Studies on the mechanism of the cis to trans epimerization of cis 1,2,3-trisubstituted-1,2,3,4-tetrahydro-beta-carbolines into their corresponding trans diastereomers via kinetic analysis

It is well known that Nb-benzyl tryptophan alkyl esters undergo the Pictet-Spengler reaction with aldehydes to furnish both cis and trans 1,2,3,4-tetrahydro-beta-carbolines, with the trans isomer predominating. Epimerization at C-1 took place under acidic conditions to produce, exclusively, the thermodynamically more stable trans diastereomer via internal asymmetric induction. Kinetic experiments provided insight to the cis to trans epimerization mechanism involved in the Pictet-Spengler reaction of 1,2,3-trisubsituted tetrahydro-beta-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-beta-carbolines was investigated in a Hammett study and a rho value of -1.4 was determined. The data supported the presence of a positively charged intermediate, although the existence of an iminium ion intermediate or a carbocationic intermediate could not be determined from this data alone. 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 cis to trans epimerization process. In addition, the observed first order rate dependence was inconsistent with the retro Pictet-Spengler mechanism since the rate determining step in this process was determined to be deprotonation of the Nb-nitrogen atom in order for the iminium ion intermediate to be formed in the following step. Kinetic isotope experiments verified that the protonation at the indole-2 position was not rate determining in this reaction pathway. Therefore, the retro Pictet-Spengler pathway was ruled out for the cis to trans epimerization of 1,2,3-trisubstituted-1,2,3,4-tetrahydro-beta-carbolines.