Chiral Aziridine Sulﬁde N(sp3),S -Ligands for Metal-Catalyzed Asymmetric Reactions

: A series of new bidentate N,S -ligands—aziridines containing a para-substituted phenyl sulﬁde group—was synthesized and evaluated in the Pd-catalyzed Tsuji–Trost reaction and addition of diethylzinc and phenylethynylzinc to benzaldehyde. A high enantiomeric ratio for the addition reactions (up to 94.2:5.8) was obtained using the aziridine ligand bearing a p-nitro phenyl sulﬁde group. Collected results reveal a speciﬁc electronic effect that, by the presence of particular electron-donating or electron-withdrawing groups in the PhS- moiety, inﬂuences the σ -donor–metal binding and the enantioselectivity of the catalyzed reactions.


Introduction
Aziridines have established their position in modern organic synthesis thanks to a fortunate combination of properties-reactivity, stability and multidirectional transformability with high atom economy [1]. These small heterocycles can be variously functionalized on the nitrogen or both carbon atoms and serve as stable intermediates, which, through a facile ring opening with various nucleophiles, can efficiently introduce a specific puzzle to a more complex molecule [2,3]. Their utility is even greater when chirality is considered. In a fused three-membered ring system, the chiral center is always adjacent to the nitrogen donor, constituting an alluring ligand for asymmetric synthesis [4,5]. Till now, enantiopure aziridines were broadly evaluated as reagents and catalysts in asymmetric reactions [6]. As heterobidentate ligands, with incorporated heteroatoms such as oxygen, in the form of alcohols, ethers or phenols; phosphorus, as phosphines; and sulfur, as sulfides and disulfides, they can efficiently improve the stereoselectivity of the transition metal-catalyzed carbon-carbon bond formation in various types of reactions, including alkenylzinc addition to aldehydes (compounds 1 [7], 2 [8], 3 [9,10], 6 [11]) and to enones (derivative 4 [12]), Friedel-Crafts alkylation of indoles (phosphine 5 [13]) and Pd-catalyzed allylic alkylation (N,S-ligands 7 [14] and 8 [15])-examples are presented in Figure 1.
Divergent electronic effects of heteroatoms can improve the selectivity of the reaction due to the different bindings of the two donors to the central metal atom. N(sp3),S-bidentate aziridine-based ligands, presented in Figure 1, are known to enantioselectively promote metal-catalyzed asymmetric reactions; however, the scope of investigations is limited to the work of Braga [11,14] and Song [15]. The aim of this work was to obtain a series of new aziridine sulfide ligands and evaluate which specific feature-steric or electronic effectinfluences the enantioselectivity of the carbon-carbon bond formation by two common Divergent electronic effects of heteroatoms can improve the selectivity of the reaction due to the different bindings of the two donors to the central metal atom. N(sp3),S-bidentate aziridine-based ligands, presented in Figure 1, are known to enantioselectively promote metal-catalyzed asymmetric reactions; however, the scope of investigations is limited to the work of Braga [11,14] and Song [15]. The aim of this work was to obtain a series of new aziridine sulfide ligands and evaluate which specific feature-steric or electronic effect-influences the enantioselectivity of the carbon-carbon bond formation by two common protocols: synthesis of secondary alcohols through diethylzinc and phenylethynylzinc addition to aldehydes and palladium-catalyzed asymmetric allylic alkylation. The obtained compounds will combine (a) a bulky trityl moiety attached to the aziridine nitrogen, providing a steric hindrance that may direct the side of metal-donor coordination, and (b) an electron withdrawing (EWG) or electron donating (EDG) group, at the phenylsulfanyl substituent, decreasing or increasing the electron density on the sulfur atom, thus modulating the strength of the S-[M] binding ( Figure 2).

Results and Discussion
The first step of the research involved the synthesis of N-trityl aziridine tosylate 13 that was performed by a multistep procedure presented by Schneider et al. [16] starting from L-serine methyl ester 9. The substrate 9 was transformed to the corresponding Ntrityl derivative 10 which was cyclized to aziridine 11 by treatment with mesyl chloride. Further reduction with lithium aluminum hydride yielded the aziridine alcohol 12, next  Divergent electronic effects of heteroatoms can improve the selectivity of the reaction due to the different bindings of the two donors to the central metal atom. N(sp3),S-bidentate aziridine-based ligands, presented in Figure 1, are known to enantioselectively promote metal-catalyzed asymmetric reactions; however, the scope of investigations is limited to the work of Braga [11,14] and Song [15]. The aim of this work was to obtain a series of new aziridine sulfide ligands and evaluate which specific feature-steric or electronic effect-influences the enantioselectivity of the carbon-carbon bond formation by two common protocols: synthesis of secondary alcohols through diethylzinc and phenylethynylzinc addition to aldehydes and palladium-catalyzed asymmetric allylic alkylation. The obtained compounds will combine (a) a bulky trityl moiety attached to the aziridine nitrogen, providing a steric hindrance that may direct the side of metal-donor coordination, and (b) an electron withdrawing (EWG) or electron donating (EDG) group, at the phenylsulfanyl substituent, decreasing or increasing the electron density on the sulfur atom, thus modulating the strength of the S-[M] binding ( Figure 2).

Results and Discussion
The first step of the research involved the synthesis of N-trityl aziridine tosylate 13 that was performed by a multistep procedure presented by Schneider et al. [16] starting from L-serine methyl ester 9. The substrate 9 was transformed to the corresponding Ntrityl derivative 10 which was cyclized to aziridine 11 by treatment with mesyl chloride. Further reduction with lithium aluminum hydride yielded the aziridine alcohol 12, next converted to the tosylate 13. To obtain the final sulfanylaziridines, further nucleophilic substitution of the tosyl group was planned to be performed through the formation of a thiophenolate PhS − M + . However, at elevated temperatures, cleavage of the aziridine ring

Results and Discussion
The first step of the research involved the synthesis of N-trityl aziridine tosylate 13 that was performed by a multistep procedure presented by Schneider et al. [16] starting from L-serine methyl ester 9. The substrate 9 was transformed to the corresponding N-trityl derivative 10 which was cyclized to aziridine 11 by treatment with mesyl chloride. Further reduction with lithium aluminum hydride yielded the aziridine alcohol 12, next converted to the tosylate 13. To obtain the final sulfanylaziridines, further nucleophilic substitution of the tosyl group was planned to be performed through the formation of a thiophenolate PhS − M + . However, at elevated temperatures, cleavage of the aziridine ring was observed, furnishing the allylic amine 14. Optimization involved modification of the temperature and solvent and estimation of the influence of base exchange. Obtained data are summarized in Table 1. was observed, furnishing the allylic amine 14. Optimization involved modification of the temperature and solvent and estimation of the influence of base exchange. Obtained data are summarized in Table 1. The highest yield of the final aziridine was obtained when 10% of water was added to the solvent. The increased solubility of the used base-lithium hydroxide-elevated the rate of the product formation. The procedure was efficient for all variously p-substituted ligands (yields: 64-80%) ( Figure 3).  The highest yield of the final aziridine was obtained when 10% of water was added to the solvent. The increased solubility of the used base-lithium hydroxide-elevated the rate of the product formation. The procedure was efficient for all variously p-substituted ligands (yields: 64-80%) ( Figure 3). Symmetry 2021, 13, x FOR PEER REVIEW 3 of 10 was observed, furnishing the allylic amine 14. Optimization involved modification of the temperature and solvent and estimation of the influence of base exchange. Obtained data are summarized in Table 1. The highest yield of the final aziridine was obtained when 10% of water was added to the solvent. The increased solubility of the used base-lithium hydroxide-elevated the rate of the product formation. The procedure was efficient for all variously p-substituted ligands (yields: 64-80%) ( Figure 3).  Next, the catalytic properties of synthesized sulfanylaziridines were evaluated. The Pd-catalyzed Tsuji-Trost reactions between racemic 1,3-diphenyl-2-propenyl acetate and dimethyl malonate were carried out on a 0.2 mmol scale with 10 mol% of chiral ligands 15-19. The selected reaction conditions were based on our previous research. We observed Symmetry 2021, 13, 502 4 of 10 that increasing the amount of catalyst does not improve the yield and enantiomeric excess of the process. Alternatively, lowering the quantity of the catalyst decreases the overall enantioselectivity [17][18][19]. Results are presented in Table 2. Next, the catalytic properties of synthesized sulfanylaziridines were evaluated. The Pd-catalyzed Tsuji-Trost reactions between racemic 1,3-diphenyl-2-propenyl acetate and dimethyl malonate were carried out on a 0.2 mmol scale with 10 mol% of chiral ligands 15-19. The selected reaction conditions were based on our previous research. We observed that increasing the amount of catalyst does not improve the yield and enantiomeric excess of the process. Alternatively, lowering the quantity of the catalyst decreases the overall enantioselectivity [17][18][19]. Results are presented in Table 2. 70 52:48 a The reactions were carried out on a 0.2 mmol scale, 10 mol% of ligand L*, 2.5 mol% of [Pd(η 3 -C3H5)Cl]2, dimethyl malonate (3 equiv), BSA (3 equiv) and AcOK (3 mol%) in acetonitrile (1.5 mL) at 25 °C for 3-4 days; b enantiomeric excess was determined by HPLC.
The highest enantiomeric excess was observed for the unsubstituted aziridine 15. The overall enantioselectivity of all reactions was low, indicating that the N-trityl group prevents an efficient Het- [M] binding. This demonstrates that when the nitrogen atom is too sterically hindered, weak N-Pd coordination decreases the power of the nitrogen atom as the π-acceptor. In coordination with the weak S-Pd binding, the selectivity of the nucleophilic attack towards the carbon atoms of the formed palladium-allyl complex is only moderate.
Further activity evaluation involved the synthesis of secondary alcohols by the addition of diethylzinc to benzaldehyde. Basing on known literature reports [20][21][22], we used 10 mol% of catalyst as the most common reaction condition. Results are collected in Table  3. For unsubstituted aziridine 15 and compounds with additional electron-donating groups 16-19, the reaction proceeded with low enantiomeric excess. However, in the case of 4-nitrophenyl derivative 19, the final secondary alcohol was obtained with a high excellent enantiomeric ratio. We can assume that when the binding power of the sulfur atom is diminished, through the electron-withdrawing effect of the p-NO2 group, the increased The highest enantiomeric excess was observed for the unsubstituted aziridine 15. The overall enantioselectivity of all reactions was low, indicating that the N-trityl group prevents an efficient Het- [M] binding. This demonstrates that when the nitrogen atom is too sterically hindered, weak N-Pd coordination decreases the power of the nitrogen atom as the π-acceptor. In coordination with the weak S-Pd binding, the selectivity of the nucleophilic attack towards the carbon atoms of the formed palladium-allyl complex is only moderate.
Further activity evaluation involved the synthesis of secondary alcohols by the addition of diethylzinc to benzaldehyde. Basing on known literature reports [20][21][22], we used 10 mol% of catalyst as the most common reaction condition. Results are collected in Table 3. Next, the catalytic properties of synthesized sulfanylaziridines were evaluated. The Pd-catalyzed Tsuji-Trost reactions between racemic 1,3-diphenyl-2-propenyl acetate and dimethyl malonate were carried out on a 0.2 mmol scale with 10 mol% of chiral ligands 15-19. The selected reaction conditions were based on our previous research. We observed that increasing the amount of catalyst does not improve the yield and enantiomeric excess of the process. Alternatively, lowering the quantity of the catalyst decreases the overall enantioselectivity [17][18][19]. Results are presented in Table 2. The highest enantiomeric excess was observed for the unsubstituted aziridine 15. The overall enantioselectivity of all reactions was low, indicating that the N-trityl group prevents an efficient Het- [M] binding. This demonstrates that when the nitrogen atom is too sterically hindered, weak N-Pd coordination decreases the power of the nitrogen atom as the π-acceptor. In coordination with the weak S-Pd binding, the selectivity of the nucleophilic attack towards the carbon atoms of the formed palladium-allyl complex is only moderate.
Further activity evaluation involved the synthesis of secondary alcohols by the addition of diethylzinc to benzaldehyde. Basing on known literature reports [20][21][22], we used 10 mol% of catalyst as the most common reaction condition. Results are collected in Table  3. For unsubstituted aziridine 15 and compounds with additional electron-donating groups 16-19, the reaction proceeded with low enantiomeric excess. However, in the case of 4-nitrophenyl derivative 19, the final secondary alcohol was obtained with a high excellent enantiomeric ratio. We can assume that when the binding power of the sulfur atom is diminished, through the electron-withdrawing effect of the p-NO2 group, the increased For unsubstituted aziridine 15 and compounds with additional electron-donating groups 16-19, the reaction proceeded with low enantiomeric excess. However, in the case of 4-nitrophenyl derivative 19, the final secondary alcohol was obtained with a high excellent enantiomeric ratio. We can assume that when the binding power of the sulfur atom is diminished, through the electron-withdrawing effect of the p-NO 2 group, the increased affinity of the N(sp3) atom to the metal center significantly increases the formation of one enantiomer. The catalytic properties of compound 19 were further tested on several benzaldehydes. In all cases, the result was repetitively selective, confirming the promising catalytic activity of ligand 19 (Table 4). affinity of the N(sp3) atom to the metal center significantly increases the formation of one enantiomer. The catalytic properties of compound 19 were further tested on several benzaldehydes. In all cases, the result was repetitively selective, confirming the promising catalytic activity of ligand 19 (Table 4).  Finally, the catalytic activity of all ligands 15-19 was tested in the addition of phenylethynylzinc to benzaldehyde (Table 5). Table 5. Results of phenylethynylzinc addition to benzaldehyde promoted by ligands 15-19.

Ligand
Enantiomer The resultant enantiomeric ratio was moderate for all derivatives; however, the best result was also observed for the p-nitrosubstituted aziridine 19.

General
Melting points were measured with a Büchi Tottoli SPM-20 heating unit (Büchi Labortechnik AG, Flawil, Switzerland) and were uncorrected. NMR spectra were recorded on a Bruker Avance III/400 or Bruker Avance III/700 (Karlsruhe, Germany) for 1H and 176.1 MHz or 100.6 MHz for 13C. Chemical shifts were recorded relative to SiMe4 (δ0.00) or solvent resonance (CDCl3 δ7.26, CD3OD δ3.31). Multiplicities were given as: s (singlet), Finally, the catalytic activity of all ligands 15-19 was tested in the addition of phenylethynylzinc to benzaldehyde (Table 5). affinity of the N(sp3) atom to the metal center significantly increases the formation of one enantiomer. The catalytic properties of compound 19 were further tested on several benzaldehydes. In all cases, the result was repetitively selective, confirming the promising catalytic activity of ligand 19 (Table 4).  Finally, the catalytic activity of all ligands 15-19 was tested in the addition of phenylethynylzinc to benzaldehyde (Table 5). Table 5. Results of phenylethynylzinc addition to benzaldehyde promoted by ligands 15-19.

Ligand
Enantiomer The resultant enantiomeric ratio was moderate for all derivatives; however, the best result was also observed for the p-nitrosubstituted aziridine 19.

Synthesis of f (S)-(1-Tritylaziridin-2-yl)Methanol 12
The aziridine ester 11 (4.30 g, 12.56 mmol) was dissolved in THF (70 mL) and cooled to 0 • C, and LiAlH 4 (1.19 g, 31.33 mmol) was added portion-wise. After 24 h of stirring at room temperature, the mixture was cooled to 0 • C and 2 M aqueous NaOH was added dropwise until the gray residue turned to white solid. The resulting suspension was washed with Et 2 O and decantated several times. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated. The crude product was used without further purification [16]. Yield: 96%.

General Procedure for the Asymmetric Addition of Diethylzinc to Aldehydes
Toluene (0.5 mL) and Et2Zn (1 M in hexane, 0.376 mmol) were added to a 25 mL round-bottom flask under argon atmosphere. The catalyst (15)(16)(17)(18)(19) (10% mol, 0.0126 mmol) in toluene (0.5 mL) was then added and the mixture was stirred for 20 min at room temperature. After cooling to 0 • C in an ice bath, the solution of benzaldehyde (1 M in toluene, 0,126 mmol, 126 µL) was added to the reaction flask. After stirring overnight, the reaction was quenched with a saturated solution of NH 4 Cl (3 mL). The reaction mixture was extracted with diethyl ether (3 × 10 mL). The combined organic layers were washed with 1 M HCl (5 mL) and saturated NaCl solution (5 mL) and dried over anhydrous MgSO 4 . After filtration, the solvent was removed on a rotary evaporator to afford the product alcohol, which was analyzed on GC [25].

General Procedure for the Asymmetric Addition of Phenylethynylzinc to Benzaldehyde
In a 25 mL flask under argon toluene (0.5 mL), Et 2 Zn (1 M in hexane, 0.26 mmol, 0.26 mL) and phenylacetylene (0.286 mmol) were placed and stirred for 30 min at room temperature. Then, the catalyst (15-19) (10% mol, 0.013 mmol) in toluene (0.5 mL) was added and the mixture was stirred for 20 min at room temperature. The flask was cooled to 0 • C in an ice bath and the solution of benzaldehyde (1 M in toluene, 0,13 mmol, 130 µL) was added. After stirring overnight, the reaction was quenched with a saturated solution of NH 4 Cl (3 mL). The reaction mixture was extracted with diethyl ether (3 × 10 mL). The combined organic layers were washed with 1 M HCl (5 mL) and saturated NaCl solution (5 mL) and dried over anhydrous MgSO 4 . After filtration, the solvent was removed on a rotary evaporator under vacuum to give the product alcohol, in agreement with published data [26], which was analyzed on a chiral HPLC column (Chiracel OJ column, n-hexane/i-PrOH 80:20, flow rate 0.7 mL/min, λ 254 nm, t(1) 14.34 min, t(2) 24.32 min) [25].

Conclusions
This article presents an efficient methodology for the synthesis of new N(sp 3 ),Sbidentate aziridine-based ligands. The addition of 10% of water to the used solvent significantly increased the yield of the product, indicating that the solubility of the used base is crucial for the nucleophile (PhS − M + ) formation. The catalytic activity of all ligands was tested in the Pd-catalyzed Tsuji-Trost reaction and addition of diethylzinc and phenylethynylzinc to benzaldehyde. The obtained results conclude that the N-trityl moiety can presumably prevent the N-Pd coordination, decreasing the enantioselectivity of the reaction. In the case of the diethylzinc addition to benzaldehyde, the highest e.r. (94.2:5.8) was observed for the (S)-2-((4-nitrophenylsulfanyl)methyl)-1-tritylaziridine. This suggests that the EWG, through the reduction in the electron density on the sulfur atom, increases the N-Zn coordination. It can be concluded that in the case of this type of ligand, 2-(phenylsulfanyl)methylaziridines' steric and electronic effects that enhance the N-[M] coordination correspond to the improvement in the enantioselectivity of the performed reactions.