- Total synthesis of (±)-Calanolide A
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The total synthesis of (±)-Calanolide A, incorporating a ring-forming sequence different from previous procedures, is described.
- Rehder, Ken S.,Kepler, John A.
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- Total Synthesis of (+/-)-Calanolide A, a Non-Nucleoside Inhibitor of HIV-1 Reverse Transcriptase
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The first syntheses of (+/-)-calanolide A and the related (+/-)-calanolides C and D have been carried out in a short sequence using a Lewis acid-promoted Claisen rearrangement to establish the chromene ring.
- Chenera, Balan,West, Michael L.,Finkelstein, Joseph A.,Dreyer, Geoffrey B.
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- Novel Approach for Synthesis of (+/-)-Calanolide A and Its Anti-HIV Activity
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Anti-HIV agent (+/-)-calanolide A (1) has been synthesized.The key intermediate, chromone 5, was synthesized by the sequence of Pechmann reaction, acylation and chromenylation by 4,4-dimethoxy-2-methylbutan-2-ol.The anti-HIV activity for synthetic (+/-)-1 has been determined and compared with the natural product.
- Kucherenko, Alla,Flavin, Michael T.,Boulanger, William A.,Khilevich, Albert,Shone, Robert L.,et al.
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- A versatile approach for synthesis of 2,3-dimethyl chroman-4-ones, intermediate for calanolide anti-HIV agents, via aldol/Mitsunobu reactions
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Combined aldol/Mitsunobu reactions have been employed for the first time for synthesis of 2,3-dimethyl chroman-4-ones, intermediates for calanolide anti-HIV agents. Thus, the lithium enolate of chromene 1 reacted with acetaldehyde at -78°C to afford the aldol products 4 and 5. Under Mitsunobu conditions (Ph3P/DEAD), the syn aldol product 4 led to the formation of trans-2,3-dimethyl chroman-4-one 2 while the anti aldol product 5 yielded both trans and cis derivative (2 and 3). The use of other phosphorous and azo compounds in this reaction has also been investigated.
- Khilevich, Albert,Rizzo, John D.,Flavin, Michael T.,Sheinkman, Abram K.,Mar, Aye,Kucherenko, Alla,Yan, Changren,Dzekhtser, Sergey,Brankovic, Darko,Lin, Lin,Liu, Jinjun,Rizzo, Thomas M.,Xu, Ze-Qi
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- Structure-activity modifications of the HIV-1 inhibitors (+)-calanolide A and (-)-calanolide B
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The Δ7,8 olefinic linkages within (+)-calanolide A (1) and (-)- calanolide B (2) were catalytically reduced to determine impact on the anti- HIV activity of the parent compounds. In addition, a series of structure modifications of the C-12 hydroxyl group in (-)-calanolide B was made to investigate the importance of that substituent to the HIV-1 inhibitory activity of these coumarins. A total of 14 analogs were isolated or prepared and compared to (+)-calanolide A and (-)-calanolide B in the NCI primary anti-HIV assay. While none of the compounds showed activity superior to the two unmodified leads, some structure-activity requirements were apparent from the relative anti-HIV potencies of the various analogs.
- Galinis, Deborah L.,Fuller, Richard W.,McKee, Tawnya C.,Cardellina II, John H.,Gulakowski, Robert J.,McMahon, James B.,Boyd, Michael R.
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- Concise Synthesis of Anti-HIV-1 Active (+)-Inophyllum B and (+)-Calanolide A by Application of (-)-Quinine-Catalyzed Intramolecular Oxo-Michael Addition
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(-)-Quinine-catalyzed intramolecular oxo-Michael addition (IMA) of 7-hydroxy-5-methoxy-8-tigloylcoumarins was developed for the enantioselective construction of 2,3-dimethyl-4-chromanone systems in the context of the asymmetric synthesis of anti-HIV-1 act
- Sekino, Etsuko,Kumamoto, Takuya,Tanaka, Tomohiro,Ikeda, Tomoko,Ishikawa, Tsutomu
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p. 2760 - 2767
(2007/10/03)
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- Preparation of a trans-calanolide ketone intermediate and chiral separation of calanolide alcohols to give racemic calanolide A
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The method of the invention comprises a process for synthesizing a trans-calanolide A ketone intermediate used in the synthesis of racemic trans-calanolide A. The invention further comprises a method for removing a racemic calanolide B diastereomer from a
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- PROCESSES FOR PREPARING CALANOLIDE A AND INTERMEDIATES THEREOF
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The present invention provides a production method of Calanolide A according to the following method wherein each symbol is as defined in the specification, as a more convenient and industrially practical method for the synthesis of Calanolide A from an easily available starting material.
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Page/Page column 21
(2008/06/13)
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- Methods for preparing antiviral calanolide compounds
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The present invention relates to methods for preparing 2,2-dimethyl-5-acyloxy-10-propyl-2H,8H-benzo[ 1,2-b:3,4-b ′]dipyran-8-one (5) and 2,2-dimethyl-5-hydroxy- 10-propyl-2H,8H-benzo[1,2-b:3,4-b ′]dipyran-8-one (6) and their use as intermediates for the synthesis of antiviral calanolide compounds. For example, Fries rearrangement on compound 5 or Friedel-Crafts reaction on 6, yields intermediate 2,2-dimethyl-5-hydroxy-6-propionyl-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (4), which, in turn, can be converted to (+)-calanolide A and (?)-calanolide B. The coupling of compound 6 with the appropriate chiral molecule under Mitsunobu or nucleophilic displacement leads to the asymmetric synthesis of antiviral calanolide compounds.
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- Methods for preparing antiviral calanolide compounds
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The present invention relates to methods for preparing 2,2-dimethyl-5-acyloxy-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (5) and 2,2-dimethyl-5-hydroxy-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (6) and their use as intermediates for the synthesis of antiviral calanolide compounds. For example, Fries rearrangement on compound 5 or Friedel-Crafts reaction on 6, yields intermediate 2,2-dimethyl-5-hydroxy-6-propionyl-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (4), which, in turn, can be converted to (+)-calanolide A and (?)-calanolide B. The coupling of compound 6 with the appropriate chiral molecule under Mitsunobu or nucleophilic displacement leads to the asymmetric synthesis of antiviral calanolide compounds.
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- Method for treating and preventing mycobacterium infections
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Calanolides and analogues thereof that demonstrate potent mycobacterium activity are provided. Also provided is a method of using calanolides and analogues thereof for treating or preventing mycobacterium infections. The calanolides and analogues thereof provided are obtained via syntheses employing chromene 4 and chromanone 7 as key intermediates.
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- Calanolide analogues and methods of their use
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Calanolide analogues that demonstrate potent antiviral activity against many viruses are provided. Also provided is a method of using calanolide analogues for treating or preventing viral infections. The calanolide analogues provided are obtained via syntheses employing chromene 4 and chromanone 7 as key intermediates.
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- Enantioselective total synthesis of anti HIV-1 active (+)-calanolide A through a quinine-catalyzed asymmetric intramolecular oxo-Michael addition
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Enantioselective total synthesis of anti HIV-1 active (+)-calanolide A was achieved by a quinine-catalyzed asymmetric intramolecular oxo-Michael addition as a key step. (C) 2000 Elsevier Science Ltd.
- Tanaka, Tomohiro,Kumamoto, Takuya,Ishikawa, Tsutomu
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p. 10229 - 10232
(2007/10/03)
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- Method for the preparation of (+)-calanolide a and analogues thereof
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A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (±)-8a. Separation and enzyme-mediated resolution of (±)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (+)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.
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- Method for the preparation of (+)-calanolide A and analogues thereof
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A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (±)-8a. Separation and enzyme-mediated resolution of (±)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (+)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.
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- Synthesis of (+)-calanolide A, an anti-HIV agent, via enzyme-catalyzed resolution of the aldol products
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The synthesis of (+)-calanolide A (1), an anti-HIV-1 agent, is described. A TiCl4-mediated aldol reaction of compound 2 stereoselectively produced the desired syn diastereomer (±)-5, which was resolved by a lipase-catalyzed acylation reaction. Under Mitsunobu conditions (Ph3P/DEAD), the syn aldol product (+)-5 led to the formation of trans-2,3-dimethyl chroman-4-one [(+)-3] with 94% ee, while the anti aldol product (+)-6 yielded both trans and cis derivatives (+)-3 and (+)-4 with 60% and 68% ee, respectively. Luche reduction on (+)-3 led to (+)-1 and (+)-calanolide B in a ratio of 9:1. Copyright (C) Elsevier Science Ltd.
- Khilevich, Albert,Mar, Aye,Flavin, Michael T.,Rizzo, John D.,Lin, Lin,Dzekhtser, Sergey,Brankovic, Darko,Zhang, Heping,Chen, Wei,Liao, Shuyuan,Zembower, David E.,Xu, Ze-Qi
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p. 3315 - 3326
(2007/10/03)
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- Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (±)-calanolide A and its enantiomers
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The anti-HIV agent (±)-calanolide A (1) has been synthesized in a five- step approach starting with phloroglucinol [→ 5 → 6 → 11 → 18 → (±)- 1], which includes Pechmann reaction, Friedel-Crafts acylation, chromenylation with 4,4-dimethoxy-2-methylbutan-2-ol, cyclization, and Luche reduction. Cyclization of chromene 11 to chromanone 18 was achieved by employing either acetaldehyde diethyl acetal or paraldehyde in the presence of trifluoroacetic acid and pyridine or PPTS. Luche reduction of chromanone 18 at lower temperature preferably yielded (±)-1. Reduction of chromone 12, synthesized by Kostanecki-Robinson reaction from chromene 11, failed to afford (±)-1. The synthetic (±)-1 has been chromatographically resolved into its optically active forms, (+)- and (-)-1. The anti-HIV activities for synthetic (±)-1, as well as resultant (+)- and (-)-1, have been determined. Only (+)-1 accounted for anti-HIV activity, which was similar to the data reported for the natural product, and (-)-1 was inactive.
- Flavin, Michael T.,Rizzo, John D.,Khilevich, Albert,Kucherenko, Alla,Sheinkman, Abram K.,Vilaychack, Vilayphone,Lin, Lin,Chen, Wei,Greenwood, Eugenia Mata,Pengsuparp, Thitima,Pezzuto, John M.,Hughes, Stephen H.,Flavin, Thomas M.,Cibulski, Michael,Boulanger, William A.,Shone, Robert L.,Xu, Ze-Qi
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p. 1303 - 1313
(2007/10/03)
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- Synthesis of [12-3H]-(±)-calanolide A
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[12-3H]-(±)-Calanolide A (9) was synthesized in five steps from readily available phloroglucinol (1). Stereoselective Luche reduction of transketone 8 with cerium(III) chloride and sodium borotritide in methanol gave 338 μCi of 9 with a specific activity of 63.0 mCi/mmol.
- Rehder, Ken S.,Hristova-Kazmierski, Maria K.,Kepler, John A.
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p. 1077 - 1081
(2007/10/03)
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- Synthesis of the Calophyllum coumarins. Part 2
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Synthetic routes leading to the synthesis of the natural 4-phenyl, 4-propyl and 4-methyl coumarins isolated from Calophyllum sp. are presented. 4-Aryl or -alkyl, 8- and 6-acyl 5,7-dihydroxy coumarins were chromenylated and then methylated at the 5 or 7 positions.A 4-step hydrobromination-bromination-double dehydrobromination sequence converted the 2-methylbutanoyl side chain into the (E)-2-methylbut-2-enoyl (tigloyl) group to give calophyllolide, oblongulide, their natural 4-propyl analogue and the corresponding regioisomers.Demethylation and cyclisation of the tigloyl group gave inophyllums C and E, tomentolides A and B, and calanolide D.Sodium boranuide reduction of the 2,3-dimethylchromanone ring afforded inophyllums A, B, D and P, soulattrolide, calanolides A-C, costatolide, and cordatolides A and B.The structures of calanolides C and D, oblongulide and apetatolide have been reassigned.The previously unknown stereochemistry about the 2,3-dimethylchromanone ring of tomentolides A and B has been established as trans.
- Palmer, Christopher,Josephs, Jonathan
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p. 3135 - 3152
(2007/10/03)
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- Synthesis of the calophyllum coumarins
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Synthetic routes leading to the synthesis of the natural 4-alkyl and 4- phenyl coumarins isolated from Calophyllum sp. are reported. The reported structures of calanolides C and D and oblongutide are incorrect and have been corrected by unambiguous synthesis.
- Palmer, Christopher J.,Josephs, Jonathan L.
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p. 5363 - 5366
(2007/10/02)
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