De Novo Asymmetric Synthesis of Natural and Unnatural Oligosaccharide Motifs

With the support of the Chemical Synthesis Program (SYN) in the Division of Chemistry (CHE), Professor George O’Doherty and his research team at Northeastern University will work to develop new methods and strategies for the construction of complex, oligosaccharide structural motifs. Of the bio-polymers/oligomers, including proteins, DNA (2'-deoxyribonucleic acid) and RNA (ribonucleic acid), oligosaccharides stand unique in terms of their limited synthetic accessibility.

Specifically, modern synthetic chemistry has established methods for the rapid assembly of peptide and nucleotide oligomers with both natural and unnatural subunits. In comparison, the ability to assemble carbohydrates into oligomeric motifs is limited in the ability to practically prepare the full range of accessible regio- and stereo-isomeric structures.

These synthetic limitations inhibit the study and use of oligosaccharide motifs as new materials and therapeutics. The broader impacts of this project are to (i) the long-term benefits to science that generalizable oligosaccharide synthesis methods will bring and (ii) the training that these studies engender to a diverse set of students. In addition to the creation of new oligosaccharide structures and new methods for their assembly, these projects will give students training in the concepts and techniques of multi-step complex molecule synthesis.

The students who take up these challenges come from a range of backgrounds and experience levels. This diverse group of students (high school, undergraduate, graduate and postdoctoral) is significantly made up of women and under-represented students from the US and around the world. The skills in organic synthesis that these students gain are highly valued by the biotechnology, pharmaceutical and material science industries, where most of them find employment.

This project aims to develop new synthetic methods to access a wider range of carbohydrate monomers and the resulting natural and unnatural oligosaccharide motifs. This unique synthetic approach heavily relies on the use of transition metal catalysis unlike most oligosaccharide synthesis methods. First asymmetric catalysis for the stereoselective synthesis of the carbohydrate monomers will be pursued.

Then an underexploited approach; namely, transition metal-mediated glycosylation or cyclitolization will be used to regio- and stereo-selectively assemble the carbohydrate monomers, or their carbocyclic analogues, into (pseudo)oligosaccharide motifs. The use of asymmetric catalysis for the synthesis of the monomers allows a degree of stereochemical flexibility to the approach that more traditional methods do not readily offer.

The glycosylation reaction assembles double bonds containing carbohydrate monomers, which also engenders a degree of structural flexibility as well as allows for the minimal use of alcohol protections. Avoiding protecting groups can significantly reduce the amount of chemical waste generated. Overall, the project aims to fundamentally change oligosaccharide synthesis and in turn also change the application of carbohydrate chemistry to real-world problems in chemical biology, and eventually, medicinal chemistry.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.