Total synthesis of (−)-cylindrocyclophane A facilitated by C−H functionalization

(-)-Cylindrocyclophane A is a 22-membered C<sub>2</sub>-symmetric [7.7]paracyclophane that bears bis-resorcinol functionality and six stereocenters. We report a synthetic strategy for (-)-cylindrocyclophane A that uses 10 C-H functionalization reactions, resulting in a streamlined route with high enantioselectivity and efficiency (17 steps). The use of chiral dirhodium tetracarboxylate catalysis enabled the C-H functionalization of primary and secondary positions, which was complemented by palladium-catalyzed C(sp<sup>2</sup>)-C(sp<sup>2</sup>) cross-couplings, resulting in the rapid formation of the macrocyclic core and all stereocenters with high regio-, diastereo-, and enantioselectivity. The use of a late-stage palladium-catalyzed fourfold C(sp<sup>2</sup>)-H acetoxylation installed the bis-resorcinol moieties. This research exemplifies how multilaboratory collaborations can produce substantial modernizations of complex total synthesis endeavors.

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Publication Details

Journal
Science
Published
2024-11-07
DOI
https://doi.org/10.1126/science.adp2425
Citations
20
Primary Topic
Axial and Atropisomeric Chirality Synthesis
Type
article
Field-Weighted Citation Impact
5.00

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article

Total synthesis of (−)-cylindrocyclophane A facilitated by C−H functionalization

Tyler D. Casselman, Aaron T. Bosse, Lorraine Hunt, Brian M. Stoltz et al.
20 citations
Science
Axial and Atropisomeric Chirality Synthesis
5.00
article

Total synthesis of (−)-cylindrocyclophane A facilitated by C−H functionalization

Tyler D. Casselman, Aaron T. Bosse, Lorraine Hunt, Brian M. Stoltz, Scott C. Virgil, Elizabeth L. Goldstein, Austin C. Wright, Huw M. L. Davies, Jin‐Quan Yu, Hojoon Park, Camila A. Suarez
article en
20 citations

Abstract

(-)-Cylindrocyclophane A is a 22-membered C<sub>2</sub>-symmetric [7.7]paracyclophane that bears bis-resorcinol functionality and six stereocenters. We report a synthetic strategy for (-)-cylindrocyclophane A that uses 10 C-H functionalization reactions, resulting in a streamlined route with high enantioselectivity and efficiency (17 steps). The use of chiral dirhodium tetracarboxylate catalysis enabled the C-H functionalization of primary and secondary positions, which was complemented by palladium-catalyzed C(sp<sup>2</sup>)-C(sp<sup>2</sup>) cross-couplings, resulting in the rapid formation of the macrocyclic core and all stereocenters with high regio-, diastereo-, and enantioselectivity. The use of a late-stage palladium-catalyzed fourfold C(sp<sup>2</sup>)-H acetoxylation installed the bis-resorcinol moieties. This research exemplifies how multilaboratory collaborations can produce substantial modernizations of complex total synthesis endeavors.

ScienceVol. 386(6722)
California Institute of Technology (US), Scripps Research Institute (US), Emory University (US)
National Science Foundation, Emory University, California Institute of Technology, National Institutes of Health, National Institute of General Medical Sciences, Division of Chemistry
Industry, innovation and infrastructure
Openalex Percentile: Top 4%
Axial and Atropisomeric Chirality Synthesis
5.00
DOIOpen Access PDFOpenAlex
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