|
【结 构 式】 
|
【分子编号】10653 【品名】(4aS,8aS)-8-(Hydroxymethyl)-4a-methyl-5-(tert-butyldimethylsilyloxy)-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-one ethyleneketal 【CA登记号】 |
【 分 子 式 】C20H36O4Si 【 分 子 量 】368.58894 【元素组成】C 65.17% H 9.84% O 17.36% Si 7.62% |
合成路线1
该中间体在本合成路线中的序号：(XXXVI)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：(IV)A new total synthesis of paclitaxel has been described: This synthesis starts from 2-methyl-2-(3-oxobutyl)cyclohexane-1,3-dione (I), which by a multistep synthesis (Helv Chim Acta 1950, 33: 2215) yields (S)-Wieland Miesher ketone (II). This compound is converted by a known process (J Org Chem 1992, 57: 3274) to the ketal (III), which by reaction with trimethylsulfonium iodide and potassium hexamethyldisilazide (KHMDS) affords the hydromethyl derivative (IV). The cyclization of (IV) according to J Org Chem 1992, 57: 3274 yields the oxetane derivative (V), which is benzylated and deprotected, affording the ketone (VI). A multistep ring cleavage of (VI) according to Angew Chem Int Ed Engl 1995, 34: 452 gives the aldehyde (VII), which is condensed with the lithium compound (VIII) (obtained from the corresponding iodo compound (IX) and BuLi) to afford the dienic ketone (X). The epoxidation of (X) with m-chloroperbenzoic acid (m-CPBA) followed by reduction with H2 over Pd/C yields compound (XI) with a tertiary hydroxy group, which by reaction with carbonyl diimidazole (CDI) and NaH affords the cyclic carbonate (XII). The reduction of (XII) with L-selectride in THF gives the saturated ketone (XIII), which is converted to the corresponding vinyl trifluoromethanesulfonate (XIV) by known methods. The cleavage of the dimethyl acetal group with pyridinium p-toluenesulfonate (PPTS) followed by chain elongation with methylenetriphenylphosphorane affords the allyl derivative (XV), which is submitted to cyclization with palladium triphenylphosphine complex, affording compound (XVI) with the basic ring system of paclitaxel. The previous change of the tert-butyldimethylsilyl (TBDMS) protecting group to a triethylsilyl (TES) group (less difficult to remove when the functionality of the tetracyclic structure is more complex) is performed with tetrabutylammonium fluoride (TBAF) and TES-Tf, yielding compound (XVII). The epoxidation of (XVII) with m-CPBA as usual affords epoxide (XVIII).
| 【1】 Masters, J.J.; Young, W.B.; Snyder, L.B.; Link, J.T.; Danishefsky, S.J.; A total synthesis of Taxol. Angew Chem. Int Ed Engl 1995, 34, 16, 1723. |
| 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) | 10692 | 2-Methyl-2-(3-oxobutyl)-1,3-cyclohexanedione | C11H16O3 | 详情 | 详情 | |
| (II) | 10693 | (8aS)-8a-Methyl-3,4,8,8a-tetrahydro-1,6(2H,7H)-naphthalenedione; (S)-(+)-3,4,8,8A-Tetrahydro-8a-methyl-1,6(2h,7h)-naphthalenedione | 33878-99-8 | C11H14O2 | 详情 | 详情 |
| (III) | 10650 | 5'-(tert-Butyl-dimethyl-silanyloxy)-4'a-methyl-octahydro-spiro[[1,3]dioxolane-2,2'-naphthalen]-8'-one | C19H34O4Si | 详情 | 详情 | |
| (IV) | 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 | |
| (V) | 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 | |
| (VI) | 10697 | (2aR,4S,4aS,8aS,8bS)-8b-(Benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-4a-methyldecahydro-7H-naphtho[2,1-b]oxet-7-one | C25H38O4Si | 详情 | 详情 | |
| (VII) | 10698 | (1S,2S,3S,4S,6R)-1-(Benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-(2,2-dimethoxyethyl)-3-methyl-7-oxabicyclo[4.2.0]octane-2-carbaldehyde | C26H42O6Si | 详情 | 详情 | |
| (VIII) | 10699 | [5-Cyano-4,6,6-trimethyl-5-[(trimethylsilyl)methyl]-1,3-cyclohexadien-1-yl]lithium | C14H22LiNSi | 详情 | 详情 | |
| (IX) | 10700 | 5-Iodo-2,6,6-trimethyl-1-[(trimethylsilyl)methyl]-2,4-cyclohexadiene-1-carbonitrile | C14H22INSi | 详情 | 详情 | |
| (X) | 10701 | 5-[(S)-[(1S,2R,3S,4S,6R)-1-(Benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-(2,2-dimethoxyethyl)-3-methyl-7-oxabicyclo[4.2.0]oct-2-yl](hydroxy)methyl]-2,6,6-trimethyl-2,4-cyclohexadien-1-one | C35H54O7Si | 详情 | 详情 | |
| (XI) | 10702 | (5S)-5-[(S)-[(1S,2R,3S,4S,6R)-1-(Benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-(2,2-dimethoxyethyl)-3-methyl-7-oxabicyclo[4.2.0]oct-2-yl](hydroxy)methyl]-5-hydroxy-2,6,6-trimethyl-2-cyclohexen-1-one | C35H56O8Si | 详情 | 详情 | |
| (XII) | 10703 | (4S,5S)-4-[(1S,2R,3S,4S,6R)-1-(Benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-(2,2-dimethoxyethyl)-3-methyl-7-oxabicyclo[4.2.0]oct-2-yl]-6,6,8-trimethyl-1,3-dioxaspiro[4.5]dec-8-ene-2,7-dione | C36H54O9Si | 详情 | 详情 | |
| (XIII) | 10704 | (4S,5S)-4-[(1S,2R,3S,4S,6R)-1-(Benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-(2,2-dimethoxyethyl)-3-methyl-7-oxabicyclo[4.2.0]oct-2-yl]-6,6,8-trimethyl-1,3-dioxaspiro[4.5]decane-2,7-dione | C36H56O9Si | 详情 | 详情 | |
| (XIV) | 10705 | (4S,5S)-4-[(1S,2R,3S,4S,6R)-1-(Benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-(2,2-dimethoxyethyl)-3-methyl-7-oxabicyclo[4.2.0]oct-2-yl]-6,6,8-trimethyl-2-oxo-1,3-dioxaspiro[4.5]dec-7-en-7-yl trifluoromethanesulfonate | C37H55F3O11SSi | 详情 | 详情 | |
| (XV) | 10706 | (4S,5S)-4-((1S,2R,3S,4S,6R)-3-allyl-1-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-7-oxabicyclo[4.2.0]oct-2-yl)-6,6,8-trimethyl-2-oxo-1,3-dioxaspiro[4.5]dec-7-en-7-yl trifluoromethanesulfonate | C36H51F3O9SSi | 详情 | 详情 | |
| (XVI) | 10707 | (1S,5S,6R,7S,10R,12S,13S)-7-(Benzyloxy)-12-[[tert-butyl(dimethyl)silyl]oxy]-13,17,20,20-tetramethyl-15-methylene-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-3-one | C35H50O6Si | 详情 | 详情 | |
| (XVII) | 10708 | (1S,5S,6R,7S,10R,12S,13S)-7-(Benzyloxy)-13,17,20,20-tetramethyl-15-methylene-12-[(triethylsilyl)oxy]-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-3-one | C35H50O6Si | 详情 | 详情 | |
| (XVIII) | 10709 | (1S,4S,5S,7R,10S,11R,12S,16S,19R)-10-(Benzyloxy)-4,19,21,21-tetramethyl-2-methylene-5-[(triethylsilyl)oxy]-8,13,15,20-tetraoxahexacyclo[14.4.1.0(1,19).0(4,11).0(7,10).0(12,16)]henicosan-14-one | C35H50O7Si | 详情 | 详情 |