β-Silyl Acrylates in Asymmetric [3 + 2 ... - ACS Publications

May 6, 2018 - Notably, the 3-silylpyrrolidines can easily be converted to pyrrolidine azasugar .... eoselectivities (90:10, 94:6 dr) (Table 3, entries...
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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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β‑Silyl Acrylates in Asymmetric [3 + 2] Cycloadditions Affording Pyrrolidine Azasugar Derivatives Fei Tian, Fu-Sheng He, Hua Deng, Wu-Lin Yang,* and Wei-Ping Deng* School of Pharmacy and Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China

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S Supporting Information *

ABSTRACT: A highly efficient copper(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with 3-silyl unsaturated esters has been developed, providing elegant access to chiral 3-silylpyrrolidine derivatives bearing contiguous stereogenic centers in moderate-to-excellent yields (up to 99%) with high diastereo- and enantioselectivities (dr up to >99:1; ee up to 96%). Notably, the 3-silylpyrrolidines can easily be converted to pyrrolidine azasugar derivatives with potential biological activities by the reduction of two ester groups and carbon−silicon bond oxidation.

O

On the other hand, chiral pyrrolidines have long been considered “privileged scaffolds” in various biologically active natural products and pharmaceuticals.6 Notably, 3-silylpyrrolidines exhibit useful biological activities. For instance, carbine−gold complex 57a can inhibit the proliferation of different human cancer cell lines, and compound 6 is another antitumor agent (Figure 2).7b Additionally, 3-silylpyrrolidines can conveniently be converted to 3-hydroxypyrrolidine derivatives by oxidation of the carbon−silicon bond, and these are found in many biologically active compounds and pharmaceuticals.8 In this context, the construction of 3silylpyrrolidine compounds has attracted increasing attention.9

rganosilicon compounds are garnering increasing attention in medicinal chemistry1 and material science2 due to their interesting chemical, physical, and bioactive properties. In particular, more viable candidates as drugs can come from introducing silicon in place of carbon in bioactive compounds. The process, known as silasubstitution, can lead to increased metabolic stability, alternative bond polarization, lipophilicity, and changed bond angles. For instance, sila derivatives 2 showed almost equivalent inhibition in the p38 MAP kinase enzyme assay compared to 1 (BIRB-796),3 and sila-venlafaxine 4 exhibited a better ability to inhibit noradrenaline reuptake than venlafaxine 3 (Figure 1).4 In addition, organosilicon compounds are useful intermediates in rearrangement reactions and for the construction of carbon− carbon bonds and widely applied in organic synthesis.5

Figure 2. Selected examples of biologically active compounds containing 3-silylpyrrolidine or 3-hydroxypyrrolidine skeleton. Received: May 6, 2018

Figure 1. Examples of some drugs and their silicon isosteres. © XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.8b01430 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

ligand L8 were then examined (Table 1, entries 2−8). Gratifyingly, planar-chiral ferrocene P,N-ligand L3 exhibited the optimal reaction outcome in terms of the yield and enantioselectivity, giving the target cycloadduct 11aa in excellent yield (97%) with high enantioselectivity (87%) and moderate diastereoselectivity (88:12). Subsequently, exploration of the metal source14 showed that Cu(CH3CN)4BF4 was the best choice with respect to the yield and enantioselectivity, whereas Cu(MeCN)4PF6 and Cu(CF3SO3)2 gave lower yields and enantioselectivities, and AgCO2CF3 gave rise to a dramatic increase in diastereoselectivity, but lowered enantioselectivity (Table 1, entries 9−11). Furthermore, screening of other bases and solvents did not show any better results (see Table S1). In addition, lowering the reaction temperature from 0 to −40 °C led to obvious improvement in the enantioselectivity but a slight decrease in diastereoselectivity and yield (Table 1, entries 12−14), and further lowering the reaction temperature to −60 °C did not show any better enantioselectivity, but lowered yield. With the optimized reaction conditions in hand, the generality and substrate scope of this process were examined. To begin with, 3-silyl unsaturated esters 10 were investigated under the optimized conditions to test the dipolarophile scope of this asymmetric 1,3-dipolar cycloaddition, and the results are summarized in Table 2. By changing the silyl group of 3-

However, the enantioselective synthesis of 3-silylpyrrolidines bearing multiple contiguous stereogenic centers remains a distinct challenge. In view of the catalytic asymmetric 1,3dipolar cycloaddition of azomethine ylides possessing unique superiority in the synthesis of structurally diverse pyrrolidines,10−12 as well as combining our continuing interest in the cycloaddition of azomethine ylides,13 we now demonstrate the first copper(I)-catalyzed asymmetric [3 + 2] cycloaddition of azomethine ylides with 3-silyl unsaturated esters to generate 3silylpyrrolidines in high yield and stereoselectivity. Such compounds can conveniently be converted to pyrrolidine azasugar derivatives by the reduction of two ester groups and carbon−silicon bond oxidation. To validate our hypothesis, we chose imino ester 9a and βdimethylphenylsilyl-acrylate 10a as the model substrates for probing this reaction (Table 1). We commenced our Table 1. Optimization for the Catalytic Asymmetric 1,3Dipolar Cycloaddition of Azomethine Ylide 9a with βDimethylphenylsilyl Acrylate 10aa

Table 2. Substrate Scope of 3-Silyl Unsaturated Esters 10a

entry

ligand

metal

time (h)

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12d 13e 14f 15g

L1 L2 L3 L4 L5 L6 L7 L8 L3 L3 L3 L3 L3 L3 L3

Cu(MeCN)4BF4 Cu(MeCN)4BF4 Cu(MeCN)4BF4 Cu(MeCN)4BF4 Cu(MeCN)4BF4 Cu(MeCN)4BF4 Cu(MeCN)4BF4 Cu(MeCN)4BF4 Cu(MeCN)4PF6 Cu(CF3SO3)2 AgCO2CF3 Cu(MeCN)4BF4 Cu(MeCN)4BF4 Cu(MeCN)4BF4 Cu(MeCN)4BF4

1 1 1 1 1 1 1 1 1 1 1 4 6 7 24

89 94 97 88 77 77 78 71 91 88 93 97 95 94 72

eec (%); drc 44; 55; 87; 23; 61; −65; −44; −34; 81; 80; 73; 90; 92; 95; 95;

94:6 93:7 88:12 96:4 92:8 98:2 98:2 97:3 89:11 88:12 98:2 87:13 85:15 85:15 86:14

entry

10, R1/R2

time (h)

11, yieldb (%)

1 2 3 4 5

10a, PhMe2Si/Me 10b, Ph2MeSi/Me 10c, Ph3Si/Me 10d, Ph2MeSi/Et 10d, Ph3Si/Et

5 7 10 7 10

11aa, 94 11ab, 98 11ac, 82 11ad, 92 11ae, 80

eec (%); drd 95; 95; 94; 95; 95; >

85:15 95:5 92:8 93:7 99:1

a

Unless otherwise stated, reactions were carried out with 0.225 mmol of 9a and 0.15 mmol of 10 in 1.5 mL of THF at −40 °C. bIsolated yield of two diastereomers. cThe ee was determined by chiral HPLC analysis; the ee refers to the major diastereomer. dThe dr was determined by 1H NMR spectroscopy.

silyl-unsaturated esters from dimethylphenylsilyl to methyldiphenylsilyl and triphenylsilyl groups, the corresponding chiral 3-silylpyrrolidine derivatives 11aa−ac could still be obtained in high yields (82−98%) and excellent enantioselectivities (94−95% ee), and notably, utilizing β-methyldiphenylsilyl-acrylate 10b resulted in a remarkable improvement in diastereoselectivity (Table 2, entries 1−3). Changing the ester groups of the 3-silyl-unsaturated esters from methyl to ethyl groups gave the corresponding products (11ad,ae) in high yields (80−92%) with excellent enantioselectivities (95% ee) and excellent diastereoselectivities (93:7, > 99:1 dr) (Table 2, entries 4 and 5). Next, we confirmed β-methyldiphenylsilyl acrylate 10b as a model substrate to test a series of imino esters derived from glycinate, and the results are shown in Table 3. The ester groups of imino esters (9b,c) were varied (Et, Bn), giving the corresponding products (11bb,cb) in good yields (70−92%), excellent enantioselectivities (91−96% ee) and high diastereoselectivities (90:10, 94:6 dr) (Table 3, entries 1 and 2).

a

Unless otherwise stated, reactions were carried out with 0.15 mmol of 9a and 0.1 mmol of 10a in 1.0 mL of THF at room temperature. b Isolated yield of two diastereomers. cThe dr and ee were determined by chiral HPLC analysis; the ee referred to the major diastereomer. d Reaction conducted at 0 °C. eReaction conducted at −20 °C. f Reaction conducted at −40 °C. gReaction conducted at −60 °C.

investigation using 10 mol % of Cu(CH3CN)4BF4/planarchiral ferrocene P,N-ligand (Phosferrox) L1 complex as the catalyst and Cs2CO3 as the base in THF at room temperature (Table 1, entry 1). To our delight, the reaction finished after 1 h and gave the desired cycloadduct 11aa in 89% yield with moderate enantioselectivity (44%) and excellent diastereoselectivity (94:6). Encouraged by this promising result, different chiral ligands, including planar-chiral ferrocene P,N-ligands L2L5, N,O-ligand L6, monophos ligand L7, and bisphosphine B

DOI: 10.1021/acs.orglett.8b01430 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 3. Substrate Scope of Azomethine Ylides 9a

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

9, R1/R2 9b, p-ClC6H4/Et 9c, p-ClC6H4/Bn 9d, o-ClC6H4/Me 9e, m-ClC6H4/Me 9f, p-BrC6H4/Me 9g, m-BrC6H4/Me 9h, p-CO2MeC6H4/ Me 9i, o-MeC6H4/Me 9j, m-MeC6H4/Me 9k, p-MeC6H4/Me 9l, p-MeOC6H4/Me 9m, Ph/Me 9n, 2-naphthyl/Me 9o, 2-thienyl/Me 9p, Cy/Me

Scheme 1. Gram-Scale Experiment

time (h)

11, yieldb (%)

5 24 7 24 6 24 24

11bb, 92 11cb, 70 11db, 92 11eb, 63 11fb, 99 11gb, 61 11hb, 82

96; 91; 96; > 82; 95; 81; 95;

94:6 90:10 99:1 94:6 94:6 92:8 94:6

6 17 6 6 7 7 24 24

11ib, 99 11jb, 95 11kb, 99 11 lb, 96 11mb, 93 11nb, 96 11ob, 76 11pb, 46

94; 92; 91; 91; 95; 94; 93; 91(96)e;

94:6 94:6 93:7 90:10 94:6 94:6 92:8 58:42

eec (%); drd

a

Unless otherwise stated, reactions were carried out with 0.225 mmol of 9 and 0.15 mmol of 10b in 1.5 mL of THF at −40 °C. bIsolated yield of two diastereomers. cThe ee was determined by chiral HPLC analysis; the ee refers to the major diastereomer. dThe dr was determined by 1H NMR spectroscopy. eThe ee refers to the minor diastereomer.

Figure 3. Proposed transition states and the absolute configuration determination of the cycloadduct 11db.

shielded by the bulky phenyl group on the oxazoline ring of the Phosferrox ligand, which facilitates the attack of dipolarophile 10b from the “top” face (transition state II), thus affording 11db in high stereoselectivity. The absolute configuration of the major diastereoisomer of 11db was assigned as exo(2R,3S,4S,5R) by single-crystal X-ray crystallographic analysis (Figure 3, see the Supporting Information for details), which could be applied to all cycloadducts. As mentioned above, the pyrrolidine azasugar 8 (Figure 2) is a moderate inhibitor of α-glucosidase from yeast. However, there are only two methods reported for the synthesis of the pyrrolidine azasugar, which both suffer from harsh reaction conditions and low yield.8c,d We chose cycloadduct 11db as an example to illustrate this novel route to pyrrolidine azasugar derivatives. Initially, the corresponding N-tosylated pyrrolidine 12 was obtained in excellent yield (96%). Treatment of 12 with LiAlH4 delivered the corresponding pyrrolidine 13 in 89% yield without loss of the ee value; it was then converted to optically pure 3-hydroxypyrrolidine 14 in 89% yield in the presence of boron trifluoride/acetic acid complex, potassium fluoride, and hydrogen peroxide. Finally, the chiral 3hydroxypyrrolidine 14 was deprotected efficiently to construct chiral pyrrolidine azasugar derivative 15 in 76% yield in the presence of hydrobromic acid and phenol (Scheme 2). In conclusion, we have demonstrated a highly efficient chiral Ph-Phosferrox/Cu(CH3CN)4BF4 catalytic system for the asymmetric 1,3-dipolar cycloaddition of azomethine ylides with 3-silyl unsaturated esters, affording 3-silylpyrrolidines in moderate to excellent yields (up to 99%) with high diastereoand enantioselectivities (dr up to >99:1; ee up to 96%). Notably, this is the first example of catalytic stereoselective construction of 3-silylpyrrolidines, which suggests a highly efficient synthetic protocol of potential importance to medicinal chemistry and diversity-oriented synthesis. It is

Then a series of azomethine ylides 9 bearing electron-deficient (Table 3, entries 3−7), electron-rich (Table 3, entries 8−11), and electron-neutral (Table 3, entries 12 and 13) groups on the aryl ring were employed. The cycloaddition process could also proceed smoothly, affording high yields (82−99%) with high diastereo- and enantioselectivities (90:10 → 99:1 dr, 91− 96% ee). Notably, the cycloaddition process of imino esters 9e or 9g with β-methyldiphenylsilyl acrylate 10b led to a decrease in yield and enantioselectivity of the desired cycloadducts (Table 3, entries 4 and 6). The heteroaryl imino ester 9o derived from 2-thenaldehyde worked efficiently in this transformation, resulting in the desired cycloadduct 11ob in high yield (76%), with excellent diastereo- and enantioselectivity (92:8 dr, 93% ee) (Table 3, entry 14). Additionally, less reactive aliphatic-substituted imino ester 9p was also tolerated in this reaction with the desired adduct 11pb being obtained in moderate yield (46%) with poor diastereoselectivity (58:42 dr) but excellent enantioselectivity (91%, 96% ee respectively of two diastereomers) (Table 3, entry 15). To demonstrate the synthetic utility of this catalytic system, the asymmetric 1,3-dipolar cycloaddition between 9d and 10b was carried out on gram scale, affording 11db in 85% yield with >99:1 dr and 96% ee (>99% ee, after recrystallization) (Scheme 1). The high stereoselectivity observed in this asymmetric 1,3dipolar cycloaddition can be justified by the proposed transition states (Figure 3). As shown in proposed transition state I, the steric repulsion between PPh2 group of the Phosferrox ligand and bulky silicon group of dipolarophile 10b blocks the dipolarophile’s approach toward azomethine ylide. Additionally, the “bottom” face of the azomethine ylide is C

DOI: 10.1021/acs.orglett.8b01430 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

2013, 56, 388. (e) Min, G. K.; Hernandez, D.; Skrydstrup, T. Efficient Routes to Carbon-Silicon Bond Formation for the Synthesis of Silicon-Containing Peptides andAzasilaheterocycles. Acc. Chem. Res. 2013, 46, 457. (2) Organosilicon Chemistry V: From Molecules to Materials; Auner, N., Weis, J., Eds.; Wiley-VCH: Weinheim, 2004. (3) (a) Barnes, M. J.; Conroy, R.; Miller, D. J.; Mills, J. S.; Montana, J. G.; Pooni, P. K.; Showell, G. A.; Walsh, L. M.; Warneck, J. B. H. Trimethylsilylpyrazoles as Novel Inhibitors of p38 MAP Kinase: A New Use of Silicon Bioisosteres in Medicinal Chemistry. Bioorg. Med. Chem. Lett. 2007, 17, 354. (b) Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore, T.; Graham, A. G.; Hickey, E.; Klaus, B.; Madwed, J.; Moriak, M.; Moss, N.; Pargellis, C.; Pav, S.; Proto, A.; Swinamer, A.; Tong, L.; Torcellini, C. Pyrazole urea-Based Inhibitors of p38 MAP Kinase: from Lead Compound to Clinical Candidate. J. Med. Chem. 2002, 45, 2994. (4) Daiss, J. O.; Burschka, C.; Mills, J. S.; Montana, J. G.; Showell, G. A.; Warneck, J. B. H.; Tacke, R. Sila-venlafaxine A. Sila-analogue of the Serotonin/Noradrenaline Reuptake Inhibitor Venlafaxine: Synthesis, Crystal Structure Analysis, and Pharmacological Characterization. Organometallics 2006, 25, 1188. (5) (a) Chabaud, L.; James, P.; Landais, Y. Allylsilanes in Organic Synthesis - Recent Developments. Eur. J. Org. Chem. 2004, 2004, 3173. (b) Zhang, H.-J.; Priebbenow, D. L.; Bolm, C. Acylsilanes: valuable organosilicon reagents in organic synthesis. Chem. Soc. Rev. 2013, 42, 8540. (c) Cui, Y.-M.; Lin, Y.; Xu, L.-W. Catalytic Synthesis of Chiral Organoheteroatom Compounds of Silicon, Phosphorus, and Sulfur via Asymmetric Transition Metal-Catalyzed C-H Functionalization. Coord. Chem. Rev. 2017, 330, 37. (6) (a) Michael, J. P. Indolizidine and Quinolizidine Alkaloids. Nat. Prod. Rep. 2008, 25, 139. (b) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among US FDA Approved Pharmaceuticals: Miniperspective. J. Med. Chem. 2014, 57, 10257. (7) (a) Kolundžić, F.; Murali, A.; Pérez-Galán, P.; Bauer, J. O.; Strohmann, C.; Kumar, K.; Waldmann, H. A Cyclization−Rearrangement Cascade for the Synthesis of Structurally Complex Chiral Gold (i) Aminocarbene Complexes. Angew. Chem., Int. Ed. 2014, 53, 8122. (b) Kazuo, S.; Nobusachi, Y. Japan Patent No JP 03017057 A 1991. (8) (a) Babu, Y. S.; Chand, P.; Ghosh, A. K.; Kotian, P. L.; Kumar, S. V. World Patent No. WO2006002231A1 2006. (b) Clinch, K.; Evans, G. B.; Furneaux, R. H.; Kelly, P. M.; Schramm, V. L.; Lyler, P. C.; Woolhouse, A. D. World Patent No. WO2008030119A1 2008. (c) Blanco, M.-J.; Sardina, F. J. C-3- and C-4-Alkylated Polyhydroxypyrrolidines: Enantiospecific Syntheses and Glycosidase Inhibitory Activity. J. Org. Chem. 1998, 63, 3411. (d) Espeel, P. E. R.; Piens, K.; Callewaert, N.; Van der Eycken, J. Synthesis of Isofagomine and a New C6 Pyrrolidine Azasugar with Potential Biological Activity. Synlett 2008, 2008, 2321. (9) (a) Schaus, J. V.; Jain, N.; Panek, J. S. Asymmetric Synthesis of Homoallylic Amines and Functionalized Pyrrolidines via Direct Amino-Crotylation of in Situ Generated Imines. Tetrahedron 2000, 56, 10263. (b) Restorp, P.; Fischer, A.; Somfai, P. Stereoselective Synthesis of Functionalized Pyrrolidines via a [3 + 2]-Annulation of N-Ts-α-Amino Aldehydes and 1,3-Bis(silyl)propenes. J. Am. Chem. Soc. 2006, 128, 12646. (c) Restorp, P.; Dressel, M.; Somfai, P. Synthesis of Functionalized Pyrrolidines by a Highly Stereoselective [3 + 2]-Annulation Reaction of N-Tosyl-α-Amino Aldehydes and 1,3Bis (silyl) propenes. Synthesis 2007, 2007, 1576. (d) Wu, J.; Zhu, K.C.; Yuan, P.-W.; Panek, J. S. Bifunctional Homoallylic Carbamates from Chiral Silane Additions to in Situ Generated N-Acyl Iminium Ions. Org. Lett. 2012, 14, 3624. (e) MacDonald, T. P.; Shupe, B. H.; Schreiber, J. D.; Franz, A. K. Counterion Effects in the Catalytic Stereoselective Synthesis of 2, 3′-Pyrrolidinyl Spirooxindoles. Chem. Commun. 2014, 50, 5242. (f) Chastanet, J.; Roussi, G. Study of the Regiochemistry and Stereochemistry of the [3 + 2] Cycloaddition between Nonstabilized Azomethine Ylides Generated from Tertiary Amine N-Oxides and Various Dipolarophiles. J. Org. Chem. 1988, 53, 3808. (g) Otero-Fraga, J.; Suárez-Pantiga, S.; Montesinos-Magraner,

Scheme 2. Synthesis of Optically Pure Pyrrolidine Azasugar Derivative from Cycloadduct 11db

noteworthy that we have demonstrated a facile route to optically pure 5-substituted pyrrolidine azasugar with potential bioactivity from chiral 3-silylpyrrolidines. Further investigations in the area of 3-silylpyrrolidines synthesis and applications are ongoing in our laboratories.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01430. Experimental details, characterization of new compounds, crystallographic data, NMR and HPLC spectra (PDF) Accession Codes

CCDC 1841262 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Wei-Ping Deng: 0000-0002-4232-1318 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (No. 21772038), the Shanghai Sailing Program (No. 18YF140560), and the Fundamental Research Founds for the Central Universities.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b01430 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Chem. - Eur. J. 2013, 19, 6739. (c) Yang, W.-L.; Liu, Y.-Z.; Luo, S.; Yu, X.; Fossey, J. S.; Deng, W.-P. The Copper-Catalyzed Asymmetric Construction of a Dispiropyrrolidine Skeleton via 1,3-Dipolar Cycloaddition of Azomethine Ylides to α-Alkylidene Succinimides. Chem. Commun. 2015, 51, 9212. (d) Yang, W.-L.; Li, C.-Y.; Qin, W.J.; Tang, F.-F.; Yu, X.; Deng, W.-P. Cu(I)-Catalyzed Chemoselective and Stereoselective [3 + 3] Cycloaddition of Azomethine Ylides with 2-Indolylnitroethylenes: Facile Access to Highly Substituted Tetrahydro-γ-Carbolines. ACS Catal. 2016, 6, 5685. (e) He, F.-S.; Li, C.-S.; Deng, H.; Zheng, X.; Yang, Z.-T.; Deng, W.-P. The Facile and Stereoselective Synthesis of Pyrrolidine β-Amino Acids via Copper(I)Catalyzed Asymmetric 1,3-Dipolar Cycloaddition. Org. Chem. Front. 2017, 4, 52. (f) Deng, H.; He, F.-S.; Li, C.-S.; Deng, W.-P. Enantioselective Construction of Tricyclic Pyrrolidine-Fused Benzo[b]thiophene 1,1-Dioxide Derivatives via Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition. Org. Chem. Front. 2017, 4, 2343. (g) Liu, Y.-Z.; Shang, S.-J.; Yang, W.-L.; Luo, X.; Deng, W.-P. Stereoselective Synthesis of Pyrrolidines Containing a 3-Fluoro Quaternary Stereocenter via Copper (I)-Catalyzed Asymmetric 1,3Dipolar Cycloaddition. J. Org. Chem. 2017, 82, 11141. (14) Copper and silver salts are widely applied in the asymmetric 1,3-dipolar cycloadditions of azomethine ylides, compared to other Lewis acid metal sources; see refs 12a and 12g.

M.; Rhein, D.; Mendoza, A. Direct and Stereospecific [3 + 2] Synthesis of Pyrrolidines from Simple Unactivated Alkenes. Angew. Chem., Int. Ed. 2017, 56, 12962. (10) For the pioneering work, see: (a) Longmire, J. M.; Wang, B.; Zhang, X. Highly Enantioselective Ag (I)-Catalyzed [3 + 2] Cycloaddition of Azomethine Ylides. J. Am. Chem. Soc. 2002, 124, 13400. (b) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Catalytic Asymmetric 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides-A Simple Approach to Optically Active Highly Functionalized Proline Derivatives. Angew. Chem., Int. Ed. 2002, 41, 4236. (11) For selected recent works about asymmetric [3 + 2] cycloaddition reactions of azomethine ylides, see: (a) Zhu, G.; Wei, Q.; Chen, H.; Zhang, Y.; Shen, W.; Qu, J.; Wang, B. Asymmetric [3 + 2] Cycloddition of 3-Amino Oxindole-Based Azomethine Ylides and α,β-Enones with Divergent Diastereocontrol on the Spiro[pyrrolidineoxindoles]. Org. Lett. 2017, 19, 1862. (b) Yu, B.; Bai, X.- F.; Lv, J.-Y.; Yuan, Y.; Cao, J.; Zheng, Z.-J.; Xu, Z.; Cui, Y.-M.; Yang, K.-F.; Xu, L.W. Enantioselective Synthesis of Chiral Imidazolidine Derivatives by Asymmetric Silver/Xing-Phos-Catalyzed Homo-1,3-Dipolar [3 + 2] Cycloaddition of Azomethine Ylides. Adv. Synth. Catal. 2017, 359, 3577. (c) Jia, Z.-J.; Shan, G.; Daniliuc, C. G.; Antonchick, A. P.; Waldmann, H. Enantioselective Synthesis of the Spirotropanyl Oxindole Scaffold through Bimetallic Relay Catalysis. Angew. Chem., Int. Ed. 2018, DOI: 10.1002/anie.201712882. (d) Xu, S.; Zhang, Z.M.; Xu, B.; Liu, Y.; Zhang, J. Enantioselective Regiodivergent Synthesis of Chiral Pyrrolidines with Two Quaternary Stereocenters via Ligand-Controlled Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloadditions. J. Am. Chem. Soc. 2018, 140, 2272. (e) Feng, B.; Lu, L.-Q.; Chen, J.-R.; Feng, G.; He, B.-Q.; Lu, B.; Xiao, W.-J. Umpolung of Imines Enables Catalytic Asymmetric Regio-reversed [3 + 2] Cycloadditions of Iminoesters with Nitroolefins. Angew. Chem., Int. Ed. 2018, 57, 5888. (12) For recent reviews about asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides, see: (a) Stanley, L. M.; Sibi, M. P. Enantioselective Copper-Catalyzed 1,3-Dipolar Cycloadditions. Chem. Rev. 2008, 108, 2887. (b) Chen, Q.-A.; Wang, D.-S.; Zhou, Y.- G. Bifunctional AgOAc-Catalyzed Asymmetric Reactions. Chem. Commun. 2010, 46, 4043. (c) Adrio, J.; Carretero, J. C. Novel Dipolarophiles and Dipoles in the Metal-Catalyzed Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Ylides. Chem. Commun. 2011, 47, 6784. (d) Narayan, R.; Potowski, M.; Jia, Z.-J.; Antonchick, A. P.; Waldmann, H. Catalytic Enantioselective 1,3-Dipolar Cycloadditions of Azomethine Ylides for Biology-Oriented Synthesis. Acc. Chem. Res. 2014, 47, 1296. (e) Maroto, E. E.; Izquierdo, M.; Reboredo, S.; Marco-Martínez, J.; Filippone, S.; Martín, N. Chiral Fullerenes from Asymmetric Catalysis. Acc. Chem. Res. 2014, 47, 2660. (f) Adrio, J.; Carretero, J. C. Recent Advances in the Catalytic Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides. Chem. Commun. 2014, 50, 12434. (g) Hashimoto, T.; Maruoka, K. Recent Advances of Catalytic Asymmetric 1,3-Dipolar Cycloadditions. Chem. Rev. 2015, 115, 5366. (h) Bdiri, B.; Zhao, B.-J.; Zhou, Z.-M. Recent Advances in the Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Ylides and Dipolarophiles. Tetrahedron: Asymmetry 2017, 28, 876. (i) Döndas, H. A.; de Gracia Retamosa, M.; Sansano, J. M. Current Trends towards the Synthesis of Bioactive Heterocycles and Natural Products Using 1,3-Dipolar Cycloadditions (1,3-DC) with Azomethine Ylides. Synthesis 2017, 49, 2819. (j) Fang, X.; Wang, C.-J. Catalytic Asymmetric Construction of Spiropyrrolidines via 1,3-Dipolar Cycloaddition of Azomethine Ylides. Org. Biomol. Chem. 2018, 16, 2591. (13) (a) Wang, M.; Wang, Z.; Shi, Y.-H.; Shi, X.-X.; Fossey, J. S.; Deng, W.-P. An exo- and Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Ylides with Alkylidene Malonates Catalyzed by a N,OLigand/Cu(OAc)2-Derived Chiral Complex. Angew. Chem., Int. Ed. 2011, 50, 4897. (b) Wang, Z.; Luo, S.; Zhang, S.; Yang, W.-L.; Liu, Y.Z.; Li, H.; Luo, X.; Deng, W.-P. Catalytic Asymmetric Construction of Quaternary α-Amino Acid Containing Pyrrolidines through 1,3Dipolar Cycloaddition of Azomethine Ylides to α-Aminoacrylates. E

DOI: 10.1021/acs.orglett.8b01430 Org. Lett. XXXX, XXX, XXX−XXX