合成路线1

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.