Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose.

Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (), currently in phase 2 clinical trials.

A Modular Approach to the Synthesis of gem-Disubstituted Cyclopropanes.

A diastereoselective, Pd-catalyzed Suzuki-Miyaura coupling reaction of geminal bis(boryl)cyclopropanes has been developed. The reaction offers a highly modular approach to the synthesis of tertiary cyclopropylboronic esters. The resulting boronic esters may be further functionalized to afford a range of gem-disubstituted cyclopropanes, which represent an important structural motif in the pharmaceutical industry.

Enantioselective propargylation and allenylation reactions of ketones and imines.

Enantioselective propargylation and allenylation reactions pose an interesting challenge because they require control of regioselectivity as well as enantioselectivity. This review presents recent advances in enantioselective propargylation and allenylation reactions of ketones and imines. In this context, a brief discussion of the possible mechanisms of these transformations and consequences for regioselectivity is provided.

Functional-group-tolerant, nickel-catalyzed cross-coupling reaction for enantioselective construction of tertiary methyl-bearing stereocenters.

The first Negishi nickel-catalyzed stereospecific cross-coupling reaction of secondary benzylic esters is reported. A series of traceless directing groups is evaluated for ability to promote cross-coupling with dimethylzinc. Esters with a chelating thioether derived from commercially available 2-(methylthio)acetic acid are most effective.