Continuous consecutive reactions for asymmetric syntheses

Background: An organic compound that contains an asymmetric carbon atom exhibits two non- superimposable isomers. Although these isomers, called enantiomers, have identical chemical and physical properties, they may exhibit markedly different biological effects. Enantiomerically pure drugs are therefore crucially important in pharmaceutical research, but they are significantly more difficult to synthesize, especially on a larger scale. The synthesis of such complex chiral products typically requires a large number of distinct reaction steps and involves significant drawbacks such as low overall yields, low productivity, low reproducibility, need for time-consuming work-up and purification procedures and a large amount of waste produced. Hypothesis: In some cases, single-enantiomer drugs and active pharmaceutical ingredients (APIs) can be produced using readily available enantiopure building blocks, but catalytic asymmetric transformations offer a more general approach using simple achiral components as starting materials. Amongst chiral catalytic techniques, organocatalysis, which utilizes small organic molecules as suitable metal-free catalysts, is especially appealing due to beneficial features such as high stability, non-toxicity and low-cost. Methodology: We are aiming to develop previously unprecedented, efficient and sustainable methodologies for the enantioselective synthesis of advanced chiral intermediates of blockbuster drugs with a special emphasis on large-scale production. Our first goal is the assignment of the asymmetric key steps and the development of the corresponding enantioselective reactions using cheap and readily available amino acids and amino acid derivatives as environmentally benign organocatalysts. We would like to exploit the benefits of flow chemistry and continuous processing. The organocatalysts will be immobilized on solid supports and the reactions will be carried out in filled reaction columns where systematic tuning of the catalystsubstrate contact time (i.e., residence time) will ensure excellent reaction rates and enantiomeric purities. To minimize process costs, expensive or labile components will be prepared in situ using cheap starting materials by means of various flow processes. By exploiting extend parameter spaces and unprecedented reaction windows (e.g., high-pressure/high-temperature conditions), we are aiming to minimize the number of synthesis steps necessary towards the desired APIs. Following successful optimization of the individual reactions, we will combine multistep syntheses into telescoped flow processes and perform continuous consecutive reactions involving key asymmetric transformations uninterrupted, without the isolation of any intermediates. Novelty: Such a beneficial combination of heterogeneous organocatalysis and continuous-flow multistep reaction design is not yet known from the literature for the asymmetric synthesis of advanced pharmaceutical intermediates, and therefore the proposed project has significant novelty.

An organic compound that contains an asymmetric carbon atom exhibits two non-superimposable isomers. Although these isomers, called enantiomers, have identical chemical and physical properties, they may exhibit markedly different biological effects. Enantiomerically pure drugs are therefore crucially important in pharmaceutical research, but they are significantly more difficult to synthesize, especially on a larger scale. The synthesis of such complex chiral products typically requires a large number of distinct reaction steps and involves significant drawbacks such as low overall yields, low productivity, low reproducibility, need for time-consuming work-up and purification procedures and a large amount of waste produced. In some cases, single-enantiomer drugs and active pharmaceutical ingredients (APIs) can be produced using readily available enantiopure building blocks, but catalytic asymmetric transformations offer a more general approach using inexpensive achiral components as starting materials. Amongst chiral catalytic techniques, organocatalysis, which utilizes small organic molecules as suitable metal-free catalysts, is especially appealing due to beneficial features such as high stability, non-toxicity and low-cost. Within the framework of this project, we established novel methodologies for the enantioselective synthesis of advanced chiral intermediates of important drug molecules with a special emphasis on scalable production and sustainability. Flow chemistry has recently emerged as an enabling tool to simplify, integrate and scale-up chemical synthesis. Instead of well-defined batches, it employs continuous streams of reactants to facilitate chemical reactions. Our first milestone was the assignment of the asymmetric key steps and the development of the corresponding enantioselective reactions using environmentally benign organocatalysts in continuous flow mode. To ensure ease of use and recyclability, organocatalysts were immobilized on solid supports and the reactions were carried out on filled reaction columns where systematic tuning of the reaction conditions ensured excellent reaction rates and enantiomeric purities. Expensive or labile reaction components were prepared in situ using readily available starting materials. By exploiting extend parameter spaces and unprecedented reaction routes, we were able to minimize the number of synthesis steps necessary towards the desired APIs. Following successful optimization of the individual reaction steps, multistep syntheses were next combined into telescoped flow processes, without the isolation of any intermediates. By taking advantage of this modern synthesis strategy, we managed develop novel protocols for the synthesis of key intermediates of important drugs, such as paroxetine which is a blockbuster antidepressant. As compared with earlier synthesis methods, our approach offers key advances in terms of sustainability, cost-effectivity and scalability.