Underexploited Microbial Arene Oxidation Iron Carbonyl Approach to Valuable Chirons

制药、农用化学品和精细化学品工业依赖于从更简单的前体构建复杂的分子。这些前体本身就是由更简单的前体等制成的，但每一次化学合成最终都必须有一个或多个起始材料。这些起始材料来自天然来源，要么是石化原料，要么是碳水化合物、氨基酸等生物分子。其中一些构成了手性池，这意味着它们已经定义了3D结构，使它们成为快速构建高空间复杂性分子的理想选择(许多药物就是这样)。不幸的是，并不是所有可能的3D结构在手性池中都可用。我们建议的核心是通过生产一个新的手性起始材料库来扩大手性池，这将使到目前为止无法获得的复杂分子的合成成为可能。我们将通过使用一种特定的细菌菌株来做到这一点，这种细菌已经被培育出来，因为它能够进行化学反应，而这种化学反应是没有人工可用的。具体地说，细菌可以进行氧化来代谢芳香化合物，芳香化合物是廉价的起始材料，因为它们不在手性池中，因为它们是平的。然而，这样产生的化合物是手性的，所以只需一步就能增加很大的价值，特别是因为一个小的细菌培养物可以处理大量的芳香起始物质。在过去的二十年里，几个小组已经证明了这种方法的合成效用，但可用的微生物衍生构建块的范围受到产生它们的酶的选择性的限制(它们只处理某些芳香化合物，并且只提供某些产品)。因此，我们提出了一种串联的化学酶方法-将细菌代谢的产物进行简短、健壮、高产量的化学合成，这将提供仅通过细菌代谢无法获得的全新的构建单元。从可持续性的角度来看，这种方法有几个优点--在室温或接近室温的情况下，使用细菌进行合成是可能的，因此能量需求最小。此外，所使用的氧化剂只是空气中的氧气，因此不需要有毒的重金属。我们将生产的积木有许多用途。例如，我们将能够用它们来合成肌醇的新衍生物，这是一种最近显示出作为阿尔茨海默病治疗剂的分子。此外，从相同的构筑块，我们将能够合成新的氮杂糖。这些化合物可以与体内的糖苷酶相互作用。糖苷酶与许多疾病有关，目前最畅销的许多药物是氮杂糖，包括治疗流感的达菲和瑞乐沙，治疗糖尿病的格卢考韦和巴森，以及治疗泰萨克病的扎维斯卡。因此，我们期望我们的新手性构建基体库最终为合成用于治疗各种疾病的新药候选铺平道路。

The pharmaceutical, agrochemical and fine chemicals industries rely on the construction of complex molecules from simpler precursors. These precursors will themselves have been made from simpler precursors and so on, but every chemical synthesis ultimately has to have a starting material or materials. These starting materials come from natural sources, either petrochemical feedstocks or biomolecules such as carbohydrates, amino acids, etc. Some of these constitute the chiral pool , meaning they have defined 3D structures that make them ideal for the rapid construction of molecules of high spatial complexity (as is the case for many drugs). Unfortunately, not all possible 3D structures are available in the chiral pool. The core of our proposal is to augment the chiral pool by producing a library of new chiral starting materials that will enable the synthesis of complex molecules that have thus far been inaccessible. We will do this by using a particular strain of bacteria, which has been bred for its ability to carry out a chemical reaction for which there is no man-made equivalent available. Specifically, the bacteria can carry out an oxidation to metabolise aromatic compounds, cheap starting materials which are not in the chiral pool, since they are flat. The compounds so produced *are* chiral, however, so significant value is added in a single step, especially since a small bacterial culture can process a large quantity of aromatic starting material. The synthetic utility of this approach has been demonstrated by several groups in the last twenty years, but the range of microbially-derived building blocks available is restricted by the selectivity of the enzymes that produce them (they only process certain aromatic compounds and they only give certain products). Hence, we propose a tandem chemoenzymatic approach - taking the products of bacterial metabolism and subjecting them to short, robust, high-yielding chemical syntheses that will provide wholly novel building blocks that are not available through bacterial metabolism alone. This approach carries several advantages from a sustainability perspective - using bacteria to do synthesis is possible at or near room temperature, so energy requirements are minimal. Also, the oxidant used is simply oxygen from the air, so no toxic heavy metals are required.We have numerous applications in mind for the building blocks we will produce. For example, we will be able to use them to synthesise novel derivatives of inositols, a type of molecule which has recently shown promise as a therapeutic agent for Alzheimer's disease. Furthermore, from the same building blocks, we will be able to synthesise new azasugars. These are compounds which can interact with glycosidase enzymes in the body. Glycosidases are involved in many diseases, and many current top-selling drugs are azasugars, including Tamiflu and Relenza for influenza, Glucobay and Basen for diabetes and Zavesca for Tay-Sach's disease. We therefore expect our library of new chiral building blocks ultimately to pave the way for the synthesis of new drug candidates for the treatment of various diseases.