Total synthesis of (-)-cylindrocyclophane A facilitated by C-H functionalization.
basic_science · Level V
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- Record sourced from PubMed, PMID 39509484.
- Also identified by DOI 10.1126/science.adp2425 and PMC identifier 11648813.
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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.