N-Phosphinoylimines have recently begun to attract significant attention from synthetic chemists for the preparation of nitrogen-containing molecules. Several methods have been developed for the synthesis, or in situ generation, of these reactive electrophilic species. N-Phosphinoylimines undergo a wide range of reactions, including nucleophilic additions and cycloadditions. These imines are also effective electrophiles in a number of diastereoselective and enantioselective reactions. An advantage of using N-phosphinoylimines is that the reaction products can be easily deprotected under mild acidic conditions, leading to amines. This review outlines the preparation and uses of N-phosphinoylimines with particular emphasis on their applications in stereoselective processes.

[reaction: see text] The cinchona alkaloid-catalyzed dimerization of monosubstituted ketenes generated in situ from the reaction of acid chlorides and diisopropylethylamine yields ketene dimers in high yields and enantioselectivities. This reaction tolerates sterically demanding and functionally diverse substituents. Kinetic studies suggest that the rate-determining step for the reaction is the deprotonation of the acid chloride by the tertiary amine to form ketene and that the stereochemistry-forming step is addition of an ammonium enolate with ketene.

GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs. Compound 24 demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.

Chiral chroman derivatives are important pharmacophores in natural and synthetic bioactive molecules. The discovery of catalytic asymmetric methods for the synthesis of these compounds is an important goal. Ruthenium-catalyzed asymmetric transfer hydrogenation under strongly basic conditions has been found to induce dynamic kinetic resolution of β-substituted chromanones, producing valuable chromanols in high yields and with high levels of stereocontrol. The reaction proceeds by base-catalyzed racemization of the β-stereocenter through a conjugate elimination/conjugate addition pathway in concert with a highly selective ketone transfer hydrogenation step. Computational analysis of the catalyst, substrate, and transition state structures has revealed the driving interactions for diastereoselectivity as well as unexpected CH–O stabilizing interactions between the catalyst sulfonamide and the reacting substrate.

α- and β-substitution of dihydrocinnamates has been shown to increase the biological activity of various drug candidates. Recently, we identified enantio- and diastereopure α-methyl-β-cyclopropyldihydrocinnamates to be important pharmacophores in one of our drug discovery programs and endeavored to devise an asymmetric hydrogenation strategy to improve access to this valuable framework. We used high throughput experimentation to define stereoconvergent Suzuki-Miyaura cross-coupling conditions affording (Z)-α-methyl-β-cyclopropylcinnamates and subsequent ruthenium-catalyzed asymmetric hydrogenation conditions affording the desired products in excellent enantio- and diastereoselectivities. These conditions were executed on multigram to kilogram scale to provide three key enantiopure α-methyl-β-cyclopropyldihydrocinnamates with high selectivity.