Novel heterocyclic methodologies and total syntheses

具有药用价值的生物活性化合物的合成是一个持续的挑战，对于寻找疾病和其他医院感染的新治疗方法至关重要。大多数化合物显示出对这些病理的生物学特性，具有杂环或多环骨架，如文多灵（抗癌药物长春碱的重要亚基）以及其他相关生物碱。不幸的是，这些产品的天然量通常很低，需要破坏生态系统才能为患者提供治疗。因此，支持基础研究以发现新的合成工具来快速生产这些结构的主要核心及其潜在类似物是极其重要的。在这种情况下，本提案中提出的研究计划将分为两个不同的互补部分，致力于开发新的环境方法，使杂环基序的快速形成及其在生物活性天然产物全合成中的直接应用。 我们想扩展我们的研究计划，高价碘化学开发新的应用，如不对称脱芳[2+3]环加成过程，使来自石油的芳香族核心的多环吲哚啉亚基的形成。我们将开发一种氧化脱芳烃Diels-Alder（和相关的环加成过程），将允许简单的芳烃转化为含有季碳中心的官能化多环系统。 我们还设想将这种策略应用于吲哚，以产生新的有趣的功能化结构。 此外，进一步的策略，我们以前的研究计划涉及碘烷将被描述为生产复杂的生物碱，如文多灵，deethylibophylidine，等。 我们还将在我们的实验室中开发一种新的专业知识，基于我们有希望的结果来开发功能性保护基团。事实上，我们的目标是改变保护基方法，其不仅是官能度调节剂，而且是所需靶标的最终部分，其可以在脱保护步骤期间通过Truce-Smiles重排并入，其将通过气体逸出仅释放二氧化硫作为副产物。这种策略应迅速导致吲哚和吲哚啉亚基和它们的直接应用在生物活性化合物，如他勃松宁或aspidospermidine的全合成，以说明这种环境友好的方法的潜力。

Synthesis of bioactive compounds of pharmaceutical interests represents a continuing challenge and is crucial for finding new treatments for diseases and other nosocomial infections. Most of the compounds demonstrating biological properties against these pathologies possess a heterocyclic or a polycyclic skeleton such as vindoline (an important subunit of the anticancer drug vinblastine) as well as others related alkaloids. Unfortunately, the natural amount of these products is generally low and would require damaging an ecosystem to provide treatments to patients. Consequently, it is extremely important to support fundamental research to discover new synthetic tools to produce the main core of these structures quickly as well as their potential analogs. In this context, the research program presented in this proposal will be divided into two different and complementary parts dedicated to the development of novel environmental methodologies enabling the rapid formation of heterocyclic motifs and their direct applications in total synthesis of bioactive natural products. We would like to extend our research program on hypervalent iodine chemistry to develop novel applications such as an asymmetric dearomatizing [2+3] cyclo-addition process enabling the formation of polycyclic indoline subunits from aromatic cores derived from petroleum. We will develop an oxidative dearomatizing Diels-Alder (and related cycloaddition processes) that would allow transforming simple aromatics into functionalized polycyclic systems containing a quaternary carbon center. We also envisage applying this strategy to indoles to produce new interesting functionalized structures. In addition, further strategies to our previous research program involving iodanes will be described to produce complex alkaloids such as vindoline, deethylibophylidine, etc. We will also develop a new expertise in our laboratory based on our promising results to develop a functional protecting group. Indeed, we aim to change the protecting group approach, which would not be only a functionality modulator but also a final moiety of the desired target that could be incorporated during the deprotecting step via a Truce-Smiles rearrangement that would release only sulfur dioxide as a byproduct by gas evolution. This strategy should rapidly lead to indole and indoline subunits and their direct applications in total synthesis of bioactive compounds such as tabersonine or aspidospermidine to illustrate the potential of this environmentally friendly approach.