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

• Published in: Helvetica chimica acta Vol. 86; no. 11; pp. 3787 - 3817
• Main Authors: Böhm, Matthias, Lorthiois, Edwige, Meyyappan, Muthuppalaniappan, Vasella, Andrea
• Format: Journal Article
• Language: English
• Published: Zürich WILEY-VCH Verlag 01.11.2003; WILEY‐VCH Verlag; Wiley
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; ACID-DERIVATIVES; ASYMMETRIC-SYNTHESIS; DIELS-ALDER REACTION; RING DISTORTION; GLYCOSYL-ENZYME INTERMEDIATE; COVALENT-INTERMEDIATE; TRANSITION-STATE; CATALYTIC MECHANISM; SUBSTRATE DISTORTION; RAY CRYSTAL-STRUCTURE
• ISSN: 0018-019X; 1522-2675
• DOI: 10.1002/hlca.200390320

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: Ki=1.0 μM, mixed type, α=1.9; at pH 5.5: Ki=0.63 μM, 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: Ki=1.2⋅103 μM, mixed type, α=1.1; at pH 5.5: Ki=0.25⋅103 μM, 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: Ki=69 μM). The N‐unsubstituted isoquinuclidine (−)‐2 is a poor inhibitor (at pH 4.5: IC50=7.3⋅103 μM). 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.