Changing the Synthesis Landscape with Boron at the Helm: from Chiral Organometallics to Assembly Line Synthesis

化学在科学中是独一无二的，因为它有能力不断地自我更新，因为它有能力研究它所创造的东西。创造分子是化学发展的起点，它最终导致社会的进步。在这种情况下，有机分子的合成是许多研究学科的中心，从医学到材料。然而，尽管取得了重大进展，与化学合成有关的问题和困难严重限制了这些学科的增长和发展速度。这些领域受到化学家容易制造的东西的限制，而不是科学家的想象力。为了应对在快速变化的科学环境中跨越新学科边界的新挑战，我们需要在有机合成中发展更快速和更强大的技术。我们的建议是从本质上“生长”一个碳链，在特定的地方附着特定的取代基，并具有特定的立体化学，这样，在序列的最后，一个复杂的目标分子可能是天然产物，药物或合成材料，基本上一步就能生产出来。这是一个雄心勃勃的目标。“生长”阶段是使用带有良好离去基的手性碳离子（类碳）进行的，它与硼酯反应生成同源（放大）硼酯。重复这个反应，在新的硼酯上使用不同的碳离子，使第二个生长步骤发生。增长步骤可以比作添加乐高积木，直到创建一个模型。这一过程与自然界在聚酮生物合成中进化出的[聚酮合成酶（PKS）]的非凡机制有共鸣。事实上，通过类碳化合物及其立体化学（乐高积木）的变化，应该可以获得具有特定形状的各种分子，从而能够对复杂分子进行快速的结构-活性研究。硼酯中间体是稳定的有机金属试剂，易于控制其形状。我们计划着手一种激活这些中间体的新方法，以便将它们转化为具有新功能的更广泛的分子。这种新颖的方法将极大地扩展现成的手性有机分子的版图。分子的（期望的）性质是由它的形状和功能决定的。能够控制这些关键特征是化学的核心，也是推动生物化学和材料化学发展的动力。我们的目标是创造新的工具，使我们能够轻松地合成各种分子，并控制它们的形状和功能。我们提出的合成程序将为科学提供一个额外的新工具。

Chemistry is unique amongst the sciences in that it has the power to constantly rejuvenate itself since it has the ability to study what it also creates. Creating molecules is where the developments in chemistry begin, which ultimately leads to the advancements in society. Within this context, the synthesis of organic molecules is central to many research disciplines from medicine to materials. However, despite substantial progress, the problems and difficulties associated with chemical syntheses severely limit the rate of growth and development of these disciplines. These fields are constrained by what chemists can make easily, rather than by the imagination of the scientists. In order to meet the emerging challenges across new disciplinary boundaries in a rapidly changing scientific landscape we require a step-change in the development of more rapid and robust techniques in organic synthesis. Our proposal is to essentially 'grow' a carbon chain with specific substituents attached at specific places and with specific stereochemistry, so that so that at the end of the sequence a complex target molecule which may be a natural product, pharmaceutical or synthetic material will be produced essentially in one step. This is a hugely ambitious goal. The 'growth' phase is conducted using a chiral carbanion with a good leaving group attached (a carbenoid) which reacts with a boronic ester to give a homologated (enlarged) boronic ester. Repeating this reaction, using a different carbanion on the new boronic ester enables a second growth step to take place. The growth steps can be likened to adding lego pieces until a model has been created. Such a process has resonance with the remarkable machinery nature has evolved [polyketide synthases (PKS)] in its biosynthesis of polyketides. Indeed, by variation of the carbenoid and its stereochemistry (lego pieces) a diverse range of molecules with specific shape should be accessible thus enabling rapid structure-activity studies on complex molecules. The boronic ester intermediates are stable organometallic reagents which are easily accessible with control over their shape. We plan to embark on a novel method of activation of these intermediates so that they can be transformed into a much broader range of molecules bearing new functionality. Such novel methodology would significantly expand the landscape of readily available chiral organic molecules. The (desired) properties of a molecule are defined by its shape and functionality. Being able to control these critical features lies at the heart of chemistry and is what drives much of biological and materials chemistry. We aim to create new tools to enable us to easily synthesise a broad array of molecules with control over their shape and functionality. Our proposed synthesis program will provide an additional new tool to enable science.