MICROFLUIDIC REACTOR TECHNOLOGY IN OLIGOSACCHARIDE SYNTHESIS

Although carbohydrates offer new therapeutic opportunities in biomedical field, the industrial implementation of carbohydrate-based drugs is yet greatly thwarted by the difficulties and challenges inherent in oligosaccharide synthesis, especially for large scale preparation. Any tool or new technology enabling a cost-effective improvement of the lead generation process is therefore highly desirable in order to reduce the manufacturing costs of carbohydrate drugs. During last years, continuous-flow synthesis in microreactors has gained a great deal of attention featuring practical advantages such as high reproducibility, easy scalability and fast reaction optimization using small amounts of reagents or synthetic intermediates. This technique may therefore offer an effective support to make carbohydrates more attractive targets for drug discovery processes. In addition, also basic research in academia can benefit from microreactor technology as a tool to improve the organic synthesis of oligosaccharides. Here I report a systematic exploration of the glycosylation reaction, the most important and difficult transformation in oligosaccharide synthesis, carried out in microreactors under continuous-flow conditions. Various trichloroacetimidates and thioglycosides have been investigated as glycosyl donors in this study, using both primary and secondary glycosyl acceptors. Each microfluidic glycosylation has been compared with the same reaction performed under traditional conditions, in order to highlight advantages and drawbacks of microreactors technology. As a significant example of multistep continuous-flow synthesis, we also describe the preparation of a trisaccharide by means of two consecutive glycosylations performed in two interconnected microreactors. Furthermore I report preliminary study on the synthesis of glycosyl phosphodiester under microfluidic conditions for the preparation of short oligomers of Neisseria Meningitidis type X capsular polysaccharide fragments.