Unexpected Racemization in the Course of the Acetalization of (+)-(S)-5-Methyl-Wieland–Miescher Ketone with 12-Ethanediol and TsOH under Classical Experimental Conditions

摘要

(+)-( ) and (−)-( )-5-methyl-Wieland-Miescher ketone (+)- and (−)- , are important synthons in the diastereo and enantioselective syntheses of biological and/or pharmacological interesting compounds. A key step in these syntheses is the chemoselective C(1)O acetalization to (+)- and (−)- , respectively. Various procedures for this transformation have been described in the literature. Among them, the classical procedure based on the use of 1,2-ethanediol and TsOH in refluxing benzene in the presence of a Dean-Stark apparatus. Within our work on bioactive natural products, it occurred to us to observe the partial racemization of (+)- in the course of the acetalization of (+)- by means of the latter methodology. Aiming to investigate this drawback, which, to our best knowledge, has no precedents in the literature, we acetalized with 1,2-ethanediol and TsOH in refluxing benzene and in the presence of a Dean–Stark apparatus under various experimental conditions, enantiomerically pure (+)- . It was found that the extent of racemization depends on the TsOH/(+)- and 1,2-ethanediol/(+)- ratios. Mechanism hypotheses for this partial and unexpected racemization are provided.