Highly Efficient Asymmetric [3+2] Cycloaddition Promoted by Chiral Aziridine-Functionalized Organophosphorus Compounds

1. Introduction

Asymmetric synthesis including organocatalysis is still one of the most important and intensively researched methodologies for creating new carbon-carbon bonds [1]. Within the above methodology, new trends are emerging, including, for example, photocatalysis [2] and asymmetric synthesis using free radicals [3]. Among the very wide variety of asymmetric reactions, stereodifferentiating pericyclic reactions [4], including cycloadditions [5], deserve special mention. Among the products of asymmetric cycloaddition reactions, chiral systems containing a pyrrolidine ring often play a key role in biological and pharmacological research [6]. They may have a wide spectrum of activity - antibacterial, cytotoxic, antifungal, etc. [7]. Examples of substances containing a pyrrolidine motif available on the pharmaceutical market are Telaprevir which is an antiviral agent used in the treatment of chronic hepatitis C virus infection [8], ombitasvir also used as a strong inhibitor of SARS-CoV-2 [8], levetiracetam commonly used in the treatment of focal epilepsy [9], and sunitinib, i.e., a tyrosine kinase inhibitor used in the treatment of gastrointestinal stromal tumor and renal cell carcinoma [8].

Based on our experience in the field of asymmetric synthesis using heteroorganic ligands and organocatalysts [10], and taking into account the significant importance of chiral pyrrolidine systems in several areas of life and science [8], we decided to carry out an asymmetric [3+2] cycloaddition of azomethine ylides to nitrostyrene [6], using chiral, optically pure organophosphorus derivatives of aziridines as catalysts, namely phosphines [11], phosphine oxides [12], and aziridine-containing imines [13a,b]. The purpose of this decision was also to expand the scope of applicability of the chiral catalysts we had previously obtained.

2. Results and Discussion

2.1. Synthesis of the Chiral Catalysts and the Starting Materials

We started from the synthesis of the corresponding chiral catalysts 1-12 (Figure 1). Aziridine phosphines 1-4 were obtained from the corresponding phosphine oxides 5-8 via triethoxysilane and titanium(IV) isopropoxide [11]. Aziridine phosphine oxides 5-8 were synthesized starting from o-bromoanisole and diphenylphosphinic chloride as described previously [12]. In turn, imines 10-12 were obtained using previously described protocols [13a,b]. Finally, phosphine oxide bearing NH-aziridine subunit 9 was prepared from (S)-2-phenylaziridine and diphenylphosphinic chloride in the presence of sec-BuLi [14].

Secondly, the corresponding imino esters 13-15 (Figure 2) being substrates for in situ generation of azomethine ylides were prepared from the appropriate glycine esters and benzaldehyde in the presence of triethylamine according to literature general protocol [15].

2.2. Asymmetric [3+2]-Cycloaddition Reactions

All the aziridine derivatives 1-12 were examined for catalytic activity in the asymmetric [3+2]-cycloaddition reaction occurring between trans-β-nitrostyrene and ethyl imino ester 14 (Scheme 1). These reactions were catalyzed by an in situ generated catalytic system consisting of copper triflate, chiral ligand and DBU as a basic additive. After appropriate purification of crude mixtures by column chromatography three diastereomeric products 16-18 were obtained. Two of them were identified based on the literature data as products exo 17b and endo 18b (Scheme 1) [16a-b]. However, compound 16b has not been described in the literature. The effectiveness of the ligands was determined based on the analysis of the optical purity of the obtained products using the HPLC method on a column with chiral support. The results are summarized in Table 1.

The analysis of the results showed that the use of structurally similar aziridine ligands led to similar outcomes. The highest chemical yield of the asymmetric [3+2]-cycloaddition, up to 71%, was achieved using ligands with an imine group however, the products were formed without significant diastereoselectivity. Aziridine phosphine ligands resulted in the formation of diastereomeric products in a similar ratio, with only the aziridine-phosphine ligand 2 shifting the equilibrium towards the formation of product exo 17b additionally with excellent enantioselectivity (up to 98% ee). In all cases, products 16b and 17b were formed in enantiomerically enriched forms, while compound 18b always formed racemic mixtures. Unexpectedly, the use of ligand 9 containing an NH-aziridine group led to the formation of racemic product endo 18b predominating over products 16b and 17b.

In the next stage, it was decided to conduct an asymmetric [3+2]-cycloaddition reaction, but instead of ethyl imino ester 14, methyl imino ester 13 was used. The second substrate and the other reaction conditions remained unchanged (Scheme 2) (Table 2). (S)-Isopropyl aziridine phosphine oxide 6 was used as the ligand. In this reaction, two diastereomeric products were achieved and also identified based on the literature-described ¹H-NMR spectra as the exo 17a product [16a], which was formed with a 70% enantiomeric excess. Based on the ¹H-NMR spectrum, the second of the formed diastereomers was also identified as the 4-epi-endo 16a product [6]. However, the third endo product, formed in the previous reaction with ethyl imino ester 14, was not obtained this time.

In the next approach, the reaction was carried out using tert-butyl ester 15 as the substrate (Scheme 3). In this reaction, three diastereomeric products 16-18 were obtained again, and their configuration was determined based on the literature data as 4-epi-endo 16c, exo 17c, and endo 18c.¹⁷ Interestingly, in this reaction, product 16c was formed in a small amount racemic form (Table 3).

In summary, after identifying all three products, it was concluded that the reaction proceeds according to a concerted mechanism resulting initially in the formation of two products with exo 17 and endo 18 configurations. The formation of an additional diastereomeric product 16 should be impossible when trans-β-nitrostyrene is used as a substrate. Therefore, based on the literature reports, it is believed that product 18 undergoes epimerization under basic conditions (the aziridine ring exhibits basic character). Epimerization involves a change in the configuration of a substituent at a single stereogenic center and is a process described in the literature [6] for both methyl and tert-butyl imino esters (e.g., involving triethylamine). It is assumed that the aziridine ligands act as chiral bases, causing selective epimerization of product 18 to product 16. Methyl derivatives are most susceptible to this change - no endo product was observed because the entirety underwent epimerization. However, tert-butyl derivatives are the most resistant to epimerization - only trace amounts of product 16c were observed. Differences in the quantity of product formed during the epimerization process may result from steric hindrance present in individual compounds.

To confirm the epimerization process, an additional experiment was conducted involving the reaction of pure product 18b with the in situ generated catalytic system consisting of aziridine chiral ligand, copper triflate, and DBU (Scheme 4). The reaction was conducted under analogous conditions to the cycloaddition reaction. This test confirmed that the mixture contained the 4-epi-endo product 16b along with the initial endo compound 18b in a ratio of 0.6:1.0, demonstrating that the formation of product 16b occurred under the influence of the utilized catalytic system and confirming the previously assumed theory of epimerization.

4. Materials and Methods

4.1. General Information

All reagents were used as obtained from commercial suppliers, unless otherwise noted. The corresponding chiral catalysts 1-12, exactly, aziridine phosphines [11], aziridine phosphine oxides [12], phosphine oxide containing NH-aziridine subunit [14], and aziridine-containing imines [13a, b] were prepared according to literature report. Also, imino esters 13-15, being substrates for in situ generation of azomethine ylides were obtained using general protocol [15]. NMR spectra for solutions in deuterated chloroform (CDCl₃) were recorded at 600 MHz (¹H NMR) and 150 MHz (¹³C NMR) on a Bruker Avance III spectrometer, using the solvent as an internal standard. The following abbreviations were used to describe NMR spectra: δ, chemical shift (ppm); J, coupling constants (Hz); s, singlet; br.s, broad singlet; d, doublet; dd, double-doublet; t, triplet; q, quartet and m, multiplet. Column chromatography was performed on silica gel using a solvent mixture of hexane/ethyl acetate as eluents (9:1). The enantiomeric excess (ee) values were determined by high-performance liquid chromatography (HPLC) on a chiral packed column (Chiralcel OD-H) using hexane and isopropanol as the mobile phase.

4.2. Asymmetric [3+2]-Cycloaddition Reaction Catalyzed by Aziridine Derivatives 1-12 – General Procedure

A copper triflate (CuOTf)₂·C₆H₆ (0.1 mmol) and ligand (0.1 mmol) were placed in a flask, the whole mixture was cooled to 0 °C, then DBU (12 μL) and anhydrous THF (4 mL) were added. The catalytic system was generated for 4 hours at 0 °C. The mixture was cooled to -15 °C and imino ester (0.5 mmol) was added, stirred for 10 minutes, after which trans-β-nitrostyrene (0.5 mmol) was added. The resulting mixture was stirred for 48 hours at low temperature and then the solvent was evaporated in vacuo. The crude products were separated via column chromatography on silica gel (hexane:ethyl acetate 9:1). All the aziridine derivatives 1-12 were examined for catalytic activity in the asymmetric [3+2]-cycloaddition of ethyl imino ester 14. In the asymmetric [3+2]-cycloaddition of methyl imino ester 13 and tert-butyl imino ester 15 only catalyst 6 was examined.

Characterization of Compounds 16a-c, 17a-c, and 18b-c

(2R,3S,4S,5R)-Ethyl 4-Nitro-3,5-diphenylpyrrolidine-2-carboxylate (4-epi-endo) 16b; yellow sticky oil, 45 mg, 26%

¹H NMR (600 MHz, CDCl₃) δ: 7.58 – 7.56 (m, 2H), 7.45 – 7.43 (m, 2H), 7.39 – 7.33 (m, 4H), 7.29 – 7.28 (m, 2H), 5.16 (dd, J = 3.7 Hz, J = 7.6 Hz, 1H), 5.10 (d, J = 3.7 Hz, 1H), 4.70 (d, J = 3.7 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 4.07 – 4.05 (m, 1H), 2.93 (br.s, 1H), 1.24 (t, J = 7.1 Hz, 3H).

¹³C{¹H} NMR (150 MHz, CDCl₃) δ: 172.5, 140.2, 133.2, 129.0, 128.8, 128.4, 128.2, 126.8, 96.5, 65.8, 63.3, 61.6, 52.6, 14.0.

Anal. Calcd. for C₁₉H₂₀N₂O₄: C, 67.05; H, 5.92; N, 8.23; O, 18.80; Found: C, 66.85; H, 5.75; N, 8.09; O, 19.31.

(2R,3R,4S,5R)-Ethyl 4-Nitro-3,5-diphenylpyrrolidine-2-carboxylate (exo) 17b [16a]; yellow sticky oil, 51 mg, 30%

¹H NMR (600 MHz, CDCl₃) δ: 7.60 – 7.59 (m, 2H), 7.47 – 7.41 (m, 3H), 7.34 – 7.29 (m, 5H), 5.24 (t, J = 8.2 Hz, 1H), 4.79 (br.s, 1H), 4.51 (d, J = 9.0 Hz, 1H), 4.42 (t, J = 8.2 Hz, 1H), 3.89 – 3.83 (m, 1H), 3.76 – 3.70 (m, 1H), 2.77 (br.s, 1H), 0.85 (t, J = 7.1 Hz, 3H).

¹³C{¹H} NMR (150 MHz, CDCl₃) δ: 171.4, 137.7, 136.2, 129.1, 129.0, 128.8, 128.1, 128.0, 126.9, 95.3, 67.6, 64.2, 61.1, 53.8, 13.5.

(2R,3S,4R,5R)-Ethyl 4-Nitro-3,5-diphenylpyrrolidine-2-carboxylate (endo) 18b [16b]; yellow sticky oil, 48 mg, 28%

¹H NMR (600 MHz, CDCl₃) δ: 7.45 – 7.33 (m, 10H), 5.33 (dd, J = 3.8 Hz, J = 6.5 Hz, 1H), 4.96 (br.s, 1H), 4.37 – 4.25 (m, 2H), 4.24 (dd, J = 3.8 Hz, J = 7.5 Hz, 1H), 4.16 – 4.15 (m, 1H), 3.39 (br.s, 1H),1.29 (t, J = 7.5 Hz, 3H).

¹³C{¹H} NMR (150 MHz, CDCl₃) δ: 171.3, 138.7, 134.6, 129.3, 128.8, 128.1, 127.6, 126.5, 97.1, 67.8, 67.6, 61.7, 55.6, 14.1.

(2R,3S,4S,5R)-Methyl 4-Nitro-3,5-diphenylpyrrolidine-2-carboxylate (4-epi-endo) 16a [6]; yellow sticky oil, 4 mg, 2%

¹H NMR (600 MHz, CDCl₃) δ: 7.35 – 7.34 (m, 2H), 7.34 – 7.33 (m, 2H), 7.33 – 7.32 (m, 4H), 7.29 – 7.27 (m, 2H), 5.14 (dd, J = 3.7 Hz, J = 8.2 Hz, 1H), 5.07 (d, J = 3.7 Hz, 1H), 4.57 (d, J = 9.3 Hz, 1H), 3.91 (t, J = 8.2 Hz, 1H), 2.84 (br.s, 1H), 1.39 (s, 9H).

¹³C{¹H} NMR (150 MHz, CDCl₃) δ: 171.7, 140.2, 133.4, 129.0, 128.7, 128.4, 128.3, 126.8, 96.7, 82.2, 65.9, 64.1, 53.5, 27.9.

(2R,3R,4S,5R)-Tert-butyl 4-Nitro-3,5-diphenylpyrrolidine-2-carboxylate (exo) 17c [6]; yellow sticky oil, 72 mg, 42%

¹H NMR (600 MHz, CDCl₃) δ: 7.40 – 7.39 (m, 2H), 7.34 – 7.29 (m, 8H), 5.17 (t, J = 7.7 Hz, 1H), 4.75 (d, J = 6.7 Hz, 1H), 4.43 (d, J = 8.9 Hz, 1H), 4.35 – 4.32 (m, 1H), 2.74 (br.s, 1H), 1.08 (s, 9H).

¹³C{¹H} NMR (150 MHz, CDCl₃) δ: 170.0, 137.8, 137.2, 129.1, 128.9, 128.8, 128.4, 128.0, 126.9, 96.0, 81.9, 67.4, 64.6, 53.4, 27.4.

(2R,3S,4R,5R)-Tert-butyl 4-Nitro-3,5-diphenylpyrrolidine-2-carboxylate (endo) 18c [6]; yellow sticky oil, 51 mg, 30%

¹H NMR (600 MHz, CDCl₃) δ: 7.37 – 7.28 (m, 10H), 5.33 – 5.32 (m, 1H), 4.94 (br.s, 1H), 4.14 – 4.12 (m, 1H), 4.03 (br.s, 1H), 3.36 (br.s, 1H), 1.48 (s, 9H).

¹³C{¹H} NMR (150 MHz, CDCl₃) δ: 170.5, 138.8, 134.7, 129.2, 128.8, 128.7, 128.0, 127.6, 126.5, 97.1, 82.5, 68.2, 67.8, 56.1, 28.0.

5. Conclusions

In summary, the obtained ligands containing both arylphosphine or arylphosphinyl groups, an imine group, and an optically pure chiral aziridine ring proved to be efficient catalysts for the asymmetric [3+2]-cycloaddition reaction. The use of the aforementioned catalysts led to the formation of three products: 4-epi-endo 16, exo 17, and endo 18, of which products 4-epi-endo 16 and exo 17 typically were formed in enantiomerically enriched forms. Meanwhile, product endo 18 always forms as a racemic mixture. Compounds 17 and 18 were the products of a reaction occurring according to a concerted mechanism, whereas the formation of product 16 can be explained by the epimerization of product 18 under catalytic reaction conditions, which was confirmed by an independently conducted experiment. Differences in the quantity of the product formed during the epimerization process may result from steric hindrance present in different compounds.