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【结 构 式】 
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【分子编号】37856 【品名】5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronic acid 【CA登记号】 |
【 分 子 式 】C14H17BO5 【 分 子 量 】276.09698 【元素组成】C 60.9% H 6.21% B 3.92% O 28.97% |
合成路线1
该中间体在本合成路线中的序号：(XIX)The intermediate naphthaleneboronic acid (XIX) has been obtained as follows: The bromination of the 3-methylphenyl methoxymethyl ether (X) with NBS gives the dibromo compound (XI), which is treated with sodium phenylsulfinate to afford the sulfone (XII). The condensation of (XII) with methyl crotonate (XIII) by means of LDA and KOH gives the butyric acid (XIV), which is cyclized to the tetralone (XV) by means of trifluoroacetic anhydride (TFAA). The aromatization of (XV) by means of t-BuOK or NaOH yields the 5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthol (XVI), which is methylated with dimethyl sulfate to afford the methyl ether (XVII). The reaction of (XVII) with trimethyl borate and n-BuLi gives the boronic ester (XVIII), which is hydrolyzed with water and ammonium chloride yielding the desired naphthaleneboronic acid (XIX). Alternatively, the naphthaleneboronic acid (XIX) has been obtained as follows: The reaction of 2,4-dibromophenol methoxymethyl ether (XX) with n-BuLi and cyclohexyl(isopropyl)amine gives the benzyne intermediate (XXI), which, without isolation is cyclized with the lithium enolate of 3-methylcrotonic acid dimethylamide (XXII) to afford the previously described naphthol (XVI), which is purified by chromatography.
| 【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 37848 | 1-(methoxymethoxy)-3-methylbenzene; methoxymethyl 3-methylphenyl ether | C9H12O2 | 详情 | 详情 | |
| (XI) | 37849 | [4-bromo-3-(bromomethyl)phenoxy]methyl methyl ether; 1-bromo-2-(bromomethyl)-4-(methoxymethoxy)benzene | C9H10Br2O2 | 详情 | 详情 | |
| (XII) | 37850 | 2-bromo-5-(methoxymethoxy)benzyl phenyl sulfone; [2-bromo-5-(methoxymethoxy)benzyl](dioxo)phenyl-lambda(6)-sulfane | C15H15BrO4S | 详情 | 详情 | |
| (XIII) | 26361 | methyl (E)-2-butenoate | 623-43-8 | C5H8O2 | 详情 | 详情 |
| (XIV) | 37851 | 4-[2-bromo-5-(methoxymethoxy)phenyl]-3-methyl-4-(phenylsulfonyl)butyric acid | C19H21BrO6S | 详情 | 详情 | |
| (XV) | 37852 | 5-bromo-8-(methoxymethoxy)-3-methyl-4-(phenylsulfonyl)-3,4-dihydro-1(2H)-naphthalenone | C19H19BrO5S | 详情 | 详情 | |
| (XVI) | 37853 | 5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthol | C13H13BrO3 | 详情 | 详情 | |
| (XVII) | 37854 | 5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthyl methyl ether; 5-bromo-1-methoxy-8-(methoxymethoxy)-3-methylnaphthalene | C14H15BrO3 | 详情 | 详情 | |
| (XVIII) | 37855 | dimethyl 5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronate | C16H21BO5 | 详情 | 详情 | |
| (XIX) | 37856 | 5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronic acid | C14H17BO5 | 详情 | 详情 | |
| (XX) | 37857 | (2,4-dibromophenoxy)methyl methyl ether; 2,4-dibromo-1-(methoxymethoxy)benzene | C8H8Br2O2 | 详情 | 详情 | |
| (XXI) | 37858 | 1-bromo-4-(methoxymethoxy)-1,3-cyclohexadien-5-yne; 4-bromo-1,3-cyclohexadien-5-yn-1-yl methoxymethyl ether | C8H7BrO2 | 详情 | 详情 | |
| (XXII) | 37859 | C8H14LiNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)The condensation of the isoquinoline intermediate (IX) with the naphthaleneboronic acid intermediate (XIX) by means of palladium tetrakis(triphenylphosphine) and NaHCO3 in refluxing ethanol/toluene gives a 5:4 mixture of the (S) and (R) atropaisomers (XXIII), which, without separation, are treated with methanolic HCl to eliminate the methoxymethyl protecting groups and yield a mixture of (S) and (R) (XXIV). The dimerization of this mixture by means of silver oxide in dichloromethane affords a mixture of the (R,R), (R,S) and (S,S) dimers (XXV), which is deprotected with H2 over Pd/C in methanol/dichloromethane and submitted to HPLC to obtain the target (R,S) atropaisomer.
| 【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (S)-(XXIV) | 37861 | 4-[(1R,3R)-2-benzyl-6,8-bis(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-8-methoxy-6-methyl-1-naphthol | C44H43NO4 | 详情 | 详情 | |
| (S)-(XXIII) | 38319 | (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-(4,5-dimethoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline; benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-(4,5-dimethoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether | C46H47NO5 | 详情 | 详情 | |
| (R)-(XXIII) | 63435 | 2-benzyl-6,8-bis(benzyloxy)-5-[5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthyl]-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline; benzyl 2-benzyl-6-(benzyloxy)-5-[5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthyl]-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether | C46H47NO5 | 详情 | 详情 | |
| (R)-(XXIV) | 63438 | 4-{1,3-dimethyl-2-(phenylmethyl)-6,8-bis[(phenylmethyl)oxy]-1,2,3,4-tetrahydro-5-isoquinolinyl}-6-methyl-8-(methyloxy)-1-naphthalenol | C44H43NO4 | 详情 | 详情 | |
| (IX) | 37847 | benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline | C32H32INO2 | 详情 | 详情 | |
| (XIX) | 37856 | 5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronic acid | C14H17BO5 | 详情 | 详情 | |
| (XXV) | 37862 | C88H82N2O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIX)The intermediate naphthaleneboronic acid (XIX) has been obtained as follows: The bromination of the 3-methylphenyl methoxymethyl ether (X) with NBS gives the dibromo compound (XI), which is treated with sodium phenylsulfinate to afford the sulfone (XII). The condensation of (XII) with methyl crotonate (XIII) by means of LDA and KOH gives the butyric acid (XIV), which is cyclized to the tetralone (XV) by means of trifluoroacetic anhydride (TFAA). The aromatization of (XV) by means of t-BuOK or NaOH yields the 5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthol (XVI), which is methylated with dimethylsulfate to afford the methyl ether (XVII). The reaction of (XVII) with trimethyl borate and n-BuLi gives the boronic ester (XVIII), which is hydrolyzed with water and ammonium chloride yielding the desired naphthaleneboronic acid (XIX). Alternatively, the naphthaleneboronic acid (XIX) has been obtained as follows: The reaction of 2,4-dibromophenol methoxymethyl ether (XX) with n-BuLi and cyclohexyl(isopropyl)amine gives the benzyne intermediate (XXI), which, without isolation is cyclized with the lithium enolate of 3-methylcrotonic acid dimethylamide (XXII) to afford the previously described naphthol (XVI), which is purified by chromatography.
| 【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 37848 | 1-(methoxymethoxy)-3-methylbenzene; methoxymethyl 3-methylphenyl ether | C9H12O2 | 详情 | 详情 | |
| (XI) | 37849 | [4-bromo-3-(bromomethyl)phenoxy]methyl methyl ether; 1-bromo-2-(bromomethyl)-4-(methoxymethoxy)benzene | C9H10Br2O2 | 详情 | 详情 | |
| (XII) | 37850 | 2-bromo-5-(methoxymethoxy)benzyl phenyl sulfone; [2-bromo-5-(methoxymethoxy)benzyl](dioxo)phenyl-lambda(6)-sulfane | C15H15BrO4S | 详情 | 详情 | |
| (XIII) | 26361 | methyl (E)-2-butenoate | 623-43-8 | C5H8O2 | 详情 | 详情 |
| (XIV) | 37851 | 4-[2-bromo-5-(methoxymethoxy)phenyl]-3-methyl-4-(phenylsulfonyl)butyric acid | C19H21BrO6S | 详情 | 详情 | |
| (XV) | 37852 | 5-bromo-8-(methoxymethoxy)-3-methyl-4-(phenylsulfonyl)-3,4-dihydro-1(2H)-naphthalenone | C19H19BrO5S | 详情 | 详情 | |
| (XVI) | 37853 | 5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthol | C13H13BrO3 | 详情 | 详情 | |
| (XVII) | 37854 | 5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthyl methyl ether; 5-bromo-1-methoxy-8-(methoxymethoxy)-3-methylnaphthalene | C14H15BrO3 | 详情 | 详情 | |
| (XVIII) | 37855 | dimethyl 5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronate | C16H21BO5 | 详情 | 详情 | |
| (XIX) | 37856 | 5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronic acid | C14H17BO5 | 详情 | 详情 | |
| (XX) | 37857 | (2,4-dibromophenoxy)methyl methyl ether; 2,4-dibromo-1-(methoxymethoxy)benzene | C8H8Br2O2 | 详情 | 详情 | |
| (XXI) | 37858 | 1-bromo-4-(methoxymethoxy)-1,3-cyclohexadien-5-yne; 4-bromo-1,3-cyclohexadien-5-yn-1-yl methoxymethyl ether | C8H7BrO2 | 详情 | 详情 | |
| (XXII) | 37859 | C8H14LiNO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIX)The condensation of the isoquinoline intermediate (IX) with the naphthaleneboronic acid intermediate (XIX) by means of palladium tetrakis(triphenylphosphine) and NaHCO3 in refluxing ethanol/toluene gives a 5:4 mixture of the (S) and (R) atropaisomers (XXIII), which, without separation, are treated with methanolic HCl to eliminate the methoxymethyl protecting groups and yield a mixture of (S) and (R) (XXIV). The debenzylation of this mixture by means of H2 over Pd/C in methanol/dichloromethane affords a mixture of the target (S-biar) compound, along with its (R-biar)-atropaisomer that are separated by HPLC.
| 【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (S)-(XXIV) | 37861 | 4-[(1R,3R)-2-benzyl-6,8-bis(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-8-methoxy-6-methyl-1-naphthol | C44H43NO4 | 详情 | 详情 | |
| (S-biar) | 38308 | (1R,3R)-5-(4-hydroxy-5-methoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydro-6,8-isoquinolinediol | C23H25NO4 | 详情 | 详情 | |
| (S)-(XXIII) | 38319 | (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-(4,5-dimethoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline; benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-(4,5-dimethoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether | C46H47NO5 | 详情 | 详情 | |
| (R)-(XXIII) | 63435 | 2-benzyl-6,8-bis(benzyloxy)-5-[5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthyl]-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline; benzyl 2-benzyl-6-(benzyloxy)-5-[5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthyl]-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether | C46H47NO5 | 详情 | 详情 | |
| (R)-(XXIV) | 63438 | 4-{1,3-dimethyl-2-(phenylmethyl)-6,8-bis[(phenylmethyl)oxy]-1,2,3,4-tetrahydro-5-isoquinolinyl}-6-methyl-8-(methyloxy)-1-naphthalenol | C44H43NO4 | 详情 | 详情 | |
| (IX) | 37847 | benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline | C32H32INO2 | 详情 | 详情 | |
| (XIX) | 37856 | 5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronic acid | C14H17BO5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIX)The intermediate naphthaleneboronic acid (XIX) has been obtained as follows: The bromination of the 3-methylphenyl methoxymethyl ether (X) with NBS gives the dibromo compound (XI), which is treated with sodium phenylsulfinate to afford the sulfone (XII). The condensation of (XII) with methyl crotonate (XIII) by means of LDA and KOH gives the butyric acid (XIV), which is cyclized to the tetralone (XV) by means of trifluoroacetic anhydride (TFAA). The aromatization of (XV) by means of t-BuOK or NaOH yields the 5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthol (XVI), which is methylated with dimethylsulfate to afford the methyl ether (XVII). The reaction of (XVII) with trimethyl borate and n-BuLi gives the boronic ester (XVIII), which is hydrolyzed with water and ammonium chloride yielding the desired naphthaleneboronic acid (XIX). Alternatively, the naphthaleneboronic acid (XIX) has been obtained as follows: The reaction of 2,4-dibromophenol methoxymethyl ether (XX) with n-BuLi and cyclohexyl(isopropyl)amine gives the benzyne intermediate (XXI), which, without isolation is cyclized with the lithium enolate of 3-methylcrotonic acid dimethylamide (XXII) to afford the previously described naphthol (XVI), which is purified by chromatography.
| 【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 37848 | 1-(methoxymethoxy)-3-methylbenzene; methoxymethyl 3-methylphenyl ether | C9H12O2 | 详情 | 详情 | |
| (XI) | 37849 | [4-bromo-3-(bromomethyl)phenoxy]methyl methyl ether; 1-bromo-2-(bromomethyl)-4-(methoxymethoxy)benzene | C9H10Br2O2 | 详情 | 详情 | |
| (XII) | 37850 | 2-bromo-5-(methoxymethoxy)benzyl phenyl sulfone; [2-bromo-5-(methoxymethoxy)benzyl](dioxo)phenyl-lambda(6)-sulfane | C15H15BrO4S | 详情 | 详情 | |
| (XIII) | 26361 | methyl (E)-2-butenoate | 623-43-8 | C5H8O2 | 详情 | 详情 |
| (XIV) | 37851 | 4-[2-bromo-5-(methoxymethoxy)phenyl]-3-methyl-4-(phenylsulfonyl)butyric acid | C19H21BrO6S | 详情 | 详情 | |
| (XV) | 37852 | 5-bromo-8-(methoxymethoxy)-3-methyl-4-(phenylsulfonyl)-3,4-dihydro-1(2H)-naphthalenone | C19H19BrO5S | 详情 | 详情 | |
| (XVI) | 37853 | 5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthol | C13H13BrO3 | 详情 | 详情 | |
| (XVII) | 37854 | 5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthyl methyl ether; 5-bromo-1-methoxy-8-(methoxymethoxy)-3-methylnaphthalene | C14H15BrO3 | 详情 | 详情 | |
| (XVIII) | 37855 | dimethyl 5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronate | C16H21BO5 | 详情 | 详情 | |
| (XIX) | 37856 | 5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronic acid | C14H17BO5 | 详情 | 详情 | |
| (XX) | 37857 | (2,4-dibromophenoxy)methyl methyl ether; 2,4-dibromo-1-(methoxymethoxy)benzene | C8H8Br2O2 | 详情 | 详情 | |
| (XXI) | 37858 | 1-bromo-4-(methoxymethoxy)-1,3-cyclohexadien-5-yne; 4-bromo-1,3-cyclohexadien-5-yn-1-yl methoxymethyl ether | C8H7BrO2 | 详情 | 详情 | |
| (XXII) | 37859 | C8H14LiNO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIX)The condensation of the isoquinoline intermediate (IX) with the naphthaleneboronic acid intermediate (XIX) by means of palladium tetrakis(triphenylphosphine) and NaHCO3 in refluxing ethanol/toluene gives a 5:4 mixture of the (S) and (R) atropaisomers (XXIII), which, without separation, are treated with methanolic HCl to eliminate the methoxymethyl protecting groups and yield a mixture of (S) and (R) (XXIV). The debenzylation of this mixture by means of H2 over Pd/C in methanol/dichloromethane affords a mixture of the target (R-biar) compound, along with its (S-biar)-atropaisomer that are separated by HPLC.
| 【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (S)-(XXIV) | 37861 | 4-[(1R,3R)-2-benzyl-6,8-bis(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-8-methoxy-6-methyl-1-naphthol | C44H43NO4 | 详情 | 详情 | |
| (R-biar) | 38308 | (1R,3R)-5-(4-hydroxy-5-methoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydro-6,8-isoquinolinediol | C23H25NO4 | 详情 | 详情 | |
| (S)-(XXIII) | 38319 | (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-(4,5-dimethoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline; benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-(4,5-dimethoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether | C46H47NO5 | 详情 | 详情 | |
| (R)-(XXIII) | 63435 | 2-benzyl-6,8-bis(benzyloxy)-5-[5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthyl]-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline; benzyl 2-benzyl-6-(benzyloxy)-5-[5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthyl]-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether | C46H47NO5 | 详情 | 详情 | |
| (R)-(XXIV) | 63438 | 4-{1,3-dimethyl-2-(phenylmethyl)-6,8-bis[(phenylmethyl)oxy]-1,2,3,4-tetrahydro-5-isoquinolinyl}-6-methyl-8-(methyloxy)-1-naphthalenol | C44H43NO4 | 详情 | 详情 | |
| (IX) | 37847 | benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline | C32H32INO2 | 详情 | 详情 | |
| (XIX) | 37856 | 5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronic acid | C14H17BO5 | 详情 | 详情 |