Assignment of the stereochemistry of the isomers of IQNP

The isomers of 1-azabicyclo[2.2.2]oct-3-yl {alpha}-hydroxy-{alpha}-(1-iodo-1-propen-3-yl)-{alpha}-phenylacetate (IQNP) are attractive for in vivo imaging of muscarinic receptors (mAChR). Although the stereocenter of the quinuclidinyl ring has been studied, the isomers of IQNP are oils and the configuration of the acetate center has not been elucidated. An improved synthesis of the acetate moiety (3) via a chiral intermediate has been developed and allows assignment of the configuration of the acetate. 1,3-dioxolan-4-one (1), (condensation of R- or S-mandelic acid and pivaldehyde) was alkylated with propargyl bromide, treated with base and esterified to afford R-(-)- or S-(+)-3. R- and S-3 were prepared in a 94:6 and 98:2 enantiomeric excess, respectively (HPLC analysis). R- and S-3 were utilized to synthesize the various isomers of IQNP. By comparing the optical rotation, HPLC and NMR of these isomers to those prepared by classical resolution allows the assignment of E-R, R-IQNP as the isomer demonstrating binding to M{sub 1} mAChR subtype and Z-R, R-IQNP as the isomer binding to M{sub 1} and M{sub 2}mAChR subtypes. This route also permits a simplified route for the preparation of the isomers of IQNP.