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甘氨酸模板的用途，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β-取代(在某些情况下，β-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。在未来的授权期内，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，用于不对称全合成柱状精浆；(2)开发新的分子内偶氮甲亚胺叶立德偶极环加成反应，用于不对称全合成帕劳胺；(3)非对映选择性羟醛和内酯官能化方法，应用于以面选择性分子内SN2‘环化反应为特征的短期不对称奎宁全合成；(4)利用新的非对映选择性亚甲基亚甲基偶极环加成策略，缩合，不对称全合成长春花素A和甘草胺；(5)面选择性分子内SN2‘环化反应不对称全合成螺喹唑啉和丙氨蝶酮。一个较短期的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。

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.