A scalable and efficient synthesis of the GPR40 agonist MK-8666 was developed from a simple pyridine building block. The key step to set the stereochemistry at two centers relied on an enzymatic dynamic kinetic reduction of an unactivated ketone. Directed evolution was leveraged to generate an optimized ketoreductase that provided the desired trans alcohol in >30:1 dr and >99% ee. Further, it was demonstrated that all four diastereomers of this hydroxy-ester could be prepared in high yield and selectivity. Subsequently, a challenging intramolecular displacement was carried out to form the cyclopropane ring system with perfect control of endo/exo selectivity. The endgame coupling strategy relied on a Pd-catalyzed C-O coupling to join the headpiece chloropyridine with the benzylic alcohol tailpiece.

The title compound, C15H13ClO2, was synthesized by a Reformatsky reaction in an aqueous medium. The two benzene rings are approximately parallel. Molecules are connected by intermolecular O—H⋯O hydrogen bonds, forming extended chains in the a axis direction.

The title compound, C23H23NO4S, crystallizes in the space group P. The S atom of the sulfonyl group has a distorted tetrahedral geometry. Intermolecular N—H⋯O hydrogen bonds are formed between the amino and carbonyl groups of two mol­ecules related by a center of symmetry.

Key indicatorsSingle-crystal X-ray study T = 293 K Mean '(C±C) = 0.004 A Ê R factor = 0.042 wR factor = 0.111 Data-to-parameter ratio = 16.3For details of how these key indicators were automatically derived from the article, seeView of the molecule of (I), showing the atom-labeling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Key indicatorsSingle-crystal X-ray study T = 293 K Mean '(C±C) = 0.005 A Ê R factor = 0.049 wR factor = 0.148 Data-to-parameter ratio = 16.5For details of how these key indicators were automatically derived from the article, see