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Catalytic and Stereoselective C-C-Heteroatom Bond Forming Reactions

催化和立体选择性 C-C-杂原子键形成反应

基本信息

批准号：
10623833
负责人：
Masayuki Wasa
金额：
$ 45.7万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2028-06-30
项目状态：
未结题

项目摘要

Strategies to access desirable analogues of natural products and pharmaceuticals in efficient, practical, cost-effective, and stereoselective manners are central to organic synthesis and drug discovery. Total synthesis of such analogues is often lengthy and inefficient, thus increasing the time required to secure the desired molecules, as well as the cost of preparing compounds that are important to human healthcare. Particularly attractive but challenging are schemes that enable direct transformation of ubiquitous but otherwise chemically inert C–H bonds that are contained in the polyfunctional bioactive molecules. We will develop catalytic processes that entail oxidation of amine, ether, or thioether-based small molecule drugs into the corresponding enamine, enol ether or thioenol ether derivatives; such intermediates will then be coupled with various chemical tagging agents to generate – in a single operation – a library of drug derivatives. The resulting compounds will contain ‘clickable’ handles that can be used as a handle for bioconjugation. Some will carry tags for structure-activity relationship studies (e.g., biotin, fluorophore), and/or photoaffinity labels for chemoproteomics (e.g., arylazide, diazirine). Various desirable analogues of N, O, and/or S-based medicinal agents will thus become readily accessible; preparation of these entities by total synthesis would either be impossible or substantially more cumbersome. A combination of Lewis acid and Brønsted base catalysts will be used to promote the proposed transformations. We will utilize the above strategies to design pathways that are significantly more efficient and broadly applicable than those previously disclosed. Among the medicinally relevant molecules that will be subjected to the late-stage functionalization are important anticancer agents such as alectinib, carfilzomib, and venetoclax.

以高效、实用、经济有效和立体选择性的方式是有机合成和药物的核心发现号。这种类似物的完全合成通常是冗长和低效的，因此增加了获得所需分子所需的时间，以及制备化合物的成本对人类健康很重要。特别有吸引力但具有挑战性的计划是使无处不在但在其他方面化学惰性的C-H键能够直接转化为包含在多官能团生物活性分子中。我们将开发催化过程，需要将胺、乙醚或硫醚类小分子药物氧化成相应的烯胺、烯醇醚或硫代烯醚衍生物；然后将这些中间体与在一次操作中生成一个药物库的各种化学标记剂衍生品。生成的复合体将包含可被用作用于生物接合的手柄。一些将携带用于结构-活性关系研究的标签(例如，生物素、荧光团)和/或用于化学蛋白质组学的光亲和标记(例如芳拉齐特、二氮杂环)。因此，基于N、O和/或S的药物的各种理想的类似物将容易地成为可获得的；通过完全合成来制备这些实体要么是不可能的，要么是要麻烦得多。路易斯酸和布朗斯特碱催化剂的组合将用于促进拟议的转型。我们将利用上述策略来设计比以前更有效和更广泛适用的途径已披露。在医学上相关的分子中，将受到后期的影响功能化是重要的抗癌药物，如阿莱替尼、卡非佐米和文奈德。