NOVEL APPROACHES TO ANTITUMOR AND ANTIVIRAL AGENTS

这个项目的目的是开发进化的新化学原理。 前所未有的策略来解决创造分子的问题 重要的抗肿瘤药物、肿瘤化合物的结构 促进剂和抗病毒剂。通过实施反应性控制 过渡金属，特别是Pd，在pi-烯丙基体系上可能有大量的 在不同类别的化合物中的含义。首批目标将是 核苷及其碳环类似物。一种新的概念 使用双金属体系的羟甲基化可能会引入几乎 无处不在的羟甲基侧链。实用的不对称合成 碳环系统将包括奈普诺星、卡维韦、BCA和 环丙沙星。将这一概念外推到核苷可以针对一个 由AZT、DDI、DDDC、D4A、咪唑宾、法扎拉滨、 大黄素和米可霉素Z，每一种都是为了突出 这种新奇化学的不同特征。一个新的推动力探索了 形成具有异常氨基酸的环肽对生物多样性的适用性 充分利用宏观环化的效率，如 抗肿瘤药物，胶质结合蛋白。形成异常的偏好 环的大小将针对丝裂霉素模拟物FR900482进行探索。 紫杉烷家族的一种策略可能会从催化钯的简易性中浮现出来 先是大环化，然后是跨环环化。一种新型的Pd催化剂 大环化过程可能会创造一种新的战略 新卡西诺他汀。 一种新的环异构化概念--Pd催化环化 α，omega-enynes。测试其化学选择性及其机会 对于不对称诱导靶标的生物碱，蓖麻碱和 有丝分裂素类和表鬼臼毒素突出的木脂素类化合物。一个 对于后者来说，令人难以置信的简短综合可能来自于 一个伴生过程--钯催化烷基化烯炔的环化反应。 环异构化反应及相关的钯催化的烯炔环还原反应 开启了一种新型萜类抗肿瘤药物的战略 包括非那奇霉素、皂苷和FR111142，它们检测到 这一新工艺的区域和对映体选择性的重要方面。 Pd(O)催化的烯炔异构体的开发为 桥头双人大环桥自行车的合成 债券。测试功能并置的多功能性可以 为代表的不同成员制定有效的战略，顺序如下 不断增加的复杂性，由玫瑰红素，莽草素和紫杉醇组成。真实的 在对合成方法进行测试之前，不能对其进行判断 战场“--一个复杂的合成目标。 抗病毒和抗肿瘤药物带来的挑战具有高度的代表性 对它们的使用进行了有意义的测试。

The aim of this project is to develop new chemical principles that evolve into unprecedented strategies to solve problems of creating molecular architecture of compounds of importance as antitumor agents, tumor promoters and antiviral agents. The imposition of reactivity control by transition metals, especially Pd, on pi-allyl systems may have vast implications in diverse classes of compounds. The first targets will be nucleosides and their carbocyclic analogues. A new concept for hydroxymethylation using a double metal system may introduce the almost omnipresent hydroxymethyl side chain. Practical asymmetric syntheses of carbocyclic systems will include neplanocin, carbovir, BCA and cyclaradine. extrapolation of this concept to nucleosides can target a broad array illustrated by AZT, DDI, DDDC, d4A, mizoribine, fazarabine, chryscandin and mikkomycin Z, each of which is chosen to highlight a different feature of this novel chemistry. A new thrust explores the applicability of forming cyclic peptides possessing unusual amino acids to capitalize on the efficiency of macrocyclizations as illustrated by the antitumor agents, the glidobactins. Preferences for formation of unusual ring sizes will be explored directed towards the mitomycin mimic FR900482. A strategy for the taxane family may emerge from the ease of Pd catalyzed maorocyclization followed by transannular cyclization. A new Pd catalyzed macrocyclization process may create a novel strategy toward neocarzinostatin. A new concept for cycloisomerization invokes the Pd catalyzed cyclization of alpha, omega-enynes. Testing its chemoselectivity and its opportunity for asymmetric induction targets the alkaloids castanaspermine and mitomycins and the lignans highlighted by epipodophyllotoxin. An incredibly short synthesis to the latter may emerge from the creation of a companion process - Pd catalyzed alkylative enyne cyclization. Cycloisomerization and a related Pd catalyzed cycloreduction of enynes opens the strategy to a novel class of terpenoid antitumor agents including phenazinomycin, saponaceolide, and FR111142 which examine important aspects of regio- and enantioselectivity of this new process. The development of a Pd(O) catalyzed enyne metatheses opens an avenue for the synthesis of large ring bridge bicycles possessing bridgehead double bonds. Testing the versatility of the juxtaposition of functionality may lead to effective strategies for diverse members represented, in order of increasing complexity, by roseophilin, shikodomedin and taxol. The true mettle of synthetic methods cannot be judged until it is tested in "the field of battle" - a complex synthetic target. The diversity of the challenges posed by antiviral and antitumor agents represent highly meaningful tests of their use.