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Bicyclo[3.2.0]heptane as a Core Structure for Conformational Locking of 1,3‐Bis‐Pharmacophores, Exemplified by GABA
Author(s) -
Vorberg Raffael,
Trapp Nils,
Carreira Erick M.,
Müller Klaus
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201605179
Subject(s) - bicyclic molecule , pharmacophore , heptane , stereochemistry , chemistry , molecule , crystal structure , crystallography , organic chemistry
The synthesis and X‐ray crystal structures of syn and anti 4‐ N ‐Boc‐aminobicyclo[3.2.0]heptane‐1‐carboxylic acids are described. The placement of the N ‐Boc‐amino groups in the two stereoisomers in either pseudo‐equatorial or pseudo‐axial positions renders the molecules conformationally locked, with N ‐Boc‐protected γ‐aminobutyric acid (GABA) embedded within the bicyclic core. Despite the different conformations of the urethane and distinct crystal packing, the bicyclic core units of the two stereoisomers adopt virtually identical structures. They correspond to in silico models of the parent bicyclic core and a systematic array of disubstituted derivatives. The study documents an intrinsic property of the bicyclo[3.2.0]heptane core to favor adoption of a boat‐like conformation, which is largely unaffected by various substitution patterns. The structural concepts are useful in the design of molecules with spatial and directional fixation of pharmacophoric groups.