Karel M. J. Brands

Reaction development and mechanistic study of a ruthenium catalyzed intramolecular asymmetric reductive amination en route to the dual Orexin inhibitor Suvorexant (MK-4305).

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.

Synthesis of an Estrogen Receptor Beta Agonist

Significance: The target tetrahydrofluorene is an estrogen receptor β agonist that is of interest for the treatment of symptoms associated with reduced estrogen levels in post-menopausal women. The large-scale synthesis depicted features a chiral auxiliary mediated dialkylation to construct the quaternary center in G with excellent stereocontrol. Note the intramolecular enolate alkylation F → G in which phenoxide ion is the leaving group. Comment: This route delivered more than 30 kg of drug candidate in 21% overall yield through a longest linear sequence of 13 steps and with >99% ee. For syntheses of related tetrahydrofluorenes, see: M. A. Huffman et al. Tetrahedron 2007, 63, 4459; J. P. Scott et al. Org. Process Res. Dev. 2008, 12, 723; D. J. Wallace, R. A. Reamer Tetrahedron Lett. 2013, 54, 4425. N O

Synthesis of Suvorexant

Significance: Orexins A and B are excitatory neuropeptides that stimulate wakefulness. Suvorexant is a dual orexin receptor antagonist that is in phase III clinical trials for the treatment of insomnia. The key step in the asymmetric synthesis depicted is a tandem enzymatic transamination– annulation sequence (F → G → H). Comment: A previous synthesis of suvorexant (N. A. Strotman et al. J. Am. Chem. Soc. 2011, 133, 8362) involved an asymmetric Ru-catalyzed reductive amination in the construction of the diazepane ring. The present route benefits from the circumvention of transition-metal catalysis and dichloromethane as solvent. A B C

A Practical Synthesis of Lithium 3-Fluoropyridine-2-carboxylate

Abstract A practical and efficient method for the preparation of lithium 3-fluoropyridine-2-carboxylate as well as its four regioisomer is described. 3-Fluoropyridine can be regioselectively lithiated on C-2 or C-4 depending on the reaction conditions. A quench procedure with carbon dioxide was developed which conveniently provides the lithium carboxylate in high yield and purity.