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1,3-二取代双环[2.1.0]戊烷（housane）衍生物的合成方法。该方法依托双(三甲基硅基)氨基锂（lithium bis(trimethylsilyl)amide）介导的分子内环化反应，以带有C4位离去基团与C3位额外取代基的三取代环戊烷羧酸酯为底物，此类底物可由环戊-3-烯羧酸酯合成得到。该合成路线可实现顺式与反式两种1,3-二取代房烷-1-羧酸的非对映选择性制备，反应规模最高可达80克。尤为重要的是，本研究还合成了双环γ-氨基酸——即γ-氨基丁酸（γ-aminobutyric acid）类似物——。研究表明，双环[2.1.0]戊烷结构对对应衍生物的酸度系数（pKa）无显著影响；相较于环戊烷，该结构仅使衍生物的亲水性小幅提升，油水分配系数（Log P）增加0.07~0.25个单位。X射线衍射（X-ray diffraction）研究结果显示，顺式和反式1,3-二取代房烷可被视为对应环戊烷衍生物的扁平化类似物，其五元环固定为信封式构象（envelope conformation）。