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

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.