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

Assessment on facile Diels–Alder approach of α-pyrone and terpenoquinone for the expedient... In this scenario, the Diels–Alder reaction is the most prof- 1 Introduction itable approach for the facile synthesis of complex natural The development of innovative pharmaceutical agents compounds with a pharmaceutical grade [7–9]. Further- from natural origin (like marine products) has played a more, the DAR envisioned a highly-atom economical and tremendous role in the modern drug discovery. To date, creative transformation for the development of stereose- a wide variety of complex marine natural products have lective novel drug agents [8, 9]. Likewise, the Diels–Alder been acknowledged as a lead agents to ameliorate the trig- reaction also has a wide choice of variety of industrial gers of various disease like diabetes, microbial infections, applications which includes hetero-DARs, intramolecu- cardiovascular disease, hypertension, immune related lar [4 + 2] cycloadditions, and catalytic reactions for the problems and neurological disorders, etc. [1, 2]. In this stereoselctive transformations. Thus, the Diels–Alder regard, α-pyrone (syn. 2-pyrones) and terpenoquinone cyclization has an amazing strategy in synthetic organic compromising marine compounds have received consid- chemistry and medicinal chemistry applications. erable attention in the medicinal chemistry. Since, they Further, our efforts have continued towards in the Diels– have exhibited wide-variety of pharmacological activi- Alder reactions [10–12], cycloadditions [13–15], and adept- ties such as antibiotic, anticancer, antimicrobial, antima- ness in the structural studies of bioactive natural products larial, and neuroprotective tactics [3, 4]. In addition, the [16–20]. Therefore, the present appraisal aims to emphasize analogues of α-pyrone and terpenoquinones have been the role of Diels–Alder approach of α-pyrones and terpeno- accredited as an imperative bioactive-synthons in numer- quinone in the constructive cycles of natural complexes. ous complex natural products [5]. Therefore, the design Equally, it highlights various Diels–Alder approaches for the and development of α-pyrone and terpenoquinone ana- design and development for bioactive natural compounds logues have become an important strategy in current drug through medicinal chemistry approaches. innovations through adaptive synthetic approaches [3, 6]. R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 3 of 21 conferring to the biosynthetic origin the role of α-pyrone 2 Diels–Alder approach of α‑pyrone synthon was essential for the unusual oxygen pattern of to the pragmatic synthesis of natural highly strained macrocylic analogue 7 presence. compounds Equally, Shin and co-workers reported a total synthe- The chromophore α-pyrone serves as a versatile build - sis of the anti-tumor agent, trans-Dihydronarciclasine ing block in numerous bioactive natural marine products 15 over a Diel-Alder cyclization (Scheme  2) [23]. An such as albidopyrone (antidiabetic), salinipyrone A (anti- important strategy in the synthesis of phenanthridone cancer), wailupemycin A (antimicrobial), tipranavir (anti- 15 was the outline of ring B accomplished through a HIV), pyrenes I–II (anti-infective), and gombapyrone A high selective endo-adduct 10 in 99% yield by the Diels– (glycogen synthase kinase-3β inhibitor) (Fig.  1) [3, 21]. Alder cyclization of α-pyrone derivative 9 with styrene Therefore, there is considerable interest among research - derivative 8. Further, the α,β-unsaturated cyclic adduct ers in drug innovation owing to the unique structural 10 was transformed into a methyl carbamate 13, and and pharmaceutical properties of α-pyrone marine com- then ensuing Bischler-Napieralski reaction of it acylated pounds. In addition, the developments of highly effi - derivative 13 resulted the targeted trans-phenanthridone cient synthetic tactics are needed to access the versatile 15. Later, Cho and his co-worker developed a more effi - analogues of bioactive α-pyrones. Considering all these cient route for large-scale production of 15 by enforcing prominence, an assessment of Diels–Alder approach for the limitations of Bischler-Napisrealski cyclization reac- the expedient synthesis of α-pyrones are summarized as tion of the ester intermediate [24]. Therefore, from the underneath. total synthesis of 15, it has been expanded that α-pyrone Baran and Burns demonstrated the constructive total synthon 9 plays an essential role in the biogenesis of synthesis of an important anti-cancer indeno-tetrahy- trans-dihydronarciclasine. dropyridine analogue i.e., (±)-haouamine A (7) through Further, Tam and Cho demonstrated another interest- a sequential reactions of Stille coupling of pyrone and ing natural antitumor alkaloid i.e., (±)-crinine (19) by Diel-Alder cyclization (Scheme  1) [22]. The introduc - Still coupling and Diels–Alder cyclization approaches tion of α-pyrone chore 2 into the indeno-tetrahydropyr- (Scheme  3) [25]. Primarily, the synthesis of alkaloid 19 dine intermediate 1 by the Still coupling procedure was involves the regioselective coupling of the α-pyrone an important strategy in the synthesis of haouamine A. analogue 9 and aryltin derivative 16 prompted to the As well, another synthetic challenge was the unusual required α-pyrone diene 17 in 72% yield. Subsequently, macrocyclization achieved through the pyrone-alkyne the Diels–Alder cyclization of 17 with TBS vinyl ether Diels–Alder reaction of 5, which embedded leaving of occasioned the mixture of endo/exo-bicyclolactones CO group by a pseudo-boat configuration 6 and subse - (18a/b) in a 2:1 ratio. Further, the sequential reactions quent aromatization of viable precursor to 7. Therefore, O O O O OH O O O OH Pyrone In =1 OH OH Pyrone II n= 3 SalinipyroneA Albidopyrone (Anti-infective) (anticancer) (antidiabetic,PTP1B) CF OH N OH O O O O OH HO OH Tipranavir (anti-HIV) GombapyroneA H CO 3 O (Anti-Alzheimer, GSK-3 ) Wailupemycin A (antimicrobial) Fig. 1 Structures of some nominated biologically potent α-pyrone marine compounds [3, 21] Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 4 of 21 Scheme 1 Synthesis of haoumine A involving pyrone-alkyne Diels–Alder cyclization Scheme 2 Synthesis of trans-dihydronarciclasine through endo-selective Diels–Alder cyclization of endo-bicyclolactone 18a provide the total synthesis of agent to treat psychological disorders, anxiety, depressive tetrahydroisoquinoline alkaloid 19. Thus, from the stated state, alcohol and drug addictive conditions, and neuro- synthetic approach, the regioselective pyrone-aryltin logical disorders [26, 27]. Further, Tam and Cho deliber- coupling and Diels–Alder cyclization plays a title role in ated the facile total synthesis of joubertinamine (26) over the synthesis of endo-bicyclolactone 18a, a key interme- a Still coupling and Diels–Alder cyclization strategies diate of (±)-crinine. (Scheme  4) [26]. As similar to the crinine (19) synthesis, Likewise, an sceletium alkaloid (±)-joubertinamine the regioselctive coupling and Diels–Alder cyclization of (26) has been accredited an pharmaceutically important α-pyrone 9 was facilitated the essential key cyclohexene R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 5 of 21 Scheme 3 Synthesis of endo-bicyclolactone, a key intermediate of crinine by Still coupling and Diels–Alder cyclization methodologies Scheme 4 Synthesis of joubertinamine through Still coupling and Diels–Alder cyclization paths intermediate 24. Subsequently, the PCC oxidation and aryl stannane 27. Further, the ring-opening of a selec- then witting reactions accomplished the target com- tive diastereomeric adduct 28 and then, followed by pound, joubertinamine 26. hydroxyl protection, amination and carbamate erection Galanthamine is a biologically important cyclic ter- occasioned the respective, MOM ether and ester func- tiary amine class alkaloid used to treat the symptoms of tionalized compound 29. Then after, DIBAL reduction, Alzheimer disease [28]. In this regard, Chang et  al.[29] Dess-Martin peroxidation (DMP) followed by Witting demonstrated an efficient synthetic strategy for the total olefination caused in a diastereomeric mixture of enol synthesis of galanthamine (32) through tandem C3-selec- ether derivative 30 in 46% yield. Similarly, accompany- tive Still coupling and IMDA approaches as described in ing TFA hydrolysis, reductive amination provided the Scheme  5. Essentially, the endo-tetracyclolactone adduct tetracycle-alkaloid derivative 31. Finally, the sequence 28 was achieved over a Stille coupling of α-pyrone 9 with reactions of DMP, debromination and the L-selectride Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 6 of 21 Scheme 5 An efficient approach for the total synthesis of Galanthamine through tandem C3-selective Still coupling and IMDA approaches reduction furnished galanthamine (32) in 48% yield. cyclohex-3-enecarboxylate derivative 44. Consequent Therefore, the stereoselective tandem Still coupling/ sequential reactions of Curtius rearrangement, lithium IMDA reaction of α-pyrone 9 was the key strategies to hydroxide treatment resulted in a bicyclic amide 45 as attain the endo-cyclic adduct 28 in the effective total syn - described in path A, Scheme 7. Further the amide 45 was thesis of galanthamine. imperiled to Pictet–Spengler reaction; Pd/C hydrogena- Likewise, the continuing efforts of Tam and colleagues tion and LiAlH reduction accomplish the total synthesis [30] have pronounced a unified approach to the total syn - of α-lycorane (46). thesis of various tetrahydroisoquinoline alkaloids such Equally, the key intermediate cycohex-3-enecrboxylate as (±)-crinine 19, (±)-crinamine 39, and (±)-6a-epi- 44 was subjected to dihydroxylation with OsO /NMO crinamine 40 (Scheme  6). Primarily, the key bicyclolac- and the Curtius rearrangement motivated the diol lactam tone intermediate 18a was achieved by Still coupling and 48 in 51% yield [32]. Further, the protection of hydroxyl Diels–Alder reaction of α-pyrone synthon 9 as described groups with TsOH/Me CO and then, followed by car- in Scheme  3. Further, the endo-bicyclolactone 18a was bonyl reduction with LiAlH led to the bicyclic pyrroli- transformed into respective key cyclohexene deriva- dine 49 as shown in path B, Scheme  7. The concomitant tives 33–38 as illustrated in scheme  6. Further, diverse Bischeler–Napieralski reaction of bicyclic pyrrolidine 49 sequential reactions were transformed into respective, cyclized to tetracyclic amide analogue 50 in 76% yield. crinine-type alkaloids 19, 39 and 40. Therefore, α-pyrone Finally, the amide derivative was subjected to a series of analogue was an imperative enophile synthon in the bio- various 8 step-reactions such as protection; deprotection genetic Diels–Alder approach of various complex natural of hydroxyl, and reduction conditions were furnished the compounds. target derivative 1-deoxylycorine (51). Lycorine, lycorane, and 1-deoxylycorine are the most Likewise, Shin et  al.[33] demonstrated the amended attention-grabbing and pharmacologically important total synthesis of ( ±)-lycorine (62) with the provision pyrrolo[de]phenanthridine natural alkaloids [31, 32]. of chiral bicyclolactone alcohol 54 through Diels–Alder The total synthesis of α-lycorane (46) initiated by the cyclization of pyrone 9 and β-borylstyrene 52 (Scheme 8). Diels–Alder reaction of the α-pyrone derivative 9 with a Further, the hydroxyl lactone 54 was subjected to acidic styrene dienophile 41 which motivated the 10:1 mixture methanolysis and followed by Eschenmoser-Claisen rear- of diastereomeric cyclic adducts [32]. Further, the reduc- rangement occasioned the key intermediate cyclohex- tive debromination of nominated endo-cyclic adduct 3-enecarboxylate derivative 56. Subsequently, a sequence with Zn occasioned the desired bicyclic lactone 42. Sub- of reactions such as mCPBA epoxidation, Mitsunobu sequent, acid-catalyzed methylation and the Eschen- reaction, epoxide ring-opening, and Pictet-Spengler con- moser–Claisen rearrangement prompted the important ditions afforded the tetracyclic lactam 61 in 70% yield. R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 7 of 21 Scheme 6 Synthesis of crinine-type alkaloids through an important enophile α-pyrone synthon derived Diels–Alder approach Finally, the L iAlH reduction of diacetate tetracyclic lac- depends on the substrate α-pyrone amide-tethered inter- tam 61 prompted the ( ±)-lycorine (62) at a yield of 41%. mediate I (63) and II (71), which are readily accessible Sato and co-workers [34] demonstrated the total through augmented studies. Further, the sequential reac- synthesis of another important anti-tumor scaffold tions of the Diels–Alder cyclic adduct (i.e. indole deriva- (+)-pseudodeflectusin (68) by Diels–Alder and lactoni - tives) were renovated to corresponding derivatives such zation methods (Scheme  9). Primarily, the base-pro- as garcilamine, mesembrine and Δ -mesembrenone. The moted Diels–Alder cyclization of 7-hydroxy-α-pyrone success of the stated intramolecular Diels–Alder cycli- analogue 63 with an alkyne 64, prompted the desired zation of α-pyrone analogues 63 and 71 have yielded (-)-(R)-bromomellein 65 as an exclusively cyclic adduct diverse indole and hydroindole group alkaloids in a low in 78% yield. Further, the isochromanone adduct was step-count methodology. adapted into tricyclic furanone intermediate 67 through Likewise, (±)-pancratistatin (81) and ( ±)-1-epi-pan- the sequential reactions of alkylation with methyl bro- cratistatin (83) are two important anti-cancer Amarylli- moacetate, lactonization with TMSSnBu /CsF in dif- daceae tricyclic alkaloids of natural origin [36]. Initially, fident conditions. Therefore, cascade reactions of Jung and co-workers [37] demonstrated the total syn- regioselective DAR and lactonization accomplished from thesis of (±)-pancratistatin (81) by the cascade reactions 7-hydroxy-α-pyrone (63) are prominent in the synthesis of Diels–Alder cyclization, Curtius rearrangement and of ( +)-pseudodeflectusin 68. Bischler-Napieralski procedures. Later, the Cho group Likewise, Gan et  al. [35], established an efficient and developed an advance synthetic procedure for both the expedient intramolecular pyrone Diels–Alder cycli- (±)-pancratistatin (81) and (±)-1-epi-pancratistatin zation approach for the synthesis of Amaryllidacceae (83), by identical reaction procedure with same starting alkaloids viz., garcilamine (70), Δ -mesembrenone (73) materials of β-borylstyrene 75 (Scheme  11) [38]. Pri- and mesembrine (74) as described in Scheme  10. The marily, the dienophile β-borylstyrene undergoes DAR adeptness and regioselectivity of the [4 + 2] cyclization cyclization with α-pyrone (9, as diene) occasioned the Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 8 of 21 Scheme 7 The efficient α-pyrone Diels–Alder approach for expedient synthesis of pyrrolo[de]phenanthridine alkaloids, α-lycorane and 1-deoxylycorine endo-bicyclolactone 76 exclusively in 86% yield. Sub- Horner-Wadsworth-Emmons reaction procedures. Fur- sequent oxidation with sodium perborate stemmed the ther, the intramolecular Diels–Alder cyclization of cas- desired biclolactone alcohol 77 in 81% yield, and then cade substrate under microwave conditions occasioned the debromination, methanolysis primes to the key inter- the cavicularin 87 in 80% yield and its regioisomer 88 mediate i.e., cyclohexene-diol 78. Further, the Curtius at a yield of 58%, respectively. Therefore, the pyrone rearrangement and Bischler-Napieralski reactions of cor- Diels–Alder substrate 84 is essential for the construct responding tetraol intermediates occasioned the targeted of conformationally macrocyclic bis(bibenzyl) natural alkaloids 81 and 83, respectively. Therefore, the stated metabolites. total synthesis of 81 and 83 became worthwhile with the Basiliolide and transtaganolides are pharmacologi- formation of endo-cyclicadduct 76 in the inverse electron cally important natural metabolites with a novel frame- demand Diels–Alder cyclization of the α-pyrone deriva- work of oxabicyclo[2.2.2]octene core derivatives [41]. tive 9 with β-borylstyrene 75. u Th s, the concise strategies and stoichiometric reagents Further, conformationally chiral molecule cavicu- are required to accomplish the total synthesis of unusual larin 87 has been reported to attract the attention of complex tricyclic substrates on an industrial scale. As this researchers due to its unique molecular architecture aspect, Larsson et  al. [42] proposed a strategic synthesis and interesting biological activities [39, 40]. As a result, for transtaganolides E (90) and F (91) that were poten- Zhao and Beaudry [40], demonstrated a facile synthetic tially beneficial as analogue synthons for basiliolides and strategy for chiral macrocyclic bis(bibenzyl) derivative, transtaganolides. Initially, a geranylated α-pyrone Diels– cavicularin (87) by a controlled regiochemical approach Alder substrate 88 was imperiled to Ireland–Claisen of intramolecular Diels–Alder reaction as described rearrangement to attain a rearranged α-pyrone acid in Scheme  12. Initially, the appropriate key Diels– derivative 89. Further, the high pressure 1.5 GPa/50  °C Alder substrate of vinyl sulfonyl and α-pyrone sub- conveys an IMDA cyclization accomplished the 2:1 dias- stituted phenanthrene analogue 84 was achieved by a tereomeric mixture of transtaganolide E and F in 61% sequential reactions like Claisen-like condensation and yield as illustrated in Scheme 13. R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 9 of 21 Scheme 8 Synthesis of ( ±)-lycorine involving α-pyrone –Diels–Alder cyclization approach Scheme 9 Synthesis of (+)-pseudodeflectusin through cascade reactions of regioselective DAR and lactonization accomplished from 7-hydroxy-α-pyrone Further, Gordon et  al. [43] shortened the total syn- Scheme  14. Initially, the pyrone Diels–Alder substrate thesis of transtaganolide and basiliolide class-com- 92 with electron donating groups was achieved by Negi- pounds through Ireland-Claisen rearrangement (ICRA) shi cross-coupling, and the subsequent one-pot tandem and Diels–Alder cascade approaches as described in ICRA and Diels–Alder sequence reactions resulted in Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 10 of 21 Scheme 10 An efficient and expedient intramolecular α-pyrone-Diels–Alder cyclization approach for the synthesis of Amaryllidacceae alkaloids Scheme 11 Synthesis of (±)-pancratistatin and (±)-1-epi-pancratistatin form Diels–Alder cyclization of β- borylstyrene with α-pyrone R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 11 of 21 Scheme 12 The microwave accustomed intramolecular Diels–Alder cyclization approach for expedient synthesis cavicularin Scheme 13 An IMDA cyclization of a geranylated α-pyrone Diels–Alder substrate for the facile synthesis of transtaganolides E and F 2:1 diastereomeric mixture of transtaganolides C (95) agent [44]. To the expedient synthesis of continuous and D (96). Equally, the acrylated α-pyrone Diels–Alder stereogenic tricyclic triterpenoid 109, Xu et  al. [45], substrate 92 under Ireland-Claisen condition provided proposed a facile transannular Diels–Alder cyclization a 1:2 mixture of C8 diastereomeric 97 in 65% yield. Fur- procedure as illustrated in Scheme  15. Primarily, the ther, the diastereomeric mixture was transformed into key Diels–Alder template of α-pyrone analogue 102 was corresponding tricyclic silyl esters 98, and then palla- achieved over a Boger’s lactonization procedure of highly dium driven [5 + 2] annulation caused the basiliolide strained cyclodec-5-enone 101 with dimethyl methoxy- C (99) and epi-basiliolide C (100), respectively. Thus, methylenemalonate. The subsequent epimerization reac - the α-pyrone Diels–Alder template 92 and its electron- tion of the (+)-α-pyrone analogue 102 in DBU/toluene donating methoxy alkynyl group play a key role in the at 100  °C occasioned the expected (−)-α-pyrone deriva- facile synthesis of the structurally complex transta- tive 103. Further, conducting the transannular Diels– ganolides and basiliolodes. Alder cyclisation of epimerized pyrone derivative 103 in Similarly, vinigrol (109) is another interesting natural DCB/mW at 200  °C procured the strained tricylic ester molecule with a complex molecular framework and is 104 as major product. Succeeding, selective epoxidation prominent as a potent antihypertensive and antitumor by O , reductive cleave peroxide linkage, and directive 2 Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 12 of 21 Scheme 14 Total synthesis of transtaganolide and basiliolide class-compounds by Ireland-Claisen rearrangement (ICRA) and Diels–Alder cascade approaches Burgess’s reaction conditions are the sequence reactions sequence reactions occasioned the (+)-eutipoxide B. concerning to the completion of the total synthesis of Therefore, the efficient and regioselectivity of asym - (−)-vinigrol (109). Therefore, the epimerized product metric Diels–Alder reaction of 3-hydroxy-2-pyrone (−)-α-pyrone analogue 103 synthesis and transannular with dienophile presents a key role in the synthesis of Diels–Alder reaction are the key targets in the synthesis chiral oxygenated cyclohexene epoxide metabolites. of highly strained tricyclic diterpenoid i.e. (−)-vinigrol. Similarly, Tam et  al. [48] demonstrated an efficient Another interesting biologically active oxygenated strategic synthetic approach for the pentacyclic enone cyclohexene epoxide, eutipoxide B (120) was widely intermediate 131 towards biologically imperative Aspi- produced by phytopathogenic fungus Eutypa lata[46]. dosperma alkaloid 132 (Scheme  17). The synthesis was Consistently, Shimizu et al.[47] projected the total syn- commenced with the attainment of endo-bicyclolac- thesis of eutipoxide B (120) through the base cincho- tone 122 in 37% yield by the Diels–Alder cyclization nine promoted asymmetric-Diels–Alder cyclization of of 3-(2-nitrophenyl)-5-bromo-α-pyrone 121 with silyl 3-hydroxy-2-pyrone 110 with electron deficient dieno - vinyl ether. Further, the chronological reactions count- phile 111 convinced the optically active cyclicadduct ing methanolysis, hydroxyl protection, and the perox- 112 at a yield of 74% (Scheme  16). Consequent reac- ide oxidation, and Zn-reduction were driven the indole tions such as methylation, reduction of silyl ether deriv- ester derivative 125 construction. Subsequently, the ative and oxidative cleavage, followed by epoxidation Still coupling with vinyl stannate, ester-group reduc- and Swern oxidation were prompted the chiral epoxy tion, and followed by van Leusen TosMIC homologa- cyclohexane-3-carbaldehyde 117. Further, treatment tion conditions were prompted the nitrile analogue with 2-methylpropenyl Grignard reagent and deprotec- 128 in 61% yield. Likewise, reduction of nitrile, and tion of TBS ether resulted in a 94% yield of the desired then heating with aqueous formaldehyde impinged the (−)-eutipoxide B (120). Though, the base catalyst cin - imino-Diels–Alder cyclization prompted the formation chonidine used rather than cinchonine, the Diels–Alder of important pentacylic enone derivative 131. There - reaction results the (−)-cyclicadduct with 82% yield fore, the α-pyrone Diels–Alder cyclization plays a key and > 95% diastereomeric excess, and the succeeding R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 13 of 21 Scheme 15 A facile transannular Diels–Alder cyclization route for the synthesis of (−)-vinigrol Scheme 16 The total synthesis of eutipoxide B through the base promoted asymmetric-Diels–Alder cyclization of α-pyrone approach Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 14 of 21 Scheme 17 The imino-Diels–Alder cyclization impelled synthesis of pentacylic enone derivative, an analogue of Aspidosperma alkaloid role in pentacyclic enone intermediate synthesis for the prompted the prenylcyclohexene 138. As well, the con- proposed Aspidosperma alkaloid. secutive reactions like Dess-Martin oxidation, Seyferth- Equally, (+)-iso-A82775C (141) is a fascinating dias- Gilbert homologation, and VO(OEt) /TBHP epoxidation tereomic cyclohexene epoxide derivative, deliberated an gave the exclusive diastereomer 140. Finally, anti-selec- important biosynthetic intermediate of various drugs tive copper facilitated S 2′ reaction of diastereomeric for instance chloropupukeananin, pestaloficinols, and epoxide 140 and the TBAF deprotection reactions suc- pestalofones, etc. [49]. Further, it displays an essential ceeded the (+)-iso-A82775C (141) synthesis in 30% yield. role in the biosynthesis of chloropupukeanin (142), a Therefore, the intermolecular Diels–Alder reaction of potent inhibitor of HIV-1 replication and human tumor α-pyrone 133 and the sequential metalation reactions are cells pathogenesis [50]. Given the importance of fun- the prominent strategies to achieve the (+)-iso-A82775C gal metabolite A82775C, Suzuki et  al. [51] commenced of cholropupukeananin (142) synthesis. its total synthesis through enantioselective Diels– As well, a resorcyclic acid lactone (−)-neocosmosin A Alder cyclization, Stille coupling and cross-metathesis (146) was isolated from the fungus Neocosmospora sp., approaches as described in Scheme  18. Principally, the and has been shown to have strong binding properties Diels–Alder reaction of 4-bromo-3-hydroxy α-pyrone with cannabinoid receptors and human opioid [52]. As 133 with methyl 2-chloroacrylate 134 occasioned the this aspect, Lee and Cho [53], demonstrated an efficient optically active endo-cyclic adduct 135 at 67% ee with the and rapid access to neocosmosin A through IMDA and presence of cinchonine base. Further, the sequential reac- cycloreversion approaches as described in Scheme  19. tions such as TES protection, DIBAL reduction, Criegee The target synthesis was motivated by the achievement oxidation by Pb(OAc) occasioned the cyclohexanone of chiral-IMDA α-pyrone substrate 143 by various opti- derivative 136 in 43% yield. Afterwards, the diastereose- mized studies. Consequently, the IMDA reaction of lective reduction of ketone derivative with NaBH(OAc) , α-pyrone bromopropiolate substrate 143 gave the cor- followed by TES protection of hydroxyls ensued the 1,3- responding dibromobenzo macrocyclic lactone 144 in diol 137. Likewise, the Stille coupling with allylSn(n- 64% yield. Further, on exposed to Miyaura reaction and Bu) and Cross-metathesis by Grubb’s catalyst (II) were then followed by oxidation of borate derivative prompted 3 R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 15 of 21 Scheme 18 The intermolecular Diels–Alder reaction of α-pyrone assisted prominent strategies for the synthesis of (+)-iso-A82775C, a key intermediate of chloropupukeananin Scheme 19 The IMDA cyclization α-pyrone approach to the expedient synthesis of (−)-neocosmosin A Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 16 of 21 natural terpenoquinone, the standing review empha- the (−)-macrocyclic resorcinol 145 in 71% yield. Finally, sized the application of Diels–Alder cyclization approach the perceptive methylation of less-hindered hydroxyl to its expedient synthesis. In addition, the terpenoqui- with MeI/K CO accomplished the (−)-neocosmosin A 2 3 nones are resourceful dienophiles that triggered lavish (146) in 78% yield. Therefore, the intramolecular Diels– DAR approaches to the constructive complex natural Alder reaction of the α-pyrone substrate to achieve the products. Further, the Diels–Alder reaction was a facile macrolides like neocosmosin A is an efficient synthetic synthetic approach for the quick generation of regio- and strategy. steroselective complex products with creditable yields. From this aspect, a bioactive sesquiterpene quinone i.e. 3 Diels–Alder approach for the expedient cyclozonarone (152) was widely distributed in marine terpenoquinone arbitrated natural compounds algae Dictyopteris undulata [60], and it absolute configu - As well, terpenoquinone is another interesting stencil ration was (−)-(5R,10R)-cyclozonarone revealed by Cor- found in numerous marine natural products like ses- tes et  al. [61] over an enantioselective synthesis. Later, quiterpene benzoquinones, meroterpenes, meroses- Schroder et  al. [62] demonstrated the fruitful total syn- quiterpenes, norsesquiterpenes, and tetracarbocyclics, thesis of (−)-cyclozonarone through an expedient Diels– etc. [54–56]. Therefore, the substantial attention has Alder cyclization approach as illustrated in Scheme  20. been paid to the terpenoquinone cohesive natural com- Initially, the dehydration reaction of ( +)-albicanol pounds due to its extensive pharmacological properties 147 with Tf O/pyridine occasioned the drima-(8,12), [6, 56]. In this regard, various studies have revealed that (9,11)-diene 148 in 68% yield, which then subjected to certain marine sponges were richest source of bioac- Diels–Alder reaction with benzoquinone 149 resulted a tive terpenoquinones that imperative as antibacterial, mixture of enolization-oxidation cyclic adducts 150 and anticancer, antitumor, antimalarial, and anti-HIV thera- 151 in 75–89% yield. Subsequently, on oxidation of cyclic peutic agents [6, 56–59]. Therefore, some examples of adduct mixture with DDQ primes to (−)-cyclozonarone isolated terpenoquinones and their pharmacologically 152 in 92% yield. Whereas, the targeted sesquiterpene significance are appended in Fig.  2. Considering the quinone 152 was achieved in 35% yield on extending structural diversity and biological prominence of the Fig. 2 Some examples of terpenoquinone articulate bioactive natural molecules [6, 56–59] R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 17 of 21 Scheme 20 Diels–Alder reaction approach for the synthesis of (−)-cyclozonarone the Diels–Alder reaction time to 36  h without subse- antineoplastic properties (Scheme  21). Primarily, the quent DDQ oxidation. Therefore, the pragmatic synthe - cycloaddition reaction of three labdanic diterpenoids 153 sis of 152 was achieved through a controlled Diel-Alder with p-benzoquinone 149 occasioned the corresponding cyclization of diene derivative with benzoquinone over a hydroquinones 155 together with autoxidized quinones static reaction period as described in Scheme 20. 156 and 157 as described in method A, Scheme 21. Fur- Likewise, Miguel del Corral et  al. [63], demonstrated ther, the oxidation of hydroquinones 155 with DDQ was the facile Diels–Alder cycloaddition procedure for ses- stemmed to the respective naphthohydroquinone 158. quiterpenoid quinones/hydroquinones with interesting Also, the Diels–Alder reaction of myrceocommunic Scheme 21 The facile Diels–Alder cycloaddition procedure for the synthesis of sesquiterpenoid quinones/hydroquinones Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 18 of 21 Scheme 22 Diels–Alder cyclization procedure for the synthesis of an active aldehyde intermediate of 8-Ephipuupehedione derivatives 153 with naphthoquinone 159 was stimu- aldehyde intermediate 166 in 71% yield. Therefore, lated the respective diterpenyl anthraquinone 160 and the Diel-Alder cyclization was the static approach that hydroxyanthraquinone 161 as illustrated in method B, ensued 166 in persuasive yields. Subsequent, Baeyer– Scheme  21. In addition, the stated diterpenylquinones Villiger oxidation of 166, saponification, and DDQ (156–158) and diterpenylhydroquinones (160 and 161) oxidation were motivated the 8-ephipuupehedione have been found to be substantial cytotoxic in 0.1–21 µM metabolite 171. against various human tumor cells such as lung carci- As well, the halenaquinone (179), a marine penta- noma (A-549), colon carcinoma (HT-29), murine leuke- cyclic polyketide metabolite with unusual molecu- mia (P-388), and malignant melanoma (MEL-28). lar structure, has been acknowledged as a potent Likewise, another marine anti-leukemia sesquit- antimicrobial agent [66]. Further, Kienzler et  al. erpene 8-ephipuupehedione 171 was found to be [67], demonstrated the asymmetric total synthesis a potent inhibitor of cell-proliferation and associ- of (−)-halenaquinone 179 through inverse-electron ated cancer-pathogenesis paths [64]. As the aspect, demand Diels–Alder cyclization (IEDDAC) approach Alvarez-Manzaneda et  al.[65], demonstrated an facile as labelled in Scheme  23. Primarily, the vinyl furyl car- Diels–Alder cyclization procedure for the synthesis of binol 174 was achieved in 92% yield through C–C func- aldehyde intermediate 166, an essential key synthon tionalized organometallic coupling of pre-prepared [65, for the formation of marine metabolites like ent-chro- 68] furanocyclohexanol 172 and aryl vinyl stannane mazonarol 168 and 8-ephipuupehedione 171 as shown 173. Succeeding desilylation, oxidative demethylation, in Scheme  22. Primarily, the tricyclic pyran diene frag- and metal oxidation of secondary hydroxyls occasioned ment 162 was synthetized from sclareol oxide, which the highly stable key intermediate vinyl quinone of 176. then cycloaddition with α-chloroacrylonitile (dieno- Auxiliary, the high-pressure 10 kbar driven intramo- phile) by DAR procedure provided the regioselctive lecular IEDDAC resulted in the respective tetracyclic cyclic adduct 163 in 70%. Afterwards, the successive adduct 178 at rt, and the subsequent oxidization with treatments of cyclic adduct with DBU/C H , DDQ/ MnO /PhH afford the aromatized (− )-halenaquinone 6 6 2 dioxane and DIBAL/ THF stemmed the essential key (179) in 60% yield. R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 19 of 21 Scheme 23 Diels–Alder reaction approach for the concise synthesis of (−)-halenaquinone Declarations 4 Conclusions In essence, the Diels–Alder reaction is a versatile syn- Competing interests thetic approach to construct the highly complex molecu- All the authors declare that there is no competitive interest related to this work. lar structures of bioactive natural compounds for clinical and therapeutic applications. Further, the existing assess- Author details ment highlighted the role of α-pyrone and terpenoqui- Ural Federal University, 19 Mira St., Ekaterinburg 620002, Russian Federation. Natural Products Division, Department of Chemistry, Sri Venkateswara Univer- none in the synthesis of important bioactive natural sity, Tirupati 517502, India. Ural Division of the Russian Academy of Sciences, compounds by Diels–Alder approach. Moreover, the pre- I. Ya. Postovsky Institute of Organic Synthesis, 22 S. Kovalevskoy St., Ekaterin- sent review may be beneficial as a template for the future burg 620219, Russian Federation. development of new therapeutic leads, and as a key appli- Received: 9 January 2022 Accepted: 11 March 2022 ance for their drug discovery challenges. Abbreviations AIBN: Azobisisobutyronitrile; BHT: Butylated Hydroxytoulene; DAR: Diels–Alder References reaction; DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene; DIBAL: Diisobutylalu- 1. Hu Y, Chen J, Hu G, Yu J, Zhu X, Lin Y, Chen S, Yuan J. Statistical research on minium hydride; DMAP: 4-Dimethylaminopyridine; DPPA: Diphenylphos- the bioactivity of new marine natural products discovered during the 28 phoryl azide; HIV: Human Inmmunodeficiency Virus; IEDDAC: Inverse years from 1985 to 2012. Mar Drugs. 2015;13(2015):202–21. https:// doi. electron demand Diels–Alder cyclization; NaHMDS: Sodium bis(trimethylsilyl) org/ 10. 3390/ md130 10202. amide; NMO: N-Methylmorpholine-N-oxide; TABF: Tetrabutylammonium 2. Ghareeb MA, Tammam MA, El-Demerdash A, Atanasov AG. Insights about fluoride; TBSCl: Tert-butyldimethylsilyl Chloride; TBDPSCl: Tert-butyldiphe - clinically approved and preclinically investigated marine natural products. nylsilyl Chloride; TPAP: Tetrapropylammonium perruthenate; TMSSnBu : Curr Res Biotech. 2020;2:88–102. https:// doi. org/ 10. 1016/j. crbiot. 2020. 09. Trimethylsilyltri-n-butyltin. 3. Lee JS. Recent advances in the synthesis of 2-pyrones. Mar Drugs. Acknowledgements 2015;13:1581–620. https:// doi. org/ 10. 3390/ md130 31581. This work was financially supported by the Grants Council of the President of 4. Marcos IS, Conde A, Moro RF, Basabe P, Diez D, Urones JG. Synthesis of the Russian Federation (# HШ-2700.2020.3) and Russian Scientific Foundation quinone/hydroquinone-sesquiterpenes. Tetrahedron. 2010;66:8280–90. (Grant # 21-13-00304). https:// doi. org/ 10. 1016/j. tet. 2010. 08. 038. 5. 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Assessment on facile Diels–Alder approach of α-pyrone and terpenoquinone for the expedient synthesis of various natural scaffolds

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Abstract

In this scenario, the Diels–Alder reaction is the most prof- 1 Introduction itable approach for the facile synthesis of complex natural The development of innovative pharmaceutical agents compounds with a pharmaceutical grade [7–9]. Further- from natural origin (like marine products) has played a more, the DAR envisioned a highly-atom economical and tremendous role in the modern drug discovery. To date, creative transformation for the development of stereose- a wide variety of complex marine natural products have lective novel drug agents [8, 9]. Likewise, the Diels–Alder been acknowledged as a lead agents to ameliorate the trig- reaction also has a wide choice of variety of industrial gers of various disease like diabetes, microbial infections, applications which includes hetero-DARs, intramolecu- cardiovascular disease, hypertension, immune related lar [4 + 2] cycloadditions, and catalytic reactions for the problems and neurological disorders, etc. [1, 2]. In this stereoselctive transformations. Thus, the Diels–Alder regard, α-pyrone (syn. 2-pyrones) and terpenoquinone cyclization has an amazing strategy in synthetic organic compromising marine compounds have received consid- chemistry and medicinal chemistry applications. erable attention in the medicinal chemistry. Since, they Further, our efforts have continued towards in the Diels– have exhibited wide-variety of pharmacological activi- Alder reactions [10–12], cycloadditions [13–15], and adept- ties such as antibiotic, anticancer, antimicrobial, antima- ness in the structural studies of bioactive natural products larial, and neuroprotective tactics [3, 4]. In addition, the [16–20]. Therefore, the present appraisal aims to emphasize analogues of α-pyrone and terpenoquinones have been the role of Diels–Alder approach of α-pyrones and terpeno- accredited as an imperative bioactive-synthons in numer- quinone in the constructive cycles of natural complexes. ous complex natural products [5]. Therefore, the design Equally, it highlights various Diels–Alder approaches for the and development of α-pyrone and terpenoquinone ana- design and development for bioactive natural compounds logues have become an important strategy in current drug through medicinal chemistry approaches. innovations through adaptive synthetic approaches [3, 6]. R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 3 of 21 conferring to the biosynthetic origin the role of α-pyrone 2 Diels–Alder approach of α‑pyrone synthon was essential for the unusual oxygen pattern of to the pragmatic synthesis of natural highly strained macrocylic analogue 7 presence. compounds Equally, Shin and co-workers reported a total synthe- The chromophore α-pyrone serves as a versatile build - sis of the anti-tumor agent, trans-Dihydronarciclasine ing block in numerous bioactive natural marine products 15 over a Diel-Alder cyclization (Scheme  2) [23]. An such as albidopyrone (antidiabetic), salinipyrone A (anti- important strategy in the synthesis of phenanthridone cancer), wailupemycin A (antimicrobial), tipranavir (anti- 15 was the outline of ring B accomplished through a HIV), pyrenes I–II (anti-infective), and gombapyrone A high selective endo-adduct 10 in 99% yield by the Diels– (glycogen synthase kinase-3β inhibitor) (Fig.  1) [3, 21]. Alder cyclization of α-pyrone derivative 9 with styrene Therefore, there is considerable interest among research - derivative 8. Further, the α,β-unsaturated cyclic adduct ers in drug innovation owing to the unique structural 10 was transformed into a methyl carbamate 13, and and pharmaceutical properties of α-pyrone marine com- then ensuing Bischler-Napieralski reaction of it acylated pounds. In addition, the developments of highly effi - derivative 13 resulted the targeted trans-phenanthridone cient synthetic tactics are needed to access the versatile 15. Later, Cho and his co-worker developed a more effi - analogues of bioactive α-pyrones. Considering all these cient route for large-scale production of 15 by enforcing prominence, an assessment of Diels–Alder approach for the limitations of Bischler-Napisrealski cyclization reac- the expedient synthesis of α-pyrones are summarized as tion of the ester intermediate [24]. Therefore, from the underneath. total synthesis of 15, it has been expanded that α-pyrone Baran and Burns demonstrated the constructive total synthon 9 plays an essential role in the biogenesis of synthesis of an important anti-cancer indeno-tetrahy- trans-dihydronarciclasine. dropyridine analogue i.e., (±)-haouamine A (7) through Further, Tam and Cho demonstrated another interest- a sequential reactions of Stille coupling of pyrone and ing natural antitumor alkaloid i.e., (±)-crinine (19) by Diel-Alder cyclization (Scheme  1) [22]. The introduc - Still coupling and Diels–Alder cyclization approaches tion of α-pyrone chore 2 into the indeno-tetrahydropyr- (Scheme  3) [25]. Primarily, the synthesis of alkaloid 19 dine intermediate 1 by the Still coupling procedure was involves the regioselective coupling of the α-pyrone an important strategy in the synthesis of haouamine A. analogue 9 and aryltin derivative 16 prompted to the As well, another synthetic challenge was the unusual required α-pyrone diene 17 in 72% yield. Subsequently, macrocyclization achieved through the pyrone-alkyne the Diels–Alder cyclization of 17 with TBS vinyl ether Diels–Alder reaction of 5, which embedded leaving of occasioned the mixture of endo/exo-bicyclolactones CO group by a pseudo-boat configuration 6 and subse - (18a/b) in a 2:1 ratio. Further, the sequential reactions quent aromatization of viable precursor to 7. Therefore, O O O O OH O O O OH Pyrone In =1 OH OH Pyrone II n= 3 SalinipyroneA Albidopyrone (Anti-infective) (anticancer) (antidiabetic,PTP1B) CF OH N OH O O O O OH HO OH Tipranavir (anti-HIV) GombapyroneA H CO 3 O (Anti-Alzheimer, GSK-3 ) Wailupemycin A (antimicrobial) Fig. 1 Structures of some nominated biologically potent α-pyrone marine compounds [3, 21] Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 4 of 21 Scheme 1 Synthesis of haoumine A involving pyrone-alkyne Diels–Alder cyclization Scheme 2 Synthesis of trans-dihydronarciclasine through endo-selective Diels–Alder cyclization of endo-bicyclolactone 18a provide the total synthesis of agent to treat psychological disorders, anxiety, depressive tetrahydroisoquinoline alkaloid 19. Thus, from the stated state, alcohol and drug addictive conditions, and neuro- synthetic approach, the regioselective pyrone-aryltin logical disorders [26, 27]. Further, Tam and Cho deliber- coupling and Diels–Alder cyclization plays a title role in ated the facile total synthesis of joubertinamine (26) over the synthesis of endo-bicyclolactone 18a, a key interme- a Still coupling and Diels–Alder cyclization strategies diate of (±)-crinine. (Scheme  4) [26]. As similar to the crinine (19) synthesis, Likewise, an sceletium alkaloid (±)-joubertinamine the regioselctive coupling and Diels–Alder cyclization of (26) has been accredited an pharmaceutically important α-pyrone 9 was facilitated the essential key cyclohexene R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 5 of 21 Scheme 3 Synthesis of endo-bicyclolactone, a key intermediate of crinine by Still coupling and Diels–Alder cyclization methodologies Scheme 4 Synthesis of joubertinamine through Still coupling and Diels–Alder cyclization paths intermediate 24. Subsequently, the PCC oxidation and aryl stannane 27. Further, the ring-opening of a selec- then witting reactions accomplished the target com- tive diastereomeric adduct 28 and then, followed by pound, joubertinamine 26. hydroxyl protection, amination and carbamate erection Galanthamine is a biologically important cyclic ter- occasioned the respective, MOM ether and ester func- tiary amine class alkaloid used to treat the symptoms of tionalized compound 29. Then after, DIBAL reduction, Alzheimer disease [28]. In this regard, Chang et  al.[29] Dess-Martin peroxidation (DMP) followed by Witting demonstrated an efficient synthetic strategy for the total olefination caused in a diastereomeric mixture of enol synthesis of galanthamine (32) through tandem C3-selec- ether derivative 30 in 46% yield. Similarly, accompany- tive Still coupling and IMDA approaches as described in ing TFA hydrolysis, reductive amination provided the Scheme  5. Essentially, the endo-tetracyclolactone adduct tetracycle-alkaloid derivative 31. Finally, the sequence 28 was achieved over a Stille coupling of α-pyrone 9 with reactions of DMP, debromination and the L-selectride Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 6 of 21 Scheme 5 An efficient approach for the total synthesis of Galanthamine through tandem C3-selective Still coupling and IMDA approaches reduction furnished galanthamine (32) in 48% yield. cyclohex-3-enecarboxylate derivative 44. Consequent Therefore, the stereoselective tandem Still coupling/ sequential reactions of Curtius rearrangement, lithium IMDA reaction of α-pyrone 9 was the key strategies to hydroxide treatment resulted in a bicyclic amide 45 as attain the endo-cyclic adduct 28 in the effective total syn - described in path A, Scheme 7. Further the amide 45 was thesis of galanthamine. imperiled to Pictet–Spengler reaction; Pd/C hydrogena- Likewise, the continuing efforts of Tam and colleagues tion and LiAlH reduction accomplish the total synthesis [30] have pronounced a unified approach to the total syn - of α-lycorane (46). thesis of various tetrahydroisoquinoline alkaloids such Equally, the key intermediate cycohex-3-enecrboxylate as (±)-crinine 19, (±)-crinamine 39, and (±)-6a-epi- 44 was subjected to dihydroxylation with OsO /NMO crinamine 40 (Scheme  6). Primarily, the key bicyclolac- and the Curtius rearrangement motivated the diol lactam tone intermediate 18a was achieved by Still coupling and 48 in 51% yield [32]. Further, the protection of hydroxyl Diels–Alder reaction of α-pyrone synthon 9 as described groups with TsOH/Me CO and then, followed by car- in Scheme  3. Further, the endo-bicyclolactone 18a was bonyl reduction with LiAlH led to the bicyclic pyrroli- transformed into respective key cyclohexene deriva- dine 49 as shown in path B, Scheme  7. The concomitant tives 33–38 as illustrated in scheme  6. Further, diverse Bischeler–Napieralski reaction of bicyclic pyrrolidine 49 sequential reactions were transformed into respective, cyclized to tetracyclic amide analogue 50 in 76% yield. crinine-type alkaloids 19, 39 and 40. Therefore, α-pyrone Finally, the amide derivative was subjected to a series of analogue was an imperative enophile synthon in the bio- various 8 step-reactions such as protection; deprotection genetic Diels–Alder approach of various complex natural of hydroxyl, and reduction conditions were furnished the compounds. target derivative 1-deoxylycorine (51). Lycorine, lycorane, and 1-deoxylycorine are the most Likewise, Shin et  al.[33] demonstrated the amended attention-grabbing and pharmacologically important total synthesis of ( ±)-lycorine (62) with the provision pyrrolo[de]phenanthridine natural alkaloids [31, 32]. of chiral bicyclolactone alcohol 54 through Diels–Alder The total synthesis of α-lycorane (46) initiated by the cyclization of pyrone 9 and β-borylstyrene 52 (Scheme 8). Diels–Alder reaction of the α-pyrone derivative 9 with a Further, the hydroxyl lactone 54 was subjected to acidic styrene dienophile 41 which motivated the 10:1 mixture methanolysis and followed by Eschenmoser-Claisen rear- of diastereomeric cyclic adducts [32]. Further, the reduc- rangement occasioned the key intermediate cyclohex- tive debromination of nominated endo-cyclic adduct 3-enecarboxylate derivative 56. Subsequently, a sequence with Zn occasioned the desired bicyclic lactone 42. Sub- of reactions such as mCPBA epoxidation, Mitsunobu sequent, acid-catalyzed methylation and the Eschen- reaction, epoxide ring-opening, and Pictet-Spengler con- moser–Claisen rearrangement prompted the important ditions afforded the tetracyclic lactam 61 in 70% yield. R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 7 of 21 Scheme 6 Synthesis of crinine-type alkaloids through an important enophile α-pyrone synthon derived Diels–Alder approach Finally, the L iAlH reduction of diacetate tetracyclic lac- depends on the substrate α-pyrone amide-tethered inter- tam 61 prompted the ( ±)-lycorine (62) at a yield of 41%. mediate I (63) and II (71), which are readily accessible Sato and co-workers [34] demonstrated the total through augmented studies. Further, the sequential reac- synthesis of another important anti-tumor scaffold tions of the Diels–Alder cyclic adduct (i.e. indole deriva- (+)-pseudodeflectusin (68) by Diels–Alder and lactoni - tives) were renovated to corresponding derivatives such zation methods (Scheme  9). Primarily, the base-pro- as garcilamine, mesembrine and Δ -mesembrenone. The moted Diels–Alder cyclization of 7-hydroxy-α-pyrone success of the stated intramolecular Diels–Alder cycli- analogue 63 with an alkyne 64, prompted the desired zation of α-pyrone analogues 63 and 71 have yielded (-)-(R)-bromomellein 65 as an exclusively cyclic adduct diverse indole and hydroindole group alkaloids in a low in 78% yield. Further, the isochromanone adduct was step-count methodology. adapted into tricyclic furanone intermediate 67 through Likewise, (±)-pancratistatin (81) and ( ±)-1-epi-pan- the sequential reactions of alkylation with methyl bro- cratistatin (83) are two important anti-cancer Amarylli- moacetate, lactonization with TMSSnBu /CsF in dif- daceae tricyclic alkaloids of natural origin [36]. Initially, fident conditions. Therefore, cascade reactions of Jung and co-workers [37] demonstrated the total syn- regioselective DAR and lactonization accomplished from thesis of (±)-pancratistatin (81) by the cascade reactions 7-hydroxy-α-pyrone (63) are prominent in the synthesis of Diels–Alder cyclization, Curtius rearrangement and of ( +)-pseudodeflectusin 68. Bischler-Napieralski procedures. Later, the Cho group Likewise, Gan et  al. [35], established an efficient and developed an advance synthetic procedure for both the expedient intramolecular pyrone Diels–Alder cycli- (±)-pancratistatin (81) and (±)-1-epi-pancratistatin zation approach for the synthesis of Amaryllidacceae (83), by identical reaction procedure with same starting alkaloids viz., garcilamine (70), Δ -mesembrenone (73) materials of β-borylstyrene 75 (Scheme  11) [38]. Pri- and mesembrine (74) as described in Scheme  10. The marily, the dienophile β-borylstyrene undergoes DAR adeptness and regioselectivity of the [4 + 2] cyclization cyclization with α-pyrone (9, as diene) occasioned the Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 8 of 21 Scheme 7 The efficient α-pyrone Diels–Alder approach for expedient synthesis of pyrrolo[de]phenanthridine alkaloids, α-lycorane and 1-deoxylycorine endo-bicyclolactone 76 exclusively in 86% yield. Sub- Horner-Wadsworth-Emmons reaction procedures. Fur- sequent oxidation with sodium perborate stemmed the ther, the intramolecular Diels–Alder cyclization of cas- desired biclolactone alcohol 77 in 81% yield, and then cade substrate under microwave conditions occasioned the debromination, methanolysis primes to the key inter- the cavicularin 87 in 80% yield and its regioisomer 88 mediate i.e., cyclohexene-diol 78. Further, the Curtius at a yield of 58%, respectively. Therefore, the pyrone rearrangement and Bischler-Napieralski reactions of cor- Diels–Alder substrate 84 is essential for the construct responding tetraol intermediates occasioned the targeted of conformationally macrocyclic bis(bibenzyl) natural alkaloids 81 and 83, respectively. Therefore, the stated metabolites. total synthesis of 81 and 83 became worthwhile with the Basiliolide and transtaganolides are pharmacologi- formation of endo-cyclicadduct 76 in the inverse electron cally important natural metabolites with a novel frame- demand Diels–Alder cyclization of the α-pyrone deriva- work of oxabicyclo[2.2.2]octene core derivatives [41]. tive 9 with β-borylstyrene 75. u Th s, the concise strategies and stoichiometric reagents Further, conformationally chiral molecule cavicu- are required to accomplish the total synthesis of unusual larin 87 has been reported to attract the attention of complex tricyclic substrates on an industrial scale. As this researchers due to its unique molecular architecture aspect, Larsson et  al. [42] proposed a strategic synthesis and interesting biological activities [39, 40]. As a result, for transtaganolides E (90) and F (91) that were poten- Zhao and Beaudry [40], demonstrated a facile synthetic tially beneficial as analogue synthons for basiliolides and strategy for chiral macrocyclic bis(bibenzyl) derivative, transtaganolides. Initially, a geranylated α-pyrone Diels– cavicularin (87) by a controlled regiochemical approach Alder substrate 88 was imperiled to Ireland–Claisen of intramolecular Diels–Alder reaction as described rearrangement to attain a rearranged α-pyrone acid in Scheme  12. Initially, the appropriate key Diels– derivative 89. Further, the high pressure 1.5 GPa/50  °C Alder substrate of vinyl sulfonyl and α-pyrone sub- conveys an IMDA cyclization accomplished the 2:1 dias- stituted phenanthrene analogue 84 was achieved by a tereomeric mixture of transtaganolide E and F in 61% sequential reactions like Claisen-like condensation and yield as illustrated in Scheme 13. R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 9 of 21 Scheme 8 Synthesis of ( ±)-lycorine involving α-pyrone –Diels–Alder cyclization approach Scheme 9 Synthesis of (+)-pseudodeflectusin through cascade reactions of regioselective DAR and lactonization accomplished from 7-hydroxy-α-pyrone Further, Gordon et  al. [43] shortened the total syn- Scheme  14. Initially, the pyrone Diels–Alder substrate thesis of transtaganolide and basiliolide class-com- 92 with electron donating groups was achieved by Negi- pounds through Ireland-Claisen rearrangement (ICRA) shi cross-coupling, and the subsequent one-pot tandem and Diels–Alder cascade approaches as described in ICRA and Diels–Alder sequence reactions resulted in Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 10 of 21 Scheme 10 An efficient and expedient intramolecular α-pyrone-Diels–Alder cyclization approach for the synthesis of Amaryllidacceae alkaloids Scheme 11 Synthesis of (±)-pancratistatin and (±)-1-epi-pancratistatin form Diels–Alder cyclization of β- borylstyrene with α-pyrone R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 11 of 21 Scheme 12 The microwave accustomed intramolecular Diels–Alder cyclization approach for expedient synthesis cavicularin Scheme 13 An IMDA cyclization of a geranylated α-pyrone Diels–Alder substrate for the facile synthesis of transtaganolides E and F 2:1 diastereomeric mixture of transtaganolides C (95) agent [44]. To the expedient synthesis of continuous and D (96). Equally, the acrylated α-pyrone Diels–Alder stereogenic tricyclic triterpenoid 109, Xu et  al. [45], substrate 92 under Ireland-Claisen condition provided proposed a facile transannular Diels–Alder cyclization a 1:2 mixture of C8 diastereomeric 97 in 65% yield. Fur- procedure as illustrated in Scheme  15. Primarily, the ther, the diastereomeric mixture was transformed into key Diels–Alder template of α-pyrone analogue 102 was corresponding tricyclic silyl esters 98, and then palla- achieved over a Boger’s lactonization procedure of highly dium driven [5 + 2] annulation caused the basiliolide strained cyclodec-5-enone 101 with dimethyl methoxy- C (99) and epi-basiliolide C (100), respectively. Thus, methylenemalonate. The subsequent epimerization reac - the α-pyrone Diels–Alder template 92 and its electron- tion of the (+)-α-pyrone analogue 102 in DBU/toluene donating methoxy alkynyl group play a key role in the at 100  °C occasioned the expected (−)-α-pyrone deriva- facile synthesis of the structurally complex transta- tive 103. Further, conducting the transannular Diels– ganolides and basiliolodes. Alder cyclisation of epimerized pyrone derivative 103 in Similarly, vinigrol (109) is another interesting natural DCB/mW at 200  °C procured the strained tricylic ester molecule with a complex molecular framework and is 104 as major product. Succeeding, selective epoxidation prominent as a potent antihypertensive and antitumor by O , reductive cleave peroxide linkage, and directive 2 Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 12 of 21 Scheme 14 Total synthesis of transtaganolide and basiliolide class-compounds by Ireland-Claisen rearrangement (ICRA) and Diels–Alder cascade approaches Burgess’s reaction conditions are the sequence reactions sequence reactions occasioned the (+)-eutipoxide B. concerning to the completion of the total synthesis of Therefore, the efficient and regioselectivity of asym - (−)-vinigrol (109). Therefore, the epimerized product metric Diels–Alder reaction of 3-hydroxy-2-pyrone (−)-α-pyrone analogue 103 synthesis and transannular with dienophile presents a key role in the synthesis of Diels–Alder reaction are the key targets in the synthesis chiral oxygenated cyclohexene epoxide metabolites. of highly strained tricyclic diterpenoid i.e. (−)-vinigrol. Similarly, Tam et  al. [48] demonstrated an efficient Another interesting biologically active oxygenated strategic synthetic approach for the pentacyclic enone cyclohexene epoxide, eutipoxide B (120) was widely intermediate 131 towards biologically imperative Aspi- produced by phytopathogenic fungus Eutypa lata[46]. dosperma alkaloid 132 (Scheme  17). The synthesis was Consistently, Shimizu et al.[47] projected the total syn- commenced with the attainment of endo-bicyclolac- thesis of eutipoxide B (120) through the base cincho- tone 122 in 37% yield by the Diels–Alder cyclization nine promoted asymmetric-Diels–Alder cyclization of of 3-(2-nitrophenyl)-5-bromo-α-pyrone 121 with silyl 3-hydroxy-2-pyrone 110 with electron deficient dieno - vinyl ether. Further, the chronological reactions count- phile 111 convinced the optically active cyclicadduct ing methanolysis, hydroxyl protection, and the perox- 112 at a yield of 74% (Scheme  16). Consequent reac- ide oxidation, and Zn-reduction were driven the indole tions such as methylation, reduction of silyl ether deriv- ester derivative 125 construction. Subsequently, the ative and oxidative cleavage, followed by epoxidation Still coupling with vinyl stannate, ester-group reduc- and Swern oxidation were prompted the chiral epoxy tion, and followed by van Leusen TosMIC homologa- cyclohexane-3-carbaldehyde 117. Further, treatment tion conditions were prompted the nitrile analogue with 2-methylpropenyl Grignard reagent and deprotec- 128 in 61% yield. Likewise, reduction of nitrile, and tion of TBS ether resulted in a 94% yield of the desired then heating with aqueous formaldehyde impinged the (−)-eutipoxide B (120). Though, the base catalyst cin - imino-Diels–Alder cyclization prompted the formation chonidine used rather than cinchonine, the Diels–Alder of important pentacylic enone derivative 131. There - reaction results the (−)-cyclicadduct with 82% yield fore, the α-pyrone Diels–Alder cyclization plays a key and > 95% diastereomeric excess, and the succeeding R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 13 of 21 Scheme 15 A facile transannular Diels–Alder cyclization route for the synthesis of (−)-vinigrol Scheme 16 The total synthesis of eutipoxide B through the base promoted asymmetric-Diels–Alder cyclization of α-pyrone approach Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 14 of 21 Scheme 17 The imino-Diels–Alder cyclization impelled synthesis of pentacylic enone derivative, an analogue of Aspidosperma alkaloid role in pentacyclic enone intermediate synthesis for the prompted the prenylcyclohexene 138. As well, the con- proposed Aspidosperma alkaloid. secutive reactions like Dess-Martin oxidation, Seyferth- Equally, (+)-iso-A82775C (141) is a fascinating dias- Gilbert homologation, and VO(OEt) /TBHP epoxidation tereomic cyclohexene epoxide derivative, deliberated an gave the exclusive diastereomer 140. Finally, anti-selec- important biosynthetic intermediate of various drugs tive copper facilitated S 2′ reaction of diastereomeric for instance chloropupukeananin, pestaloficinols, and epoxide 140 and the TBAF deprotection reactions suc- pestalofones, etc. [49]. Further, it displays an essential ceeded the (+)-iso-A82775C (141) synthesis in 30% yield. role in the biosynthesis of chloropupukeanin (142), a Therefore, the intermolecular Diels–Alder reaction of potent inhibitor of HIV-1 replication and human tumor α-pyrone 133 and the sequential metalation reactions are cells pathogenesis [50]. Given the importance of fun- the prominent strategies to achieve the (+)-iso-A82775C gal metabolite A82775C, Suzuki et  al. [51] commenced of cholropupukeananin (142) synthesis. its total synthesis through enantioselective Diels– As well, a resorcyclic acid lactone (−)-neocosmosin A Alder cyclization, Stille coupling and cross-metathesis (146) was isolated from the fungus Neocosmospora sp., approaches as described in Scheme  18. Principally, the and has been shown to have strong binding properties Diels–Alder reaction of 4-bromo-3-hydroxy α-pyrone with cannabinoid receptors and human opioid [52]. As 133 with methyl 2-chloroacrylate 134 occasioned the this aspect, Lee and Cho [53], demonstrated an efficient optically active endo-cyclic adduct 135 at 67% ee with the and rapid access to neocosmosin A through IMDA and presence of cinchonine base. Further, the sequential reac- cycloreversion approaches as described in Scheme  19. tions such as TES protection, DIBAL reduction, Criegee The target synthesis was motivated by the achievement oxidation by Pb(OAc) occasioned the cyclohexanone of chiral-IMDA α-pyrone substrate 143 by various opti- derivative 136 in 43% yield. Afterwards, the diastereose- mized studies. Consequently, the IMDA reaction of lective reduction of ketone derivative with NaBH(OAc) , α-pyrone bromopropiolate substrate 143 gave the cor- followed by TES protection of hydroxyls ensued the 1,3- responding dibromobenzo macrocyclic lactone 144 in diol 137. Likewise, the Stille coupling with allylSn(n- 64% yield. Further, on exposed to Miyaura reaction and Bu) and Cross-metathesis by Grubb’s catalyst (II) were then followed by oxidation of borate derivative prompted 3 R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 15 of 21 Scheme 18 The intermolecular Diels–Alder reaction of α-pyrone assisted prominent strategies for the synthesis of (+)-iso-A82775C, a key intermediate of chloropupukeananin Scheme 19 The IMDA cyclization α-pyrone approach to the expedient synthesis of (−)-neocosmosin A Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 16 of 21 natural terpenoquinone, the standing review empha- the (−)-macrocyclic resorcinol 145 in 71% yield. Finally, sized the application of Diels–Alder cyclization approach the perceptive methylation of less-hindered hydroxyl to its expedient synthesis. In addition, the terpenoqui- with MeI/K CO accomplished the (−)-neocosmosin A 2 3 nones are resourceful dienophiles that triggered lavish (146) in 78% yield. Therefore, the intramolecular Diels– DAR approaches to the constructive complex natural Alder reaction of the α-pyrone substrate to achieve the products. Further, the Diels–Alder reaction was a facile macrolides like neocosmosin A is an efficient synthetic synthetic approach for the quick generation of regio- and strategy. steroselective complex products with creditable yields. From this aspect, a bioactive sesquiterpene quinone i.e. 3 Diels–Alder approach for the expedient cyclozonarone (152) was widely distributed in marine terpenoquinone arbitrated natural compounds algae Dictyopteris undulata [60], and it absolute configu - As well, terpenoquinone is another interesting stencil ration was (−)-(5R,10R)-cyclozonarone revealed by Cor- found in numerous marine natural products like ses- tes et  al. [61] over an enantioselective synthesis. Later, quiterpene benzoquinones, meroterpenes, meroses- Schroder et  al. [62] demonstrated the fruitful total syn- quiterpenes, norsesquiterpenes, and tetracarbocyclics, thesis of (−)-cyclozonarone through an expedient Diels– etc. [54–56]. Therefore, the substantial attention has Alder cyclization approach as illustrated in Scheme  20. been paid to the terpenoquinone cohesive natural com- Initially, the dehydration reaction of ( +)-albicanol pounds due to its extensive pharmacological properties 147 with Tf O/pyridine occasioned the drima-(8,12), [6, 56]. In this regard, various studies have revealed that (9,11)-diene 148 in 68% yield, which then subjected to certain marine sponges were richest source of bioac- Diels–Alder reaction with benzoquinone 149 resulted a tive terpenoquinones that imperative as antibacterial, mixture of enolization-oxidation cyclic adducts 150 and anticancer, antitumor, antimalarial, and anti-HIV thera- 151 in 75–89% yield. Subsequently, on oxidation of cyclic peutic agents [6, 56–59]. Therefore, some examples of adduct mixture with DDQ primes to (−)-cyclozonarone isolated terpenoquinones and their pharmacologically 152 in 92% yield. Whereas, the targeted sesquiterpene significance are appended in Fig.  2. Considering the quinone 152 was achieved in 35% yield on extending structural diversity and biological prominence of the Fig. 2 Some examples of terpenoquinone articulate bioactive natural molecules [6, 56–59] R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 17 of 21 Scheme 20 Diels–Alder reaction approach for the synthesis of (−)-cyclozonarone the Diels–Alder reaction time to 36  h without subse- antineoplastic properties (Scheme  21). Primarily, the quent DDQ oxidation. Therefore, the pragmatic synthe - cycloaddition reaction of three labdanic diterpenoids 153 sis of 152 was achieved through a controlled Diel-Alder with p-benzoquinone 149 occasioned the corresponding cyclization of diene derivative with benzoquinone over a hydroquinones 155 together with autoxidized quinones static reaction period as described in Scheme 20. 156 and 157 as described in method A, Scheme 21. Fur- Likewise, Miguel del Corral et  al. [63], demonstrated ther, the oxidation of hydroquinones 155 with DDQ was the facile Diels–Alder cycloaddition procedure for ses- stemmed to the respective naphthohydroquinone 158. quiterpenoid quinones/hydroquinones with interesting Also, the Diels–Alder reaction of myrceocommunic Scheme 21 The facile Diels–Alder cycloaddition procedure for the synthesis of sesquiterpenoid quinones/hydroquinones Rammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 18 of 21 Scheme 22 Diels–Alder cyclization procedure for the synthesis of an active aldehyde intermediate of 8-Ephipuupehedione derivatives 153 with naphthoquinone 159 was stimu- aldehyde intermediate 166 in 71% yield. Therefore, lated the respective diterpenyl anthraquinone 160 and the Diel-Alder cyclization was the static approach that hydroxyanthraquinone 161 as illustrated in method B, ensued 166 in persuasive yields. Subsequent, Baeyer– Scheme  21. In addition, the stated diterpenylquinones Villiger oxidation of 166, saponification, and DDQ (156–158) and diterpenylhydroquinones (160 and 161) oxidation were motivated the 8-ephipuupehedione have been found to be substantial cytotoxic in 0.1–21 µM metabolite 171. against various human tumor cells such as lung carci- As well, the halenaquinone (179), a marine penta- noma (A-549), colon carcinoma (HT-29), murine leuke- cyclic polyketide metabolite with unusual molecu- mia (P-388), and malignant melanoma (MEL-28). lar structure, has been acknowledged as a potent Likewise, another marine anti-leukemia sesquit- antimicrobial agent [66]. Further, Kienzler et  al. erpene 8-ephipuupehedione 171 was found to be [67], demonstrated the asymmetric total synthesis a potent inhibitor of cell-proliferation and associ- of (−)-halenaquinone 179 through inverse-electron ated cancer-pathogenesis paths [64]. As the aspect, demand Diels–Alder cyclization (IEDDAC) approach Alvarez-Manzaneda et  al.[65], demonstrated an facile as labelled in Scheme  23. Primarily, the vinyl furyl car- Diels–Alder cyclization procedure for the synthesis of binol 174 was achieved in 92% yield through C–C func- aldehyde intermediate 166, an essential key synthon tionalized organometallic coupling of pre-prepared [65, for the formation of marine metabolites like ent-chro- 68] furanocyclohexanol 172 and aryl vinyl stannane mazonarol 168 and 8-ephipuupehedione 171 as shown 173. Succeeding desilylation, oxidative demethylation, in Scheme  22. Primarily, the tricyclic pyran diene frag- and metal oxidation of secondary hydroxyls occasioned ment 162 was synthetized from sclareol oxide, which the highly stable key intermediate vinyl quinone of 176. then cycloaddition with α-chloroacrylonitile (dieno- Auxiliary, the high-pressure 10 kbar driven intramo- phile) by DAR procedure provided the regioselctive lecular IEDDAC resulted in the respective tetracyclic cyclic adduct 163 in 70%. Afterwards, the successive adduct 178 at rt, and the subsequent oxidization with treatments of cyclic adduct with DBU/C H , DDQ/ MnO /PhH afford the aromatized (− )-halenaquinone 6 6 2 dioxane and DIBAL/ THF stemmed the essential key (179) in 60% yield. R ammohan et al. Natural Products and Bioprospecting (2022) 12:12 Page 19 of 21 Scheme 23 Diels–Alder reaction approach for the concise synthesis of (−)-halenaquinone Declarations 4 Conclusions In essence, the Diels–Alder reaction is a versatile syn- Competing interests thetic approach to construct the highly complex molecu- All the authors declare that there is no competitive interest related to this work. lar structures of bioactive natural compounds for clinical and therapeutic applications. Further, the existing assess- Author details ment highlighted the role of α-pyrone and terpenoqui- Ural Federal University, 19 Mira St., Ekaterinburg 620002, Russian Federation. Natural Products Division, Department of Chemistry, Sri Venkateswara Univer- none in the synthesis of important bioactive natural sity, Tirupati 517502, India. Ural Division of the Russian Academy of Sciences, compounds by Diels–Alder approach. Moreover, the pre- I. Ya. Postovsky Institute of Organic Synthesis, 22 S. Kovalevskoy St., Ekaterin- sent review may be beneficial as a template for the future burg 620219, Russian Federation. development of new therapeutic leads, and as a key appli- Received: 9 January 2022 Accepted: 11 March 2022 ance for their drug discovery challenges. Abbreviations AIBN: Azobisisobutyronitrile; BHT: Butylated Hydroxytoulene; DAR: Diels–Alder References reaction; DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene; DIBAL: Diisobutylalu- 1. Hu Y, Chen J, Hu G, Yu J, Zhu X, Lin Y, Chen S, Yuan J. Statistical research on minium hydride; DMAP: 4-Dimethylaminopyridine; DPPA: Diphenylphos- the bioactivity of new marine natural products discovered during the 28 phoryl azide; HIV: Human Inmmunodeficiency Virus; IEDDAC: Inverse years from 1985 to 2012. Mar Drugs. 2015;13(2015):202–21. https:// doi. electron demand Diels–Alder cyclization; NaHMDS: Sodium bis(trimethylsilyl) org/ 10. 3390/ md130 10202. amide; NMO: N-Methylmorpholine-N-oxide; TABF: Tetrabutylammonium 2. 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Published: Dec 1, 2022

Keywords: α-Pyrone; Diels–Alder reaction (DAR); Marine natural compounds; Terpenoquinone; Total synthesis

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