Enamine/Dienamine and Brønsted Acid Catalysis: Elusive Intermediates, Reaction Mechanisms, and Stereoinduction Modes Based on in Situ NMR Spectroscopy and Computational Studies

Abstract

Over the years, the field of enantioselective organocatalysis has seen unparalleled growth in the development of novel synthetic applications with respect to mechanistic investigations. Reaction optimization appeared to be rather empirical than rational. This offset between synthetic development and mechanistic understanding was and is generally due to the difficulties in detecting reactive intermediates and the inability to experimentally evaluate transition states. Thus, the first key point for mechanistic studies is detecting elusive intermediates and characterizing them in terms of their structure, stability, formation pathways, and kinetic properties. The second key point is evaluating the importance of these intermediates and their properties in the transition state. In the past 7 years, our group has addressed the problems with detecting elusive intermediates in organocatalysis by means of NMR spectroscopy and eventually theoretical calculations. Two main activation modes were extensively investigated: secondary amine catalysis and, very recently, Brønsted acid catalysis. Using these examples, we discuss potential methods to stabilize intermediates via intermolecular interactions; to elucidate their structures, formation pathways and kinetics; to change the kinetics of the reactions; and to address their relevance in transition states. The elusive enamine in proline-catalyzed aldol reactions is used as an example of the stabilization of intermediates via inter- and intramolecular interactions; the determination of kinetics on its formation pathway is discussed. Classical structural characterization of intermediates is described using prolinol and prolinol ether enamines and dienamines. The Z/E dilemma for the second double bond of the dienamines shows how the kinetics of a reaction can be changed to allow for the detection of reaction intermediates. We recently started to investigate substrate-catalyst complexes in the field of Brønsted acid catalysis. These studies on imine/chiral phosphoric acid complexes show that an appropriate combination of highly developed NMR and theoretical methods can provide detailed insights into the complicated structures, exchange kinetics, and H-bonding properties of chiral ion pairs. Furthermore, the merging of these structural investigations and photoisomerization even allowed the active transition state combinations to be determined for the first time on the basis of experimental data only, which is the gold standard in mechanistic investigations and was previously thought to be exclusively the domain of theoretical calculations. Thus, this Account summarizes our recent mechanistic work in the field of organocatalysis and explains the potential methods for addressing the central questions in mechanistic studies: stabilization of intermediates, elucidation of structures and formation pathways, and addressing transition state combinations experimentally.

Recent Advances in the Application of Vibrational Circular Dichroism Spectroscopy for the Characterization of Asymmetric Catalysts

“…Like for the thiourea catalysts discussed above, the perfect match between experimental and computed spectra also confirms the underlying computed conformational preferences of 15a . Thereby the VCD analysis supports all previous results from complex NMR analysis . The enamine prefers an E ‐configuration of the C=C bond, the C–N bond is in an s‐trans conformation and the C α –C ε bond is preferentially in sc‐exo conformation (cf.…”

“…Thereby the VCD analysis supports all previous results from complex NMR analysis. [42] The enamine prefers an E-configuration of the C=C bond, the C-N bond is in an s-trans conformation and the C α -C ε bond is preferentially in sc-exo conformation (cf. Scheme 6).…”

“…The different reactivities of 15a–c , allowed us to characterize the enamine intermediates 15a/b and the reaction towards oxazolidine 16 by VCD spectroscopy . As representatives for the results of this investigation, the experimental and computed IR and VCD spectra of enamine 15a are shown in Figure .…”

Online reaction monitoring by single-scan 2D NMR under flow conditions

“…The concentrations of reactants, products and sideproducts, reaction kinetics, and the nature of intermediates are examples of information that are accessed with monitoring methods, which then contribute to the design, optimization and mechanistic understanding of chemical reactions. [1][2][3] Nuclear magnetic resonance (NMR) spectroscopy is an efficient and widely used tool for reaction monitoring. Reaction progress can to some extent be monitored offline, by sampling periodically a fraction of the reaction mixture.…”

Unusually high α-proton acidity of prolyl residues in cyclic peptides

“…[12][13][14][15][16][17] The superior abilities of proline derivatives as organocatalysts compared with other amino acids is oen ascribed to the increased nucleophilicity of the prolyl secondary amine and inuence on cis/trans isomerism in enamine intermediates. [18][19][20][21][22][23][24] Mayr and co-workers have demonstrated a 100fold increased nucleophilicity of the secondary amino group of proline towards reaction with diarylcarbenium ions relative to the primary amino groups of other amino acids. 25 Myers and Raines recently reported a detailed kinetic study of the hydrogen-deuterium exchange reactions of cyclohexanone catalysed by proline derivatives in aqueous solution.…”