Gram-Scale Synthesis of Brevianamide Alkaloids.

随着我们全球人口的迅速增长，我们必须努力降低与生产有机物质、我们的药品、农用化学品和高科技材料相关的经济和环境成本。这个项目旨在模拟生物过程，努力改进我们制造这些非常重要的物质的方式。这类似于工程师在开发更好、更高效的飞机时如何从鸟类和其他飞行动物中获得灵感。通过这种“仿生”方法，我们将调查和了解大自然利用预先准备的、高度选择性的化学反应来快速构建复杂分子的高度复杂的方式。我们将通过合成从各种曲霉和青霉真菌中分离出来的次生代谢物--短胺生物碱来展示这种仿生策略的力量。这些生物碱仅以毫克量被分离出来，因此阻碍了对其生物学功能的充分研究。这项研究项目中提出的化学合成将产生克级数量的这些高度重要和复杂的分子，这将使进一步合作研究它们的生物学特征成为可能。例如，据报道，布雷维胺S对结核分枝杆菌的筛选替代品卡米特-盖林具有选择性抗菌活性，这暗示了一种新的作用机制，可能会为下一代结核病药物的开发提供信息。不幸的是，可以从杂色曲霉的发酵和提取中分离出的天然短胺S的数量阻碍了对这一非常有前途的生物活性的更深入的研究。总而言之，这项研究的预期结果将是显著超过这一系列天然产品所有以前方法的独特有效的合成策略，将在有机合成中更广泛使用的新合成方法，以及用于生物/药物研究的目标天然产品的实际数量。

With our rapidly increasing global population we must endeavor to reduce the economic and environmental cost associated with producing organic substances; our medicines, agrochemicals and high-tech materials. This project aims to mimic biological processes in an effort to improve the way in which we can make these highly important substances. This is akin to how engineers take inspiration from birds and other flying animals when developing better and more efficient planes. Through this "biomimetic" approach we will investigate and learn about the highly sophisticated way Nature utilizes predisposed, highly selective, chemical reactivity to rapidly construct complex molecules. We will demonstrate the power of this biomimetic strategy by synthesizing the brevianamide alkaloids, secondary metabolites isolated from various Aspergillus and Penicillium fungi. These alkaloids have only been isolated in milligram quantities, which has thus hampered full investigation into their biological function. The chemical syntheses proposed in this research project will produce gram-scale quantities of these highly important and complex molecules, which will enable further collaborative investigations into their biological profiles. Brevianamide S, for example, has been reported to exhibit selective antibacterial activity against Bacille Calmette-Guérin (a screening surrogate for Mycobacterium tuberculosis), suggestive of a new mechanism of action that could inform the development of next-generation TB drugs. Unfortunately, the quantity of natural brevianamide S that can be isolated from fermentation and extraction of Aspergillus versicolor has impeded greater investigation into this very promising biological activity. In summary, the expected outcome of this research will be uniquely efficient synthetic strategies that significantly surpass all previous approaches to this family of natural products, new synthetic methodology that will be of wider use in organic synthesis, and practical quantities of the target natural products for biological/medicinal research.