Cu(I)/TF–BiphamPhos-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with dimethyl itaconate and 2-methyleneglutarate

Abstract

Catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with dimethyl itaconate and 2-methyleneglutarate was realized with the Cu(I)/TF–BiphamPhos complex as the catalyst for the efficient construction of pyrrolidine derivatives bearing one unique all carbon-quaternary and two tertiary stereogenic centers. The current catalytic system exhibited excellent diastereoselectivity (> 20 : 1), good enantioselectivity (88–>99% ee) and broad substrate scope under mild conditions.

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Introduction

Highly functionalized pyrrolidines bearing multiple stereogenic centers are one of the most important heterocyclic motifs, which are widely observed in many natural alkaloids and marketed pharmaceuticals.¹ Enantiomerically enriched pyrrolidine derivatives were also successfully employed as organocatalysts, chiral ligands and also useful building blocks in organic synthesis.² Among the developed methodologies for the optically active pyrrolidines syntheses, catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with electron-deficient olefins is one of the most powerful and atom-economical carbon–carbon bond-forming reaction³ that provides an efficient approach and diversity-oriented synthesis (DOS)⁴ for the construction of a variety of structurally and stereochemically diversified pyrrolidines from the readily-available starting materials. Since the first example on the catalytic asymmetric 1,3-dipolar cycloaddition of in situ-generated azomethine ylide reported in 2002,⁵ much endeavours have been made to developing catalytic asymmetric protocols for 1,3-dipolar cycloaddition, in which various types of chiral metal complexes and chiral organocatalysts have been successfully employed as the efficient catalysts to afford stereochemically diversified pyrrolidine derivatives with moderate to high enantio-/diastereoselectivities in the last decade.⁶ Although various electron-deficient alkenes have been utilized as the dipolarophiles in azomethine ylide-involved 1,3-dipolar cycloaddition, most of them are limited to maleates, fumarates, maleimides, acrylates, nitroalkenes, and vinyl phenyl sulfones.^3,6 Dimethyl itaconate or 2-methyleneglutarate, which were commonly used as substrates in asymmetric hydrogenation reactions,⁷ have been seldom employed as dipolarophiles in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides. To the best of our knowledge, only one racemic example has been reported involving itaconate as the dipolarophile so far.⁸ In view of the simultaneous formation of one unique all carbon-quaternary⁹ and two tertiary stereogenic centers in the pyrrolidine rings, it is a great challenge to control both diastereoselectivity and enantioselectivity in dimethyl itaconate and 2-methyleneglutarate-involved asymmetric 1,3-dipolar cycloaddition reaction (Scheme 1). In continuation of the interest in construction of biologically active and enantioenriched pyrrolidines,¹⁰ we herein reported the first catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides to dimethyl itaconate or 2-methyleneglutarate with excellent levels of diastereoselectivity and enantioselectivity. The current methodology could diversify the existing methodology for the facile access to the biologically active pyrrolidine derivatives.

Scheme 1 Catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides using dimethyl itaconate as the dipolarophiles.

Results and discussion

Initially, N-benzylidene glycine methyl ester 2a was selected as the 1,3-dipole precursor and dimethyl itaconate 1 as the dipolarophile to investigate the stereoselective control in the presence of the combined metal salts and chiral ligand TF–BiphamPhos,^10a and the representative results are listed in Table 1. The 1,3-dipolar cycloaddition reaction occurred smoothly and finished in 4 h with 3 mol% AgOAc/(S)-TF–BiphamPhos (L1) as the catalyst and 15 mol% Et₃N as base in dichloromethane at room temperature, the desired cycloadduct 3a bearing a unique all carbon-quaternary and two tertiary stereogenic centers was obtained as a single isomer in good yield with exclusive diastereoselectivity (dr > 20 : 1) and moderate enantioselectivity of 40% ee (Table 1, entry 1), which indicated that dimethyl itaconate could be applied as an effective dipolarophile in the azomethine ylide-involved 1,3-dipolar cycloaddition reaction for the synthesis of highly functionalized pyrrolidine derivatives. Encouraged by these promising results, we further pursue to improve the enantioselective control of this reaction. To our gratification, the enantioselectivity was greatly increased to 73% ee with maintained high diastereoselectivity for this cycloaddition by switching the metal precursor from AgOAc into Cu(CH₃CN)₄BF₄ (entry 2), which revealed that the corresponding active intermediate generated from chiral Cu(I)/TF–BiphamPhos coordinated by in situ-formed azomethine ylide has more favourable interactions with the dipolarophile itaconate and hence afforded higher enantioselectivity control than that from Ag(I)/TF–BiphamPhos complex. Next, Cu(CH₃CN)₄BF₄ was selected as the metal precursor for subsequent survey of other TF–BiphamPhos ligands with different substituents either on the phenyl ring of diaryl phosphine group or on the chiral backbone. It was found that the enantioselectivity in this 1,3-dipolar cycloaddition was greatly affected by both the electronic effect and steric effect of the chiral ligand: deteriorative effect on the enantioselectivity was observed when the phenyl ring on the phosphorous atom of ligand (L1) was replaced by xylyl group (L2) or cyclohexyl group (L4) (entries 3 and 5). Similar enantioselective control were observed with chiral ligand bearing the strongly electron-withdrawing 3,5-bis(trifluoromethyl)-phenyl group (L3) (entry 4). Further ligand variant showed that TF–BiphamPhos (L5) was the most effective chiral ligand providing 3a exclusively in 92% yield and 81% ee within 8 h (Table 1, entry 6). Next, the solvent effect on this annulation was also investigated, CH₂Cl₂ was revealed to be the best solvent in terms of the yield and enantioselectivity while polar solvents such as methanol and acetonitrile were less effective for this transformation (Table 1, entries 6–10). 90% ee with full conversion and exclusive diastereoselectivity was realized through reducing the reaction temperature to −20 °C with DCM as the solvent (Table 1, entry 12). Thus, the optimized reaction conditions were established as 3 mol% of Cu(CH₃CN)₄BF₄/L5 and 15 mol% Et₃N in DCM at −20 °C.

Table 1 Catalytic asymmetric 1,3-dipolar cycloaddition of imino ester 2a with dimethyl itaconate 1a^a

Entry	L	[M]	Solvent	T (°C)	Time (h)	Yield^b (%)	ee^c (%)
a All reactions were carried out with 0.23 mmol of 1a and 0.35 mmol of 2a in 2 mL solvent.b Isolated yield.c Dr was determined by the crude ^1H NMR and ee was determined by HPLC analysis.
1	L1	AgOAc	DCM	rt	12	91	40
2	L1	Cu(CH3CN)4BF4	DCM	rt	8	90	73
3	L2	Cu(CH3CN)4BF4	DCM	rt	8	79	60
4	L3	Cu(CH3CN)4BF4	DCM	rt	8	81	74
5	L4	Cu(CH3CN)4BF4	DCM	rt	8	52	65
6	L5	Cu(CH3CN)4BF4	DCM	rt	8	92	81
7	L5	Cu(CH3CN)4BF4	Et2O	rt	12	79	73
8	L5	Cu(CH3CN)4BF4	MeCN	rt	12	31	75
9	L5	Cu(CH3CN)4BF4	EtOAc	rt	8	78	77
10	L5	Cu(CH3CN)4BF4	MeOH	rt	12	90	65
11	L5	Cu(CH3CN)4BF4	DCM	−10	12	88	83
12	L5	Cu(CH3CN)4BF4	DCM	−20	20	81	90

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Under the optimized reaction conditions, we investigated the substrate scope of this 1,3-dipolar cycloaddition of dimethyl itaconate 1a with respect to azomethine ylide. As shown in Table 2, a series of representative imino esters derived from various aromatic aldehydes and glycinate reacted smoothly with dimethyl itaconate 1a leading to the corresponding adducts (3a–3j) in good yields (76–95%), excellent diastereoselectivity (dr > 20 : 1) and high enantio-selectivities (88–>99%) at −20 °C within 18–24 h. It appears that the electronic property of the substituents on the aryl rings has little effect on the stereoselectivities. Imino esters bearing electron-neutral group (Table 2, entry 1), electron-deficient group (entries 2–4), and electron-rich groups (entries 5–10) on the aryl rings all worked well in this cycloaddition. On the contrary, the substituent pattern of the aromatic rings has some effect on the enantioselectivities. A little lower enantioselectivities was observed for meta-chloro and meta-methyl-substituted imino esters 2d and 2g (entries 4 and 7). Remarkably, comparable excellent diastereoselectivity and enantio-selectivity were still obtained for the sterically hindered ortho-chloro, ortho-methyl, ortho-methoxyl-substituted imino esters 2c, 2f and 2i (entries 3, 6 and 9). However, no cycloaddition occurred when the less reactive alkyl substituted imino ester was tested under the optimal reaction conditions (entry 12). Notably, α-methyl substituted imino ester 3k derived from alanine was also tolerated in this transformation, affording the desired pyrrolidines bearing one all-carbon quaternary and one nitrogen-substituted quaternary stereogenic centers in good yield with the maintained exclusive diastereoselectivity (> 20 : 1) and excellent enantioselectivity (93% ee) (entry 11). The absolute configuration of the cycloadduct 3c was determined to be (2R,4S,5S) by X-ray analysis† (Fig. 1), and the relative and absolute configuration of all other cycloadducts was tentatively assigned by analogy.

Table 2 Substrate scope of Cu(I)/L5-catalyzed asymmetric 1,3-dipolar cycloaddition of various imino esters 2 with dimethyl itaconate 1a^a

Entry	R^1	R^2	3	Yield^b (%)	ee^c (%)
a All reactions were carried out with 0.23 mmol of 1a and 0.35 mmol of 2 in 2 mL CH2CI2. CuBF4 = Cu(CH3CN)4BF4.b Isolated yield.c Dr was determined by the crude ^1H NMR and ee was determined by HPLC analysis.
1	Ph (2a)	H	3a	81	90
2	p-CI-C6H4 (2b)	H	3b	85	91
3	o-CI-C6H4 (2c)	H	3c	86	93
4	m-CI-C6H4 (2d)	H	3d	90	88
5	p-Me-C6H4 (2e)	H	3e	95	>99
6	o-Me-C6H4 (2f)	H	3f	92	94
7	m-Me-C6H4 (2g)	H	3g	93	89
8	p-MeO-C6H4 (2h)	H	3h	81	92
9	o-MeO-C6H4 (2i)	H	3i	76	94
10	m-MeO-C6H4 (2j)	H	3j	88	90
11	Ph (2k)	Me	3k	82	93
12	Bu (2I)	H	—	—	—

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Fig. 1 ORTEP representation of the cycloadduct (2R,4S,5S)-3c at 15% probability for the drawing of thermal ellipsoids.

To further investigate the generality of the dipolarophile for this 1,3-dipolar cycloaddition reaction, dimethyl 2-methyleneglutarate was also tested under the optimal reaction conditions. As shown in Fig. 2, dimethyl 2-methyleneglutarate 1b has also proven to be excellent dipolarophile in this annulation producing the corresponding cycloadducts 3l and 3m in high yields with high diastereoselectivities and excellent enantioselectivities.

Fig. 2 The results of 1,3-dipolar cycloaddition of azomethine ylides with dimethyl 2-methyleneglutarate as the dipolarophile.

The stereochemical results of this annulation can be explained through the proposed transition state in Fig. 3. Azomethine ylide is coordinated to the chiral copper(I) metallic center in such way to form tetracoordinated active species,^6k,11 subsequently followed by the annulation with dimethyl itaconate from the Si face (C=N) of the ylide giving rise to the cycloadduct 3a in endo-configuration. The carbonyl group connected to unsaturated C=C bond in dimethyl itaconate could coordinate more preferentially with the Cu(I) center than another one, which may benefit for stabilizing the negatively charged oxygen atom. It cannot eliminate the possible hydrogen-bonding interaction between the carbonyl group in the dipolarophile and the NH₂ group in the ligand TF–BiphamPhos.¹²

Fig. 3 Proposed transition state.

Conclusions

In conclusion, we reported a Cu(I)/TF–BiphamPhos-catalyzed asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides with dimethyl itaconate and 2-methyleneglutarate to provide a series of highly substituted pyrrolidines bearing one unique all-carbon quaternary and two tertiary stereogenic centers for the first time. Excellent stereoselective control and broad substrate scope were uniformly observed for various azomethine ylides. The easy availability of the substrates and the bioactive importance of the enantioenriched pyrrolidine derivatives make the present methodology particularly interesting in organic synthesis. Further studies on the mechanistic details and its application are ongoing in this laboratory.

Experimental

General

All reactions were carried out using standard Schlenk techniques unless specified other otherwise. The degassed dry solvents are used throughout each experiment. ¹H NMR spectra were recorded on a VARIAN Mercury 300 MHz spectrometer in CDCl₃. Chemical shifts are reported in ppm with the internal TMS signal at 0.0 ppm as a standard. The data are reported as (s = single, d = double, t = triple, q = quartet, m = multiple or unresolved, brs = broad single, coupling constant(s) in Hz, integration). ¹³C NMR spectra were recorded on a VARIAN Mercury 75 MHz spectrometer in CDCl₃. Chemical shifts are reported in ppm with the internal chloroform signal at 77.0 ppm as a standard. Commercially obtained reagents were used without further purification. All reactions were monitored by TLC with silica gel-coated plates. Diastereomeric ratios were determined from crude ¹H NMR. Enantiomeric excesses were determined by HPLC, using a chiralpak IA, a chiralpak AS-H, chiralpak AD-H, or chiralcel OD-H column with hexane and i-PrOH as solvents. Dimethyl 2-methyleneglutarate¹³ and imino esters,^10a were prepared according to the literature procedure. Chiral ligands L1–L5 were prepared according to the literature procedure reported by us.^10a

Synthetic details

General procedure for asymmetric 1,3-dipolar cycloaddition of azomethine ylides with dimethyl itaconate catalyzed by Cu(CH₃CN)₄BF₄/(S)-TF–BiphamPhos (L5) complex. Under argon atmosphere, (S)-TF–BiphamPhos L5 (6.1 mg, 0.0076 mmol) and Cu(CH₃CN)₄BF₄ (2.2 mg, 0.0069 mmol) were dissolved in 2 mL of DCM. After stirring at room temperature for about 0.5 h, the reaction mixture was dropped to −20 °C. Then, imino ester substrate (0.35 mmol), Et₃N (0.03 mmol) and dimethyl itaconate (0.23 mmol) were added sequentially. Once starting material was consumed (monitored by TLC), the mixture was filtered through celite and the filtrate was concentrated to dryness. The product was purified by column chromatography to give the corresponding cycloadduct, which was then directly analysed by HPLC to determine the enantiomeric excess.

(2R,4S,5R)-Dimethyl 4-(2-methoxy-2-oxoethyl)-5-phenylpyrrolidine-2,4-dicarboxylate (3a). The title compound was prepared according to the general procedure as described above in 81% yield (62 mg) as white solid. M.p. 147–148 °C; [α]²⁵_D = +16.2 (c 1.09, CHCl₃); ¹H NMR (CDCl₃, TMS, 300 MHz) δ 7.33–7.23 (m, 5H), 4.09 (s, 1H), 4.05 (dd, J₁ = 6.3 Hz, J₂ = 15.9 Hz, 1H), 3.85 (s, 3H), 3.65 (s, 3H), 3.25 (s, 3H), 3.11 (d, J = 16.8 Hz, 1H), 3.06–3.01 (m, 1H), 2.58 (br, 1H), 2.51 (d, J = 16.8 Hz, 1H), 2.28 (dd, J₁ = 9.6 Hz, J₂ = 13.8 Hz, 1H); ¹³C NMR (CDCl₃, TMS, 75 MHz) δ 173.9, 172.8, 171.4, 137.1, 128.2, 126.5, 72.4, 58.7, 56.0, 52.1, 51.6, 51.4, 40.2, 39.6; IR (KBr) ν 2954, 2923, 2844, 2396, 1736, 1460, 1437, 1359, 1117, 1082, 1005, 926, 889, 669 cm⁻¹. HRMS calcd for C₁₇H₂₁NO₆ + H⁺: 336.1447, found 336.1442. The product was analyzed by HPLC to determine the enantiomeric excess: 90% ee (Chiralpak IA, i-propanol–hexane = 30/70, flow rate 1.0 mL min⁻¹, λ = 220 nm); t_r = 13.96 and 18.29 min.

(2R,4S,5R)-Dimethyl 5-(4-chlorophenyl)-4-(2-methoxy-2-oxoethyl)pyrrolidine-2,4-dicarboxylate (3b). The title compound was prepared according to the general procedure as described above in 85% yield (72 mg) as white solid. M.p. 167–168 °C; [α]²⁵_D = +31.4 (c 1.10, CHCl₃); ¹H NMR (CDCl₃, TMS, 300 MHz) δ 7.30 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 4.07 (s, 1H), 4.01 (dd, J₁ = 6.3 Hz, J₂ = 9.3 Hz, 1H), 3.84 (s, 3H), 3.66 (s, 3H), 3.29 (s, 3H), 3.09 (d, J = 16.8 Hz, 1H), 3.03 (dd, J₁ = 6.3 Hz, J₂ = 13.8 Hz, 1H), 2.51 (d, J = 17.1 Hz, 1H), 2.27 (dd, J₁ = 9.3 Hz, J₂ = 13.8 Hz, 1H); ¹³C NMR (CDCl₃, TMS, 75 MHz) δ 173.8, 172.5, 171.2, 136.1, 133.7, 128.3, 128.0, 71.3, 58.4, 55.9, 52.1, 51.6, 51.5, 40.1, 39.0; IR (KBr) ν 2952, 2399, 1736, 1490, 1438, 1354, 1094, 1010, 669 cm⁻¹. HRMS calcd for C₁₇H₂₀ClNO₆ + H⁺: 370.1057, found 370.1062. The product was analyzed by HPLC to determine the enantiomeric excess: 91% ee (Chiralpak AS-H, i-propanol–hexane = 40/60, flow rate 1.0 mL min⁻¹, λ = 220 nm); t_r = 7.63 and 11.66 min.

(2R,4S,5S)-Dimethyl 5-(2-chlorophenyl)-4-(2-methoxy-2-oxoethyl)pyrrolidine-2,4-dicarboxylate (3c). The title compound was prepared according to the general procedure as described above in 86% yield (73 mg) as white solid. M.p. 160–161 °C; [α]²⁵_D = +24.7 (c 1.28, CHCl₃); ¹H NMR (CDCl₃, TMS, 300 MHz) δ 7.47–7.45 (m, 1H), 7.37–7.35 (m, 1H), 7.26–7.20 (m, 3H), 4.79 (s, 1H), 4.03 (m, 1H), 3.84 (s, 3H), 3.65 (s, 3H), 3.32 (d, J = 17.7 Hz, 1H), 3.26 (s, 3H), 3.11 (dd, J₁ = 6.9 Hz, J₂ = 13.8 Hz, 1H), 2.63 (d, J = 17.4 Hz, 1H), 2.26 (dd, J₁ = 9.0 Hz, J₂ = 13.8 Hz, 1H); ¹³C NMR (CDCl₃, TMS, 75 MHz) δ 173.8, 172.7, 171.6, 135.6, 133.6, 129.5, 129.0, 127.9, 126.7, 66.4, 58.5, 56.7, 52.1, 51.6, 51.5, 40.7, 39.5; IR (KBr) ν 2954, 2923, 2849, 1739, 1437, 1361, 1120, 1080, 1037, 1000, 668 cm⁻¹. HRMS calcd for C₁₇H₂₀ClNO₆ + H⁺: 370.1057, found 370.1060. The product was analyzed by HPLC to determine the enantiomeric excess: 93% ee (Chiralpak AS-H, i-propanol–hexane = 40/60, flow rate 1.0 mL min⁻¹, λ = 220 nm); t_r = 6.48 and 13.44 min.

(2R,4S,5R)-Dimethyl 5-(3-chlorophenyl)-4-(2-methoxy-2-oxoethyl)pyrrolidine-2,4-dicarboxylate (3d). The title compound was prepared according to the general procedure as described above in 90% yield (76 mg) as white solid. M.p. 163–164 °C; [α]²⁵_D = +30.4 (c 1.60, CHCl₃); ¹H NMR (CDCl₃, TMS, 300 MHz) δ 7.26 (m, 3H), 7.16 (m, 1H), 4.05–3.99 (m, 2H), 3.85 (s, 3H), 3.66 (s, 3H), 3.31 (s, 3H), 3.10 (d, J = 17.1 Hz, 1H), 3.04 (dd, J₁ = 6.3 Hz, J₂ = 13.8 Hz, 1H), 2.51 (d, J = 16.8 Hz, 1H), 2.26 (dd, J₁ = 9.6 Hz, J₂ = 13.8 Hz, 1H); ¹³C NMR (CDCl₃, TMS, 75 MHz) δ 173.8, 172.5, 171.2, 139.7, 134.1, 129.5, 128.3, 126.9, 124.9, 71.5, 58.5, 56.0, 52.2, 51.7, 51.5, 40.2, 39.0; IR (KBr) ν 2954, 2928, 2853, 2399, 1738, 1598, 1575, 1437, 1360, 1118, 1081, 1002, 872, 668 cm⁻¹. HRMS calcd for C₁₇H₂₀ClNO₆ + H⁺: 370.1057, found 370.1058. The product was analyzed by HPLC to determine the enantiomeric excess: 88% ee (Chiralpak IA, i-propanol–hexane = 30/70, flow rate 1.0 mL min⁻¹, λ = 220 nm); t_r = 18.79 and 28.93 min.

(2R,4S,5R)-Dimethyl 4-(2-methoxy-2-oxoethyl)-5-(p-tolyl)-pyrrolidine-2,4-dicarboxylate (3e). The title compound was prepared according to the general procedure as described above in 95% yield (76 mg) as white solid. M.p. 155–156 °C; [α]²⁵_D = +32.2 (c 1.39, CHCl₃); ¹H NMR (CDCl₃, TMS, 300 MHz) δ 7.12 (m, 4H), 4.02–3.98 (m, 2H), 3.84 (s, 3H), 3.64 (s, 3H), 3.29 (s, 3H), 3.09 (d, J = 17.1 Hz, 1H), 3.03 (dd, J₁ = 6.0 Hz, J₂ = 14.1 Hz, 1H), 2.47 (d, J = 16.8 Hz, 1H), 2.32 (s, 3H), 2.27–2.22 (m, 1H); ¹³C NMR (CDCl₃, TMS, 75 MHz) δ 174.1, 173.0, 171.5, 137.9, 133.7, 129.0, 126.4, 72.4, 58.7, 55.9, 52.2, 51.7, 51.5, 40.2, 39.8, 21.0; IR (KBr) ν 2994, 2953, 2854, 1737, 1606, 1515, 1436, 1359, 1323, 1205, 1117, 1079, 1020, 897, 811 cm⁻¹. HRMS calcd for C₁₈H₂₃NO₆ + H⁺: 350.1604, found 350.1611. The product was analyzed by HPLC to determine the enantiomeric excess: >99% ee (Chiralpak AD-H, i-propanol–hexane = 30/70, flow rate 1.0 mL min⁻¹, λ = 220 nm); t_r = 15.04 and 23.32 min.

(2R,4S,5R)-Dimethyl 4-(2-methoxy-2-oxoethyl)-5-(o-tolyl)-pyrrolidine-2,4-dicarboxylate (3f). The title compound was prepared according to the general procedure as described above in 92% yield (74 mg) as white solid. M.p. 136–137 °C; [α]²⁵_D = +1.8 (c 1.29, CHCl₃); ¹H NMR (CDCl₃, TMS, 300 MHz) δ 7.37–7.15 (m, 4H), 4.48 (s, 2H), 4.05–3.99 (m, 1H), 3.84 (s, 3H), 3.65 (s, 3H), 3.27 (s, 3H), 3.13 (d, J = 16.5 Hz 1H), 3.07 (dd, J₁ = 7.2 Hz, J₂ = 14.1 Hz, 1H), 2.56 (d, J = 16.5 Hz, 1H), 2.30 (s, 3H), 2.26 (dd, J₁ = 9.0 Hz, J₂ = 13.5 Hz, 1H); ¹³C NMR (CDCl₃, TMS, 75 MHz) δ 174.0, 173.0, 171.3, 136.0, 135.8, 130.6, 127.7, 126.0, 125.7, 67.0, 58.8, 56.7, 51.7, 51.5, 40.7, 39.7, 20.0; IR (KBr) ν 2954, 2928, 1738, 1458, 1437, 1357, 1319, 1118, 1077, 1005, 668 cm⁻¹. HRMS calcd for C₁₈H₂₃NO₆ + H⁺: 350.1604, found 350.1608. The product was analyzed by HPLC to determine the enantiomeric excess: 94% ee (Chiralpak AD-H, i-propanol–hexane = 30/70, flow rate 1.0 mL min⁻¹, λ = 220 nm); t_r = 6.31 and 10.75 min.

(2R,4S,5R)-Dimethyl 4-(2-methoxy-2-oxoethyl)-5-(m-tolyl)-pyrrolidine-2,4-dicarboxylate (3g). The title compound was prepared according to the general procedure as described above in 93% yield (75 mg) as white solid. M.p. 132–133 °C; [α]²⁵_D = +10.2 (c 1.29, CHCl₃); ¹H NMR (CDCl₃, TMS, 300 MHz) δ 7.24–7.18 (m, 1H), 7.11–7.03 (m, 3H), 4.04–3.99 (m, 2H), 3.85 (s, 3H), 3.65 (s, 3H), 3.28 (s, 3H), 3.10 (d, J = 17.1 Hz, 1H), 3.04 (dd, J₁ = 5.7 Hz, J₂ = 13.8 Hz, 1H); 2.48 (d, J = 16.8 Hz, 1H), 2.34 (s, 3H), 2.26 (dd, J₁ = 9.9 Hz, J₂ = 13.8 Hz, 1H); ¹³C NMR (CDCl₃, TMS, 75 MHz) δ 173.9, 173.0, 171.5, 137.9, 136.6, 129.0, 128.2, 127.2, 123.7, 72.5, 58.7, 56.0, 52.2, 51.7, 51.4, 40.2, 39.8, 21.3; IR (KBr) ν 2952, 2923, 2852, 1735, 1435, 1358, 1201, 1176, 1122, 1078, 1003, 879, 795, 781, 699 cm⁻¹. HRMS calcd for C₁₈H₂₃NO₆ + H⁺: 350.1604, found 350.1610. The product was analyzed by HPLC to determine the enantiomeric excess: 89% ee (Chiralpak AD-H, i-propanol–hexane = 30/70, flow rate 1.0 mL min⁻¹, λ = 220 nm); t_r = 14.35 and 31.06 min.

(2R,4S,5R)-Dimethyl 4-(2-methoxy-2-oxoethyl)-5-(4-methoxyphenyl) pyrrolidine-2,4-dicarboxylate (3h). The title compound was prepared according to the general procedure as described above in 81% yield (68 mg) as white solid. M.p. 148–149 °C; [α]²⁵_D = +25.9 (c 1.19, CHCl₃); ¹H NMR (CDCl₃, TMS, 300 MHz) δ 7.16 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.03 (s, 1H), 3.99 (dd, J₁ = 12.3 Hz, J₂ = 18.6 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.65 (s, 3H), 3.30 (s, 3H), 3.08 (d, J = 17.1 Hz, 1H), 3.02 (dd, J₁ = 6.3 Hz, J₂ = 14.1 Hz, 1H), 2.47 (d, J = 17.1 Hz, 1H), 2.26 (dd, J₁ = 9.6 Hz, J₂ = 13.8 Hz, 1H); ¹³C NMR (CDCl₃, TMS, 75 MHz) δ 174.0, 173.0, 171.5, 159.4, 129.0, 127.7, 113.6, 72.0, 58.6, 55.9, 55.1, 52.2, 51.6, 51.5, 40.2, 39.6; IR (KBr) ν 2954, 2928, 1736, 1612, 1515, 1438, 1112, 1035, 669 cm⁻¹. HRMS calcd for C₁₈H₂₃NO₇ + H⁺: 366.1553, found 366.1551. The product was analyzed by HPLC to determine the enantiomeric excess: 92% ee (Chiralpak AS-H, i-propanol–hexane = 40/60, flow rate 1.0 mL min⁻¹, λ = 220 nm); t_r = 6.49 and 13.04 min.

(2R,4S,5R)-Dimethyl 4-(2-methoxy-2-oxoethyl)-5-(2-methoxyphenyl) pyrrolidine-2,4-dicarboxylate (3i). The title compound was prepared according to the general procedure as described above in 76% yield (64 mg) as white solid. M.p. 142–143 °C; [α]²⁵_D = +4.4 (c 1.10, CHCl₃); ¹H NMR (CDCl₃, TMS, 300 MHz) δ 7.26–7.21 (m, 2H), 6.95–6.85 (m, 2H), 4.59 (s, 1H), 4.00 (dd, J₁ = 6.0 Hz, J₂ = 9.6 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.64 (s, 3H), 3.27 (s, 3H), 3.20 (d, J = 17.7 Hz, 1H), 3.04 (dd, J₁ = 6.6 Hz, J₂ = 14.1 Hz, 1H), 2.53 (d, J = 17.4 Hz, 1H), 2.24 (dd, J₁ = 9.9 Hz, J₂ = 13.8 Hz, 1H); ¹³C NMR (CDCl₃, TMS, 75 MHz) δ 173.9, 173.4, 172.0, 156.9, 128.9, 126.7, 124.8, 120.3, 110.4, 65.3, 58.8, 56.1, 55.2, 52.1, 51.6, 51.5, 40.5, 40.4; IR (KBr) ν 2999, 2952, 2923, 2852, 1736, 1601, 1579, 1493, 1437, 1358, 1324, 1246, 1204, 1176, 1115, 1079, 1026, 900, 759 cm⁻¹. HRMS calcd for C₁₈H₂₃NO₇ + H⁺: 366.1553, found 366.1560. The product was analyzed by HPLC to determine the enantiomeric excess: 94% ee (Chiralpak AD-H, i-propanol–hexane = 30/70, flow rate 1.0 mL min⁻¹, λ = 220 nm); t_r = 10.74 and 24.50 min.

(2R,4S,5R)-Dimethyl 4-(2-methoxy-2-oxoethyl)-5-(3-methoxyphenyl) pyrrolidine-2,4-dicarboxylate (3j). The title compound was prepared according to the general procedure as described above in 88% yield (74 mg) as white solid. M.p. 137–138 °C; [α]²⁵_D = +17.9 (c 1.13, CHCl₃); ¹H NMR (CDCl₃, TMS, 300 MHz) δ 7.24–7.22 (m, 1H), 6.84–6.81 (m, 3H), 4.04–3.99 (m, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.66 (s, 3H), 3.30 (s, 3H), 3.13 (d, J = 17.1 Hz, 1H), 3.04 (dd, J₁ = 6.0 Hz, J₂ = 13.8 Hz, 1H), 2.49 (d, J = 17.1 Hz, 1H), 2.27 (dd, J₁ = 9.6 Hz, J₂ = 13.8 Hz, 1H); ¹³C NMR (CDCl₃, TMS, 75 MHz) δ 174.0, 172.8, 171.5, 159.5, 138.8, 129.3, 118.8, 113.4, 112.6, 72.4, 58.8, 56.1, 55.1, 52.2, 51.7, 51.5, 40.3, 39.6; IR (KBr) ν 2954, 2925, 2844, 1737, 1602, 1492, 1456, 1437, 1360, 1112, 1077, 1049, 998, 699, 666 cm⁻¹. HRMS calcd for C₁₈H₂₃NO₇ + H⁺: 366.1553, found 366.1558. The product was analyzed by HPLC to determine the enantiomeric excess: 90% ee (Chiralcel OD-H, i-propanol–hexane = 30/70, flow rate 1.0 mL min⁻¹, λ = 220 nm); t_r = 15.82 and 28.07 min.

(2R,4S,5R)-Dimethyl 4-(2-methoxy-2-oxoethyl)-2-methyl-5-phenylpyrrolidine-2,4-dicarboxylate (3k). The title compound was prepared according to the general procedure as described above in 82% yield (66 mg) as white solid. M.p. 124–125 °C; [α]²⁵_D = +25.0 (c 1.83, CHCl₃); ¹H NMR (CDCl₃, TMS, 300 MHz) δ 7.33–7.19 (m, 5H), 4.15 (s, 1H), 3.86 (s, 3H), 3.64 (s, 3H), 3.42 (d, J = 14.1 Hz, 1H), 3.28 (s, 3H), 3.07 (d, J = 17.1 Hz, 1H), 2.41 (d, J = 17.1 Hz, 1H), 1.85 (d, J = 14.1 Hz, 1H), 1.52 (s, 3H); ¹³C NMR (CDCl₃, TMS, 75 MHz) δ 177.1, 173.0, 171.5, 136.3, 128.4, 128.3, 126.5, 71.6, 65.0, 57.7, 52.5, 51.7, 51.4, 48.4, 40.5, 29.0; IR (KBr) ν 2950, 2397, 1735, 1487, 1359, 1084, 1008, 673 cm⁻¹. HRMS calcd for C₁₈H₂₃NO₆ + H⁺: 350.1604, found 350.1605. The product was analyzed by HPLC to determine the enantiomeric excess: 93% ee (Chiralcel AD-H, i-propanol–hexane = 20/80, flow rate 1.0 mL min⁻¹, λ = 220 nm); t_r = 8.67 and 9.82 min.

(2R,4R,5R)-Dimethyl 5-(4-chlorophenyl)-4-(3-methoxy-3-oxopropyl)pyrrolidine-2,4-dicarboxylate (3l). The title compound was prepared according to the general procedure as described above in 85% yield (75 mg) as white solid. M.p. 155–156 °C; [α]²⁵_D = +28.1 (c 1.05, CHCl₃); ¹H NMR (CDCl₃, TMS, 300 MHz) δ 7.29 (d, J = 8.4 Hz), 7.23 (d, J = 8.4 Hz), 4.10 (s, 1H), 4.03 (dd, J₁ = 6.0 Hz, J₂ = 9.0 Hz, 1H), 3.84 (s, 3H), 3.68 (s, 3H), 3.27 (s, 3H), 2.72 (dd, J₁ = 6.0 Hz, J₂ = 13.2 Hz, 1H), 2.36–2.26 (m, 3H), 2.15 (dd, J₁ = 9.6 Hz, J₂ = 13.5 Hz, 1H), 1.86–1.80 (m, 1H); ¹³C NMR (CDCl₃, TMS, 75 MHz) δ 174.0, 173.1, 172.9, 136.7, 133.6, 128.2, 128.1, 72.7, 58.4, 52.2, 51.7, 51.5, 37.5, 31.0, 30.8; IR (KBr) ν 2997, 2953, 2918, 2844, 1732, 1489, 1435, 1377, 1304, 1203, 1176, 1117, 1089, 1013, 986, 834, 694 cm⁻¹. HRMS calcd for C₁₈H₂₂ClNO₆ + H⁺: 384.1214, found 384.1219. The product was analyzed by HPLC to determine the enantiomeric excess: 93% ee (Chiralpak AS-H, i-propanol–hexane = 40/60, flow rate 1.0 mL min⁻¹, λ = 220 nm); t_r = 6.93 and 10.29 min.

(2R,4R,5R)-Dimethyl 4-(3-methoxy-3-oxopropyl)-5-(4-methoxyphenyl)pyrrolidine-2,4-dicarboxylate (3m). The title compound was prepared according to the general procedure as described above in 81% yield (71 mg) as white solid. M.p. 140–141 °C; [α]²⁵_D = +25.0 (c 1.83, CHCl₃); ¹H NMR (CDCl₃, TMS, 300 MHz) δ 7.18 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 4.07 (s, 1H), 4.02 (dd, J₁ = 6.3 Hz, J₂ = 9.9 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.67 (s, 3H), 3.28 (s, 3H), 2.70 (dd, J₁ = 5.7 Hz, J₂ = 13.2 Hz, 1H), 2.36–2.25 (m, 3H), 2.14 (dd, J₁ = 9.3 Hz, J₂ = 12.9 Hz, 1H), 1.82–1.79 (m, 1H); ¹³C NMR (CDCl₃, TMS, 75 MHz) δ 174.1, 173.3, 173.2, 159.2, 129.7, 127.7, 113.5, 73.3, 58.5, 58.3, 55.1, 52.2, 51.6, 51.4, 38.0, 31.1, 31.0; IR (KBr) ν 2997, 2953, 2847, 2360, 2342, 1736, 1698, 1685, 1600, 1578, 1260, 1161, 1027, 835, 669 cm⁻¹. HRMS calcd for C₁₉H₂₅NO₇ + H⁺: 380.1709, found 380.1706. The product was analyzed by HPLC to determine the enantiomeric excess: 99% ee (Chiralpak AS-H, i-propanol–hexane = 40/60, flow rate 1.0 mL min⁻¹, λ = 220 nm); t_r = 8.68 and 13.41 min.

Acknowledgements

We gratefully acknowledge financial support from the 973 Program (2011CB808600), NSFC (21172176) and Hubei Province NSF (ZRZ0273).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental section, crystal data for (2R,4S,5S)-3c: C₁₇H₂₀ClNO₆, M_r = 369.79, T = 296 K, orthorhombic, space group P2₁2₁2₁, a = 9.8397(12), b = 10.1420(13), c = 17.897(2) Å, V = 1786.1(4) ų, Z = 4, 11 885 reflections measured, 3273 unique (R_int = 0.0332) which were used in all calculations. The final wR₂ = 0.0870 (all data), Flack χ = 0.03(6). CCDC 985571. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra02195a

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