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D-GLUCONHYDROXIMO-1,5-LACTAM AND RELATED N-ARYLCARBAMATES - THEORETICAL CALCULATIONS, STRUCTURE, SYNTHESIS, AND INHIBITORY EFFECT ON BETA-GLUCOSIDASES

TitleD-GLUCONHYDROXIMO-1,5-LACTAM AND RELATED N-ARYLCARBAMATES - THEORETICAL CALCULATIONS, STRUCTURE, SYNTHESIS, AND INHIBITORY EFFECT ON BETA-GLUCOSIDASES
Publication TypeJournal Article
Year of Publication1993
AuthorsHOOS, R, NAUGHTON, AB, THIEL, W, VASELLA, A, WEBER, W, RUPITZ, K, Withers, SG
JournalHELVETICA CHIMICA ACTA
Volume76
Pagination2666-2686
ISSN0018-019X
Abstract

The known D-gluconhydroximo-1,5-lactam (= D-glucono- 1,5-lactam oxime) 7a, its nitrogen isotopomers 7b and 7c, and the N-arylcarbamates 26-29 were synthesized from 2,3,4,6-tetra-0-benzyl-D-glucono-1,5-lactam (11a) and its nitrogen isotopomer 11b to establish the controversial structure of 7a and to study the inhibition of beta-glucosidases by the N-arylcarbamates 26-29. Conversion of 11a with Lawesson's reagent yielded a mixture of the thionolactam 15a and its manno-configurated isomer 16a, which was transformed into a mixture of the benzylated hydroximo-lactam 13a and the manno-isomer 17a. Debenzylation (Na/NH3) and acetylation of this mixture led to the gluco-configurated pentaacetate 14a and the manno-isomer 18a. Treatment of 11a with Et3O-BF4 and then with H2NOH gave exclusively the benzylated D-gluconhydroximo-1,5-lactam (benzylated D-nojirilactam oxime) 13a, which was transformed into 14a. Deacetylation of 14a yielded the hydroximo-lactam 7a. The isotopomers 7b and 7c were obtained by analogous reaction sequences, using either (NH3)-N-15 or (NH2OH)-N-15.HCl. To prepare the acetylated N-arylcarbamates 20-25, 13a was debenzylated and acetylated (–> 14a), followed by selective deacetylation to the tetraacetate 19a and treatment with the appropriate isocyanates. The structure of the 2-chlorophenyl carbamate 21 was established by X-ray analysis. Deacetylation of 20-23 led to the N-arylcarbamates 26-29. The N-15-NMR spectra of 7b, 7c, and of their precursors 13b, 13c, 14b, and 14c, show that the C=N bond in all these lactam oximes is exocyclic as predicted from semiempirical and ab initio SCF-MO calculations on the structure of acetamide oxime and 5-pentanelactam oxime. According to these calculations, 5-pentanelactam oxime is a (Z)-configurated, flattened chair. X-ray analysis established the structure Of D-glucono-1,5-lactam oxime (7a) in the solid state, where it adopts a conformation between C-4(1) and H-4(3). In H2O, 7a is a flattened C-4(1). The calculations also predict that protonation at the exocyclic N-atom strengthens the conjugation between the endocyclic N-atom and the hydroxyimino group, and leads to a half-chair conformation. This is evidenced by the chemical shift differences in the N-15-NMR spectra observed upon protonation of 7b and 7c. The hydroximolactam 7a and the N-arylcarbamates 26-29 are competitive inhibitors of the beta-glucosidases from sweet almond (emulsin) and from Agrobacterium faecalis (= Abg), with K(I) values between 8 and 21 . 10(-6) m against emulsin (at pH 6.8) and between 0.15 and 1.2-10(-6) m against Abg (at pH 7.0).

DOI10.1002/hlca.19930760723