7‐Oxanorbornane and Norbornane Mimics of a Distorted β‐D‐Mannopyranoside: Synthesis and Evaluation as β‐Mannosidase Inhibitors

Abstract

The racemic 7-oxanorbornanyl and norbornanyl aminoalcohols 3, 4, 42, 45, and 46 were synthesized and tested as snail b-mannosidase inhibitors. The amino tetraol 3 was obtained from the known sulfonyl acrylate 9 and furan 10. Esterification provided 11 that underwent an intramolecular Diels-Alder reaction to the 7-oxanorbornene 12. Reduction of 12 to 13, desulfonylation, isopropylidenation, and cis-dihydroxylation gave 16. A second isopropylidenation to 17, followed by debenzylation and a Mitsunobu-Gabriel reaction provided 19 that was deprotected via 20 to 3. Diels-Alder cycloaddition of furfuryl acetate and maleic anhydride to 21, followed by alcoholysis of the anhydride, cis-dihydroxylation, isopropylidenation, and Barton decarboxylation gave the ester 25. Deacetylation to 26 and a Mitsunobu-Gabriel reaction led to 27 that was transformed into the NBoc analogue 29, reduced to the alcohol 30, and deprotected to 4. The 1-aminonorbornane 5 was obtained from Thiele's Acid 31. Diels-Alder cycloaddition of the cyclopentadiene obtained by thermolysis of the diester 32, methanolysis of the resulting anhydride 33, dihydroxylation, isopropylidenation, Barton decarboxylation, and Curtius degradation led to the benzyl carbamate 39 that was reduced to the alcohol 40, transformed into the N-Boc carbamate 41, and deprotected to 5. The alcohol 40 was also transformed into the benzylamine 42, aniline 45, and hydroxylamine 46. Snail b-mannosidase was hardly inhibited by 3, 4, 42, 45, and 46. Only the amino triol 5 proved a stronger inhibitor. The inhibition by 5 depends on the pH value (at pH 3.5: K i = 1900 mM; at pH 4.5: K i = 340 mM; at pH 5.5: K i = 110 mM). The results illustrate the strong dependence of the inhibition by bicyclic mimics upon the precise geometry and orientation of the amino group as determined by the scaffold. It is in keeping with the hypothesis that the reactive conformation imposed by snail b-mannosidase is close to aIntroduction. -The design, synthesis, and study of glycosidase inhibitors continue to attract interest, fuelled by the potential of strong and selective glycosidase inhibitors to act as drugs (e.g., against lysosomal storage disorders such as Gaucher's disease , and their use as tools in the elucidation of the mechanism of action of glycosidases on the basis of structure-activity relations, kinetic studies, and information provided by the structure determination of enzyme-inhibitor complexes [7]. Transition-state analogues promise to be most useful. Their design is based upon existent information about the mechanism of action, and particularly about the transition state of the rate-determining step, while their study may contribute to a more detailed understanding of the mechanisms of action as summarised in several reviews [8] [9]. Partial transition-state mimics may be thought of as being closer to a point of the reaction coordinate that either precedes, or follows the transition state of interest, and there are reasons to hypothesise that those preceding the rate-determining transition s...

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

“…(7)); 1.61 -1.68 (m, HÀC (5)); 1.68 -1.76 (m, H endo ÀC(6), H'ÀC (7)); 2.02 (br. s, HÀC (4) C-NMR (100 MHz, CD 3 OD; assignments based on a HSQC spectrum): 32.68 (t, C(6)); 34.52 (t, C (7) 3 ) We have already reported a marked dependence of the inhibition on the pH in the assay [8], corroborating the hypothesis that the inhibitor binds to the glycosidase in the unprotonated form. 4 (7)); 1.68 -1.74 (m, HÀC (5)); 1.86 (br.…”

“…See [8]. The b-glucosidases and 4-nitrophenyl b-D-glucopyranoside were purchased from Sigma, and used without any further purification.…”

“…A comparison of the inhibition constants with those obtained for snail b-mannosidase has to account for the different pH of the assays. 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].…”

“…Stable mimics of the individual acceptable conformers may act as selective inhibitors and contribute in assessing the conformational itinerary enforced by a specific glycosidase. It was claimed that inhibitors mimicking such distorted conformers should be inherently more selective than mimics of an intermediate oxocarbenium cation and be more sensitive to small geometric changes [7] [8]. In keeping with these considerations, the manno-configured isoquinuclidine 1 [9] mimicking a 1,4 B/ 1 S 3 conformation inhibits snail b-mannosidase rather strongly (K i = 1 mM at pH 4.5), while the gluco-configured diastereoisomer 2 is almost inactive against b-glucosidases, and the (racemic) manno-configured norbornane 3 is only a modest b-mannosidase inhibitor (K i % 50 mM; extrapolated to the Dmanno-enantiomer).…”

“…-Deprotection of the known acetal 5 [8] in EtSH/EtOH provided the triol 6 (88%; Scheme) that was silylated with t BuPh 2 A C H T U N G T R E N N U N G SiCl [12] to yield 83% of the diol 7. Treatment of 7 with benzoyl chloride (BzCl) afforded the regioisomeric monobenzoates 8/9 82 : 18 (91%) that could not be separated on account of a facile Bz-group migration.…”