Tsuji-Trost Reaction of Non-Derivatized Allylic Alcohols.

Abstract

Palladium-catalyzed allylic substitution of non-derivatized enantioenriched allylic alcohols with a variety of uncharged N-, S-, C- and O-centered nucleophiles using a bidentate BiPhePhos ligand is described. A remarkable effect of the counter ion (X) of the XPd[κ2 -BiPhePhos][η3 -C3 H5 ] was observed. When ClPd[κ2 -BiPhePhos][η3 -C3 H5 ] (complex I) was used as catalyst, non-reproducible results were obtained. Study of the complex by X-ray crystallography, 31 P NMR spectroscopy, and ESI-MS showed that a decomposition occurred where one of the phosphite ligands was oxidized to the corresponding phosphate, generating ClPd[κ1 -BiPhePhosphite-phosphate][η3 -C3 H5 ] species (complex II). When the chloride was exchanged to the weaker coordinating OTf- counter ion the more stable Pd[κ2 -BiPhePhos][η3 -C3 H5 ]+ +[OTf] - (complex III) was formed. Complex III performed better and gave higher enantiospecificities in the substitution reactions. Complex III was evaluated in Tsuji-Trost reactions of stereogenic non-derivatized allylic alcohols. The desired products were obtained in good to excellent yields (71-98 %) and enantiospecificities (73-99 %) for both inter- and intramolecular substitution reactions with only water generated as a by-product. The methodology was applied to key steps in total synthesis of (S)-cuspareine and (+)-lentiginosine. A reaction mechanism involving a palladium hydride as a key intermediate in the activation of the hydroxyl group is proposed in the overall transformation.