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

• 批准号: 10178042
• 负责人: Masayuki Wasa
• 金额: $ 39.13万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178042
• 关键词: Acids; Alcohols; Amines; Biological; Breslow Thickness; Carbon; Deoxy Sugars; Ethers; Healthcare; Human; Hydrogen Bonding; Lead; Methods; Metoprolol; Oxycodone; Pathway interactions; Preparation; Process; Reaction; Research; Ritalin; Route; Scheme; Secure; Silanes; Time; Vyvanse; base; catalyst; cost; cost effective; design; enolate; inorganic phosphate; method development; operation; trichloroacetamide

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.

项目摘要 含有手性α-取代的胺和醚的有机分子可以应用于 无数与医学相关的分子的合成。这些有价值的化合物已经被 通过其中使用“间接”引入碳基立体中心的途径制备 非对映体或对映体选择性方法，其需要制备含有 α-取代的离去基团（例如，ZnI、卤化物、三氟甲磺酸盐、三氯乙酰亚胺酸盐、磷酸盐）; 方法导致冗长和有点低效的途径，增加了所需的时间 以获得所需的分子，这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： 不仅必须通过使用 易于获得且具有成本效益的催化剂，扩大了兼容基材的范围 是必须的特别具有挑战性的是导致手性α-取代的胺的方案， 醚通过对映体，非对映体和区域选择性活化，否则不反应的α- 氨基或α-醚C-H键。我们将开发结合联合收割机和 亲核试剂的分类（烯醇化物、Breslow中间体、烯胺、（杂）芳烃，和 烯丙基硅烷、胺和醇）和胺或醚，以在单一操作中生成 非对映体纯和高度对映体富集的产物。所得化合物 将包含一个或两个立体中心。有些还带有α-或β-氨基羰基单元 作为α-（杂）芳基、α-烯丙基氨基单元，它们是生物活性中不可或缺的结构单元 分子。其它基团带有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; 否则，这些实体的准备将需要几个操作， 以中等选择性进行。手性有机硼烷催化剂和刘易斯酸助催化剂 将用于促进拟议的转型。我们将利用上述战略， 设计比先前公开的那些显著更有效的路径。我们将 开发可用于生物活性物质后期功能化的催化方法， 重要的胺和醚分子。在医学相关的分子中， 进行后期官能化的是欣百达，Sensipar，哌醋甲酯， 美托洛尔、维凡斯和奥施康定，以及各种脱氧糖分子。