Conformational Analysis of the cis- and trans-Adducts of the Pictet−Spengler Reaction. Evidence for the Structural Basis for the C(1)−N(2) Scission Process in the cis- to trans-Isomerization

Abstract

The stable conformations of both the trans- and cis-1,3-disubstituted Nb-benzyl stereoisomers of the Pictet - Spengler reaction have been determined by NMR spectroscopy and X-ray crystallography in order to better understand the C(1) -N(2) cis- to trans-isomerization process. In the Na-H series, the chair conformation was preferred for the trans-isomer 3a, while the cis-isomer 3b existed predominantly in the boat form. However, in the Na-methyl series (1a, 1b, 2a, 2b), both the cis (1b, 2b) and trans (1a, 2a) diastereomers existed in the chair conformation to relieve the A(1,2)-strain between the Na-methyl function and the substituent at C(1). The difference in the preferred conformations of the cis-isomers in the Na-H and Na-methyl series (as compared to the preferred conformations in the trans-isomers) can be employed to understand the reduced rate of epimerization of cis-2b into trans-2a as compared to 3b into 3a. This provides the structural basis for the carbocation-mediated intermediate in the C(1) - N(2) scission process.

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

“…This epimerization afforded 100% stereoselective formation of the trans diastereomer, specifically at C-1, under standard acidic conditions of TFA/CH 2 Cl 2 25. Similar findings have been observed by Han et al37 during a conformational study of cis and trans N a -methyl and N a -H substituted N b -benzyl diesters. Evidence from simple kinetic studies is in agreement with the presence of the carbocationic intermediate 6 in these isomerizations.…”

“…Among the three potential intermediates ( 6 , 7 , 8 ) depicted in Figure 1, the cis to trans epimerization process, which proceeds by protonation of the N b -nitrogen atom with concomitant cleavage of the C(1)–N(2) bond followed by reclosure to the trans isomer, cation 6 is the most consistent with recent evidence 25,34,35,37. Importantly, intermediate 7 has been excluded on the basis of epimerizations carried out in CF 3 COOD 25.…”

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.…”

Syntheses of chiral 1,3-disubstituted tetrahydro-β-carbolines via CIAT process: highly stereoselective Pictet–Spengler reaction of d-tryptophan ester hydrochlorides with various aldehydes

“…There are three reasonable pathways 10,11,[47][48][49] for the CIAT process. Path A involves double migration of the double bond catalyzed by acid.…”