Synthesis of chiral 2-(N-Boc-azetidin-3-yl)-2-alkylpropanoic acids as novel GABA derivatives

Abstract

An efficient protocol providing easy access to chiral 2-(N-Boc-azetidin-3-yl)-2-alkylpropanoic acids as novel GABA derivatives is described. In the first stage of the synthesis, alkylated phosphonates and N-Boc-azetidin-3-one were converted to the corresponding N-Boc-azetidine-3-ylidenes via a Horner–Wadsworth–Emmons reaction; these were then subjected to a standard hydrogenation procedure. The subsequent reaction of racemic amino esters with sodium hydroxide in methanol afforded the target racemic N-Boc-amino acids as major products. The optically active enantiomers of 2-(N-Boc-azetidin-3-yl)-2-alkylpropanoic acids were prepared via optical resolution of the racemates using (S)-4-benzyl-2-oxazolidinone as the resolving agent to obtain the diastereomeric pairs. After isolation of the pure diastereomers, they were treated with lithium hydroxide and hydrogen peroxide to give the corresponding enantiomerically pure 2-(N-Boc-azetidin-3-yl)-2-alkylpropanoic acids, respectively. Unambiguous structural assignments were based on ¹H, ¹³C, ¹⁵N, and ³¹P NMR spectroscopy; HRMS; and single-crystal X-ray diffraction data.

Graphical abstract