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Preparation of Conformationally Constrained α 2 Antagonists:The Bicyclo[3.1.0]hexane Approach
Author(s) -
Bonnaud Bernard,
Funes Philippe,
Jubault Nathalie,
Vacher Bernard
Publication year - 2005
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200500143
Subject(s) - chemistry , cyclopropanation , diazo , bicyclic molecule , intramolecular force , stereochemistry , selectivity , hexane , rhodium , enantioselective synthesis , combinatorial chemistry , medicinal chemistry , organic chemistry , catalysis
The aim of the research was to discover antagonists at α 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 precursors, 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 α 2A vs. α 2B and α 2C receptor subtypes, and consequently were prepared in enantiomerically pure form. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)