The Grubbs Reaction in Organic Synthesis: Part One of Three

We last reviewed organic synthesis applications of the Grubbs reaction on April 19, 2004. The (relatively) robust nature of the commercially-available catalyst and its commercial availability have spurred the expanding exploration of the scope of this reaction. Through this month, we will feature some recent highlights. (Part Two / Part Three)

The most straightforward application of the Grubbs reaction is to effect homologation of a terminal vinyl group. One concern with the use of the second generation Grubbs catalyst 3 is the cost, about $100/mmol. In conjunction with a total synthesis of the macrolide RK-397, Frank McDonald of Emory reported (J. Am. Chem. Soc. 2004, 126, 2495. DOI: 10.1021/ja039618+) that the conversion of 1 to 2 required 10 mol % of 3, but that it proceeded efficiently with just 2 mol % of the Hoveyda Ru catalyst 4 (J. Am. Chem. Soc. 2000, 122. 8168. DOI: 10.1021/ja001179g) . The alkene so prepared was cleanly trans. An advantage of 4 is that it avoids the use of the expensive PCy₃. We will refer to 3 as G2 and to 4 as H2.

Because of the functional group tolerance of the Grubbs catalyst 3, it will operate even with complex substrates. In the course of a total synthesis of (-)-cytisine, Giordano Lesma and Alessandra Silvani of the University of Milan reported (Org. Lett. 2004, 6, 493. DOI: 10.1021/ol0361507) that 5 could be cyclized efficiently to 6.

The even more spectacular cyclization of 7 to Arenastatin A 8 was reported (Tetrahedron Lett. 2004, 45, 5309. DOI: 10.1016/j.tetlet.2004.04.164) by Gunda Georg of the University of Kansas. In this case, the catalyst used was the first generation Grubbs catalyst, 9.