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

Jing Pan,Si-Ju Bi,Xun-Lei Lv,Wei-Cheng Zhou,Liang Chen,Kuai-Le Lin,Ting Zhou,Wei-Yuan Liu

doi:10.1055/s-0041-1740944

Jing Pan, Si-Ju Bi + Show 6 more

Open Access

https://doi.org/10.1055/s-0041-1740944

Copy DOI

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.

Highlights

Human cytomegalovirus (HCMV) infections remain a prevalent cause for morbidity and mortality in immunosuppressed solid-organ and bone-marrow transplant patients, and the most frequent cause of opportunistic viral infection following transplantation.[1,2]
Our data suggested that monoquaternary ammonium salts, both from cinchonidine (C1–C4) and quinine (Q1– Q4), had a good effect on enantioselectivity; for example, both entry 1 and entry 8 gave the enantiomeric ratio of 8a:8b at 79:21
The results further demonstrated that the benzyl substituted with two trifluoromethyl was better than that substituted with one trifluoromethyl (C1 versus C2 or C3; Q1 versus Q2 or Q3), so compound Q1 could be considered as the potential phase-transfer catalyst (PTC)

Summary

Introduction

Human cytomegalovirus (HCMV) infections remain a prevalent cause for morbidity and mortality in immunosuppressed solid-organ and bone-marrow transplant patients, and the most frequent cause of opportunistic viral infection following transplantation.[1,2] The incidence of HCMV infection in the general population ranges from 36 to 90%, and the seropositivity increases with age and tends to be highest among lower socioeconomic groups.[3,4] Letermovir is a novel antiviral compound currently used for the prevention of HCMV infections. Before the approval of letermovir, the first line of systemic anti-HCMV drugs includes ganciclovir, foscarnet, and cidofovir, which are derivatives of nucleosides and all target the DNA polymerase, yet, associated with significant side effects such as clinically significant myelosuppression,[5,6] leading to the limited use of them in HCMV therapy.[7] developing a safe and effective agent for HCMV therapy has been an area of unmet need that is urgently needed in cytomegalovirus (CMV) management. Unlike other anti-CMV therapies, letermovir disturbs the late stages of viral replication rather than inhibiting the viral DNA polymerase,[9,10] with no significant myelotoxicity or nephrotoxicity appearing.[11]

Methods

Results

Conclusion