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组成部分。大多数生物结构，以及许多使生命发挥功能的分子，都是以某种方式由氨基酸构建的。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。虽然自然界通常只使用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。问题是天然氨基酸转化为经修饰的合成氨基酸受到分子结构以及可使用的试剂类型的严格限制。在这个项目中，我们建议开发一种概念上的新方法，从天然氨基酸中合成氨基酸，避免其中的一些问题。它允许将环结构引入到氨基酸中，并且重要的是，它避免使用重金属，例如钯，其是昂贵的，遭受潜在的供应短缺，并且如果残留物留在可能用于医学的分子中会引起问题。我们打算探索的化学方法利用了一个相当被忽视和低估的功能分子片段，该片段基于尿液中发现的著名废物尿素的结构。通过修饰的脲分子将氨基酸分子连接到新片段，使伴侣紧密接触，并允许它们以正常条件下不可能的方式反应。这个反应是如此的不寻常，以至于我们需要详细地研究这个反应是如何绕过通常已经确立的化学反应性规则的，这个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）方面有所帮助。

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.