Methods for the synthesis of polyhydroxylated piperidines by diastereoselective dihydroxylation: Exploitation in the two-directional synthesis of aza-C-linked disaccharide derivatives

Abstract

Background: Many polyhydroxylated piperidines are inhibitors of the oligosaccharide processing enzymes, glycosidases and glycosyltransferases. Aza-C-linked disaccharide mimetics are compounds in which saturated polyhydroxylated nitrogen and oxygen heterocycles are linked by an all-carbon tether. The saturated oxygen heterocycle has the potential to mimic the departing sugar in a glycosidase-catalysed reaction and aza-C-linked disaccharide mimetics may, therefore, be more potent inhibitors of these enzymes. Results: The scope, limitations and diastereoselectivity of the dihydroxylation of stereoisomeric 2-butyl-1-(toluene-4-sulfonyl)-1,2,3,6- tetrahydro-pyridin-3-ols is discussed. In the absence of a 6-substituent on the piperidine ring, the Upjohn (cat. OsO4, NMO, acetone-water) and Donohoe (OsO4, TMEDA, CH2Cl2) conditions allow complementary diastereoselective functionalisation of the alkene of the (2R*,3R*) diastereoisomer. However, in the presence of a 6-substituent, the reaction is largely controlled by steric effects with both reagents. The most synthetically useful protocols were exploited in the two-directional synthesis of aza-C-linked disaccharide analogues. A two-directional oxidative ring expansion was used to prepare bis-enones such as (2R,6S,2′S)-6-methoxy-2-(6-methoxy-3-oxo-3,6-dihydro-2H-pyran-2-ylmethyl) -1-(toluene-4-sulfonyl)-1,6-dihydro-2H-pyridin-3-one from the corresponding difuran. Selective substitution of its N,O acetal was possible. The stereochemical outcome of a two-directional Luche reduction step was different in the two heterocyclic rings, and depended on the conformation of the ring. Finally, two-directional diastereoselective dihydroxylation yielded seven different aza-C-linked disaccharide analogues. Conclusion: A two-directional approach may be exploited in the synthesis of aza-C-linked disaccharide mimetics. Unlike previous approaches to similar molecules, neither of the heterocyclic rings is directly derived from a sugar, allowing mimetics with unusual configurations to be prepared. The work demonstrates that highly unsymmetrical molecules may be prepared using a two directional approach. The deprotected compounds may have potential as inhibitors of oligosaccharide- processing enzymes and as tools in chemical genetic investigations. © 2005 Kennedy et al; licensee Beilstein-Institut.