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

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.