- Total synthesis of the anti-inflammatory and pro-resolving lipid mediator MaR1n-3 DPAutilizing an sp3-sp3 Negishi cross-coupling reaction
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The first total synthesis of the lipid mediator MaR1n-3 DPA (5) has been achieved in 12% overall yield over 11 steps. The stereoselective preparation of 5 was based on a Pd-catalyzed sp3-sp3 Negishi cross-coupling reaction and a stereocontrolled Evans-Nagao acetate aldol reaction. LC-MS/MS results with synthetic material matched the biologically produced 5. This novel lipid mediator displayed potent pro-resolving properties stimulating macrophage efferocytosis of apoptotic neutrophils.
- Tungen, J.o. Eivind,Aursnes, Marius,Dalli, Jesmond,Arnardottir, Hildur,Serhan, Charles Nicholas,Hansen, Trond Vidar
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- An efficient total synthesis of leukotriene B4
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Lipid mediators have attracted great interest from scientists within the chemical, medicinal, and pharmaceutical research community. One such example is leukotriene B4 which has been the subject of many pharmacological studies. Herein, we report a convergent and stereoselective synthesis of this potent lipid mediator in 5% yield over 10 steps in the longest linear sequence from commercial starting materials. The key steps were a stereocontrolled acetate-aldol reaction with Nagao's chiral auxiliary and a Z-selective Boland reduction. All spectroscopic data were in agreement with those previously reported.
- Primdahl, Karoline Gangestad,Tungen, Jorn Eivind,Aursnes, Marius,Hansen, Trond Vidar,Vik, Anders
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- Evolution of a Strategy for the Total Synthesis of (+)-Cornexistin
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Herein is given a full account of the evolution of the first total synthesis of (+)-cornexistin. Initial efforts were based on masking the reactive maleic anhydride moiety as a 3,4-substituted furan and on forming the nine-membered carbocycle in an intramolecular Conia-ene or Nozaki–Hiyama–Kishi (NHK) reaction. Those strategies suffered from low yields and were jeopardized by a late-stage installation of the Z-alkene, as well as the stereocenters along the eastern periphery. These issues were addressed by employing a chiral-pool strategy that involved construction of the crucial stereocenters at C2, C3 and C8 at an early stage with installation of the maleic anhydride as late as possible. The successful approach featured an intermolecular NHK coupling to install the Z-alkene, a syn-Evans-aldol reaction to forge the stereocenters along the eastern periphery, an intramolecular allylic alkylation to close the nine-membered carbocycle, and a challenging stepwise hydrolysis of a β-keto nitrile to furnish the maleic anhydride.
- Wildermuth, Raphael E.,Steinborn, Christian,Barber, David M.,Mühlfenzl, Kim S.,Kendlbacher, Mario,Mayer, Peter,Wurst, Klaus,Magauer, Thomas
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- New naphthoquinone and monoterpenoid from Plumbago zeylanica
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New naphthoquinone 2 and new monoterpenoid 3 were isolated from the stems of Plumbago zeylanica, and their structures were determined on the basis of 2D NMR spectroscopy. Absolute configuration of 3 was established by synthesis of its enantiomer. The new naphthoquinone 2 showed potent inhibitory activity against nuclear factor κB (NF-κB), equivalent to that of parthenolide, a known potent inhibitor of NF-κB.
- Ohira, Susumu,Yokogawa, Yoshiaki,Tsuji, Shinji,Mitsui, Taichi,Fukukawa, Tatsuhiko,Hayashi, Ken-Ichiro,Kuboki, Atsuhito,Matsuura, Nobuyasu,Iinuma, Munekazu,Nozaki, Hiroshi
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- Stereoselective synthesis of the specialized pro-resolving and anti-inflammatory mediator resolvin E1
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The n-3 polyunsaturated fatty acids eicosapentaenoic acid, docosahexaenoic acid and n-3 docosapentaenoic acid, act as substrates for the biosynthesis of specialized pro-resolving lipid mediators. Resolvin E1, produced from eicosapentaenoic acid, was the first specialized pro-resolving lipid mediator reported. This oxygenated polyunsaturated fatty acid displays a plethora of interesting biological activities, and has entered initial clinical trial development programs. The Evans-Nagao aldol reaction, a stereoselective alkyne reduction and a Z-selective Wittig reaction, were utilized for the stereocontrolled synthesis of resolvin E1 presented herein. In addition, results from HPLC analysis revealed that the synthetic material matched authentic resolvin E1.
- Nesman, Jannicke Irina,Tungen, J?rn Eivind,Vik, Anders,Hansen, Trond Vidar
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- PROCESS FOR THE PREPARATION OF (1S,3S,7S,10R,11S,12S,16R)-7,11-DIHYDROXY-8,8,10,12,16-PENTAMETHYL-3-[(1E)-1-METHYL-2-(2-METHYL-4-THIAZOLYL)ETHENYL]-17-OXA-4-AZABICYCLO[14.1.0]HEPTADECANE-5,9-DIONE AND INTERMEDIATES THEREOF
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The present invention relates to an improved process for the preparation of (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-2-(2- methyl-4-thiazolyl)ethenyl]- 17-oxa-4-azabicyclo[ 14.1.0]heptadecane-5,9-dione represented by the following structural formula I and intermediates thereof. The present invention also provides novel intermediate compounds useful for the preparation of compound of formula I and its intermediates.
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Page/Page column 39
(2015/06/25)
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- SYNTHETIC PRECURSOR OF EPOTHILONE FOR IMPROVING PRODUCTION OF EPOTHILONE AND METHOD FOR PREPARING EPOTHILONE USING THE SAME
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The present invention relates to a compound for increasing production of epothilone in actinomyces, and to a method for producing epothilone with increased yield. The method for producing epothilone of the present invention includes a step of culturing actinomyces in which epothilone-biosynthesizing genes in Sorangium cellulosum including epoD, epoE, epoF, orf6, orf3, and orf14 are introduced in a culture medium. According to the present invention, it is possible to increase the production yield of epothilone in actinomyces, even in actinomyces in which epoA, epoP, epoB, and epoC are not introduced therein.COPYRIGHT KIPO 2016
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Paragraph 0071; 0072; 0076
(2016/10/10)
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- Stereoselective synthesis of 12,13-cyclopropyl-epothilone B and side-chain-modified variants
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A general strategy has been devised for the stereoselective synthesis of 12,13-cyclopropyl-epothilone B and side-chain-modified variants thereof, which relies on late stage introduction of the heterocycle through Wittig olefination of ketone 14. Formation of the macrocycle was achieved through RCM-based ring closure and introduction of the cyclopropane moiety involved a highly selective Charette cyclopropanation of allylic alcohol 7.
- Schiess, Raphael,Gertsch, Juerg,Schweizer, W. Bernd,Altmann, Karl-Heinz
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supporting information; experimental part
p. 1436 - 1439
(2011/05/13)
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- First asymmetric total syntheses of (-)-subincanadines A and B, skeletally rearranged pentacyclic monoterpenoid indole alkaloids in Aspidosperma subincanum
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We achieved the first asymmetric total syntheses of novel Aspidosperma indole alkaloids, (-)-subincanadines A and B, which involve an intramolecular diastereoselective Pictet-Spengler cyclization and an intramolecular Nozaki-Hiyama-Kishi reaction as key steps in the total syntheses.
- Suzuki, Kenta,Takayama, Hiromitsu
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p. 4605 - 4608
(2007/10/03)
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- THIA-EPOTHILONE DERIVATIVES FOR THE TREATMENT OF CANCER
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The present invention relates to new Macrocycles of formula (I) and their use for the treatment of cancer.
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- Multi-step application of immobilized reagents and scavengers: A total synthesis of epothilone C
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The total synthesis of the cytotoxic antitumour natural product epothilone C has provided a stage for the exploitation and further development of immobilized reagent methods. A stereoselective convergent synthetic strategy was applied, incorporating polymer-supported reagents, catalysts, scavengers and catch-and-release techniques to avoid frequent aqueous work-up and chromatographic purification.
- Storer, R. Ian,Takemoto, Toshiyasu,Jackson, Philip S.,Brown, Dearg S.,Baxendale, Ian R.,Ley, Steven V.
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p. 2529 - 2547
(2007/10/03)
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- Method for producing epothilone B and derivatives, and intermediate products for this method
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The invention relates to a method for producing epothilone B and derivatives, and to intermediate products for this method. According to the novel method, the epothilone B or derivatives are produced in high yields from the C1-C6, C7-C10 and C11-C20-fragm
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- A total synthesis of epothilones using solid-supported reagents and scavengers
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A total synthesis of epothilone C(1) with concomitant formal synthesis of epothilone A is described, using immobilized reagents and scavengers to effect multistep synthetic transformations and purifications.
- Storer, R. Ian,Takemoto, Toshiyasu,Jackson, Philip S.,Ley, Steven V.
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p. 2521 - 2525
(2007/10/03)
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- Flexible routes to the 5-hydroxy acid fragment of the cryptophycins
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Two solutions to establishing the anti stereochemistry of the vicinal stereocenters in the 5-hydroxy acid subunit of cryptophycin, based on initial Evans syn aldol reactions between an N-(propionyl)oxazolidinone 4 and a C3 aldehyde, were developed. In the first route, the secondary hydroxy group was inverted by use of Mitsunobu reaction conditions, whereas the second route features an inversion of the methyl-bearing stereocenter, achieved by reductive removal of the chiral auxiliary, elimination to afford the terminal alkene, and anti-selective hydroboration. The aryl part can be attached either by Wittig-Horner olefination or by a modified Julia coupling. Both routes provide the hydroxy acid 16 in a very efficient manner. The substrate for the hydroboration, alkene 22, could also be obtained from (S)-malic acid. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Phukan, Prodeep,Sasmal, Sanjita,Maier, Martin E.
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p. 1733 - 1740
(2007/10/03)
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- Intermediates for the synthesis of epothilones and methods for their preparation
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The invention relates to a method of synthesis for a compound of formula (I), wherein R is a heterocyclyl moiety and X1, X2, X3and X4are, independently of each other, protecting groups, which is appropriate for the synthesis of epothilone B and desoxyepothione B.
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Page column 20
(2010/01/30)
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- Total Syntheses of Epothilones B and D
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Total syntheses of the microtubule stabilizing antitumor drugs epothilone B and D are described, starting from optically pure (S)-malic acid and methyl (R)-3-hydroxy-2-methylpropionate. The synthesis is highly convergent by coupling the three fragments C1-C6 (fragment D), C7-C10 (fragment C), and C11-C21 (fragment B). Key steps are two stereoselective Wittig type olefinations to generate the 12,13- and 16,17-double bonds, an enantioselective Mukaiyama aldol addition to synthesize fragment D, and a sulfone anion allyl iodide alkylation to connect fragments B and C. Finally fragment D was attached to the B + C fragment via aldol addition.
- Mulzer, Johann,Mantoulidis, Andreas,Oehler, Elisabeth
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p. 7456 - 7467
(2007/10/03)
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- Syntheses of (-)-epothilone B
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Two efficient routes for the total synthesis of (-)-epothilone B are reported. One strategy is based on ring-closing metathesis, and a second synthesis on a macrolactonization. The key fragments are available on large scale to provide sufficient material for biological tests. Thiazole fragment 4 was obtained by an improved route starting from (S)-malic acid. The first synthesis is based on our preceding paper. The critical trisubstituted double bond C12-13 in our second approach was constructed by a highly efficient Pd- mediated coupling reaction. Ring closure was achieved by macrolactonization.
- Schinzer, Dieter,Bauer, Armin,Schieber, Jennifer
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p. 2492 - 2500
(2007/10/03)
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- Easy access to the epothilone family - Synthesis of epothilone B
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An easy access to four out of five naturally occurring epothilones (A- E, 1-5) is reported. Key steps are an enantioselective Mukaiyama type aldol reaction, (E)- and (Z)-selective olefinations, and a sulfone alkylation.
- Mulzer, Johann,Mantoulidis, Andreas,Oehler, Elisabeth
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p. 8633 - 8636
(2007/10/03)
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- Synthesis of epothilones: Stereoselective routes to epothilone B
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In connection with our studies of the total syntheses of epothilones we report our efforts on the syntheses of epothilone B using a macro-lactonization and a metathesis approach. Key reaction for the solution of the acyclic stereoselection is a stereoselective aldol reaction.
- Schinzer, Dieter,Bauer, Armin,Schieber, Jennifer
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p. 861 - 864
(2007/10/03)
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- A new efficient synthesis of nicotianamine and 2′-deoxymugineic acid
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Nicotianamine and 2′-deoxymugineic acid, phytosiderophores, have been efficiently synthesized, which will be suitable for large scale production of these plant physiologically important compounds. The synthetic method for 2′,3″-dideoxy-3″-oxomugineic acid was also investigated.
- Shioiri, Takayuki,Irako, Naoko,Sakakibara, Sachiko,Matsuura, Fumiyoshi,Hamada, Yasumasa
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p. 519 - 530
(2007/10/03)
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- Stereoselective Intramolecular Cyclopropanations: Enantioselective Syntheses of 1α,25-Dihydroxyvitamin D3 A-Ring Precursors
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Two efficient enantioselective syntheses of an A-ring precursor to 1α,25-dihydroxyvitamin D3 have been developed.The key step in these sequences involves the stereoselective cyclopropanation of a chiral γ-alkoxy-α-diazo-β-keto ester.In one sequence, the 1α-hydroxy group was introduced in the first step by a diastereoselective ene reaction and in the other sequence by use of (S)-malic acid as starting material.Both routes eliminate the need for a SeO2 oxidation.
- Dauben, William G.,Hendricks, Robert T.,Pandy, Bipin,Wu, Shung C.,Zhang, Xiaoming,Luzzio, Michael J.
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p. 2385 - 2388
(2007/10/02)
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