Synthesis and Structural Characterization of 3,6‐Disubstituted Bicyclo[3.2.0]heptane Building Blocks: Promising Saturated Bicyclic Isosteres of Cycloalkanes/Benzene

A reliable methodology for the multigram preparation of diastereomerically enriched 3,6‐disubstituted bicyclo[3.2.0]heptane building blocks is proposed. The strategy is based on [2 + 2] cycloaddition of 3‐substituted cyclopentene derivatives and dichloroketene, followed by a diastereoselective reduction reaction. Despite both steps lacking stereospecificity, the target bicyclic racemic building blocks (including amino acids and amino alcohols) could be obtained as pure diastereomers on up to a 34.4 g scale. Structural characterization of the title scaffolds using exit vector plot formalism showed their potential for cycloalkane/benzene isosteric replacements in medicinal chemistry.