Aromataic ring umpolung: developments and key applications in total synthesis of several natural products

合成具有药用价值的新生物活性化合物是一项持续的挑战，对于寻找癌症、心血管疾病和其他医院感染的新疗法至关重要。大多数显示出对这些疾病有用的生物学特性的化合物具有杂环或多环骨架，如强的松、考兰烷衍生物、奈布林、芬德莱定、莱科flexine、东莨菪酸、桂烯酮或hispidospermidin。不幸的是，这些产品的天然含量通常很低，并且需要破坏生态系统才能为患者提供治疗。因此，开发新的合成方法来快速获得这些结构是非常重要的。在此背景下，本提案中提出的研究计划致力于开发符合umpolung概念的新方法，并涉及对环境无害的高价碘试剂。在第一部分中，我们建议开发前所未有的由烯醇醚介导的氧化碳-碳形成，一种不对称催化过程来有效地去对称前手性二烯酮系统或一种氧化多环化方法来快速获得复杂的结构。这些方法都符合“绿色化学”的理念。这些转化的目的是获得有价值的支架，可以快速用于天然产物的全合成。在第二部分中，我们计划实现一些列举的目标的合成，它们的化学结构可以用我们的方法快速复制。本研究项目提供的结果应有助于知识的进步，通过发现不同的新方法应用于生物活性产品的直接合成。生成的大多数结构都可以用于药物开发测试。此外，通过该计划培训的学生可能会为具有健康益处潜力和中长期加拿大工业影响的突破性研究做出贡献。

Synthesis of new bioactive compounds of pharmaceutical interest represents a continuing challenge and is crucial for finding new treatments for cancer, cardiovascular diseases and other nosocomial infections. Most of the compounds demonstrating useful biological properties against these diseases possess a heterocyclic or a polycyclic skeleton such as prednisone, kaurane derivatives, neblinine, fendleridine, lycoflexine, scopaldulcic acid, laurencenone or hispidospermidin. Unfortunately, the natural amount of these products is generally low and would require damaging an ecosystem to provide treatment to patients. Consequently, it is extremely important to develop new synthetic methods to obtain these structures quickly. In this context, the research program presented in this proposal is dedicated to the development of novel methodologies fitting within the umpolung concept and involving environmentally benign hypervalent iodine reagents. In a first part, we propose to develop unprecedented oxidative carbon-carbon formations mediated from enol-ethers, an asymmetric catalytic process to desymmetrize efficiently prochiral dienone systems or an oxidative polycyclisation method for the rapid access of elaborated structures. These methods are in agreement with the concept of "green chemistry". The aim of these transformations is to get valuable scaffolds that could be rapidly used in total synthesis of natural products. In a second part, we plan to achieve the synthesis of some of the enumerated targets, whose chemical structures could be quickly reproduced with our methodologies. Results afforded by this research programme should contribute to the knowledge advancement by the discovery of different novel methodologies applied to the direct synthesis of bioactive products. Most of the structures generated could be tested for pharmaceutical developments. In addition, students trained through this program are likely to contribute to ground breaking research with health benefit potential and medium- to long-term Canadian industrial impact.