A Modular Synthesis of Some Biologically Relevant Cyclic Peptides through Late-Stage Functionalization

Abstract

A modular synthesis of some cyclic peptides related to a class of histone deacetylase inhibitors is reported. The synthesis utilizes a late-stage functionalization of a cyclic tetrapeptide scaffold to link the pendant alkyl chain through cross metathesis. It is observed that while the cross-metathesis reaction of a terminal olefin having a β-substituent is marginally successful with the scaffold, the corresponding reaction with an α,β-unsaturated ketone/ester is more promising. The utility of the protocol is demonstrated through the preparation of three cyclic tetrapeptides structurally related to the novel histone deacetylase inhibitors FR-225497 and trapoxin B.

Key words

peptides - macrocycles - cross metathesis - modular synthesis - catalysis

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