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基石。大多数生物结构，以及许多允许生命运作的分子，都是以某种方式由氨基酸构成的。由于这个原因，当化学家设计分子与生命相互作用时——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，但合成化合物原则上可以由数百万种可能的替代品构成，其中许多可能是由现成的自然版本制成的。问题是，从天然氨基酸到改性合成氨基酸的转化受到分子结构和可使用试剂类型的严格限制。在本项目中，我们提出了一种从天然氨基酸合成氨基酸的概念新方法，以避免这些问题。它允许将环状结构引入到氨基酸中，重要的是它避免了使用重金属，如钯，这是昂贵的，遭受潜在的供应短缺，并且如果残留在潜在的医学用途分子中会引起问题。我们建议探索的化学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的片段连接起来，使它们紧密接触，并使它们能够以正常条件下不可能发生的方式发生反应。所产生的反应是如此的不寻常，以致我们需要详细地研究这种反应是如何绕过通常公认的化学反应规律的。该反应将为化学家们提供一种高效构建简单结构的新方法，并将在设计和生产具有潜在药物价值的分子或其他生物医学领域发挥作用。

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.