The Enantioselective Organocatalytic [1,2]-Rearrangement of Allylic Ammonium Ylides

The [1,2]-rearrangement of allylic ammonium ylides is traditionally observed as a competitive minor pathway alongside the thermally allowed [2,3]-sigmatropic rearrangement. The challenges associated with developing a catalytic enantioselective variant are amplified as concerted [1,2]-rearrangements are forbidden, with these processes proposed to proceed through homolytic C-N bond fission of the ylide, followed by stereoselective radical-radical recombination. 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 unprecedented levels of enantiocontrol (up to 97:3 er) and up to total selectivity over the thermally allowed [2,3]-rearrangement. Key factors in favouring the [1,2]-rearrangement include exploitation of (i) disubstituted terminal allylic substituents, (ii) cyclic N-substituted ammonium salts and (iii) elevated reaction temperatures. Mechanistic studies involving 13C-labelling 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 with 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 a-amino radical at either the primary or tertiary site of an intermediate allylic radical. Electrostatic interactions involving the bromide counterion and the rearrangement transition states control the facial selectivity of the [1,2]- and [2,3]-rearrangements, while the difficulty of forming a bond in the more sterically hindered tertiary position of the allylic substituent disfavors the formation of the [2,3]-product. These results will impact further investigations and understanding into enantioselective radical-radical reactions.