D ‐Gluconhydroximo‐1,5‐lactam and Related N‐Arylcarbamates Theoretical Calculations, Structure, Synthesis, and Inhibitory Effect on β‐Glucosidases

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‐O‐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 β‐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 15NH3 or 15NH2OHHCl. 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 15N‐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 4C1 and 4H3. In H2O, 7a is a flattened 4C1. 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 15N‐NMR spectra observed upon protonation of 7b and 7c. The hydroximolactam 7a and the N‐arylcarbamates 26–29 are competitive inhibitors of the β‐glucosidases from sweet almond (emulsin) and from Agrobacterium faecalis (= Abg), with KI values between 8 and 21·10−6M against emulsin (at pH 6.8) and between 0.15 and 1.2·10−6M against Abg (at pH 7.0).