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From the building blocks of nature to disease-battling therapeutics and vaccines, carbohydrates have had a profound impact on evolution, society, economy, and human health. Numerous applications of these essential biomolecules in many areas of science and technology exist, most of which can be found in the area of the development of therapeutic agents and diagnostic platforms. Although carbohydrates are desirable for the biological and medical communities, these molecules are very challenging targets for chemists because of the need for functionalization, protecting and leaving group manipulations, controlling anomeric stereoselectivity, etc. With the participation of more than 180 co-workers/trainees, the Demchenko laboratory (Glycoworld) has developed many innovative tools for the synthesis and application of carbohydrates in the following major areas.
From the building blocks of nature to disease-battling therapeutics and vaccines, carbohydrates have had a profound impact on evolution, society, economy, and human health. Numerous applications of these essential biomolecules in many areas of science and technology exist, most of which can be found in the area of the development of therapeutic agents and diagnostic platforms. Although carbohydrates are desirable for the biological and medical communities, these molecules are very challenging targets for chemists because of the need for functionalization, protecting and leaving group manipulations, controlling anomeric stereoselectivity, etc. With the participation of more than 180 co-workers/trainees, the Demchenko laboratory (Glycoworld) has developed many innovative tools for the synthesis and application of carbohydrates in the following major areas.
Development of new reagents, protecting groups, and building blocks
The application of partially protected building blocks is fundamental to carbohydrate chemistry. Poor accessibility to building blocks hampers the development of all synthetic methods, and researchers experience significant setbacks because they must continue to remake building blocks. There are no universal building blocks, protecting groups, reagents, or methods for the synthesis of glycans. The Demchenko lab has been working on developing new protecting groups and advanced synthetic intermediates that will provide streamlined access to regioselectively protected building blocks. Many of these projects involve undergraduate trainees who become co-authors on articles and presentations. In recent years, we have also initiated a program dedicated to the development of new catalysts and protocols for catalytic activation and modification of carbohydrates.
Stereocontrolled glycosylation: reactions and mechanism
Many complex sugars have an oligomeric sequence wherein monosaccharides are linked via O-glycosidic linkages. This linkage is obtained by a glycosylation reaction, which, despite significant progress, remains challenging due to the requirement to achieve complete stereocontrol and to suppress side reactions. To address these challenges, my lab introduced the thioimidate glycosylation approach, discovered the O-2/O-5 cooperative effect in glycosylation, and invented an ether-type participating group. The Demchenko team developed many methods for 1,2-cis glycosylation, including bromine-activated glycosidation of thioglycosides, H-bond-mediated aglycone delivery, and a metal-coordination approach to controlling stereoselectivity. More recently, the Demchenko lab invented a concept of the regenerative glycosylation reaction, developed glycosyl donors with switchable stereoselectivity, and introduced the 4K reaction that demonstrates how traditional Koenigs-Knorr glycosylations can be enhanced by cooperative acid catalysis.
Development of expeditious strategies for oligosaccharide synthesis
Glycosylation represents only one challenge that oligosaccharide synthesis researchers face; often, additional protecting or leaving group manipulations between each glycosylation step are required. This becomes increasingly inefficient at advanced stages of the assembly, often leading to a dramatic drop in yield, and, consequently, a decrease in the availability of oligosaccharides. To address these challenges, the Demchenko lab introduced the following strategies for expeditious oligosaccharide synthesis: the temporary deactivation concept, the inverse armed-disarmed strategy, electronically superarmed and superdisarmed building blocks, templated oligosaccharide synthesis, and the reverse orthogonal strategy. The Demchenko group also developed five new sets of leaving groups for orthogonal activation.
New technologies for the automated glycan assembly
More recently, the Demchenko lab has been working on automated technologies for oligosaccharide synthesis: STICS (Surface-Tethered Iterative Carbohydrate Synthesis) and HPLC-assisted automated synthesis (HPLC-A). The general idea for developing the HPLC-A is that a computer interface coupled with standard HPLC components will allow recording a successful automated sequence as a computer program that can then be reproduced with the “press of a button.” The application of this user-friendly platform for simple and transformative automation to produce glycans is currently being investigated with the involvement of undergraduate and high school students. In collaboration with Keith Stine, we have been working on implementing nanomaterials as supports for solid-phase automated synthesis.
Biomedical studies: development of glycopharmaceuticals
The synthetic methods discussed in the previous sections have been applied to the synthesis of biologically important or therapeutically relevant molecules. Our lab synthesized and studied carbohydrate molecules to determine their involvement in biological processes associated with various human diseases. Recent collaborative projects include syntheses of tumor-associated glycosphingolipids that mediate the metastasis of carcinomas (with Stine) and those involved in the pathogenesis of Krabbe disease (with Sands). The Demchenko lab has obtained glycoconjugates of S. pneumoniae, serogroups 6 and 14 (with Nahm), as well as Staph. aureus types 5 and 8 (with Pfizer), important bacterial pathogens. The Demchenko group has synthesized a series of glycopeptides as anti-septicemia (with Nichols and Kontoyianni) and anti-cancer therapeutics (with Spadaro). A series of our compounds have been investigated as imaging reagents in vivo (with Wang). We have also been studying thioimidates (with Byers and with Daniellou) and aminosugars (with Orlean and Price) as inhibitors or substrates for various enzymes.
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