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较简单的前体构建复杂的分子。这些前体本身将由更简单的前体等制成，但每一种化学合成最终都必须有一种或多种起始材料。这些起始材料来自天然来源，无论是石化原料还是生物分子，如碳水化合物，氨基酸等，其中一些构成了手性池，这意味着它们具有定义的3D结构，使其成为快速构建高空间复杂性分子的理想选择（许多药物就是这种情况）。不幸的是，并非所有可能的3D结构都可以在手性池中使用。我们建议的核心是通过生产新的手性起始材料库来增加手性库，这将使迄今为止无法合成的复杂分子成为可能。我们将通过使用一种特殊的细菌菌株来做到这一点，这种细菌的培育是因为它能够进行一种化学反应，而这种化学反应是没有人造的。具体地，细菌可以进行氧化以代谢芳香族化合物，芳香族化合物是不在手性池中的廉价起始材料，因为它们是平坦的。然而，如此产生的化合物是手性的，因此在一个步骤中增加了显着的价值，特别是因为一个小的细菌培养物可以处理大量的芳香族起始材料。在过去的二十年里，这种方法的合成效用已经被几个小组证明，但是可用的微生物衍生的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族化合物，并且它们只产生某些产物）。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短，强，高产的化学合成，这将提供完全新的结构单元，这些结构单元不能单独通过细菌代谢获得。从可持续性的角度来看，这种方法具有几个优点-使用细菌在室温或接近室温的条件下进行合成是可能的，因此能源需求最小。此外，所用的氧化剂仅为空气中的氧气，因此不需要有毒的重金属。我们对所生产的建筑砌块有多种应用。例如，我们将能够用它们来合成肌醇的新衍生物，肌醇是一种最近显示出有希望作为阿尔茨海默病治疗剂的分子。此外，从相同的结构单元，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。糖基化酶与许多疾病有关，许多目前最畅销的药物都是氮杂糖，包括用于流感的达菲和瑞乐沙，用于糖尿病的拜唐苹和贝森以及用于泰-萨氏病的Zelucca。因此，我们期望我们的新手性构建单元库最终为合成用于治疗各种疾病的新候选药物铺平道路。

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.