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).

Efficient Boron−Copper Additions to Aryl-Substituted Alkenes Promoted by NHC−Based Catalysts. Enantioselective Cu-Catalyzed Hydroboration Reactions

Yunmi Lee and Amir H. Hoveyda
J. Am. Chem. Soc., 2009, 131, 3160–3161
DOI:10.1021/ja809382c

Summary: This paper describes the development of a Cu-catalyzed formal hydroboration of olefinic substrates (styrene derivatives). The reaction is highly regio and stereoselective affording the organoboron products in moderate to high yield. The reaction utilizes a copper NHC complex (0.5-7.5 mol%) and pinacolatoboron as the boron source. In the asymmetic variant the er's range from 86/14 to 99/1.

Rhodium-Catalyzed Asymmetric Synthesis of 3,3-Disubstituted 1-Indanones

Ryo Shintani, Keishi Takatsu, Tamio Hayashi

Angewandte Chemie International Edition; 2006, 46, 3537-3737
DOI: 10.1002/anie.200700226

Summary: Chiral indanones that are difficult to obtain by other synthetic methods can be prepared via an enantioselective addition of aryl boronates to aryl alkynyl ketones. The resulting substituted indanones arrive from a tandem Rh-catalyzed C-H functionalization-cyclization sequence. This reaction utilizes a rhodium catalyst system with the asymmetric induction originating from a chiral bisphosphine ligand.

Palladium-Catalyzed Benzene Arylation: Incorporation of Catalytic Pivalic Acid as a Proton Shuttle and a Key Element in Catalyst Design

Marc Lafrance and Keith Fagnou

J. Am. Chem. Soc., 2006, 128, 16496 -16497

DOI: 10.1021/ja067144j

Summary: C-H activation processes represent an important area of synthetic exploration since the starting materials required are less functionalized and potentially less expensive. A Pd-pivalic acid co-catalyst system has been utilized in the direct arylation of benzene and aryl bromides. Experimental and computational studies indicate that the pivalate anion is a key component in the palladation/C-H bond breaking event. Additionally, aryl chorides and iodides were found to be poor substrates.

8 examples: 55-85%

C-C Bond Activation with Selective Functionalization: Preparation of Unsymmetrical Biaryls from Benzonitriles

Joseph A. Miller
Tetrahedron Letters; 2001, 42, 6991–6993
DOI:10.1016/S0040-4039(01)01476-9

Summary: Nickel catalysts have been known to coordinate and subsequently activate the C-CN bond of nitrile compounds. However, a practical procedure to perform a cross-coupling reaction with these substrates and an appropriate organometallic was unknown until the present work. Thus, reaction of a benzonitrile with an aryl Grignard derivative in the presence of a Ni catalyst, such as [NiCl2(PMe3)2], provides the corresponding unsymmetrical biaryl in high yield and with high selectivity. Ligand screening found that trimethylphosphine was the most effective ligand. The Grignard reagent was modified (for example, ArMgOt-Bu) to reduce the amount of direct addition of the organomagnesium reagent to the nitrile. This group has also expanded the methodology to alkyl, alkenyl, and alkynyl organometallics.

16 examples, 69-97% yield
PDF

Rhodium-Catalyzed Arylative and Alkenylative Cyclization of 1,5-Enynes Induced by Geminal Carbometalation of Alkynes

Yiyun Chen and Chulbom Lee
J. Am. Chem. Soc., 2006, 128, 15598 -15599
DOI: 10.1021/ja067125+

Summary: A Rh(I)-catalyzed alkyne-boronic acid addition-cyclization has been developed to afford various alkenyl ketone derivatives. The reaction is believed to proceed through a metal vinylidene complex which eventually undergoes an intramolecular conjugate addition to provide the desired cyclized ketone adduct.

10 examples : Reaction Optimization (0-65% yield)
19 examples: Reaction Scope (11-84% yield)
2 examples: Deuterated substrates for mechanistic studies