Sequential Michael addition, cross-coupling and [3 + 2] cycloaddition reactions within the coordination sphere of chiral Ni(ii) Schiff base complexes derived from dehydroamino acids: pathways to the asymmetric synthesis of structurally diverse O-substituted serine and threonine analogs

Abstract

An approach to the synthesis of a series of novel, enantiomerically pure analogs of β-hydroxy-α-amino acids is reported. The method involves the introduction of the acetylene group into their side chain, followed by further elaboration of the terminal alkyne moiety. The asymmetric synthesis of alkyl- and aryl-substituted derivatives of (S)-O-propargylserine and (S)-allo-O-propargylthreonine (de >90%) was achieved through the nucleophilic Michael addition of the deprotonated congeners of propargyl alcohols to the CC bond of the square-planar Ni(II) Schiff base complexes of dehydroamino acids (dehydroalanine and dehydroaminobutyric acid) with the chiral auxiliary (S)-BPB. Both (S)-O-propargylserine and (S)-allo-O-propargylthreonine were isolated with high enantiomeric purity (81–98% ee). The terminal alkyne group was further modified: Glaser reaction enabled formation of the dienyne products; Sonogashira cross-coupling gave rise to arylacetylene motifs, whereas [3 + 2]-cycloaddition reactions with 2-nirtophenylazide produced analogs of O-substituted (S)-serine and (S)-allo-threonine containing a 1,2,3-triazole group. All target amino acids were isolated with high enantiomeric purity (ee >98%). The developed approach provides an opportunity to synthesize new O-substituted analogs of β-hydroxy-α-amino acids with a diverse set of substituents in the side chain.