Enantioselective Sulfonimidamide Acylation via a Cinchona Alkaloid-Catalyzed Desymmetrization: Scope, Data Science, and Mechanistic Investigation

Abstract

Methods to access chiral sulfur(VI) pharmacophores are of interest in medicinal and synthetic chemistry. We report the desymmetrization of unprotected sulfonimidamides via asymmetric acylation with a cinchona-phosphinate catalyst. The desired products are formed in excellent yield and enantioselectivity with no observed bis-acylation. A data-science-driven approach to substrate scope evaluation was coupled to high throughput experimentation (HTE) to facilitate statistical modeling in order to inform mechanistic studies. Reaction kinetics, catalyst structural studies, and density functional theory (DFT) transition state analysis elucidated the turnover-limiting step to be the collapse of the tetrahedral intermediate and provided key insights into the catalyst-substrate structure-activity relationships responsible for the origin of the enantioselectivity. This study offers a reliable method for accessing enantioenriched sulfonimidamides to propel their application as pharmacophores and serves as an example of the mechanistic insight that can be gleaned from integrating data science and traditional physical organic techniques.

Figure 1.

(A) Medicinally relevant molecules containing sulfur(VI) functional groups. (B) Previously reported desymmetrization of sulfonimidamides. (C) This work.

Figure 2.

(A) HTE screening of cinchona-derived catalysts to identify leads. (B) Optimization of cinchona-phosphinate catalysts and reaction solvent. Standard reaction conditions were as follows: 1a (0.16 mmol, 1.0 equiv), 2a (0.48 mmol, 3.0 equiv), and catalyst 3 (0.032 mmol, 20 mol %) in THF (3.2 mL, 0.05 M) at −35 °C. ^aRelative product area % as determined by SFC analysis. ^bEnantiomeric ratio (er) of product in the crude reaction mixture, as determined by chiral SFC analysis.

Figure 3.

Exploration of the sulfonimidamide substrate scope. (A) Sulfonimidamide substrate scope. Reaction conditions: substrate 1 (1.00 mmol, 1.0 equiv), 2a (3.00 mmol, 3.0 equiv), and catalyst 3e (0.20 mmol, 20 mol %) in THF (20.0 mL, 0.05 M) at −35 °C. ^aIsolated yield after purification. ^ber of the isolated product, as determined by chiral SFC analysis. ^cAbsolute configuration was determined by X-ray crystallographic analysis. (B) PCA of synthetically feasible sulfonimidamides (43.5% of the total variance depicted with two principal components), selected substrates are labeled, and black crosses indicate substrates screened using HTE.

Figure 4.

Exploration of the electrophile scope. Reaction conditions: 1a (0.16 mmol, 1.0 equiv), electrophile 2 (0.48 mmol, 3.0 equiv), and catalyst 3e (0.032 mmol, 20 mol %) in THF (3.2 mL, 0.05 M) at −35 °C. ^aRelative product area % as determined by UPLC-MS/SFC analysis. ^ber of the product in the crude reaction mixture, as determined by chiral SFC analysis.

Figure 5.

Application of this methodology to synthesize chiral sulfonimidamide analogs of sulfonamide-containing drug candidates.

Figure 6.

Statistical modeling of the substrate catalyst relationship. (A) Employment of a combinatorial matrix approach for HTE screening of enantioselectivity for 17 sulfonimidamide substrates against 10 cinchona-phosphinate catalysts. (B) Data were curated for statistical model validation. (C) Multivariate linear regression (MLR) model for enantioselectivity built from Boltzmann averaged descriptors and depictions of the molecular descriptors included in the model. Computational method: M06-2X/def2-TZVP//B3LYP-D3BJ/6-31G(d,p).

Figure 7.

Experimental mechanistic investigation results. (A) Carbonyl region from a ReactIR waterfall plot for the reaction of 1a and 2a with catalyst 3e under the standard catalytic conditions, showing the conversion of 2a and the formation of 4aa. (B) Reaction profiles for a series of experiments using varying initial concentrations of catalyst 3e, the quinoline N-oxide catalyst derivative 3o, and the uncatalyzed background reaction. (C) Catalyst derivatives used to elucidate active site(s). Reaction conditions: 1a (0.16 mmol, 1.0 equiv), 2a (0.48 mmol, 3.0 equiv), and catalyst 3 (0.032 mmol, 20 mol %) in THF (3.2 mL, 0.05 M) at −35 °C. ^aRelative product area % determined by SFC analysis. ^ber of the product in the crude reaction mixture was determined by chiral SFC analysis.

Figure 8.

Substrate-catalyst hydrogen-bonding interactions. (A) Hydrogen-bond acceptor sites on cinchona-phosphinate catalyst 3e. (B) The schematic model and illustrative optimized structure showing the catalyst-substrate binding mode with two hydrogen-bonds.

Figure 9.

Calculated transition state structures and energy barriers for tetrahedral intermediate formation and tetrahedral intermediate collapse. Computational method: ωB97XD/def2TZVPP (SMD(THF))//ωB97XD/def2SVP.

Figure 10.

(A) Tetrahedral intermediate collapse transition state structures of catalyst 3e leading to the (S)-enantiomer and the (R)-enantiomer. (B) Substrate volume plotted against catalyst buried volume with the measured ΔΔG^‡ overlaid as a heatmap. The gray-shaded region indicates a high enantioselectivity. ^aData points for catalysts 3k and 3h overlap in the plot because they have nearly the same %V_bur. (C) Transition states for the tetrahedral intermediate collapse of catalyst 3g. (D) Impact of quinoline rotamers of catalyst 3k on the overall dipole moment and ground state energies. (E) Reaction profiles for various catalysts and the uncatalyzed background reaction. (F) MLR model for enantioselectivity trained without catalysts 3g, 3h, and 3k and depictions of the molecular descriptors from the lowest energy conformer included in the model (12 reactions were used as external validation, and a Kennard Stone algorithm was used to split the remaining 107 reactions 50:50 into training:test sets).