Expanding the Chemical Space of 1,2-Difunctionalized Cyclobutanes

An efficient approach to the synthesis of previously unavailable or hardly accessible 1,2-difunctionalized cyclobutanes (mostly with NH₂/NHBoc, OH, SH, or SO₂F groups attached to the carbocycle either directly or via a CH₂ unit) relying on the divergent strategy is described. This class of compounds provides sp³-enriched and conformationally restricted building blocks that are of special demand for medicinal chemistry. The target compounds were prepared not only as pure racemic (±)-cis- and (±)-trans-diastereomers but in some cases also as single enantiomers. The developed procedures are readily scaled up and allow obtaining the target compounds on an up to hundred-gram scale. On the basis of the results of 20 X-ray diffraction experiments, structural characterization of the 1,2-difunctionalized cyclobutane core was performed using the extended Cremer-Pople puckering parameters and exit vector (EVP) plots.