Issue Date: November 21, 2011 | Web Date: December 12, 2011
No reaction is more elegant, more heartwarmingly satisfying than the Diels-Alder reaction. No reaction is also more nuanced. It appears deceptively simple and yet has the ability to create immense structural complexity often without additional reagents and sometimes solvent-free. Straightforward enough for an undergraduate organic chemistry class, yet intricate enough to spend several days in a graduate organic chemistry class reading into the engrossing story that is the Diels-Alder reaction. It is by far my favorite reaction.
First reported in 1928 by Otto Diels and his graduate student Kurt Alder, the chemists at once saw the importance of their work and wanted the exclusive rights to utilize their reaction. They write in their 1928 paper: “The possibility of synthesis of complex compounds related to or identical with natural products such as terpenes, sesquiterpenes, perhaps even alkaloids, has been moved to the near prospect. ... We explicitly reserve for ourselves the application of the reaction developed by us to the solution of such problems” (Liebigs Ann. Chem., DOI: 10.1002/jlac.19284600106). Fortunately for us, this exclusivity no longer applies.
Stripped of all its layers of complexity, at its core, the Diels-Alder reaction is a reaction of a conjugated diene (4 π electrons, in the s-cis conformation) and an alkene (2 π electrons, called the dienophile) to form a cyclohexene ring—the reaction is classified as a [4 + 2] cycloaddition.This is the bare-bones Diels-Alder reaction we all remember from undergraduate organic chemistry classes.
Peter Vollhardt’s 1980 synthesis of estrone showcases a beautiful example of an intramolecular Diels-Alder reaction. Under thermal conditions, the benzocyclobutene undergoes a 4π electrocyclic ring opening to give an intermediate o-quinodimethane—a perfectly situated and highly reactive diene. The pendant dienophile readily reacts with this diene to close the last two rings of the cholesterol framework.
Similarly, E. J. Corey’s 1969 prostaglandin F2α synthesis is a retrosynthetic masterpiece which every aspiring organic chemist needs to study. Only a five-membered ring exists in the product, yet Corey had the vision to see that carbon atoms 6–11 (prostaglandin numbering) could form the six carbon atoms of the cyclohexene Diels-Alder product. Diels-Alder reaction of the cyclopentadiene derivative and a ketene equivalent yielded a bridged bicyclic product. Conversion to the ketone, followed by Baeyer-Villiger oxidation, gave the bridged bicyclic lactone. A few steps later, the bridged lactone had been converted into the fused lactone that we now call the Corey lactone, in homage to the organic chemistry giant.
The Diels-Alder reaction is not merely restricted to the synthetic lab; nature also enjoys a good Diels-Alder reaction from time to time. And who can forget the endiandric acids from the pericyclic chemistry unit in their graduate organic chemistry class? The unsaturated acid with seven double bonds is a naturally occurring polyene. Once formed, the molecule spontaneously undertakes three separate pericyclic reactions to form an incredible amount of molecular complexity as a single pair of enantiomers. Initial 8π conrotatory electrocyclization yields a cyclooctatriene. A 6π disrotatory electrocyclization forms a fused bicycle. Depending on which diastereomer is formed in this electrocyclization, the bicycle is in perfect orientation to perform one of two Diels-Alder reactions to form either endiandric acid B or endiandric acid C. All this occurs nonenzymatically in nature.
Where would we be without the Diels-Alder reaction? Two σ bonds, a ring, and up to four new contiguous stereocenters prepared in one elegant reaction. Through judicious choice of starting materials, an enormous amount of molecular complexity can be formed. My students always laugh at me for having a favorite reaction. I don’t care. The Diels-Alder reaction will always be my favorite.
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