Synthesis of a GPR40 Receptor Agonist

Significance

The G-protein coupled receptor GPR40 modulates insulin secretion. Two asymmetric syntheses of the GPR40 agonist shown above are based on asymmetric conjugate alkynylation reactions. The shortest route entails the addition of a 1-propynylzinc reagent to the acceptor C in the presence of cinchonidine (1.5 equiv, $34/mol) as a chiral mediator to give adduct D in 82% yield (er > 99:1). The longer second route involves a diastereoselective addition of 1-propynylmagnesium chloride to the oxazapanedione acceptor E.