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Abstract

Protected aldols (i.e., true aldols derived from aldehydes) with either syn- or anti- stereochemistry are versatile intermediates in many oligopropionate syntheses. Traditional stereoselective approaches to such aldols typically require several nonstrategic operations. Here we report two highly enantioselective and diastereoselective catalytic Mukaiyama aldol reactions of the TBS- or TES- enolsilanes of propionaldehyde with aromatic aldehydes. Our reactions directly deliver valuable silyl protected propionaldehyde aldols in a catalyst controlled manner, either as syn- or anti- isomer. We have identified a privileged IDPi catalyst motif that is tailored for controlling these aldolizations with exceptional selectivities. We demonstrate how a single atom modification in the inner core of the IDPi catalyst, replacing a CF₃-group with a CF₂H-group, leads to a dramatic switch in enantiofacial differentiation of the aldehyde. The origin of this remarkable effect was attributed to tightening of the catalytic cavity via unconventional C–H hydrogen bonding of the CF₂H group.