Assessment on facile Diels–Alder approach of α-pyrone and terpenoquinone for the expedient synthesis of various natural scaffolds

The development of highly facile synthetic procedures for the expedient synthesis of complex natural molecules is always in demand. As this aspect, the Diels–Alder reaction (DAR) has a versatile approach to the synthesis of complex natural compounds and highly regio-/stereoselcetive heterocyclic scaffolds. Additionally, α-pyrone and terpenoquinone are two versatile key intermediates that are prevalent in various bioactive natural compounds for instance, (±)-crinine, (±)-joubertinamine, (±)-pancratistatin, (−)-cyclozonarone, and 8-ephipuupehedione, etc. Hence, the current review summarizes the Diels–Alder reaction application of α-pyrone and terpenoquinone to the constructive synthesis of various natural products over the past two decades (2001–2021). Equally, it serves as a stencil for the invention and development of new synthetic strategies for high-complex molecular structured natural and heterocyclic molecules. Graphical Abstract


Introduction
The development of innovative pharmaceutical agents from natural origin (like marine products) has played a tremendous role in the modern drug discovery. To date, a wide variety of complex marine natural products have been acknowledged as a lead agents to ameliorate the triggers of various disease like diabetes, microbial infections, cardiovascular disease, hypertension, immune related problems and neurological disorders, etc. [1,2]. In this regard, α-pyrone (syn. 2-pyrones) and terpenoquinone compromising marine compounds have received considerable attention in the medicinal chemistry. Since, they have exhibited wide-variety of pharmacological activities such as antibiotic, anticancer, antimicrobial, antimalarial, and neuroprotective tactics [3,4]. In addition, the analogues of α-pyrone and terpenoquinones have been accredited as an imperative bioactive-synthons in numerous complex natural products [5]. Therefore, the design and development of α-pyrone and terpenoquinone analogues have become an important strategy in current drug innovations through adaptive synthetic approaches [3,6].
In this scenario, the Diels-Alder reaction is the most profitable approach for the facile synthesis of complex natural compounds with a pharmaceutical grade [7][8][9]. Furthermore, the DAR envisioned a highly-atom economical and creative transformation for the development of stereoselective novel drug agents [8,9]. Likewise, the Diels-Alder reaction also has a wide choice of variety of industrial applications which includes hetero-DARs, intramolecular [4 + 2] π cycloadditions, and catalytic reactions for the stereoselctive transformations. Thus, the Diels-Alder cyclization has an amazing strategy in synthetic organic chemistry and medicinal chemistry applications.

Graphical Abstract
Page 3 of 21 Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 2 Diels-Alder approach of α-pyrone to the pragmatic synthesis of natural compounds The chromophore α-pyrone serves as a versatile building block in numerous bioactive natural marine products such as albidopyrone (antidiabetic), salinipyrone A (anticancer), wailupemycin A (antimicrobial), tipranavir (anti-HIV), pyrenes I-II (anti-infective), and gombapyrone A (glycogen synthase kinase-3β inhibitor) ( Fig. 1) [3,21]. Therefore, there is considerable interest among researchers in drug innovation owing to the unique structural and pharmaceutical properties of α-pyrone marine compounds. In addition, the developments of highly efficient synthetic tactics are needed to access the versatile analogues of bioactive α-pyrones. Considering all these prominence, an assessment of Diels-Alder approach for the expedient synthesis of α-pyrones are summarized as underneath.
Baran and Burns demonstrated the constructive total synthesis of an important anti-cancer indeno-tetrahydropyridine analogue i.e., (±)-haouamine A (7) through a sequential reactions of Stille coupling of pyrone and Diel-Alder cyclization (Scheme 1) [22]. The introduction of α-pyrone chore 2 into the indeno-tetrahydropyrdine intermediate 1 by the Still coupling procedure was an important strategy in the synthesis of haouamine A. As well, another synthetic challenge was the unusual macrocyclization achieved through the pyrone-alkyne Diels-Alder reaction of 5, which embedded leaving of CO 2 group by a pseudo-boat configuration 6 and subsequent aromatization of viable precursor to 7. Therefore, conferring to the biosynthetic origin the role of α-pyrone synthon was essential for the unusual oxygen pattern of highly strained macrocylic analogue 7 presence.
Equally, Shin and co-workers reported a total synthesis of the anti-tumor agent, trans-Dihydronarciclasine 15 over a Diel-Alder cyclization (Scheme 2) [23]. An important strategy in the synthesis of phenanthridone 15 was the outline of ring B accomplished through a high selective endo-adduct 10 in 99% yield by the Diels-Alder cyclization of α-pyrone derivative 9 with styrene derivative 8. Further, the α,β-unsaturated cyclic adduct 10 was transformed into a methyl carbamate 13, and then ensuing Bischler-Napieralski reaction of it acylated derivative 13 resulted the targeted trans-phenanthridone 15. Later, Cho and his co-worker developed a more efficient route for large-scale production of 15 by enforcing the limitations of Bischler-Napisrealski cyclization reaction of the ester intermediate [24]. Therefore, from the total synthesis of 15, it has been expanded that α-pyrone synthon 9 plays an essential role in the biogenesis of trans-dihydronarciclasine.
Further, Tam and Cho demonstrated another interesting natural antitumor alkaloid i.e., (±)-crinine (19) by Still coupling and Diels-Alder cyclization approaches (Scheme 3) [25]. Primarily, the synthesis of alkaloid 19 involves the regioselective coupling of the α-pyrone analogue 9 and aryltin derivative 16 prompted to the required α-pyrone diene 17 in 72% yield. Subsequently, the Diels-Alder cyclization of 17 with TBS vinyl ether occasioned the mixture of endo/exo-bicyclolactones (18a/b) in a 2:1 ratio. Further, the sequential reactions of endo-bicyclolactone 18a provide the total synthesis of tetrahydroisoquinoline alkaloid 19. Thus, from the stated synthetic approach, the regioselective pyrone-aryltin coupling and Diels-Alder cyclization plays a title role in the synthesis of endo-bicyclolactone 18a, a key intermediate of (±)-crinine. Likewise, an sceletium alkaloid (±)-joubertinamine (26) has been accredited an pharmaceutically important agent to treat psychological disorders, anxiety, depressive state, alcohol and drug addictive conditions, and neurological disorders [26,27]. Further, Tam and Cho deliberated the facile total synthesis of joubertinamine (26) over a Still coupling and Diels-Alder cyclization strategies (Scheme 4) [26]. As similar to the crinine (19) synthesis, the regioselctive coupling and Diels-Alder cyclization of α-pyrone 9 was facilitated the essential key cyclohexene Galanthamine is a biologically important cyclic tertiary amine class alkaloid used to treat the symptoms of Alzheimer disease [28]. In this regard, Chang et al. [29] demonstrated an efficient synthetic strategy for the total synthesis of galanthamine (32) through tandem C3-selective Still coupling and IMDA approaches as described in Scheme 5. Essentially, the endo-tetracyclolactone adduct 28 was achieved over a Stille coupling of α-pyrone 9 with aryl stannane 27. Further, the ring-opening of a selective diastereomeric adduct 28 and then, followed by hydroxyl protection, amination and carbamate erection occasioned the respective, MOM ether and ester functionalized compound 29. Then after, DIBAL reduction, Dess-Martin peroxidation (DMP) followed by Witting olefination caused in a diastereomeric mixture of enol ether derivative 30 in 46% yield. Similarly, accompanying TFA hydrolysis, reductive amination provided the tetracycle-alkaloid derivative 31. Finally, the sequence reactions of DMP, debromination and the L-selectride reduction furnished galanthamine (32) in 48% yield. Therefore, the stereoselective tandem Still coupling/ IMDA reaction of α-pyrone 9 was the key strategies to attain the endo-cyclic adduct 28 in the effective total synthesis of galanthamine. Likewise, the continuing efforts of Tam and colleagues [30] have pronounced a unified approach to the total synthesis of various tetrahydroisoquinoline alkaloids such as (±)-crinine 19, (±)-crinamine 39, and (±)-6a-epicrinamine 40 (Scheme 6). Primarily, the key bicyclolactone intermediate 18a was achieved by Still coupling and Diels-Alder reaction of α-pyrone synthon 9 as described in Scheme 3. Further, the endo-bicyclolactone 18a was transformed into respective key cyclohexene derivatives 33-38 as illustrated in scheme 6. Further, diverse sequential reactions were transformed into respective, crinine-type alkaloids 19, 39 and 40. Therefore, α-pyrone analogue was an imperative enophile synthon in the biogenetic Diels-Alder approach of various complex natural compounds.
Equally, the key intermediate cycohex-3-enecrboxylate 44 was subjected to dihydroxylation with OsO 4 /NMO and the Curtius rearrangement motivated the diol lactam 48 in 51% yield [32]. Further, the protection of hydroxyl groups with TsOH/Me 2 CO and then, followed by carbonyl reduction with LiAlH 4 led to the bicyclic pyrrolidine 49 as shown in path B, Scheme 7. The concomitant Bischeler-Napieralski reaction of bicyclic pyrrolidine 49 cyclized to tetracyclic amide analogue 50 in 76% yield. Finally, the amide derivative was subjected to a series of various 8 step-reactions such as protection; deprotection of hydroxyl, and reduction conditions were furnished the target derivative 1-deoxylycorine (51).
Basiliolide and transtaganolides are pharmacologically important natural metabolites with a novel framework of oxabicyclo[2.2.2]octene core derivatives [41]. Thus, the concise strategies and stoichiometric reagents are required to accomplish the total synthesis of unusual complex tricyclic substrates on an industrial scale. As this aspect, Larsson et al. [42] proposed a strategic synthesis for transtaganolides E (90) and F (91) that were potentially beneficial as analogue synthons for basiliolides and transtaganolides. Initially, a geranylated α-pyrone Diels-Alder substrate 88 was imperiled to Ireland-Claisen rearrangement to attain a rearranged α-pyrone acid derivative 89. Further, the high pressure 1.5 GPa/50 °C conveys an IMDA cyclization accomplished the 2:1 diastereomeric mixture of transtaganolide E and F in 61% yield as illustrated in Scheme 13.
As well, a resorcyclic acid lactone (−)-neocosmosin A (146) was isolated from the fungus Neocosmospora sp., and has been shown to have strong binding properties with cannabinoid receptors and human opioid [52]. As this aspect, Lee and Cho [53], demonstrated an efficient and rapid access to neocosmosin A through IMDA and cycloreversion approaches as described in Scheme 19. The target synthesis was motivated by the achievement of chiral-IMDA α-pyrone substrate 143 by various optimized studies. Consequently, the IMDA reaction of α-pyrone bromopropiolate substrate 143 gave the corresponding dibromobenzo macrocyclic lactone 144 in 64% yield. Further, on exposed to Miyaura reaction and then followed by oxidation of borate derivative prompted

Scheme 18
The intermolecular Diels-Alder reaction of α-pyrone assisted prominent strategies for the synthesis of (+)-iso-A82775C, a key intermediate of chloropupukeananin
3 Diels-Alder approach for the expedient terpenoquinone arbitrated natural compounds As well, terpenoquinone is another interesting stencil found in numerous marine natural products like sesquiterpene benzoquinones, meroterpenes, merosesquiterpenes, norsesquiterpenes, and tetracarbocyclics, etc. [54][55][56]. Therefore, the substantial attention has been paid to the terpenoquinone cohesive natural compounds due to its extensive pharmacological properties [6,56]. In this regard, various studies have revealed that certain marine sponges were richest source of bioactive terpenoquinones that imperative as antibacterial, anticancer, antitumor, antimalarial, and anti-HIV therapeutic agents [6,[56][57][58][59]. Therefore, some examples of isolated terpenoquinones and their pharmacologically significance are appended in Fig. 2. Considering the structural diversity and biological prominence of the natural terpenoquinone, the standing review emphasized the application of Diels-Alder cyclization approach to its expedient synthesis. In addition, the terpenoquinones are resourceful dienophiles that triggered lavish DAR approaches to the constructive complex natural products. Further, the Diels-Alder reaction was a facile synthetic approach for the quick generation of regio-and steroselective complex products with creditable yields. From this aspect, a bioactive sesquiterpene quinone i.e. cyclozonarone (152) was widely distributed in marine algae Dictyopteris undulata [60], and it absolute configuration was (−)-(5R,10R)-cyclozonarone revealed by Cortes et al. [61] over an enantioselective synthesis. Later, Schroder et al. [62] demonstrated the fruitful total synthesis of (−)-cyclozonarone through an expedient Diels-Alder cyclization approach as illustrated in Scheme 20. Initially, the dehydration reaction of ( +)-albicanol 147 with Tf 2 O/pyridine occasioned the drima-(8,12), (9,11)-diene 148 in 68% yield, which then subjected to Diels-Alder reaction with benzoquinone 149 resulted a mixture of enolization-oxidation cyclic adducts 150 and 151 in 75-89% yield. Subsequently, on oxidation of cyclic adduct mixture with DDQ primes to (−)-cyclozonarone 152 in 92% yield. Whereas, the targeted sesquiterpene quinone 152 was achieved in 35% yield on extending the Diels-Alder reaction time to 36 h without subsequent DDQ oxidation. Therefore, the pragmatic synthesis of 152 was achieved through a controlled Diel-Alder cyclization of diene derivative with benzoquinone over a static reaction period as described in Scheme 20. Likewise, Miguel del Corral et al. [63], demonstrated the facile Diels-Alder cycloaddition procedure for sesquiterpenoid quinones/hydroquinones with interesting antineoplastic properties (Scheme 21). Primarily, the cycloaddition reaction of three labdanic diterpenoids 153 with p-benzoquinone 149 occasioned the corresponding hydroquinones 155 together with autoxidized quinones 156 and 157 as described in method A, Scheme 21. Further, the oxidation of hydroquinones 155 with DDQ was stemmed to the respective naphthohydroquinone 158. Also, the Diels-Alder reaction of myrceocommunic Scheme 20 Diels-Alder reaction approach for the synthesis of (−)-cyclozonarone

Scheme 21
The facile Diels-Alder cycloaddition procedure for the synthesis of sesquiterpenoid quinones/hydroquinones derivatives 153 with naphthoquinone 159 was stimulated the respective diterpenyl anthraquinone 160 and hydroxyanthraquinone 161 as illustrated in method B, Scheme 21. In addition, the stated diterpenylquinones (156-158) and diterpenylhydroquinones (160 and 161) have been found to be substantial cytotoxic in 0.1-21 µM against various human tumor cells such as lung carcinoma (A-549), colon carcinoma (HT-29), murine leukemia (P-388), and malignant melanoma (MEL-28). Likewise, another marine anti-leukemia sesquiterpene 8-ephipuupehedione 171 was found to be a potent inhibitor of cell-proliferation and associated cancer-pathogenesis paths [64]. As the aspect, Alvarez-Manzaneda et al. [65], demonstrated an facile Diels-Alder cyclization procedure for the synthesis of aldehyde intermediate 166, an essential key synthon for the formation of marine metabolites like ent-chromazonarol 168 and 8-ephipuupehedione 171 as shown in Scheme 22. Primarily, the tricyclic pyran diene fragment 162 was synthetized from sclareol oxide, which then cycloaddition with α-chloroacrylonitile (dienophile) by DAR procedure provided the regioselctive cyclic adduct 163 in 70%. Afterwards, the successive treatments of cyclic adduct with DBU/C 6 H 6 , DDQ/ dioxane and DIBAL/ THF stemmed the essential key aldehyde intermediate 166 in 71% yield. Therefore, the Diel-Alder cyclization was the static approach that ensued 166 in persuasive yields. Subsequent, Baeyer-Villiger oxidation of 166, saponification, and DDQ oxidation were motivated the 8-ephipuupehedione metabolite 171.