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. 2023 Jun:1224:114122.
doi: 10.1016/j.comptc.2023.114122. Epub 2023 Apr 6.

Stereoselective glycosylation reactions with 2-deoxyglucose: a computational study of some catalysts

Spencer Haisha  1 , Hien M Nguyen  2 , H Bernhard Schlegel  2
Affiliations

Stereoselective glycosylation reactions with 2-deoxyglucose: a computational study of some catalysts

Spencer Haisha et al. Comput Theor Chem. 2023 Jun.

Abstract

2-Deoxy glycosides are important components of many oligosaccharides with antibiotic and anti-cancer activity, but their synthesis can be very challenging. Phenanthrolines and substituted pyridines promote stereoselective glycosylation of 1-bromo sugars via a double SN2 mechanism. Pyridine reacting with α-bromo, 2-deoxyglucose was chosen to model this reaction. The first step involves displacement of bromide by pyridine which can be rate limiting because bromide ion is poorly solvated in the non-polar solvents used for these reactions. We examined a series of small molecules to bind bromide and stabilize this transition state. Geometry optimization and vibrational frequencies were calculated using M06-2X/6-31+G(d,p) and SMD implicit solvation for diethyl ether. More accurate energies were obtained with M06-2X/aug-cc-pVTZ and implicit solvation. Urea, thiourea, guanidine and cyanoguanidine bind bromide more strongly than alkylamines, (NH2CH2CH2)nNH3-n. Compared to the uncatalyzed reaction, urea, thiourea and cyanoguanidine lower the free energy of the transition state by 3 kcal/mol while guanidine lowers the barrier by 2 kcal/mol.

Keywords: 2-deoxyglucose; DFT; catalysis; glycosylation.

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Conflict of interest statement

Conflict of Interest Statement The authors declare that they have no known conflict of interests that could have appeared to influence the work reported in this paper. Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
Complexes of Br− with (a) 1,2-diaminoethane, (b) bis(2-aminoethyl)amine and (c) tris(2-aminoethyl)amine (H-Br− distances in Å).
Figure 2.
Figure 2.
Complexes of Br− with (a) urea, (b) thiourea, (c) guanidine and (d) cyanoguanidine (H-Br− distances in Å).
Figure 3.
Figure 3.
Transition structures for the SN2 reaction of pyridine 1-bromo, 2-deoxyglucose catalyzed by (a) urea, (b) thiourea, (c) guanidine and (d) cyanoguanidine (distances in Å). For the uncatalyzed reaction R(C1-N) = 2.163 Å and R(C1-Br) = 2.815 Å.
Figure 4.
Figure 4.
Post-transition state minima for pyridine displacing Br− in 1-bromo, 2-deoxyglucose complexed with (a) urea, (b) thiourea, (c) guanidine and (d) cyanoguanidine (H-Br− distances in Å)
Figure 5.
Figure 5.
Enthalpy profile for the reaction with and without the catalyzing ligands.
Figure 6.
Figure 6.
Free energy profile for the reaction with and without the catalyzing ligands.
Scheme 1.
Scheme 1.
Glycosylation reactions to form α- and β-2-deoxy glycosides.
Scheme 2.
Scheme 2.
First step in the glycosylation of α-bromo, 2-deoxyglucose catalyzed by pyridine. The glycosylation is completed in a second SN2 reaction, in which the ROH nucleophile displaces the pyridine.
See this image and copyright information in PMC

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