Synthesis and Physicochemical Characterization of 2‐Azabicyclo[3.2.0]heptane Building Blocks

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 commences from readily available starting materials and is easily scalable (up to 32.8 g). Utility of the synthesized intermediates is demonstrated by the preparation of a series of exo ‐ and endo ‐isomeric amino alcohols and monoprotected diamines—valuable building blocks for drug discovery. Their potential for isosteric replacements is evaluated by measuring physicochemical properties, as well as structural studies and exit vector plot analysis.