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

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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.

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