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Monday, April 11, 2005
Douglass Taber
University of Delaware

Ru-Mediated Intramolecular Alkene Metathesis: Improved Substrate and Catalyst Design

As alkene metathesis is applied to more and more challenging substrates, difficulties have arisen, that in turn have driven creative solutions. One such is the relay ring-forming metathesis strategy put forward (J. Am. Chem. Soc. 2004, 126, 10210. ) by Thomas Hoye of the University of Minnesota. For metathesis to proceed, the catalyst must first interact with one of the two alkenes. If neither is reactive, the metathesis will not work. Professor Hoye conceived the idea that a pendant reactive alkene could interact quickly with the catalyst, then lose a cyclic alkene to generate the requisite intermediate carbene complex. In addition to its utility for cyclizing unreactive dienes, this strategy can be used to steer metathesis when more than one option is available. Cyclization of 6, for instance, delivers nearly equal amounts of 3 and 4. Cyclization of 1, on the other hand, delivers predominantly 4, while cyclization of 5 gives 3. Note that selectivity is higher with the first-generation Grubbs catalyst (G1) than with the second generation catalyst (G2).

This strategy has already been found useful in natural product synthesis. In the course of a synthesis of V-ATPase inhibitor oximidine III, John Porco of Boston University has described (Angew. Chem. Int. Ed. 2004, 43, 3601. ) the cyclization of 7 to 8. In the absence of the pententyl director, the initial complexation of the Ru catalyst was with the 1,3-diene, leading to allylidene complex and so effectively killing the catalyst. In this case, the Hoveyda catalyst 8 provided a cleaner product than G2 did.

The usual metathesis catalysts G1, G2 and 8 exist in the reaction medium primarily in the resting form, so 5-10 mol% of catalyst is often required to drive reactions to completion. Warren Piers of the University of Calgary has prepared (Angew. Chem. Int. Ed. 2004, 43, 6161. ) a rapidly-initiating Ru catalyst 12 that does not have such a resting state. This catalyst, which is stable to ambient air and moisture and can be maintained in refluxing CD2Cl2 for several hours with no sign of decomposition, is effective at loadings of 0.1 mol %.

D. F. Taber, Org. Chem. Highlights 2005, April 11.