Pleuromutillin, a potent diterpene antibacterial natural product is of considerable synthetic interest due to its highly functionalized eight-membered ring embedded within a trans-hydrindanone core. Among various total syntheses reported, the Reisman group published an approach utilizing a samarium diiodide-mediated ketyl radical cyclization which successfully yielded an advanced synthetic intermediate possessing the eight-membered ring with correct stereochemistry (below, top reaction). In stark contrast, upon their attempts to cyclize a 11,12-bis-epimer of the cyclization precursor under the same reductive conditions led to a completely unexpected product with drastic changes regarding the ring system’s connectivity (below, bottom reaction).
1) Suggest a plausible mechanism for this transformation.
2) Propose a rationale on how the stereoinversion of C11 and C12 affects the outcome of the cyclization process.
For reference:
Farney, E. P., Feng, S. S., Schäfers, F., & Reisman, S. E. (2018).
“Total synthesis of (+)-Pleuromutilin.”
Journal of the American Chemical Society, 140(4), 1267–1270.
DOI: 10.1021/jacs.7b13260