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【结 构 式】 
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【分子编号】64913 【品名】methyl 5,6-bis{[(methyloxy)methyl]oxy}octahydro-1H-indole-2-carboxylate 【CA登记号】 |
【 分 子 式 】C14H25NO6 【 分 子 量 】303.35564 【元素组成】C 55.43% H 8.31% N 4.62% O 31.64% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Synthesis of the perhydroindole intermediate (XIII): The alkylation of the N-protected glutamate (I) with allyl bromide (II) by means of LiHMDS in THF gives the protected chiral allyl glutamate (III) (1), which is cyclized by means of TFA in dichloromethane to yield the pyroglutamate (IV). The reduction of (IV) with LiHBEt3 in THF affords the hydroxy compound (V), which is treated with Ac2O and DMAP in dichloromethane to provide the expected hemiaminal derivative (VI). The reaction of (VI) with allyl tributylstannane (VII) by means of BF3/Et2O in toluene gives the diallyl pyrrolidine (VIII), which is submitted to a ring closure by olefin metathesis using a Grubbs Ru catalyst in dichloromethane to yield the hexahydroindole derivative (IX). The reaction of (IX) with mCPBA in dichloromethane affords the epoxide (X), which is hydrolyzed with TFA to yield the dihydroxy compound (XI). The reaction of (XI) with Mom-Cl and DIEA in dichloromethane provides the bis mom ether (XII), which is treated with H2 over Pd/C in methanol to yield the desired perhydroindole intermediate (XIII) (2).
| 【1】 Hanessian, S.; Margarita, R.; 1,3-Asymmetric induction in dianionic allylation reactions of amino acid derivatives-synthesis of functionally useful enantiopure glutamates, pipecolates and pyroglutamates. Tetrahedron Lett 1998, 39, 33, 5887. |
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 64903 | dimethyl 2-({[(phenylmethyl)oxy]carbonyl}amino)pentanedioate | C15H19NO6 | 详情 | 详情 | |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 64904 | dimethyl 2-({[(phenylmethyl)oxy]carbonyl}amino)-4-(2-propenyl)pentanedioate | C18H23NO6 | 详情 | 详情 | |
| (IV) | 64905 | 2-methyl 1-(phenylmethyl) 5-oxo-4-(2-propenyl)-1,2-pyrrolidinedicarboxylate | C17H19NO5 | 详情 | 详情 | |
| (V) | 64906 | 2-methyl 1-(phenylmethyl) 5-hydroxy-4-(2-propenyl)-1,2-pyrrolidinedicarboxylate | C17H21NO5 | 详情 | 详情 | |
| (VI) | 64907 | 2-methyl 1-(phenylmethyl) 5-(acetyloxy)-4-(2-propenyl)-1,2-pyrrolidinedicarboxylate | C19H23NO6 | 详情 | 详情 | |
| (VII) | 40599 | Allyltributyltin; Tributyl-2-propenylstannane | 24850-33-7 | C15H32Sn | 详情 | 详情 |
| (VIII) | 64908 | 2-methyl 1-(phenylmethyl) 4,5-di(2-propenyl)-1,2-pyrrolidinedicarboxylate | C20H25NO4 | 详情 | 详情 | |
| (IX) | 64909 | 2-methyl 1-(phenylmethyl) 2,3,3a,4,7,7a-hexahydro-1H-indole-1,2-dicarboxylate | C18H21NO4 | 详情 | 详情 | |
| (X) | 64910 | 4-methyl 3-(phenylmethyl) octahydro-3H-oxireno[2,3-f]indole-3,4-dicarboxylate | C18H21NO5 | 详情 | 详情 | |
| (XI) | 64911 | 2-methyl 1-(phenylmethyl) 5,6-dihydroxyoctahydro-1H-indole-1,2-dicarboxylate | C18H23NO6 | 详情 | 详情 | |
| (XII) | 64912 | 2-methyl 1-(phenylmethyl) 5,6-bis{[(methyloxy)methyl]oxy}octahydro-1H-indole-1,2-dicarboxylate | C22H31NO8 | 详情 | 详情 | |
| (XIII) | 64913 | methyl 5,6-bis{[(methyloxy)methyl]oxy}octahydro-1H-indole-2-carboxylate | C14H25NO6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)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 |