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 following 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 the total synthesis of natural products. Furthermore, novel synthesis-relevant methodologies are also selected and presented herein.

Syntheses from 2017

Total Synthesis of Paeoveitol

Paeoveitol can be isolated as a mixture of enantiomers from the root of Paeonia veitchii [11] and demonstrates immunomodulation and anti-inflammatory properties.[13] For the total synthesis of both enantiomers of paeoveitol, Li et al. envisioned the construction of the annulated 6/5/6/6-skeleton through a hetero-Diels–Alder reaction. This strategy generates two ring systems and three stereocenters in one single step. In the key step, the two reagents 1 and 2 are used to establish both paeoveitol enantiomers by simply varying the chirality of the phosphoric acid catalysts 3 and 4 (Scheme [1]).[14]

Total Synthesis of Hispidanin A

The asymmetric dimeric diterpenoids hispidanins A–D were isolated from the rhizome of Isodon hispidia in 2010 and show significant cytotoxicity against various tumor cell lines.[15] Deng et al. synthesized hispidanin A by following a six-step sequence. The intermolecular Diels–Alder reaction furnishes the spiro six-membered ring by joining totarane (5) and labdadienolide (6) (a naturally occurring compound) in the endgame of the synthesis (Scheme [2]). The fact that this transformation occurs at room temperature suggests that a Diels–Alder reaction could also be involved in the biosynthetic pathway of this natural product.[16]

Another entry to the hispidanin family was described by Li et al. who envisioned a bioinspired total synthesis of hispidanine A. The target molecule was furnished via an intermolecular Diels–Alder reaction between diterpenoid 8 (a totarane-derived precursor) and labdadienolide (6) (a natural product isolated from Isodon yuennanensis). The reaction can be either assisted by an erbium catalyst or promoted through exposure to elevated temperatures (Scheme [3]). While elevated temperatures have been noted to facilitate the transformation, the catalyst plays only a marginal role in the mediation of the process. Its sole purpose lied in scavenging electrons and thus preventing the undesired polymerization of the starting material.[17]

In contrast to the synthesis proposed by Deng et al. (Scheme [2]), the approach employed by Li et al. (Scheme [3]) required harsher conditions. This observation suggests that the presence of the keto group in intermediate 5 could facilitate the formation of the Diels–Alder cycloaddition product and leads to an improved yield.

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 E-configured α,β-unsaturated ester 9 and silyl enol ether 10, the reaction furnishing the C-ring precursor 11 (Scheme [4]).[18]

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]

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.

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 et al. The total synthesis of various aristolactam alkaloids 16 was achieved via ruthenium-catalyzed C–H bond activation (17 → 18), followed by a [4+2]-cycloaddition (Scheme [7]). This method provided a facile access to the aristolactam skeleton by utilizing readily available starting materials (18 and 19). Lactam-containing aristolactams are extracted from plants belonging to the Aristolochiaceae 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]

Synthesis of Dihydroisocoumarins

Dihydroisocoumarins 31 exhibit various biological properties such as antitumor, antioxidant, antimicrobial and anti-inflammatory activities. Zhang et al. proposed the synthesis of chiral dihydroisocoumarins through an inverse-electron-demand hetero-Diels–Alder cycloaddition between ortho-quinone methides (32 → 33) and azlactones 34 in the presence of chiral phosphoric acid catalysts (Scheme [11]).[26]

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]).

Biomimetic Synthesis of (±)-Verrubenzospirolactone

Lam et al. proposed the biomimetic synthesis of (±)-verrubenzospirolactone by using a late-stage, exo-selective, intramolecular Diels–Adler reaction between the 2H-chromene 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 intermediate 43 (Scheme [14]). 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 α,β-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]

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]

Phosphoric Acid Catalyzed Piperidone Synthesis

Weilbeer et al. presented an enantioselective, phosphoric acid catalyzed synthesis of 4-alkyl-substituted 2-piperidones 67 through a formal aza-Diels–Alder reaction between imines 68 and β-alkyl-substituted vinylketene silyl acetal 69 (Scheme [20]). In this approach the desired heterocycle is constructed via an in situ generated Mannich intermediate, which undergoes a [4+2]-cyclization and desilylation to give the final product.[39]

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]

Syntheses From 2018

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.

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.[43]

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]

The Divergent Total Synthesis of (–)-Enmein, (–)-Isodocarpin and (–)-Sculponin R

Pan et al. have described a divergent total synthesis of the enmein-type Isodon natural products (–)-enmein, (–)-isodocarpin, and (–)-sculponin R through a common, early-stage Diels–Alder reaction between maleic anhydride derivative 87 and Danishefsky-type dienes 88 and 89 (Scheme [26]). Through the published route, the authors were able to access the target compounds via the common key intermediate 90.[45]

Synthesis of Jerantinine C

Jiang et al. established a versatile route to oxygenated aspidospermine alkaloids, including vinblastine and vindoline, as well as jerantinines A–C by starting with the [4+2]-cycloaddition of 3-ethyl-5-bromo-2-pyrone 94 and the chiral enecarbamate 95 (Scheme [27]). The performed intermolecular inverse-electron-demand Diels–Alder reaction afforded a bicyclic reaction intermediate 96, which further yielded jerantinine C. Isolated from Tabernaemontana corymbosa, jerantinine C was found to show significant cytotoxic activity.[46]

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 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 et al. described the synthesis of the new xanthone 105, wherein both the pyrone and the second aromatic ring were forged in a single step by an intramolecular cycloaddition reaction. This sequence involved 2-(1,2-dichlorovinyloxy) aryldienones 106 (Scheme [30]), generated in situ from 2-(1,2-dichlorovinyloxy) arylketones 107 and crotonaldehydes 108.[49]

Total Synthesis of (±)-4-Methylenegermine

The total synthesis of (±)-4-methylenegermine was reported through a remarkable and highly stereoselective Diels–Alder cycloaddition (Scheme [31]).[50] [51] By way of a bis-(3-tert-butyl-4-hydroxy-5-methylphenyl)sulfide mediated transformation, which acts as a radical inhibitor, the coupling between precursor 112 and the pyridine-derived enone 113 was successfully carried out. The reaction leads to the selective formation of four stereocenters with high exo/endo- and facial-selectivities.[51]

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, ortho-quinone 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 ortho-quinone 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. exploited o-quinone methides for the construction of a wide range of chromanes (119, 120 and 121). Using an N,N′-dioxide/Sc(III) complex catalyzed inverse-electron-demand­ oxa-Diels–Alder reaction between fulvenes 122, 123 and 124 and o-quinone methides (formed in situ from 118, 125 and 127), they successfully synthesized a wide variety of optically active chromanes (Scheme [33]). Zhang et al. performed the reactions with good yields and enantioselectivities at low temperatures using a slight excess of the chiral ligand.[53]

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] The synthetic strategy proposed by Wu and Dockendorff facilitated the exploration of unaddressed structure–activity relationships of sordarin-type inhibitors, which may lead to the identification of antifungal agents with improved properties.

Synthesis of Indolines via a Diels–Alder Reaction Cascade

Indolines 132 and α-pyrones 133 represent prominent motifs both in natural products and in bioactive derivatives thereof. Shen et al. showed that through a [4+2]-cycloaddition, in situ generated α-pyrones (134 → 133) can readily undergo further Diels–Alder reactions, with a cascade of transformations resulting in the formation of highly decorated indolines 132 (Scheme [35]). After initially preparing α-pyrone-amines 133 from propiolic acids 135, the authors were able to extend the methodology further. By inserting a second alkyne residue in the starting material 136, the stage for a cyclization cascade was set. The formed pyrone intermediate therefore undergoes an intramolecular cyclization (133 → 137) in a [4+2] fashion, finally giving the desired heterocycles.[56]

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 α,β-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]

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 6π-electrocyclization, 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]

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]

Total Synthesis of an Alkaloid Derived from Isatis indigotica

Davison et al. reported the total synthesis of thiopyran-containing 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 IC₅₀ values.[61]

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]).[62]

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

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-electron-demand hetero-Diels–Alder reaction to assemble the 3,4-dihydropyran moiety. This biomimetic key step proceeds in a regio- and stereoselective manner. The cycloaddition between α-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 and B have been isolated from Acremonium strictum and Stereum hirsutum­, respectively.[65]

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 reaction, but also establishing a highly selective and convenient route for accessing complex natural product architectures.[66]

Total Synthesis of (–)-Daphenylline

Xu et al. have described a 19-step total synthesis of (–)-daphenylline, the construction of the A/B/C/D-tetracyclic core being achieved via an intramolecular Diels–Alder reaction (Scheme [46]). The transformation conveniently yielded the desired intermediate 187 in good yield and with exclusive endo-selectivity. (–)-Daphenylline is isolated from the genus Daphniphyllum longeracemosum and is reported to possess promising medicinal properties such as modulation of nerve growth factors, vasorelaxation, anticancer and antioxidant.[67]

Synthesis of Dihydropyrans and Octalins via Chiral Azide Cyclization

Thirupathi et al. exploited the reactivity of vinyl azides 189 and 190 for the preparation of 3,4-dihydropyrans 191 and octalins 192 via an asymmetric Cu(II)-catalyzed Diels–Alder reaction. By tuning the substitution pattern of azides 189 and 190 and by using various unsaturated keto esters 193, the copper/BOX-assisted cyclization can proceed in two different manners. While azides 189 led to the formation of dihydropyrans 191 via a [4+2] inverse-electron-demand­ hetero-Diels–Alder pathway, azides 190 yield the substituted octalins 192 through a normal [4+2] Diels–­Alder reaction (Scheme [47]). Both these skeletons are recurrent motifs in (bioactive) natural products and pharmaceuticals.[68]

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]

Synthesis of Indolone Alkaloids via C–H Activation/Diels–Alder/Retro-Diels–Alder Domino Alkyne Annulation

For the preparation of annulated indolone alkaloids 196 and 197, Zhu et al. used a complex domino sequence consisting of a transition-metal-mediated C–H activation and both Diels–Alder and retro-Diels–Alder reactions. In the first step of the sequence (Scheme [49]), the coupling between functionalized pyrido-pyridones 198 and 199 and propargylic carbonates 200 and 201 was mediated by the presence of a non-toxic Mn(I) catalyst. The reaction proceeds via the formation of highly reactive allene species 202, thus setting the stage for an intramolecular Diels–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 bi- and 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]

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 α-humulene-isomer 215 to afford neosetophomone 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]

Synthesis of trans-Clerodanes via an exo-Selective­ Diels–Alder Reaction

Wåhlander et al. reported the total synthesis of the trans-clerodane skeleton, as an illustration of the versatility of the EtAlCl₂-mediated exo-selective intermolecular [4+2]-cycloaddition. The Diels–Alder reaction between N-tigloylis­oxazolidinone 218 and O-silylated 2-vinylcyclohex-2-enol 219 led to the formation of the required octalin skeleton 220 (Scheme [53]). This key transformation, as part of a four-step sequence, provides an epimeric mixture of the exo-adducts.[75]

Formal Synthesis of Mycoleptodiscin A

In 2013 Cubilla-Rios et al. isolated mycoleptodiscin A, an alkaloid belonging to the indolo sesquiterpenoid family from the endophytic fungus Mycoleptodiscus sp.[76a] This class of natural products shows significant biological importance for anticancer and antimalarial research.[76a] The first total synthesis of mycoleptodiscin A was published in 2015,[76b] while later, in 2019, Xue et al. reported a formal synthesis of the natural product by starting from (+)-sclareolide and utilizing a Ti(IV)-promoted photoenolization with subsequent intramolecular cyclization as the key step (Scheme [54]).[77] While the photoenolization of 221 (→ 222 → 223) sets the stage for the Diels–Alder reaction, the cyclo­addition step proceeds in a highly diastereoselective fashion, yielding 224 as the sole product. Further derivatization finally results in the formation of 225, the intermediate used by Zhou et al. in the total synthesis of mycoleptodiscin A.[76b]

Synthesis of Tetrahydroisoindolinones

Xu et al. have described a dehydro-Diels–Alder reaction under metal-free conditions for the synthesis of tetrahydroisoindolinones 227. Thus, optically active and highly decorated tetrahydroisoindolinones were accessed via an exclusive endo-selective [4+2]-cycloaddition between prenyl derivatives 228 and N-substituted maleimides 229. The use of DDQ enabled the reaction by the in situ generation of the required dienes (Scheme [55]). This new one-pot protocol not only features excellent functional group tolerance and high degrees of derivatization of the reactants, but also provides an efficient access to biologically active tetra­hydroisoindolinones in good to excellent yields.[78]

Synthesis of Tetrahydropyrazolo[4′,3′:5,6] pyrano[3,4-c]quinolones

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 ZnBr₂ and exclusively yielded the endo(cis)-configured products 230.[79]

Towards Lycorine Alkaloids: Synthesis of 8-Hydroxyphenanthridines

Gulbrandsen et al. achieved the synthesis of 8-hydroxyphenanthridines 235, 236 and 237 by exploiting a highly efficient microwave-assisted intramolecular Diels–Alder reaction on furans (IMDAF) protocol. By conveniently reacting N-alkyl-ortho-furylanilines 238, 239 and 240 in the presence of catalytic amounts of hydrochloric acid (Scheme [57]), the formation of the annulated 5/6/6/6-ring system is achieved in one step via an endo-selective [4+2]-cycloaddition followed by a cycloreversion.[80]

Syntheses from 2020

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]

Total Synthesis of Talatisamine

Kamakura et al. proposed the total synthesis of the C₁₉-diterpenoid 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]

Synthesis of Tetrahydrocarbazoles via the in situ Formation of Vinylindoles

In 2020, Noland and Abzhabarov presented a three-component 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, anti-inflammatory 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 β-naphthols 263 to para-quinone methides 264, generated in situ from propargylic alcohols 265, and a subsequent intramolecular dearomative 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]

Enantioselective Synthesis of Chiral [2,3]-Fused Indolines

Fused indoline motifs form parts of many indole-bearing alkaloid natural products. Zhao et al. synthesized chiral [2,3]-fused indolines 267 by using a dearomatizing inverse-electron-demand Diels–Alder reaction between highly substituted indoles 268 and 2-(2-nitrovinyl)-1,4-benzoquinone (269), the process being mediated by a chiral bisoxazoline/zinc catalyst complex (Scheme [63]).[86]

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]

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.

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]

A Solvent-Free, Silica-Catalyzed Synthesis of Divergent Chromenones

Suri et al. envisioned the synthesis of divergent chromenones 279 via a three-component, solvent-free, one-pot approach consisting of a Knoevenagel/hetero-Diels–Alder reaction cascade. By reacting 1,3-cycloalkanediones 280 with benzaldehyde derivatives 281 and terminal alkynes/alkenes 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 8π-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-1018 was isolated from the fungal strain Humicola sp. 1018 in a screen against Plutella xylostella, the diamond back moth, which accounts for massive agricultural losses worldwide.[93]

Conclusion

The Diels–Alder reaction is one of the most pivotal transformations in natural products syntheses. Despite its innumerable applications, there are still new developments and refinements which simplify access to natural products and ultimately pave the way for using natural products in medical applications. Even over the short period covered by this short review (2017–2020), the large number of published syntheses relying at some point on a Diels–Alder reaction proves its modern-time relevance and value. While classic approaches remain of high relevance, modern adaptations extend the substrate scope significantly.

Furthermore, even if the focus of this work lies in highlighting the impact of modern Diels–Alder methodologies in natural product syntheses, the numerous examples presented also attest to the importance of the Diels–Alder reaction for biomimetic syntheses, metal-assisted catalysis and asymmetric synthesis.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors are grateful to Mr. D. Lübken for his kind suggestions and corrections.

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Corresponding Authors

Publication History

Received: 28 April 2021

Accepted after revision: 21 June 2021

Accepted Manuscript online:
21 June 2021

Article published online:
04 August 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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