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 β-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 N-Boc 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 β-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: Ki = 1900 μM; at pH 4.5: Ki = 340 μm; at pH 5.5: Ki = 110 μm). 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 β-mannosidase is close to a 1,4B/1S3.