|
【结 构 式】 
|
【分子编号】53351 【品名】tert-butyl (4S)-4-({7-[5-((2S)-3-{[(1S)-3-amino-1-(tert-butoxycarbonyl)-3-oxopropyl]amino}-2-{[(benzyloxy)carbonyl]amino}-3-oxopropyl)-2-(benzyloxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate 【CA登记号】n/a |
【 分 子 式 】C51H59N5O11 【 分 子 量 】918.05656 【元素组成】C 66.72% H 6.48% N 7.63% O 19.17% |
合成路线1
该中间体在本合成路线中的序号：(XV)The crossed aldol condensation of 7-iodo-2,3-dihydro-1H-indol-2-one (VIII) with the chiral oxazolidine-carbaldehyde (IX) by means of LDA in THF gives a mixture of (Z)-(X) and (E)-(XI) isomers, which is isomerized to the desired (E)-(XI) compound by treatment with I2 . The condensation of (XI) with the borinated tyrosine intermediate (VII) catalyzed with PdCl2(dppf)2 yields the diaryl compound (XII), whose ester group is hydrolyzed with LiOH in THF/water to afford the carboxylic acid (XIII). The condensation of (XIII) with L-asparagine tert-butyl ester (XIV) by means of EDC and 1-hydroxy-7-azabenzotriazole (HOAt) in THF provides adduct (XV), which is oxidized with OsO4, NMO and 1,4-bis(9-O-dihydroquinidinine)phthalazine ((DHOD)2PHAL) in tert-butanol/water to give the glycol (XVI). The cleavage of the oxazolidine ring of (XVI) by means of pyridinium p-toluenesulfonate (PPTS) yields the trihydroxy compound (XVII).
| 【1】 Lin, S.N.; Danishefsky, S.J.; The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides. Angew Chem. Int Ed 2002, 41, 3, 512. |
| 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) | 53343 | methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate | n/a | C31H36BNO7 | 详情 | 详情 |
| (VIII) | 53344 | 7-iodo-1,3-dihydro-2H-indol-2-one | n/a | C8H6INO | 详情 | 详情 |
| (IX) | 53345 | tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | n/a | C11H19NO4 | 详情 | 详情 |
| (X) | 53346 | tert-butyl (4S)-4-[(7-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | n/a | C19H23IN2O4 | 详情 | 详情 |
| (XI) | 53348 | tert-butyl (4S)-4-[(7-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | n/a | C19H23IN2O4 | 详情 | 详情 |
| (XII) | 53347 | tert-butyl (4S)-4-({7-[2-(benzyloxy)-5-((2S)-2-{[(benzyloxy)carbonyl]amino}-3-methoxy-3-oxopropyl)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | n/a | C44H47N3O9 | 详情 | 详情 |
| (XIII) | 53349 | (2S)-3-[4-(benzyloxy)-3-(3-{(E)-[(4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidin-4-yl]methylidene}-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoic acid | n/a | C43H45N3O9 | 详情 | 详情 |
| (XIV) | 53350 | tert-butyl (2S)-2,4-diamino-4-oxobutanoate | 63094-81-5（盐酸盐） | C8H16N2O3 | 详情 | 详情 |
| (XV) | 53351 | tert-butyl (4S)-4-({7-[5-((2S)-3-{[(1S)-3-amino-1-(tert-butoxycarbonyl)-3-oxopropyl]amino}-2-{[(benzyloxy)carbonyl]amino}-3-oxopropyl)-2-(benzyloxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | n/a | C51H59N5O11 | 详情 | 详情 |
| (XVI) | 53352 | tert-butyl (4R)-4-[(R)-{(3S)-7-[5-((2S)-3-{[(1S)-3-amino-1-(tert-butoxycarbonyl)-3-oxopropyl]amino}-2-{[(benzyloxy)carbonyl]amino}-3-oxopropyl)-2-(benzyloxy)phenyl]-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl}(hydroxy)methyl]-2,2-dimethyl-1,3-oxazolid | n/a | C51H61N5O13 | 详情 | 详情 |
| (XVII) | 53353 | tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1,3-dihydroxypropyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate | n/a | C48H57N5O13 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)The crossed aldol condensation of 7-iodo-2,3-dihydro-1H-indol-2-one (VIII) with the chiral oxazolidine-carbaldehyde (IX) by means of LDA in THF gives a mixture of (Z)-(X) and (E)-(XI) isomers, which is isomerized to the desired (E)-(XI) compound by treatment with I2 . The condensation of (XI) with the borinated tyrosine intermediate (VII) catalyzed with PdCl2(dppf)2 yields the diaryl compound (XII), whose ester group is hydrolyzed with LiOH in THF/water to afford the carboxylic acid (XIII). The condensation of (XIII) with L-asparagine tert-butyl ester (XIV) by means of EDC and 1-hydroxy-7-azabenzotriazole (HOAt) in THF provides adduct (XV), which is oxidized with OsO4, NMO and 1,4-bis(9-O-dihydroquinidinine)phthalazine ((DHOD)2PHAL) in tert-butanol/water to give the glycol (XVI). The cleavage of the oxazolidine ring of (XVI) by means of pyridinium p-toluenesulfonate (PPTS) yields the trihydroxy compound (XVII).
| 【1】 Lin, S.N.; Danishefsky, S.J.; The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides. Angew Chem. Int Ed 2002, 41, 3, 512. |
| 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) | 53343 | methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate | n/a | C31H36BNO7 | 详情 | 详情 |
| (VIII) | 53344 | 7-iodo-1,3-dihydro-2H-indol-2-one | n/a | C8H6INO | 详情 | 详情 |
| (IX) | 53345 | tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | n/a | C11H19NO4 | 详情 | 详情 |
| (X) | 53346 | tert-butyl (4S)-4-[(7-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | n/a | C19H23IN2O4 | 详情 | 详情 |
| (XI) | 53348 | tert-butyl (4S)-4-[(7-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | n/a | C19H23IN2O4 | 详情 | 详情 |
| (XII) | 53347 | tert-butyl (4S)-4-({7-[2-(benzyloxy)-5-((2S)-2-{[(benzyloxy)carbonyl]amino}-3-methoxy-3-oxopropyl)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | n/a | C44H47N3O9 | 详情 | 详情 |
| (XIII) | 53349 | (2S)-3-[4-(benzyloxy)-3-(3-{(E)-[(4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidin-4-yl]methylidene}-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoic acid | n/a | C43H45N3O9 | 详情 | 详情 |
| (XIV) | 53350 | tert-butyl (2S)-2,4-diamino-4-oxobutanoate | 63094-81-5（盐酸盐） | C8H16N2O3 | 详情 | 详情 |
| (XV) | 53351 | tert-butyl (4S)-4-({7-[5-((2S)-3-{[(1S)-3-amino-1-(tert-butoxycarbonyl)-3-oxopropyl]amino}-2-{[(benzyloxy)carbonyl]amino}-3-oxopropyl)-2-(benzyloxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | n/a | C51H59N5O11 | 详情 | 详情 |
| (XVI) | 53352 | tert-butyl (4R)-4-[(R)-{(3S)-7-[5-((2S)-3-{[(1S)-3-amino-1-(tert-butoxycarbonyl)-3-oxopropyl]amino}-2-{[(benzyloxy)carbonyl]amino}-3-oxopropyl)-2-(benzyloxy)phenyl]-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl}(hydroxy)methyl]-2,2-dimethyl-1,3-oxazolid | n/a | C51H61N5O13 | 详情 | 详情 |
| (XVII) | 53353 | tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1,3-dihydroxypropyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate | n/a | C48H57N5O13 | 详情 | 详情 |