C. Jimeno, M. A. Pericàs, H. Wessel
Oct 4, 2011
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Influential Citations
6
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ChemMedChem
Abstract
Bicyclo[3.1.0]hexane and diverse heteroanalogues containing nitrogen, oxygen, or sulfur atoms in the five-membered ring have been recognized as interesting core structures of small molecules with diverse biological activities. They have been used as conformationally locked analogues of nucleoside building blocks and as intrinsically interesting building blocks in numerous other applications. They have been reported as intermediates in natural compound synthesis, or as constituents of bioactive compounds, 19] novel materials, and catalysts. Methanoproline 1, a naturally occurring inhibitor of proline metabolism, and 3-azabicyclo[3.1.0]hex-6-ylamine 2, a constituent of the potent broad-spectrum antibiotic trovafloxacin, are particularly prominent examples. They led to the design of the hybrid structure 3 as a conformationally locked basic amino acid analogue. Other ways to embed amino acid units such as glutamate into the bicyclo[3.1.0]hexane scaffold are illustrated by structure 4 or its corresponding 2-oxaand 2-thia-analogues 5 and 6 (Figure 1). Such compounds or further functionalized derivatives have been described by various research groups 22] and have resulted in highly potent metabotropic glutamate receptor antagonists or agonists. In all these examples, an extended conformation of the glutamate moiety was attempted and achieved. To the best of our knowledge, the prototypic 2aminobicyclo[3.1.0]hexane-6-carboxylic acid 7 a and its C2 epimer 8 a have not yet been prepared. Both contain an embedded g-aminobutyric acid (GABA) unit. Based on the structural results obtained for the bicyclic glutamate analogues, 6, 7] the GABA unit in 7 a,b should be locked in a fully extended conformation. In contrast, the corresponding C2 epimer 8 a,b should lock the GABA unit in a distinctly different conformation, depending on the conformational robustness of the bicyclic core system. A bicyclo[3.1.0]hexane core structure with or without embedded heteroatoms in the five-membered ring could, in principle, adopt three distinct conformations. An envelope conformation with an essentially planar five-membered ring (see Figure 2 b) is typically encountered for five-membered rings with conjugated exocyclic double bonds (e.g. , lactones, lactams, anhydrides, imides). For saturated (hetero)bicyclo[3.1.0] systems, five-membered ring envelope conformations are expected due to the structural constraints by the annelated cyclopropane unit (exerting a similar constraint as an endocyclic double bond), with the flap either anti (chair-type, Figure 2 a) or syn (boat-type, Figure 2 c) to the cyclopropane unit.