The Synthesis of Bioactive Polycyclic Natural Products

描述（由申请人提供）：本研究项目的目标是在合成复杂生物活性分子的过程中发现和发展新的反应方法。我们提出的研究将集中于开发能够合成许多生物活性多环天然产物中普遍存在的核心结构和立体化学亚基的方法。我们开发的过程将在各种结构的合成中找到效用，目前还没有有效的合成路线图。重要的是，本应用程序中提出的方法将在本文描述的环境之外有用，并将为合成化学的从业者（学术界，政府和工业）提供一套新的重要工具，以获取合成的关键构建块。本基金申请中提出的研究重点是a)开发新的钯和铜催化的对映选择性烷基化和质子化反应，这些反应可以产生合成的重要组成部分，b)利用这些新方法合成融合、螺旋和桥环系统阵列，以及c)在合成许多天然和非天然生物活性小分子中实施这些新工具。具体地说，我们概述了变绿素、原山核桃皮B、木脂素和communesin生物碱的方法。从生物学的角度来看，这些分子很重要，但也可以作为我们新技术的试验场。由于这种方法，我们将获得a)新颖的，与医学相关的结构，b)合成它们的通用平台，以及c)新的合成方法，这将有利于许多不同的应用。

DESCRIPTION (provided by applicant): 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 development of methods 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 is currently no efficient synthetic roadmap. Importantly, the methods presented in this application will be useful outside of the contexts described herein and will arm practitioners of synthetic chemistry (in academics, government, and industry) with a new set of important tools to access crucial building blocks for synthesis. The research proposed in this grant application is focused on a) the development of new palladium- and copper-catalyzed enantio-selective alkylation and protonation reactions that produce important building blocks for synthesis, b) the utilization of these novel methods for the synthesis of fused, spiro, and bridged ring system arrays, and c) the implementation of these new tools in the syntheses of numerous natural and non-natural bioactive small molecules. Specifically, we outline approaches to variecolin, przewalskin B, the rocaglate lignans, and the communesin alkaloids. These molecules are important from a biological standpoint, but 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 benefit a host of diverse applications. PUBLIC HEALTH RELEVANCE: At the core of chemistry rests the power to manipulate the elements for the preparation of specific arrays of atoms in a predictable and reliable fashion. As synthetic chemists, our capacity to construct molecules with exquisite precision is unique in the sciences. In this proposal we outline a number of new approaches toward constructing important linkages and implementing these methods in highly complex situations of relevance to human medicine.