Organic Chemistry Portal
Organic Chemistry Highlights

Monday, June 26, 2006
Douglass Taber
University of Delaware

Creative Applications of Alkene and Alkyne Metathesis in Total Synthesis: (+)-8-epi-Xanthatin, (+)-Longicin, Latrunculin A, and Garsubellin A

Alkene and alkyne metathesis, well-developed synthetic methods, are now often employed in natural product synthesis. The total syntheses outlined here are noteworthy for their creative application of these reactions.

The sesquiterpene (+)-8-epi-xanthatin (5), isolated from the aerial parts of the genus Xanthium, has been shown to inhibit the in vitro proliferation of several cultured human tumor cell lines. Stephen F. Martin of the University of Texas has described (Org. Lett. 2005, 7, 4621. DOI: 10.1021/ol051711a) a succinct assembly of 5, starting with the addition of the enolate of 2 to the aldehyde 1. The key step in the synthesis is the domino intramolecular metathesis - intermolecular metathesis, using the second-generation Grubbs catalyst, that converts 3 into 5.

The Annonacea acetogenin (+)-longicin (8) is spectacularly more toxic toward malignant cells than toward normal cells. Stephen Hanessian has recently (Org. Lett. 2005, 7, 3989. DOI: 10.1021/ol051483k) reported the first total synthesis of 8. The assembly of the carbon skeleton of 8 was accomplished expeditiously by convergent esterification of a tetrahydrofuran precursor with the enantiomerically-pure alkoxy acid to give 6, followed by alkene metathesis to give 7. It is striking that macrolide formation, once considered one of the most technically challenging of all organic synthesis transformations, can now be used for routine homologation.

Exposure of cultured cells in vitro to latrunculin A (11) leads to disruption of the actin cytoskeleton. The total synthesis of 11 by Alois Fürstner of the Max-Planck-Institut, Mülheim (Angew. Chem. Int. Ed. 2005, 44, 3462. DOI: 10.1002/anie.200500390) addressed whether alkyne metathesis could be carried out in the presence of two reactive alkenes, one of which was also easily reducible. In fact, the cyclization of 9 to 10 proceeded efficiently. Partial hydrogenation of 10 then delivered the Z, E-diene of 11.

The polyprenylated phloroglucin garsubellin A (17), an inducer of choline acetyltransferase, presents many synthetic challenges, from the easily-hydrolyzed nonenolizable tricarbonyl system to the three quaternary centers of the central cyclohexanone ring. The synthesis reported (J. Am. Chem. Soc. 2005, 127, 14200. DOI: 10.1021/ja055301t) by Motomu Kanai and Masakatsu Shibasaki of the University of Tokyo used as a key step the cyclization of 14 to 16. The catalyst of choice in this case was the Hoveyda Ru complex 15. Although the synthesis was carried to completion in the racemic series, the authors did demonstrate that alkylation of the enolate 12 of cyclohexenone using the elegant chiral amine procedure developed by the late Kenji Koga delivered the starting enone 13 in high ee.

D. F. Taber, Org. Chem. Highlights 2006, November 26.