合成路线1

The condensation of 3-[2-(hydroxymethyl)thiazol-4-yl]-2-methylpropenal (I) with acetone (II) gives the racemic aldol derivative (III), which is submitted to a enantioselective retroaldol reaction catalyzed by antibodies 84G3, 85H6 or 93F3, yielding the chiral aldol (IV) with 99% ee purity. The protection of the OH groups of (IV) with TbdmsCl and imidazole affords the bis silyl ether (V), which is oxidized with Tms-OTf, trifluoroacetone and oxone to provide the hydroxyketone (VI). The reduction of (VI) with NaBH4 in methanol gives the vicinal diol (VII), which is cleaved with Pb(OAc)4 to yield the aldehyde (VIII). The Wittig reaction of (VIII) with methyltriphenylphosphonium iodide (IX) and BuLi in THF affords the olefin (X), which is desilylated with TBAF in THF and selectively monosilylated at the primary alcohol with Tbdms-Cl and DIEA to give the secondary alcohol (XI). The esterification of (XI) with the known carboxylic acid (XII) (see later) by means of EDC in dichloromethane yields the ester (XIII), which is submitted to a ring-closing metathesis catalyzed by the Grubb's catalyst in dichloromethane to afford the protected macrolactone (XIV). The desilylation of (XIV) with HF and pyridine in THF gives the precursor (XV), which is finally epoxidated with H2O2 and KHCO3 in methanol to yield the target epothilone E.