Lobatamide C: Total Synthesis, Stereochemical Assignment, Preparation of Simplified Analogues, and V-ATPase Inhibition Studies

The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide
C, as well as synthesis of simplified lobatamide analogues, is reported. Cu(I)-mediated enamide formation
methodology has been developed to prepare the highly unsaturated enamide side chain of the natural
product and analogues. A key fragment coupling employs base-mediated esterification of a β-hydroxy
acid and a salicylate cyanomethyl ester. Three additional stereoisomers of lobatamide C have been prepared
using related synthetic routes. The stereochemistry at C8, C11, and C15 of lobatamide C was assigned by
comparison of stereoisomers and X-ray analysis of a crystalline derivative. Synthetic lobatamide C,
stereoisomers, and simplified analogues have been evaluated for inhibition of bovine chromaffin granule
membrane V-ATPase. The salicylate phenol, enamide NH, and ortho-substitution of the salicylate ester
have been shown to be important for V-ATPase inhibitory activity.