Conformational Analysis of Indole Alkaloids Corynantheine and Dihydrocorynantheine by Dynamic ¹H NMR Spectroscopy and Computational Methods:  Steric Effects of Ethyl vs Vinyl Group

Abstract

1H NMR (400 MHz) spectra of the indole alkaloid dihydrocorynantheine recorded at room temperature show the presence of two conformers near coalescence. Low temperature 1H NMR allowed characterization of the conformational equilibrium, which involves rotation of the 3-methoxypropenoate side chain. Line-shape analysis yielded enthalpy of activation DeltaH(double dagger) = 71 +/- 6 kJ/mol, and entropy of activation DeltaS(double dagger) = 33 +/- 6 J/mol.K. The major and minor conformation contains the methyl ether group above and below the plane of the ring, respectively, as determined by low-temperature NOESY spectra, with free energy difference DeltaG degrees = 1.1 kJ/mol at -40 degrees C. In contrast to dihydrocorynantheine, the corresponding rotamers of corynantheine are in the fast exchange limit at room temperature. The activation parameters determined for corynantheine were DeltaH(double dagger) = 60 +/- 6 kJ/mol and DeltaS(double dagger) = 24 +/- 6 J/mol.K, with DeltaG degrees = 1.3 kJ/mol at -45 degrees C. The difference in the exchange rates of the rotamers of corynantheine and dihydrocorynantheine (respectively, 350 s(-1) and 9 s(-1) at 0 degrees C) reflects the difference in the steric bulk of the vinyl and the ethyl group. The conformational equilibria involving the side chain rotation as well as inversion of the bridgehead nitrogen in corynantheine and dihydrocorynantheine was studied by force-field (Amber and MMFF) and ab initio (density-functional theory at the B3LYP/6-31G level) computational methods, the results of which were in good agreement with the 1H NMR data. However, the calculations identified the rotamers as essentially isoenergetic, the experimental energy differences being to small to be reproduced exactly by the theory. Comparison of density-functional and force-field calculations with experimental results identified Amber as giving the most accurate results in the present case.

Diverse Asymmetric Quinolizidine Synthesis: A Stereodivergent One‐Pot Approach

“…For the one-pot reaction of p-methoxycinnamaldehyde 1c with the methyl and ethyl esters 14a, b under kinetic and thermodynamic conditions gave 11ba-20ca, cb and 11bb-20ca, cb, respectively, in good diastereoselectivity. As been previously observed for the methoxy derivatives (vide supra), the methyl ester derivative 11ba-20ca was isolated in moderate enantioselectivity whereas the selectivity increased substantially for the corresponding ethyl ester derivative 11ba-20cb (Table 7, entries [11][12][13][14].…”

“…The corresponding reactions of the ethyl ester 3b and cinnamaldehyde 1a gave similar yields and diastereoselectivity but a pronounced increase in enantioselectivity (Table 8, entries 5 and 6). The same trend of increased enantioselectivity was also observed for the corresponding reactions with o-nitrocinnamaldehyde 1b and p-methoxycinnamaldehyde 1c (Table 8, entries [7][8][9][10][11][12][13][14]. The diastereoselectivity in the reaction with tin(IV) chloride turned out to be independent of which cinnamaldehyde was used and gave the thermodynamic product 11bb-10 with approximately 75:25 diastereomeric ratio (Table 8) with the exception of the methyl ester 3a in combination with o-nitrocinnamaldehyde 1b that gave 11ba-10ba and 11bb-10bb in a 1:1 mixture (Table 8, entry 8).…”

“…On the other hand, the epimer hirsutine has the indole moiety in an axial position giving this compound a V-shaped conformation that is very different in geometry compared to dihydrocorynantheine. [13] Furthermore, the axial indolo group will make hirsutine thermodynamically less stable compared to the all-equatorial epimer, dihydrocorynantheine. This means that special considerations have to be taken into account during the synthesis of the desired epimer.…”

“…-a]quinolizidine 9 was obtained in 89% ee from the methyl ester 2a and in > 99% ee from the ethyl ester 2b (Table 3, entries [11][12][13][14].…”

Relaxant effects of an alkaloid-rich fraction from Aspidosperma ulei root bark on isolated rabbit corpus cavernosum

“…22 1 H NMR analysis of this fraction (F [3][4][5] ) revealed the presence of three major indole-type alkaloids, which were identified as uleine, nor-uleine and tetrahydro-3,14,4,21-elipticin ( Figure 1) based on spectral details and in comparison with literature data. 24 …”