Leveraging Protecting Groups, Lewis Bases, and Backside Attack for 1,2-cis-Selective Glycosylation

With the support of the Chemical Synthesis (SYN) Program in the Division of Chemistry, Dr. Justin Ragains of Louisiana State University will work with undergraduate and graduate students in his organic chemistry laboratory to develop new approaches to the synthesis of oligosaccharides. Oligosaccharides are polymers of carbohydrates attached at specific loci and in controlled fashion in three-dimensional space.

However, isolation of oligosaccharides from their natural sources is not a practical approach to obtaining authentic samples of specific oligosaccharides. The variety of biologically relevant carbohydrates requires that the community continue to develop controlled methods for their de novo synthesis. In the research planned here, key building blocks in the laboratory synthesis of oligosaccharides will be synthesized.

An understanding of organic chemistry will then be used to ensure that the building blocks bond to one another in the correct three-dimensional orientation, an important problem in oligosaccharide synthesis. Successful execution of this research will advance the science of oligosaccharide synthesis and provide tools to study the chemical biology of carbohydrates with potentially important implications for biomedical research.

Planned public outreach activities include partnering with Lousiana State University’s Upward Bound program to teach low-income, first-generation high school students about chemistry and basic skills in the chemistry lab to help prepare these students for future pursuits of science studies.

Dr. Ragains and his students will study the 1,2-cis-selective glycosylation of alcohols with glycosylation electrophiles including trichloroacetimidates, N-phenyltrifluoroacetimidates, and thioglycosides. The aforementioned glycosylation electrophiles will be substituted with electron-withdrawing protecting groups, and glycosylations will be performed with a series of alcohols in the presence of Lewis-basic additives.

The synergy of electron-withdrawing protecting groups and Lewis bases is proposed to promote high 1,2-cis selectivity. The activation of thioglycosides using in-situ-generated benzynes will also be studied, and unique mechanistic features of this reaction will also be exploited for the development of 1,2-cis-selective glycosylation. Furthermore, synthetic approaches to 1,2-cis-selective glycosylation developed herein will be leveraged toward the synthesis of a synthetically challenging and 1,2-cis glycoside-rich tetrasaccharide repeating unit from the multidrug-resistant Acinetobacter baumannii strain D78.

The successful execution of this work will advance the understanding of the challenge of 1,2-cis-selective glycosylation and provide steps toward a generalized approach to this transformation. This work has potential long term implications for glycoscience and glycobiology studies in general.

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.