Novel Approaches to Antitumor and Antiviral Agents

抗肿瘤和抗病毒药物的治疗重要性需要继续努力，以确定更好的合成策略。选择以这种生物活性闻名的一类化合物作为目标，该项目开发了新的化学原理，这些原理可能演变为创建这种分子结构的史无前例的策略。由钯和钼衍生的催化剂上的不对称烯丙基烷基化反应需要重新考虑合成策略，但也带来了前所未有的潜力。开发新的范例使核苷摆脱对碳水化合物原料的依赖，真正有可能简化和简化合成，以同样容易的方式提供两种对映体系列，并允许获得不寻常的类似物。这种化学方法可以使碳环类似物像呋喃类化合物一样容易获得。一种影响糖基化的新方法可能提供以星形孢子素、K252a和吲哚卡巴佐菌素为代表的第一个非对映控制系统。利用串联的钯催化过程，第一个过程是不对称烯丙基烷基化，通过一个新的类别提供了进入不同结构的途径，如呋喃喹诺酮、大环如耳霉素和糖苷酶抑制剂，布鲁森内酯可能有助于确定蛋白质靶标以及导致新的治疗方法。了解像佛波醇这样的促癌剂的现象，将源于能够接触到像卡拉马糖酸这样的抑制这种作用的药物。根据金属催化的分子间和分子内加成反应的概念，创建了一系列新的反应，从而产生了几个新的战略见解。基于Ru催化的烯型反应，对一类日益增长的高活性试剂--两性内酯进行逆合成分析，可以以高度收敛、高效和简单的方式进行。将炔-烯烃偶联与钯催化的不对称烯丙基烷基化反应相结合，为合成新型14元大环内酯化合物Callipeltoside打开了机会，该化合物可抑制人类非小肺癌的增殖，并保护感染HIV病毒的细胞。通过对钯催化剂的改性，将烯烃-烯烃类反应转变为一种新的歧化反应过程。这种新的化学提供了桥联大环化合物的途径，如新亚油酸，一种新型的吉马兰内酯倍半萜，表现出良好的抗肿瘤活性。通过获得一系列非常多样化的结构类型，发现新的治疗剂的最佳机会出现了。

The therapeutic importance of antitumor and antiviral agents requires a continued effort to define better synthetic strategies. Choosing classes of compounds known for this type of biological activity as targets, this project develops new chemical principles that may evolve into unprecendented strategies for creating such molecular architectures. Asymmetric allylic alkylation with catalysts derived from palladium and molybdenum requires a rethinking of synthetic strategy, but also brings unprecedented potential power. Developing new paradigms for making nucleosides free of a dependence on carbohydrate starting materials has the real prospect of simplifying and streamlining syntheses, providing either enantiomeric series with equal ease, and allowing access to unusual analogues. This chemistry can make carbocyclic analogues as easily available as the furanose ones. A novel way to effect glycosylations may provide the first diastereocontrolled systems represented by staurosporine, K252a, and indocarbazostatin. Using tandem palladium catalyzed processes, the first one of which is an asymmetric allylic alkylation provides an entry to such diverse structures as the furaquinocins, macrocycles like cochleamycin, and glycosidase inhibitors by a new class, the broussonetines which may help to define protein targets as well as lead to new therapies. Understanding the phenomena of tumor promoting agents like phorbol will derive from having access to agents like karamatsuic acid which inhibits such actions. Creation of a family of new reactions derived from the concept of metal catalyzed inter-and intramolecular addition reactions leads to several new strategic insights. Based upon a Ru catalyzed ene type reaction, retrosynthetic analysis of a number of a growing class of highly active agents, the amphidinolides, may be broached in a highly convergent, efficient and simple fashion. Wedding the alkyne-alkene coupling to a palladium catalyzed asymmetric allylic alkylation opens the opportunity to the novel 14-membered macrolide, callipeltoside, which inhibits proliferation of human non-small lung carcinoma as well as protect cells infected with the HIV virus. Modifications of the palladium catalyst shifts the alkyne-alkene ene-type reaction into a novel metathesis process. This new chemistry provides access to bridged macrobicyclics as illustrated by neoliacinic acid, a new type of germacranolide-sesquiterpene exhibiting good antitumor activity. By accessing a very diverse range of structural types, the best opportunities to discover new therapeutic agents arise.