Asymmetric Total Synthesis of Phomarol

The first and asymmetric total synthesis of phomarol, an uncommon C25 steroid, is described. The synthetically challenging benzocycloheptane motif, found in phomarol and some other naturally occurring molecules, was synthesized efficiently using a very mild acid-promoted type I [5 + 2] cycloaddition, followed by regio- and chemoselective cleavage of the C-O bond and aromatization cascade. This work is the first example of using the hydrogen bonding between the hydroxy group and oxidopyrylium ylide to control the stereoselectivity of cycloadditions. The highly functionalized tetrahydropyran ring of phomarol was produced efficiently based on our suggested biomimetic pathway. [GRAPHICS] .

Automated summary

This study describes the first and asymmetric total synthesis of phomarol, a rare C25 steroid, using a mild acid-promoted type I [5 + 2] cycloaddition followed by regio- and chemoselective bond cleavage and aromatization cascade. The stereoselectivity of cycloadditions was controlled using hydrogen bonding between the hydroxy group and oxidopyrylium ylide. The highly functionalized tetrahydropyran ring of phomarol was efficiently produced based on a suggested biomimetic pathway.