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

Abstract

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 pK a 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 fivemembered ring.

Diastereoselective synthesis of 1,1,3,3-tetrasubstituted cyclobutanes enabled by cycloaddition of bicyclo[1.1.0]butanes

“…Due to their potential application in medicinal chemistry, the synthesis and reactivity studies of housanes have garnered growing attention. 12 We further examined the reaction of housanes 4 with 4-methyl-3 H -1,2,4-triazole-3,5(4 H )-dione 2 (Table 2). A dramatic steric effect of the substituent (R 2 ) on housanes 4 was observed.…”

Synthesis of Spirocyclic β‐ and γ‐Sultams by One‐Pot Reductive Cyclization of Cyanoalkylsulfonyl Fluorides

“…This is somewhat different from the case of the corresponding spirocyclic derivative 16 (Figure 3): although the pyrrolidine ring also adopts the envelope conformation, it is the spirocyclic carbon atom which outstands from the mean plane formed by other five‐membered ring atoms by 0.575 Å. Exit vector plot (EVP) analysis [67–70] of the corresponding bifunctional scaffolds shows that despite some differences, their overall geometry is similar and corresponds to the truly three‐dimensional relative disposition of the corresponding groups attached to the variation points (Table 5).…”

One-Pot Synthesis of Difluorobicyclo[1.1.1]pentanes from α-Allyldiazoacetates

“…A reasonable mechanism to explain the role of substituents on the product outcome from the reaction of bicyclo[1.1.0]­butane 24 with difluorocarbene is shown in Scheme . Previously, it has been proposed that the insertion of difluorocarbene is a stepwise process beginning with attack of the difluorocarbene on the central C1–C3 bond of the bicyclo[1.1.0]­butane, followed by recombination of the resultant zwitterion to form a 2,2-difluorobicyclo[1.1.1]­pentane. ,,, In the case of 3-substituted bicyclo[1.1.1]­pentanes 21a – g and 22a – b , the products are stable and isolable, , and this was confirmed in our studies (Table ).…”

“…The modularity of the diazo compound starting material has broader potential. Extending the alkene-diazo linker should allow facile access to expanded ring systems including bicyclo[2.1.0]­pentanes and bicyclo[3.1.0]­hexanes which have thus far been unexplored as substrates for the difluorocarbene reaction but could generate novel interesting caged architectures, difluorobicyclo[2.1.1]­hexane and difluorobicyclo[3.1.1]­heptane. , Similar caged compounds have recently garnered significant interest as meta - and ortho- substituted phenyl-bioisosteres for medicinal applications. ,, To this effect, diazo compounds were synthesized, and the intramolecular cyclopropanation was performed to generate the novel bicyclo[2.1.0]­pentane 28 and bicyclo[3.1.0]­hexane 29 . Both products were afforded in excellent yield, highlighting the robustness of this chemistry despite the modular design of the diazo compound precursors (Scheme ).…”