Preparation of conformationally constrained α2 antagonists:: The bicyclo[3.1.0]hexane approach

The aim of the research was to discover antagonists at alpha(2) receptor subtypes potentially more selective than known compounds. We focused on new, conformationally restricted analogues of atipamezole. The key step in the synthetic sequences leading to target compounds relied on a rhodium-catalyzed intramolecular cyclopropanation reaction, the outcome of which varied with the nature of the diazo styrene precursor. Thus, depending on the substitution pattern of the double bond and the electronic properties of the diazo pre-cursors, the cyclopropanes 2 or 7, naphtalenes 8, or pyrazolines 17 were formed. The byproducts 8 and 17 originated from different, nonoverlapping mechanisms. Among the racemates synthesized, three compounds (1a, 22a, and 22b) showed increased selectivity for alpha(2A) vs. alpha(2B) and alpha(2C) receptor subtypes, and consequently were prepared in enantiomerically pure form. (c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005).