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A catalytic asymmetric cross-coupling approach to the synthesis of cyclobutanes
Nature Chemistry ( IF 19.2 ) Pub Date : 2021-07-01 , DOI: 10.1038/s41557-021-00725-y
F Wieland Goetzke 1 , Alexander M L Hell 1 , Lucy van Dijk 1 , Stephen P Fletcher 1
Affiliation  

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.



中文翻译:

一种催化不对称交叉偶联合成环丁烷的方法

立体定义的四元环是生物活性分子中的常见基序,也是有机合成中的通用中间体。然而,复杂的手性环丁烷的合成在很大程度上是一个未解决的问题,需要通用和模块化的合成方法。在这里,我们报告了由 Rh 催化的不对称碳金属化引发的环丁烯和芳基硼酸之间的一系列不对称交叉偶联反应。在最初的碳化之后,Rh-环丁基中间体经历了链行走或 C-H 插入,因此总体上可以观察到各种加成,例如还原性 Heck 反应、1,5-加成和高烯丙基取代。这些高度立体选择性转化的合成适用性在候选药物贝拉哌酮和 PF-04862853 的简明合成中得到证明。我们预计这种方法将被合成和药物化学家广泛采用。虽然这里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。

更新日期:2021-07-01
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