Study of the Cis to Trans Isomerization of 1-Phenyl-2,3-disubstituted Tetrahydro-β-carbolines at C(1). Evidence for the Carbocation-Mediated Mechanism

The present study was undertaken to shed light on the mechanism of the epimerization of cis-1,2,3-trisubstituted tetrahydro-β-carbolines into the trans isomers via a potential carbocationic intermediate at C(1). In order to study the pathway involved in C(1)−N(2) bond cleavage, the electronic character of the carbon atom at C-1 was altered by substitution of electron-rich and electron-poor phenyl rings at this position. This provided direct evidence of the effects of charge at the proposed site of the carbocationic intermediate. In this regard, a diverse set of 1-(phenyl substituted)-2-benzyl-3-ethoxycarbonyl-1,2,3,4-tetrahydro-β-carbolines has been synthesized via the Pictet−Spengler reaction by condensation of l-tryptophan derivatives with electron-poor and electron-rich aromatic aldehydes. The epimers involved in the isomerization mechanism were investigated by dynamic 1H and 13C NMR spectroscopic and X-ray crystallographic analyses. The kinetic studies, which involved conversion of cis diastereomers into their trans counterparts, were carried out in dilute TFA/CH2Cl2. The 1-(4-methoxyphenyl) cis diastereomer epimerized at a much faster rate into the corresponding trans diastereomer than the related 1-(4-nitrophenyl) cis diastereomer epimerized. These observations provide support for the carbocationic intermediate in the C(1)−N(2) scission process. The understanding of this epimerization process is of importance when Pictet−Spengler reactions are carried out under acidic conditions during the synthesis of indole alkaloids.