jo9b03044_si_003.cif (187.75 kB)

Building the Housane: Diastereoselective Synthesis and Characterization of Bicyclo[2.1.0]pentane Carboxylic Acids

Download (187.75 kB)
posted on 06.01.2020 by Volodymyr V. Semeno, Vadym O. Vasylchenko, Bohdan V. Vashchenko, Dmytro O. Lutsenko, Rustam T. Iminov, Olesia B. Volovenko, Oleksandr O. Grygorenko
An approach to 1,3-disubstitued bicyclo[2.1.0]­pentane (housane) derivatives was developed. The method relied on lithium bis­(trimethylsilyl)­amide-mediated intramolecular cyclization of trisubstitued cyclopentane carboxylates bearing a leaving group (at the C-4 position) and an additional substituent (at the C-3 atom), in turn synthesized from cyclopent-3-ene carboxylate. The synthetic sequence allowed for the preparation of both cis- and trans-1,3-disubstituted housane-1-carboxylic acids in diastereoselective manner on up to 80 g scale. In particular, bicyclic γ-amino acidsγ-aminobutyric acid analogueswere synthesized. It was shown that the bicyclo[2.1.0]­pentane did not significantly affect pKa of the corresponding derivatives and slightly increased their hydrophilicity (by 0.07–0.25 Log P units) as compared to cyclopentane. X-ray diffraction studies showed that cis- and trans-1,3-disubstituted housanes can be considered as flattened analogues of the corresponding cyclopentane derivatives with fixed envelope conformation of the five-membered ring.