Synthesis and binding affinity studies of muscarinic receptor antagonists related to dehydrohimbacine

Abstract

The intramolecular Diels−Alder reaction of bromo-substituted nonatrienoate 24 leads to a mixture of the anti-adducts 25a and 25b, in which the trans-fused lactone 25b, the result of an expected exo-addition, predominates (6.2:1 stereoselectivity). Further introduction of a 2,6-transdisubstituted piperidine ring (26 and 27) via palladium catalyzed cross-coupling reactions (Stille and Sonogashira) affords intermediates that are easily transformed into dehydrohimbacine derivatives 14a, 14b, 15a, and 15b. Binding affinity studies for the muscarine receptors M 1 , M 2 , M 3 , and M 4 show that 15a possesses a 18-fold selectivity for the M 2 relative to the M 1 receptor, but with concomittant loss in affinity compared to the naturally occurring (+)-himbacine (1), a recognized muscarinic receptor antagonist.

On the Origin of Cis/Trans Stereoselectivity in Intramolecular Diels−Alder Reactions of Substituted Pentadienyl Acrylates: A Comprehensive Density Functional Study

“…This paper presents the results of a DFT computational study into cis / trans selectivity in the IMDA reactions of 9- E -substituted and 9- Z- substituted pentadienyl acrylates covering a wide range of 9-substituents, an important goal being to understand the origin of the anomalous trans selectivity displayed by the 9- Z -CO 2 Me substituent and to learn whether unsaturated 9- Z -substituents other than ester groups also exhibit trans selectivity. Endo / exo selectivities of inter molecular DA reactions between substituted ethylenes and butadiene were also computed in order to understand better the origin of cis / trans selectivity in this synthetically important system. , …”