Synthesis of Amino Acid-Containing Natural Products

含氨基酸天然产物的合成

• 批准号: 8069232
• 负责人: Robert Michael Williams
• 金额: $ 24.13万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069232
• 关键词: 3-hydroxybutanal; Alkaloids; Amino Acids; Area; Biological; Biological Factors; Catalysis; Cell Nucleus; Chemistry; Complex; Cyclization; Cyclopentane; Development; Family; Glycine; Goals; Grant; Guanidines; Health; Laboratories; Lactones; Literature; Mannich Bases; Marines; Methodology; Methods; Nitrogen; Palau' amine; Panamanian; Pentas; Quinine; Quinuclidines; Rana; Reaction; Saxitoxin; Side; Sodium Channel; Stemona; Synthesis Chemistry; System; Technology; Work; alantrypinone; analog; base; cycloaddition; cylindrospermopsin; cytotoxic; flexibility; interest; manzamine A; member; method development; nakadomarin A; nitrone; novel; programs; spiroquinazoline; stereochemistry; ylide

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.

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实用性的计划，用于不对称合成复杂的、密集功能化的氨基酸和光学纯形式的衍生物。为即将到来的资助周期选择的具体目标是根据以下标准选择的：（1）合成目标的氨基酸侧链均包含2-取代（在某些情况下，2,3-多取代）； (2) 合成靶点具有生物医学意义且重要； (3) 文献中普遍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）硝酮偶极环加成反应，应用于假定的代谢活化的圆柱精蛋白衍生物的不对称全合成； (2) 开发新型分子内偶氮甲碱叶立德偶极环加成反应，用于帕劳胺及其同系物的不对称全合成； (3) 非对映选择性羟醛和内酯官能化方法，用于奎宁的短时间、不对称全合成，具有表面选择性、Pd 催化的分子内 SN2' 环化反应； (4) 利用新型非对映选择性偶氮甲碱叶立德偶极环加成策略来简明、不对称地全合成 nakadomarin A 和曼扎明生物碱； (5) 操纵表面选择性分子内SN2'环化反应，用于螺喹唑啉和阿兰曲品酮的不对称全合成； (6) 功能化恶嗪酮的分子内 Pauson-Khand 反应构建百部百部醇 (百部生物碱家族的成员)； (7)基于曼尼希的zetikitoxin和石房蛤毒素的全合成方法。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。公共卫生相关性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。该提案描述了进一步开发合成技术的实用性的计划，以构建氨基酸，以不对称合成复杂的、密集功能化的氨基酸和光学纯形式的衍生物。该技术已被世界各地的学术和工业实验室广泛利用，以制造具有生物医学相关性的含氮化合物。

项目成果

Toward palau'amine: Hg(OTf)2-catalyzed synthesis of the cyclopentane core.

• DOI: 10.1002/chem.200900622
• 发表时间: 2009-07-06
• 期刊: CHEMISTRY-A EUROPEAN JOURNAL
• 影响因子: 4.3
• 作者: Namba, Kosuke;Kaihara, Yukari;Yamamoto, Hirofumi;Imagawa, Hiroshi;Tanino, Keiji;Williams, Robert M.;Nishizawa, Mugio
• 通讯作者: Nishizawa, Mugio

New Tricks in Amino Acid Synthesis: Applications to Complex Natural Products.

氨基酸合成的新技巧：在复杂天然产物中的应用。

• 发表时间: 2009
• 期刊: ACS symposium series. American Chemical Society
• 作者: Williams,RobertM;Burnett,CameronM
• 通讯作者: Burnett,CameronM

Efficient Synthesis of the Cyclopentanone Fragrances (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone and Magnolione.

环戊酮香料 (Z)-3-(2-氧代丙基)-2-(戊-2-烯-1-基)环戊酮和木兰酮的高效合成。

• DOI: 10.1016/j.tet.2013.11.066
• 发表时间: 2014
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: Pan,Guojun;Williams,RobertM
• 通讯作者: Williams,RobertM

Studies on the Biosynthesis of Chetomin: Enantiospecific Synthesis of a Putative, Late-Stage Biosynthetic Intermediate.

• DOI: 10.1016/j.tet.2012.10.075
• 发表时间: 2013-01-01
• 期刊: TETRAHEDRON
• 影响因子: 2.1
• 作者: Welch, Timothy R.;Williams, Robert M.
• 通讯作者: Williams, Robert M.

Synthetic Studies on Palau'amine. Construction of the Cyclopentane Core via an Asymmetric 1,3-Dipolar Cycloaddition.

• DOI: 10.1016/j.tetlet.2010.10.037
• 发表时间: 2010-12-15
• 期刊: TETRAHEDRON LETTERS
• 影响因子: 1.8
• 作者: Namba, Kosuke;Inai, Makoto;Sundermeier, Uta;Greshock, Thomas J.;Williams, Robert M.
• 通讯作者: Williams, Robert M.