Advances in the Development of Synthetic Methods for Complex Molecule Synthesis

拟议的研究计划旨在开发新的战略和新的合成方法和试剂，以有效地形成碳-碳和碳-杂原子键。能够选择性地产生产物的方法特别重要，因为它们可以用于复杂分子的可控和可预测的合成。 本提案中概述的具体项目包括环加成反应、电环化反应和Sigmatrotic反应的开发。将确定这些方法的范围，并酌情确定反应的机理。此外，了解控制反应性和选择性的参数将有助于开发预测模型。 允许使用实际条件和稳定试剂快速构建分子复杂性的反应序列和多米诺骨牌反应具有特殊的价值。所开发的合成方法将直接应用于生物相关和结构复杂的靶分子的合成，包括具有抗癌或抗菌活性的天然产物，如大环脱肽和生物碱。实例目标是海洋海绵生物碱，agelamadin和nagelamide，我们的目标是通过电环化方法合成。 具有广泛适用性的通用方法、反应和试剂最终会给其他合成有机化学家带来实际好处，无论是在学术实验室还是商业实验室。总体而言，拟议的计划不仅将促进科学技术的基础研究，还将为对制药、生物技术、医药、农用化学品和高科技材料领域的研究和开发职业感兴趣的学生提供一个培训和研究环境。

The proposed research program is aimed at the development of novel strategies and new synthetic methods and reagents for the efficient formation of carbon-carbon and carbon-heteroatom bonds. Methods that can generate products in a selective manner, whether in a site-selective, chemoselective or stereoselective fashion are of particular importance, since they can then be used for the controlled and predictable synthesis of complex molecules. Specific projects outlined in the current proposal include the development of cycloaddition, electrocyclization and sigmatropic reactions. The scope of these methods and, where appropriate, the mechanism of the reactions will be determined. In addition, obtaining an understanding of the parameters which control reactivity and selectivity will allow the development of predictive models. Reaction sequences and domino reactions that allow for the rapid construction of molecular complexity using practical conditions and stable reagents are of particular value. The synthetic methods that are developed will be applied directly to the syntheses of biologically relevant and structurally complex target molecules, including natural products which display anticancer or antibiotic activity, such as macrocyclic depsipeptides and alkaloids. Example targets are the marine sponge alkaloids agelamadin and nagelamide which we aim to synthesize through an electrocyclization approach. General methods, reactions, and reagents that are of broad applicability ultimately result in practical benefits to other synthetic organic chemists, both in academic labs and commercial labs. Overall the proposed program will not only advance basic research in science and technology, but will also provide a training and research environment for students interested in research and development careers in the pharmaceutical, biotechnology, medicinal, agrochemical, and high-tech materials sectors.