Site-Selective Catalysis for Organic Synthesis

描述(申请人提供)：我们希望为复杂分子的选择性官能化开发一种新的范例。我们的方法是基于生物活性物质中普遍存在的官能团的基本反应的发展。这一建议的主要重点是开发以羟基、胺和芳烃C-H键的官能化为目标的易于制造的催化剂库。因此，我们希望发展的主要反应是羟基转移反应(酰化、磷酸化、磺化和硫代羰化)、胺基转移反应和亲电芳香取代反应。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对它们进行研究，使它们真正适用于复杂的分子领域。选择性多元醇衍生物反应本身对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能被用作额外的、增值转化的跳板(例如置换反应、除氧等)。多胺中催化的、位置选择性的胺功能化几乎是未知的，我们已经启动了利用可推广的催化剂平台开发这些过程的第一步。含多环芳烃的复杂天然产物中C-H键的位置选择性官能化也是如此。我们对每一种基本化学反应的研究都始于对映体选择性反应的考察。这些过程对不对称催化领域具有重要意义。在所提出的反应类型中，对映体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构建的构件。但是，对于我们的总体目标来说，意义可能更大，因为这些研究定义了催化原理，以及随后可能应用于复杂的生物活性天然产物的现场选择性修饰的催化剂支架。这些研究使得在区域选择性催化这一研究较少的领域进行系统和基础研究成为可能。最后，我们将新的催化剂文库应用于包括凋亡素、新霉素、万古霉素和替考拉宁在内的重要生物制剂的选择性衍生化反应中。在每一种情况下，都进行了合作，以便我们研究的影响将延伸到我们自己的实验室之外，帮助从事自然产品生物学研究的同事，我们将使其多样化。 与公共健康相关：我们希望开发选择性合成复杂天然产品支架的新范例。这一领域的进展将使高效合成复杂的生物活性分子成为可能。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。

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. PUBLIC HEALTH RELEVANCE: We wish to develop new paradigms for the selective synthesis of complex natural product scaffolds. Progress in this field will enable efficient syntheses 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.