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Organic Chemistry Highlights

Total Synthesis

Monday, June 2, 2014
Douglass F. Taber
University of Delaware

The Li Synthesis of Daphenylline

The genus Daphniphyllum consists of 25-30 species of evergreen trees and shrubs of south Asia. The leaves and roots are widely used in Chinese herbal medicine. About 250 alkaloids, many with complex polycyclic structures, have been isolated from these species. Of these, Daphenylline (3) is unique in incorporating a benzene ring. Ang Li of the Shanghai Institute of Organic Chemistry envisioned (Nature Chem. 2013, 5, 679. DOI: 10.1038/nchem.1694) a route to 3 based on the diastereoselective intramolecular Michael cyclization of 1 to 2.

Following the work of Piers (J. Org. Chem. 1996, 61, 8439. DOI: 10.1021/jo961605+), the preparation of 1 began with the Birch reduction of 4, followed by hydrolysis. Epoxidation followed by elimination and acetylation led to the racemic acetate 5. Hydrolysis with pig liver esterase left one enantiomer of the acetate, that was transesterified with methoxide to give 6 in high ee.

Mitsunobu coupling of 6 with the o-nitrobenzenesulfonamide 7 gave 8. After some experimentation, selective α' silylation was effected with TBDPSOTf, setting the stage for gold-catalyzed Conia cyclization to 9. Deprotection of the amine followed by acylation with 10 gave 1, that cyclized smoothly to 2 as a 10:1 ratio of diastereomers.

The arene of 3 was constructed by converting 2 into the corresponding vinyl triflate. Pd-mediated coupling with 11 gave 12. Under irradiation with strict exclusion of oxygen, 12 cyclized to the dihydro aromatic, that on warming with DBU in the presence of air was oxidized to 13.

To close the last ring of 3, the ketone 13 was further oxidised to the enone 14. Desilylation of 14 followed by exposure to Ph3P/I2 gave the iodide 15, that was cyclized under reductive free radical conditions to 16.

The hydrogenation of 16 under Pd catalysis delivered the incorrect diastereomer, perhaps because migration to the endocyclic alkene preceded reduction. This problem was solved by using the Crabtree Ir catalyst. Modified Krapcho decarbomethoxylation then gave 17, that was reduced to Daphenylline (3).

D. F. Taber, Org. Chem. Highlights 2014, June 2.