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

中文翻译：

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新型 GABA 衍生物手性 2-(N-Boc-氮杂环丁烷-3-基)-2-烷基丙酸的合成

摘要

描述了一种有效的方案，可以轻松获得手性 2-( N -Boc-氮杂环丁烷-3-基)-2-烷基丙酸作为新型 GABA 衍生物。在合成的第一阶段，烷基化膦酸酯和N -Boc-氮杂环丁烷-3-酮通过Horner-Wadsworth-Emmons反应转化为相应的N -Boc-氮杂环丁烷-3-亚基；然后将这些进行标准氢化程序。随后外消旋氨基酯与氢氧化钠在甲醇中反应，得到目标外消旋N -Boc-氨基酸作为主要产物。以( S )-4-苄基-2-恶唑烷酮为拆分剂，通过外消旋体的光学拆分制备了2-( N -Boc-氮杂环丁烷-3-基)-2-烷基丙酸的光学活性对映体，得到非对映体对。分离出纯的非对映体后，用氢氧化锂和过氧化氢处理它们，分别得到相应的对映体纯的2-( N -Boc-氮杂环丁烷-3-基)-2-烷基丙酸。明确的结构归属基于 ¹ H、  ¹³ C、¹⁵ N 和³¹ P NMR 光谱；人力资源管理系统；和单晶X射线衍射数据。

图形概要