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.

https://www.ch.ic.ac.uk/local/organic/pericyclic/DA.pdf

The Diels--Alder reaction in total synthesis.

One hundred years after the birth of Kurt Alder and seventy-five years after the discovery of his famous reaction, one of the most important and fascinating transformations in chemistry, research on that process continues to surprise, excite, delight, and inform the chemical community. This article is based on presentations given first at the University of Cologne, Germany (Kurt Alder lecture, 1992), then at the Roger Adams Award Symposium (1993), and later at the Burgenstock Conference of 2001, and describes research by our group on the development and understanding of enantioselective versions of the Diels-Alder reactions. The elements of this review include (1) development of new chiral Lewis acid catalysts for highly enantioselective (>25:1) [4+2] cycloadditions; (2) the fine mechanistic details and pre-transition-state assemblies of these reactions; (3) the fundamental understanding of catalytic activity and enantioselectivity for highly enantioselective Diels-Alder processes; and (4) applications to the synthesis of complex molecules. The range and power of the Diels-Alder reaction have steadily increased over seven decades. The end of this remarkable development is not in sight, a high compliment to this field of Science and to its great inventor.

Catalytic enantioselective Diels--Alder reactions: methods, mechanistic fundamentals, pathways, and applications.

The [2 + 2] photocycloaddition is undisputedly the most important and most frequently used photochemical reaction. In this review, it is attempted to cover all recent aspects of [2 + 2] photocycloaddition chemistry with an emphasis on synthetically relevant, regio-, and stereoselective reactions. The review aims to comprehensively discuss relevant work, which was done in the field in the last 20 years (i.e., from 1995 to 2015). Organization of the data follows a subdivision according to mechanism and substrate classes. Cu(I) and PET (photoinduced electron transfer) catalysis are treated separately in sections 2 and 4, whereas the vast majority of photocycloaddition reactions which occur by direct excitation or sensitization are divided within section 3 into individual subsections according to the photochemically excited olefin.

http://pubs.acs.org/doi/pdf/10.1021/acs.chemrev.5b00723

Recent Advances in the Synthesis of Cyclobutanes by Olefin [2+2] Photocycloaddition Reactions

Synthesis of piperidines

In den letzten Jahrzehnten hat wohl keine andere Reaktion das Forschungsgebiet der Totalsynthese mehr gepragt als die Diels-Alder-Reaktion. Mit einer Vielzahl von Anwendungen dieser grosartigen pericyclischen Reaktion, oftmals als entscheidendes Element einer eleganten Kaskadenreaktion zur Herstellung komplexer Molekulstrukturen, ermoglichte die Diels-Alder-Cycloaddition die Losung einer Reihe unterschiedlicher, von der Natur in Form von Naturstoffen gestellter Syntheseprobleme. Zur Feier des hundertjahrigen Jubilaums von Alders Geburtstag soll dieser Aufsatz die ungemeine Leistungsfahigkeit der von ihm entdeckten Reaktion anhand ausgewahlter Beispiele im Kontext der Totalsynthese verdeutlichen und ihre Vielseitigkeit sowie ihr gewaltiges, noch immer nicht vollstandig erfasstes Potential unterstreichen.

Die Diels‐Alder‐Reaktion in der Totalsynthese

Catalyzed asymmetric diels-alder reaction of benzoquinone. Total synthesis of (-)-ibogamine.

The DielsAlder reaction of 1,4-benzoquinone with 1,3-dienes catalyzed by Mikami's [Ti{(S)-binol(2−)}Cl2] complex (binol=[1,1′-binaphthalene]-2,2′-diol) gives cycloadducts in good yield and in high enantiomer excess. A model is proposed to explain the observed absolute configuration of cycloadducts, and the reaction is used as the key step in an asymmetric synthesis leading to the alkaloid (−)-ibogamine.

Catalyzed Asymmetric Diels ? Alder Reactions of Benzoquinone. Total Synthesis of (−)‐Ibogamine

2-Azabicyclo[2.2.2]oct-5-enes bearing an endo alkenyl substituent were synthesized by Diels−Alder addition of methyl vinyl ketone to a 1,6-dihydropyridine derived from methyl nicotinate. Although 1,5-dienes with this skeleton were unreactive under thermal conditions, they were photochemically reactive. Irradiation of these dienes through a Corex filter resulted in intramolecular [2 + 2] cycloaddition to give “parallel” and “crossed” photoadducts along with small amounts of a hexahydroisoquinoline. The latter is thought to represent leakage of a diradical intermediate responsible for the parallel photoadduct. The new 2-azatetracyclo[4.4.0.0.4,907,10]decane and 3-azatetracyclo[6.1.1.0.2,705,9]decane structures formed in the photochemical reactions are thermally stable.

Intramolecular Photocycloaddition of Unsaturated Isoquinuclidines. Synthesis of 2-Azatetracyclo[4.0.0.4,907,10]decanes and 3-Azatetracyclo[6.1.1.0.2,705,9]decanes

The Diels-Alder addition of diene 2 with benzoquinone catalyzed by (S)-BINOL-TiCl(2) produced cycloadduct 5 in >65% yield and 87% ee. The cycloadduct was transformed into (-)-ibogamine in nine steps (10% overall yield from benzoquinone). A model for the transition state leading to 5 is proposed.

Younggi Choi

Papers

Catalyzed asymmetric diels-alder reaction of benzoquinone. Total synthesis of (-)-ibogamine.

Catalyzed Asymmetric Diels ? Alder Reactions of Benzoquinone. Total Synthesis of (−)‐Ibogamine

Intramolecular Photocycloaddition of Unsaturated Isoquinuclidines. Synthesis of 2-Azatetracyclo[4.0.0.4,907,10]decanes and 3-Azatetracyclo[6.1.1.0.2,705,9]decanes

Catalyzed Asymmetric Diels—Alder Reaction of Benzoquinone. Total Synthesis of (-)-Ibogamine.