The development of a synthesis of an ORL-1 receptor antagonist is described. The key process improvements in the synthetic sequence include a multikilogram bromination process and the development of a convergent coupling strategy. The process improvements resulted in the production of the active pharmaceutical ingredient (API) on a multikilogram scale.

Serotonin norepinephrine reuptake inhibitor (SNRI) pyrrolidinyl ether 2 was synthesized by employing a dynamic kinetic resolution (DKR) with enantio- and diastereoselective hydogenation on β-keto-γ-lactam 8 to afford β-hydroxy-γ-lactam 9 with 96% ee and 94% de. Reduction of 9 and purification via the dibenzoyl-(l)-tartaric acid diastereomeric salt 16 enriched the ee and de to 100%. While screening hydrogenation reaction systems with ruthenium-BINAP catalysts to prepare 9, it was found that adding catalytic HCl and LiCl enabled higher yields. In addition, the rate and equilibrium of the DKR-hydrogenation of 8 to give 9 was studied by online NMR and chiral HPLC, which indicated that one of the enantiomers of 8 was reducing faster to 9 than the equilibration of the stereocenter of 8.

This contribution describes the demonstration of an asymmetric synthesis of a glucokinase activator via protonation of the enolate generated from an alkylaryl ketene and (R)-pantolactone. Additionally, a one-pot hydrolysis/oxidation protocol with lithium hydroperoxide was developed to afford a chiral sulfone acid without degradation of the labile stereocenter.

This communication describes proof of concept for an enantioselective enzyme-based synthesis of diarylmethanol (S)-1 to access mGlu2 receptor potentiators. A ketoreductase (KRED) screen was applied to benzophenone 8 to afford chiral diarylmethanol (S)-9, which is a useful intermediate for the preparation of chiral diarylmethanol (S)-1. In addition, a more practical synthesis of benzophenone 8 was demonstrated utilizing Friedel–Crafts acylation and radical bromination chemistry.

A practical synthesis of the glycogen synthase kinase-3 (GSK3) inhibitor bisarylmaleimide 1 has been accomplished employing Pictet-Spengler methodology to access the indole 7-position in preparing the benzodiazepine tricyclic fragment. A seven-step linear sequence that starts with commercially available 5-fluoroindole 7 affords the bisarylmaleimide 1 in 33% overall yield.

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Mild methods for conducting Knorr chemistry with beta-ketonitriles were developed. This enabled the preparation of 4-cyanopenta-substituted pyrroles and gave access to alpha-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid ( AMPA) receptor potentiators for biological evaluation. In addition, a series of alkyl and aryl beta-ketonitriles were employed in Knorr cyclizations to probe steric tolerance and the possibility of direct introduction of aromatic moieties via Knorr chemistry.