The Diels–Alder Reaction in Total Synthesis

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.     

Synthesis of Benzo[g]isochromenes through Photo‐Dehydro‐Diels–Alder Reaction

The Photo‐Dehydro‐Diels–Alder (PDDA) reaction is shown to be a versatile method for the preparation of highly functionalized naphthalenes. Thus, ketones 1 could be cyclized to the 1H‐benzo[g]isochromen‐4‐(3H)‐ones 11 and 12 , mostly in good yields. The influence of various substituents on the regioselectivity of the reaction was investigated, and the mechanism is discussed based on theoretical calculations.     

Synthesis and Characterization of a Novel Diels–Alder Adduct of Codeine

The Diels–Alder reaction was applied to 4,5‐epoxymorphinan opioids to generate a novel aromatic cycloadduct at C(7) C(8): Thermolytic cleavage of sultine 8 produced the reactive diene o‐quinodimethane 7 which condensed favorably with codeine ( 11 ), but not with codeinone ( 9 ) or 14‐hydroxycodeinone ( 10 ), producing the desired tetrahydronaphtho adduct 12 with (7R,8R) geometry (Scheme). The configuration of the cycloadduct was determined by 1D‐ and 2D‐NMR experiments. The unanticipated reactivity of these codeine derivatives was investigated by quantum‐mechanical calculations, and it was determined that steric effects of the 6‐keto and 14‐hydroxy group likely precluded condensation by raising the molecular energy of their respective transition states.     

Fourfold Diels–Alder Reaction of Tetraethynylsilane

A series of ethynylated silanes, including tetraethynylsilane, was treated with tetraphenylcyclopentadienone at 300 °C under microwave irradiation to give the aromatized Diels–Alder adducts as sterically encumbered mini‐dendrimers with up to 20 benzene rings. The sterically most congested adducts display red‐shifted emission through intramolecular π–π interactions in the excited state.     

Liquid‐Crystalline Ionic Liquids as Ordered Reaction Media for the Diels–Alder Reaction

Liquid‐crystalline ionic liquids (LCILs) are ordered materials that have untapped potential to be used as reaction media for synthetic chemistry. This paper investigates the potential for the ordered structures of LCILs to influence the stereochemical outcome of the Diels–Alder reaction between cyclopentadiene and methyl acrylate. The ratio of endo‐ to exo‐product from this reaction was monitored for a range of ionic liquids (ILs) and LCILs. Comparison of the endo:exo ratios in these reactions as a function of cation, anion and liquid crystallinity of the reaction media, allowed for the effects of liquid crystallinity to be distinguished from anion effects or cation alkyl chain length effects. These data strongly suggest that the proportion of exo‐product increases as the reaction media is changed from an isotropic IL to a LCIL. A detailed molecular dynamics (MD) study suggests that this effect is related to different hydrogen bonding interactions between the reaction media and the exo‐ and endo‐transition states in solvents with layered, smectic ordering compared to those that are isotropic.     

Bioinspired Intramolecular Diels–Alder Reaction: A Rapid Access to the Highly‐Strained Cyclopropane‐Fused Polycyclic Skeleton

A bioinsipred gold‐catalyzed tandem Diels–Alder/Diels–Alder reaction of an enynal and a 1,3‐diene, forming the highly‐strained benzotricyclo[3.2.1.0^2,7]octane skeleton, was reported. In contrast, a Diels–Alder/Friedel–Crafts tandem reaction occurred instead when silver salts were used as the catalyst. Although both reactions experienced the similar Diels–Alder reaction of a pyrylium intermediate with a 1,3‐diene, they have different reaction mechanisms. The former proceeded with a stepwise Diels–Alder reaction, while the latter one with a concerted one.     

Industrial Applications of the Diels–Alder Reaction

The Diels–Alder reaction is one of the most popular transformations for organic chemists to generate molecular complexity efficiently. Surprisingly, little is known about its industrial application for the synthesis of pharmacologically active ingredients, agrochemicals, and flavors and fragrances. This Review highlights selected examples, with a focus on large‐scale applications (>1 kg) from a process research and development perspective.     

Intramolecular Hetero‐Diels–Alder Reactions Catalyzed by BiCl3: Stereoselective Synthesis of Benzo‐Annelated Decahydrofuro[3,2‐h][1,6]naphthyridine Derivatives

A novel, efficient synthesis of a series of functionalized, benzo‐annelated decahydrofuro[3,2‐h][1,6]naphthyridine derivatives 3 has been achieved. The protocol is based on the intramolecular hetero‐Diels–Alder (IMHDA) reaction of in situ formed imines derived from an N‐prenylated sugar aldehyde 1 and different aromatic amines 2 in the presence of bismuth(III) chloride as catalyst. The reactions could be run under very mild conditions at room temperature, and were complete within 30 min, affording exclusively and stereoselectively the corresponding trans‐fused products 3 in good‐to‐excellent yields (Table).     

Reactivity and Selectivity of Captodative Olefins as Dienes in Hetero‐Diels–Alder Reactions

The reactivity and selectivity of the the captodative olefins 1‐acylvinyl benzoates 1a – 1f and 3a as heterodienes in hetero‐Diels–Alder reactions in the presence of electron‐rich dienophiles is described. Heterodienes 1 undergo regioselective cycloaddition with the alkyl vinyl etherdienophiles 6a , b and 9 to give the corresponding dihydro‐2H‐pyrans 7, 8 , and 10 under thermal conditions. The reactivity of these cycloadditions depends, to a large extent, on the electronic demand of the substituent in the aroyloxy group of the heterodiene. Frontier‐molecular‐orbital (FMO; ab initio) and density‐functional‐theory (DFT) calculations of the ground and transition states account for the reactivity and regioselectivity observed in these processes.     

Quinones as Dienophiles in the Diels–Alder Reaction: History and Applications in Total Synthesis

In the canon of reactions available to the organic chemist engaged in total synthesis, the Diels–Alder reaction is among the most powerful and well understood. Its ability to rapidly generate molecular complexity through the simultaneous formation of two carbon? carbon bonds is almost unrivalled, and this is reflected in the great number of reported applications of this reaction. Historically, the use of quinones as dienophiles is highly significant, being the very first example investigated by Diels and Alder. Herein, we review the application of the Diels–Alder reaction of quinones in the total synthesis of natural products. The highlighted examples span some 60 years from the landmark syntheses of morphine (1952) and reserpine (1956) by Gates and Woodward, respectively, through to the present day examples, such as the tetracyclines.     

exo‐Selective Asymmetric Diels–Alder Reaction Catalyzed by Diamine Salts as Organocatalysts

An organocatalyst formed from a binaphthyl‐substituted diamine and trifluoromethanesulfonic acid exhibited unprecedented levels of exo selectivity in the Diels–Alder reaction of α,β‐unsaturated aldehydes with cyclopentadiene. A novel axially chiral diamine was also designed as an organocatalyst for an asymmetric variant of this reaction, in which the desired cycloadducts were formed with high diastereo‐ and enantioselectivities. The highest diastereoselectivity observed was greater than 20:1 in favor of the exo cycloadduct in the asymmetric Diels–Alder reaction of crotonaldehyde with cyclopentadiene.     

Cascade Olefin Isomerization/Intramolecular Diels–Alder Reaction Catalyzed by N‐Heterocyclic Carbenes

The addition of an N‐heterocyclic carbene to the carbonyl group of an α,β,γ,δ‐unsaturated enol ester affords a hemiacetal azolium intermediate that enables a cascade olefin isomerization/Diels–Alder reaction, for which mechanistic studies implicate Lewis base catalysis. Preliminary studies into the utility of the products have been undertaken with reductive and oxidative cleavage, giving materials for potential use in complex‐target synthesis.     

Regio‐ and Stereochemical Studies on the Nitroso‐Diels–Alder Reaction with 1,2‐Disubstituted Dienes

The regioselectivity of the nitroso‐Diels–Alder reaction between unsymmetrical acyclic dienes and Boc‐nitroso (Boc=tert‐butoxycarbonyl) reagent or the Wightman chiral chloronitroso reagents has been studied. With the Boc‐nitroso reagent, the selectivity is a consequence of steric effects at the C1‐position in the diene and electronic effects at the C2‐position in the diene. The combination of an unprotected hydroxyethyl side chain at C1 and an electron‐withdrawing group at C2 allows complete regioselectivity in favour of the proximal isomer. The same isomer was obtained exclusively with the chiral nitroso reagent with high enantioselectivities. A model based on steric effects is proposed.     

Diels–Alder Cycloaddition Reactions in Sustainable Media

Diels–Alder cycloaddition reaction is one of the most powerful strategies for the construction of six-membered carbocyclic and heterocyclic systems, in most cases with high regio- and stereoselectivity. In this review, an insight into the most relevant advances on sustainable Diels–Alder reactions since 2010 is provided. Various environmentally benign solvent systems are discussed, namely bio-based derived solvents (such as glycerol and gluconic acid), polyethylene glycol, deep eutectic solvents, supercritical carbon dioxide, water and water-based aqueous systems. Issues such as method’s scope, efficiency, selectivity and reaction mechanism, as well as sustainability, advantages and limitations of these reaction media, are addressed.