Expanding the Frontiers of Higher-Order Cycloadditions

Abstract

The concept of pericyclic reactions and the explanation of their specificity through orbital symmetries introduced a new way of understanding reactions and looking for new ones. One of the 1965 Woodward−Hoffmann communications described "the (as yet unobserved) symmetry-allowed 6 + 4 combination", the prediction of a new field of "higher-order" cycloadditions, involving more than six electrons. Later these authors predicted exo-stereoselectivity for the [6 + 4]-cycloaddition. Chemists rushed to test this prediction (for the most part successfully). For more than half a century, chemists have hunted for additional higher-order cycloadditions. The application of catalysis within organic chemistry allows the accomplishment of previously unattainable reactions, including higherorder cycloadditions.The many examples of [8 + 2], [6 + 4], and cycloadditions of even higher electroncounts discovered since the Woodward−Hoffmann rules were introduced illustrate the difficulty in predicting which of these transformations will occur when two highly unsaturated molecules react. Periselectivity has been a challenge, and the development of enantioselective variants has been elusive. While progress was made, the rise of organocatalysis in asymmetric synthesis has led to a surge of interest in stereoselective versions of higher-order cycloadditions. Through organocatalytic activation of conjugated cyclic polyenes and heteroaromatic compounds, asymmetric [8 + 2]-, [6 + 4]-, and [10 + 4]-cycloadditions have been realized by our groups. In this century, [6 + 4]-cycloadditions have been found also to occur in enzyme-catalyzed reactions for the biosynthesis of spinosyn A, heronamide, and streptoseomycin natural products. A whole new class of enzymes, the pericyclases that catalyze pericyclic reactions, has been discovered. A remarkable aspect of these recent developments is the cross-disciplinary research involved: from organic synthesis to computational studies integrated with experimental studies of reaction mechanisms, intermediates, and dynamics, to understanding mechanisms of enzyme catalysis and engineering of enzymes. This Account describes how our groups have been involved in the expansion of the higher-order cycloaddition frontiers. We describe both the history and recent progress in higher-order cycloadditions, and how these advances have been made by our collaborative experimental and computational studies. Progress in asymmetric organocatalysis, incorporating enantioselective higher-order cycloadditions in organic synthesis, and the stereoselective synthesis of important scaffolds will be highlighted. Experimental progress and computational modeling with density functional theory (DFT) has identified ambimodal cycloaddition pathways and led to the realization that multiple products of pericyclic reactions are linked by common transition states. Molecular dynamic simulations have provided fundamental understanding of factors controlling periselectivity and have led to discoveries of a group of enzymes, the pericyclases, whic...

Evolution of the Diels–Alder Reaction Mechanism since the 1930s: Woodward, Houk with Woodward, and the Influence of Computational Chemistry on Understanding Cycloadditions

“…On the third visit, Woodward seemed rather impatient with me.T hat date might have been February 4, because Hoffmannsn otebook on "Feb.3eve," 1965 contained an entry (Figure 11 < xfigr11) that Woodward proposed that the reaction of cyclopentadiene and cycloheptatriene should be tried. [49] Woodward told me," Roald Hoffmann and Ih ave atheory of cycloadditions about to be published. We propose that the [6+ +4] cycloaddition should occur.…”

Die Evolution des Diels‐Alder‐Reaktionsmechanismus seit den 1930er Jahren: Woodward, Houk zusammen mit Woodward und der Einfluss der Computerchemie auf das Verständnis von Cycloadditionen

“…Abbildung 12 zeigt ein besonders erfreuliches Beispiel fürd ie komplementäre Mischung von Blau und Grün: Das Gemälde des amerikani- ]-Cycloaddition von Cyclopentadien mit Cycloheptatrien. [49] Dies wurde zu Houks erstem Forschungsprojekt im Doktoratsstudium.…”

“…Februar 1965, wo die Orbitalkorrelationsdiagramme für[4 + +4]-, [6+ +2]-und [6+ +4]-Cycloadditionen erstmals beschriebenw urden. Darunter befindets ich ein Vorschlag von Woodward füreine [6+ +4]-Cycloaddition von Cyclopentadien mit Cycloheptatrien [49]. Dies wurde zu Houks erstem Forschungsprojekt im Doktoratsstudium.…”

Huisgen's 1,3‐Dipolar Cycloadditions to Fulvenes Proceed via Ambimodal [6+4]/[4+2] Transition States

“…Such ambimodal transition states have been found to be quite common for reaction of conjugated dienes, and of trienes with dienes . The reaction in Figure is the first example of an ambimodal transition state involving a Huisgen 1,3‐dipole.…”