Pictet–Spengler condensation of the antiparkinsonian drug l-DOPA with d-glyceraldehyde. Opposite kinetic effects of Fe3+ and Cu2+ ions and possible implications for the origin of therapeutic side effects Original Research Article

In 0.05 M phosphate buffer, pH 7.4, and at 37 °C, l-DOPA, a widely used antiparkinsonian drug, reacted smoothly with d-glyceraldehyde to afford diastereoisomeric (1R,1′S,3S)-3-carboxy-1-(1′,2′-dihydroxyethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (1) and (1S,1′S,3S)-3-carboxy-1-(1′,2′-dihydroxyethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (2) in an approx. 3:2 ratio. The prevalent formation of 1 over 2 reflects stereoselective cyclisation of a transient Schiff base in accord with the Felkin–Anh model. Fe3+ ions, present at relatively high levels in parkinsonian brains, markedly accelerated formation of 1 and 2, whereas Cu2+ decreased the reaction rate, due apparently to different sites of chelate formation between l-DOPA and the metal ions. Both metal ions markedly decreased the stereoselectivity of the reaction. Product 1 exhibited chelating properties toward metal ions comparable or stronger than those of l-DOPA. These results throw new light on the effects of transition metal ions on the Pictet–Spengler reaction and suggest a possible role of tetrahydroisoquinoline products from l-DOPA and carbohydrate metabolites in the severe side effects of the drug.