Selective Peptide-Based Oxidation Catalysts for Bioactive Molecule Synthesis

 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。我们的方法将扩展现已得到验证的“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多肽中。基于多肽的支架将提供负责选择性的分子环境。本课程将探讨对映体选择性反应，以及涉及区域、化学和位置选择性的反应。该项目开始于以前未知的烯烃环氧化和Baeyer-Villiger氧化的催化循环，其中羧酸起催化作用。我们现在准备为这两个古老的过程探索这一独特的催化策略，这两个过程中的每个过程都与中间过酸部分结合，以实现机械上不同的功能：在环氧化反应中，过氧酸起着亲电试剂的作用；在 Baeyer-Villiger氧化，过氧酸起亲核剂的作用。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。我们打算推动那些古老的催化剂失效的环氧化反应的前沿，包括应用于问题。 当存在多个烯烃时，涉及远程烯烃官能化。我们还将考察这些催化剂对共轭多烯的定点和对映选择性氧化反应，这些催化剂通常存在于复杂的天然产品中。我们还将继续研究高取代、富含电子的芳烃的选择性环氧化反应，如吲哚、呋喃和吡咯；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。我们计划极大地扩展我们对不对称Baeyer-Villiger氧化的研究，这是一类从不对称催化的观点来看确实不发达的催化反应。这些研究还将导致探索在含有多个酮位的天然产物上进行的选择性Baeyer-Villiger氧化反应。这项工作将使一系列积极的应用成为可能，包括依赖催化剂的生物活性天然产物的多样化。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。因此，合作和计划也已经到位，以便我们的研究的影响将延伸到我们自己的实验室之外，帮助从事复杂分子合成的同事，以及对我们获得的新的天然产品类似物进行生物学评估。

 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.