l-tert-Leucine-Derived AmidPhos–Silver(I) Chiral Complexes for the Asymmetric [3+2] Cycloaddition of Azomethine Ylides

Abstract

The l-tert-leucine-derived AmidPhos/silver(I) catalytic system has been developed for the asymmetric [3+2] cycloaddition of azomethine ylides with electronic-deficient alkenes with or without Et₃N. Under optimal conditions, highly functionalized endo-4-pyrrolidines were obtained with modest to high yields (up to 99% yield) and enantioselectivities (up to 98% ee).

Key words

l-tert-leucine - amidophosphane - silver(I) - [3+2] cycloaddition - azomethine ylide

Five-membered nitrogenous heterocycles, in particular, the highly substituted pyrrolidines are useful building blocks for biologically active molecules,[1] as the structural motifs are widely present in many natural alkaloids and pharmaceutically useful agents. In recent years, synthesis of this five-membered heterocyclic compounds have been the focus of attention.[2] The 1,3-dipolar cycloaddition reaction of azomethine ylides to electron-deficient alkenes is one of the most useful tool for constructing highly substituted pyrrolidines. Since the first catalytic asymmetric 1,3-dipolar cycloaddition reported by Zhang employing the AgOAc/xylyl-FAP/i-Pr₂NEt system,[3] several examples of the formation of optically pure pyrrolidines based on a combination of chiral metal Lewis acids and organic or inorganic bases have thus far been reported to catalyze the process with high endo/exo diastereo- and enantioselectivities.[4] [5] [6] Despite these impressive advances, there are still some problems that need to be explored for the reaction. First, the effect of the extra bases on the substrates adaptability has hardly been systematically studied.[7] Second, synthesis of pyrrolidine derivatives containing aliphatic, heterocyclic substituents and 2-quaternary stereocenter with high enantioselectivities with small amounts of catalysts loading are still limited.[8]

Scheme 1 Mechanism of Ag₂CO₃-catalyzed 1,3-dipolar cycloaddition

In previous papers, the most accepted mechanism for the 1,3-dipolar cycloaddition reaction of azomethine ylides to electron-deficient alkenes has been proposed.[9] Coordination of the iminoester to a chiral metal catalyst, followed by deprotonation with base to form the reactive metal-bound azomethine ylide dipole, which reacts with dipolarophiles, was followed by elimination of cycloadduct to regenerate the chiral catalyst (Scheme [1]). Thus, for the catalytic system, an excess amount of base such as a tertiary amine or an inorganic base was involved. However, a few researchers reported that extra bases are not necessary for their catalytic systems, because the metal salt bearing a moderately charged with a basic ligand anion would facilitate deprotonation of the iminoester to generate the azomethine ylide.[4c] [9b] [10] Whether such a catalytic system require an extra base or not, we believe that the deprotonation of the iminoester can be accelerated by an suitable base, which is advantageous to improve the reaction rate and enantioselectivities, especially for those slower reaction substrates containing aliphatic, heterocyclic, and α-substituted iminoesters. Here, we examined the substrate adaptability of 1,3-dipolar cycloaddition reaction of azomethine ylides to dipolarophiles catalyzed by the chiral l-tert-leucine-derived AmidPhos/Ag₂CO₃ catalytic system by small amounts of catalyst loading with or without base.

Recently, our group reported a new Ag₂CO₃/CA-AA-AmidPhos catalytic system which was applied to asymmetric 1,3-dipolar cycloaddition of azomethine ylides.[11] Through the studies of the reactivity of precatalyst in the cycloaddition, we found the Ag₂CO₃/l-valine-derived amidophosphane 1a system can efficiently catalyze the cy­cloaddition of iminoesters 3a with diethyl maleate in toluene at room temperature with high enantioselective (84% ee) in the absence of base (Table [1], entry 1), only the endo isomer 4a was detected by ¹H NMR analysis of reaction mixtures.

Table 1 Screening Studies of Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides with Diethyl Maleate 2a ^a

Entry	Precat.	Baseb	Yield (%)c	ee (%)d
1	1a	–	97	84
2	1b	–	84	70
3	1c	–	85	83
4	1d	–	97	88
5	1e	–	90	90
6	1f	–	89	84
7	1g	–	>99	94
8	1h	–	96	89
9	1i	–	72	25
10	1j	–	69	–24
11	1g	K2CO3	91	94
12	1g	Et3N	>99	94
13	1g	DBU	90	87
14	1g	DABCOe	74	92
15	1g	i-Pr2NEt	96	93
16	1g	DMAPe	72	92

^a Reaction conditions: iminoester 3 (0.3 mmol), diethyl maleate (0.31 mmol), Ag₂CO₃ (1 mol%), precatalyst (2 mol%), toluene (1.4 mL).

^b Base (5 mol%).

^c Isolated yields based on 3a.

^d Determined by HPLC.

^e No response after 5 h.

Encouraged by these results, the effect of ligands derived from amino acids on the conversions and the enantio­selectivities was investigated in toluene (Table [1]).[12] Phenylalanine- and phenylglycine-derived ligands 1b,c were not very effective by comparison with ligand 1a with slightly lower enantioselectivities (Table [1], entries 2 and 3). Delightfully, high enantioselectivity (88% ee) was achieved with the l-tert-leucine-derived ligand 1d (Table [1], entry 4). Next, the influence of the size and chirality of substituent on the terminal amide group was also studied (Table [1], entries 5–8). Four ligands were synthesized by replacing the benzyl group in 1d to 1-(2-naphthyl)methyl (1e), methyl (1f), (S)-1-phenylethyl (1g), and (R)-1-phenylethyl (1h), respectively. We were pleased to find that the precatalyst 1g, with a (S)-1-phenylethyl moiety incorporated, afforded the desired adduct with >99% yield and 94% ee (Table [1], entry 7). However, when two hydrogen atoms on the terminal amide group are replaced by dibenzyl and dimethyl groups, respectively, the enantioselectivities were sharply decreased (Table [1], entries 9 and 10).

To further optimize the process, different bases were also studied. When the reaction was run with K₂CO₃, the enantioselectivity was maintained, and the yield was slightly decreased (Table [1], entry 11). Extra Et₃N had no particular effect on the yield and ee value (Table [1], entry 12). Other organic bases were also used under the same conditions, lower enantioselectivities (87–93% ee) were obtained (Table [1], entries 13–16). Thus, the optimal conditions for the asymmetric cycloaddition of azomethine ylides are Ag₂CO₃/1g/toluene with or without Et₃N at room temperature.

1,3-Cycloaddition reaction of various iminoesters 3 and diethyl maleate (2a) in the presence of ligand 1g was investigated under the optimized experimental conditions with or without Et₃N. Usually the increase in reaction rate will bring a lower selectivity, but the chiral silver AmidPhos catalysis performance of the 1,3-dipolar cycloaddition showed extraordinary results. As shown in Table [2,]α-iminoesters 3a–g from aromatic aldehydes with different steric hindrance and electronic properties reacted with diethyl maleate (2a) to afford the corresponding endo-4a–f adducts exclusively in high yields (84–99%) and excellent enantiselectivties (91–98% ee) in the presence of ligand 1g with or without Et₃N (Table [2], entries 1–7). Notably, when R⁴ was heteroaromatic groups (Table [2], entries 8 and 9), aliphatic cyclohexyl (Table [2], entry 10), the endo-4h–j adducts were successfully obtained with increased yields (56–85%) and higher enantioselectivities (92–93% ee) in 6–24 hours with extra Et₃N compared to Ag₂CO₃/1g catalytic system (Table [2], entries 8–10).

Table 2 Variation of the R⁴ Substituent on 3 for the Cycloaddition with Diethyl Maleate 2a ^a

Entry	R4	Baseb	Time (h)	Yield (%)c	ee (%)d
1	3a Ph	–	3	4a >99	94
		Et3N	3	4a >99	94
2	3b 4-MeC6H4	–	6	4b 84	91
		Et3N	6	4b 85	91
3	3c 4-MeOC6H4	–	24	4c 91	96
		Et3N	18	4c 91	98
4	3d 4-FC6H4	–	20	4d >99	96
		Et3N	18	4d >99	96
5	3e 4-ClC6H4	–	5	4e >99	94
		Et3N	5	4e >99	94
6	3f 4-BrC6H4	–	36	4f 87	92
		Et3N	18	4f 89	93
7	3g 1-naphthyl	–	4	4g 90	91
		Et3N	4	4g 90	91
8	3h 2-furyl/H	–	24	4h 70	82
		Et3N	8	4h 80	93
9	3i 3-pyridyl, H	–	24	4i 77	84
		Et3N	6	4i 85	92
10	3j cyclohexyl, H	–	48	4j 38	86
		Et3N	24	4j 56	92
11	3k 2-naphthyl	–	4	4k 88	96
12	3l 3,4-ClC6H3	–	30	4l 65	87
13	3m 2-ClC6H4	–	30	4m 87	90

^a Reaction conditions: iminoester 3 (0.3 mmol), diethyl maleate (0.31 mmol), Ag₂CO₃ (1 mol%), precatalyst 1g (2 mol%), toluene (1.4 mL).[13]

^b Et₃N (5 mol%).

^c Isolated yields based on 4.

^d Determined by HPLC.

In addition, when R⁴ was 2-naphthyl, 3,4-ClC₆H₃, and 2-ClC₆H₄, the endo-4k–m adducts were also successfully obtained with high enantioselectivities (87–96% ee) and yields (65–88%) by using Ag₂CO₃/1g catalytic system without Et₃N (Table [2], entries 11–13).

The scopes and limitations of the protocol with regard to the 2-substituted azomethine ylides 3 and the maleates 2 were also explored in a similar manner as shown in Table [3]. The reaction of iminoesters 3n–p derived from alanine with the maleates 2 using Ag₂CO₃/1g catalytic system without Et₃N led to pyrrolidines 4n–p with a quaternary center at the 2-position with sole endo selectivities and excellent enantioselectivities ranging from 91–92% (Table [3], entries 1–3). When the Ag₂CO₃/1g catalytic system was added Et₃N, slightly improved reactivity and enantioselectivity (94–96% ee) were obtained (Table [3], entries 1–3).

Table 3 Ag₂CO₃/1g-Catalyzed Enantioselective Cycloaddition of Various 1,3-Dipolar 3n–s with 2a ^a

Entry	3 R4, R5	Baseb	Time (h)	Yield (%)c	ee (%)d
1	3n Ph, Me	–	24	4n 98	91
		Et3N	18	4n >99	96
2e	3n Ph, Me	–	24	4o 76	92
		Et3N	18	4o 83	96
3	3p 4-MeC6H4, Me	–	40	4p 67	91
		Et3N	30	4p 79	94
4	3q Ph, Bn	–	48	4q 89	88
		Et3N	24	4q >99	94
5	3r Ph, 3-indolylmethyl	–	48	4r 56	74
		Et3N	24	4r 65	87
6	3s Ph, Ph	–	72f	4s 22	62
		Et3N	72f,g	4s 47	82

^a Reaction conditions: iminoester 3 (0.3 mmol), diethyl maleate (0.31 mmol), Ag₂CO₃ (1 mol%), precatalyst 1g (2 mol%), toluene (1.4 mL).

^b Et₃N (5 mol%).

^c Isolated yields based on 4.

^d Determined by HPLC.

^e Dimethyl maleate 2b was used.

^f No reaction completely.

^g endo/exo >92:8.

Furthermore, we also examined the iminoesters derived from phenylalanine (Table [3], entry 4), tryptophan (Table [3], entry 5), and phenylglycine (Table [3], entry 6) with or without Et₃N. We found the Et₃N had significantly positive influences on the reaction rate, yields, and enantioselectivities. Especially, when R⁵ was benzyl or 3-indolylmethyl group, the reaction time was sharply shortened to 24 hours with higher enantioselectivities (94%, 87% ee; Table [3], entries 4 and 5). Moreover, when R⁵ was Phenyl group, the enantio­selectivity was also increased from 62% to 82% with extra Et₃N, albeit the reaction did not go to completion (Table [3], entry 6).

We also probed other four dipolarophiles in the cy­cloaddition with 3a as outlined in Figure [1]. Only the endo adducts were isolated in all cases. The iminoester 3a reacted perfectly with dimethyl maleate in 94% ee. For dimethyl fumarate and methyl acrylate, much lower enantioselectivities were observed with 30% and 46% ee, respectively. N-Methylmaleimide as a popular dipolarophile in the reported literature was also used to react with α-iminoester 3a with 99% yield and 97% ee.[7b]

Figure 1 Cycloaddition of 3a with other dipolarophiles catalysed by Ag₂CO₃/1g

In conclusion, we have developed the l-tert-leucine-derived AmidPhos-silver(I) catalytic system for the asymmetric [3+2] cycloaddition of azomethine ylides with diethyl maleate in high yields and excellent levels of enantioselectivities by using a combination of 2 mol% of ligand 1g and 1 mol% of Ag₂CO₃ with or without Et₃N. The study showed the addition of extra Et₃N greatly accelerated the reaction rate, increase the yields and the enantioselectivities as well, especially for heterocyclic, aliphatic, and 2-substituted azomethine ylides. In addition, dimethyl maleate, dimethyl fumarate, N-methylmaleimide, and methyl acrylate were also used to react with α-iminoester 3a with high yield and modest to high enantioselectivities. Further investigation of the reaction scope and detailed mechanism study are under way.

Acknowledgment

We are grateful to the Natural Science Foundation of China (No. 21202042), the Hunan Provincial Natural Science Foundation of China (Nos. 13JJ4090, 2015JJ3063), the Natural Science Foundation of Hunan University of Technology (No. 2014HZX01), Zhuzhou Municipal Science and Technology Program and Graduate student innovation fund of Hunan Province (CX2016B642) for support of this research.

• References and Notes

• 1a Denhart DJ, Griffith DA, Heathcock CH. J. Org. Chem. 1998; 63: 9616
• 1b Overman LE, Tellew JE. J. Org. Chem. 1996; 61: 8338
• 1c Alvarez-Ibarra C, Csákÿ AG, López de Silanes I, Quiroga ML. J. Org. Chem. 1997; 62: 479
• 1d Obst U, Betschmann P, Lerner C, Seiler P, Diederich F. Helv. Chim. Acta 2000; 83: 855
• 1e Sebahar PR, Williams RM. J. Am. Chem. Soc. 2000; 122: 5666

Recent reviews of catalytic asymmetric 1,3-dipolar cycloaddition:
• 2a Mukherjee S, Yang J.-W, Hoffmann S, List B. Chem. Rev. 2007; 107: 5471
• 2b Stanley LM, Sibi MP. Chem. Rev. 2008; 108: 2887
• 2c MacMillan DW. C. Nature (London, U.K.) 2008; 455: 304
• 2d Adrio J, Carretero JC. Chem. Commun. 2011; 47: 6784
• 2e Moyano A, Rios R. Chem. Rev. 2011; 111: 4703
• 2f Albrecht Ł, Jiang H, Jørgensen KA. Angew. Chem. Int. Ed. 2011; 50: 8492
• 2g Maroto EE, Izquierdo M, Reboredo S, Marco-Martínez J, Filippone S, Martín N. Acc. Chem. Res. 2014; 47: 2660
• 2h Adrio J, Carretero JC. Chem. Commun. 2014; 50: 12434
• 2i Han M.-Y, Jia J.-Y, Wang W. Tetrahedron Lett. 2014; 55: 784
• 2j Hashimoto T, Maruoka K. Chem. Rev. 2015; 115: 5366
• 3 Longmire JM, Wang B, Zhang X. J. Am. Chem. Soc. 2002; 124: 13400

Recent references on chiral silver catalyst:
• 4a Xue Z.-Y, Liu T.-L, Lu Z, Huang H, Tao H.-Y, Wang C.-J. Chem. Commun. 2010; 46: 1727
• 4b Oura I, Shimizu K, Ogata K, Fukuzawa S. Org. Lett. 2010; 12: 1752
• 4c Yamashita Y, Imaizumi T, Guo X.-X, Kobayashi S. Chem. Asian J. 2011; 6: 2550
• 4d Yamashita Y, Imaizumi T, Kobayashi S. Angew. Chem. Int. Ed. 2011; 50: 4893
• 4e Jing X, He C, Dong D, Yang L, Duan C. Angew. Chem. Int. Ed. 2012; 51: 10127
• 4f Guernon H, Legault CY. Organometallics 2013; 32: 1988
• 4g Kudryavtsev KV, Ivantcova PM, Churakov AV, Wiedmann S, Luy B, Muhle-Goll C, Zefirov NS, Bräse S. Angew. Chem. Int. Ed. 2013; 52: 12736
• 4h Gerosa GG, Spanevello RA, Suárez AG, Sarotti AM. J. Org. Chem. 2015; 80: 7626

Recent references on chiral copper catalyst:
• 5a Robles-Machín R, González-Esguevillas M, Adrio J, Carretero JC. J. Org. Chem. 2010; 75: 233
• 5b Arai T, Mishiro A, Yokoyama N, Suzuki K, Sato H. J. Am. Chem. Soc. 2010; 132: 5338
• 5c Zhang C, Yu S.-B, Hu X.-P, Wang D.-Y, Zheng Z. Org. Lett. 2010; 12: 5542
• 5d Wang M, Wang Z, Shi Y.-H, Shi X.-X, Fossey JS, Deng W.-P. Angew. Chem. Int. Ed. 2011; 50: 4897
• 5e Kim HY, Li J.-Y, Kim S, Oh K. J. Am. Chem. Soc. 2011; 133: 20750
• 5f González-Esguevillas M, Adrio J, Carretero JC. Chem. Commun. 2012; 48: 2149
• 5g Conde E, Bello D, de Cózar A, Sánchez M, Vázquez MA, Cossío FP. Chem. Sci. 2012; 3: 1486
• 5h Castelló LM, Nájera C, Sansano JM, Larrañaga O, de Cózar A, Cossío FP. Org. Lett. 2013; 15: 2902
• 5i Arai T, Ogawa H, Awata A, Sato M, Watabe M, Yamanaka M. Angew. Chem. Int. Ed. 2015; 54: 1595
• 5j Li J.-Y, Kim HY, Oh K. Org. Lett. 2015; 17: 1288
• 5k Wang Z, Yu X, Tian B.-X, Payne DT, Yang W.-L, Liu Y.-Z, Fossey JS, Deng W.-P. Chem. Eur. J. 2015; 21: 10457
• 5l He F.-S, Zhu H, Wang Z, Gao M, Yu X, Deng W.-P. Org. Lett. 2015; 17: 4988
• 5m Li C.-Y, Yang W.-L, Luo X.-Y, Deng W.-P. Chem. Eur. J. 2015; 21: 19048
• 5n Tang F.-F, Yang W.-L, Yu X, Deng W.-P. Catal. Sci. Technol. 2015; 5: 3568
• 5o Yang W.-L, Tang F.-F, He F.-S, Li C.-Y, Yu X, Deng W.-P. Org. Lett. 2015; 17: 4822
• 5p Han F.-Z, Yu S.-B, Zhang C, Hu X.-P. Tetrahedron 2016; 72: 2616
• 5q Pascual-Escudero A, de Cózar A, Cossío FP, Adrio J, Carretero JC. Angew. Chem. Int. Ed. 2016; 55: 15334 ; and references cited therein

Select references on other chiral metal catalysts. Zn:
• 6a Gothelf AS, Gothelf KV, Hazell RG, Jørgensen KA. Angew. Chem. Int. Ed. 2002; 41: 4236
• 6b Dogan O, Koyuncu H, Garner P, Bulut A, Youngs WJ, Panzner M. Org. Lett. 2006; 8: 4687

Nickel:
• 6c Shi J.-W, Zhao M.-X, Lei Z.-Y, Shi M. J. Org. Chem. 2008; 73: 305
• 6d Arai T, Yokoyama N, Mishiro A, Sato H. Angew. Chem., Int. Ed. 2010; 49: 7895

Calcium:
• 6e Saito S, Tsubogo T, Kobayashi S. J. Am. Chem. Soc. 2007; 129: 5364
• 6f Tsubogo T, Saito S, Seki K, Yamashita YS, Kobayashi S. J. Am. Chem. Soc. 2008; 130: 13321

Gold:
• 6g Martín-Rodríguez M, Nájera C, Sansano JM, de Cózar A, Cossío FP. Chem. Eur. J. 2011; 17: 14224
• 7a Oderaotoshi Y, Cheng W, Fujitomi S, Kasano Y, Minakata S, Komatsu M. Org. Lett. 2003; 5: 5043
• 7b Nájera C, de Gracia Retamosa M, Martin-Rodríguez M, Sansano JM, de Cózar A, Cossío FP. Eur. J. Org. Chem. 2009; 5622
• 8a Kim HY, Shih H.-J, Knabe W.-E, Oh K. Angew. Chem. Int. Ed. 2009; 48: 7420
• 8b Wang C.-J, Liang G, Xue Z.-Y, Gao F. J. Am. Chem. Soc. 2008; 130: 17250
• 9a Oderaotoshi Y, Cheng WJ, Fujitomi S, Kasano Y. Org. Lett. 2003; 5: 5043
• 9b Zeng W, Zhou Y.-G. Org. Lett. 2005; 7: 5055
• 9c Zeng W, Chen G.-Y, Zhou Y.-G, Li Y.-X. J. Am. Chem. Soc. 2007; 129: 750
• 10a Zeng W, Zhou Y.-G. Tetrahedron Lett. 2007; 48: 4619
• 10b Yamashita Y, Imaizumi T, Kobayashi S. Angew. Chem. Int. Ed. 2011; 50: 4893
• 11 Wang H.-F, Deng Q.-F, Zhou Z.-P, Hu S.-Q, Liu Z.-G, Zhou L.-Y. Org. Lett. 2016; 18: 404
• 12 Synthesis of the Representative Ligand 1g The 1g′ (334 mg, 1 mmol), which was synthesized according to the procedure of the Supporting Information, was dissolved in CH₂Cl₂ (10 mL) and TFA (1 mL) was added dropwise at 0 °C. Then the reaction mixture was stirred for 18 h at r.t. All volatile compounds were removed in vacuo, and the residue was dissolved in water and treated with the sat. Na₂CO₃ solution. The resulting mixture was extracted with CH₂Cl₂ (3×), and the combined organic layers were dried over Na₂SO₄. After filtration and then evaporation of the solvent, the crude free amine was obtained without purification for the next step. To the solution of the free amine in CH₂Cl₂ (8 mL) was added O-benztriazole-1-N,N,N′,N′-tetraethyluronium hexafluorophosphate (HBTU, 417 mg, 1.1 mmol), followed by the addition of diisopropylethylamine (367 μL, 2.2 mmol) and 2-(diphenylphosphino)benzoic acid (306 mg, 1 mmol), The reaction mixture was then stirred for 18 h at r.t. The mixture was combined with CH₂Cl₂ and water, and the organic layer was separated, washed with sat. NaHCO₃ (2×), and dried over Na₂SO₄. The solvent was removed in vacuo to afford the crude product as colorless oil, which was purified by flash chromatography (15% EtOAc in hexane) yielding the ligand 1g. White solid (407 mg, 78%); mp 77–79 °C; [α]_D ³⁰ –25.6 (c 0.88, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.63–7.62 (m, 1 H), 7.40–7.20 (m, 17 H), 7.02–6.95 (m, 1 H), 6.71–6.70 (m, 1 H), 6.62 (br s, 1 H), 5.12–5.08 (m, 1 H), 4.38–4.35 (m, 1 H), 1.44 (d, J = 6.8 Hz, 3 H), 0.84 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃; C–P coupling not removed): δ = 169.3, 168.9, 143.0, 136.7, 134.5, 133.9, 133.8, 133.7, 133.6, 130.5, 129.1, 128.8, 128.6, 128.6, 128.6, 128.5, 127.8, 127.8, 127.3, 126.3, 61.3, 49.1, 34.7, 26.6, 21.8. ³¹P NMR (162 MHz, CDCl₃) δ = –10.4. ESI-HRMS: m/z calcd for C₃₃H₃₅N₂O₂P [M + H]⁺: 523.2509; found: 523.2511.
• 13 General Procedure of 1,3-Dipole Cycloaddition Ligand of 1g (3.132 mg, 0.006 mmol) and Ag₂CO₃ (0.83 mg, 0.003 mmol) were dissolved in toluene (1.4 mL). The reaction mixture was stirred for 1 h at r.t., followed by the addition of the activated olefins (0.33 mmol), Et₃N (0.015 mmol), and imine substrate (0.3 mmol). Once starting material was consumed (monitored by TLC), the mixture purified by column chromatography to give the corresponding cycloaddition product, which was then directly analyzed by chiral HPLC. (2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(Pyridin-3-yl)pyrolidine-2,3,4-tricarboxylate (4i) White solid, yield 89 mg (85%); mp 102–105 °C; [α]_D ³⁰ +50.2 (c 0.90, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 8.60–8.52 (m, 2 H), 7.79 (d, J = 7.2 Hz, 1 H), 7.29–7.26 (m, 1 H), 4.51 (d, J = 6.4 Hz, 1 H), 4.17–4.12 (m, 3 H), 3.81 (s, 3 H), 3.78–3.63 (m, 4 H), 3.37 (br s, 1 H), 1.25 (t, J = 7.2 Hz, 3 H), 0.84 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.7, 170.2, 170.0, 149.0, 148.9, 134.3, 133.1, 123.2, 62.8, 62.2, 61.2, 60.6, 52.4, 52.3, 50.9, 14.0, 13.6. The ee value was 92%, t _R (major) = 9.28 min, t _R (minor) = 10.83 min (Chiralcel AS-H, λ = 230 nm, i-PrOH–hexanes = 50:50, flow rate = 0.8 mL/min). ESI-HRMS: m/z calcd for C₁₇H₂₂N₂O₆ [M + H]⁺ 351.1551; found: 351.1554. (2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(3,4-Dichlorophenyl)-pyrolidine-2,3,4-tricarboxylate (4l) White solid, yield 81 mg (65%); mp 127–128 °C; [α]_D ³⁰ +46.8 (c 1.00, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.48 (s, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 4.39 (d, J = 6.8 Hz, 1 H), 4.14–4.08 (m, 3 H), 3.79 (s, 3 H), 3.78–3.67 (m, 3 H), 3.59–3.55 (m, 1 H), 3.27 (brs, 1 H), 1.22 (t, J = 6.8 Hz, 3 H), 0.89 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.7, 170.0, 137.8, 132.3, 131.6, 130.2, 129.1, 126.3, 64.0, 61.9, 61.2, 60.6, 52.3, 52.2, 51.1, 14.0, 13.6. The ee value was 87%, t _R (major) = 7.75 min, t _R (minor) = 13.00 min (Chiralcel AS-H, λ = 230 nm, i-PrOH–hexanes = 50:50, flow rate = 0.8 mL/min). ESI-HRMS: m/z calcd for C₁₈H₂₁Cl₂N₁O₆ [M + H]⁺: 418.0819; found: 418.0824. (2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(2-Chlorophenyl)-pyrrolidine-2,3,4-tricarboxylate (4m) Colorless oil, yield 100 mg (87%); [α]_D ³⁰ +60.1 (c 1.02, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.48 (dd, J = 7.6, 1.6 Hz, 1 H), 7.35 (dd, J = 7.6, 1.6 Hz, 1 H), 7.28–7.20 (m, 2 H), 4.72 (d, J = 6.8 Hz, 1 H), 4.14–4.08 (m, 3 H), 3.92 (dd, J = 8.4, 6.8 Hz, 1 H), 3.83 (s, 3 H), 3.77 (dd, J = 8.8, 8.8 Hz, 1 H), 3.70–3.60 (m, 2 H), 3.40 (br s, 1 H), 1.21 (t, J = 7.2 Hz, 3 H), 0.78 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.1, 170.3, 169.9, 134.5, 133.3, 129.1, 128.8, 127.4, 126.7, 62.0, 61.1, 61.0, 60.3, 52.3, 51.0, 50.2, 14.0, 13.5. The ee value was 90%, t _R (major) = 8.22 min, t _R (minor) = 16.46 min (Chiralcel AS-H, λ = 230 nm, i-PrOH–hexanes = 50:50, flow rate = 0.8 mL/min). ESI-HRMS: m/z calcd for C₁₈H₂₂Cl₁NO₆ [M + H]⁺: 384.1208; found: 384.1212. (2R,3R,4S,5R)-3,4-Diethyl 2-Methyl 2,5-Diphenylpyrrolidine-2,3,4-tricarboxylate (4s) Colorless oil, yield 60 mg (47%); [α]_D ³⁰ +15.1 (c 0.90, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.87 (d, J = 7.6 Hz, 2 H), 7.45–7.37 (m, 4 H), 7.35–7.25 (m, 4 H), 4.49 (d, J = 7.2 Hz, 1 H), 4.36–4.22 (m, 2 H), 4.05 (br s, 1 H), 3.91 (d, J = 8.0 Hz, 1 H), 3.70 (s, 3 H), 3.69–3.64 (m, 1 H), 3.55–3.44 (m, 2 H), 1.35 (t, J = 7.2 Hz, 3 H), 0.75 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.7, 171.5, 170.2, 139.4, 137.8, 128.7, 128.6, 128.2, 128.1, 128.1, 127.8, 127.8, 126.6, 126.4, 76.0, 63.9, 61.2, 60.3, 57.2, 53.6, 52.7, 14.0, 13.5. The ee value was 82%, t _R (minor) = 9.13 min, t _R (major) = 10.87 min (Chiralcel AD-H, λ = 210 nm, i-PrOH–hexanes = 15:85, flow rate = 0.8 mL/min). ESI-HRMS: m/z calcd for C₂₄H₂₇N₁O₆ [M + H]⁺: 426.1911; found: 426.1914.