Study of the Cis to Trans Isomerization of1-Phenyl-2,3-disubstituted Tetrahydro-fl-carbolines at C(1). Evidencefor the Carbocation-Mediated Mechanism

摘要

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 atC(1). In order to study the pathway involved in C(1)-N(2) bond cleavage, the electronic character of thecarbon atom at C-1 was altered by substitution of electron-rich and electron-poor phenyl rings at thisposition. This provided direct evidence of the effects of charge at the proposed site of the carbocationicintermediate. In this regard, a diverse set of 1-(phenyl substituted)-2-benzy1-3-ethoxycarbony1-1,2,3,4-tetrahydro-f3-carbolines has been synthesized via the Pictet- Spengler reaction by condensation ofL-tryptophan derivatives with electron-poor and electron-rich aromatic aldehydes. The epimers involvedin the isomerization mechanism were investigated by dynamic ~1 H and ~(13)CNMR spectroscopic and X-raycrystallographic analyses. The kinetic studies, which involved conversion of cis diastereomers into theirtrans counterparts, were carried out in dilute TFA/CH2C12. The 1-(4-methoxyphenyl) cis diastereomerepimerized 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 inthe C(1)-N(2) scission process. The understanding of this epimerization process is of importance whenPictet-Spengler reactions are carried out under acidic conditions during the synthesis of indole alkaloids.