|
【结 构 式】 
|
【分子编号】44437 【品名】(5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one 【CA登记号】 |
【 分 子 式 】C29H60O4Si2 【 分 子 量 】528.964 【元素组成】C 65.85% H 11.43% O 12.1% Si 10.62% |
合成路线1
该中间体在本合成路线中的序号：(VI)The synthesis of intermediate tridecenoic acid (VII) has been performed as follows: The condensation of previously reported 1,3-dioxane intermediate (I) (see intermediate (X) in scheme no. 22255601a) with 2(S)-methyl-6-heptenal (II) by means of LDA in THF gives the hydroxyundecenone (III), which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (IV). The silylation of (IV) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (V), which is selectively monodesilylated with CSA to provide the primary alcohol (VI). Finally, this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the desired tridecenoic acid intermediate (VII).
| 【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523. |
| 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) | 27176 | 2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone | C12H22O3 | 详情 | 详情 | |
| (II) | 27185 | (2S)-2-methyl-6-heptenal | C8H14O | 详情 | 详情 | |
| (III) | 44434 | (4R,5S,6S)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-5-hydroxy-2,4,6-trimethyl-10-undecen-3-one | C20H36O4 | 详情 | 详情 | |
| (IV) | 44435 | (3S,6R,7S,8S)-1,3,7-trihydroxy-4,4,6,8-tetramethyl-12-tridecen-5-one | C17H32O4 | 详情 | 详情 | |
| (V) | 44436 | (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one | C35H74O4Si3 | 详情 | 详情 | |
| (VI) | 44437 | (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one | C29H60O4Si2 | 详情 | 详情 | |
| (VII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)The condensation of (XI) with phosphonate (XII) by means of NaH in THF furnishes the unsaturated ester (XIII). The reduction of the double bond of (XIII) with H2 over Rh/Al2O3, followed by reduction of the ester group with DIBAL and oxidation of the resulting alcohol with DMP, gives rise to the aldehyde (XIV). The Wittig condensation of (XIV) with phosphonium salt (XV) by means of BuLi in THF yields the terminal olefin (XVI), which is selectively desilylated with Ts-OH to afford the primary alcohol (XVII). Finally, this compound is oxidized to the target carboxylic acid intermediate (XVIII) with DMP and NaClO2 in dichloromethane/THF.
| 【1】 Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 45549 | (3S,4S,5R,8S)-4,8,10-tris[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyl-6-oxodecanal | C32H68O5Si3 | 详情 | 详情 | |
| (XII) | 35909 | ethyl 3-(diethoxyphosphoryl)propanoate | 3699-67-0 | C9H19O5P | 详情 | 详情 |
| (XIII) | 45550 | ethyl (E,5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxo-2-dodecenoate | 2463-77-6 | C36H74O6Si3 | 详情 | 详情 |
| (XIV) | 45551 | (5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxododecanal | 94-59-7 | C34H72O5Si3 | 详情 | 详情 |
| (XV) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (XVI) | 44436 | (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one | C35H74O4Si3 | 详情 | 详情 | |
| (XVII) | 44437 | (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one | C29H60O4Si2 | 详情 | 详情 | |
| (XVIII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXX)The reaction of 3-methyl-2-butenylmagnesium bromide (XVI) with propanal (XVII) gives racemic hexenol (XVIII), which is submitted to enzymatic resolution with ChiroCLEC-PC dry enzyme, yielding the R-enantiomer (XIX). The esterification of (XIX) with bromoacetyl bromide (XX) and dimethylaniline (DMA) affords the corresponding ester (XXI), which is oxidized with O3 and trimethyl phosphite and cyclized with SmI2 in THF to provide the chiral tetrahydropyranone (XXII). The reduction of (XXII) with Red-Al, followed by cyclization with 2-methoxypropene (XXIII) and PPTS, gives the acetonide (XXIV), which is oxidized with PPTS and NMO to provide the protected dihydroxyketone (XXV). The condensation of the ketone (XXV) with 2(S)-methyl-6-heptenal (XXVI) by means of LDA in THF gives the hydroxyundecenone (XXVII), which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (XXVIII). The silylation of (XXVIII) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (XXIX), which is selectively monodesilylated with CSA to provide the primary alcohol (XXX). Finally, this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the target tridecenoic acid intermediate (XII).
| 【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523. |
| 【2】 Taylor, R.E.; et al.; A formal total synthesis of epothiolone A: Enantioselective preparation of the C1-C6 and C7-C12 fragments. J Org Chem 1998, 63, 25, 9580. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 27170 | chloro(3-methyl-2-butenyl)magnesium | C5H9ClMg | 详情 | 详情 | |
| (XVII) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (XVIII) | 27171 | 4,4-dimethyl-5-hexen-3-ol | C8H16O | 详情 | 详情 | |
| (XIX) | 27172 | (3R)-4,4-dimethyl-5-hexen-3-ol | C8H16O | 详情 | 详情 | |
| (XX) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XXI) | 27173 | (1R)-1-ethyl-2,2-dimethyl-3-butenyl 2-bromoacetate | C10H17BrO2 | 详情 | 详情 | |
| (XXII) | 27174 | (4S,6R)-6-ethyl-4,5,5-trimethyltetrahydro-2H-pyran-2-one | C10H18O2 | 详情 | 详情 | |
| (XXIII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (XXIV) | 27175 | (3R)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanol | C12H24O3 | 详情 | 详情 | |
| (XXV) | 27176 | 2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone | C12H22O3 | 详情 | 详情 | |
| (XXVI) | 27185 | (2S)-2-methyl-6-heptenal | C8H14O | 详情 | 详情 | |
| (XXVII) | 44434 | (4R,5S,6S)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-5-hydroxy-2,4,6-trimethyl-10-undecen-3-one | C20H36O4 | 详情 | 详情 | |
| (XXVIII) | 44435 | (3S,6R,7S,8S)-1,3,7-trihydroxy-4,4,6,8-tetramethyl-12-tridecen-5-one | C17H32O4 | 详情 | 详情 | |
| (XXIX) | 44436 | (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one | C35H74O4Si3 | 详情 | 详情 | |
| (XXX) | 44437 | (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one | C29H60O4Si2 | 详情 | 详情 | |
| (XXX) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(LIV)The condensation of (XLVIII) with phosphonate (XLIX) by means of NaH in THF furnishes the unsaturated ester (L). The reduction of the double bond of (L) with H2 over Rh/Al2O3, followed by reduction of the ester group with DIBAL and oxidation of the resulting alcohol with DMP, gives rise to the aldehyde (LI). The Wittig condensation of (LI) with phosphonium salt (LII) by means of BuLi in THF yields the terminal olefin (LIII), which is selectively desilylated with TsOH to afford the primary alcohol (LIV). Finally, this compound is oxidized to the target carboxylic acid intermediate (XII) with DMP and NaClO2 in dichloromethane/THF.
| 【1】 Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603. |
| 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) | 35909 | ethyl 3-(diethoxyphosphoryl)propanoate | 3699-67-0 | C9H19O5P | 详情 | 详情 |
| (XII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 | |
| (XLVIII) | 45549 | (3S,4S,5R,8S)-4,8,10-tris[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyl-6-oxodecanal | C32H68O5Si3 | 详情 | 详情 | |
| (L) | 45550 | ethyl (E,5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxo-2-dodecenoate | 2463-77-6 | C36H74O6Si3 | 详情 | 详情 |
| (LI) | 45551 | (5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxododecanal | 94-59-7 | C34H72O5Si3 | 详情 | 详情 |
| (LII) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (LIII) | 44436 | (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one | C35H74O4Si3 | 详情 | 详情 | |
| (LIV) | 44437 | (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one | C29H60O4Si2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The condensation of already reported 1,3-dioxane intermediate (I) (see intermediate (X) in scheme no. 22255601a) with 2(S)-methyl-6-heptenal (II) by means of LDA in THF gives the hydroxyundecenone (III), which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (IV). The silylation of (IV) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (V), which is selectively monodesilylated with CSA to provide the primary alcohol (VI). Finally, this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the desired tridecenoic acid intermediate (VII).
| 【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523. |
| 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) | 27176 | 2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone | C12H22O3 | 详情 | 详情 | |
| (II) | 27185 | (2S)-2-methyl-6-heptenal | C8H14O | 详情 | 详情 | |
| (III) | 44434 | (4R,5S,6S)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-5-hydroxy-2,4,6-trimethyl-10-undecen-3-one | C20H36O4 | 详情 | 详情 | |
| (IV) | 44435 | (3S,6R,7S,8S)-1,3,7-trihydroxy-4,4,6,8-tetramethyl-12-tridecen-5-one | C17H32O4 | 详情 | 详情 | |
| (V) | 44436 | (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one | C35H74O4Si3 | 详情 | 详情 | |
| (VI) | 44437 | (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one | C29H60O4Si2 | 详情 | 详情 | |
| (VII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XVII)The condensation of (XI) with phosphonate (XII) by means of NaH in THF furnishes the unsaturated ester (XIII). The reduction of the double bond of (XIII) with H2 over Rh/Al2O3, followed by reduction of the ester group with DIBAL and oxidation of the resulting alcohol with DMP, gives rise to the aldehyde (XIV). The Wittig condensation of (XIV) with phosphonium salt (XV) by means of BuLi in THF yields the terminal olefin (XVI), which is selectively desilylated with Ts-OH to afford the primary alcohol (XVII). Finally, this compound is oxidized to the target carboxylic acid intermediate (XVIII) with DMP and NaClO2 in dichloromethane/THF.
| 【1】 Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 45549 | (3S,4S,5R,8S)-4,8,10-tris[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyl-6-oxodecanal | C32H68O5Si3 | 详情 | 详情 | |
| (XII) | 35909 | ethyl 3-(diethoxyphosphoryl)propanoate | 3699-67-0 | C9H19O5P | 详情 | 详情 |
| (XIII) | 45550 | ethyl (E,5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxo-2-dodecenoate | 2463-77-6 | C36H74O6Si3 | 详情 | 详情 |
| (XIV) | 45551 | (5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxododecanal | 94-59-7 | C34H72O5Si3 | 详情 | 详情 |
| (XV) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (XVI) | 44436 | (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one | C35H74O4Si3 | 详情 | 详情 | |
| (XVII) | 44437 | (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one | C29H60O4Si2 | 详情 | 详情 | |
| (XVIII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 |