General Methods for Synthesis of Bioactive Materials

描述(申请人提供)：该研究计划的主要目标是发明和开发有效的化学合成方法，使复杂的多功能分子能够以实用的方式制备成单一对映体。我们的目标是在生物医学相关分子中常见的结构基序，但用现有的化学方法很难或不可能制备。建议研究的重点之一是开发实用化学来不对称合成两个杂环基元，这两个杂环基元存在于许多具有生物活性的天然产物--环二氧基哌嗪和叔烷基杂环胺中。拟议的研究还将继续发展我们的通用方法来构建包含四元碳立体中心的复杂多功能分子。我们开发的新的化学合成方法将在不存在化学合成条目的结构复杂的生物活性生物碱的对映选择性全合成的背景下进行评估。我们的总合成目标包括(A)含有与环色胺片段融合的二硫代二氧基哌嗪环的生物碱，如生物连结素A、胶质拉定A、瘦素D和轮枝菌素A，(B)卡帕卡辛生物碱A和F，以及(C)普通素A。我们将合作进行研究，以确认和评估卡帕卡辛生物碱的抗疟疾特性，并对本研究计划中准备的新结构进行广泛的表型筛选。从长远来看，本研究开发的新的有机合成方法的可获得性将有助于发现和生产用于治疗医学疾病的改进药物。与公众健康相关拟议研究的目的是开发新的化学转化，允许通过化学合成从廉价的起始材料中制备具有生物活性的有机分子。这种新的化学将在新药的发现和生产以及生命过程的分子水平研究中具有价值。

DESCRIPTION (provided by applicant): The overarching objective of this research program is to invent and develop efficient chemical synthesis methods that allow complex polyfunctional molecules to be prepared as single enantiomers in practical fashion. We target structural motifs that are commonly found in molecules of biomedical relevance, yet are difficult, or impossible, to prepare with existing chemical methods. One emphasis of the proposed research is the development of practical chemistry for the asymmetric synthesis of two heterocyclic motifs that are found in numerous biologically active natural products, epidithiodioxopiperazines and tertiary carbinyl heterocyclic amines. The proposed studies will also continue our development of versatile methods for constructing complex polyfunctional molecules containing quaternary carbon stereocenters. The new chemical synthesis methods we develop will be evaluated in the context of the enantioselective total synthesis of structurally complex, biologically active alkaloids, for which no chemical synthesis entry exists. Our total synthesis targets include (a) alkaloids that contain an epidithiodioxopiperazine ring fused to a cyclotryptamine fragment, such as bionectin A, gliocladine A, leptosin D, and verticillin A, (b) the kapakahine alkaloids A and F, and (c) communensin A. We will collaborate in studies to confirm and evaluate the antimalarial properties of kapakahine alkaloids and in broad phenotypic screening of the novel structures prepared in this program of research. In the long term, the availability of the new organic synthesis methods that are developed in this research will facilitate discovery and production of improved drugs for treating medical disorders. PUBLIC HEALTH RELEVANCE The aim of the proposed research is to develop new chemical transformations that allow biologically active organic molecules to be prepared from inexpensive starting materials by chemical synthesis. This new chemistry will be of value in the discovery and production of new medicines, as well as in molecular-level studies of life processes.