Highly diastereoselective additions to polyhydroxylated pyrrolidine cyclic imines: ready elaboration of aza-sugar scaffolds to create diverse carbohydrate-processing enzyme probes.

Journal article

Representative diastereomeric, erythritol and threitol polyhydroxylated pyrrolidine imine scaffolds have been rapidly elaborated to diversely functionalized aza-sugars through highly diastereoselective organometallic (RM) additions (R=Me, Et, allyl, hexenyl, Ph, Bn, pMeO-Bn). The yields for these additions have all been substantially enhanced from previously optimised levels (<58 %) for normal additions using a reverse addition procedure (e.g. R=Ph; 44 % normal mode --> 78 % reverse mode). The high diastereoselectivities (>98 % de for all except R=Me) are consistent with additions that are controlled by the configuration of the C-2 centre adjacent to the azomethine imine carbon and the conformation of the pyrrolidine imine. The high potential of this method was demonstrated by concise syntheses of 1-epi- and 2-epi-desacetylanisomycins. In addition, the late stage addition of hydrophobic substituents, which this imine addition methodology allows, enabled the preparation of novel aza-sugars with enhanced inhibitory potential. This was highlighted by the screening of a representative selection of these "hydrophobically-modified" aza-sugars against a diverse panel of 12 non-mammalian and human carbohydrate-processing enzymes. This identified a novel nanomolar alpha-galactosidase inhibitor (IC(50)=250 nM) and a novel highly selective glucosylceramide synthase inhibitor (IC(50)=52 microM, no alpha-glucosidase inhibition at 1 mM). Furthermore, analysis of the structure-activity relationships of racemic series of inhibitors allowed some validation of Fleet's mirror-image enzyme active site postulate.

Authors: Chapman, T; Courtney, S; Hay, P; Davis, B

• Publication status: Published
• Journal: Chemistry (Weinheim an der Bergstrasse, Germany)
• Volume: 9
• Issue: 14
• Pages: 3397-3414
• Publication date: 2003-07-01
• DOI: 10.1002/chem.200304718
• EISSN: 1521-3765
• ISSN: 0947-6539
• Language: English
• Keywords: heterocycles; asymmetric synthesis; azasugars; enzyme catalysis; carbohydrates