Synthesis of Polyketides and Terpenes

聚酮化合物和萜烯的合成

• 批准号: 7847436
• 负责人: David A Evans
• 金额: $ 42.41万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-05 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847436
• 关键词: 3-hydroxybutanal; Address; Antibiotics; Antineoplastic Agents; Biological; Biological Factors; Biology; Carbon; Chemicals; Complex; Conceptions; Coupling; Development; Discipline; Evaluation; Event; Family; Goals; Grant; Hallucinogens; Intention; Medicine; Methodology; Organic Synthesis; Peptide Fragments; Peptide Synthesis; Phorbol; Phorbols; Polynucleotides; Process; Psychotropic Drugs; Reaction; Research; Series; Structure; Tars; Technology; Terpenes; Terramycin; Tetracyclines; Tumor Promoters; aflastatin A; amphidinol 3; analog; chemical reaction; chemical synthesis; chemotherapeutic agent; clinically significant; cytotoxic; design; drug candidate; drug discovery; enolate; improved; innovation; marine natural product; new technology; novel strategies; peloruside A; polysaccharide peptide; predictive modeling; salvinorin A; tool

DESCRIPTION (provided by applicant): The objectives of this ongoing proposed research are to make creative contributions to the synthesis of complex naturally occurring substances possessing clinically significant biological activity. This grant will continue to develop new stereoselective reactions and the application of this methodology to the asymmetric synthesis of complex polyketide antibiotics and antineoplastic agents. The synthesis targets will include amphinidinol 3, aflastatin 3, (+) peloruside A, salvinorin A, phorbol, and the tetracycline family of antibiotics. An important new approach in the synthesis of polycyclic structures from acyclic precursors has been illustrated in the design of salvinorin A, phorbol, and tetracycline. All of these syntheses begin with bond constructions that are stereochemically regulated by acyclic stereocontrol. The carbon framework is then assembled by a series of intramolecular, transannular processes from medium-ring macrocycles. Along with polynucleotides, peptides, and polysaccharides, polyketides represent the fourth broad family of naturally occurring materials that are assembled from common subunits. In extending the comparison with peptide synthesis, polyketide assembly through complex aldol bond constructions is a far greater challenge that the analogous peptide fragment assembly analogy since up to two new stereocenters are created during the fragment coupling event. Our long term objective in this grant has been the development of all of the methodology to assemble polyketide-derived natural products. This objective includes the development of chiral enolate methodology, the study of remote stereocenters on carbonyl and enolate pi-face selectivities, and the development of predictive models for double stereodifferentiating aldol addition reactions. The goal is to improve reaction design predictability. The polyketide targets are amphidinol A, aflastatin 3, peloruside, and salvinorin A. Chemical synthesis provides the capacity to produce chemotherapeutic agents, and chemical reactions are the irreplaceable tools of the medicinal chemist engaged in the drug discovery process. Advances in chemical reaction technology reduce the interval between the conception of the chemical entity as a potential drug candidate and its synthesis for subsequent biological evaluation. As a consequence, organic synthesis is a critical discipline that continues to have an important impact on the fields of both medicine and biology.

描述（由申请人提供）：这项正在进行的拟议研究的目标是对具有临床显著生物活性的复杂天然存在物质的合成做出创造性贡献。这笔拨款将继续发展新的立体选择反应，并将这种方法应用于复杂的聚酮类抗生素和抗肿瘤药物的不对称合成。合成的靶点将包括amphinidinol 3、aflastatin 3、（+）peloruside A、salvinorin A、phorbol和四环素家族抗生素。从无环前体合成多环结构的一个重要的新方法已经在salvinorin A， phorbol和四环素的设计中得到了说明。所有这些合成都是从由非环立体控制的立体化学调节的键结构开始的。然后，碳骨架通过一系列分子内、跨环过程从中环大环组装。与多核苷酸、多肽和多糖一起，多酮类化合物代表了由共同亚基组装而成的第四大类天然物质。在扩展与肽合成的比较中，通过复杂的醛醇键构建聚酮组装比类似的肽片段组装类比更具挑战性，因为在片段偶联事件中产生了多达两个新的立体中心。我们在这笔拨款中的长期目标是开发所有组装聚酮衍生天然产品的方法。这一目标包括手性烯醇酯方法学的发展，羰基和烯醇酯远端立体中心选择性的研究，以及双立体分化醛醇加成反应的预测模型的发展。目标是提高反应设计的可预测性。聚酮靶点是两性酚A、黄萎病素3、佩洛苷和salvinorin A。化学合成提供了生产化疗药物的能力，化学反应是药物化学家在药物发现过程中不可替代的工具。化学反应技术的进步缩短了从化学实体作为潜在候选药物的概念到随后进行生物学评价的合成之间的间隔。因此，有机合成是一门关键学科，继续对医学和生物学领域产生重要影响。

项目成果

A macrocyclic approach to tetracycline natural products. Investigation of transannular alkylations and Michael additions.

• DOI: 10.1021/ol302691j
• 发表时间: 2012-11
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: J. Wzorek;Thomas F Knöpfel;Ioannis Sapountzis;D. A. Evans

Total synthesis of (+)-azaspiracid-1. An exhibition of the intricacies of complex molecule synthesis.

• DOI: 10.1021/ja804659n
• 发表时间: 2008-12-03
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Evans, David A.;Kvaerno, Lisbet;Dunn, Travis B.;Beauchemin, Andre;Raymer, Brian;Mulder, Jason A.;Olhava, Edward J.;Juhl, Martin;Kagechika, Katsuji;Favor, David A.
• 通讯作者: Favor, David A.