Solvent Switching in Continuous Multistep Chemoenzymatic Synthesis: Telescoping Enzymatic Synthesis of Chiral, Pyridine-Containing Amines with Cross-Coupling as a Case Study
Pablo Díaz-Kruik, David Roura Padrosa, Eimear Hegarty, Hansjoerg Lehmann, Radka Snajdrova and Francesca Paradisi*,
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引用次数: 0
Abstract
Chiral α-(hetero)aryl primary amines are gaining momentum for their biological activities and their use as building blocks in more complex molecules. Here we report a continuous chemoenzymatic strategy from 2-acetyl-6-bromopyridine enabled by careful solvent selection and phase switching. Combining a first biocatalytic transamination reaction performed by TsRTA in a biphasic system in continuous flow, with inline Boc-protection and Suzuki coupling of a (substituted)phenylboronic acid, achieves conversions up to >99% toward tert-butyl (R)-(1-(6-(substituted) phenylpyridin-2-yl)ethyl)carbamate as the final product. This strategy not only constitutes an important example of chemoenzymatic combinations in continuous flow but also highlights the importance of the reaction design to minimize waste (through unreacted substrate recirculation), avoid time intensive workups (through inline extractions), and achieve the product in a space time yield of 68 mg L–1 h–1 with excellent enantiomeric excess (99% ee).
期刊介绍:
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools,process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.