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【结 构 式】 
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【药物名称】Fredericamycin A, NSC-305263, NSC-601617(sodium salt), KFM-A 【化学名称】(S)-6',7'-Dihydro-4,9,9'-trihydroxy-6-methoxy-3'-[1(E),3(E)-pentadienyl]spiro[2H-benz[f]indene-2,8'-[8H]cyclopent[g]isoquinoline-1,1',3,5,8(2H)-pentone 【CA登记号】80455-68-1 【 分 子 式 】C30H21NO9 【 分 子 量 】539.50317 |
【开发单位】National Cancer Institute (Originator) 【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, ONCOLYTIC DRUGS |
合成路线1
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
The intermediate tricyclic carbaldehyde has been obtained by two different methods: 1. The dicarboxylic ester (I) is methylated with Me-I and Ag2O in dioxane to give the dimethoxy compound (II), which is reduced with LiAlH4 in THF to obtain the dicarbinol (III). Monoesterification of (III) with benzoyl chloride and pyridine in dichloromethane yields the monobenzoate (IV), which is oxidized with DMP to afford the carbaldehyde (V). The Grignard reaction of (V) with methylmagnesium bromide and MeLi in THF provides the diol (VI), which is oxidized with oxalyl chloride to furnish the desired intermediate carbaldehyde (VII). 2. The reaction of the tricyclic ketone (VIII) with phosphonium bromide (IX) by means of tBu-OK in THF gives methylene derivative (X), which by hydroboration with BH3 and H2O2 in THF yields the carbinol (XI). The oxidation of (XI) with DPP affords the carbaldehyde (XII), which is condensed with the 1-aminopyrrolidine (XIII) to afford the hydrazone (XIV). The acylation of (XIV) with acetyl chloride and LDA in THF provides the acetyl derivative (XV), which is finally treated with oxalic acid go give the desired intermediate carbaldehyde (VII).
| 【1】 Kita, Y.; et al.; Total synthesis of the antitumor antribiotic (±)-fredericamycin A by a linear approach. Chemistry (Weinheim) 2000, 6, 21, 3897. |
| 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) | 48755 | dimethyl 9-hydroxy-3-methyl-1-oxo-1,2,6,7-tetrahydro-8H-cyclopenta[g]isoquinoline-8,8-dicarboxylate | C17H17NO6 | 详情 | 详情 | |
| (II) | 48756 | dimethyl 1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopenta[g]isoquinoline-8,8-dicarboxylate | C19H21NO6 | 详情 | 详情 | |
| (III) | 48757 | [8-(hydroxymethyl)-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]methanol | C17H21NO4 | 详情 | 详情 | |
| (IV) | 48758 | [8-(hydroxymethyl)-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]methyl benzoate | C24H25NO5 | 详情 | 详情 | |
| (V) | 48759 | (8-formyl-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methyl benzoate | C24H23NO5 | 详情 | 详情 | |
| (VI) | 48760 | 1-[8-(hydroxymethyl)-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]-1-ethanol | C18H23NO4 | 详情 | 详情 | |
| (VII) | 48761 | 8-acetyl-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-8-carbaldehyde | C18H19NO4 | 详情 | 详情 | |
| (VIII) | 48762 | 1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopenta[g]isoquinolin-8-one | C15H15NO3 | 详情 | 详情 | |
| (IX) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (X) | 48763 | 1,9-dimethoxy-3-methyl-8-methylene-7,8-dihydro-6H-cyclopenta[g]isoquinoline; 1-methoxy-3-methyl-8-methylene-7,8-dihydro-6H-cyclopenta[g]isoquinolin-9-yl methyl ether | C16H17NO2 | 详情 | 详情 | |
| (XI) | 48764 | (1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methanol | C16H19NO3 | 详情 | 详情 | |
| (XII) | 46913 | (2R)-2-(methoxymethyl)pyrrolidinylamine; (2R)-2-(methoxymethyl)-1-pyrrolidinamine | 59983-39-0 | C6H14N2O | 详情 | 详情 |
| (XIII) | 48765 | 1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-8-carbaldehyde | C16H17NO3 | 详情 | 详情 | |
| (XIV) | 48766 | N-[(E)-(1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methylidene]-N-[(2R)-2-(methoxymethyl)pyrrolidinyl]amine; (2R)-N-[(E)-(1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methylidene]-2-(methoxymethyl)-1-pyrrolidinamine | C22H29N3O3 | 详情 | 详情 | |
| (XV) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (XVI) | 48767 | 1-[1,9-dimethoxy-8-([[(2R)-2-(methoxymethyl)pyrrolidinyl]imino]methyl)-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]-1-ethanone | C24H31N3O4 | 详情 | 详情 |
合成路线3
The reaction of carbaldehyde (VII) with phenylsulfanylacetylene (XVII) by means of LiHMDS in toluene gives the intermediate lithium alcoxide (XVIII), which is condensed with benzoyl chloride (XIX) to yield the ester (XX). The migration of the aroyl group of (XX) to the methyl ketone group under basic medium (LiHMDS) affords diketone (XXI), which is oxidized with DMP, complexed with Co2(CO)8 and debenzylated, providing the cobalt complex (XXII). The cycloaddition of (XXII) by means of Me2SiCl2, chloranil in refluxing toluene, followed by protection of the peri-OH groups with tBu2Si(OTf)2 and oxidation of the sulfanyl group with MCPBA, gives the polycyclic spiro compound (XXIII). The reaction of (XXIII) with chloroacetate (XXIV) by means of Ts-OH yields the chloroacetoxy compound (XXV). Selective demethylation of (XXV) with trimethylsilyl iodide affords the pyridinone (XXVI), which is oxidized with SeO2 in dioxane to provide the carbaldehyde (XXVII). The condensation of (XXVII) with phosphonium bromide (XXVIII) by means of BuLi in THF furnishes the alkylated precursor (XXIX), which is finally deprotected by means of BBr3 in dichloromethane and oxidized by air to afford the target compound.
| 【1】 Kita, Y.; et al.; Total synthesis of the antitumor antribiotic (±)-fredericamycin A by a linear approach. Chemistry (Weinheim) 2000, 6, 21, 3897. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 48761 | 8-acetyl-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-8-carbaldehyde | C18H19NO4 | 详情 | 详情 | |
| (XVII) | 48768 | ethynyl phenyl sulfide; 1-(ethynylsulfanyl)benzene | C8H6S | 详情 | 详情 | |
| (XVIII) | 48769 | C26H24LiNO4S | 详情 | 详情 | ||
| (XIX) | 48770 | 2-(benzyloxy)-4,5-dimethoxybenzoyl chloride | C16H15ClO4 | 详情 | 详情 | |
| (XX) | 48771 | 1-(8-acetyl-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)-3-(phenylsulfanyl)-2-propynyl 2-(benzyloxy)-4,5-dimethoxybenzoate | C42H39NO8S | 详情 | 详情 | |
| (XXI) | 48772 | 1-[2-(benzyloxy)-4,5-dimethoxyphenyl]-3-[8-[1-hydroxy-3-(phenylsulfanyl)-2-propynyl]-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]-1,3-propanedione | C42H39NO8S | 详情 | 详情 | |
| (XXII) | 48773 | 1-[1,9-dimethoxy-3-methyl-8-[3-(phenylsulfanyl)-2-propynoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]-3-(2-hydroxy-4,5-dimethoxyphenyl)-1,3-propanedione | C35H31NO8S | 详情 | 详情 | |
| (XXIII) | 48774 | C44H45NO9S | 详情 | 详情 | ||
| (XXIV) | 48775 | 1-ethoxyvinyl 2-chloroacetate | C6H9ClO3 | 详情 | 详情 | |
| (XXV) | 48776 | C40H42ClNO10 | 详情 | 详情 | ||
| (XXVI) | 48777 | C39H40ClNO10 | 详情 | 详情 | ||
| (XXVII) | 48778 | C39H38ClNO11 | 详情 | 详情 | ||
| (XXVIII) | 48753 | (E)-2-butenyl(triphenyl)phosphonium bromide | C22H22BrP | 详情 | 详情 | |
| (XXIX) | 48779 | C43H44ClNO10 | 详情 | 详情 |
合成路线4
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 |
合成路线5
The Sharpless epoxidation of (XV) gives the cis-epoxide (XVI), which by esterification with (-)-camphanic acid (XVII) by means of DEAD and PPh3 under Mitsunobu conditions yields, after chromatographic separation, the trans-epoxide ester (XVIII). The rearrangement of (XVIII) by means of BF3/Et2O in dichloromethane affords the spiro compound (XIX), which is treated with silylated ethyleneglycol and Tms-OTf to provide the ethyleneketal (XX). The hydrolysis if the ester group of (XX) with NaOH, followed by oxidation of the resulting alcohol with DMP, gives the partially protected diketone (XXI). The sulfenylation of (XXI) by means of PhS-SO2Ph and LiHMDS yields the bis-phenyl sulfanyl derivative (XXII), which is treated with TFA and oxidized with MCPBA to afford the phenylsulfinyl compound (XXIII). The cyclization of (XXIII) with the homophthalic anhydride (XXIV) (obtained from trimethoxybromobenzene (XXV)) by means of NaH, followed by methylation of the resulting OH group with Me-I and K2CO3, provides the spiro-hexacyclic compound (XXVI). The selective demethylation of (XXVI) with NaBr and Ts-OH gives the pyridinone derivative (XXVII), which is oxidized with SeO2 to yield the carbaldehyde (XXVIII).
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XVI) | 48740 | C19H21NO4 | 详情 | 详情 | ||
| (XVII) | 48741 | 4,7,7-trimethylbicyclo[2.2.1]heptane-2-carboxylic acid | C11H18O2 | 详情 | 详情 | |
| (XVIII) | 48742 | C30H37NO5 | 详情 | 详情 | ||
| (XIX) | 48743 | C30H37NO5 | 详情 | 详情 | ||
| (XX) | 48744 | C32H41NO6 | 详情 | 详情 | ||
| (XXI) | 48745 | C21H23NO5 | 详情 | 详情 | ||
| (XXII) | 48746 | C33H31NO5S2 | 详情 | 详情 | ||
| (XXIII) | 48747 | C25H21NO5S | 详情 | 详情 | ||
| (XXIV) | 48748 | 4,5,7,8-tetramethoxy-1H-isochromene-1,3(4H)-dione | C13H14O7 | 详情 | 详情 | |
| (XXV) | 48749 | 1-Bromo-2,4,5-trimethoxybenzene | C9H11BrO3 | 详情 | 详情 | |
| (XXVI) | 48750 | C32H31NO9 | 详情 | 详情 | ||
| (XXVII) | 48751 | C31H29NO9 | 详情 | 详情 | ||
| (XXVIII) | 48752 | C31H27NO10 | 详情 | 详情 |
合成路线6
The condensation of the carbaldehyde (XXVIII) with the phosphonium bromide (XXIX) by means of BuLi gives the precursor (XXX), which is finally demethylated with BBr3 and submitted to oxidation by air to yield the target compound.
| 【1】 Kita, Y.; et al.; Enantioselective total synthesis of a potent antitumor antibiotic, fredericamycin A. J Am Chem Soc 2001, 123, 14, 3214. |