Reexamination of CeCl3 and InCl3 as Activators in the Diastereoselective Mukaiyama Aldol Reaction in Aqueous Media

Abstract

A search for suitable reaction conditions in Mukaiyama-type aldol condensations activated by CeCl₃ and InCl₃ revealed that the reaction proceeds best in i-PrOH/H₂O (95:5). Contrary to literature precedent, no reaction was observed in pure water, and the encountered destruction of the starting silyl enol ether can be ascribed to initial hydrolysis of the Lewis acid. As anticipated from the dual parameter (pK_h, WERC value) characteristics of CeCl₃ and InCl₃, the former proved more efficient as Lewis acid-promoter, in terms of reaction speed and yield. Nevertheless, InCl₃ was a superior catalyst during evaluation of the diastereoselectivity of the process. In this regard, determination of diastereoselectivity as a function of time showed that the InCl₃-catalyzed reaction is irreversible, whereas the CeCl₃-catalyzed reaction is a reversible process. In both cases, formation of the syn product is kinetically preferred, although (InCl₃) = 1.50 kcal/mol versus (CeCl₃) = 0.38 kcal/mol. Molecular modeling (semiempirical PM3, ab initio HF/3-21G*, hybrid B3LYP/3-21G*, and B3LYP/LANL2DZ) of the diastereoselective aldol reaction promoted by InCl₃ supports a “closed”, Zimmermann−Traxler transition state.