Recent applications of intramolecular Diels–Alder reaction in total synthesis of natural products

Abstract

Diels–Alder (D–A) reaction is undoubtedly the most powerful [4 + 2] cycloaddition reaction in organic synthesis. It has been always considered as a model and a symbol of cycloaddition reactions. Intramolecular D–A reactions (IMDA) are also well recognized and can be employed in one or more steps for the total synthesis of several natural products. In this report, we wish to highlight the recent applications of IMDA as a key step in the total synthesis of biologically active natural products, including alkaloids and terpenes.

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Majid M. Heravi

Majid M. Heravi was born in 1952 in Mashhad, Iran. He received his B.Sc. degree from the National University of Iran in 1975 and his M.Sc. and Ph.D. degrees from Salford University, England, in 1977 and 1980. He completed his doctoral thesis under the supervision of the late Jim Clarck at Salford University. He started his career as a research fellow in Daroupakksh (a pharmaceutical company) in 1981 Tehran, Iran and joined as an assistant professor in Ferdowsi University of Mashhad Iran. In 1999 he moved to Alzahra University Tehran, Iran as professor of chemistry, where he is still working. He has previously been a visiting professor at UC Riverside, California, USA and Hamburg University, Hamburg, Germany. His research interests focus on heterocyclic chemistry, catalysis and organic methodology.

Vaezeh Fathi Vavsari

Vaezeh Fathi Vavsari was born in 1983 in Sari, Iran. She received her B.Sc. degree in Applied Chemistry from Ferdowsi University of Mashhad, Iran (2009) and her MSc. degree in Organic Chemistry at Khaje Nasir Toosi University of Technology, Tehran, Iran (2013) under the supervision of Dr. Saeed Balalaie. She is currently working towards her PhD. in Organic chemistry at Alzahra University under the supervision of Dr. Ghodsi Mohammadi Ziarani. Her research field is organic synthesis by the use of amino acids in the presence of nanostructure silica as catalysts.

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1. Introduction

The thermal 1,4-cycloaddition of a double/triple bond to a conjugated diene is recognized as the Diels–Alder (D–A) reaction.^1–3 Commonly, Diels–Alder adducts are employed to create synthons, which often have exceptional advantages with respect to their use in the synthesis of complex targets.^4–6 Intramolecular D–A reactions (IMDA) are also well-established as versatile and useful reactions and have found several applications in synthetic organic chemistry.^7–13 Significantly, the D–A reaction can be conducted in an asymmetric fashion (ADA reaction) with high stereo-selectivity due to D–A is believed to be a concerted reaction.^14–21 These ADA reactions are very appealing and valuable, since they can generate four chiral centers in the desired product, simultaneously. Notably, ADA reactions can also be employed in intramolecular fashion (AIMDA reaction); such reactions often proceed with high enantio- and diastereoselectivities.^22–24 Due to the usefulness and the exceptionally powerful nature of the IMDA reaction, it is anticipated as a widely-accepted and versatile approach, being employed in one or more steps of the total synthesis of some important naturally occurring products, especially those bearing bridged polycyclic moieties.^25–27 In fact, due to the high degree of chemo-, regio- and diastereo-selectivity attained from this reaction,^28–30 it is still the strategy of choice when the construction of a ring with a high level of stereo-selectivity is required. Thus, this reaction has attracted much attention from organic synthetic chemists and is documented nearly every day, judging by the mounting number of citations of associated articles in the chemical literature. The AIMDA reaction has also been a common reaction in the laboratories where asymmetric synthesis prevails. It is still stirring up the interest of asymmetric organic chemists, particularly those who are chiefly engaged with the total synthesis of naturally occurring products, especially those exhibiting various biological potencies.

This theme has always been highly fascinating and thus has been reviewed comprehensively and broadly in recent years^31–33 This report covers virtually all relevant endeavors and accomplishments on the applications of the D–A reaction as a key step in the total synthesis of a wide variety of natural products. The D–A reaction is employed, often as a key step, especially when high stereo-selectivity along with ring formation is required as a part of the total synthesis of natural products.

The role of IMDA in the total synthesis of naturally occurring products has been previously reviewed.^11,34–36 Due to our interest in the applications of named reactions in organic synthesis,^37–41 the total synthesis of natural products^42–47 and asymmetric synthesis,^48,49 we wish to underscore the recent and current applications of the IMDA reaction as a key step in the total synthesis of biologically active natural products, particularly alkaloids and terpenes. This includes a number of recently achieved total syntheses of some important biologically and pharmacologically active natural products that were much desired. It should be mentioned that the minutiae of all the steps of the total syntheses of selected targets are out of the scope of this review and are not discussed in detail, basically due to space limitations. However, they are obtainable from the primary sources provided in this report in the Reference section. Nevertheless, where the stereo-chemical outcomes of the total synthesis are particularly important, and especially when the enantio-selective D–A reaction is required, a systematic and precise description is given.

2. Terpenoids

Terpenoids form one of the most important and widespread classes of natural products in the plant kingdom and have several uses in human fitness, health and sustenance. Their molecular diversity has resulted in the finding of more than 40 000 different structures in numerous classes; many of these compounds have been established as important pharmaceutical agents and aids, such as the well-known and well-established anticancer agent paclitaxel (Taxol) 1 (Fig. 1) and terpenoid-derived indole alkaloids. Notably, a majority of terpenoids can be isolated only in low yields from natural sources. To circumvent this drawback, plant cell cultures have been modified as an alternative production tactic. Metabolic engineering and modification of whole plants and plant cell cultures is an efficient and successful strategy. It enhances the terpenoid yield and modifies the terpenoid structures to achieve desired properties such as increased flavor, enhanced fragrance and intensified color. Current advances in essential terpenoid metabolic routes, especially in the secondary metabolism, have increased knowledge regarding the direction of terpenoid build up. Applications of promising plant systems biology approaches have also enabled metabolic modifications in terpenoid assembly.⁵⁰

Fig. 1 The structure of Taxol as a diterpene.

Terpenoids constitute the most abundant natural products in the plant kingdom and are rich resources for drug innovations. Current endeavors into the research, improvement and development of anti-cancer drugs derived from natural products have resulted in the identification of various terpenoids that inhibit cancer cell propagation and metastasis via different mechanisms.⁵¹

2.1. Sesquiterpenoids

2.1.1. Total synthesis of ent-ledol. Ledol 2 is a toxic sesquiterpenoid isolated from (Ledum palustre), marsh rosemary, which is a scented evergreen bush originating in peaty soils in northern Europe, Asia and North America. It shows expectorant and antitussive potency.^52,53 Rhododendron tomentosum L. plants were usually collected at the flowering stage. The essential oils were prepared via hydrodistillation of air-dried aerial parts in a Clevenger-type apparatus in accordance with the European Pharmacopoeia. ent-Ledol was obtained from this extract as a greyish-yellow, oily mass with a distinctive flavor and aroma. Quantitative analysis of this essential oil was achieved using GC and GC-Mass.⁵⁴

Kündig and co-workers reported the total synthesis of ent-ledo 3 by manipulating the asymmetric IMDA reaction of triene 4 (Scheme 1). Initially, a Ru catalyst, (S,S)-5 was employed to catalyze the reaction between 2,6-lutidine and triene 4 in CH₂Cl₂ to obtain a yellow-orange solution. After further stirring at ambient temperature (r.t.) under a N₂ atmosphere, the solution was evaporated to give a crude solid, which gave pure (S)-6 after flash column chromatography. The latter was then transformed into the desired ent-ledol, 3, in several steps.⁵⁵ Similar Ru catalysis was previously employed in IMDA reactions of enals with various dienes.^56,57

Scheme 1 Total synthesis of ent-ledol.

2.1.2. Total synthesis of khusiol. The sesquiterpenoid natural product, 11-O-debenzoyltashironin, and the corresponding benzoate ester, tashironin, were isolated from the pericarps of the eastern Asian plant Illicium merrillianum. The pericarps of I. merrillianum were dried, powdered and then extracted with MeOH at ambient temperature to afford a pale yellow crude liquid. Upon column chromatography on silica gel, seven fractions (A–G) were obtained. 11-O-Debenzoyltashironin 7 was then isolated from fraction B and characterized by NMR and HRMS.⁵⁸ Sharma and co-workers attempted the total synthesis of khusiol 9. They started from a chemoenzymatic approach to achieve a tricyclic carbon framework of 11-O-benzoyltashironin, producing compounds 7 and 8. Using this method, they presented the first enantio-selective total synthesis of the sesquiterpenoid, khusiol 9.⁵⁹ An effective and versatile approach to the synthesis of 1,2-cyclopentannulated and 1,2-cyclopentannulated bicyclo[2.2.2]octanes, albeit in enantiomeric form, was reported by Australian researchers. The key elements were based on the initial transformation of the enzymatically-derived and enantiomerically pure cis-1,2-hydrocatechol, 10, into the alkene-tethered systems, 12 and then 13. The latter was then subjected to IMDA reactions by heating in mesitylene in the presence of butylated hydroxytoluene as a free radical chain inhibitor to give the adduct 14 in reasonable yield.⁶⁰ Notably, this reaction was improved by the Banwell group for the total synthesis of sesquiterpenoid khusiol 9, which is illustrated in Scheme 2.⁵⁹

Scheme 2 Total synthesis of Khusiol.

2.1.3. Synthesis of (−)-presilphiperfolan-1-ol and (−)-9-epi-presilphiperfolan-1-ol. (−)-epi-Presilphiperfolan-1-ol 15, a triquinane sesquiterpene, was initially isolated from the essential oil of Anemia tomentosa var. anthriscifolia. The leaves of Anemia tomentosa are specifically utilized as a remedy for bronchitis in Brazil, as a traditional medicine. Anemia tomentosa var. anthriscifolia leaves are also habitually used as a digestive abettor, expectorant, and flu remedy in Argentina. In order to characterize the structure of 15, the essential oils of A. tomentosa var. anthriscifolia were separated using silica–gel column chromatography to obtain initially 18 fractions. From these fractions, compound 15 was obtained. The structural information was obtained using far-reaching 1D- and 2D-NMR analyses, as well as using GC-MS, chiral bidimensional GC, dehydration reactions, and a comparative (GIAO/DFT) theoretical study of the ¹³C NMR chemical shifts of 15 with those of its well-known isomers (presilphiperfolan-1-ol 16).^61,62 Hong and Stoltz and co-workers reported the novel asymmetric total synthesis of the (−)-epi-presilphiperfolan-1-ol, 15. Their synthetic approach commenced with simultaneous acylation/alkylation of commercially available 3-isobutoxycycloheptenone, 17, utilizing methyl iodide and isoprenol-derived carbamate, 18. After several reaction steps, the resultant gem-dimethyl acylcyclopentene, 19, was transformed into the respective silyl dienol ether, 22, followed by IMDA bicyclization, which progressed efficiently and smoothly to provide a mixture of diastereomers, 23 and 24. After chromatographic separation, having pure α-hydroxyketone, 23, available, the latter was subjected to Wittig methylenation and several other transformations, including PtO₂-catalyzed hydrogenation and desilylation using TBAF, to give 15 and 16 (Scheme 3).⁶³

Scheme 3

2.1.4. Synthesis of 3,5,5,7-sesquiterpenoids echinopine A and B. 3,5,5,7-Sesquiterpenoids echinopine A and B (25 and 26), were initially isolated from the root of Echinops spinosus. The roots of E. spinosus were initially dried, chopped into small pieces and then extracted with MeOH. The extract was subjected to silica gel normal phase column chromatography (CC) and RP-HPLC to provide compounds 25 and 26.⁶⁴ Its total synthesis was reported by Peixoto and co-workers.⁶⁵ Alkenyl aldehyde, 28, was initially prepared from alkyne 27 via its conjugate addition to acrolein with subsequent partial hydrogenation employing a Lindlar catalyst. Compound 28 was subjected to the Hosomi–Sakurai reaction, providing alcohol 30 in a 75% yield albeit as an inseparable diastereomeric mixture in favor of the syn isomer (syn/anti ca. 3 : 1). After several steps, compound 30 was converted to compound 31. The planned cycloisomerization/IMDA occurred efficiently and cleanly to afford diene enoate, 32, as the sole noticeable component in the crude reaction mixture. This in situ created intermediate was subjected subsequently to IMDA under prolonged heating (160 °C), to afford the [5,6,7] tricycle, 33, with a 75% overall yield from 32. An endo transition state, which can be electronically stabilized via secondary orbital interactions, was occupied during the IMDA process. More importantly, the configuration of the TBS ether (C10) had no appreciable effect on the competence and selectivity of either the cycloisomerization or the Diels–Alder reaction. Subsequently, compound 34 was synthesized from 33 in several steps manipulating functional group transformations (Scheme 4).⁶⁵ Spectroscopic data of tricycle 34 were compared to that reported previously⁶⁶ and was found to be identical. Therefore, the pathway was established as a formal synthesis of echinopine A (25) and B (26).

Scheme 4

2.2. Diterpenoids

2.2.1. Total synthesis of (−)-scabronines A and G, and (−)-episcabronine A. (−)-Scabronines G (35) and A (36) (Fig. 2) are two well-known members of the diterpenoid family. They were initially isolated from the bitter mushroom, Sarcodon scabrosus. The fruit part of S. scabrosus can be extracted with MeOH. After several fractionations, the fraction obtained by chloroform–MeOH elution was purified via reverse-phase HPLC on ODS. Finally elution using MeOH–H₂O (7 : 3) provided scabronine A (36) as a colorless amorphous solid. Scabronine G (35) was purified in the same way as scabronine A.⁶⁷ These compounds were traditionally used for the treatment of Alzheimer's, Parkinson's, and Huntington's disease symptoms.^68,69 The first total synthesis of (−)-episcabronine A (37) involves a highly stereoselective cascade. The total synthesis starts from the salicyl aldehyde derivative, 38. Initially, the latter was transformed into the terminal alkyne phosphate, 39, followed by treatment with isopropylmagnesium chloride. Removal of the TIPS group provided a chiral allene, 40. Treatment of the latter with phenyliodine(III) diacetate (PIDA) gave an o-benzoquinone mono-dimethylacetal, 41. Next an intramolecular Inverse-Electron-Demand Diels–Alder (IEDDA) reaction made progress sluggishly at ambient temperature and notably required seven days for completion, to afford 41 as the sole product in 95% ee. Subsequently, the latter was used in the synthesis of compound 42, which is the key intermediate for the total synthesis of (−)-scabronines, G (35) and A (36), and (−)-episcabronine A (37) (Scheme 5). Significantly, the total synthesis of (−)-scabronine G (35) presents a highly stereoselective oxidative dearomatization/IEDDA reaction cascade, as the first ever reported total synthesis of (−)-scabronine A (36), presenting a highly stereoselective oxa-Michael/protonation/acetalization cascade. The first reported total synthesis of (−)-episcabronine A (37) comprises yet another highly stereoselective cascade.⁷⁰

Fig. 2 (−)-Scabronine A and G are extracted from Sarcodon scabrosus.

Scheme 5

2.2.2. Synthesis of (±)-atisine and (±)-isoazitine. The plant, Aconitum heterophyllum (Atis), was found in the Himalayan Mountains at high altitudes. Interestingly, the root of this plant has been used as a traditional native Indian medicine against fevers and malaria for a long time. It has been known for a long time that the aforementioned root contains, atisine (44), which belongs in the category of simpler aconite alkaloids. A finely-powdered batch of heterophyllum roots was initially extracted exhaustively using common organic solvents such as ethanol. The extract was subjected to repeated fractional column chromatography. One of the fractions contained bulk alkaloids chiefly consisting of atisine (44).^71–75 Atisine (44) and isoazitine (45) (Scheme 6) are both atisine-type C₂₀-diterpenoid alkaloids, bearing a pentacyclic scaffold, characteristic of azabicyclo[3.3.1]nonane and bicyclo[2.2.2]octane moieties. The assembly of azabicyclo[3.3.1]nonane and bicyclo[2.2.2]octane ring systems has been the chief challenge and the main endeavor in several laboratories. Liu and his research group utilized a cascade of oxidative dearomatization/IMDA cycloaddition to achieve the construction of the bicyclo[2.2.2]octane ring system for the total synthesis of the diterpenoid alkaloids, 44 and 45. In this line, 48 was treated with a Wittig reagent, 46, and subjected to olefination to provide the E-isomer of styrene, 49. In the following reaction scheme, 50 is synthesized via a series of chemical transformations involving functional group conversion. The latter, after oxidation of the phenolic hydroxyl group, was subjected to an oxidative dearomatization/IMDA cascade reaction. When xylene was used as a solvent, the obtained masked ortho-quinone was submitted to thermal activation (150 °C) to furnish 51, which is a pentacyclic compound, as a single isomer in good yield. The endo form of 51 was established and confirmed by NOESY (due to the vital correlation between H-14 and H-20) and single crystal X-ray diffraction of the product. The same strategy has been used for the assemblage of (±)-isoazitine, 45, in 22 steps (Scheme 6).⁷⁶

Scheme 6

2.2.3. Synthesis of maoecrystal V core. Recently Maoecrystal V 53, a terpenoid with selective cytotoxic activities and novel architectural moieties was isolated and its structure was revealed. It was initially isolated from the traditional, medicinally used Chinese herb, Isodon eriocalyx, (Fig. 3) grown in the Jiangchuan prefecture of Yunnan province. Leaves of I. eriocalyx (Dunn.) were collected in China, on September 10, 1994, for the first time. After meticulous extraction using methanol, the extract was fractionally column chromatographed on silica to give several fractions. Further column chromatography gave the purest natural product, which was first identified by Prof. H. W. Li. Dried.⁷⁷ Nicolaou and co-workers initially approached the pentacyclic scaffold of this target. They envisaged that the target could be constructed from a bicyclic precursor via an IMDA of intermediate 56, which can introduce two additional rings simultaneously, with subsequent intramolecular cyclopropanation/dearomatization/ring opening cascades to create the final target, 58 (Scheme 7).⁷⁸ Dong and his group applied Nicolaou's pathway for the synthesis of highly functionalized tetracyclic lactones, 63 and 64 (Scheme 8).⁷⁹ In another work, an effective and stereo-selective pathway was employed for the synthesis of the tricyclic core structure of maoecrystal V from a simple aromatic precursor. A tandem oxidative dearomatization of suitably appended o-hydroxymethylphenol 65 under IMDA conditions afforded a tricyclic adduct, bearing a bridged bicyclo[2.2.2]octanone scaffold, 67, annulated with the lactone ring. Manipulation of the oxirane ring and the double bond provided the desired intermediate, 68 (Scheme 9).⁸⁰ Later, Peng and Danishefsky designed a sequence including the IMDA reaction of a less poly-functionalized and symmetrical precursor. Their pathway to providing the IMDA precursor, 74, started from typical vinylogous acylation, from substrates 69 and 70, which led to intermediate 71, bearing one of the requisite quaternary carbon centers. The latter was then transformed to the target IMDA substrate, 74, after several steps. On this occasion, compound 74 was easily subjected to thermal IMDA cyclization in fair yield to create the expected cycloadduct, 75, which then afforded maoecrystal V core, 76 (Scheme 10).⁸¹

Scheme 7

Scheme 8

Scheme 9

Fig. 3 Isodon eriocalyx⁸² and Maoecrystal V.

Scheme 10

2.2.4. Total synthesis of caribenol A. Caribenol A (77) was initially isolated from the West Indian Gorgonian Octocoral, Pseudopterogorgia elisabethae. It is a member of a family of new norditerpenes with important biological properties. In a research project focused on finding novel anticancer drugs, two P. elisabethae chemotypes collected from Colombia were studied. From these species, a myriad of structurally diverse terpenoids were isolated. They showed many interesting structural features as well as exhibiting biological activities. The extracts were subjected to size exclusion chromatography with subsequent flash column chromatography and normal-phase HPLC to obtain caribenols A and B.⁸³ The first total synthesis of caribenol A (77) was performed and revealed in 2010.⁸⁴ The research group have completed their work by conducting the asymmetric construction of the [5-7-6] tricyclic core of caribenol A (77) via the IMDA reaction as the key step in their approach.⁸⁵ Due to their reactivity and selectivity, proven for IMDA reactions, they are often highly substrate-dependent, especially when 1,3-butadienes are used as the substrates. The reaction was started by testing the IMDA reaction of 79, which could be easily synthesized via the reaction sequence illustrated in Scheme 11. The desired and planned IMDA product could be constructed in the presence of a catalytic amount of 2,6-di-tert-butyl-4-methylphenol (BHT), resulting in the generation of 80 in excellent yield. In the following reaction, the D–A product, 80, was transformed into the caribenol, A (77), in several steps, manipulating different functional group transformations.^84,85

Scheme 11

2.2.5. Total synthesis of vinigrol. Vinigrol 81 was initially isolated from Virgaria nigra, a fungus, as an antihypertensive and platelet aggregation-inhibiting substance. For isolation, fermentation broth was initially filtered and the mycelium was extracted by discontinuous mixing. The solvent extract was concentrated under reduced pressure. After adjusting to pH 7.0, the active component was extracted with EtOAc (3 liters). The concentrated extract was subjected to silica gel column chromatography. For further purification, the separated vinigrol was crystallized from a mixture of EtOAc/n-heptane.^86,87 After optimization of the oxidative dearomatization reaction, starting from compound 82, Yang and co-worker were pleased with the high yields of the IMDA cycloadduct, 83 (Scheme 12). In the following reaction, the latter was coupled via the Heck cyclization cascade, giving the carbocyclic core of vinigrol in just two steps from a simple and common precursor. The synthesis includes a number of distinguished conversions such as: (a) a straight hydrogenation in very complex surroundings, (b) selenium-dioxide-mediated deprotection along with olefin isomerization, (c) Wharton fragmentation, and eventually (d) exceptional tactical applications and deprotection of a trifluoroethyl ether.⁸⁸

Scheme 12

2.2.6. Synthesis of salvinorin A core. Neo-clerodane diterpenes, such as salvinorin A (Fig. 4), show fascinating biological activities.⁸⁹ Salvinorin A (85) is the first isolated and identified diterpene hallucinogen, isolated from Salvia divinorum (Labiatae). For isolation, dried leaves of Salvia divinorum, which was collected from Mexico, were extracted with chloroform. The extract, as a green residue, was separated into thirteen fractions by chromatography. The sixth and seventh fractions were found to have salvinorin A as ascertained by TLC. Further purification was achieved by crystallization from methanol, affording salvinorin A (85) as colorless crystals.⁹⁰ A relatively short pathway, starting from 3-furaldehyde, 86, reaching to a bicyclic frame work for the synthesis of 90, was developed via applying a highly diastereoselective acrylate IMDA cycloaddition as the crucial step. An initial attempt involving a conjugate methylation of a dienyl lactone was unsuccessful. However, a streamlined sequence employing an all-surrounding IMDA reaction of an even sterically overcrowded 1,3-diene, 89, was found to be fruitful. For this purpose, 89 was heated under pressure at 180 °C in a sealed tube in the presence of small amounts of BHT to provide a 61% yield of cycloadducts. In this reaction, the diastereomer, 90, was found to be the major product. The relative configurations of four possible diastereomers were characterized by NOESY experiments (Scheme 13).⁹¹

Fig. 4 The structure of Salvinorin A is extracted from Salvia divinorum.

Scheme 13

2.2.7. Total synthesis of taxanes. Taxanes form a large family of terpenes comprising over 350 members, the most famous of which is Taxol (paclitaxel), a billion-dollar anticancer drug. The extract from Taxus brevifolia bark powder, was silica gel chromatographed to provide a hydrocarbon fraction. This fraction, containing a very complex mixture of sesquiterpene and diterpene hydrocarbons, was then purified by column chromatography to give an oily material. Further passage through silica gel with subsequent reversed-phase column chromatography gave taxadiene, 91, in a relatively pure form.⁹² Mendoza and co-workers reported the first practical and operational, scalable synthetic procedure towards these natural products through the succinct synthesis of (1)-taxa-4(5),11(12)-dien-2-one, 91. The latter has a suitable functional handle, being convertible to more oxidized members of its family. An enantio-selective approach to the taxane family of natural products, interestingly, was achieved in as few as seven steps, commencing from a commercially purchasable common starting material, 92, in 18–20% overall yield. Compound 94 was treated with BF₃·OEt₂ to afford a tricyclic compound, (+)-95. The desired diketone, 95, was provided in reasonable yield, along with its diastereomer, albeit in low yield, but with complete diastereo-selectivity. Now, only one more carbon remained to be assembled to complete the taxane scaffold: this was accomplished via enol triflate generation, followed by Negishi coupling to give taxadienone, 96, in high yield over two steps, which can then transform to taxadiene, 91. To this end, a three-step deoxygenation sequence was performed in reasonable yield (Scheme 14). This pathway provides a gram-scale synthesis of the ‘parent’ taxane, taxadiene, which is, delightfully, the largest amount of this natural terpene ever either isolated or synthesized in fairly pure form. The characteristic 6-8-6 tricyclic system of the taxane family, bearing a bridgehead alkene, is produced via a vicinal difunctionalization D–A strategy. Asymmetry is induced via an enantio-selective conjugate addition, which generates a full-carbon quaternary stereogenic center, in a way which all other stereocentres were remained intact via full substrate control. This study lays an important foundation for an intended access to partially oxidized taxane analogues and a bench scale laboratory synthesis of Taxol itself.⁹³

Scheme 14

2.3. Meroterpenoids

2.3.1. Synthesis of (−)-isoglaziovianol. The cordiachromes, an abnormal class of meroterpenoids, can be formed and found either as the quinone or quinol form. Most of them bear a cis-fused decalin motif with one noticeable exclusion: that is glaziovianol, 97, which is the only member of the family recognized to date that carries a transfused decalin. The aforementioned natural product was initially isolated from the trunk Heartwood of Auxemma glazioviana, a tree endemic to the north east of Brazil. Dried and powdered Heartwood was initially thoroughly extracted with EtOH at ambient temperature. Repetitive chromatography on silica gel afforded glaziovianol, 97.⁹⁴ Isoglaziovianol (98) synthesis was started by Tsuji–Trost asymmetric alkylation^95,96 of para-methoxybenzyl alcohol, 99, with the easily prepared racemic vinyl epoxide, 100. The provided tertiary allylic ether was initially transformed to the respective quinone, 102 in high regio- and enantio-selectivity (85% isolated yield and 93% ee), via several steps. It is worthwhile to mention that the latter is inaccessible, since it is simultaneously and rapidly subjected to an intramolecular vinyl quinone D–A (VQDA) reaction at ambient temperature. This most probably happens through generation of the endo transition state, with subsequent nucleophilic trapping of the resulting isoquinone methide, 103. Over-oxidation of the resulting hydroquinone provided the tetracyclic quinone, 104, with a relatively poor overall yield. Oxidative removal of the PMB group, followed by reduction, then afforded hydroquinone, 98. The latter carries the foundation of glaziovianol, 97 (Scheme 15).⁹⁷

Scheme 15

2.3.2. Synthesis of andibenin B core. In 1976, Dunn and co-workers for the first time obtained and reported the crystallographic structure of a novel metabolite meroterpenoid, andibenin B (105), isolated from the static cultures of Aspergillus variecolor (Scheme 16). The mother liquor from static cultures of the fungus was extracted, providing a brown semi-solid oil, which was first isolated and purified by crystallization.⁹⁸ A concise synthesis of the bicyclo[2.2.2]octane (106) cores of andibenin B through a nature-inspired IMDA was disclosed by Spangler and Sorensen; it was accomplished in only 10 steps, obtaining a 14% overall yield based on 2,6-dimethylbenzoquinone, 107. The latter was converted to allylic alcohol, 108 in several steps. Compound 108 was transformed into an epimeric mixture of carbinols, 109, 110 and 111 upon heating to 80 °C in toluene via Diels–Alder cycloaddition. The yield of isolated product for this reaction was high. The allylic alcohol, 108, gives both the possible Diels–Alder regioisomers in a 1 : 1.8 ratio (109/110), slightly favoring the desired regioisomer, 110. This cycloaddition allows the assembly of a sterically overcrowded bicycle and concurrently generates three new all-carbon quaternary chiral centers in a well-organized manner. Oxidation of 110 and 111, using Dess–Martin periodinane (DMP), was subsequently performed to give the corresponding ketone, 106, in good yield.⁹⁹

Scheme 16

3. Alkaloids

Alkaloids are a group of natural chemical compounds, which chiefly contain basic nitrogen atoms.¹⁰⁰ However, this group may also contain some interrelated compounds with neutral and even weak acidic properties. Some synthetic compounds with similar structures are also termed alkaloids.¹⁰¹ In addition to carbon, hydrogen and nitrogen, alkaloids may also contain oxygen, sulfur and, more infrequently, other elements, such as chlorine, bromine, and phosphorus.¹⁰² In the alkaloids, a wide variety of organism such as bacteria, fungi, plants, and animals are involved. They are usually purified from crude extracts of these organisms by acid–base extraction. Interestingly, many alkaloids are toxic to other organisms. They often have biological and pharmacological activities and are usually used as prescribed recreational drugs, and in entheogenic rituals. Examples are the local anesthetic and stimulant, cocaine, the psychedelic psilocin and the stimulants, caffeine and nicotine.¹⁰³ The notorious morphine, 112, is the major active constituent of opium, which is actually extracted from the immature seed capsule of the opium poppy. Morphine, 112, and linked opiates are generally analgesics. In spite of their grim side effects, including physical and psychological addiction, it remains one of the most extensively used drugs to treat severe pain. Codeine, 113, methylated morphine, is frequently used in cough medicines as an antitussive agent. It is also a weak analgesic (Fig. 5).¹⁰³ Acetylated morphine, heroin, which not long ago was used as an analgesic, is nowadays a street drug.

Fig. 5 Morphine and Codeine from Papaver somniferum.

3.1. Total synthesis of (−)-himandrine

The Galbulimima alkaloid (−)-himandrine (114) is a topologically interesting substance. It was initially isolated from the bark of Galbulimima belgraveana, a tree indigenous to New Guinea and northern Australia. A neutral fraction was provided by exhaustive extraction with methanol. The basic material, which was recovered from methanol solution, gave a small amount of himbosine. The bases in the mother liquor were also recovered and purified by column chromatography on alumina. The major alkaloid fraction was then separated into the desired alkaloids, namely himbacine, himbeline, himandravine, himgravine, himbosine and himandrine.^104,105 Movassaghi and co-worker performed and reported the total synthesis of (−)-himandrine, 114, for the first time. They started from an enone and an iminium chloride and followed an annulation methodology.¹⁰⁶ Remarkable features of this chemistry include the diastereoselective D–A reaction for an efficient synthesis of the trans-decalin (117) bearing tricycle, (−)-118, in an enantiomerically pure form. A solution of tetraenal, (−)-116, at 95 °C, gave the desired trans-decalin aldehyde, (−)-117, as the major endo Diels–Alder product (75%, dr = 5 : 1). The reaction of the aldehyde, (−)-117, with titanium tetrachloride gave the corresponding Mukaiyama aldol product,¹⁰⁷ which upon treatment with Martin sulfurane¹⁰⁸ gave the oxygen and acid sensitive enone, (−)-118, in good yield over two steps. This formal [3 + 3] annulation protocol to secure the formation of a CDE-ring system (see A–F, rings of himandrine 114 in Scheme 17), with whole diastereoselectivity. As a results this biogenetically motivated oxidative spirocyclization occurred converting 118 to (−)-114.¹⁰⁶ Upon oxidative cyclization of the dienic sulfonamide, 119, in the presence of iodobenzene diacetate in TFA, followed by a tandem IMDA reaction, desymmetrization of a “locally symmetrical” dienone 120 (Scheme 18) with good levels of diastereoselectivity is achieved, resulting in precious synthetic intermediates for the himandrine alkaloids (Scheme 19).^109,110

Scheme 17

Scheme 18 Model tandem phenolic oxidative amidation-IMDA reaction giving the framework of himandrine.

Scheme 19

3.2. Total synthesis of (+)- and (−)-fusarisetin A

Ahn and co-workers attempted the successful isolation of a biologically intriguing natural product, fusarisetin A, from a soil fungus, Fusarium sp. This compound showed remarkable inhibition of acinar morphogenesis as well as cell migration and incursion with no appreciable cytotoxicity. Fusarium sp. was used to inoculate seed culture medium PD broth. This culture broth was filtered and extracted. The extract was column chromatographed to obtain seven fractions. One of the fractions was purified by reverse-phase HPLC to yield 126.¹¹¹ The total synthesis of (−)-fusarisetin A (126) was firstly reported to have been achieved in 13 steps, resulting in the re-assignment of the absolute configuration of the actual natural product (Scheme 20). The synthesis involved a Lewis acid-mediated IMDA reaction, along with Pd-catalyzed O → C allylic rearrangement, followed by a chemo-selective Wacker oxidation and a sequential Dieckmann condensation/hemiketalization cascade. Compound 130 is believed to derive from a linear precursor such as 129 via a diastereo-selective IMDA reaction. BF₃·OEt₂ was recognized as an efficient promoter for this conversion. trans-Decalin, 130, was transformed to 126 as a sole isolable diastereomer in several steps to give a 63% yield. The desired target of the D–A substrate, 129, could be installed from the reaction of known (S)-(−)-citronellal, 128, and phosphonates via double Horner−Wadsworth−Emmons (H–W–E) olefinations.¹¹² In an alternative work, polyene, ent-133, was selected as the precursor for the IMDA reaction. This was provided from the reaction of (S)-(−)-citronellal, 128, with a 62% overall yield, expectedly as a mixture of E–Z isomers. Interestingly, this mixture can be subjected to photochemically-induced isomerisation in the presence of a catalytic amount of iodine to give the trans polyene, 133, as the sole product. Skipping purification, this isomer can be submitted to an Et₂AlCl-catalyzed IMDA reaction, which produced the desired trans-decalin aldehyde, ent-134, with high stereoselectivity (dr > 10 : 1, 82% yield). The latter was transformed into (+)-fusarisetin A (126) in several further steps (Scheme 21).^113,114

Scheme 20

Scheme 21

Equisetin 138, a fungal metabolite, was initially isolated from the white mold, Fusarium equiseti. Fusarium equiseti was initially grown on an autoclaved white corn grit medium at ambient temperature; upon extraction, it afforded a substance that was shown to inhibit some gram-positive bacteria, including mycobacteria.¹¹⁵ Employing a two-step procedure, (+)-citronellal, 128, was transformed into aldehyde 135. Conversion of 135 to the unsaturated aldehyde, ent-133, was achieved using a sequential Wittig reaction, diisobutyl aluminium hydride (DIBAL-H) reduction/Dess–Martin periodinane (DMP) oxidation. The IMDA reaction efficiently and easily transformed the aldehyde, ent-133, to the trans-decalin, 137, mediated by BF₃·OEt₂, which in turn was converted to equisetin, 138, via four step reactions using different organic transformation methodologies.^116,117 The conversion of equisetin 138 to (+)-fusarisetin A (126) was conducted as a one-pot reaction via straight addition of Zn to the O₂-scavenger oxidative radical sequence and 126 was obtained in fair yield over the sequential (Scheme 22).¹¹⁷ An Indian researcher group synthesized compound 139, beginning from (+)-citronellal 128. The next objective of the Julia–Kocienski olefination between aldehyde 139 and sulphone 140 was stereo-selectivity in the presence of KHMDS to furnish a triene ester, which was converted to the Diels–Alder precursor, 141, in two steps. The endo transition state favored the IMDA reaction of 141 under Lewis acid catalysis (BF₃·OEt₂) and furnished the fully functionalized decalin, 142, with a trans ring junction and seven out of ten chiral centers, with a 72% yield (Scheme 23).¹¹⁸ Kong and co-workers used (+)-citronellal, 128, for the synthesis of another triene, ent-129, which was converted to trans-decalin, ent-130 (dr = 8 : 1), through an IMDA reaction promoted by BF₃·OEt₂. Then, trans-decalin, ent-130 was used for the synthesis of cryptocin, 143, and then for the synthesis of (+)-fusarisetin A (126) (Scheme 24).¹¹⁹

Scheme 22

Scheme 23

Scheme 24

3.3. Synthesis of the decalin core of codinaeopsin

Codinaeopsin, 144 (Fig. 6), a tryptophan–polyketide hybrid, is a natural product with auspicious antimalarial properties. It belongs to a family of fungal metabolites that have a decalin scaffold derived from a linear polyketide united with an alkoxyaminal segment to provide α-acyl-γ-hydroxy lactams. A novel tryptophan–polyketide hybrid, codinaeopsin, was initially isolated from an endophytic fungus, which was fermented. Upon extraction of the fermentation broth, followed by silica gel flash column chromatography, several fractions were obtained. Fractions containing the active component, identified by TLC, were collected and purified further by reverse-phase HPLC. In this way a pure codinaeopsin, 144, the active ingredient, was obtained.¹²⁰ Ramanathan and co-workers reported the synthesis of the decalin core of codinaeopsin, via an IMDA reaction. A convergent synthesis was accessible to synthesize the precursors for the IMDA reaction in 10 steps commencing from trimethylphenol, 145. The exo cycloadducts, 149a–b, were obtained from thermal, IMDA reactions of substrates carrying a Weinreb amide or ester conjugated dienophile, and the endo adducts, 149c–d, were obtained from Lewis acid-catalyzed reactions of the substrates with a formyl group (Scheme 25).¹²¹

Fig. 6 Endophytic fungus produces Codinaeopsin.

Scheme 25

3.4. Synthesis of isopalhinine A core

Isopalhinine A (150), one of the most complex members of the palhinin family, is a lycopodium alkaloid, which was initially isolated from Palhinhaea cernua, carrying an extraordinary pentacyclic architecture (Fig. 7). The whole plant of P. cernua was initially collected. A sample which was already air-dried and powdered was then extracted several times. After being partitioned using common procedure, the alkaloid parts were subjected to column chromatography to afford four fractions. The third fraction was then subjected to further column chromatography on silica gel to give four sub-fractions. The first fraction was further chromatographed on silica gel to afford isopalhinine A 150.¹²² The latter has a C4–C16 linkage resulting in a tricyclo[4.3.1.0]decane (isotwistane) core. In 2014, Sizemore and co-workers presented a synthetic pathway to the isotwistane core, 151, using a sequential Morita−Baylis−Hillman/intramolecular Diels–Alder (IMDA) protocol.¹²³ Employing cyclohexenone, 152, as a starting material, eneone, 153, was produced (Scheme 26). The IMDA reaction of enone 153, imposing condition A (TMSOTf, Et₃N), with subsequent heating in dichlorobenzene, has resulted in a mixture of regioisomers containing mainly isotwistane, 156, which is not appropriate for the synthesis of palhinine lycopodiums. Thus, in an alternative attempt, condition B (heating enone 153 to 90 °C in DMF mediated by excess TMSCl and Et₃N) was employed to gain the desired IMDA products as diastereomeric isotwistanes, 151a and 151b, in relatively high yield (Scheme 26). This regio-selectivity of the IMDA reaction is induced by the conditions used for silyl enol ether, 155, formation, imposing a set of conditions for obtaining the core of cardionine and alternative conditions for producing the desired isotwistane core of isopalhinine.¹²³

Fig. 7 The structure of synthetic compound 151 which is similar to isopalhinine A.

Scheme 26

3.5. Synthesis of borreverine alkaloids

Borreria verticillata, a very common tropical plant, is used in outdated pharmacopeia to cure cutaneous infections. The borreverine alkaloids extracted from this plant showed an antimicrobial action in vitro.¹²⁴ Isoborreverine, 157, and dimethylisoborreverine, 158, exhibited anti-malarial properties, and were initially isolated from F. Ambiosis by Riche and co-workers in 1977.¹²⁵ Dethe and co-workers reported a relatively brief total synthesis of isoborreverine, 157, and dimethylisoborreverine, 158. The reaction of the methyl ester of indole acetic acid, 159, with NBS in CCl₄ at ambient temperature afforded the bromination product, which then, under Stille coupling and subsequent reduction of the ester group in the latter, employed LAH as a reductive agent to provide the crucial intermediate, 160, in good yield. The tertiary alcohol, 160, generated the intermediate, 161, after which an IMDA reaction resulted in the isoborreverine analogues, 162a and 162b. Compound 162a was then transformed into the desired target natural products, 157 and 158, through two steps (Scheme 27).¹²⁶

Scheme 27

3.6. Daphniphyllum alkaloids synthesis

Recently, several new alkaloids containing atypical frameworks such as calyciphyllines C-M, have been isolated from Daphniphyllum calycinum.^127,128 Further work on the obtained extracts has led to the isolation of three new alkaloids, calyciphyllines N-P. The crude alkaloids were passed over an amino silica gel column, with subsequent purification using column chromatography, to afford calyciphylline N (164, 0.00031% yield).¹²⁹ The total synthesis of the structurally complex Daphniphyllum alkaloid (−)-calyciphylline N, 164, has been accomplished with a relatively linear sequence of 37 steps starting from the known alcohol, (−)-165. The synthesis was performed in the presence of Et₂AlCl, to accomplish a highly stereo-selective, substrate-controlled IMDA reaction. Due to the instability of 167 on silica gel, the mixture was further processed without column chromatography separation. Whereas the thermal D–A reaction resulted in a mixture of all possible diastereomers as far as could be determined by ¹H NMR spectroscopy; interestingly, Et₂AlCl-catalyzed cyclization afforded a 9 : 1 mixture of diastereomers, in which the desired cycloadduct, (−)-168, was the major compound. Subsequently a transannular enolate alkylation, followed by an efficient sequential Stille carbonylation/Nazarov cyclization was performed. Finally a high-risk diastereo-selective hydrogenation of a fully substituted conjugated diene ester, 164, was conducted (Scheme 28).¹³⁰

Scheme 28

The Daphniphyllum alkaloids, which were initially isolated from the genus of Daphniphyllum (Daphniphyllaceae), represent a huge and growing group of structurally complex natural products.^131–133 Daphenylline, 169, with an extraordinary rearranged 22-nor-calyciphylline framework, was initially isolated from the fruits of Daphniphyllum longeracemosum. This fruit was extracted after being subjected to work up and column silica gel chromatography to give three fractions. The third fraction was further subjected to column chromatography to afford daphenylline, 169.¹³⁴ An efficient sequential DA/oxidative aromatization strategy for the synthesis of the fused all-carbon DEF tricyclic skeleton, 170, of the structurally novel Daphniphyllum alkaloid daphenylline, 169, has been achieved. A Lewis acid-promoted IMDA reaction with subsequent oxidative aromatization was performed to synthesize the poly-substituted aryl ring as well as the 5/6/7 tricyclic skeleton. Remarkably, Et₂AlCl was found to be effective in promoting the desired D–A reaction, and provided 173 along with a trace amount of oxidative aromatization product. This was determined by ¹H NMR spectroscopy. It is worthy to mention that other Lewis acids, when examined, were found to be ineffective in this reaction (Scheme 29).¹³⁵

Scheme 29

3.7. Lycopodium lucidulum alkaloids synthesis

The Lycopodium alkaloids were initially extracted from club moss Lycopodium lucidulum. The Lycopodium alkaloids symbolize a structurally complex family of heterocyclic natural products with different structural types. Within the Lycopodium family, there is a plentiful subclass of compounds, including lycolucine, 174, and the structurally appropriate dihydrolycolucine, 175, (Fig. 8). Separation of the weak bases of L. lucidulum was achieved by exhaustive distribution between a moving phase and a stationary phase, followed by widespread TLC and column chromatography over alumina. Finally, two isomeric alkaloids, namely lucidine A and lucidine B, were obtained, as well as lycolucine, 174, and a dihydrolycolucine, 175.^136,137 An approach to the synthesis of the Lycopodium alkaloid dihydrolycolucine, 175, has been studied. Appropriate synthetic pathways were achieved based on N-acylpyridinium salt (176) chemistry to synthesize the target fragments, 179, that could finally react with the natural product. Key and crucial reactions involve IMDA cycloadditions and retro-Mannich ring-openings to form both the AB and the EF ring segments. The ring C precursor, 183, was synthesized via pyridine substitution along with directed lithiation chemistry. Subsequent Suzuki cross-coupling of rings C and EF resulted in the CEF ring segment. Notably, preliminary attempts at the closure of the seven-membered D ring were unproductive (Scheme 30).¹³⁸

Fig. 8 Lycolucine and dihydrolycolucine are extracted from Lycopodium lucidulum.

Scheme 30

3.8. Synthesis of uncialamycin core

In 2005, Davies, and co-workers revealed the structure of uncialamycin, 184, a new “enediyne” natural product, which was isolated from an unknown streptomycete obtained from the surface of a lichen, Cladonia uncialis.¹³⁹ The imino IMDA reaction permits a fast access to polysubstituted quinolines in a facile and direct way. By using this procedure, the chiral quinoline motif of the uncialamycin can be prepared. Desrat and co-workers discovered that BF₃·OEt₂ in the presence of DDQ can promote the intramolecular, sequential Povarov reaction¹⁴⁰/oxidative aromatization providing substituted quinolones, 187. The dienophile used could be either an alkene or an alkyne without an appreciable effect on the yield of cyclization. However, only one equiv. of DDQ is enough in the case of the cycloaddition reaction with the alkynes while two equiv. for the reaction with alkenes is necessary. In the absence of DDQ, the cycloaddition reaction is still occurs. However the quinolone obtains as a mixture with an amine resulted from a hydrogen atom transfer from the dihydro- or tetrahydroquinoline to the starting imine 186. These reaction conditions were employed to synthesize the chiral quinoline motif, 187, of the enediyne uncialamycin, 184 (Scheme 31). The C26 stereogenic center of the uncialamycin was set at the start of the synthesis from a well-established enantio-selective reduction of α-alkyne ketone.¹⁴¹

Scheme 31

4. Summary

The Diels–Alder (DA) reaction is known as a symbol of the powerful [4 + 2] cycloaddition reactions in organic synthesis. Intramolecular DA reactions (IMDA) are also well-established and are frequently used as a versatile methodology in organic synthesis. They have also found several applications in the total synthesis of natural products. IMDA plays an important role in the total synthesis of natural products since it forms a 6-membered ring often found in many natural products. This reaction permits the construction of polycyclic molecules that can also include a heterocycle. Furthermore, the obtained products are often enantio or diastereo-rich compounds, which confirm the importance of this reaction in asymmetric synthesis. A variety of catalysts promote IMDA reactions, in which BF₃·OEt₂ is the one most used.

Acknowledgements

The authors gratefully acknowledge the partial financial support from the Research Council of Alzahra University. Dedicated to Professor Saeed Balalaie whom we believe has devoted his life to promote organic chemistry in Iran, from several points of view. In particular, VF as an author of this review feels obliged to express her deep gratitude for the educations inspirations and encouragements received as his student.

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