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。该提案描述了计划，以进一步开发实用的恶嗪酮为基础的甘氨酸模板在我们的实验室开发的复杂的，密集的功能化的氨基酸和衍生物的光学纯的形式的不对称合成。已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）合成目标在生物医学上是有趣的和重要的;（3）文献中通常缺乏获得这些类型物质的方法。在即将到来的资助期内，我们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，应用于柱精子蛋白酶的假定代谢活化衍生物的不对称全合成;（2）分子内偶氮甲亚胺叶立德偶极环加成反应在帕劳'胺及其同系物不对称全合成中的应用;（3）非对映选择性羟醛和内酯官能化方法，用于以表面选择性Pd催化的分子内SN 2 '环化反应为特征的奎宁的短的不对称全合成;（4）利用新的非对映选择性偶氮甲碱叶立德偶极环加成策略用于nakadomarin A和manzamine生物碱的简洁的不对称全合成;（5）操作表面选择性的分子内SN 2 '环化反应，用于不对称全合成螺喹唑啉和丙氨色酮;（6）在官能化恶嗪酮上的分子内Pauson-Khand反应，以构建百部生物碱家族的成员tuberostemoninol;（7）基于Mannich的泽替毒素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品的合成类似物进行生物学研究。本申请的目的是深入研究存在较差或较低效方法的氨基酸问题。该提案描述了进一步开发合成技术的实用性以构建用于不对称合成光学纯形式的复杂的、密集官能化的氨基酸和衍生物的氨基酸的计划。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。

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.