Catalysts and Strategies for Alkene Metathesis

The Grubbs second generation catalyst (G2) continues to be the workhorse for academic investigations of synthetic applications of olefin metathesis. The requirement by Materia for licensing fees even for research investigations using G2 have made this catalyst much less attractive for industry-based researchers. There is a real interest in the development of alternative catalysts that are robust, active and easily prepared. Pierre Dixneuf of the Université de Rennes has found (Angew. Chem. Int. Ed. 2005, 44, 2576. DOI: 10.1002/anie.200462865) that exposure of the arene Ru complex 2 to a propargyl ether such as 3 generates in situ a very active metathesis catalyst. The catalyst so generated is apparently an 18-electron species, in contrast to the 16-electron G2. The complex 2, "a microcrystalline red powder" is prepared by addition of PCy₃ to the commercially-available [(p-cymene)RuCl₂]₂ followed by treatment of the product with AgOTf.

Amir H. Hoveyda of Boston College has reported (J. Am. Chem. Soc. 2005, 127, 8526. DOI: 10.1021/ja051330s) the development of a family of chiral Mo metathesis catalysts that convert prochiral dienes such as 5 and 8 into the cyclized product with high ee. Note that the six examples in the paper that were optimized to ≥ 90% ee required four different chiral Mo catalysts. This would not be a concern for manufacturing, where it would be worth the time to find the catalyst that gave the best results.

Several years ago, Professor Hoveyda designed the chelated Ru complex 12a as a versatile and stable metathesis catalyst. Dennis P. Curran of the University of Pittsburgh has now introduced (J. Org. Chem. 2005, 70, 1636. DOI: 10.1021/jo048001n) the fluorous-tagged Ru catalyst 12b. The fluorous tag allows the facile recovery of most of the active catalyst. The advantages of this are two-fold: the valuable catalyst can be re-used, and there will potentially be less Ru contamination in the cyclized product.

Ring-forming metathesis does not inevitably proceed smoothly. Johann Mulzer of the Universität Wien had planned (Org. Lett. 2005, 7, 1311. DOI: 10.1021/ol0500923) to set the trisubstituted alkene of epithilone by cyclization of the ester 13. In fact, however, this gave only the undesired dimer. There are two factors that disfavor the cyclization of 13: the ester prefers the extended rather than the lactone conformation, and the product eight-membered ring would have substantial transannular ring strain. The alternative bis silyl ether 14 does not have such conformational issues - indeed, the buttressing of the dialkyl silyl group favors cyclization. Further, the nine-membered cyclic ether product has significantly less transannular strain. Unlike 13, the bis ether 14 cyclized smoothly.

Congratulations to the recipients of the 2005 Nobel Prize in Chemistry!
The five Organic Chemistry Highlights columns for the month of October will be devoted to organic synthesis applications of alkene metathesis.