Department of Chemistry , University of California , Berkeley , California 94720 , United States.
J Am Chem Soc. 2019 Aug 21;141(33):13066-13073. doi: 10.1021/jacs.9b04440. Epub 2019 Aug 7.
Although much effort has been spent on the enantioselective synthesis of tertiary alkyl fluorides, the synthesis of compounds containing such a stereogenic center within an array of stereocenters, particularly two vicinal ones, remains a synthetic challenge, and no method to control the configuration of each stereogenic center independently has been reported. We describe a strategy to achieve such a stereodivergent synthesis of vicinal stereogenic centers, one containing a fluorine atom, by forming the connecting carbon-carbon bond with a catalyst system comprising an iridium complex that controls the configuration at the electrophilic carbon and a copper catalyst that controls the configuration at the nucleophilic fluorine-containing carbon. These reactions occur with alkyl- and aryl-substituted allylic esters and the unstabilized enolates of azaaryl ketones, esters, and amides in high yield, diastereoselectivity, and enantioselectivity (generally >90% yield, >20:1 dr, 97-99% ee). Access to all four stereoisomers of products demonstrates the precise control of the two configurations independently. This methodology extends to the stereodivergent construction of vicinal quaternary and tertiary stereocenters in similarly high yield and selectivity. DFT calculations uncover the origin of stereoselectivity of copper enolate in allylic substitution.
尽管在立体选择性合成三级烷基氟化物方面已经付出了大量努力，但在包含多个立体中心的化合物中合成含有这种手性中心的化合物，特别是两个相邻的手性中心，仍然是一个合成挑战，并且尚未报道能够独立控制每个手性中心构型的方法。我们描述了一种通过形成连接碳-碳键的策略来实现这种相邻立体中心的立体发散合成，其中一个含有氟原子，该策略使用包含控制亲电碳原子构型的铱配合物和控制亲核含氟碳原子构型的铜催化剂的催化剂体系。这些反应以高收率、高非对映选择性和高对映选择性（通常>90%收率、>20:1 dr、97-99%ee）发生，涉及烷基和芳基取代的烯丙基酯以及未稳定的氮杂芳基酮、酯和酰胺的烯醇化物。所有四种产物立体异构体的获得证明了对两种构型的独立精确控制。该方法学可扩展至类似高收率和选择性的相邻季碳和三级立体中心的立体发散构建。DFT 计算揭示了铜烯醇化物在烯丙基取代中的立体选择性的起源。
