Mechanistic Studies of Highly Enantio- and Diastereoselective Aza-Petasis–Ferrier Rearrangement Catalyzed by Chiral Phosphoric Acid

The precise mechanism of the highly anti- and
enantioselective aza-Petasis–Ferrier (APF) rearrangement of
hemiaminal vinyl ethers catalyzed by a chiral phosphoric acid was
investigated by undertaking experimental and theoretical studies.
The APF rearrangement is characterized by the following unique mechanistic
features: (i) efficient optical kinetic resolution of the starting
racemic hemiaminal vinyl ether, (ii) enantioconvergent process from
racemic hemiaminal vinyl ethers to optically active β-amino
aldehyde products, and (iii) anomalous temperature effects on the
enantioselectivity (enantioselectivity increases as reaction temperature
increases). The following experiments were conducted to elucidate
the unique mechanistic features as well as to uncover the overall
scheme of the present rearrangement: (A) X-ray crystallographic analysis
of the recovered hemiaminal vinyl ether to determine its absolute
configuration, (B) rearrangements of enantiomerically pure hemiaminal
vinyl ethers to validate the stereochemical relationship between the
hemiaminal vinyl ethers and β-amino aldehydes, (C) theoretical
studies on the transition states of the C–O bond cleavage and
C–C bond formation steps to gain an insight into the optical
kinetic resolution of the hemiaminal vinyl ether and the origin of
the stereoselectivity, as well as to elucidate the overall scheme
of the present rearrangement, and (D) crossover experiments of two
hemiaminal vinyl ethers having different vinyl ether and aliphatic
substituents to comprehend the mechanism of the anomalous temperature
effect and the enantioconvergent process. The results of experiments
and theoretical studies fully support the proposed mechanism of the
present anti- and enantioselective APF rearrangement.