Organocatalytic Enantioselective [1,2]-Stevens Rearrangement of Azetidinium Salts

An organocatalyzed enantioselective [1,2]-Stevens rearrangement of ammonium ylides is reported. Using an isothiourea Lewis base organocatalyst, azetidinium salts underwent ring expansion to generate 4-alkylideneproline derivatives in high yield and good er. Products are readily recrystallizable to provide er’s of up to >99.5:0.5. Product configuration was established through X-ray crystallography and was opposite that predicted based on existing stereochemical models for this catalyst class. DFT calculations revealed that the facial selectivity of new bond formation is dictated by the pyramidalization of the enolate alpha-carbon in the ring-opening transition state. Notably, it is the catalyst benzylic hydrogen, and not the stereodirecting catalyst Ph, that influences this facial selectivity by stabilizing the developing pyramidalization of the enolate alpha-carbon in the transition state leading to the major enantiomer of product. Finally, under these reaction conditions, a tetrahydroisoquinolinium salt also underwent ring expansion to generate a benzazepine product as a single diastereomer in modest er. This result illustrates that this catalytic strategy for enantioselective [1,2]-Stevens rearrangement can be adapted for use with other synthetically- and medicinally-useful heterocyclic amine scaffolds.