An asymmetric synthesis of the C(17)-C(27)-segment of bryostatin 1 has been described: The asymmetric dihydroxylation of 1,4(E)-hexadiene (I) with AD-mix-beta in tert-butanol gives the diol (II), which is protected with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF, yielding the bis(silyl) ether (III). The oxidation of (III) with OsO4 and NaIO4 affords the aldehyde (IV), which is condensed with triphenylphosphoranylideneacetic acid ethyl ester (V) in dichloromethane to give 5(R),6(R)-bis(tert-butyldimethylsilyloxy)-2(E)-heptenoic acid ethyl ester (VI). The reduction of (VI) with dibutylaluminum hydride (DIBAL-H) yields the primary alcohol (VII), which is epoxidized with (-)-DET, Ti(OPr)4 and tert-butyl peroxide in dichloromethane to the epoxy-alcohol (VIII). The reductive opening of the epoxide ring of (VIII) with REDAL affords the diol (IX), which by reaction with 4-methoxybenzaldehyde dimethylacetal [PMB(OMe)2] and PPTS in DMF is converted to the acetal (X). The reductive cleavage of (X) with DIBAL-H in dichloromethane affords 5(R),6(R)-bis(tert-butyldimethylsilyloxy)-3(S)-(4-methoxybenzyloxy)-1-h eptanol (XI), which is oxidized with oxalyl chloride to the corresponding aldehyde (XII). The condensation of (XII) with phosphorane (V) in dichloromethane gives 7(R),8(R)-bis(tert-butyldimethylsilyloxy)-5(S)-(4-methoxybenzyloxy)-2(E)-nonenoic acid ethyl ester (XIII), which is asymmetrically dihydroxylated with AD-mix-beta as before to the dihydroxy ester (XIV). The protection of (XIV) by reaction with 2,2-dimethoxypropane and PPTS yields the isopropylidene ketal (XV), which is submitted to a Claisen condensation with the lithium enolate of methyl isobutyrate, affording the keto ester (XVI). Selective deprotection of (XVI) with HF.pyridine affords the diol (XVII), which is acylated with pivaloyl chloride (Pv-Cl) and pyridine in dichloromethane, giving the bispivaloyloxy derivative (XVIII). A new selective deprotection of (XVIII) with DDQ in dichloromethane yields the hydroxy ester (XIX), which is submitted to cyclization with Amberlyst-15 H+ and acetyl chloride in methanol to afford the perhydrofuropyran derivative (XX). The oxidation of the hydroxy group of (XX) with RuCl3 and NaIO4 in acetonitrile/CCl4 gives the corresponding ketonic compound (XXI), which is finally submitted to a condensation with triphenylphosphoranylideneacetic acid methyl ester in dichloromethane to afford 2(E)-[5(S)-[2(R),3(R)-bis(pivaloyloxy)butyl]-3a(S)-methoxy-2,2-dimethyl-7a(S)-perhydrofuro[3,2-a]pyran-7-ylidene]acetic acid methyl ester (XXII), which includes the C(17)-C(27)-fragment of bryostatin 1 with the correct stereochemistry.

C1-C9 Fragment: The condensation of 2,2-dimethyl-4,4-diphenyl-3-butenal (I) with the chiral oxazolidinone (II) by means of dibutylboron triflate gives the chiral ketol (III), which is dechlorinated with Zn and AcOH in THF yielding the beta-hydroxyimide (IV). The reduction of (IV) with LiBH4 in methanol/THF affords the chiral diol (V), which is treated with 4-methoxybenzaldehyde dimethyl acetal and PPTS in dichloromethane to give the cyclic ketal (VI). The regioselective reduction of (VI) with DIBAL in dichloromethane yields the monoprotected diol (VII), which is oxidized to aldehyde (VIII) with oxalyl chloride in DMSO. The condensation of (VIII) with the bis(trimethylsilyl)dienol ether (IX) by means of TiCl2(i-PrO)2 in toluene affords the ketoester (X), which by stereoselective reduction with (AcO)3BHNMe4 in acetonitrile/acetic acid gives the dihydroxyester (XI) with high stereoselectivity. The lactonization of (XI) by means of PPTS in refluxing benzene yields the hydroxylactone (XII), which is silylated with TBDMS-OTf and 2,6-lutidine in dichloromethane affording the silylated lactone (XIII). Opening of the lactone ring with aniline and Me3Al in dichloromethane gives the monoprotected dihydroxyamide (XIV), which is ozonolyzed with O3 in CH2Cl2/MeOH yielding the cyclic lactol (XV). Acetylation of (XV) with acetic anhydride and pyridine affords the acetate (XVI), which by reaction with TMS-SPh, ZnI2 and tetrabutylammonium iodide is converted regioselectively into the phenylsulfanyl derivative (XVII). Finally, this compound is oxidized with m-chloroperbenzoic acid (MCPBA) in EtOAc to provide the desired C1-C9 subunit fragment (XVIII).

C10-C16 Fragment: The stereocontrolled reduction of ketoester (XIX) with Me4NHB(OAc)3 in acetonitrile/AcOH gives the dihydroxyester (XX), which is dehydrated to the lactone (XXI) with PPTS in refluxing benzene. The protection of (XXI) with triethylsilyl chloride as usual affords the fully silylated lactone (XXII), which is condensed with benzyloxymethyllithium in THF and reduced with BF3/Et2O and triethylsilane giving the benzyloxymethyl derivative (XXIII). The selective deprotection of (XXIII) with BF3/Et2O yields the 4-hydroxy derivative (XXIV), which is desilylated with TBAF in THF to give the diol (XXV). The silylation of (XXV) with TBDMS-OTf and lutidine in dichloromethane yields the fully protected compound (XXVI), which is debenzylated with H2 over Pd/C in acetic acid/ethyl acetate affording the carbinol (XXVII). Finally, this compound is oxidized with oxalyl chloride and triethylamine in DMSO to provide (XXVIII), the desired C10-C16 fragment.

C17-C27 Fragment: The monotosylation of 2,2-dimethylpropane-1,3-diol (XXIX) with TsCl and pyridine in CH2Cl2 gives the monotosylate (XXX), which is condensed with thiophenol by means of NaH in hot DMF yielding the phenylsulfanyl derivative (XXXI). The oxidation of (XXXI) with MCPBA in dichloromethane affords the corresponding sulfone (XXXII), which is oxidized with oxalyl chloride in DMSO to give the aldehyde (XXXIII). The Grignard reaction of (XXXIII) with 4-pentenylmagnesium bromide (XXXIV) in ethyl ether/CH2Cl2 yields the secondary alcohol (XXXV), which is oxidized with oxalyl chloride in DMSO to the ketone (XXXVI). The dihydroxylation of the double bond of (XXXVI) with K2OsO4 in t-BuOH/H2O followed by oxidation with NaIO4 in t-BuOH/H2O/THF affords the keto aldehyde (XXXVII), which is condensed with the chiral butanone (XXXVIII) by means of (-)-diisopinocampheyl chloride ((-)-DIP-Cl) and Et3N in dichloromethane to give aldol (XXXIX). The SmI2 catalyzed Tishchenko reduction of (XXXIX) in the presence of 4-nitrobenzaldehyde yields the diastereomerically pure 4-nitrobenzoate (XL), which is silylated with TBDMS-OTf to afford the protected ketone (XLI). The hydrolysis of the 4-nitrobenzoate group of (XLI) with LiOH in THF/MeOH/H2O gives the alcohol (XLII), which is cyclized by means of camphorsulfonic acid (CSA) in refluxing benzene yielding the dihydropyran (XLIII), the desired C17-C27 fragment. The intermediate, the chiral butanone (XXXVIII) has been obtained as follows: The optical resolution of 3-methyl-4-phenyl-3-buten-2-ol (XLIV) with (+)-DIPT gives the (R)-isomer (XLV), which is protected with p-methoxybenzyl bromide and NaH yielding the benzyl ether (XLVI). Finally, (XLVI) is ozonolyzed with O3 in MeOH / CH2Cl2 dichloromethane to afford the desired intermediate (XXXVIII).

Fragment coupling: Coupling of the C10-C16 fragment (XXVIII) with the C17-C27 fragment (XLIII) by means of BuLi, Ac2O and Mg in THF gives (XLVII), which is selectively deprotected with TBAF yielding the carbinol (XLVIII). The reaction of (XLVIII) with triflic anhydride and lutidine in CH2Cl2 affords the triflate (IL), which is coupled with the C1-C9 fragment (XVIII) by means of n-BuLi in THF giving the tricyclic intermediate (L). The opening of the lactol ring of (L) with triethylsilyl chloride and imidazole yields the silylated hydroxyketone (LI), which is treated first with tert-butoxycarbonyl anhydride and then with the lithium salt of benzyl alcohol in order to convert the phenylcarboxamide of (LI) into the benzyl ester (LII). The epoxidation of the dihydropyran double bond of (LII) with MCPBA followed by epoxide opening with MeOH and oxidation of the resulting alcohol with DMP in CH2Cl2 gives the oxoketal (LIII).

The reaction of (LIII) with HF in pyridine/methanol gives the desilylated tricyclic intermediate (LIV), which is resilylated with TESCl and DMAP in dichloromethane and debenzylated by reaction with 1,4-cyclohexadiene over Pd/C to afford the free hydroxyacid (LV). The cyclization of (LV) by means of 2,4,6-trichlorobenzoyl chloride, i-PrNEt2 and DMAP gives the macrocycle (LVI), which is selectively deprotected with PPTS in methanol/HC(OEt)3/dichloromethane, and oxidized with Dess Martin periodinane (DMP) in pyridine/dichloromethane yielding the diketone (LVII). The reaction of (LVII) with the Fuji's chiral phosphonate (LVIII) by means of NaHMDS in THF affords the C13 enoate (LIX), which is condensed with methyl glyoxylate by means of KHMDS in THF to give the C21 enoate (LX). The stereoselective reduction of the carbonyl group of (LX) with BH3/SMe2 catalyzed by the oxazaborolidine (A), followed by esterification with methoxyacetic anhydride provides the methoxyacetate (LXI).

The desilylation and C9 demethylation of (LXI) with PPTS in THF/H2O gives the dihydroxy intermediate (LXII), which is deacetylated with Na2CO3 in MeOH to yield the trihydroxy intermediate (LXIII). The demethylation of the C19 methoxy group of (LXIII) with TsOH in CH3CN/H2O affords the tetrahydroxy compound (LXIV), which is selectively acylated at the C20 hydroxy group with 2(E),4(E)-octadienoic acid (LXV) by means of diisopropylcarbodiimidde (DIP) and DMAP in CH2Cl2 providing the ester (LXVI). The elimination of the 4-methoxybenzyl protecting groups of (LXVII) by means of DDQ in a buffered solution gives the precursor Bryostatin 2 (LXVII).

The selective silylation of (LXVII) with TBMDSCl, Et3N and DMAP in DMF gives the 26-TBDMS ether (LXVIII), which is acetylated with Ac2O and pyridine yielding the 7-acetate (LXIX). Finally, (LXIX) is desilylated with HF in acetonitrile.