Natural Product Synthesis and Development of Synthesis-Enabling Methodologies

天然产物的合成和合成方法的开发

• 批准号: RGPIN-2020-05909
• 负责人: Boukouvalas, John
• 金额: $ 1.75万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748655
• 关键词: Natural; Product; Synthesis; Development; Enabling

The ability to synthesize organic molecules rapidly and efficiently is inextricably linked to the success of R&D efforts and sustained profitability in the pharmaceutical, agrochemical and fine-chemical industries. Natural products have been refined over millions of years for biological interactions, and as such, they represent an unsurpassed source of life-saving drugs and drug leads. However, their limited availability from the natural source can hamper biological assessment. This is particularly common for compounds isolated from unculturable microbes and marine organisms, where recollection is often problematic or impossible. In such cases, chemical synthesis is the only option for supplying the material needed for pharmacological investigation. A practical and flexible synthesis can also serve as a blueprint for generating custom-designed analogues of superior therapeutic performance. Hence, the prime objective of our research is to develop new methods and strategies enabling rapid and efficient access to natural products of biological importance. Our target molecules include the marine terpenoids niphateolide A (anticancer) and hippolide J (antifungal), which have yet to succumb to chemical synthesis, and fungal butenolides such as aurantricholides A-B that have eluded biological investigation due to their scarcity in nature and inefficiency of their current synthesis (<1% yield). These molecules instill unique synthetic challenges, providing a strong impetus to invent new methodologies and expand upon the discoveries and creative contributions of my talented co-workers. The goal is to achieve maximum increase in target-relevant complexity while minimizing step count, cost and chemical waste. One way of accomplishing this is through strategic implementation of reaction cascades and one-pot procedures. Reaction cascades allow two or more bond-forming transformations to be performed under the same conditions sequentially without the need for work-up and product isolation between successive synthesis steps. Besides improving efficiency, this approach makes the synthesis substantially greener as it reduces the amount of solvents used in the synthesis, work-up and product isolation, and contaminated aqueous waste generated from cleaning equipment and glassware. The proposed research will have application in the synthesis of a variety of other biologically important natural products and small molecules. Collaborations are in place to evaluate the synthesized compounds as antimicrobial, anticancer and herbicidal agents. In the long term, this research may have an impact on the discovery of new healing drugs and agrochemicals. The target oriented nature of the work ensures that students will acquire broad-based training in organic synthesis and invaluable problem-solving skills. Such skills and expertise are of paramount importance to the rapidly growing pharmaceutical industry in Canada.

快速高效合成有机分子的能力与制药、农用化学品和精细化学品行业研发工作的成功和持续盈利能力密不可分。天然产品已经经过数百万年的生物相互作用，因此，它们代表了拯救生命的药物和药物先导物的无与伦比的来源。然而，它们从自然来源的有限供应可能会妨碍生物评估。这对于从不可培养的微生物和海洋生物中分离出的化合物尤其常见，在这些化合物中，回忆通常是有问题的或不可能的。在这种情况下，化学合成是提供药理学研究所需材料的唯一选择。一个实用和灵活的合成也可以作为一个蓝图，用于产生定制设计的类似物的上级治疗性能。 因此，我们研究的主要目标是开发新的方法和策略，使人们能够快速有效地获得具有生物重要性的天然产品。我们的目标分子包括海洋萜类化合物niphateolide A（抗癌）和hippolide J（抗真菌），它们还没有屈服于化学合成，以及真菌丁烯内酯，如aurantricholides A-B，由于它们在自然界中的稀缺性和目前合成的效率（<1%产率），它们逃避了生物学研究。这些分子带来了独特的合成挑战，为发明新方法提供了强大的动力，并扩大了我才华横溢的同事们的发现和创造性贡献。目标是最大限度地增加目标相关的复杂性，同时最大限度地减少步骤数、成本和化学废物。实现这一目标的一种方法是通过战略实施反应级联和一锅法。反应级联允许在相同条件下顺序地进行两个或更多个成键转化，而不需要在连续合成步骤之间进行后处理和产物分离。除了提高效率外，这种方法还使合成基本上更绿色，因为它减少了合成、后处理和产物分离中使用的溶剂的量，以及清洁设备和玻璃器皿产生的受污染的水性废物。 这项研究将应用于合成各种其他生物学上重要的天然产物和小分子。正在进行合作，以评估合成的化合物作为抗菌剂、抗癌剂和除草剂。从长远来看，这项研究可能会对发现新的治疗药物和农用化学品产生影响。 工作的目标导向性，确保学生将获得有机合成和宝贵的解决问题的技能基础广泛的培训。这些技能和专业知识对加拿大迅速发展的制药业至关重要。