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要的有机分子，如药品和农用化学品。这一问题的内在原因是有必要在环境友好的条件下可预见地形成新的化学键。不幸的是，目前合成化学家使用的许多方法本质上都是浪费的，并且会产生一个(或多个)废物分子以及每个产品分子。这项提议侧重于一种这样的化学反应--Mitsunobu反应。该反应最初是在20世纪60年代开发的，至今仍在以最初的形式使用，其中包括使用两种化学计量化学试剂-其中一种有毒且具有爆炸性。因此，一个典型的反应产生的废物几乎是产品的两倍。尽管效率很低，但该反应每天都在世界各地的实验室进行，因为它代表了通过反转构型进行醇的亲核取代的最先进方法。因此，不需要化学计量试剂的催化Mitsunobu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需要克服，到目前为止还没有描述通用的解决方案。在这个建议中，我们描述了前所未有的催化Mitsunobu反应，这些反应是由一类新的有机催化剂介导的。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，只产生水作为唯一的副产品，并且与传统的化学计量反应具有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，我们还描述了催化对映体收敛Mitsunobu反应，允许拆分外消旋醇而不牺牲不想要的对映体。这代表了一种用于生产高价值对映体富集物的醇的动力学拆分的新方法。最后，我们展示了新的催化反应如何应用于有价值的活性药物成分和中间体的非常短和有效的合成。这个雄心勃勃的项目基于激动人心的初步结果，这些结果清楚地证明了新催化歧管的化学可行性。十多年来，制药制造商一直在寻求这种类型的催化反应，葛兰素史克已经认识到这一项目的潜在商业应用。因此，这项申请是在他们的全力支持下与海伦·斯奈登博士(GSK绿色化学负责人)作为项目合作伙伴共同提出的。申请者已经在这个领域工作了五年多，他以前在磷催化方面的经验使他成为这个项目的得天独厚的人选。在EPSRC的支持下，我们现在可以为未来的研究开辟有机催化的新领域，并提高英国制药业的竞争力，该行业负责170亿GB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.