Conformational Interlocking in Axially Chiral Methyl N-(2',4'-Dimethylnicotinoyl)-N-methylphenylalaninates

Article abstract of DOI:10.1021/jo00001a005

Axial chiral 2,4-dimethylnicotinamides incorporating a protected N-methylphenylalanine moiety (1;2) have been prepared to serve as NAD⁺ model precursors.Starting from L- or D-methyl N-methylphenylalaninate hydrochloride ((S)- or (R)-4), the M-syn diastereomer 1a or its P-syn enantiomer 2a, were isolated in fair yield by a combination of rotamerization, helical isomerization, and crystallization.Evidence is presented for a strong conformational preference in solution not only at the amide bond but also at the chiral center (C-2) and at the benzylic carbon (C-3).The conformational interdependence compares well with the spatial arrangement in crystals of analogous axially chiral nicotinamide derivatives.Due to a preferred syn orientation of the amide carbonyl and C-2-H, the phenyl ring of the less polar syn diastereomers resides near the C-2' methyl group either at the α side of the pyridine ring in 1a or at the β side in 2a.In these syn diastereomers the S chirality in the amino acid residue (i. e., in 1a) corresponds to a CO UP or M helicity, the R chirality (i.e., in 2a) to a CO DOWN or P orientation.Conversely, the phenyl ring of the more polar syn diastereomers 1b (P conformer) and 2b (M conformer) resides preferentially in the vicinity of the C-4'methyl group.