Development of novel oxidation reactions using hypervalent iodine reagentsand their application to total synthesis of biologically active natural products

Recently, hypervalent Iodine(III) reagents have been used extensively in or ganic synthesis. In particular, phenyliodine (III) diacetate (PIDA) and phe nyliodine (III) bis(trifluoroacetate) (PIFA) have received a great deal of attention due to low toxicity, ready availability, easy handling, and react ivities similar to that of heavy metal reagents or anodic oxidation. In con trast to the widely explored phenolic oxidation using PIDA or PIFA, reactio ns of phenol ethers with hypervalent iodine reagents have been limited and have yielded mostly iodonium salts. We found unexpectedly that the reaction of p-substituted phenol ethers with PIFA in the presence of some nucleophi les in polar and poorly nucleophilic solvents such as 2,2,2-trifluoroethano l and 1,1,1,3,3,3-hexafluoro-2-propanol caused a novel and straightforward nucleophilic substitution reaction on the aromatic ring via a cation radica l intermediate [ArH+.]. Successful application of PIFA-induced umpolung of electron-rich aromatic ring reactivity allowed intramolecular cyclization r eactions of phenol ethers leading to novel and efficient preparations of sy nthetically useful products such as biaryl compounds, quinone-imines, and s ulfur-containing heterocycles. Using these methods, the first total synthes is of potent cytotoxic marine alkaloid, makaluvamine F was also achieved.