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Synthesis and Evaluation as Glycosidase Inhibitors of Carbasugar‐Derived Spirodiaziridines, Spirodiazirines, and Spiroaziridines
Author(s) -
Kapferer Peter,
Birault Véronique,
Poisson JeanFrançois,
Vasella Andrea
Publication year - 2003
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200390178
Subject(s) - chemistry , diazirine , aziridine , cyclohexanone , trimethylsilyl , enzyme , stereochemistry , yeast , azide , hydrolysis , organic chemistry , biochemistry , catalysis , ring (chemistry)
The spirodiaziridines 6 and 9 , potential inhibitors of α ‐ and β ‐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 (p K HA =2.6) and the diazirine 7 did not inhibit the β ‐glucosidases from almonds, the β ‐glucosidase from Caldocellum saccharolyticum , and the α ‐glucosidase from yeast. The N ‐benzyl diaziridine 9 is a very weak inhibitor of the α ‐glucosidase, but did not inhibit the β ‐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 (p K HA =6.8) is a weak irreversible inhibitor of the β ‐glucosidase from Caldocellum saccharolyticum and a weak reversible inhibitor of the α ‐glucosidase from yeast, but did not inhibit the β ‐glucosidases from almonds. The poorly stable aziridine 21 weakly inhibited the three enzymes. Similarly, 1‐epivalidamine (p K HA =8.4) proved only a weak inhibitor. The known cyclopentylamine 34 (p K 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.