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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。
Objective To prepare the key lipid tripeptide intermediate 4’-alkoxy-1,1’-biphenyl-4-carboxylate tripeptide which can be used in the synthesis of a new class of caspofungin class cyclo-lipopeptide antifungal agents. Methods L-proline tert-butyl ester was used as starting material and was sequentially coupled with N- (9-fluorenylmethoxycarbonyl) -L-threonine tert-butyl ether (a) or N- (9- fluorenylmethoxycarbonyl) L-serine t-butyl ether (b) is condensed, deprotecting N-protecting group followed by condensation with Nα- (9-fluorenylmethoxycarbonyl) -Nδ-benzyloxycarbonyl-L-ornithine, 4’-alkoxy-1,1’-biphenyl-4-carboxylic acid-N-hydroxybenzotriazole “active ester ” Results Eight lipopeptides, 1ae ~ 1ah and 1be ~ 1bh, were synthesized in a total yield of 67.4% ~ 80.0%. Their structures were confirmed by electrospray ionization mass spectrometry (ESI-MS) and elemental analysis. Conclusion The synthetic route has the advantages of mild reaction conditions, easy operation and high total yield.