The Synthesis of Bioactive Polycyclic Natural Products

生物活性多环天然产物的合成

• 批准号: 7459760
• 负责人: BRIAN M STOLTZ
• 金额: $ 28.75万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-02 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459760
• 关键词: Alkylation; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Antineoplastic Agents; Applications Grants; Architecture; Area; Aromatase Inhibition; Biological; Biological Factors; Biology; Breathing; California; Carbon; Chemicals; Chemistry; Complex; DNA Sequence Rearrangement; Development; Discipline; Elements; Facility Construction Funding Category; Government; Human; Industry; Institutes; Medicine; Methodology; Methods; Molecular; Numbers; Organometallic Chemistry; Palladium; Paroxetine; Phosphotransferases; Preparation; Principal Investigator; Process; Public Health; Range; Reaction; Research; Rest; Route; Science; Structure; Synthesis Chemistry; System; Techniques; Technology; Testing; Work; c new; chemical synthesis; coping; cyclic ketone; interest; method development; new technology; novel; novel strategies; physical property; programs; protonation; small molecule; tool

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.

描述（由申请人提供）：该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。我们提出的研究将侧重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。我们开发的工艺将可用于合成各种复杂的生物活性分子，但目前尚无有效的合成路线图。重要的是，本申请中提出的方法将在本文描述的上下文之外有用，并将为合成化学从业者（学术界、政府和工业界）提供一组新的重要工具来获取合成的关键构建模块。本拨款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，产生重要的合成构件，b）开发合成稠环系统阵列的新方法， c) 在合成众多天然和非天然生物活性小分子中应用这些新工具。具体来说，我们概述了 dichroanone、liphagal、cyanthiwigin G、platensimycin、paroxetine 和 ineleeganolide 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。通过这种方法，我们将能够获得a）新颖的、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，我们以精湛的精度构建分子的能力在科学中是独一无二的。在本提案中，我们概述了一些建立重要联系的新方法，并在与人类医学相关的高度复杂的情况下实施这些方法。