Geng Huihui, Chen Xiaobei, Gui Jingjing, Zhang Yueteng, Shen Zuyuan, Qian Pengfei, Chen Junwei, Zhang Shilei, Wang Wei
State Key Laboratory of Bioengineering Reactor, and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, 130 Meilong Road, Shanghai, 200237, China.
Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, China.
Nat Catal. 2019;2(12):1071-1077. doi: 10.1038/s41929-019-0370-z. Epub 2019 Oct 28.
The recent surge in applications of deuterated pharmaceutical agents has created an urgent demand for synthetic methods that efficiently generate deuterated building blocks. Here we show that N-heterocyclic carbenes (NHC) promote a reversible hydrogen-deuterium exchange (HDE) reaction with simple aldehydes, which leads to a practical approach to synthetically valuable C-1 deuterated aldehydes. The reactivity of the well-established NHC catalysed formation of Breslow intermediates from aldehydes is reengineered to overcome the overwhelmingly kinetically favorable, irreversible benzoin condensation reaction and achieve the critical reversibility to drive the formation of desired deuterated products when an excess of DO is employed. Notably, this operationally simple and cost-effective protocol serves as a general and truly practical approach to all types of 1-D-aldehydes including aryl, -alkyl and -alkenyl aldehydes and enables chemoselective late-stage deuterium incorporation into complex, native therapeutic agents and natural products with uniformly high levels (>95%) of deuterium incorporation for a total of 104 substrates tested.
近年来，氘代药物制剂的应用激增，迫切需要能够高效生成氘代结构单元的合成方法。在此，我们表明氮杂环卡宾（NHC）能促进与简单醛的可逆氢-氘交换（HDE）反应，从而为合成有价值的C-1氘代醛提供了一种实用方法。对已确立的由醛通过NHC催化形成布雷斯洛中间体的反应性进行了重新设计，以克服动力学上极为有利的不可逆安息香缩合反应，并在使用过量的D₂O时实现关键的可逆性，以驱动所需氘代产物的形成。值得注意的是，这种操作简单且成本效益高的方法是一种通用且真正实用的方法，适用于所有类型的1-D-醛，包括芳基、烷基和烯基醛，并能够在总共测试的104种底物中，以均匀的高氘掺入水平（>95%）实现化学选择性后期氘掺入复杂的天然治疗剂和天然产物中。
