Novel heterocyclic methodologies and total syntheses

新型杂环方法和全合成

• 批准号: RGPIN-2016-05005
• 负责人: Canesi, Sylvain
• 金额: $ 2.62万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709479
• 关键词: Novel; heterocyclic; methodologies; total; syntheses

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.

合成具有药用价值的生物活性化合物是一项持续的挑战，对于寻找疾病和其他医院感染的新疗法至关重要。大多数具有抗这些病理生物学特性的化合物具有杂环或多环骨架，如长春碱（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，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的类似物是极其重要的。在此背景下，本提案中提出的研究计划将分为两个不同且互补的部分，致力于开发新的环境方法，使杂环基序能够快速形成，并直接应用于生物活性天然产物的全合成。