Concise Enantioselective Synthesis of Oxygenated Steroids via Sequential Copper(II)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions.
Concise Enantioselective Synthesis of Oxygenated Steroids via Sequential Copper(II)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions.
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DOI：
10.1021/jacs.5b08528
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发表时间：
2015-11-18
影响因子：
15
通讯作者：
Nagorny P
中科院分区：
文献类型：
--
作者：
Cichowicz NR;Kaplan W;Khomutnyk Y;Bhattarai B;Sun Z;Nagorny P
描述了一种新的可扩展的对映选择性官能化含氧类固醇的方法。该策略是基于手性双（恶唑啉）铜（II）配合物催化的环状酮酯和烯酮的对映选择性和非对映选择性迈克尔反应，以安装邻位的季和叔立体中心。此外，铜（II）盐作为高活性催化剂用于传统上不反应的ββ′-烯酮和取代的ββ′-酮酯的迈克尔反应，导致前所未有的迈克尔加合物含有邻位全碳季中心也被证明。迈克尔加合物随后经历碱促进的非对映选择性羟醛级联反应，产生天然或非天然的类固醇骨架。实验和计算研究表明，由Δ5-不饱和度的存在所引起的扭转应变效应是天然Cardenoprotein支架形成的关键控制因素。所描述的方法能够方便地产生多环分子，包括改性的甾体支架以及挑战性合成Hajos-Parrish和Wieland-Miescher酮。
A new scalable enantioselective approach to functionalized oxygenated steroids is described. This strategy is based on chiral bis(oxazoline) copper(II) complex-catalyzed enantioselective and diastereoselective Michael reactions of cyclic ketoesters and enones to install vicinal quaternary and tertiary stereocenters. In addition, the utility of copper(II) salts as highly active catalysts for the Michael reactions of traditionally unreactive ββ′-enones and substituted ββ′-ketoesters that results in unprecedented Michael adducts containing vicinal all-carbon quaternary centers is also demonstrated. The Michael adducts subsequently undergo base-promoted diastereoselective aldol cascade reactions resulting in the natural or unnatural steroid skeletons. The experimental and computational studies suggest that the torsional strain effects arising from the presence of the Δ5-unsaturation are key controling elements for the formation of the natural cardenolide scaffold. The described method enables expedient generation of polycyclic molecules including modified steroidal scaffolds as well as challenging-to-synthesize Hajos-Parrish and Wieland-Miescher ketones.