Asymmetric Synthesis of alpha-Amino Acids

本研究的重点是开发实现以下天然产物的不对称全合成所需的合成方法：（1）偶氮甲碱叶立德偶极环加成反应应用于螺胰前列腺素A的不对称全合成； (2)应用于圆柱精蛋白的分子内硝酮环加成； (3)曼尼希型反应构建α、β-二氨基酸及其在卷曲霉素1B不对称全合成中的应用； (4) 肽等排体方法学的进一步发展及其在亮组蛋白不对称全合成中的应用； (5) 内酯同系物方法开发应用于N-乙酰神经氨酸的不对称全合成； (6) 开发立体选择性方法来构建具有三个连续立体中心的肽电子等排体； (7) 开发α-烷基异丝氨酸衍生物的制备方法； (8) 开发新型分子内偶氮甲碱叶立德偶极环加成反应，应用于帕洛胺的不对称全合成； (9) 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 SN2 环化反应为特征的奎宁的短时、不对称全合成。有机和高分子化学项目通过这一续奖，支持科罗拉多州立大学化学系 Robert M. Williams 博士的研究。 Williams 教授的工作重点是复杂、光学纯、密集功能化的氨基酸和氨基酸衍生物的不对称合成。 该方法将扩展到具有有趣且重要的生物学特性的天然产物的制备。 该研究对制药行业以及研究生和博士后学生的培训具有广泛的影响。

The focus of this research will be the development of the synthetic methodology necessary to achieve the asymmetric total synthesis of the following naturalproducts: (1) azomethine ylid dipolar cycloaddition reactions as applied to the asymmetric total synthesis of spirotryprostatin A; (2) intramolecular nitrone cycloadditions as applied to cylindrospermopsin; (3) Mannich-type reactions to construct alpha, beta-diamino acids and application to the asymmetric total synthesis of capreomycin 1B; (4) further development of peptide isostere methodologies and application to the asymmetric total synthesis of leuhistin; (5) lactone homologation methodology development as applied to the asymmetric total synthesis of N-acetylneuraminic acid; (6) development of stereoselective methods to construct peptide isosteres with three contiguous stereogenic centers; (7) development of methodology to prepare alpha-alkyl-isoserine derivatives; (8) development of novel intramolecular azomethine ylid dipolar cycloaddition reactions for application to the asymmetric total synthesis of palauamine; (9) diastereoselective aldol and lactone functionalization methods for application to a short, asymmetric total synthesis of quinine featuring a facially selective intramolecular SN2 cyclization reaction.With this renewal award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Robert M. Williams of the Department of Chemistry at Colorado State University. Professor Williams will focus his work on the asymmetric synthesis of complex, optically pure, densely functionalized amino acids and amino acid derivatives. The methodology will be extended to the preparation of natural products having interesting and important biological properties. The research has broad impacts for the pharmaceutical industry and for the training of graduate and postdoctoral students.