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.

A temperature‐dependent relay of chirality is based on the inversion of the nitrogen lone pair in cyclic azasugars. Elimination from the conformation preferred at a given temperature leads to a cyclic imine, and in a subsequent nucleophilic attack the stereochemical information is relayed.

Carbohydrates Carbohydrates U 0500 Nitrogen Inversion as a Diastereomeric Relay in Azasugar Synthesis: The First Synthesis of Adenophorine. -The total synthesis of (-)-adenophorine (I) is achieved exploiting the configurational dynamics at the nitrogen in azasugar chloramines. -(MAUGHAN, M. A. T.; DAVIES, I. G.; CLARIDGE, T. D. W.; COURTNEY, S.; HAY, P.; DAVIS*, B. G.; Angew. Chem., Int. Ed. 42 (2003) 32, 3788-3792; Dyson Perrins Lab., Dep. Chem., Univ. Oxford, Oxford OX1 3QY, UK; Eng.) -M. Paetzel 51-178