Mechanistic Studies on the <i>Cis</i> to <i>Trans</i> Epimerization of Trisubstituted 1,2,3,4-Tetrahydro-β-carbolines

2010-06-04T00:00:00Z (GMT) by Michael L. Van Linn James M. Cook
It is well-known that <i>N</i><sub>b</sub>-benzyltryptophan alkyl esters undergo the Pictet−Spengler reaction with aldehydes to furnish both <i>cis</i>- and <i>trans</i>-1,2,3,4-tetrahydro-β-carbolines, with the <i>trans</i> isomer predominating. Epimerization at C-1 took place under acidic conditions to produce, exclusively, the thermodynamically more stable <i>trans</i> diastereomer via internal asymmetric induction. Recent kinetic experiments provided insight into the <i>cis</i> to <i>trans</i> epimerization mechanism involved in the Pictet−Spengler reaction of 1,2,3-trisubsituted tetrahydro-β-carbolines. Since the epimerization reaction had been shown to be sensitive to electronic effects at C-1, the rate data for a series of 1-phenyl-substituted 1,2,3,4-tetrahydro-β-carbolines was investigated via a Hammett study. Analysis of the data supported the presence of a positively charged intermediate with a ρ value of −1.4, although the existence of an iminium ion intermediate or a carbocationic intermediate could not be determined from this data alone. Analysis of the rate of epimerization demonstrated first-order kinetics with respect to TFA following the initial protonation of the substrate. This observation was consistent with the formation of a doubly protonated intermediate as the rate-determining step in the carbocation-mediated <i>cis</i> to <i>trans</i> epimerization process. In addition, the observed first-order rate dependence was inconsistent with the retro-Pictet−Spengler mechanism since protonation at the indole-2 position was not rate determining as demonstrated by kinetic isotope effects. Based on this kinetic data, the retro-Pictet−Spengler pathway was ruled out for the <i>cis</i> to <i>trans</i> epimerization of 1,2,3-trisubstituted 1,2,3,4-tetrahydro-β-carbolines, while the olefinic mechanism had been ruled out by experiments carried out in TFA-<i>d</i>.