New Methods and Strategies for the Concise Synthesis of Complex Indole Alkaloids

项目摘要，摘要 该计划的目标是为立体控制的化学物质开发广泛有效的化学物质。 化学家和药物化学家使用的复杂结构的合成。研究计划分为以下几部分 有两个明确的目标，每个目标都为获得不同类别的天然产品打开了大门。目标1描述了 开发一种未探索的脱芳烃-克莱森重排，允许C2官能化 吲哚的位置，从而使立体控制的不对称合成2，2-二取代吲哚成为可能 衍生品。这种新的Claisen重排变换将被结合到Efficient的设计中 含有吲哚的天然产品的策略。目的2介绍两个[4+3]-环加成反应的研究进展 吲哚稠环庚烷的基本合成路线及其在反应中的应用 具有复杂生物活性的模糊天然产物的合成。研究计划在整个过程中都得到支持 具有令人信服的初步结果，合成应用程序旨在最大限度地利用 方法，同时解决复杂目标带来的未得到满足的综合挑战。新化学 预计将对参与药物开发的有机和药物化学家广泛有用， 化学合成和天然产物研究。最终产品的总合成努力和许多 先进的中间体将被提交到筛选设施进行生物测试。建议的项目 将为研究生和博士后提供化学合成和博士后培训 解决问题，为他们在制药行业和学术界的成功职业生涯做好准备。

PROJECT SUMMARY, ABSTRACT The objective of this program is to develop broadly effective chemistry for the stereocontrolled chemical synthesis of complex structures of use to chemists and medicinal chemists. The research plan is divided into two Specific Aims, each opening access to distinct classes of natural products. Aim 1 describes the development of an unexplored, dearomative-Claisen rearrangement, which allows functionalization of the C2 position of indoles, thereby enabling the stereocontrolled, asymmetric synthesis of 2,2-disubstituted indoline derivatives. This new Claisen rearrangement transform will be incorporated into the design of efficient strategies to indoline-containing natural products. Aim 2 presents the development of two [4+3]-cycloaddition based routes for the synthesis of indole-fused cycloheptanes and the application of this chemistry to the synthesis of the intricate and bioactive ambiguine natural products. The research plan is supported throughout with compelling preliminary results, and the synthesis applications are designed to make maximal use of the methodology, while addressing unmet synthetic challenges posed by the complex targets. The new chemistry is expected to be broadly useful to organic and pharmaceutical chemists involved in drug development, chemical synthesis, and natural product research. The final products of the total synthesis efforts and many advanced intermediates will be submitted to a screening facility for biological testing. The proposed projects will provide excellent training to graduate students and postdoctoral associates in chemical synthesis and problem solving, preparing them for successful careers in the pharmaceutical industry and academia.