Isoquinuclidine Mimics of β‐D‐Glucopyranosides: Differences and Similarities in the Mechanism of Action of some β‐D‐Glucosidases and a β‐D‐Mannosidase

Abstract

Duilio Arigoni, in dankbarer und freundschaftlicher Verbundenheit, zum 75. herzlich zugeeignetThe d-gluco-isoquinuclidines 3 and 4 were prepared and tested as inhibitors of the b-glucosidases from Caldocellum saccharolyticum and from sweet almonds; the results are compared to the inhibition of snail bmannosidase by the d-manno-isoquinuclidines 1 and 2. Exploratory experiments in the racemic series showed that treatment of the ester epoxide 6 with benzyl alcoholates leads only to epimerisation, transesterification, and formation of the cyclopropane 9. Ring opening of the reduced epoxide 13 by NaN 3 proceeded regioselectively to provide 14. Treatment of the C(6)ÀO-triflate 16 with AcOCs induced a rearrangement; the reaction with NaN 3 gave the C(5)-azido derivative 14. The acetoxy triflate 18, however, reacted with AcOCs to provide the desired gluco-isoquinuclidine 19. Similarly, the enantiomerically pure acetoxy triflate 22 provided the d-glucoisoquinuclidine 24, which was reduced and deprotected to provide 3 and 4. The deoxy analogues 30 and 31 were obtained by reductive deiodination of the iodide 27, derived from 22. The d-gluco-isoquinuclidines 3, 4, 30, and 31 are much weaker inhibitors of b-glucosidases than the d-manno-analogues 1 and 2 of snail b-mannosidase. The N-benzyl derivative 3 is a weaker inhibitor than the N-unsubstituted analogue in the gluco-series, while it is a much stronger inhibitor in the manno-series. A consideration of the pK HA values of the isoquinuclidines 1 ± 4 and the pH value of the enzyme assays suggests that the d-gluco-isoquinuclidines are poor mimics of the shape of a reactive, enzyme-bound gluco-conformer, while the d-manno-analogues are reasonably good mimics of a reactive, enzyme-bound manno-conformer. The inhibition results may also suggest that the glycosidase induced lengthening of the scissile bond and rehybridisation of the anomeric centre are more strongly correlated with the change of the ground-state conformation during hydrolysis of b-d-glucopyranosides than of b-d-mannopyranosides.

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

“…The results of the bromination of the cyclohex-3-en-1-amines 7 ) 8, 9, 11, 13, 14, and 16 depend on the structure of the starting material and on the reaction conditions. Similarly as observed in the bromination of 8 and 9, the C(6)-substituted trifluoroacetamide 14 led to a higher proportion of the 1,4-trans-configured product than the C (6) 6 ) For a related bromo-carbamoylation, see [53]. 7 ) For a report on the dependence of the stereoselectivity of the dibromination and bromohydroxylation of 3a,4,5,7a-tetrahydro-3H-benzoxazol-2-one (allylic C,O bond) upon the N-protecting group and the reaction conditions, see [51].…”

“…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.…”

Substrate Distortion by a Lichenase Highlights the Different Conformational Itineraries Harnessed by Related Glycoside Hydrolases

“…This leads to the possibility of specific, targeted inhibition of clinically relevant enzymes. In this context, a large number of mannosidase inhibitors have been proposed in recent times with amidines, [25] pyridines [26] and isoquinuclidines, [27] and functionalized mannostatin and aminocyclopentitetrol analogues [21] that are notable for their binding to mannosidases.…”

First Total Synthesis of (+)‐Adenophorine, a Naturally Occurring Inhibitor of Glycosidases

“…Epoxidation of tetrahydropyridine trans-11 with a freshly distilled solution of dimethyldioxirane (DMDO) in acetone [19,20] afforded a crude 81:19 mixture of endo/exo epoxides. The known epoxide endo-12 [11] was isolated in a consistent 60 % yield after separation by flash chromatography (Scheme 3).…”