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

Neil A. Strotman, Carl A. Baxter, Karel M. J. Brands, Ed Cleator, Shane W. Krska, Robert A. Reamer, Debra J. Wallace, Timothy J. Wright

J. Am. Chem. Soc., 2011, 133, 8362–8371

DOI: 10.1021/ja202358f

Summary: Suvorexant (MK-4305) is a potent dual Orexin antagonist under development for the treatment of sleep disorders at Merck. The key transformation is an intramolecular asymmetric Ru-catalyzed transfer hydrogenation (using a modified Noyori RuCl(p-cymene)(DPEN) complex) of an in-situ generated cyclic imine resulting in the formation of the desired diazepane in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO2 (derived from the formic acid) has pronounced effect on reaction outcome.  Studies have determined that the efficiency of the Ru-catalyst, the composition of the resulting amine (i.e. carbamate formation), and the reaction kinetics are mediated by the amount of CO2 generated during the reaction. The efficiency of the reductive-amination can be enhanced by either purging of the CO2 or by trapping the thus formed nucleophilic secondary amines.

References:

1) Org. Process Res. Dev., 2011, 15, 367–375  (DOI: 10.1021/op1002853)

2) http://www.kanto.co.jp/english/siyaku/pdf/fuseishokubai_02.pdf

Rhodium-Catalyzed Reductive Cleavage of Carbon−Cyano Bonds with Hydrosilane: A Catalytic Protocol for Removal of Cyano Groups

Mamoru Tobisu, Ryo Nakamura, Yusuke Kita and Naoto Chatani

J. Am. Chem. Soc., 2009, 131, 3174–3175

DOI: 10.1021/ja810142v

Summary: Recently, transition metal activation of the C-CN bond has been an area of intense synthetic activity. Much of the previous work has been centered around Ni(0) mediated C-C bond formation. The Chatani group has developed a rhodium-catalyzed hydrosilane mediated reductive cleavage of the C−CN bond. The reaction has a large synthetic scope including decyanation of aryl- and alkyl nitriles. Additionally, the reaction has a very good functional group tolerence and can be performed in the presence of ester, ether, amino and amide groups. This synthetic method was also demonstrated in several examples where a cyano group was present as a removable ortho-directing group (via a C-H functionalization process).