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

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

Supplementary Information

Detailed information for the synthesis of the catalysts C1–C8, Q1–Q7, as well as the chiral HPLC diagrams of 8 is provided and available online only.

Publikationsverlauf

Eingereicht: 20. Oktober 2021

Angenommen: 11. November 2021

Artikel online veröffentlicht:
30. Dezember 2021

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