alpha-Arylation and alpha-Vinylation of Enolates: New Reactivity from the Urea Linkage

氨基酸是构成生命的最简单的构件。大多数生物结构，以及许多让生命发挥作用的分子，都是以某种方式由氨基酸构成的。出于这个原因，当化学家设计与生命相互作用的分子时--例如新药--他们经常转向氨基酸结构。尽管自然界通常只使用20种氨基酸，但原则上可以从数百万种可能的替代品中构建合成化合物，其中许多可能是由现成的天然版本制成的。问题是，将天然氨基酸转化为改性合成氨基酸在分子结构和可使用的试剂类型方面都受到严格的限制。在这个项目中，我们建议开发一种从天然氨基酸制备合成氨基酸的概念上的新方法，从而避免这些问题中的一些。它允许将环结构引入氨基酸，重要的是它避免使用重金属，如钯，因为重金属昂贵，存在潜在的供应短缺，如果残留在潜在的医学用途分子中，就会造成问题。我们建议探索的化学利用了一种相当被忽视和低估的功能分子片段，其基础是在尿液中发现的著名废物尿素的结构。通过修饰的尿素分子将氨基酸分子与新片段连接起来，使伴侣能够密切接触，并允许他们以在正常情况下不可能发生的方式进行反应。这种反应的结果是如此不寻常，以至于我们需要详细地研究该反应是如何绕过通常公认的化学反应规则的。该反应将为化学家提供一种有效地构建简单结构的新方法，并将在设计和生产具有潜在价值的分子如药物或其他生物医学领域中有用。

Amino acids are the simplest building blocks from which life is built. Most biological structures, and many of the molecules which allow life to function, are built in some way from amino acids. For this reason, when chemists design molecules to interact with life - new drugs for example - they often turn to amino acid structures. Although Nature typically uses just 20 amino acids, synthetic compounds can in principle be built from millions of possible alternatives, many of which may be made from the readily available natural versions. The problem is that the conversion of a natural amino acid to a modified synthetic one is subject to severe restrictions with regard to molecular structure and also the type of reagents that can be used. In this project, we propose to develop a conceptually new way of making synthetic amino acids from natural ones which avoids some of these problems. It allows ring structures to be introduced to the amino acids, and importantly it avoids using heavy metals, such as palladium, which are expensive, suffer from potential supply shortages, and cause problems if residues remain in molecules of potential use in medicine. The chemistry we propose to explore makes use of a rather neglected and underestimated functional molecular fragment based on the structure of the famous waste product found in urine: urea. Linking the molecule of amino acid to the new fragment through a modified urea molecule brings the partners into close contact and allows them to react in ways that would be impossible under normal conditions. The reaction that results is so unusual that we shall need to investigate in detail the way that the reaction circumvents the usual well established rules of chemical reactivity.The reaction will offer to chemists a new way of building simple structures efficiently, and will be useful in the design and production of molecules of potential value as drugs or in other fields of biomedicine.