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

Abstract

Duilio Arigoni, in dankbarer und freundschaftlicher Verbundenheit, zum 75. herzlich zugeeignet 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 mannoisoquinuclidine 3 (twelve steps; ca. 11% from 10). Catalysis by quinine of the analogous cycloaddition of 10 to (À)-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 (À)-2 and (À)-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 b-mannosidase. Its inhibition strength and type depends on the pH (at pH 4.5: K i 1.0 mm, mixed type, a 1.9; at pH 5.5: K i 0.63 mm, mixed type, a 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

Electrophilic Bromination of N‐Acylated Cyclohex‐3‐en‐1‐amines: Synthesis of 7‐Azanorbornanes

“…The chemical shift for the C(1) d of 18, 21, 22, and 23 (73.8 ± 74.5 ppm) evidences the dihydrooxazine and not the azetidine structure. These d values are similar to those for C(6) of 2-(trifluoromethyl)-(78.6 and 75.7 ppm [64]), 2-methyl-(72.26 ppm [62]), and 2-phenyl-4,5-dihydro-6H- [1,3]oxazines (74.2 ppm [65]). The chemical-shift values for the C(5) and C(8) ds of the bromo-1,3-oxazines 18, 22, and 23 are similar to each other (46.7 ± 51.3 ppm) and were not assigned separately.…”

“…± According to the principle of stereoelectronic control, hydrolysis of glycopyranosides with an equatorial aglycon requires an anti-or syn-periplanar arrangement of a C(5)O lone pair and the scissile bond and, thus, a distortion of the ground-state chair conformation [1] [2]. Substrates or inhibitors adopting such a conformation have been observed in the crystal structure of their complexes with several b-glycosidases (see [3] and refs. cit.…”

“…They may bind as mimics of isofagomine that adopts a 4 C 1 conformation, but they may as well adopt a distorted chair conformation. The isoquinuclidine 1, a 2-azabicyclo[2.2.2]octane (Scheme 1), mimicking a slightly distorted 1,4 B conformer of a b-d-mannopyranoside inhibits selectively snail b-mannosidase (K i 1.0 mm at pH 4.5, mixed type inhibition) [3], while the analogous mimic 2 of a b-d-glucopyranoside is a very poor inhibitor of several b-glucosidases [6] 1 ); these observations have been taken as evidence that the enzymatic hydrolysis of b-d-glucopyranosides and b-d-mannopyranosides proceed via different reactive conformations [3] [6]. The high inhibitory selectivity of the isoquinuclidines 1 and 2 shows that bicyclic hydroxylated amines mimicking reactive conformations of b-d-glycopyranosides are attractive as potential glycosidase inhibitors.…”

Norbornane Mimics of Distorted β‐D‐Glucopyranosides – Inhibitors of β‐D‐Glucopyranosidases?

“…The pK HA value suggests that, at pH 4.5, only one in 10 000 molecules of 3 (pK HA = 8.6 [8]) is not protonated. Snail b-mannosidase is inhibited by 3 5.5 times more strongly at pH 5.5 than at pH 4.5 [17]. Thus, an inhibitor geometrically corresponding to 3, but with a hypothetical pK HA of 4.5 should inhibit ca.…”

Synthetic Routes to Three Novel Scaffolds for Potential Glycosidase Inhibitors

“…[8] The isoquinuclidine 3, a mimic of the β-d-mannopyranoside 1,4 B conformer, [9] as well as the iminosugar 4, [10] are the results of inhibitor design and synthetic efforts. The search for efficient and selective glycosidase inhibitors challenges transition-state-analogue design [11] and organic synthesis.…”