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【结 构 式】 
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【分子编号】10666 【品名】(2aR,4S,11S,12aR,12bS)-11-(Methoxymethyl)-4a,8,13,13-tetramethyl-4,12b-bis(tert-butyldimethylsilyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benz[1,2-b]oxete-5,6,12-trione 6,6-propyleneditihoketal 【CA登记号】 |
【 分 子 式 】C37H64O7S2Si2 【 分 子 量 】741.21396 【元素组成】C 59.96% H 8.7% O 15.11% S 8.65% Si 7.58% |
合成路线1
该中间体在本合成路线中的序号：(IL)2) The silylation of the hydroxyketal (XXXI) with TBDMS-Tf in dichloromethane gives the corresponding silyl ether (XXXII), which is treated sequentially with borane in THF, with H2O2 and tetrapropylammonium perruthenate catalyst to afford ketone (XXXIII). The reaction of (XXXIII) with KHMDS and TFNP in anhydrous THF yields the enol triflate (XXXIV), which by addition of CO catalyzed by triphenylphosphine and Pd(OAc)2 in methanol is converted to the methyl ester (XXXV). The reduction of (XXXV) with DIBAL in hexane gives the alcohol derivative (XXXVI), which by OsO4 oxidation in acetone/water gives the triol (XXXVII). The dehydration of (XXXVII) by previous silylation with TMS-Cl and reaction with trifluoromethanesulfonic anhydride in dichloromethane affords the oxetane derivative (XXXVIII), which is submitted to deketalization with CLTS to yield the ketone (XXXIX). The dehydrogenation of (XXXIX) by reaction with lithium diisopropylamide TMS-Cl and Pd(OAc)2 in THF gives the enone (XL), which is silylated with TBDMS-Cl in DMF to the fully silylated enone (XLI). The enolization of (XLI) with butyllithium and TMS-Cl followed by ozonolysis with O3 in dichloromethane yields the dialdehyde (XLII), which is submitted to a selective ketalization of the less hindered aldehyde group, affording the monoketal (XLIII). The addition of the lithium dithiane derivative (XLIV) to (XLIII) followed by a Swern oxidation of the intermediate alcohol gives the ketone (XLV), which is deketalized in acidic medium to yield the keto aldehyde (XLVI). The addition of the vinyllithium compound (XLVII) to (XLVI) gives the Diels-Alder precursor (XLVIII), which is submitted to cyclization by heating to afford the polycyclic compound (II) with the basic skeleton of paclitaxel.
| 【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 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| (IL) | 10666 | (2aR,4S,11S,12aR,12bS)-11-(Methoxymethyl)-4a,8,13,13-tetramethyl-4,12b-bis(tert-butyldimethylsilyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benz[1,2-b]oxete-5,6,12-trione 6,6-propyleneditihoketal | C37H64O7S2Si2 | 详情 | 详情 | |
| (XXXI) | 10648 | 4'a-Methyl-3',4',4'a,5',6',7'-hexahydro-1'H-spiro[[1,3]dioxolane-2,2'-naphthalen]-5'-ol | C13H20O3 | 详情 | 详情 | |
| (XXXII) | 10649 | tert-Butyl-dimethyl-(4'a-methyl-3',4',4'a,5',6',7'-hexahydro-1'H-spiro[[1,3]dioxolane-2,2'-naphthalen]-5'-yloxy)-silane | C19H34O3Si | 详情 | 详情 | |
| (XXXIII) | 10650 | 5'-(tert-Butyl-dimethyl-silanyloxy)-4'a-methyl-octahydro-spiro[[1,3]dioxolane-2,2'-naphthalen]-8'-one | C19H34O4Si | 详情 | 详情 | |
| (XXXIV) | 10651 | Trifluoro-methanesulfonic acid 5'-(tert-butyl-dimethyl-silanyloxy)-4'a-methyl-3',4',4'a,5',6',8'a-hexahydro-1'H-spiro[[1,3]dioxolane-2,2'-naphthalen]-8'-yl ester | C20H33F3O6SSi | 详情 | 详情 | |
| (XXXV) | 10652 | 5'-(tert-Butyl-dimethyl-silanyloxy)-4'a-methyl-3',4',4'a,5',6',8'a-hexahydro-1'H-spiro[[1,3]dioxolane-2,2'-naphthalene]-8'-carboxylic acid methyl ester | C21H36O5Si | 详情 | 详情 | |
| (XXXVI) | 10653 | (4aS,8aS)-8-(Hydroxymethyl)-4a-methyl-5-(tert-butyldimethylsilyloxy)-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-one ethyleneketal | C20H36O4Si | 详情 | 详情 | |
| (XXXVII) | 10654 | 5'-(tert-Butyl-dimethyl-silanyloxy)-8'-hydroxymethyl-4'a-methyl-octahydro-spiro[[1,3]dioxolane-2,2'-naphthalene]-7',8'-diol | C20H38O6Si | 详情 | 详情 | |
| (XXXVIII) | 10655 | (2'aR,4'S,4'aS,8'aS)-4'a-Methyl-4'-(tert-butyldimethylsilyloxy)perhydrospiro[1,3-dioxolane-2,7'-naphtho[1,2-b]oxet]-8'b-ol | C20H36O5Si | 详情 | 详情 | |
| (XXXIX) | 10656 | (2aR,4S,4aS,8aS,8bS)-4-[[tert-butyl(dimethyl)silyl]oxy]-8b-hydroxy-4a-methyldecahydro-7H-naphtho[2,1-b]oxet-7-one | C18H32O4Si | 详情 | 详情 | |
| (XL) | 10657 | (2aR,4S,4aS,8aS,8bS)-4-[[tert-Butyl(dimethyl)silyl]oxy]-8b-hydroxy-4a-methyl-1,2a,3,4,4a,8,8a,8b-octahydro-7H-naphtho[2,1-b]oxet-7-one | C18H30O4Si | 详情 | 详情 | |
| (XLI) | 10658 | (2aR,4S,4aS,8aS,8bS)-4,8b-bis[[tert-Butyl(dimethyl)silyl]oxy]-4a-methyl-1,2a,3,4,4a,8,8a,8b-octahydro-7H-naphtho[2,1-b]oxet-7-one | C24H44O4Si2 | 详情 | 详情 | |
| (XLII) | 10659 | (1S,2S,3S,4S,6R)-1,4-Bis[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-7-oxabicyclo[4.2.0]octane-2,3-dicarbaldehyde | C22H42O5Si2 | 详情 | 详情 | |
| (XLIII) | 10660 | (1S,2S,3S,4S,6R)-1,4-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-(1,3-dioxolan-2-yl)-3-methyl-7-oxabicyclo[4.2.0]octane-3-carbaldehyde | C24H46O6Si2 | 详情 | 详情 | |
| (XLIV) | 10661 | [2-(1-Isopropenyl-2-methyl-1-propenyl)-1,3-dithian-2-yl]lithium | C11H17LiS2 | 详情 | 详情 | |
| (XLV) | 10662 | [(1S,2S,3S,4S,6R)-1,4-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-(1,3-dioxolan-2-yl)-3-methyl-7-oxabicyclo[4.2.0]oct-3-yl][2-(1-isopropenyl-2-methyl-1-propenyl)-1,3-dithian-2-yl]methanone | C35H62O6S2Si2 | 详情 | 详情 | |
| (XLVI) | 10663 | (1S,2S,3S,4S,6R)-1,4-Bis[[tert-butyl(dimethyl)silyl]oxy]-3-[[2-(1-isopropenyl-2-methyl-1-propenyl)-1,3-dithian-2-yl]carbonyl]-3-methyl-7-oxabicyclo[4.2.0]octane-2-carbaldehyde | C33H58O5S2Si2 | 详情 | 详情 | |
| (XLVII) | 10664 | [1-(Methoxymethoxy)vinyl]lithium | C4H7LiO2 | 详情 | 详情 | |
| (XLVIII) | 10665 | 1-((1S,2S,3S,4S,6R)-1,4-Bis[[tert-butyl(dimethyl)silyl]oxy]-3-[[2-(1-isopropenyl-2-methyl-1-propenyl)-1,3-dithian-2-yl]carbonyl]-3-methyl-7-oxabicyclo[4.2.0]oct-2-yl)-2-(methoxymethoxy)-2-propen-1-one | C37H64O7S2Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IL)The stereoselective reduction of the lesshindered ketonic group of (II) followed by benzoylation yields the polycyclic ketone (L), which is submitted to an allylic oxidation to afford the unsaturated dione (LI). The sequential selective reduction of the less hindered ketone with a bulky borohydride gives an alpha-alcohol, which is then benzylated with benzyl chloride and finally treated with H2 and Raney Nickel to eliminate the dithiane group and afford the polycyclic ketone (LII). The regioselective Franklin Davis hydroxylation of (LII) followed by desilylation with TBAF and peracetylation with acetic anhydride yields the triacetoxy ketone (LIII), which is debenzylated by hydrogenation with H2 over Pd/C to the secondary alcohol (LIV). The attachment of the propenoyl side-chain of paclitaxel to (LIV) according to J Amer Chem Soc 1988, 110: 5917 gives the protected paclitaxel derivative (LV), which is submitted to a selective deacetylation to the paclitaxel precursor (LVI). Finally, this compound is deprotected to paclitaxel.
| 【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 |
|---|---|---|---|---|---|---|
| (IL) | 10666 | (2aR,4S,11S,12aR,12bS)-11-(Methoxymethyl)-4a,8,13,13-tetramethyl-4,12b-bis(tert-butyldimethylsilyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benz[1,2-b]oxete-5,6,12-trione 6,6-propyleneditihoketal | C37H64O7S2Si2 | 详情 | 详情 | |
| (L) | 10667 | (2aR,4S,11S,12S,12aR,12bS)-12-(Benzoyloxy)-11-(methoxymethyl)-4a,8,13,13-tetramethyl-4,12b-bis(tert-butyldimethylsilyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benz[1,2-b]oxete-5,6-dione 6,6-propyleneditihoketal | C44H70O8S2Si2 | 详情 | 详情 | |
| (LI) | 10668 | (2aR,4S,11S,12S,12aR,12bS)-12-(Benzoyloxy)-11-(methoxymethyl)-4a,8,13,13-tetramethyl-4,12b-bis(tert-butyldimethylsilyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benz[1,2-b]oxete-5,6,9-trione 6,6-propyleneditihoketal | C44H68O9S2Si2 | 详情 | 详情 | |
| (LII) | 10669 | (1S,2S,3R,4S,7R,9S,10S,15S)-15-(benzyloxy)-4,9-bis[[tert-butyl(dimethyl)silyl]oxy]-1-(methoxymethoxy)-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C48H72O9Si2 | 详情 | 详情 | |
| (LIII) | 10670 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,9,12-tris(acetoxy)-15-(benzyloxy)-1-(methoxymethoxy)-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C42H50O13 | 详情 | 详情 | |
| (LIV) | 10671 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,9,12-tris(acetoxy)-15-hydroxy-1-(methoxymethoxy)-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C35H44O13 | 详情 | 详情 | |
| (LV) | 10672 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,9,12-tris(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(2-ethoxyethoxy)-3-phenylpropanoyl]oxy]-1-(methoxymethoxy)-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C55H65NO17 | 详情 | 详情 | |
| (LVI) | 10673 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(2-ethoxyethoxy)-3-phenylpropanoyl]oxy]-9-hydroxy-1-(methoxymethoxy)-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C53H63NO16 | 详情 | 详情 |