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

项目摘要 该计划的目标是发展广泛有效的化学立体控制化学 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 两个特定目标，每个目标都开放了对不同类别天然产品的访问。目标1描述了 开发了一种未经探索的脱芳-克莱森重排，其允许C2 吲哚的位置，从而能够立体控制的，不对称合成2，2-二取代的吲哚啉 衍生物.这种新的Claisen重排变换将被纳入到设计高效的 含吲哚啉的天然产物的战略。目的2介绍了两个[4+3]-环加成反应的研究进展 合成吲哚稠合环庚烷的基本路线以及该化学在合成吲哚稠合环庚烷中的应用 合成复杂的、具有生物活性的苦荞麦碱天然产物。整个研究计划得到支持 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 这是一个新的挑战，它将在方法学方面取得进展，同时应对复杂目标带来的尚未应对的综合挑战。化学新 预期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。最终产品的总合成的努力和许多 高级中间体将提交给筛选设施进行生物试验。拟议项目 将为研究生和博士后提供化学合成方面的优秀培训， 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.