【结 构 式】 |
【分子编号】53353 【品名】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 【CA登记号】n/a |
【 分 子 式 】C48H57N5O13 【 分 子 量 】912.00648 【元素组成】C 63.22% H 6.3% N 7.68% O 22.81% |
合成路线1
该中间体在本合成路线中的序号:(XVII)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:(XVII)The selective protection of the primary OH group of (XVII) with Tips-Cl and imidazole yields the silyl ether (XVIII), which is treated with TFA in dichloromethane to afford the carboxylic acid (XIX). The macrolactamization of (XIX) by means of EDC, HOAt and DIEA in DMF/dichloromethane provides the macrolactam (XX), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to furnish the aminophenol (XXI). The condensation of (XXI) with racemic 3-methyl-2-oxopentanoic acid (XXII) by means of EDC and HOAt in DMF/dichloromethane gives the amide (XXIII) as a diastereomeric mixture. The desilylation of (XXIII) by means of HF and pyridine gives the tetrahydroxy compound (XXIV), which is fully resilylated with Tes-OTf and lutidine in dichloromethane to yield the tetra-silyl ether (XXV).
【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 |
---|---|---|---|---|---|---|
(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 |
(XVIII) | 53354 | tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate | n/a | C57H77N5O13Si | 详情 | 详情 |
(XIX) | 53355 | (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoic acid | n/a | C53H69N5O13Si | 详情 | 详情 |
(XX) | 53356 | benzyl (10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-23-(benzyloxy)-10,11-dihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-ylcarbamate | n/a | C48H59N5O10Si | 详情 | 详情 |
(XXI) | 53357 | 2-[(10S,11R,12R,15S,18S)-18-amino-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-15-yl]acetamide | n/a | C33H47N5O8Si | 详情 | 详情 |
(XXII) | 46950 | 3-methyl-2-oxopentanoic acid | C6H10O3 | 详情 | 详情 | |
(XXIII) | 53358 | N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide | n/a | C39H55N5O10Si | 详情 | 详情 |
(XXIV) | 53359 | N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-12-(hydroxymethyl)-9,14,17-trioxo-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide | n/a | C30H35N5O10 | 详情 | 详情 |
(XXV) | 53360 | N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-12-{[(triethylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide | n/a | C54H91N5O10Si4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XVII)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4
该中间体在本合成路线中的序号:(XVII)The selective protection of the primary OH group of (XVII) with Tips-Cl and imidazole yields the silyl ether (XVIII), which is treated with TFA in dichloromethane to afford the carboxylic acid (XIX). The macrolactamization of (XIX) by means of EDC, HOAt and DIEA in DMF/dichloromethane provides the macrolactam (XX), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to furnish the aminophenol (XXI). The condensation of (XXI) with racemic 3-methyl-2-oxopentanoic acid (XXII) by means of EDC and HOAt in DMF/dichloromethane gives the amide (XXIII) as a diastereomeric mixture. The desilylation of (XXIII) by means of HF and pyridine gives the tetrahydroxy compound (XXIV), which is fully resilylated with Tes-OTf and lutidine in dichloromethane to yield the tetra-silyl ether (XXV).
【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 |
---|---|---|---|---|---|---|
(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 |
(XVIII) | 53354 | tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate | n/a | C57H77N5O13Si | 详情 | 详情 |
(XIX) | 53355 | (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoic acid | n/a | C53H69N5O13Si | 详情 | 详情 |
(XX) | 53356 | benzyl (10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-23-(benzyloxy)-10,11-dihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-ylcarbamate | n/a | C48H59N5O10Si | 详情 | 详情 |
(XXI) | 53357 | 2-[(10S,11R,12R,15S,18S)-18-amino-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-15-yl]acetamide | n/a | C33H47N5O8Si | 详情 | 详情 |
(XXII) | 46950 | 3-methyl-2-oxopentanoic acid | C6H10O3 | 详情 | 详情 | |
(XXIII) | 53358 | N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide | n/a | C39H55N5O10Si | 详情 | 详情 |
(XXIV) | 53359 | N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-12-(hydroxymethyl)-9,14,17-trioxo-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide | n/a | C30H35N5O10 | 详情 | 详情 |
(XXV) | 53360 | N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-12-{[(triethylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide | n/a | C54H91N5O10Si4 | 详情 | 详情 |