Skip to main content
Skip to main menu

Slideshow

Probing the Mechanism(s) of Sialidation Reactions Using Cation Clocks

Emmanuel Onobun
Emmanuel Onobun
Graduate Student, Department of Chemistry
University of Georgia
ONLINE ONLY
Organic Seminar

The first part of my talk centers on the application of cation clock reactions for the determination of relative reaction kinetics in sialidation reactions. The formation of glycosidic bonds is perhaps the most important bond forming reaction in glycoscience, playing a critical role in the assembly of all glycoconjugates. In general, the control of the glycosylation reaction is a key ingredient to engineering better stereoselective oligosaccharide synthesis irrespective of the assembly strategy used. Thus, an increasing demand for efficient and stereoselective glycosylation reactions is a major challenge in the field. Optimization of existing methods for glycosylation necessitates a detailed understanding of their mechanisms, and as such, mechanistic studies have received much attention from physical organic chemists. In view of this, we previously developed a simple cation clock method for determination of the relative kinetics and molecularity of glycosylation reactions with specific applications to the gluco- and manno- series. Herein, we describe the application of our cation clock method in the investigation of the concentration dependence of glycosyl acceptors in sialidation reactions utilizing 2-(hydroxycarbonyl)benzyl (HCB) glycosides as probes for the study. The formation of β-O-sialoside is demonstrated to proceed with a strong dependence on the concentration of the acceptor alcohol, whereas formation of the α-O-sialoside is less concentration dependent. The second part of my talk focuses on the preparation of glycosyl dibutyl phoshates in the 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) and pseudaminic acid series and their application to the formation of C-glycosides. Among sialic and octulosonic acid thioglycosyl donors, KDO and pseudaminic acid display greater selectivity for the formation of equatorial Oglycosides than legionaminic acid and neuraminic acid. As with the thioglycosides, the side chains of both KDO and pseudaminic acid glycosyl phoshate donors adopted very predominantly the strongly electron-withdrawing tg conformation of their side chains, which is reflected in the excellent equatorial selectivity of both donors in the formation of exemplary O-glycosides. With respect to C-glycoside formation on the other hand contrasting results were observed: the KDO donor was either relatively unselective or selective for formation of the axial C-glycoside, while the pseudaminic acid donor was selective for the formation of the equatorial C-glycoside. These observations are rationalized in terms of the greater electron-withdrawing ability of the azides in the pseudaminic acid donor compared to the corresponding acetoxy groups in the KDO resulting in reaction through tighter ion pairs even at the SN1 end of the general glycosylation mechanism. The contrast in axial vs equatorial selectivity between C- and O-glycosylation cautions against the extrapolation of models for SN1 type glycosylation with weak nucleophiles to the explanation of O-glycosylation.

Onobun seminar graphic

References:

1. Singleton, D. A.; Thomas, A. A. High Precision Simultaneous Determination of Multiple Small Kinetic Isotope Effects at Natural Abundance. J. Am. Chem. Soc. 1995, 117, 9357− 9358.

2. Huang, M.; Retailleau, P.; Bohé, L.; Crich, D. Cation Clock Permits Distinction between the Mechanisms of α- and β-O- and β-C-Glycosylation in the Mannopyranose Series; Evidence for the Existence of a Mannopyranosyl Oxocarbenium Ion. J. Am. Chem. Soc. 2012, 134, 14746−14749.

3. Adero, P. O.; Furukawa, T.; Huang, M.; Mukherjee, D.; Retailleau, P.; Bohé, L.; Crich, D. Cation Clock Reactions for the Determination of Relative Reaction Kinetics in Glycosylation Reactions: Applications to Gluco- and Mannopyranosyl Sulfoxide and Trichloroacetimidate Type Donors. J. Am. Chem. Soc. 2015, 137, 10336−10345.

4. Amarasekara, H.; Crich, D. Synthesis and Intramolecular Glycosylation of Sialyl MonoEsters of o-Xylylene Glycol. The Importance of Donor Configuration and Nitrogen Protecting Groups on Cyclization Yield and Selectivity; Isolation and Characterization of a N-Sialyl Acetamide Indicative of Participation by Acetonitrile. Carbohydr. Res. 2016, 435, 113−120.

5. Dhakal, B.; Crich, D. Synthesis and Stereocontrolled Equatorially Selective Glycosylation Reactions of a Pseudaminic Acid Donor: Importance of the Side Chain Conformation, and Regioselective Reduction of Azide Protecting Groups. J. Am. Chem. Soc. 2018, 140, 15008-15015.

6. Popik, O.; Dhakal, B.; Crich, D. Stereoselective Synthesis of the Equatorial Glycosides of Legionaminic Acid. J. Org. Chem. 2017, 82, 6142-6152.

7. Adero, P. O.; Amarasekara, H.; Wen, P.; Bohé, L.; Crich, D. The Experimental Evidence in Support of Glycosylation Mechanisms at the SN1-SN2 Interface. Chem. Rev. 2018, 118, 8242-8284.

8. Kim, K. S.; Kim, J. H.; Lee, Y. J.; Lee, Y. J.; Park, J. 2-(Hydroxycarbonyl)benzyl Glycosides: A Novel Type of Glycosyl Donors for Highly Efficient αMannopyranosylation and Oligosaccharide Synthesis by Latent-Active Glycosylation. J. Am. Chem. Soc. 2001, 123, 8477-8481.

9. Ngoje, P.; Crich, D. Stereocontrolled Synthesis of the Equatorial Glycosides of 3-DeoxyD-manno-oct-2-ulosonic Acid (KDO): Role of Side Chain Conformation. J. Am. Chem. Soc. 2020, 142, 7760-7764.

10. Onobun, E.; Crich, D. Synthesis of 3-Deoxy-D-manno-oct-2-ulosonic Acid (KDO) and Pseudaminic Acid C-Glycosides. J. Org. Chem. 2020, Just accepted

Support Us

We appreciate your financial support. Your gift is important to us and helps support critical opportunities for students and faculty alike, including lectures, travel support, and any number of educational events that augment the classroom experience. Click here to learn more about giving.

Every dollar given has a direct impact upon our students and faculty.

Got More Questions?

Undergraduate inquiries: chemreg@uga.edu 

Registration and credit transferschemreg@uga.edu

AP Credit, Section Changes, Overrides, Prerequisiteschemreg@uga.edu

Graduate inquiries: tharrop@uga.edu

Contact Us!

Assistant to the Department Head: Kelli Porterfield, 706-542-1919 

Main office phone: 706-542-2626 

Fax: 706-542-9454

Head of the Department: Prof. Gary Douberly