中国科学院上海有机所殷亮团队的一项最新研究，实现了铜(I)催化的2-酰基咪唑的对映选择性α-烷基化。该研究于2024年12月3日发表于国际一流学术期刊《美国化学会杂志》上。

据介绍，简单羧酸衍生物的催化不对称α-烷基化是一个具有挑战性的问题，因为难以获得高的催化效率和控制对映选择性。

该研究以铜(I)-(R)-DTBM-SEGPHOS配合物为催化剂，以2-酰基咪唑为前亲核试剂，实现了简单羧酸衍生物的催化不对称α-烷基化的一般方法。各种烷基亲电试剂，包括烯丙基溴、苄基溴、丙炔溴和未活化的烷基磺酸盐，可作为高效的烷基化试剂。

该反应具有反应方式简单、官能团耐受性好、对映体选择性高等优点。2,4,6-三甲基苯酚是提高产量的有效添加剂。

初步的¹H NMR实验表明，2-酰基咪唑与铜(I)催化剂的预配位，可能使2-酰基咪唑的α-氢酸化，从而易于生成稳定的铜(I)烯醇化物。最后，研究人员通过AZD2716（一种有效的分泌型磷脂酶A2抑制剂）的不对称形式合成，证明了本方法的合成效用。

附：英文原文

Title: Copper(I)-Catalyzed Enantioselective α-Alkylation of 2-Acylimidazoles

Author: Zong-Ci Liu, Hong-Ming Zhang, Yi Li, Zi-Qing Wang, Liang Yin

Issue&Volume: December 3, 2024

Abstract: Catalytic asymmetric α-alkylation of simple carboxylic acid derivatives is a challenging issue due to the difficulties in achieving high catalytic efficiency and controlling the enantioselectivity. Herein, by using a copper(I)-(R)-DTBM-SEGPHOS complex as a catalyst and 2-acylimidazoles as pronucleophiles, a general method for the catalytic asymmetric α-alkylation of simple carboxylic acid derivatives is accomplished. Various alkyl electrophiles, including allyl bromides, benzyl bromides, propargyl bromide, and unactivated alkyl sulfonates, serve as efficient alkylation reagents. The reaction enjoys the advantages of an easy reaction protocol, good functional group tolerance, and high enantioselectivity. 2,4,6-Trimethylphenol is found as an effective additive to increase yields. Preliminary 1H NMR experiments indicate the precoordination of 2-acylimidazoles to a copper(I) catalyst, which might acidify the α-hydrogens of 2-acylimidazoles and allow facile generation of stabilized copper(I) enolates. Finally, the synthetic utility of the present method is demonstrated by the asymmetric formal synthesis of AZD2716, a potent secreted phospholipase A2 inhibitor.

DOI: 10.1021/jacs.4c12154

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c12154