The True Catalyst Revealed: The Intervention of Chiral Ca and Mg Phosphates in Brønsted Acid Promoted Asymmetric Mannich Reactions

Abstract

The acetylacetone-benzaldimine Mannich reaction catalyzed by Mg(II) and Ca(II) salts of chiral phosphoric acids (CPA) has been investigated computationally by QM/MM methods. Enantioselectivity in this reaction is both larger than and in the opposite sense to that observed for the same reaction catalyzed by the protic CPA catalyst alone. We present a mechanistic model from which the characteristic differences between these metal and metal-free catalysts, which can coexist in the same reaction mixture, can be understood. Alkaline earth salts with chiral phosphate counterions are found to be more catalytically active than the protic form, and the Ca(II) and Mg(II) CPA salts react via different mechanisms, with a higher coordination number favored by calcium over magnesium. In the well-ordered chiral cavities around these metal centers, asymmetric induction arises from the steric interaction with the imine protecting group in the unfavorable pathway, with both substrates adopting well-defined conformations. These mechanistic models have allowed us to rationalize the stereochemical outcome across a range of bimolecular reactions promoted by divalent metal phosphates formed with different CPAs.

Stereospecific 1,3-H Transfer of Indenols Proceeds via Persistent Ion-Pairs Anchored by NH···π Interactions

“…Ion-pairing interactions have long been recognized as a versatile strategy to induce reactivity and selectivity in organic chemistry. , However, while many computational studies of selectivity have been performed using density functional theory (DFT), mechanisms that proceed via ion-pairs have proved challenging to compute. A lack of directionality in ion-pairing interactions often leads to a vast conformational space.…”

Computational Insights into Privileged Stereocontrolling Interactions Involving Chiral Phosphates and Iminium Intermediates

“…In much the same manner, the term has been applied to certain catalysts; this terminology can be deployed to describe the participation of key NCIs that may be transferred from one mechanistic scenario to another. For example, chiral phosphoric acids (CPAs) have appeared to provide effective Brønsted acid catalysis for many organic reactions, and these often proceed through a standard mechanistic paradigm in which both reactants, electrophile and nucleophile, are activated by the catalyst through hydrogen bonding (Figure B). − Chiral phosphates also provide effective catalysis for many organic reactions with similar substrate types, but much less is known about how the catalyst imparts high enantioselectivities (Figure C). − This leads to the following questions. (1) Considering the commonality in catalyst structure for different mechanistic regimes, can similar stereocontrol elements be invoked?…”

Interrogating the thionium hydrogen bond as a noncovalent stereocontrolling interaction in chiral phosphate catalysis

“…The size difference between TRIP and AdDIP is 30 atoms, ONIOM calculations allow larger systems like TS with AdDIP to be explored efficiently. While these computational methods have been shown to give reliable results in a large variety of systems, [52][53][54][55][56][57] we were mindful of the possibility of error. Consequently, the lowest energy structures found from these calculations were submitted to full DFT geometry optimizations with B3LYP and uB97xD functionals to conrm the validity of our ONIOM results.…”