Synthesis of Polyketides and Terpenes

聚酮化合物和萜烯的合成

• 批准号: 7460700
• 负责人: David A Evans
• 金额: $ 40.66万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460700
• 关键词: 3-hydroxybutanal; Address; Antibiotics; Antineoplastic Agents; Biological; Biological Factors; Biology; Carbon; Chemicals; Class; Complex; Conceptions; Coupling; Development; Discipline; Evaluation; Event; Facility Construction Funding Category; Family; Goals; Grant; Hallucinogens; Intention; Medicine; Methodology; Object Attachment; Organic Synthesis; Peptide Fragments; Peptide Synthesis; Pharmaceutical Preparations; Phorbol; Phorbols; Polynucleotides; Process; Psychotropic Drugs; Reaction; Research; Series; Structure; Tars; Technology; Terpenes; Terramycin; Tetracycline; Tetracyclines; Tumor Promoters; aflastatin A; amphidinol 3; analog; chemical reaction; chemical synthesis; chemotherapeutic agent; clinically significant; cytotoxic; design; 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）：这项正在进行的研究的目标是为合成具有临床意义的生物学活性的复杂自然发生的物质做出创造性贡献。该赠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聚酮化合物抗生素和抗肿瘤剂的不对称合成。合成靶标将包括二苯二甲醇3，阿映蛋白3，（+）peloruside A，salvinorin A，Phorbol和抗生素四环素家族。在Salvinorin A，Phorbol和Tetracycline的设计中，已经说明了从无环前体合成多环状结构的一种重要新方法。所有这些合成始于由无环立体控制在化学调节的键结构开始。然后，碳框架由中环大环的一系列分子内跨性别过程组装。与多核苷酸，肽和多糖一起，聚酮化合物代表了由共同亚基组装的第四个自然存在的材料家族。在扩展与肽合成的比较时，通过复杂的藻键构建体的聚酮化合物组装是一个更大的挑战，即类似的肽片段组装类比，因为在片段耦合事件中最多创建了多达两个新的立体中心。我们在这笔赠款中的长期目标是开发组装聚酮化合物衍生的天然产品的所有方法。该目标包括开发手性烯醇酸化方法，对羰基上的远程立体中心的研究和Pi-face选择性的研究以及开发了双立体差异化aldol添加反应的预测模型。目的是提高反应设计可预测性。聚酮化合物靶标是二苯酚A，脂肪蛋白3，peloruside和salvinorinA。化学合成提供了产生化学疗法剂的能力，化学反应是从事药物发现过程的药物化学家的不可替代工具。化学反应技术的进步减少了化学实体作为潜在药物的概念与随后的生物学评估的合成之间的间隔。结果，有机综合是一项关键学科，它继续对医学和生物学领域产生重要影响。