Diastereoselective Synthesis of the Acid Part of a New Muscarinic M3 Receptor Antagonist

Diastereoselective synthesis of (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid 1, an important component of a novel muscarinic M3 receptor antagonist 3, was achieved via Michael addition of an enolate of chiral dioxolane 4 to (−)-dicyclopentadiene 9 in 90% de as a key step. The desired Michael adduct 10, which was easily isolated by recrystallization of a mixture of diastereomers, was submitted to retrograde Diels–Alder reaction. Subsequent hydrogenation of the resultant enone 12 gave the key intermediate 5 in 91% chemical yield from 10.