Abstract
The first synthesis of the antifungal antibiotic tautomycin, a potent protein phosphatase inhibitor, has been achieved via aldol coupling of two large subunits, a right-hand C1-C21 ketone and a left-hand aldehyde (left from C22). The C1-C10 segment was synthesized through a remote stereochemical control process using a spiroketal template After joining with the C11-C18 segment, the spiroketal moiety was selectively constructed. Then the right-hand C1-C21 ketone was synthesized via Roush asymmetric crotylboration. The left-hand aldehyde was prepared by esterification of a C21-C26 segment and a dialkylmaleic anhydride segment. The C21-C26 segment was synthesized through a regioselective opening of an epoxy alcohol and the dialkylmaleic anhydride segment was through a diastereoselective olefination. Completely stereoselective assemblage of the two subunits, the right-hand and the left-hand, was achieved employing the Mukaiyama aldol reaction. Further functional group manipulations including desilylation, oxidation at C2, and deprotection of tert-butyl ester with concomitant anhydride formation provided tautomycin which was identical with the natural product. As a preliminary study, derivatizations and degradation of the natural product were also examined to support the total synthesis.
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