Reaction Development and Mechanistic Study of a Ruthenium Catalyzed Intramolecular Asymmetric Reductive Amination en Route to the Dual Orexin Inhibitor Suvorexant (MK-4305)

Abstract

The first example of an intramolecular asymmetric reductive amination of a dialkyl ketone with an aliphatic amine has been developed for the synthesis of Suvorexant (MK-4305), a potent dual Orexin antagonist under development for the treatment of sleep disorders. This challenging transformation is mediated by a novel Ru-based transfer hydrogenation catalyst that provides the desired diazepane ring in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO(2), produced as a necessary byproduct of this transfer hydrogenation reaction, has pronounced effects on the efficiency of the Ru catalyst, the form of the amine product, and the kinetics of the transformation. A simple kinetic model explains how product inhibition by CO(2) leads to overall first-order kinetics, but yields an apparent zero-order dependence on initial substrate concentration. The deleterious effects of CO(2) on reaction rates and product isolation can be overcome by purging CO(2) from the system. Moreover, the rate of ketone hydrogenation can be greatly accelerated by purging of CO(2) or trapping with nucleophilic secondary amines.

Enantioselective Construction of the Biologically Significant Dibenzo[1,4]diazepine Scaffold via Organocatalytic Asymmetric Three‐Component Reactions

“…So, the subsequent evaluation of MS was performed at 60 8C, which indicated that 3 MS was better than 4 and 5 MS both in regard to enantioselectivity and reactivity (entry 1 vs. 3 and 4). Then, the reagent ratio was carefully tuned with the aim to enhance the enantioselectivity (entries [5][6][7][8][9][10]. The presence of excess 3a was detrimental to the enantioselectivity of the reaction (entries 5 and 6 vs. 1).…”

“…In fact, the catalytic asymmetric construction of the structurally rigid seven-membered diazepine motif had met with little success [4] until Strotman and coworkers developed a Ru-catalyzed intramolecular asymmetric reductive amination to construct a highly enantioselective diazepine framework [Eq. [5] In spite of this elegant work, the catalytic enantioselective approaches to construct a chiral diazepine moiety are still underdeveloped and full of challenges. [5] In spite of this elegant work, the catalytic enantioselective approaches to construct a chiral diazepine moiety are still underdeveloped and full of challenges.…”

Synthetic methods Part (ii) oxidation and reduction methods

“…120 Strotman et al, using a variant of Noyori's (S,S)-RuCl(p-cymene)(N-tosyl-1,2-diphenylethylenediamine) catalyst, demonstrated the first intramolecular reductive amination between dialkyl ketones and aliphatic amines giving high yields as well as high enantioselectivity (Scheme 37). 121 The new method was used in the synthesis of the dual orexin inhibitor Suvorexant (MK-4305). A novel Au-catalyst for reductive amination has been developed by Zhang et al, in which they generate Ph 3 PAuOTf in-situ from Ph 3 PAuCl and AgOTf.…”

Asymmetric Hydroamination and Reductive Amination in Total Synthesis

“…After careful crystallization from methanol as the Very recently, Strotman and co-workers from Merck revealed the upgradation of the previous methodology by exploiting asymmetric reductive amination protocol. 118 This transformation could be made possible by using a novel Ru-based transfer hydrogenation catalyst that afforded the diazepane ring 95 as its HCl salt in 87% overall yield with >99.5% ee (Scheme 39.27). This is the first report of an intramolecular asymmetric reductive amination of a dialkyl ketone.…”

“…This drug is marketed by Merck. Recently, Strotman and co-workers reported on the first example of an intramolecular asymmetric reductive amination of a dialkyl ketone with an appropriate aliphatic amine 97 for the synthesis of Suvorexant (MK-4305) 118. The synthesis of MK-4305 showcases a perfect example of the reductive amination protocol.…”