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存在不良或不太有效的方法的氨基酸问题。本提案描述了进一步开发我们实验室开发的基于oxazin酮的甘氨酸模板的用途，用于不对称合成复杂的、密集功能化的氨基酸及其光学纯形式的衍生物。为即将到来的资助周期选择的特定靶点是根据以下标准选择的：(1)合成靶点在氨基酸侧链中都含有2-取代（在某些情况下，2,3-多取代）；(2)合成靶点具有重要的生物医学意义；(3)一般来说，文献中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)硝基酮偶极环加成反应应用于假定的代谢激活的柱精子素衍生物的不对称全合成；(2)开发了新的分子内偶极环加成反应，应用于帕劳胺及其同系物的不对称全合成；(3)非对映选择性醛醇和内酯功能化方法，应用于具有表面选择性、pd催化的分子内SN2'环化反应的奎宁的短时间、不对称全合成；(4)利用新型非对映选择性亚甲酰基偶极环加成策略，进行了简洁、不对称的中adomarin a和manzamine生物碱的全合成；(5)利用表面选择性SN2’环化反应合成螺旋喹唑啉和丙氨酸锥氨酸酮；(6)功能化恶嗪酮分子内Pauson-Khand反应合成火龙花生物碱家族成员火龙花甾醇；(7)基于mannich的zetikitoxin和saxitoxin全合成方法。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。此应用程序的目的是深入研究存在较差或较不有效的方法的氨基酸问题。本提案描述了进一步发展合成技术的计划，以构建氨基酸的不对称合成，以光学纯形式密集功能化的复杂氨基酸及其衍生物。该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.