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).