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Organic Chemistry Highlights

Total Synthesis

Monday, August 2, 2021
Douglass F. Taber
University of Delaware

The Gao Synthesis of Cephanolide A

The hexacyclic lactone cephanolide A (3) was isolated from the Chinese plum-yew Cephalotaxus sinensis. A key step in the route to 3 established by Shuanhu Gao of East China Normal University was the cyclization of the aldehyde 1 to the enone 2 (Angew. Chem. Int. Ed. 2020, 59, 20417. DOI: 10.1002/anie.202009562).

The preparation of 1 began with commercial quinic acid (4). Protection with 5 followed by reduction of the ester to the triol and periodate cleavage gave the intermediate ketone, that was dehydrated to the enone 6. Conjugate addition proceeded with high diastereoselectivity, to yield, after enolate trapping and regeneration, the allyl carbonate 7. Pd-catalysed rearrangement followed again by formation of the most stable enol ether led to 8. Axial hydroxymethylation followed by protection and trapping of the enolate delivered the enol triflate 9, that was coupled with the aryl boronate 10 to complete the assembly of 1.

Activation of the aldehyde with Lewis acid followed by Prins cyclization led to the alcohol 11, that was oxidized to the enone 2.

Deprotection of 2 followed by hydroxyl-directed conjugate reduction delivered the ketone 12. Oxidation of the primary alcohol to the aldehyde followed by deprotection then gave the intermediate lactol, that was oxidized to the lactone 13, thus differentiating the two secondary alcohols. The ketone of 13 was reduced to the secondary benzylic alcohol. Oxidative cleavage of the alkene followed by Friedel-Crafts cyclization was then accompanied by tetrahydrofuran formation, leading to 14. Alkene hydrogenation followed by demethylation completed the synthesis of cephanolide A (3).

D. F. Taber, Org. Chem. Highlights 2021, August 2.