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.

Keywords: OH activation; Tsuji-Trost reaction; asymmetric catalysis; cuspareine; palladium.