Skip to content
Research Article Open access CC BY 4.0

4-Hydroxy-2-pyrones: Synthesis, Natural Products, and Application

Vladislav V. Fedin, Dmitrii L. Obydennov, Sergei A. Usachev, Vyacheslav Y. Sosnovskikh

Organics · pp. 539–561 · Published 15 Dec 2023

10.3390/org4040037

Abstract

4-Hydroxy-2-pyrones are of interest as potential biorenewable molecules for a sustainable transition from biomass feedstock to valuable chemical products. This review focuses on the methodologies for the synthesis of 4-hydroxy-2-pyrones published over the last 20 years. These pyrones as polyketides are widespread in Nature and possess versatile bioactivity that makes them an attractive target for synthesis and modification. Biosynthetic paths of the pyrones are actively developed and used as biotechnological approaches for the construction of natural and unnatural polysubstituted 4-hydroxy-2-pyrones. The major synthetical methods are biomimetic and are based on the cyclization of tricarbonyl compounds. Novel chemical methods of de novo synthesis based on alkyne cyclizations using transition metal complexes and ketene transformations allow for straightforward access to 4-hydroxy-2-pyrones and have been applied for the construction of natural products. Possible directions for further pyrone ring modification are discussed.

Ketene Chemistry Alkyne Ring (chemistry) Natural product Combinatorial chemistry Biochemical engineering Organic chemistry

References (129)

  1. 1 Dobler, 2021, 2-Pyrone—A Privileged Heterocycle and Widespread Motif [DOI]
  2. 2 Lee, 2015, Recent Advances in the Synthesis of 2-Pyrones [DOI]
  3. 3 Singh, 2020, Pyrone-derived marine natural products: A review on isolation, bio-activities and synthesis [DOI]
  4. 4 Ahmad, 2021, Emergence of 2-Pyrone and Its Derivatives, from Synthesis to Biological Perspective: An Overview and Current Status [DOI]
  5. 5 Bhat, 2017, α-pyrones: Small molecules with versatile structural diversity reflected in multiple pharmacological activities-an update [DOI]
  6. 6 2016, Biosynthesis of α-pyrones [DOI]
  7. 7 Dickinson, 1993, Microbial Pyran-2-ones and Dihydropyran-2-ones [DOI]
  8. 8 McGlacken, 2005, 2-Pyrone natural products and mimetics: Isolation, characterisation and biological activity [DOI]
  9. 9 Bhat, 2017, α-Pyrones and their hydroxylated analogs as promising scaffolds against Mycobacterium tuberculosis [DOI]
  10. 10 Xiong, Z., Wang, R., Xia, T., Zhang, S., Ma, S., and Guo, Z. (2023). Natural Products and Biological Activity from Actinomycetes Associated with Marine Algae. Molecules, 28. [DOI]
  11. 11 Obydennov, 2020, Triacetic acid lactone as a bioprivileged molecule in organic synthesis [DOI]
  12. 12 Jilalat, 2017, Dehydroacetic acid (Part 1): Chemical and pharmacological properties
  13. 13 Fadda, 2016, Reactivity of Dehydroacetic Acid in Organic Synthesis [DOI]
  14. 14 Chen, 2021, Production of Piperidine and δ-Lactam Chemicals from Biomass-Derived Triacetic Acid Lactone [DOI]
  15. 15 Demarteau, 2023, Biorenewable and circular polydiketoenamine plastics [DOI]
  16. 16 Sajjad, 2021, Ring opening polymerization of β-acetoxy-δ-methylvalerolactone, a triacetic acid lactone derivative [DOI]
  17. 17 Ortin, 2022, Persulfate-promoted synthesis of biphenyl compounds in water from biomass-derived triacetic acid lactone [DOI]
  18. 18 Obydennov, 2018, Bio-based triacetic acid lactone in the synthesis of azaheterocycles via a ring-opening transformation [DOI]
  19. 19 Kornev, 2020, Reactions of 3-functionalized chromones with triacetic acid lactone [DOI]
  20. 20 Obydennov, 2018, Synthesis of Multifunctionalized 2,3-Dihydro-4-pyridones and 4-Pyridones via the Reaction of Carbamoylated Enaminones with Aldehydes [DOI]
  21. 21 Huo, 2022, Triacetic Acid Lactone and 4-Hydroxycoumarin as Bioprivileged Molecules for the Development of Performance-Advantaged Organic Corrosion Inhibitors [DOI]
  22. 22 Liu, Y., Jin, Y., Xu, P., Deng, L., Liu, H., and Wang, F. (2023). Recent advances and perspectives on the biomass-derived production of the platform chemical triacetic acid lactone by engineered cell factories. Biochem. Eng. J., 197. [DOI]
  23. 23 Chia, 2012, Triacetic acid lactone as a potential biorenewable platform chemical [DOI]
  24. 24 Onda, 2017, Reinvestigation of the Biomimetic Cyclization of 3,5-Diketo Esters: Application to the Total Synthesis of Cyercene A, an α-Methoxy-γ-Pyrone-Containing Polypropionate [DOI]
  25. 25 Garey, 1996, An Approach to Substituted 4-Hydroxypyran-2-ones: The Total Synthesis of Phenoxan [DOI]
  26. 26 Shimamura, 2007, Total Synthesis and Biological Evaluation of Verticipyrone and Analogues [DOI]
  27. 27 Ishibashi, 1996, Total synthesis of phenoxan and a related pyrone derivative [DOI]
  28. 28 Sharma, 2011, Total Synthesis of Polypropionate-Derived γ-Pyrone Natural Products
  29. 29 Burkhardt, 2018, Synthesis and Absolute Configuration of Natural 2-Pyrones [DOI]
  30. 30 Rodriguez, 2007, Total synthesis of cyercene A and the biomimetic synthesis of (±)-9,10-deoxytridachione and (±)-ocellapyrone A [DOI]
  31. 31 Liang, 2005, Stereoselective Synthesis of Cyercene A and the Placidenes [DOI]
  32. 32 Ramesh, 2012, First total synthesis of salinipyrone A using highly stereoselective vinylogous Mukaiyama aldol reaction [DOI]
  33. 33 Shishido, 2010, Concise and Efficient Synthesis of 4-Hydroxy-2-pyrones from Pentane-2,4-diones [DOI]
  34. 34 Hoffmann, 1987, Functionalization of 3,5,6-trialkyl-4-hydroxy-2-pyrones in the 6-α position [DOI]
  35. 35 Minassi, 2012, A Multicomponent Carba-Betti Strategy to Alkylidene Heterodimers—Total Synthesis and Structure–Activity Relationships of Arzanol [DOI]
  36. 36 Zhang, 2002, An Efficient Stereoselective Total Synthesis of dl-Sesquicillin, a Glucocorticoid Antagonist [DOI]
  37. 37 Katoh, 2014, Total Synthesis of Diterpenoid Pyrones, Nalanthalide, Sesquicillin, Candelalides A–C, and Subglutinols A, B [DOI]
  38. 38 Arndt, 1940, Dehydroacetic acid [DOI]
  39. 39 Sarhan, 2020, A novel synthetic approach to pyran-2,4-dione scaffold production: Microwave-assisted dimerization, cyclization, and expeditious regioselective conversion into β-enamino-pyran-2,4-diones [DOI]
  40. 40 Bouthillette, 2017, Isolation of the antibiotic pseudopyronine B and SAR evaluation of C3/C6 alkyl analogs [DOI]
  41. 41 Dhage, 2014, One-pot synthesis and evaluation of novel 3-aryl-6-ethoxycarbonyl-4-hydroxy-2H-pyran-2-one as a potent cytotoxic agent [DOI]
  42. 42 Schmidt, 2006, Synthesis of the bis-potassium salts of 5-hydroxy-3-oxopent-4-enoic acids and their use for the efficient preparation of 4-hydroxy-2H-pyran-2-ones and other heterocycles [DOI]
  43. 43 Lokot, 1999, A new approach to the synthesis of 3,6- and 5,6-dialkyl derivatives of 4-hydroxy-2-pyrone. Synthesis of rac-germicidin [DOI]
  44. 44 Marsico, G., Ciccone, M.S., Masi, M., Freda, F., Cristofaro, M., Evidente, A., Superchi, S., and Scafato, P. (2020). Synthesis and Herbicidal Activity Against Buffelgrass (Cenchrus ciliaris) of (±)-3-deoxyradicinin. Molecules, 24. [DOI]
  45. 45 Katritzky, 2005, Facile Syntheses of 2,2-Dimethyl-6-(2-oxoalkyl)-1,3-dioxin-4-ones and the Corresponding 6-Substituted 4-Hydroxy-2-pyrones [DOI]
  46. 46 Basset, 2010, Studies on the resorcylates: Biomimetic total syntheses of (+)-montagnetol and (+)-erythrin [DOI]
  47. 47 Reber, 2018, Total Synthesis of Pyrophen and Campyrones A–C [DOI]
  48. 48 Corbet, 2012, Total Synthesis of Neurymenolide  A Based on a Gold-Catalyzed Synthesis of 4-Hydroxy-2-pyrones [DOI]
  49. 49 2018, Gold Catalysis for Heterocyclic Chemistry: A Representative Case Study on Pyrone Natural Products [DOI]
  50. 50 Liu, 2019, Gold(I)-Catalyzed Intermolecular Rearrangement Reaction of Glycosyl Alkynoic β-Ketoesters for the Synthesis of 4-O-Glycosylated 2-Pyrones [DOI]
  51. 51 Lee, 2014, Total Synthesis and Configurational Validation of (+)-Violapyrone C [DOI]
  52. 52 Luo, 2011, Syntheses of α-Pyrones Using Gold-Catalyzed Coupling Reactions [DOI]
  53. 53 Gayyur, 2020, Gold-catalyzed homo- and cross-annulation of alkynyl carboxylic acids: A facile access to substituted 4-hydroxy 2H-pyrones and total synthesis of pseudopyronine A [DOI]
  54. 54 Shimizu, 1993, Reduction of α-Pyrone Derivatives with Borane-Methyl Sulfide Complex [DOI]
  55. 55 Sheibani, 2004, A convenient one-pot synthesis of substituted 2-pyrone derivatives [DOI]
  56. 56 Nejadshafiee, 2013, A one-pot reaction of (chlorocarbonyl) phenyl ketene with β-ketoamides and thiochromen-2-one [DOI]
  57. 57 German, 1982, Hexafluorodehydroacetic acid [DOI]
  58. 58 Fedin, V.V., Usachev, S.A., Obydennov, D.L., and Sosnovskikh, V.Y. (2022). Reactions of Trifluorotriacetic Acid Lactone and Hexafluorodehydroacetic Acid with Amines: Synthesis of Trifluoromethylated 4-Pyridones and Aminoenones. Molecules, 27. [DOI]
  59. 59 Perrone, 2015, A direct synthesis of 3-acyl-4-hydroxy-2-pyranone derivatives via palladium-catalyzed carbonylation of α-chloroketones. A cascade reaction involving acylketenes [DOI]
  60. 60 Castillo, 2020, Periselectivity in the aza-Diels–Alder Cycloaddition between α-Oxoketenes and N-(5-Pyrazolyl)imines: A Combined Experimental and Theoretical Study [DOI]
  61. 61 Hosokawa, 2006, The first total synthesis and structural determination of actinopyrone A [DOI]
  62. 62 Usachev, 2012, 2-Cyano-6-(trifluoromethyl)-4H-pyran-4-one: A novel versatile CF3-containing building block [DOI]
  63. 63 Obydennov, 2020, Synthesis and some chemical properties of 2-cyano-4-pyrone [DOI]
  64. 64 Lu, 2023, Total Synthesis of the 2,5-Disubstituted γ-Pyrone E1 UAE Inhibitor Himeic Acid A [DOI]
  65. 65 Obydennov, 2013, An improved synthesis and some reactions of diethyl 4-oxo-4H-pyran-2,5-dicarboxylate [DOI]
  66. 66 Majumdar, 2022, Synthesis of Pyrimidine-Annelated Heterocycles: Regioselective Heterocyclization of 5-(Cyclohex-2-enyl)-1,3-dimethyl-6-hydroxyuracil [DOI]
  67. 67 Lei, 2019, Design and Synthesis of Novel 4-Hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one Derivatives for Use as Herbicides and Evaluation of Their Mode of Action [DOI]
  68. 68 Penta, S. (2017). Useful Synthons in Organic Synthesis, Elsevier. [1st ed.].
  69. 69 Guan, 2020, Palladium-Catalyzed Selective Carbofunctionalization of Inert γ-C(sp3)–O Bonds with 4-Hydroxypyridin-2(1H)-ones and 4-Hydroxy-2H-pyran-2-ones [DOI]
  70. 70 Storm, 2018, Exploring fungal polyketide C-methylation through combinatorial domain swaps [DOI]
  71. 71 Ohyoshi, 2020, Total Synthesis and Structure-Activity Relationship Studies of Phelligridins C and D, and Phellifur opyranone A [DOI]
  72. 72 Kikuchi, 2009, New diterpene pyrone-type compounds, metarhizins A and B, isolated from entomopathogenic fungus, Metarhizium flavoviride and their inhibitory effects on cellular proliferation [DOI]
  73. 73 Fang, 2010, Synthesis and Biological Evaluation of Polyenylpyrrole Derivatives as Anticancer Agents Acting through Caspases-Dependent Apoptosis [DOI]
  74. 74 Zhang, 2012, Enantioselective Biomimetic Total Syntheses of Katsumadain and Katsumadain C [DOI]
  75. 75 Lim, 2016, Exploiting the Biosynthetic Potential of Type III Polyketide Synthases [DOI]
  76. 76 Tan, 2020, A polyketoacyl-CoA thiolase-dependent pathway for the synthesis of polyketide backbones [DOI]
  77. 77 Bentley, 1967, Biosynthesis of Tropolones in Penicillium stipitatum. VII.1,2 The Formation of Polyketide Lactones and Other Nontropolone Compounds as a Result of Ethionine Inhibition [DOI]
  78. 78 Igarashi, 2023, Development of a drug discovery approach from microbes with a special focus on isolation sources and taxonomy [DOI]
  79. 79 Palkina, 2021, Therapeutic potential of hispidin—Fungal and plant polyketide [DOI]
  80. 80 Lee, 2011, Styrylpyrone-class compounds from medicinal fungi Phellinus and Inonotus spp., and their medicinal importance [DOI]
  81. 81 Robinson, 2014, Ability of three yellow pigment producing fungi to colour wood under controlled conditions [DOI]
  82. 82 Purtov, 2015, The chemical basis of fungal bioluminescence [DOI]
  83. 83 Han, 2013, Phaeolschidins A–E, Five Hispidin Derivatives with Antioxidant Activity from the Fruiting Body of Phaeolus schweinitzii Collected in the Tibetan Plateau [DOI]
  84. 84 Chen, 2016, New α-glucosidase inhibitors from marine algae-derived Streptomyces sp. OUCMDZ-3434 [DOI]
  85. 85 Graziani, 2005, Phaeochromycins, A-E, Anti-inflammatory Polyketides Isolated from the Soil Actinomycete Streptomyces phaeochromogenes LL-P018 [DOI]
  86. 86 Ma, 2017, Germicidins H–J from Streptomyces sp. CB00361 [DOI]
  87. 87 Petersen, 1993, Germicidin, an autoregulative germination inhibitor of Streptomyces viridochromogenes NRRL B-1551 [DOI]
  88. 88 Zhang, 2013, Violapyrones A–G, α-Pyrone Derivatives from Streptomyces violascens Isolated from Hylobates hoolock Feces [DOI]
  89. 89 Brachmann, 2013, Pyrones as bacterial signaling molecules [DOI]
  90. 90 Bauer, 2015, Biosynthetic Origin of the Antibiotic Pseudopyronines A and B in Pseudomonas putida BW11M1 [DOI]
  91. 91 Long, 2023, Mechanistic Insight into the Inhibitory Activity of Elasnin-Based Coating against Early Marine Biofilms [DOI]
  92. 92 Motuhi, S.-E., Feizbakhsh, O., Foll-Josselin, B., Baratte, B., Delehouzé, C., Cousseau, A., Fant, X., Bulinski, J.C., Payri, C.E., and Ruchaud, S. (2019). Neurymenolide A, a Novel Mitotic Spindle Poison from the New Caledonian Rhodophyta Phacelocarpus neurymenioides. Mar. Drugs, 17. [DOI]
  93. 93 Hohmann, 2009, Albidopyrone. A new α-pyrone-containing metabolite from marine-derived Streptomyces sp. NTK 227 [DOI]
  94. 94 Raju, 2013, Nocardiopsins C and D and nocardiopyrone A: New polyketides from an Australian marine-derived Nocardiopsis sp. [DOI]
  95. 95 Liu, Z., Liu, H., and Zhang, W. (2020). Natural Polypropionates in 1999–2020: An Overview of Chemical and Biological Diversity. Mar. Drugs, 18. [DOI]
  96. 96 Nuzzo, 2016, Exiguapyrone and exiguaone, new polypropionates from the Mediterranean cephalaspidean mollusc Haminoea exigua [DOI]
  97. 97 Ding, L., Ren, L., Li, S., Song, J., Han, Z., He, S., and Xu, S. (2019). Production of New Antibacterial 4-Hydroxy-α-Pyrones by a Marine Fungus Aspergillus niger Cultivated in Solid Medium. Mar. Drugs, 17. [DOI]
  98. 98 Awakawa, 2015, Salinipyrone and Pacificanone Are Biosynthetic Byproducts of the Rosamicin Polyketide Synthase [DOI]
  99. 99 Xian, 2021, Capsulactone: A new 4-hydroxy-α-pyrone derivative from an endophytic fungus Penicillium capsulatum and its antimicrobial activity [DOI]
  100. 100 Gregg, 2012, Total synthesis and structural elucidation of ent-micropyrone and (+)-ascosalipyrone [DOI]
  101. 101 Yamazaki, 2018, A new protein tyrosine phosphatase 1B inhibitory α-pyrone-type polyketide from Okinawan plant-associated Aspergillus sp. TMPU1623 [DOI]
  102. 102 Yi, 2013, Progostone Synthesis and antimicrobial evaluation of pogostone and its analogues [DOI]
  103. 103 Huang, 2014, Insecticidal activity of pogostone against Spodoptera litura and Spodoptera exigua (Lepidoptera: Noctuidae) [DOI]
  104. 104 Seshime, 2010, Identification of csypyrone B1 as the novel product of Aspergillus oryzae type III polyketide synthase CsyB [DOI]
  105. 105 Sucipto, 2015, In vitro reconstitution of a-pyrone ring formation in myxopyronin biosynthesis [DOI]
  106. 106 Krome, 2022, Corallopyronin A: Antimicrobial discovery to preclinical development [DOI]
  107. 107 Evidente, 1994, Fusapyrone and deoxyfusapyrone, two antifungal α-Pyrones From Fusarium semitectum [DOI]
  108. 108 Kil, 2023, Resolving a Natural Product Cold Case: Elucidation of Fusapyrone Structure and Absolute Configuration and Demonstration of Their Fungal Biofilm Disrupting Properties [DOI]
  109. 109 Altomare, 2004, Structure–Activity Relationships of Derivatives of Fusapyrone, an Antifungal Metabolite of Fusarium semitectum [DOI]
  110. 110 Lim, Y.J., Choi, E., Park, S.-H., and Kwon, H.-J. (2020). Genetic localization of the orevactaene/epipyrone biosynthetic gene cluster in Epicoccum nigrum. Bioorg. Med. Chem. Lett., 30. [DOI]
  111. 111 Lee, A.J., Cadelis, M.M., Kim, S.H., Swift, S., Copp, B.R., and Villas-Boas, S.G. (2020). Epipyrone A, a Broad-Spectrum Antifungal Compound Produced by Epicoccum nigrum ICMP 19927. Molecules, 25. [DOI]
  112. 112 Uchida, 2005, New Sesquicillins, Insecticidal Antibiotics Produced by Albophoma sp.
  113. 113 Lin, 2014, Biological Evaluation of Subglutinol A As a Novel Immunosuppressive Agent for Inflammation Intervention [DOI]
  114. 114 Kaifuchi, 2015, Sartorypyrone D: A new NADH-fumarate reductase inhibitor produced by Neosartorya fischeri FO-5897 [DOI]
  115. 115 Lin, 2023, A heterologous expression platform in Aspergillus nidulans for the elucidation of cryptic secondary metabolism biosynthetic gene clusters: Discovery of the Aspergillus fumigatus sartorypyrone biosynthetic pathway [DOI]
  116. 116 Kanokmedhakul, 2011, Bioactive meroterpenoids and alkaloids from the fungus Eurotium chevalieri [DOI]
  117. 117 Tsukada, 2020, Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones [DOI]
  118. 118 Hashimoto, 2014, Fungal type III polyketide synthases [DOI]
  119. 119 Abe, 2010, Engineered Biosynthesis of Plant Polyketides: Structure-Based and Precursor-Directed Approach [DOI]
  120. 120 Zhou, 2023, Reshaping the 2-Pyrone Synthase Active Site for Chemoselective Biosynthesis of Polyketides [DOI]
  121. 121 Kalaitzis, 2013, Discovery, Biosynthesis, and Rational Engineering of Novel Enterocin and Wailupemycin Polyketide Analogues [DOI]
  122. 122 Pluskal, 2019, The biosynthetic origin of psychoactive kavalactones in kava [DOI]
  123. 123 Zhou, 2016, Biosynthesis of phlorisovalerophenone and 4-hydroxy-6-isobutyl-2-pyrone in Escherichia coli from glucose [DOI]
  124. 124 Huang, 2022, Intrinsic Ability of the β-Oxidation Pathway To Produce Bioactive Styrylpyrones [DOI]
  125. 125 Bergmann, 2022, Cultivation of Inonotus hispidus in Stirred Tank and Wave Bag Bioreactors to Produce the Natural Colorant Hispidin [DOI]
  126. 126 Pogorevc, 2019, Production optimization and biosynthesis revision of corallopyronin A, a potent anti-filarial antibiotic [DOI]
  127. 127 Yi, 2023, Biosynthesis-Guided Discovery and Engineering of α-Pyrone Natural Products from Type I Polyketide Synthases [DOI]
  128. 128 Pan, 2019, Combinatorial Enzymatic Synthesis of Unnatural Long-Chain β-Branch Pyrones by a Highly Promiscuous Enzyme [DOI]
  129. 129 Li, 2021, Precursor Supply Increases the Accumulation of 4-Hydroxy-6-(4- hydroxyphenyl)-α-pyrone after NRPS–PKS Gene Expression [DOI]

Cited by 10

Organic Chemistry in the Creation of Molecules with Practically Useful Properties

Yu. Yu. Belyakova, I. A. Yaremenko, A. O. Terent’ev · Russian Journal of General Chemistry · 2026

Showing 3 of 10 known citations — external sources report more than can currently be individually listed.

Article metrics

Real usage data collected on this platform.

0

Page views

0

PDF downloads

0

Outbound clicks

10

Citations

Views by country

Approximate, from request IP at view time — not citizenship or institution. Countries with fewer than 5 views are grouped as "Other".

No views recorded yet.

Traffic sources

Referring site, by host.

No traffic recorded yet.

Views and downloads exclude known bots/crawlers. Citations combines this platform's own DOI-resolved index with each external source's own reported total — see Cited by above for individually listed citing works. Last refreshed 0 seconds ago.