Natural Product Synthesis and Development of Synthesis-Enabling Methodologies

快速有效地合成有机分子的能力与制药、农化和精细化工行业研发工作的成功和持续盈利密不可分。经过数百万年的生物相互作用，天然产品得到了提炼，因此，它们是救命药物和药物先导的无与伦比的来源。然而，它们从自然来源获得的有限可能会阻碍生物学评估。这对于从不可培养的微生物和海洋生物中分离出来的化合物尤其常见，在这些生物中，回忆往往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，以产生定制设计的类似物的卓越治疗性能。因此，我们研究的主要目标是开发新的方法和战略，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hipolde J(抗真菌)，它们尚未屈服于化学合成，以及真菌Butenolide，如Auantricholes A-B，由于它们在自然界中的稀缺性和目前合成效率低下(&lt；1%)而逃脱了生物学研究。这些分子注入了独特的合成挑战，提供了强大的动力来发明新的方法，并扩大了我有才华的同事的发现和创造性贡献。其目标是最大限度地增加与目标相关的复杂性，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性地实施反应级联和一锅法。反应级联允许在相同的条件下连续进行两个或多个成键转化，而不需要在连续的合成步骤之间进行加工和产物分离。除了提高效率外，这种方法还使合成更加环保，因为它减少了合成、加工和产品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含水废物。这项拟议的研究将在合成各种其他具有重要生物意义的天然产物和小分子方面得到应用。目前正在进行合作，以评估合成的化合物是否为抗菌、抗癌和除草剂。从长远来看，这项研究可能会对新的治愈药物和农用化学品的发现产生影响。这项工作的目标导向性质确保学生将获得广泛的有机合成培训和宝贵的解决问题的技能。这些技能和专业知识对加拿大快速发展的制药业至关重要。

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.