Aldol Reactions of Conformationally Stable Axially Chiral Thiohydantoin Derivatives

Two novel axially chiral ortho-trifluoromethylphenyl thiohydantoin derivatives have been prepared atroposelectively from the reaction of R and S alanine methyl ester HCl salts with ortho-trifluoromethylphenyl isothiocyanate in the presence of triethyl amine. It was found that after purification of the crude product by simple recrystallization, the R amino acid esters yielded thiohydantoins having solely M axial chirality whereas the S ones returned the P isomers only. This result prompted us to perform sterically controlled aldol reactions on M and P thiohydantoin atropisomers. It was found that during the aldol reaction of 3-o-trifluoromethyl-5-methylthiohydantoins, the o-trifluoromethyl group of the M isomers efficiently shielded the Si face of the intermediate and in this way, enabled the selective formation of only the R configured aldol products at C5 of the heterocyclic ring. The P thiohydantoins, on the other hand, yielded only the S C5 configured aldol products as a result of the Re face shielding of the ortho-trifluoromethyl group of intermediate enolates. A noteworthy face selectivity of the benzaldehyde molecule was not observed (anti/syn only 3/2) during the aldolization of trifluoromethylphenyl derivatives of thiohydantoins. Aldol reactions were also done using the previously synthesized axially chiral thiohydantoins with ortho-Cl, Br, and I phenyl substituents which had predominantly P conformations (P/M ratios > 95%), and the stereochemical outcomes were compared with those of the ortho-trifluoromethyl substituted ones. 80–90% face selectivity of the benzaldehyde molecule was observed for the axially chiral o-halophenyl substituted thiohydantoins. The syntheses done with axially chiral 3-ortho-trifluoromethylphenyl- and 3-ortho-iodophenyl-5-methyl thiohydantoins enabled stereoselective formation of quaternized chiral carbon centers at C5 of the thiohydantoin ring.