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.

本研究开发了一种针对1,3-二取代的 bicyclo[2.1.0]pentane（houseane）衍生物的方法。该方法基于锂双（三甲基硅基）酰胺介导的分子内环化反应，该反应涉及三取代的环戊烷羧酸盐，这些羧酸盐携带一个离去基团（位于C-4位置）和一个额外的取代基（位于C-3原子），而这些取代基是通过环戊-3-烯羧酸盐合成的。合成途径允许以手性选择性的方式，在80克规模上制备cis-和trans-1,3-二取代的houseane-1-羧酸。特别是，合成了双环γ-氨基酸（γ-氨基丁酸类似物）。研究表明，bicyclo[2.1.0]pentane对相应衍生物的pKa值影响不显著，且与环戊烷相比，略微增加了其亲水性（0.07–0.25 Log P单位）。X射线衍射研究表明，cis-和trans-1,3-二取代的houseane可以视为相应环戊烷衍生物的扁平类似物，其五元环具有固定的包结构型。