title: Mechanistic studies on the cis to trans epimerization of trisubstituted 1,2,3,4-tetrahydro-beta-carbolines.
abstract: It is well-known that N(b)-benzyltryptophan 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. Recent kinetic experiments provided insight into the cis to trans epimerization mechanism involved in the Pictet-Spengler reaction of 1,2,3-trisubstituted 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 via a Hammett study. Analysis of the data supported the presence of a positively charged intermediate with a rho 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 cis to trans 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 cis to trans epimerization of 1,2,3-trisubstituted 1,2,3,4-tetrahydro-beta-carbolines, while the olefinic mechanism had been ruled out by experiments carried out in TFA-d.
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 North Cramer Street, Milwaukee, Wisconsin 53211, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Van Linn
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
mesh_terms: D002243:Carbolines / Q000737:chemistry*; D007536:Isomerism; D007700:Kinetics; D055601:Organic Chemistry Phenomena; D014364:Tryptophan / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D002243:Carbolines; D014364:Tryptophan