Stereoselective synthesis of α-Galactosides Kate E. Donaghy, Dionissia A. Pepe, Joseph J. Ruddy, Eoghan M. McGarrigle Centre for Synthesis and Chemical Biology, University College Dublin, Ireland Nature employs carbohydrates as an integral source of structural biodiversity across all organisms. It is understood that the biological properties of these natural products can be fine-tuned via alteration of glycosidic patterns, particularly with respect to stereochemistry. Consequently, stereochemical control in glycosylation reactions is a significant objective within the field of carbohydrate chemistry. [1] This work is concerned with stereochemical control in α-galactosidation reactions. α-Galactoside units are found in many biologically important compounds, for example in cancer-associated mucin-type glycans. [2] However, existing methods for the α-selective synthesis of galactosides that are broadly applicable to a range of galactosyl substrates are limited. [3-6] Thus, further understanding around the stereochemistry of α-galactosidations is required. This poster will describe a highly α-selective methodology for galactosidation that employs an orthogonal para -substituted benzoate protecting group at position four of the galactosyl donor. Seven galactosyl donors were prepared in yields up to 17% over 6 steps. It was found that donors bearing para -electron-withdrawing substituents, for example a para -nitro substituent, afforded the highest α-selectivities. Interestingly, this was contradictory to existing mechanistic proposals described in the literature that suggest reaction via a dioxolenium ion intermediate. [6-8] Computational investigations, a Hammett study on the effect of this benzoyl para -substituent and investigation into the influence of acceptor nucleophilicity on glycosylation stereoselectivity have allowed for the proposal of a rationale for the excellent α-stereoselectivity described herein. This has contributed significantly to our understanding of these α-galactosylation reactions and has allowed for further development of the methodology in terms of scope and application. [9] The scope of glycosylation has been expanded to accommodate galactosyl-α-1,2-, α-1,3-, α-1,4-, and α-1,6- linkages with exclusive α-selectivities and isolated yields up to 74%. The protecting group tolerance of the methodology is under investigation and includes benzyl, benzylidene and benzoyl groups thus far. This glycosylation has also been applied to the synthesis of a trisaccharide as well as a derivative of the mucin-type core-8 structure. [9] Work towards the application of this methodology to the synthesis of biologically relevant α-fucoside compounds will also be reported.
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