Carbohydrates are the most abundant class of natural products with a distinctive role in different biological processes, like protein folding, cell−cell communication, and immune response. In addition, synthetic carbohydrate-based compounds found wide application in chemical biology and medicinal chemistry as diagnostics, therapeutics, and vaccines, drug delivery systems, and molecular receptors. Carbohydrates are still relatively untapped pool of new therapeutics, however, advances in functional understanding of carbohydrate-participating biological processes, enabled carbohydrates to take over a prominent role in drug design. Screening of compound libraries is the most available and easy-to-use tool in searching for biologically active molecules. However, a continuous decrease in drug-discovery success suggests deficiencies of currently used libraries. Small-molecule libraries typically represent collections of a large number of structurally similar compounds, that is, the “chemical space” covered is infinitely small. In contract, the ideal chemical library would contain discrete, stereochemically rich, structurally diverse and complex molecules. The concept of expanding the chemical space by developing large collections of structurally diverse molecules is one of the main challenges nowadays.
As a part of our ongoing project, we aim to expand the chemical space of glycomimetics by using multicomponent reactions. Multicomponent reactions (MCRs) offer an attractive one-pot strategy for generating a library of highly functionalized and complex compounds like glycomimetics. Of particular interest is a distinct group of MCRs, isocyanide-based MCRs (e.g., Passerini, Ugi reaction), widely exploited for the generation of drug-like molecules. We developed a smooth multicomponent strategy to access libraries of diverse compounds comprising carbohydrate unit(s) by utilizing, isopropylidene-protected carbohydrate-derived aldehydes and ketones in the Passerini and Ugi reaction. We applied this methodology to access both, simple N-alkylated C-glycosyl amino acid derivatives and densely functionalized glycomimetics bearing up to four carbohydrate. Also, we showed that the strategy can be used for the synthesis of homo- and hetero-multivalent glycomimetics. Access to highly valuable building blocks based on α-hydroxy C-glycosyl acids or more complex systems is elaborated by simple post-condensation methodologies.
- Vlahovicek-Kahlina, K., Vazdar, M., Jakas, A., Smrečki, V., and Jeric, I. Synthesis of Glycomimetics by Diastereoselective Passerini reaction. J. Org. Chem., 2018, 83, 13146–13156.