Preparation and Applications of New Highly Active P-Chiral Phosphine Oxide Catalysts

用于制药和相关工业应用的高价值精细化学品的制造工艺需要低成本、高效和安全的技术，对环境的影响最小。催化方法在这方面特别有吸引力，并且催化不对称还原领域（其中氢气元素在适当控制选择性的情况下添加到合适的基底上）已经通过与氢气结合使用过渡金属催化剂而占主导地位。该领域现在已经相当成熟，并且尽管在许多应用中使用，但是仍然遭受与使用氢气相关的安全问题以及过渡金属催化剂和配体的成本和回收。近年来，使用有机分子作为催化剂的替代方法变得越来越有吸引力，使用氢气的替代品，例如异丙醇和三氯硅烷。用于后者的催化剂通常被分类为刘易斯碱，并且通常是容易获得的低分子量物质。通常只需要10%的催化剂就可以有效地生产所需的产物，通常具有优异的产率和对一种异构体的选择性，尽管这类催化剂的活性足以仅使用1%。我们实验室最近的研究已经开发出一种催化剂，可以常规使用，仅使用1%的活性物质。最近的工作已经建立了一种改进的催化剂，其活性高出两个数量级，并且仅需要0.01%，代表了世界上用于这种类型的转化的最活性的催化物质。我们对这种新催化剂活性的独特理解使我们能够开发基于氧化膦的新催化剂结构，这是迄今为止尚未开发的用于该反应的催化剂。该提案旨在开发有效的化学方法来制备这些催化剂，然后评估，优化和验证它们在制备手性胺中的用途，手性胺是一类在大约三分之一的活性药物成分中发现的分子。与我们目前的合资企业并行，这项新技术可以为制药行业提供令人兴奋的低成本制造解决方案，同时降低使用氢气和过渡金属物种的成本和风险。使用环境可接受的溶剂，几乎没有浪费，进一步突出了这一过程的好处。与此同时，我们的目标是将这些新的催化剂物种应用于各种化学转化的选择，从而举例说明它们作为新兴的新型催化剂的用途。

The manufacturing processes that lead to high value fine chemicals used in pharmaceutical and related industrial applications require low-cost, efficient and safe technologies that have minimal environmental impact. Catalytic processes are especially attractive in this respect, and the area of catalytic asymmetric reduction, where the elements of hydrogen gas are added across a suitable substrate with suitable control of the selectivity, has been dominated by the use of transition metal catalysts in conjunction with hydrogen gas. This field is now fairly mature, and although employed in many applications, still suffers from the safety issues associated with using hydrogen gas and the cost and recovery of transition metal catalysts and ligands. In recent years, alternative processes which employ organic molecules as catalysts have become increasingly attractive, using alternatives to hydrogen gas, such as isopropanol and trichlorosilane. Catalysts for the latter are usually classified as Lewis bases and are typically easily accessible, low molecular weight species. Usually just 10% of a catalyst is required to efficiently produce the desired product, usually in excellent yield and selectivity for one isomer over another, although a few catalysts of this class are active enough for only 1% to be employed.Recent research from our laboratories has developed a catalyst that may be used routinely with only 1% of the active species being employed. More recent work has established an improved catalyst that is two orders of magnitude more active, and with only 0.01% needed, represents the most active catalytic species in the world for this type of transformation. Our unique understanding of the activity of this new catalyst has allowed us to develop new catalyst architectures based on phosphine oxides, a hitherto unexplored class of catalyst for this reaction. This proposal aims to develop efficient chemical methods to prepare these catalysts and then evaluate, optimise and exemplify their use in the preparation of chiral amines, a class of molecule found in around a third of all active pharmaceutical ingredients. In parallel with our current ventures, this new technology could offer an exciting low cost manufacturing solution for the pharmaceutical industry, at the same time reducing the cost and risk of using hydrogen gas and transition metal species. The use of environmentally acceptable solvents, with little waste, further accentuate the benefits of this process.In parallel with this, we aim to apply these new catalyst species in a selection of varied chemical transformations, thus exemplifying their use as an emerging new class of catalyst.