The Diels-Alder reaction: a mainstay of organic chemistry

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The Diels-Alder reaction is one of the most important in Organic Chemistry and plays a role in the synthesis and manufacture of many products including pharmaceutical ingredients (including vitamins and drugs), agrochemicals (including fungicides), flavors, fragrances, and more. The reaction is also found in nature, in the synthesis of natural products.

Background:

*Boger, D. & Weinreb, S. (1987). Hetero Diels-Alder Methodology in Organic Synthesis. Organic Chemistry: A Series of Monographs, volume 47. 366 pages. [PDF–partial] [Cited by]

Organic Chemistry: A Series of Monographs, Volume 47: Hetero Diels-Alder Methodology in Organic Synthesis focuses on the use of hetero Diels-Alder reactions as pivotal steps in natural product total syntheses. The publication first offers information on N-sulfinyl compounds and sulfur diimides and imino dienophiles. Discussions focus on sulfur dioxide and related compounds, selenium dioxide, sulfur diimide cycloadditions, regiochemical, stereochemical, and mechanistic aspects, iminium salts and neutral imines, oximino compounds, and intramolecular cycloadditions. The text then takes a look at nitroso and thionitroso dienophiles and carbonyl dienophiles. The manuscript elaborates on thiocarbonyl and selenocarbonyl dienophiles and miscellaneous dienophiles. Topics include nitriles, azo compounds, selenoaldehydes, thioketones, thioesters, dithioesters, and related compounds, and thiophosgene and related compounds. The text also ponders on oxabutadienes, thiabutadienes, and azabutadienes. The publication is a valuable reference for chemists and readers interested in the Hetero Diels-Alder methodology.”

*Nicolaou, K. C., Snyder, S. A., Montagnon, T., & Vassilikogiannakis, G. (2002). The Diels-Alder reaction in total synthesis.Angewandte Chemie (International Ed.in English), 41(10), 1668-1698. [PDF] [Cited by]

The Diels–Alder reaction has both enabled and shaped the art and science of total synthesis over the last few decades to an extent which, arguably, has yet to be eclipsed by any other transformation in the current synthetic repertoire. With myriad applications of this magnificent pericyclic reaction, often as a crucial element in elegant and programmed cascade sequences facilitating complex molecule construction, the Diels–Alder cycloaddition has afforded numerous and unparalleled solutions to a diverse range of synthetic puzzles provided by nature in the form of natural products. In celebration of the 100th anniversary of Alder’s birth, selected examples of the awesome power of the reaction he helped to discover are discussed in this review in the context of total synthesis to illustrate its overall versatility and underscore its vast potential which has yet to be fully realized.”

*Ose, T., Watanabe, K., Mie, T., Honma, M., Watanabe, H., Yao, M., . . . Tanaka, I. (2003). Insight into a natural Diels-Alder reaction from the structure of macrophomate synthase.Nature, 422(6928), 185-189. [Cited by]

“The Diels–Alder reaction, which forms a six-membered ring from an alkene (dienophile) and a 1,3-diene, is synthetically very useful for construction of cyclic products with high regio- and stereoselectivity under mild conditions. It has been applied to the synthesis of complex pharmaceutical and biologically active compounds. Although evidence on natural Diels–Alderases has been accumulated in the biosynthesis of secondary metabolites, there has been no report on the structural details of the natural Diels–Alderases. The function and catalytic mechanism of the natural Diels–Alderase are of great interest owing to the diversity of molecular skeletons in natural Diels–Alder adducts. Here we present the 1.70 Å resolution crystal structure of the natural Diels–Alderase, fungal macrophomate synthase (MPS), in complex with pyruvate. The active site of the enzyme is large and hydrophobic, contributing amino acid residues that can hydrogen-bond to the substrate 2-pyrone. These data provide information on the catalytic mechanism of MPS, and suggest that the reaction proceeds via a large-scale structural reorganization of the product.”

For specific examples of the use of the Diels-Alder reaction, search the Science Primary Literature Database.

Questions? Please let me know (engelk@grinnell.edu).

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