3,6-Difunctionalized Bicyclo[3.2.0]heptanes – Promising Cycloalkane/Benzene Isosteres

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 lacked stereospecificity, the target bicyclic building blocks (including amino acids and amino alcohols) could be obtained as pure (1R*,3R*,5S*,6R*) (exo,exo) or (1R*,3R*,5S*,6R*) (exo,endo) isomers on up to 34.4 g scale. Structural characterization of the title scaffolds using exit vector plot (EVP) formalism showed their potential for cycloalkane/benzene isosteric replacements in medicinal chemistry.