The intramolecular oxa-Michael reaction for tetrahydropyran formation : mechanism and synthesis

Abstract

Bistramides are a class of complex natural products containing three fragments, namely tetrahydropyran, amino acid and spiroketal. With respect to the biological relevance of Bistramide family, they have attracted much attention by the synthetic community. However, to our knowledge, no total synthesis of Bistramide D has been reported. Thus far, our laboratory has completed the synthesis of the THP ring and amino acid units, and has devised a route to the spiroketal. The current work describes a new synthetic approach towards the scale-up synthesis of THP ring. Our research group has had a longstanding interest in the synthesis of THP-containing natural products. The base- and acid-catalysed intramolecular oxa-Michael reaction proved to be a widely applicable method for the stereoselective elaboration of the THP ring. Despite the vast amount of precedents in syntheses, no clear explanation for the origin of stereocontrol has been disclosed. Thus, we provide a tangible explanation for the observed selectivity, which is based on a combined DFT and experimental study. The structural clarification of misassigned natural products has a long history and continues to be a recurring predicament. In this context, the ambiguous structural elucidation and the insufficient NMR data of Cryptoconcatone H prompted us to embark on a synthesis of the reported structure. The cis-THP core of the proposed structure was established via a tandem deprotection – intramolecular oxa-Michael cyclisation. Our synthetic study provides evidence that the proposed structure of the isolated natural product is incorrect.