Novel reaction discovery with rapid high-throughput experimentation via infrared spectroscopy and enzymatic electrochemical oxidation of alcohols
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Abstract
Scientists in academia as well as pharmaceutical companies have been devoting numerous research efforts towards green chemistry since the establishment of the Pollution Prevention Act of 1990. The overarching goal of green chemistry is to incorporate environmentally benign reaction design into routine and novel synthesis in order to minimize the use of toxic substances and waste while maximizing the overall efficiency of reaction processes. Both projects reported here encompass the idea of sustainability and productivity. High-throughput screening (HTS) and high-throughput experimentation (HTE) has been widely used in the field of biochemistry to rapidly identify pharmacological targets. However, this method has been underused in organic chemistry due to the complexity of reaction design, strain in reagent handling, as well as the difficulty of data analysis and structure determination. Utilization of HTE in organic chemistry can increase the output of chemists and decrease wastes. A well-designed chemical HTE platform has the potential to generate enormous volumes of empirical standardized data that not only could be used for reaction optimization, but also readily integrated into a near-AI computational system in the future for reaction model prediction and discovery.
A functional screening and analysis platform was developed to investigate the Petasis Borono-mannich reaction space and to explore possible novel reactivities. Using this system, more than 3000 distinctive microscale reactions were processed in under 6 months with 74% accuracy. By triaging the IR results, we prioritized time and efforts on analyzing and reproducing reactions with moderate to excellent yields. This helped to identify previously unknown reactivities, allowing for reproduction of novel reactions at bench scales, as well as furthering mechanistic studies of uncommon reaction partners such as thiophenol and pyrone. This preliminary success suggests that this platform could be transferable to other multicomponent reactions such as the Suzuki cross-couplings and Buchwald-Hartwig aminations.
With deepened understanding of reagent selection and stereoselectivity of the catalyzed Petasis reactions from the HTS platform, we examined the possibility of electrochemical enzymatic catalysis. Galactose oxidase is known to selectively eliminate the pro-S hydrogen during oxidation of alcohol reagents due to the steric constraints of the active site. Electrochemistry tend to feature mild reaction conditions and fast turn over, while enzymatic catalysis is economical and nontoxic. By combining these two methods, a mild, diastereoselective oxidation could be achieved to provide the aldehyde component in the highly enantioselective, transition-metal-free Petasis reaction.
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2024