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【结 构 式】 
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【分子编号】48311 【品名】(1S,6S,7R,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl 4-nitrobenzenesulfonate 【CA登记号】 |
【 分 子 式 】C31H40N2O8SSi 【 分 子 量 】628.81878 【元素组成】C 59.21% H 6.41% N 4.45% O 20.35% S 5.1% Si 4.47% |
合成路线1
该中间体在本合成路线中的序号：(XVI)The condensation of 2,2-dimethyl-1,3-dioxan-5-one (I) with aminoacetaldehyde dimethyl acetal (II) followed by acetylation with Ac2O/Et3N afforded the amido dioxin (III). Retro Diels-Alder reaction of dioxin (III) in warm benzonitrile generated the amidoacrolein (V), which was trapped in situ with the silyloxydiene (IV) to yield the cycloadduct (VI). Aldol cyclization between the acetamide and aldehyde functionalities of (VI) in the presence of t-BuOK produced the spiro lactam (VII). Subsequent aldol condensation between the acetal and silyl enolate functions of (VII) under acidic conditions furnished the tricyclic hydroxy ketone (VIII). Reduction of the keto group of (VIII) with NaBH(OAc)3 produced the C-4 axial alcohol (IX). Silylation of both hydroxyl groups of (IX) followed by selective cleavage of the C-2 silyl ether provided the C-4 mono silylated derivative (X). The free C-2 hydroxyl group of (X) was then oxidized to the corresponding ketone (XI) under Swern conditions. The potassium enolate of (XI) was stereoselectively alkylated with p-methoxybenzyl bromide (XII) to yield (XIII). Reduction of the keto group of (XIII) with Red-Al gave rise to the alcohol (XIV) in the undesired equatorial configuration. Inversion of the C-2 stereogenic center of (XIV) was achieved via formation of the sulfonate ester (XVI) with 4-nitrobenzenesulfonyl chloride (XV).
| 【1】 Maeng, J.-H.; Funk, R.L.; Total synthesis of the immunosuppressant FR901483 via an amidoacrolein cycloaddition. Org Lett 2001, 3, 8, 1125. |
| 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) | 46538 | 2,2-dimethyl-1,3-dioxan-5-one | C6H10O3 | 详情 | 详情 | |
| (II) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (III) | 48300 | N-(2,2-dimethoxyethyl)-N-(2,2-dimethyl-4H-1,3-dioxin-5-yl)acetamide | C12H21NO5 | 详情 | 详情 | |
| (IV) | 48301 | triisopropyl[(1-methylene-2-propenyl)oxy]silane; 1-methylene-2-propenyl triisopropylsilyl ether | C13H26OSi | 详情 | 详情 | |
| (V) | 48302 | N-(2,2-dimethoxyethyl)-N-(1-formylvinyl)acetamide | C9H15NO4 | 详情 | 详情 | |
| (VI) | 48303 | N-(2,2-dimethoxyethyl)-N-[1-formyl-4-[(triisopropylsilyl)oxy]-3-cyclohexen-1-yl]acetamide | C22H41NO5Si | 详情 | 详情 | |
| (VII) | 48304 | 1-(2,2-dimethoxyethyl)-8-[(triisopropylsilyl)oxy]-1-azaspiro[4.5]deca-3,7-dien-2-one | C22H39NO4Si | 详情 | 详情 | |
| (VIII) | 48305 | (1S,7R,8R)-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,9-dione | C11H13NO3 | 详情 | 详情 | |
| (IX) | 48306 | (1S,7R,8S,9S)-7,9-dihydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C11H15NO3 | 详情 | 详情 | |
| (X) | 48307 | (1S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C17H29NO3Si | 详情 | 详情 | |
| (XI) | 48308 | (1S,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,7-dione | C17H27NO3Si | 详情 | 详情 | |
| (XII) | 27490 | 1-(bromomethyl)-4-methoxybenzene | C8H9BrO | 详情 | 详情 | |
| (XIII) | 48309 | (1S,6S,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,7-dione | C25H35NO4Si | 详情 | 详情 | |
| (XIV) | 48310 | (1S,6S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C25H37NO4Si | 详情 | 详情 | |
| (XV) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (XVI) | 48311 | (1S,6S,7R,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl 4-nitrobenzenesulfonate | C31H40N2O8SSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)Displacement of the nosylate group of (XVI) with rubidium acetate in the presence of crown ether furnished the desired acetate ester (XVIII) accompanied by the elimination byproduct (XVII). Alcohol (XIX), obtained by basic hydrolysis of the acetate ester (XVIII), was protected as the silyl ether (XX) using triethylsilyl triflate. Hydrogenation of the lactam double bond of (XX) over PtO2 gave the saturated lactam (XXI). The azido group was introduced by reaction of the lithium enolate of lactam (XXI) with trisyl azide to afford a diastereomeric mixture from which the desired azide (XXII) was isolated by column chromatography. Simultaneous reduction of the lactam and azide functional groups of (XXII) with concomitant removal of the triethylsilyl protecting group was accomplished by treatment of (XXII) with LiAlH4. The resulting amine (XXIII) was then acylated with benzyl chloroformate to give carbamate (XXIV).
| 【1】 Maeng, J.-H.; Funk, R.L.; Total synthesis of the immunosuppressant FR901483 via an amidoacrolein cycloaddition. Org Lett 2001, 3, 8, 1125. |
| 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) | 48311 | (1S,6S,7R,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl 4-nitrobenzenesulfonate | C31H40N2O8SSi | 详情 | 详情 | |
| (XVII) | 48312 | (1S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodeca-2,6-dien-4-one | C25H35NO3Si | 详情 | 详情 | |
| (XVIII) | 48313 | (1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl acetate | C27H39NO5Si | 详情 | 详情 | |
| (XIX) | 48314 | (1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C25H37NO4Si | 详情 | 详情 | |
| (XX) | 48315 | (1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C31H51NO4Si2 | 详情 | 详情 | |
| (XXI) | 48316 | (1R,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodecan-4-one | C31H53NO4Si2 | 详情 | 详情 | |
| (XXII) | 48317 | (1S,3S,6S,7S,8R,9S)-3-azido-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodecan-4-one | C31H52N4O4Si2 | 详情 | 详情 | |
| (XXIII) | 48318 | (1S,3S,6S,7S,8R,9S)-3-amino-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodecan-7-ol | C25H42N2O3Si | 详情 | 详情 | |
| (XXIV) | 48319 | benzyl (1S,3S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-ylcarbamate | C33H48N2O5Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)The condensation of acetonide (I) with 2-aminoacetaldehyde dimethylacetal (II) by means of Ac2O and TEA gives the acetylated enamine (III), which is cyclocondensed with the silylated butadiene (IV) in hot benzonitrile to yield the cycloadduct (V). The cyclization of (V) by means of tBu-OK in ethyl acetate/THF, followed by desilylation with TFA, affords the tricyclic lactam (VI), which is reduced with NaBH(OAc)3 to provide the dihydroxy compound (VII). The silylation of both OH groups of (VII) by means of Tbdms-Cl, followed by selective desilylation of the equatorial silyl ether with TBAF, gives the corresponding alcohol (VIII), which is submitted to a Swern oxidation to yield the ketone (IX). The condensation of (IX) with 4-methoxybenzyl bromide (X) by means of tBu-OK and Red-Al affords the hydroxylated adduct (XI); however, the resulting alcohol presents an unnatural equatorial configuration that is inverted by its esterification with 4-nitrophenylsulfonyl chloride to furnish (XII), followed by acetoxylation of (XII) with rubidium acetate and 18-crown-6, to provide the desired axial acetoxy compound (XIII). The hydrolysis of (XIII) with KOH in methanol gives the corresponding alcohol (XIV), which is silylated with Tes-Otf to yield the bis silyl ether (XV). The reduction of the double bond of (XV) with H2 over PtO2 affords the saturated compound (XVI), which is treated with triethylsilylazide and LDA to provide at the azido compound (XVII). The reduction of lactam and azido groups by means of LiAlH4, followed by protection of the resulting amino group with benzyloxycarbonyl chloride and Na2CO3, gives the benzyl carbamate (XVIII).
| 【1】 Maeng, J.-H.; Funk, R.L.; Total synthesis of the immunosuppressant FR901483 via an amidoacrolein cycloaddition. Org Lett 2001, 3, 8, 1125. |
| 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) | 46538 | 2,2-dimethyl-1,3-dioxan-5-one | C6H10O3 | 详情 | 详情 | |
| (II) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (III) | 48300 | N-(2,2-dimethoxyethyl)-N-(2,2-dimethyl-4H-1,3-dioxin-5-yl)acetamide | C12H21NO5 | 详情 | 详情 | |
| (IV) | 48301 | triisopropyl[(1-methylene-2-propenyl)oxy]silane; 1-methylene-2-propenyl triisopropylsilyl ether | C13H26OSi | 详情 | 详情 | |
| (V) | 48303 | N-(2,2-dimethoxyethyl)-N-[1-formyl-4-[(triisopropylsilyl)oxy]-3-cyclohexen-1-yl]acetamide | C22H41NO5Si | 详情 | 详情 | |
| (VI) | 48305 | (1S,7R,8R)-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,9-dione | C11H13NO3 | 详情 | 详情 | |
| (VII) | 48306 | (1S,7R,8S,9S)-7,9-dihydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C11H15NO3 | 详情 | 详情 | |
| (VIII) | 48307 | (1S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C17H29NO3Si | 详情 | 详情 | |
| (IX) | 48308 | (1S,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,7-dione | C17H27NO3Si | 详情 | 详情 | |
| (X) | 27490 | 1-(bromomethyl)-4-methoxybenzene | C8H9BrO | 详情 | 详情 | |
| (XI) | 48310 | (1S,6S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C25H37NO4Si | 详情 | 详情 | |
| (XII) | 48311 | (1S,6S,7R,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl 4-nitrobenzenesulfonate | C31H40N2O8SSi | 详情 | 详情 | |
| (XIII) | 48313 | (1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl acetate | C27H39NO5Si | 详情 | 详情 | |
| (XIV) | 48314 | (1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C25H37NO4Si | 详情 | 详情 | |
| (XV) | 48315 | (1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C31H51NO4Si2 | 详情 | 详情 | |
| (XVI) | 48316 | (1R,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodecan-4-one | C31H53NO4Si2 | 详情 | 详情 | |
| (XVII) | 48317 | (1S,3S,6S,7S,8R,9S)-3-azido-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodecan-4-one | C31H52N4O4Si2 | 详情 | 详情 | |
| (XVIII) | 48319 | benzyl (1S,3S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-ylcarbamate | C33H48N2O5Si | 详情 | 详情 |