Development of a Concise and Robust Route to a Key Fragment of MCL-1 Inhibitors via Stereoselective Defluoroborylation.

MCL-1 is an attractive target for cancer therapy. We recently discovered highly potent and selective MCL-1 inhibitors containing a fluoroalkene fragment for which an efficient route to the main chiral -fluoro-BPin fragment was needed. The key step of this synthesis is a highly stereoselective defluoroborylation of a -difluorovinyl intermediate.

Serendipitous discovery of a pH-dependant atropisomer bond rotation: toward a write-protectable chiral molecular switch?

Owing to slow rotation of a sterically constrained dimethylamide substituent, two slowly interconverting enantiomers of a preclinical candidate for pharmaceutical development, 1, (6-(3-Chloro-4-fluoro-benzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-[2,6]naphthyridine-1-carboxylic acid dimethylamide) are observed by chiral chromatography. Isolation of pure enantiomer by preparative chiral chromatography followed by enantiopurity analysis over time allowed for a study of the kinetics of enantiomer interconversion under a variety of conditions. Relatively slow racemization was observed in alcohol solvents, with a half life on the order of 5-10 h.

Stereoselective synthesis of an anti-HIV drug candidate.

The asymmetric synthesis of a Merck anti-HIV drug candidate is described. The target molecule contains four stereogenic centers, three of which are located in a highly functionalized cyclopentane unit. The convergent synthesis involves the preparation of two key advanced intermediates: the cyclopentane unit and a substituted pyrazole unit.

Efficient synthesis of NK(1) receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation.

An efficient stereoselective synthesis of the orally active NK(1) receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation.

Crystallization-induced diastereoselection: asymmetric synthesis of substance P inhibitors.

A novel three-component condensation followed by a crystallization-induced asymmetric transformation is used to build this key substance P inhibitor intermediate in a short synthetic sequence.