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【结 构 式】 
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【分子编号】34985 【品名】methyl (5R,6S,7S)-7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-8-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate 【CA登记号】 |
【 分 子 式 】C29H40O9Si 【 分 子 量 】560.7167 【元素组成】C 62.12% H 7.19% O 25.68% Si 5.01% |
合成路线1
该中间体在本合成路线中的序号：(XXXI)The bromination of 7-methylnaphtho[2,3-d][1,3]benzodioxole-6-carboxylic acid methyl ester (XVII) with NBS and AIBN in refluxing CCl4 gives the bromomethyl derivative (XVIII), which is treated with allyl alcohol (XIX) and NaH in THF yielding the corresponding allyl ether (XIX). The condensation of (XIX) with the chiral auxiliary (XX) by means of triethylamine and pyridine in acetonitrile affords the oxazolidine (XXII), which is treated with (PPh3)3RhCl and 1,4-diazabicyclo[2.2.2]octane in refluxing propanol giving the carbinol (XXIII). The protection of (XXIII) with TBDMS-Cl, Et3N and DMAP provides the silyl ether (XXIV), which is arylated with 3,4,5-trimethoxyphenyllithium (XXV) in THF giving intermediate (XXVI). Opening of the oxazoline ring of (XXVI) with TFA and acetic anhydride yields the carboxylic ester (XXVII), which is treated with Ti(O-i-Pr)4 in hot ethanol to afford the lactone (XXVIII). The reaction of (XXVIII) with NaOH in methanol, methylation with diazomethane and silylation with TBDMS-Cl gives the carboxylic ester (XXIX), which is treated with NBS in DMSO/THF to afford the chiral bromohydrine (XXX). The debromination of (XXX) with Bu3SnH and AIBN in refluxing toluene provides the hydroxyester (XXXI).
| 【1】 Andrews, R.C.; et al.; Asymetric total synthesis of (-)-podophyllotoxin. J Am Chem Soc 1988, 110, 23, 7854. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 34972 | methyl 7-methylnaphtho[2,3-d][1,3]dioxole-6-carboxylate | C14H12O4 | 详情 | 详情 | |
| (XVIII) | 34973 | methyl 7-(bromomethyl)naphtho[2,3-d][1,3]dioxole-6-carboxylate | C14H11BrO4 | 详情 | 详情 | |
| (XIX) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
| (XX) | 34974 | methyl 7-[(allyloxy)methyl]naphtho[2,3-d][1,3]dioxole-6-carboxylate | C17H16O5 | 详情 | 详情 | |
| (XXI) | 34975 | (2S,3R)-3-amino-4-methoxy-2-butanol | C5H13NO2 | 详情 | 详情 | |
| (XXII) | 34976 | (4R,5R)-2-[7-[(allyloxy)methyl]naphtho[2,3-d][1,3]dioxol-6-yl]-4-(methoxymethyl)-5-methyl-4,5-dihydro-1,3-oxazole; allyl [7-[(4R,5R)-4-(methoxymethyl)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]naphtho[2,3-d][1,3]dioxol-6-yl]methyl ether | C21H23NO5 | 详情 | 详情 | |
| (XXIII) | 34977 | [7-[(4R,5R)-4-(methoxymethyl)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]naphtho[2,3-d][1,3]dioxol-6-yl]methanol | C18H19NO5 | 详情 | 详情 | |
| (XXIV) | 34978 | (4R,5R)-2-[7-([[tert-butyl(dimethyl)silyl]oxy]methyl)naphtho[2,3-d][1,3]dioxol-6-yl]-4-(methoxymethyl)-5-methyl-4,5-dihydro-1,3-oxazole; tert-butyl(dimethyl)silyl [7-[(4R,5R)-4-(methoxymethyl)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]naphtho[2,3-d][1,3]dioxol-6-yl]methyl ether | C24H33NO5Si | 详情 | 详情 | |
| (XXV) | 34979 | (3,4,5-trimethoxyphenyl)lithium | C9H11LiO3 | 详情 | 详情 | |
| (XXVI) | 34980 | (4R,5R)-2-[(5R)-7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-(3,4,5-trimethoxyphenyl)-5,6-dihydronaphtho[2,3-d][1,3]dioxol-6-yl]-4-(methoxymethyl)-5-methyl-4,5-dihydro-1,3-oxazole; tert-butyl(dimethyl)silyl [(8R)-7-[(4R,5R)-4-(methoxymethyl)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-8-(3,4,5-trimethoxyphenyl)-7,8-dihydronaphtho[2,3-d][1,3]dioxol-6-yl]methyl ether | C33H45NO8Si | 详情 | 详情 | |
| (XXVII) | 34981 | (1R,2R)-2-(acetamido)-3-methoxy-1-methylpropyl (5R)-7-[(acetoxy)methyl]-5-(3,4,5-trimethoxyphenyl)-5,6-dihydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C31H37NO11 | 详情 | 详情 | |
| (XXVIII) | 34982 | (5R)-5-(3,4,5-trimethoxyphenyl)-5,9-dihydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(8H)-one | C22H20O7 | 详情 | 详情 | |
| (XXIX) | 34983 | methyl (5R,6S)-7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-(3,4,5-trimethoxyphenyl)-5,6-dihydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C29H38O8Si | 详情 | 详情 | |
| (XXX) | 34984 | methyl (5R,6R,7R)-7-bromo-7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-8-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C29H39BrO9Si | 详情 | 详情 | |
| (XXXI) | 34985 | methyl (5R,6S,7S)-7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-8-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C29H40O9Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXI)The oxidation of (XXXI) with pyridinium dichromate (PDC) gives the ketoester (XXXII). The reaction of (XXXII) with formaldehyde/NaOH and then with p-toluenesulfonic acid gives the hydroxymethyl lactone (XXXIII), which is submitted to a thermal extrusion of formaldehyde yielding (XXXIV). The regioselective reduction of the ketonic group of (XXXIV) with LiAl(OtBU)3H in THF affords hydroxylactone (XXXV) with undesired steric configuration at the lactone ring. The silylation of (XXXV) with TBDMS-OTf affords the silyl ether (XXXVI), which is isomerized with LiHMDS in THF giving (XXXVII) with the right configuration. Finally, this compound is desilylated to the target compound with triethylammonium fluoride in acetonitrile.
| 【1】 Andrews, R.C.; et al.; Asymetric total synthesis of (-)-podophyllotoxin. J Am Chem Soc 1988, 110, 23, 7854. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXI) | 34985 | methyl (5R,6S,7S)-7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-8-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C29H40O9Si | 详情 | 详情 | |
| (XXXII) | 34986 | methyl (5R,6S,7S)-7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C29H38O9Si | 详情 | 详情 | |
| (XXXIII) | 34987 | (5aS,8aS,9R)-5a-(hydroxymethyl)-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxole-5,8-dione | C23H22O9 | 详情 | 详情 | |
| (XXXIV) | 34988 | (5aR,8aS,9R)-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxole-5,8-dione | C22H20O8 | 详情 | 详情 | |
| (XXXV) | 34989 | (5R,5aS,8aR,9R)-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one | C22H22O8 | 详情 | 详情 | |
| (XXXVI) | 34990 | (5R,5aS,8aR,9R)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one | C28H36O8Si | 详情 | 详情 | |
| (XXXVII) | 34991 | (5R,5aR,8aR,9R)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one | C28H36O8Si | 详情 | 详情 |