Bernard Bonnaud

Preparation of Conformationally Constrained α2-Antagonists: The Bicyclo[3.2.0]heptane Approach

The aim of this research was to discover α2-receptor antagonist subtypes that are more selective than known compounds. We focused on rigid molecules possessing a benzo-fused bicyclo[3.2.0]heptane skeleton. The synthetic route used relied upon the intramolecular [2+2] cycloaddition of styrylketene precursors. The cycloaddition was remarkably efficient and delivered multigram quantities of the cycloadduct 2. Studies of the removal of the ketone group in 2 revealed a facile opening of the four-membered ring. Upon thermal elimination of TCI-13-endo (TCI = thiocarbonylimidazole) and TCI-13-exo, different products were obtaineddepending on the stereochemistry of the OH function of the precursor. Distinct mechanisms were proposed to account for the divergent outcomes observed. Double bond reductions from either methylcyclobutene or methylenecyclobutane isomers were thoroughly investigated in order to optimize the stereocontrol at the C-1 position. Hydrogenation of the internal π-bond produced an endo-1-methylcyclobutane derivative with high diastereoselectivity, whereas the exo-1-methyl isomer was best isolated by chromatographic separation of the acid 37. Finally, the prototypic imidazolidines 1, unsubstituted and bearing a methyl group at C-1, were synthesized for biological evaluation.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)