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【结 构 式】 
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【分子编号】10526 【品名】(1S,5S,6R,7S,8S,10S,11S,13R)-7,8,10-trihydroxy-7-(hydroxymethyl)-11,15,18,18-tetramethyl-3,12-dioxo-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-13-yl acetate 【CA登记号】 |
【 分 子 式 】C23H32O10 【 分 子 量 】468.50108 【元素组成】C 58.97% H 6.88% O 34.15% |
合成路线1
该中间体在本合成路线中的序号：(XV)A total synthesis of paclitaxel has been reported: 1) The starting material is the previously known bicyclic diol ester (I), which is silylated with tert-butyldimethylsilyl trifluoromethylsulfonyl (TBSTf) and reduced with LiAlH4 in ether at 0 C to give the hydroxy lactone (II). The reaction of (II) with camphorsulfonic acid (CSA) and then with tert-butyldiphenylsilyl chloride (TPSCl) followed by a treatment with benzyl bromide and KH in ether yields the fully protected lactone (III), which is reductively opened with LiAlH4 in ether at 25 C (a simultaneous partial desilylation takes place), affording the triol (IV). The reaction of (IV) with 2,2-dimethoxypropane and CSA gives the acetonide (V), which is oxidized with tetrapropylammonium perruthenate (TPAP) to the aldehyde (VI). The condensation of (VI) with the previously known sulfonyl hydrazone (VII) by means of BuLi in THF gives the methanol derivative (VIII), which is epoxidized with VO(AcAc)2 and tert-butyl hydroperoxide in benzene, yielding the epoxide (IX). Opening of the epoxide (IX) with LiAlH4 in ether affords the 1,2-diol (X), which is treated with phosgene and KH to give the cyclic carbonate (XI). The desilylation of (XI) with tetrabutylammonium fluoride (TBAF) followed by oxidation with TPAP in acetonitrile/dichloromethane yields the dialdehyde (XII), which is cyclized by means of TiCl3 and Zn-Cu, affording the racemic vicinal diol (XIII); the suitable active enantiomer is obtained by optical resolution with 1(S)-(-)-camphanic acid chloride. Selective acetylation of (XIII) with acetic anhydride and dimethylaminopyridine (DMAP) followed by oxidation with TPAP and N-methylmorpholine N-oxide (NMO) gives the acetoxy ketone (XIV). The hydroboration of (XIV) with BH3 followed by oxidation with H2O2 and hydrolysis of the acetonide group with HCl yields the trihydroxy compound (XV).
| 【1】 Yang, Z.; Liu, J.J.; Nicolaou, K.C.; et al.; Total synthesis of taxol. Nature 1994, 367, 6464, 630. |
| 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) | 10512 | ethyl (3aR,4S,5S,7aS)-5,7a-dihydroxy-4-methyl-1-oxo-1,3,3a,4,5,7a-hexahydro-2-benzofuran-4-carboxylate | C12H16O6 | 详情 | 详情 | |
| (II) | 10513 | (3aR,4R,5S,7aS)-5,7a-Bis[[tert-butyl(dimethyl)silyl]oxy]-4-(hydroxymethyl)-4-methyl-3a,4,5,7a-tetrahydro-2-benzofuran-1(3H)-one | C22H42O5Si2 | 详情 | 详情 | |
| (III) | 10514 | (3aR,4R,5S,7aS)-7a-[[Tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4-(hydroxymethyl)-4-methyl-3a,4,5,7a-tetrahydro-2-benzofuran-1(3H)-one | C16H28O5Si | 详情 | 详情 | |
| (IV) | 10515 | (1S,4S,5S,6R)-5-Ethyl-1,6-bis(hydroxymethyl)-5-methyl-2-cyclohexene-1,4-diol | C11H20O4 | 详情 | 详情 | |
| (V) | 10516 | (5S,8S,9S,10R)-9-Ethyl-10-(hydroxymethyl)-2,2,9-trimethyl-1,3-dioxaspiro[4.5]dec-6-en-8-ol | C14H24O4 | 详情 | 详情 | |
| (VI) | 10517 | (5S,6S,7S,8S)-7-Ethyl-8-hydroxy-2,2,7-trimethyl-1,3-dioxaspiro[4.5]dec-9-ene-6-carbaldehyde | C14H22O4 | 详情 | 详情 | |
| (VII) | 10518 | N'-[3-(Hydroxymethyl)-2,2,4-trimethyl-3-cyclohexen-1-ylidene]-2,4,6-triisopropylbenzenesulfonohydrazide | C31H54N2O3SSi | 详情 | 详情 | |
| (VIII) | 10519 | (5S,8S,9S,10R)-9-Ethyl-10-[(S)-hydroxy[5-(hydroxymethyl)-4,6,6-trimethyl-1,4-cyclohexadien-1-yl]methyl]-2,2,9-trimethyl-1,3-dioxaspiro[4.5]dec-6-en-8-ol | C24H38O5 | 详情 | 详情 | |
| (IX) | 10520 | (5S,8S,9S,10R)-9-Ethyl-10-[(S)-hydroxy[(6S)-3-(hydroxymethyl)-2,2,4-trimethyl-7-oxabicyclo[4.1.0]hept-3-en-1-yl]methyl]-2,2,9-trimethyl-1,3-dioxaspiro[4.5]dec-6-en-8-ol | C24H38O6 | 详情 | 详情 | |
| (X) | 10521 | (5S,8S,9S,10R)-9-Ethyl-10-[(S)-hydroxy[(1S)-1-hydroxy-3-(hydroxymethyl)-2,2,4-trimethyl-3-cyclohexen-1-yl]methyl]-2,2,9-trimethyl-1,3-dioxaspiro[4.5]dec-6-en-8-ol | C24H40O6 | 详情 | 详情 | |
| (XI) | 10522 | (4S,5S)-4-[(5S,6R,7S,8S)-7-Ethyl-8-hydroxy-2,2,7-trimethyl-1,3-dioxaspiro[4.5]dec-9-en-6-yl]-7-(hydroxymethyl)-6,6,8-trimethyl-1,3-dioxaspiro[4.5]dec-7-en-2-one | C25H38O7 | 详情 | 详情 | |
| (XII) | 10523 | (5S,6R,7S,8S)-8-Hydroxy-6-[(4S,5S)-7-(hydroxymethyl)-6,6,8-trimethyl-2-oxo-1,3-dioxaspiro[4.5]dec-7-en-4-yl]-2,2,7-trimethyl-1,3-dioxaspiro[4.5]dec-9-ene-7-carbaldehyde | C24H34O8 | 详情 | 详情 | |
| (XIII) | 10524 | (3'S,4S,8'R,9'S,9'aR,10'S,13'aR,13'bS)-10'-Benzyloxy-8',9'-dihydroxy-2,2,6',9'a,14',14'-hexamethyl-4',5',8',9',9'a,10',13'a,13'b-octahydro-13'H-spiro[1,3-dioxolane-4,13'-3'a,7'-methanobenzo[3,4cyclodeca[1,2-d][1,3]dioxol]-2'-one | C24H34O8 | 详情 | 详情 | |
| (XIV) | 10525 | (3'S,4S,8'R,9'aS,10'S,13'aR,13'bS)-8'-Acetoxy-10'-benzyloxy-2,2,6',9'a,14',14'-hexamethyl-4',5',8',9',9'a,10',13'a,13'b-octahydro-13'H-spiro[1,3-dioxolane-4,13'-3'a,7'-methanobenzo[3,4cyclodeca[1,2-d][1,3]dioxole]-2',9'-dione | C26H34O9 | 详情 | 详情 | |
| (XV) | 10526 | (1S,5S,6R,7S,8S,10S,11S,13R)-7,8,10-trihydroxy-7-(hydroxymethyl)-11,15,18,18-tetramethyl-3,12-dioxo-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-13-yl acetate | C23H32O10 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)Compound (XV) is selectively acetylated with acetic anhydride and DMAP to the diol (XVI). The replacement of the benzyl protecting group by a triethylsilyl (TES) group in (XVI) by debenzylation with H2 over Pd(OH)2/C followed by treatment with TESCl in pyridine and deacetylation with K2CO3 in methanol affords the silylated triol (XVII). The formation of the oxetane ring is carried out by treatment of (XVII) with trimethylsilyl chloride (TMSCl) and pyridine (silylation of the primary alcohol), subsequent reaction with Tf2O (activation of the secondary alcohol), and cyclization by acidic treatment with CSA to give compound (XVIII) with the oxetane ring and a tertiary OH group. The acetylation of (XVIII) with acetic anhydride and DMAP affords compound (XIX) with the tertiary acetoxy group. The reaction of (XIX) with phenyllithium gives the benzoyloxy derivative (XX), which is oxidized with pyridinium chlorochromate (PCC) to yield the diketone (XXI). The reduction of (XXI) with NaBH4 in methanol affords compound (XXII) with the appropriate secondary hydroxy group, which is acylated with Ojima's beta-lactam (XXIII) by means of sodium bis(trimethylsilyl)amide to give the silylated paclitaxel (XXIV). Finally, this compound is deprotected with HF/pyridine.
| 【1】 Yang, Z.; Liu, J.J.; Nicolaou, K.C.; et al.; Total synthesis of taxol. Nature 1994, 367, 6464, 630. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 10526 | (1S,5S,6R,7S,8S,10S,11S,13R)-7,8,10-trihydroxy-7-(hydroxymethyl)-11,15,18,18-tetramethyl-3,12-dioxo-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-13-yl acetate | C23H32O10 | 详情 | 详情 | |
| (XVI) | 10527 | (1S,5S,6R,7S,8S,10S,11S,13R)-7-[(acetoxy)methyl]-7,8,10-trihydroxy-11,15,18,18-tetramethyl-3,12-dioxo-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-13-yl acetate | C25H34O11 | 详情 | 详情 | |
| (XVII) | 10528 | (1S,5S,6R,7S,8S,10S,11S,13R)-7,8-dihydroxy-7-(hydroxymethyl)-11,15,18,18-tetramethyl-3,12-dioxo-10-[(triethylsilyl)oxy]-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-13-yl acetate | C29H46O10Si | 详情 | 详情 | |
| (XVIII) | 10529 | (1S,5S,6R,7S,10R,12S,13S,15R)-7-hydroxy-13,17,20,20-tetramethyl-3,14-dioxo-12-[(triethylsilyl)oxy]-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-15-yl acetate | C29H44O9Si | 详情 | 详情 | |
| (XIX) | 10530 | (1S,5S,6R,10R,12S,13S,15R)-15-(acetoxy)-13,17,20,20-tetramethyl-3,14-dioxo-12-[(triethylsilyl)oxy]-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-7-yl acetate | C31H46O10Si | 详情 | 详情 | |
| (XX) | 10531 | (1S,2S,3R,4S,7R,9S,10S,12R)-4,12-bis(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C37H52O10Si | 详情 | 详情 | |
| (XXI) | 10488 | (1S,2S,3R,4S,7R,9S,10S,12R)-4,12-bis(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-11,15-dioxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C37H50O11Si | 详情 | 详情 | |
| (XXII) | 10473 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C37H52O11Si | 详情 | 详情 | |
| (XXIII) | 10490 | (3R,4S)-1-Benzoyl-4-phenyl-3-[(triethylsilyl)oxy]-2-azetanone | C22H27NO3Si | 详情 | 详情 | |
| (XXIV) | 10535 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | n/a | AB | 详情 | 详情 |