Sustainable Phosphorus Chemistry: Catalytic Asymmetric SN2 Reactions

这项提议描述了创新的新化学，它将通过使磷成分具有催化作用来改变磷介导的取代反应，从而消除磷废物。这将大大减少学术和工业化学家每天使用的磷中介过程的经济和环境足迹，并使化学的全部商业潜力得以实现。此外，世界上磷矿的供应正在耗尽，新的催化反应是当前方法的可持续替代。磷矿是大多数有机磷化合物的原料。尽管已经取得了一百多年的进展，但许多支撑化学合成的转化，例如活化醇的SN2反应，本质上是浪费的。自20世纪60年代以来，有机化学家一直使用磷介导的反应，如Mitsunobu反应，合成包括药物在内的重要精细化学品。然而，目前，这种化学方法每生产一分子产品，至少会产生一个磷废物分子。这严重影响了化学物质的环境和经济足迹，十多年来，该行业一直在寻求解决这个问题的办法。例如，来自葛兰素史克、辉瑞、默克、礼来、先灵葆雅和阿斯利康的过程化学家最近撰写的一份报告称，“理想的Mitsunobu反应本质上是催化的”，最重要的是，“需要进一步研究使这种转化变得绿色，以实现其在商业应用中的全部潜力”。为了满足这些需求，迫切需要新的可持续的磷化学。这一大胆的计划与“拨打分子”的宏大挑战相一致，将提供在磷中具有催化作用的备受追捧的取代反应。这将极大地减少下游废物，并在制药和农用化学品合成中开辟一系列新的应用，使英国工业受益。此外，将探索被许多人错误地认为是非活性化合物的膦氧化物的新的基础化学。最后，所描述的新策略也适用于许多其他重要的磷介导的反应，因此形成了一个新的催化平台。这项建议的好处是：(A)令人兴奋的初步结果表明所建议的化学是可以交付的；(B)协作的实验、理论和机械方法；(C)PI减少了教学负担(作为一名新的学术人员)，使他能够密切监测进展并推动项目向前发展。

This proposal describes innovative new chemistry that will transform phosphorus-mediated substitution reactions by rendering them catalytic in the phosphorus component and, therefore, devoid of phosphorus waste. This will substantially reduce the economic and environmental footprint of phosphorus-mediated processes that are used by academic and industrial chemists on a daily basis and allow the full commercial potential of the chemistry to be realized. Furthermore, the world's supply of phosphate rock, the material from which most organophosphorus compounds are derived, is running out and the new catalytic reactions represent a sustainable alternative to current methods. Despite over one hundred years of progress many of the transformations that underpin chemical synthesis, e.g SN2 reactions of activated alcohols, are inherently wasteful. Since the 1960s organic chemists have used phosphorus-mediated reactions, such as the Mitsunobu reaction, for the synthesis of important fine chemicals including pharmaceuticals. However, at present, this chemistry generates at least one molecule of phosphorus waste for every molecule of product produced. This impacts heavily on the environmental and economic footprint of the chemistry and for over a decade industry has been asking for a solution to this problem. For example, a recent report authored by process chemists from GlaxoSmithKline, Pfizer, Merck, Lilly, Schering-Plough and AstraZeneca stated that "the ideal Mitsunobu reaction would be catalytic in nature" and, most significantly, "future research towards making this transformation green is required to realize its full potential in commercial applications". To meet these demands new sustainable phosphorus chemistry is urgently required. This adventurous programme, that is aligned with the "Dial-a-Molecule" grand challenge, will deliver highly sought after substitution reactions that are catalytic in phosphorus. This will dramatically reduce downstream waste and open up a range of new applications in pharmaceutical and agrochemical synthesis that will benefit UK industry. Moreover, new fundamental chemistry of phosphine oxides, incorrectly assumed by many to be unreactive compounds, will be explored. Finally, the new strategy described is applicable to many other important phosphorus-mediated reactions and, therefore, forms a new platform for catalysis. This proposal benefits from: (a) exciting preliminary results that indicate the chemistry proposed is deliverable; (b) a collaborative experimental, theoretical and mechanistic approach and (c) the PI's reduced teaching load (as a new academic) allowing him to closely monitor progress and drive the project forward.