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【结 构 式】 
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【分子编号】22413 【品名】(10R,11S,12R)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-dipyrano[2,3-f:2,3-h]chromen-2-one 【CA登记号】 |
【 分 子 式 】C22H26O5 【 分 子 量 】370.44544 【元素组成】C 71.33% H 7.07% O 21.59% |
合成路线1
该中间体在本合成路线中的序号：(XI)1) The cyclization of phloroglucinol (I) with butyrylacetic acid ethyl ester (II) by means of concentrated sulfuric acid gives 5,7-dihydroxy-4-propyl-2H-1-benzopyran-2-one (III), which is condensed with propionyl chloride by means of AlCl3 in nitrobenzene, yielding the 8-propionyl derivative (V). The cyclization of (V) with 3-hydroxy-3-methylbuytyraldehyde dimethylacetal (VI) in refluxing pyridine affords the benzodipyran (VII), which is cyclized again with paraldehyde or acetaldehyde dimethylacetal by means of p-toluenesulfonic acid and trifluoroacetic acid in pyridine at 140 C to give a mixture of the diastereomeric racemates (VIII) and (IX), which are separated by column chromatography. The reduction of racemate (VIII) with NaBH4 /CeCl3 in ethanol yields a new mixture of the racemic hydroxy epimers (X) (racemic calanolide A) and (XI), which are separated by semipreparative HPLC. Racemic calanolide A (X) is finally submitted to optical resolution by semipreparative chiral HPLC.
| 【1】 Flavin, M.T.; Sheinkman, A.K.; Boulanger, W.A.; Khilevich, A.; Shone, R.L.; Rizzo, J.D.; Xu, Z.-Q.; Kucherenko, A.; Novel approach for synthesis of (±)-calanolide A a. Tetrahedron Lett 1995, 36, 31, 5475. |
| 【2】 Flavin, M.T.; Rizzo, J.D.; Khilevich, A.; et al.; Synthesis, chromatographic resolution, and anti-hu. J Med Chem 1996, 39, 6, 1303. |
| 【3】 Castañer, J.; Leeson, P.; Sorbera, L.A.; Calanolide A. Drugs Fut 1999, 24, 3, 235. |
| 【4】 Bokesch, H.R.; Cardellina, J.H. II; Boyd, M.R.; McKee, T.C.; Resolution and comparative anti-HIV evaluation of the enantiomers of calanolides A and B. Bioorg Med Chem Lett 1995, 5, 9, 1011. |
| 【5】 Boyd, M.R.; Cardellina, J.H. II; Gustafson, K.R.; McMahon, J.B.; Fuller, R.W.; Cragg, G.M.; Kashman, Y. (US Department of Health & Human Services); Calanolide antiviral cpds., compsns. and uses ther. EP 0633887; JP 1996502948; JP 1996507311; US 5591770; WO 9320082; WO 9428000 . |
| 【6】 Brankovic, D.; Flavin, M.T.; Vilaychack, V.; Liao, S.; Zembower, D.; Lin, L.; Dzekhster, S.; Rizzo, J.D.; Mar, A.; Xu, Z.-Q.; Khilevich, A.; Liu, J. (MediChem Research, Inc.); Method for the preparation of (+)-calanolide A and. WO 9838193 . |
| 【7】 Cragg, G.M.; Buckheit, R.W. Jr.; Fuller, R.W.; Gustafson, K.R.; Boyd, M.R.; Currens, M.J.; Cardellina, J.H. II; McMahon, J.B.; Hughes, S.H.; Kashman, Y.; The calanolides, a novel HIV-inhibitory class of c. J Med Chem 1992, 35, 15, 2735. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 11799 | 1,3,5-Benzenetriol; Fluoroglucinol | 108-73-6 | C6H6O3 | 详情 | 详情 |
| (II) | 12516 | ethyl 3-oxohexanoate; ethyl butyrylacetate | 3249-68-1 | C8H14O3 | 详情 | 详情 |
| (III) | 22405 | 5,7-dihydroxy-4-propyl-2H-chromen-2-one | C12H12O4 | 详情 | 详情 | |
| (IV) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (V) | 22407 | 5,7-dihydroxy-8-propionyl-4-propyl-2H-chromen-2-one | C15H16O5 | 详情 | 详情 | |
| (VI) | 22408 | 4,4-dimethoxy-2-methyl-2-butanol | C7H16O3 | 详情 | 详情 | |
| (VII) | 22409 | 5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one | C20H22O5 | 详情 | 详情 | |
| (VIII) | 22410 | (10R,11R)-6,6,10,11-tetramethyl-4-propyl-10,11-dihydro-2H,6H,12H-dipyrano[2,3-f:2,3-h]chromene-2,12-dione | C22H24O5 | 详情 | 详情 | |
| (IX) | 22411 | (10R,11S)-6,6,10,11-tetramethyl-4-propyl-10,11-dihydro-2H,6H,12H-dipyrano[2,3-f:2,3-h]chromene-2,12-dione | C22H24O5 | 详情 | 详情 | |
| (X) | 22412 | (10R,11S,12S)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-dipyrano[2,3-f:2,3-h]chromen-2-one | C22H26O5 | 详情 | 详情 | |
| (XI) | 22413 | (10R,11S,12R)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-dipyrano[2,3-f:2,3-h]chromen-2-one | C22H26O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XX)2) The condensation of 5,7-dihydroxy-4-propyl-2H-1-benzopyran-2-one (III) with N-methylformanilide (XII) by means of POCl3 in hot dichloromethane gives the carbaldehyde (XIII), which is cyclized with 3-chloro-3-methyl-1-butyne (XIV) by means of ZnCl2 /K2CO3 in hot 2-butanone/DMF, yielding the benzodipyran-carbaldehyde (XV). The enantioselective reaction of (XV) with 2(E)-butene and the chiral borane (+)-(E)-crotyldiisopinocamphenylborane (XVI) affords the single (R, R)-enatiomer (XVII). The selective silylation of (XVII) with TBDMS-Cl as usual gives the monosilyl ether (XVIII), which is cyclized by means of mercuric acetate and NaBH4 in THF, yielding the silylated (10R,11R,12R)-benzotripyran (XIX). The desilylation of (XIX) with tetrabutylammonium fluoride in THF gives the (10R,11S,12R)-benzotripyran (XX) (calanolide B), which is converted into calanolide A by inversion of the C-12 OH-group carried out with a modified Mitsunobu reaction with dimethyl azodicarboxylate (DEAD)/trimethylphosphine/chloroacetic acid in toluene/THF, followed by treatment with NH4OH in methanol.
| 【1】 Tagliaferri, F.; Deshpande, P.P.; Yan, S.; Victory, S.F.; Baker, D.C.; Synthesis of optically active calanoides A and B. J Org Chem 1995, 60, 10, 2964. |
| 【2】 Castañer, J.; Leeson, P.; Sorbera, L.A.; Calanolide A. Drugs Fut 1999, 24, 3, 235. |
| 【3】 Tagliaferri, F.; Yan, S.; Deshpande, P.P.; Baker, D.C.; Victory, S.F. (University of Tennessee, Knoxville); Synthesis of optically active calanolides A and B . US 5608085; WO 9626934 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17343 | 2-Butene-cis; (Z)-2-butene | 590-18-1 | C4H8 | 详情 | 详情 | |
| (III) | 22405 | 5,7-dihydroxy-4-propyl-2H-chromen-2-one | C12H12O4 | 详情 | 详情 | |
| (XII) | 20360 | methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline | 93-61-8 | C8H9NO | 详情 | 详情 |
| (XIII) | 22415 | 5,7-dihydroxy-2-oxo-4-propyl-2H-chromene-8-carbaldehyde | C13H12O5 | 详情 | 详情 | |
| (XIV) | 22416 | 3-chloro-3-methyl-1-butyne | 1111-97-3 | C5H7Cl | 详情 | 详情 |
| (XV) | 22417 | 5-hydroxy-2,2-dimethyl-8-oxo-10-propyl-2H,8H-pyrano[2,3-f]chromene-6-carbaldehyde | C18H18O5 | 详情 | 详情 | |
| (XVI) | 22418 | (E)-2-butenyl[bis(2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)]borane | C24H41B | 详情 | 详情 | |
| (XVII) | 22419 | 5-hydroxy-6-[(1R,2R)-1-hydroxy-2-methyl-3-butenyl]-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one | C22H26O5 | 详情 | 详情 | |
| (XVIII) | 22420 | 6-((1R,2R)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-3-butenyl)-5-hydroxy-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one | C28H40O5Si | 详情 | 详情 | |
| (XIX) | 22421 | (10R,11R,12R)-12-[[tert-butyl(dimethyl)silyl]oxy]-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-dipyrano[2,3-f:2,3-h]chromen-2-one | C28H40O5Si | 详情 | 详情 | |
| (XX) | 22413 | (10R,11S,12R)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-dipyrano[2,3-f:2,3-h]chromen-2-one | C22H26O5 | 详情 | 详情 |