Pulvinone

Chembox new
Name = Pulvinone
ImageFile = Pulvinone.png IUPACName = 5-Phenylmethylene-4-hydroxy-3-phenylfuran-2(5"H")-one
OtherNames =
Section1 = Chembox Identifiers
SMILES =
CASNo = 4941-88-2 (mixture of "E"- and "Z"-isomers), 78376-10-0 ("Z"-isomer), 100074-80-4 ("E"-isomer)
Section2 = Chembox Properties
Formula = C₁₇H₁₂O₃
MolarMass = 322,33 g/mol
Appearance = Yellow needles
Density = ? g/cm³, ?
Solubility =
* Soluble in Diethylether, Chloroform and Ethanol
* Insoluble in water
MeltingPt = 243-247 °C R. Ramage, G. J. Griffiths, F. E. Shutt, J. N. A. Sweeney, "J. Chem. Soc., Perkin Trans. 1" 1984, 1539-1545 [DOI: [http://dx.doi.org/10.1039/P19840001539 10.1039/P19840001539] ] .]
BoilingPt =
Section3 = Chembox Structure
CrystalStruct =
Dipole =
Section7 = Chembox Hazards
ExternalMSDS = ?
MainHazards = ?
Section8 = Chembox Related
Function = ?
OtherFunctn = ?
OtherCpds = Pulvinic acid, Vulpinic acid

Pulvinone, an organic compound belonging to the esters, lactones, alcohols and butenolides classes, is a yellow crystalline solid. Although the pulvinone is not a natural product, several naturally occurring hydroxylated derivatives are known. These hydroxylated pulvinones are produced by fungal species, such as the in Europe common Larch Bolete ("Boletus elegans", also known as "Suillus grevillei"), or by moulds such as "Aspergillus Terreus".

History

Fungi - such as boleti -, moulds and lichens produce a wide range of pigments made up of one (monomer) or several (oligomers) units of pulvinic acid. In 1831, in the course of a study of the constituents of lichens ("Cetraria Vulpina"), the French chemist and pharmacist Antoine Bebert discovered a compound named "vulpinic acid", the first known naturally occurring methyl ester of pulvinic acid. More details about the structure of this pigment were disclosed in 1860 by the German chemists Franz Möller and Adolph Strecker."Canstatt's Jahresbericht über die Fortschritte in der Pharmacie und verwandte Wissenschaften in allen Ländern", Harvard Universität, Jahrgang 10 (1861)] While trying to elucidate the structure of vulpinic acid, the German chemist Adolf Spiegel A. Spiegel, "Ber. Dtsch. Chem. Ges." 1880, "13", 2, 1629-1635 [DOI: [http://dx.doi.org/10.1002/cber.18800130293 10.1002/cber.18800130293] ] .] A. Spiegel, "Ber. Dtsch. Chem. Ges." 1880, "13", 2, 2219-2221 [DOI: [http://dx.doi.org/10.1002/cber.188001302237 10.1002/cber.188001302237] ] .] A. Spiegel, "Ber. Dtsch. Chem. Ges." 1881, "14", 1, 873-874 [DOI: [http://dx.doi.org/10.1002/cber.188101401183 10.1002/cber.188101401183] ] .] A. Spiegel, "Ber. Dtsch. Chem. Ges." 1881, "14", 2, 1686-1696 [DOI: [http://dx.doi.org/10.1002/cber.18810140230 10.1002/cber.18810140230] ] .] found in 1880 that the vulpinic acid could be saponified to a diacid. He named the resulting diacid pulvinic acid. The German chemist Jacob VolhardJ. Volhard, "Annal. Chem." 1894, "282", 1-21 [DOI: [http://dx.doi.org/10.1002/jlac.18942820102 10.1002/jlac.18942820102] ] .] elucidated the constitution of pulvinic acid by synthesizing it through the basic hydrolysis of a corresponding dicyanocompound. In the process, he also obtained small amounts of a side-product. One year later Ludwig Claisen and Th. EwanL. Claisen, Th. Ewan, "Annal. Chem.", 1895, "284", 245-299 [DOI: [http://dx.doi.org/10.1002/jlac.18952840302 10.1002/jlac.18952840302] ] .] achieved the synthesis of this side-product and characterized it as the 5-benzylidene-4-hydroxy-3-phenylfuran-2(5H)-one. Claisen and Ewan described it as "das der Pulvinsäure zu Grunde liegende Lacton" (the lactone underlying the structure of pulvinic acid): that was the origin of the name pulvinone.

Natural occurrence

Interestingly, it is only a century after the synthesis of the first pulvinone that the word "Pulvinone" turned into a collective term. In 1973, Edwards and Gill isolated the first naturally occurring hydroxylated pulvinone derivative.R. L. Edwards, M. Gill, "J. Chem. Soc., Perkin Trans. 1" 1973, 1921-1929. [DOI: [http://dx.doi.org/10.1039/P19730001921 10.1039/P19730001921] ] .] This trihydroxylated pulvinone was found as one of the main pigments responsible for the yellow colour of the stem and caps of the European mushroom Larch Bolete ("Boletus elegans", also known as "Suillus grevillei").In the very same year 1973, Seto and coworkers also found hydroxylated pulvinones in cultures of the mould Aspergillus terreus.N. Ojima, S. Takenaka, S. Seto, "Phytochemistry (Elsevier)" 1973, "12", 2527-2529.] N. Ojima, K. Ogura, S. Seto, "J. Chem. Soc., Chem. Commun." 1975, 717-718.] N. Ojima, S. Takenaka, S. Seto, "Phytochemistry (Elsevier)" 1975, "14", 573-576.] To insist on their origin - and thereby differentiate them from the hydroxylated pulvinones found in "Suillus grevillei" - Seto and coworkers named these compounds "Aspulvinones".N. Ojima, I. Takahashi, K. Ogura, S. Seto, "Tetrahedron Lett." 1976, "17", 1013-1014.] I. Takahashi, N. Ojima, K. Ogura, S. Seto, "Biochemistry" 1978, "17", 2696-2702.] M. Kobayashi, N. Ojima, K. Ogura, S. Seto, "Chem. Lett." 1979, 579-582.] H. Sugiyama, N. Ojima, M. Kobayashi, Y. Senda, J. Ishiyama, S. Seto, "Agric. Biol. Chem." 1979, "43", 403-4.] The "aspulvinone" terminology also incorporates a letter, indicating the order of chromatographic elution of these compounds (hence, the least polar aspulvinone was named Aspulvinone A, the one eluting next Aspulvinone B, etc...).

Like many other yellow pigments in fungi and lichens, pulvinones can be traced back from the pulvinic acid pathway. The "pulvinone" structural unit is found in a number of natural products. All monomeric (such as "pulvinic acid" itself, "vulpinic acid", "comphidic acid", the "aspulvinones" and the "Kodaistatins"L. Vértesy, H.-J. Burger, J. Kenja, M. Knauf, H. Kogler, E. F. Paulus, N. V. S. Ramakrishna, K. H. S. Swamy, E. K. S. Vijayakumar, P. Hammann, "J. Antibiot." 2000, "53", 677-686.] ) or oligomeric ("Badiones"B. Steffan, W. Steglich, "Angew. Chem., Int. Ed." 1984, 23, 6, 445-447. [DOI: [http://dx.doi.org/10.1002/anie.198404451 10.1002/anie.198404451] ] .] , "Norbadione"M. Gill, D. A. Lally, "Phytochemistry" 1985, "24", 1351-1354. [DOI: [http://dx.doi.org/10.1016/S0031-9422(00)81131-0 10.1016/S0031-9422(00)81131-0] ] .] T. Le Gall, C. Mioskowski, B. Amekraz "et al." "Angew. Chem., Int. Ed." 2003, 42, 11, 1289-1293. [DOI: [http://dx.doi.org/10.1002/anie.198404451 10.1002/anie.198404451] ] .] , "Aurantricholon"D. Klostermeyer, L. Knops, T. Sindlinger, K. Polborn, W. Steglich "Eur. J. Org. Chem." 2000, 4, 603-609. [DOI: [http://dx.doi.org/10.1002/anie.200390332 10.1002/anie.200390332] ] .] ) derivatives of the pulvinic acid contain the "pulvinone" structural element.So far, all naturally occurring pulvinone derivatives were found to be "Z"-configured.

Pharmacological properties

* Rehse "et al"K. Rehse, J. Wagenknecht, N. Rietbrock, "Arch. Pharm. (Weinheim, Ger.)" 1978, "311", 986-991.] K. Rehse, U. Emisch, "Arch. Pharm. (Weinheim, Ger.)" 1982, "315", 1020-1025.] K. Rehse, J. Schinke, G. Bochert, "Arch. Pharm. (Weinheim, Ger.)" 1979, "312", 390-394.] K. Rehse, J. Lehmke, "Arch. Pharm. (Weinheim, Ger.)" 1985, "318", 11-14.] showed the anti-coagulant activity of some pulvinones in rats.
* At the beginning of the 80s, the companies ICI and Smith Kline & French patented a large number of derivatives of the vulpinic acid because of their anti-inflammatory, anti-fever and pain-killing properties. Yet vulpinic acid - as well as many of its derivatives - is a cytotoxic compound. Since pulvinones exhibit a lower cytotoxicity compared to vlupinic acid and its derivatives, Organon investigated the pharmaceutical potential of more than 100 pulvinones A. C. Campbell, M. S. Maidment, J. H. Pick, D. F. M. Stevenson, "J. Chem. Soc., Perkin Trans. 1" 1985, 1567-1576. [DOI: [http://dx.doi.org/10.1039/P19850001567 10.1039/P19850001567] ] .] . To date, the results of these studies were not fully disclosed.
* In 2005, the Wyeth company patented biphenyl-substituted pulvinonesC. E. Caufield, S. A. Antane, K. M. Morris, S. M. Naughton, D. A. Quagliato, P. M. Andrae, A. Enos, J. F. Chiarello, J. (Wyeth, and Brother Ltd., USA), "WO 2005019196", "US 2005054721", 2005.] S. A. Antane, C. E. Caufield, W. Hu, D. Keeney, P. Labthavikul, K. M. Morris, S. M. Naughton, P. J. Petersen, B. A. Rasmussen, G. Singh, Y. Yang, "Bioorg. Med. Chem. Lett." 2006, 176-180. [DOI: [http://dx.doi.org/10.1016/j.bmcl.2005.09.021 10.1016/j.bmcl.2005.09.021] ] .] due to their promising activity against Gram-positive bacteria, including otherwise resistant bacteria. However, pulvinone-based antibiotics were so far only patented for animal use.

Chemical properties

Pulvinone is a lactone, more precisely an intramolecular ester of the "trans-1,4-diphenyl-2,3-dihydroxy-1,3-butadiene-1-carboxylic acid", from which it can be prepared through removal of one equivalent of water:
The central 5-membered ring core of pulvinone reveals a 4-hydroxy-butenolide structure. They are essentially found in their enol form, which exhibits acidic properties due to the relative lability of the hydroxylic proton. 4-hydroxy-butenolides such as pulvinones are therefore referred to as tetronic acids, and belong to the larger category of vinylogous acids.

Biosynthesis

The fungal biosynthesis starts from aromatic aminoacids such as phenylalanine and tyrosine; after oxydeamination to the corresponding arylpyruvic acid, the pulvinone skeleton is formed by a sequence of dimerisation, oxidative ring-cleavage and decarboxylation.M. Gill, W. Steglich, "Prog. Chem. Org. Nat. Prod.", 1987, "51", 1-317. Springer-Verlag.]

Synthesis

Jacob Volhard was the first to synthesise vulpinic acid, pulvinic acid and pulvinoneJ. Volhard, "Annal. Chem." 1894, "282", 1-21 [DOI: [http://dx.doi.org/10.1002/jlac.18942820102 10.1002/jlac.18942820102] ] .] .To date, 11 total syntheses of pulvinones were reported:
* 1895 by Claisen and EwanL. Claisen, Th. Ewan, "Annal. Chem.", 1895, "284", 245-299 [DOI: [http://dx.doi.org/10.1002/jlac.18952840302 10.1002/jlac.18952840302] ] .] ,
* 1975 and 1979 by Knight and PattendenD. W. Knight, G. Pattenden, "J. Chem. Soc., Chem. Commun." 1975, 876-877 [DOI: [http://dx.doi.org/10.1039/C39750000876 10.1039/C39750000876] ] .] , D. W. Knight, G. Pattenden, "J. Chem. Soc., Perkin Trans. 1" 1979, 70-76 [DOI: [http://dx.doi.org/10.1039/P19790000070 10.1039/P19790000070] ] .] ,
* 1979 by Jerris, Wovkulich and Amos B. Smith IIIP. J. Jerris, P. M. Wovkulich, A. B. Smith III, "Tetrahedron Lett." 1979, 20, 4517-20 [DOI: [http://dx.doi.org/10.1016/S0040-4039(01)86637-5 10.1016/S0040-4039(01)86637-5] ] .] ,
* 1984 by Ramage "et al."R. Ramage, G. J. Griffiths, F. E. Shutt, J. N. A. Sweeney, "J. Chem. Soc., Perkin Trans. 1" 1984, 1539-1545 [DOI: [http://dx.doi.org/10.1039/P19840001539 10.1039/P19840001539] ] .] ,
* 1985 by Campbell "et al."A. C. Campbell, M. S. Maidment, J. H. Pick, D. F. M. Stevenson, "J. Chem. Soc., Perkin Trans. 1" 1985, 1567-1576. [DOI: [http://dx.doi.org/10.1039/P19850001567 10.1039/P19850001567] ] .] ,
* 1990 by Gill "et al."M. Gill, M. J. Kiefel, D. A. Lally, A. Ten, "Aust. J. Chem." 1990, "43", 1497-518.] ,
* 1991 by Pattenden, Turvill and ChorltonG. Pattenden, M. W. Turvill, A. P. Chorlton, "J. Chem. Soc., Perkin Trans. 1" 1991, "10", 2357-2361. [DOI: [http://dx.doi.org/10.1039/P19910002357 10.1039/P19910002357] ] .] ,
* 2005 by Caufield "et al."C. E. Caufield, S. A. Antane, K. M. Morris, S. M. Naughton, D. A. Quagliato, P. M. Andrae, A. Enos, J. F. Chiarello, J. (Wyeth, and Brother Ltd., USA), "WO 2005019196", "US 2005054721", 2005.] ,
* 2006 by Antane "et al."S. A. Antane, C. E. Caufield, W. Hu, D. Keeney, P. Labthavikul, K. M. Morris, S. M. Naughton, P. J. Petersen, B. A. Rasmussen, G. Singh, Y. Yang, "Bioorg. Med. Chem. Lett." 2006, 176-180. [DOI: [http://dx.doi.org/10.1016/j.bmcl.2005.09.021 10.1016/j.bmcl.2005.09.021] ] .] ,
* 2007 by Kaczybura and BrücknerN. Kaczybura, R. Brückner "Synthesis" 2007, 118-130. [DOI: [http://dx.doi.org/10.1055/s-2006-950378 10.1055/s-2006-950378] ] .] ,
* 2007 by Bernier, Moser and BrücknerD. Bernier, F. Moser, R. Brückner "Synthesis" 2007, 15, 2240-2248. [DOI: [http://dx.doi.org/10.1055/s-2007-983800 10.1055/s-2007-983800] ] .] D. Bernier, R. Brückner "Synthesis" 2007, 15, 2249-2272. [DOI: [http://dx.doi.org/10.1055/s-2007-983803 10.1055/s-2007-983803] ] .] .

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