Two Distinct Conformations of GABA Locked by Embedding in the Bicyclo[3.1.0]hexane Core Structure

Bicyclo[3.2.0]heptane as a Core Structure for Conformational Locking of 1,3‐Bis‐Pharmacophores, Exemplified by GABA

“…Focusing on the observations with pronounced nonplanar five‐membered ring units ( θ 1 >20°), we find 125 boat‐type versus eight chair‐type structures. The scatter plot in Figure is very similar to that obtained for (hetero)bicyclo[3.1.0]hexane structures, and thus confirms our expectations based on theoretical considerations. The prevalence of boat‐shaped structures in (hetero)bicyclo[3.2.0]heptane systems devoid of embedded conjugated units is even more pronounced, as indicated by a syn / anti ratio of >15:1 as compared to a ratio of about 12:1 for (hetero)bicyclo[3.1.0]hexane systems .…”

“…The scatter plot in Figure is very similar to that obtained for (hetero)bicyclo[3.1.0]hexane structures, and thus confirms our expectations based on theoretical considerations. The prevalence of boat‐shaped structures in (hetero)bicyclo[3.2.0]heptane systems devoid of embedded conjugated units is even more pronounced, as indicated by a syn / anti ratio of >15:1 as compared to a ratio of about 12:1 for (hetero)bicyclo[3.1.0]hexane systems . Therefore, in analogy to bicyclo[3.1.0]hexane, but for different reasons, there is an intrinsic tendency for bicyclo[3.2.0]heptane to adopt a boat‐shaped conformation, more or less independently of substitution patterns and embedded heteroatoms.…”

“…The specific and conformationally robust shape of the bicyclo[3.1.0]hexane core structure has been successfully used in various applications in the design of biologically active compounds as well as building blocks in medicinal chemistry. A priori, the homologous bicyclo[3.2.0]heptane system appears to be more flexible than its bicyclo[3.1.0]hexane counterpart, and the specific conformation‐determining interactions of vicinal exocyclic bonds at the bridgehead and adjacent positions in the five‐membered ring are somewhat mitigated in the bicyclo[3.2.0]heptane system (Figure ). However, model calculations at different levels of sophistication on the anti ‐ or chair‐type bicyclo[3.2.0]heptane system indicate other severe repulsive interactions, that is, those of the pseudoaxial C−H bonds at C2 and C4 with the nearly eclipsed respective C−C bonds of the cyclobutane unit, as well as highly unfavorable transannular CH⋅⋅⋅CH interactions between C2 and C7 as well as C4 and C6, with H⋅⋅⋅H interatomic distances well below van der Waals contact distances (Figure , middle).…”

“…These represent the substitution patterns 1 x 4 x and 1 x 4 n , respectively, which have essentially no correlations to spatial and exit vector dispositions of well‐staggered acyclic 1,3‐bis‐pharmacophores (Figure ). This selection of γ‐amino acid derivatives follows our previous study of epimeric disubstituted bicyclo[3.1.0]hexane derivatives and corresponds to embedding ( N ‐Boc‐protected) γ‐aminobutyric acid (GABA) into the bicyclic core structure.…”

Crystal structure of (3R)-3-benzyl-4-[(tert-butoxycarbonyl)amino]butanoic acid

“…The title enantiomeric compound was synthesized according to Loukas et al (2003) and Felluga et al (2008). For related structures, see: Pihko & Koskinen (1998); Jimeno et al (2011). For solution conformation of oligomers based on monosubstituted -amino acids, see: Guo et al (2012); Kang & Byun (2012).…”