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

Abstract

It is well known that N b -benzyl tryptophan alkyl esters undergo the Pictet-Spengler reaction with aldehydes to furnish both cis and trans 1,2,3,4-tetrahydro-β-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-trisubsituted tetrahydro-β-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-β-carbolines was investigated via a Hammett study. Analysis of the data supported the presence of a positively charged intermediate with a ρ 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 firstorder 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-β-carbolines, while the olefinic mechanism had been ruled out by experiments carried out in TFA-d.

The Pictet–Spengler Reaction in Nature and in Organic Chemistry

“…The thermodynamically more-stable trans isomer could be obtained exclusively from the cis/trans mixture by epimerization of the N b -substituted cis isomer under acidic conditions (trifluoroacetic acid; Scheme 16). [113,114] The epimerization proceeded by protonation of the N b nitrogen atom followed by cleavage of the C(1)ÀN(2) bond to generate a carbocation, which can be recyclized to provide the thermodynamically more-stable trans diastereomer. This epimerization afforded efficient control over the formation of the trans isomer under acidic conditions.…”

Copper‐Mediated Deoxygenative Trifluoromethylation of Benzylic Xanthates: Generation of a CCF3 Bond from an O‐Based Electrophile

“…For certain reactions, the separation of the dibenzothiophene byproduct from the trifluoromethylated product was challenging (3 o, 3 p and 5 g). For these select cases, treatment of the reaction mixture with m-CPBA allowed the oxidized dibenzothiophene to be separated by column chromatography in lower yields than suggested by 19 F NMR spectroscopy.…”

“…[18a, 19] Moreover, a weaker correlation between log-A C H T U N G T R E N N U N G (k X /k H ) and s p (1 = À2.06 AE 0.03, r 2 = 0.964) and a scattered plot of logA C H T U N G T R E N N U N G (k X /k H ) versus s p C excluded a pathway involving homolytic cleavage of the C À O bond to generate neutral radicals. [18][19][20] Although the value of 1 + is negative, the magnitude is less than many S N 1-type reactions of benzylic elec- Table 3. Cu 0 -mediated trifluoromethylation of racemic a-branched benzylic xanthates 4.…”

“…[a,b] [a] Reaction conditions: (AE)-4 a-g (1.0 equiv), 2 a (4.0 equiv), Cu 0 (5.4 equiv), anhydrous CH 3 CN (c = 0.1 m), 60 8C, 9 h, under an atmosphere of N 2 . [b] Yields were determined by 19 F NMR analysis using benzotrifluoride as an internal standard (average of two runs) and the figures in parentheses refer to the isolated yields after purification (average of two runs).…”

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).…”