Total Synthesis of Lobatamides A and C.

Abstract

The total synthesis of lobatamides A (1 a) and C (1 c) via a common bislactone intermediate is reported. The allylic aryl moiety including a trisubstituted Z-olefin was constructed by hydroboration of a 1,1-disubstituted allene and subsequent Migita-Kosugi-Stille coupling. Although the seco acid proved to be highly unstable even in the presence of weak bases, Zhao macrolactonization under acidic conditions via the α-acyloxyenamide successfully provided the common bislactone intermediate. Hydrozirconation-iodination of the terminal alkyne and subsequent copper-mediated coupling with primary amides proceeded successfully in the presence of the sensitive bislactone framework. The developed synthetic route enables the late-stage installation of enamide side chains, which are crucial structures for V-ATPase inhibition.