Catalytic Enantioselective [2,3]-Rearrangements of Allylic Ammonium Ylides: A Mechanistic and Computational Study

A mechanistic study of the isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium ylides is described. Reaction kinetic analyses using 19F NMR and density functional theory computations have elucidated a reaction profile and allowed identification of the catalyst resting state and turnover-rate limiting step. A catalytically relevant catalyst–substrate adduct has been observed, and its constitution elucidated unambiguously by 13C and 15N isotopic labeling. Isotopic entrainment has shown the observed catalyst–substrate adduct to be a genuine intermediate on the productive cycle toward catalysis. The influence of HOBt as an additive upon the reaction, catalyst resting state, and turnover-rate limiting step has been examined. Crossover experiments have probed the reversibility of each of the proposed steps of the catalytic cycle. Computations were also used to elucidate the origins of stereocontrol, with a 1,5-S···O interaction and the catalyst stereodirecting group providing transition structure rigidification and enantioselectivity, while preference for cation−π interactions over C–H···π is responsible for diastereoselectivity.


Typical Kinetic Profile and Analysis
Typical 19 F { 1
The reaction was monitored for ~2000 s taking a 13   S24 Reaction Kinetics Figure S17 shows the rate dependency of each reaction component. Reactions were performed as per the typical kinetic procedure. The concentration of one component is varied away from the "optimised conditions" of (+)-BTM (6.8 mM), HOBt (6.8 mM), iPr2NH (47.8 mM), ammonium salt 25a (34 mM), 253K.
Rate data was extracted from the gradient of 1 st order log-plots of the concentration of ammonium salt, in the pseudo-steady state (after ~3000 s). S25

Probing Effect of Catalyst Enantiopurity
To probe the relationship between the enantiopurity of the (+)-BTM catalyst the enantiomeric excess of the product, 25a was treated under standard catalytic conditions, using five different samples of catalyst with different enantiopurities. Stock solutions of (+)-BTM with different enantiopurities were prepared by mixing the appropriate quantities of (+)-BTM and (−)-BTM in MeCN (4 mL, 0.055 mmol total of BTM).
The enantiopurity of the catalyst stock solutions was measured via chiral HPLC analysis.
Scheme S7: System choosen to probe non-linear effects of catalyst enantiopurity.
To measure a secondary kinetic isotope effect at the C(3) position, independent rate measurements was initially used. Following the standard kinetic procedure the kobs of C(3)-H 25a and C(3)-D 25a were measured independently, in the steady state period, three times and an average taken to determine a SKIE. kH/kD 1.11 The error in kobs between independent kinetic experiments for the C(3)-D 25a is larger than calculated kH/kD hence the measurement of a SKIE at the C(3) via independent rate measurement was inconclusive. equiv., 17 mM) in d3-MeCN/d6-DMSO (9:1), the standard kinetic procedure was subsequently followed.
Initially a control experiment was performed to determine the effect of the introduced m-deutero substituent. 3,4 The isotopologue ratio H/D in the remaining substrate was plotted as a function of fractional conversion. The data was then fitted to a first-order exponential fit. Once the effect of m-dueteration was determined, the desired experiment could be performed, and the istopologue ratio in the substrate as function of fractional conversion could also be fitted to a first order exponential.

Hammett analysis by independent rate measurement
Following the standard kinetic procedure, the requisite ammonium salt (0.024 mmol, 1.0 equiv.) was treated with a 100 µL aliquot of a 2 mL stock solution, containing (+)-BTM, and iPr2NH, in d3-MeCN/d6-DMSO (9:1). First order rate constants were extracted within the pseudo-steady state and compared.
The sample was removed from the spectrometer and placed in a −20 °C cooling bath (CO2 (s), acetone) a 100 µL aliquot of a 2 mL stock solution, containing (+)-BTM (0.096 mmol), and iPr2NH (0.672 mmol), in d3-MeCN/d6-DMSO (9:1). The sample returned to the spectrometer and the kinetic run initiated (24 spectra, 91 s delay between spectra). First-order rate constants were extracted from the decay of each of the substrates.  Table S2: Ammonium salts and δF: chemical shift, used in Hammett analysis.

Addition of Additives at t=0
Following the standard kinetic procedure, additives were added to the 2 mL stock solution and a 100 µL sample was added at −20 °C as usual, after a t=0 19 F { 1 H} NMR spectra, kinetic analysis was then started. S40

Addition of Additives at t>0
Following the standard kinetic procedure, catalytic reaction were run to the time stated, then removed from the NMR spectrometer and the appropriate additive was added neat at −20 °C, the NMR tube was then returned to the spectrometer and kinetic run initiated.

Minor Diastereoisomer
Addition of a genuine sample of the minor diastereomer, anti-26a, into the catalytic reaction within the pseudo-steady-state period of the reaction, demonstrated that the minor diastereomer does not degrade over the course of the reaction, Figure S30.

Reversibility of Product Release
Following standard kinetic procedure A solution of (E)-N- (

General Procedure C: Synthesis of Allylic Bromides from Allylic Alcohols
A solution of allylic alcohol (1.0 equiv.) in Et2O (0.33 M) was cooled to 0 °C and treated with PBr3 (0.4 equiv.) and stirred for 1 h, the reaction was quenched by the dropwise addition of aq. sat. NaHCO3 (equal volume), the mixture was allowed to warm to rt. The layers were then separated, the aqueous layer extracted with Et2O (2 × equal volume), the combined organic layers washed with brine (equal volume), dried over MgSO4 and concentrated in vacuo to give allylic bromides, which were used directly.

General Procedure H: Catalytic [2,3]-Rearrangement of Allylic Ammonium Salts
A flamed dried Schlenk was charged with (+)-BTM (0.2 equiv.) and HOBt (0.2 equiv.) in MeCN (0.07 M with respect to the ammonium salt). iPr2NH (1.4 equiv.) was added and the solution was cooled to −20 °C and stirred for five min. The corresponding ammonium salt (1.0 equiv.) was added and the reaction stirred for 16 h, after which the reaction was quenched by the addition of aq. 1 M NaOH (equal volume) and extracted with CH2Cl2 (3 × equal volume). The combined organic layers were washed with brine (equal volume) dried over MgSO4 and concentrated in vacuo, the crude residue was analysed by 1 H and 19 F NMR to determine diastereoselectivity then purified by flash column chromatography to give the syn rearranged activated ester (typically >95:5 dr). 1 M NaOMe in MeOH was freshly prepared before use, by dissolving Na metal in anhydrous methanol at 0 °C and stirring for 30 min at rt.

(±)-4-Nitrophenyl (syn)-2-(dimethylamino)-3-(3-fluoro-4-iodophenyl)pent-4-enoate SI-9
Following general procedure I, where: The vibrational contribution to the enthalpy (Hvib) is given by: Finally, the zero-point vibrational energy (ZPVE) is calculated as:                                                                                                                           Table S5: Computational protocol for obtaining the lowest energy pathway of the direct acylation mechanism. Activated PNPO ester ammonium substrate. For each ground state and transition state, the explicit coordination of the structure and the remaining possible complexes was included in calculating the ∆G/∆G ‡ of each state. The difference between direct complexation and infinite separation is given by "•••" and "+", respectively. Barriers highlighted in blue are the lowest computed barriers and thermodynamics for each state.  Table S7: Select computed interatomic distances and estimations of the bond order using Wiberg bond index (NAO basis) for the enolate-ylide model systems.