Asymmetric synthesis and affinity of potent sialyltransferase inhibitors based on transition-state analogues

Inhibitors that are structurally related to the transition-state model of the proposed S(N)1-type mechanism of sialyl transfer, exhibit particularly high binding affinities to a( 2 - 6) sialyltransferases. Furthermore, replacing the neuraminyl residue with a simple aryl or hetaryl ring and substituting the carboxylate group for a phosphonate moiety, improves both binding affinity and synthetic accessibility. Herein we report on the synthesis and inhibition of a wide range of novel, potent transition-state analogue based alpha(2-6) sialyltransferase inhibitors comprising a planar anomeric carbon, an increased distance between the anomeric carbon and the CMP leaving group, and at least two negative charges. We also present a short, efficient asymmetric synthesis of the most promising benzyl inhibitors, providing rapid access to large quantities of highly potent, stereochemically-pure (> 96% de) inhibitors for further biological investigation (e.g. (R)-3b, K-i = 70 nM).