Theoretical Insights into the Regioselectivity of a Pictet-Spengler Reaction: Transition State Structures Leading to Salsolinol and Isosalsolinol

The mechanism of the cyclization step of the Pictet-Spengler reaction between acetaldehyde and dopamine to give salsolinol and isosalsolinol was studied computationally, using density functional theory. The preferential formation in acidic media of salsolinol, the product of para-cyclization, and the requirement of a neutral pH for the formation of the ortho-cyclized isosalsolinol are explained in terms of 2 different mechanistic routes with an iminium ion or a phenolate-iminium zwitterion as starting reactants. Copyright © 2016 John Wiley & Sons, Ltd.