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【结 构 式】 
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【分子编号】31493 【品名】methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(1H-indol-3-yl)propanoate 【CA登记号】 |
【 分 子 式 】C20H16N2O4 【 分 子 量 】348.35812 【元素组成】C 68.96% H 4.63% N 8.04% O 18.37% |
合成路线1
该中间体在本合成路线中的序号：(I)The compound was originally isolated from the fungal source N. gypsea var. incurvata. The synthesis of this compound was further described. Treatment of N-phthaloyltryptophan methyl ester (I) with tert-butyl hypochlorite and triethylamine at -78 C led to the formation of the intermediate 3-chloroindolenine (II), which was reacted with B-prenyl-9-BBN (III) to yield the 3-(1,1-dimethylpropenyl)indole (IV). Removal of the phthalimide protecting group of (IV) by hydrazinolysis provided aminoester (V). Protection of (V) as the tert-butyl carbamate, followed by ester hydrolysis with LiOH afforded the N-Boc-amino acid (VI). Coupling of protected amino acid (VI) with aminoester (V) by means of BOP-Cl gave dipeptide (VII). After removal of the Boc protecting group of (VII) with trifluoroacetic acid, ammonia-catalyzed cyclization provided diketopiperazine (VIII). Alternatively, diketopiperazine (VIII) was obtained by thermal cyclization of two molecules of aminoester (V) at 140 C. Oxidative cyclization by means of dimethyldioxirane (IX) produced a 1:1:2 mixture of syn:syn, anti:anti, and syn:anti diastereoisomeric heptacyclic compounds. Finally, the target syn:anti isomer was isolated by chromatography.
| 【1】 Schkeryantz, J.M.; et al.; Total synthesis of gypsetin, deoxybrevianamide E, brevianamide E, and tryprostatin B: Novel constructions of 2,3-disubstituted indoles. J Am Chem Soc 1999, 121, 51, 11964. |
| 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) | 31493 | methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(1H-indol-3-yl)propanoate | C20H16N2O4 | 详情 | 详情 | |
| (II) | 31494 | methyl (2S)-3-(3-chloro-3H-indol-3-yl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoate | C20H15ClN2O4 | 详情 | 详情 | |
| (III) | 31495 | 9-(3-methyl-2-butenyl)-9-borabicyclo[3.3.1]nonane | C13H23B | 详情 | 详情 | |
| (IV) | 31496 | methyl (2S)-3-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoate | C25H24N2O4 | 详情 | 详情 | |
| (V) | 31497 | methyl (2S)-2-amino-3-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]propanoate | C17H22N2O2 | 详情 | 详情 | |
| (VI) | 31498 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]propionic acid | C21H28N2O4 | 详情 | 详情 | |
| (VII) | 31499 | methyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]propanoyl]amino)-3-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]propanoate | C38H48N4O5 | 详情 | 详情 | |
| (VIII) | 31500 | (3S,6S)-3,6-bis[[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]methyl]-2,5-piperazinedione | C32H36N4O2 | 详情 | 详情 | |
| (IX) | 31501 | 3,3-dimethyl-1,2-dioxirane | C3H6O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The compound was originally isolated from Aspergillus fumigatus. The synthesis of this compound was further described. Treatment of N-phthaloyltryptophan methyl ester (I) with tert-butyl hypochlorite and triethylamine at -78 C led to the formation of the intermediate 3-chloroindolenine (II). Reaction of tributyl prenyl stannane (III) with boron trichloride generated in situ the transient boron reagent (IV), which after condensation with chloroindolenine (II) produced the 3-prenylindole (V). Subsequent removal of the phthalimide protecting group of (V) by hydrazinolysis provided aminoester (VI). Coupling of (VI) with acid fluoride (VIII), (generated from N-Boc-L-proline (VII) and cyanuric fluoride), gave rise to amide (IX). The Boc protecting group of (IX) was cleaved employing iodotrimethylsilane, and the resulting aminoester (X) was then cyclized with methanolic ammonia to produce the target diketopiperazine.
| 【1】 Schkeryantz, J.M.; et al.; Total synthesis of gypsetin, deoxybrevianamide E, brevianamide E, and tryprostatin B: Novel constructions of 2,3-disubstituted indoles. J Am Chem Soc 1999, 121, 51, 11964. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 26782 | Cyanuric fluoride; 2,4,6-trifluoro-1,3,5-triazine | 675-14-9 | C3F3N3 | 详情 | 详情 |
| (I) | 31493 | methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(1H-indol-3-yl)propanoate | C20H16N2O4 | 详情 | 详情 | |
| (II) | 31494 | methyl (2S)-3-(3-chloro-3H-indol-3-yl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoate | C20H15ClN2O4 | 详情 | 详情 | |
| (III) | 31502 | tributyl(3-methyl-2-butenyl)stannane | C17H36Sn | 详情 | 详情 | |
| (IV) | 31503 | dichloro(1,1-dimethyl-2-propenyl)borane | C5H9BCl2 | 详情 | 详情 | |
| (V) | 31504 | methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]propanoate | C25H24N2O4 | 详情 | 详情 | |
| (VI) | 31505 | methyl (2S)-2-amino-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]propanoate | C17H22N2O2 | 详情 | 详情 | |
| (VII) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (VIII) | 31506 | tert-butyl (2S)-2-(fluorocarbonyl)-1-pyrrolidinecarboxylate | C10H16FNO3 | 详情 | 详情 | |
| (IX) | 31507 | tert-butyl (2S)-2-[[((1S)-2-methoxy-1-[[2-(3-methyl-2-butenyl)-1H-indol-3-yl]methyl]-2-oxoethyl)amino]carbonyl]-1-pyrrolidinecarboxylate | C27H37N3O5 | 详情 | 详情 | |
| (X) | 31508 | methyl (2S)-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]-2-[[(2S)pyrrolidinylcarbonyl]amino]propanoate | C22H29N3O3 | 详情 | 详情 |