^§ Undergraduate researcher.

Abstract

A concise and modular asymmetric synthesis of the calcium channel blocker (S)-verapamil is described. This approach employs an enantioselective rhodium-catalyzed allylic alkylation reaction between an α-isopropyl-substituted benzylic nitrile and allyl benzoate to construct the challenging acyclic quaternary stereocenter. The terminal olefin then serves as a convenient synthetic handle for a hydroamination to introduce the phenethylamine moiety, furnishing (S)-verapamil in three steps and 55% overall yield, thus providing the most efficient synthesis of this important pharmaceutical reported to date. Furthermore, given the modular nature of the synthesis, it can be readily modified to prepare structurally related bioactive agents.

中文翻译：

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使用对映选择性铑催化的烯丙基烷基化反应的简捷模块化三步合成（S）-维拉帕米

^§本科生研究员。

抽象

描述了钙通道阻滞剂（S）-维拉帕米的简明和模块化的不对称合成。该方法在α-异丙基取代的苄腈和苯甲酸烯丙酯之间采用对映体选择性的铑催化的烯丙基烷基化反应来构建具有挑战性的无环季铵立体中心。然后，末端烯烃用作加氢胺化以引入苯乙胺部分的方便的合成方法，分三步提供（S）-维拉帕米，总产率为55％，从而提供了迄今为止报道的这一重要药物的最有效合成方法。此外，鉴于合成的模块性质，可以容易地对其进行修饰以制备与结构相关的生物活性剂。