近日，英国牛津大学教授Stephen P. Fletcher及其研究小组研制了催化不对称交叉偶联法合成环丁烷。相关论文于2021年7月1日发表在《自然化学》杂志上。

本文报道了一系列由铑催化的不对称碳金属化引发的环丁烯与芳基硼酸之间的不对称交叉偶联反应。在初始碳化后，Rh催化环丁基中间体进行链行走或C-H插入，进而观察到各种各样的加成反应，如还原Heck反应、1,5加成和同烯基取代。这些高度立体选择性转换的合成适用性在候选药物Belaperidone和PF-04862853的简明合成中得到了证明。

该研究团队预计这种方法将被合成和药物化学家广泛采用。虽然本文报道的碳金属化方法以Rh和芳基硼酸为例，但它可能适用于其他金属和亲核试剂。

据介绍，立体定向四元环是生物活性分子中常见的基元，是有机合成中的通用中间体。然而，复杂、手性环丁烷的合成是一个很大的难题，需要通用和模块化的合成方法。

附：英文原文

Title: A catalytic asymmetric cross-coupling approach to the synthesis of cyclobutanes

Author: F. Wieland Goetzke, Alexander M. L. Hell, Lucy van Dijk, Stephen P. Fletcher

Issue&Volume: 2021-07-01

Abstract: Stereodefined four-membered rings are common motifs in bioactive molecules and versatile intermediates in organic synthesis. However, the synthesis of complex, chiral cyclobutanes is a largely unsolved problem and there is a need for general and modular synthetic methods. Here we report a series of asymmetric cross-coupling reactions between cyclobutenes and arylboronic acids which are initiated by Rh-catalysed asymmetric carbometallation. After the initial carborhodation, Rh–cyclobutyl intermediates undergo chain-walking or C–H insertion so that overall a variety of additions such as reductive Heck reactions, 1,5-addition and homoallylic substitution are observed. The synthetic applicability of these highly stereoselective transformations is demonstrated in the concise syntheses of the drug candidates Belaperidone and PF-04862853. We anticipate this approach will be widely adopted by synthetic and medicinal chemists. While the carbometallation approach reported here is exemplified with Rh and arylboronic acids, it is likely to be applicable to other metals and nucleophiles.

DOI: 10.1038/s41557-021-00725-y

Source: https://www.nature.com/articles/s41557-021-00725-y