Sustainable Phosphorus Chemistry: Catalytic Asymmetric SN2 Reactions

该提案描述了创新的新化学，将转化磷介导的取代反应，使其在磷成分中具有催化作用，因此，没有磷废物。这将大大减少学术界和工业化学家每天使用的磷介导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，作为大多数有机磷化合物的来源，世界上磷矿的供应正在耗尽，而新的催化反应是目前方法的可持续替代方案。尽管一百多年来取得了进步，但许多作为化学合成基础的转化，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，有机化学家已经使用磷介导的反应，如Mitsunobu反应，来合成包括药物在内的重要精细化学品。然而，目前，这种化学反应每产生一分子产品，至少会产生一分子磷废物。这严重影响了化学的环境和经济足迹，十多年来，工业一直在寻求解决这个问题的办法。例如，最近由葛兰素史克、辉瑞、默克、礼来、先灵葆雅和阿斯利康的工艺化学家撰写的一份报告指出，“理想的光信反应本质上是催化的”，最重要的是，“未来需要对这种转化进行绿色研究，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。这个冒险的项目与“Dial-a-Molecule”大挑战相一致，将提供在磷中具有催化作用的高度追求的取代反应。这将大大减少下游浪费，并在制药和农化合成方面开辟一系列新的应用，这将有利于英国工业。此外，将探索被许多人错误地认为是非活性化合物的磷化氢氧化物的新基本化学。最后，所描述的新策略适用于许多其他重要的磷介导反应，因此，形成了一个新的催化平台。该提案受益于：(a)令人兴奋的初步结果表明，所提出的化学是可交付的；(b)实验、理论和机械的合作方法，以及(c) PI减轻了教学负担（作为一名新学者），使他能够密切监测进度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.