Mechanistic insights on the magnesium(II) ion-activated reduction of methyl benzoylformate with chelated NADH peptide beta-lactam models.
Mechanistic details of the Mg(2+) ion-activated enantioselective reduction of methyl benzoylformate have been investigated at a B3LYP/6-31G* theory level, using peptide NADH models 1 rigidified with a beta-lactam ring. Computation of the reaction pathway revealed important structural differences between the intermediate NADH/Mg(2+)/ArCOCO(2)R ternary complexes 3 and the corresponding transition states leading to enantiomeric methyl mandelates. Thus, ternary complexes showed the dihydronicotinamide moiety placed quasiequatorial to a seven-membered chelation pseudoplane including the two amide carbonyls and the Mg(2+) cation, whereas productive transition states were strongly deformed with the dihydronicotinamide group oriented quasiaxial to the chelation pseudoplane. This chelation model was further applied to acyclic nonrigidified NADH models and, based on the fluxional mobility of the peptide chain bonds, experimental enantioselectivities were correctly predicted. Parallel experiments were also conducted in deuterated acetonitrile, using NMR techniques, to study the structure of the binary complexes 2 (NADH/Mg(2+)) and ternary complexes 3 (NADH/Mg(2+)/PhCOCO(2)Me). Finally, owing to the incorporation of two diastereotopic trimethylsilyl NMR-tags in the beta-lactam-NADH peptidomimetics, a nonproductive ternary complex predicted by calculations could be observed and its structure characterized on the basis of ROESY experiments and molecular modeling.
Aizpurua
Jesus M
JM
Departamento de Química Orgánica-I, Universidad del País Vasco, Joxe Mari Korta R&D Center. Avda, Tolosa-72, 20018 San Sebastián, Spain. jesusmaria.aizpurua@ehu.es
Palomo
Claudio
C
Fratila
Raluca M
RM
Ferrón
Pablo
P
Benito
Ana
A
Gómez-Bengoa
Enrique
E
Miranda
José I
JI
Santos
José I
JI
D002412:Cations; D002614:Chelating Agents / Q000494:pharmacology; D002625:Chemistry, Organic / Q000379:methods*; D006038:Glyoxylates / Q000737:chemistry*; D007477:Ions; D008274:Magnesium / Q000737:chemistry*; D008333:Mandelic Acids / Q000737:chemistry*; D008968:Molecular Conformation; D015394:Molecular Structure; D009243:NAD / Q000737:chemistry*; D009536:Niacinamide / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D013237:Stereoisomerism; D047090:beta-Lactams / Q000737:chemistry*
D002412:Cations; D002614:Chelating Agents; D006038:Glyoxylates; D007477:Ions; D008333:Mandelic Acids; D010455:Peptides; D047090:beta-Lactams; D009243:NAD; D009536:Niacinamide; C012482:phenylglyoxylic acid; D008274:Magnesium