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【结 构 式】 
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【分子编号】35414 【品名】methyl (E)-9-(3-isopropyl-2-methoxyphenyl)-6-methyl-3-oxo-6-nonenoate 【CA登记号】 |
【 分 子 式 】C21H30O4 【 分 子 量 】346.4668 【元素组成】C 72.8% H 8.73% O 18.47% |
合成路线1
该中间体在本合成路线中的序号：(XI)An enantioselective total synthesis of chloride (MOM-Cl) and NaH in THF gives the methoxymethyl ether (II), which is methylated with n-BuLi and methyl iodide in THF yielding the 6-methyl derivative (III). The condensation of (III) with 3-methyl-2-butenyl bromide (IV) by means of s-BuLi in THF affords compound (V), which is deprotected with LiBF4 and TMSCl in acetonitrile to give the phenol (VI). Methylation of (VI) with dimethyl sulfate and K2CO3 in refluxing acetone provides the ether (VII), which is hydroxylated at the terminal methyl group with SeO2 and tert-butyl hydroperoxide (TBHP) in dichloromethane giving alcohol (VIII). The reaction of (VIII) with methanesulfonyl chloride and then with LiBr affords the corresponding alkenyl bromide (IX), which is condensed with methyl acetoacetate (X) by means of NaH and n-BuLi in THF providing the ketoester (XI).
| 【1】 Ye, X.-Y.; Yang, D.; Xu, M.; Enantioselective total synthesis of (-)-triptolide, (-)-triptonide, (+)-triptophenolide, and (+)-triptoquinomide. J Org Chem 2000, 65, 7, 2208. |
| 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) | 37653 | 2-isopropylphenol | 88-69-7 | C9H12O | 详情 | 详情 |
| (II) | 37654 | 1-isopropyl-2-(methoxymethoxy)benzene; (2-isopropylphenoxy)methyl methyl ether | C11H16O2 | 详情 | 详情 | |
| (III) | 37655 | 1-isopropyl-2-(methoxymethoxy)-3-methylbenzene; (2-isopropyl-6-methylphenoxy)methyl methyl ether | C12H18O2 | 详情 | 详情 | |
| (IV) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (V) | 37656 | 1-isopropyl-2-(methoxymethoxy)-3-(4-methyl-3-pentenyl)benzene; [2-isopropyl-6-(4-methyl-3-pentenyl)phenoxy]methyl methyl ether | C17H26O2 | 详情 | 详情 | |
| (VI) | 37657 | 2-isopropyl-6-(4-methyl-3-pentenyl)phenol | C15H22O | 详情 | 详情 | |
| (VII) | 37658 | 1-isopropyl-2-methoxy-3-(4-methyl-3-pentenyl)benzene; 2-isopropyl-6-(4-methyl-3-pentenyl)phenyl methyl ether | C16H24O | 详情 | 详情 | |
| (VIII) | 37659 | (E)-5-(3-isopropyl-2-methoxyphenyl)-2-methyl-2-penten-1-ol | C16H24O2 | 详情 | 详情 | |
| (IX) | 37660 | 2-[(E)-5-bromo-4-methyl-3-pentenyl]-6-isopropylphenyl methyl ether; 1-[(E)-5-bromo-4-methyl-3-pentenyl]-3-isopropyl-2-methoxybenzene | C16H23BrO | 详情 | 详情 | |
| (X) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (XI) | 35414 | methyl (E)-9-(3-isopropyl-2-methoxyphenyl)-6-methyl-3-oxo-6-nonenoate | C21H30O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)The transesterification of ketoester (XI) with the menthol derivative (XII) gives the chiral ester (XIII), which is cyclized by means of manganic acetate and ytterbium trifluoromethanesulfonate in trifluoroethanol yielding the octahydrophenanthrene (XIV). The enolization of (XIV) with KHMDS and N,N-bis(trifluoromethylsulfonyl)aniline in THF affords the enol triflate (XV), which is reduced at the ester group with DIBAL in dichloromethane giving the hydroxymethyl derivative (XVI). The cyclization of (XVI) with CO by means of Pd(PPh3)4 and tributylamine in acetonitrile yields the cyclic lactone (XVII), which is oxidized with CrO3 in acetic acid affording the furophenanthrenedione (XVIII). Demethylation of (XVIII) with BBr3 in dichloromethane gives the phenolic intermediate (XIX), which is reduced with NaBH4 in methanol to yield the diol (XX). The selective epoxidation of (XX) with NaIO4 in methanol/water gives the ketoepoxide (XXI), which by a new epoxidation with trifluoroacetone and oxone in aqueous acetonitrile affords the diepoxide (XXII). A further new epoxidation of (XXII) with H2O2 and NaOH in methanol gives the keto-triepoxide (XXIII), which is finally reduced to (-)-triptolide with NaBH4 and Eu(FOD)3 in methanol.
| 【1】 Ye, X.-Y.; Yang, D.; Xu, M.; Enantioselective total synthesis of (-)-triptolide, (-)-triptonide, (+)-triptophenolide, and (+)-triptoquinomide. J Org Chem 2000, 65, 7, 2208. |
| 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) | 35414 | methyl (E)-9-(3-isopropyl-2-methoxyphenyl)-6-methyl-3-oxo-6-nonenoate | C21H30O4 | 详情 | 详情 | |
| (XII) | 35415 | (1S,2R,5S)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexanol | 65253-04-5 | C16H24O | 详情 | 详情 |
| (XIII) | 35416 | (1S,2R,5S)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl (E)-9-(3-isopropyl-2-methoxyphenyl)-6-methyl-3-oxo-6-nonenoate | C36H50O4 | 详情 | 详情 | |
| (XIV) | 35417 | (1S,2R,5S)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl (1R,4aS,10aS)-7-isopropyl-8-methoxy-4a-methyl-2-oxo-1,2,3,4,4a,9,10,10a-octahydro-1-phenanthrenecarboxylate | C36H48O4 | 详情 | 详情 | |
| (XV) | 35418 | (1S,2R,5S)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl (4aS,10aR)-7-isopropyl-8-methoxy-4a-methyl-2-[[(trifluoromethyl)sulfonyl]oxy]-3,4,4a,9,10,10a-hexahydro-1-phenanthrenecarboxylate | C37H47F3O6S | 详情 | 详情 | |
| (XVI) | 35419 | (4aS,10aR)-1-(hydroxymethyl)-7-isopropyl-8-methoxy-4a-methyl-3,4,4a,9,10,10a-hexahydro-2-phenanthrenyl trifluoromethanesulfonate | C21H27F3O5S | 详情 | 详情 | |
| (XVII) | 35420 | (3bR,9bS)-7-isopropyl-6-methoxy-9b-methyl-3b,4,5,9b,10,11-hexahydrophenanthro[1,2-c]furan-1(3H)-one | C21H26O3 | 详情 | 详情 | |
| (XVIII) | 35421 | (3bR,9bS)-7-isopropyl-6-methoxy-9b-methyl-3,3b,4,9b,10,11-hexahydrophenanthro[1,2-c]furan-1,5-dione | C21H24O4 | 详情 | 详情 | |
| (XIX) | 35422 | (3bR,9bS)-6-hydroxy-7-isopropyl-9b-methyl-3,3b,4,9b,10,11-hexahydrophenanthro[1,2-c]furan-1,5-dione | C20H22O4 | 详情 | 详情 | |
| (XX) | 28059 | (3bR,5S,9bS)-5,6-dihydroxy-7-isopropyl-9b-methyl-3b,4,5,9b,10,11-hexahydrophenanthro[1,2-c]furan-1(3H)-one | C20H24O4 | 详情 | 详情 | |
| (XXI) | 28060 | (5aS,9aR,10aS,11aR)-8-isopropyl-5a-methyl-4,5,5a,10a,11,11a-hexahydro-1H-oxireno[2',3':8a,9]phenanthro[1,2-c]furan-3,9-dione | C20H22O4 | 详情 | 详情 | |
| (XXII) | 35423 | (1aS,1bS,6bS,7aS,8aS,11aS)-10-isopropyl-1b-methyl-1b,3,6,6b,7,7a-hexahydrodioxireno[2',3':8a,9:2',3':4b,5]phenanthro[1,2-c]furan-4,9(2H,11aH)-dione | C20H22O5 | 详情 | 详情 | |
| (XXIII) | 37661 | (3bS,4aS,5aS,6aS,7aS,7bS,8aS,8bS)-6a-isopropyl-8b-methyl-3b,4,4a,7a,7b,8b,9,10-octahydrotrioxireno[2',3':6,7:2',3':8a,9:2',3':4b,5]phenanthro[1,2-c]furan-1,6(3H,6aH)-dione | C20H22O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The transesterification of ketoester (I) with menthol derivative (II) gives the chiral ester (III), which is cyclized by means of manganic acetate and yterbium trifluoromethanesulfonate in trifluoroethanol yielding the octahydrophenanthrene (IV). The enolization of (IV) with KHMDS and N,N-bis(trifluoromethylsulfonyl)aniline in THF affords the enol triflate (V), which is reduced at the ester group with DIBAL in dichloromethane giving the hydroxymethyl derivative (VI). The cyclization of (VI) with CO by means of Pd(PPh3)4 and tributylamine in acetonitrile yields the cyclic lactone (VII), which is oxidized with CrO3 in acetic acid affording the furophenanthrenedione (VIII). The demethylation of (VIII) with BBr3 in dichloromethane gives the phenolic intermediate (IX), which is reduced with NaBH4 in methanol to yield the diol (X). The selective epoxidation of (X) with NaIO4 in methanol/water gives the ketoepoxide (XII), which by a new epoxidation with trifluoroacetone and oxone in aqueous acetonitrile affords the diepoxide (XII). A further new epoxidation of (XII) with H2O2 and NaOH in methanol gives the target (-)-Triptonide.
| 【1】 Ye, X.-Y.; Yang, D.; Xu, M.; Enantioselective total synthesis of (-)-triptolide, (-)-triptonide, (+)-triptophenolide, and (+)-triptoquinomide. J Org Chem 2000, 65, 7, 2208. |
| 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) | 35414 | methyl (E)-9-(3-isopropyl-2-methoxyphenyl)-6-methyl-3-oxo-6-nonenoate | C21H30O4 | 详情 | 详情 | |
| (II) | 35415 | (1S,2R,5S)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexanol | 65253-04-5 | C16H24O | 详情 | 详情 |
| (III) | 35416 | (1S,2R,5S)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl (E)-9-(3-isopropyl-2-methoxyphenyl)-6-methyl-3-oxo-6-nonenoate | C36H50O4 | 详情 | 详情 | |
| (IV) | 35417 | (1S,2R,5S)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl (1R,4aS,10aS)-7-isopropyl-8-methoxy-4a-methyl-2-oxo-1,2,3,4,4a,9,10,10a-octahydro-1-phenanthrenecarboxylate | C36H48O4 | 详情 | 详情 | |
| (V) | 35418 | (1S,2R,5S)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl (4aS,10aR)-7-isopropyl-8-methoxy-4a-methyl-2-[[(trifluoromethyl)sulfonyl]oxy]-3,4,4a,9,10,10a-hexahydro-1-phenanthrenecarboxylate | C37H47F3O6S | 详情 | 详情 | |
| (VI) | 35419 | (4aS,10aR)-1-(hydroxymethyl)-7-isopropyl-8-methoxy-4a-methyl-3,4,4a,9,10,10a-hexahydro-2-phenanthrenyl trifluoromethanesulfonate | C21H27F3O5S | 详情 | 详情 | |
| (VII) | 35420 | (3bR,9bS)-7-isopropyl-6-methoxy-9b-methyl-3b,4,5,9b,10,11-hexahydrophenanthro[1,2-c]furan-1(3H)-one | C21H26O3 | 详情 | 详情 | |
| (VIII) | 35421 | (3bR,9bS)-7-isopropyl-6-methoxy-9b-methyl-3,3b,4,9b,10,11-hexahydrophenanthro[1,2-c]furan-1,5-dione | C21H24O4 | 详情 | 详情 | |
| (IX) | 35422 | (3bR,9bS)-6-hydroxy-7-isopropyl-9b-methyl-3,3b,4,9b,10,11-hexahydrophenanthro[1,2-c]furan-1,5-dione | C20H22O4 | 详情 | 详情 | |
| (X) | 28059 | (3bR,5S,9bS)-5,6-dihydroxy-7-isopropyl-9b-methyl-3b,4,5,9b,10,11-hexahydrophenanthro[1,2-c]furan-1(3H)-one | C20H24O4 | 详情 | 详情 | |
| (XI) | 28060 | (5aS,9aR,10aS,11aR)-8-isopropyl-5a-methyl-4,5,5a,10a,11,11a-hexahydro-1H-oxireno[2',3':8a,9]phenanthro[1,2-c]furan-3,9-dione | C20H22O4 | 详情 | 详情 | |
| (XII) | 35423 | (1aS,1bS,6bS,7aS,8aS,11aS)-10-isopropyl-1b-methyl-1b,3,6,6b,7,7a-hexahydrodioxireno[2',3':8a,9:2',3':4b,5]phenanthro[1,2-c]furan-4,9(2H,11aH)-dione | C20H22O5 | 详情 | 详情 |