Total Synthesis of the Serine/Threonine-Specific Protein Phosphatase Inhibitor Tautomycin¹

A convergent, asymmetric synthesis of the protein phosphatase inhibitor, tautomycin, is described. The natural product was constructed by joining two major fragments of comparable complexity at the C21−C22 bond. Absolute stereochemistry of the C1−C21 ketone originates from (S)-citronellene and (2R,3S)-geraniol epoxide. The anti stereochemical relationships at C6−C7 and C18−C19 were introduced with Duthaler's chiral titanium propionic enolate. Syn stereochemical relationships at C13−C14 and C23−C24 were established using an Evan's oxazolidinone chiral auxiliary. The spiroketal was efficiently constructed via a one-pot double-alkylation−spirocyclization sequence with acetone N,N-dimethylhydrazone serving as the central linchpin. Final coupling of the two halves using a chelation-controlled Mukaiyama aldol addition followed by deprotection yielded synthetic tautomycin that is identical to the natural product.