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【结 构 式】 
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【分子编号】10640 【品名】(1S,3R,4S,7S,8S,10R,13S)-7-(benzyloxy)-13-[[tert-butyl(dimethyl)silyl]oxy]-1,2,5-trihydroxy-8,12,15,15-tetramethyl-9-oxo-4-[(phenylsulfanyl)methyl]tricyclo[9.3.1.0(3,8)]pentadec-11-en-10-yl acetate 【CA登记号】 |
【 分 子 式 】C41H58O8SSi 【 分 子 量 】739.05822 【元素组成】C 66.63% H 7.91% O 17.32% S 4.34% Si 3.8% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)The intramolecular pinacolic cyclization of (XXI) by means of SmI2 yields the compound (XXII) with the basic ABC subskeleton of paclitaxel. Selective acetylation and silylation of (XXII) with acetic anhydride/pyridine and TBDMS-Cl gives the trihydroxy compound (XXIII), which is oxidized with oxalyl chloride as usual to the trione (XXIV). Selective reduction of (XXIV) with Zn(BH4)2 yields the dihydroxydione (XXV), which is selectively benzoylated and, after benzyl protection of the remaining hydroxy groups, affords the protected dione (XXVI). Selective reduction of (XXVI) with L-selectride followed by oxidation of the sulfanyl group to sulfinyl and its elimination by heating gives a methylene double bond, which is oxidized in situ with MCPBA and OsO4 to the vicinal triol (XXVII). The cyclization of (XXVII) according to Tetrahedron Lett 1991, 47: 9823 affords the hydroxy ketone (XXVIII) with the basic skeleton of paclitaxel. Acetylation of (XXVIII) with acetic anhydride/pyridine followed by selective elimination of the TBDMS group affords the secondary alcohol (XXIX). The attachment of the propenoyl side-chain of paclitaxel to (XXIX) according to J Amer Chem Soc 1988, 110: 5917 gives the protected paclitaxel derivative (XXX), which is finally deprotected by hydrogenolysis with H2 over Pd/C.
| 【1】 Danishefsky, S.J.; Bornmann, W.G.; Queneau, Y.; Magee, T.V.; Krol, W.J. (Sloan-Kettering Institute); Total synthesis of taxol. US 5416225 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXII) | 10639 | (1S,3R,4S,7S,8S,10R,13S)-7-(Benzyloxy)-1,2,5,10,13-pentahydroxy-8,12,15,15-tetramethyl-4-[(phenylsulfanyl)methyl]tricyclo[9.3.1.0(3,8)]pentadec-11-en-9-one | C33H42O7S | 详情 | 详情 | |
| (XXIII) | 10640 | (1S,3R,4S,7S,8S,10R,13S)-7-(benzyloxy)-13-[[tert-butyl(dimethyl)silyl]oxy]-1,2,5-trihydroxy-8,12,15,15-tetramethyl-9-oxo-4-[(phenylsulfanyl)methyl]tricyclo[9.3.1.0(3,8)]pentadec-11-en-10-yl acetate | C41H58O8SSi | 详情 | 详情 | |
| (XXIV) | 10641 | (1S,3R,4S,7S,8S,10R,13S)-7-(benzyloxy)-13-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-8,12,15,15-tetramethyl-2,5,9-trioxo-4-[(phenylsulfanyl)methyl]tricyclo[9.3.1.0(3,8)]pentadec-11-en-10-yl acetate | C41H54O8SSi | 详情 | 详情 | |
| (XXV) | 10642 | (1S,2S,3R,4S,7S,8S,10R,13S)-7-(benzyloxy)-13-[[tert-butyl(dimethyl)silyl]oxy]-1,2-dihydroxy-8,12,15,15-tetramethyl-5,9-dioxo-4-[(phenylsulfanyl)methyl]tricyclo[9.3.1.0(3,8)]pentadec-11-en-10-yl acetate | C41H56O8SSi | 详情 | 详情 | |
| (XXVI) | 10643 | (1S,2S,3R,4S,7S,8S,10R,13S)-10-(acetoxy)-1,7-bis(benzyloxy)-13-[[tert-butyl(dimethyl)silyl]oxy]-8,12,15,15-tetramethyl-5,9-dioxo-4-[(phenylsulfanyl)methyl]tricyclo[9.3.1.0(3,8)]pentadec-11-en-2-yl benzoate | C55H66O9SSi | 详情 | 详情 | |
| (XXVII) | 10644 | (1S,2S,3R,4S,5R,7S,8S,10R,13S)-10-(acetoxy)-1,7-bis(benzyloxy)-13-[[tert-butyl(dimethyl)silyl]oxy]-4,5-dihydroxy-4-(hydroxymethyl)-8,12,15,15-tetramethyl-9-oxotricyclo[9.3.1.0(3,8)]pentadec-11-en-2-yl benzoate | C49H64O11Si | 详情 | 详情 | |
| (XXVIII) | 10645 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetoxy)-1,9-bis(benzyloxy)-15-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C49H62O10Si | 详情 | 详情 | |
| (XXIX) | 10646 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,9-bis(benzyloxy)-15-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C45H50O11 | 详情 | 详情 | |
| (XXX) | 10647 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(2-ethoxyethoxy)-3-phenylpropanoyl]oxy]-1,9-bis(benzyloxy)-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C65H71NO15 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation of phenol (I) with ethyl bromoacetate (II) by means of NaH in refluxing dimethoxyethane gives phenoxyacetate (III), which by condensation with dimethyl methylphosphonate (IV) by means of butyllithium in THF is converted into dimethyl 2-oxo-3-phenoxypropylphosphonate (V). The Wittig condensation of (V) with (2'alpha-hydroxy-4'alpha-p-phenylbenzoyloxy)-5'beta-formylcyclopent-1’alpha-yl)acetic acid 1,2'-lactone (VI) by means of NaH in methoxyethane affords the phenoxylactone (VII), which is reduced witl aluminium isopropoxide in refluxing toluene to yield the hydroxylactone (VIII). The hydrolysis of (VIII) with K2CO3 in methanol gives the dihydroxylactone (IX), which is protected with dihydropyran and p-toluenesulfonic acid in methylene chloride giving the bis-tetrahydropyranyloxylactone (X). The reduction of (X) with diisobutylaluminium hydride in toluene yields [2'alpha-hydroxy-4'alpha-tetrahydropyranyloxy-5'beta-(3''alpha-tetrapyranyloxy-4''-phenoxybut-1''-trans-en-1''-yl)cyclopent-1'alpha-yl]acetaldehyde 1,2-hemiacetal (XI), which is condensed with 4-pentynoate (XII) by means of methyllithium and diisopropylamine in ether to afford the acetylenic prostaglandin derivative (XIII). The acetylation of (XIII) with acetic anhydride - triethylamine and dimethylaminopyridine in methylene chloride gives the diacetoxy compound (XIV), which by treatment with Cu2I2 and methyllithium in ether is converted into the cumulenic prostaglandin (XV). The elimination of the tetrahydropyran groups with acetic acid yields the dihydroxy-acetoxy ester (XVI), which is fully hydrolyzed with K2ClO3 in MeOH affording 8R-9alpha,11alpha,15alpha-trihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid (XVII). Finally this compound is methylated with diazomethane in ether
| 【1】 Serradell, M.N.; Castaner, J.; Adaikan, P.G.; Kottegoda, S.R.; Fenprostalene. Drugs Fut 1984, 9, 11, 817. |
| 【2】 Muchowski, J.M.; et al. (Syntex (USA) Inc.); US 3985791 . |
| 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) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (II) | 10640 | (1S,3R,4S,7S,8S,10R,13S)-7-(benzyloxy)-13-[[tert-butyl(dimethyl)silyl]oxy]-1,2,5-trihydroxy-8,12,15,15-tetramethyl-9-oxo-4-[(phenylsulfanyl)methyl]tricyclo[9.3.1.0(3,8)]pentadec-11-en-10-yl acetate | C41H58O8SSi | 详情 | 详情 | |
| (III) | 32040 | ethyl 2-phenoxyacetate | 2555-49-9 | C10H12O3 | 详情 | 详情 |
| (IV) | 13607 | dimethyl methylphosphonate | 756-79-6 | C3H9O3P | 详情 | 详情 |
| (V) | 32041 | dimethyl 2-oxo-3-phenoxypropylphosphonate | 40665-68-7 | C11H15O5P | 详情 | 详情 |
| (VI) | 32042 | (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C21H18O5 | 详情 | 详情 | |
| (VII) | 32043 | (3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C30H26O6 | 详情 | 详情 | |
| (VIII) | 32044 | (3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate | C30H28O6 | 详情 | 详情 | |
| (IX) | 32045 | (3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one | C17H20O5 | 详情 | 详情 | |
| (X) | 32046 | (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one | C29H40O7 | 详情 | 详情 | |
| (XI) | 32047 | (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol | C29H42O7 | 详情 | 详情 | |
| (XII) | 51633 | methyl 4-pentynoate | C6H8O2 | 详情 | 详情 | |
| (XIII) | 32049 | methyl 6-hydroxy-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate | C35H50O9 | 详情 | 详情 | |
| (XIV) | 32050 | methyl 6-(acetoxy)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate | C39H54O11 | 详情 | 详情 | |
| (XV) | 32051 | methyl 7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4,5-heptadienoate | C37H52O9 | 详情 | 详情 | |
| (XVI) | 32052 | methyl 7-[(1R,2R,3R,5S)-5-(acetoxy)-3-hydroxy-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]cyclopentyl]-4,5-heptadienoate | C25H32O7 | 详情 | 详情 | |
| (XVII) | 32053 | 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]cyclopentyl]-4,5-heptadienoic acid | C22H28O6 | 详情 | 详情 |