Organocatalytic Mitsunobu Activation for Streamlined Pharmaceutical Synthesis

当今科学家面临的主要挑战之一是需要以节能和无污染的方式生产必需的有机分子，如药物和农用化学品。这个问题的本质是必须在环境友好的条件下可预测地形成新的化学键。不幸的是，目前合成化学家使用的许多方法本质上是浪费的，并且产生一个（或多个）废物分子沿着每个产物分子。本提案集中于一个这样的化学反应-Mitsunobu反应。该反应最初是在20世纪60年代开发的，目前仍以其原始形式使用，其中涉及使用两种化学计量的化学试剂-其中一种是有毒和爆炸性的。因此，一个典型的反应产生的废物几乎是产品的两倍。尽管效率非常低，但该反应每天都在世界各地的实验室中进行，因为它代表了最先进的醇类亲核取代与构型反转的方法。因此，不需要化学计量试剂的催化光信反应将对化学合成领域产生重大影响。然而，仍然有基本的化学挑战，以克服和没有一般的解决方案已被描述到date.In此提案中，我们描述了前所未有的催化Mitsunobu反应介导的一个新的家庭的有机催化剂。最重要的是，我们的新催化反应不需要任何额外的化学试剂，产生水作为唯一的副产物，并与传统的化学计量反应相同的可预测的立体化学结果。因此，它们代表了现有方法的非常强大的替代方案。此外，我们还描述了催化的对映会聚Mitsunobu反应，该反应允许拆分外消旋醇而不牺牲不需要的对映体。这为醇类化合物的动力学拆分提供了一种新的途径，可用于生产高价值的对映体富集产物。最后，我们展示了如何新的催化反应可以应用在非常短和有效的合成有价值的活性药物成分和中间体。 这个雄心勃勃的项目是基于令人兴奋的初步结果，清楚地证明了新的催化歧管的化学可行性。十多年来，制药商一直在要求这种类型的催化反应，该项目的潜在商业应用已经得到葛兰素史克的认可。因此，本申请是在他们与Helen Sneddon博士（GSK绿色化学负责人）作为项目合作伙伴的全力支持下提出的。申请人已经在该领域工作了五年多，他以前在磷催化方面的经验使他能够独特地完成该项目。在EPSRC的支持下，我们现在可以为未来的研究开辟一个新的有机催化领域，并提高英国制药行业的竞争力，该行业负责170亿英镑的出口和16%的世界畅销药物。

One of the major challenges facing scientists today is the need to produce essential organic molecules such as pharmaceuticals and agrochemicals in an energy efficient and non-polluting fashion. Inherent in this problem is the necessity to form new chemical bonds predictably and under environmentally benign conditions. Unfortunately, at present many of the methods used by synthesis chemists are inherently wasteful and produce one (or more) molecules of waste along with every molecule of product. This proposal focusses on one such chemical reaction - the Mitsunobu reaction. Originally developed in the 1960s, the reaction is still being used in its original form, which involves the use of two stoichiometric chemical reagents - one of which is toxic and explosive. As a result, a typical reaction generates nearly twice as much waste as product. Despite this very poor level of efficiency, the reaction is carried out in laboratories around the world on a daily basis because it represents the state-of-the-art method for nucleophilic substitution of alcohols with inversion of configuration. For this reason a catalytic Mitsunobu reaction, in which no stoichiometric reagents are required, would have a major impact on the field of chemical synthesis. However, there remain fundamental chemical challenges to overcome and no general solution has been described to date.In this proposal we describe unprecedented catalytic Mitsunobu reactions that are mediated by a new family of organocatalysts. Most significantly, our new catalytic reactions do not require any additional chemical reagents, generate water as the sole by-product and occur with the same predictable stereochemical outcome as the conventional stoichiometric reactions. Therefore, they represent very powerful alternatives to existing methods. Furthermore, we also describe catalytic enantioconvergent Mitsunobu reactions that allow resolution of racemic alcohols without sacrificing the unwanted enantiomer. This represents a new approach to the kinetic resolution of alcohols for the production of high value enantiomerically enriched products. Finally, we demonstrate how the new catalytic reactions can be applied in very short and efficient syntheses of valuable active pharmaceutical ingredients and intermediates. This highly ambitious project is based upon exciting preliminary results that clearly demonstrate chemical feasibility of the new catalysis manifold. Pharmaceutical manufacturers have been asking for catalytic reactions of this type for over a decade and the potential commercial applications of this project have been recognised by GlaxoSmithKline. For this reason, this application is made with their full support in collaboration with Dr Helen Sneddon (Head of GSK Green Chemistry) as a project partner. The applicant has been working in the this area for over five years and his previous experience in phosphorus catalysis makes him uniquely placed to deliver this project. With EPSRC support now we can open up a new area of organocatalysis for future research and enhance the competitiveness of the UK pharmaceutical industry, which is responsible for £17bn of exports and 16% of the world's best selling drugs.