Merging novel cascade reactions and flow chemistry to expand the glycochemical space – SweetDom

The overarching goal of this project is to expand the glycochemical space while pursuing a sustainability-oriented approach. The first objective is to exploit the high synthetic potential of bifunctional exo-glycals in novel catalytic cascade cyclizations. Such domino processes enable the one-step construction of the tricyclic carbohydrate-containing fragment of relevant anthracycline and flavonoid products. The list includes serjanione A and regio-distinct isomers having a different connectivity of the pyranose and aromatic moiety such as the anti-cancer clinical candidate menogaril. In close collaboration between the academic and industrial partners, state-of-the-art technologies will be used to optimize the cascade reactions and gain insights into the mechanistic pathways at play, utilizing continuous flow chemistry, artificial intelligence (AI), and automated synthesis. Industrial partner’s high-throughput synthesis robot will enable the generation of a large body of data by varying multiple experimental parameters to train the AI model. By allowing a high control on these parameters, flow chemistry makes it possible to handle unstable species, intercept them via external trapping and favored one reaction pathway over the other one to develop a regio-divergent cascade process. The cascade cyclizations will be applied to the first total synthesis of serjanione A and related relevant glycobenzoxocines. A second application concerns the regio-divergent synthesis of bio-inspired libraries. The advantages to be gained by using readily available carbohydrate and aromatic building blocks in cascade synthesis are expected to be high in terms of synthetic accessibility and opportunity for SAR optimization. The high-throughput synthesis robot will be used to speed up the synthesis of these libraries.Such a system will also facilitate the scale-up of the most promising molecules, whose cytotoxic activity will be assessed across a range of relevant cancer cell lines.