Asymmetric Hydrogen Bonding Catalysis for the Synthesis of Dihydroquinazoline-Containing Antiviral, Letermovir Cheol K. Chung,* Zhijian Liu,* Katrina W. Lexa, Teresa Andreani, Yingju Xu, Yining Ji, Daniel A. DiRocco, Guy R. Humphrey, and Rebecca T. Ruck Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States S Supporting Information *
Scheme 1. Asymmetric PTC Route for Letermovir
ABSTRACT: A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriﬂamides are shown to be highly eﬀective in activating α,β-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.
symmetric Brønsted acid catalysis continues to attract broad interest in organic synthesis as a powerful tool for conducting stereoselective transformations.1 Recently, it has emerged as a greener, milder alternative to metal-based Lewis acid catalysis in activating imines, carbonyls, and nitro groups in a suite of aldol-type reactions.2 For conjugate addition reactions, however, the application of Brønsted acid catalysis has been largely limited to neutral or weakly basic nucleophiles as strong bases will interact with known prospective catalysts, reducing their ability to activate the carbonyl group.3 In addition, the typical electrophiles are α,β-unsaturated ketones or nitroalkenes, with only a few examples involving esters or amides as Michael acceptors due to the reduced Lewis basicity of the corresponding carbonyl oxygen atoms.4 Development of a catalytic system capable of incorporating these less reactive substrate classes would represent signiﬁcant progress in Brønsted acid catalysis. Recently, we reported an asymmetric synthesis of letermovir (4), an experimental drug currently in phase III clinical trial for the treatment of human cytomegalovirus (CMV) infection (Scheme 1).5 In this work, the dihydroquinazoline core of 4 is constructed via an aza-conjugate addition reaction by using the bis-quaternary ammonium salt 2 as phase-transfer catalyst (PTC).6 However, the PTC route suﬀered from a series of challenges, including the inherent instability of the catalyst under basic conditions and moderate enantioselectivity. Combined with other operational restraints arising from the biphasic nature of the reaction, these concerns rendered the PTC approach less attractive and reliable for inclusion in our manufacturing route.7 Given the prevalence of the 3,4dihydroquinazoline core in medicinally important targets, a © 2017 American Chemical Society
more robust, eﬃcient asymmetric synthesis of the core was expected to be broadly applicable in medicinal chemistry.8 To that end, we conducted a survey of alternative chiral promoters, aided by high-throughput experimentation tools. Herein, we report the discovery of a novel asymmetric Brønsted acid catalysis for the intramolecular aza-conjugate addition of a guanidinyl nucleophile to an α,β-unsaturated ester, that is highly eﬃcient, readily scalable, and broadly applicable to the synthesis of enantioenriched 3,4-dihydroquinazolines. We began our investigation by screening a variety of metalbased chiral Lewis acids and chiral nucleophilic catalysts to promote the cyclization. Though these attempts were mostly unsuccessful due to the lack of reactivity or enantioselectivity, we observed a signiﬁcant background cyclization in polar protic solvents. For instance, starting material 1 readily underwent a racemic cyclization in 2,2,2-triﬂuoroethanol (100%, 15 min), methanol (100%, l h), or 2-propanol (78%, 22 h). Conversely, the background reaction was suppressed in aprotic solvents such as toluene and DMSO (