Dedicated to Professor Wolfgang Steglich on the occasion of his 70th birthday
The spirodiaziridines 6 and 9, potential inhibitors of aand b-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 b-glucosidases from almonds, the b-glucosidase from Caldocellum saccharolyticum, and the aglucosidase from yeast. The N-benzyl diaziridine 9 is a very weak inhibitor of the a-glucosidase, but did not inhibit the b-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, LiAlH 4 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 b-glucosidase from Caldocellum saccharolyticum and a weak reversible inhibitor of the a-glucosidase from yeast, but did not inhibit the b-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.