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

Pradipta Das, Michael D. Delost, Munaum H. Qureshi, Jianhua Bao, Jason S. Fell, Kendall N. Houk, Jon T. Njardarson

Research output: Contribution to journalArticlepeer-review

Abstract

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 anti-relationship. For fluoride-substituted nucleophiles, a Mannich/amino-Cope cascade proceeds to afford chiral acyclic products with two new stereocenters in a syn-relationship. Bromide- and chloride-substituted nucleophiles appear to proceed via the same pathway as the fluoride albeit with the added twist of a 3-exo-trig 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 E to Z, the configurations at the R1 and X 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 (X = N3, SMe, or SCF3) or boat-like (X = F, Cl, or Br) transition state to afford amino-Cope-like products or β-lactam in the case of X = NO2.

Original languageEnglish (US)
Pages (from-to)5793-5804
Number of pages12
JournalJournal of the American Chemical Society
Volume143
Issue number15
DOIs
StatePublished - Apr 21 2021

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Fingerprint

Dive into the research topics of 'Dramatic Effect of γ-Heteroatom Dienolate Substituents on Counterion Assisted Asymmetric Anionic Amino-Cope Reaction Cascades'. Together they form a unique fingerprint.

Cite this