Amine-linked diglycosides: Synthesis facilitated by the enhanced reactivity of allylic electrophiles, and glycosidase inhibition assays

Ian Cumpstey,Inmaculada Robina,Elias Pershagen,Dominic S Alonzi,Tashfeen Akhtar,Jens Frigell,Elena Moreno-Clavijo,Terry D Butters

doi:10.3762/bjoc.7.128

Ian Cumpstey, Inmaculada Robina + Show 6 more

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https://doi.org/10.3762/bjoc.7.128

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Abstract

Diglycose derivatives, consisting of two monosaccharides linked at non-anomeric positions by a bridging nitrogen atom, have been synthesised. Conversion of one of the precursor monosaccharide coupling components into an unsaturated derivative enhances its electrophilicity at the allylic position, facilitating coupling reactions. Mitsunobu coupling between nosylamides and 2,3-unsaturated-4-alcohols gave the 4-amino-pseudodisaccharides with inversion of configuration as single regio- and diastereoisomers. A palladium-catalysed coupling between an amine and a 2,3-unsaturated 4-trichloroacetimidate gave a 2-amino-pseudodisaccharide as the major product, along with other minor products. Derivatisation of the C=C double bond in pseudodisaccharides allowed the formation of Man(N4–6)Glc and Man(N4–6)Man diglycosides. The amine-linked diglycosides were found to show weak glycosidase inhibitory activity.

Highlights

We have been interested in synthesising molecules consisting of two monosaccharides linked by formal condensation without using the anomeric position [1]
We found that the choice of Lewis acid used in the Ferrier reaction of 3 with ethanol was critical for a satisfactory yield of the unsaturated glycoside 4 to be achieved; phosphomolybdic acid [32] gave the product (α:β, 8:1) in 63% yield
Triflamides and nosylamides were effective as nucleophiles in Mitsunobu coupling reactions with allylic alcohols

Summary

Introduction

We have been interested in synthesising molecules consisting of two monosaccharides linked by formal condensation without using the anomeric position [1]. Mitsunobu coupling between nosylamides and 2,3-unsaturated-4-alcohols gave the 4-amino-pseudodisaccharides with inversion of configuration as single regio- and diastereoisomers. A palladium-catalysed coupling between an amine and a 2,3-unsaturated 4-trichloroacetimidate gave a 2-amino-pseudodisaccharide as the major product, along with other minor products.

Results

Conclusion