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取代胺的有机分子可以应用于 无数药相关分子的合成。这些有价值的化合物已经 通过使用“间接”引入碳的立体中心的路线准备 需要制备包含的中间体的映射方法或对映选择性方法 α取代的离开组（例如，Zni，卤化物，三叶酸盐，三氯乙酸，磷酸盐）；这样的 方法导致冗长且效率低下的途径增加所需时间 为了保护所需的分子，大大增加了制备化合物的成本 对人类的医疗保健很重要。还有选择性和底物范围的问题： 不仅必须通过使用 易于访问且具有成本效益的催化剂，兼容基材范围的扩展 是势在必行的。特别挑战是导致手性α取代胺的方案和 通过对映的，对映射和调节性激活的乙烯 氨基或α-螺丝骨C – H键。我们将开发结合一个催化过程 各种核phobiles（Enolates，Breslow中间体，Enamies，（Hetero）领域， 烯丙基硅烷，胺和醇）以及胺或醚在单个操作中产生 - a 非映体纯净且高度映体富集的产物。产生的化合物 将包含一个或两个立体中心。有些也将携带α-或β-氨基羰基单元 如α-（杂种）芳基，在生物学活性中是必不可少的构件 分子。其他人则将携带α-酰基，β-羰基，α-（杂种）芳基，α-氨基，α-烷氧基部分。 因此，各种手性α-取代的胺和醚化合物将很容易获得。 这些实体的准备否则将需要一些行动，有时可以 以中等的选择性进行。手性有机甲催化剂和路易斯酸共催化剂 将用于促进拟议的转换。我们将利用上述策略来 设计途径比先前披露的途径要高得多。我们将 开发可用于生物学的晚期功能的催化过程 重要的胺和乙醚分子。在与药物相关的分子中 经受晚期功能的作用是c cymbalta，sensipar，哌醋甲酯， 美托洛尔，vyvanse和oxycontin，以及各种脱氧糖分子。