Synthesis and evaluation as glycosidase inhibitors of carbasugar-derived spirodiaziridines, spirodiazirines, and spiroaziridines

The spirodiaziridines 6 and 9, potential inhibitors of alpha- and beta-glucosidases, were prepared from the validoxylamine A-derived cyclohexanone 5. The trimethylsilyl protecting groups of 5 are crucial for the formation of 6 in good yields. Oxidation of 6 gave 7 The diaziridine 6 (pK(HA) = 2.6) and the diazirine 7 did not inhibit the beta-glucosidases from almonds, the beta-glucosidase from Caldocellum saccharolyticum, and the alpha-glucosidase from yeast. The N-benzyl diaziridine 9 is a very weak inhibitor of the alpha-glucosidase, but did not inhibit the beta-glucosidases. To see whether the weak inhibition is due to the low basicity of the diaziridines or to geometric factors, we prepared the spiro-aziridines 21 and 25 and 1-epivalidamine (32). The known cyclohexanone 10 was methylenated and epoxidised to 16 and 17 Azide opening of 16 and 17, mesylation, LiAlH4 reduction, and deprotection gave the aziridines 21 and 25 respectively 1-Epivalidamine (32) was prepared from the known carba-glucose 29. The aziridine 25 (pK(HA) = 6.8) is a weak irreversible inhibitor of the,beta-glucosidase from Caldocellum saccharolyticum and a weak reversible inhibitor of the alpha-glucosidase from yeast, but did not inhibit the beta-glucosidases from almonds. The poorly stable aziridine 21 weakly inhibited the three enzymes. Similarly, 1-epivalidamine (pK(HA) = 8.4) proved only a weak inhibitor. The known cyclopentylamine 34 (pK(HA) = 7.9), however, is a micromolar inhibitor of these enzymes. The much stronger inhibition by 34 is related to the pseudoaxial orientation of its amino group.