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【结 构 式】 
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【分子编号】48738 【品名】10,11-dimethoxy-8-methyl-2,3,4,5-tetrahydro-1H-indeno[5,4-g]isoquinolin-1-one 【CA登记号】 |
【 分 子 式 】C19H19NO3 【 分 子 量 】309.3648 【元素组成】C 73.77% H 6.19% N 4.53% O 15.52% |
合成路线1
该中间体在本合成路线中的序号：(I)The asymmetric reduction of the carbonyl group of tetracyclic compound (I) by means of BH3 and a chiral borane catalyst in THF gives the (R)-alcohol (II), which by a Sharpless epoxidation yields the chiral epoxide (III). The reaction of the (cis)-(III) with (-)-camphanic acid (IV), DAD and PPh3 under Mitsunobu conditions affords after chromatographic purification the (trans)-camphanate (V), which is submitted to a rearrangement reaction by means of BF3/Et2O in dichloromethane to provide the tetracyclic spiro compound (VI). The protection of the ketonic group of (VI) by means of silylated ethyleneglycol and Tms-OTf gives the cyclic ketal (VII), which is treated with NaOH in methanol and the resulting alcohol oxidized with DMP in dichloromethane to yield the monoprotected diketone (VIII). The disulfenylation of (VIII) affords the disulfide (IX), which by treatment with TFA and oxidation with MCPBA provides the unsaturated sulfinyl (X). The cyclization of (X) with the homophthalic anhydride (XI) (obtained from trimethoxybromobenzene (XII)), followed by methylation of the resulting free OH group with MeI and K2CO3 in DMF furnishes the spiro-hexacyclic compound (XIII). The selective demethylation of (XIII) with Tms-I in dichloromethane gives the pyridinone derivative (XIV), which is oxidized at the methyl group with SeO2 to yield the carbaldehyde (XV). The condensation of (XV) with the phosphonium bromide (XVI) by means of BuLi in THF affords the precursor (XVII), which is finally demethylated with BBr3 and submitted to oxidation by air to provide the target compound.
| 【1】 Kitagaki, S.; Kita, Y.; Fujioka, H.; Iio, K.; Yoshida, Y.; Higuchi, K.; Akai, S.; Asymmetric total synthesis of fredericamycin A. Angew Chem. Int Ed Engl 1999, 38, 5, 683. |
| 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) | 48738 | 10,11-dimethoxy-8-methyl-2,3,4,5-tetrahydro-1H-indeno[5,4-g]isoquinolin-1-one | C19H19NO3 | 详情 | 详情 | |
| (II) | 48739 | (1R)-10,11-dimethoxy-8-methyl-2,3,4,5-tetrahydro-1H-indeno[5,4-g]isoquinolin-1-ol | C19H21NO3 | 详情 | 详情 | |
| (III) | 48740 | C19H21NO4 | 详情 | 详情 | ||
| (IV) | 48741 | 4,7,7-trimethylbicyclo[2.2.1]heptane-2-carboxylic acid | C11H18O2 | 详情 | 详情 | |
| (V) | 48742 | C30H37NO5 | 详情 | 详情 | ||
| (VI) | 48743 | C30H37NO5 | 详情 | 详情 | ||
| (VII) | 48744 | C32H41NO6 | 详情 | 详情 | ||
| (VIII) | 48745 | C21H23NO5 | 详情 | 详情 | ||
| (IX) | 48746 | C33H31NO5S2 | 详情 | 详情 | ||
| (X) | 48747 | C25H21NO5S | 详情 | 详情 | ||
| (XI) | 48748 | 4,5,7,8-tetramethoxy-1H-isochromene-1,3(4H)-dione | C13H14O7 | 详情 | 详情 | |
| (XII) | 48749 | 1-Bromo-2,4,5-trimethoxybenzene | C9H11BrO3 | 详情 | 详情 | |
| (XIII) | 48750 | C32H31NO9 | 详情 | 详情 | ||
| (XIV) | 48751 | C31H29NO9 | 详情 | 详情 | ||
| (XV) | 48752 | C31H27NO10 | 详情 | 详情 | ||
| (XVI) | 48753 | (E)-2-butenyl(triphenyl)phosphonium bromide | C22H22BrP | 详情 | 详情 | |
| (XVII) | 48754 | C35H33NO9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)The intermediate propionic aldehyde (VI) has been obtained by two different ways: 1. The cyclization of 2-methoxy-4,6-dimethylpyridine-3-carboxylic acid methyl ester (I) with the cyclohexenone derivative (II) by means of LDA, followed by aromatization with DDQ gives the tricyclic ketone (III), which is methylated with Me-I and K2CO3 to yield the dimethoxyketone (IV). The desilylation of (IV) with TBAF affords the propanol derivative (V), which is finally submitted to a Swern oxidation to provide the desired intermediate, the propionic aldehyde (VI). 2. The reaction of pyridine-3-carboxylate (I) with LDA and CO2 gives the dicarboxylic hemiester (VII), which is hydrolyzed with KOH and anhydrized to yield the homophthalic anhydride (VIII). The cyclization of (VIII) with the alpha-sulfinylcyclohexenone (IX) by means of NaH affords the tricyclic ketone (X), which is methylated with Me-I and K2CO3 to provide the dimethoxyketone (XI). Finally, the ethyleneketal group of (XI) is hydrolyzed with TFA to furnish the desired intermediate, the propionic aldehyde (VI). The cyclization of (VI) by means of SmI2 gives the tetracyclic diol (XII), which is submitted to a Swern oxidation to yield the alpha-hydroxyketone (XIII). The dehydration of (XIII) by means of the Burgess reagent yields the cyclohexenone derivative (XIV), which is finally asymmetrically reduced to the (R)-alcohol (XV) by means of BH3 using a chiral borane as catalyst.
| 【1】 Kita, Y.; et al.; Enantioselective total synthesis of a potent antitumor antibiotic, fredericamycin A. J Am Chem Soc 2001, 123, 14, 3214. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 48787 | (2-ethoxyethynyl)(trimethyl)silane; ethyl 2-(trimethylsilyl)ethynyl ether | C7H14OSi | 详情 | 详情 | ||
| (I) | 48780 | methyl 2-methoxy-4,6-dimethylnicotinate | C10H13NO3 | 详情 | 详情 | |
| (II) | 48781 | 6-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2-cyclohexen-1-one | C15H28O2Si | 详情 | 详情 | |
| (III) | 48782 | 8-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-10-hydroxy-1-methoxy-3-methyl-7,8-dihydrobenzo[g]isoquinolin-9(6H)-one | C24H35NO4Si | 详情 | 详情 | |
| (IV) | 48783 | 8-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,10-dimethoxy-3-methyl-7,8-dihydrobenzo[g]isoquinolin-9(6H)-one | C25H37NO4Si | 详情 | 详情 | |
| (V) | 48784 | 8-(3-hydroxypropyl)-1,10-dimethoxy-3-methyl-7,8-dihydrobenzo[g]isoquinolin-9(6H)-one | C19H23NO4 | 详情 | 详情 | |
| (VI) | 48785 | 3-(1,10-dimethoxy-3-methyl-9-oxo-6,7,8,9-tetrahydrobenzo[g]isoquinolin-8-yl)propanal | C19H21NO4 | 详情 | 详情 | |
| (VII) | 48786 | 2-[2-methoxy-3-(methoxycarbonyl)-6-methyl-4-pyridinyl]acetic acid | C11H13NO5 | 详情 | 详情 | |
| (VIII) | 48788 | 8-methoxy-6-methyl-1H-pyrano[3,4-c]pyridine-1,3(4H)-dione | C10H9NO4 | 详情 | 详情 | |
| (IX) | 48789 | 6-[2-(1,3-dioxolan-2-yl)ethyl]-2-(phenylsulfinyl)-2-cyclohexen-1-one | C17H20O4S | 详情 | 详情 | |
| (X) | 48790 | 8-[2-(1,3-dioxolan-2-yl)ethyl]-10-hydroxy-1-methoxy-3-methyl-7,8-dihydrobenzo[g]isoquinolin-9(6H)-one | C20H23NO5 | 详情 | 详情 | |
| (XI) | 48793 | 8-[2-(1,3-dioxolan-2-yl)ethyl]-1,10-dimethoxy-3-methyl-7,8-dihydrobenzo[g]isoquinolin-9(6H)-one | C21H25NO5 | 详情 | 详情 | |
| (XII) | 48791 | 10,11-dimethoxy-8-methyl-1,2,3,3a,4,5-hexahydro-11bH-indeno[5,4-g]isoquinoline-1,11b-diol | C19H23NO4 | 详情 | 详情 | |
| (XIII) | 48792 | 11b-hydroxy-10,11-dimethoxy-8-methyl-2,3,3a,4,5,11b-hexahydro-1H-indeno[5,4-g]isoquinolin-1-one | C19H21NO4 | 详情 | 详情 | |
| (XIV) | 48738 | 10,11-dimethoxy-8-methyl-2,3,4,5-tetrahydro-1H-indeno[5,4-g]isoquinolin-1-one | C19H19NO3 | 详情 | 详情 | |
| (XV) | 48739 | (1R)-10,11-dimethoxy-8-methyl-2,3,4,5-tetrahydro-1H-indeno[5,4-g]isoquinolin-1-ol | C19H21NO3 | 详情 | 详情 |