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【结 构 式】 
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【分子编号】34966 【品名】ethyl (5R,6R)-8-oxo-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 】C23H24O8 【 分 子 量 】428.43876 【元素组成】C 64.48% H 5.65% O 29.87% |
合成路线1
该中间体在本合成路线中的序号：(XI)The isomerization of trans-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]benzodioxole-6-carboxylic acid ethyl ester (XI) with LDA gives the corresponding cis isomer (XII), which is treated with trimethylsilyl triflate yielding the silylated enol ether (XIII). The reaction of (XIII) with benzyloxymethyl chloride and TiCl4 affords the benzyloxymethyl derivative (XIV), which is reduced at the ketonic group with LiBH4 giving the lactone (XV). The debenzylation of (XV) with H2 over Pd/C yields the carbinol (XVI), which is rearranged to the target compound with DCC in acidic medium.
| 【1】 Kaneko, T.; et al.; Total synthesis of (±) podophyllotoxin. Tetrahedron Lett 1987, 28, 5, 517. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14560 | Benzyl chloromethyl ether; 1-[(chloromethoxy)methyl]benzene | 3587-60-8 | C8H9ClO | 详情 | 详情 | |
| (XI) | 34966 | ethyl (5R,6R)-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C23H24O8 | 详情 | 详情 | |
| (XII) | 34967 | ethyl (5R,6S)-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C23H24O8 | 详情 | 详情 | |
| (XIII) | 34968 | ethyl (5R,6R)-5-(3,4,5-trimethoxyphenyl)-8-[(trimethylsilyl)oxy]-5,6-dihydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C26H32O8Si | 详情 | 详情 | |
| (XIV) | 34969 | ethyl (5R,6R,7R)-7-[(benzyloxy)methyl]-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C31H32O9 | 详情 | 详情 | |
| (XV) | 34970 | (1R,11R,12R,15R)-15-[(benzyloxy)methyl]-11-(3,4,5-trimethoxyphenyl)-5,7,14-trioxatetracyclo[10.2.1.0(2,10).0(4,8)]pentadeca-2(10),3,8-trien-13-one | C29H28O8 | 详情 | 详情 | |
| (XVI) | 34971 | (1R,11R,12R,15R)-15-(hydroxymethyl)-11-(3,4,5-trimethoxyphenyl)-5,7,14-trioxatetracyclo[10.2.1.0(2,10).0(4,8)]pentadeca-2(10),3,8-trien-13-one | C22H22O8 | 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 intermediate trans-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetra-hydronaphtho[2,3-d][1,3]benzodioxole-6-carboxylic acid ethyl ester (XI) has been obtained by several different ways: (a) The condensation of benzophenone (XXXVIII) with diethyl malonate (XXXIX) by means of t-BuOK gives the alkylidenemalonate (XL), which is hydrogenated with H2 over Pd/C to the alkylmalonate hemiester (XLI). The reaction of (XLI) with acetyl chloride affords the mixed anhydride (XLII), which is finally cyclized to the target (XI) by means of SnCl4. (b) The cyclization of the malonic ester derivative (XLIII) by means of Ti(CF3--CO2)3 gives the 5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho [2,3-d][1,3]dioxole-6,6-dicarboxylic acid dimethyl ester (XLIV), which is finally oxidized and decarboxylated with NBS and NaOH in methanol to afford the target intermediate (XI). (c) The cyclization of the benzylidenemalonate (XLV) with the aryllithium derivative (XLVI) gives the 8-methoxy-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6,6-dicarboxylic acid dimethyl ester (XLVII), which is demethylated with TFA and oxidized with CrO3 and pyridine to the target compound (XI). (d) The cyclopropanation of the chalcone (XLVIII) with (ethoxycarbonyl) (dimethylsulfonium)methylide (XLIX) gives the cyclopropanecarboxylate (L), which is finally rearranged with BF3/Et2O to the target intermediate (IX).
| 【1】 Ward, R.S.; Synthesis of podophyllotoxin and related compounds. Synthesis 1992, 719. |
| 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) | 11966 | 2-(Dimethylsulfonium)acetic acid ethyl ester inner salt | C6H12O2S | 详情 | 详情 | |
| (XI) | 34966 | ethyl (5R,6R)-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C23H24O8 | 详情 | 详情 | |
| (XXXVIII) | 34992 | 1,3-benzodioxol-5-yl(3,4,5-trimethoxyphenyl)methanone | C17H16O6 | 详情 | 详情 | |
| (XXXIX) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (XL) | 34993 | (E)-4-(1,3-benzodioxol-5-yl)-3-(ethoxycarbonyl)-4-(3,4,5-trimethoxyphenyl)-3-butenoic acid | C23H24O9 | 详情 | 详情 | |
| (XLI) | 34994 | 4-(1,3-benzodioxol-5-yl)-3-(ethoxycarbonyl)-4-(3,4,5-trimethoxyphenyl)butyric acid | C23H26O9 | 详情 | 详情 | |
| (XLII) | 34995 | acetic 3-(1,3-benzodioxol-5-yl)-2-(ethoxycarbonyl)-3-(3,4,5-trimethoxyphenyl)butyric anhydride | C25H28O10 | 详情 | 详情 | |
| (XLIII) | 34996 | diethyl 2-[2-(1,3-benzodioxol-5-yl)ethyl]-2-(3,4,5-trimethoxybenzyl)malonate | C26H32O9 | 详情 | 详情 | |
| (XLIV) | 34997 | diethyl 5-(3,4,5-trimethoxyphenyl)-7,8-dihydronaphtho[2,3-d][1,3]dioxole-6,6(5H)-dicarboxylate | C26H30O9 | 详情 | 详情 | |
| (XLV) | 34998 | diethyl 2-(3,4,5-trimethoxybenzylidene)malonate | C17H22O7 | 详情 | 详情 | |
| (XLVI) | 34999 | [6-(2-bromo-1-methoxyethyl)-1,3-benzodioxol-5-yl]lithium | C10H10BrLiO3 | 详情 | 详情 | |
| (XLVII) | 35000 | diethyl 8-methoxy-5-(3,4,5-trimethoxyphenyl)-7,8-dihydronaphtho[2,3-d][1,3]dioxole-6,6(5H)-dicarboxylate | C27H32O10 | 详情 | 详情 | |
| (XLVIII) | 35001 | (E)-1-(1,3-benzodioxol-5-yl)-3-(3,4,5-trimethoxyphenyl)-2-propen-1-one | C19H18O6 | 详情 | 详情 | |
| (L) | 35002 | ethyl 2-(1,3-benzodioxol-5-ylcarbonyl)-3-(3,4,5-trimethoxyphenyl)cyclopropanecarboxylate | C23H24O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)The cyclization of 3,4,5-trimethoxycinnamic acid ethyl ester (LI) with malonic acid ethyl ester potassium salt (LII) by means of Mn(OAc)3 gives the tetrahydrofuranone (LIII), which is acylated with 1,3-benzodioxol-5-ylcarbonyl chloride (LIV) yielding the tetrahydrofuranone (LV). Finally, this compound is rearranged and decarboxylated with SnCl4 to the target intermediate (XI).
| 【1】 Ward, R.S.; Synthesis of podophyllotoxin and related compounds. Synthesis 1992, 719. |
| 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) | 34966 | ethyl (5R,6R)-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C23H24O8 | 详情 | 详情 | |
| (LI) | 35003 | ethyl (E)-3-(3,4,5-trimethoxyphenyl)-2-propenoate | C14H18O5 | 详情 | 详情 | |
| (LII) | 35004 | potassium 3-methoxy-3-oxopropanoate | 38330-80-2 | C4H5KO4 | 详情 | 详情 |
| (LIII) | 35005 | 4-ethyl 3-methyl (3S,4R,5R)-2-oxo-5-(3,4,5-trimethoxyphenyl)tetrahydro-3,4-furandicarboxylate | C18H22O9 | 详情 | 详情 | |
| (LIV) | 28821 | 1,3-benzodioxole-5-carbonyl chloride | 20850-43-5 | C8H5ClO3 | 详情 | 详情 |
| (LV) | 35006 | 4-ethyl 3-methyl (3S,4R,5R)-3-(1,3-benzodioxol-5-ylcarbonyl)-2-oxo-5-(3,4,5-trimethoxyphenyl)tetrahydro-3,4-furandicarboxylate | C26H26O12 | 详情 | 详情 |