Introduction

Pyrrolidine, as frequent structural motif in natural products, occupies significant place in organic, medicinal, and pharmaceutical chemistry [1,2,3,4]. It is widely present in biologically active molecules and pharmaceutical drug candidates, classifying pyrrolidine derivatives as a group of attractive synthetic targets. Consequently, these five-membered heterocycles are useful building blocks in the organic synthesis [5,6,7,8,9,10,11,12,13]. Pyrrolidine’s ring is a key structural fragment of l-proline and other organocatalysts derived from it [14,15,16,17]. Pyrrolidine-containing compounds also exert the broad spectrum of potential therapeutic properties like analgesic [18], antibacterial [19,20,21], antitumor [22], anti-inflammatory [23, 24], and enzyme inhibiting [25].

Over the past 3 decades, several synthetic routes toward pyrrolidine core were developed [26,27,28,29,30], and pathways based on [3 + 2] dipolar cycloadditions prevail as the most suitable and used [31]. The leading species employed for this purpose are azomethine ylides acting as dipoles. Wide range of dipolarophiles like α,β-unsaturated carboxylic derivatives [32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50], nitroalkenes [51,52,53,54,55,56,57], alkenylsulfones [58,59,60,61,62,63,64,65,66], enones [67,68,69,70], and allenes [71,72,73] were examined, concluding that the cycloadditions of alkenes have been extremely versatile and economical processes [74,75,76,77,78,79,80,81,82,83,84].

Our ongoing studies are directed toward enones comprising the exploration and the evaluation of their synthetic potential. Particularly, the focus is on the vinyl species and synthesis of novel compounds. In that context, we earlier reported several transformations of the ferrocene-containing enones, which resulted by the obtaining of numerous new compounds [85,86,87,88,89,90]. We also disclosed that vinyl ketones, despite their tendency toward polymerization, could provide easy access to aryltetrahydropyrazolo[1,2-a]pyrazol-1(5H)-ones through the cycloaddition with N,N′-cyclic azomethine imines [89,90,91].

Accordingly, the reaction between azomethine ylides and vinyl ketones was excellent platform for continuation of research. Although the [3 + 2] cycloadditions of azomethine ylides to systems containing conjugated vinyl and C=O groups were studied [27, 74, 92,93,94,95,96,97,98], the attention was not dedicated to ylides having alkyl substituent on the carbon C2 (between nitrogen and ester group, Scheme 1). We found only Grigg’s reports dealt with these dipoles [74, 93, 94]. In addition, the range of used vinyl α,β-unsaturated ketones is limited to but-3-en-2-one and series of chromenones utilized by Grigg [94]. Introducing of the acyl substituent into heterocyclic structure would increase the significance of the products as synthetic intermediates, since the transformability of carbonyl fragments provides multiply oriented approach to further derivatization. Bearing all previously mentioned in mind, we considered supplementing the field by the investigation of the reaction diversity and synthesis of new highly substituted pyrrolidine derivatives. Therefore, in this paper the dipolar cycloaddition between azomethine ylides and vinyl ketones is reported.

scheme 1

Results and discussion

The established route to the azomethine ylides includes a deprotonation of the imino ester obtained from carbonyl compound and ester of the amino acid, followed by coordination of the formed α-carbanion to metal ion [99]. Several metal salts proved to be useful, substantially influencing the stability of the ylide and stereoselectivity of the reaction [100]. Among them, silver acetate (AgOAc) is distinguished as the most efficient salt providing high yield of the one stereoisomer [32].

Our initial screening was oriented toward exploration of the potentially suitable solvents, catalysts, and bases. As a test reaction, the cycloaddition of but-3-en-2-one (1a) to azomethine ylide generated from methyl 2-(benzylideneamino)propanoate (2a) was selected (Table 1). At first, we screened solvents (Table 1, entries 2–10) among which the three—acetone, 1,4-dioxane, and acetonitrile provide high yields (Table 1, entries 2, 9, 10). However, we observed more than four products in acetone and 1,4-dioxane, unlike the products mixture in acetonitrile which contained only two diastereoisomers. Therefore, acetonitrile (MeCN) was considered as solvent of choice and we have continued initial investigation using it.

Table 1 Screening studies of 1,3-dipolar cycloaddition of azomethine ylide obtained from 2a to but-3-en-2-one (1a)
figure a
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In the next segment of research, 13 salts along with AgOAc were examined as catalysts and data collected by analysis of 1H NMR spectra of the crude reaction mixtures are inserted in Table 1 (entries 11–23). Only the Ag+ and Cu+ ions gave satisfactory results (Table 1, entries 2, 11, and 20), while all other examined metal cations were inactive, except Mn3+ which afforded products in yield of 18% (Table 1, entry 16). Furthermore, they expressed inhibiting activity, since the reaction took place in yield of 63% without the presence of salt (Table 1, entry 1). However, the procedures performed in the absence of metal cations suffered from low stereoselectivity. Surprisingly, Li+ ion failed to provide products (Table 1, entries 22 and 23), despite it was mentioned earlier as a good catalyst [99,100,101]. The attempts to alter the initially used base, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), with cheaper pyridine or triethylamine did not make any improvement (Table 1, entries 24 and 25), given that the reaction yields were particularly lower (65 and 29%, respectively). Therefore, we considered it was optimal to perform the further examinations in the presence of AgOAc and DBU.

The reaction between 1a and 2a might afford four products (3a, 4a, 5a, and 6a, see scheme in Table 1). The results collected during initial investigations agreed with our expectations. It was predicted that the one cycloadduct will be favorably formed, with respect that the reaction conditions should exclude 5a and 6a (products of the exo-cycloaddition) [101]. Indeed, after stirring the reaction mixture of 1a and 2a for 45 min (Table 2, entry 2) we detected the presence of two diastereoisomers by analysis of 1H NMR spectra of the crude reaction mixture. One, methyl 4-acetyl-2-methyl-5-phenylpyrrolidine-2-carboxylate (4a), was isolated by column chromatography (65%) and its structure was confirmed by spectroscopic methods. On the other hand, though the second diastereoisomer (3a) was spotted, we failed to isolate it.

Table 2 Substrate scope of reactions between vinyl ketones 1 and imino esters 2
Full size table

With these conditions in hand, we combined four enones (1a–1d) and 13 imino esters (2a–2m) intending to examine the scope of the reaction. The data are summarized in Table 2. Interestingly, all enones containing substituent R1 bigger than methyl (Table 2, entries 10–28) exclusively gave products with cis-orientation of aryl and acyl group. Contrary to these examples, methyl vinyl ketone afforded mixtures of pyrrolidines with dominant trans-substituted (at C4 and C5) derivative (Table 2, entries 1–9). All cycloadditions ran smoothly with good overall yields, enabling isolation of one, main diastereoisomer. The other cycloadducts were detected using NMR spectroscopy, but they were present in negligible small quantities which made their isolation rather hard and almost impossible. The exception was 2d which gave both successfully isolated diastereoisomers (3c and 4c), as well as 2e providing inseparable mixture of 3d and 4d.

The structural identification of the products was performed on the basis of their 1H NMR spectra. We observed significant differences in the area between 4.3 and 5.3 ppm. In this range of chemical shifts, signals originated from hydrogen bonded to C5 appeared as well-defined doublets. Although they were characterized by similar coupling constants (J = 7.2–9.4 Hz), their chemical shifts differed by about 1 ppm. The diastereoisomers with cis-orientation (3a, 3aa, 3c, 3d, 3h–3m, and 3o–3z) exhibited peaks at higher shifts (δ = 4.58–5.29 ppm), while trans-derivatives’ (4a–4f) signals appeared at somewhat lower values (δ = 4.39–4.73 ppm). The values of the coupling constants assigned to these stereoisomers were close, whereby the one attributed to the derivative with cis-oriented substituents was always higher (ca. 0.5–1.0 Hz). We also noticed different shapes of signals of diastereotopic protons C3-Ha and C3-Hb depicted on the Fig. 1. However, the key role in the assignment of the correct molecular structure had acetyl groups of 3a and 4a. We noticed that the aryl substituent strongly influenced acetyl group in 3a, shifting its singlet to values about 1.50 ppm. The magnetic anisotropy of aryl group was also spotted in 1H NMR spectra of 4a where C4-H moiety was detected at 3.11 ppm (instead of 3.42 ppm) and the peak of the alanine originated methyl group was moved from 1.60 to 1.50 ppm. The spatial arrangement of substituents in 3a and 4a, after all, were approved by observing their noticeable interactions in NOESY spectra. The anisotropy influence, as expected, was absent in 1H NMR spectra 34g and 34n, limiting structural identification of these two pyrrolidine derivatives.

Fig. 1
figure 1

1H NMR spectral differences of 3a and 4a; a1H NMR spectrum of 3a; b1H NMR spectrum of 4a

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The stereochemical outcome of the cycloadditions suggests that reaction has proceeded following the endo-mechanism. We proposed models for the intermediates. This is illustrated in Scheme 2, where the plausible reaction mechanism between 1a and 2a is presented. Azomethine ylide is capable to adopt W- or S-shaped conformation [101]. The presence of Ag+ ion (0.3 equiv), DBU (0.1 equiv), along with acetonitrile as solvent, favors formation of the W-shaped dipole, wherefore there was not possibility for reaction to follow the pathway B. We assume that cycloadduct 3a was formed primarily and easily underwent isomerization affording product 4a with trans-orientation of substituents at C4 and C5. To confirm the proceeding of the isomerization process, we submitted again 1a to the reaction with 2a in a significantly shorter period. To our surprise, overall reaction yield was satisfactory high after only 15 min (82%) with preferably formed cis-derivate 3a (3a/4a ratio was 66:34) which was isolated after usual work up (Table 2, entry 1). Otherwise, the reaction mixture after 3 h contained almost pure 4a (yield 65%). Epimerization of similar systems has already been reported [101, 102], but we observed that the spontaneous process occurs in cases when methyl vinyl ketone (1a) was reactant. Additionally, the reaction in shorter time (15 min) was performed employing 1a and 2b to give 3aa, also the product with cis-orientation of substituents (Table 2, entry 3).

scheme 2

Also, we monitored the reaction between 1a and 2a in CD3CN recording 1H NMR spectra. The results presented in Fig. 2 confirmed the isomerization process. At the beginning of the monitoring (Fig. 2, spectrum 1) doublet at ca. 4.35 ppm originated by C5-H from 4a was absent and it has become stronger with time (Fig. 2, spectra 31, 35, and 36). Simultaneously, signal assigned to 3a (doublet at ca. 4.65 ppm) remains almost unchanged.

Fig. 2
figure 2

1H NMR spectra of the monitored reaction between 1a and 2a in CD3CN

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In contrast to 1a, all other enones (1b–1d) predominantly gave products with cis-orientation of substituents at C4–C5 pyrolidine’s fragment. These products did not undergo isomerization, confirming the proposed endo-mechanism of the cycloaddition.

The mechanism of isomerization was also studied by A. Sarotti et al. [102] who proved that it takes place through retro-Mannich//Mannich cascade under acidic conditions. Following this pathway, we proposed intermediates which participate in epimerization processes of 3a and 3h. To gain insight, the calculations at DFT level of theory were performed in Gaussian 09 software [103], using B3LYP density functional theory method (6-31G basis set) for the diastereoisomers 3a, 3h, 4a, 4h, and corresponding intermediates I and II (Fig. 3). Both trans-derivatives 4a and 4h are characterized by lower free energy values. The free energy difference of I and 3a is 70.71 kJ/mol, while the same one in the case of II and 3h is 74.48 kJ/mol. This might be a significant difference, since it was not observed the epimerization of 3h.

Fig. 3
figure 3

Differences in free energy values for the diastereoisomers 3a, 3h, 4a, 4h, and corresponding intermediates I and II

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Conclusion

Vinyl ketones have been employed in the reaction with azomethine ylides providing easy access to the first time synthesized (2R)-methyl 4-acyl-5-aryl-2-methylpyrrolidine-2-carboxylates in a moderate chemical yields (up to 88%). Products were easily isolated as pure diastereoisomers. But-3-en-2-one (1a), as example of vinyl ketones which contains small group, predominantly afforded pure products 4a–4f, unlike other vinyl substrates those dominantly gave diastereoisomers 3h–3m, 3o–3z with the different orientation of substituents. Using quite simple and fast procedure, 28 pyrrolidine derivatives, which could be of interest for the studies of organocatalysis and bioactivity, were synthesized and isolated.

Experimental

All reagents were purchased from commercial suppliers (Sigma–Aldrich, Merck, Fluka) and used without further purification, except the solvents which were purified by distillation and dried. α-Imino esters 2 were prepared according to literature [101]. Enones 1c and 1d were prepared using synthetic strategy consisting of (1) Friedel–Crafts acylation with 3-chloropropanoyl chloride, and (2) dehydrohalogenation of the obtained chloroketones, which were carried out according to the literature procedures [104, 105]. Spectral characteristics of obtained enones agreed with literature data [106,107,108].

All reactions were monitored by thin-layer chromatography (TLC) on Silica gel 60 F254 precoated Al foils (200 μm layer thickness, Sigma–Aldrich). The spots on TLC were visualized by fluorescence quenching with UV light at 254 nm and I2, when necessary. Column chromatography was performed using silica gel 0.060–0.200 mm, 60 A (Acros Organics).

Infrared spectra were recorded using a Perkin-Elmer Spectrum One FT-IR spectrometer. 1H and 13C NMR spectra were recorded in CDCl3 on Varian Gemini 2000 as indicated. Chemical shifts (δ, ppm) are relative to tetramethylsilane (TMS) with the resonance of the undeuterated solvent or TMS as internal standard. 1H NMR data are reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, dd = doublet of doublets, ddd = doublet of doublets of doublets, t = triplet, q = quartet, dq = doublet of quartets, m = multiplet), coupling constants (J, Hz), integration, and assignation. Data for 13C NMR spectra are presented in terms of chemical shifts. Microanalyses of carbon, hydrogen, and nitrogen were carried out with a Carlo Erba 1106 microanalyzer; these results agreed favorably with the calculated values.

General procedure for the syntheses of α-imino esters

The α-imino esters 2 were prepared by a slight modification of the reported procedure [101]. Anhydrous sodium sulfate (284 mg, 2 mmol, 2 equiv.) and 111 mg Et3N (1.1 mmol, 1.1 equiv.) were added to the solution of the methyl/ethyl ester hydrochloride of the l-alanine (154/168 mg, 1.1 mmol, 1.1 equiv.) in 5 cm3 anhydrous dichloromethane. The suspension was stirred at room temperature for 1 h, and the corresponding aldehyde (benzaldehyde, p-methoxybenzaldehyde, o-methoxybenzaldehyde, m-methoxybenzaldehyde, p-chlorobenzaldehyde, p-tolylaldehyde, o-tolylaldehyde, cyclohexanecarbaldehyde, 1-naphtylaldehyde, or 2-naphtylaldehyde, 1 mmol, 1 equiv.) was added. The mixture was stirred overnight and then sodium sulfate was filtered off. The organic solution was washed with aq. NaHCO3, dried (Na2SO4 anh.), and concentrated in vacuo to afford the crude α-imino esters 2; these were used for the cycloaddition reactions without further purification.

General procedure for the syntheses of enones

The enones 1c and 1d were synthesized by the following procedure: a mixture of 700 mg 3-chloropropanoyl chloride (5.5 mmol, 1.1 equiv.) and 801 mg AlCl3 (6 mmol, 1.2 equiv.) in 40 cm3 dichloromethane was cooled to 0 °C. An aromatic compound (toluene or thiophene, 5 mmol, 1 equiv.) was added dropwise and the mixture was left to stir overnight at ambient temperature. The reaction mixture was poured out into an ice water, extracted with dichloromethane, and dried over anhydrous Na2SO4. The solvent was then removed by distillation and the crude product was diluted with 20 cm3 diethyl ether and 2 cm3 triethylamine. This mixture was stirred at room temperature for 60 h, afterwards extracted with diethyl ether and dried (Na2SO4 anh.). Evaporation of the solvent afforded the crude enones 1c and 1d, which was used in further reactions without purification.

General procedure for the [3 + 2] cycloaddition reactions

In a 10 cm3 flask, the corresponding enone (1.1 mmol, 1.1 equiv.) and the α-imino ester (1 mmol, 1 equiv.) were dissolved in the anhydrous acetonitrile to afford a final α-imino ester’s concentration of 0.5 M. In the absence of light, 52 mg silver acetate (0.3 mmol, 0.3 equiv.) and 15 mg DBU (0.1 mmol, 0.1 equiv.) were added. The mixture was stirred at room temperature for 45 min and afterwards the precipitated silver acetate was filtered off and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, n–hexane:ethyl acetate = 4:1). The purity of the products was checked by TLC (20%, v:v, ethyl acetate in n-hexane), 1H and 13C NMR spectroscopy, and elemental analyses.

Methyl (2R,4R,5S)-4-acetyl-2-methyl-5-phenylpyrrolidine-2-carboxylate (3a, C15H19NO3)

Pale yellow liquid; 67 mg, yield 51%; Rf = 0.4 (n-Hex : EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.38–7.15 (m, 5H, Ph), 4.64 (d, J = 8.9 Hz, 1H, C5-H), 3.76 (s, 3H, RCOOMe), 3.42 (ddd, J = 8.9, 7.9, 7.2 Hz, 1H, C4-H), 2.76 (bs, 1H, N–H), 2.44 (dd, J = 13.4, 7.9 Hz, 1H, C3-Ha), 2.28 (dd, J = 13.4, 7.2 Hz, 1H, C3-Hb), 1.60 (s, 3H, C2-Me), 1.52 (s, 3H, MeCOR) ppm; 13C NMR (50 MHz, CDCl3): δ = 208.1, 177.7, 140.1, 128.4, 127.8, 127.5, 65.5, 64.0, 56.6, 52.5, 37.7, 30.8, 25.5 ppm; IR (neat): \(\bar{\nu }\) = 3322, 3041, 2980, 1725, 1704, 1459, 1193, 1160, 851, 713 cm−1.

Methyl (2R,4R,5R)-4-acetyl-2-methyl-5-phenylpyrrolidine-2-carboxylate (4a, C15H19NO3)

Pale yellow liquid; 85 mg, yield 65%; Rf = 0.4 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.49–7.24 (m, 5H, Ph), 4.41 (d, J = 8.3 Hz, 1H, C5-H), 3.76 (s, 3H, RCOOMe), 3.11 (ddd, J = 9.9, 8.3, 6.9 Hz, 1H, C4-H), 2.76 (bs, 1H, N–H), 2.63 (dd, J = 13.2, 6.9 Hz, 1H, C3-Ha), 2.12 (dd, J = 13.2, 9.9 Hz, 1H, C3-Hb), 1.98 (s, 3H, MeCOR), 1.50 (s, 3H, C2-Me) ppm; 13C NMR (50 MHz, CDCl3): δ = 207.5, 177.2, 142.4, 128.4, 127.5, 127.0, 65.2, 64.1, 59.5, 52.4, 38.8, 30.1, 26.9 ppm; IR (neat): \(\bar{\nu }\) = 3345, 3028, 2952, 1731, 1713, 1456, 1361, 1266, 1176, 1106, 702 cm−1.

Ethyl (2R,4R,5S)-4-acetyl-2-methyl-5-phenylpyrrolidine-2-carboxylate (3aa, C16H21NO3)

Pale yellow liquid; 76 mg, yield 59%; Rf = 0.5 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.38–7.16 (m, 5H, Ph), 4.63 (d, J = 9.0 Hz, 1H, C5-H), 4.21 (q, J = 7.1 Hz, 2H, RCOOCH2CH3), 3.40 (ddd, J = 9.0, 8.0, 7.3 Hz, 1H, C4-H), 2.68 (bs, 1H, N–H), 2.44 (dd, J = 13.3, 8.0 Hz, 1H, C3-Ha), 2.27 (dd, J = 13.3, 7.3 Hz, 1H, C3-Hb), 1.59 (s, 3H, C2-Me), 1.52 (s, 3H, MeCOR), 1.29 (t, J = 7.1 Hz, 3H, RCOOCH2CH3) ppm; 13C NMR (50 MHz, CDCl3): δ = 208.1, 177.3, 140.3, 128.5, 128.3, 127.7, 127.5, 127.1, 65.4, 63.9, 61.3, 56.6, 37.5, 30.7, 25.4, 14.4 ppm; IR (neat): \(\bar{\nu }\) = 3351, 3031, 2978, 1724, 1456, 1371, 1265, 1184, 1106, 1022, 702 cm−1.

Methyl (2R,4R,5R)-4-acetyl-5-(4-chlorophenyl)-2-methylpyrrolidine-2-carboxylate (4b, C15H18ClNO3)

Pale yellow liquid; 78 mg, yield 63%; Rf = 0.5 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.44–7.34 (m, 2H, p-ClPh), 7.32–7.24 (m, 2H, p-ClPh), 4.41 (d, J = 8.1 Hz, 1H, C5-H), 3.75 (s, 3H, RCOOMe), 3.13–2.91 (m, 1H, C4-H), 2.82 (bs, 1H, N–H), 2.58 (dd, J = 13.2, 6.9 Hz, 1H, C3-Ha), 2.12 (dd, J = 13.2, 9.9 Hz, 1H, C3-Hb), 2.00 (s, 3H, MeCOR), 1.49 (s, 3H, C2-Me) ppm; 13C NMR (50 MHz, CDCl3): δ = 207.4, 177.3, 141.6, 133.1, 128.6, 128.4, 65.1, 63.1, 59.8, 52.5, 39.0, 30.1, 27.1 ppm; IR (neat): \(\bar{\nu }\) = 3339, 2954, 1730, 1713, 1490, 1361, 1267, 1176, 1103, 1015, 831 cm−1.

Methyl (2R,4R,5S)-4-acetyl-5-(2-methoxyphenyl)-2-methylpyrrolidine-2-carboxylate (3c, C16H21NO4)

Pale yellow liquid; 39 mg, yield 55%; Rf = 0.2 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.41 (dd, J = 7.5, 1.2 Hz, 1H, o-MeOPh), 7.27–7.17 (m, 1H, o-MeOPh), 6.92 (t, J = 7.5 Hz, 1H, o-MeOPh), 6.83 (d, J = 8.2 Hz, 1H, o-MeOPh), 4.81 (d, J = 8.2 Hz, 1H, C5-H), 3.84 (s, 3H, o-MeOPh), 3.76 (s, 3H, RCOOMe), 3.58 (ddd, J = 8.3, 8.2, 5.9 Hz, 1H, C4-H), 2.68 (bs, 1H, N–H), 2.50 (dd, J = 13.4, 8.3 Hz, 1H, C3-Ha), 2.19 (dd, J = 13.4, 5.9 Hz, 1H, C3-Hb), 1.62 (s, 3H, C2-Me), 1.58 (s, 3H, MeCOR) ppm; 13C NMR (50 MHz, CDCl3): δ = 208.9, 177.8, 156.5, 128.5, 127.8, 127.6, 120.8, 110.0, 65.3, 58.6, 55.3, 54.7, 52.5, 38.3, 30.2, 25.6 ppm; IR (neat): \(\bar{\nu }\) = 3334, 2953, 2838, 1728, 1601, 1490, 1463, 1244, 1162, 1110, 758 cm−1.

Methyl (2R,4R,5R)-4-acetyl-5-(2-methoxyphenyl)-2-methylpyrrolidine-2-carboxylate (4c, C16H21NO4)

Pale yellow liquid; 33 mg, yield 68%; Rf = 0.1 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.62 (dd, J = 7.5, 1.4 Hz, 1H, o-MeOPh), 7.24 (dt, J = 8.0, 1.9 Hz, 1H, o-MeOPh), 6.96 (td, J = 7.5, 0.9 Hz, 1H, o-MeOPh), 6.84 (d, J = 8.0 Hz, 1H, o-MeOPh), 4.73 (d, J = 7.2 Hz, 1H, C5-H), 3.77 (s, 6H, o-MeOPh, RCOOMe), 3.09 (ddd, J = 9.6, 7.2, 5.7 Hz, 1H, C4-H), 2.86 (bs, 1H, N–H), 2.61 (dd, J = 13.2, 5.7 Hz, 1H, C3-Ha), 2.08 (s, 3H, MeCOR), 2.03 (dd, J = 13.2, 9.6 Hz, 1H, C3-Hb), 1.50 (s, 3H, C2-Me) ppm; 13C NMR (50 MHz, CDCl3): δ = 208.3, 177.5, 156.7, 131.1, 128.3, 127.5, 120.8, 110.3, 65.8, 59.3, 58.1, 55.1, 52.6, 39.2, 29.4, 27.1 ppm; IR (neat): \(\bar{\nu }\) = 3361, 2952, 1731, 1489, 1464, 1362, 1244, 757 cm−1.

Methyl (2R,4R)-4-acetyl-5-(4-methoxyphenyl)-2-methylpyrrolidine-2-carboxylate (3d, 4d, C16H21NO4)

Pale yellow liquid; 93 mg, yield 64%; Rf = 0.4 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3) cis: δ = 7.25–7.18 (m, 2H, p-MeOPh), 6.84–6.78 (m, 2H, p-MeOPh), 4.59 (d, J = 9.0 Hz, 1H, C5-H), 3.79 (s, 3H, p-MeOPh), 3.76 (s, 3H, RCOOMe), 3.38 (ddd, J = 9.0, 8.0, 7.5 Hz, 1H, C4-H), 2.85 (bs, 1H, N–H), 2.41 (dd, J = 13.4, 8.0 Hz, 1H, C3-Ha), 2.27 (dd, J = 13.4, 7.5 Hz, 1H, C3-Hb), 1.58 (s, 3H, C2-Me), 1.55 (s, 3H, MeCOR); trans: δ = 7.40–7.32 (m, 2H, p-MeOPh), 6.91–6.84 (m, 2H, p-MeOPh), 4.32 (d, J = 8.5 Hz, 1H, C5-H), 3.77 (s, 3H, p-MeOPh), 3.75 (s, 3H, RCOOMe), 3.17–3.00 (m, 1H, C4-H), 2.85 (bs, 1H, N–H), 2.63 (dd, J = 13.3, 7.1 Hz, 1H, C3-Ha), 2.10 (dd, J = 13.3, 9.8 Hz, 1H, C3-Hb), 1.96 (s, 3H, MeCOR), 1.49 (s, 3H, C2-Me) ppm; 13C NMR (50 MHz, CDCl3): δ = 208.4, 207.8, 177.8, 177.4, 159.2, 159.1, 134.3, 132.2, 128.6, 128.3, 113.9, 113.8, 65.4, 65.1, 64.1, 63.4, 59.6, 56.6, 55.4, 55.3, 52.6, 52.5, 38.9, 37.6, 31.0, 30.3, 27.1, 25.5 ppm.

Methyl (2R,4R,5R)-4-acetyl-5-(3-methoxyphenyl)-2-methylpyrrolidine-2-carboxylate (4e, C16H21NO4)

Pale yellow liquid; 48 mg, yield 67%; Rf = 0.3 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.22 (d, J = 7.8, Hz, 1H, m-MeOPh), 7.09–6.95 (m, 2H, m-MeOPh), 6.84–6.75 (m, 1H, m-MeOPh), 4.39 (d, J = 8.1 Hz, 1H, C5-H), 3.81 (s, 3H, m-MeOPh), 3.76 (s, 3H, RCOOMe), 3.16–3.01 (m, 1H, C4-H), 2.64 (bs, 1H, N–H), 2.62 (dd, J = 13.2, 6.7 Hz, 1H, C3-Ha), 2.10 (dd, J = 13.2, 9.9 Hz, 1H, C3-Hb), 2.00 (s, 3H, MeCOR), 1.50 (s, 3H, C2-Me) ppm; 13C NMR (50 MHz, CDCl3): δ = 207.7, 177.5, 159.9, 144.7, 129.5, 119.4, 113.1, 112.7, 65.3, 64.1, 59.8, 55.4, 52.6, 39.1, 30.2, 27.1 ppm; IR (neat): \(\bar{\nu }\) = 3336, 2953, 2838, 1732, 1713, 1601, 1488, 1456, 1436, 1265, 1166, 1107, 1045, 785 cm−1.

Methyl (2R,4R,5R)-4-acetyl-2-methyl-5-(naphthalen-2-yl)-pyrrolidine-2-carboxylate (4f, C19H21NO3)

Pale yellow liquid; 63 mg, yield 68%; Rf = 0.4 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.88–7.73 (m, 4H, Nph), 7.58 (dd, J = 8.6, 1.7 Hz, 1H, Nph), 7.50–7.40 (m, 2H, Nph), 4.58 (d, J = 8.2 Hz, 1H, C5-H), 3.77 (s, 3H, RCOOMe), 3.18 (ddd, J = 9.8, 8.2, 6.9 Hz, 1H, C4-H), 2.94 (bs, 1H, N–H), 2.67 (dd, J = 13.2, 6.9 Hz, 1H, C3-Ha), 2.15 (dd, J = 13.2, 9.8 Hz, 1H, C3-Hb), 1.96 (s, 3H, MeCOR), 1.53 (s, 3H, C2-Me) ppm; 13C NMR (50 MHz, CDCl3): δ = 207.7, 177.5, 140.2, 133.4, 133.2, 128.4, 127.9, 127.7, 126.1, 126.0, 125.8, 125.0, 65.4, 64.4, 59.6, 52.6, 39.1, 30.3, 27.1 ppm; IR (neat): \(\bar{\nu }\) = 3342, 3058, 2951, 1729, 1712, 1361, 1268, 1194, 1169, 1105, 860, 820, 751 cm−1.

Methyl 4-acetyl-5-cyclohexyl-2-methylpyrrolidine-2-carboxylate (34g, C15H25NO3)

Pale yellow liquid; 70 mg, yield 62%; Rf = 0.5 (n-Hex:EtOAc = 4:1, v/v, I2); 1H NMR (200 MHz, CDCl3): δ = 3.73 (s, 3H, RCOOMe), 3.11 (ddd, J = 9.0, 6.7, 4.1 Hz, 1H, C4-H), 2.92 (dd, J = 9.1, 6.7 Hz, 1H, C5-H), 2.55 (dd, J = 14.0, 9.0 Hz, 1H, C3-Ha), 2.49 (bs, 1H, N–H), 2.24 (s, 3H, MeCOR), 1.96–1.53 (m, 5H), 1.82 (dd, J = 14.0, 4.1 Hz, 1H, C3-Hb), 1.49 (s, 3H, C2-Me), 1.46–0.85 (m, 5H) ppm; 13C NMR (50 MHz, CDCl3): δ = 211.1, 177.7, 68.1, 65.3, 53.0, 52.5, 39.5, 39.0, 31.2, 31.08, 31.06, 26.4, 25.9, 25.8, 25.7 ppm; IR (neat): \(\bar{\nu }\) = 3361, 2926, 2852, 1732, 1700, 1450, 1354, 1192, 1160, 1105 cm−1.

Methyl (2R,4R,5S)-2-methyl-5-phenyl-4-propionylpyrrolidine-2-carboxylate (3h, C16H21NO3)

Pale yellow liquid; 100 mg, yield 73%; Rf = 0.5 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.42–7.15 (m, 5H, Ph), 4.62 (d, J = 8.8 Hz, 1H, C5-H), 3.76 (s, 3H, RCOOMe), 3.42 (ddd, J = 8.8, 8.0, 7.1 Hz, 1H, C4-H), 2.73 (bs, 1H, N–H), 2.43 (dd, J = 13.3, 8.0 Hz, 1H, C3-Ha), 2.29 (dd, J = 13.3, 7.1 Hz, 1H, C3-Hb), 1.92 (dq, J = 18.0, 7.2 Hz, 1H, CH3CH2COR), 1.72 (dq, J = 18.0, 7.2 Hz, 1H, CH3CH2COR), 1.61 (s, 3H, C2-Me), 0.51 (t, J = 7.2 Hz, 3H, CH3CH2COR) ppm; 13C NMR (50 MHz, CDCl3): δ = 210.6, 177.6, 139.8, 128.1, 127.5, 127.4, 65.4, 64.1, 55.5, 52.3, 37.7, 37.0, 25.2, 7.0 ppm; IR (neat): \(\bar{\nu }\) = 3333, 3031, 2973, 1728, 1705, 1449, 1273, 1114, 756 cm−1.

Methyl (2R,4R,5S)-2-methyl-4-propionyl-5-(p-tolyl)pyrrolidine-2-carboxylate (3i, C17H23NO3)

Pale yellow liquid; 117 mg, yield 82%; Rf = 0.5 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.21–7.02 (m, 4H, p-MePh), 4.58 (d, J = 8.8 Hz, 1H, C5-H), 3.75 (s, 3H, RCOOMe), 3.40 (ddd, J = 8.8, 7.8, 7.2 Hz, 1H, C4-H), 2.69 (bs, 1H, N–H), 2.42 (dd, J = 13.3, 7.8 Hz, 1H, C3-Ha), 2.30 (s, 3H, p-MePh), 2.29 (dd, J = 13.3, 7.2 Hz, 1H, C3-Hb), 1.93 (dq, J = 17.9, 7.2 Hz, 1H, CH3CH2COR), 1.73 (dq, J = 17.9, 7.2 Hz, 1H, CH3CH2COR), 1.60 (s, 3H, C2-Me), 0.54 (t, J = 7.2 Hz, 3H, CH3CH2COR) ppm; 13C NMR (50 MHz, CDCl3): δ = 210.8, 177.7, 137.1, 136.8, 128.8, 127.2, 65.4, 64.0, 55.6, 52.3, 37.7, 37.1, 25.2, 21.0, 7.1 ppm; IR (neat): \(\bar{\nu }\) = 3335, 2976, 2951, 1729, 1458, 1267, 1194, 1111, 817 cm−1.

Methyl (2R,4R,5S)-5-(4-chlorophenyl)-2-methyl-4-propionylpyrrolidine-2-carboxylate (3j, C16H20ClNO3)

Pale yellow liquid; 93 mg, yield 64%; Rf = 0.4 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.42–7.11 (m, 4H, p-ClPh), 4.59 (d, J = 9.0 Hz, 1H, C5-H), 3.75 (s, 3H, RCOOMe), 3.40 (ddd, J = 9.0, 8.0, 7.5 Hz, 1H, C4-H), 2.82 (bs, 1H, N–H), 2.41 (dd, J = 13.4, 8.0 Hz, 1H, C3-Ha), 2.28 (dd, J = 13.4, 7.5 Hz, 1H, C3-Hb), 1.96 (dq, J = 18.3, 7.2 Hz, 1H, CH3CH2COR), 1.75 (dq, J = 18.3, 7.2 Hz, 1H, CH3CH2COR), 1.59 (s, 3H, C2-Me), 0.56 (t, J = 7.2 Hz, 3H, CH3CH2COR) ppm; 13C NMR (50 MHz, CDCl3): δ = 210.2, 177.6, 138.7, 133.2, 128.9, 128.3, 65.4, 63.2, 55.2, 52.4, 37.6, 37.3, 25.2, 7.1 ppm; IR (neat): \(\bar{\nu }\) = 3342, 2975, 2952, 1729, 1490, 1273, 1195, 1110, 1015 cm−1.

Methyl (2R,4R,5S)-5-(4-methoxyphenyl)-2-methyl-4-propionylpyrrolidine-2-carboxylate (3k, C17H23NO4)

Pale yellow liquid; 102 mg, yield 67%; Rf = 0.2 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.25–7.08 (m, 2H, p-MeOPh), 6.90–6.75 (m, 2H, p-MeOPh), 4.58 (d, J = 8.9 Hz, 1H, C5-H), 3.77 (s, 3H, p-MeOPh), 3.76 (s, 3H, RCOOMe), 3.42 (ddd, J = 8.9, 7.9, 7.2 Hz, 1H, C4-H), 2.41 (dd, J = 13.4, 7.9 Hz, 1H, C3-Ha), 2.29 (dd, J = 13.4, 7.2 Hz, 1H, C3-Hb), 1.95 (dq, J = 18.2, 7.2 Hz, 1H, CH3CH2COR), 1.74 (dq, J = 18.2, 7.2 Hz, 1H, CH3CH2COR), 1.60 (s, 3H, C2-Me), 0.56 (t, J = 7.2 Hz, 3H, CH3CH2COR) ppm; 13C NMR (50 MHz, CDCl3): δ = 210.8, 177.6, 158.9, 131.8, 128.5, 113.6, 65.4, 63.6, 55.4, 55.2, 52.3, 37.6, 37.2, 25.2, 7.2 ppm; IR (neat): \(\bar{\nu }\) = 3342, 2973, 2954, 1728, 1610, 1512, 1248, 1180, 1111 cm−1.

Methyl (2R,4R,5S)-2-methyl-5-(naphthalen-1-yl)-4-propionylpyrrolidine-2-carboxylate (3l, C20H23NO3)

Pale yellow liquid; 64 mg, yield 88%; Rf = 0.5 (n-Hex: EtOAc = 4:1, v/v);1H NMR (200 MHz, CDCl3): δ = 8.08 (d, J = 7.9 Hz, 1H, Nph), 7.90–7.35 (m, 6H, Nph), 5.29 (d, J = 7.7 Hz, 1H, C5-H), 3.78 (s, 3H, RCOOMe), 3.70 (ddd, J = 8.2, 7.7, 4.5 Hz, 1H, C4-H), 2.74 (bs, 1H, N–H), 2.61 (dd, J = 13.5, 8.2 Hz, 1H, C3-Ha), 2.32 (dd, J = 13.5, 4.5 Hz, 1H, C3-Hb), 1.80 - 1.51 (m, 1H, CH3CH2COR), 1.70 (s, 3H, C2-Me), 2.21 (dq, J = 18.0, 7.2 Hz, 1H, CH3CH2COR), 0.27 (t, J = 7.2 Hz, 3H, CH3CH2COR) ppm; 13C NMR (50 MHz, CDCl3): δ = 211.4, 178.1, 134.6, 133.6, 131.1, 129.1, 128.0, 126.3, 125.6 (2C), 124.4, 122.7, 65.0, 60.6, 54.6, 52.6, 38.4, 36.7, 25.7, 7.0 ppm; IR (neat): \(\bar{\nu }\) = 3332, 3052, 2974, 2937, 1728, 1457, 1270, 1195, 1111, 802, 778 cm−1.

Methyl (2R,4R,5S)-2-methyl-5-(naphthalen-2-yl)-4-propionylpyrrolidine-2-carboxylate (3m, C20H23NO3)

Pale yellow liquid; 51 mg, yield 60%; Rf = 0.4 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.84–7.72 (m, 4H, Nph), 7.49–7.41 (m, 2H, Nph), 7.38 (dd, J = 8.7, 1.2 Hz, 1H, Nph), 4.79 (d, J = 8.7 Hz, 1H, C5-H), 3.78 (s, 3H, RCOOMe), 3.50 (ddd, J = 8.7, 7.9, 6.9 Hz, 1H, C4-H), 2.82 (bs, 1H, N–H), 2.49 (dd, J = 13.4, 7.9 Hz, 1H, C3-Ha), 2.36 (dd, J = 13.4, 6.9 Hz, 1H, C3-Hb), 1.92 (dq, J = 18.0, 7.2 Hz, 1H, CH3CH2COR), 1.68 (dq, J = 18.0, 7.2 Hz, 1H, CH3CH2COR), 1.66 (s, 3H, C2-Me), 0.41 (t, J = 7.2 Hz, 3H, CH3CH2COR) ppm; 13C NMR (50 MHz, CDCl3): δ = 210.8, 177.8, 137.4, 133.2, 133.0, 128.1, 128.0, 127.7, 126.3, 126.2, 125.9, 125.7, 65.8, 64.6, 55.7, 52.6, 38.1, 37.3, 25.4, 7.3 ppm; IR (neat): \(\bar{\nu }\) = 3460, 3059, 2976, 1728, 1458, 1270, 1193, 1112, 859, 821, 751 cm−1.

Methyl 5-cyclohexyl-2-methyl-4-propionylpyrrolidine-2-carboxylate (34n, C16H27NO3)

Pale yellow liquid; 115 mg, yield 82%; Rf = 0.4 (n-Hex:EtOAc = 4:1, v/v, I2); 1H NMR (200 MHz, CDCl3): δ = 3.72 (s, 3H, RCOOMe), 3.15 (ddd, J = 8.7, 6.5, 4.1 Hz, 1H, C4-H), 2.93 (dd, J = 9.0, 6.5 Hz, 1H, C5-H), 2.54 (q, J = 7.2 Hz, 2H, CH3CH2COR), 2.52 (dd, J = 13.7, 8.7 Hz, 1H, C3-Ha), 2.46 (bs, 1H, N–H), 1.97 - 1.52 (m, 5H), 1.80 (dd, J = 13.7, 4.1 Hz, 1H, C3-Hb), 1.49 (s, 3H, C2-Me), 1.46–0.86 (m, 6H), 1.05 (t, J = 7.2 Hz, 3H, CH3CH2COR) ppm; 13C NMR (50 MHz, CDCl3): δ = 213.8, 177.7, 68.5, 65.5, 52.4, 52.1, 40.2, 39.0, 37.2, 31.4, 31.0, 26.4, 26.0, 25.8, 25.5, 7.9 ppm; IR (neat): \(\bar{\nu }\) = 3363, 2926, 2852, 1732, 1700, 1449, 1267, 1196, 1107 cm−1.

Methyl (2R,4R,5S)-5-(2-methoxyphenyl)-2-methyl-4-propionylpyrrolidine-2-carboxylate (3o, C17H23NO4)

Pale yellow liquid; 76 mg, yield 58%; Rf = 0.2 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.36 (dd, J = 7.7, 1.5 Hz, 1H, o-MeOPh), 7.20 (td, J = 7.9, 1.5 Hz, 1H, o-MeOPh), 6.89 (t, J = 7.9 Hz, 1H, o-MeOPh), 6.81 (d, J = 8.2 Hz, 1H, o-MeOPh), 4.79 (d, J = 8.2 Hz, 1H, C5-H), 3.84 (s, 3H, o-MeOPh), 3.75 (s, 3H, RCOOMe), 3.57 (ddd, J = 8.3, 8.2, 5.6 Hz, 1H, C4-H), 2.61 (bs, 1H, N–H), 2.49 (dd, J = 13.4, 8.3 Hz, 1H, C3-Ha), 2.18 (dd, J = 13.4, 5.6 Hz, 1H, C3-Hb), 1.97 (dq, J = 17.9, 7.3 Hz, 1H, CH3CH2COR), 1.79 (dq, J = 17.9, 7.3 Hz, 1H, CH3CH2COR), 1.63 (s, 3H, C2-Me), 0.50 (t, J = 7.2 Hz, 3H, CH3CH2COR) ppm; 13C NMR (50 MHz, CDCl3): δ = 211.7, 177.9, 156.4, 128.2, 127.7, 127.5, 120.6, 109.8, 65.3, 58.6, 55.2, 53.7, 52.4, 38.4, 36.5, 25.5, 7.2 ppm; IR (neat): \(\bar{\nu }\) = 3426, 2972, 2941, 1728, 1490, 1463, 1243, 1113, 757 cm−1.

Methyl (2R,4R,5S)-5-(3-methoxyphenyl)-2-methyl-4-propionylpyrrolidine-2-carboxylate (3p, C17H23NO4)

Pale yellow liquid; 45 mg, yield 64%; Rf = 0.3 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.19 (d, J = 8.0, Hz, 1H, m-MeOPh), 6.90–6.81 (m, 2H, m-MeOPh), 6.80–6.72 (m, 1H, m-MeOPh), 4.58 (d, J = 8.8 Hz, 1H, C5-H), 3.78 (s, 3H, o-MeOPh), 3.75 (s, 3H, RCOOMe), 3.39 (ddd, J = 8.8, 7.8, 6.9 Hz, 1H, C4-H), 2.63 (bs, 1H, N–H), 2.42 (dd, J = 13.4, 7.8 Hz, 1H, C3-Ha), 2.28 (dd, J = 13.4, 6.9 Hz, 1H, C3-Hb), 1.94 (dq, J = 17.8, 7.1 Hz, 1H, CH3CH2COR), 1.75 (dq, J = 17.8, 7.2 Hz, 1H, CH3CH2COR), 1.61 (s, 3H, C2-Me), 0.57 (t, J = 7.2 Hz, 3H, CH3CH2COR) ppm; 13C NMR (50 MHz, CDCl3): δ = 210.7, 177.8, 159.7, 141.8, 129.3, 119.9, 113.4, 113.1, 65.6, 64.3, 55.7, 55.4, 52.5, 37.8, 37.2, 25.4, 7.4 ppm; IR (neat): \(\bar{\nu }\) = 3345, 2972, 2941, 1729, 1601, 1488, 1457, 1271, 1046, 786, 704 cm−1.

Ethyl (2R,4R,5S)-2-methyl-4-propionyl-5-(o-tolyl)pyrrolidine-2-carboxylate (3q, C18H25NO3)

Pale yellow liquid; 54 mg, yield 69%; Rf = 0.5 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.52–7.38 (m, 1H, o-MePh), 7.20–7.04 (m, 3H, o-MePh), 4.68 (d, J = 8.2 Hz, 1H, C5-H), 4.21 (q, J = 7.1 Hz, 2H, RCOOCH2CH3), 3.43 (ddd, J = 8.3, 8.2, 5.3 Hz, 1H, C4-H), 2.56 (bs, 1H, N–H), 2.51 (dd, J = 13.5, 8.3 Hz, 1H, C3-Ha), 2.37 (s, 3H, o-MePh), 2.26 (dd, J = 13.5, 5.3 Hz, 1H, C3-Hb), 1.92 (dq, J = 17.6, 7.2 Hz, 1H, CH3CH2COR), 1.63 (s, 3H, C2-Me), 1.57 (dq, J = 17.6, 7.2 Hz, 1H, CH3CH2COR), 1.29 (t, J = 7.1 Hz, 3H, RCOOCH2CH3), 0.47 (t, J = 7.2 Hz, 3H, CH3CH2COR) ppm; 13C NMR (50 MHz, CDCl3): δ = 211.1, 177.4, 137.5, 135.2, 130.2, 127.3, 126.6, 126.2, 65.0, 61.3, 60.7, 53.8, 37.9, 36.3, 25.6, 19.7, 14.4, 7.2 ppm; IR (neat): \(\bar{\nu }\) = 3338, 2977, 2938, 1719, 1461, 1374, 1267, 1187, 1108, 761 cm−1.

Methyl (2R,4R,5S)-2-methyl-4-(4-methylbenzoyl)-5-phenylpyrrolidine-2-carboxylate (3r, C21H23NO3)

Pale yellow liquid; 103 mg, yield 66%; Rf = 0.4 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.55–7.40 (m, 2H, p-MePh), 7.15–6.89 (m, 7H, Ph, p-MePh), 4.80 (d, J = 8.8 Hz, 1H, C5-H), 4.28 (pseudo q, J = 8.6 Hz, 1H, C4-H), 3.78 (s, 3H, RCOOMe), 2.87 (bs, 1H, N–H), 2.62–2.40 (m, 2H, C3-Ha, C3-Hb), 2.30 (s, 3H, p-MePh), 1.66 (s, 3H, C2-Me) ppm; 13C NMR (50 MHz, CDCl3): δ = 199.0, 177.9, 143.2, 140.3, 135.3, 128.8, 128.2, 127.8, 127.6, 127.1, 65.8, 64.8, 52.5, 50.7, 38.4, 25.3, 21.6 ppm; IR (neat): \(\bar{\nu }\) = 3347, 3029, 2948, 2924, 1719, 1671, 1607, 1455, 1256, 1194, 1161 cm−1.

Methyl (2R,4R,5S)-5-(2-methoxyphenyl)-2-methyl-4-(4-methylbenzoyl)pyrrolidine-2-carboxylate (3s, C22H25NO4)

Pale yellow liquid; 59 mg, yield 81%; Rf = 0.3 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.46 (d, J = 8.0 Hz, 2H, p-MePh), 7.32 (dd, J = 7.7, 1.8 Hz, 1H, o-MeOPh), 7.01 (d, J = 8.1 Hz, 2H, p-MePh), 7.02–6.91 (m, 1H, o-MeOPh), 6.83–6.72 (m, 1H, o-MeOPh), 6.37 (d, J = 8.3 Hz, 1H, o-MeOPh), 4.94 (d, J = 8.4 Hz, 1H, C5-H), 4.45 (ddd, J = 8.4, 8.1, 6.7 Hz, 1H, C4-H), 3.79 (s, 3H, RCOOMe), 3.46 (s, 3H, o-MeOPh), 2.62 (dd, J = 13.2, 8.1 Hz, 1H, C3-Ha), 2.57 (bs, 1H, N–H), 2.37 (dd, J = 13.2, 6.7 Hz, 1H, C3-Hb), 2.30 (s, 3H, p-MePh), 1.69 (s, 3H, C2-Me) ppm; 13C NMR (50 MHz, CDCl3): δ = 200.7, 178.0, 155.9, 142.7, 129.1, 128.6, 128.4, 128.1, 127.9, 127.7, 120.2, 109.1, 65.9, 59.3, 54.4, 52.5, 48.9, 39.5, 25.5, 21.7 ppm; IR (neat): \(\bar{\nu }\) = 3435, 2952, 2840, 1730, 1678, 1606, 1490, 1464, 1245, 1181, 1107, 1028, 756 cm−1.

Methyl (2R,4R,5S)-5-(3-methoxyphenyl)-2-methyl-4-(4-methylbenzoyl)pyrrolidine-2-carboxylate (3t, C22H25NO4)

Pale yellow liquid; 72 mg, yield 78%; Rf = 0.2 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.49 (d, J = 8.1 Hz, 2H, p-MePh), 7.06 (d, J = 8.1 Hz, 2H, p-MePh), 6.98–6.86 (m, 1H, m-MeOPh), 6.65 (d, J = 7.7 Hz, 1H, m-MeOPh), 6.58 - 6.48 (m, 2H, o-MeOPh), 4.78 (d, J = 9.3 Hz, 1H, C5-H), 4.27 (pseudo q, J = 8.5, 1H, C4-H), 3.79 (s, 3H, RCOOMe), 3.56 (s, 3H, m-MeOPh), 2.63 (bs, 1H, N–H), 2.51 (m, 2H, C3-Ha, C3-Hb), 2.32 (s, 3H, p-MePh), 1.66 (s, 3H, C2-Me) ppm; 13C NMR (50 MHz, CDCl3): δ = 199.0, 177.9, 159.0, 143.2, 142.0, 135.4, 128.8, 128.7, 128.3, 120.1, 113.3, 113.1, 65.8, 64.8, 55.0, 52.5, 50.7, 38.3, 25.3, 21.6 ppm; IR (neat): \(\bar{\nu }\) = 3352, 2952, 2836, 1728, 1678, 1607, 1456, 1258, 1181, 1110, 1043, 788, 702 cm−1.

Methyl (2R,4R,5S)-5-(4-methoxyphenyl)-2-methyl-4-(4-methylbenzoyl)pyrrolidine-2-carboxylate (3u, C22H25NO4)

Pale yellow liquid; 86 mg, yield 57%; Rf = 0.1 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.58–7.42 (m, 2H, p-MePh), 7.14–7.02 (m, 2H, p-MePh), 6.98–6.87(m, 2H, p-MeOPh), 6.62–6.48 (m, 2H, p-MeOPh), 4.77 (d, J = 9.3 Hz, 1H, C5-H), 4.25 (ddd, J = 9.3, 8.7, 7.8 Hz, 1H, C4-H), 3.79 (s, 3H, RCOOMe), 3.64 (s, 3H, p-MeOPh), 2.83 (bs, 1H, N–H), 2.55 (dd, J = 13.2, 8.7 Hz, 1H, C3-Ha), 2.48 (dd, J = 13.2, 7.8 Hz, 1H, C3-Hb), 2.32 (s, 3H, p-MePh), 1.65 (s, 3H, C2-Me) ppm; 13C NMR (50 MHz, CDCl3): δ = 199.2, 177.9, 158.6, 143.1, 135.3, 132.6, 128.8, 128.8, 128.3, 113.1, 65.7, 64.2, 55.2, 52.5, 50.8, 38.3, 25.3, 21.7 ppm; IR (neat): \(\bar{\nu }\) = 3435, 2952, 1728, 1677, 1608, 1512, 1250, 1181, 1110, 1034, 823 cm−1.

Methyl (2R,4R,5S)-5-(4-chlorophenyl)-2-methyl-4-(4-methylbenzoyl)pyrrolidine-2-carboxylate (3v, C21H22ClNO3)

Pale yellow liquid; 109 mg, yield 63%; Rf = 0.4 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.54–7.40 (m, 2H, p-MePh), 7.18–7.04 (m, 2H, p-MePh), 6.96 (s, 4H, p-ClPh), 4.78 (d, J = 9.4 Hz, 1H, C5-H), 4.26 (ddd, J = 9.4, 8.8, 8.3 Hz, 1H, C4-H), 3.79 (s, 3H, RCOOMe), 2.88 (bs, 1H, N–H), 2.55 (dd, J = 13.1, 8.8 Hz, 1H, C3-Ha), 2.45 (dd, J = 13.1, 8.3 Hz, 1H, C3-Hb), 2.33 (s, 3H, p-MePh), 1.64 (s, 3H, C2-Me) ppm; 13C NMR (50 MHz, CDCl3): δ = 198.5, 177.7, 143.4, 139.0, 135.0, 132.6, 129.0, 128.8, 128.1, 127.6, 65.6, 63.7, 52.4, 50.3, 38.0, 25.2, 21.5 ppm; IR (neat): \(\bar{\nu }\) = 3435, 2952, 1729, 1678, 1607, 1281, 1182, 1110, 1015, 821 cm−1.

Methyl (2R,4R,5S)-2-methyl-5-phenyl-4-(thiophene-2-carbonyl)pyrrolidine-2-carboxylate (3w, C18H19NO3S)

Yellow liquid; 103 mg, yield 63%; Rf = 0.3 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.46–7.34 (m, 2H, Th), 7.18–6.84 (m, 8H, Ph, Th), 4.76 (d, J = 8.8 Hz, 1H, C5-H), 4.12 (ddd, J = 8.8, 7.8, 7.6 Hz, 1H, C4-H), 3.77 (s, 3H, RCOOMe), 2.83 (bs, 1H, N–H), 2.57 (dd, J = 13.2, 7.8 Hz, 1H, C3-Ha), 2.49 (dd, J = 13.2, 7.6 Hz, 1H, C3-Hb), 1.67 (s, 3H, C2-Me) ppm; 13C NMR (50 MHz, CDCl3): δ = 192.1, 177.6, 145.0, 139.4, 133.4, 131.7, 127.6, 127.5, 127.5, 127.2, 65.7, 65.4, 52.4, 52.3, 38.2, 25.2 ppm; IR (neat): \(\bar{\nu }\) = 3420, 3348, 3090, 2949, 2926, 1716, 1648, 1416, 1112, 731 cm−1.

Methyl (2R,4R,5S)-5-(4-methoxyphenyl)-2-methyl-4-(thiophene-2-carbonyl)pyrrolidine-2-carboxylate (3x, C19H21NO4S)

Yellow liquid; 88 mg, yield 54%; Rf = 0.1 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.45 (d, J = 4.9 Hz, 1H, Th), 7.41 (d, J = 3.6 Hz, 1H, Th), 7.14–7.00 (m, 2H, p-MeOPh), 6.94 (dd, J = 4.9, 3.6 Hz, 1H, Th), 6.73–6.47 (m, 2H, p-MeOPh), 4.76 (d, J = 8.8 Hz, 1H, C5-H), 4.09 (pseudo q, J = 8.8 Hz, 1H, C4-H), 3.79 (s, 3H, RCOOMe), 3.66 (s, 3H, p-MeOPh), 2.99 (bs, 1H, N–H), 2.66–2.38 (m, 2H, C3-Ha, C3-Hb), 1.67 (s, 3H, C2-Me) ppm; 13C NMR (50 MHz, CDCl3): δ = 192.3, 177.5, 158.9, 145.2, 133.5, 131.9, 131.4, 128.9, 127.7, 113.3, 65.9, 65.1, 55.3, 52.7, 52.5, 38.4, 25.2 ppm; IR (neat): \(\bar{\nu }\) = 3432, 3095, 2954, 2936, 1727, 1655, 1512, 1416, 1245, 839, 728 cm−1.

Ethyl (2R,4R,5S)-5-(2-methoxyphenyl)-2-methyl-4-(thiophene-2-carbonyl)pyrrolidine-2-carboxylate (3y, C20H23NO4S)

Yellow liquid; 44 mg, yield 65%; Rf = 0.3 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.48 (dd, J = 3.9, 1.0 Hz, 1H, Th), 7.43–7.34 (m, 2H, Th, o-MeOPh), 6.98 (dd, J = 8.0, 1.8 Hz, 1H, o-MeOPh), 6.91 (ddd, J = 4.9, 3.9, 0.6 Hz, 1H, Th), 6.85–6.73 (m, 1H, o-MeOPh), 6.48 (dd, J = 8.2, 1.1 Hz, 1H, o-MeOPh), 4.95 (d, J = 8.1 Hz, 1H, C5-H), 4.35–4.20 (m, 1H, C4-H), 4.24 (q, J = 7.1 Hz, 2H, RCOOCH2CH3), 3.60 (s, 3H, o-MeOPh), 2.64 (dd, J = 13.3, 8.2 Hz, 1H, C3-Ha), 2.62 (bs, 1H, N–H), 2.34 (dd, J = 13.3, 5.9 Hz, 1H, C3-Hb), 1.68 (s, 3H, C2-Me), 1.31 (t, J = 7.1 Hz, 3H, RCOOCH2CH3) ppm; 13C NMR (50 MHz, CDCl3): δ = 193.5, 177.4, 155.9, 145.2, 133.3, 131.4, 128.0, 127.6, 127.4, 127.2, 120.3, 109.1, 65.7, 61.3, 59.5, 54.6, 50.6, 39.2, 25.3, 14.4 ppm; IR (neat): \(\bar{\nu }\) = 3336, 3077, 2978, 2937, 1723, 1660, 1490, 1464, 1417, 1244, 1184, 1106, 1026, 755, 727 cm−1.

Ethyl (2R,4R,5S)-5-(3-methoxyphenyl)-2-methyl-4-(thiophene-2-carbonyl)pyrrolidine-2-carboxylate (3z, C20H23NO4S)

Yellow liquid; 62 mg, yield 67%; Rf = 0.3 (n-Hex:EtOAc = 4:1, v/v); 1H NMR (200 MHz, CDCl3): δ = 7.45 (dd, J = 4.9, 1.1 Hz, 1H, Th), 7.41 (dd, J = 3.8, 1.1 Hz, 1H, Th), 7.02–6.85 (m, 2H, Th, m-MeOPh), 6.79–6.65 (m, 2H, m-MeOPh), 6.57 (ddd, J = 8.2, 2.6, 1.0 Hz, 1H, m-MeOPh), 4.75 (d, J = 8.8 Hz, 1H, C5-H), 4.24 (q, J = 7.1 Hz, 2H, RCOOCH2CH3), 4.09 (ddd, J = 8.9, 7.8, 7.7 Hz, 1H, C4-H), 3.63 (s, 3H, m-MeOPh), 2.73 (bs, 1H, N-H), 2.51 (dd, J = 13.3, 7.7 Hz, 1H, C3-Ha), 2.47 (dd, J = 13.3, 7.8 Hz, 1H, C3-Hb), 1.66 (s, 3H, C2-Me), 1.32 (t, J = 7.1 Hz, 3H, RCOOCH2CH3) ppm; 13C NMR (50 MHz, CDCl3): δ = 192.1, 177.3, 159.1, 145.3, 141.4, 133.4, 131.7, 128.7, 127.6, 120.1, 113.4, 113.0, 65.7, 65.4, 61.3, 55.2, 52.4, 38.1, 25.3, 14.4 ppm; IR (neat): \(\bar{\nu }\) = 3345, 3077, 2978, 2937, 1723, 1659, 1602, 1466, 1417, 1263, 1182, 1155, 1108, 1043, 855, 791, 728 cm−1.