The Synthesis of Bioactive Polycyclic Natural Products

项目概要/摘要： 本研究计划的目标是发现和开发新的反应 合成复杂生物活性分子的方法学。我们提出的 研究将集中在调查和优化技术，使 在许多生物活性， 多环天然产物。我们开发的过程将在 合成目前没有有效合成方法的各种结构 路线图重要的是，本申请中提出的方法在外部将是有用的。 本文所述的背景，并将武装合成化学的从业者（在 学术，政府和工业实验室），并提供一套新的重要工具， 获得用于合成的对映体富集的和功能多样的化学构件。 在这项拨款申请中提出的研究重点是a）开发 新的钯和铱催化的立体选择性烷基化反应 用于合成的密集取代的无环结构单元，B）开发新的 用于不对称烷基化和酰化方法的镍-和铜-催化剂， 这些新方法的发展，特别是用于制备全碳 四元立体中心和四元中心阵列，以及d）实施 这些新的策略在高度复杂的，生物活性的双吲哚生物碱的合成。 具体来说，我们概述了方法leucophyllidine，strempeliopidine， 诺普利木汀。这些分子不仅从生物学的角度来看很重要， 也是我们新技术的试验场。由于这种 方法，我们将获得a）新的，医学相关的结构，B）一个通用的 c）新的合成方法，将影响到许多 不同的应用。

Project Summary/Abstract: The objective of this research program is to discover and develop new reaction methodology en route to the synthesis of complex bioactive molecules. Our proposed studies will focus on the investigation and optimization of technologies that enable the synthesis of core structural and stereochemical subunits prevalent in many bioactive, polycyclic natural products. The processes that we develop will find utility in the synthesis of a variety of structures for which there are currently no efficient synthetic roadmaps. Importantly, the methods presented in this application will be useful outside of the contexts described herein and will arm practitioners of synthetic chemistry (in academic, government, and industrial laboratories) with a new set of important tools to access enantioenriched and functionally diverse chemical building blocks for synthesis. The research proposed in this grant application is focused on a) the development of new palladium- and iridium-catalyzed stereoselective alkylation reactions that produce densely substituted, acyclic building blocks for synthesis, b) the development of novel nickel- and copper-catalysis for asymmetric alkylation and acylation processes, c) the development of these novel methods specifically for the preparation of all-carbon quaternary stereocenters and arrays of quaternary centers, and d) the implementation of these new tactics in the syntheses of highly complex, bioactive bis-indole alkaloids. Specifically, we outline approaches to leucophyllidine, strempeliopidine, and norpleiomutine. These molecules are not only important from a biological standpoint, they also serve as a testing ground for our new technologies. As a consequence of this approach, we will have access to a) novel, medicinally relevant structures, b) a general platform for their synthesis, and c) new synthetic methodology that will impact a host of diverse applications.