In-cage recombination facilitates the enantioselective organocatalytic [1,2]-rearrangement of allylic ammonium ylides

Will Hartley, Kevin Kasten, Mark David Greenhalgh, Taisiia Feoktistova, Henry Wise, Jacqueline Laddusaw, Aileen Bernadette Frost, Sean Ng, Alexandra Martha Zoya Slawin, Bela Ernest Bode, Paul Cheong, Andrew David Smith*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The [1,2]-rearrangement of allylic ammonium ylides is traditionally observed as a competitive minor pathway alongside the thermally allowed [2,3]-sigmatropic rearrangement. Concerted [1,2]-rearrangements are formally forbidden, with these processes believed to proceed through homolytic C–N bond fission of the ylide, followed by radical–radical recombination. The challenges associated with developing a catalytic enantioselective [1,2]-rearrangement of allylic ammonium ylides therefore lie in biasing the reaction pathway to favor the [1,2]-reaction product, alongside controlling a stereoselective radical–radical recombination event. Herein, a Lewis basic chiral isothiourea facilitates catalytic [1,2]-rearrangement of prochiral aryl ester ammonium salts to generate unnatural α-amino acid derivatives with up to complete selectivity over the [2,3]-rearrangement and with good to excellent enantiocontrol. Key factors in favoring the [1,2]-rearrangement include exploitation of disubstituted terminal allylic substituents, cyclic N-substituted ammonium salts, and elevated reaction temperatures. Mechanistic studies involving 13C-labeling and crossover reactions, combined with radical trapping experiments and observed changes in product enantioselectivity, are consistent with a radical solvent cage effect, with maximum product enantioselectivity observed through promotion of “in-cage” radical–radical recombination. Computational analysis indicates that the distribution between [1,2]- and [2,3]-rearrangement products arises predominantly from C–N bond homolysis of an intermediate ammonium ylide, followed by recombination of the α-amino radical at either the primary or tertiary site of an intermediate allylic radical. Electrostatic interactions involving the bromide counterion control the facial selectivity of the [1,2]- and [2,3]-rearrangements, while the sterically hindered tertiary position of the allylic substituent disfavors the formation of the [2,3]-product. These results will impact further investigations and understanding of enantioselective radical–radical reactions.
Original languageEnglish
Pages (from-to)1101-1111
Number of pages11
JournalJournal of the American Chemical Society
Volume147
Issue number1
Early online date23 Dec 2024
DOIs
Publication statusPublished - 8 Jan 2025

Keywords

  • Cations
  • Rearrangement
  • Recombination
  • Salts
  • Stereoselectivity

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