新型环六脂肽抗真菌剂全合成关键脂三肽片段的合成

Preparation of Key Lipotripeptide Segments for Total Synthesis of Novel Cyclohexalipopeptide Antifungal Agents

目的制备用于全合成新型卡泊芬净类环六脂肽抗真菌剂的关键脂三肽片段(4″-烷氧基-1,1:′4,′1″-三联苯-4-甲酰)-三肽(1)。方法以L-脯氨酸甲酯(4)为原料,经与N-叔丁氧羰基-L-苏氨酸(a)或N-叔丁氧羰基-L-缬氨酸(b)缩合、脱叔丁氧羰基后与Nα-(9-芴甲氧羰基)-Nδ-叔丁氧羰基-L-鸟氨酸缩合、脱9-芴甲氧羰基后与4″-烷氧基-1,1:′4,′1″-三联苯-4-甲酸-N-羟基苯并三氮唑"活泼酯"(Ⅰc~Ⅰg)缩合5步反应制备目标脂三肽1。结果以65.2%~85.4%的总收率合成了10个脂三肽lac^1ag和1b c^1bg,其结构经电喷雾质谱(ESI-MS)和氢谱(1H-NMR)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。

OBJECTIVE To prepare（4″-alkoxy-1,1′： 4′,1″-terphenyl-4-carbonyl）-tripeptides（1）,the key lipotripeptide segments for the total synthesis of novel caspofungin-like cyclohexalipopeptide antifungal agents.METHODS Starting from L-Pro-OMe（4）,the target compound lac^1ag and 1bc^1bg were prepared via 5 steps including condensation with Boc-L-Thr-OH（a） or Boc-L-Val-OH（b）,then deprotection of N-Boc,coupling with Nα-Fmoc-Nδ-Boc-L-Orn-OH followed by deprotection of Nα-Fmoc and reaction with 4″-alkoxy-1,1′：4′,1″-terphenyl-4-carboxylic acid N-hydroxybenzotriazole active ester（Ic^Ig）.RESULTS 10 target compound lac^1ag and 1bc^1bg were synthesized in an overall yield ranged from 65.2% to 85.4%.Their structures were confirmed by ESI-MS and 1H-NMR spectra.CONCLUSION The process has several advantages of facile reaction conditions,convenient operation and high yield.