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【结 构 式】 
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【分子编号】53366 【品名】(10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-N-[(Z)-1-propenyl]-10,11,23-tris[(triethylsilyl)oxy]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxamide 【CA登记号】n/a |
【 分 子 式 】C51H80N6O10Si3 【 分 子 量 】1021.48714 【元素组成】C 59.97% H 7.89% N 8.23% O 15.66% Si 8.25% |
合成路线1
该中间体在本合成路线中的序号：(XXXII)The oxidation of the primary silyl ether of (XXV) with the Jones reagent gives a mixture of the carboxylic acid derivatives (XXVI) and (XXVII), which is condensed with the silylated amine (XVIII) by means of EDC and HOAT in DMF/dichloromethane to yield a mixture of the corresponding amides (XXIX) and (XXX). The rearrangement of the mixture (XXIX) + (XXX) in refluxing o-xylene affords provided a mixture of the (E)-propenylamides (XXXI) and (XXXII), which is desilylated by means of HF and pyridine in THF to give compound (XXXIII) as a diastereomeric mixture that is separated by RP-HPLC to afford the target TMC-95A.
| 【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 |
|---|---|---|---|---|---|---|
| (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 |
| (XXVI) | 53361 | (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-23-hydroxy-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-10,11-bis[(triethylsilyl)oxy]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxylic acid | n/a | C42H61N5O11Si2 | 详情 | 详情 |
| (XXVII) | 53362 | (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxylic acid | n/a | C48H75N5O11Si3 | 详情 | 详情 |
| (XXVIII) | 53368 | 1-(triethylsilyl)-2-propen-1-amine; 1-(triethylsilyl)-2-propenylamine | n/a | C9H21NSi | 详情 | 详情 |
| (XXIX) | 53363 | (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-23-hydroxy-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-10,11-bis[(triethylsilyl)oxy]-N-[1-(triethylsilyl)-2-propenyl]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxylic acid | n/a | C51H80N6O10Si3 | 详情 | 详情 |
| (XXX) | 53364 | (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-N-[1-(triethylsilyl)-2-propenyl]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxylic acid | n/a | C57H94N6O10Si4 | 详情 | 详情 |
| (XXXI) | 53365 | (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-23-hydroxy-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-N-[(Z)-1-propenyl]-10,11-bis[(triethylsilyl)oxy]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxilic acid | n/a | C45H66N6O10Si2 | 详情 | 详情 |
| (XXXII) | 53366 | (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-N-[(Z)-1-propenyl]-10,11,23-tris[(triethylsilyl)oxy]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxamide | n/a | C51H80N6O10Si3 | 详情 | 详情 |
| (XXXIII) | 53367 | (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-N-[(Z)-1-propenyl]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxamide | n/a | C33H38N6O10 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXII)The oxidation of the primary silyl ether of (XXV) with the Jones reagent gives a mixture of the carboxylic acid derivatives (XXVI) and (XXVII). This mixture is condensed with the silylated amine (XXVIII) by means of EDC and HOAt in DMF/dichloromethane to yield a mixture of the corresponding amides (XXIX) and (XXX). The rearrangement of the mixture (XXIX) + (XXX) in refluxing o-xylene affords provided a mixture of the (E)-propenylamides (XXXI) and (XXXII), which is desilylated by means of HF and pyridine in THF to give compound (XXXIII) as a diastereomeric mixture that is separated by RP-HPLC to afford the target TMC-95B.
| 【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 |
|---|---|---|---|---|---|---|
| (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 |
| (XXVI) | 53361 | (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-23-hydroxy-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-10,11-bis[(triethylsilyl)oxy]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxylic acid | n/a | C42H61N5O11Si2 | 详情 | 详情 |
| (XXVII) | 53362 | (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxylic acid | n/a | C48H75N5O11Si3 | 详情 | 详情 |
| (XXVIII) | 53368 | 1-(triethylsilyl)-2-propen-1-amine; 1-(triethylsilyl)-2-propenylamine | n/a | C9H21NSi | 详情 | 详情 |
| (XXIX) | 53363 | (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-23-hydroxy-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-10,11-bis[(triethylsilyl)oxy]-N-[1-(triethylsilyl)-2-propenyl]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxylic acid | n/a | C51H80N6O10Si3 | 详情 | 详情 |
| (XXX) | 53364 | (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-N-[1-(triethylsilyl)-2-propenyl]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxylic acid | n/a | C57H94N6O10Si4 | 详情 | 详情 |
| (XXXI) | 53365 | (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-23-hydroxy-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-N-[(Z)-1-propenyl]-10,11-bis[(triethylsilyl)oxy]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxilic acid | n/a | C45H66N6O10Si2 | 详情 | 详情 |
| (XXXII) | 53366 | (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-N-[(Z)-1-propenyl]-10,11,23-tris[(triethylsilyl)oxy]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxamide | n/a | C51H80N6O10Si3 | 详情 | 详情 |
| (XXXIII) | 53367 | (10S,11R,12S,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-18-[(3-methyl-2-oxopentanoyl)amino]-9,14,17-trioxo-N-[(Z)-1-propenyl]-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaene-12-carboxamide | n/a | C33H38N6O10 | 详情 | 详情 |