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合成各种复杂的生物活性分子中找到实用性，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（在学术界，政府和工业中）提供一套新的重要工具来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)开发合成融合环系统阵列的新方法，以及c)在合成众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，我们概述了对二氯酮，脂脂，青花色素G，铂霉素，帕罗西汀和内酯的方法。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。与公共卫生的相关性：化学的核心在于以可预测和可靠的方式操纵元素以制备特定原子阵列的能力。作为合成化学家，我们精确构建分子的能力在科学领域是独一无二的。在本建议中，我们概述了一些新的方法来构建重要的联系，并在高度复杂的情况下实施这些方法与人类医学相关。

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 complex, biologically active molecules 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 provide practitioners of synthetic chemistry (in academics, government, and industry) 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- catalyzed enantio-selective alkylation and protonation reactions that produce important building blocks for synthesis, b) the development of novel methods for the synthesis of fused 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 dichroanone, liphagal, cyanthiwigin G, platensimycin, paroxetine, and ineleganolide. 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. Relevance to Public Health: 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.