Unraveling the Concerted Reaction Mechanism of the Noncatalyzed Mukaiyama Reaction between C,O,O‐Tris(trimethylsilyl)ketene Acetal and Aldehydes Using Density Functional Theory

The uncatalyzed Mukaiyama aldol reaction between C,O,O-
tris(trimethylsilyl)ketene acetal and aldehydes bearing alkyl, vinyl, and
aromatic substituents has been studied theoretically using density functional
theory with the M06-2X exchange−correlation functional. These DFT
calculations mostly demonstrate that (i) the syn product is both kinetically
and thermodynamically favored, (ii) the diastereoselectivity of the
uncatalyzed reaction is larger than observed for the reaction catalyzed by
HgI2 and it is inverted with respect to the latter, (iii) solvents with larger
dielectric constants increase the activation barrier but reduce the
diastereoselectivity, (iv) the concerted reaction is preferred over the
stepwise reaction, and (v) the OSiMe3 group in geminal lowers the
activation barrier and increases the energy of reaction. Analyzing the
concerted mechanism unravels four types of cyclic transition states, two pro-anti and two pro-syn. Then, the relative energy of the most stable transition state of each type as well as of the corresponding anti and syn products shows that the syn reaction path is located at lower Gibbs enthalpy than the anti reaction path for all substituents.