- Stereoselective total synthesis of (?)-pyrenophorin
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Abstract: Stereoselective total synthesis of (?)-pyrenophorin was accomplished from commercially available starting material 2-bromo epoxide using regioselective ring opening and the intermolecular Mitsunobu cyclization as key steps. Graphic abstract: [Figure not available: see fulltext.].
- Edukondalu, Perugu,Sreenivasulu, Reddymasu,Raju, Rudraraju Ramesh
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- Stereoselective total synthesis of (-)-pyrenophorin
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Background: Homo and hetero dimers of macrodilacto cyclic compounds were observed frequently in nature and they were built with different types of functional groups, chemical skeletons and ring sizes. Natural products with macrodiolide frameworks are also known to exhibit a wide range of biological properties including antibiotic, antifungal, antihelmintic, phytotoxic, and antileukemic activities. The main aim of this paper was the stereoselective total synthesis of (-)-Pyrenophorin from commercially available starting material (S)-propylene oxide with high yields. Methods: Stereoselective total synthesis of (-)-Pyrenophorin was done by hydrolytic kinetic resolution, Wittig olefination followed by Mitsunobu reaction. Results: The disconnection approach analysis (retrosynthetic) of (-)-Pyrenophorin envisions that it would be synthesized through the hydroxyl-acid via cyclo dimerisation under the Mitsunobu reaction conditions and followed by deprotection of cyclic ketals. Hydroxy-acid would be achieved from alcohol, while the alcohol would be obtained from (S)-propylene oxide. Conclusion: The total synthesis of target molecules achieved from commercially available starting materials, soft reaction conditions, decrease of reaction conditions and high purities with large yields. These type of biologically potent target molecules total synthesis was very important in industrial point of view.
- Ramakrishna, Kolluri,Sreenivasulu, Reddymasu,Vidavalur, Siddaiah,Reddy, Boggu Jagan Mohan
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- Macrodiolide Diversification Reveals Broad Immunosuppressive Activity That Impairs the cGAS-STING Pathway
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The development of new immunomodulatory agents can impact various areas of medicine. In particular, compounds with the ability to modulate innate immunological pathways hold significant unexplored potential. Herein, we report a modular synthetic approach to the macrodiolide natural product (?)-vermiculine, an agent previously shown to possess diverse biological effects, including cytotoxic and immunosuppressive activity. The synthesis allows for a high degree of flexibility in modifying the macrocyclic framework, including the formation of all possible stereoisomers. In total, 18 analogues were prepared. Two analogues with minor structural modifications showed clearly enhanced cancer cell line selectivity and reduced toxicity. Moreover, these compounds possessed broad inhibitory activity against innate immunological pathways in human PBMCs, including the DNA-sensing cGAS-STING pathway. Initial mechanistic characterization suggests a surprising impairment of the STING-TBK1 interaction.
- Biltoft, Mette,Jakobsen, Martin R.,Jennet, Kira M.,Kristensen, Tobias F.,Liu, Han,Ottosen, Rasmus N.,Poulsen, Thomas B.,Svenningsen, Esben B.
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supporting information
p. 18734 - 18741
(2021/07/19)
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- Diversity of antimicrobial pyrenophorol derivatives from an endophytic fungus, Phoma sp.
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Pyrenophorol (1) and (-)-dihydropyrenophorin (3), two known macrodiolides, were isolated together with four new analogues (2, 4-6) and three ring-opened derivatives (7-9) from Phoma sp., an endophytic fungus isolated from Lycium intricatum from Gomera. The structures of the new compounds were elucidated by detailed spectroscopic analysis, comparison with reported data, and chemical interconversion. The absolute configurations were determined by chemical correlations and a modified Mosher's method. The diversity of these seven newly discovered metabolites not only extends the pyrenophorol macrocyclic family, but also gives insight into the biosynthetic interconnections, in particular by isolation of the open-chain precursors. Preliminary studies showed antimicrobial activity of these compounds against the fungus Microbotryum violaceum, the alga Chlorella fusca, and the bacteria Escherichia coli and Bacillus megaterium. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Zhang, Wen,Krohn, Karsten,Egold, Hans,Draeger, Siegfried,Schulz, Barbara
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experimental part
p. 4320 - 4328
(2009/04/11)
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- Formation of macrocycles via ring-closing olefin metathesis
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The enhanced metathesis activity of 1,3-dimesityl-4,5-dihydroimidazole-2-ylidene ruthenium carbene catalyst 3 significantly increases the feasibility of synthesizing macrocyclic compounds. Catalyst 3 exhibits sufficient activity in RCM to dimerize α,β-unsaturated ester substrates and afford the corresponding head-to-tail (E,E)-dimeric (and trimeric) macrocycles. The dimerization appears to be under thermodynamic control with the product mixture dependent not only on the electronic and steric nature of the substrate but also on concentration.
- Choon Woo Lee,Grubbs
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p. 7155 - 7158
(2007/10/03)
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- Exploiting the reversibility of olefin metathesis. Syntheses of macrocyclic trisubstituted alkenes and (R,R)-(-)-pyrenophorin.
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[figure: see text] The formation of the trisubstituted cycloalkene 7 by RCM of diene 5 proceeds via the acyclic dimer 6, thus demonstrating the ready reversibility of olefin metathesis if catalyzed by "second generation" ruthenium carbene complexes such as 2-4. When applied to acrylate 11, these catalysts trigger a cyclooligomerization process that evolves with time and serves as key step en route to the lactide antibiotic (-)-pyrenophorin 8.
- Fuerstner,Thiel,Ackermann
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p. 449 - 451
(2007/10/03)
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- A Nitrile Oxide Cycloaddition Approach to (-)-Pyrenophorin, and Rosefuran.
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Nitrile oxide cycloaddition chemistry has been conveniently applied as carbon-carbon bond forming reaction for the assemblage of the functionalized carbon atom fragments required for the synthesis of two simple but different targets such as the macrolide antibiotic (-)-pyrenophorin 1 and rosefuran 2, a trace component of the high prized oil of rose.In both cases, an intermediate 3,5-disubstituted isoxazoline ring system has been used as serviceable precursor of the the salient structural feature of the targets, namely a γ-oxoacrylate moiety, common to many biologically active compounds, and a β,γ-dihydroxyketone functionality, easily converted by mild acid treatment to rosefuran.
- Barco, Achille,Benetti, Simonetta,Risi, Carmela De,Pollini, Gian P.,Zanirato, Vinicio
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p. 7721 - 7726
(2007/10/02)
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- A New Approach to the Synthesis of γ-Hydroxy-α,β-unsaturated Macrolides and (-)-Pyrenophorin by Intramolecular C=C Bond Formation with Oxidative Functionalization from ω-alkanal
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The title compounds were prepared via the intramolecular condensation reaction of 12-tridecanal(or dodecanal) or via the combination of inter- and intramolecular condensation of 5-hexanal in the presence of piperidine.
- Nokami, Junzo,Taniguchi, Takuya,Gomyo, Shintaro,Kakihara, Toshio
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p. 1103 - 1106
(2007/10/02)
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- Total Synthesis of (-)-Pyrenophorin via Cobalt(II) Porphyrin-Catalyzed Oxygenation of Ethyl (2E,4E,7R)-7-Acetoxy-2,4-octadienoate
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(-)-Pyrenophorin was synthesized by the Mitsunobu reaction of (2E,7S)-4,4-ethylenedioxy-7-hydroxy-2-octenoic acid which has been prepared via cobalt(II) porphyrin-catalyzed oxygenation of ethyl (2E,4E,7S)-7-acetoxy-2,4-octadienoate.
- Matsushita, Yoh-ichi,Furusawa, Hiroshi,Matsui, Takanao,Nakayama, Mitsuru
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p. 1083 - 1084
(2007/10/02)
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- Preparation of macrodiolides via a common chiral building block. Total synthesis of (-)-pyrenophorin and (-)-pyrenophorol
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Macrodiolides (-)-pyrenophorin and (-)-pyrenophorol have been synthesized utilizing a C2 symmetric (R,R)-diepoxide as a common enantiopure chiral building block.
- Machinaga, Nobuo,Kibayashi, Chihiro
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p. 841 - 844
(2007/10/02)
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- SYNTHESIS OF (+/-)-PYRENOPHORIN AND (+/-)-COLLETALLOL
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Pyrenephorin 1 and colletallol 3 were synthesized in their racemic forms from the corresponding hydrocarboxylic acids 9 and 14 via stereoselective formation of the requisite trans double bonds after macrocyclization.
- Wakamatsu, Takeshi,Yamada, Satoshi,Ozaki, Yoshiko,Ban, Yoshio
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p. 1989 - 1992
(2007/10/02)
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- NOVEL SYNTHETIC ROUTE γ-OXO-ACRYLATES Application to the synthesis of Pyrenophorin antibiotic
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We report a new method for the synthesis of γ-oxo-acrylates which allows the direct introduction of suitably functionalised four carbon skeleton.
- Dumont, W.,Vermeyen, C.,Krief, A.
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p. 2883 - 2886
(2007/10/02)
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- Enamines of 2,2-bis(ethylthio)ethanal: a convenient route to γ-keto crotonate derivatives
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A new α-oxoaldehyde reagent, 2,2-bis(ethylthio)ethanal 1, has been prepared in high yield from ethanedial.Alkylation of the potassium salt of the enamines of 1 with various alkylating agents followed by in situ hydrolysis of the intermediate imine afforded high yields of the alkylation products of 1.This new reagent was used in the synthesis of a chiral potential precursor of the macrocyclic fragment of cytochalasins A,B, and F, as well as in the syntheses of the physiologically active diolides pyrenophorin and norpyrenophorin.
- Bates, Gordon S.,Ramaswamy, S.
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p. 2466 - 2475
(2007/10/02)
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- A SHORT-STEP SYNTHESIS OF (+/-)-PYRENOPHORIN UTILIZING 3-ALKENOATE AS A MASKED SYNTHON OF 4-OXO-2-ALKENOATE
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The use of 3-alkenoate as a masked synthon of 4-oxo-2-alkenoate was established by a three step conversion of 3-noneonate into 4-oxo-2-nonenoate through epoxidation, isomerization to an allyl silyl ether, and oxidation in a high overall yield.This method was applied to the short step synthesis of pyrenophorin from 7-oxo-3-octenoic acid.
- Fujisawa, Tamotsu,Takeuchi, Masashi,Sato, Toshio
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p. 1795 - 1798
(2007/10/02)
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- SYNTHESIS OF (+/-)-PYRENOPHORIN UTILIZING 1,3-DIPOLAR CYCLOADDITION OF SILYL NITRONATE FOR THE CONSTRUCTION OF 16-MEMBERED RING
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1-Methyl-4-nitrobutyl acrylate underwent 1,3-dipolar cycloaddition via its silyl nitronate to give isoxazoline derivative of 16-membered dilactone after acid treatment, from which (+/-)-pyrenophorin was synthesized.
- Asaoka, Morio,Mukuta, Takashi,Takei, Hisashi
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p. 735 - 738
(2007/10/02)
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- A Short Synthesis of (R,R)-(-)-Pyrenophorin from (S)-Propylene Oxide and a 3-Pentenoic Acid d5-Reagent
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Analysis of the known syntheses of pyrenophorin (1) (Scheme 1) reveals that they all rest upon the use of reagents with d1-, d3-, or a2-reactivity umpolung for the establishment of at least one of the 1,4-distances of functional groups.A different approach, outlined in Scheme 2, has now been realized: the non-conjugated and the conjugated 7-hydroxyoctenoic acids 10 and 11, obtained from dienone dianion derivatives of type 3 and d,l- or (S)-methyloxirane, are converted to the macrodiolides 12 and 13, respectively.These are directly oxidized with introduction of an oxygen function at position 4, see 13 -> 1 and 12 -> 16 -> 17 -> 1.The overall transformation of the γ,δ-unsaturated ketone 18 to pyrenophorin (1) in 27 percent yield takes six steps, partly without purification of intermediates.
- Mali, Raghao S.,Pohmakotr, Manat,Weidmann, Beat,Seebach, Dieter
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p. 2272 - 2284
(2007/10/02)
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- The Reaction of 2-(Trialkylsiloxy)furans with Lead(IV) Acetate. The Synthesis of dl-Pyrenophorin
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The reaction of 2-(trimethylsiloxy)furans with lead(IV) acetate afforded the corresponding α,β-unsaturated γ-acetoxy-γ-lactones in good yields.The lactones were easily converted into the corresponding 3-acylacrylic acids.Utilizing this reaction, dl-pyrenophorin was synthesized.
- Asaoka, Morio,Yanagida, Noboru,Sugimura, Naoyuki,Takei, Hisashi
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p. 1061 - 1064
(2007/10/02)
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