Building the Housane: Diastereoselective Synthesis and Characterization of Bicyclo[2.1.0]pentane Carboxylic Acids
J. Org. Chem. 2020, 85 (4), 2321-2337
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 LogP 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.