Organic Chemistry Portal
Organic Chemistry Highlights

Monday, October 25, 2004
Douglass Taber
University of Delaware

Alkyne Metathesis in Synthesis: Syntheses of (+)-Ferrugine and Anatoxin-α

Although much emphasis has been placed on the importance of alkene metathesis in organic synthesis, alkyne metathesis is also significant. Metathesis reactions of alkynes with alkenes and metathesis reactions of alkynes with alkynes have both been carried out efficiently.

An enantiospecific synthesis of the potent anti-Alzheimer's agent (+)-ferruginine 1 and two enantiospecific syntheses of the potent anti-Alzheimer's agent anatoxin-α 2 were submitted essentially simultaneously earlier this year. In each case, the starting material used was the inexpensive pyroglutamic acid 3, and in each case the synthesis depended on Ru-catalyzed alkyne-alkene metathesis.

The first report, received on February 25th, by Varinder Aggarwal of Bristol University (Org. Lett. 2004, 6, 1469. DOI: 10.1021/ol049665m) is representative of all three. Ohira homologation of the aldehyde 6 gave the enyne 8. A detailed study showed that the alkyne-alkene metathesis was proceeding cleanly, but that the product 10 was then decomposed by the Ru catalyst. Use of the less reactive first generation Grubbs catalyst 9 gave clean conversion of 8 to 10.

The second report (Tetrahedron Lett. 2004, 45, 4397. DOI: 10.1016/j.tetlet.2004.03.171) , received on February 27th, was from Miwako Mori at Hokkaido University. The cyclization of 11 to form the seven-membered ring gave only low yields. Cyclization of the silyl derivative 12, in contrast, proceeded efficiently, with concomitant desilylation.

The third report (Org. Lett. 2004, 6, 1329. DOI: 10.1021/ol049631e) , received on February 29th, was from Stephen Martin at the University of Texas. The starting material in this case was the other enantiomer of pyroglutamic acid 3, to deliver the natural enantiomer, (+)-anatoxin-α 2. Metathesis was carried out on the eneyne 15, again using the second-generation Grubbs catalyst 13. Selective oxidative cleavage then led to 2.

Mark Overhand of Leiden University recently reported (Tetrahedron Lett. 2004, 45, 4379. DOI: 10.1016/j.tetlet.2004.03.181) an example of alkyne-alkyne metathesis, the cyclization of 17 to 19. For this reaction, a tungsten catalyst was used.

D. F. Taber, Org. Chem. Highlights 2004, October 25.