1-Azatricyclo[3.3.1.1(3,7)]decan-2-one (3), the parent compound of a rare class of 90°-twisted amides, has finally been synthesized, using an unprecedented transformation. These compounds are of special interest as transition-state mimics for the enzyme-catalyzed cis-trans rotamer interconversion of amides involved in peptide and protein folding and function. The stabilization of the amide group in its high energy, perpendicular conformation common to both systems is shown for the rigid tricyclic system to depend, as predicted by calculation, on its methyl group substitution pattern, making 3 by some way the most reactive known "amide".
The synthesis of a number of heterobicyclo[3.3.1]nonane derivatives possessing carbonyl, amino, or carboxyl groups is reported. The synthetic scheme is concise and practical, based on optimized reaction conditions for each step and an orthogonal protection group strategy. Procedures for the key synthetic steps (double annulation of α-bromomethyl acrylates to enamines and a Caglioti reaction) were improved significantly. This makes the compounds attractive for medicinal chemistry as potential chemically diverse 3D-scaffolds applicable in drug design.Saturated carbo-and heterobicyclic systems are used frequently in contemporary drug design. These systems represent the so-called 3D-scaffolds; 1 when functionalized at appropriate positions they can interact efficiently with biological targets. In principle, bicyclic scaffolds allow for wide variations of the functional group disposition in space, enhancing the chances of finding derivatives with optimal pharmacological characteristics. In order to exploit this potential to the full, chemists have developed flexible and practical synthetic approaches to bicyclic scaffolds functionalized at different positions. 2 We report here on the synthesis of a library of bicyclo[3.3.1]nonane-derived compounds possessing heteroatoms N, O, and S in the bicyclic skeleton (target compounds 1). Structural and chemical diversity of the synthesized library could be of great value for finding derivatives with improved pharmacokinetic properties, and enhanced efficiency and selectivity of interaction with biological targets. Such diversity has been the focus of the drug discovery process over the past decade. 3 The concept of diversity-oriented synthesis (DOS) was introduced, designating preparation of collections of structurally complex and diverse compounds from simple starting materials. 4 The bicyclic compounds described in this paper could be introduced into DOS by linear or branching functionalization methodology. 5 We explore this potential, aiming at improvements of known synthetic procedures and designing new ones.Construction of the [3.3.1]bicyclic system was performed by a well-documented strategy, based on the double annulation of α-bromomethyl acrylates 2 to enamines 3 (Scheme 1). The strategy was elaborated almost a half a century ago for synthesis of carbo-bicyclic derivatives, 6 and has already proved its efficiency in preparations of 3-azabicyclo[3.3.1]nonanes, 7 3-oxabicyclo[3.3.1]nonanes, 8 and 3-phenyl-3-phosphabicyclo[3.3.1]nonane-3-oxide. 9 A formal [3+3] cycloaddition annulation was also reported recently for rapid direct construction of the bicyclo[3.3.1] skeleton. 10
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