SYNTHESIS OF ANTIMITOTIC NATURAL PRODUCTS

有许多天然和合成的化合物通过与微管结合而干扰微管功能。柯拉辛A是从加勒比海蓝藻Lyngbya Majuscula中分离得到的一种新型抗有丝分裂药物。不对称全合成是以高度立体控制的方式进行的。反应的关键步骤是(1)利用手性烯丙基钛试剂和双不对称Simmons-Smith环丙化反应引入三个手性中心；(2)Wittig和Wittig-Horner反应生成C(3-4)和C(7-10)烯烃；(3)将噻唑烷直接转化为噻唑啉。合成了四个噻唑啉部分结构的立体异构体，以确定其三个手性中心的绝对构型。此外，还合成了一系列古拉菌素A的侧链类似物，并考察了它们对体外微球聚合的影响。这些侧链类似物显示出微弱的或没有抗微管蛋白的活性，这表明咖喱素A的侧链受到微管蛋白的限制性识别。黑曲霉毒素D是从黑粉球的水提物中分离得到的次要成分，具有很强的抗微管蛋白活性。在这些化合物中发现的共同结构是13元核心结构，这似乎是负责抗微管蛋白活性的亚结构。通过还原除去黄曲霉毒素A的亚砜侧链，得到了合成其类似物的重要中间体--黄曲霉毒素D。酚羟基或甲氨基组的甲基化导致抗微管蛋白活性的消失。合成了无甘氨酸残基的鱼腥草素-乌司他辛类抗生素的新型类似物-13元环肽。

There are number of natural and synthetic compounds that interfere with microtubule function by binding to tubulim. Curacin A,isolated from a Caribbean cyanobacterium Lyngbya majuscula, was found to be a novel antimitotic agent. Asymmetric total synthesis of curacin A was performed in a highly stereo-controlled manner. The key steps were (1) an asymmetric allylation using a chiral allyltitanium reagent and a double-asymmetric Simmons-Smith cyclopropanation to introduce three chiral centers, (2) Wittig and Wittig-Horner reactions to construct the C(3-4) and C(7-10) alkenes, and (3) a direct conversion of the thiazolidine to thiazoline. The four stereoisomers of a partial structure at the thiazoline moiety were also synthesized to elucidate the absolute configurations of three chiral centers in curacin A.In addition, A series of side chain analogs of curacin A were synthesized and the effect to in vitro micritubule polymerization was examined. These side chain analogs showed weak or no anti-tubulin activity suggesting that the side chain of curacin A was restrictly recognized by microtubule proteins. Ustiloxin D,isolated as the minor component of ustiloxins from the water extract of false smut balls, exhibits potent anti-tubulin activity. The common structure found in these class of compounds is 13-membered core structure, which seems to be responsible substructure for anti-tubulin activity. Reductive removal of sulfoxide side chain of ustiloxin A gave ustiloxin D,an important intermediate for the symthesis of its analogs. Methylation of phenolic hydroxyl group or methylamino geoup resulted in disappearance of the antitubulin activity. The 13-membered cyclic peptides, novel analogs of phomopsin-ustiloxin class of antibiotics without glycine residue, were also synthesized.