Kennedy, A., Nelson, A. and Perry, A. (2005) Methods for the synthesis of polyhydroxylated piperidines by diastereoselective dihydroxylation: Exploitation in the two-directional synthesis of aza-C-linked disaccharide derivatives. Beilstein Journal of Organic Chemistry, 1 (2). ISSN 1860-5397
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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, twodirectional 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.
| Item Type: | Article |
|---|---|
| Copyright, Publisher and Additional Information: | © 2005 Kennedy et al; licensee Beilstein-Institut. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Academic Units: | The University of Leeds > Faculty of Maths and Physical Sciences (Leeds) > School of Chemistry (Leeds) |
| Depositing User: | Sherpa Assistant |
| Date Deposited: | 06 Jan 2006 |
| Last Modified: | 08 Feb 2013 17:02 |
| Published Version: | http://bjoc.beilstein-journals.org/content/1/1/2 |
| Status: | Published |
| Refereed: | Yes |
| Identification Number: | 10.1186/1860-5397-1-2 |
| URI: | http://eprints.whiterose.ac.uk/id/eprint/919 |
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