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Organic Chemistry Highlights

Total Synthesis

Monday, October 3, 2005
Douglass Taber
University of Delaware

Synthesis of (+)-Cyanthiwigin U

The cyanthin diterpenes show physiological activity ranging from cytotoxicity to nerve-growth factor stimulation. Andrew J. Phillips of the University of Colorado recently described (J. Am. Chem. Soc. 2005, 127, 5334. DOI: 10.1021/ja0509836) a concise enantioselective synthesis of cyanthiwigin U (3), based on the metathesis conversion of 1 to 2, using the second generation Grubbs catalyst.

It was clear that 1 would be derived from a Diels-Alder adduct. There has been a great deal of work in recent years around the development of enantioselective catalysts for the Diels-Alder reaction, but the catalysts that have been developed to date only work with activated dienophile-diene combinations. For less reactive dienes, it is still necessary to use chiral auxiliary control. One of the more effective of those was the known camphor-derived tertiary alcohol, so that was used in this project. Diels-Alder cycloaddition of the diene 4 with the enantiomerically-pure enone 5 led to the adduct 6 with high diastereocontrol. Oxidative cleavage led to the acid 7, which was carried on to the bis-enone 1.

The two-directional tandem metathesis of 1 to 2 proceeded smoothly using 20 mol % of the second generation Grubbs catalyst under an atmosphere of ethylene. The conversion of 2 to 3 took advantage of the differing reactivity of the two ketones. Addition of hydride to 2 from the less hindered face of the less hindered ketone delivered 4. Addition of isopropyl lithium to the surviving ketone followed by oxidative rearrangement of the resulting tertiary allylic alcohol and concomitant oxidation of the secondary allylic alcohol gave the diketone 10. Selective addition of methyl lithium to the less hindered of the two ketones, again from the more open face, then gave 3.

The elegantly concise strategy displayed here for the enantioselective and diastereoselective construction of the tricyclic enone 3, by two-directional tandem methathesis of the Diels-Alder derived diketone 1, should have some generality.

D. F. Taber, Org. Chem. Highlights 2005, October 3.