Organic Chemistry Portal
Organic Chemistry Highlights

Monday, January 28, 2008
Douglass F. Taber
University of Delaware

Alkene Metathesis: Synthesis of Kainic Acid, Pladienolide B and Amphidinolide Y

As alkene metathesis has developed into one of the tools of organic synthesis, many practical questions have arisen. In the course of a synthesis (Org. Lett. 2007, 9, 1635. DOI: 10.1021/ol0631197) of the important neuropharmacological tool (-)-kainic acid (7), Tohru Fukuyama of the University of Tokyo prepared the key intermediate 1 by chiral auxiliary mediated coupling of crotonyl chloride with acetadehyde. Dibal reduction gave the hemiaminal, which underwent reductive amination with glycine methyl ester, leading to the alkene 2. Alkene metathesis of the derived ester 3 to form the unsaturated lactone 4 was then examined in detail. It was found that 0.5 mol % of the second generation Hoveyda catalyst was sufficient to cyclize 3 to 4 in 92% yield. With 0.8 mol %, the yield was 99%. The key to the efficacy of this cyclization was the use of 1,2-dichloroethane at reflux as the reaction solvent.

The macrolide pladienolide D (14) induces in vivo tumor regression in several human cancer xenograft models. This activity was important enough that a team at Esai Co., Ltd in Tsukuba headed by Yoshihiko Kotake undertook the total synthesis (Angew. Chem. Int. Ed. 2007, 46, 4350. DOI: 10.1002/anie.200604997). Their approach used two alkene metathesis steps. To prepare the substrate for the macrolide construction, the alcohol 8 and the acid 9, each prepared by chiral auxiliary control, were coupled to give the ester 10. An extensive investigation led to alkene metathesis conditions that were satisfactory, the use of the second generation Hoveyda catalyst in refluxing toluene. A significant competing side reaction was the migration of the monosubstituted alkene of 10 to make the alkenyl ether.

The second alkene metathesis step was the coupling of 12 with 13. The most effective catalyst in this case was the second generation Grubbs. Note that the free alcohol 13 participated successfully in the cross-coupling. According to the authors, this is one of just a few examples of successful cross coupling of an alkene adjacent to a quaternary center.

The stereocontrolled construction of trisubstituted alkenes by metathesis is a particular challenge. In his synthesis (Org. Lett. 2007, 9, 2585. DOI: 10.1021/ol0710360) of amphidinolide Y (21), a modestly cytotoxic macrolide antibiotic, Wei-Min Dai of Zhejian University and the Hong Kong University of Science and Technology took up this challenge. The substrate for cyclization was prepared by coupling the acid 15 with the alcohol 16, followed by selective deprotection and oxidation. Medium-ring conformational effects played an important role in this metathesis. The cyclization was also attempted with the TES ethers of the two diastereomeric secondary alcohols corresponding to the ketone of 17. One of those diastereomers cyclized modestly well. The other diastereomer did not cyclize at all.

D. F. Taber, Org. Chem. Highlights 2008, January 28.