Deoxynegamycin, VRC-3573
Chemical Name: 2-[2-[3(R),6-Diaminohexanoyl]-1-methylhydrazino]acetic acid; 3(R),6-Diaminohexanoic acid 2-(carboxymethyl)-2-methylhydrazide
CAS No. 58773-33-4
项目整合开发状态: Preclinical
项目研究机构: Vicuron Pharmaceuticals (Originator)
合成路线:Protection of (R)-beta-lysine (I) by means of benzyl S-(4,6-dimethylpyrimidin-2-yl)thiol carbonate (II) affords the bis-(benzyloxycarbonyl) derivative (III).After activation of the carboxyl group of (III) as the corresponding succinimidyl ester (IV),its coupling with 1-methylhydrazinoacetic acid (V) furnishes hydrazide (VI).The benzyloxycarbonyl protecting groups of (VI) are finally removed by catalytic hydrogenolysis to provide the title compound.
合成路线:In a different procedure,starting from negamycin (I),protection with benzyl S-(4,6-dimethylpyrimidin-2-yl)thiol carbonate (II) yields the bis-(benzyloxycarbonyl) derivative (III).Subsequent esterification of acid (III) employing diazomethane leads to methyl ester (IV).The free hydroxyl group of (IV) is then converted to the mesylate (V) by means of methanesulfonyl chloride in cold pyridine.Further mesylate group displacement in (V) with NaI gives rise to the alkyl iodide (VI).Finally,simultaneous cleavage of the N-carbobenzoxy groups and iodide hydrogenolysis in (VI) is accomplished by hydrogenation in the presence of Pd/BaCO3.
📌 参考资料/链接：
参考文献标题:delta-Substd.negamycin derivs.and syntheses
文献作者:Umezawa,H.; Kondo,S.(Microbial Chemistry Research Foundation)
参考来源:US 4065495
📄 详细内容
合成路线:In a closely related method,N5-(benzyloxycarbonyl)-N2-Boc-(R)-ornithine (I) is coupled to diazomethane,via activation with isobutyl chloroformate,to afford the diazo ketone (II).Rearrangement of (II) in the presence of silver benzoate gives the beta-lysine derivative (III).After saponification of the methyl ester (III),the resultant carboxylic acid (IV) is coupled to benzyl 1-methylhydrazinoacetate (V) yielding hydrazide (VI).Hydrogenolysis of the N-carbobenzoxy groups of (VI) provides the Boc-protected precursor (VII),which is finally deprotected to the title compound under acidic conditions.
参考文献标题:Conformationally restricted analogs of deoxynegamycin
文献作者:Raju,B.; Anandan,S.K.; Gu,S.; et al.
参考来源:42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002,San Diego) 2002,Abst F-1684
合成路线:In an alternative method,N,N'-bis-(benzyloxycarbonyl)-(R)-ornithine (I) is treated with PCl5 to afford the corresponding acid chloride,which is then converted to diazo ketone (II) with ethereal diazomethane.Rearrangement of (II) under Arndt-Eistert conditions in the presence of silver benzoate leads to the beta-lysine derivative (III).After saponification of the methyl ester (III),the resultant carboxylic acid (IV) is coupled to ethyl 1-methylhydrazinoacetate (V) via the mixed anhydride with isobutyl chloroformate,to give hydrazide (VI).Alkaline hydrolysis of the ethyl ester (VI) yields acid (VII).The N-carbobenzoxy groups are finally removed by hydrogenolysis to furnish the title compound.
参考文献标题:The synthesis of deoxynegamycin and some related compounds
文献作者:Curran,W.V.; Boothe,J.H.
参考来源:J Antibiot 1978,31(9),914