Synthesis and Biosynthesis of Pyran and Spiroketal Structural Units

吡喃和螺缩酮结构单元的合成和生物合成

• 批准号: 8456204
• 负责人: Richard E. Taylor
• 金额: $ 27.94万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456204
• 关键词: Acetates; Anabolism; Antifungal Agents; Biochemical; Biological; Biological Factors; Biomimetics; Carbon; Chemicals; Collaborations; Complex; Cyclization; Cyclopropanes; Development; Esters; Ethers; Evolution; Generations; Label; Learning; Macrolides; Marines; Methodology; Methods; Modification; Molecular Conformation; Organic Synthesis; Organism; Pattern; Process; Propionates; Proteins; Pyrans; Research; Role; Route; United States National Institutes of Health; Universities; Work; ambruticin; analog; anticancer activity; base; cyclopropane; design; epoxidase; feeding; interest; preference; professor; programs; public health relevance; thioester

DESCRIPTION (provided by applicant): Our overall program is interested in fundamental issues regarding the evolution and chemotherapeutic potential of polyketide natural products. Using the power of organic synthesis, we seek to learn about the specific structural features found in polyketides, their effect on conformation, and the importance of conformation on biological activity. An underlying theme of this work is the development of practical methods applicable to the synthesis of stereochemically complex structural fragments found in polyketide natural products. During the research period, cationic cyclopropane methodology previously developed in our lab will provide access to ambruticin J, the putative biosynthetic intermediate to the antifungal agent ambruticin S. This material will be used to explore both chemical as well as biochemical conversion of ambruticin J to ambruticin S. The biochemical studies, performed in collaboration with Rolf Muller (University of Saarland) will provide fundamental information regarding the role of several post-PKS proteins including the epoxidase, AmbJ. In addition, intermediates necessary for ambruticin J synthesis will be converted to several labelled SNAC esters for feeding studies with the producing organism as well as isolated proteins. Analysis of the feeding studies will provide important information with regard to the unique biosynthesis of these cyclopropane containing polyketides. Section II of the Research Plan proposes new methodology, ether-transfer, applicable to the synthesis of acyclic polyketide fragments, pyran structural units and spiroketals. Like the cyclopropane methodology, ether-transfer is an efficient process that proceeds through a unique carbocationic intermediate and rapidly modifies simple starting materials into stereochemically complex synthetic fragments. Applications of the methodology include an efficient synthesis of the polyketides, diospongin A and B as well as neopeltolide. Biological and conformational studies on the neopeltolide polyketide core are proposed as a precursor to analogue design.

描述（由申请人提供）：我们的总体计划是关于聚酮化合物天然产物的演变和化疗潜力的基本问题。利用有机合成的力量，我们试图了解聚酮化合物中发现的特定结构特征，它们对构象的影响，以及构象对生物活性的重要性。这项工作的一个基本主题是开发适用于合成聚酮化合物天然产物中立体化学复杂结构片段的实用方法。在研究期间，我们实验室先前开发的阳离子环丙烷方法将提供获得安布鲁特星J的途径，安布鲁特星J是抗真菌剂安布鲁特星S的假定生物合成中间体。该材料将用于探索安布霉素J向安布霉素S的化学和生物化学转化。与Rolf Muller（萨尔兰大学）合作进行的生化研究将提供有关几种PKS后蛋白质（包括环氧酶AmbJ）作用的基本信息。此外，安布霉素J合成所需的中间体将转化为几种标记的SNAC酯，用于生产生物体以及分离蛋白质的饲养研究。喂养研究的分析将提供重要的信息，关于这些环丙烷含聚酮化合物的独特的生物合成。研究计划的第二部分提出了新的方法，醚转移，适用于合成无环聚酮片段，吡喃结构单元和螺缩酮。与环丙烷方法一样，醚转移是一种有效的方法，通过独特的碳阳离子中间体进行，并将简单的起始材料快速改性为立体化学复杂的合成片段。该方法的应用包括有效合成的聚酮化合物，diospongin A和B以及neopeltolide。生物学和构象的neopeltolide聚酮核心的研究提出了类似物设计的先驱。

项目成果

Stereoselective synthesis of the C9-C19 fragment of lyngbyaloside B and C via ether transfer.

• DOI: 10.1021/ol301455p
• 发表时间: 2012-07-06
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Stefan, Eric;Taylor, Richard E.
• 通讯作者: Taylor, Richard E.

Conformation-guided analogue design identifies potential antimalarial compounds through inhibition of mitochondrial respiration.

构象引导的类似物设计通过抑制线粒体呼吸来识别潜在的抗疟化合物。

• DOI: 10.1039/c8ob01257a
• 发表时间: 2018
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Larsen,ErikM;Chang,Chia-Fu;Sakata-Kato,Tomoyo;Arico,JosephW;Lombardo,VinceM;Wirth,DyannF;Taylor,RichardE
• 通讯作者: Taylor,RichardE

Toward an enantioselective synthesis of (-)-zampanolide: preparation of the C9-C20 region.

(-)-zampanolide 的对映选择性合成：C9-C20 区域的制备。

• DOI: 10.1021/ol301383a
• 发表时间: 2012
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Wilson,MatthewR;Taylor,RichardE
• 通讯作者: Taylor,RichardE

Concise enantioselective synthesis of diospongins A and B.

薯海绵素 A 和 B 的简明对映选择性合成。

• DOI: 10.1016/j.tet.2013.05.081
• 发表时间: 2013
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: Stefan,Eric;Nalin,AnselP;Taylor,RichardE
• 通讯作者: Taylor,RichardE

Total Synthesis and Structural Reassignment of Lyngbyaloside C Highlighted by Intermolecular Ketene Esterification.

• DOI: 10.1002/chem.201502132
• 发表时间: 2015-07-20
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Chang CF;Stefan E;Taylor RE
• 通讯作者: Taylor RE