Recent Applications of the Diels–Alder Reaction in the Synthesis of Natural Products (2017–2020)

Abstract The Diels–Alder reaction has long been established as an extremely useful procedure in the toolbox of natural product chemists. It tolerates a wide spectrum of building blocks of different complexity and degrees of derivatization, and enables the formation of six-membered rings with well-defined stereochemistry. In recent years, many total syntheses of natural products have been reported that rely, at some point, on the use of a [4+2]-cycloaddition step. Among classic approaches, several modifications of the Diels–Alder reaction, such as hetero-Diels–Alder reactions, dehydro-Diels–Alder reactions and domino-Diels–Alder reactions, have been employed to extend the scope of this process in the synthesis of natural products. Our short review covers applications of the Diels–Alder reaction in natural product syntheses between 2017 and 2020, as well as selected methodologies which are inspired by, or that can be used to access natural products. 1 Introduction 2 Syntheses from 2017 3 Syntheses from 2018 4 Syntheses from 2019 5 Syntheses from 2020 6 Conclusion


Introduction
The Diels-Alder reaction, first observed in 1928 by Otto Diels and Kurt Alder as the [4+2]-cycloaddition between a conjugated diene and a dienophile, 1 has become synonymous with the synthesis of six-membered rings. By follow-ing a concerted pathway, the reaction tolerates a wide variety of substrates and architectures. Furthermore, the reaction affords a high degree of control of both the regio and stereoselectivity. 2,3 Given its high versatility, the Diels-Alder reaction rapidly proved its scope over time, with overall proof lying in the many total synthetic approaches relying on it for the construction of various natural products. While many of these approaches and strategies have been reviewed by different research groups over the years, the continuous development of modern synthetic organic chemistry makes it necessary to provide regular updates of recent advances, not only for research, but also for educational purposes.
While classic Diels-Alder methodologies are represented by the neutral, hetero-and inverse-electron-demand variants, 1,4 more recent approaches include domino-type variations, 5 the retro-Diels-Alder reaction, 6 as well as the dehydro 7 and hexadehydro-Diels-Alder reactions. 8 Furthermore, as highlighted in Xu's 2017 review, 9 the aza-Diels-Alder reaction can, similar to the previously mentioned variants, be successfully employed for the construction of numerous natural products and architectures. In 2018, Yang and Gao reviewed the scope of the Diels-Alder reactions of ortho-quinone methide derivatives with various electrophiles in total syntheses, emphasizing the versatility and broad scope of the protocol. 10,11 Meanwhile, Lacerda et al. described several hetero variants for the synthesis of polycyclic natural products. 12 In this short review, we endeavor to highlight selected Diels-Alder reactions reported in the literature between 2017 and 2020 that provide new strategies and tactics for

Total Synthesis of Lancifodilactone G Acetate
Lancifodilactone G was first isolated in 2005 from the medicinal plant Schisandra lancifolia by Sun and co-workers. 18 This member of the schinortriterpenoid family shows promising medicinal properties, such as anti-HIV, antihepatitic and antitumor. In 2017 Liu et al. published a 28-step total synthesis of the C/D/E ring system of lancifodilactone G. This successful route took advantage of an early stage oxazaborolidine-catalyzed Diels-Alder reaction between the Econfigured ,-unsaturated ester 9 and silyl enol ether 10, the reaction furnishing the C-ring precursor 11 (Scheme 4). 18 Scheme 4 The Diels-Alder step in the total synthesis of lancifodilactone G acetate

Biocatalytic Total Synthesis of Ikarugamycin
The bacterial polycyclic tetramate macrolactam ikarugamycin was first isolated in 1972 by Jomonet et al. from Streptomyces phaeochromogenes and demonstrates remarkable antileukemic and anti-inflammatory properties. The biocatalytic total synthesis of ikarugamycin was described by Greunke et al. (Scheme 5). In this strategy the enzymes IkaB (an oxidoreductase) and IkaC (an alcohol dehydrogenase) guide the stereogenic outcome of a spontaneous intramolecular Diels-Alder reaction starting from precursor 12. 19 Scheme 5 The Diels-Alder key step in the biocatalytic total synthesis of ikarugamycin

Total Synthesis of Xestolactone A
For the total synthesis of natural products bearing tricyclic systems such as isofuranonaphthalenone, nodulones A-C and xestolactones, Baire et al. envisioned the application of a dehydro-Diels-Alder reaction for the construction of the core skeleton 13 (Scheme 6). 20 This reaction, reminiscent of the Bergman cyclization, is believed to generate an allenylic intermediate, which upon a 1,5-hydride shift generates the desired benzene moiety. Besides its application in the synthesis of this natural product, it serves as a new general strategy for the de novo construction of aromatic compounds. Scheme 6 A dehydro-Diels-Alder key step in the total synthesis of xestolactone A Xestolactone A was isolated from the fungus Nodulisporium and was reported to display antimalarial and antitubercular properties. 20

Total Synthesis of Aristolactams
Another example of a dehydro-Diels-Alder reaction successfully used in the total synthesis of a natural product was described by Reddy

Special Topic Synthesis
lochiaceae family and possess several biological properties such as anti-inflammatory, antiplatelet, antimycobacterial, neuroprotective and antitumor activities. 21

Synthesis of Selaginpulvilin D
For the construction of the fluorene framework 21 of selaginpulvilin D, Baire and Chinta successfully employed an intramolecular tetradehydro-Diels-Alder reaction (Scheme 8). Selaginpulvilin D was isolated from S. pulvinata and is reported to have significant phosphodiesterase-4 inhibitory activity. 22

Synthesis of Xanthenes
Since xanthenes are important scaffolds, with applications spanning from the field of medicinal chemistry to their use as dyes and sensors in photovoltaics, novel routes for their preparation are always in demand. Jian et al. were able to synthesize 9-aryl and 9-cinnamyl-substituted xanthenes 24 through Diels-Alder reactions between o-quinone methides 25 and in situ generated arynes 19 (Scheme 9). 23

Total Synthesis of Curcusones I and J
In the racemic total synthesis of curcusones I and J, Li and Dai utilized a stereoselective exo-selective Diels-Alder reaction for the construction of reaction intermediate 26 (Scheme 10). Prior to the [4+2]-cycloaddition, a tandem gold-catalyzed furan formation and furan-allene [4+3]-cycloaddition (27 → 29) were carried out in one step to furnish, after further derivatization, the 5,7-fused, oxa-bridged ring system 30. 24 Qiu et al. isolated the curcusones in 2017 from the roots of Jatropha curcas, with the tricyclic natural products reportedly showing antimalarial, antitumor, neurotrophic, antimicrobial and anti-HIV properties. 25

Total Synthesis of Magellanine
McGee et al. described the construction of the core of magellanine (37), 27 a Lycopodium-type alkaloid isolated from Muylenus mogellanicu, 28 via a gold(I)-catalyzed intramolecular dehydro-Diels-Alder cycloaddition (formation of 38) between the enol ether moiety and the enyne tail of precursor 39 (Scheme 12). Lam et al. proposed the biomimetic synthesis of (±)-verrubenzospirolactone by using a late-stage, exo-selective, intramolecular Diels-Adler reaction between the 2Hchromene moiety and the diene tail of 40 (Scheme 13). 29,30 While this transformation was reported to occur in nature, its origin appears to be non-enzymatic. Through a rather concise total synthesis, Lam et al. applied the Diels-Alder protocol for the construction of the verrubenzospirolactone skeleton, simultaneously achieving the required stereochemistry. The stereogenic outcome of the transformation is reported to be strongly dependent of the configuration of the starting material, which can undergo an in situ thermal isomerization (40 ↔ 41), thus setting the stage for the formation of the required exo-configured transition state. Furthermore, Lam et al. also observed the Pd-induced isomerization of the Diels-Alder precursor (40 → 41), thus resulting in an improved yield of the overall transformation by enabling the required arrangement of the lactone moiety. Verrubenzospirolactone was isolated from the coral species Sinularia verruca and is reported to possess antitumoral, antimicrobial and anti-inflammatory properties. 31

Total Synthesis of Homodimericin A
The first entry to the total synthesis of homodimericin A was reported by Feng et al. who proposed a thermal Diels-Alder reaction step for their approach towards this hexacyclic natural product. This reaction was employed for the construction of the D/E/F-ring system from the complex . Homodimericin A, a secondary metabolite which exhibits antibacterial activity against Streptomyces sp., was isolated from Trichoderma harzianum, a soil fungus from which it is released to combat oxidative stress induced by various species of bacteria. 32 A Diels-Alder reaction was also employed by Huang et al. in their biomimetic total synthesis of homodimericin A. Starting from the same precursor 43 as Feng et al. (Scheme 14), the late-stage transformation proceeded in an intramolecular fashion between the complex benzoquinone and the diene moieties of precursor 43 (Scheme 15) yielding 45 and 46 as the products. 33 In contrast to the previously discussed approach, the protocol followed by Huang led to the formation of the target compound in a lower yield.

Total Synthesis of (-)-Cycloclavine
McCabe and Wipf successfully carried out the enantioselective total synthesis of (-)-cycloclavine in just 8 steps, one of which was an anti-selective, intramolecular, microwave-assisted Diels-Alder reaction (Scheme 16). 34 Interestingly, the ,-unsaturated ketone 47 was converted into its silyl enol ether derivative 48, thus generating in situ a diene motif which reacted in an intramolecular fashion with the exo-methylene to yield the corresponding tricycle 49 in a very elegant and straightforward manner.
The ergot alkaloid cycloclavine, isolated from the seeds of Ipomoea hildebrandtii and from the fungi Aspergillus japonicus, is reported to have insecticidal and antiparasitic activity. 34

Synthesis of Spirooxindoles
A hetero-Diels-Alder reaction has been employed by Jayakumar et al. for the synthesis of spirooxindole frameworks 50 and 51 (Scheme 17), which are prevalent in many naturally occurring compounds such as surugatoxin 1. The asymmetric exo-selective cycloaddition between alkylidene oxindoles 52 or 53 and 2-aza-3-silyloxybutadienes 54 or 55 afforded the desired products in good yields, the processes being catalyzed by complexes of various metal salts possessing a chiral N,N′-dioxide ligand 56. 35

Special Topic Synthesis
Scheme 17 An asymmetric exo-selective Diels-Alder reaction for the construction of spirooxindoles 50 and 51

Total Synthesis of Andranginine
Tooriyama et al. successfully completed the total synthesis of andranginine, a natural product which belongs to the indolomonoterpenic alkaloid family. An intramolecular Diels-Alder reaction and an asymmetric Morita-Baylis-Hillman reaction were employed for the synthesis (Scheme 18). Andranginine was firstly isolated from Craspidospermum verticillatum 36 and is reported to possess various biological properties such as antirheumatic, cholinergic and anti-inflammatory activity. 37 In the context of medicinal chemistry/drug discovery, natural product scaffolds constitute promising starting structures, modulations of which can be investigated to enrich the chemical diversity and enlarge their biological applications. Therefore, the Diels-Alder reaction represents a powerful tool to modify known pharmacologically active natural motifs. The following sections comprise novel protocols for the synthesis of valuable pharmacophores such as indoles 59, piperidones 67, 5/6/4-annulated tricycles 70, and tetrahydroquinolines 76.

Synthesis of Indole-Ring-Bearing Natural Products via a Palladium-Catalyzed Tandem Allylic Isomerization/Furan Diels-Alder Reaction
Among small heterocyclic aromatic systems, substituted indoles 59 are one of the most widespread motifs in both natural products as well as in synthetic pharmaceuticals. Due to their significant biological importance and broad natural prevalence, new and efficient ways for accessing these motifs represent an important challenge. Xu and Wipf managed to exploit and elaborate previous work concerning the construction of indole rings via an intramolecular Diels-Alder cycloaddition to a tethered furan (IMDAF) (60 → 59). Their palladium-catalyzed, microwave-assisted [4+2]-cycloaddition approach allowed not only the use of a wider spectrum of building blocks, but also a higher degree of functionalization of the final skeleton (Scheme 19). 38

Synthesis of Spirocyclic 5/6/4-Ring Systems
Compounds bearing spirocyclic motifs (e.g., 70 and 71) represent interesting targets in natural product synthesis as well as in medicinal chemistry. Therefore, novel methodologies allowing their rapid and efficient assembly are beneficial. Llona-Minguez et al. proposed a rapid and efficient route for assembling highly complex systems bearing a spiro-cyclobutane moiety 71 via a multicomponent aza-Diels-Alder reaction between in situ formed heterocyclic imines (72 + 73 → 74) and cyclopentadiene (75), the products of the reaction being subsequently dihydroxylated (71 → 70) (Scheme 21). 40

Synthesis of Tetrahydroquinolines
For the synthesis of optically active tetrahydroquinolines 76, Jarrige et al. envisioned the intramolecular Povarov reaction, or the inverse-electron-demand aza-Diels-Alder reaction of N-arylamines 77 with electron-rich dienophiles such as 4-(E)-propenylphenol derivatives 78. The chiral phosphoric acid catalyzed variant afforded the target compounds in good yields and enantiomeric ratios (Scheme 22). Tetrahydroquinolines are important scaffolds in many natural products and biologically active compounds. 41

Total Synthesis of (+)-Sarcophytin
In 2018, Nannini et al. described the total synthesis of (+)-sarcophytin, a secondary metabolite isolated from Sarcophyton elegans, the architecture of the main core being addressed by an intramolecular Diels-Alder reaction between the enone-and the ester-derived dienoate moieties of precursor 79 (Scheme 23). While the absolute configuration was still debated prior to the total synthesis, the authors were able to show that the title compound can be accessed via a Diels-Alder reaction from the (1S,12S)-configured precursor 80.

Scheme 23
An intramolecular Diels-Alder step in the total synthesis of (+)-sarcophytin The final configuration at position C1 was later installed by epimerization. Furthermore, it was shown that the Diels-Alder reaction strictly required a (Z)-configured ester moiety, in contrast to initial assumptions. 42

Total Synthesis of Azitine
Liu et al. reported the total synthesis of the tetracyclic natural product azitine (from Consolida helleospontica) via a 12-step route, in which a crucial step in the construction of the backbone is represented by a [4+2]-cycloaddition (Scheme 24). By performing an oxidative dearomatization of precursor 81 → 82 (via 83), the stage was set for the intramolecular Diels-Alder reaction to occur between the olefinic tail and the newly formed cyclohexadienone ketal moiety to furnish the tricyclic azitine precursor 82.

Total Synthesis of Maoecrystal P
A key step in the synthesis of the diterpene maoecrystal P described by Su et al. was the assembly of the tricyclic skeleton 84 via an intermolecular Diels-Alder reaction (Scheme 25). Maoecrystal P, isolated from the Chinese medicinal plant Isodon eriocalyx was previously reported to show significant cytotoxic activity. 44

Scheme 25
An intermolecular Diels-Alder reaction in the total synthesis of maoecrystal P

Total Synthesis of (±)-Phomoidride D
The anticancer and cholesterol-lowering fungal secondary metabolite phomoidride D was synthesized by Wood et al. in a highly efficient and stereoselective fashion. One of the key transformations of the approach consisted of a Pb(OAc) 4 -induced late-stage tandem phenolic oxidation/intramolecular Diels-Alder cycloaddition of 97 to give 98/99 (Scheme 28). While the phenolic oxidation (97 → 100) sets Scheme 24 An oxidative dearomatization followed by an intramolecular Diels-Alder reaction furnishes the tricyclic semi-framework of azitine  the stage for the cycloaddition to occur, the stereocenters of the skeleton were installed via a Diels-Alder reaction (100 → 101). 47

Total Synthesis of (±)-Hypocrolide A
Qiao et al. described the total synthesis of (±)-hypocrolide A via a concise 8-step sequence, the crucial transformation being an intramolecular Diels-Alder reaction of intermediate 102 mediated by TsOH (Scheme 29). The botryane hypocrolide A possesses a complex skeleton with the construction of the six stereocenters being the major challenge. Botryanes, secondary metabolites obtained from Botrytis cinerea, belong to the sesquiterpenes and display antibiotic properties. 48

Synthesis of Xanthones by an Intramolecular Diels-Alder Reaction Involving 2-(1,2-Dichlorovinyloxy) Aryldienones
Xanthones represent a widespread motif among naturally occurring benzo-fused heterocycles, their bioactive properties spanning from anticancer and antibacterial to antiviral and antihypertensive activities. Otrubova

Synthesis of Inulavosin
Gong et al. have described the synthesis of the natural product inulavosin, a dimer of thymol derivative 115, from readily available and inexpensive starting materials by using a Ga(OTf) 3 -catalyzed hetero-Diels-Alder reaction (Scheme 32). Starting from thymol derivative 115, orthoquinone methide 116 is formed in situ and subsequently trapped by the initially formed dehydration product 117, thus leading to the formation of the natural product in one effective step. Isolated from the roots of Inula nervosa, inulavosin works as a natural melanogenesis inhibitor, also possessing piscicidal, antibacterial and antifungal properties. 52

Synthesis of a Chromane-Based Library
One of the most common types of reactive intermediates used for the synthesis of natural products are orthoquinone methides. They react readily with nucleophiles and show high electrophilic character, especially when they bear a highly polarized 1-oxabutadiene moiety, e.g., compound 118. Furthermore, their tendency for aromatization makes them a good scaffold for conjugate reactions. Zhang et al.

Synthesis of a Sordarin-Inspired Bicycle
Wu and Dockendorff envisioned the synthesis of a novel sordarin-derived scaffold by reacting acrylonitrile with a highly functionalized cyclopentadiene precursor 127 in a [4+2]-cycloaddition fashion. 54 The desired exo-arranged product 128 was isolated from the racemate 129 only after further conversion of the mixture (Scheme 34). 55 Sordarin was isolated from the fungus Sordaria araneosa and it has been reported to show antifungal, antibacterial and antipathogenic properties. 54

Special Topic Synthesis
dressed structure-activity relationships of sordarin-type inhibitors, which may lead to the identification of antifungal agents with improved properties.

NHC-Catalyzed Synthesis of Pyranyl Carboxylates
Oxygen-bearing heterocycles such as pyran 138 represent important skeletons prevalent in many natural products and bioactive molecules. Many of these compounds are reported to exhibit antiviral, anticonvulsant and anticancer properties. For a novel approach towards the synthesis of pyranyl carboxylates 138, Hu et al. utilized an NHC-mediated formal Diels-Alder reaction between an ,-unsaturated ketone 139 and an allenoate 140 (Scheme 36). Even though N-heterocyclic carbenes 141 have been widely used as organocatalysts in various carbon-carbon bond-forming reactions, their use to study the scope of the synthesis of annulated small heterocycles represents a novel aspect in this field. While this work aims to highlight novel applications of the Diels-Alder reaction for the synthesis of natural products, it is mandatory to summarize novel, generic [4+2]-methodologies as well. 57

Scheme 36
An NHC-catalyzed formal Diels-Alder reaction furnishing pyranyl carboxylates 138, the complex reaction mechanism being partially highlighted in the lower part of the scheme (142 → 144)

Synthesis of Indolines and Carbazoles via a Dual Gold-Catalyzed Tetradehydro-Diels-Alder Reaction
A gold-catalyzed formal tetradehydro-Diels-Alder reaction has been reported by Wang et al. for the purpose of synthesizing various indolines and carbazoles 146 (Scheme 37). By starting from dialkyne-substituted amines 147, the reaction initially proceeds with the formation of an N-heterocycle (148 → 149) via a gold-induced 5-exo-dig cyclization, thus setting the stage for the thermal 6-electrocy-

Special Topic Synthesis
clization, which is described as a formal tetradehydro-Diels-Alder reaction. Contrary to the standard tetradehydro-Diels-Alder reaction, Wang's adaptation proceeds without the requirement of a dilute reaction mixture and the use of radical-trapping agents, thus making it a practical protocol. 58

Scheme 37
A general approach towards the synthesis of indolines and carbazoles 146 via a dual gold-catalyzed tetradehydro-Diels-Alder reaction, with the crucial mechanistic steps highlighted

Asymmetric Synthesis of Tetrahydrocarbazoles
Gu et al. used an inverse-electron-demand Diels-Alder reaction for the synthesis of optically active tetrahydrocarbazoles 150 by starting from electron-deficient 2,3-disubstituted indole dienes 151 and crotonaldehyde (152) as substrates (Scheme 38). The use of chiral secondary amines 153 as organocatalysts resulted in high enantio-and diastereoselectivities. 59 Davison et al. reported the total synthesis of thiopyrancontaining spirooxindole 154, a new alkaloid isolated from the root extracts of Isatis tinctoria var indigotica, a plant used in Chinese folk medicine for the treatment of fever, viral and infectious diseases. For this purpose, the construction of the natural product was achieved via a biomimetic intermolecular thio-Diels-Alder reaction between an in situ generated 2-oxindole-derived sulfenamide (155 → 156) with the diene tail of the 1,2,4-thiadiazole derivative 157 (Scheme 39). This process successfully furnished the targeted spiro-dihydrothiopyran-oxindole-bearing alkaloid. 60

Synthesis of Spiropyrrolidones
The synthesis of spiro-arranged systems has always represented a complex task in synthetic organic chemistry. Huang et al. were able to construct optically active spiropyrrolidones 158 in a highly efficient and selective fashion via a metal-assisted [4+2]-cycloaddition. While the in situ generated chiral copper complex mediates the hetero-Diels-Alder reaction between 2,3-dioxopyrrolidines 159 and Danishefsky's diene 160, it also guides the stereogenic outcome. The process resulted in the successful synthesis of various spiropyrrolidones in good yields and especially high enantioselectivities (Scheme 40). From a medicinal point of view, both synthetic and naturally occurring spiropyrrolidone-bearing compounds have gained interest due to their potent histone deacetylase inhibitory properties, with many members of this family showing promising IC 50 values. 61

Scheme 40
The synthesis of optically active spiropyrrolidones 158 via a copper-catalyzed hetero-Diels-Alder reaction

A Formal Synthesis of (+)-Aplykurodinone-1
Lee and Cho utilized an intramolecular Diels-Alder reaction for the construction of the literature-known Danishefsky's ketone 161, as part of a formal synthesis of (+)-aplykurodinone-1, a terpene natural product with anticancer properties extracted from Syphonato geographica. The tethered 2-pyrone-derivative 162 reacts with the enone tail in an intramolecular fashion. An internal hydrogen bond controlled the stereogenic outcome of this reaction (Scheme 41

Special Topic Synthesis
Scheme 41 An overview of an asymmetric intramolecular Diels-Alder reaction furnishing the Danishefsky ketone 161, a known intermediate in the total synthesis of (+)-aplykurodinone-1

Diastereoselective Synthesis of Novel Spiro-Indanone-Fused Pyrano[3,2-c]chromenes
Chiral indane moieties are widely distributed among pharmacologically active natural products. In recent years, oxindole-fused pyranochromenes have shown significant biological properties such as molluscicide, anticancer and anthelmintic activities. As a result of the combination of these two natural bioactive scaffolds, spiro-indanone-fused pyrano[3,2-c]chromene derivatives 164 became interesting targets from a medicinal point of view, and were found to possess moderate to high levels of anticancer activities in in vitro studies. Therefore, Panda et al. have established a new and concise route toward their preparation via an oxa-hetero-Diels-Alder reaction (Scheme 42). 63 By using variously substituted chromenes 165 as dienes and ninhydrin (166) as a dienophile, the authors were able to furnish the target skeleton through a Diels-Alder reaction in a highly efficient and partly diastereoselective fashion. In terms of stereocontrol, the preparation of optically pure derivatives was only possible by employing arylated chromene derivatives. The presence of a phenyl group in the proximity of the oxygen atom controlled the diastereoselectivity of the process and provided the endo-isomer as the major product. 63

Total Synthesis of (-)-Artemisinin
Krieger et al. were able to successfully synthesize the unnatural enantiomer of the antimalarial drug artemisinin. 64 For the construction of the decalin system an intramolecular Diels-Alder reaction of 167 was successfully carried out. The process yielded a mixture of three diastereomers, 168, 169 and 170, two of which were jointly converted further (Scheme 43). Through their successful synthesis of the (-)-enantiomer, the authors were able to demonstrate that the binding of the antimalarial drug artemisinin was not specific, thus elucidating a crucial aspect regarding the mode of action of this terpene. 64

Syntheses from 2019 4.1 A General Biomimetic Synthesis of the Skeletons of Xenovulene A and Sterhirsutins A and B
For the synthesis of the skeletons of xenovulene A and sterhirsutins A and B, Li et al. utilized an inverse-electrondemand hetero-Diels-Alder reaction to assemble the 3,4dihydropyran moiety. This biomimetic key step proceeds in a regio-and stereoselective manner. The cycloaddition between -humulene (171) and ribose-derived vinyl ketone 172 (Scheme 44) yielded both endo-and exo-products 173. Their separation, followed by further derivatization, provided the desired skeletons of the two naturally occurring meroterpenes. Xenovulene A and sterhirsutins A

Scheme 43
The Diels-Alder step in the total synthesis of (-)-artemisinin. Two of the generated diastereomers are further converted to give the target compound.

Diversified Cycloisomerization of 1,6-Enynes
Zheng et al. reported an elaborate, diversified sequence involving a metal-catalyzed cycloisomerization followed by an asymmetric, Lewis acid promoted [4+2]-cyclization of 1,6-enynes 175. By following a metal-assisted path, the in situ generated highly reactive dienes 176, 177 and 178 were subsequently trapped with various electron-deficient dienophiles (179 and 180) to furnish the desired Diels-Alder products 181, 182 and 183 (Scheme 45). To probe the scope of the newly established protocol, nearly fifty optically pure compounds were successfully prepared in high yields and enantioselectivities, the approach thus not only pushing the methodological frontiers of the Diels-Alder re-action, but also establishing a highly selective and convenient route for accessing complex natural product architectures. 66

Special Topic Synthesis
Scheme 46 An intramolecular Diels-Alder reaction furnishes the A/B/C/D-tetracyclic core 187 in the total synthesis of (-)-daphenylline

Biosynthesis of Ilicicolin H
Zhang et al. have described the role of the pericyclase enzyme IccD in the biosynthesis of ilicicolin H. Through an inverse-electron-demand Diels-Alder reaction, the decalin core 194 of the natural product is furnished through a flavoenzyme IccE mediated epimerization (Scheme 48). 69 Ilicicolin H is a fungal product isolated from Gliocadium roseum. 70

Special Topic Synthesis
Alder reaction to occur. Subsequent to the [4+2]-cycloaddition, a retro-Diels-Alder reaction takes place to furnish the desired alkaloids 196 and 197. 71

Synthesis of Fused Bi-and Tricyclic Heterocycles through Cycloisomerization and Tandem Diels-Alder Reactions
Zhou et al. proposed a rhodium-catalyzed cycloisomerization of 1,6-allenenes 205, followed by a tandem endo-selective Diels-Alder reaction for the synthesis of fused biand tricyclic nitrogen-bearing heterocycles 206 and 207 (Scheme 50). After the transition-metal-catalyzed process initiates the cascade, the exclusive regio-and diastereoselective Diels-Alder reaction can occur between the in situ generated exocyclic 1,3-diene and N-phenylmaleimide (208) to furnish the desired cyclic compounds. The process proceeds in good yields and affords a variety of heterocycles. 72 Scheme 50 A Diels-Alder reaction leads to the formation of fused bi-and tricyclic heterocycles 206 and 207 after a metal-mediated cycloisomerization of 1,6-allenenes 205

Stereoselective Synthesis of Dihydrochromenochromenes
Ukis and Schneider have reported the synthesis of optically active substituted dihydrochromenochromenes 209 and 210 via an intramolecular Diels-Alder reaction between the in situ generated ortho-quinone methide moiety of the precursors 211 and 212 and the dienophile tail. The process is mediated by BINOL-derived chiral phosphoric acids (Scheme 51). By varying the geometry of the double bond, the authors were able to prepare both endo-(cis)-and exo-(trans)-cycloaddition products in good yields and high diastereo-and enantioselectivities. Chromanes are widely distributed in Nature and are widespread biological motifs in drugs displaying anti-inflammatory, cytotoxic and antiviral effects. 73

Biosynthesis of the Tropolonic Sesquiterpenes Neosetophomone B and Euppenifeldin
Chen et al. described an enzymatic intermolecular hetero-Diels-Alder reaction as part of the biosynthesis of the meroterpenoid anticancer agents neosetophomone B and euppenifeldin (Scheme 52). The enzyme EupfF, of fungal origin, acts as a Diels-Alderase. The enzymatic Diels-Alder reaction occurs between the tropolonic ortho-quinone methide species 213 (originating from stipitaldehyde 214) and the -humulene-isomer 215 to afford neosetophomone

Special Topic Synthesis
B in a highly chemoselective fashion. To access euppenifeldin, the authors reported that a second Diels-Alder reaction take places between neosetophomone B and an additional tropolonic ortho-quinone methide unit, 213. 74 Kiamehr et al. described the synthesis of tetracyclic dihydroquinolinones 230 via a Knoevenagel/hetero-Diels-Alder reaction cascade. This scaffold could ideally serve as a template for medicinal chemistry libraries. By using pyrazolones 231 and anthranilic aldehydes 232, this one-pot synthesis results in the formation of the target architectures 230 in good diastereo and regioselectivities (Scheme 56). The reaction is catalyzed by ZnBr 2 and exclusively yielded the endo(cis)-configured products 230. 79

A One-Pot, Three-Component Synthesis of Tetrahydroquinolines
Wang et al. reported the synthesis of complex tetrahydroquinolines 241 (242 and 243) through a solvent-free (ball-milling method), one-pot Diels-Alder reaction catalyzed by phosphotungstic acid (Scheme 58). This protocol consists of a three-component reaction in which functionalized anilines 244, benzaldehydes 245 and styrenes 246 react to furnish the desired scaffolds. Furthermore, by using para-or meta-dibenzaldehydes as reactants, the corresponding dimeric tetrahydroquinolines 242 and 243 can be accessed in good yields. Tetrahydroquinolines are widely found in natural products and are important pharmacophores bearing various properties, such as excellent antithrombotic efficacies in rabbit thrombosis models. 81 Scheme 58 A one-pot, solvent-free synthesis of complex tetrahydroquinolines 241 (242 and 243) through a Diels-Alder reaction Kamakura et al. proposed the total synthesis of the C 19diterpenoid alkaloid talatisamine in 33 steps by utilizing an intramolecular Diels-Alder reaction as the key protocol for the generation of the two central rings (247 and 248) (Scheme 59), which further rearranged to yield the B/C ring system. Talatisamine, isolated from Aconitum species, shows a wide range of biological activity as an analgesic, anti-inflammatory, antipyretic, antiepileptic and hypotensive agent. Furthermore, talatisamine serves as a potent antiarrhythmic due to its selective inhibition of K + channels. 82

The Asymmetric Synthesis of Complex Tetrahydrochromeno[4,3-b]quinolines
Gandon et al. utilized a Povarov reaction for the highly enantio-and diastereoselective synthesis of complex and structurally diverse trans,trans-trisubstituted tetrahydrochromeno [4,3-b]quinolines 251. Primary anilines 252 act as azadiene precursors in aza-Diels-Alder reactions catalyzed by bulky chiral phosphoric acids (Scheme 60). By following a sequential path, the [4+2]-cyclization (formation of 253) with a subsequent [H]-shift occurs after an initial Mannich/Friedel-Crafts reaction cascade forming 254. Furthermore, the presence of OH groups at the para-position of the cinnamyl ester 255 and the ortho-position of aniline 256 has proven to be crucial for the stereogenic outcome of the reaction, the two serving as H-bond donors and thus guiding the docking of the chiral phosphoric acid catalyst to the substrate. With a wide array of examples, the authors were able to highlight the versatility and applicability of this process. Tetrahydroquinolines are constituents of many natural products and are biologically important scaffolds in drugs used as ulcerogenic, anticancer, anti-inflammatory and antibacterial agents. 83 Scheme 60 An initial Mannich/Friedel-Crafts reaction cascade sets the stage for a Diels-Alder reaction in the synthesis of trans,trans-trisubstituted tetrahydrochromeno [4,3-b]quinolines 251

Synthesis of Tetrahydrocarbazoles via the in situ Formation of Vinylindoles
In 2020, Noland and Abzhabarov presented a threecomponent reaction for the synthesis of tetrahydrocarbazoles 256. Through the [4+2]-cycloaddition between an in situ generated vinylindole 257 (258 + 259) and N-phenylmaleimides 260 (Scheme 61), the Diels-Alder reaction proceeds in an exclusive endo-fashion, yielding the desired adducts 261. Substituted indole motifs are linked to significant biological activities such as anticancer, antiinflammatory and antimicrobial. 84

Synthesis of Polycyclic Systems by the Dearomatization of Phenols
The Diels-Alder-based dearomatization of phenols was developed by Wang et al. as a strategy for the synthesis of complex, highly decorated polycyclic compounds 262. The process is catalyzed by a bulky BINOL-derived chiral phosphoric acid (Scheme 62). By following a path consisting of a dearomative 1,8-addition of -naphthols 263 to para-quinone methides 264, generated in situ from propargylic alcohols 265, and a subsequent intramolecular dearomative

Special Topic Synthesis
Diels-Alder reaction, the authors were able to prepare a wide array of complex polycycles, thus expanding the applicability of dearomatization strategies as routine protocols. Furthermore, the authors discovered that the addition of a catalytic amount of pyridine improved the enantioselectivity of the overall procedure. 85

Total Synthesis of Tetrodotoxin
Murakami et al. accomplished the total synthesis of tetrodotoxin in which a Diels-Alder reaction was used as a simple, yet highly efficient initial key step (Scheme 64). The coupling of alkyne 271 and siloxydiene 272 resulted in the successful and quantitative formation of the cis-fused bicycle 273 as the sole product. Tetrodotoxin is a pufferfish toxin and is currently being trialed for human use as an analgesic. 87 Scheme 64 A highly convenient Diels-Alder reaction furnishes the tricyclic intermediate 273 in the total synthesis of tetrodotoxin

Total Synthesis of Marinoquinoline A via the Thermal Conversion of an Allenyl Oxazole
Osano et al. synthesized marinoquinoline A via a modified intramolecular Diels-Alder reaction between an in situ generated allene (274 → 275) and the oxazole moiety of precursor 274 (Scheme 65). 88 Subsequent ring opening followed by spontaneous aromatization of precursor 276 results in the formation of the desired 6-azaindole reaction intermediate 277, which undergoes further conversion to furnish the desired pyrroloquinoline-bearing title compound.

Scheme 65
An intramolecular Diels-Alder reaction furnishes the 6azaindole precursor 277 in the synthesis of marinoquinoline A In addition, this Diels-Alder protocol also illustrates the versatility of the oxazole ring in the preparation of other ring systems, such as azaindoles. Marinoquinoline A (isolated from the seaweed bacterium Rapidithrix thailandica by a team at HZI), as well as other 6-azaindoles, possess a range of pharmaceutical properties such as antifungal, antibacterial, cytotoxic and antimalarial activity. 88

Special Topic Synthesis
282 in the presence of magnetically recoverable silica, an initial Knoevenagel reaction occurs to furnish exo-enone 283, thus setting the stage for the [4+2]-heterocycloaddition (Scheme 66). The chromene core is a widespread motif in both natural products and important pharmaceuticals with anthelmintic, anticancer, molluscicide and anti-HIV-1 activities. 89

Total Synthesis of (-)-Canataxpropellane
Gaich et al. successfully completed the total synthesis of (-)-canataxpropellane, a complex taxane diterpene isolated from Taxus canadensis. While the 26 steps linear synthesis comprises a wide array of transformations, the first step of the sequence is represented by an almost endo-exclusive Diels-Alder reaction between the in situ generated isobenzofuran 284 and enone 285 (Scheme 67). This highly effective and selective transformation results in the formation of the tricyclic intermediate 286, which is further converted into the target natural product (-)-canataxpropellane. 90

A Bioinspired Total Synthesis of Brevianamides A and B
Godfrey et al. proposed a concise, bioinspired synthesis of brevianamides A and B in just seven steps, the sequence relying on (+)-dehydrodeoxybrevianamide E as an intermediate and concomitantly a Diels-Alder precursor. After an initial diastereoselective epoxidation of the indole moiety of (+)-dehydrodeoxybrevianamide E (Scheme 68), an intramolecular epoxide opening generated polycyclic intermediates 288 and 289, which were isolated and further converted via a complex cyclization cascade. The cascade, comprised of a retro-5-exo-trig cyclization, led to opening of the previously installed pyrrolidine ring and set the stage for a [1,2]-alkyl shift to occur, the shifted terminal alkene-tail representing the diene for the later Diels-Alder reaction. Tautomerization of the piperazine moiety finally led to the formation of the required dienophile, thus allowing a spontaneous, diastereoselective [4+2]-cycloaddition to take place. Finally, the desired alkaloids, (-)-brevianamide B and (+)-brevianamide A, were successfully isolated as the major reaction products. 91 Brevianamides A and B were first isolated by Birch and Wright in 1969 from the fungus Penicillium brevicompactum, and are reported to show insecticidal properties. 92

Bioinspired Synthesis of (-)-PF-1018
Quintela-Varela et al. have reported the synthesis of the tetramic acid polyketide of fungal origin (-)-PF-1018. In their approach, they envisioned a cascade consisting of a Stille coupling between intermediate 290 and stannane 291, followed by an 8-electrocyclization of 292 (to 293) with a subsequent Diels-Alder reaction (293 → 294) as the key step of the process (Scheme 69). As a result, reaction intermediate 294 was successfully prepared and isolated as the sole product of the cascade. The natural product (-)-PF-