英国圣安德鲁斯大学Andrew David Smith团队通过异硫脲与Brønsted酸协同对映选择性催化合成α-芳基-β2-氨基酯。相关研究成果于2021年3月1日发表在国际顶尖学术期刊《德国应用化学》。

该文研究了在异硫脲和Brnsted酸协同催化下，通过芳基乙酸酯的对映选择性氨基甲基化合成具有高收率和对映选择性的α-芳基-β2-氨基酯。探讨了这一工艺的范围和局限性（25个实例，高达94%的产率和96:4 er），并将其应用于（S）-文拉法辛·HCl和（S）-纳基那丁B的合成。

机理研究与遵循的C（1）-烯酸铵途径相一致，而不是替代的动态动力学拆分工艺。对照研究表明，（i）观察到催化剂和产物er之间存在线性关系；（ii）酰基铵离子可用作预催化剂；（iii）可逆异硫脲加成原位生成的亚胺离子可用作生产性预催化剂的非循环中间体。

附：英文原文

Title: Enantioselective Synthesis of α‐Aryl‐β2‐Amino‐esters via Cooperative Isothiourea and Brønsted Acid Catalysis

Author: Andrew David Smith, Feng Zhao, Chang Shu, Claire M. Young, Cameron Carpenter-Warren, Alexandra M. Z. Slawin

Issue&Volume: 2021-03-01

Abstract: The synthesis of α‐aryl‐β  2  ‐amino esters through enantioselective aminomethylation of an arylacetic acid ester in high yields and enantioselectivity via cooperative isothiourea and Brnsted acid catalysis is demonstrated. The scope and limitations of this process are explored (25 examples, up to 94% yield and 96:4 er), with applications to the synthesis of (  S  )‐Venlafaxine·HCl and (  S  )‐Nakinadine B. Mechanistic studies are consistent with a C(1)‐ammonium enolate pathway being followed rather than an alternative dynamic kinetic resolution process. Control studies indicate that (i) a linear effect between catalyst and product er is observed; (ii) an acyl ammonium ion can be used as a precatalyst; (iii) reversible isothiourea addition to an in situ generated iminium ion leads to an off‐cycle intermediate that can be used as a productive precatalyst.

DOI: 10.1002/anie.202016220

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202016220