An Efficient Chemical Synthesis of Lassomycin Enabled by an On-Resin Lactamisation-Off-Resin Methanolysis Strategy and Preparation of Chemical Variants

Abstract

An efficient synthesis of the naturally occurring cyclic peptide lassomycin that bears a unique Asp-Gly isopeptide bond and a C-terminal methyl ester is described. On-resin cyclisation between 1Gly and side chain 8Asp and a subsequent solution-phase transesterification reaction afforded synthetic lassomycin in high yield. Several analogues were also prepared using the optimised methodology. None of the cyclised peptides, including the synthetic natural product, exhibited any significant activity against Mycobacterium tuberculosis. Comparison of the spectroscopic data for synthetic lassomycin with naturally occurring lassomycin concluded they were otherwise identical.