Highly Diastereoselective Additions to Polyhydroxylated Pyrrolidine Cyclic Imines: Ready Elaboration of Aza-Sugar Scaffolds To Create Diverse Carbohydrate-Processing Enzyme Probes

• Published in: Chemistry : a European journal 2003-07, Vol.9 (14), p.3397-3414
• Main Authors: Chapman, Timothy M., Courtney, Steve, Hay, Phil, Davis, Benjamin G.
• Format: Article
• Language: English
• Subjects: asymmetric synthesis; azasugars; carbohydrates; enzyme catalysis; heterocycles
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200304718

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 (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 α‐galactosidase inhibitor (IC50=250 nM) and a novel highly selective glucosylceramide synthase inhibitor (IC50=52 μM, no α‐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. Ideal scaffolds for elaboration by efficient and stereoselective reactions with Grignards are provided by aza‐sugar imines (see scheme). An array of novel “hydrophobically‐modified” five‐membered ring aza‐sugars were generated as probes of 12 carbohydrate‐processing enzymes and used in structure–activity relationship studies to identify potent inhibitors.