Selective Peptide-Based Oxidation Catalysts for Bioactive Molecule Synthesis

用于生物活性分子合成的选择性肽基氧化催化剂

• 批准号: 8886125
• 负责人: Scott J Miller
• 金额: $ 30.44万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886125
• 关键词: Alkenes; Aspartic Acid; Biological; Biological Factors; Carboxylic Acids; Catalysis; Chemistry; Collaborations; Complex; Development; Electrons; Environment; Epoxy Compounds; Evaluation; Furans; Goals; Hydrogen Bonding; Hydrogen Peroxide; Indoles; Ketones; Laboratories; Lead; Libraries; Methods; Modification; Molecular; Oxides; Peptides; Pharmaceutical Chemistry; Phase; Polyenes; Process; Pyrroles; R peptide; Reaction; Relative (related person); Research; Site; Site-Directed Mutagenesis; Solutions; Staging; Time; Work; analog; base; catalyst; combinatorial; complex R; design; frontier; functional group; halogenation; interest; metal complex; oxidation; peptide A; peptide B; polyol; public health relevance; scaffold; stereochemistry; success; tool

 DESCRIPTION (provided by applicant): We wish to develop a new paradigm for the selective oxidation of complex molecules. Our approach will extend the development of the now-validated paradigm of "aspartic acid catalysis." We will also develop additional catalysis paradigms based on catalytic ketones and metal complexes. All of the catalytic centers to be developed will be incorporated into peptides. The peptide-based scaffolds will provide the molecular environment that will be responsible for selectivity. Enantioselective reactions, as well as those that deal wih regio-, chemo- and site-selectivity will be explored. This project began with previously unknown catalytic cycles for olefin epoxidation and the Baeyer-Villiger oxidation, wherein a carboxylic acid functions as a catalytic moiety. We are now poised to explore this unique catalytic strategy for these two venerable processes, each of which engages an intermediate peracid moiety for a mechanistically distinct function: in epoxidation, the peracid functions as an electrophile; in the Baeyer-Villiger oxidation, the peracid functions as a nucleophile. Our specific goals include development of ever-more active and selective catalysts for each process. We intend to push the frontiers for epoxidations wherein venerable catalysts fail, including applications to problems involving remote olefin functionalization when several alkenes are present. We will also examine these catalysts for site- and enantioselective oxidations of conjugated polyenes, so commonly found in complex natural products. We will also continue our studies of selective epoxidations of highly substituted, electron-rich arenes, such as indoles, furans and pyrroles; the products of these reactions will be relevant to natural product synthesis, as well as for the synthesis of natural product analogs. We plan to expand greatly our study of enantioselective Baeyer-Villiger oxidations, a class of catalytic reactions that are truly under-developed from the standpoint of enantioselective catalysis. These studies will also lead to explorations of site-selective Baeyer-Villiger oxidations performed on natural products containing multiple ketone sites. This work will enable an aggressive set of applications involving the catalyst-dependent diversification of biologically active natural products. All the while, this work will be conducted in an environment where mechanistic studies will be performed to enhance our understanding of the selective reactions we discover. So too, collaborations and plans are in place so that the impact of our studies will extend beyond our own laboratory, assisting colleagues engaged in complex molecule synthesis, and in the biological evaluation of the new natural product analogs we obtain.

 描述（由申请人提供）：我们希望开发一种用于复杂分子的选择性氧化的新范例。我们的方法将扩展现在验证的“天冬氨酸催化”范例的发展。“我们还将开发基于催化酮和金属络合物的其他催化范例。所有待开发的催化中心都将被整合到肽中。基于肽的支架将提供负责选择性的分子环境。对映选择性反应，以及那些涉及区域，化学和位点选择性将被探讨。该项目始于以前未知的烯烃环氧化和Baeyer-Villiger氧化的催化循环，其中羧酸作为催化部分起作用。我们现在准备探索这两个古老过程的独特催化策略，其中每一个都涉及一个中间过酸部分，用于机械上不同的功能：在环氧化中，过酸作为亲电体;在环氧化中，过酸作为亲电体。 Baeyer-Villiger氧化，过酸作为亲核试剂起作用。我们的具体目标包括为每种工艺开发活性和选择性更高的催化剂。我们打算推动环氧化的前沿，其中古老的催化剂失败，包括应用于问题 包括当存在几种烯烃时的远距离烯烃官能化。我们还将研究这些催化剂的共轭多烯，所以常见于复杂的天然产物的网站和对映体选择性氧化。我们还将继续研究高度取代的富电子芳烃，如吲哚，呋喃和吡咯的选择性环氧化反应;这些反应的产物将与天然产物合成以及天然产物类似物的合成有关。我们计划大大扩展我们的研究对映选择性Baeyer-Villiger氧化，一类催化反应，是真正欠发达的对映选择性催化的立场。这些研究还将导致对含有多个酮位点的天然产物进行位点选择性Baeyer-Villiger氧化的探索。这项工作将使一组积极的应用程序，涉及催化剂依赖的生物活性天然产物的多样化。一直以来，这项工作将在进行机制研究的环境中进行，以增强我们对发现的选择性反应的理解。同样，合作和计划也已经到位，以便我们研究的影响将超出我们自己的实验室，帮助从事复杂分子合成的同事，以及我们获得的新天然产物类似物的生物学评价。