The Synthesis of Bioactive Polycyclic Natural Products

描述（由申请人提供）：本研究计划的目的是发现和开发合成复杂生物活性分子的新反应方法。我们提出的研究将集中在开发的方法，使许多生物活性，多环天然产物中普遍存在的核心结构和立体化学亚基的合成。我们开发的方法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，本申请中提出的方法在本文所述的背景之外将是有用的，并且将为合成化学的从业者（学术界、政府和工业界）提供一组新的重要工具来获得用于合成的关键构件。在该授权申请中提出的研究集中于a）开发新的钯催化的对映选择性烷基化和质子化反应，其产生用于合成的重要结构单元，B）开发用于合成稠环系统阵列的新方法，以及c）在许多天然和非天然生物活性小分子的合成中实施这些新工具。具体而言，我们概述了二色酮，liphagal，cynthiwigin G，platensimycin，帕罗西汀，和ineleganaline的方法。这些分子从生物学的角度来看很重要，但也是我们新技术的试验场。作为这种方法的结果，我们将获得a）新颖的、医学上相关的结构，B）用于其合成的通用平台，以及c）将有益于许多不同应用的新合成方法。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的原子阵列。作为合成化学家，我们以精密的精度构建分子的能力在科学界是独一无二的。在这份提案中，我们概述了一些新的方法，以建立重要的联系，并在高度复杂的情况下实施这些方法的相关人类医学。

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.