TY - JOUR
T1 - In-cage recombination facilitates the enantioselective organocatalytic [1,2]-rearrangement of allylic ammonium ylides
AU - Hartley, Will
AU - Kasten, Kevin
AU - Greenhalgh, Mark David
AU - Feoktistova, Taisiia
AU - Wise, Henry
AU - Laddusaw, Jacqueline
AU - Frost, Aileen Bernadette
AU - Ng, Sean
AU - Slawin, Alexandra Martha Zoya
AU - Bode, Bela Ernest
AU - Cheong, Paul
AU - Smith, Andrew David
N1 - Funding: The research leading to these results has received funding from Syngenta and the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (W.C.H., CRITICAT, EP/L016419/1; K.K., EP/T023643/1; A.B.F., EP/J018139/1). A.D.S. and K.K. thank the EPSRC Programme Grant “Boron: Beyond the Reagent” (EP/W007517) for support. P.H.-Y.C. is the Bert and Emelyn Christensen Professor and gratefully acknowledges financial support from the Stone Family of OSU. Financial support from the National Science Foundation (NSF) (CHE-1352663) is acknowledged. T.F., H.B.W., J.M.L., and P.H.-Y.C. acknowledge computing infrastructure in part provided by the NSF Phase-2 CCI, Center for Sustainable Materials Chemistry (CHE-1102637).
PY - 2025/1/8
Y1 - 2025/1/8
N2 - 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.
AB - 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.
KW - Cations
KW - Rearrangement
KW - Recombination
KW - Salts
KW - Stereoselectivity
U2 - 10.1021/jacs.4c14516
DO - 10.1021/jacs.4c14516
M3 - Article
SN - 0002-7863
VL - 147
SP - 1101
EP - 1111
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 1
ER -