Strategy for synthesizing O-protected (S)-α-substituted serine analogs via sequential Ni(ii)-complex-mediated cross-coupling and cycloaddition reactions

Abstract

A strategy for the synthesis of enantiomerically enriched O-protected α-substituted (S)-serine analogs involving a sequence of several named reactions in the coordination sphere of a square-planar Ni(II) Schiff base complex of dehydroalanine and the chiral auxiliary (S)-BPB was developed. The Michael addition of the methylate to the double bond of the dehydroalanine moiety yielded the O-methylserine complex, serving as an O-protected precursor of serine for subsequent transformations. The synthesis of α-substituted serines—(S)-α-benzylserine, (S)-α-allylserine, and (S)-α-propargylserine—was then achieved via electrophilic C_α-alkylation of the O-methylserine moiety using alkyl halides. The amino acid side chain was further modified. Thus, the terminal alkyne group of the α-propargylserine complex was subjected to Glaser and Sonogashira cross-coupling reactions and [3+2] cycloaddition, while the terminal alkene group of the α-allylserine was modified by Heck reaction. All target α-substituted analogs of O-methyl-(S)-serine were obtained with high enantiomeric purity (ee >98%) and can serve as ready-made O-protected components for peptide synthesis. This strategy paves the way for the synthesis of novel enantiomerically pure α-substituted β-hydroxy-α-amino acids with structurally diverse side chains and various O-protecting groups (Bn, iPr, tBu, etc).