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: 8045107
• 负责人: Scott J Miller
• 金额: $ 29.92万
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045107
• 关键词: Alkenes; Arachidonic Acids; Area; Aspartate; Aspartic Acid; Biological; Biological Factors; Carboxylic Acids; Catalysis; Collaborations; Complex; Development; Electrons; Employee Strikes; Environment; Esters; Evaluation; Family; Geldanamycin; Generations; Goals; Hydrogen Peroxide; Indoles; Ketones; Laboratories; Lead; Libraries; Methods; Modification; Oligomycins; Peptides; Pharmaceutical Chemistry; Polyenes; Process; Reaction; Research; Scheme; Site; Site-Directed Mutagenesis; Solutions; Steroids; Testing; Work; analog; base; catalyst; frontier; functional group; novel; oxidation; polyol; scaffold; success; tool; tv watching

DESCRIPTION (provided by applicant): We wish to develop a new paradigm for the selective oxidation of complex molecules. Our approach is based on the unified development of the now-validated approach of "aspartic acid catalysis." More generally, we have documented previously unknown catalytic cycles for olefin epoxidation and the Baeyer-Villiger oxidation, wherein a carboxylic acid functions as a catalytic moiety. We are particularly eager to explore this unique catalytic strategy for these two venerable processes, which engage an intermediate peracid moiety for mechanistically distinct functions: 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 in remote, isolated olefin functionalization. We will also explore selective epoxidations of highly substituted, electron-rich arenes, such as indoles, that are relevant to natural product synthesis. We will expand the catalysts' diversity through the synthesis of libraries that will be applied to the regioselective epoxidation of polyene-containing natural products. These same catalysts will also be applied to 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 carbonyl sites. 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 are in place so that the impact of our studies will expand beyond our own laboratory, assisting colleagues engaged in complex molecule total synthesis, and in the biological evaluation of the new natural product analogs we obtain. PUBLIC HEALTH RELEVANCE: We wish to develop a new paradigm for the selective oxidation of complex molecules. Success in this endeavor will enable efficient synthesis of complex, biologically active molecules. A particular emphasis will be on natural product diversification, which is a long-standing problem in the field of medicinal chemistry.

描述（由申请人提供）：我们希望开发一种用于复杂分子选择性氧化的新范例。我们的方法基于现已验证的“天冬氨酸催化”方法的统一开发。更一般地，我们已经记录了用于烯烃环氧化和Baeyer-Villiger氧化的先前未知的催化循环，其中羧酸充当催化部分。我们特别渴望探索这两个古老过程的独特催化策略，它们利用中间过酸部分来实现机械上不同的功能：在环氧化中，过酸充当亲电试剂；在拜尔-维利格氧化中，过酸充当亲核试剂。我们的具体目标包括为每个过程开发活性更高、选择性更强的催化剂。我们打算推动环氧化反应的前沿，其中古老的催化剂会失效，包括应用于远程、孤立的烯烃官能化问题。我们还将探索与天然产物合成相关的高度取代、富电子芳烃（例如吲哚）的选择性环氧化。我们将通过合成库来扩展催化剂的多样性，这些库将应用于含多烯天然产物的区域选择性环氧化。这些相同的催化剂也将应用于对映选择性Baeyer-Villiger氧化反应，这是一类从对映选择性催化角度来看确实尚未开发的催化反应。这些研究还将探索对含有多个羰基位点的天然产物进行位点选择性拜耳-维利格氧化。一直以来，这项工作将在进行机理研究的环境中进行，以增强我们对所发现的选择性反应的理解。同样，合作也已到位，以便我们研究的影响将扩展到我们自己的实验室之外，协助同事从事复杂分子的全合成，以及我们获得的新天然产物类似物的生物学评估。 公共健康相关性：我们希望开发一种复杂分子选择性氧化的新范例。这一努力的成功将使复杂的生物活性分子的有效合成成为可能。特别强调天然产物多样化，这是药物化学领域长期存在的问题。