Underexploited Microbial Arene Oxidation Iron Carbonyl Approach to Valuable Chirons

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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.