title: Bicyclo[3.2.0]heptane as a Core Structure for Conformational Locking of 1,3-Bis-Pharmacophores, Exemplified by GABA.
abstract: 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.
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Raffael
authors.initials: R
authors.lastname: Vorberg
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Nils
authors.identifier: http://orcid.org/0000-0002-9075-3967
authors.initials: N
authors.lastname: Trapp
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Erick M
authors.identifier: http://orcid.org/0000-0003-1472-490X
authors.initials: EM
authors.lastname: Carreira
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.
authors.forename: Klaus
authors.identifier: http://orcid.org/0000-0003-3184-476X
authors.initials: K
authors.lastname: Müller
mesh_terms: D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry; D018360:Crystallography, X-Ray; D006536:Heptanes / Q000138:chemical synthesis / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D005680:gamma-Aminobutyric Acid / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D001643:Bridged Bicyclo Compounds; D002264:Carboxylic Acids; D006536:Heptanes; D005680:gamma-Aminobutyric Acid
keywords: GABA; X-ray diffraction; conformation analysis; locked conformation; small ring systems