Modular Total Synthesis and Antimycobacterial Activity of Rufomycins.

Abstract

The rufomycins are a family of nonribosomal cyclic peptides isolated from the deep sea-dwelling Streptomyces atratus. Herein, we describe the total synthesis of six congeners in the rufomycin family. Synthesis was achieved through a modular solid-phase strategy, incorporating synthetic nonproteinogenic amino acids: l-2-amino-4-hexenoic acid, tert-prenyl-l-tryptophan (and related (S)-epoxide), and N-methyl-δ-hydroxy-l-leucine. Following macrolactamization, these peptides were further diversified through late-stage oxidation and secondary cyclization to furnish a library of six synthetic natural products. Rufomycins 4 and 22, bearing an unusual 6-hydroxypiperidin-2-one structural motif, exhibited impressive activity against the virulent H37Rv strain of Mycobacterium tuberculosis (MIC50 = 350-670 nM).