Site-Selective Catalysis for Organic Synthesis

有机合成的位点选择性催化

基本信息

批准号：
8664871
负责人：
Scott J Miller
金额：
$ 31.97万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2016-05-31
项目状态：
已结题

项目摘要

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.

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功能化的新范例。我们的方法基于生物活性剂中普遍存在的官能团基本反应的发展。该提案的主要重点是开发易于制造的催化剂库，以羟基、胺和芳烃 C-H 键的功能化为目标。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芳香族取代。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开发，我们现在希望在适当的承诺水平上研究它们，以使它们真正适用于复杂的分子领域。选择性多元醇衍生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额外的增值转化（例如置换反应、脱氧反应等）的跳板。多胺内的催化、位点选择性胺官能化实际上是未知的，我们已经通过通用催化剂平台启动了开发这些工艺的第一步。复杂的含多环芳烃的天然产物中的位点选择性 C-H 键官能化也是如此。我们对这些基本化学反应的研究都是从检查对映选择性反应开始的。这些过程对于不对称催化领域很重要。在所提出的反应类型中对映选择性反应的发展提供了前所未有的单一对映体形式的构建块的途径。但是，由于这些研究定义了催化原理和催化剂支架，因此对我们总体目标的意义可能更大，然后可以将其应用于复杂的生物活性天然产物的位点选择性修饰。这些研究使得在研究较少的区域选择性催化领域进行系统和基础研究成为可能。最后，我们将应用新的催化剂库来选择性衍生重要且令人着迷的生物制剂，包括凋亡素、新霉素、万古霉素和替考拉宁。在每种情况下，我们都会进行合作，以便我们研究的影响力超越我们自己的实验室，协助从事我们将多样化的天然产品的生物学研究的同事。