Aldol Reactions of Axially Chiral 5-Methyl-2-(o-aryl)imino-3-(o-aryl)-thiazolidine-4-ones

Abstract

Axially chiral 5-methyl-2-(o-aryl)imino-3-(o-aryl)-thiazolidine-4-ones have been subjected to aldol reactions with benzaldehyde to produce secondary carbinols which have been found to be separable by HPLC on a chiral stationary phase. Based on the reaction done on a single enantiomer resolved via a chromatographic separation from a racemic mixture of 5-methyl-2-(α-naphthyl)imino-3-(α-naphthyl)-thiazolidine-4-one by HPLC on a chiral stationary phase, the aldol reaction was shown to proceed via an enolate intermediate. The axially chiral enolate of the thiazolidine-4-one was found to shield one face of the heterocyclic ring rendering face selectivity with respect to the enolate. The selectivities observed at C-5 of the ring varied from none to 11.5:1 depending on the size of the ortho substituent. Although the aldol reaction proceeded with a lack of face selectivity with respect to benzaldehyde, recrystallization returned highly diastereomerically enriched products.

Aldol Reactions of Conformationally Stable Axially Chiral Thiohydantoin Derivatives

“…First, the thiohydantoin was treated with LDA (lithium diisopropylamide) for 1 h to form the enolate by the abstraction of hydrogen at C-5 of the heterocyclic ring and then, benzaldehyde was added and the reaction was continued for 3 h (Scheme ). , …”

“…First, the thiohydantoin was treated with LDA (lithium diisopropylamide) for 1 h to form the enolate by the abstraction of hydrogen at C-5 of the heterocyclic ring and then, benzaldehyde was added and the reaction was continued for 3 h (Scheme 1). 22,23 The previously reported thiohydantoins (2−5) have been synthesized predominantly in P conformations (P/M ratios > 95%). 3 Starting with a 3:6:91:0 isomeric ratio of SM/RP/SP/ RM 3 of 2 would be equivalent to starting with 97% P and 3% M because upon the formation of the intermediate enolate after reaction with LDA, the C5 would be planar and thus loose its chirality, whereas the chiral axis will persist.…”

“…S amino acids returned P thiohydantoins, whereas R returned M. We presumed that the CF 3 substituent, which is known to cause a high barrier to rotation from previous studies, 20,21 or the halo substituents Cl, Br, or I will efficiently hinder the enolate attack on the aldehyde from the side where it stands, so that the attack will take place from the other side, and in this way, render an asymmetric synthesis. We had previously reported the aldol reactions of axially chiral 3-(o-aryl)thiazolidine-4-ones 22 and oxazolidinediones 23 where starting compounds were racemic and therefore returned racemic products.…”