Mitsuru Kitamura

Metal‐catalyzed cyclization reactions of diazonaphthoquinones with glycidol were examined. The results revealed the formation of naphthodioxane derivatives. In this reaction, a metal carbene, generated from diazonaphthoquinone in the presence of a metal catalyst, reacts with the hydroxyl group of glycidol to produce an O─H insertion product. The phenolic hydroxyl group of this product then reacts with an internal epoxide to yield a cyclization product. Rh catalysts were proved to be broadly effective for the cyclization reactions, while Pd catalysts were effective for certain substrates.

A synthetic method for the CDEFG substructure of kosinostatin was developed using the cyclization of the di-para-nosyl 3-(2-hydroxyethyl)pyrrolidin-2-imine derivative. The key to the success of this cyclization was the choice of the para-nosyloxy (p-NsO) group as the leaving group. This selection enabled the cyclization to proceed under mild reaction conditions, leading to the first construction of a kosinostatin-type scaffold. The method was further applied to the synthesis of the ABCDEFG ring of kosinostatin aglycon.

The diazo-transfer reaction of nonactivated ketone under mild reaction conditions was developed. Various nonactivated ketones such as aryl methyl ketones, sec-alkyl methyl ketones, and cyclic ketones were transformed into their corresponding alpha-diazoketones in one step by treating 2-azido-1,3-bis(2,6-diisopropylphenyl)imidazolium hexafluorophosphate (IPrAP) in the presence of (Pr2NH)-Pr-i in ethylene glycol. In the reaction of IPrAP with prim-alkyl methyl ketone and prim-alkyl aryl ketones, migratory amidation proceeded under the reaction conditions to afford the corresponding amides.

Formal syntheses of teadenols A and B are achieved via a key Pd-catalyzed 6-endo cyclization of a phenol possessing a vinyl ­epoxide moiety. Although 5-exo and 6-endo cyclizations compete during cyclizations of epoxides with a nucleophilic moiety at the 5-position, 6-endo cyclization is realized by using a palladium catalyst.

The first efficient diazo‐transfer reaction of phenols is described. o‐Quinone diazides (diazoquinones) were prepared from phenols in high yields by the diazo‐transfer reaction using 2‐azido‐1,3‐bis(2,6‐diisopropylphenyl)imidazolium hexafluorophosphate (IPrAP, 2‐PF₆), which is a safe and stable crystalline. The reaction efficiently proceeded in methanol in the presence of a base. Phenols substituted with electron‐donating groups reacted more smoothly than those having electron withdrawing groups. Reactive phenols were diazotized by IPrAP with ⁱPr₂NH as a base, and low reactive phenols were diazotized with N,N‐dimethyl‐4‐aminopyridine (DMAP). Furthermore, the formed diazoquinones reacted with sodium azide in 2‐methoxyethanol and afforded the corresponding azidophenol in high yields.

We developed a new acetalization method of ketones and aldehydes under non‐acidic conditions using diazophenanthrenequinone and PdBr₂. The formed acetals that have a phenanthrene skeleton withstand under mild acidic conditions. Removal of acetals was successfully proceeded under strong acidic or oxidation conditions using aqueous ceric ammonium nitrate (CAN) to afford corresponding ketones and aldehydes.

A selective transesterification starting with tris(2,2,2-trifluoroethyl) phosphate has been developed. This method involves a three-step substitution for 2,2,2-trifluoroethoxy groups and enables the facile synthesis of mixed unsymmetric phosphate triesters from three different alcohols. The substitution of the trifluoroethoxy group at the phosphorus proceeds selectively in the presence of DBU or lithium alkoxides. This method can be applied for the preparation of phospholipids.

Direct azidation of phenols was developed. By treating chloroimidazolinium chloride 1b and sodium azide with phenol in the presence of a secondary amine in methoxyethanol, ortho‐azidation of phenol was achieved.