Reaction of dopamine with D-glyceraldehyde under biomimetic conditions: stereoselective formation of tetrahydroisoquinolines and rate-accelerating effects of transition metal ions.
In 0.05 M phosphate buffer, pH 7.4, and at 37 degrees C, dopamine underwent a smooth Pictet-Spengler condensation with D-glyceraldehyde and D,L-glyceraldehyde-3-phosphate to afford diastereoisomeric tetrahydroisoquinolines. In the case of D-glyceraldehyde 1a/1b were formed in ca. 2:1 ratio. Treatment with carbonyldiimidazole converted 1a and 1b into the corresponding oxazinoisoquinolinones 2a and 2b which were separated and stereochemically characterised by NMR analysis. Transition metal ions commonly occurring in biological systems (e.g. Cu2+ and Fe3+) markedly accelerated the formation of 1a-1b without affecting the product ratio. Mechanistic evidence suggested the reversible generation of Schiff base intermediates, detected by 1H NMR, which undergo stereoselective cyclisation according to the Felkin-Anh model. Metal-chelation at the catechol group facilitates the rate-determining nucleophilic attack to the imine moiety by enhancing the electron density at the site of cyclisation. These results highlight an apparently overlooked effect of transition metal ions on the Pictet-Spengler reaction under biomimetic conditions and provide a chemical basis to postulate a role of carbohydrate metabolites as modulatory agents of dopaminergic neurotransmission via conversion to potentially bioactive tetrahydroisoquinoline derivatives.
Manini
P
P
Department of Organic and Biological Chemistry, University of Naples Federico II, Italy.
d'Ischia
M
M
Lanzetta
R
R
Parrilli
M
M
Prota
G
G
D000054:Acceleration; D004298:Dopamine / Q000737:chemistry*; D005985:Glyceraldehyde / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007546:Isoquinolines / Q000737:chemistry*; D008670:Metals / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013696:Temperature
D007546:Isoquinolines; D008670:Metals; D005985:Glyceraldehyde; D004298:Dopamine