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: 8197614
• 负责人: Scott J Miller
• 金额: $ 29.8万
• 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/8197614
• 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; public health relevance; 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(申请人提供)：我们希望为复杂分子的选择性氧化开发一种新的范例。我们的方法是基于现已得到验证的“天冬氨酸催化”方法的统一开发。更广泛地说，我们记录了以前未知的烯烃环氧化和Baeyer-Villiger氧化的催化循环，其中羧酸起催化部分的作用。我们特别渴望为这两个古老的过程探索这一独特的催化策略，这两个过程都使用了一个中间过酸部分来实现机械上不同的功能：在环氧化中，过酸起着亲电试剂的作用；在Baeyer-Villiger氧化中，过酸起着亲核试剂的作用。我们的具体目标包括为每一种工艺开发更具活性和选择性的催化剂。我们打算推动传统催化剂失效的环氧化反应的前沿，包括应用于遥远的、孤立的烯烃功能化问题。我们还将探索与天然产物合成相关的高取代、富含电子的芳烃的选择性环氧化反应，如吲哚。我们将通过合成文库来扩大催化剂的多样性，这些文库将应用于含多烯的天然产物的区域选择性环氧化。这些催化剂还将应用于对映选择性Baeyer-Villiger氧化反应，这类催化反应从对映选择性催化的观点来看是真正不发达的。这些研究还将导致探索在含有多个羰基的天然产物上进行的选择性Baeyer-Villiger氧化反应。在此期间，这项工作将在一个环境中进行，其中将进行机械研究，以增强我们对我们发现的选择性反应的理解。同样，我们也进行了合作，以便我们的研究的影响将扩展到我们自己的实验室之外，帮助从事复杂分子全合成的同事，以及对我们获得的新的天然产品类似物进行生物学评估。 与公共健康相关：我们希望为复杂分子的选择性氧化开发一种新的范例。这一努力的成功将使高效合成复杂的、具有生物活性的分子成为可能。将特别强调天然产物的多样化，这是药物化学领域的一个长期问题。