Synthesis of Amino Acid-Containing Natural Products

描述(由申请人提供)：本申请的目的是深入研究氨基酸问题，对这些问题存在较差或较不有效的方法。这项提案描述了进一步开发我们实验室开发的基于恶嗪酮的甘氨酸模板的用途，该模板用于光学纯形式的复杂的、密集官能化的氨基酸和衍生物的不对称合成。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)合成目标都在氨基酸侧链中含有2-取代(在某些情况下，2，3-多取代)；(2)合成目标具有生物医学意义和重要性；以及(3)文献中普遍缺乏获得这些类型物质的方法学。在即将到来的赠款期间，计划开发新的合成方法，以实现下列天然产物的不对称全合成：(1)硝酮偶极环加成反应，用于假定具有代谢活性的圆柱状精原蛋白衍生物的不对称全合成；(2)开发新的分子内氨甲亚胺叶立德偶极环加成反应，用于不对称全合成帕劳胺及其同系物；(3)非对映选择性羟醛和内酯官能化方法，用于短期的不对称全合成奎宁，其特点是面选择性的，Pd催化的分子内SN2‘环化反应；(4)利用新的非对映选择性亚甲基偶极环加成策略进行简明的不对称全合成；(5)表面选择性的分子内SN2‘环化反应用于螺喹唑啉和丙酮类的不对称全合成；(6)官能化恶嗪酮的分子内Pauson-Khandd反应，以构建茎生物碱家族的成员--百里香酚；以及(7)基于Mannich的方法全合成玉米赤霉毒素和茶多酚。在每个领域，将对具有生物活性的天然产物的合成类似物进行生物学研究。公共卫生相关性本应用程序的目的是深入研究氨基酸问题，对这些问题存在较差或较不有效的方法。这项提案描述了进一步发展合成技术的用途，以构建氨基酸，用于光学纯形式的复杂的、密集官能化的氨基酸及其衍生物的不对称合成。这项技术已被世界各地的学术和工业实验室广泛用于制造具有生物医学意义的含氮化合物。

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 oxazinone-based 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 2-substitution (in some cases, 2,3-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 putative metabolically activated derivatives of cylindrospermopsin; (2) development of novel intramolecular azomethine ylid dipolar cycloaddition reactions for application to the asymmetric total synthesis of palau'amine and congeners; (3) diastereoselective aldol and lactone functionalization methods for application to a short, asymmetric total synthesis of quinine featuring a facially selective, Pd-catalyzed 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 reactions for the asymmetric total synthesis of spiroquinazoline and alantrypinone; (6) intramolecular Pauson-Khand reactions on functionalized oxazinones to construct tuberostemoninol, a member of the stemona alkaloid family; and (7) Mannich-based approaches to the total synthesis of zetikitoxin and saxitoxin. In each area, biological studies of synthetic analogs of the biologically active natural products will be undertaken. PUBLIC HEALTH RELEVANCE 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 synthetic technology to construct amino acids for the asymmetric synthesis of complex, densely functionalized amino acids and derivatives in optically pure form. This technology has been utilized extensively by academic and industrial laboratories all over the world to make nitrogen-containing compounds of biomedical relevance.