Enantioselective Allenoate-Claisen Rearrangement Using Chiral Phosphate Catalysts

Herein we report the first highly
enantioselective allenoate-Claisen rearrangement using doubly axially
chiral phosphate sodium salts as catalysts. This synthetic method
provides access to β-amino acid derivatives with vicinal stereocenters
in up to 95% ee. We also investigated the mechanism of enantioinduction
by transition state (TS) computations with DFT as well as statistical
modeling of the relationship between selectivity and the molecular
features of both the catalyst and substrate. The mutual interactions
of charge-separated regions in both the zwitterionic intermediate
generated by reaction of an amine to the allenoate and the Na+-salt of the chiral phosphate leads to an orientation of the
TS in the catalytic pocket that maximizes favorable noncovalent interactions.
Crucial arene–arene interactions at the periphery of the catalyst
lead to a differentiation of the TS diastereomers. These interactions
were interrogated using DFT calculations and validated through statistical
modeling of parameters describing noncovalent interactions.