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【结 构 式】

【分子编号】10514

【品名】(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

【CA登记号】

【 分 子 式 】C16H28O5Si

【 分 子 量 】328.48082

【元素组成】C 58.5% H 8.59% O 24.35% Si 8.55%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(III)

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
Extended Information