Diastereo- and Enantioselective Synthesis of 2,2-Disubstituted

Jul 12, 2017 - ... Adjacent Quaternary and Tertiary Stereocenters. Koilpitchai Sivamuthuraman, Nandarapu Kumarswamyreddy, and Venkitasamy Kesavan. Che...
6 downloads 12 Views 1MB Size
Download PDF
Article pubs.acs.org/joc

Cite This: J. Org. Chem. 2017, 82, 10812-10822

Diastereo- and Enantioselective Synthesis of 2,2-Disubstituted Benzofuran-3-one Bearing Adjacent Quaternary and Tertiary Stereocenters Koilpitchai Sivamuthuraman, Nandarapu Kumarswamyreddy, and Venkitasamy Kesavan* Chemical Biology Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai-600036, India S Supporting Information *

ABSTRACT: The first highly diastereo- and enantioselective synthesis of armeniaspirol analogues was achieved using L-proline derived bifunctional squaramide which outperformed commonly used organocatalysts. Excellent yield (up to 99%) with diastereoselectivity (up to 99:1) and enantioselectivity (up to 99%) were obtained for a wide range of substrates.

■

INTRODUCTION Spirofuranone-lactam cores are important structural motifs in many of the natural products and display a broad spectrum of biological activities.1 For instance, pseurotin-A,2 Synerazole,3 Cephalimysin A,4 F-838,5 and Azaspirene6 contain spirofuranone-lactam cores. It is evident from the literature that minor changes on the core scaffold imbibe different pharmacological properties (Figure 1A−E). In addition, Armeniaspirol7 A−C, which possess spirobenzofuranone-lactams, are also known for their antibiotic activity (Figure 1F). In recent years, elegant organocatalytic approaches are emerging in the literature toward the enantioselective construction of bioactive natural product analogues.8 Due to the importance of spirobenzofuranone-lactams, dedicated efforts were made by synthetic chemists to synthesize these derivatives.9 Huang et al. developed a one-pot domino strategy toward the synthesis of CF3 -containing γ-lactams and spirobenzofuranone-lactam scaffolds H of antibacterial armeniaspirol analogues from readily available acyclic precursors (Scheme 1). 10 Reaction between vinyl azides and 4hydroxycoumarins in the presence manganese(II) acetate resulted in the formation of spirobenzofuranone-lactams K (Scheme 1).11 Despite these enormous efforts by synthetic chemists, the enantioselective synthesis of spirobenzofuranonelactams, e.g, analogues of armeniaspirol, is yet to be reported in the literature. Pharmacological activity of spirobenzofuranonelactams motivated us to develop a methodology to synthesize © 2017 American Chemical Society

armeniaspirol analogues in an enantioselective manner. Methyl 3-oxo-2,3-dihydrobenzofuran-2-carboxylate 1 was chosen as the reactant with nitroolefins 2 for the construction of spirobenzofuranone-lactams 4 using bifunctional organocatalysts (Scheme 1). The 2,2-disubstituted benzofuran-3-one is an important precursor for the synthesis of armeniaspirol analogues. However, identification of a suitable catalyst for an enantioselective transformation of this nature is a formidable task since it involves creation of adjacent quaternary and tertiary stereocenters.

■

RESULTS AND DISCUSSION For our preliminary investigation, we chose Michael addition of methyl 3-oxo-2,3-dihydrobenzofuran-2-carboxylate 1a to nitroolefin 2a as a model reaction using 10 mol % of cinchonine thiourea I in CH2Cl2 at room temperature. The reaction proceeded smoothly to provide 75% yield of the expected product with very poor diastereo- and enantioselectivity (Table 1, entry 1). We expanded our search by employing other thioureas (II−V). Although the desired product was isolated in good yields, stereoselectivity was found to be poor to moderate (Table 1, entries 2−5). Squaramides are known for their efficiency in inducing enantioselectivity in asymmetric transformations in which thioureas do not provide sufficient Received: May 8, 2017 Published: July 12, 2017 10812

DOI: 10.1021/acs.joc.7b01105 J. Org. Chem. 2017, 82, 10812−10822

Article

The Journal of Organic Chemistry

Figure 1. Biologically important spirofuranone-lactams.

Scheme 1. Strategy To Access Spirobenzofuranone-Lactams

difference in the energy of activation.12 Exploration of various squaramides VI−XIII in the Michael addition of methyl 3-oxo2,3-dihydrobenzofuran-2-carboxylate 1a with nitroolefin 2a did not bring in desired results (Table 1 entries 6−13). Among these catalysts, quinidine derived squaramide IX induced good diastereo- and enantioselectivity (Table 1, entry 9). However, it did not match our expectations. Recently, our group proved that L-proline derived bifunctional squaramide XIV outperformed in inducing diastereo- as well as enantioselectivity for the synthesis of spirooxindole-fused pyranopyrazoles.13 In this context, we were delighted to observe that squaramide catalyst XIV (10 mol %) catalyzed the formation of Michael adduct 3a in excellent yield (95%) with excellent diastereo(97:03) and enantioselectivity (98% ee) (Table 1, entry 14). Thus, squaramide XIV was identified as the most suitable catalyst for the synthesis of synthon 3a with adjacent quaternary and tertiary stereocenters in excellent diastereoand enantioselectivity. Next, the catalyst efficiency was checked by decreasing catalyst loading. It is important to notice that there is no significant change in the yield, diastereoselectivity, and enantioselectivity at room temperature when 5 or 2 mol % of

the catalyst was used (Table 1, entries 15 and 16). Further decreasing catalyst loading, when 1 and 0.5 mol % of the catalyst were used (Table 1, entries 17 and 18), slowed the reaction rate, which leads to significant change in the yield, but not in diastereo- and enantioselectivity at room temperature. Next, when 1.2 equiv of the nitrostyrene was used (Table 1, entry 19), there is no significant change in the yield, but a decrease in diastereo- and enantioselectivity was observed at room temperature. Encouraged by the positive outcome in generating adjacent quaternary and tertiary chiral centers in product 3, we explored the substrate generality for the synthesis of spirobenzofuranone precursor 3 under the optimized reaction conditions (2 mol % of catalyst XIV and dicholoromethane at ambient temperature). First, the influence of ortho substituents in the benzene ring of nitroolefins 2 on yield, diastereoselectivity, and enantioselectivity was tested. It is evident that the ortho substituents like bromo, methoxy, cyano, and hydroxyl on nitroolefins did not hamper the catalytic efficiency and stereoselectivity of the reaction (Table 2, entries 2−6). Products 3b−3e were isolated in excellent yields (89−99%) and enantioselectivity (91−98%). A slight diminishing in diastereoselectivity was observed for 10813

DOI: 10.1021/acs.joc.7b01105 J. Org. Chem. 2017, 82, 10812−10822

Article

The Journal of Organic Chemistry Table 1. Catalyst Screening for the Creation of Adjacent Quaternary and Tertiary Chiral Centersa

entry

catalyst

yieldb(%)

drc (%) major:minor

eec (%) major/minor

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15e 16f 17g 18h 19i

I II III IV V VI VII VIII IX X XI XII XIII XIV XIV XIV XIV XIV XIV

75 82 81 81 90 70 86 81 90 75 86 80 80 95 95 98 90 82 98

68:32 65:35 60:40 62:38 89:11 58:42 67:33 59:41 85:15 67:33 65:35 58:42 63:37 97:03 98:02 98:02 98:2 98:2 92:8

4/48 rac/−51d 10/48 15/33 50/rac 20/17 rac/−10d 56/50 86/44 46/58 rac/24 rac/27 rac/rac 98 99 99 98 99 90

The reactions were carried out with 1a (0.13 mmol), 2a (0.26 mmol), and catalyst (10 mol %, 0.013 mmol) in 0.5 mL of CH2Cl2 at 25 °C. Isolated yield. cDetermined by chiral HPLC analysis on chiral stationary phase. dMinus sign indicates the opposite enantiomer. eCatalyst (5 mol %, 0.0065 mmol) used. fCatalyst (2 mol %, 0.0026 mmol) used. gCatalyst (1 mol %, 0.0013 mmol) used; the reaction was completed at 2 h. hCatalyst (0.5 mol %, 0.00065 mmol) used; the reaction was completed at 6 h. iNitrostyrene (1.2 equiv, 0.156 mmol) used. a b

ortho-nitro substituted nitroolefin. However, the yield and enantioselectivity remained unaffected (Table 2, entry 6). Various differently substituted nitroolefins 3g−3r containing halogens, electron-releasing or electron-withdrawing groups reacted efficiently to yield the corresponding products 3f−3r in excellent yields (86−98%) and very high enantioselectivities

(89−96% ee) along with excellent diastereoselectivities (91:9 to 98:2) (Table 2, entries 7−18). Heteroaromatic nitroolefins were well tolerated at −10 °C, and the desired products were obtained in excellent yields, diastereoselectivities, and enantioselectivities (Table 2, entries 19 and 20). Aliphatic nitroolefins did not affect catalytic efficiency as well as stereoinduction of 10814

DOI: 10.1021/acs.joc.7b01105 J. Org. Chem. 2017, 82, 10812−10822

Article

The Journal of Organic Chemistry Table 2. Substrate Scope for Spirobenzofuranone-Lactams Precursora

entry

R1, R2, R3

3

yieldb (%)

drc

eec (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14d 15 16 17 18 19e 20e 21 22 23 24 25 26e 27e 28e

Me, H, C6H5 Me, H, 2-BrC6H4 Me, H, 2-OMeC6H4 Me, H, 2-CNC6H4 Me, H, 2-NO2C6H4 Me, H, 2-OHC6H4 Me, H, 3-FC6H4 Me, H, 3-ClC6H4 Me, H, 3-BrC6H4 Me, H, 3-OMeC6H4 Me, H, 3-Br-4-OMeC6H3 Me, H, 4-FC6H4 Me, H, 4-ClC6H4 Me, H, 4-BrC6H4 Me, H, 4-MeC6H4 Me, H, 4-OMeC6H4 Me, H, 4-NO2C6H4 Me, H, 1-naphthyl Me, H, 2-furfuryl Me, H, 2-thiophenyl Me, H, 2-Ph ethyl Me, H, C3H7 Me, H, C4H9 Me, H, C6H13 Et, H, C6H5 Me, Cl, C6H5 Me, Br, C6H5 Me, I, C6H5

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p 3q 3r 3s 3t 3u 3v 3w 3x 3y 3z 3aa 3ab

98 99 89 95 91 94 98 96 97 93 96 94 98 97 86 97 94 94 95 98 98 99 97 98 98 98 92 89

98:02 98:02 94:06 93:07 89:11 98:02 94:06 98:02 97:03 96:04 93:07 91:09 97:03 95:05 93:07 95:05 96:04 92:08 99:01 97:03 98:02 99:01 99:01 99:01 99:01 99:01 99:01 99:01

99 92 91 94 90 98 93 93 94 96 90 86 96 96 89 92 95 93 98 92 80 99 99 99 99 99 99 99

a

The reactions were carried out with 1 (0.13 mmol), 2 (0.26 mmol), and catalyst XIV (0.0026 mmol) in 0.5 mL of CH2Cl2 at rt for 0.5−1.0 h. Isolated yield after column chromatography purification. cDetermined by Chiral HPLC analysis on chiral stationary phase. dCCDC 1504306. e Reaction was performed at −10 °C. b

Table 3. Synthesis of Spirofuranone-Lactama

the reaction (Table 2, entries 21−24). After evaluating the substrate scope of nitroolefins, we moved to the change in the benzofuranone ester group such as ethyl 3-oxo-2,3-dihydrobenzofuran-2-carboxylate reacted with nitrostyrene to yield the corresponding adduct 3y in quantitative yield and excellent stereoselectivity (Table 2, entry 25). Next, we turned our attention to the substitutions on the C-5 position of the benzofuranone moiety. The electronic properties of the substituents at the C-5 position of benzofuranone seemed to have no influence on either the yield or the enantioselectivity (Table 2, entries 26−28). After demonstrating the efficiency of catalyst XIV in the enantioselective synthesis of precursor of the spirobenzofuranone-lactams 3, they were successfully transformed into the desired biologically active spirobenzofuranone-lactams of armeniaspirol analogues through reductive cyclization. The highlight of this protocol is that no erosion in enantioselectivity was observed for cyclized products 4a−h (Table 3, entries 1− 8). The absolute configuration of Michael addition products 3n and cyclization product 4a was determined as (8R, 9S) via single-crystal X-ray analysis.14 A plausible transition-state model15,19 is proposed herewith to account for the formation of the major stereoisomer of the

entry 1 2 3 4 5 6 7 8

d

R1

4

yieldb (%)

drc (%)

eec (%)

C6H5 4-Br-C6H4 2-F-C6H4 2-Cl-C6H4 2,4-Cl2-C6H3 4-CN-C6H5 C3H7 C6H13

4a 4b 4c 4d 4e 4f 4g 4h

60 69 84 74 80 88 70 65

89:11 99:01 98:02 92:08 94:06 96:04 99:01 99:01

94 98 98 91 96 94 99 99

a Michael adduct 3 (1equiv), zinc dust (20 equiv), acetic acid (5 mL), heated to 60 °C for 4 h. bIsolated yield after column chromatography purification. cDetermined by chiral HPLC analysis on chiral stationary phase. dCCDC 1504305.

precursor of the spirobenzofuranone-lactam 3a. The chiral tertiary amine part of catalyst XIV enables the deprotonation 10815

DOI: 10.1021/acs.joc.7b01105 J. Org. Chem. 2017, 82, 10812−10822

Article

The Journal of Organic Chemistry

2,3-dihydro-3-hydroxy-2-hydroxyalkyl benzofurans natural product analogues with 70% yield and excellent diastereoselectivity (>20:1). This method enables one to diversify new molecular scaffolds with spirofuranone-lactams which are widely embedded in biologically active natural products. For the first time in the literature, these scaffolds were synthesized in an enantioselective manner.

from benzofuranone 1a and hydrogen bonding of nitroolefins with the squaramide moiety. These interactions provide steric bias in the transition state which facilitates the Si-face attack of benzofuranone 1a to the nitroolefins 2a, leading to formation of spirobenzofuranone-lactam precursor 3a with (8R, 9S) configuration (Figure 2).

■

EXPERIMENTAL SECTION

General Remarks. All reactions were carried out in a flame-dried flask. Solvents used for reactions and column chromatography were commercial grade and distilled prior to use. THF, toluene, and dioxane were dried over sodium/benzophenone, whereas dichloromethane (DCM) and dichloroethane (DCE) were dried over CaH2. Solvents (hexane, ethyl acetate) TLC was performed on precoated Merck silica gel aluminum plates with 60F254 indicator, visualized by irradiation with UV light. Dragendorff, ceric ammonium molybdate (CAM), and alkaline KMNO4 were used as TLC staining solution. Column chromatography was performed using silica gel Merck 100−200 and 230−400 mesh. 1H NMR and 13C NMR were recorded on 400 MHz, 500 MHz and 100 and 125 MHz using CDCl3, DMSO-d6, and acetone-d6 as solvent, and multiplicity is indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), dt (doublet of triplet), td (triplet of doublet), ddd (doublet of doublet of doublet), ddt (doublet of doublet of triplet), qd (quartet of doublet). Coupling constants J are reported in Hz. Chemical shift are presented in δ. High resolution mass spectra were obtained by ESI using an orbitrap elite mass spectrometer; IR spectra were recorded on an FT/IR-420 spectrometer and are reported in terms of frequency of absorption (ν, cm−1). Melting points were measured in open capillaries and are uncorrected. Optical rotations are reported as follows: [α]Drt (c in g per 100 mL, solvent). The 2-substituted benzofuran-3(2h)-ones were synthesized according to known literature procedures.17 The catalysts such as thiourea18a and squaramide18b,c and catalyst V, XIV13 were synthesized according to known literature procedures. I. Representative Experimental Procedure for the Michael Addition Reaction. To a 30 min stirred solution of trans-nitrostyrene (38.5 mg, 0.26 mmol) and catalyst XIV (1.3 mg, 0.0026 mmol) in dry CH2Cl2 (0.5 mL) was added methyl 3-oxo-2,3-dihydrobenzofuran-2carboxylate (25 mg, 0.13 mmol) at room temperature. The reaction mixture was stirred at rt until the consumption of methyl 3-oxo-2,3dihydrobenzofuran-2-carboxylate (0.5−1.0 h), which was monitored by TLC. The crude mixture was purified by flash column chromatography over silica gel with a gradient from 92:8 hexane:EtOAc to 80:20 hexane:EtOAc to furnish 3a−3ab. Analytical Data for Michael Addition Products. Methyl(S)-2((R)-2-nitro-1-phenylethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3a). General experimental procedure I was followed to prepare the Michael Addition product 3a. The desired product was obtained as a colorless solid (43 mg, 98% yield); m.p.: 120−123 °C; [α]D 26 = +92.679 (c 0.56, CHCl3). The compound 3a 99% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 35.13 min, tR (minor) = 39.80 min; 1HNMR (500 MHz, CDCl3) δ = 7.58 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.39−7.33 (m, 1H), 7.25−7.16 (m, 3H), 7.13− 7.06 (m, 3H), 6.98 (t, J = 7.4 Hz, 1H), 5.14−4.99 (m, 2H), 4.71 (dd, J = 10.4, 4.7 Hz, 1H), 3.83 (s, 3H) 13C NMR (126 MHz, CDCl3) δ = 193.2, 172.3, 165.2, 138.8, 131.8, 129.2, 128.7, 128.6, 125.0, 123.1, 119.3, 113.1, 91.0, 75.5, 54.0, 46.8; IR (ν, cm−1): 3034, 2958, 2923, 2361, 2110, 1987, 1898, 1744, 1707, 1607, 1549, 1496, 1377, 1324, 1296, 1280, 1191, 1145, 1084, 1052, 982, 866, 818, 782, 701, 674, 562; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H15NO6Na 364.0792; Found 364.0789. Methyl(S)-2-((R)-1-(2-bromophenyl)-2-nitroethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3b). General experimental procedure I was followed to prepare the Michael addition product 3b. The desired product was obtained as a foamy solid (54 mg, 99% yield); [α]D26 = +43.330 (c 3.0, CHCl3). The compound 3b 92% ee was

Figure 2. Plausible transition state model for the Michael adduct.

Reduction of Michael adduct 3a would result in 2,3-dihydro3-hydroxy-benzofurans molecules which are present in natural products such as brosimacutin G, avicenol A, smyrindiol, xanthoarnol, vaginidiol, and vaginol (Figure 3).16

Figure 3. Important 2,3-dihydro-3-hydroxy-benzofurans natural products.

Compound 3a was treated with sodium borohydride in methanol at 0 °C for 1 h, followed by acetylation in dichloromethane at ambient temperature, which resulted in the product 5 in 70% yield with excellent diastereoselectivity (>20:1) (Scheme 2). Synthons or intermediates leading to the Scheme 2. Synthesis of Dihydrobenzofuran

synthesis of one or more natural product analogues are desirable in organic synthesis. By synthesizing dihydrobenzofurans 5, we have established the synthetic versatility of synthon 3a which is present in natural products.

■

CONCLUSION In summary, a robust route for the synthesis of armeniaspirol natural product analogues was achieved in excellent diastereoselectivity (up to 99%) and enantioselectivity (up to 99%). The Michael addition products further transformed into the 10816

DOI: 10.1021/acs.joc.7b01105 J. Org. Chem. 2017, 82, 10812−10822

Article

The Journal of Organic Chemistry

was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 79.36 min, tR (minor) = 89.19 min; 1H NMR (500 MHz, CDCl3) δ = 7.86 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 8.4 Hz, 2H), 7.49−7.33 (m, 2H), 7.21 (d, J = 8.2 Hz, 1H), 7.13 (t, J = 7.3 Hz, 1H), 5.67−5.52 (m, 1H), 5.43 (dd, J = 13.9, 3.8 Hz, 1H), 5.34 (dd, J = 13.9, 10.1 Hz, 1H), 3.76 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.0, 171.7, 164.7, 151.0, 139.4, 132.8, 129.6, 128.6, 127.9, 125.6, 125.4, 123.7, 118.6, 113.4, 89.8, 73.8, 54.0, 39.3; IR (ν, cm−1): 2958, 1749, 1722, 1610, 1567, 1476, 1377, 1326, 1299, 1249, 1193, 1148, 1093, 1021, 920, 893, 856, 785, 646, 587, 514; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H14N2O8Na 409.0642; Found 409.0649. Methyl(S)-2-((R)-1-(3-fluorophenyl)-2-nitroethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3g). General experimental procedure I was followed to prepare the Michael addition product 3g. The desired product was obtained as a foamy solid (46 mg, 98% yield); [α]D26 = −51.897 (c 1.95, CHCl3). The compound 3g 93% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 95:5, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 45.29 min, tR (minor) = 54.85 min; 1H NMR (500 MHz, CDCl3) δ = 7.64 (ddd, J = 8.4,7.2,1.4 Hz, 1H), 7.43 (dd, J = 7.7, 0.8 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.11 (dt, J = 6.0, 8.0 Hz, 1H), 7.08− 7.01 (m, 2H), 6.97 (td, J = 9.6, 2.1 Hz, 1H), 6.83 (ddt, J = 8.4, 2.5, 0.9 Hz, 1H), 5.13−5.01 (m, 2H), 4.77−4.69 (m, 1H), 3.85 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.3, 172.2, 165.0, 162.4 (d, J = 245.8 Hz), 139.1, 134.3 (d, J = 7.2 Hz), 130.2 (d, J = 8.2 Hz), 125.2 (d, J = 2.7 Hz), 125.1, 123.3, 119.2, 116.1 (d, J = 22.3 Hz), 115.7 (d, J = 20.7 Hz), 113.1, 90.7, 75.2, 54.1, 46.3; IR (ν, cm−1): 2957, 2924, 1750, 1724, 609, 1566, 1462, 1377, 1325, 1299, 1229, 1195, 1165, 1078, 1021, 983, 893, 796, 652, 584; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H14NO6FNa 382.0697; Found 382.0701. Methyl(S)-2-((R)-1-(3-chlorophenyl)-2-nitroethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3h). General experimental procedure I was followed to prepare the Michael addition product 3h. The desired product was obtained as a foamy solid (47 mg, 96% yield); [α]D 26 = −47.842 (c 1.9, CHCl3). The compound 3h 93% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 27.56 min, tR (minor) = 38.22 min; 1H NMR (500 MHz, CDCl3) δ = 7.62 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.41 (td, J = 7.1, 0.9 Hz, 1H), 7.24−7.19 (m, 2H), 7.14−6.99 (m, 4H), 5.10−4.99 (m, 2H), 4.67 (dd, J = 9.9, 5.2 Hz, 1H), 3.83 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.0, 172.2, 165.0, 139.1, 134.5, 134.0, 129.8, 129.2, 128.9, 127.6, 125.1, 123.3, 119.2, 113.1, 90.6, 75.2, 54.1, 46.3; IR (ν, cm−1): 2958, 2926, 1750, 1724, 1611, 1566, 1476, 1377, 1325, 1295, 1251, 1195, 1147, 1084, 1022, 917, 895, 863, 788, 696, 589; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H14NO6ClNa 398.0402; Found 398.0404. Methyl(S)-2-((R)-1-(3-bromophenyl)-2-nitroethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3i). General experimental procedure I was followed to prepare the Michael addition product 3i. The desired product was obtained as a pale yellow solid (53 mg, 97% yield); m.p.: 75−78 °C. [α]D29 = −38.320 (c 2.5, CHCl3). The compound 3i 94% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 24.33 min, tR (minor) = 32.58 min; 1H NMR (500 MHz, CDCl3) δ = 7.66−7.61 (m, 1H), 7.44−7.37 (m, 2H), 7.26−7.20 (m, 2H), 7.16 (d, J = 7.9 Hz, 1H), 7.06−6.97 (m, 2H), 5.11−4.98 (m, 2H), 4.66 (dd, J = 9.6,5.5 Hz, 1H), 3.83 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.0, 172.2, 165.0, 139.1, 134.3, 132.1, 131.9, 130.1, 128.1, 125.1, 123.3, 122.6, 119.2, 113.1, 90.6, 75.2, 54.1, 46.3; IR (ν, cm−1): 2957, 2923, 1749, 1723, 1610, 1564, 1461, 1376, 1324, 1297, 1252, 1197, 1147, 1083, 1025, 995, 917, 894, 863, 796, 696, 588, 560; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H14NO6BrNa 442.9897; Found 442.9898. Methyl(S)-2-((R)-1-(3-methoxyphenyl)-2-nitroethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3j). General experimental procedure I was followed to prepare the Michael addition product 3j. The desired product was obtained as a pale yellow solid (55 mg, 94%

determined by chiral HPLC column (Chiralpak OJ-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 70.55 min, tR (minor) = 67.30 min; 1H NMR (500 MHz, CDCl3) δ = 7.69− 7.62 (m, 1H), 7.56−7.45 (m, 2H), 7.32 (dd, J = 7.7, 1.7 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.10−6.96 (m, 3H), 5.38 (dd, J = 10.4, 4.1 Hz, 1H), 5.27−5.17 (m, 1H), 5.16−5.01 (m, 1H), 3.82 (s, 3H) 13C NMR (126 MHz, CDCl3) δ = 192.5, 172.1, 165.1, 139.0, 134.0, 132.8, 130.0, 128.2, 127.6, 127.0, 125.3, 123.3, 119.1, 113.3, 90.6, 75.3, 54.0, 43.9; IR (ν, cm−1): 2957, 2925, 1750,1725, 1610, 1555, 1463, 1377, 1324, 1298, 1249, 1194, 1147, 1080, 1021, 980, 893, 758, 648, 584; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H14NO6BrNa 441.9897; Found 441.9912. Methyl(S)-2-((R)-1-(2-methoxyphenyl)-2-nitroethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3c). General experimental procedure I was followed to prepare the Michael addition product 3c. The desired product was obtained as a foamy solid (43 mg, 89% yield). [α]D26 = −22.000 (c 0.95, CHCl3). The compound 3c 91% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 25.60 min, tR (minor) = 34.08 min; 1H NMR (500 MHz, CDCl3) δ = 7.60 (ddd, J = 8.4,7.2,1.4 Hz, 1H), 7.44−7.39 (m, 1H), 7.21−7.14 (m, 2H), 7.12−7.06 (m, 1H), 7.01 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.67 (t, J = 7.6 Hz, 1H), 5.25 (dd, J = 9.8, 5.0 Hz, 1H), 5.15−5.01 (m, 2H), 3.81 (s, 3H), 3.77 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.0, 172.1, 165.5, 157.6, 138.5, 129.8, 129.2, 125.0, 122.9, 121.1, 120.5, 119.3, 113.1, 111.5, 91.0, 75.4, 55.8, 53.8, 39.7; IR (ν, cm−1): 2957, 2843, 1749, 1724, 1608, 1564, 1462, 1378, 1323, 1295, 1248, 1196, 1147, 1076, 1054, 982, 893, 870, 792, 701, 588; HRMS (ESI) m/z: [M + Na]+ Calcd for C19H17O7NNa 394.0897; Found 394.0905. Methyl(S)-2-((R)-1-(2-cyanophenyl)-2-nitroethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3d). General experimental procedure I was followed to prepare the Michael addition product 3d. The desired product was obtained as a white solid (43 mg, 98% yield), m.p.: 127−130 °C. [α]D33 = −44.341(c 2.05, CHCl3).The compound 3d 94% ee was determined by chiral HPLC column (Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 36.25 min, tR (minor) = 43.39 min; 1H NMR (500 MHz, CDCl3) δ = 7.64 (dt, J = 7.9, 1.3 Hz, 1H), 7.47−7.34 (m, 5H), 7.20 (d, J = 8.5 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 5.15−5.03 (m, 2H), 4.78 (dd, J = 10.4, 4.7 Hz, 1H), 3.84 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 192.8, 172.1, 164.8, 139.4, 137.4, 132.6, 132.3, 130.1, 126.7, 125.2, 123.6, 119.0, 118.0, 113.1, 112.8, 90.4, 74.8, 54.2, 46.4; IR (ν, cm−1): 3057, 2958, 2923, 2231, 2074, 1749, 1722, 1609, 1564, 1460, 1376, 1325, 1297, 1249, 1194, 1147, 1078, 1021, 981, 917, 894, 872, 805, 757, 657, 561; HRMS (ESI) m/z: [M + Na] + Calcd for C19H14N2O6Na 389.0744; Found 389.0741. Methyl(S)-2-((R)-1-(2-hydroxyphenyl)-2-nitroethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3e). General experimental procedure I was followed to prepare the Michael addition product 3e. The desired product was obtained as a pale yellow solid (44 mg, 95% yield) m.p.: 133−135 °C. [α]D26 = −10.303 (c 1.65, THF). The compound 3e 98% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 38.56 min, tR (minor) = 43.28 min; 1H NMR (500 MHz, CDCl3) δ = 7.70−7.61 (m, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.15 (dd, J = 7.7,1.4 Hz, 1H), 7.09−6.99 (m, 2H), 6.80−6.75 (m, 1H), 6.69 (t, J = 7.6 Hz, 1H), 5.80 (br. s., 1H), 5.27 (t, J = 7.4 Hz, 1H), 5.12−5.04 (m, 2H), 3.86 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 194.3, 172.5, 165.1, 153.8, 139.2, 129.9, 128.6, 125.2, 123.2, 121.4, 119.8, 119.0, 117.9, 113.2, 91.5, 75.1, 54.0, 39.1; IR (ν, cm−1): 3435(br), 2955, 2924, 1749,1721, 1609, 1566, 1476, 1378, 1326, 1297, 1248, 1149, 1073, 1021, 981, 919, 894, 871, 797, 701, 589, 514; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H15O7NNa 380.0741; Found 380.0743. Methyl(S)-2-((R)-2-nitro-1-(2-nitrophenyl)ethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3f). General experimental procedure I was followed to prepare the Michael addition product 3f. The desired product was obtained as a yellow solid (48 mg, 96% yield), m.p.: 52− 55 °C. [α]D26 = +183.111 (c 1.8, CHCl3). The compound 3f 90% ee 10817

DOI: 10.1021/acs.joc.7b01105 J. Org. Chem. 2017, 82, 10812−10822

Article

The Journal of Organic Chemistry yield), m.p.: 125−130 °C. [α]D26 = −37.296 (c 2.7, CHCl3). The compound 3j 96% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 53.63 min, tR (minor) = 48.34 min; 1H NMR (500 MHz, CDCl3) δ = 7.62 (ddd, J = 8.6,7.2,1.6 Hz, 1H), 7.45−7.40 (m, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.07−6.99 (m, 2H), 6.82 (d, J = 7.6 Hz, 1H), 6.79−6.74 (m, 1H), 6.66 (ddd, J = 8.4, 2.5, 0.8 Hz, 1H), 5.13−4.99 (m, 2H), 4.70 (dd, J = 4.7, 10.4 Hz, 1H), 3.85 (s, 3H), 3.67 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.1, 172.3, 165.2, 159.4, 138.8, 133.4, 129.6, 125.2, 123.1, 121.4, 119.4, 114.8, 114.5, 113.0, 91.0, 75.5, 55.1, 54.0, 46.7; IR (ν, cm−1): 2958, 2839, 1748, 1722, 1608, 1563, 1493, 1377, 1323, 1296, 1248, 1196, 1148, 1091, 1022, 917, 888, 857, 787, 699, 571; HRMS (ESI) m/z: [M + Na]+ Calcd for C19H17O7NNa 394.0897; Found 394.0893. Methyl(S)-2-((R)-1-(3-bromo-4-methoxyphenyl)-2-nitroethyl)-3oxo-2,3-dihydrobenzofuran-2-carboxylate (3k). General experimental procedure I was followed to prepare the Michael addition product 3k. The desired product was obtained as a foamy solid (55 mg, 94% yield). [α]D26 = −24.778 (c 2.7, CHCl3). The compound 3k 90% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 48.36 min, tR (minor) = 63.49 min; 1H NMR (500 MHz, CDCl3) δ = 7.59−7.52 (m, 1H), 7.40−7.31 (m, 2H), 7.23−7.13 (m, 1H), 7.07 (dd, J = 8.5, 2.2 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 6.57 (d, J = 8.5 Hz, 1H), 5.00−4.87 (m, 2H), 4.61−4.51 (m, 1H), 3.79−3.74 (m, 3H), 3.68 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.1, 172.3, 165.0, 155.9, 139.1, 133.5, 130.0, 125.2, 125.1, 123.3, 119.2, 113.1, 111.9, 111.7, 90.9, 74.8, 56.2, 54.0, 45.7; IR (ν, cm−1): 2956, 2845, 1749, 1722, 1608, 1564, 1497, 1377, 1325, 1292, 1255, 1193, 1147, 1082, 1019, 988, 895, 863, 799, 701, 594; HRMS (ESI) m/z: [M + Na]+ Calcd for C19H16O7NBrNa 472.0002; Found 472.0009. Methyl(S)-2-((R)-1-(4-fluorophenyl)-2-nitroethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3l). General experimental procedure I was followed to prepare the Michael addition product 3l. The desired product was obtained as a yellow solid (44 mg, 94% yield); m.p.: 73− 75 °C. [α]D26 = +101.500 (c 0.6, CHCl3). The compound 3l 86% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 95:5, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 31.96 min, tR (minor) = 65.19 min; 1H NMR (500 MHz,CDCl3) δ = 7.58−7.51 (m, 1H), 7.36−7.30 (m, 1H), 7.17−7.10 (m, 3H), 6.98−6.92 (m, 1H), 6.73 (t, J = 8.5 Hz, 2H), 5.04−4.89 (m, 2H), 4.69−4.58 (m, 1H), 3.76 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.1, 172.3, 165.1, 162.6 (d, J = 246.8 Hz), 139.0, 131.0 (d, J = 8.25 Hz), 127.6 (d, J = 3.12 Hz), 125.1, 123.3, 119.2, 115.7 (d, J = 21.37 Hz), 113.0, 90.9, 75.4, 54.0, 46.0; IR (ν, cm−1): 2957, 2924, 1750, 1724, 1609, 1566, 1462, 1377, 1325, 1299, 1229, 1195, 1165, 1078, 1021, 983, 893, 796, 652, 584; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H14NO6FNa 382.0697; Found 382.0698. Methyl(S)-2-((R)-1-(4-chlorophenyl)-2-nitroethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3m). General experimental procedure I was followed to prepare the Michael addition product 3m. The desired product was obtained as a white solid (48 mg, 98% yield); m.p.: 103−105 °C. [α]D26 = −17.107 (c 2.8, CHCl3). The compound 3m 96% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 23.13 min, tR (minor) = 27.22 min; 1H NMR (500 MHz, CDCl3) δ = 7.62 (ddd, J = 8.4, 7.2,1.4 Hz, 1H), 7.41 (dd, J = 7.7,0.8 Hz, 1H), 7.21−7.14 (m, 3H), 7.11−7.07 (m, 2H), 7.05−7.00 (m, 1H), 5.09−4.97 (m, 2H), 4.69 (dd, J = 10.4, 5.0 Hz, 1H), 3.82 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.0, 172.2, 165.0, 139.1, 134.7, 130.9, 130.5, 129.1, 125.2, 123.3, 119.2, 113.0, 90.7, 75.3, 54.1, 46.1; IR (ν, cm−1): 2958, 2926, 1750, 1724, 1611, 1566, 1476, 1377, 1325, 1295, 1251, 1195, 1147, 1084, 1022, 917, 895, 863, 788, 696, 589; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H14NO6ClNa 398.0402; Found 398.0408. Methyl(S)-2-((R)-1-(4-bromophenyl)-2-nitroethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3n). General experimental procedure I was followed to prepare the Michael addition product 3n. The desired product was obtained as a white solid (53 mg, 97% yield) m.p.: 130−132 °C. [α]D26 = +151.400 (c 0.5, CHCl3). The compound 3n

96% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 26.02 min, tR (minor) = 29.74 min; 1H NMR (500 MHz, CDCl3) δ = 7.63 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.42 (dd, J = 7.7, 0.8 Hz, 1H), 7.27−7.25 (m, 1H), 7.25−7.22 (m, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.14−7.08 (m, 2H), 7.07−7.01 (m, 1H), 5.09−4.97 (m, 2H), 4.68 (dd, J = 10.4, 5.0 Hz, 1H), 3.83 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.0, 172.2, 165.0, 139.1, 131.9, 131.0, 130.8, 125.2, 123.4, 123.0, 119.2, 113.0, 90.7, 75.2, 54.1, 46.1; IR (ν, cm−1): 2957, 2925, 2079, 1749, 1722, 1610, 1564, 1461, 1378, 1325, 1299, 1249, 1182, 1147, 1079, 1027, 981, 893, 870, 794, 701, 550; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H14NO6BrNa 441.9897; Found 441.9904. Methyl(S)-2-((R)-2-nitro-1-(p-tolyl)ethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3o). General experimental procedure I was followed to prepare the Michael addition product 3o. The desired product was obtained as a white solid (43 mg, 86% yield) m.p.: 125− 127 °C. [α]D26 = +387.143 (c 0.21, CHCl3). The compound 3o 89% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 59.74 min, tR (minor) = 65.50 min; 1H NMR (500 MHz, CDCl3) δ = 7.66−7.58 (m, 1H), 7.44−7.38 (m, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.14−7.08 (m, J = 8.2 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1H), 6.95−6.87 (m, J = 8.2 Hz, 2H), 5.13−4.98 (m, 2H), 4.69 (dd, J = 10.6,4.6 Hz, 1H), 3.84 (s, 3H), 2.17 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.3, 172.3, 164.2, 138.8, 138.4, 129.3, 129.0, 128.8, 125.0, 123.0, 119.4, 113.1, 91.1, 75.6, 53.9, 46.5, 21.0; IR (ν, cm−1): 3039, 2956, 2924, 2361, 2327, 1931, 1778, 1744, 1712, 1609, 1564, 1472, 1380, 1324, 1297, 1246, 1191, 1145, 1080, 1051, 978, 890, 870, 793, 719, 654, 530; HRMS (ESI) m/z: [M + Na]+ Calcd for C19H17O6NNa 378.0948; Found 378.0946. Methyl(S)-2-((R)-1-(4-methoxyphenyl)-2-nitroethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3p). General experimental procedure I was followed to prepare the Michael addition product 3p. The desired product was obtained as a foamy solid (47 mg, 97% yield). [α]D26 = −21.450 (c 2.0, CHCl3). The compound 3p 92% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 43.06 min, tR (minor) = 50.38 min; 1H NMR (500 MHz, CDCl3) δ = 7.66−7.58 (m, 1H), 7.45−7.38 (m, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.19−7.12 (m, 2H), 7.05−6.97 (m, 1H), 6.69−6.60 (m, 2H), 5.12−4.96 (m, 2H), 4.69 (dd, J = 10.6, 4.6 Hz, 1H), 3.85 (s, 3H), 3.67 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.3, 172.3, 165.2, 159.6, 138.8, 130.3, 125.0, 123.6, 123.1, 119.4, 114.2, 113.0, 91.2, 75.7, 55.1, 53.9, 46.2; IR (ν, cm−1): 2956, 2924, 1748, 1722, 1610, 1564, 1461, 1378, 1325, 1299, 1249, 1182, 1147, 1079, 1027, 981, 893, 870, 794, 701, 550; HRMS (ESI) m/z: [M + Na]+ Calcd for C19H17O7NNa 394.0897; Found 394.0898. Methyl(S)-2-((R)-2-nitro-1-(4-nitrophenyl)ethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3q). General experimental procedure I was followed to prepare the Michael addition product 3q. The desired product was obtained as a yellow solid (47 mg, 94% yield), m.p.: 67−70 °C. [α]D26 = −9.760 (c 2.5, CHCl3). The compound 3q 95% ee was determined by chiral HPLC column (Chiralpak AS-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 74.18 min, tR (minor) = 85.18 min; 1H NMR (500 MHz, CDCl3) δ = 7.92 (d, J = 8.8 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.45− 7.29 (m, 3H), 7.14 (d, J = 8.2 Hz, 1H), 6.97 (t, J = 7.4 Hz, 1H), 5.13− 4.96 (m, 2H), 4.76 (dd, J = 10.4, 4.7 Hz, 1H), 3.77 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 192.7, 172.1, 164.7, 147.9, 139.4, 130.3, 125.3, 123.9, 123.7, 123.7, 119.0, 113.1, 90.3, 74.9, 54.2, 46.1 IR (ν, cm−1): 3081, 2959, 2362, 1750, 1724, 1609, 1567, 1461, 1377, 1324, 1298, 1251, 1195, 1148, 1079, 1022, 982, 894, 853, 759, 699, 585; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H14N2O8Na 409.0642; Found 409.0623. Methyl(S)-2-((R)-1-(naphthalen-1-yl)-2-nitroethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3r). General experimental procedure I was followed to prepare the Michael addition product 3r. The desired product was obtained as a pale yellow solid (48 mg, 94% yield) m.p.: 55−58 °C. [α]D26 = +112.00 (c 2.2, CHCl3).The compound 3r 10818

DOI: 10.1021/acs.joc.7b01105 J. Org. Chem. 2017, 82, 10812−10822

Article

The Journal of Organic Chemistry

110 °C. [α]D26 = −74.279 (c 2.2, CHCl3).The compound 3v 99% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 95:5, flow rate = 0.5 mL/min, λ = 254 nm), tR (major) = 42.72 min, tR (minor) = 49.69 min; 1H NMR (500 MHz, CDCl3) δ = 7.73−7.67 (m, 2H), 7.24 (d, J = 8.2 Hz, 1H), 7.21−7.15 (m, 1H), 4.83 (dd, J = 13.6, 4.7 Hz, 1H), 4.58 (dd, J = 13.4, 6.1 Hz, 1H), 3.77 (s, 3H), 3.34−3.26 (m, 1H), 1.55−1.45 (m, 1H), 1.45−1.35 (m, 1H), 0.94 (t, J = 7.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ = 194.4, 172.5, 165.3, 139.1, 125.1, 123.2, 119.6, 113.6, 91.8, 74.6, 53.7, 43.2, 20.8, 11.3; IR (ν, cm−1): 2968, 2882, 1750, 1722, 1609, 1564, 1461, 1359, 1324, 1298, 1252, 1197, 1147, 1083, 1025, 969, 918, 893, 871, 796, 700, 637, 514. HRMS (ESI) m/z: [M + Na]+ Calcd for C14H15O6NNa 316.0792; Found 316.0791. Methyl(S)-2-((R)-4-methyl-1-nitropentan-2-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3w). General experimental procedure I was followed to prepare the Michael addition product 3w. The desired product was obtained as a pale yellow liquid (41 mg, 97% yield). [α]D32 = −95.773 (c 2.25, CHCl3). The compound 3w 99% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 98:2, flow rate = 0.5 mL/min, λ = 254 nm), tR (major) = 41.82 min, tR (minor) = 55.71 min; 1H NMR (500 MHz, CDCl3) δ = 7.74−7.66 (m, 2H), 7.26−7.24 (m, 1H), 7.21−7.16 (m, 1H), 4.83 (dd, J = 13.2, 5.4 Hz, 1H), 4.51 (dd, J = 13.2, 5.0 Hz, 1H), 3.78−3.74 (m, 3H), 3.45−3.38 (m, 1H), 1.63−1.55 (m, 1H), 1.33 (ddd, J = 14.1, 9.9, 4.4 Hz, 1H), 1.15−1.05 (m, 1H), 0.87 (dd, J = 12.9, 6.6 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ = 194.4, 172.5, 165.3, 139.1, 125.1, 123.2, 119.6, 113.6, 91.8, 75.3, 53.6, 40.0, 36.6, 25.3, 23.3, 21.3; IR (ν, cm−1): 2958, 2871, 1750, 1720, 1608, 1563, 1461, 1378, 1324, 1298, 1232, 1199, 1148, 1102, 1035, 938, 918, 889, 851, 790, 700, 665, 517; HRMS (ESI) m/z: [M + Na]+ Calcd for C16H19O6NNa 344.1105; Found 344.1096. Methyl(S)-2-((R)-1-nitrooctan-2-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3x). General experimental procedure I was followed to prepare the Michael addition product 3x. The desired product was obtained as a pale yellow liquid (44 mg, 98% yield). [α]D32 = −115.590 (c 1.7, CHCl3). The compound 3x 99% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 98:2, flow rate = 0.5 mL/min, λ = 254 nm), tR (major) = 35.87 min, tR (minor) = 44.98 min; 1H NMR (500 MHz, CDCl3) δ = 7.74−7.67 (m, 2H), 7.25 (d, J = 8.2 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 4.83 (dd, J = 13.4, 4.9 Hz, 1H), 4.55 (dd, J = 13.4, 5.8 Hz, 1H), 3.77 (s, 3H), 3.38−3.31 (m, 1H), 1.40−1.28 (m, 5H), 1.27−1.14 (m, 7H), 0.83 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ = 194.4, 172.5, 165.3, 139.1, 125.1, 123.2, 119.6, 113.6, 91.8, 75.0, 53.6, 41.8, 31.4, 28.9, 27.7, 26.6, 22.4, 14.0; IR (ν, cm−1) 2954, 2928, 1750, 1720, 1609, 1563, 1461, 1379, 1324, 1298, 1247, 1196, 1148, 1030, 1025, 938, 914, 890, 851, 791, 699, 571. HRMS (ESI) m/z: [M + Na]+ Calcd for C18H23O6NNa 372.1418; Found 372.1418. Ethyl(S)-2-((R)-2-nitro-1-phenylethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3y). General experimental procedure I was followed to prepare the Michael addition product 3y. The desired product was obtained as a pale yellow liquid (42 mg, 98% yield). [α]D26 = −27.833 (c 1.8, CHCl3). The compound 3y 99% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 25.73 min, tR (minor) = 30.23 min; 1H NMR (500 MHz, CDCl3) δ = 7.58 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.37 (dd, J = 7.7, 0.8 Hz, 1H), 7.24−7.21 (m, 2H), 7.19 (d, J = 8.5 Hz, 1H), 7.12−7.08 (m, 3H), 7.00−6.95 (m, 1H), 5.10 (dd, J = 13.2, 10.4 Hz, 1H), 5.01 (dd, J = 13.2, 4.7 Hz, 1H), 4.72 (dd, J = 10.7, 4.4 Hz, 1H), 4.30 (q, J = 6.9 Hz, 2H), 1.29 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.3, 172.3, 164.6, 138.7, 131.9, 129.2, 128.6, 128.5, 125.0, 123.0, 119.3, 113.0, 91.1, 75.5, 63.5, 46.8, 14.0; IR (ν, cm−1): 3034, 2983, 1746, 1723, 1610, 1564, 1475, 1377, 1323, 1298, 1252, 1197, 1147, 1083, 1025, 969, 918, 897, 871, 757, 672, 580, 559; HRMS (ESI) m/z: [M + Na]+ Calcd for C19H17O6NNa 378.0948; Found 378.0947. Methyl(S)-5-chloro-2-((R)-2-nitro-1-phenylethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3z). General experimental procedure I was followed to prepare the Michael addition product 3z. The desired product was obtained as a foamy solid (40 mg, 98% yield). [α]D31 =

93% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 28.72 min, tR (minor) = 37.57 min; 1H NMR (500 MHz, CDCl3) δ = 8.38 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.67−7.56 (m, 4H), 7.51−7.43 (m, 2H), 7.22 (d, J = 7.9 Hz, 2H), 7.13 (t, J = 7.7 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 5.79 (dd, J = 9.5, 5.4 Hz, 1H), 5.26−5.13 (m, 2H), 3.86 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.7, 192.5, 172.3, 165.5, 139.4, 138.8, 133.9, 132.1, 130.8, 129.5, 129.4, 128.9, 128.8, 128.5, 126.9, 126.8, 126.1, 126.0, 125.8, 125.4, 125.2, 125.2, 124.5, 123.7, 123.6, 123.3, 123.0, 119.3, 113.7, 113.0, 92.4, 91.1, 76.4, 75.5, 54.0, 53.3, 41.2, 39.3; IR (ν, cm−1): 3051, 2957, 2924, 1749, 1723, 1610, 1566, 1461, 1377, 1324, 1297, 1252, 1197, 1147, 1083, 1025, 969, 918, 893, 871, 796, 700, 598; HRMS (ESI) m/ z: [M + Na]+ Calcd for C22H17O6NNa 414.0948; Found 414.0948. Methyl(S)-2-((S)-1-(furan-2-yl)-2-nitroethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3s). General experimental procedure I was followed to prepare the Michael addition product 3s. The desired product was obtained as a yellow solid (41 mg, 95% yield) m.p.: 112− 115 °C. [α]D32 = +71.429(c 1.75, CHCl3). The compound 3s 98% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 28.70 min, tR (minor) = 38.95 min; 1H NMR (500 MHz, CDCl3): δ = 7.64 (ddd, J = 8.5, 7.1, 1.4 Hz, 1H), 7.50−7.55 (m, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.04−7.12 (m, 2H), 6.19 (d, J = 3.5 Hz, 1H), 6.10 (dd, J = 3.5, 1.9 Hz, 1H), 5.11 (dd, J = 13.6, 10.4 Hz, 1H), 4.99 (dd, J = 13.6, 4.1 Hz, 1H), 4.82 (dd, J = 10.4, 4.1 Hz, 1H), 3.81−3.83 ppm (m, 3H). 13C NMR (126 MHz, CDCl3) δ = 193.2, 172.4, 164.9, 146.1, 143.1, 193.3, 138.9, 125.1, 123.1, 118.8, 113.4, 110.5, 90.0, 73.6, 54.0, 41.2; IR (ν, cm−1): 2958, 2924, 2339, 2126, 1750, 1723, 1610, 1566, 1461, 1377, 1324, 1297, 1252, 1197, 1147, 1083, 1025, 969, 918, 893, 871, 796, 702, 653, 599; HRMS (ESI) m/z: [M + Na]+ Calcd for C16H13O7NNa 354.0584; Found 354.0584. Methyl(S)-2-((R)-2-nitro-1-(thiophen-2-yl)ethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3t). General experimental procedure I was followed to prepare the Michael addition product 3t. The desired product was obtained as a white solid (44 mg, 98% yield) m.p.: 195− 197 °C. [α]D28 = −7.241 (c 2.9, CHCl3). The compound 3t 92% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 37.73 min, tR (minor) = 42.50 min; 1H NMR (400 MHz, CDCl3) δ = 7.64 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 7.50−7.44 (m, 1H), 7.24 (td, J = 8.4, 0.7 Hz, 1H), 7.08−7.02 (m, 2H), 6.96−6.92 (m, 1H), 6.75 (dd, J = 5.1, 3.5 Hz, 1H), 5.11−5.04 (m, 1H), 5.03−4.91 (m, 2H), 3.83 (s, 3H) 13C NMR (101 MHz, CDCl3) δ = 192.9, 172.6, 164.9, 138.9, 133.3, 129.1, 126.7, 126.6, 125.1, 123.2, 119.3, 113.4, 90.6, 76.7, 54.0, 42.9; IR (ν, cm−1): 3123, 3047, 2957, 2922, 1744, 1705, 1609, 1563, 1478, 1377, 1325, 1284, 1258, 1196, 1151, 1079, 1021, 981, 915, 890, 870, 795, 724, 566; HRMS (ESI) m/z: [M + Na]+ Calcd for C16H13O6NSNa 370.0356; Found 370.0348. Methyl(S)-2-((R)-1-nitro-4-phenylbutan-2-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3u). General experimental procedure I was followed to prepare the Michael addition product 3u. The desired product was obtained as a pale yellow liquid (47 mg, 98% yield). [α]D26 = −73.059 (c 2.55, CHCl3).The compound 3u 80% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 0.5 mL/min, λ = 254 nm), tR (major) = 32.54 min, tR (minor) = 39.16 min; 1H NMR (500 MHz, CDCl3) δ = 7.72−7.66 (m, 2H), 7.23 (d, J = 7.9 Hz, 3H), 7.19−7.14 (m, 2H), 7.08−7.03 (m, 2H), 4.89 (dd, J = 13.6, 4.7 Hz, 1H), 4.63 (dd, J = 13.4, 6.1 Hz, 1H), 3.76 (s, 3H), 3.45−3.35 (m, 1H), 2.74− 2.58 (m, 2H), 1.78−1.65 (m, 2H). 13C NMR (126 MHz, CDCl3) δ = 194.3, 172.5, 165.3, 140.3, 139.2, 128.5, 128.3, 126.4, 125.2, 123.3, 119.5, 113.6, 91.6, 74.9, 53.7, 41.5, 33.2, 29.7; IR (ν, cm−1): 3028, 2955, 1750, 1721, 1609, 1563, 1475, 1380, 1324, 1298, 1252, 1196, 1147, 1085, 1025, 969, 918, 893, 871, 796, 698, 638; HRMS (ESI) m/ z: [M + Na]+ Calcd for C20H19O6NNa 392.1105; Found 392.1107. Methyl(S)-2-((R)-1-nitrobutan-2-yl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3v). General experimental procedure I was followed to prepare the Michael addition product 3v. The desired product was obtained as a white solid (37.5 mg, 99% yield) m.p.: 108− 10819

DOI: 10.1021/acs.joc.7b01105 J. Org. Chem. 2017, 82, 10812−10822

Article

The Journal of Organic Chemistry

45.9; IR (ν, cm−1): 3262(br), 2924, 2361, 1705, 1610, 1478, 1460, 1324, 1299, 1239, 1146, 1106, 1073, 971, 894, 862, 758, 699, 548. HRMS (ESI) m/z: [M + Na]+ Calcd for C17H13O3NNa 302.0788; Found 302.0789. (2S,4′R)-4′-(4-Bromophenyl)-3H-spiro[benzofuran-2,3′-pyrrolidine]-2′,3-dione (4b). General experimental procedure II was followed to prepare the reductive cyclized product 4b. The desired product was obtained as a white solid (130 mg, 69% yield) m.p.: 135− 140 °C. [α]D31 = +41.402 (c 1.07, THF). The compound 4b 98% ee was determined by chiral HPLC column (Chiralpak OD-H, hexane/iPrOH = 80:20, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 27.21 min, tR (minor) = 32.59 min; 1H NMR (500 MHz, CDCl3) δ = 7.65 (dd, J = 7.7, 0.8 Hz, 2H), 7.57 (ddd, J = 8.6,7.2,1.6 Hz, 1H), 7.43−7.37 (m, 2H), 7.16−7.12 (m, 2H), 7.11−7.03 (m, 2H), 4.11 (t, J = 7.4 Hz, 1H), 3.95 (ddd, J = 10.0, 7.6, 0.9 Hz, 1H), 3.74 (dd, J = 10.1, 7.3 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ = 197.8, 172.4, 170.4, 138.7, 133.2, 131.7, 130.4, 124.7, 122.9, 122.1, 120.4, 113.4, 90.4, 47.5, 45.8; IR (ν, cm−1): 3237 (br), 2923, 2050, 1699, 1608, 1477, 1459, 1323, 1279, 1237, 1145, 1106, 1073, 1010, 970, 894, 862, 754, 667, 595, 558; HRMS (ESI) m/z: [M + Na]+ Calcd for C17H12O3NBrNa 379.9893; Found 379.9893. (2S,4′R)-4′-(2-Fluorophenyl)-3H-spiro[benzofuran-2,3′-pyrrolidine]-2′,3-dione (4c). General experimental procedure II was followed to prepare the reductive cyclized product 4c. The desired product was obtained as a pale yellow solid (140 mg, 84% yield) m.p.: 191−195 °C. [α]D31 = +44.361 (c 4.15, THF). The compound 4c 98% ee was determined by chiral HPLC column (Chiralpak OD-H, hexane/iPrOH = 80:20, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 19.46 min, tR (minor) = 35.92 min; 1H NMR (400 MHz, DMSO-d6) δ = 8.94 (s, 1H), 7.71−7.61 (m, 2H), 7.49 (dt, J = 7.7, 1.7 Hz, 1H), 7.33−7.24 (m, 1H), 7.22−7.04 (m, 4H), 4.36 (t, J = 7.2 Hz, 1H), 3.91−3.83 (m, 1H), 3.83−3.75 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ = 198.0, 171.8, 168.3, 160.4 (d, J = 305.1 Hz), 138.9, 130.0 (d, J = 4.5 Hz), 129.5 (d, J = 10.7 Hz), 124.3 (d, J = 4.1 Hz), 124.0, 122.8, 121.9 (d, J = 17.8 Hz), 119.7, 115.0 (d, J = 27.5 Hz), 113.1, 90.4, 79.1, 43.3; IR (ν, cm−1): 3236 (br), 3055, 2927, 1708, 1610, 1492, 1477, 1459, 1324, 1298, 1239, 1146, 1102, 1070, 974, 894, 868, 731, 701, 632, 567. HRMS (ESI) m/z: [M + Na]+ Calcd for C17H12O3NFNa 320.0693; Found 320.0691. (2S,4′R)-4′-(2-Chlorophenyl)-3H-spiro[benzofuran-2,3′-pyrrolidine]-2′,3-dione (4d). General experimental procedure II was followed to prepare the reductive cyclized product 4d. The desired product was obtained as a pale yellow solid (120 mg, 74% yield) m.p.: 65−70 °C. [α]D31 = +95.477 (c 3.25, THF). The compound 4d 91% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 20.22 min, tR (minor) = 50.77 min; 1H NMR (500 MHz, CDCl3) δ = 7.74−7.64 (m, 2H), 7.56 (ddd, J = 8.5, 7.1, 1.4 Hz, 1H), 7.49 (dd, J = 7.6, 1.6 Hz, 1H), 7.34−7.26 (m, 2H), 7.24−7.19 (m, 1H), 7.11−7.07 (m, 1H), 7.03 (d, J = 8.5 Hz, 1H), 4.65 (dd, J = 7.4, 3.6 Hz, 1H), 4.13 (dd, J = 10.2, 7.4 Hz, 1H), 3.69 (ddd, J = 10.3, 3.7, 0.8 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ = 198.0, 173.1, 170.3, 138.5, 135.0, 133.7, 129.5, 129.0, 128.8, 127.2, 124.8, 122.8, 119.6, 113.5, 90.2, 45.4, 42.7; IR (ν, cm−1): 3238 (br), 2924, 1701, 1609, 1475, 1435, 1365, 1324, 1297, 1237, 1145, 1103, 1072, 971, 894, 848, 751, 698, 675, 591, 571. HRMS (ESI) m/z: [M + Na]+ Calcd for C17H12O3NClNa 336.0398; Found 336.0401. (2S,4′R)-4′-(2,4-Dichlorophenyl)-3H-spiro[benzofuran-2,3′-pyrrolidine]-2′,3-dione (4e). General experimental procedure II was followed to prepare the reductive cyclized product 4e. The desired product was obtained as a pale yellow solid (160 mg, 80% yield) m.p.: 105−110 °C. [α]D31 = +31.250 (c 4.0, THF). The compound 4e 96% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 16.96 min, tR (minor) = 55.43 min; 1H NMR (400 MHz, DMSO-d6) δ = 8.97 (s, 1H), 7.74−7.65 (m, 2H), 7.61−7.54 (m, 2H), 7.48 (dd, J = 8.5,2.3 Hz, 1H), 7.21−7.14 (m, 2H), 4.49 (dd, J = 7.6, 4.5 Hz, 1H), 3.93 (dd, J = 10.4, 7.9 Hz, 1H), 3.72 (dd, J = 10.5, 4.7 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ = 198.0, 172.2, 167.8, 139.1, 134.9, 132.9, 132.6, 130.7, 128.6, 127.6, 124.2, 123.0, 119.2, 113.2,

−30.059 (c 1.7, CHCl3).The compound 3z 99% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 25.69 min, tR (minor) = 28.49 min; 1H NMR (400 MHz, CDCl3): δ = 7.53 (dd, J = 8.8, 2.3 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.16−7.22 (m, 3H), 7.10−7.16 (m, 3H), 4.96−5.12 (m, 2H), 4.71 (dd, J = 10.4, 4.8 Hz, 1H), 3.83 (s, 3H); 13C NMR (101 MHz, CDCl3) δ = 192.1, 170.6, 164.7, 138.7, 131.5, 129.2, 128.9, 128.8, 128.7, 124.3, 120.4, 114.4, 91.9, 75.3, 54.1, 46.7; IR (ν, cm−1): 3035, 2958, 2925, 2096, 1752, 1725, 1605, 1564, 1494, 1377, 1340, 1269, 1242, 1182, 1122, 1090, 1021, 977, 899, 866, 734, 674, 563, 522; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H14O6NClNa 398.0402; Found 398.0401. Methyl(S)-5-bromo-2-((R)-2-nitro-1-phenylethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3aa). General experimental procedure I was followed to prepare the Michael addition product 3aa. The desired product was obtained as a foamy solid (36 mg, 92% yield). [α]D31 = −32.143 (c 1.4, CHCl3). The compound 3aa 99% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 27.19 min, tR (minor) = 31.25 min; 1H NMR (500 MHz, CDCl3): δ = 7.65 (dd, J = 8.8, 2.2 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.18−7.22 (m, 2H), 7.08−7.15 (m, 4H), 4.98−5.10 (m, 2H), 4.71 (dd, J = 10.4, 4.7 Hz, 1H), 3.83 (s, 3H). 13C NMR (126 MHz, CDCl3): δ = 191.8, 171.0, 164.7, 141.4, 131.6, 129.1, 128.9, 128.8, 127.4, 121.0, 115.7, 114.8, 91.8, 75.3, 54.1, 46.7.IR (ν, cm−1): 3035, 2956, 2923, 1751, 1726, 1603, 1564, 1495, 1376, 1341, 1270, 1243, 1178, 1121, 1089, 1022, 977, 899, 866, 734, 660, 561; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H14O6NBrNa 441.9897; Found 441.9899. Methyl(S)-5-iodo-2-((R)-2-nitro-1-phenylethyl)-3-oxo-2,3-dihydrobenzofuran-2-carboxylate (3ab). General experimental procedure I was followed to prepare the Michael addition product 3ab. The desired product was obtained as a pale yellow solid (33 mg, 89% yield) m.p.: 72−75 °C. [α]D32 = −41.417 (c 1.2, CHCl3). The compound 3ab 99% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 30.49 min, tR (minor) = 36.68 min; 1H NMR (500 MHz, CDCl3) δ = 7.82 (dd, J = 8.8,1.9 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.21−7.18 (m, 2H), 7.15−7.11 (m, 3H), 7.00 (d, J = 8.5 Hz, 1H), 5.10−4.97 (m, 2H), 4.70 (dd, J = 10.2, 4.9 Hz, 1H), 3.83 (s, 3H) 13 C NMR (126 MHz, CDCl3) δ = 191.5, 171.7, 164.7, 146.9, 133.6, 131.6, 129.1, 128.9, 128.8, 121.6, 115.2, 91.4, 85.3, 75.3, 54.1, 46.6.IR (ν, cm−1): 3035, 2958, 2925, 1751, 1727, 1599, 1565, 1495, 1376, 1340, 1273, 1243, 1178, 1121, 1089, 1022, 977, 896, 864, 736, 660, 563, 519; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H14O6NINa 489.9758; Found 489.9758. II. General Procedure for Synthesis of Reductive Cyclization Product. A 50 mL oven-dried round-bottom flask with well-stirring was filled with zinc powder (20 equiv), and then Michael addition products 3 (4a, 4g, 4h (0.1 g scale), 4b−4f (0.2 g scale) 1 equiv) and acetic acid (2.5 mL) were added to the flask at room temperature. After the mixture was stirred at 60 °C for 4 h, the reaction mass was basified using saturated NaHCO3 solution. After being basified, the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4 and concentrated. The crude mixture was purified by flash column chromatography over silica gel with a gradient from 70:30 hexane:EtOAc to 60:40 hexane:EtOAc to furnish 4a−h. Analytical Data for Reductive Cyclized Product. (2S,4′R)-4′Phenyl-3H-spiro[benzofuran-2,3′-pyrrolidine]-2′,3-dione (4a). General experimental procedure II was followed to prepare the reductive cyclized product 4a. The desired product was obtained as a pale yellow semisolid (48 mg, 60% yield). [α]D31 = +188.600 (c 0.5, CHCl3). The compound 4a 94% ee was determined by chiral HPLC column (Chiralpak OD-H, hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 23.54 min, tR (minor) = 43.26 min; 1H NMR (500 MHz, CDCl3) δ = 7.67−7.61 (m, 1H), 7.54 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.47−7.40 (m, 1H), 7.28−7.24 (m, 5H), 7.09−7.01 (m, 2H), 4.16 (t, J = 7.3 Hz, 1H), 4.01−3.93 (m, 1H), 3.82 (dd, J = 9.8, 7.3 Hz, 1H) 13C NMR (126 MHz, CDCl3) δ = 198.1, 172.5, 170.5, 138.5, 134.2, 128.7, 128.6, 128.5, 128.0, 124.6, 122.6, 120.5, 113.4, 90.7, 48.1, 10820

DOI: 10.1021/acs.joc.7b01105 J. Org. Chem. 2017, 82, 10812−10822

Article

The Journal of Organic Chemistry 90.2, 43.9, 41.9; IR (ν, cm−1): 3267 (br), 2924, 2854, 2072, 1705, 1610, 1590 1475, 1475, 1384, 1324, 1298, 1235, 1145, 1104, 1073, 971, 894, 866, 755, 674, 548, 510; HRMS (ESI) m/z: [M + Na]+ Calcd for C17H11O3NCl2Na 370.0008; Found 370.0004. 4-((2S,4′R)-2′,3-Dioxo-3H-spiro[benzofuran-2,3′-pyrrolidin]-4′yl)benzonitrile (4f). General experimental procedure II was followed to prepare the reductive cyclized product 4f. The desired product was obtained as a white solid (153 mg, 88% yield) m.p.: 95−100 °C. [α]D31 = −16.410 (c 1.95, THF).The compound 4f 94% ee was determined by chiral HPLC column (Chiralpak OD-H, hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 48.30 min, tR (minor) = 94.20 min; 1H NMR (500 MHz, DMSO-d6) δ = 8.96 (s, 1H), 7.78−7.74 (m, 2H), 7.73−7.62 (m, 2H), 7.47−7.42 (m, 2H), 7.20−7.14 (m, 2H), 4.27 (t, J = 7.1 Hz, 1H), 3.90−3.84 (m, 1H), 3.73 (dd, J = 10.1,6.9 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ = 198.4, 172.2, 168.8, 141.3, 139.6, 132.8, 132.7, 130.1, 129.2, 124.6, 123.5, 120.4, 119.0, 113.7, 111.0, 91.4, 47.1, 44.6; IR (ν, cm−1): 3271 (br), 2956, 2229, 1702, 1608, 1476, 1459, 1324, 1299, 1239, 1146, 1106, 1073, 971, 894, 862, 758, 699, 548; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H12O3N2Na 327.0740; Found 327.0739. (2S,4′R)-4′-Isobutyl-3H-spiro[benzofuran-2,3′-pyrrolidine]-2′,3dione (4g). General experimental procedure II was followed to prepare the reductive cyclized product 4g. The desired product was obtained as a foamy solid (53 mg, 70% yield). [α]D29 = +127.286 (c 3.5, CHCl3). The compound 4g 99% ee was determined by chiral HPLC column (Phenomenex Amylose-2, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 26.43 min, tR (minor) = 40.95 min; 1H NMR (500 MHz, CDCl3) δ = 7.74−7.62 (m, 2H), 7.19 (d, J = 8.2 Hz, 1H), 7.16−7.11 (m, 1H), 6.91 (br. s., 1H), 3.67 (ddd, J = 9.3, 7.9, 1.1 Hz, 1H), 3.23 (dd, J = 9.5, 7.3 Hz, 1H), 3.05 (td, J = 14.6, 7.4 Hz, 1H), 1.42−1.31 (m, 3H), 0.88−0.77 (m, 6H) 13C NMR (126 MHz, CDCl3) δ = 198.8, 172.8, 170.9, 138.5, 124.7, 122.6, 120.7, 113.4, 91.3, 45.4, 40.4, 36.1, 25.8, 22.9, 22.2; IR (ν, cm−1): 3248 (br), 2956, 2874, 1704, 1609, 1466, 1366, 1194, 1103, 991, 890, 758, 672, 632; HRMS (ESI) m/z: [M + Na]+ Calcd for C15H17O3NNa 282.1101; Found 282.1104. (2S,4′R)-4′-Hexyl-3H-spiro[benzofuran-2,3′-pyrrolidine]-2′,3dione (4h). General experimental procedure II was followed to prepare the reductive cyclized product 4h. The desired product was obtained as a yellow liquid (53 mg, 65% yield). [α]D29 = +130.867 (c 3.0, CHCl3). The compound 4h 99% ee was determined by chiral HPLC column (Chiralpak OD-H, hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm), tR (major) = 20.05 min, tR (minor) = 24.54 min; 1H NMR (500 MHz, CDCl3) δ = 7.74−7.62 (m, 2H), 7.21 (d, J = 8.5 Hz, 1H), 7.19−7.12 (m, 2H), 3.70 (ddd, J = 9.6,7.7, 0.9 Hz, 1H), 3.24 (dd, J = 9.5, 6.9 Hz, 1H), 3.00−2.91 (m, 1H), 1.60−1.45 (m, 2H), 1.26−1.12 (m, 8H), 0.83 (t, J = 6.9 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ = 198.9, 172.8, 171.1, 138.4, 124.7, 122.6, 120.6, 113.4, 91.3, 45.3, 42.5, 31.4, 29.1, 27.3, 27.1, 22.4, 14.0; IR (ν, cm−1): 3246 (br), 2956, 2930, 2871, 1700, 1610, 1476, 1386, 1147, 991, 913, 891, 855, 757, 731, 671, 630; HRMS (ESI) m/z: [M + Na]+ Calcd for C17H21O3N Na 310.1414; Found 310.1416. III. General Procedure for Reduction Reaction. To a stirred solution of Michael addition product 3a (1 equiv) in methanol (2 mL) at 0 °C was added NaBH4 (1 equiv) portion wise, and the reaction mixture was stirred for 1 h. After completion of the reaction, it was quenched with aqueous ammonium chloride solution, followed by extracted in dichloromethane, and the solvent was evaporated under reduced pressure. The crude reaction mixture was dissolved in dichloromethane and treated with acetyl chloride in the presence of Et3N at 0 °C for 2 h. After completion of the reaction, it was diluted with CH2Cl2 and washed with water. The layers were separated, and the aqueous layer was again extracted with CH2Cl2. The combined organic layers were washed with brine and dried over anhydrous NaSO4 and concentrated. The crude mixture was purified by flash column chromatography over silica gel (80:20 hexane/EtOAc) to furnish 5. Methyl(2S,3R)-3-acetoxy-2-((R)-2-nitro-1-phenylethyl)-2,3-dihydrobenzofuran-2-carboxylate (5). General experimental procedure III was followed to prepare the product 5. The desired product was

obtained as a pale yellow semisolid (53 mg, 70% yield). [α]D31 = +82.211 (c 0.95, CHCl3). 1H NMR (500 MHz, CDCl3) δ = 7.47−7.44 (m, 1H), 7.42−7.27 (m, 6H), 7.02−6.95 (m, 2H), 6.50 (s, 1H), 5.15 (dd, J = 13.6, 10.4 Hz, 1H), 4.96 (dd, J = 13.6, 2.8 Hz, 1H), 4.52 (dd, J = 10.6, 2.7 Hz, 1H), 3.67 (s, 3H), 2.13 (s, 3H); 13C NMR (126 MHz, CDCl3) δ = 171.0, 169.8, 159.2, 134.6, 131.9, 129.1, 128.9, 128.8, 128.7, 127.1, 124.2, 122.4, 111.0, 91.9, 76.2, 53.4, 46.3, 20.9; IR (ν, cm−1): 3034, 2954, 1741, 1598, 1564, 1471, 1375, 1290, 1214, 1119, 1077, 1017, 978, 925, 883, 837, 755, 700, 591, 564; HRMS (ESI) m/z: [M + Na]+ Calcd for C20H19O7NNa 408.1054; Found 408.1046.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01105. Copies of 1H and 13NMR spectra, HPLC chromatogram, and crystallographic data (PDF) Crystallographic data for compound 3n (CIF) Crystallographic data for compound 4a (CIF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Venkitasamy Kesavan: 0000-0002-7720-0268 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We acknowledge the Board of Research in Nuclear Sciences, Mumbai, India (35/14/01/2015-BRNS/10464), for financial support. K.S. and N.K. thank the Council of Scientific & Industrial Research (CSIR), New Delhi, for a fellowship. We thank Dr. Sudha Devi for crystallographic analysis, SAIF-IIT Madras, and SAIF-IIT Madras for spectral analysis (NMR and IR). We thank the Department of Biotechnology IIT Madras for LCMS. We thank Prof. Anju Chadha for the AUTOPOL IV Polarimeter.

■

REFERENCES

(1) (a) Mo, X.; Li, Q.; Ju, J. RSC Adv. 2014, 4, 50566−50593. (b) Aoki, S.-y.; Oi, T.; Shimizu, K.; Shiraki, R.; Takao, K.-i.; Tadano, K.-i. Bull. Chem. Soc. Jpn. 2004, 77, 1703−1716. (2) (a) Su, Z.; Tamm, C. Helv. Chim. Acta 1995, 78, 1278−90. (b) Bloch, P.; Tamm, C.; Bollinger, P.; Petcher, T. J.; Weber, H. P. Helv. Chim. Acta 1976, 59, 133−137. (3) (a) Hayashi, Y.; Shoji, M.; Mukaiyama, T.; Gotoh, H.; Yamaguchi, S.; Nakata, M.; Kakeya, H.; Osada, H. J. Org. Chem. 2005, 70, 5643−5654. (b) Igarashi, Y.; Yabuta, Y.; Furumai, T. J. Antibiot. 2004, 57, 537−540. (4) (a) Lathrop, S. P.; Rovis, T. A Chem. Sci. 2013, 4, 1668−1673. (b) Yamada, T.; Imai, E.; Nakatuji, K.; Numata, A.; Tanaka, R. Tetrahedron Lett. 2007, 48, 6294−6296. (5) (a) Yamada, T.; Kitada, H.; Kajimoto, T.; Numata, A.; Tanaka, R. J. Org. Chem. 2010, 75, 4146−4153. (b) Hayashi, Y.; Sankar, K.; Ishikawa, H.; Nozawa, Y.; Mizoue, K.; Kakeya, H. Bioorg. Med. Chem. Lett. 2009, 19, 3863−3865. (6) (a) Sugi, M.; Nagase, R.; Misaki, T.; Nakatsuji, H.; Tanabe, Y. Eur. J. Org. Chem. 2016, 2016, 4834−4841. (b) Emoto, M.; Yano, K.; Choijamts, B.; Sakai, S.; Hirasawa, S.; Wakamori, S.; Aizawa, M.; Nabeshima, K.; Tachibana, K.; Kanomata, N. Anticancer Res. 2015, 35, 2739−2746. (c) Hayashi, Y.; Shoji, M.; Yamaguchi, J.; Sato, K.; Yamaguchi, S.; Mukaiyama, T.; Sakai, K.; Asami, Y.; Kakeya, H.; Osada, H. J. Am. Chem. Soc. 2002, 124, 12078−12079. 10821

DOI: 10.1021/acs.joc.7b01105 J. Org. Chem. 2017, 82, 10812−10822

Article

The Journal of Organic Chemistry (7) (a) Dufour, C.; Wink, J.; Kurz, M.; Kogler, H.; Olivan, H.; Sable, S.; Heyse, W.; Gerlitz, M.; Toti, L.; Nusser, A.; Rey, A.; Couturier, C.; Bauer, A.; Broenstrup, M. Chem. - Eur. J. 2012, 18, 16123−16128. (b) Couturier, C.; Bauer, A.; Rey, A.; Schroif-Dufour, C.; Broenstrup, M. Bioorg. Med. Chem. Lett. 2012, 22, 6292−6296. (8) Recent reviews for organocatalysts: (a) Govender, T.; Arvidsson, P. I.; Maguire, G. E. M.; Kruger, H. G.; Naicker, T. Chem. Rev. 2016, 116, 9375−9437. (b) Wang, Y.; Lu, H.; Xu, P.-F. Acc. Chem. Res. 2015, 48, 1832−1844. (c) Sun, B.-F. Tetrahedron Lett. 2015, 56, 2133−2140. (d) Abbasov, M. E.; Romo, D. Nat. Prod. Rep. 2014, 31, 1318−1327. (e) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167−178. (9) (a) Kundu, A.; Pathak, S.; Debnath, K.; Pramanik, A. Tetrahedron Lett. 2014, 55, 3960−3968. (b) Karthikeyan, K.; Perumal, P. T. Synlett 2009, 2009, 2366−2370. (10) Huang, L.; Lin, J.-S.; Tan, B.; Liu, X.-Y. ACS Catal. 2015, 5, 2826−2831. (11) Guo, S.; Chen, B.; Zhao, D.; Chen, W.; Zhang, G. Adv. Synth. Catal. 2016, 358, 3010−3014. (12) (a) Zhao, B.-L.; Du, D.-M. Chem. Commun. 2016, 52, 6162− 6165. (b) Kaya, U.; Chauhan, P.; Hack, D.; Deckers, K.; Puttreddy, R.; Rissanen, K.; Enders, D. Chem. Commun. 2016, 52, 1669−1672. (c) Deng, Y.-H.; Zhang, X.-Z.; Yu, K.-Y.; Yan, X.; Du, J.-Y.; Huang, H.; Fan, C.-A Chem. Commun. 2016, 52, 4183−4186. (d) Deng, Y.-H.; Zhang, X.-Z.; Yu, K.-Y.; Yan, X.; Du, J.-Y.; Huang, H.; Fan, C.-A. Chem. Commun. 2016, 52, 4183−4186. (e) Montesinos-Magraner, M.; Vila, C.; Rendon-Patino, A.; Blay, G.; Fernandez, I.; Munoz, M. C.; Pedro, J. R. ACS Catal. 2016, 6, 2689−2693. (f) Zhao, K.; Zhi, Y.; Wang, A.; Enders, D. ACS Catal. 2016, 6, 657−660. (g) Bera, K.; Namboothiri, I. N. N. J. Org. Chem. 2015, 80, 1402−1413. (h) Ni, X.; Li, X.; Wang, Z.; Cheng, J.-P. Org. Lett. 2014, 16, 1786−1789. (13) Kumarswamyreddy, N.; Kesavan, V. Org. Lett. 2016, 18, 1354− 1357. (14) Please see the Supporting Information. (15) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119−125. (16) (a) Enders, D.; Fronert, J.; Bisschops, T.; Boeck, F. Beilstein J. Org. Chem. 2012, 8, 1112−1117. (b) Zou, Y.; Lobera, M.; Snider, B. B. J. Org. Chem. 2005, 70, 1761−1770. (c) Ito, C.; Katsuno, S.; Kondo, Y.; Tan, H. T.; Furukawa, H. Chem. Pharm. Bull. 2000, 48, 339−343. (d) Alami, I.; Clerivet, A.; Naji, M.; Van Munster, M.; Macheix, J. J. Phytochemistry 1999, 51, 733−736. (e) Rajendran, K.; Mesta, C. K.; Paknikar, S. K.; Bhattacharyya, S. C. Indian J. Chem. 1970, 8, 200−201. (17) Zhao, L.; Huang, G.; Guo, B.; Xu, L.; Chen, J.; Cao, W.; Zhao, G.; Wu, X. Org. Lett. 2014, 16, 5584−5587. (18) (a) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967−1969. (b) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416−14417. (c) Konishi, H.; Lam, T. Y.; Malerich, J. P.; Rawal, V. H. Org. Lett. 2010, 12, 2028−203. (19) Jin, H.; Cho, S. M.; Lee, J.; Ryu, D. H. Org. Lett. 2017, 19, 2434−2437.

10822

DOI: 10.1021/acs.joc.7b01105 J. Org. Chem. 2017, 82, 10812−10822