Geometric control of a pyridoxal-catalyzed aldol condensation

A chiral cyclophane derivative of pyridoxal has been synthesized that has amino groups oriented specifically over one face of the cofactor. The compound catalyzes the formation of threonine and allo-threonine from glycine and acetaldehyde with enantioinductions that are a function of pH, reversing the optical selectivity between low pH and high pH. The stereochemical results are compared with those of structurally related pyridoxal cyclophanes that lack titratable catalytic groups. Explanations are advanced for this stereochemical reversal and for the otherwise surprising preference of most of these compounds to react on the more hindered face of the pyridoxal. Models indicate that the transamination intermediate is distorted by the transannular chain, and stereoelectronic arguments predict that this distortion should lead to reaction on the face that carries the chain, as observed. The stereochemical reversal with the attached (dimethylamino)alkyl group, as a function of pH, may reflect catalysis by the protonated form, but metal coordination by the basic form cannot be excluded.