Holzapfel-Meyers-Nicolaou modification

The Holzapfel-Meyers-Nicolaou modification is a significant improvement over the traditional Hantzsch conditions. However, racemization can still occur in some circumstances. For example, the two-step Hantzsch reaction of thioamide 12 with bromide... 

The Holzapfel-Meyers-Nicolaou modification is a significant improvement over the traditional Hantzsch conditions. However, racemization can still occur in some circumstances. For example, the two-step Hantzsch reaction of thioamide 20 with bromide 19 furnishes thiazole 21 with 60-85% enantiomeric excess due to partial epimerization at the a-stereogenic center. The epimerization issue is obviated when thioamide 20 is replaced with the ketal-protected thioamide 22. Reaction of 19 with 22 delivers 23 with good optical purity (> 96% ee). This thiazole represents the core structure of the potent thiopeptide antibiotic nosiheptide. ... 

In contrast to the intermolecular Hantzsch reaction, which has been widely used, intramolecular examples have been scarce in the literature. Recently, an elegant Hantzsch macrocylization has been applied to the synthesis of IB-01211. ° Application of the Holzapfel-Meyers-Nicolaou modification to a-bromoketone-thioamide 27 brings about intramolecular thiazole formation with concomitant dehydration of the primary alcohol to give IB-01211 in moderate yield. This reaction is remarkable, especially considering the fact that the macrocyclization through amide formation at either bond a or b fails to produce any cyclized product. 

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