Computational Approach to Diarylprolinol-Silyl Ethers in Aminocatalysis

Abstract

Asymmetric organocatalysis has witnessed a remarkable development since its "re-birth" in the beginning of the millenium. In this rapidly growing field, computational investigations have proven to be an important contribution for the elucidation of mechanisms and rationalizations of the stereochemical outcomes of many of the reaction concepts developed. The improved understanding of mechanistic details has facilitated the further advancement of the field. The diarylprolinol-silyl ethers have since their introduction been one of the most applied catalysts in asymmetric aminocatalysis due to their robustness and generality. Although aminocatalytic methods at first glance appear to follow relatively simple mechanistic principles, more comprehensive computational studies have shown that this notion in some cases is deceiving and that more complex pathways might be operating. In this Account, the application of density functional theory (DFT) and other computational methods on systems catalyzed by the diarylprolinol-silyl ethers is described. It will be illustrated how computational investigations have shed light on the structure and reactivity of important intermediates in aminocatalysis, such as enamines and iminium ions formed from aldehydes and α,β-unsaturated aldehydes, respectively. Enamine and iminium ion catalysis can be classified as HOMO-raising and LUMO-lowering activation modes. In these systems, the exclusive reactivity through one of the possible intermediates is often a requisite for achieving high stereoselectivity; therefore, the appreciation of subtle energy differences has been vital for the efficient development of new stereoselective reactions. The diarylprolinol-silyl ethers have also allowed for novel activation modes for unsaturated aldehydes, which have opened up avenues for the development of new remote functionalization reactions of poly-unsaturated carbonyl compounds via di-, tri-, and tetraenamine intermediates and vinylogous iminium ions. Computational studies have played a pivotal role in the elucidation of the regioselectivities observed for such systems because these pose a challenge due to the presence of multiple reactive sites in these intermediates. Charge distribution and π-orbital coefficient calculations have been applied to explain the observed regioselectivity of the given reactions. The calculation of more elaborate energetic pathways has allowed for in silico identification of high-energy intermediates, such as zwitterions, and transition-state structures, which have also provided information on the driving force controlling the reaction course and outcome.

Rigorous Conformational Analysis of Pyrrolidine Enamines with Relevance to Organocatalysis

“…The magnitude of Δ E , Δ G gas , and Δ G sol shows that neither the high enantioselectivity nor the reversal of the enantioselectivity can originate from a stability difference in the s‐ cis and s‐ trans enamines alone. This is in agreement with several other theoretical investigations that also reported small electronic energy difference between s‐ cis and s‐ trans conformers (without extensive conformational analysis) . Our results are also in agreement with experimental studies which detected aldehyde‐ and ketone‐derived enamines in s‐ cis as well as s‐ trans conformations .…”

Proline bulky substituents consecutively act as steric hindrances and directing groups in a Michael/Conia-ene cascade reaction under synergistic catalysis

“…Furthermore, when pyrrolidine was used as the catalyst, the same dr was observed at rt although this catalyst is not chiral (Table 1, entries 1 and 6). These results suggest that this Michael reaction is reversible and that the conversion and dr are primarily determined by the energy of the different diastereomers of Int-Ald (thermodynamically controlled stereoselectivity)41 rather than the energy of the transition states of C–C bond formation ( TS-I , kinetically controlled stereoselectivity).…”

“…Before designing the computational study of this reaction,39–41 different experiments were performed to collect data on mechanistic parameters of this process. Reaction kinetics assessed when using different amounts of the proline ( I ) and Pd catalysts were studied by NMR spectroscopy.…”

Stereodivergent Aminocatalytic Synthesis of Z‐ and E‐Trisubstituted Double Bonds from Alkynals

“…To explain the observed Z / E regioselectivities, we addressed the theoretical investigation of the possible reaction pathways between the acetylene‐containing iminum cationic species derived from catalysts 3 a or 4 a , and the corresponding nucleophile to generate the product 5 Aa (Scheme ). Geometry optimizations were carried out using the M06 functional with 6‐31G(d,p) basis set, including acetone solvent effects by means of a SMD continuum model, which is a standard methodology previously used for related aminocatalytic systems . Electronic energies were refined by single‐point calculations at M06/6‐311++G(d,p) also including solvent effects.…”