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

Abstract

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 1 H and 13 C 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/ CH 2 Cl 2 . 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.*To whom correspondence should be addressed. . † University of Wisconsin-Whitewater. ‡ University of Wisconsin-Milwaukee. § Naval Research Laboratory. Supporting Information Available: 1 H and 13 C NMR spectra of compounds 2a-e, 3a-e, 4a-e and 5a-e; COSY, HSQC, and HMBC 2D spectra for compounds 4a-e and 5a-e; X-ray crystallographic data and ORTEP plots for 2e, 3e, 4a, and 5a · HCl. This material is available free of charge via the Internet at

Design, synthesis, and biological evaluation of callophycin A and analogues as potential chemopreventive and anticancer agents

“…The N -alkylation was carried out by the method reported by Cook’s group. 23 A reaction mixture of secondary amine 2a or 2b and various bromides in acetonitrile was heated at reflux for 2-5 h in the presence of N,N -diisopropylethylamine (DIPEA, Hunig’s base). Subsequent purification by flash column chromatography on silica gel gave the alkylation products 5a-f in 62-84% yields.…”

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

“…The conformation of the C-ring was found to be important during the epimerization process; ultimately the p -orbital of the developing carbocation was thought to overlap well with the indole π-electrons. In efforts aimed to investigate the mechanism of the isomerization at C-1, a set of readily accessible electron-donating and electron-withdrawing substituted aromatic aldehydes have been reacted with L-tryptophan ethyl ester, followed by N b -benzylation, to provide optically active cis and trans 1,2,3-trisubsituted-tetrahydro-β-carbolines 26. In a general sense, electron-rich substituents on aromatic rings at the C-1 position enhanced the rate of the cis to trans epimerization 26.…”

“…In efforts aimed to investigate the mechanism of the isomerization at C-1, a set of readily accessible electron-donating and electron-withdrawing substituted aromatic aldehydes have been reacted with L-tryptophan ethyl ester, followed by N b -benzylation, to provide optically active cis and trans 1,2,3-trisubsituted-tetrahydro-β-carbolines 26. In a general sense, electron-rich substituents on aromatic rings at the C-1 position enhanced the rate of the cis to trans epimerization 26. This result was in agreement with the proposed carbocationic mechanism of epimerization, although the retro Pictet-Spengler process could not be completely ruled out at that time 26.…”

The Chiral Pool in the Pictet–Spengler Reaction for the Synthesis of β-Carbolines

“…If the reaction mechanism involved the spiroindolenine, the trans-isomer of which is more stable, the following ring expansion was therefore stereospecific. When a mixture of isomers was obtained, the thermodynamically more stable trans isomer could be exclusively obtained by epimerization of the cis isomer under acidic conditions [19][20][21]. Between the two possible mechanisms of the epimerization process, the protonation of the Nb, followed by ring-opening and closure to give the more stable isomer was demonstrated to occur (Scheme 3).…”