4'-烷氧基-1,1'-联苯-4-羧酸脂三肽的合成
Synthesis of 4'-alkoxy-1,1'-bisphenyl-4-carboxylic acid lipotripeptides
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摘要: 目的 制备用于全合成新型卡泊芬类环六脂肽抗真菌剂的关键脂三肽中间体4'-烷氧基-1,1'-联苯-4-羧酸脂三肽。 方法 以L-脯氨酸叔丁酯为原料,依次经与N-(9-芴甲氧羰基)-L-苏氨酸叔丁醚(a)或N-(9-芴甲氧羰基)-L-丝氨酸叔丁醚(b)缩合、脱N-保护基后与Nα-(9-芴甲氧羰基)-Nδ-苄氧羰基-L-鸟氨酸缩合、再脱Nα-保护基后与4'-烷氧基-1,1'-联苯-4-羧酸-N-羟基苯并三氮唑"活泼酯"(Ie~If)缩合5步反应制备目标脂三肽1。 结果 以67.4%~80.0%的总收率合成了8个脂三肽1ae~1ah和1be~1bh,其结构经电喷雾质谱(ESI-MS)和元素分析确证。 结论 该合成路线具有反应条件温和、操作简便、总收率高的优点。Abstract: Objective To prepare 4'-alkoxy-1,1'-bisphenyl-4-carboxylic acid lipotripeptides , which is the key intermediates for total synthesis of novel caspofungin-like cyclohexalipopeptide antifungal agents. Methods Starting from Pro-O-t-Bu , the target compound 1 were prepared via 5 steps including condensation with N-Fmoc-L-Thr(O-t-Bu)-OH (a) or N-Fmoc-L-Ser(O-t-Bu)-OH (b), then removed of N-Fmoc group and coupling with Nα-Fmoc-Nδ-Cbz-L-Orn-OH followed by removal of Nα-Fmoc group and reaction with 4'-alkoxy-1,1-4-carboxylic acid N-hydroxybenzotriazole ester (Ie~If). Results 8 target compounds 1ae~1af and 1be~1bf had been synthesized in an overall yield ranged from 67.4% to 80.0%. The structures were confirmed by ESI-MS spectra and elemental analysis. Conclusion The process developed had several adventages of facile reaction conditions, convenient workup and high yield.
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Key words:
- medicinal chemistry /
- synthesis /
- lipotripeptide /
- caspofungin /
- cyclohexalipopeptide /
- antifungal agent
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[1] Georgopapadakou NH. Update on antifungals targeted to the cell wall:focus on beta-1,3-glucan synthase inhibitors[J]. Expert Opin Invest Drugs, 2001, 10(2): 269. [2] 郑玉果,朱宝泉,陈代杰. 芬净类抗真菌抗生素的研究开发和临床应用[J]. 世界临床药物,2007, 28(2): 738. [3] Klein LL, Li L, Chen HJ, et al. Total synthesis and antifungal evaluation of cyclic aminohexapeptides[J]. Bioorg Med Chem, 2000, 8(7): 1677. [4] Journet M, Cai DW, DiMichele LM, et al. Semisynthesis of an antifungal lipopeptide echinocandin[J]. J Org Chem, 1999, 64(7): 2411. -
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