Chiral phosphoric acid-catalyzed stereodivergent synthesis of trisubstituted allenes and computational mechanistic studies

• Published in: Nature communications Vol. 11; no. 1; pp. 5527 - 12
• Main Authors: Wang, Jiawen, Zheng, Sujuan, Rajkumar, Subramani, Xie, Jinglei, Yu, Na, Peng, Qian, Yang, Xiaoyu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.11.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 119/118; 639/638/403/933; 639/638/403/934; 639/638/403/935; 639/638/77/883; 639/638/77/889; Acids; Allene; Asymmetric synthesis; Asymmetry; Catalysis; Catalysts; Chemical synthesis; Chemists; Chirality; Computer applications; Density functional theory; Divergence; Enantiomers; Humanities and Social Sciences; multidisciplinary; Natural products; Phosphoric acid; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19294-8

Chiral molecules with multiple stereocenters are widely present in natural products and pharmaceuticals, whose absolute and relative configurations are both critically important for their physiological activities. In spite of the fact that a series of ingenious strategies have been developed for asymmetric diastereodivergent catalysis, most of these methods are limited to the divergent construction of point chirality. Here we report an enantioselective and diastereodivergent synthesis of trisubstituted allenes by asymmetric additions of oxazolones to activated 1,3-enynes enabled by chiral phosphoric acid (CPA) catalysis, where the divergence of the allenic axial stereogenicity is realized by modifications of CPA catalysts. Density functional theory (DFT) calculations are performed to elucidate the origin of diastereodivergence by the stacking- and stagger-form in the transition state (TS) of allene formation step, as well as to disclose a Münchnone-type activation mode of oxazolones under Brønsted acid catalysis. Despite of the high demand of chiral allenes, their asymmetric synthesis remains a challenge for organic chemists. Here, the authors report a stereodivergent synthesis of trisubstituted allenes via asymmetric additions of oxazolones to activated 1,3-enynes enabled by modification of chiral phosphoric acid catalysts.