Synthesis of Amino Acid-Containing Natural Products

含氨基酸天然产物的合成

基本信息

批准号：
7153515
负责人：
Robert Michael Williams
金额：
$ 21.54万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2007-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7153515
关键词：
3-hydroxybutanal Alkaloids Amino Acids Area Binding Biochemical Biological Biological Factors Catalysis Cell Nucleus Class Collaborations Complex Cyclization Cyclopentane Cytochrome P450 DNA DNA Damage Data Development Facility Construction Funding Category Glycine Goals Grant Guanidines Laboratories Lactones Libraries Literature Marines Methodology Methods Object Attachment Palau&apos amine Pentas Principal Investigator Proteasome Inhibitor Protein Biosynthesis Purpose Quinine Quinuclidines Reaction Research Personnel Roentgen Rays Series Side Synthesis Chemistry System Uracil alantrypinone analog base cycloaddition cylindrospermopsin cytotoxic guanidinium hepatotoxin inhibitor/antagonist interest manzamine A method development multicatalytic endopeptidase complex nakadomarin A nitrone novel oxindole programs spiroquinazoline tumor initiation ylide

项目摘要

DESCRIPTION (provided by applicant): The purpose of this application is to delve into amino acid problems to which poor or less effective methodologies exist. This proposal describes plans to further develop the utility of the glycine templates developed in our laboratory for the asymmetric synthesis of complex, densely functionalized amino acids and derivatives in optically pure form. The specific targets that have been selected for the upcoming grant cycle have been chosen by the following criteria: (1) the synthetic targets all contain beta-substitution (in some cases, beta,gamma-polysubstitution) in the amino acid side chain; (2) the synthetic targets are biomedically interesting and important; and (3) methodologies to access these types of substances are, in general, lacking in the literature. During the coming grant period, plans are described to develop new synthetic methodologies necessary to achieve the asymmetric total synthesis of the following natural products: (1) nitrone dipolar cycloaddition reactions as applied to the asymmetric total synthesis of cylindrospermopsin; (2) development of novel intramolecular azomethine ylid dipolar cycloaddition reactions for application to the asymmetric total synthesis of palau'amine; (3) diastereoselective aldol and lactone functionalization methods for application to a short, asymmetric total synthesis of quinine featuring a facially selective intramolecular SN2' cyclization reaction; (4) utilization of novel diastereoselective azomethine ylide dipolar cycloaddition strategies for a concise, asymmetric total synthesis of nakadomarin A and the manzamine alkaloids; (5) manipulation of a facially selective intramolecular SN2' cyclization reaction for the asymmetric total synthesis of spiroquinazoline and alantrypinone. A shorter-term goal will be devoted to completion of the asymmetric total synthesis of the proteasome inhibitors TMC-95A/B and synthetic analogs. In each area (except the quinine project), biological studies of synthetic analogs of the biologically active natural products will be undertaken.

描述（由申请人提供）：本申请的目的是深入研究存在较差或不太有效的方法的氨基酸问题。该提案描述了进一步开发我们实验室开发的甘氨酸模板的实用性的计划，用于不对称合成复杂的、密集功能化的氨基酸和光学纯形式的衍生物。为即将到来的资助周期选择的具体靶标是根据以下标准选择的：（1）合成靶标在氨基酸侧链中均含有β-取代（在某些情况下，β，γ-多取代）； (2) 合成靶点具有生物医学意义且重要； (3) 文献中普遍缺乏获取这些类型物质的方法。在即将到来的资助期内，计划开发新的合成方法，以实现以下天然产物的不对称全合成：（1）硝酮偶极环加成反应应用于圆柱精蛋白的不对称全合成； (2) 开发新型分子内偶氮甲碱叶立德偶极环加成反应，应用于帕劳胺的不对称全合成； (3)非对映选择性羟醛和内酯官能化方法，用于奎宁的短时、不对称全合成，具有表面选择性分子内SN2'环化反应； (4) 利用新型非对映选择性偶氮甲碱叶立德偶极环加成策略来简明、不对称地全合成 nakadomarin A 和 manzamine 生物碱； (5)操纵表面选择性分子内SN2'环化反应用于螺喹唑啉和alantrypinone的不对称全合成。短期目标将致力于完成蛋白酶体抑制剂TMC-95A/B和合成类似物的不对称全合成。在每个领域（奎宁项目除外），将开展生物活性天然产物的合成类似物的生物学研究。