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 K_I 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).