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

Abstract

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.

Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

“…A similar reasoning was argued by Chapman et al to explain the a-lrhamnosidase inhibitory activity of 8 (K i = 3.0 mm). [56] However, Kim et al proposed a role as aglycone for hydrophobic substituents at C-2 of pyrrolidines such as 9 (K i = 3.4 mm). [57] Table 4.…”

“…The lack of activity of 4 ah suggests that the hydroxymethyl moiety present in this pyrrolidine might have a deleterious effect on the activity against the enzyme. This effect could also contribute to the lower activity observed for 4 a or 10 compared to their counterparts 11 [58] or 12 [56] (K i = 5.5 and 5.9 mm, respectively). Figure 9.…”

“…It has been suggested that the a-l-rhamnosidase inhibition shown by some pyrrolidines can be rationalized in terms of stereochemical similarities with a-l-rhamnose. [56,57] Considering the structure of naringin, a natural substrate of a-l-rhamnosidase, it is apparent that the stereochemistry of 4 o (i.e., 2S,3S,4S,5S) matches that of the rhamnose moiety at C-3, C-4, and C-5. This would place the 5-butyl group of 4 o on the same location as the 5-methyl group of rhamnose.…”

Glycosphingolipids—Nature, Function, and Pharmacological Modulation

“…[197] Two studies by Davis and co-workers have also identified several pyrrolidine inhibitors (48)(49)(50)(51)(52). [210,211] GØn-isson and co-workers have developed pyrrolidines that mimic the sphingosine backbone (53)(54)(55)(56), with 55 proving to be a potent GCS inhibitor. [212] Finally, BlØriot and co-workers recently reported moderately active azepane-based inhibitors of GCS (57)(58)(59)(60).…”

Recent Advances in the Total Synthesis of Piperidine Azasugars

“…Subsequent N-chlorination with NCS in DCM led to the N-chloropiperidine 123 in excellent yield (93 %). A regioselective HCl elimination process developed by the authors [61] with DBU in refluxing Et 2 O was carried out on 123 to prepare the crude imine 124. This was then treated directly with EtMgBr in a mixture of Et 2 O and dioxane.…”