Download PDF
Synfacts 2023; 19(10): 0969
DOI: 10.1055/s-0042-1752219
Synthesis of Heterocycles

Synthesis of Substituted 2-Oxabicyclo[2.1.1]hexanes via [2π+2σ] Cycloadditions with Bicyclobutanes

Authors

    Contributor(s):

  • Mark Reed

  • Nick Michel (Paraza Pharma)

Liang Y, Paulus F, Daniliuc CG, Glorius F. * Westfälische Wilhelms-Universität Münster, Germany
Catalytic Formal [2π+2σ] Cycloaddition of Aldehydes with Bicyclobutanes: Expedient Access to Polysubstituted 2-Oxabicyclo[2.1.1]hexanes.

Angew. Chem. Int. Ed. 2023;
62: e202305043
DOI: 10.1002/anie.202305043
CrossrefPubMedSearch in Google Scholar
Further Information
 
 PDF Download Permissions and Reprints

Key words

cycloaddition - bicyclobutanes - Lewis acid catalysis

Significance

Frequent challenges in medicinal chemistry campaigns revolve around modulating the physiochemical properties of candidate molecules. Such parameters that are of paramount importance to ADME/Tox properties are the solubility/lipophilicity of the molecule, and the fraction of sp3-hybridized carbons (Fsp3). Incorporation of 2-oxabicyclo[2.1.1]hexanes (2-oxa-BCHs) as phenyl bioisosteres favorably addresses both the Fsp3, and the solubility (by introducing a polar oxygen atom) of potential drug molecules. Synthetic methods to access these highly substituted 2-oxa-BCHs are thus desirable, as they allow for diverse avenues of discovery towards medicinal agents. Previous synthetic efforts targeting this important structural motif have been limited, and modular access towards these saturated ring systems could prove to be highly beneficial to the chemistry community.


 

Comment

The authors described an elegant [2π+2σ] cycloaddition reaction of strained bicyclobutanes (BCBs) 1 and aldehydes 2. The authors found that a mild Lewis acid (BF3 ·OEt2) is crucial for the transformation, as well as a BCB bearing an acyl pyrazole. (Hetero)aryl and aliphatic aldehydes were tolerated in the reaction, which furnished 2-oxa-BCHs 4a–e in moderate to good yields. BCBs 1 bearing other Ar groups could be prepared and used efficiently in the reaction (4c). The authors also found that epoxides 3 could be used in the reaction instead of aldehydes (4d,e). Control reactions indicated that under the standard reaction conditions, epoxides 2 underwent a LA-mediated isomerization to aldehydes 5, which then participated in the cycloaddition reaction. The authors also demonstrated that the necessary acyl-pyrazole functionality could be used for downstream transformations, which further strengthened the practicality of this method.


 

 

Publication History

Article published online:
14 September 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


  Permissions and Reprints