Synthesis of pyran and related natural products

This study was aimed at preparing dihydropyrans (DHPs) for the synthesis of 2,6-disubstituted tetrahydropyrans (THPs) in a diastereoselective manner.
In an attempt to develop a novel methodology for the synthesis of DHPs from δ-hydroxy-β-ketoester and thioamide in the presence of Lewis acid, unexpected dihydrothiopyran (DHT) formed as the sole product in the reaction instead of the expected DHP. A thorough investigation of the DHT forming-reaction showed that it is a promising method to synthesize 2,6-disubstituted DHT compounds. Various substituents at C2 and C6 positions were incorporated into the DHT by using different δ-hydroxy-β-ketoesters and thioamides.
This methodology was applied to the first total synthesis of citreothiopyrane A in 4% yield over three steps. The synthesis of a number of citreothiopyrane A analogs with different substituents at C6 position was also achieved.
N-heterocyclic carbene and quinuclidine were tested to promote the formation of δ-hydroxy-β-ketoesters form diketene, but the only product identified was the methyl acetoacetonate and stable quinuclidine-enolate respectively.
In the investigation of (-)-apicularen A synthesis, it was proposed that the THP core could be accessed by the asymmetric Maitland-Japp reaction, using Chan’s diene and two synthesized aldehydes. However, it was found that the aldehyde with ketal protecting group is too unstable under Lewis acid condition. Further improvements are needed, such as using a more acid-stable protecting group, or by replacement of the aldehyde functionality.