Organic Chemistry Portal
Organic Chemistry Highlights

Monday, September 27, 2004
Douglass Taber
University of Delaware

The Grubbs Reaction in Organic Synthesis: Part Three 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. This month, we are featuring some recent highlights. (Part One / Part Two).

A simple yet powerful application of the Grubbs reaction is specific homologation of a terminal vinyl group. When there is more than one alkene in the molecule, suitably disposed, one would worry about competing cyclization. In studies directed toward the cryptophycins, Mark Lautens of the University of Toronto has reported (Org. Lett. 2004, 6, 1883. DOI: 10.1021/ol049883f) that the second generation Grubbs catalyst 2 smoothly converts 1 to 3. The alternative cyclization product 4 is produced only in trace amounts.

As illustrated above, free alcohols are compatible with the Grubbs reaction. In the course of a synthesis of (+)-puraquinonic acid, Derrick Clive of the University of Alberta reported (J. Org. Chem. 2004, 69, 4116. DOI: 10.1021/jo040115b) that the very easily oxidized alcohol 5 maintains its enantiomeric excess as it is cyclized with the catalyst 2 to give 6.

The Grubbs reaction is an equilibration, and so would not be expected to be generally effective for the preparation of medium rings. Radomir Saicic of the University of Belgrade, Serbia and Montenegro, has reported (Org. Lett. 2004, 6, 1221. DOI: 10.1021/ol049875z) an elegant solution to this problem. The diene 7 is easily prepared by alkylation of cyclopentanone (or cyclohexanone) carboxylate, followed by the addition of allyl magnesium chloride. Exposure to the first-generation Grubbs catalyst 8 easily forms the six-membered ring, to give 9. Subsequent Grob fragmentation then delivers 10. Nine, ten, and eleven-membered rings were prepared using this approach.

Enyne metathesis can also be used with highly substituted substrates. Catherine Lièvre of the Université de Picardie reports (J. Org. Chem. 2004, 69, 3400. DOI: 10.1021/jo035437e) that enynes such as 11, readily prepared from carbohydrate precursors, are cyclized by the second generation Grubbs catalyst 2 to the enantiomerically-pure cyclic dienes, exemplified by 12.

Enyne metathesis can also be used to prepare more complex structures. A key step in the synthesis of (+)-viroallosecurinine reported (Tetrahedron Lett. 2004, 45, 5211. DOI: 10.1016/j.tetlet.2004.05.031) by Toshio Honda of Hoshi University in Tokyo is the selective cyclization of 13 to 15. In this case, the nitro Hoveyda-type catalyst 14 was used.

Applications of the Grubbs reaction continue to be developed. This is an update, not the final word.

D. F. Taber, Org. Chem. Highlights 2004, September 27.