Absolute Configuration of Natural Diastereoisomers of 6β-Hydroxyhyoscyamine by Vibrational Circular Dichroism

Abstract

The absolute configuration of the two natural diastereoisomers of 6beta-hydroxyhyoscyamine has been determined using vibrational circular dichroism (VCD) spectroscopy. The predicted VCD and IR spectra of (3R,6R,2'S)-6beta-hydroxyhyoscyamine (1) and (3S,6S,2'S)-6beta-hydroxyhyoscyamine (2) were calculated using density functional theory (DFT) with the B3LYP functional and 6-31G(d) basis set and considering the eight lower energy conformations of each diastereoisomer. In both cases, the first four conformers showed the N-Me group in the syn orientation, permitting the formation of a hydrogen bond between the hydroxy group at the tropane ring and the tertiary nitrogen atom. In addition the eight conformers showed an intramolecular hydrogen bond between the hydroxy and carbonyl groups of the tropic ester moiety. The calculated IR spectra of both molecules showed good agreement with the experimental spectra, while comparison of the experimental and calculated VCD spectra showed that the absolute configuration of dextrorotatory 6beta-hydroxyhyoscyamine is (3R,6R,2'S), while the levorotatory isomer is (3S,6S,2'S).

Absolute configuration of tropane alkaloids bearing two α,β‐unsaturated ester functions using electronic CD spectroscopy: Application to (R,R)‐trans‐3‐hydroxysenecioyloxy‐6‐senecioyloxytropane

“…This type of stabilization is known to occur in both enantiomers of the 6-hydroxy compounds where the CH 3 is in axial conformation. 8 Then the side chains were added and their conformations studied. To reduce the number of degrees of freedom because of the methyls and À ÀCH 2 OH, we replaced these groups with hydrogens and used as generic side chains R 1 , R 2 5 OÀ ÀCOÀ ÀCH¼ ¼CH 2 .…”

“…In the lowest energy structure shown in Figure 2, the dihedral angles are y 1 5 133. 8 , y 2 5 242.3 and u 1 , u 2 5 0 corresponding to the 3-cis/6-cis. Because the amplitudes of the CD spectra can vary significantly as a function of y 1 and y 2 (see supplementary material), the contributions of relatively low-probability conformations with strong CD spectra may contribute more to the weighted average CD spec- trum than the spectrum of the lowest energy structure.…”

“…Because of the high energy barrier of the s-cis to s-trans conformational change, we could not apply the method based on molecular dynamic developed by Bringmann et al 6,7 Note that a method using vibrational CD spectroscopy has been recently developed to ascertain the absolute configuration of diastereoisomers of monosubstituted 6b-hydroxyhyoscyamine. 8 …”

DFT‐GIAO 1H and 13C NMR prediction of chemical shifts for the configurational assignment of 6β‐hydroxyhyoscyamine diastereoisomers

“…[4] The absolute configurations of the two naturally occurring diastereoisomeric forms of the tropane alkaloid 6β-hydroxyhyoscyamine (3R,6R,2 S 1 and 3S,6S,2 S 2) have been assigned recently using vibrational circular dischroism (VCD) spectroscopy, [5] showing that the dextrorotatory form corresponds to structure 1, whereas the levorotatory form corresponds to structure 2 (Scheme 1). Beyond these findings, some unusual spectroscopic characteristics of these molecules remain unexplained.…”

“…[41] In the present work, we account on the use of 1 H and 13 C NMR chemical shift predictions within the gauge including/invariant atomic orbitals-density functional theory (GIAO-DFT) approximation for the determination of the configuration of both diastereoisomers of 6β-hydroxyhyoscyamine and to explain the differences observed between their NMR spectra. For this purpose, we took advantage of the energetic and geometric data of both naturally occurring diastereoisomers of 6β-hydroxyhyoscyamine as calculated [5] for the determination of their absolute configuration as 3R,6R,2 S 1 and 3S,6S,2 S 2, which were used as the starting point of the current work. The corresponding molecular structures were further minimized at a higher level of DFT, and the corresponding chemical shifts were computed and compared with the experimental data which resulted to be in agreement with published values.…”