Concise Enantioselective Synthesis of the Ten-Membered Lactone Cephalosporolide G and Its C-3 Epimer

A short and highly stereo-selective sequence for the first enantioselective total synthesis of the naturally occurring 10-membered lactone, which was obtained in only eight steps, was reported. The macrolactone ring was carried out by the use of a high-yielding pyridinium chlorochromate (PCC)-mediated oxidative cleavage of a bicyclic intermediate, generated in a domino sequence from a p-peroxyquinol. The synthesis was started with (-)-rhododendrol, which was obtained by enzymatic resolution of the racemic derivative. Phenol (R)-5 was submitted to an oxidative dearomatisation process with singlet oxygen, generated from Oxone in the presence of NaHCO3. The treatment of compound peroxyquinol with para-toluene sulfonic acid followed by Triton B gave, in one step and 49% yield, the tricyclic epoxide bicyclic derivative. A similar route was employed for the synthesis of the C-3 diastereoisomer of the natural product, which was obtained in only 7 steps and 15.2% overall yield.