Site-Selective Catalysis for Organic Synthesis

描述（由申请人提供）：我们希望开发用于复杂分子的选择性官能化的新范例。我们的方法是基于生物活性剂中普遍存在的官能团的基本反应的发展。该提案的主要重点是开发易于制造的催化剂库，其目标是羟基，胺和芳烃C-H键的官能化。因此，我们希望开发的主力反应是羟基转移反应（酰化、磷酸化、磺酰化和硫代羰基化）、胺基转移反应和亲电子芳族取代反应。这些过程中的每一个都在我们的实验室中得到了不同程度的发展，我们现在希望在适当的承诺水平上研究它们，使它们真正适用于复杂的分子领域。选择性多元醇衍生化反应本身对于天然产物类似物的生成具有价值。此外，我们将研究的反应可以用作附加的、增值的转化的跳板（例如，置换反应、脱氧等）。多胺中的催化、位点选择性胺官能化几乎是未知的，我们已经开始了用可推广的催化剂平台开发这些工艺的第一步。在复杂的多环芳烃天然产物中的位置选择性C-H键官能化也是如此。我们对这些基本化学反应中的每一个的研究都是从对映选择性反应的考察开始的。这些过程在不对称催化领域具有重要意义。在所提出的反应类型中的对映选择性反应的发展通常提供了前所未有的以单一对映体形式的结构单元。但是，我们的总体目标的意义可能会更大，因为这些研究定义了催化原理，催化剂支架，然后可以应用于复杂的，生物活性的天然产物的位点选择性修饰。这些研究使得在区域选择性催化的较少研究的竞技场中能够进行系统的和基础的研究。最后，我们将应用新的催化剂库选择性衍生化的重要和迷人的生物制剂，包括蒿甲醚，新霉素，万古霉素和替考拉宁。在每一种情况下，我们都进行了合作，使我们的研究的影响超出了我们自己的实验室，帮助从事我们将多样化的天然产品的生物学研究的同事。

DESCRIPTION (provided by applicant): We wish to develop a new paradigm for the selective functionalization of complex molecules. Our approach is predicated on the development of fundamental reactions of functional groups that are ubiquitous in bioactive agents. The main emphasis of this proposal is the development of simple-to-make catalyst libraries that target functionalization of hydroxyl groups, amines and arene C-H bonds. Thus, the workhorse reactions we wish to develop are hydroxyl group transfer reactions (acylation, phosphorylation, sulfonylation and thiocarbonylation), amine group transfer reactions, and electrophilic aromatic substitutions. Each of these processes has been developed to varying degrees in our laboratory, and we now wish to study them at appropriate levels of commitment to render them truly applicable in complex molecular arenas. Selective polyol derivatization reactions have value in and of themselves for natural product analog generation. Moreover, the reactions we will study may be used as a springboard for additional, value-added transformations (e.g., displacement reactions, deoxygenations, inter alia). Catalytic, site-selective amine functionalization within polyamines is virtually unknown, and we have initiated first steps for the development of these processes with a generalizable catalyst platform. So too of site-selective C-H bond functionalization in complex polycyclic arene-containing natural products. Our study of each of these fundamental chemical reactions begins with examination of enantioselective reactions. These processes are important to the field of asymmetric catalysis. Development of enantioselective reactions in the proposed reaction types affords generally unprecedented access to building blocks in single enantiomer form. But, the significance for our overall goals may be even greater as these studies define catalysis principles, and catalyst scaffolds that may then be applied to the site-selective modification of complex, bioactive natural products. These studies enable systematic and fundamental research in the less well-studied arena of regioselective catalysis. In the end, we will apply the new catalyst libraries to the selective derivatization of important and fascinating biological agents, including apoptolidin, neomycin, vancomycin and teicoplanin. In each case, collaborations are in place so that the impact of our studies will extend beyond our own laboratory, assisting colleagues engaged in biological studies of the natural products we will diversify.