2-Azabicyclo[3.2.0]heptane as a Bicyclic Isostere for Medicinal Chemistry: Synthesis and Physicochemical Characterization

A convenient approach to the synthesis of diastereopure 6- and 2,6-substituted 2-azabicyclo[3.2.0]hexanes is reported. The method is based on the sequential construction of the cyclobutane and pyrrolidine rings of the target bicyclic system via [2 + 2] ketene cycloaddition and lactam formation, respectively. Although the key cycloaddition step had modest stereoselectivity (dr 2:1), the target bicyclic product could be obtained as a pure diastereomer without using chromatographic purification. The reaction sequence commenced from readily available starting materials and was easily scalable (up to 32.8 g). Utility of the synthesized intermediates was demonstrated by the preparation of a series of (monoprotected) exo- and endo-isomeric amino alcohols and diamines – valuable building blocks for drug discovery. Their potential for isosteric replacements was evaluated by measuring physicochemical properties, as well as structural studies and exit vector plot (EVP) analysis.