Hindered rotation versus racemisation in axially chiral thiohydantoin derivatives

Abstract

In this project 5-benzyl-3-(aryl)-2-thiohydantoin and 5-isobutyl-3-(aryl)-2-thiohydantoin derivatives have been synthesized by reacting aryl isothiocyanates with S-phenylalanine methyl ester hydrochloride or with S-leucine methyl ester hydrochloride in the presence of triethylamine (TEA). The synthesized compounds have a chirality center at C5 of the heterocyclic ring. The 3-phenyl derivatives 1 and 4 have been found to exist in R or S enantiomeric forms. When the phenyl ring carried an ortho substituent (compounds 2, 3, 5 and 6), the compounds were shown to become axially chiral, the N3-C(aryl) bond being the chirality axis. The axially chiral derivatives were shown to exist in unequal amounts of SM, SP, RM and RP stereoisomeric forms. Although the syntheses started with an optically pure amino acid ester, the products were found to get racemized at C5 during the reactions. However for the axially chiral derivatives, a high prevalence of the P isomers over the M isomers have been obtained. The isomeric assignments were done by comparing the 1H NMR spectra with the HPLC chromatograms. The stereoisomers were resolved micropreparatively by HPLC on chiral stationary phases. The conversion type (racemization or rotation) of each separated isomer has been determined by HPLC analyses. It has been found that although the stereoisomers converted to each other only by rotation in toluene, in ethanol racemization was accompanied with rotation depending on the temperature of the thermal interconversion experiment. The energy barriers for the rotation and racemization processes have been determined. The resolved enantiomer of 5-isobutyl-3-phenyl-2-thiohydantoin was found to racemize at a faster rate than that of the 5-benzyl derivative. The occurance of racemization was further proved through Hydrogen/Deutereum exchange reactions via 1H NMR experiments done in CD3OD. The synthesized compounds will further be exploited in sterically controlled face-selective enolate reactions.