Chemical Resolution of C,N‑Unprotected α‑Substituted β‑Amino Acids Using Stable and Recyclable Proline-Derived Chiral Ligands

We report the first purely chemical method for the resolution of C,N-unprotected racemic α-substituted β-amino acids (β2-AAs) using thermodynamically stable and recyclable chiral proline-derived ligands. The ligands and racemic β2-AAs along with Ni­(II) could form a pair of Ni­(II) complex diastereoisomers with a desirable diastereoselectivity (dr up to 91:9). Enantiomerically pure C,N-unprotected β2-AAs could be obtained by simple hydrolysis of an isolated favored Ni­(II) complex. The method featured unique versatility compared with enzymatic approaches and characterized by its broad synthetic generality, good stereochemical outcome, and mild reaction conditions, thus making it a powerful supplement in the field of chemical resolution of β2-AAs.

本研究报道了首例采用热力学稳定且可回收的手性脯氨酸衍生配体，实现C、N未保护外消旋α取代β氨基酸（β2-AAs）化学拆分的纯化学方法。该配体与外消旋β2-AAs结合镍(II)可形成一对具有优异非对映选择性的镍(II)配合物非对映异构体，其非对映选择性比（dr）最高可达91:9。通过对分离得到的优势镍(II)配合物进行简单水解，即可获得对映体纯的C、N未保护β2-AAs。相较于酶促拆分方法，该方法具有独特的通用性，且具备合成普适性广、立体化学效果优异、反应条件温和等特点，因此可作为β2-AAs化学拆分领域的有力补充手段。