Sun Guangwu, Liu Herui, Dong Baobiao, Zhang Yuchao, Zhao Zilong, Gao Bing
State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China.
Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Sci Adv. 2025 Apr 4;11(14):eadv2010. doi: 10.1126/sciadv.adv2010.
Amines are ubiquitous components in pharmaceuticals. Increasing saturated substitutions (-hybridized carbon) at the amino center and the number of chiral centers can enrich the molecular diversity and chemical space, ultimately enhancing the success of drug development. However, the synthesis of such advanced amines is challenging due to a higher level of structural complexity and stereo-control. Here, we report a modular protocol for short de novo synthesis of bis-α-chiral amines. This protocol uses commercially available Ellman sulfinamide, -butanesulfinamide (BS), as the exclusive chiral source to selectively produce all possible stereoisomers. Sequential formation of contiguous α-amino chiral carbons is achieved by chirality induction and transfer mechanisms that are both enabled by BS, the stereoselective imine functionalization and alkyne-participated rearrangement reaction. The second step we developed is crucial for high diastereoselectivity, which is problematic in previous methods. The other coupling partners used in this protocol are abundant feedstocks, providing desirable chemical diversity in the products.
胺类是药物中普遍存在的成分。在氨基中心增加饱和取代基（sp³杂化碳）和手性中心的数量可以丰富分子多样性和化学空间，最终提高药物开发的成功率。然而，由于结构复杂性和立体控制水平较高，此类高级胺的合成具有挑战性。在此，我们报告了一种用于从头短合成双-α-手性胺的模块化方案。该方案使用市售的埃尔曼亚磺酰胺，即叔丁基亚磺酰胺（BS），作为唯一的手性源，以选择性地产生所有可能的立体异构体。通过由BS实现的手性诱导和转移机制、立体选择性亚胺官能化和炔烃参与的重排反应，实现了连续α-氨基手性碳的顺序形成。我们开发的第二步对于高非对映选择性至关重要，这在以前的方法中是个问题。该方案中使用的其他偶联伙伴是丰富的原料，可在产物中提供理想的化学多样性。
