Organic Chemistry Portal
Organic Chemistry Highlights

Monday, December 11, 2006
Douglass Taber
University of Delaware

Advances in the Diels-Alder Reaction: Synthesis of (±)-Lycoridine and of Dolabellatrienone

Cyclic dienes such as 1 are reluctant participants in Diels-Alder cycloaddition. W. Dean Harman of the University of Virginia has shown (J. Am. Chem. Soc. 2006, 128, 1426. DOI: 10.1021/ja0553654) that such dienes are activated by complexation to Mo. After cycloaddition, exposure of the product to air liberates the product 4.

Cyclohexenone 5 is a sluggish dienophile, requiring activation by AlCl3. Francesco Fringuelli and Ferdinando Pizzo of the Università di Perugia have developed (Org. Lett. 2006, 8, 2487. DOI: 10.1021/ol060569q) a somewhat milder alternative, AlCl3 complexed to THF. Operationally, a catalytic amount (5 mol %) of AlCl3 and exactly twice that much THF were combined. The diene 6 and the dienophile 5 were then added, in this case in a 2:1 ratio, without additional solvent. After 12 hours at 30 °C, the cycloadduct 7 was isolated in 80% yield. Increasing or decreasing the amount of THF dropped the efficiency of the reaction.

Effective procedures for the α-methylenation of aldehydes go back at least sixty years (J. Am. Chem. Soc. 1948, 70, 1694. DOI: 10.1021/ja01185a006). Nevertheless, the results reported (J. Org. Chem. 2006, 71, 2538. DOI: 10.1021/jo052529q) by Petri M. Pihko of Helsinki University of Technology are compelling. Using 37% aqueous formaldehdye and 10 mol % of the dimeric peptide L-Pro-β-Ala, they were able to effect α-methylenation of sensitive aldehydes such as 8 and 10.

α-Substituted acroleins are difficult substrates for enantioselective catalysis. Kazuaki Ishihara of Nagoya University has developed polyamine catalysts that direct cycloaddition of α-substituted acroleins with high enantioselectivity. For cyclopentadiene 12 and the dienophile 13 (Org. Lett. 2006, 8, 2229. DOI: 10.1021/ol060490l), the polyamine of choice is 14, 5 mol %, activated with an equimolar amount of Tf2NH.

Ben L. Feringa and Gerard Roelfes of the University of Groningen have taken advantage (Chem. Comm. 2006, 635. DOI: 10.1039/b516552k) of the inherently chiral environment of DNA to direct the absolute sense of Diels-Alder cycloaddition.

Two particularly elegant applications of the intramolecular Diels-Alder reaction have recently been reported. Albert Padwa of Emory University has shown (Org. Lett. 2006, 8, 247. DOI: 10.1021/ol052524f) that Pd-mediated coupling of 19 and 20 directly delivers the cycloadduct 21. This was carried on over several steps to the Amaryllidaceae alkaloid lycoricidine 22.

E.J. Corey of Harvard University has applied (J. Am. Chem. Soc. 2006, 128, 740. DOI: 10.1021/ja0576379) the chiral Diels-Alder catalysts he has developed to the cyclization of the triene 23. The adduct 24 was carried on to the dolabellane marine natural product dolabellatrienone 25.

D. F. Taber, Org. Chem. Highlights 2006, December 11.