Terprenin
Chemical Name: 3',6'-Dimethoxy-4-(3-methyl-2-butenyloxy)-p-terphenyl-2',3,4''-triol
CAS No. 197899-11-9
项目整合开发状态: Preclinical
项目研究机构: Shionogi (Originator)
合成路线:1.The Suzuki coupling of arylboronic acid (I) with 3-bromo-2,5-dimethoxybenzaldehyde (II) with concomitant desilylation provided biphenyl aldehyde (III).After protection of the phenolic hydroxyl as the mesylate (IV),selective bromination of (IV) in the presence of NaOAc in AcOH provided bromoaldehyde (V).A Baeyer-Villiger oxidation of the aldehyde group of (V) with m-chloroperbenzoic acid,followed by acid hydrolysis of the intermediate formate ester,produced phenol (VI).which was coupled with protected boronic acid (VII) in the presence of Pd(PPh3)4 to yield terphenyl (VIII).Mesylation of the hydroxyl groups of (VIII) and further hydrogenolytic cleavage of the benzyl ether gave phenol (X).Then,alkylationof (X) with prenyl bromide (XI) provided prenyl ether (XII).The mesylate groups of (XII) were finally removed by hydrolysis with KOH to furnish the title compound.
合成路线:2.In an alternative synthesis,5-bromosalicylaldehyde (XIII) was alkylated with bromoacetaldehyde dimethyl acetal (XIV) to afford ether (XV).Further Baeyer-Villiger reaction with (XV) produced phenol (XVI),which was cyclized to the benzodioxine (XVII) with p-TsOH.Lithiation of (XVII),followed by reaction with triisopropyl borate and hydrolytic work-up,gave boronic acid (XVIII).Aldehyde (II) was treated with MCPBA yielding phenol (XIII),which was iodinated in the presence of tert-butylamine to give the bromo iodo derivative (XIV).Sequential Suzuki coupling of bromo iodo compound (XIV) with boronic acid (XVIII) yielding (XIX),and then with boronic acid (I) provided terphenyl (XX).Hydrolysis of the methyl acetal of (XX) using p-TsOH gave cyclic hemiacetal (XXI).Finally,Wittig reaction of (XXI) with the phosphorane prepared from isopropyl triphenylphosphonium iodide and n-BuLi provided the title compound.
📌 参考资料/链接：
参考文献标题:Total synthesis of terprenin,a novel immunosuppressive p-terphenyl derivative
文献作者:Yonezawa,S.; Komurasaki,T.; Kawada,K.; Tsuri,T.; Fuji,M.; Kugimiya,A.; Haga,N.; Mitsumori,S.; Inagaki,M.; Nakatani,T.; Tamura,Y.; Takechi,S.; Taishi,T.; Ohtani,M.
参考来源:J Org Chem 1998,63(17),5831
📄 详细内容
合成路线:1.The Suzuki coupling of arylboronic acid (I) with 3-bromo-2,5-dimethoxybenzaldehyde (II) with concomitant desilylation provided biphenyl aldehyde (III).After protection of the phenolic hydroxyl as the mesylate (IV),selective bromination of (IV) in the presence of NaOAc in AcOH provided bromoaldehyde (V).A Baeyer-Villiger oxidation of the aldehyde group of (V) with m-chloroperbenzoic acid,followed by acid hydrolysis of the intermediate formate ester,produced phenol (VI).which was coupled with protected boronic acid (VII) in the presence of Pd(PPh3)4 to yield terphenyl (VIII).Mesylation of the hydroxyl groups of (VIII) and further hydrogenolytic cleavage of the benzyl ether gave phenol (X).Then,alkylationof (X) with prenyl bromide (XI) provided prenyl ether (XII).The mesylate groups of (XII) were finally removed by hydrolysis with KOH to furnish the title compound.
合成路线:2.In an alternative synthesis,5-bromosalicylaldehyde (XIII) was alkylated with bromoacetaldehyde dimethyl acetal (XIV) to afford ether (XV).Further Baeyer-Villiger reaction with (XV) produced phenol (XVI),which was cyclized to the benzodioxine (XVII) with p-TsOH.Lithiation of (XVII),followed by reaction with triisopropyl borate and hydrolytic work-up,gave boronic acid (XVIII).Aldehyde (II) was treated with MCPBA yielding phenol (XIII),which was iodinated in the presence of tert-butylamine to give the bromo iodo derivative (XIV).Sequential Suzuki coupling of bromo iodo compound (XIV) with boronic acid (XVIII) yielding (XIX),and then with boronic acid (I) provided terphenyl (XX).Hydrolysis of the methyl acetal of (XX) using p-TsOH gave cyclic hemiacetal (XXI).Finally,Wittig reaction of (XXI) with the phosphorane prepared from isopropyl triphenylphosphonium iodide and n-BuLi provided the title compound.
参考文献标题:Terprenins,novel immunosuppressants produced by Aspergillus candidus
文献作者:Kamigauchi,T.; Sakazaki,R.; Nagashima,K.; Kawamura,Y.; Yasuda,Y.; Matsushima,K.; Tani,H.; Takahashi,Y.; Ishii,K.; Suzuki,R.; Koizumi,K.; Nakai,H.; Ikenishi,Y.; Terui,Y.
参考来源:J Antibiot 1998,51(4),445