Synthesis of Two Stereoisomers of a Natural Cyclotetrapeptide and Four Stereoisomeric Diheteropeptins Through Late-Stage Scaffold Diversification

Abstract

A concise synthetic route has been developed to access two stereoisomers 5a-b of a biologically enticing naturally occurring cyclic tetrapeptide through late-stage diversification of the cyclopeptidic scaffold 8. A cross-metathesis reaction of this template with the olefins 9a-b, preparaed from enantiomeric methyl lactates 10, produced the α,β-unsaturated ketones 7a-b which on subsequent hydrogenation produced the desired targets 5a-b in good overall yields.These two stereo-isomers, 5a-b, were then used for the preparation of four stereoisomers of the closely related and biologically relevant cyclic tetrapeptide diheteropeptin 1. A syn-selective reduction of the hydroxyketones 5a-b with lithium tri-tert-butoxyaluminium hydride produced the syn-isomers 1a and 1c, whereas an anti-selective reduction with lithium triethylborohydride produced the pseudo-enantiomeric targets 1b and 1d with similar yield and selectivity. Thus, an ensemble of six cyclic tetrapeptides with stereochemical diversity was generated from the common template 8 in two-three steps.