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Organic Chemistry Highlights

Total Synthesis

Monday, June 6, 2011
Douglass F. Taber
University of Delaware

The Li/Yang Synthesis of ()-Maoecrystal V

Maoecrystal V (3), isolated from the Chinese medicinal herb Isodon eriocalyx, shows selective inhibition of HeLa cells at low nanomolar concentration (IC50 = 60 nm). Chuang-Chuang Li of Shenzen Graduate School of Peking University and Zhen Yang of Peking University, Beijing designed (J. Am. Chem. Soc. 2010, 132, 16745. DOI: 10.1021/ja108907x) the first total synthesis of 3, based on the intramolecular Diels-Alder cyclization of 1 to 2.

The preparation of 1 began with the ketone 4. Methoxycarbonylation of 4 followed by coupling with 6 delivered 7. As would be expected, hydride reduction of the cyclic β-keto ester proceeded with high diastereocontrol to give the undesired trans diastereomer. Fortunately, the bulky tetrabutylammonium borohydride delivered the cis diastereomer, that could then be reduced to the diol 8. Rh-catalyzed carbene insertion into the O-H bond followed by condensation with formaldehyde then completed the preparation of the precursor 10.

Deprotection of 10 followed by oxidation presumably gave 1. There are two faces to the diene of 1, and then the acetoxylated stereogenic center, so four products are possible. In the event, three of the four were observed, of which 2 was the major.

To complete the synthesis of 3, the secondary alcohol of 11 was introduced by allylic bromination followed by radical reduction and trapping with TEMPO. The acetoxy group was reduced off, then the more reactive alkene was removed by selective hydrogenation. Oxidation and base treatment then delivered the equilibrium mixture of ()-Maoecrystal V (3) and its methyl epimer.

The synthesis of 3 as reported led to the racemate of the natural product. The starting cyclohexene 1 can be prepared (Tetrahedron Lett. 2000, 41, 3871. DOI: 10.1016/S0040-4039(00)00542-6) from 2,2-dimethylcyclohexane-1,3-dione (12). Yeast reduction of the prochiral 12 is known to proceed with high (S)-induction. It may be that a route could be devised from the reduction product 13 to enantiomerically-pure 7.

D. F. Taber, Org. Chem. Highlights 2011, June 6.