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.     

The Plakotenins: Biomimetic Diels–Alder Reactions,Total Synthesis,Structural Investigations,and Chemical Biology

The total synthesis of plakotenin, a cytotoxic marine natural product, using a biomimetic Diels–Alder reaction is described in detail. Two approaches were used, whereby the Diels–Alder reaction occurs at different stages of the synthesis. Homo‐ and nor‐plakotenin, related natural products, were also prepared, as well as iso‐plakotenin, a diastereoisomer of plakotenin. The syntheses prove the relative and absolute stereochemistry of the latter. The chemical biology of the plakotenins was investigated on selected compounds.     

Total Syntheses of Periconiasins A–E

The first and collective total syntheses of periconiasins A–E, a group of naturally occurring cytochalasans, were achieved by a series of rationally designed or bioinspired transformations. Salient features of the syntheses include a tandem aldol condensation/Grob fragmentation to assemble the linear polyketide–amino acid hybrid precursor, a Diels–Alder macrocylization to construct the 9/6/5 tricyclic core of periconiasins A–C, and a transannular carbonyl–ene reaction to forge the polycyclic framework of periconiasins D and E.     

Bio‐inspired Domino oxa‐Michael/Diels–Alder/oxa‐Michael Dimerization of para‐Quinols

A bio‐inspired, pyrrolidine‐mediated, dimerization of para‐quinols has been developed. It represents one of the most complex, yet general, dimerization reactions ever disclosed, selectively forming four new bonds, four new rings, and eight new contiguous stereogenic centres. The para‐quinol starting materials are easily handled, bench‐stable compounds, accessed in just one step from aromatic feedstocks. The reaction can be scaled up to give grams of polycyclic material, primed for further elaboration.     

A Formal Total Synthesis of Taxol Aided by an Automated Synthesizer

A 36‐step synthesis was carried out in automated synthesizers to provide a synthetic key intermediate of taxol. A key step involved a microwave‐assisted alkylation reaction to construct the ABC ring system from an AC precursor. Subsequent formation of the D ring afforded baccatin III, a well‐known precursor of taxol.     

Cycloadditions in the Total Synthesis of Sporolide B

Closing rings: A recent total synthesis of sporolide B by the Nicolaou group is highlighted by two advantageous cycloadditions. Firstly, a regioselective [2+2+2] cycloaddition of highly elaborate substrates assembles the halogenated aromatic ring and subsequently an ortho‐quinone [4+2] cyclization closes stereoselectively the dioxane‐containing macrocycle. These approaches should be considered in complex target syntheses.

     

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.     

Biomimetic Dopamine‐Diels–Alder Switches

Mussel adhesives function as tools for surface modifications of a wide variety of materials due to their remarkable adhesion properties. Herein, a combination of bioinspired mussel adhesives based on a dopamine derivative, polymer chemistry, and well‐established Diels–Alder (DA) chemistry leads to a bioinspired switchable surface system that possesses the capability of attaching and detaching specific polymers on demand. A dopaminemaleimide compound, which has been attached to a gold surface under maritime conditions undergoes DA‐ and retro‐DA‐click‐conjugations with cyclopentadiene‐carrying PEG chains. The surface attachment and the subsequent DA/rDA cycles are evidenced via XPS analysis.

     

Biomimetic Total Synthesis of Santalin Y

A biomimetic total synthesis of santalin Y, a structurally complex but racemic natural product, is described. The key step is proposed to be a (3+2) cycloaddition of a benzylstyrene to a “vinylogous oxidopyrylium”, which is followed by an intramolecular Friedel–Crafts reaction. This cascade generates the unique oxafenestrane framework of the target molecule and sets its five stereocenters in one operation. Our work provides rapid access to santalin Y and clarifies its biosynthetic relationship with other colorants isolated from red sandalwood.     

Biomimetic Total Synthesis of (±)‐Pallavicinolide A

Piecing it together : The first total synthesis of naturally occurring diterpene pallavicinolide A was achieved. Notable features are highlighted by three key biomimetic transformations: a base‐promoted Grob fragmentation, a singlet oxygen oxidation, and an intramolecular Diels–Alder cycloaddition.

     

Synthesis of Bis(indole) Alkaloids from Arundo donax: The Ynindole Diels–Alder Reaction,Conformational Chirality,and Absolute Stereochemistry

Bis(indole) alkaloids from Arundo donax were synthesized using the first ynindole Diels–Alder reaction. The alkaloids are chiral, having stable enantiomeric conformations with half‐lives of racemization of t_1/2=4150–25100 seconds at room temperature. Their absolute stereochemistry was determined using the exciton chirality method.     

Divergent Biomimetic Total Syntheses of Ganocins A–C,Ganocochlearins C and D,and Cochlearol T

A divergent synthetic approach to six Ganoderma meroterpenoids, namely ganocins A–C, ganocochlearins C and D, and cochlearol T, has been developed for the first time. This synthetic route features a two‐phase strategy which includes early‐stage rapid construction of a common planar tricyclic intermediate followed by highly selective late‐stage transformations into various Ganoderma meroterpenoids. Key to the strategy are a bioinspired intramolecular hetero‐Diels–Alder reaction and Stahl‐type oxidative aromatization, allowing efficient formation of the common tricyclic phenol intermediate. A nucleophilic dearomatization of the phenol unit, combined with a regioselective 1,4‐reduction of the resulting dienone, enabled rapid access to ganocins B and C. Additionally, site‐selective Mukaiyama hydration, followed by an intramolecular oxa‐Michael addition/triflation cascade, served as a key strategic element in the chemical synthesis of ganocin A.     

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.