RSL3中间体的简便合成
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摘要
以D-色氨酸为原料,通过酯化、Pictet-Spengler两步反应,简便有效地合成了RSL3的关键中间体——(1S,3R)-1-[4-(甲氧羰基)苯基]-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-3-羧酸甲酯盐酸盐。对Pictet-Spengler反应条件进行了考察。结果表明:当n(D-色氨酸甲酯盐酸盐)∶n(4-甲酰基苯甲酸甲酯)=1∶1.1、乙腈为反应溶剂,回流反应6 h,通过减压抽滤即可得到trans-构型产物(RSL3中间体),总收率为61.5%。产物及中间体经过~1HNMR、~1H-~1H NOESY和ESI-MS进行确认。
(1S,3R)-methyl-1-[(4-(methoxycarbonyl)phenyl)]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate hydrochloride,the key intermediate of RSL3,was synthesized by an efficient and practical method from D-tryptophan through a two-step reaction,involving esterification and Pictet-Spengler reaction.Pictet-Spengler reaction conditions for the synthesis of target product were investigated.The optimal conditions were obtained as follows:the molar ratio of D-tryptophan methyl ester hydrochloride to methyl 4-formylbenzoate was 1∶1.1,the mixture was stirred in acetonitrile and refluxed for 6 h.The trans-isomer(RSL3 intermediate)was obtained by suction filtration,with the total yield of 61.5%.The structures of the intermediate and final products were confirmed by ~1HNMR,~1H-~1H NOESY and ESI-MS.
(1S,3R)-methyl-1-[(4-(methoxycarbonyl)phenyl)]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate hydrochloride,the key intermediate of RSL3,was synthesized by an efficient and practical method from D-tryptophan through a two-step reaction,involving esterification and Pictet-Spengler reaction.Pictet-Spengler reaction conditions for the synthesis of target product were investigated.The optimal conditions were obtained as follows:the molar ratio of D-tryptophan methyl ester hydrochloride to methyl 4-formylbenzoate was 1∶1.1,the mixture was stirred in acetonitrile and refluxed for 6 h.The trans-isomer(RSL3 intermediate)was obtained by suction filtration,with the total yield of 61.5%.The structures of the intermediate and final products were confirmed by ~1HNMR,~1H-~1H NOESY and ESI-MS.
引文
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[2]We?wer M,Bittker J A,Lewis T A,et al.Development of small-molecule probes that selectively kill cells induced to express mutant RAS[J].Bioorganic&Medicinal Chemistry Letters,2012,22(4):1822-1826.
[3]Doll S,Proneth B,Tyurina Y Y,et al.ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition[J].Nature Chemical Biology,2017,13(1):91-98.
[4]D?chert J,Schoeneberger H,Rohde K,et al.RSL3 and Erastin differentially regulate redox signaling to promote Smac mimeticinduced cell death[J].Oncotarget,2016,7(39):63779-63792.
[5]Shintoku R,Takigawa Y,Yamada K,et al.Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3[J].Cancer Science,2017,108(11):2187-2194.
[6]Ma Yangmin(马养民),Li Yanchao(李延超),Yan Qianru(闫倩茹),et al.A new synthesis method of tetrahydro-β-carboline Diketopiperazine[J].Chemical World(化学世界),2012,53(3):165-168.
[7]Xiao S,Shi X X,Xing J,et al.Synthesis of tadalafil(Cialis)from L-tryptophan[J].Tetrahedron Asymmetry,2009,20(18):2090-2096.
[8]Stockwell B,Yang W S.Oncogenic-ras-signal dependent lethal compounds:US2010081654(A1)[P].2010.
[9]Wu C Y,Sun C M.Parallel synthesis of 1,2,3,4-tetrahydro-β-carbolines using microwave irradiation[J].Synlett,2002,(10):1709-1711.
[10]Dong J,Meng T Z,Shi X X,et al.Highly stereoselective transformation of(1S,3S)-cis-1,3-disubstituted tetrahydro-β-carbolines into(1S,3R)-trans-1,3-disubstituted tetrahydro-β-carbolines:an improved asymmetric synthesis of tadalafil from L-tryptophan[J].Tetrahedron:Asymmetry,2013,24(15/16):883-893.
[11]Meng T Z,Shi X X,Qu H Y,et al.Highly diastereoselective crystallization-induced asymmetric transformation of 1,3-disubstitutedtetrahydro-β-carbolines in water[J].Rsc Advances,2017,7(75):47753-47757.
[12]Ma Yangmin(马养民),Liu Bin(刘斌).Synthesis and characterization of heterocyclic amino acid esters[J].Science and Technology of Food Industry(食品工业科技),2011,32(1):187-189.
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