Kinetic understanding of asymmetric amplification in amino-alcohol catalyzed organozinc additions

Abstract

The dynamic features of Noyori’s mechanism for the dimethylaminoisoborneol (DAIB) catalyzed alkylzinc addition to benzaldehyde have been investigated using the whole set of differential equations that describe the evolution of 19 species (starting products, intermediates, final compounds) involved in 36 coupled reversible or non-reversible processes. Using all the data available in the literature regarding the kinetic and thermodynamic parameters, the modeling confirms that the non-linear correlation between the enantiomeric excess of the chiral auxiliary (ee aux) and that of the product (ee prod) originates from the accumulation of the heterochiral alkylzinc amino alkoxide dimer (a reservoir effect). The variations of the enantiomeric excess of the product versus the benzaldehyde conversion are shown. Inhibition by the product can be understood by considering a reversible interaction between the alkoxide produced and the monomeric alkylzinc amino alkoxide catalyst. The effect of the order of the reactant addition on the ee prod and the rate of reaction as observed with 1-piperidino-3,3-dimethyl-2-butanol (PDB) instead of DAIB can be simulated without changing the relative thermodynamic stabilities of the homo- and heterochiral dimers although at the expense of a slowing-down of their equilibration rates.