Dynamic Stereochemistry of a Biphenyl‐Bisprolineamide Model Catalyst and its Imidazolidinone Intermediates

Abstract

In this study, we characterize the dynamic stereochemistry of a biphenyl‐2,2’‐bis(proline amide) catalyst in chloroform and DMSO as representative weakly and strongly hydrogen bonding solvents. Using vibrational circular dichroism (VCD) spectroscopy and density functional theory (DFT) based spectra calculations, we show that the preferred axial stereochemistry of the catalyst is determined by solute‐solvent interactions. Explicitly considering solvation with DMSO molecules is found to be essential to correctly predict the conformational preferences of the catalyst. Furthermore, we investigate the stereochemistry of the corresponding enamines and imidazolidinones that are formed upon reaction with isovaleraldehyde. The enamines are found to rapidly convert to endo‐imidazolidinones and the thermodynamically favored exo‐imidazolidinones are formed only slowly. The present study demonstrates that the stereochemistry of these imidazolidinones can be deduced directly from the VCD spectra analysis without any further detailed analysis of NMR spectra. Hence, we herein exemplify the use of VCD spectroscopy for an in situ characterization of intermediates relevant in asymmetric catalysts.

Modelling solute–solvent interactions in VCD spectra analysis with the micro-solvation approach

“…Herein, we will focus on four cases (Fig. 2), namely a chiral donor–acceptor-donor motif based on 2,6-pyridinediyl-dialkylamide ( DAD ), 40 the asymmetric catalyst 2,2′-biphenyl-bisprolineamide ( BPA ), 12 the octahedral transition metal complex cation Ni[dipen] 3 2+ (dipen = 1,2-diphenyl ethylene diamine), 41 and the cyclic tetrapeptide cyclo(Boc-Cys-Pro-Gly-Cys-OMe) . Common to all four examples is the fact that their VCD spectra were strongly affected by a change of the solvent (mostly from rather non-interacting CDCl 3 to strongly hydrogen-bonding DMSO-d 6 ) showing at least partial inversion of signs.…”

“…Likewise, any intermolecular interactions that alter conformational preferences or that affect the VCD signature of single conformer must also be considered explicitly in the spectra calculations. Hence, although we extensively utilized this sensitivity, for instance, to study substrate-catalyst interactions in asymmetric catalysis [8][9][10][11][12] and other stereochemical aspects, [13][14][15][16][17] it can quickly turn into a major obstacle in routine AC determinations due to strong interactions solvent molecules.…”

Solvation of serine-based model peptides and the role of the intramolecular OH·O hydrogen bond in interpreting VCD spectra

“…[4][5][6] In this regard, especially strong solute-solvent interactions can easily become a major pitfall in the spectral analysis, as they may cause spectral changes that cannot be predicted yet without explicitly considering solvent molecules. [7][8][9][10] While cutting-edge molecular dynamics (MD) simulations could basically capture these effects on the fly, [11][12][13] they quickly become computationally costly and require dedicated experts to carry them out. Hence, it has become customary to consider micro-solvated structures, i.e., hydrogen bonded clusters of the solute and a few explicitly placed solvent molecules, to model VCD spectra.…”

Matrix effects in MI-VCD spectra of two chiral oxiranes and their potential microscopic origin

“…Hence, besides being an established tool for the determination of absolute configurations (AC), [5][6][7] VCD spectroscopy has revealed a unique sensitivity to conformational changes and intermolecular interactions. While in particular solvent effects were found to influence VCD spectra, [8][9][10][11][12][13] intermolecular interactions in catalysis, [14][15][16][17] supramolecular chemistry, [18][19][20][21][22][23][24][25][26] and biomolecules [27][28][29] have also been investigated.…”