【结 构 式】 |
【分子编号】43984 【品名】methyl 6-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-1-cyclohexene-1-carboxylate 【CA登记号】 |
【 分 子 式 】C11H13Cl3O5 【 分 子 量 】331.57932 【元素组成】C 39.85% H 3.95% Cl 32.08% O 24.13% |
合成路线1
该中间体在本合成路线中的序号:(II)The enantioselective condensation of 2-bromovanillin (I) with cyclohexenecarboxylate (II) by means of the chiral phosphine ligand (III) gives the chiral aryl ether (IV), which is reduced with DIBAL to yield the diol (V). The protection of (V) with Tbdms-OTf affords the bis silyl ether (VI), which is cyclized by means of Pd(OAc)2 to furnish the tetrahydrodibenzofuran (VII). The deprotection of (VII) with TBAF gives the diol (VIII), which is chemoselectively oxidized with MnO2 to yield the hydroxyaldehyde (IX). The reductocondensation of (IX) with methylamine and NaBH3CN affords the secondary amine (X), which is protected with Boc2O, providing the carbamate (XI). The oxidation of (XI) with DMP gives the aldehyde (XII), which is condensed with the phosphonium bromide (XIII) and NaHMDS, yielding the vinyl ether (XIV). The deprotection and cyclization of (XIV) by means of TFA affords the seven-member ring hemiaminal (XV), which is reduced with NaBH3CN to provide deoxygalanthamine (XVI). The epoxidation of (XVI) with dimethyldioxirane (DMDO) and TsOH furnishes the epoxide (XVII), which is regioselectively opened with diphenyl diselenide and NaBH4 to give the alpha-hydroxy selenide (XVIII). Elimination of the selenide group of (XVIII) by oxidation with NaIO4 at 80 C yielded isogalanthamine (XIX), which is finally isomerized to the target compound by treatment with Osborn's rhenium catalyst (Ph3SiO-ReO3).
【1】 Trost, B.M.; Toste, F.D.; Enantioselective total synthesis of (-)-galanthamine. J Am Chem Soc 2000, 122, 45, 11262. |
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) | 26230 | 2-bromo-3-hydroxy-4-methoxybenzaldehyde | C8H7BrO3 | 详情 | 详情 | |
(II) | 43984 | methyl 6-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-1-cyclohexene-1-carboxylate | C11H13Cl3O5 | 详情 | 详情 | |
(III) | 43985 | 2-(diphenylphosphino)-N-((1S,2S)-2-[[2-(diphenylphosphino)benzoyl]amino]-1,2-diphenylethyl)benzamide | C52H42N2O2P2 | 详情 | 详情 | |
(IV) | 43986 | methyl (6S)-6-(2-bromo-3-formyl-6-methoxyphenoxy)-1-cyclohexene-1-carboxylate | C16H17BrO5 | 详情 | 详情 | |
(V) | 43987 | [(6S)-6-[2-bromo-3-(hydroxymethyl)-6-methoxyphenoxy]-1-cyclohexen-1-yl]methanol | C15H19BrO4 | 详情 | 详情 | |
(VI) | 43988 | 3-bromo-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-[[(1S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-cyclohexen-1-yl]oxy]phenyl methyl ether; ([(6S)-6-[2-bromo-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-6-methoxyphenoxy]-1-cyclohexen-1-yl]methoxy)(tert-butyl)dimethylsilane | C27H47BrO4Si2 | 详情 | 详情 | |
(VII) | 43989 | [(5aS,9aS)-9a-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-1-yl]methyl tert-butyl(dimethyl)silyl ether; [[(5aS,9aS)-9a-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-1-yl]methoxy](tert-butyl)dimethylsilane | C27H46O4Si2 | 详情 | 详情 | |
(VIII) | 43990 | [(5aS,9aS)-9a-(hydroxymethyl)-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-1-yl]methanol | C15H18O4 | 详情 | 详情 | |
(IX) | 43991 | (5aS,9aS)-9a-(hydroxymethyl)-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-1-carbaldehyde | C15H16O4 | 详情 | 详情 | |
(X) | 43992 | [(4aS)-6-methoxy-9-[(methylamino)methyl]-4,4a-dihydrodibenzo[b,d]furan-9(3H)-yl]methanol | C16H21NO3 | 详情 | 详情 | |
(XI) | 43993 | tert-butyl [(5aS,9aS)-9a-(hydroxymethyl)-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-1-yl]methyl(methyl)carbamate | C21H29NO5 | 详情 | 详情 | |
(XII) | 43994 | tert-butyl [(5aS,9aR)-9a-formyl-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-1-yl]methyl(methyl)carbamate | C21H27NO5 | 详情 | 详情 | |
(XIII) | 25649 | (methoxymethyl)(triphenyl)phosphonium bromide | C20H20BrOP | 详情 | 详情 | |
(XIV) | 43995 | tert-butyl [(5aS,9aR)-4-methoxy-9a-[(Z)-2-methoxyethenyl]-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-1-yl]methyl(methyl)carbamate | C23H31NO5 | 详情 | 详情 | |
(XV) | 43996 | (4aS,8aR)-11-methyl-5,6,11,12-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-3-yl methyl ether; (4aS,8aR)-3-methoxy-11-methyl-5,6,11,12-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine | C17H19NO2 | 详情 | 详情 | |
(XVI) | 43997 | (4aS,8aS)-3-methoxy-11-methyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine; (4aS,8aS)-11-methyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-3-yl methyl ether | C17H21NO2 | 详情 | 详情 | |
(XVII) | 43998 | (1aS,3aR,4aS,4bR)-11-methoxy-7-methyl-2,3,3a,4a,5,6,7,8-octahydro-1aH-oxireno[2',3':4,5][1]benzofuro[3a,3,2-ef][2]benzazepine; (1aS,3aR,4aS,4bR)-7-methyl-2,3,3a,4a,5,6,7,8-octahydro-1aH-oxireno[2',3':4,5][1]benzofuro[3a,3,2-ef][2]benzazepin-11-yl methyl ether | C17H21NO3 | 详情 | 详情 | |
(XVIII) | 43999 | (4aS,7S,8S,8aR)-3-methoxy-11-methyl-7-(phenylselanyl)-5,6,7,8,9,10,11,12-octahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-8-ol | C23H27NO3Se | 详情 | 详情 | |
(XIX) | 44000 | (4aS,8R,8aR)-3-methoxy-11-methyl-5,8,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-8-ol | C17H21NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(II)The condensation of 2-bromo-3-hydroxy-4-methoxybenzaldehyde (I) with the cyclohexenecarboxylate (II) by means of a Pd catalyst and a chiral auxiliary gives the chiral aryl ether (III), which is treated with methyl orthoformate and Ts-OH in methanol to yield the dimethylacetal (IV). The reduction of the ester group of (IV) by means of DIBAL affords the methanol derivative (V), which is treated with acetone cyanohydrin, PPh3 and Ts-OH to provide the acetonitrile derivative (VI). The cyclization of (VI) by means of Pd(OAc)2 and Ag2CO3 in refluxing toluene leads to the tetrahydro dibenzofuran derivative (VII), which is diastereoselectively oxidized by means of SeO2 in hot dioxane to give the chiral secondary alcohol (VIII). The reaction of (VIII) with methylamine in methanol yields the methylimine (IX), which is submitted to reductocyclization by means of DIBAL to afford the tetracyclic intermediate (X). This compound, without isolation, is reduced with NaBH3CN to provide the target galanthamine.
【1】 Trost, B.M.; Tang, W.P.; An efficient enantioselective synthesis of (-)-galanthamine. Angew Chem. Int Ed 2002, 41, 15, 2795. |
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) | 26230 | 2-bromo-3-hydroxy-4-methoxybenzaldehyde | C8H7BrO3 | 详情 | 详情 | |
(II) | 43984 | methyl 6-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-1-cyclohexene-1-carboxylate | C11H13Cl3O5 | 详情 | 详情 | |
(III) | 43986 | methyl (6S)-6-(2-bromo-3-formyl-6-methoxyphenoxy)-1-cyclohexene-1-carboxylate | C16H17BrO5 | 详情 | 详情 | |
(IV) | 60065 | methyl (6S)-6-[2-bromo-3-(dimethoxymethyl)-6-methoxyphenoxy]-1-cyclohexene-1-carboxylate | C18H23BrO6 | 详情 | 详情 | |
(V) | 60066 | {(6S)-6-[2-bromo-3-(dimethoxymethyl)-6-methoxyphenoxy]-1-cyclohexen-1-yl}methanol | C17H23BrO5 | 详情 | 详情 | |
(VI) | 60067 | 2-[(6S)-6-(2-bromo-3-formyl-6-methoxyphenoxy)-1-cyclohexen-1-yl]acetonitrile | C16H16BrNO3 | 详情 | 详情 | |
(VII) | 60068 | 2-[(4aS)-9-formyl-6-methoxy-4,4a-dihydrodibenzo[b,d]furan-9(3H)-yl]acetonitrile | C16H15NO3 | 详情 | 详情 | |
(VIII) | 60069 | 2-[(3R,4aS)-9-formyl-3-hydroxy-6-methoxy-4,4a-dihydrodibenzo[b,d]furan-9(3H)-yl]acetonitrile | C16H15NO4 | 详情 | 详情 | |
(IX) | 60070 | 2-[(3R,4aS)-3-hydroxy-6-methoxy-9-[(methylimino)methyl]-4,4a-dihydrodibenzo[b,d]furan-9(3H)-yl]acetonitrile | C17H18N2O3 | 详情 | 详情 | |
(X) | 60071 | (4aS,6R,8aS)-3-methoxy-11-methyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-6,10-diol | C17H21NO4 | 详情 | 详情 |