Synthesis of a C1-C21 subunit of the protein phosphatase inhibitor tautomycin: A formal total synthesis

The synthesis of a C1-C21 subunit of tautomycin is described. The convergen t route employs enantioenriched allenylstannane and zinc reagents derived f rom (S)-3-butyn-2-ol methanesulfonate. These reagents react with appropriat e aldehyde segments to yield syn and anti adducts with high diastereoselect ivity. The derived lithioalkynes are joined stepwise to a CO equivalent, (M eONMe)(2)-C=O, to afford an intermediate ketone which is converted to the c ore spiroketal moiety of tautomycin upon acid treatment. Chain elongation b y another addition of the aforementioned allenylzinc reagent to a spiroketa l aldehyde proceeds with high diastereoselectivity to install the remaining stereocenters. The resulting homopropargylic alcohol adduct is converted t o a methyl ketone through intramolecular hydrosilylation of the alkyne and Tamao oxidation of the derived five-membered siloxane. This ketone proved i dentical to an intermediate employed by Chamberlin in a prior total synthes is of tautomycin.