Reaction Development Using Amphoteric Reagents and Organocatalysts

大多数治疗疾病和改善我们生活质量的药物都是从激烈的药物化学努力中产生的。临床候选药物是从数千种潜在的分子中选出的，每一种分子都经过设计，平均经过8步合成，并经过彻底的测试。化学创新是这一努力的核心，工业界迅速采用新技术，以提高药物发现过程的效率。我们的项目集中在开发新的反应和催化剂，用于合成含氮原子的关键结构亚基，这些亚基存在于95%以上的候选药物中。最终，这些反应提供了更有效的生物活性分子的形成，并能够形成新的化合物，用于结构-活性关系研究和药物开发。从绿色化学的角度来看，这些努力也很重要，因为提高效率的反应本身也会最大限度地减少“化学废物”的产生，而“化学废物”仍然是与药物开发和生产相关的一个重要问题。本研究中开发和针对的反应使用廉价的试剂和催化剂，允许在农用化学品和散装化学品的合成中的额外应用。基于在使用羟胺和肼合成含氮分子中获得的动力，将开发新的“不寻常”异氰酸酯家族的反应性。这将为一个具有重要工业意义的领域提供新的试剂和策略：每年使用数百万吨异氰酸酯形成价值超过100亿美元的产品。同时，将开发使用醛作为简单催化剂的反应，从酶中汲取灵感，以及它们如何加速困难的分子间反应。一个特别的重点将是表明，这些醛催化各种困难的水合和水解反应，通过邻近效应，模仿水解酶和水合酶的催化功能。除了为目前工业上使用的条件提供急需的替代品（例如在药物中形成非天然氨基酸）之外，这些研究还将显示简单醛作为催化剂在负责“生命起源”的化学中的重要性。作为这项研究的一部分，学生将接受培训，非常适合未来在药物化学，农业化学和散装化学（异氰酸酯）部门的工作。还将寻求因发现上述新技术而可能产生的商业和技术转让机会。

Most pharmaceuticals that cure diseases and improve our quality of life have emerged from intense medicinal chemistry efforts. Clinical candidates are selected from thousands of potential molecules, each of which has been designed, synthesized in an average of 8 steps, and thoroughly tested. Chemical innovation is at the core of this endeavour, and new technologies are rapidly adopted by industry in an effort to improve the efficiency of the drug discovery process. Our program is centred on the development of new reactions and catalysts for the synthesis of key structural subunits containing nitrogen atoms, which are present in >95% of drug candidates tested. Ultimately, these reactions provide more efficient formation of biologically-active molecules and enable the formation of new compounds for structure-activity relationship studies and drug development. These efforts are also important from a Green Chemistry perspective, as reactions that result in increased efficiency also inherently minimize the generation of “chemical waste”, which remains an important issue associated with the development and production of pharmaceuticals.******The reactions developed and targeted in this research make use of inexpensive reagents and catalysts, allowing additional applications in the synthesis of agrochemicals and bulk chemicals. Building on momentum gained in the synthesis of nitrogen-containing molecules using hydroxylamines and hydrazines, the reactivity of new families of “unusual” isocyanates will be developed. This will provide new reagents and strategies in a field of significant industrial importance: millions of tons of isocyanates are used annually to form products that are worth >$ 10 billion. In parallel, reactions using aldehydes as simple catalysts will be developed, drawing inspiration from enzymes, and how they accelerate difficult intermolecular reactions. A special focus will be to show that these aldehydes catalyze a variety of difficult hydration and hydrolysis reactions through a proximity effect, mimicking the catalytic function of hydrolase and hydratase enzymes. Beyond providing much needed alternatives to the conditions currently used industrially (for example to form unnatural amino-acids in pharmaceuticals), these studies will show the importance of simple aldehydes as catalysts in the chemistry responsible for the “origin of life”.***As part of this research, students will receive training that is ideally suited for future work in medicinal chemistry, agrochemistry and bulk chemistry (isocyanates) sectors. Business and technology transfer opportunities that could result from the discovery of the new technologies described above will also be pursued.**