Origins of the substituent effects in the aldol condensation of axially chiral thiohydantoins: a computational study

Aldol reactions are one of the most fundamental organic reactions involving the formation of carbon-carbon bonds that are commonly used in the synthesis of complex molecules through the condensation of an enol or enolate with a carbonyl group. The aldol reaction of thiohydantoin derivatives with benzaldehyde starts with hydrogen removal from C5 by lithium diisopropylamide (LDA) to form the enolate. Benzaldehyde adds to the enolate either at the less or more hindered site. The formed products have 3 chiral centers; thus they exist in 8 isomeric forms, RMS*/SPR*, RMR*/SPS*, SMR*/RPS*, and SMS*/RPR*, which are enantiomeric couples. Experimentally the axial chirality of the reactant is protected throughout the reaction; if the starting thiohydantoin is the M isomer, only RMS*, RMR*, SMR*, and SMS* diastereomers can be obtained. In this study, we aim to report a theoretical study of the aldol reactions between benzaldehyde and thiohydantoin derivatives conducted at the M06-2X/6-311+G(d,p) level of theory using the CPCM solvation model for THF as solvent, at 195 K. The investigation of the effect of substituents at C5 (stereocenter) and X positions on selectivity was performed by varying the substituents RCH₃, XCF₃; RCH₃, XCl; RCH₂Ph, XCF₃; RCH(CH₃)₂, and XCF₃. Agreement of calculations (M06-2X/6-311+G(d,p)/CPCM(THF)) with experiment suggests that the enantioselectivity is predominantly governed by thermodynamic control.