Synthesis of enantiomerically enriched β-N-amino (S)-α-alanine analogs via sequential reactions on a chiral Ni(ii) complex

Abstract

A concise synthetic route to enantiomerically enriched β-N-substituted (S)-α-diaminopropanoic acids is reported. An acetylene group was introduced into the alanine side chain by nucleophilic Michael addition of substituted propargylamines to the dehydroalanine moiety in a chiral Ni(II) complex, which afforded β-N-propargylamino derivatives in high ee (≈90%). Subsequent Glaser, Sonogashira, and [3 + 2]-cycloaddition reactions delivered structurally diverse products with ee up to 99%. The isolated auxiliary (S)-BPB can be recovered and reused without any loss of enantiointegrity. Biological screening of the products identified (S)-3-(N-(1-phenylethyl)-N-(prop-2-ynyl)amino)-2-aminopropanoic acid as a moderate bacterial collagenase inhibitor (IC₅₀ = 0.69 mM), demonstrating the potential of this platform for enzyme inhibitor development.