Efficient Catalytic and Asymmetric and Cycloaddition Routes to Future Medicines

通过合成将原材料转化为高价值商品是创造财富的基本行为，也是经济活动的晴雨表。这一提议涉及到新反应的发展，这些反应可用于在相对温和的条件下，从简单、廉价的起始材料快速组装高价值分子。这项研究计划的结果将导致更有效的合成，这是对环境负责的制造的关键目标。具体来说，我们已经开发了环加成反应，使分子与生物碱天然产物非常相似，具有药用价值。我们预计这种环加合物将用于新的生物靶点的调节，并可能对未来农用化学品和药物的开发具有直接价值。因此，这种合成的广泛用途在未来的应用中提供了持久的经济和科学价值。具有特定对称性或手性的分子对于获得选择性药物分子是非常重要的。没有不对称版本的环加成反应的例子，因此，我们已经着手研究和发明的反应，有效地提供环加合物作为单独的立体异构体。我们计划通过完成一种复杂的生物碱天然产物securinine的非常简洁的合成来展示这些新的，强大的反应。从本质上讲，我们计划打破高效生产这种生物碱的记录。Securinine特别有趣，因为有报道称它能导致结肠癌细胞的选择性控制关闭（凋亡）。一种可靠、高产的类似物途径可能有助于确定这种化合物起作用的生物学途径，并最终为未来发现治疗癌症的新疗法提供信息。这一建议将产生可轻易转移到高价值工业的专门知识，并将培训这一重要经济部门的下一代创新者。

The transformation of raw materials into high value goods by synthesis is a fundamental act of wealth creation and a barometer of economic activity. This proposal involves development of new reactions that can be used to quickly assemble high value molecules from simple, cheap starting materials using relatively benign conditions. The results of this research program will lead to more efficient synthesis, a key objective for environmentally responsible manufacturing.Specifically, we have developed cycloaddition reactions that give molecules that closely resemble alkaloid natural products with medicinal value. We anticipate that such cycloadducts will be useful for modulation of novel biological targets and may have direct value for development of future agrochemicals and pharmaceuticals. The broad utility of this synthesis therefore offers lasting economic and scientific value from its application in future.Molecules with specific symmetry, or handedness, are very important for obtaining selective pharmaceutical molecules. There are no examples of an asymmetric version of the proposed cycloaddition reactions, thus we have set out to investigate and invent reactions that efficiently deliver cycloadducts as individual stereoisomers.We plan to showcase these new, powerful reactions by completing a very concise synthesis of a complex alkaloid natural product called securinine. Essentially, we plan to break the record for efficient production of this alkaloid. Securinine is particularly interesting because it has been reported to cause selective controlled shut-down (apoptosis) of colon cancer cells. A reliable, high yielding route to analogues may help identification of the biological pathway by which this compound works and ultimately inform future discovery of novel therapies for the treatment of cancer.This proposal will generate know-how that can be easily transferred to high value industries and will train the next generation of innovators in this vital economic sector.