Atroposelective synthesis and reactions of axially chiral thiohydantoins

Abstract

Nonracemic axially chiral thiohydantoins were synthesized atroposelectively by the reaction of ortho-arylisothiocyanates with amino acid ester salts in the presence of triethylamine (TEA). However, the synthesis of the nonaxially chiral derivatives gave racemic thiohydantoins. When a large substituent was present at C5, more racemization at this position was seen. The isomer compositions of the studied compounds have been determined by 1H NMR together with HPLC analyses with chiral stationary phases. In most cases a high prevalence of the P isomers over the M ones has been obtained. The barriers to rotation determined around the N(sp2)-C(aryl) chiral axis were found to be dependent upon the size of the ortho-halo aryl substituents. In addition, aldol reactions of the synthesized thiohydantoins with benzaldehyde and 4-nitrobenzaldehyde were carried out. The isomeric products were identified by 1H NMR and it was found that the selectivity observed at the benzylic carbon was due to the preference of the phenyl group to be present at the equatorial position of the six membered ring formed as a result of an intramolecular H-bonding. In addition, it was shown that the o-aryl substituents at N3 had directing effects on the attachment of the electrophile to C5 of the heterocyclic ring. Lastly, the synthesized thiohydantoins were reduced to the corresponding stable hemiaminals (O, N-hemiacetals) by LiAlH4. The isomeric assignments were done through one or two dimensional NMR spectrometry and by HPLC analyses on chiral stationary phases. The stereoselectivity of the reactions with respect to the chiral axis was found to originate from the conformational preferences of the axially chiral hemiaminals which in turn arose from either a tendency for an intramolecular hydrogen bond formation or out of steric reasons. The stereodynamics of the axially chiral hemiaminals leading to their conformational preferences were investigated.