In their recent Organic Letters paper entitled the Syntheses of Chloroisosulochrin and Isosulochrin and Biomimetic Elaboration to Maldoxin, Maldoxone, Dihydromaldoxin, and Dechlorodihydromaldoxin, the Snider lab at Brandeis developed an efficient biomimetic synthesis of maldoxin (4), the biological precursor of several cytotoxic natural products recently isolated from the plant endophytic fungus Pestalotiopsis fici. Chloroisosulochrin (1) was synthesized for the first time and elaborated to maldoxin (4) by a three-step biomimetic route consisting of oxidative cyclization to give spirofuranone 2, acid catalyzed ring opening to yield dihydromaldoxin (3) and a second oxidative cyclization to form maldoxin (4).
Electrophilic chlorination of phenols usually takes place unselectively at both ortho and para positions. For the synthesis of chloroisosulochrin, they developed an ortho selective chlorination using 2,2,6,6-tetramethylpiperidine and sulfuryl chloride. Presumably a hindered N-chloroamine is formed, which hydrogen bonds to the phenol and delivers electrophilic chlorine intramolecularly.
