Synthesis and Evaluation as Glycosidase Inhibitors of Isoquinuclidines Mimicking a Distorted β ‐Mannopyranoside

Racemic and enantiomerically pure manno ‐configured isoquinuclidines were synthesized and tested as glycosidase inhibitors. The racemic key isoquinuclidine intermediate was prepared in high yield by a cycloaddition (tandem Michael addition/aldolisation) of the 3‐hydroxy‐1‐tosyl‐pyridone 10 to methyl acrylate, and transformed to the racemic N ‐benzyl manno ‐isoquinuclidine 2 and the N ‐unsubstituted manno ‐isoquinuclidine 3 (twelve steps; ca. 11% from 10 ). Catalysis by quinine of the analogous cycloaddition of 10 to (−)‐8‐phenylmenthyl acrylate provided a single diastereoisomer in high yield, which was transformed to the desired enantiomerically pure D ‐ manno ‐isoquinuclidines (+)‐ 2 and (+)‐ 3 (twelve steps; 23% from 10 ). The enantiomers (−)‐ 2 and (−)‐ 3 were prepared by using a quinidine‐promoted cycloaddition of 10 to the enantiomeric (+)‐8‐phenylmenthyl acrylate. The N ‐benzyl D ‐ manno ‐isoquinuclidine (+)‐ 2 is a selective and slow inhibitor of snail β ‐mannosidase. Its inhibition strength and type depends on the pH (at pH 4.5: K i =1.0 μ M , mixed type, α =1.9; at pH 5.5: K i =0.63 μ M , mixed type, α =17). The N ‐unsubstituted D ‐ manno ‐isoquinuclidine (+)‐ 3 is a poor inhibitor. Its inhibition strength and type also depend on the pH (at pH 4.5: K i =1.2⋅10 3  μ M , mixed type, α =1.1; at pH 5.5: K i =0.25⋅10 3  μ M , mixed type, α =11). The enantiomeric N ‐benzyl L ‐ manno ‐isoquinuclidine (−)‐ 2 is a good inhibitor of snail β ‐mannosidase, albeit noncompetitive (at pH 4.5: K i =69 μ M ). The N ‐unsubstituted isoquinuclidine (−)‐ 2 is a poor inhibitor (at pH 4.5: IC 50 =7.3⋅10 3  μ M ). A comparison of the inhibition by the pure manno ‐isoquinuclidines (+)‐ 2 and (+)‐ 3 , (+)‐ 2 /(−)‐ 2 1 : 1, and (+)‐ 3 /(−)‐ 3 1 : 1 with the published data for racemic 2 and 3 led to a rectification of the published data. The inhibition of snail β ‐mannosidase by the isoquinuclidines 2 and 3 suggests that the hydrolysis of β ‐ D ‐mannopyranosides by snail β ‐mannosidase proceeds via a distorted conformer, in agreement with the principle of stereoelectronic control.