Catalytic and Stereoselective C-C-Heteroatom Bond Forming Reactions

项目摘要 含有手性α取代胺和醚的有机分子可以应用于 合成了无数与医学相关的分子。这些有价值的化合物一直是 由其中碳基立体生成中心被引入的路线制备而成 要求制备含有以下物质的中间体的非对映或对映选择性方法 α取代的离开基团(例如，锌、卤化物、三氟酸盐、三氯乙酰亚胺、磷酸盐)； 方法会导致冗长且有些低效的路径，从而增加所需的时间 为了确保所需分子的安全，大大增加了制备化合物的成本 对人类健康很重要。还有选择性和底物范围的问题： 不仅要实现高对映选择性和非对映选择性，还必须通过使用 易于获得且经济高效的催化剂，在兼容底物的范围内扩展 势在必行。特别具有挑战性的是导致手性α取代胺和 乙醚通过对映体、非对映体和区域选择性地激活本来没有反应的α- 氨基或α-醚基C-H键。我们将开发催化过程，将 各种亲核试剂(烯醇酸盐、布雷斯洛中间体、烯胺、(杂环)芳烃和 烯丙基硅烷、胺和醇)和胺或醚在一次操作中生成 非对映体纯度和高度对映体浓缩物。由此产生的化合物 将包含一个或两个立体中心。有些还会带有α-或β-氨基羰基单元 作为α-(杂)芳基，α-烯丙基的氨基单位，是生物活性中不可或缺的构件 分子。其他将携带α-酰基、β-羰基、α-(杂)芳基、α-氨基、α-烷氧基醚部分。 因此，各种手性α取代的胺和醚化合物将变得容易获得； 这些实体的准备否则将需要几个操作，这些操作有时可能 以适度的选择性继续进行。手性有机硼烷催化剂和Lewis酸助催化剂 将用于促进拟议的转型。我们将利用上述战略来 设计的路径比之前披露的路径效率要高得多。我们会 开发可应用于生物后期功能化的催化工艺 重要的胺和乙醚分子。在与医学相关的分子中， 接受后期官能化的有欣百达、森西帕尔、哌甲酯、 美托洛尔、Vyvanse和奥施康定，以及各种脱氧糖分子。

Project Summary Organic molecules containing chiral α-substituted amines and ethers can be applied to the synthesis of countless medicinally relevant molecules. These valuable compounds have been prepared by routes wherein the carbon-based stereogenic center is introduced using “indirect” diastereo- or enantioselective methods that require the preparation of intermediates that contain α-substituted leaving groups (e.g., ZnI, halides, triflate, trichloroacetimidates, phosphates); such approaches lead to lengthy and somewhat inefficient pathways that increase the time required to secure the desired molecules, substantially increasing the cost of preparing compounds that are important to human healthcare. There are also the issues of selectivity and substrate scope: not only must high enantioselectivity and diastereoselectivity be achieved through the use of readily accessible and cost-effective catalysts, expansion in the scope of compatible substrate is imperative. Particularly challenging are schemes that lead to chiral α-substituted amines and ethers through enantio-, diastereo- and regioselective activation of otherwise unreactive α- amino or α-ethereal C–H bonds. We will develop catalytic processes that combine an assortment of nucleophiles (enolates, Breslow intermediates, enamines, (hetero)arenes, and allyl silanes, amines and alcohols), and amines or ethers to generate - in a single operation - a diastereomically pure and highly enantiomerically enriched product. The resulting compounds will contain one or two stereogenic centers. Some will carry α- or β-amino carbonyl units as well as α-(hetero)aryl, α-allyl amino units that are indispensable building blocks in biologically active molecules. Others will carry α-acyl, β-carbonyl, α-(hetero)aryl, α-amino, α-alkoxy ether moieties. Various chiral α-substituted amine and ether compounds will thus become readily accessible; preparation of these entities would otherwise require several operations that can at times proceed with moderate selectivity. Chiral organoborane catalysts and Lewis acid co-catalysts will be used to promote the proposed transformations. We will utilize the above strategies to design pathways that are significantly more efficient than those previously disclosed. We will develop catalytic processes that can be applied for the late stage functionalization of biologically important amine and ether molecules. Among the medicinally relevant molecules that will be subjected to the late stage functionalization are Cymbalta, Sensipar, Methylphenidate, Metoprolol, Vyvanse and OxyContin, as well as various deoxy sugar molecules.