OM-99-2

Chemical Name: L-Glutamyl-L-valyl-L-asparaginyl-L-leucyl-psi[(S)-CH(OH)CH2]-L-alanyl-L-alanyl-L-glutamyl-L-phenylalanine; L-Glutamyl-L-valyl-L-asparaginyl-(2R,4S,5S)-5-amino-4-hydroxy-2,7-dimethyloctanoyl-L-alanyl-L-glutamyl-L-phenylalanine
项目整合开发状态: Preclinical
项目研究机构: University of Illinois (Originator), University of Oklahoma Health Sci. Cent. (Originator)
合成路线:Boc-Leucine (I) was converted to Weinreb amide (II) by activation with isobutyl chloroformate and N-methylpiperidine,followed by treatment of the resulting mixed anhydride with N,O-dimethylhydroxylamine.Reduction of (II) with LiAlH4 provided the aldehyde (III),which was condensed with the lithium anion of ethyl propiolate (IV) to furnish the acetylenic alcohol (Va-b) as an inseparable mixture of diastereomers.Catalytic hydrogenation of the triple bond of (Va-b) over Pd/BaSO4,followed by acid-catalyzed lactonization of the resulting hydroxy ester provided the diastereomeric mixture of gamma-lactones (VIa-b).After separation by column chromatography,alkylation of the desired isomer employing iodomethane and lithium hexamethyldisilazide at -78 C provided the desired alpha-methyl lactone (VII),along with a small amount of the corresponding epimer.Lactone (VII) hydrolysis using LiOH gave hydroxy acid (VIII),which was further protected as the silyl ether (IX) with tert-butyldimethylsilyl chloride and imidazole.The Boc protecting group of (IX) was selectively removed by treatment with trifluoroacetic acid in CH2Cl2 at 0 C,and the resulting amine (X) was treated with Fmoc-succinimide to provide the Fmoc-protected intermediate (XI).

合成路线:Preparation of the title compound was carried out by solid-phase peptide synthesis,starting from Wang resin bounded to N-Fmoc-phenylalanine (XII).Removal of the Fmoc group of (XII) with piperidine in DMF provided phenylalanine-resin (XIII),which was subsequently coupled with N-Fmoc-glutamic acid gamma-tert-butyl ester (XIV) in the presence of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 1-hydroxybenzotriazole (HOBt).Cleavage of the Fmoc group from the resulting protected dipeptide-resin furnished (XV).Sequential coupling-deprotection cycles with N-Fmoc-alanine (XVI),intermediate (XI) and Nalpha-Fmoc-Nbeta-trityl-asparagine (XIX) furnished the peptide resins (XVII),(XVIII) and (XX),respectively.(Scheme 28685901b).

合成路线:Coupling-deprotection cycle with N-Fmoc-valine (XXI) furnished the peptide resin (XXII).Finally,removal of the side-chain protecting groups and cleavage from the resin by means of 95% trifluoroacetic acid yielded the title compound (Scheme 28685901c).

合成路线:Boc-Leucine (I) was converted to Weinreb amide (II) by activation with isobutyl chloroformate and N-methylpiperidine,followed by treatment of the resulting mixed anhydride with N,O-dimethylhydroxylamine.Reduction of (II) with LiAlH4 provided the aldehyde (III),which was condensed with the lithium anion of ethyl propiolate (IV) to furnish the acetylenic alcohol (Va-b) as an inseparable mixture of diastereomers.Catalytic hydrogenation of the triple bond of (Va-b) over Pd/BaSO4,followed by acid-catalyzed lactonization of the resulting hydroxy ester provided the diastereomeric mixture of gamma-lactones (VIa-b).After separation by column chromatography,alkylation of the desired isomer employing iodomethane and lithium hexamethyldisilazide at -78 C provided the desired alpha-methyl lactone (VII),along with a small amount of the corresponding epimer.Lactone (VII) hydrolysis using LiOH gave hydroxy acid (VIII),which was further protected as the silyl ether (IX) with tert-butyldimethylsilyl chloride and imidazole.The Boc protecting group of (IX) was selectively removed by treatment with trifluoroacetic acid in CH2Cl2 at 0 C,and the resulting amine (X) was treated with Fmoc-succinimide to provide the Fmoc-protected intermediate (XI).

合成路线:Preparation of the title compound was carried out by solid-phase peptide synthesis,starting from Wang resin bounded to N-Fmoc-phenylalanine (XII).Removal of the Fmoc group of (XII) with piperidine in DMF provided phenylalanine-resin (XIII),which was subsequently coupled with N-Fmoc-glutamic acid gamma-tert-butyl ester (XIV) in the presence of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 1-hydroxybenzotriazole (HOBt).Cleavage of the Fmoc group from the resulting protected dipeptide-resin furnished (XV).Sequential coupling-deprotection cycles with N-Fmoc-alanine (XVI),intermediate (XI) and Nalpha-Fmoc-Nbeta-trityl-asparagine (XIX) furnished the peptide resins (XVII),(XVIII),(XX),(XXII) and (XXIII),respectively.(Scheme 28686001b).

合成路线:Sequential coupling-deprotection cycles with N- N-Fmoc-valine (XXI),and N-Fmoc-glutamic acid gamma-tert-butyl ester (XIV) furnished the peptide resins (XXII) and (XXIII),respectively.Finally,removal of the side-chain protecting groups and cleavage from the resin by means of 95% trifluoroacetic acid yielded the title compound.) (Scheme 28686001c)