Total Synthesis of the Proposed Microcyclamides MZ602 and MZ568.

Abstract

The first convergent total synthesis for the proposed structures of microcyclamides MZ602 (1) and MZ568 (2) has been accomplished in 11 linear steps with 12.5 and 16.8% overall yield, respectively. Key features of the syntheses include a one-pot cascade reaction to construct core Boc-l-Ile-Thz-OAllyl fragment 5, and a removable pseudoproline (ΨMe,Me pro) inducer assisted cyclization of thiazole-containing all-l linear peptides. The spectral data (1H NMR, 13C NMR, and HRMS) of synthetic MZ602 (1) were quite similar to those of the proposed natural microcyclamide MZ602, except to an opposite sign of the optical rotation value. Surprisingly, the synthetic MZ568 (2) presented large discrepancies in characteristic spectral data from those of the reported natural product, although the absolute configuration of key intermediate 36 was unambiguously determined by single-crystal X-ray analysis in our work. These findings revealed that the proposed structures of natural microcyclamides MZ602 and MZ568 required revision.