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DOI: 10.1055/s-0036-1588137
l-tert-Leucine-Derived AmidPhos–Silver(I) Chiral Complexes for the Asymmetric [3+2] Cycloaddition of Azomethine Ylides
Publication History
Received: 07 December 2016
Accepted after revision: 06 January 2017
Publication Date:
02 February 2017 (online)
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).
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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]
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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.
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).
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).
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]
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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.
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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.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0036-1588137.
- Supporting Information
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References and Notes
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- 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.
Recent reviews of catalytic asymmetric 1,3-dipolar cycloaddition:
Recent references on chiral silver catalyst:
Recent references on chiral copper catalyst:
Select references on other chiral metal catalysts. Zn:
Nickel:
Calcium:
Gold:
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References and Notes
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- 1b Overman LE, Tellew JE. J. Org. Chem. 1996; 61: 8338
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- 1e Sebahar PR, Williams RM. J. Am. Chem. Soc. 2000; 122: 5666
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- 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.
Recent reviews of catalytic asymmetric 1,3-dipolar cycloaddition:
Recent references on chiral silver catalyst:
Recent references on chiral copper catalyst:
Select references on other chiral metal catalysts. Zn:
Nickel:
Calcium:
Gold:
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