Expanding the Chemical Space of 1,2-Difunctionalized Cyclobutanes

Anton V Chernykh; Oleksandr V Kudryk; Oleksandr S Olifir; Alexey V Dobrydnev; Eduard Rusanov; Viktoriia S Moskvina; Dmitriy M Volochnyuk; Oleksandr O Grygorenko

doi:10.1021/acs.joc.2c02892

Expanding the Chemical Space of 1,2-Difunctionalized Cyclobutanes

J Org Chem. 2023 Mar 3;88(5):3109-3131. doi: 10.1021/acs.joc.2c02892. Epub 2023 Feb 13.

Authors

Anton V Chernykh^{1

2}, Oleksandr V Kudryk^{1

2}, Oleksandr S Olifir^{1

3}, Alexey V Dobrydnev^{1

2}, Eduard Rusanov^{4

5}, Viktoriia S Moskvina^{2

3}, Dmitriy M Volochnyuk^{1

2

4}, Oleksandr O Grygorenko^{1

2}

Affiliations

¹ Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyïv 02094, Ukraine.
² Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyïv 01601, Ukraine.
³ V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry at National Academy of Sciences of Ukraine, Akademik Kukhar Street 1, Kyïv 02094, Ukraine.
⁴ Institute of Organic Chemistry at National Academy of Sciences of Ukraine, Akademik Kukhar Street 5, Kyïv 02094, Ukraine.
⁵ Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, Zürich 8093, Switzerland.

PMID: 36780233
DOI: 10.1021/acs.joc.2c02892

Abstract

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.