Asymmetric Synthesis of Letermovir Using a Novel Phase-Transfer-Catalyzed Aza-Michael Reaction

Abstract

The development of a concise asymmetric synthesis of the antiviral development candidate letermovir is reported, proceeding in >60% yield over a total of seven steps from commercially available materials. Key to the effectiveness of this process is a novel cinchonidine-based PTC-catalyzed aza-Michael reaction to configure the single stereocenter.

Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis™ (letermovir)

“…Clearly, these descriptors are innately unique and, if combined, may synergize to provide better statistical fitting of a dataset. Thus, we hypothesized that integrating these two descriptor sets had the potential to improve a recently developed enantioselective aza-Michael conjugate addition, representing a key step in the industrial synthesis of the approved pharmaceutical, Prevymis™ (letermovir; MK-8228) 12,13…”

Industrial applications of green chemistry: Status, Challenges and Prospects

“…Greener synthesis, as published by Merck, involves a novel cinchonidine based PTC-catalyzed Aza-Michael reaction for configuring the single stereocenter as shown in Scheme 1 [17]. Also, there is an increase in overall yield by 60%, reduction in raw material cost by 93% and reduction in water usage by 90%.…”

Bromide-assisted chemoselective Heck reaction of 3-bromoindazoles under high-speed ball-milling conditions: synthesis of axitinib

“…The palladium-catalyzed vinylation of alkenes in the presence of a base, known as the Heck reaction (Mizoroki–Heck reaction), is one of the most important transition-metal-catalyzed reactions [ 1 – 2 ], which has shown itself as a powerful synthetic tool in both academic and industrial practice [ 3 – 7 ]. The transformation has been enrolled as key steps for numerous synthetic routes, including the recent President Green Chemistry Award winner route of letermovir [ 8 ].…”

“…However, the couplings of bromo and chloro derivatives with unactivated alkenes still remain challenging. Though aryl bromides are always interesting substrates for industrial applications [ 11 – 12 ], possessing the characteristics of lower cost, easier to obtain and stable to store, they face the problem of dehalogenations especially under metal-catalyzed reactions [ 8 , 13 – 18 ], affecting the reaction yield and selectivity. Currently, the Heck reaction is usually carried out by adding an excess of phase-transfer catalyst such as tetrabutylammonium bromide (TBAB) or tetrabutylammonium iodide (TBAI) to increase the reaction yield under both solvent-heating [ 19 – 23 ] and solvent-free conditions [ 24 – 27 ].…”