Pyrone Diels–Alder Routes to Indolines and Hydroindolines: Syntheses of Gracilamine,Mesembrine, and Δ7‐Mesembrenone

Although the Diels–Alder reaction has long been utilized for the preparation of numerous heterocycles, opportunities to extend its power remain. Herein, we detail a simple, modular, and robust approach that combines various amines regioselectively with 4,6‐dichloropyrone to create substrates which, under appropriate conditions, can directly deliver varied indolines and hydroindolines through [4+2] cycloadditions with substitution patterns difficult to access otherwise. As an initial demonstration of the power of the strategy, several different natural products have been obtained either formally or by direct total synthesis, with efforts toward one of these—the complex amaryllidaceae alkaloid gracilamine—affording the shortest route to date in terms of linear step count.     

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.     

Enantioselective and Regioselective Pyrone Diels–Alder Reactions of Vinyl Sulfones: Total Synthesis of (+)‐Cavicularin

The total synthesis of (+)‐cavicularin is described. The synthesis features an enantio‐ and regioselective pyrone Diels–Alder reaction of a vinyl sulfone to construct the cyclophane architecture of the natural product. The Diels–Alder substrate was prepared by a regioselective one‐pot three‐component Suzuki reaction of a non‐symmetric dibromoarene.     

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.     

Diels–Alder/Oxidative Aromatization Approach towards the All‐Carbon DEF Tricyclic Skeleton of Daphenylline

Daphenylline is a recently isolated Daphniphyllum alkaloid with an unprecedented novel hexacyclic scaffold. In this study, the synthesis of the fused all‐carbon DEF tricyclic skeleton of daphenylline has been accomplished. Key steps of the reported sequence involve Evans asymmetric allylation, aldol condensation, Diels–Alder reaction, and oxidative aromatization reactions. The developed strategy might lead to the total synthesis of daphenylline.     

Diels–Alder and Retro‐Diels–Alder Cycloadditions of (1,2,3,4,5‐Pentamethyl)cyclopentadiene to La@C2v‐C82: Regioselectivity and Product Stability

One of the most important reactions in fullerene chemistry is the Diels–Alder (DA) reaction. In two previous experimental studies, the DA cycloaddition reactions of cyclopentadiene (Cp) and 1,2,3,4,5‐pentamethylcyclopentadiene (Cp*) with La@C_2v‐C₈₂ were investigated. The attack of Cp was proposed to occur on bond 19 , whereas that of Cp* was confirmed by X‐ray analysis to be over bond o . Moreover, the stabilities of the Cp and Cp* adducts were found to be significantly different, that is, the decomposition of La@C_2v‐C₈₂Cp was one order of magnitude faster than that of La@C_2v‐C₈₂Cp*. Herein, we computationally analyze these DA cycloadditions with two main goals: First, to compute the thermodynamics and kinetics of the cycloadditions of Cp and Cp* to different bonds of La@C_2v‐C₈₂ to assess and compare the regioselectivity of these two reactions. Second, to understand the origin of the different thermal stabilities of the La@C₈₂Cp and La@C₈₂Cp* adducts. Our results show that the regioselectivity of the two DA cycloadditions is the same, with preferred attack on bond o . This result corrects the previous assumption of the regioselectivity of the Cp attack that was made based only on the shape of the La@C₈₂ singly occupied molecular orbital. In addition, we show that the higher stability of the La@C₈₂Cp* adduct is not due to the electronic effects of the methyl groups on the Cp ring, as previously suggested, but to higher long‐range dispersion interactions in the Cp* case, which enhance the stabilization of the reactant complex, transition state, and products with respect to the separated reactants. This stabilization for the La@C₈₂Cp* case decreases the Gibbs reaction energy, thus allowing competition between the direct and retro reactions and making dissociation more difficult.     

Synthesis,Biosynthesis, and Biological Activity of Diels–Alder Adducts from Morus Genus: An Update

The plants of the Moraceae family are producers of a great variety of polyphenolic natural products. Among these, the Diels–Alder type adducts (DAAs) are endowed with a unique cyclohexene scaffold, since they are biosynthesized from [4+2] cycloaddition of different polyphenolic precursors such as chalcones and dehydroprenyl polyphenols. To date, more than 150 DAAs have been isolated and characterized from Moraceous and related plants. The main source of DAAs is the mulberry root bark, also known as “Sang-Bai-Pi” in Traditional Chinese Medicine, but they have also been isolated from root bark, stem barks, roots, stems or twigs, leaves, and callus cultures of Moraceous and other related plants. Since 1980, many biological activities of DAAs have been identified, including anti-HIV, antimicrobial, anti-inflammatory, and anticancer ones. For these reasons, natural DAAs have been intensively investigated, and a lot of efforts have been made to study their biosynthesis and to establish practical synthetic access. In this review, we summarized all the updated knowledge on biosynthesis, chemoenzymatic synthesis, racemic and enantioselective total synthesis, and biological activity of natural DAAs from Moraceous and related plants.     

Enantioselective Nitroso‐Diels–Alder Reaction and Its Application for the Synthesis of (−)‐Peracetylated Conduramine A‐1

Cu^I‐catalyzed enantioselective nitroso‐Diels–Alder reactions (NDA reactions) of 2‐nitrosopyridine with various dienes are presented. The [CuPF₆(MeCN)₄]/Walphos‐CF₃ catalyst system is best suited to catalyze the NDA reaction of various dienes by using 2‐nitrosopyridine as a dienophile. In most of the cases studied, cycloadducts are obtained in quantitative yield with very good to excellent enantioselectivities. Based on DFT calculations, a model to explain the stereochemical outcome of the NDA reaction is presented. Finally, an efficient short synthesis of (?)‐peracetylated conduramine A‐1 by applying the enantioselective NDA reaction as a key step is described.     

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.

     

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.     

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.     

Chiral Dawson‐Type Hybrid Polyoxometalate Catalyzes Enantioselective Diels–Alder Reactions

Can achiral organocatalysts linked to chiral polyanionic metal oxide clusters provide good selectivity in enantioselective C?C bond formations? The answer to this question is investigated by developing a new active hybrid polyoxometalate‐based catalyst for asymmetric Diels–Alder reaction. Chirality transfer from the chiral anionic polyoxometalate to the covalently linked achiral imidazolidinone allows Diels–Alder cycloaddition products to be obtained with good yields and high enantioselectivities when using cyclopentadiene and acrylaldehydes as partners.     

Syntheses with organoboranes. IX. Vinyl- and 1-alkenyldichloroboranes as ethylene and 1-alkene equivalents for the Diels–Alder reaction

Vinyl- and 1-alkenyldichloroboranes were used as dienophiles for the Diels–Alder reaction with representative aliphatic and cyclic 1,3-dienes. The organoborane adducts were transformed into the corresponding olefins either by protonolysis or by oxidation–mesylation–reduction. Direct protonolysis of the adducts gave in most cases mixtures of olefins whereas the reduction of mesylates with lithium triethylborohydride produced pure olefins in good yields.     

Multicomponent Double Diels–Alder/Nazarov Tandem Cyclization of Symmetric Cross‐Conjugated Diynones to Generate [6‐5‐6] Tricyclic Products

The construction of complex polycyclic terpenoid products in an efficient and step‐economical manner using multicomponent and tandem processes is highly valuable. Herein, we report a tandem cyclization sequence that initiates with a multicomponent double Diels–Alder reaction of cross‐conjugated diynones, followed by a Nazarov cyclization to efficiently produce [6‐5‐6] tricyclic products with excellent regio‐ and diastereoselectivity. This methodology generates five new carbon–carbon bonds, three rings, quaternary or vicinal quaternary carbons, and stereogenic centers in a one‐pot reaction.