Organocatalytic enantioselective [2π + 2σ] cycloaddition reactions of bicyclo[1.1.0]butanes with α,β-unsaturated aldehydes.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41130965.
- Also identified by DOI 10.1038/s41467-025-64399-7 and PMC identifier 12549830.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Bicyclo[2.1.1]hexanes (BCHs), three-dimensional benzene bioisosteres characterized by high sp<sup>3</sup>-carbon content, hold great promise for diverse applications in medicinal chemistry. Although significant advances have been made in the synthesis of racemic BCHs, highly enantioselective approaches remain comparatively rare. Here we report a mild, secondary amine-catalyzed asymmetric [2π + 2σ] cycloaddition of bicyclo[1.1.0]butanes (BCBs) with α,β-unsaturated aldehydes, which overcomes key limitations of existing metal-catalyzed and photochemical methods. The protocol operates under ambient air and tolerates a wide range of BCB and aldehyde substrates bearing diverse functional groups, affording BCH scaffolds in yields of up to 84% under Supramolecular Iminium Catalysis with excellent enantioselectivity (up to 99% ee) and high diastereoselectivity (>20:1 dr). The mild conditions and operational simplicity underscore the potential of this transformation for stereoselective manufacturing of BCHs at scale. Mechanistic experiments and DFT studies support an acid-promoted dual activation of both substrates, followed by an enamine-iminium tandem catalytic process that delivers the enantioenriched products.