Mild and Selective Cooperative-Base Mediated Hydrosilylations for Improved Drug Synthesis

点击翻译按钮获取中文摘要

Project Summary/Abstract PI: Gregory O’Neil Western Washington University Title: Mild and Selective Cooperative-Base Mediated Hydrosilylations for Improved Drug Synthesis Abstract: Reduction reactions are key transformations in the synthesis of both clinical and experimental drugs used to treat various human diseases. Common reducing agents, however, can present certain hazards (e.g. sensitivity to moisture and the release of flammable H2 gas) and/or require special handling and equipment. Additionally, as the target molecules become more complex, selectivity requirements become more stringent which drives the need for new easily performed and highly selective reduction protocols. This proposal describes the use of organosilanes combined with cooperative-base activation to produce a mild, approachable, and selective reduction method with which to access various biologically active molecules. Both substrate-controlled diastereoselective hydrosilylations and chiral base-mediated enantioselective carbonyl reductions will be investigated. The intramolecularity of these reactions is also expected to render the transformations chemoselective (Aim #1). Regioselective epoxide openings will be accomplished that may feature newly designed silanes and/or Lewis base activators (Aim #2). All of these reactions are expected to generate dioxasilinane products that can then be further functionalized to generate valuable synthetic intermediates that would otherwise be challenging to prepare (Aim #3). This is to be achieved by pursuing the following specific aims: 1. Explore chemo-, regio-, and diastereoselective cooperative base-mediated intramolecular hydrosilylations. 2. Perform mechanism-based optimizations of intramolecular hydrosilylations. 3. Investigate functionalization reactions of dioxasilinane intramolecular hydrosilylation products. This work will have a significant positive impact on providing new and superior access to various important synthetic intermediates through the combination of predictable selectivity, versatility, and mild reaction conditions, as well as presenting significant training opportunities for undergraduate participants in various research methods.