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Organic Chemistry Highlights

Total Synthesis

Monday, July 4, 2016
Douglass F. Taber
University of Delaware

The Anderson Synthesis of (+)-Rubridiflordilactone A

The magnolia vine Schisandra rubriflora, the source of (-)-rubriflordilactone A, is widely used in Chinese herbal medicine. Edward A. Anderson of the University of Oxford envisioned (Angew. Chem. Int. Ed. 2015, 54, 12618. DOI: 10.1002/anie.201506366) that (+)-rubriflordilactone A (3) could be constructed by cyclizing the enantiomerically-pure triyne 1 directly to 2.

For the assembly of 1, both the left half and the right half had to be prepared in enantiomerically-pure form. To this end, the ester 4 was rearranged to 5. In this case, the direct rearrangement of the lithium enolate was more effective than the alternative via the ketene silyl acetal. The ester 5 was converted to the alkyne 6, that was silylated, then deprotected to give 7. Construction of the second alkyne led to 8.

The trisubstituted alkene of 10 was set by conjugate addition to the alkyne 9. Sharpless asymmetric epoxidation established the absolute configuration, and the authors took advantage of the marked nucleophilicity of allyl magnesium bromide (and chloride) to secure the alkylated stereogenic center of 12. Alkene cleave and functional group interchange led to 13, that was carried on to 15. The addition of the anion of the previously-prepared 8 then completed the assembly of 1.

In the event, the Co-catalyzed internal cyclotrimerization of 1 proceeded smoothly to give 2. The silyl group was oxidatively converted to the phenol, then the superfluous benzylic hydroxy group was removed reductively, to give 16. Oxidative cleavage of the pendant alkene followed by chlorination delivered 17, that was coupled with 18 to give (+)-Rubriflordilactone (3).

It is instructive to compare this synthesis to the quite different route developed (Substituted Benzenes: The Li Synthesis of Rubriflordilactone A 2015, June 15) by Ang Li of the Shanghai Institute of Organic Chemistry.

D. F. Taber, Org. Chem. Highlights 2016, July 4.