Ligand-Accelerated Cross-Coupling of C(sp2)–H Bonds with Arylboron Reagents

Keary M. Engle, Peter S. Thuy-Boun, Michael Dang, and Jin-Quan Yu

J. Am. Chem. Soc., 2011, 133, 18183–18193

DOI: 10.1021/ja203978r

A palladium catalyzed C–H functionalization between Molander's arylboronate reagents and phenylacetic acid derivatives was demonstrated. From extensive screening, this synthetic method was found to be efficacious utilizing Ac-Ile-OH as the ligand and Ag2CO3 as the oxidant. As a result, a high yielding and experimentally straightforward procedure has evolved into a useful cross-coupling protocol between arylacetic acid derivatives and aryltrifluoroborates.  The authors also found that this ligand accelertated process has superb functional group tolerance and may also be beneficial when applied to catalytic cross-coupling conditions under an oxygen atmosphere thus providing alternative "Green" conditions for this biaryl transformation.

A Highly Enantio- and Diastereoselective Molybdenum-Catalyzed Asymmetric Allylic Alkylation of Cyanoester

Conditions:
10 mol% Mo(CO)6, 15 mol% ligand, 10 mol% NaH, BSA, THF, 60 deg C
99% yield, 20/1 Branched/Linear, 11/1 dr, 97% ee

Barry M. Trost, John R. Miller, and Christopher M. Hoffman, Jr
J. Am. Chem. Soc., 2011, 133, 8165–8167

DOI: 10.1021/ja2029602

Summary: An efficacious Mo-catalyzed enantioselective allylation of various cyanoester nucleophiles provided a number of highly functionalized branched cyanoesters containing a quaternary carbon stereocenter.  This synthetic method generates the desired allylic cyanoesters products with high yield, chemoselectivity, diastereoselectivity and enantioselectivity.

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