Enantioselective Synthesis of Alkylthioetherpyrrolidine Derivatives via

Oct 31, 2017 - Enantiomeric excesses (ee) were also determined by HPLC analysis on Acchrom HPLC units, including the following instruments: pump, 6210...
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Enantioselective Synthesis of Alkylthioetherpyrrolidine Derivatives via [3+2] Cycloaddition of α‑Thioacrylates with Isocyanoacetates Zhi-Peng Wang, Zi-Rui Li, Qi Wu, Xiao-Jiao Peng, Pan-Lin Shao,* and Yun He* Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, 55 Daxuecheng South Road, Shapingba, Chongqing 401331, P.R. China S Supporting Information *

ABSTRACT: An unprecedented catalytic asymmetric method for the [3+2] cycloaddition of isocyanoacetates with αthioacrylates/α-phthalimidoacrylates has been developed with excellent enantioselectivities. The generated pyrrolines could be readily further reduced to an array of structurally various and biologically important pyrrolidine derivatives. α-Tosyloxyacrylate with isocyanoacetates as well as tosylmethylisocyanide could be used to produce 2,4-disubstituted pyrroles.

T

concise catalytic enantioselective methods to enable such valuable moieties. Activated isocyanides such as isocyanoacetates, which are invested with unique multifunctional nature, have proven to be a versatile functionality to undergo cyclization with various πsystems for heterocycle synthesis.9 In recent decades, Gong,10 Amat,11 Carretero12 et al. and our group13a reported the asymmetric cycloaddition reactions of isocyanoacetates with nitroolefins, 2-oxobutenoate esters, α,β-unsaturated ketones, maleimides, and methyleneindolinones to access pyrrolines, respectively. Our recent effort has accumulated in the use of functionalized 1,3-dipole enolates derived from isocyanoacetate, due to its isocyanide group and acidic α-CH fragment encountered chiral Brønsted Base.13 Rather than these aforementioned electron-poor olefins, we anticipated that the 1,3-dipole enolate may facilitate a [3+2] cycloaddition with the alkene bearing a captodative heteroatom substituent, such as methyl 2-(tert-butylthio)acrylate (5a), affording a 1-pyrroline derivative bearing a heteroatom-substituted quaternary stereocenter, which would undergo a facile reduction to access the corresponding pyrrolidine derivative (Scheme 1).

he pyrrolidine skeleton is ubiquitous in many biologically active natural or unnatural products,1 organocatalysts,2 and synthetic materials.3 In particular, pyrrolidine derivatives bearing heteroatom-substituted quaternary stereocenters present more opportunities to these applications.4 For example, 4-aminopyrrolidine-2,4-dicarboxylate derivatives are not only metabotropic glutamate receptor agonists and could also be employed as building blocks to form the water-soluble nanoscale molecular rods.5 As shown in Figure 1, compound

Scheme 1. Proposed Process for Pyrrolidine Derivative Formations Figure 1. Representative bioactive pyrrolidine derivatives bearing heteroatom-substituted quaternary stereocenters.

1 is the key intermediate to synthesize UCS1025A (2), an antitumor antibiotic alkaloid isolated from Acremonium sp. KY4917.6 Compound 3 and its analogues are prolinecontaining tripeptides as hepatitis C virus inhibitors. 7 Compound 4, which inhibits ERK activity, may be useful in treating a number of cancers.8 These examples highlight the wide application of alkylthioetherpyrrolidine derivatives in the discovery of new drugs. Thus, it is highly desirable to develop © 2017 American Chemical Society

Received: September 8, 2017 Published: October 31, 2017 12869

DOI: 10.1021/acs.joc.7b02266 J. Org. Chem. 2017, 82, 12869−12876

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The Journal of Organic Chemistry

the reactions were operated open to air without any exclusion of air or moisture. Owing to the operational simplicity, synthetic efficiency, and atom economy, this process would be a promising synthetic method. The relative and absolute configuration of 9a was unambiguously assigned as (2S,4R) by single-crystal X-ray diffraction analysis of the corresponding N-4-nitrophenylsulfonamide Ns-9a (Scheme 3).16

In fact, effective methods have been established toward the asymmetric construction of 4-aminopyrrolidine derivatives using azomethine ylides and α-phthalimidoacrylates through 1,3-dipolar cycloaddition by Deng et al.14 In sharp contrast, the enantioselective synthesis of pyrrolidines bearing other heteroatom (e.g., sulfur) substituent groups still remains a great challenge. On the basis of the above analysis, herein we present the implementation of this strategy, which leads to enantiomerically enriched pyrrolidine derivatives containing Sor N-substituted quaternary stereocenters. As shown in Scheme 2, the feasibility of the [3+2] cycloaddition was examined by using the readily available

Scheme 3. Derivatization of 9a for Determining the Absolute Configurationa

Scheme 2. [3+2] Cycloaddition/Reduction of α-Thioacrylate 5a and Methyl Isocyanoacetate 6aa a

a

Ns = 4-nitrobenzenesulfonyl.

With the optimized catalytic protocol in hand, a number of α-thioacrylates 5 were then examined for the cycloaddition employing CHCl3 or toluene as the solvent, and the representative results are summarized in Table 1. When CHCl3 was used as the solvent, all of the examples proceeded smoothly, thus providing the products 9a−h in uniformly high yields (80%−95%) with excellent enantioselectivities (trans = 92%−99% ee), albeit the diastereoselectivities varied from moderate to good. These substituents at the α-thioacrylates have no remarkable effect on the reactivity and selectivity. Consistent with the model reaction in Scheme 2, cycloaddition reactions employing toluene as the solvent furnished the desired products with excellent enantioselectivities (trans = 90%−99% ee) and much higher diastereoselectivites, but in somewhat lower yields (60%−75%) compared with those employing CHCl3 as the solvent. The lower yields were due to the elimination of thioether moieties of the cycloadducts to form pyrroles in the reaction conditions. Different substitution patterns on the thioether moieties of α-thioacrylates were also well tolerated. The relative and absolute configuration of these products 9 were assigned by analogy to 9a. A series of pyrrolidine derivatives 9, which bear Cγtetrasubstituted α-thioether acid moieties, were produced with the sequential asymmetric [3+2] cycloaddition/reduction of α-thioacrylates with methyl isocyanoacetate 6a. To demonstrate the practicality and operational simplicity of this [3+2] cyclization methodology, we performed the reaction with 2-(tert-butylthio)acrylate (5a) and methyl isocyanoacetate 6a on a gram scale (Scheme 4). Overall, 9a was synthesized via two steps with a 95% yield (1.3 g), without any erosion of the enantioselectivity and diastereoselectivity observed in the 0.1 mmol scale reaction (Scheme 2). This method presents the opportunity for the subsequent preparation of compound libraries for biological screening. Systematic screening is ongoing with the compounds 9a−h and related analogues, and this work will be presented in due time. We next examined the scope of the reaction with other heteroatom substituents, aiming to provide a versatile approach for drug leads. The same set of conditions could also be applicable to the nitrogen-substituted olefins. Indeed, the cyclizations of phthalimide-substituted olefins 10 and isocyanoacetates 6b furnished the desired 4-aminopyrrolidine-2,4dicarboxylic acid (APDC)-like compounds containing unique

See the Supporting Information for details.

methyl 2-(tert-butylthio)acrylate (5a) and methyl isocyanoacetate 6a as the model substrates and the chiral silver(I) complex as the catalyst, which was developed by the Dixon group.15 After a series of optimizations, we established the optimal conditions: the reaction of 5a (1.0 equiv) and 6a (1.2 equiv) in the presence of Ag2O (10 mol %) and precatalyst 7 (20 mol %) in CHCl3 at −20 °C. Gratifyingly, the expected cycloadduct 8a was generated in almost a quantitative yield as determined by 1 H NMR (400 MHz) spectroscopy with good diastereoselectivity (trans/cis = 86:14) and excellent enantioselectivity (trans = 99% ee), albeit the yield was only 80%, due to the low stability of 8a during the chromatography with silica gel. Subsequently, the isolated 1-pyrroline derivative 8a (trans) was treated with NaBH3CN/HOAc and converted into the corresponding pyrrolidine derivative 9a in a quantitative yield without erosion of enantiopurity. It should be noted that, when the crude mixture of 8a (transand cis-isomers) was reduced directly after immediate filtration through a silica gel pad, 9a was obtained in a 95% overall yield (Scheme 2). Notably, the combined operations had a negligible impact on the diastereoselectivity (trans/cis = 86:14) and enantioselectivity (trans = 98% ee). When the reaction media was switched to toluene and the reaction was carried out at ambient temperature, the diastereoselectivity was improved (trans/cis = 95:5) with a slight loss of enantioselectivity (trans = 96% ee), albeit in a moderate yield (73%). The opposite enantiomer of the product 9a could be obtained by employing the precatalyst 7′, which is the pseudeoenantiomer of 7 and is derived from quinidine. It is also worth mentioning that all of 12870

DOI: 10.1021/acs.joc.7b02266 J. Org. Chem. 2017, 82, 12869−12876

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The Journal of Organic Chemistry Table 1. Substrates Scope with Respect to α-Thioacrylate

a CHCl3 as the solvent. bToluene as the solvent. cTotal yields of the trans- and cis-isomers. dtrans/cis ratio determined by 1H NMR spectroscopy of the crude mixture. eDetermined by HPLC analysis. See the Supporting Information for details.

Scheme 5. Scope of the Nitrogen-Substituted Olefinsa

Scheme 4. Gram-Scale Synthesis of 9a

quaternary α-amino acid units in good to excellent yields, diastereoselectivities, and enantioselectivities (Scheme 5). When an electron-withdrawing group (Cl) was introduced into the phthalimide substituent, the yield, ee, and dr values decreased dramatically (11b). On the contrary, the electrondonating group benefited the enantioselectivity. The methyl group (11c) led to a better yield and ee value, and the methoxyl group (11d) provided the highest enantioselectivity (97% ee). The relative and absolute configuration of compound 11 was reconfirmed by single-crystal X-ray structure analysis of the corresponding 1-pyrroline precursor of 11b′ after recrystallization (see the Supporting Information for details).16

a

See Table 1 and the Supporting Information for details.

Alternatively, employing the optimal reaction conditions, different isocyanoacetates as well as tosylmethylisocyanide could be used to produce 2,4-disubstituted pyrroles 14 with αtosyloxyacrylate 12 in decent yields (Scheme 6). However, 12871

DOI: 10.1021/acs.joc.7b02266 J. Org. Chem. 2017, 82, 12869−12876

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The Journal of Organic Chemistry Scheme 6. Pyrrole Synthesis from α-Tosyloxyacrylatea

crude methyl 2,3-dibromopropionate as a slight yellow oil, quantitatively. The crude methyl 2, 3-dibromopropionate was dissolved in 200 mL of ether directly without further purification. To the resulting mixture was added 16.7 mL (120 mmol) of triethylamine, and the reaction was stirred at ambient temperature until reaction completion. The precipitate was filtered with a pad of Celite; the solvent was removed, and the residue was distilled in vacuo to yield 13.2 g of pure methyl 2-bromoacrylate (80% for 2 steps, bp 65 °C, 50 mmHg). This compound is not stable in air.17 To a stirring solution of methyl 2-bromoacrylate (8.0 g, 48.5 mmol) in DMF was added mercaptans (44.1 mmol); then triethylamine (8.1 mL, 58.1 mmol) was added dropwise, and the reaction was heated to 110 °C for 24 h. After completion, the reaction mixture was washed with water and extracted with EA. The combined organic solvent was removed in a vacuum to obtain a brown oil, which was distilled in a vacuum to yield the product as a colorless oil.18 Synthesis of α-Thioacrylates (General Procedure B).19 To a solution of mercaptan (19.7 mmol) in 50 mL of MeOH was added methyl α-bromopropanoate (3.3 g, 19.7 mmol); then Et3N (2.4 g, 24.0 mmol) was added dropwise at 0 °C followed by refluxing for 3 h. After the starting material was consumed completely by monitoring with TLC, the reaction mixture was extracted with dichloromethane (3 × 50 mL). The combined organic phase was dried over Na2SO4 and evaporated at 30 °C in a vacuum to give the residue, which was used in the next step without further purification. Sulfuryl chloride (1.62 g, 12.0 mmol) was added to a stirred solution of the residue (12.0 mmol) prepared above in chloroform (50 mL) at 0 °C. The reaction was stirred at 0 °C for 10 min and then refluxed with stirring at 65 °C for 10 h. After the reaction completion, the mixture was quenched with a saturated aqueous solution of NaHCO3, extracted with dichloromethane, dried over Na2SO4, and concentrated to give a pale yellow oil, which was purified on silica gel (petroleum ether/ethyl acetate = 100:1) to yield the pure product. Methyl 2-(tert-Butylthio)acrylate (5a). The general procedure A outlined above was followed to obtain 5a as a colorless oil: 6.53 g (83% yield); 1H NMR (400 MHz, CDCl3) δ 6.75 (d, J = 1.3 Hz, 1H), 6.13 (d, J = 1.3 Hz, 1H), 3.79 (s, 3H), 1.31 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.0, 137.1, 134.4, 52.7, 46.3, 30.7; HRMS (ESI) m/z calcd for C8H14NaO2S [M + Na]+ 197.0607, found 197.0606. Methyl 2-(Isopropylthio)acrylate (5b). The general procedure A outlined above was followed to obtain 5b as a colorless oil: 5.16 g (73% yield); 1H NMR (400 MHz, CDCl3) δ 6.41 (s, 1H), 5.55 (s, 1H), 3.77 (s, 3H), 3.24 (hept, J = 6.7 Hz, 1H), 1.29 (s, 3H), 1.28 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.3, 136.4, 122.4, 52.6, 35.1, 22.2; HRMS (ESI) m/z calcd for C7H12NaO2S [M + Na]+ 183.0450, found 183.0448. Methyl 2-(Octylthio)acrylate (5c). The general procedure B outlined above was followed to obtain 5c as a colorless oil: 2.21 g (80% yield); 1H NMR (400 MHz, CDCl3) δ 6.31 (s, 1H), 5.37 (s, 1H), 3.77 (s, 3H), 2.67 (t, J = 7.4 Hz, 2H), 1.64−1.59 (m, 2H), 1.40− 1.37 (m, 2H), 1.26−1.24 (m, 8H), 0.86−0.81 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.0, 137.6, 118.8, 52.5, 31.7, 31.4, 29.1, 29.0, 27.7, 22.6, 14.0; HRMS (ESI) m/z calcd for C12H22NaO2S [M + Na]+ 253.1233, found 253.1235. Methyl 2-((5-((tert-Butyldimethylsilyl)oxy)pentyl)thio)acrylate (5d). The general procedure A outlined above was followed to obtain 5d as a colorless oil: 11.73g (80% yield); 1H NMR (400 MHz, CDCl3) δ 6.33 (s, 1H), 5.39 (s, 1H), 3.79 (s, 3H), 3.58 (t, J = 6.4 Hz, 2H), 2.69 (t, J = 7.3 Hz, 2H), 1.65 (p, J = 7.3 Hz, 2H), 1.53−1.44 (m, 2H), 1.42 (dt, J = 9.0, 7.0 Hz, 2H), 1.37−1.31 (m, 2H), 0.87 (s, 9H), 0.02 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.0, 137.5, 119.0, 63.0, 52.6, 32.6, 31.4, 28.8, 27.7, 25.9, 25.4, 18.3, −5.3; HRMS (ESI) m/z calcd for C16H32NaO3SSi [M + Na]+ 355.1734, found 355.1730. Methyl 2-(Butylthio)acrylate (5e). The general procedure B outlined above was followed to obtain 5e as a colorless oil: 1.46 g (70% yield); 1H NMR (400 MHz, CDCl3) δ 6.34 (s, 1H), 5.41 (s, 1H), 3.80 (s, 3H), 2.71 (t, J = 7.4 Hz, 2H), 1.68−1.61 (m, 2H), 1.45 (h, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.1, 137.6, 119.0, 52.6, 31.1, 29.7, 22.2, 13.6;

a

Yields in parentheses when Ag2O (10 mol %) was used without the precatalyst 7.

when the reactions were executed with a catalytic amount of Ag2O (10 mol %), without the precatalyst 7, the desired pyrroles were generated in diminished yields. These results implied that the process occurred through intermediate 13, with the subsequent elimination of TsOH. In conclusion, a catalytic enantioselective cycloaddition of isocyanoacetates with α-thioacrylates/α-phthalimidoacrylates has been developed and enables the structurally diverse and biologically important pyrrolidine derivatives bearing sulfer/ nitrogen-substituted quaternary stereocenters in high yields (up to 95%) and excellent enantioselectivities (up to 99% ee). Notably, the salient features of this transformation including operational simplicity, synthetic efficiency, and atom economy, indicate the highly promising application in drug lead discovery.

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EXPERIMENTAL SECTION

General Information. 1H and 13C{1H} NMR spectra were recorded on an Agilent spectrometer at ambient temperature (1H NMR, 400 MHz; 13C{1H} NMR, 100 MHz). The chemical shifts (δ) and coupling constants (J) were expressed in ppm and Hz, respectively, and the residual solvent peak was used as an internal reference: 1H (CDCl3, δ 7.26), 1H (CD2Cl2, δ 5.32), 13C{1H} (CDCl3, δ 77.0), 13C{1H} (CD2Cl2, δ 53.8). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, hept = heptet, m = multiplet, br = broad). Melting points (mp) were obtained on an SGW X-4A. High-resolution mass spectra (HRMS) were recorded on a Bruker SolariX 7.0T FT-ICR mass spectrometer. Optical rotations were recorded on a Rudolph Autopol I automatic polarimeter. Enantiomeric excesses (ee) were determined by HPLC analysis on Agilent HPLC units, including the following instruments: pump, G1311C; detector, G1314F. Enantiomeric excesses (ee) were also determined by HPLC analysis on Acchrom HPLC units, including the following instruments: pump, 6210; detector, 6410; column, Chiralpak AD-H, OD-H, AS-H, OJ-H, IA. Unless otherwise mentioned, all of the reactions were carried out open to air. Dichloromethane (DCM), chloroform (CHCl3), and toluene were distilled from CaH2. Tetrahydrofuran (THF) and ether were dried and distilled from sodium. N,N-Dimethylformamide (DMF) was dried over CaH2 and distilled in a vacuum. Deuterated solvents were purchased from Cambridge Isotope Laboratories and used as received without further purification. Methyl isocyanoacetate (6a) and tosylmethylisocyanide (6c) were purchased from Alfa Aesar. Other chemicals were purchased from commercial suppliers and used as received without any purification. Synthesis of α-Thioacrylates (General Procedure A). To a solution of methyl acrylate (100 mmol) in 100 mL of DCM was added bromine (110 mmol, dissolved in 20 mL of DCM) dropwise below 0 °C, and the mixture was stirred at 0 °C for 12 h. After completion, the mixture was quenched with 10 mL of a saturated aqueous Na2S2O3 solution. The aqueous layer was extracted with DCM (3 × 50 mL), and the organic layers were combined and dried over Na2SO4. After filtration, the organic solvent was evaporated in a vacuum to give the 12872

DOI: 10.1021/acs.joc.7b02266 J. Org. Chem. 2017, 82, 12869−12876

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The Journal of Organic Chemistry

CDCl3) δ 3.91 (dd, J = 9.6, 5.1 Hz, 1H), 3.84 (dd, J = 12.0, 1.2 Hz, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 2.94 (dd, J = 12.0, 1.3 Hz, 1H), 2.80 (ddd, J = 13.7, 5.0, 1.3 Hz, 1H), 2.37 (ddd, J = 13.7, 9.7, 1.3 Hz, 2H), 1.32 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.4, 174.1, 59.1, 58.6, 56.8, 52.8, 52.5, 46.6, 42.5, 31.7; HRMS (ESI) m/z calcd for C12H21NNaO4S [M + Na]+ 298.1083, found 298.1076; optical rotation [α]25 D −14.9 (c 0.23, CHCl3). The absolute configuration of 9a was assigned by analogy to Ns-9a. trans/cis = 86:14. 98% ee, 94% ee [HPLC conditions: Chiralpak AD-H and OJ-H columns, n-hexane/iPrOH = 99:1, flow rate = 0.8 mL/min, wavelength = 210 nm, tR = 32.1 min (trans-minor), tR = 36.3 min (trans-major), tR = 42.5 min (cisminor), tR = 48.8 min (cis-major)]. Dimethyl (2R,4S)-4-(tert-Butylthio)pyrrolidine-2,4-dicarboxylate (ent-9a): white solid, mp 49−50 °C; Rf = 0.2 (silica gel, petroleum ether/EtOAc = 2:1); 25.4 mg (93% yield); optical rotation [α]25 D +10.3 (c 0.4, CHCl3). The absolute configuration of ent-9a was assigned by analogy to Ns-9a. trans/cis = 83:17. 96% ee, 89% ee [HPLC conditions: Chiralpak AD-H and OJ-H columns, n-hexane/i-PrOH = 99:1, flow rate = 0.8 mL/min, wavelength = 210 nm, tR = 52.5 min (trans-major), tR = 61.6 min (trans-minor), tR = 66.5 min (cis-major), tR = 79.8 min (cis-minor)]. Dimethyl (2S,4R)-4-(Isopropylthio)pyrrolidine-2,4-dicarboxylate (9b): colorless oil; Rf = 0.2 (silica gel, petroleum ether/EtOAc = 1:1); 24.3 mg (93% yield); 1H NMR (400 MHz, CDCl3) δ 3.97 (dd, J = 9.1, 6.0 Hz, 1H), 3.72(1) (s, 3H), 3.72(2) (s, 3H), 3.67 (d, J = 12.2 Hz, 1H), 3.05−2.96 (m, 2H), 2.66 (ddd, J = 13.8, 6.0, 0.8 Hz, 1H), 2.32 (dd, J = 13.8, 9.1 Hz, 1H), 2.25 (br, 1H), 1.24 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.4, 173. 1, 59.1, 57.2, 56.7, 52.7, 52.4, 40.7, 35.6, 24.8, 24.6; HRMS (ESI) m/z calcd for C11H19NNaO4S [M + Na]+ 284.0927, found 284.0924; optical rotation [α]25 D −19.2 (c 0.33, CHCl3). The absolute configuration of 9b was assigned by analogy to Ns-9a. trans/cis = 78:22. 98% ee, 96% ee [HPLC conditions: Chiralpak AD-H, OJ-H, AD-H, and OJ-H columns, n-hexane/i-PrOH = 99:1, flow rate = 0.5 mL/min, wavelength = 210 nm, tR = 117.9 min (trans-major), tR = 127.3 min (trans-minor), tR = 134.5 min (cis-minor), tR = 137.4 min (cis-major)]. Dimethyl (2S,4R)-4-(Octylthio)pyrrolidine-2,4-dicarboxylate (9c): colorless oil; Rf = 0.2 (silica gel, petroleum ether/EtOAc = 2:1); 27.2 mg (82% yield); 1H NMR (400 MHz, CDCl3) δ 4.00 (dd, J = 8.9, 6.2 Hz, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.62 (d, J = 12.2 Hz, 1H), 3.02− 2.99 (m, 1H), 2.64−2.56 (m, 3H), 2.35−2.29 (m, 1H), 2.22 (br, 1H), 1.56−1.48 (m, 2H), 1.36−1.32 (m, 2H), 1.31−1.25 (m, 8H), 0.89− 0.85 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.4, 172.6, 59.1, 57.0, 55.9, 52.7, 52.4, 40.0, 31.8, 30.7, 29.2, 29.1, 28.9, 22.6, 14.1; HRMS (ESI) m/z calcd for C16H29NNaO4S [M + Na]+ 354.1710, found 354.1709; optical rotation [α]25 D −3.1 (c 0.39, CHCl3). The absolute configuration of 9c was assigned by analogy to Ns-9a. trans/ cis = 68:32. 95% ee, 90% ee [HPLC conditions: Chiralpak OD-H and OD-H columns, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, wavelength = 210 nm, tR = 28.7 min (trans-minor), tR = 31.0 min (trans-major), tR = 38.7 min (cis-minor), tR = 42.3 min (cis-major)]. Dimethyl (2S,4R)-4-((5-((tert-Butyldimethylsilyl)oxy)pentyl)thio)pyrrolidine-2,4-dicarboxylate (9d): colorless oil; Rf = 0.2 (silica gel, petroleum ether/EtOAc = 5:1). 36.0 mg (83% yield); 1H NMR (400 MHz, CDCl3) δ 4.00 (dd, J = 8.9, 6.2 Hz, 1H), 3.73(1) (s, 3H), 3.73(2) (s, 3H), 3.64−3.57 (m, 3H), 3.00 (d, J = 12.1 Hz, 1H), 2.64− 2.57 (m, 3H), 2.32 (dd, J = 13.9, 8.9 Hz, 1H), 1.67 (br, 1H), 1.56− 1.48 (m, 4H), 1.39−1.29 (m, 4H), 0.88 (s, 9H), 0.04 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.4, 172.6, 63.1, 59.1, 57.0, 56.0, 52.7, 52.4, 40.0, 32.6, 30.7, 29.2, 28.8, 26.0, 25.4, 18.3, −5.3; HRMS (ESI) m/z calcd for C20H39NNaO5SSi [M + Na]+ 456.2210, found 456.2205; optical rotation [α]25 D −6.67 (c 0.38, CHCl3). The absolute configuration of 9d was assigned by analogy to Ns-9a. trans/cis = 68:32. 97% ee, 98% ee [HPLC conditions: Chiralpak AD-H and ODH columns, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, wavelength = 210 nm, tR = 13.4 min (trans-minor), tR = 14.2 min (trans-major), tR = 18.4 min (cis-major), tR = 21.6 min (cis-minor)]. Dimethyl (2S,4R)-4-(Butylthio)pyrrolidine-2,4-dicarboxylate (9e): colorless oil; Rf = 0.2 (silica gel, petroleum ether/EtOAc = 2:1); 24.2 mg (88% yield); 1H NMR (400 MHz, CDCl3) δ 4.00 (dd, J = 8.9, 6.3

HRMS (ESI) m/z calcd for C8H14NaO2S [M + Na]+ 197.0607, found 197.0605. General Procedure for the Synthesis of Nitrogen-Substituted Olefins.20 A stirred solution of substituted phthalimide (5.0 mmol), triphenylphosphine (131 mg, 0.5 mmol), and sodium acetate (205 mg, 2.5 mmol) in toluene (5 mL) was treated with acetic acid (150 mg, 2.5 mmol) and methyl propiolate (420 mg, 5.0 mmol) at room temperature, and the resulting mixture was heated to reflux for 24 h. The cooled reaction mixture was concentrated to remove the organic solvent, and the residue was purified by flash chromatography on silica gel using hexanes/EtOAc as an eluent to afford the corresponding product as a white solid. Methyl 2-(5-Chloro-1,3-dioxoisoindolin-2-yl)acrylate (10b): white solid, mp 95−97 °C, 0.99 g (75% yield); 1H NMR (400 MHz, CDCl3) δ 7.88−7.84 (m, 2H), 7.74 (dd, J = 8.0, 1.8 Hz, 1H), 6.69 (d, J = 0.7 Hz, 1H), 5.99 (d, J = 0.8 Hz, 1H), 3.81 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.4, 165.1, 162.5, 141.3, 134.6, 133.4, 129.8, 128.9, 128.5, 125.2, 124.3, 52.9; HRMS (ESI) m/z calcd for C12H8ClNNaO4 [M + Na]+ 288.0034, found 288.0034. Methyl 2-(5-Methyl-1,3-dioxoisoindolin-2-yl)acrylate (10c): white solid, mp 91−93 °C, 1.10 g (90% yield); 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.6 Hz, 1H), 7.71 (s, 1H), 7.56 (d, J = 7.7 Hz, 1H), 6.67 (s, 1H), 5.97 (s, 1H), 3.81 (s, 3H), 2.53 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.6, 166.4, 162.8, 145.9, 135.1, 132.2, 129.2, 129.1, 127.94, 124.4, 123.8, 52.8, 22.0; HRMS (ESI) m/z calcd for C13H11NNaO4 [M + Na]+ 268.0580, found 268.0583. Methyl 2-(5-Methoxy-1,3-dioxoisoindolin-2-yl)acrylate (10d): white solid, mp 101−103 °C, 1.04 g (80% yield); 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.21 (dd, J = 8.4, 2.3 Hz, 1H), 6.65 (d, J = 0.6 Hz, 1H), 5.97 (d, J = 0.6 Hz, 1H), 3.94 (s, 3H), 3.80 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.3, 166.2, 165.0, 162.9, 134.4, 129.1, 127.9, 125.7, 123.7, 120.6, 108.4, 56.2, 52.8; HRMS (ESI) m/z calcd for C13H11NNaO5 [M + Na]+ 284.0529, found 284.0528. Methyl 2-(Tosyloxy)acrylate (12).21 To a solution of triethylamine (6 mL) in dry THF (20 mL) and HMPA (1.0 mL) at −10 °C under a N2 atmosphere was added dropwise a solution of methyl 2oxopropanoate (5.0 g, 49.0 mmol) in dry THF (10 mL). Then a solution of TsCl (9.8 g, 51.6 mmol) in dry THF (10 mL) was slowly added at the same temperature, and the resulting mixture was stirred at −10 °C until methyl 2-oxopropanoate was consumed. The solvent was removed in vacuo, and the residue was redissolved in CH2Cl2 (50 mL). A saturated aqueous solution of NH4Cl (100 mL) was added, and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The combined organic extracts were dried over MgSO4, and the solvent was evaporated in vacuo. The residue was successively purified by flash column chromatography on silica gel (hexane/EtOAc = 20:1) to give the acrylate 12 (7.53 g, 60% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 6.07 (d, J = 2.4 Hz, 1H), 5.54 (d, J = 2.4 Hz, 1H), 3.63 (s, 3H), 2.39 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.3, 145.8, 143.0, 132.4, 129.8, 128.5, 117.1, 52.6, 21.6; HRMS (ESI) m/z calcd for C11H12NaO5S [M + Na]+ 279.0298, found 279.0298. General Procedure for the Synthesis of Pyrrolidine Derivatives. To a 10 mL tube charged with 7 (12.3 mg, 0.02 mmol) and Ag2O (2.3 mg, 0.01 mmol) was added CHCl3 (1 mL). The mixture was stirred at −20 °C for 5 min, and then the α-thioacrylate 5a (17.4 mg, 0.1 mmol) and methyl isocyanoacetate 6a (11.88 mg, 0.12 mmol) were added. The reaction mixture was stirred at −20 °C until 5a was consumed, then filtered through a pad of silica gel, and washed with ethyl acetate. The solvent was removed under reduced pressure, and then the residue was dissolved in MeOH (1 mL). NaCNBH3 (12.6 mg, 0.2 mmol) and HOAc (12.0 mg, 0.2 mmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 0.5 h, and then the solvent was concentrated and purified by flash chromatography on silica gel (hexanes/ethyl acetate = 2:1) to afford product 9a. Dimethyl (2S,4R)-4-(tert-Butylthio)pyrrolidine-2,4-dicarboxylate (9a): white solid, mp 49−51 °C; Rf = 0.2 (silica gel, petroleum ether/EtOAc = 2:1); 26.2 mg (95% yield); 1H NMR (400 MHz, 12873

DOI: 10.1021/acs.joc.7b02266 J. Org. Chem. 2017, 82, 12869−12876

Note

The Journal of Organic Chemistry

AD-H column, n-hexane/i-PrOH = 70:30, flow rate = 1.0 mL/min, wavelength = 210 nm, tR = 19.2 min (trans-minor), tR = 30.6 min (trans-major)]. 4-Methyl 2-Phenyl (2S,4R)-4-(5-Chloro-1,3-dioxoisoindolin-2-yl)pyrrolidine-2,4-dicarboxylate (11b): white solid, mp 136−138 °C; Rf = 0.2 (silica gel, petroleum ether/EtOAc = 2:1); 35.6 mg (83% yield); 1 H NMR (400 MHz, CDCl3) δ 7.82−7.78 (m, 2H), 7.72−7.70 (m, 1H), 7.42−7.40 (m, 2H), 7.27−7.25 (m, 1H), 7.15 (dt, J = 8.5, 1.1 Hz, 2H), 4.28 (dd, J = 9.6, 5.9 Hz, 1H), 4.04 (d, J = 12.9 Hz, 1H), 3.77 (d, J = 12.8 Hz, 1H), 3.72 (s, 3H), 3.24 (dd, J = 14.5, 5.9 Hz, 1H), 3.11 (dd, J = 14.4, 9.6 Hz, 1H), 2.89 (br, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.7, 171.3, 167.6, 167.2, 150.5, 141.2, 134.5, 133.3, 129.7, 129.5, 126.1, 124.8, 123.9, 121.3, 67.7, 59.5, 56.0, 53.3, 40.2; HRMS (ESI) m/z calcd for C21H17ClN2NaO6 [M + Na]+ 451.0667, found 451.0664; optical rotation [α]25 D +10.3 (c 0.38, CHCl3). The absolute configuration of 11b was assigned by analogy to 11b′. trans/cis = 90:10. 80% ee (trans) [HPLC conditions: Chiralpak IA and OJ-H columns, n-hexane/i-PrOH = 60:40, flow rate = 0.8 mL/min, wavelength = 210 nm, tR = 41.5 min (trans-minor), tR = 60.5 min (trans-major)]. 4-Methyl 2-Phenyl (2S,4R)-4-(5-Methyl-1,3-dioxoisoindolin-2-yl)pyrrolidine-2,4-dicarboxylate (11c): white solid, mp 136−138 °C; Rf = 0.1 (silica gel, petroleum ether/EtOAc = 1:1); 38.8 mg (95% yield); 1 H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.6 Hz, 1H), 7.65 (s, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.40 (t, J = 7.9 Hz, 2H), 7.25 (t, J = 7.6 Hz, 1H), 7.16−7.14 (m, 2H), 4.29 (dd, J = 9.6, 6.0 Hz, 1H), 4.03 (d, J = 12.9 Hz, 1H), 3.79 (d, J = 12.9 Hz, 1H), 3.71 (s, 3H), 3.24 (dd, J = 14.4, 6.0 Hz, 1H), 3.12 (dd, J = 14.4, 9.6 Hz, 1H), 2.80 (br, 1H), 2.52 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.8, 171.6, 168.7, 168.6, 150.5, 145.8, 135.0, 132.1, 129.5, 129.1, 126.1, 124.0, 123.4, 121.4, 67.5, 59.6, 56.1, 53.2, 40.3, 22.1; HRMS (ESI) m/z calcd for C22H20N2NaO6 [M + Na]+ 431.1214, found 431.1210; optical rotation [α]25 D +14.7 (c 0.48, CHCl3). The absolute configuration of 11c was assigned by analogy to 11b′. trans/cis = 93:7. 92% ee (trans) [HPLC conditions: Chiralpak IA and OJ-H columns, n-hexane/i-PrOH = 60:40, flow rate = 0.8 mL/min, wavelength = 210 nm, tR = 40.1 min (trans-minor), tR = 62.6 min (trans-major)]. 4-Methyl 2-Phenyl (2S,4R)-4-(5-Methoxy-1,3-dioxoisoindolin-2yl)pyrrolidine-2,4-dicarboxylate (11d): white solid, mp 67−69 °C; Rf = 0.2 (silica gel, petroleum ether/EtOAc = 1:1); 39.5 mg (93% yield); 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.31 (d, J = 2.3 Hz, 1H), 7.26−7.14 (m, 4H), 4.29 (dd, J = 9.6, 6.1 Hz, 1H), 4.02 (d, J = 12.9 Hz, 1H), 3.92 (s, 3H), 3.80 (d, J = 12.9 Hz, 1H), 3.71 (s, 3H), 3.23 (dd, J = 14.4, 6.1 Hz, 1H), 3.12 (dd, J = 14.4, 9.6 Hz, 1H), 2.67 (br, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.8, 171.6, 168.4, 168.3, 165.0, 150.6, 134.3, 129.5, 126.0, 125.2, 123.6, 121.4, 120.5, 107.9, 67.1, 59.7, 56.1, 53.2, 40.3; HRMS (ESI) m/z calcd for C22H21N2O7 [M + H]+ 425.1343, found 425.1339; optical rotation [α]D25 −18.2 (c 0.17, CHCl3). The absolute configuration of 11d was assigned by analogy to 11b′. trans/cis = 95:5. 97% ee (trans) [HPLC conditions: Chiralpak AS-H column, nhexane/i-PrOH = 70:30, flow rate = 1.0 mL/min, wavelength = 210 nm, tR = 27.5 min (trans-major), tR = 32.6 min (trans-minor)]. General Procedure for the Synthesis of Pyrrole Derivatives. To a 10 mL tube charged with 7 (12.3 mg, 0.02 mmol) and Ag2O (2.3 mg, 0.01 mmol) was added CHCl3 (1 mL). The mixture was stirred at −20 °C for 5 min, and then methyl 2-(tosyloxy)acrylate 12 (25.6 mg, 0.1 mmol) and isocyanoacetate 6a (11.88 mg, 0.12 mmol) were added. The reaction mixture was stirred at −20 °C until 12 was consumed. The organic solvent was concentrated, and the residue was purified by flash chromatography on silica gel (hexanes/ethyl acetate = 5:1) to afford product 14a. Dimethyl 1H-Pyrrole-2,4-dicarboxylate (14a): white solid, mp 91− 93 °C; Rf = 0.2 (silica gel, petroleum ether/EtOAc = 5:1); 13.0 mg (71% yield, with 7), 11.9 mg (65% yield, without 7); 1H NMR (400 MHz, CDCl3) δ 9.82 (br, 1H), 7.55 (dd, J = 3.3, 1.5 Hz, 1H), 7.29 (dd, J = 2.6, 1.5 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.4, 161.4, 127.1, 123.5, 118.0, 116.0, 51.9, 51.4; HRMS (ESI) m/z calcd for C8H9NNaO4 [M + Na]+ 206.0429, found 206.0424.

Hz, 1H), 3.73(1) (s, 3H), 3.73(2) (s, 3H), 3.62 (d, J = 12.1 Hz, 1H), 3.01 (d, J = 12.1 Hz, 1H), 2.61 (dt, J = 14.7, 6.9 Hz, 3H), 2.32 (dd, J = 13.9, 8.9 Hz, 1H), 1.67 (br, 1H), 1.55−1.48 (m, 2H), 1.41−1.35 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.3, 172.6, 59.0, 56.8, 55.8, 52.7, 52.4, 40.0, 31.2, 30.4, 22.0, 13.6; HRMS (ESI) m/z calcd for C12H22NO4S [M + H]+ 276.1264, found 276.1263; optical rotation [α]25 D −2.2 (c 0.28, CHCl3). The absolute configuration of 9e was assigned by analogy to Ns-9a. trans/cis = 66:34. 99% ee, 92% ee [HPLC conditions: Chiralcel OD-H and OJ-H columns, n-hexane/i-PrOH = 99:1, flow rate = 1.0 mL/min, wavelength = 210 nm, tR = 31.6 min (trans-minor), tR = 33.7 min (trans-major), tR = 38.2 min (cis-minor), tR = 46.1 min (cis-major)]. Dimethyl (2S,4R)-4-(Methylthio)pyrrolidine-2,4-dicarboxylate (9f): colorless oil; Rf = 0.2 (silica gel, petroleum ether/EtOAc = 1:1); 18.7 mg (80% yield); 1H NMR (400 MHz, CDCl3) δ 4.01 (dd, J = 8.8, 6.4 Hz, 1H), 3.73(1) (s, 3H), 3.73(2) (s, 3H), 3.60 (d, J = 12.2 Hz, 1H), 3.02 (dd, J = 12.1, 0.6 Hz, 1H), 2.90 (br, 1H), 2.62−2.57 (m, 1H), 2.31 (ddd, J = 14.0, 8.8, 0.6 Hz, 1H), 2.12 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.3, 172.1, 59.1, 56.7, 55.1, 52.7, 52.4, 39.4, 13.7; HRMS (ESI) m/z calcd for C9H16NO4S [M + H]+ 234.0795, found 234.0794; optical rotation [α]25 D −5.50 (c 0.20, CHCl3). The absolute configuration of 9f was assigned by analogy to Ns-9a. trans/cis = 58:42. 94% ee, 84% ee [HPLC conditions: Chiralpak AD-H and AD-H columns, n-hexane/i-PrOH = 95:5, flow rate = 0.8 mL/min, wavelength = 254 nm, tR = 55.9 min (trans-major), tR = 58.4 min (trans-minor), tR = 60.4 min (cis-major), tR = 64.9 min (cis-minor)]. Dimethyl (2S,4R)-4-(Benzylthio)pyrrolidine-2,4-dicarboxylate (9g): colorless oil; Rf = 0.2 (silica gel, petroleum ether/EtOAc = 2:3); 27.8 mg (90% yield); 1H NMR (400 MHz, CDCl3) δ 7.30−7.22 (m, 5H), 3.98 (dd, J = 8.9, 6.3 Hz, 1H), 3.83 (s, 2H), 3.73 (s, 3H), 3.65 (s, 3H), 3.60 (d, J = 12.2 Hz, 1H), 2.99 (d, J = 12.3 Hz, 1H), 2.63 (dd, J = 14.0, 6.2 Hz, 1H), 2.32 (dd, J = 14.0, 8.9 Hz, 1H), 1.81 (br, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.3, 172.3, 137.0, 128.3, 128.6, 127.3, 59.1, 57.6, 56.0, 52.6, 52.4, 40.0, 35.6; HRMS (ESI) m/z calcd for C15H19NNaO4S [M + Na]+ 332.0927, found 332.0933; optical rotation [α]D25 −40.7 (c 0.14, CHCl3). The absolute configuration of 9g was assigned by analogy to Ns-9a. trans/cis = 73:27. 92% ee, 83% ee [HPLC conditions: Chiralpak AS-H column, nhexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 210 nm, tR = 14.2 min (cis-minor), tR = 16.2 min (trans-major), tR = 26.3 min (trans-minor), tR = 30.2 min (cis-major)]. Dimethyl (2S,4R)-4-(Phenylthio)pyrrolidine-2,4-dicarboxylate (9h): colorless oil; Rf = 0.3 (silica gel, petroleum ether/EtOAc = 1:1); 27.5 mg (93% yield); 1H NMR (400 MHz, CDCl3) δ 7.46−7.44 (m, 2H), 7.39−7.32 (m, 3H), 4.07 (dd, J = 8.7, 6.8 Hz, 1H), 3.72 (s, 3H), 3.66 (s, 3H), 3.52 (d, J = 12.4 Hz, 1H), 3.08 (d, J = 12.4 Hz, 1H), 2.55−2.50 (m, 1H), 2.37 (dd, J = 14.1, 8.7 Hz, 1H), 1.71 (br, 1H); 13 C{1H} NMR (101 MHz, CDCl3) δ 174.3, 172.3, 135.8, 131.0, 129.6, 129.0, 60.8, 59.2, 55.6, 52.5, 52.4, 39.6; HRMS (ESI) m/z calcd for C14H18NO4S [M + H]+ 296.0951, found 296.0954; optical rotation [α]25 D −12.4 (c 0.23, CHCl3). The absolute configuration of 9h was assigned by analogy to Ns-9a. trans/cis = 67:33. 99% ee, 96% ee [HPLC conditions: Chiralpak AS-H column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 210 nm, tR = 12.9 min (cis-minor), tR = 16.5 min (trans-major), tR = 21.0 min (trans-minor), tR = 22.6 min (cis-major)]. 4-Methyl 2-Phenyl (2S,4R)-4-(1,3-Dioxoisoindolin-2-yl)pyrrolidine-2,4-dicarboxylate (11a): colorless oil; Rf = 0.3 (silica gel, petroleum ether/EtOAc = 1:1); 35.5 mg (90% yield); 1H NMR (400 MHz, CDCl3) δ 7.87−7.84 (m, 2H), 7.77−7.74 (m, 2H), 7.41− 7.38 (m, 2H), 7.26−7.23 (m, 1H), 7.16−7.14 (m, 2H), 4.28 (dd, J = 9.5, 6.1 Hz, 1H), 4.03 (d, J = 12.9 Hz, 1H), 3.80 (d, J = 12.9 Hz, 1H), 3.72 (s, 3H), 3.24 (dd, J = 14.5, 6.1 Hz, 1H), 3.12 (dd, J = 14.4, 9.6 Hz, 1H), 2.54 (br, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.8, 171.5, 168.5, 150.5, 134.4, 131.7, 129.5, 126.1, 123.5, 121.3, 67.7, 59.7, 56.1, 53.3, 40.3; HRMS (ESI) m/z calcd for C21H19N2O6 [M + H]+ 395.1238, found 395.1234; optical rotation [α]25 D −24.3 (c 0.17, CHCl3). The absolute configuration of 11a was assigned by analogy to 11b′. trans/cis = 95:5. 90% ee (trans) [HPLC conditions: Chiralpak 12874

DOI: 10.1021/acs.joc.7b02266 J. Org. Chem. 2017, 82, 12869−12876

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The Journal of Organic Chemistry 4-Methyl 2-Phenyl-1H-pyrrole-2,4-dicarboxylate (14b): white solid, mp 121−123 °C; Rf = 0.3 (silica gel, petroleum ether/EtOAc = 5:1); 23.3 mg (95% yield, with 7), 20.1 mg (82% yield, without 7); 1 H NMR (400 MHz, CDCl3) δ 9.64 (br, 1H), 7.61 (dd, J = 3.3, 1.5 Hz, 1H), 7.52 (dd, J = 2.6, 1.5 Hz, 1H), 7.43 (dd, J = 8.4, 7.4 Hz, 2H), 7.30−7.26 (m, 1H), 7.21−7.18 (m, 2H), 3.86 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.2, 159.2, 150.2, 129.6, 127.8, 126.1, 122.9, 121.6, 118.4, 117.3, 51.5; HRMS (ESI) m/z calcd for C13H11NNaO4 [M + Na]+ 268.0580, found 268.0580. Methyl 5-Tosyl-1H-pyrrole-3-carboxylate (14c): white solid, mp 140−141 °C; Rf = 0.2 (silica gel, petroleum ether/EtOAc = 5:1); 27.6 mg (99% yield, with 7), 24.0 mg (86% yield, without 7); 1H NMR (400 MHz, CDCl3) δ 10.09 (br, 1H), 7.81 (d, J = 7.9 Hz, 2H), 7.52 (s, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.21 (s, 1H), 3.80 (s, 3H), 2.40 (s, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 163.9, 144.6, 138.4, 130.2, 130.1, 127.4, 127.1, 118.5, 115.8, 51.6, 21.6; HRMS (ESI) m/z calcd for C13H13NNaO4S [M + Na]+ 302.0457, found 302.0463. Dimethyl (2S,4R)-4-(tert-Butylthio)-1-((4-nitrophenyl)sulfonyl)pyrrolidine-2,4-di-carboxylate (Ns-9a). To a solution of amine 9a (27.5 mg, 0.1 mmol) in 3 mL of DCM was added NsCl (44.3 mg, 0.2 mmol); the reaction mixture was cooled to 0 °C, and then Et3N (30.4 mg, 0.3 mmol) was added dropwise. The reaction was warmed to room temperature and stirred at this temperature overnight. After completion, monitored by TLC, DCM was evaporated and the residue was purified on silica gel to give 34.5 mg (75% yield) of product Ns-9a as a white solid: mp 129−131 °C; Rf = 0.3 (silica gel, petroleum ether/ EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 8.8 Hz, 2H), 8.13 (d, J = 8.9 Hz, 2H), 4.55 (dd, J = 9.1, 4.8 Hz, 1H), 4.16 (d, J = 10.4 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H), 3.59 (d, J = 10.5 Hz, 1H), 2.82 (dd, J = 13.6, 4.8 Hz, 1H), 2.49 (dd, J = 13.5, 9.1 Hz, 1H), 1.27 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.5, 171.1, 150.2, 144.2, 129.0, 124.1, 59.2, 57.4, 55.0, 52.9, 52.7, 47.4, 40.9, 31.3; HRMS (ESI) m/z calcd for C18H24N2NaO8S2 [M + Na]+ 483.0866, found 483.0864; optical rotation [α]25 D −48.7 (c 0.28, CHCl3). 98% ee [HPLC conditions: Chiralpak AD-H column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR = 21.1 min, tR = 25.7 min]. 4-Methyl 2-Phenyl (2S,4R)-4-(5-Chloro-1,3-dioxoisoindolin-2-yl)3,4-dihydro-2H-pyrrole-2,4-dicarboxylate (11b′). To a 10 mL tube charged with 7 (12.3 mg, 0.02 mmol) and Ag2O (2.3 mg, 0.01 mmol) was added CHCl3 (1 mL). The mixture was stirred at −20 °C for 5 min, and then acrylate 10b (23.1 mg, 0.1 mmol) and isocyanoacetate 6b (19.32 mg, 0.12 mmol) were added. The reaction mixture was stirred at −20 °C until 10b was consumed, then filtered through a pad of silica gel, and washed with ethyl acetate. The solvent was removed under reduced pressure and then purified by flash chromatography on silica gel (hexanes/ethyl acetate = 4:1) to afford 40.5 mg (95% yield) of product 11b′ as a white solid: mp 149−150 °C; Rf = 0.2 (silica gel, petroleum ether/EtOAc = 4:1); 1H NMR (400 MHz, CD2Cl2) δ 8.25 (d, J = 2.5 Hz, 1H), 7.85 (dd, J = 11.6, 4.7 Hz, 2H), 7.78 (dd, J = 8.0, 1.7 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H), 7.29 (dd, J = 18.6, 11.2 Hz, 1H), 7.19 (d, J = 7.8 Hz, 2H), 5.34 (ddd, J = 7.8, 5.3, 2.6 Hz, 1H), 3.79 (s, 3H), 3.36 (dd, J = 14.3, 5.3 Hz, 1H), 2.89 (dd, J = 14.3, 9.0 Hz, 1H); 13 C{1H} NMR (101 MHz, CD2Cl2) δ 169.2, 167.2, 166.5, 166.2, 162.2, 150.6, 141.3, 134.8, 133.1, 129.6, 129.5, 126.1, 125.0, 124.0, 121.4, 74.8, 74.2, 53.8, 36.3; HRMS (ESI) m/z calcd for C21H15ClN2NaO6 [M + Na]+ 449.0511, found 449.0508; optical rotation [α]25 D −30.0 (c 0.40, CHCl3). 91.5% ee (trans, recrystallization from EtOAc and petroleum ether) [HPLC conditions: Chiralpak IA column, n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, tR = 35.4 min (trans-minor), tR = 41.3 min (trans-major)].

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Crystal data for Ns-9a (CIF) Crystal data for 11b′ (CIF)

AUTHOR INFORMATION

Corresponding Authors

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

Yun He: 0000-0002-5322-7300 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (nos. 21402150, 21372267, and 21572027) for financial support. We thank Dr. Yong-Liang Shao (Lanzhou University) and Xiangnan Gong (Chongqing University) for the X-ray crystallographic analysis.

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REFERENCES

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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.joc.7b02266. NMR spectra, HPLC chromatograms, CD spectra for some products, and X-ray analysis (PDF) 12875

DOI: 10.1021/acs.joc.7b02266 J. Org. Chem. 2017, 82, 12869−12876

Note

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DOI: 10.1021/acs.joc.7b02266 J. Org. Chem. 2017, 82, 12869−12876