Structure and Conformation of Mannoamidines by Nmr and Molecular Modeling: are They Good Transition State Mimics?

Abstract

ABSTRACT The conformation of two mannose-based amidines, the N-benzylmannoamidine and a pseudo (1→6) dimannoside, has been evaluated using semi-empirical AMI calculations and 1H NMR studies. The most stable conformations of the mannoamidine ring correspond to the half-chair forms 3H4 and 4H3. The conformations (Z) or (E) about the exocyclic C-N bond depend on the substituents and it was shown that, in solution, the N-benzylmannoamidine was (E)-configured whilst the pseudo (1→6) dimannoside was (Z)-configured. Using the grid-search approach, the potential energy maps of both mannoamidines were calculated as a function of the torsion angles which define the orientation of the amidine substituent. Three stable conformers were identified for the N-benzylmannoamidine and seven for the pseudo (1→6) dimannoside. Inter-glycosidic NOE have provided evidence for a preferred conformation of the pseudo (1→6) dimannoside in solution. The transition state structure of the α-phenylmannose hydrolysis was optimized using the AMI method and compared to the N-benzylmannoamidine. The developing oxocarbenium ion is well matched by the mannoamidine ring but the orientation of the phenyl group in the inhibitor differs significantly from the position of the leaving group in the transition state. The use of sugar type amidines as haptens to obtain catalytic antibodies is then discussed.