Organic Chemistry Portal
Organic Chemistry Highlights

Monday, August 13, 2007
Douglass F. Taber
University of Delaware

The Intramolecular Diels-Alder Reaction in Natural Product Synthesis

A key step in the Gin synthesis of the hetesine alkaloid nominine reviewed last week (The Gin Synthesis of Nominine 2007, August 6) was an intramolecular Diels-Alder reaction. There have been several other recent applications of intramolecular Diels-Alder cyclizations in natural product synthesis. In the route to spiculoic acid A (3) reported (Chem. Commun. 2006, 2863. DOI: 10.1039/b607035c) by Victor Lee and Jack E. Baldwin of Oxford University, the activating electron-withdrawing ester is located at the end of the nonatriene 1. Under such circumstances, cyclization is rapid at room temperature, even in this highly substituted example, and it leads to the trans ring fusion, as illustrated.

Retrosynthetic analysis of β-erythroidine (6) suggested (Org. Lett. 2006, 8, 3689. DOI: 10.1021/ol061267r) to Raymond L. Funk of Pennsylvania State University the intramolecular Diels-Alder cyclization of the triene 4. Note that in this case, the activating carbonyl is internal on the nonatriene. Under such circumstances, the cyclization requires heating, and leads to the cis ring fusion. The contrast between the cyclization of 1 and the cyclization of 4 has been rationalized by charge transfer in this concerted but non-synchronous reaction proceeding to give initially the five-membered ring with nonatrienes such as 1, but initially the nine-membered ring with nonatrienes such as 4.

Allylic carbocations can also be effective dienophiles, as illustrated by the cyclization of 7 to 8 in the course of the synthesis of symbioimine 9 developed (Org. Lett. 2006, 8, 5605. DOI: 10.1021/ol062333s) by Barry B. Snider of Brandeis University. A very different route to symbioimine was described (Angew. Chem. Int. Ed. 2006, 45, 4767. DOI: 10.1002/anie.200601418) by Martin E. Maier of the Universität Tübingen, based on the intramolecular Diels-Alder cyclization of a decatriene.

Syntheses of 6Z-cladiellin diterpenes, but not of 6E-cladiellins, had been reported. The key to the intramolecular Diels-Alder approach to the E cladiellin diterpenes devised (J. Am. Chem. Soc. 2006, 128, 15851. DOI: 10.1021/ja065782w) by Deukjoon Kim of Seoul National University was the intramolecular alkylation that set the relative configuration of 11.

The dienophile and the diene do not have to be covalently attached for a Diels-Alder reaction to be intramolecular. In the course of preparing starting material for the synthesis of abyssomycin C (19), K. C. Nicolaou of Scripps, La Jolla found (Angew. Chem. Int. Ed. 2006, 45, 3256. DOI: 10.1002/anie.200601116) that addition of methyl acrylate 16 to the sorbic acid-derived alcohol 15 proceeded well only in the presence of the magnesium salt 17, which is presumably serving to complex the diene and the dienophile prior to cycloaddition.

Several other noteworthy advances in intramolecular Diels-Alder cyclization are reported in Tetrahedron Lett. 2006, 47, 4671, DOI: 10.1016/j.tetlet.2006.04.129; Chem. Commun. 2006, 3646, DOI: 10.1039/b605368h; J. Org. Chem. 2006, 71, 6701, DOI: 10.1021/jo061119e, and Org. Lett. 2006, 8, 5693, DOI: 10.1021/ol062067i. The work described in Chemistry Lett. 1989, 1947, DOI: 10.1246/cl.1989.1947 is also worth re-reading.

D. F. Taber, Org. Chem. Highlights 2007, August 13.