The average time for a pharmaceutical to go from its inception to FDA approval takes 10-15 years! Furthermore, in the early stages of drug discovery, upwards of ~10,000-15,000 compounds are synthesized by medicinal chemists. Of that, only ~250 compounds may make it into pre-clinical trials and only an average of ~5 make it to clinical trials! As medicinal chemists build drug libraries, they take compounds that show efficacy towards a desired target and make modifications to try and improve performance. The ability to streamline the synthesis of these various drug analogues is of great value. A large portion of commercial drugs contain heteroarenes. Thus, developing ways to selectively functionalize the C-H bonds on a given heteroarene is of great importance. One way of functionalizing these moieties is through Minisci-type reactions, that is, a radical substitution to an aromatic compound.
One aim of the proposed research is a method for heteroarene alkylation via a ketyl radical intermediate. Ketyl radicals are the product of a single electron reduction of a carbonyl. The overall strategy of this Minisci-type reaction is to first convert aliphatic aldehydes to their corresponding, ?-acetoxy iodides using acetyl iodide. In this form, non-bonding oxygen electrons are able to donate into the C-I antibonding orbital, making this C-I bond weaker. Mn2(CO)10 catalyst is initiated by visible light irradiation and then abstracts the iodide via an atom transfer mechanism to afford ketyl radicals. The ketyl radicals are further coupled with heteroarenes, and then reduced via a single electron transfer to afford the final product. The other aim of the proposed research is an environmentally benign, electrocatalytic aza-pinacol coupling. The resulting product of an aza-pinacol coupling is a ?-amino alcohol, a motif that is ubiquitous in pharmaceuticals and biologically relevant natural products. The overall strategy of this proposal is to use the cathode in an electrochemical cell to reduce added ?-acetoxy iodide. Residual iodide from the reduction can then be oxidized at the anode, affording iodine that can be removed by a sodium thiosulfate work-up. The ketyl radical is then coupled to the imine affording a nitrogen radical. An electron-withdrawing protecting group on the nitrogen could also aid in the single electron reduction of the nitrogen radical by the cathode by stabilizing the resulting nitrogen anion. Lastly, acid is added to protonate the nitrogen and affords the ?-amino alcohol. Should the proposed aims be achieved, the findings will help accelerate the delivery of clinical drug candidates. The following research will be conducted at the facilities at The Ohio State University within the Sponsor?s laboratory space.
Both of my research proposals described in my Research Strategy are relevant to public health because they include organic synthesis strategies that can be applied in drug development. As medicinal chemists build drug libraries, they take compounds that show efficacy towards a desired target and make modifications to try and improve performance; however, the synthesis of these drug candidates can take a long time. If my proposed aims are achieved, the findings will help accelerate the delivery of clinical drug candidates by offering methods for selective functionalization of heteroarenes and the synthesis of b-amino alcohols which are both ubiquitous in drugs and biologically relevant natural products.
