Dramatic Effect of γ-Heteroatom Dienolate Substituents on Counterion Assisted Asymmetric Anionic Amino-Cope Reaction Cascades.

We report a dramatic effect on product outcomes of the lithium ion enabled amino-Cope-like anionic asymmetric cascade when different γ-dienolate heteroatom substituents are employed. For dienolates with azide, thiomethyl, and trifluoromethylthiol substituents, a Mannich/amino-Cope/cyclization cascade ensues to form chiral cyclohexenone products with two new stereocenters in an -relationship. For fluoride-substituted nucleophiles, a Mannich/amino-Cope cascade proceeds to afford chiral acyclic products with two new stereocenters in a -relationship. Bromide- and chloride-substituted nucleophiles appear to proceed via the same pathway as the fluoride albeit with the added twist of a cyclization to yield chiral cyclopropane products with three stereocenters. When this same class of nucleophiles is substituted with a γ-nitro group, the Mannich-initiated cascade is now diverted to a β-lactam product instead of the amino-Cope pathway. These anionic asymmetric cascades are solvent- and counterion-dependent, with a lithium counterion being essential in combination with etheral solvents such as MTBE and CPME. By altering the geometry of the imine double bond from to , the configurations at the and stereocenters are flipped. Mechanistic, computational, substituent, and counterion studies suggest that these cascades proceed via a common Mannich-product intermediate, which then proceeds via either a chair ( = N, SMe, or SCF) or boat-like ( = F, Cl, or Br) transition state to afford amino-Cope-like products or β-lactam in the case of = NO.