Chiral 1,2,3‐Triazolium Salt Catalyzed Asymmetric Mono‐ and Dialkylation of 2,5‐Diketopiperazines with the Construction of Tetrasubstituted Carbon Centers

• Published in: Angewandte Chemie Vol. 134; no. 9
• Main Authors: Yang, Ju‐Song, Lu, Ka, Li, Chen‐Xiao, Zhao, Zu‐Hang, Zhang, Xiao‐Ming, Zhang, Fu‐Min, Tu, Yong‐Qiang
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 21.02.2022
• Subjects: 1,2,3-Triazolium Salts; 2,5-Diketopiperazines; Asymmetric Catalysis; Asymmetry; Carbon; Chemical reactions; Chemistry; Dialkylation; Phase-Transfer Catalysis; Reaction mechanisms
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202114129

Novel asymmetric mono‐ and dialkylation reactions of α‐substituted 2,5‐diketopiperazines catalyzed by new chiral spirocyclic‐amide‐derived triazolium organocatalysts have been developed, resulting in a range of enantioenriched 2,5‐diketopiperazine derivatives containing one or two tetrasubstituted carbon stereocenters. The reactions feature high yields (up to 98%), and excellent cis‐diastereo‐ and enantioselectivities (up to >20:1 dr, >99 % ee), and they provide a new asymmetric synthetic approach to important functionalized 2,5‐diketopiperazine skeletons. Furthermore, a possible reaction mechanism was proposed based on both control experiments and extensive DFT calculations. Chiral spirocyclic‐amide‐derived triazolium salts were used as new phase‐transfer organocatalysts for asymmetric alkylation to construct 2,5‐diketopiperazine motifs containing one or two tetrasubstituted carbon centers in high yields with excellent cis‐diastereoselectivity and enantioselectivity. Control experiments and DFT calculations revealed the possible reaction mechanism and the origins of the exceptional diastereo‐ and enantioselectivity.