Mechanistic Study of Palladium-Catalyzed Wacker-Type Cyclizations

Key words

Wacker-type cyclization - palladium - pyrrolidines

Significance

Recently, Stahl and co-workers had shown that a Pd(II) catalyst with a chiral pyridine–oxazoline (pyrox) ligand allowed preparation of pyrrolidines in high yield and enantioselectivity (Org. Lett. 2011, 13, 2830). In the enantioselective cyclization of γ-alkenyl tosylamides, the anionic ligand (TFA vs OAc) was found to have a significant impact on the reaction outcome, where the use of [Pd(pyrox)(OAc)₂] gave significantly diminished yield and enantioselectivity. Through a series of mechanistic investigations with a chiral, deuterated substrate probe, the authors showed the significant effect the anionic ligand has in selecting the nucleopalladation (NP) pathway of the Wacker-type cyclization, which in course determines the ancillary neutral donor’s ability to alter the stereochemical course of the pathway. This data provides the first direct correlation between NP stereo­selectivity and the enantioselectivity of the transformation.

Comment

By using ¹H NMR spectroscopy and HPLC analyses to determine H/D ratios and enantiomeric excesses, the authors were able to determine the yields of the four possible products from the reaction of a deuterated acyclic substrate under different conditions (see above). They showed that only in the trans pathway does the pyrox ligand play a significant role, thus the trans-amidopalladation (AP) pathway proceeds with high enantioselectivity, while the cis-AP pathway exhibits low enantioselectivity. The authors suggest that the carboxylate ligand acts as a Brønsted base to mediate Pd–amidate bond formation in the cis-AP pathway, whereas the TFA anionic ligand is substituted by the substrate alkene and favors the trans-AP pathway.