Enantioselective aza-Michael Cyclization Reaction Catalyzed by Quinine-Derived Monoquaternary Ammonium Salts: an Effective Route to Synthesize Letermovir

Abstract

Abstract A series of mono- or bis-quaternary ammonium salts derived from cinchonidine or quinine was synthesized and screened as potent phase-transfer catalysts for the reaction of aza-Michael cyclization, the key step in the synthesis of letermovir. During the reaction of aza-Michael cyclization, the screened monoquaternary ammonium salt quinine derivative Q1 transferred 7 to 8 with 91.9% yield and 58% ee. The application of Q1 was preferred, due to its enantioselectivity, the possibility of reuse, and the lower cost in large-scale preparation. Furthermore, the racemization condition of letermovir enantiomer was also explored for the possibility to develop the resolution/racemization process. With the optimal catalyst Q1 in hand, the synthesis of letermovir may be more convenient and economical in the future.

Keywords

• letermovir
• monoquaternary ammonium salts
• phase-transfer catalyst
• enantioselective
• aza-michael cyclization
• racemization