Vinylsilanes as useful intermediates in the synthesis of tetrahydropyrans

Abstract

Tetrahydropyrans are common motifs in biologically relevant compounds, natural and synthetic. Therefore, there is always a need to develop methodologies for their synthesis. Organosilicon compounds are useful synthetic intermediates due to the special properties that the silicon atom confers to the substrates. In particular, vinylsilanes have found numerous applications for the synthesis of heterocycles. First, we set our glance at hydroalkoxylation methods. An atom-economy hydroalkoxylation to highly substituted tetrahydropyrans was developed. Diastereoselectivity was excellent, obtaining just one diastereomer with unsubstituted and alkylsubstituted vinylsilanes. Then we focused on the silyl-Prins reaction, as a more modular approach to differently decorated tetrahydropyrans. We decided to explore the possibilities offered by SiMe2Ph vinylsilyl alcohols, in contrast with the typically used SiMe3 group. It was found that TMSOTf can promote the cyclization leading to 4-phenyl-tetrahydropyrans, through an unprecedented 1,2 silicon to carbon phenyl migration process. The scope of alcohols, aldehydes and migrating groups was studied. The disiloxanes formed can be desilylated with moderate selectivity or converted to hydroxysilanes. When a halide is used as a counter ion, the migration process is prevented. Thus, we have shown that 5 mol% of BiCl3 and 1 equivalent of TMSCl work as a catalytic system for the silyl-Prins reaction, yielding 4-silyl-4-chloro-tetrahydropyrans. Gladly, in this case silicon can be stereoselectively removed to afford 4-chlorotetrahydropyrans. This methodology was then successfully applied to the synthesis of an already described synthetic compound B with antinociceptive properties. By the use of TMSBr, brominated analogs can also be obtained, broadening the scope of the reaction. We have tried to extend this methodology to amine substrates, so far without success for neither tosyl nor benzylamines.