Modular Total Synthesis and Antimycobacterial Activity of Rufomycins

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).

鲁福霉素（rufomycins）是一类从深海生暗灰链霉菌（Streptomyces atratus）中分离得到的非核糖体环状肽家族。本文报道了鲁福霉素家族中6个同系物的全合成路线。该合成采用模块化固相策略，引入了多种非蛋白源性氨基酸：L-2-氨基-4-己烯酸、叔戊烯基-L-色氨酸（及其相关(S)-环氧衍生物）以及N-甲基-δ-羟基-L-亮氨酸。经大环内酰胺化反应后，研究人员通过后期氧化与二次环化对这些肽类进行进一步衍生，最终得到包含6种合成天然产物的化合物文库。其中，带有罕见6-羟基哌啶-2-酮结构基序的鲁福霉素4和22，对致病结核分枝杆菌（Mycobacterium tuberculosis）H37Rv毒株表现出优异的抑菌活性（半数抑菌浓度MIC50为350–670 nM）。