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Organocatalytic Mitsunobu Activation for Streamlined Pharmaceutical Synthesis

用于简化药物合成的有机催化 Mitsunobu 活化

基本信息

批准号：
EP/R030693/1
负责人：
Ross Denton
金额：
$ 50.79万
依托单位：
University of Nottingham
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FR030693%2F1
关键词：
Organocatalytic Mitsunobu Activation Streamlined Pharmaceutical

项目摘要

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.

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。这个问题的本质是需要在可预测的和无害环境的条件下形成新的化学键。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，并且在每一个产物分子的同时产生一个（或多个）废物分子。这项提议的重点是一种这样的化学反应——光信反应。该反应最初是在20世纪60年代发展起来的，目前仍以其原始形式使用，这涉及到使用两种化学计量化学试剂，其中一种是有毒和易爆的。因此，一个典型的反应产生的废物几乎是产物的两倍。尽管效率很低，但该反应每天都在世界各地的实验室进行，因为它代表了具有构型反转的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光信反应将对化学合成领域产生重大影响。然而，仍有一些基本的化学挑战需要克服，迄今为止还没有一个通用的解决方案。在这个建议中，我们描述了前所未有的催化光信反应是由一个新的有机催化剂家族介导的。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，产生水作为唯一的副产物，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收敛的Mitsunobu反应，该反应允许在不牺牲不需要的对映体的情况下拆分外消旋醇。这为生产高价值的对映体富集产品提供了一种新的醇类动力学解析方法。最后，我们展示了新的催化反应如何应用于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，制药商一直在寻求这种类型的催化反应，葛兰素史克公司已经认识到这个项目的潜在商业应用。出于这个原因，这个应用程序是在他们的全力支持下与Helen Sneddon博士（GSK绿色化学负责人）作为项目合作伙伴合作完成的。申请人已经在这个领域工作了五年多，他之前在磷催化方面的经验使他成为这个项目的独特人选。在EPSRC的支持下，我们现在可以为未来的研究开辟一个有机催化的新领域，并提高英国制药业的竞争力。英国制药业的出口额为170亿英镑，占世界上最畅销药品的16%。