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Preparation of Conformationally Constrained α 2 ‐Antagonists: The Bicyclo[3.2.0]heptane Approach
Author(s) -
Bonnaud Bernard,
Mariet Natacha,
Vacher Bernard
Publication year - 2006
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.200500541
Subject(s) - chemistry , bicyclic molecule , intramolecular force , cycloaddition , heptane , stereochemistry , ketone , ring (chemistry) , derivative (finance) , double bond , molecule , organic chemistry , catalysis , financial economics , economics
The aim of this research was to discover α 2 ‐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)