Total Synthesis of Lobatamides A and C.

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.

Copper-Catalyzed Electrophilic Enamidation Using Dioxazolones through Hydrozirconation of Alkynes.

A copper-catalyzed electrophilic enamidation starting from alkynes is reported. Hydrozirconation of an alkyne with the Schwartz reagent forms a vinyl zirconium intermediate, which directly undergoes a copper-catalyzed electrophilic enamidation with dioxazolones. High functional group tolerance of hydrozirconation enables the use of functionalized alkynes including esters. The developed conditions are successfully applied to syntheses of partial structures found in biologically active natural products.