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Catalytic Asymmetric [3 + 2] Cycloaddition Reaction Between Aurones and Isocyanoacetates: Access to Spiropyrrolines via Silver Catalysis Zhi-Peng Wang, Sichuan Xiang, Pan-Lin Shao, and Yun He J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01622 • Publication Date (Web): 11 Jul 2018 Downloaded from http://pubs.acs.org on July 11, 2018

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The Journal of Organic Chemistry

Catalytic Asymmetric [3 + 2] Cycloaddition Reaction Between Aurones and Isocyanoacetates: Access to Spiropyrrolines via Silver Catalysis

Zhi-Peng Wang,† Sichuan Xiang,† Pan-Lin Shao,*,†,‡ and Yun He*,†

† School of Pharmaceutical Sciences and Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, 55 Daxuecheng South Road, Shapingba, Chongqing 401331, People’s Republic of China. ‡ College of Innovation and Entrepreneurship, Southern University of Science and Technology, Shenzhen 518000, People’s Republic of China.

ABSTRUCT: The first enantioselective formal [3 + 2] cycloaddition of aurone analogues with isocyanoacetates was developed via chiral Ag-complex catalysis. A variety of optically enriched spiro-1-pyrrolines were obtained in excellent yields, diastero- and enantioselectivities (up to 99% yield, >20:1 dr, >99% ee). This synthetic approach represents an extremely simple, efficient and atom-economical method for spiro-1-pyrrolines synthesis. INTRODUCTION Spiro heterocyclic compounds are ubiquitous in biologically active natural products and pharmaceutically important compounds,1 two of the most important classes are spiropyrrolines

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and spiropyrrolidines, which display broad biological activities.2 In recent decades, the formal [3 + 2] cyclization of electron-deficient olefins with azomethine ylides has emerged as a powerful tool for the construction of such spiropyrrolidine derivatives.3 In particular, the aurone analogues have received extensive attention as dipolarophiles in the construction of spiroheterocycles.4,5 In 2016, Ding and Fu et al. developed the first cyclization of 2-alkylidenebenzofuran-3-one with azomethine ylides using simple functional ionic liquids as catalysts, accessing highly substituted spiropyrrolidine in good yields.5a Recently, the synthesis of spiropyrrolidine derivatives bearing four contiguous stereogenic centers was described by Albrecht et al. with moderate enantioselectivity (Scheme 1).5b Actually, concerning both the number of stereocenters and molecular complexities, the stereoselective construction of such privileged scaffold still remains an important goal in synthetic organic chemistry.

Scheme 1. The application of aurones in the synthesis of spiropyrrolidines.

Owing to the unique reactivity, isocyanoacetates have been explored as versatile building blocks for the construction of heterocyclic compounds,6 especially in the formal [3 + 2] cycloaddition reaction with olefins.7 In 2008, Gong and co-workers developed the first cinchona alkaloids catalyzed synthesis of dihydropyrroles with α-aryl isocyanoacetate and nitroolefins.7a In 2011, Escolano group reported the cooperative Brønsted base/Lewis acid cascade catalysis promoted cycloaddition of isocyanoacetates with α,β-unsaturated ketones in moderate yields and


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enantioselectivities.7b In 2012, Carretero and Adrio et al. disclosed the catalytic asymmetric formal [3 + 2] cycloaddition of isocyanoacetates with maleimides, using cationic Au(I)/DTBM-segphos complex as the catalystic system.7c At the same time, Wang and Xu et al. developed stereoselective [3 + 2] cycloaddition of α-aryl isocyanoacetates with protected methyleneindolinones to access 3,3´-pyrrolidinyl spirooxindoles catalyzed by cinchona alkaloid-based thiourea tertiary amines (Scheme 2).7d Despite these significant advances, the enantioselective cycloaddition of isocyanoacetates with aurones has yet to be demonstrated.

Scheme 2. Formal [3 + 2] cyclization of isocyanoacetates with olefins.

RESULTS AND DISCUSSION Our recent efforts have been devoted to the asymmetric synthesis of nitrogen-containing heterocycles, such as pyrrolines and pyrrolidines using functionalized 1,3-dipole enolate derived from isocyanoacetates under chiral Brønsted base conditions.8 In this work, our attention was drawn to the possibility of the cycloaddition reaction of isocyanoacetates with aurone analogues. Initial

exploration

utilized

(Z)-2-benzylidenebenzofuran-3(2H)-one

1a

and

methyl

2-isocyano-3-phenylpropanoate 2a as the model substrates catalyzed by a chiral silver(I) complex



developed by Dixon group.9 Although the 1,3-dipole enolate generated from isocyanoacetate could potentially facilitate a [4 + 3] and/or [3 + 2] Michael/cyclization reaction sequence, our studies revealed that this approach only led to the [3 + 2] cyclization, affording the spiropyrroline, and no [4 + 3] annulation product was observed (Scheme 3).

Scheme 3. Inspiration for the cyclization of isocyanoacetate with aurone analogue.

Encouraged by the preliminary result, we turned our attention to further optimize the [3 + 2] cyclization conditions. As shown in Table 1, several precatalysts 3 were screened to evaluate their ability to promote the cycloaddition of 1a and 2a at ambient temperature. To our delight, precatalyst 3a in combination with Ag2O led to high yield and stereoselectivity (entry 1). Lowering the temperature to 0

o

C afforded a better yield, diastereoselectivity and

enantioselectivity (entries 2-4). Precatalysts 3b-e with minor structural modifications were then screened (entries 5-8), and 3b afforded the best result (entry 5). Although a chiral silver complex with (S)-MOP 3f was the optimal catalyst in Gong’s work for the enantioselective cycloaddition of α-aryl isocyanoacetates with 2-oxobutenoate esters,10 3f with Ag2O afforded the desired product with poor enantioselectivity (entry 9). Varying the solvent did not benefit the enantioselectivity (entries 10-14). Thus, we identified the following optimal protocol: reaction of 1a and 2a with a molar ratio of 1.0:1.2 in the presence of Ag2O (10 mol%) and precatalyst 3b (20 mol%) in THF at 0 oC. It is worth noting that all the reactions were conducted open to air with no need for exclusion of air or moisture.


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Table 1. Optimization of reaction of aurone analogues with isocyanoacetate.a

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

3 3a 3a 3a 3a 3b 3c 3d 3e 3f 3b 3b 3b 3b 3b

T(oC) 25 0 -10 -20 0 0 0 0 0 0 0 0 0 0

solvent THF THF THF THF THF THF THF THF THF DCM toluene EA Et2O CHCl3

yield(%) 90 99 99 86 99 98 97 98 99 95 96 97 99 98

drb >20:1 >20:1 >20:1 19:1 >20:1 >20:1 19:1 16:1 12:1 19:1 >20:1 >20:1 >20:1 >20:1

ee(%)c 78 90 90 86 93 91 -40 -40 -33 92 89 92 84 84

a

Unless otherwise stated, reactions were run for 12 h. bdr ratio determined by 1H NMR

spectroscopy (400 MHz) of the reaction mixture. cee determined by HPLC analysis using a chiral stationary phase. See Supporting Information for details.

Using this catalytic protocol, a wide range of spiro-1-pyrrolines 4 were prepared as shown in Scheme 4. The electronic effects of different aryl substituents on aurones were investigated, and the reaction exhibited good insensitivity to the substitution pattern. Introduction of an electron-donating or electron-withdrawing group (5-OMe, 5-Br) to the benzofuranone moiety led to the corresponding products 4b-c in almost quantitative yields. The aurone analogues 1 could well tolerate the existence of electron-poor or electron-rich phenyl rings as R2 group, the para-,



meta-, or ortho-substituents did not affect the reaction, and furnished products 4 in excellent yields 4d-4i, albeit the halogen substituents on the para- and meta-position slightly decreased the enantioselectivity. Moreover, replacement of the R2 group of the aurone analogues with β-naphthyl, 3-indolyl, 3-pyridinyl, 2-furanyl, 2-thiophenyl and ferrocenyl, respectively, the reactions could still undergo smoothly to afford the desired products 4j-o in almost quantitative yields and good to excellent diastereo- and enantioselectivities. The conversion from spiropyrroline 4d to spiropyrrolidine 4d' was easily achieved under a simple reduction condition employing NaCNBH3/HOAc without loss of enantioselectivity. The relative and absolute configuration of 4d was unambiguously established by single crystal X-ray analysis of the pyrrolidine 4d' (2S,4'S,5'R) (Scheme 4, see Supporting Information for details).11

Scheme 4. Substrate scope of aurone analogues.


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The scope of this methodology was then extended to α-substituted isocyanoacetates 2. This reaction showed good generality and wide substrate scope. Different substitution patterns on the isocyanoacetates such as methyl (5a), isopropyl (5b), n-butyl (5c), ester (5d), cyclohexyl (5e) and allyl (5f) were all well tolerated, funishing the [3 + 2] cyclization products in uniformly high yields, diastereo- and enantioselectivities, albeit p-methoxyphenyl substituted isocyanoacetate led to the desired product 5g-h with slightly reduced yields and stereoselectivities (Scheme 5).

Scheme 5. Substrate scope of α-substituted isocyanoacetates.

Next, the substrate scope of α-unsubstituted isocyanoacetate was studied. Unfortunately, the desired product was obtained in low yield under the standard condition, due to the decomposition of spiropyrroline. To our delight, when the reaction temperature was decreased to -20 oC, the cycloadducts were obtained in uniformly good yields. As shown in Scheme 6, various aurone analogues were examined with 2b for the efficient cycloaddition to deliver 6a-6f in high yields, and excellent enantioselectivities (up to 90% yield, >99% ee). However, the methoxy group on the benzofuranone moiety led to 6f with a slight erosion of enantioselectivity. Notably, the annulation highlighted the versatility of this method to prepare spiro-1-pyrroline derivatives possessing three



contiguous stereocenters. The relative and absolute configuration of 6a was unambiguously deduced from single crystal X-ray diffraction analysis of the corresponding pyrrolidine 6a' (See Supporting Information for details).11

Scheme 6. Substrate scope of methyl isocyanoacetate and aurone analogues.

To further explore the synthetic utility of this protocol, a gram-scale reaction was also evaluated. The desired product 4a could be obtained smoothly in 98% yield, >20:1 dr and 92% ee under the standard condition, without significant loss of the reactivity and stereoselectivity (Scheme 7).

Scheme 7. Gram scale synthesis of 4a.

Finally, to validate the application potential of these cycloadducts, we chose product 5f as a model for transformation. Allylation of the imine on pyrroline moiety was readily


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achieved,12 providing the diallyl substituted pyrrolidine 7 in excellent yield and good stereoselectivity. This transformation has the potential to furnish highly substituted biologically active pyrrolidine derivatives.13 The relative configuration of 7 was assigned by its NOE analysis (Scheme 8, see Supporting Information for details).

Scheme 8. Transformation of 5f.

Although the mechanism of these reactions reported here remains to be clarified, a plausible transition-state model is depicted in Scheme 9, based on the results from our experiment and the absolute configuration of the major isomer. In this model, the α-proton of isocyanoacetate is easily deprotonated by the tertiary amine on the precatalyst due to the activation of Ag(I) chelating to the terminal carbon of the isocyano group. The center metal Ag(I) could also chelate to the amide nitrogen and the Lewis base phosphorus on precatalyst. Owing to the hindrance, the ester motif is situated below the bulky phenyl groups, and then the isocyanoacetate would attack aurone olefin from the Re-face, meanwhile, the oxygen atom of aurone is hydrogen-bonded to the precatalyst and coordinated to Ag(I) to stabilize the transition-state. Subsequently, a 5-endo-dig cyclization would take place to form the spiropyrroline product with three newly generated stereocenters.



Scheme 9. Proposed transition-state model.

CONCLUSIONS In summary, we have developed the first enantioselective formal [3 + 2] cycloaddition reaction of isocyanoacetates with aurone analogues using a chiral Ag-complex catalyst. A wide variety of isocyanoacetates and aurones with different electronic and steric properties were well tolerated in this protocol, leading to optically active spiropyrrolines bearing three contiguous stereogenic centers in excellent yields, diastero- and enantioselectivities (up to 99% yield, >20:1 dr, >99% ee). Investigations aiming at expanding the application of this approach to synthesize more promising candidates for drug discovery as well as the biological evaluation are currently ongoing in our laboratory.

EXPERIMENTAL SECTION General Information: 1H and

13

C{1H} NMR spectra were recorded on an Agilent 400M

NMR spectrometer at ambient temperature. Chemical shifts were reported in parts per million (ppm), and the residual solvent peak was used as an internal reference: 1H (chloroform δ 7.26), 13

C{1H} (chloroform δ 77.0). Data are reported as follows: chemical shift, multiplicity (s = singlet,

d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constants (Hz) and integration. Melting point (M.P.) was obtained on SGW X-4A. For thin layer chromatography (TLC), Merck pre-coated TLC plates (Merck 60 F254) were used, and compounds were


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visualized with a UV light at 254 nm. High resolution mass spectra (HRMS) were obtained 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, ID. Unless otherwise noted, all the reactions were carried out in air. Tetrahydrofuran (THF) was dried and distilled from sodium. Deuterated solvents were purchased from Cambridge Isotope Laboratories and used as received without further purification. Other chemicals were purchased from commercial suppliers and used as received without further purification. General

procedure

for

the

synthesis

of

aurones:14

To

a

solution

of

benzofuran-3(2H)-one (1.0 mmol) and benzaldehyde (1.0 mmol) in dichloromethane (10 mL) was added activated basic aluminum oxide (5.0 mmol) at room temperature with vigorously stirring. After reaction completion, aluminum oxide was filtered and washed abundantly with dichloromethane, the filtrate was concentrated to afford crude product, which was purified by flash chromatography on silica gel (hexanes/ethyl acetate = 20:1) to give the product 1a as pale yellow solid. (Z)-2-Benzylidenebenzofuran-3(2H)-one (1a). 177.8 mg, 80% yield, Rf = 0.5, (silica gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 89-90 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.93 (d, J = 7.3 Hz, 2H), 7.81 (d, J = 7.5 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.46 (t, J = 7.3 Hz, 2H), 7.40 (t, J = 7.1 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 6.90 (s,



1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 184.8, 166.2, 146.9, 136.9, 132.3, 131.5, 129.9, 128.9, 124.7, 123.5, 121.6, 113.0, 112.9. (Z)-2-Benzylidene-6-methoxybenzofuran-3(2H)-one (1b). 214.4 mg, 85% yield, Rf = 0.5, (silica gel, petroleum ether:EtOAc = 5:1), white scaly solid, M.P. 132-133 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.90 – 7.88 (m, 2H), 7.69 (t, J = 5.9 Hz, 1H), 7.45 (dd, J = 10.1, 4.6 Hz, 2H), 7.40 – 7.36 (m, 1H), 6.81 (s, 1H), 6.76 (dt, J = 8.4, 2.0 Hz, 2H), 3.92 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 183.0, 168.6, 167.5, 147.8, 132.4, 131.3, 129.6, 128.8, 125.8, 114.8, 112.2, 111.9, 96.7, 56.0. (Z)-2-Benzylidene-6-bromobenzofuran-3(2H)-one (1c). 286.1 mg, 95% yield, Rf = 0.3, (silica gel, petroleum ether:EtOAc = 10:1), pale yellow solid, M.P. 168-170 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.88 (d, J = 7.1 Hz, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.54 (s, 1H), 7.43 (dq, J = 14.3, 7.0 Hz, 3H), 7.35 (d, J = 8.1 Hz, 1H), 6.90 (s, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 183.5, 166.1, 146.8, 131.9, 131.6, 131.3, 130.2, 129.0, 127.2, 125.5, 120.7, 116.6, 114.0. (Z)-2-(2-Chlorobenzylidene)benzofuran-3(2H)-one (1d). 220.7 mg, 86% yield, Rf = 0.5, (silica gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 133-134 oC. 1H NMR (400 MHz, Chloroform-d) δ 8.35 (dd, J = 7.8, 1.6 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.68 – 7.64 (m, 1H), 7.46 (dd, J = 7.9, 1.2 Hz, 1H), 7.38 (dd, J = 8.7, 7.6 Hz, 2H), 7.32 – 7.29 (m, 2H), 7.23 (t, J = 7.5 Hz, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 184.5, 166.2, 147.6, 137.1, 135.9, 132.2, 130.6, 130.4, 130.0, 127.0, 124.8, 123.7, 121.5, 112.9, 108.0. (Z)-2-(2-Methylbenzylidene)benzofuran-3(2H)-one (1e). 193.7 mg, 82% yield, Rf = 0.5, (silica gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 101-102 oC. 1H NMR (400 MHz, Chloroform-d) δ 8.27 – 8.25 (m, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.67 – 7.63 (m, 1H), 7.34 – 7.20


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(m, 5H), 7.14 (s, 1H), 2.52 (s, 3H);

13

C{1H} NMR (101 MHz, Chloroform-d) δ 184.8, 166.2,

147.0, 139.2, 136.8, 131.2, 130.8, 130.7, 129.8, 126.4, 124.7, 123.4, 121.7, 113.0, 109.9, 20.2. (Z)-2-(3-Chlorobenzylidene)benzofuran-3(2H)-one (1f). 220.7 mg, 86% yield, Rf = 0.5, (silica gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 96-97 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.91 (s, 1H), 7.78 (t, J = 12.5 Hz, 1H), 7.72 – 7.70 (m, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.38 – 7.32 (m, 3H), 7.22 (t, J = 7.4 Hz, 1H), 6.76 (s, 1H);

13

C{1H} NMR (101 MHz,

Chloroform-d) δ 184.6, 166.2, 147.3, 137.1, 134.8, 134.0, 130.9, 130.0, 129.7, 129.6, 124.7, 123.7, 121.4, 113.0, 111.1. (Z)-2-(3-Methoxybenzylidene)benzofuran-3(2H)-one (1g). 214.4 mg, 85% yield, Rf = 0.4, (silica gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 116-117 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J = 7.7 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 6.7 Hz, 2H), 7.40 – 7.32 (m, 2H), 7.23 (t, J = 7.5 Hz, 1H), 7.98 – 6.96 (m, 1H), 6.87 (s, 1H), 3.89 (s, 3H); 13

C{1H} NMR (101 MHz, Chloroform-d) δ 184.8, 166.2, 159.8, 147.0, 136.9, 133.5, 129.8, 124.7,

124.3, 123.5, 121.6, 116.5, 115.7, 113.0, 112.9, 55.3. (Z)-2-(4-Bromobenzylidene)benzofuran-3(2H)-one (1h). 171.6 mg, 57% yield, Rf = 0.5, (silica gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 170-171 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.79 (dd, J = 12.4, 8.1 Hz, 3H), 7.69 – 7.65 (m, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.3 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 6.81 (s, 1H);

13

C{1H} NMR (101 MHz,

Chloroform-d) δ 184.6, 166.1, 147.1, 137.0, 132.8, 132.2, 131.2, 124.7, 124.3, 123.7, 121.5, 112.9, 111.5. (Z)-2-(4-Methoxybenzylidene)benzofuran-3(2H)-one (1i). 229.6 mg, 91% yield, Rf = 0.5, (silica gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 133-134 oC. 1H NMR (400 MHz,



Chloroform-d) δ 7.91 – 7.87 (m, 2H), 7.81 (dd, J = 7.6, 0.8 Hz, 1H), 7.64 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.23 – 7.19 (m, 1H), 7.00 – 6.98 (m, 2H), 6.89 (s, 1H), 3.87 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 184.5, 165.8, 161.1, 145.9, 136.5, 133.4, 125.1, 124.6, 123.3, 122.0, 114.5, 113.4, 112.9, 55.4. (Z)-2-(Naphthalen-2-ylmethylene)benzofuran-3(2H)-one (1j). 212.4 mg, 78% yield, Rf = 0.5, (silica gel, petroleum ether:EtOAc = 5:1), yellow solid, M.P. 120-121 oC. 1H NMR (400 MHz, Chloroform-d) δ 8.30 (s, 1H), 8.06 (dd, J = 8.6, 1.4 Hz, 1H), 7.85 (ddd, J = 14.1, 9.3, 3.4 Hz, 4H), 7.67 – 7.63 (m, 1H), 7.54 – 7.49 (m, 2H), 7.36 (d, J = 8.3 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.03 (s, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 184.6, 166.1, 147.1, 136.8, 133.7, 133.3, 132.3, 129.9, 128.7, 128.5, 127.72, 127.66, 127.5, 126.6, 124.7, 123.5, 121.7, 113.2, 113.0; HRMS (ESI): m/z calcd. for [C19H13O2, M+H]+: 273.0910; found: 273.0916. (Z)-2-((1H-Indol-3-yl)methylene)benzofuran-3(2H)-one (1k). 125.4 mg, 48% yield, Rf = 0.2, (silica gel, petroleum ether:EtOAc = 3:1), orange solid, M.P. 232-233 oC. 1H NMR (400 MHz, DMSO-d6) δ 12.11 (br, 1H), 8.26 (d, J = 2.6 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.75 (t, J = 7.9 Hz, 2H), 7.56 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.36 (s, 1H), 7.23 (ddd, J = 25.2, 15.5, 7.3 Hz, 3H);

13

C{1H} NMR (101 MHz, DMSO-d6) δ 182.2, 164.6, 144.6, 136.83, 136.82, 132.7,

127.1, 124.3, 123.8, 123.3, 122.7, 121.5, 119.5, 113.6, 112.8, 108.9, 108.0; HRMS (ESI): m/z calcd. for [C17H11NNaO2, M+Na]+: 284.0682; found: 284.0682. (Z)-2-(Pyridin-3-ylmethylene)benzofuran-3(2H)-one (1l). 163.0 mg, 73% yield, Rf = 0.2, (silica gel, petroleum ether:EtOAc = 5:1), yellow solid, M.P. 111-112 oC. 1H NMR (400 MHz, Chloroform-d) δ 9.05 (s, 1H), 8.61 (d, J = 4.1 Hz, 1H), 8.29 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.42 – 7.39 (m, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.26 (t, J = 7.4 Hz,


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1H), 6.85 (s, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 184.3, 166.2, 152.2, 150.06, 148.0, 137.7, 137.3, 128.6, 124.8, 123.8, 123.7, 121.3, 113.0, 108.8. (Z)-2-(Furan-2-ylmethylene)benzofuran-3(2H)-one (1m). 178.3 mg, 84% yield, Rf = 0.5, (silica gel, petroleum ether:EtOAc = 5:1), yellow solid, M.P. 119-120 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.79 (d, J = 7.4 Hz, 1H), 7.66 – 7.62 (m, 2H), 7.31 (d, J = 8.3 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 3.3 Hz, 1H), 6.89 (s, 1H), 6.60 (d, J = 1.4 Hz, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 184.0, 165.7, 148.8, 145.4, 145.0, 136.7, 124.5, 123.5, 122.0, 117.2, 113.1, 112.9, 101.6. (Z)-2-(Thiophen-2-ylmethylene)benzofuran-3(2H)-one (1n). 205.4 mg, 90% yield, Rf = 0.5, (silica gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 102-103 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.79 (ddd, J = 7.6, 1.3, 0.5 Hz, 1H), 7.64 (ddd, J = 8.6, 7.3, 1.4 Hz, 1H), 7.61 – 7.60 (m, 1H), 7.55 – 7.54 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.23 – 7.19 (m, 1H), 7.17 (s, 1H), 7.14 (dd, J = 5.1, 3.7 Hz, 1H);

13

C{1H} NMR (101 MHz, Chloroform-d) δ 183.8, 165.6,

145.3, 136.6, 135.6, 133.1, 131.7, 128.1, 124.5, 123.5, 122.2, 113.0, 107.0. [(Z)-(3-Oxo-2(3H)-benzofuranylidene)methyl]ferrocene (1o). 244.3 mg, 74% yield, Rf = 0.4, (silica gel, petroleum ether:EtOAc = 10:1), purple solid, M.P. 150-151 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J = 7.5 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 6.89 (s, 1H), 4.86 (s, 2H), 4.54 (s, 2H), 4.17 (s, 5H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 182.9, 165.4, 146.0, 136.1, 124.5, 123.0, 122.6, 116.4, 112.9, 75.1, 71.8, 71.5, 69.9. General procedure for the cycloaddition of aurones with α-substituted isocyanoacetates: THF (1 mL) was added to a 10 mL vial charged with the precatalyst 3b (12.3 mg, 0.02 mmol) and Ag2O



Page 16 of 41

(2.3 mg, 0.01 mmol). The mixture was stirred at 0 oC for 5 min, then the aurore 1a (22.2 mg, 0.1 mmol) and methyl 2-isocyano-3-phenylpropanoate 2a (22.7 mg, 0.12 mmol) were added. The reaction mixture was stirred at 0 oC until 1a was consumed, and then the reaction mixture was purified by flash chromatography on silica gel directly (eluent, petroleum ether:EtOAc = 5:1, 0.1% TEA v/v) to afford the product 4a. Methyl

(2S,4'S,5'R)-5'-benzyl-3-oxo-4'-phenyl-4',5'-dihydro-3H-spiro[benzofuran-2,3'-

pyrrole]-5'-carboxylate (4a). White solid, M.P. 58-59 oC, Rf = 0.2 (silica gel, petroleum ether: EtOAc = 3:2). 40.7mg, 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.68 (s, 1H), 7.65 – 7.60 (m, 2H), 7.38 (dd, J = 6.5, 3.1 Hz, 2H), 7.29 – 7.16 (m, 9H), 7.09 (t, J = 7.5 Hz, 1H), 4.01 (s, 1H), 3.62 (s, 3H), 3.08 (d, J = 13.4 Hz, 1H), 2.97 (d, J = 13.4 Hz, 1H);

13

C{1H} NMR (101 MHz,

Chloroform-d) δ 197.1, 172.0, 171.4, 160.4, 138.8, 135.8, 132.1, 131.5, 130.2, 128.12, 128.09, 126.8, 124.9, 122.9, 120.3, 113.5, 98.3, 86.9, 58.6, 52.2, 44.0; HRMS (ESI): m/z calcd. for [C26H22NO4, M+H]+: 412.1543; found: 412.1537. Optical Rotation: [α]25D = +101.64 (c = 2.13, MeOH). The absolute configuration of 4a was assigned by analogy to 4d'. >20:1 dr. 93% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, tR = 11.4 min (major), tR = 15.5 min (minor)] Methyl

(2S,4'S,5'R)-5'-benzyl-5-methoxy-3-oxo-4'-phenyl-4',5'-dihydro-3H-spiro

[benzofuran-2,3'-pyrrole]-5'-carboxylate (4b). White solid, M.P. 81-82 oC, Rf = 0.3 (silica gel, petroleum ether: EtOAc = 5:1). 43.2 mg, 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.68 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.39 – 7.37 (m, 2H), 7.23 (ddd, J = 20.8, 13.8, 6.4 Hz, 8H), 6.62 (dt, J = 7.3, 3.6 Hz, 1H), 6.58 (d, J = 1.5 Hz, 1H), 4.00 (s, 1H), 3.87 (s, 3H), 3.61 (s, 3H), 3.07 (d, J = 13.4 Hz, 1H), 2.95 (d, J = 13.4 Hz, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 194.4, 173.9,


Page 17 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


172.1, 168.9, 160.9, 135.9, 132.3, 131.5, 130.2, 128.12, 128.08, 128.0, 126.8, 125.9, 113.3, 112.6, 99.1, 96.3, 86.9, 58.4, 56.0, 52.2, 44.0; HRMS (ESI): m/z calcd. for [C27H23NNaO5, M+Na]+: 464.1468; found: 464.1469. Optical Rotation: [α]25D = +103.02 (c = 0.28, MeOH). The absolute configuration of 4b was assigned by analogy to 4d'. 29:1 dr. 93% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =16.1 min (major), tR = 18.4 min (minor)] Methyl (2S,4'S,5'R)-5'-benzyl-6-bromo-3-oxo-4'-phenyl-4',5'-dihydro-3H-spiro[benzofuran2,3'-pyrrole]-5'-carboxylate (4c). White solid, M.P. 73-75 oC, Rf = 0.5 (silica gel, petroleum ether: EtOAc = 5:1). 46.6 mg, 95% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.67 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 7.34 – 7.33 (m, 2H), 7.30 – 7.28 (m, 3H), 7.24 – 7.21 (m, 4H), 7.19 – 7.15 (m, 2H), 3.99 (s, 1H), 3.60 (s, 3H), 3.06 (d, J = 13.4 Hz, 1H), 2.93 (d, J = 13.4 Hz, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 195.9, 171.9, 171.3, 159.8, 135.6, 133.8, 131.8, 131.4, 130.1, 128.3, 128.1, 126.9, 125.6, 119.2, 117.0, 98.9, 87.0, 58.7, 52.3, 44.0; HRMS (ESI): m/z calcd. for [C26H20BrNNaO4, M+Na]+: 512.0468; found: 512.0471. Optical Rotation: [α]25D = +100.75 (c = 0.53, MeOH). The absolute configuration of 4c was assigned by analogy to 4d'. 24:1 dr. 94% ee. [HPLC condition: Chiralpak ID column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =43.1 min (major), tR = 56.1 min (minor)] Methyl (2S,4'S,5'R)-5'-benzyl-4'-(2-chlorophenyl)-3-oxo-4',5'-dihydro-3H-spiro[benzofuran2,3'-pyrrole]-5'-carboxylate (4d). White solid, M.P. 70-71 oC, Rf = 0.4 (silica gel, petroleum ether: EtOAc = 5:1). 44.1 mg, 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.73 (s, 1H), 7.69 – 7.66 (m, 1H), 7.65 – 7.61 (m, 2H), 7.38 (dt, J = 6.2, 2.9 Hz, 1H), 7.27 – 7.16 (m, 8H), 7.10 (t, J = 7.5 Hz, 1H), 4.91 (s, 1H), 3.66 (s, 3H), 3.13 (d, J = 13.3 Hz, 1H), 2.98 (d, J = 13.3 Hz, 1H);



13


130.3, 129.96, 129.94, 129.2, 128.1, 126.9, 126.2, 125.0, 123.1, 120.2, 113.4, 98.0, 85.9, 52.6, 52.5, 43.5; HRMS (ESI): m/z calcd. for [C26H20ClNNaO4, M+Na]+: 468.0973; found: 468.0970. Optical Rotation: [α]25D = +199.20 (c = 0.40, MeOH). The absolute configuration of 4d was assigned by analogy to 4d'. 20:1 dr. 97% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, tR = 15.6 min (major), tR = 24.7 min (minor)] Methyl

(2S,4'S,5'R)-5'-benzyl-3-oxo-4'-(o-tolyl)-4',5'-dihydro-3H-spiro[benzofuran-2,3'-

pyrrole]-5'-carboxylate (4e). White solid, M.P. 67-68 oC, Rf = 0.4 (silica gel, petroleum ether: EtOAc = 5:1). 42.1 mg, 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.72 (s, 1H), 7.61 (ddd, J = 7.3, 4.1, 1.3 Hz, 2H), 7.52 (td, J = 4.4, 2.5 Hz, 1H), 7.27 – 7.20 (m, 5H), 7.16 – 7.12 (m, 4H), 7.08 (t, J = 7.5 Hz, 1H), 4.52 (d, J = 7.7 Hz, 1H), 3.61 (s, 3H), 3.06 (d, J = 13.4 Hz, 1H), 2.97 (d, J = 13.4 Hz, 1H), 2.32 (s, 3H);

13

C{1H} NMR (101 MHz, Chloroform-d) δ 197.4, 172.4, 171.5,

160.9, 138.8, 138.5, 135.9, 131.2, 130.7, 130.5, 130.3, 128.1, 127.8, 126.8, 125.3, 124.9, 122.9, 120.1, 113.5, 98.6, 86.7, 52.7, 52.3, 44.0, 20.4; HRMS (ESI): m/z calcd. for [C27H23NNaO4, M+Na]+: 448.1519; found: 448.1512. Optical Rotation: [α]25D = +142.07 (c = 0.58, MeOH). The absolute configuration of 4e was assigned by analogy to 4d'. 20:1 dr. 94% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =18.4 min (major), tR = 31.4 min (minor)] Methyl (2S,4'S,5'R)-5'-benzyl-4'-(3-chlorophenyl)-3-oxo-4',5'-dihydro-3H-spiro[benzofuran2,3'-pyrrole]-5'-carboxylate (4f). White solid, M.P. 54-55 oC, Rf = 0.4 (silica gel, petroleum ether: EtOAc = 5:1). 43.7 mg, 98% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.67 (s, 1H), 7.65 –


Page 18 of 41

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7.61 (m, 2H), 7.41 (s, 1H), 7.26 – 7.17 (m, 9H), 7.11 (t, J = 7.5 Hz, 1H), 3.96 (s, 1H), 3.62 (s, 3H), 3.07 (d, J = 13.3 Hz, 1H), 2.96 (d, J = 13.3 Hz, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 196.8, 171.9, 171.3, 160.3, 139.1, 135.5, 134.1, 134.0, 131.4, 130.2, 129.8, 129.3, 128.4, 128.2, 127.0, 124.9, 123.2, 120.1, 113.5, 97.9, 86.9, 58.0, 52.3, 44.1; HRMS (ESI): m/z calcd. for [C26H20ClNNaO4, M+Na]+: 468.0973; found: 468.0973. Optical Rotation: [α]25D = +196.70 (c = 0.39, MeOH). The absolute configuration of 4f was assigned by analogy to 4d'. 18:1 dr. 88% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR = 21.0 min (major), tR = 31.1 min (minor)] Methyl

(2S,4'S,5'R)-5'-benzyl-4'-(3-methoxyphenyl)-3-oxo-4',5'-dihydro-3H-spiro

[benzofuran-2,3'-pyrrole]-5'-carboxylate (4g). Pale yellow solid, M.P. 57-59 oC, Rf = 0.3 (silica gel, petroleum ether: EtOAc = 5:1). 43.2 mg, 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.67 (s, 1H), 7.63 (t, J = 8.6 Hz, 2H), 7.26 – 7.17 (m, 7H), 7.10 (t, J = 7.5 Hz, 1H), 6.95 (dd, J = 4.3, 1.9 Hz, 2H), 6.81 (dd, J = 8.0, 1.8 Hz, 1H), 3.97 (s, 1H), 3.76 (s, 3H), 3.62 (s, 3H), 3.12 (d, J = 13.4 Hz, 1H), 2.98 (d, J = 13.4 Hz, 1H);

13

C{1H} NMR (101 MHz, Chloroform-d) δ 197.1,

172.0, 171.4, 160.4, 159.1, 138.9, 135.8, 133.4, 130.2, 129.0, 128.1, 126.8, 124.9, 123.9, 123.0, 120.3, 117.3, 113.5, 113.4, 98.2, 86.9, 58.5, 55.2, 52.3, 43.9; HRMS (ESI): m/z calcd. for [C27H23NNaO5, M+Na]+: 464.1468; found: 464.1462. Optical Rotation: [α]25D = +102.03 (c = 0.59, MeOH). The absolute configuration of 4g was assigned by analogy to 4d'. 30:1 dr. 93% ee. [HPLC condition: Chiralpak AD-H+OD-H column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =43.9 min (major), tR = 89.4 min (minor)] Methyl

(2S,4'S,5'R)-5'-benzyl-4'-(4-bromophenyl)-3-oxo-4',5'-dihydro-3H-spiro

[benzofuran-2,3'-pyrrole]-5'-carboxylate (4h). White solid, M.P. 53-54 oC, Rf = 0.2 (silica gel,



petroleum ether: EtOAc = 5:1). 48.5 mg, 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.67 (s, 1H), 7.65 – 7.61 (m, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.27 – 7.21 (m, 5H), 7.18 (d, J = 6.6 Hz, 3H), 7.11 (t, J = 7.5 Hz, 1H), 3.95 (s, 1H), 3.61 (s, 3H), 3.06 (d, J = 13.3 Hz, 1H), 2.95 (d, J = 13.3 Hz, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 196.9, 171.9, 171.2, 160.2, 139.0, 135.4, 133.1, 131.4, 131.1, 130.1, 128.2, 127.0, 124.9, 123.2, 122.6, 120.2, 113.4, 97.9, 86.8, 57.8, 52.3, 44.1; HRMS (ESI): m/z calcd. for [C26H20BrNNaO4, M+Na]+: 512.0468; found: 512.0470. Optical Rotation: [α]25D = +148.04 (c = 0.46, MeOH). The absolute configuration of 4h was assigned by analogy to 4d'. 26:1 dr. 83% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR = 19.8 min (major), tR = 20.4 min (minor)] Methyl

(2S,4'S,5'R)-5'-benzyl-4'-(4-methoxyphenyl)-3-oxo-4',5'-dihydro-3H-spiro

[benzofuran-2,3'-pyrrole]-5'-carboxylate (4i). Pale yellow solid, M.P. 69-70 oC, Rf = 0.3 (silica gel, petroleum ether: EtOAc = 5:1). 43.2 mg, 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.68 (s, 1H), 7.65 – 7.60 (m, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.21 (ddd, J = 10.4, 7.6, 2.2 Hz, 6H), 7.09 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 8.8 Hz, 2H), 3.94 (s, 1H), 3.75 (s, 3H), 3.62 (s, 3H), 3.11 (d, J = 13.4 Hz, 1H), 2.96 (d, J = 13.4 Hz, 1H);

13

C{1H} NMR (101 MHz, Chloroform-d) δ 197.3,

172.1, 171.4, 160.3, 159.4, 138.8, 135.9, 132.6, 130.2, 128.1, 126.8, 124.8, 123.8, 122.9, 120.3, 113.6, 113.4, 98.2, 86.7, 58.0, 55.1, 52.2, 44.0; HRMS (ESI): m/z calcd. for [C27H23NNaO5, M+Na]+: 464.1468; found: 464.1480. Optical Rotation: [α]25D = +107.57 (c = 0.60, MeOH). The absolute configuration of 4i was assigned by analogy to 4d'. 22:1 dr. 94% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =25.8 min (major), tR = 34.4 min (minor)]


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Methyl

(2S,4'S,5'R)-5'-benzyl-4'-(naphthalen-2-yl)-3-oxo-4',5'-dihydro-3H-spiro

[benzofuran-2,3'-pyrrole]-5'-carboxylate (4j). White solid, M.P. 100-101 oC, Rf = 0.4 (silica gel, petroleum ether: EtOAc = 5:1). 45.2 mg, 98% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.77 (dd, J = 13.7, 4.8 Hz, 4H), 7.59 (dd, J = 7.0, 5.4 Hz, 2H), 7.52 (d, J = 8.5 Hz, 1H), 7.46 (dd, J = 6.0, 3.2 Hz, 2H), 7.26 – 7.16 (m, 6H), 7.05 (t, J = 7.4 Hz, 1H), 4.22 (s, 1H), 3.63 (s, 3H), 3.13 – 3.05 (m, 2H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 197.2, 172.2, 171.5, 160.6, 138.9, 135.8, 133.0, 132.8, 131.0, 130.2, 129.8, 128.9, 128.1, 127.5, 127.4, 126.8, 126.3, 126.1, 124.9, 123.0, 120.2, 113.4, 98.5, 87.3, 58.9, 52.3, 44.2; HRMS (ESI): m/z calcd. for [C30H23NNaO4, M+Na]+: 484.1519; found: 484.1518. Optical Rotation: [α]25D = +193.18 (c = 0.62, MeOH). The absolute configuration of 4j was assigned by analogy to 4d'. 23:1 dr. 93% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =42.0 min (minor), tR = 47.1 min (major)] Methyl

(2S,4'S,5'R)-5'-benzyl-4'-(1H-indol-3-yl)-3-oxo-4',5'-dihydro-3H-spiro[benzofuran-

2,3'-pyrrole]-5'-carboxylate (4k). Yellow solid, M.P. 118-120 oC, Rf = 0.4 (silica gel, petroleum ether: EtOAc = 2:1). 44.2 mg, 98% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.26 (s, 1H), 7.77 (s, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.55 – 7.52 (m, 2H), 7.29 – 7.27 (m, 2H), 7.24 – 7.10 (m, 8H), 7.04 (t, J = 7.4 Hz, 1H), 4.48 (s, 1H), 3.61 (s, 3H), 3.25 (d, J = 13.5 Hz, 1H), 2.97 (d, J = 13.5 Hz, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 197.4, 172.1, 171.4, 160.4, 138.7, 136.1, 135.2, 130.2, 128.2, 128.1, 126.7, 125.0, 124.75, 122.8, 122.3, 120.6, 120.0, 119.0, 113.2, 111.0, 105.7, 98.1, 85.5, 52.2, 50.3, 44.1; HRMS (ESI): m/z calcd. for [C28H22N2NaO4, M+Na]+: 473.1472; found: 473.1472. Optical Rotation: [α]25D = +92.16 (c = 0.31, MeOH). The absolute configuration of 4k was assigned by analogy to 4d'. 8:1 dr. 94% ee. [HPLC condition: Chiralpak



Page 22 of 41

AD-H column, n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =51.4 min (major), tR = 63.9 min (minor)] Methyl

(2S,4'S,5'R)-5'-benzyl-3-oxo-4'-(pyridin-3-yl)-4',5'-dihydro-3H-spiro[benzofuran-

2,3'-pyrrole]-5'-carboxylate (4l). White solid, M.P. 72-73 oC, Rf = 0.2 (silica gel, petroleum ether: EtOAc = 2:1). 40.8 mg, 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.63 (s, 1H), 8.51 (d, J = 4.7 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.69 (s, 1H), 7.64 (dd, J = 13.4, 7.7 Hz, 2H), 7.26 – 7.10 (m, 8H), 3.99 (s, 1H), 3.62 (s, 3H), 3.04 (d, J = 13.2 Hz, 1H), 2.97 (d, J = 13.2 Hz, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 196.6, 171.8, 171.1, 160.1, 152.0, 149.4, 139.1, 138.9, 135.1, 130.1, 128.3, 128.2, 127.1, 125.0, 123.3, 123.1, 120.1, 113.5, 97.8, 86.8, 56.1, 52.4, 44.3; HRMS (ESI): m/z calcd. for [C25H21N2O4, M+H]+: 413.1496; found: 413.1494. Optical Rotation: [α]25D = +184.42 (c = 0.46, MeOH). The absolute configuration of 4l was assigned by analogy to 4d'. 16:1 dr. 88% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, tR = 17.3 min (major), tR = 22.1 min (minor)] Methyl

(2S,4'R,5'R)-5'-benzyl-4'-(furan-2-yl)-3-oxo-4',5'-dihydro-3H-spiro[benzofuran-

2,3'-pyrrole]-5'-carboxylate (4m). White solid, M.P. 42-43 oC, Rf = 0.2 (silica gel, petroleum ether: EtOAc = 5:1). 39.7 mg, 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.69 – 7.63 (m, 3H), 7.38 – 7.37 (m, 1H), 7.27 – 7.12 (m, 7H), 6.34 (d, J = 3.2 Hz, 1H), 6.28 (dd, J = 3.2, 1.8 Hz, 1H), 4.25 (s, 1H), 3.67 (s, 3H), 3.22 (d, J = 13.6 Hz, 1H), 2.97 (d, J = 13.6 Hz, 1H);

13

C{1H}

NMR (101 MHz, Chloroform-d) δ 196.8, 171.9, 171.7, 160.0, 146.0, 142.9, 139.0, 135.7, 130.2, 128.1, 126.8, 124.9, 123.0, 120.1, 113.5, 111.3, 110.5, 97.2, 86.0, 52.5, 51.9, 43.5; HRMS (ESI): m/z calcd. for [C24H19NNaO5, M+Na]+: 424.1155; found: 424.1153. Optical Rotation: [α]25D = +149.00 (c = 0.30, MeOH). The absolute configuration of 4m was assigned by analogy to 4d'.


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26:1 dr. 96% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR = 17.7 min (major), tR = 26.5 min (minor)] Methyl

(2S,4'S,5'R)-5'-benzyl-3-oxo-4'-(thiophen-2-yl)-4',5'-dihydro-3H-spiro[benzofuran-

2,3'-pyrrole]-5'-carboxylate (4n). Colorless oil, Rf = 0.4 (silica gel, petroleum ether: EtOAc = 4:1). 41.3 mg, 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.67 (dt, J = 14.1, 5.2 Hz, 3H), 7.28 – 7.07 (m, 9H), 6.95 (dd, J = 5.0, 3.7 Hz, 1H), 4.38 (s, 1H), 3.68 (s, 3H), 3.22 (d, J = 13.5 Hz, 1H), 2.97 (d, J = 13.5 Hz, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 196.9, 171.6, 171.4, 159.7, 139.0, 135.6, 131.6, 130.2, 130.0, 128.1, 126.9, 126.8, 126.4, 124.9, 123.2, 120.5, 113.9, 97.1, 85.9, 53.9, 52.4, 43.9; HRMS (ESI): m/z calcd. for [C24H19NNaO4S, M+Na]+: 440.0927; found: 440.0923. Optical Rotation: [α]25D = +226.86 (c = 0.53, MeOH). The absolute configuration of 4n was assigned by analogy to 4d'. 26:1 dr. 94% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 90:10, 40oC, flow rate = 1.0 mL/min, wavelength = 254 nm, tR = 18.5 min (major), tR = 19.6 min (minor)] Methyl

(2S,4'S,5'R)-5'-benzyl-3-oxo-4'-ferrocene-4',5'-dihydro-3H-spiro[benzofuran-2,3'-

pyrrole]-5'-carboxylate (4o). Brown solid, M.P. 90-91 oC, Rf = 0.5 (silica gel, petroleum ether: EtOAc = 5:1). 50.9 mg, 98% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.87 – 7.80 (m, 2H), 7.49 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.28 – 7.24 (m, 1H), 7.21 – 7.15 (m, 3H), 7.11 – 7.09 (m, 2H), 4.31 (dd, J = 2.3, 1.2 Hz, 1H), 4.24 (dt, J = 2.3, 1.2 Hz, 1H), 4.19 (td, J = 2.4, 1.2 Hz, 1H), 4.13 (dd, J = 3.5, 2.4 Hz, 1H), 3.97 (s, 1H), 3.69 (s, 3H), 3.62 (s, 5H), 2.87 (d, J = 13.8 Hz, 1H), 2.58 (s, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 198.7, 172.0, 171.8, 159.4, 139.0, 135.9, 130.3, 127.9, 126.6, 124.9, 123.3, 121.1, 113.6, 99.1, 85.9, 79.3, 70.7, 68.8, 68.5, 68.4, 67.4, 54.0, 52.4, 43.1; HRMS (ESI): m/z calcd. for [C30H25FeNNaO4, M+Na]+: 542.1025; found: 542.1039.



Optical Rotation: [α]25D = +44.58 (c = 0.60, MeOH). The absolute configuration of 4o was assigned by analogy to 4d'. 8:1 dr. 97% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 95:5, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =16.6 min (major), tR = 24.4 min (minor)] Methyl

(2S,4'S,5'R)-5'-methyl-3-oxo-4'-phenyl-4',5'-dihydro-3H-spiro[benzofuran-2,3'-

pyrrole]-5'-carboxylate (5a). Colorless oil, Rf = 0.4 (silica gel, petroleum ether: EtOAc = 5:1). 33.2 mg, 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.59 (dd, J = 12.4, 4.4 Hz, 2H), 7.52 (s, 1H), 7.33 (dt, J = 5.1, 3.1 Hz, 2H), 7.21 – 7.19 (m, 3H), 7.14 (d, J = 8.3 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 4.16 (s, 1H), 3.80 (s, 3H), 1.52 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 197.3, 172.7, 171.3, 160.0, 138.8, 132.3, 131.1, 128.1, 127.9, 124.8, 122.9, 120.4, 113.4, 98.4, 83.2, 56.7, 52.8, 22.6; HRMS (ESI): m/z calcd. for [C20H17NNaO4, M+Na]+: 358.1050; found: 358.1049. Optical Rotation: [α]25D = +44.41 (c = 0.51, MeOH). The absolute configuration of 5a was assigned by analogy to 4d'. 23:1 dr. 94% ee. [HPLC condition: Chiralpak OD-H column, n-hexane/i-PrOH = 95:5, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =13.6 min (major), tR = 23.6 min (minor)] Methyl

(2S,4'S,5'R)-5'-isopropyl-3-oxo-4'-phenyl-4',5'-dihydro-3H-spiro[benzofuran-

2,3'-pyrrole]-5'-carboxylate (5b). Colorless oil, Rf = 0.4 (silica gel, petroleum ether: EtOAc = 5:1). 36.0 mg, 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.58 (dd, J = 9.1, 5.7 Hz, 3H), 7.39 (dd, J = 6.4, 2.9 Hz, 2H), 7.21 (dd, J = 6.9, 3.5 Hz, 3H), 7.10 – 7.04 (m, 2H), 4.14 (d, J = 9.4 Hz, 1H), 3.84 (s, 3H), 2.20 (dt, J = 13.4, 6.7 Hz, 1H), 1.12 (d, J = 6.7 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 197.3, 172.5, 171.4, 159.9, 138.7, 132.7, 131.3, 128.0, 127.7, 124.8, 122.8, 120.3, 113.4, 98.7, 90.4, 57.2, 52.2, 32.9, 19.0, 18.5; HRMS (ESI):


Page 24 of 41

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m/z calcd. for [C22H21NNaO4, M+Na]+: 386.1363; found: 386.1360. Optical Rotation: [α]25D = +144.64 (c = 0.45, MeOH). The absolute configuration of 5b was assigned by analogy to 4d'. 16:1 dr. 94% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 95:5, 40 oC, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =17.1 min (major), tR = 20.4 min (minor)] Methyl

(2S,4'S,5'R)-5'-butyl-3-oxo-4'-phenyl-4',5'-dihydro-3H-spiro[benzofuran-2,3'-

pyrrole]-5'-carboxylate (5c). Colorless oil, Rf = 0.2 (silica gel, petroleum ether: EtOAc = 10:1). 37.4 mg, 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.60 – 7.56 (m, 3H), 7.30 (dd, J = 6.5, 2.9 Hz, 2H), 7.21 – 7.19 (m, 3H), 7.13 (d, J = 8.3 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 3.91 (s, 1H), 3.80 (s, 3H), 1.84 (td, J = 12.6, 4.1 Hz, 1H), 1.72 – 1.64 (m, 1H), 1.61 – 1.52 (m, 1H), 1.29 – 1.18 (m, 3H), 0.83 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 197.4, 172.6, 171.3, 159.9, 138.8, 132.0, 131.3, 128.0, 127.9, 124.8, 122.8, 120.3, 113.4, 98.2, 86.3, 57.9, 52.4, 37.4, 27.0, 23.1, 13.9; HRMS (ESI): m/z calcd. for [C23H24NO4, M+H]+: 378.1700; found: 378.1703. Optical Rotation: [α]25D = +78.46 (c = 0.50, MeOH). The absolute configuration of 5c was assigned by analogy to 4d'. 33:1 dr. 97% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 95:5, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =20.4 min (major), tR = 25.2 min (minor)] Methyl

(2S,4'S,5'R)-5'-(3-methoxy-3-oxopropyl)-3-oxo-4'-phenyl-4',5'-dihydro-3H-spiro

[benzofuran-2,3'-pyrrole]-5'-carboxylate (5d). White solid, M.P. 52-54 oC, Rf = 0.3 (silica gel, petroleum ether: EtOAc = 3:1). 40.0 mg, 98% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.60 – 7.54 (m, 3H), 7.29 (dd, J = 6.6, 2.9 Hz, 2H), 7.19 – 7.18 (m, 3H), 7.14 (d, J = 8.3 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 3.94 (s, 1H), 3.79 (s, 3H), 3.61 (s, 3H), 2.64 (ddd, J = 16.3, 10.7, 5.5 Hz, 1H), 2.36 (ddd, J = 16.3, 10.8, 5.3 Hz, 1H), 2.12 (dddd, J = 30.0, 13.7, 10.9, 5.4 Hz, 2H);


13

C{1H}


Page 26 of 41

NMR (101 MHz, Chloroform-d) δ 197.1, 173.4, 171.9, 171.3, 161.0, 138.9, 131.4, 131.1, 128.2, 128.1, 124.8, 122.9, 120.2, 113.5, 98.0, 85.0, 57.9, 52.7, 51.6, 32.2, 29.5; HRMS (ESI): m/z calcd. for [C23H22NO6, M+H]+: 408.1442; found: 408.1439. Optical Rotation: [α]25D = +149.47 (c = 0.52, MeOH). The absolute configuration of 5d was assigned by analogy to 4d'. 34:1 dr. 96% ee. [HPLC condition: Chiralpak OD-H column, n-hexane/i-PrOH = 90:10, 40 oC, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =12.5 min (major), tR = 28.2 min (minor)] Methyl

(2S,4'S,5'R)-5'-cyclohexyl-3-oxo-4'-phenyl-4',5'-dihydro-3H-spiro[benzofuran-

2,3'-pyrrole]-5'-carboxylate (5e). Colorless oil, Rf = 0.2 (silica gel, petroleum ether: EtOAc = 10:1). 38.7 mg, 96% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.60 – 7.56 (m, 2H), 7.54 (s, 1H), 7.39 (dd, J = 7.4, 2.2 Hz, 2H), 7.22 – 7.20 (m, 3H), 7.12 (d, J = 8.7 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 4.12 (s, 1H), 3.82 (s, 3H), 2.13 (d, J = 7.2 Hz, 1H), 1.84 – 1.79 (m, 2H), 1.55 (dd, J = 23.7, 12.4 Hz, 2H), 1.21 – 1.15 (m, 3H), 1.00 (dddd, J = 18.3, 15.6, 9.5, 3.3 Hz, 3H);

13

C{1H}

NMR (101 MHz, Chloroform-d) δ 197.4, 172.6, 171.4, 159.5, 138.7, 132.6, 131.3, 127.9, 127.7, 124.8, 122.8, 120.3, 113.4, 98.5, 90.1, 57.2, 52.2, 43.0, 29.4, 28.4, 26.5, 26.3, 26.1; HRMS (ESI): m/z calcd. for [C25H26NO4, M+H]+: 404.1856; found: 404.1857. Optical Rotation: [α]25D = +168.75 (c = 0.37, MeOH). The absolute configuration of 5e was assigned by analogy to 4d'. 17:1 dr. 97% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =13.8 min (major), tR = 31.1 min (minor)] Methyl

(2S,4'S,5'R)-5'-allyl-3-oxo-4'-phenyl-4',5'-dihydro-3H-spiro[benzofuran-2,3'-

pyrrole]-5'-carboxylate (5f). White solid, M.P. 61-63 oC, Rf = 0.2 (silica gel, petroleum ether: EtOAc = 5:1). 35.8 mg, 99% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.58 (dd, J = 10.2, 5.2 Hz, 3H), 7.31 (dd, J = 6.5, 2.9 Hz, 2H), 7.21 (dd, J = 4.9, 1.5 Hz, 3H), 7.12 (d, J = 8.3 Hz, 1H),


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7.04 (t, J = 7.5 Hz, 1H), 5.88 – 5.77 (m, 1H), 5.06 (s, 1H), 5.03 (d, J = 3.9 Hz, 1H), 3.98 (s, 1H), 3.77 (s, 3H), 2.56 (dd, J = 13.7, 7.7 Hz, 1H), 2.46 (dd, J = 13.8, 6.6 Hz, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 197.2, 172.0, 171.3, 160.5, 138.8, 132.5, 131.9, 131.3, 128.1, 128.0, 124.8, 122.9, 120.2, 118.6, 113.4, 98.2, 86.3, 57.6, 52.4, 42.0; HRMS (ESI): m/z calcd. for [C22H19NNaO4, M+Na]+: 384.1206; found: 384.1203. Optical Rotation: [α]25D = +93.03 (c = 0.55, MeOH). The absolute configuration of 5f was assigned by analogy to 4d'. 29:1 dr. 94% ee. [HPLC condition: Chiralpak ID column, n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =27.0 min (minor), tR = 30.6 min (major)] Methyl

(2S,4'S,5'S)-5'-(4-methoxyphenyl)-3-oxo-4'-phenyl-4',5'-dihydro-3H-spiro

[benzofuran-2,3'-pyrrole]-5'-carboxylate (5g). White solid, M.P. 73-75 oC, Rf = 0.3 (silica gel, petroleum ether: EtOAc = 5:1). 38.5 mg, 90% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.02 (t, J = 7.0 Hz, 2H), 6.94 (t, J = 7.4 Hz, 3H), 6.86 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 7.4 Hz, 2H), 6.72 (d, J = 8.9 Hz, 2H), 4.66 (s, 1H), 3.80 (s, 3H), 3.77 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 197.5, 172.3, 171.4, 162.0, 159.2, 138.6, 132.1, 131.9, 128.5, 128.2, 127.3, 127.2, 124.7, 122.7, 120.2, 113.4, 113.2, 98.6, 89.9, 58.2, 55.2, 53.2; HRMS (ESI): m/z calcd. for [C26H22NO5, M+H]+: 428.1492; found: 428.1495. Optical Rotation: [α]25D = +251.24 (c = 0.40, MeOH). The absolute configuration of 5g was assigned by analogy to 4d'. 5:1 dr. 85% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =27.6 min (minor), tR = 42.3 min (major)] Methyl (2S,4'S,5'S)-4'-(4-bromophenyl)-5'-(4-methoxyphenyl)-3-oxo-4',5'-dihydro-3H-spiro [benzofuran-2,3'-pyrrole]-5'-carboxylate (5h). White solid, M.P. 84-86 oC, Rf = 0.3 (silica gel,



petroleum ether: EtOAc = 5:1). 39.5 mg, 78% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.83 (s, 1H), 7.58 – 7.51 (m, 2H), 7.09 – 7.02 (m, 3H), 6.96 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.9 Hz, 2H), 6.62 (d, J = 8.5 Hz, 2H), 4.60 (s, 1H), 3.80 (s, 3H), 3.78 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 197.2, 172.2, 171.2, 161.8, 159.4, 138.9, 133.5, 131.1, 130.4, 128.2, 128.0, 124.8, 123.0, 121.8, 120.1, 113.4, 113.3, 98.1, 89.7, 57.5, 55.3, 53.3; HRMS (ESI): m/z calcd. for [C26H21BrNO5, M+H]+: 506.0598; found: 506.0597. Optical Rotation: [α]25D = +253.39 (c = 0.53, MeOH). The absolute configuration of 5h was assigned by analogy to 4d'. 5:1 dr. 90% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =20.9 min (major), tR = 33.5 min (minor)] General procedure for the cycloaddition of aurones with α-unsubstituted isocyanoacetate: THF (1 mL) was added to a 10 mL vial charged with the precatalyst 3b (12.3 mg, 0.02 mmol) and Ag2O (2.3 mg, 0.01 mmol). The mixture was stirred at -20 oC for 5 min, then the aurore 1a (22.2 mg, 0.1 mmol) and methyl isocyanoacetate 2b (11.9 mg, 0.12 mmol) were added. The reaction mixture was stirred at -20 oC until 1a was consumed, and then the reaction mixture was purified by flash chromatography on silica gel directly (eluent, petroleum ether:EtOAc = 5:1, 0.1% TEA v/v) to afford the product 6a. Methyl

(2S,4'S,5'R)-3-oxo-4'-phenyl-4',5'-dihydro-3H-spiro[benzofuran-2,3'-pyrrole]-5'-

carboxylate (6a). Colorless oil, Rf = 0.2 (silica gel, petroleum ether: EtOAc = 5:1). 26.7 mg, 83% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J = 7.7 Hz, 1H), 7.50 (dd, J = 9.2, 5.1 Hz, 2H), 7.19 – 7.16 (m, 5H), 7.03 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.22 (dd, J = 7.9, 2.9 Hz, 1H), 4.12 (d, J = 8.0 Hz, 1H), 3.77 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 197.5, 171.3, 170.1, 161.7, 138.7, 132.1, 129.2, 128.3, 127.9, 124.5, 122.8, 120.4, 113.3, 98.0, 79.7, 54.4,


Page 28 of 41

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52.7; HRMS (ESI): m/z calcd. for [C19H15NNaO4, M+Na]+: 344.0893; found: 344.0892. Optical Rotation: [α]25D = +39.6 (c = 0.50, MeOH). The absolute configuration of 6a was assigned by analogy to 6a'. 7:1 dr. 95% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =30.0 min (major), tR = 31.7 min (minor)] Methyl

(2S,4'S,5'R)-4'-(4-methoxyphenyl)-3-oxo-4',5'-dihydro-3H-spiro[benzofuran-2,3'-

pyrrole]-5'-carboxylate (6b). Colorless oil, Rf = 0.1 (silica gel, petroleum ether: EtOAc = 5:1). 30.9 mg, 88% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J = 7.8 Hz, 1H), 7.54 – 7.50 (m, 2H), 7.13 (d, J = 8.7 Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 8.7 Hz, 2H), 5.14 (dd, J = 8.1, 2.9 Hz, 1H), 4.07 (d, J = 8.1 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H); 13


123.8, 122.8, 120.4, 113.8, 113.3, 97.9, 79.7, 55.1, 53.9, 52.8; HRMS (ESI): m/z calcd. for [C20H18NO5, M+H]+: 352.1179; found: 352.1177. Optical Rotation: [α]25D = +70.2 (c = 0.31, MeOH). The absolute configuration of 6b was assigned by analogy to 6a'. 9:1 dr. 98% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH =80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =20.5 min (major), tR = 24.3 min (minor)] Methyl

(2S,4'S,5'R)-4'-(4-bromophenyl)-3-oxo-4',5'-dihydro-3H-spiro[benzofuran-2,3'-

pyrrole]-5'-carboxylate (6c). Colorless oil, Rf = 0.1 (silica gel, petroleum ether: EtOAc = 5:1). 32.8 mg, 82% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J = 7.7 Hz, 1H), 7.57 – 7.51 (m, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.10 – 7.05 (m, 3H), 6.95 (d, J = 8.4 Hz, 1H), 5.15 (dd, J = 8.0, 2.9 Hz, 1H), 4.07 (d, J = 8.0 Hz, 1H), 3.78 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 197.1, 171.2, 169.8, 161.5, 139.0, 131.6, 131.2, 130.9, 124.6, 123.1, 122.1, 120.3, 113.3, 97.7,



79.7, 53.7, 52.8; HRMS (ESI): m/z calcd. for [C19H14BrNNaO4, M+Na]+: 421.9998; found: 421.9993. Optical Rotation: [α]25D = +176.2 (c = 0.35, MeOH). The absolute configuration of 6c was assigned by analogy to 6a'. 9:1 dr. 99% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH =80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =18.0 min (major), tR = 20.6 min (minor)] Methyl

(2S,4'R,5'R)-4'-(furan-2-yl)-3-oxo-4',5'-dihydro-3H-spiro[benzofuran-2,3'-pyrrole]-

5'-carboxylate (6d). Colorless oil, Rf = 0.1 (silica gel, petroleum ether: EtOAc = 5:1). 27.1 mg, 87% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J = 7.7 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 2.8 Hz, 1H), 7.23 (s, 1H), 7.12 (t, J = 7.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.21 (s, 1H), 6.15 (d, J = 2.9 Hz, 1H), 5.33 (dd, J = 7.7, 2.8 Hz, 1H), 4.25 (d, J = 7.7 Hz, 1H), 3.83 (s, 3H); 13


123.0, 120.2, 113.3, 110.3, 108.9, 97.6, 77.6, 53.0, 47.4; HRMS (ESI): m/z calcd. for [C17H14NO5, M+H]+: 312.0866; found: 312.0868. Optical Rotation: [α]25D = +30.25 (c = 0.40, MeOH). The absolute configuration of 6d was assigned by analogy to 6a'. 5:1 dr. >99% ee. [HPLC condition: Chiralpak ID column, n-hexane/i-PrOH =80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =26.0 min (major), tR = 32.3 min (minor)] Methyl (2S,4'R,5'R)-4'-ferrocene-3-oxo-4',5'-dihydro-3H-spiro[benzofuran-2,3'-pyrrole]-5'carboxylate (6e). Pale yellow solid, M.P. 121-122 oC, Rf = 0.1 (silica gel, petroleum ether: EtOAc = 5:1). 38.6 mg, 90% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.70 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 2.7 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.08 (dd, J = 6.5, 2.7 Hz, 1H), 4.10 (d, J = 6.8 Hz, 2H), 4.05 (s, 1H), 4.01 (s, 1H), 3.98 (s, 5H), 3.93 (s, 3H), 3.83 (s, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 197.8, 171.8, 170.7, 162.4, 138.8,


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124.6, 122.9, 120.5, 113.4, 98.8, 80.4, 80.1, 68.7, 68.3, 67.83, 67.80, 67.2, 52.9, 49.2; HRMS (ESI): m/z calcd. for [C23H20FeNO4, M+H]+: 430.0736; found: 430.0736. Optical Rotation: [α]25D = -71.4 (c = 0.35, MeOH). The absolute configuration of 6e was assigned by analogy to 6a'. 10:1 dr. >99% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH =90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =39.6 min (major), tR = 47.7 min (minor)] Methyl

(2S,4'S,5'R)-6-methoxy-3-oxo-4'-phenyl-4',5'-dihydro-3H-spiro[benzofuran-2,3'-

pyrrole]-5'-carboxylate (6f). Colorless oil, Rf = 0.2 (silica gel, petroleum ether: EtOAc = 4:1). 29.9 mg, 85% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.51 – 7.48 (m, 2H), 7.23 – 7.16 (m, 5H), 6.57 (dd, J = 8.7, 2.0 Hz, 1H), 6.31 (d, J = 1.7 Hz, 1H), 5.20 (dd, J = 8.0, 2.9 Hz, 1H), 4.11 (d, J = 8.0 Hz, 1H), 3.77(1) (s, 3H), 3.77(2) (s, 3H);

13

C{1H} NMR (101 MHz, Chloroform-d) δ

194.7, 173.8, 170.1, 168.8, 162.2, 132.3, 129.2, 128.3, 127.8, 125.6, 113.5, 112.5, 98.9, 96.0, 79.6, 55.9, 54.0, 52.7; HRMS (ESI): m/z calcd. for [C20H18NO5, M+H]+: 352.1179; found: 352.1177. Optical Rotation: [α]25D = -50.0 (c = 0.35, MeOH). The absolute configuration of 6f was assigned by analogy to 6a'. 3:1 dr. 90% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH =80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =15.3 min (major), tR = 22.2 min (minor)] Methyl (2S,2'R,4'S,5'R)-2',5'-diallyl-3-oxo-4'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]5'-carboxylate (7).12 The imine 5f (108.4 mg, 0.3 mmol) and zinc powder (58.9 mg, 0.9 mmol) were placed into a glass reaction vessel, dry THF (10.0 mL), HMPA (1.0 mL) and allyl bromide (145.2 mg, 1.2 mmol) were added successively. The mixture was stirred at room temperature and monitored by TLC. When the reaction was completion, a saturated aq. NaHCO3 was added and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed three times with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography to afford the product 7 112.6 mg (93% yield), Colorless oil, Rf =



0.4 (silica gel, petroleum ether: EtOAc = 5:1). 1H NMR (400 MHz, Chloroform-d) δ 7.51 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.28 – 7.26 (m, 2H), 7.17 – 7.15 (m, 3H), 7.06 (d, J = 8.4 Hz, 1H), 6.93 (t, J = 7.4 Hz, 1H), 5.78 (ddt, J = 17.2, 10.2, 7.0 Hz, 1H), 5.61 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.06 (dd, J = 17.9, 9.3 Hz, 3H), 4.90 (d, J = 10.3 Hz, 1H), 3.76 (t, J = 7.1 Hz, 1H), 3.69 (s, 1H), 3.65 (s, 3H), 2.85 – 2.82 (m, 2H), 2.52 (dd, J = 13.8, 7.4 Hz, 1H), 2.47 (dt, J = 14.3, 7.2 Hz, 1H), 2.44 – 2.40 (m, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 200.6, 173.8, 170.8, 137.9, 134.0, 133.7, 132.8, 131.1, 127.8, 127.6, 124.0, 121.9, 121.3, 117.99, 117.96, 112.9, 97.8, 72.8, 65.7, 63.7, 52.2, 37.4, 35.0; HRMS (ESI): m/z calcd. for [C25H26NO4, M+H]+: 404.1856; found: 404.1860. Optical Rotation: [α]25D = +79.0 (c = 0.30, MeOH). The relative configurations of 7 was assigned by its NOE analysis, 87% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH =90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =9.3 min (major), tR = 13.1 min (minor)] Methyl

(2S,4'S,5'R)-5'-benzyl-4'-(2-chlorophenyl)-3-oxo-3H-spiro[benzofuran-2,3'-

pyrrolidine]-5'-carboxylate (4d'). To a solution of imine 4d (44.6 mg, 0.1 mmol) in MeOH (1 mL) was added NaCNBH3 (12.6 mg, 0.2 mmol) and HOAc (12.0 mg, 0.2 mmol) at 0 oC, then stirred at 0 oC overnight. After reaction completion, the solvent was concentrated, purified by flash chromatography on silica gel (hexanes/ethyl acetate, 6:1) to afford the product 4d' 34.9 mg (78% yield) as white solid. M.P. 122-124 oC, Rf = 0.3 (silica gel, petroleum ether: EtOAc = 5:1). 1H NMR (400 MHz, Chloroform-d) δ 7.86 (dd, J = 7.7, 1.8 Hz, 1H), 7.59 – 7.53 (m, 2H), 7.30 (dd, J = 7.7, 1.6 Hz, 1H), 7.25 – 7.09 (m, 8H), 6.99 (t, J = 7.5 Hz, 1H), 4.68 (s, 1H), 3.74 (t, J = 14.2 Hz, 1H), 3.66 (s, 3H), 3.49 (d, J = 12.3 Hz, 1H), 3.28 (t, J = 14.1 Hz, 1H), 2.99 (d, J = 13.2 Hz, 1H), 2.75 (br, 1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 200.4, 173.4, 171.1, 138.4, 136.7, 136.2, 132.5, 130.6, 130.1, 129.5, 128.8, 128.1, 126.7, 126.1, 124.6, 122.2, 120.4, 113.1, 97.1, 73.7, 56.3, 55.9, 52.4, 39.5; HRMS (ESI): m/z calcd. for [C26H23ClNO4, M+H]+: 448.1310; found: 448.1310. Optical Rotation: [α]25D = +135.06 (c = 0.77, MeOH). The absolute configuration of 4d' was


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assigned by its single crystal, 97% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH =90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR = 23.2 min (major), tR = 33.4 min (minor)] Methyl

(2S,4'S,5'R)-3-oxo-4'-phenyl-3H-spiro[benzofuran-2,3'-pyrrolidine]-5'-carboxylate

(6a'). THF (4 mL) was added to a 10 mL vial charged with the precatalyst 3b (49.2 mg, 0.08 mmol) and Ag2O (9.2 mg, 0.04 mmol). The mixture was stirred at -20 oC for 5 min, then the aurore 1a (88.8 mg, 0.4 mmol) and methyl isocyanoacetate 2b (47.5 mg, 0.48 mmol) were added. The reaction mixture was stirred at -20 oC until 1a was consumed, and then the reaction mixture was 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 (4 mL), NaCNBH3 (50.3 mg, 0.8 mmol) and HOAc (48 mg, 0.8 mmol) were added sequentially at 0 oC. After reaction completion, the solvent was concentrated, purified by flash chromatography on silica gel (hexanes/ethyl acetate, 2:1) to afford the product 51.7 mg (60% yield for two steps) as white solid. M.P. 149-150 o

C, Rf = 0.2 (silica gel, petroleum ether: EtOAc = 2:1). 1H NMR (400 MHz, Chloroform-d) δ 7.49

(d, J = 8.0 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.5 Hz, 2H), 7.14 – 7.06 (m, 3H), 6.91 (t, J = 7.3 Hz, 2H), 4.39 (d, J = 10.1 Hz, 1H), 3.80 (d, J = 10.1 Hz, 1H), 3.69 (d, J = 12.4 Hz, 1H), 3.63 (d, J = 0.8 Hz, 3H), 3.36 (d, J = 12.4 Hz, 1H), 2.45 (br, 1H);

13

C{1H} NMR (101 MHz,

Chloroform-d) δ 199.9, 173.1, 171.1, 138.2, 132.8, 129.0, 128.0, 127.7, 124.0, 121.9, 121.0, 113.0, 97.2, 65.3, 59.7, 56.5, 52.4; HRMS (ESI): m/z calcd. for [C19H18NO4, M+H]+: 324.1230; found: 324.1232. Optical Rotation: [α]25D = +51.7 (c = 0.70, MeOH). The absolute configuration of 6a' was assigned by its single crystal, >99% ee. [HPLC condition: Chiralpak AD-H column, n-hexane/i-PrOH =90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, tR =32.2 min (minor), tR



= 37.2 min (major)] AUTHOR INFORMATION Corresponding Author E-mail: [email protected] E-mail: [email protected] ORCID Zhi-Peng Wang: 0000-0001-5440-8114 Pan-Lin Shao: 0000-0001-7415-2195 Yun He: 0000-0002-5322-7300 Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (Nos. 21402150, 21572027). We sincerely thank Dr. Yong-Liang Shao (Lanzhou University) and Xiangnan Gong (Chongqing University) for the X-ray crystallographic analysis. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. HPLC chromatograms, CD spectra, X-ray analysis, and NMR spectra (PDF) REFERENCES 1. (a) Hayashi, Y.; Sankar, K.; Ishikawa, H.; Nozawa, Y.; Mizoue, K.; Kakeya, H. Total Synthesis and Determination of the Absolute Configuration of FD-838, A Naturally Occurring Azaspirobicyclic Product. Bioorg. Med. Chem. Lett. 2009, 19, 3863-3865. (b) Hayashi, Y.; Shoji,


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Spiro

Quaternary

Stereogenic

Centers

via

1,3-Dipolar

Cycloaddition

of

2-Alkylidene-1-indanone and Azomethine Ylides Promoted by Simple Imidazolium Salts. RSC Adv. 2015, 5, 70910-70914. (b) Ding, Q.; Jiang, N.; Liu, J.-J.; Ross, T. M.; Zhang, J.; Zhang, Z. Substituted Pyrrolidine-2-Carboxamides. U.S. Patent WO2010031713 (A1), March 25, 2010. (c) Bartkovitz, D. J.; Chu, X.-J.; Ding, Q.; Jiang, N.; Liu, J.-J.; Ross, T. M.; Zhang, J.; Zhang, Z. Substituted Pyrrolidine-2-Carboxamides. US2010152190 (A1), June 17, 2010. (d) Ramesha, P.; Srinivasa Rao, K.; Trivedi, R.; Sudheer Kumarb, B.; Prakashamb, R. S.; Sridharc, B. Highly


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Catalytic Asymmetric - ACS Publications

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