Synthesis of Amino Acid-Containing Natural Products

含氨基酸天然产物的合成

• 批准号: 6836552
• 负责人: Robert Michael Williams
• 金额: $ 22.71万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/6836552
• 关键词: alkaloids; aminoacid biosynthesis; biological products; chemical synthesis; cyclic peptides; drug design /synthesis /production; glycine; indoles; nitrone; protease inhibitor; pyrroles; quinine; spirane; stereoisomer

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。该提案描述了计划，以进一步开发在我们的实验室开发的甘氨酸模板的实用性，复杂的，密集的功能化的氨基酸和衍生物的光学纯的形式的不对称合成。已为即将到来的赠款周期选择的具体目标是根据以下标准选择的：（1）合成目标在氨基酸侧链中都含有β-取代（在某些情况下，β，γ-多取代）;（2）合成目标在生物医学上是有趣的和重要的;（3）文献中通常缺乏获得这些类型物质的方法。本研究计划在今后的资助期内开发新的合成方法学，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在柱精子蛋白酶的不对称全合成中的应用;（2）新的分子内偶氮甲碱叶立德偶极环加成反应在帕劳'amine的不对称全合成中的应用;（3）非对映选择性羟醛和内酯官能化方法，用于以表面选择性分子内SN 2 '环化反应为特征的奎宁的短的、不对称的全合成;（4）利用新的非对映选择性偶氮甲碱叶立德偶极环加成策略，用于nakadomarin A和manzamine生物碱的简洁的、不对称的全合成;（5）操作表面选择性的分子内SN 2 '环化反应用于螺喹唑啉和丙氨色酮的不对称全合成。短期目标将致力于完成蛋白酶体抑制剂TMC-95 A/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），将对具有生物活性的天然产品的合成类似物进行生物学研究。