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【结 构 式】

【分子编号】31494

【品名】methyl (2S)-3-(3-chloro-3H-indol-3-yl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoate

【CA登记号】

【 分 子 式 】C20H15ClN2O4

【 分 子 量 】382.80288

【元素组成】C 62.75% H 3.95% Cl 9.26% N 7.32% O 16.72%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(II)

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:(II)

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
Extended Information