Department of Chemistry, University of Colorado, Boulder, Colorado 80309, United States.
Department of Chemistry, Zhejiang University, 38 Zheda Road, Hangzhou, Zhejiang 310027, People's Republic of China.
J Am Chem Soc. 2020 Jun 24;142(25):11102-11113. doi: 10.1021/jacs.0c03298. Epub 2020 Jun 10.
Carbohydrates, one of the three primary macromolecules of living organisms, play significant roles in various biological processes such as intercellular communication, cell recognition, and immune activity. While the majority of established methods for the installation of carbohydrates through the anomeric carbon rely on nucleophilic displacement, anomeric radicals represent an attractive alternative because of their functional group compatibility and high anomeric selectivities. Herein, we demonstrate that anomeric nucleophiles such as C1 stannanes can be converted into anomeric radicals by merging Cu(I) catalysis with blue light irradiation to achieve highly stereoselective C(sp)-S cross-coupling reactions. Mechanistic studies and DFT calculations revealed that the C-S bond-forming step occurs via the transfer of the anomeric radical directly to a sulfur electrophile bound to Cu(II) species. This pathway complements a radical chain observed for photochemical metal-free conditions where a disulfide initiator can be activated by a Lewis base additive. Both strategies utilize anomeric nucleophiles as efficient radical donors and achieve a switch from an ionic to a radical pathway. Taken together, the stability of glycosyl nucleophiles, a broad substrate scope, and high anomeric selectivities observed for the thermal and photochemical protocols make this novel C-S cross coupling a practical tool for late-stage glycodiversification of bioactive natural products and drug candidates.
碳水化合物是生物体内三大主要大分子之一，在细胞间通讯、细胞识别和免疫活性等各种生物过程中发挥重要作用。虽然大多数通过端基碳原子安装碳水化合物的方法依赖于亲核取代反应，但端基自由基由于其官能团兼容性和高端基选择性，是一种很有吸引力的替代方法。在此，我们证明了端基亲核试剂，如 C1 锡烷，可以通过将 Cu(I) 催化与蓝光照射相结合，转化为端基自由基，从而实现高度立体选择性的 C(sp)-S 交叉偶联反应。机理研究和 DFT 计算表明，C-S 键形成步骤是通过端基自由基直接转移到与 Cu(II) 物种结合的硫亲电试剂上发生的。该途径补充了光化学无金属条件下观察到的自由基链，其中二硫化物引发剂可以被路易斯碱添加剂激活。这两种策略都利用端基亲核试剂作为有效的自由基供体，并实现了从离子途径到自由基途径的转变。总的来说，对于热和光化学方案，观察到糖苷亲核试剂的稳定性、广泛的底物范围和高端基选择性，使得这种新的 C-S 交叉偶联成为生物活性天然产物和药物候选物后期糖基多样化的实用工具。
