Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, September 7, 2020
Douglass F. Taber
University of Delaware

The Ohtawa/Shenvi Synthesis of Bilobalide

Bilobalide (3), a component of the extract of Ginkgo biloba leaves, has been shown to normalize memory in Down syndrome model mice. Masaki Ohtawa, now at Kitasato University, and Ryan Shenvi of Scripps-La Jolla constructed the central carbocyclic ring of 3 by the diastereoselective free radical cyclization of 1 to 2 (Nature 2019, 575, 643. DOI: 10.1038/s41586-019-1690-5).

The starting material 1 was prepared starting with the phosphorane 4. Bromination led to 5, that on reaction with 6 led to the bromide-migrated product 7.

Combination of DMF with PBr3 led to a Vilsmeier reagent that converted pinacolone (8) to the bromo aldehyde 9. Reformatsky addition of 7 to 9 then completed the assembly of 1.

Reduction of 1 with tributyltin hydride led to the free radical 10. Cyclization proceeded with 20:1 diastereoselectivity, to deliver the crystalline 2.

The diastereoselectivity of the Mukaiyama hydration of 2 depended on the solvent used. Methyl cyclohexane led to 11, while methyl t-butyl ether gave the opposite diastereomer. Similarly, the diastereoselectivity of the subsequent oxetane formation was catalyst specific. With enantiomerically pure 11 and a BINOL-derived phosophoric acid catalyst, a substantial preference for 12 could be achieved.

The intermediate 12 was oxidized with IBX to the very congested β-keto ester. Other alkylating agents failed, but alkynylation proceeded, to give a ketone that was reduced to 13. Borylation and oxidation of the alkyne led to the lactone 14, that was deprotected and rearranged to the nearly symmetrical 15. To achieve selectivity, 15 was converted to the rearranged benzoate, that on hydroxylation followed by acid treatment gave bilobalide (3).

D. F. Taber, Org. Chem. Highlights 2020, September 7.