In-Cage Recombination Facilitates the Enantioselective Organocatalytic [1,2]-Rearrangement of Allylic Ammonium Ylides

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.