alcohol (XXI), which is oxidized with (COCl)2, PTAP or DMP to afford the corresponding aldehyde (XXII). The condensation of aldehyde (XXII) with the known carboxylic acid (XXIII) by means of LDA in THF provides the linear adduct (XXIV), which is treated with Troc-Cl to protect the free OH group of (XXIV) yielding carboxylic acid (XXV).

The selective cleavage of the Sem protecting group of (XXV) by means of MgBr2, MeNO2 and BuSH gives the hydroxyacid (XXVI), which is submitted to macrolactonization by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF to yield the protected macrolactone (XXVII). The treatment of (XXVII) with Zn and NH4Cl cleaves the Troc protecting group of(XXVII) to yield lactone (XVIII), which is finally treated with HF and pyridine to afford the target epothilone D

The protection of the allyl alcohol (I) with dihydropyran and PPTS in dichloromethane gives the tetrahydropyranyl ether (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi and CuCN in THF to yield the adduct (IV). The hydroxylation of (IV) with Davis' oxaziridine, NaHMDS and CSA affords the alcohol (V), which is silylated with Tbdms-OTf and lutidine to provide the silyl ether (VII). The hydrolysis of the oxazolidinone group of (VII) with Et-SH and Et-SK in THF gives the thioester (VIII), which is methylated with Me2CuLi in ethyl ether, yielding the methyl ketone (IX). The condensation of (IX) with phosphonate (X) by means of BuLi in THF affords the diene (XI), which is treated with MgBr2 in ethyl ether in order to eliminate the THP protecting group and obtain the primary alcohol (XII). The sulfonation of (XII) with Ms2O and TEA in dichloromethane gives the mesylate (XIII), which is treated with LiBr in acetone to yield the allyl bromide (XIV). Finally, (XIV) is condensed with methyltriphenylphosphonium bromide (XV) by means of BuLi in THF affording the desired intermediate phosphonium salt (XVI).

The condensation of the known ketone (XVII) with aldehyde (XVIII) by means of LDA in THF gives the hydroxyketone (XIX), which is silylated with Tbdms-OTf and TEA in dichloromethane, yielding the silyl ether (XX). The terminal vinyl group of (XX) is cleaved oxidatively by means of OsO4 and NaIO4 in THF/water, affording the aldehyde (XXI), which is oxidized to acid (XXII) by means of NaClO2 in t-butanol/water. Acid (XXII) is esterified to methyl ester (XXIII), which is selectively deprotected at the Pmb group by hydrogenation with H2 over Pd/C in ethanol to provide the primary alcohol (XXIV). The oxidation of (XXIV) with tetrapropylammonium perruthenate (TPAP) furnishes the aldehyde (XXV), which is submitted to a Wittig condensation with the intermediate phosphonium salt (XVI) by means of LiHMDS in THF to give the adduct (XXVI). The hydrolysis of the ester group of (XXVI) with NaOH in warm isopropanol yields the carboxylic acid (XXVII), which is selectively deprotected by means of TBAF in THF to afford the hydroxyacid (XXVIII).

The macrolactonization of (XXVIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF provides the protected macrolactone (XXIX), which is deprotected with TFA in dichloromethane to give the trienic macrolactone (XXX). Selective hydrogenation of the disubstituted double bond of (XXX) by means of potassium azodicarboxylate (DKAD) and AcOH in dichloromethane yields the precursor (XXXI), which is finally epoxidized with dimethyldioxirane (XXXII) in dichloromethane to afford the target epothilone B.

The protection of the allyl alcohol (I) with dihydropyran and PPTS in dichloromethane gives the tetrahydropyranyl ether (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi and CuCN in THF, yielding the adduct (IV). The hydroxylation of (IV) with Davis' oxaziridine, NaHMDS and CSA affords the alcohol (V), which is silylated with Tbdms-OTf and lutidine, providing the silyl ether (VII). The hydrolysis of the oxazolidinone group of (VII) with Et-SH and Et-SK in THF gives the thioester (VIII), which is methylated with Me2CuLi in ethyl ether, yielding the methyl ketone (IX). The condensation of (IX) with phosphonate (X) by means of BuLi in THF affords the diene (XI), which is treated with MgBr2 in ethyl ether in order to eliminate the THP protecting group and obtain the primary alcohol (XII). The sulfonation of (XII) with Ms2O and TEA in dichloromethane gives the mesylate (XIII), which is treated with LiBr in acetone to yield the allyl bromide (XIV). Finally, (XIV) is condensed with methyltriphenylphosphonium bromide (XV) by means of BuLi in THF affording the desired intermediate phosphonium salt (XVI).

The condensation of the known ketone (XVII) (2) with aldehyde (XVIII) by means of LDA in THF gives the hydroxyketone (XIX), which is silylated with Tbdms-OTf and TEA in dichloromethane, yielding the silyl ether (XX). The terminal vinyl group of (XX) is cleaved oxidatively by means of OsO4 and NaIO4 in THF/water, affording the aldehyde (XXI), which is oxidized to acid (XXII) by means of NaClO2 in t-butanol/water. Acid (XXII) is esterified to methyl ester (XXIII), which is selectively deprotected at the Pmb group by hydrogenation with H2 over Pd/C in ethanol to provide the primary alcohol (XXIV). The oxidation of (XXIV) with tetrapropylammonium perruthenate (TPAP) furnishes the aldehyde (XXV), which is submitted to a Wittig condensation with the intermediate phosphonium salt (XVI) by means of LiHMDS in THF to give the adduct (XXVI). The hydrolysis of the ester group of (XXVI) with NaOH in warm isopropanol yields the carboxylic acid (XXVII), which is selectively deprotected by means of TBAF in THF to afford the hydroxyacid (XXVIII).

The macrolactonization of (XXVIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF provides the protected macrolactone (XXIX), which is deprotected with TFA in dichloromethane to give the trienic macrolactone (XXX). Finally, the selective hydrogenation of the disubstituted double bond of (XXX) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane yields the target epothilone D.