Modern Synthetic Methods and their Application to the Synthesis of Bioactive Target Molecules

追求更经济、更廉价的方法来创建碳-碳键一直是许多突破性的合成化学发现背后的推动力。这一研究领域的进展对更大的科学界和有机合成领域至关重要，因为它为目标分子提供了更有效的替代路线。为此，建议的研究重点是发展现代合成转化，以形成碳-碳键，并将其应用于生物相关分子的复杂目标定向合成。涉及C-H活化和官能化化学的反应是我们小组特别感兴趣的。利用这一领域开发的前沿技术，我们将探索多个研究主题，包括涉及C-H插入化学的串联反应以及手性硫醇在自由基反应途径中的用途。虽然合成功能强大，但C-H活化和官能化化学在涉及C-H插入的环状和串联过程中缺乏，如果成功，这一拟议的策略将允许获得独特的杂环部分，可能适合于合成具有生物活性的目标分子。此外，尽管自由基反应在合成和聚合物化学方面有着丰富的历史，但许多不足之处一直困扰着它们更广泛的应用，包括在诱导立体选择性转化方面的挑战。最近，在克服这些缺点方面已经取得了重大进展；然而，立体选择性转换仍处于初级阶段，我预计这将在未来几年成为一个热门话题。总体而言，这项建议的方法开发方面将构成我的研究计划的基础，并有助于推动C-H官能化和自由基反应化学的前沿。*与方法开发并行，建议的研究包括天然产物及其衍生物的生物筛选收集的准备，并将以两种方式完成。1)利用我们的反应开发平台，通过有计划的方法简化生物活性天然产物的全合成。2)生物活性分子的直接衍生化。使用现成的天然产品，我们可以直接操纵母体化合物，并在1-3个步骤中为每个天然产品创建一个独特的分子库。这种方法的好处包括为生物筛选准备一系列结构复杂的分子，开发新的合成转化的可能性(扩展我的方法计划)，以及提高学生在合成、分离和光谱分析领域的技能。最终，这一研究领域将培养成为一名成功的有机化学家所需的创造力、独创性和解决问题的技能。

The pursuit of more economical, and inexpensive ways to create carbon-carbon bonds has been a driving force behind many ground breaking synthetic chemistry discoveries. Advancements in this field of research are of paramount importance to the larger scientific community and also to the area of organic synthesis by providing more efficient alternative routes to target molecules. To this end, the proposed research focuses on the development of modern synthetic transformations for the formation of carbon-carbon bonds and their application in complex target oriented synthesis of biologically relevant molecules.****** Reactions involving C-H activation and functionalization chemistry are of particular interest to our group. Using frontline techniques developed within this area, we will explore multiple themes of research including tandem reactions involving C-H insertion chemistry and the utility of chiral thiols in radical reaction pathways. While synthetically powerful, C-H activation and functionalization chemistry is lacking in annulative and tandem processes involving C-H insertion and if successful, this proposed strategy will allow access to unique heterocyclic moieties potentially amenable to the synthesis of bioactive target molecules. Additionally, although radical reactions have a rich history in synthetic and polymer chemistry, many deficiencies have plagued their more widespread adoption including challenges in inducing stereoselective transformations. Very recently, significant strides have been made to overcome these drawbacks; however, stereoselective transformations is still in its infancy and I anticipate this will become a hot topic in the coming years. Overall, the method development aspect of this proposal will form the foundation of my research program and serve to push the frontier of C-H functionalization and radical reaction chemistry.****** In parallel with method development, the proposed research includes the preparation of biological screening collections of natural products and their derivatives, and will be completed in two ways. 1) Concise total synthesis of bioactive natural products through a planned approach, utilizing our reaction development platform. 2) Direct derivatization of bioactive molecules. Using readily available natural products, we can directly manipulate the parent compound and in 1-3 steps, create a library of unique molecules for each natural product. Benefits of this approach include the preparation of a collection of structurally complex molecules for biological screening, the possibility to develop new synthetic transformations (expanding my methods program), and student skill advancement in the areas of synthesis, isolation, and spectroscopic analyses. Ultimately, this area of research will foster the creativity, ingenuity and problem-solving skills required to be a successful organic chemist.