TOTAL SYNTHESIS OF THE SERINE THREONINE-SPECIFIC PROTEIN PHOSPHATASE INHIBITOR TAUTOMYCIN/

A convergent, asymmetric synthesis of the protein phosphatase inhibito r, tautomycin, is described. The natural product was constructed by jo ining two major fragments of comparable complexity at the C21-C22 bond . Absolute stereochemistry of the C1-C21 ketone originates from (S)-ci tronellene and (2R,3S)-geraniol epoxide. The anti stereochemical relat ionships at C6-C7 and C18-C19 were introduced with Duthaler's chiral t itanium propionic enolate. Syn stereochemical relationships at C13-C14 and C23-C24 were established using an Evan's oxazolidinone chiral aux iliary. The spiroketal was efficiently constructed via a one-pot doubl e-alkylation-spirocyclization sequence with acetone N,N-dimethylhydraz one serving as the central linchpin. Final coupling of the two halves using a chelation-controlled Mukaiyama aldol addition followed by depr otection yielded synthetic tautomycin that is identical to the natural product.