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非污染方式生产必不可少的有机分子，例如药物和农业化学物质。该问题固有的是可以预见的，并且在环境良性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，并且产生了一个（或更多）废物分子以及每个产品分子。该提案重点是这样的化学反应 - 三菱反应。该反应最初是在1960年代开发的，它仍以其原始形式使用，其中涉及两种化学计量化学试剂，其中一种是有毒和爆炸性的。结果，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，但每天都在世界各地的实验室中进行反应，因为它代表了核嗜有性替代酒精的最新方法，并反转了构型。因此，不需要化学计量试剂的催化三菱反应将对化学合成领域产生重大影响。但是，仍有基本的化学挑战需要克服，迄今为止尚未描述一般的解决方案。在此提案中，我们描述了由新的有机催化剂家族介导的前所未有的催化三孔布鲁反应。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，以与常规化学计量反应相同的可预测的立体化学结果产生水作为唯一的副产品。因此，它们代表了现有方法的非常有力的替代方案。此外，我们还描述了催化启用二甲体反应，可以在不牺牲不必要的对映异构体的情况下清除外星醇。这代表了一种新方法，用于生产高价值对映体富集产品的醇。最后，我们证明了如何在非常短有效的有价值的活性药物诱导和中间体的合成中应用新的催化反应。这个高度雄心勃勃的项目基于令人兴奋的初步结果，该结果清楚地证明了新催化歧管的化学可行性。十多年来，制药制造商一直在要求这种类型的催化反应，该项目的潜在商业应用已被葛兰素史克（Glaxosmithkline）认识到。因此，该应用程序是通过与项目合作伙伴Helen Sneddon博士（GSK Green Chemistry的负责人）合作进行的。该应用程序已经在该地区工作了五年以上，他以前在磷催化方面的经验使他独一无二地交付了该项目。现在，有了EPSRC的支持，我们可以为未来的研究开放一个新的有机催化领域，并增强英国制药行业的竞争力，该行业负责造成170亿英镑的出口和16％的世界畅销药物。