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【结 构 式】 
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【分子编号】64925 【品名】 【CA登记号】 |
【 分 子 式 】C17H30N4O4 【 分 子 量 】354.44976 【元素组成】C 57.61% H 8.53% N 15.81% O 18.06% |
合成路线1
该中间体在本合成路线中的序号：(XXVI)Synthesis of the 3-pyrroline intermediate (XXVI): The reaction of 4-hydroxy-2-methylenebutyric acid methyl ester (XIV) with Tbdps-Cl and imidazole in DMF gives the silyl ether (XV), which is reduced with DIBAL in dichloromethane to yield the butanol derivative (XVI). The reaction of (XVI) with MsCl and TEA affords the corresponding mesylate (XVII), which is condensed with allylamine (XVIII) to provide the secondary amine (XIX). The protection of the NH group of (XIX) by reaction with Boc2O and TEA gives the carbamate (XX), which is submitted to a ring closing metathesis reaction using a Grubbs Ru catalyst to yield the 3-pyrroline derivative (XXI). The cleavage of the silyl ether group of (XXI) by means of TBAF in THF affords the pyrroline ethanol derivative (XXII), which is treated with PPh3, DEAD and (PhO)2P(O)N3 in THF to provide the azido derivative (XXIII). The deprotection of the NH group of (XXIII) by means of TFA in dichloromethane gives the 3-(2-azidoethyl)-3-pyrroline (XXIV), which is treated with Goodman's reagent to yield the protected amidino derivative (XXV). Finally, the azido group of (XXV) is reduced by means of PPh3, water and AcOH to afford the desired 3-pyrroline-1-carboxamidine (XXVI).
| 【1】 Hanessian, S.; Margarita, R.; Hall, A.; Johnstone, S.; Tremblay, M.; Parlanti, L.; Total synthesis and structural confirmation of the marine natural product Dysinosin A: A novel inhibitor of thrombin and Factor VIIa. J Am Chem Soc 2002, 124, 45, 13342. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 64914 | methyl 2-(2-hydroxyethyl)-2-propenoate | C6H10O3 | 详情 | 详情 | |
| (XV) | 64915 | methyl 2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-2-propenoate | C22H28O3Si | 详情 | 详情 | |
| (XVI) | 64916 | 2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-2-propen-1-ol | C21H28O2Si | 详情 | 详情 | |
| (XVII) | 64917 | 2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-2-propenyl methanesulfonate | C22H30O4SSi | 详情 | 详情 | |
| (XVIII) | 13672 | Allylamine; 2-Propen-1-amine | 107-11-9 | C3H7N | 详情 | 详情 |
| (XIX) | 64918 | 2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-N-(2-propenyl)-2-propen-1-amine; N-[2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-2-propenyl]-N-(2-propenyl)amine | C24H33NOSi | 详情 | 详情 | |
| (XX) | 64919 | 1,1-dimethylethyl 2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-2-propenyl(2-propenyl)carbamate | C29H41NO3Si | 详情 | 详情 | |
| (XXI) | 64920 | 1,1-dimethylethyl 3-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate | C27H37NO3Si | 详情 | 详情 | |
| (XXII) | 64921 | 1,1-dimethylethyl 3-(2-hydroxyethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate | C11H19NO3 | 详情 | 详情 | |
| (XXIII) | 64922 | 1,1-dimethylethyl 3-(2-azidoethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate | C11H18N4O2 | 详情 | 详情 | |
| (XXIV) | 64923 | 2-(2,5-dihydro-1H-pyrrol-3-yl)ethyl azide; 3-(2-azidoethyl)-2,5-dihydro-1H-pyrrole | C6H10N4 | 详情 | 详情 | |
| (XXV) | 64924 | C17H28N6O4 | 详情 | 详情 | ||
| (XXVI) | 64925 | C17H30N4O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVI)Synthesis of dysinosin A: The reaction of the commercially available D-mannitol derivative (XXVII) with NaH and MeI in DMF gives the dimethoxy compound (XXVIII), which is hydrogenated with H2 over Pd/C in EtOH/EtOAc to yield the dimethoxy-D-mannitol (XXIX). The selective silylation of the primary OH groups of (XXIX) with Tbdps-Cl and imidazole affords the bis silyl ether (XXX), which is submitted to an oxidative cleavage of its vicinal diol group by means of Pb(OAc)4 to provide 2(R)-methoxy-3-(Tbdps-O)propanal (XXXI) (3). The oxidation of (XXXI) with NaClO2 gives the corresponding carboxylic acid (XXXII), which is condensed with D-leucine benzyl ester (XXXIII) by means of EDC and HOBt in dichloromethane to yield adduct (XXXIV). The reductive cleavage of the benzyl group of (XXXIV) with H2 over Pd/C in methanol affords the substituted leucine (XXXV), which is condensed with the perhydroindole intermediate (XIII) by means of Bop-Cl and DIEA in acetonitrile to provide the amide (XXXVI). The hydrolysis of the methyl ester group of (XXXVI) with LiOH in THF/MeOH gives the carboxylic acid (XXXVII), which is condensed with the aminoethyl-3-pyrroline intermediate (XXVI) by means of EDC and HOBt in dichloromethane to yield the amide intermediate (XXXVIII). The cleavage of the silyl ether group of (XXXVIII) by means of TBAF in THF affords the primary alcohol (XXXIX), which is treated with Pyr/SO3 and Bu2SnO to provide the sulfate ester (XL). Finally, this compound is fully deprotected by means of TFA in dichloromethane and purified by means of preparative HPLC to obtain the target dysinosin A (2).
| 【1】 Nicolaou, K.C.; Piscopio, A.D.; Bertinato, P.; Chakraborty, T.K.; Minowa, N.; Koide, K.; Total Synthesis of Rapamycin. Chemistry (Weinheim) 1995, 1, 5, 318. |
| 【2】 Hanessian, S.; Margarita, R.; Hall, A.; Johnstone, S.; Tremblay, M.; Parlanti, L.; Total synthesis and structural confirmation of the marine natural product Dysinosin A: A novel inhibitor of thrombin and Factor VIIa. J Am Chem Soc 2002, 124, 45, 13342. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 64913 | methyl 5,6-bis{[(methyloxy)methyl]oxy}octahydro-1H-indole-2-carboxylate | C14H25NO6 | 详情 | 详情 | |
| (XXVI) | 64925 | C17H30N4O4 | 详情 | 详情 | ||
| (XXVII) | 64926 | C20H22O6 | 详情 | 详情 | ||
| (XXVIII) | 64927 | C22H26O6 | 详情 | 详情 | ||
| (XXIX) | 64928 | 2,5-bis(methyloxy)-1,3,4,6-hexanetetrol | C8H18O6 | 详情 | 详情 | |
| (XXX) | 64929 | 2,2,13,13-tetramethyl-6,9-bis(methyloxy)-3,3,12,12-tetraphenyl-4,11-dioxa-3,12-disilatetradecane-7,8-diol | C40H54O6Si2 | 详情 | 详情 | |
| (XXXI) | 15026 | (2R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-methoxypropanal | C20H26O3Si | 详情 | 详情 | |
| (XXXII) | 64930 | 3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)propanoic acid | C20H26O4Si | 详情 | 详情 | |
| (XXXIII) | 28648 | benzyl (2R)-2-amino-4-methylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (XXXIV) | 64931 | phenylmethyl 2-{[3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)propanoyl]amino}-4-methylpentanoate | C33H43NO5Si | 详情 | 详情 | |
| (XXXV) | 64932 | N-[3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)propanoyl]leucine | C26H37NO5Si | 详情 | 详情 | |
| (XXXVI) | 64933 | methyl 1-(2-{[2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)acetyl]amino}-4-methylpentanoyl)-5,6-bis{[(methyloxy)methyl]oxy}octahydro-1H-indole-2-carboxylate | C39H58N2O10Si | 详情 | 详情 | |
| (XXXVII) | 64934 | 1-(2-{[2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-(methyloxy)acetyl]amino}-4-methylpentanoyl)-5,6-bis{[(methyloxy)methyl]oxy}octahydro-1H-indole-2-carboxylic acid | C38H56N2O10Si | 详情 | 详情 | |
| (XXXVIII) | 64935 | C55H84N6O13Si | 详情 | 详情 | ||
| (XXXIX) | 64936 | C39H66N6O13 | 详情 | 详情 | ||
| (XL) | 64937 | 2-{[(2-{1-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)({[(1,1-dimethylethyl)oxy]carbonyl}imino)methyl]-2,5-dihydro-1H-pyrrol-3-yl}ethyl)amino]carbonyl}-1-(4-methyl-2-{[2-(methyloxy)-2-(sulfonatooxy)acetyl]amino}pentanoyl)-5,6-bis{[(methyloxy)methyl]ox | C39H65N6O16S | 详情 | 详情 |