Carbohydrate Chemistry

We are interested in developing organocatalysts to promote glycosylations reactions and in developing other modern methods for use in carbohydrate chemistry.

In collaboration with Dr M Carmen Galan at the University of Bristol, we developed a highly stereoselective organocatalytic glycosylation of galactals. The readily available catalyst catalyses the addition of alcohols to galactal with virtually complete α-stereoselectivity. Our first paper on this topic was published in Angew Chem Int Ed in 2012. It was the first example of an organocatalyst giving excellent stereoselectivity in a glycosylation.

Angew Chem Int Ed 2012, 51, 9152-9155. E I Balmond, D M Coe, M C Galan,* E M McGarrigle* — α-Selective Organocatalytic Synthesis of 2-Deoxygalactosides. DOI: 10.1002/anie.201204505

In 2016 we published our a follow-up paper in J Org Chem, detailing our identification of a catalyst poision. The amine poison arose during the benzylation of galactal and co-eluted with the product during chromatography. Interestingly, the side reaction that generates the amine seems to have been overlooked despite the fact that the benzylation conditions used are very common in the literature.

J Org Chem 2016, 81, 11394-11396. A C Colgan, H Müller-Bunz, E M McGarrigle* — Benzylation Reactions in DMF Lead to an Impurity Which Acts as an Organocatalyst Poison in Thiourea-Catalyzed Glycosylations. DOI: 10.1021/acs.joc.6b01914

Also in 2016, we published an article describing the glycosylation of nitrogalactals, which enabled a synthesis of mucin type Core 6 and 7 glycopeptide monomers.

Org Lett 2016, 18, asap. S Medina, M J Harper, E I Balmond, S Miranda, G E M Crisenza, D M Coe, E M McGarrigle, M C Galan* — Stereoselective Glycosylation of 2-Nitrogalactals Catalyzed by a Bifunctional Organocatalyst. DOI: 10.1021/acs.orglett.6b01962

Subsequently, we have published an article with a cheaper, lower molecular weight catalyst at lower loading. Just 0.25 mg of thiouracil as catalyst was required to make 1 g of disaccharide product. The work evidences that the mechanism of activation is not through double H-bonding catalyst but rather by Brønsted acid/base catalysis. We also demonstrated application to the synthesis of glyconjugates and 1,1′-linked trehalose-type sugars.Chem Sci 2019, 10, 508. G A Bradshaw, A C Colgan, N P Allen, I Pongener, M B Boland, Y Ortin and E M McGarrigle* — Stereoselective organocatalyzed glycosylations – thiouracil, thioureas and monothiophthalimide act as Brønsted acid catalysts at low loadings. DOI: 10.1039/C8SC02788A

We have written a SYNPACTS article highlighting developments in the field.

Synlett 2013, 24, 2335–2339. E I Balmond, M C Galan,* E M McGarrigle* — ‘Recent Developments in the Application of Organocatalysis to Glycosylations’. DOI: 10.1055/s-0033-1338970

In the course of Ed Balmond’s PhD we also developed a method to glycosylate glucals and rhamnals using a siloxane protecting group to obtain high stereoselectivity.

Angew Chem Int Ed 2014, 53, 8190-8194. E I Balmond, D Benito-Alifonso, D M Coe, R W Alder, E M McGarrigle,* M C Galan* — A 3,4-trans-Fused Cyclic Protecting Group Facilitates α-Selective Catalytic Synthesis of 2-Deoxyglycosides. DOI:10.1002/anie.201403543

More recently, we have developed catalytic Appel conditions for the synthesis of glycosyl chlorides (building on pioneering work by Denton in the synthesis of alkyl chlorides), and then developed a method for the synthesis of challenging β-mannosylations and rhamnosylations. The latter paper was important in that it demonstrated high selectivity could be achieved without depending on conformational restraints imposed by protecting groups on the glycosyl donor. A wide range of useful glycoside linkages can be made using the method.

Org Biomol Chem 2019, 17, 7531-7535. I Pongener, K Nikitin  and  E M McGarrigle* — Synthesis of Glycosyl Chlorides using Catalytic Appel Conditions. DOI: 10.1039/C9OB01544B 

Chem Sci 2021, 12, 10070-10075. I Pongener, D A Pepe, J J Ruddy, E M McGarrigle*— Stereoselective β-mannosylations and β-rhamnosylations from glycosyl hemiacetals mediated by lithium iodide. DOI: 10.1039/D1SC01300A

We are currently pursuing these glycosylation reactions with a view to inventing better catalysts, expanding the substrate scope of these systems, and developing a deeper understanding of the origins of the stereoselectivity in these reactions.