CHIRALITY 26:121–127 (2014)

Highly Enantioselective Michael Addition Promoted by a New Diterpene-Derived Bifunctional Thiourea Catalyst: A Doubly Stereocontrolled Approach to Chiral Succinimide Derivatives ZHONG-TAI SONG,1 TAO ZHANG,1,2 HAI-LONG DU,1 ZHI-WEI MA,1 CHANG-HUA ZHANG,1 AND JING-CHAO TAO1* 1 College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China 2 School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China

ABSTRACT A doubly stereocontrolled organocatalytic asymmetric Michael addition to the synthesis of substituted succinimides is described. Starting from aldehydes and maleimides, both enantiomers of the succinimides could be obtained in high to excellent yields (up to 98%) and enantioselectivities (up to 99%) when one of the two special chiral diterpene-derived bifunctional thioureas was individually used as a catalyst. Moreover, these catalysts can be efficiently used in large-scale catalytic synthesis with the same level of yield and enantioselectivity. Chirality 26:121–127, 2014. © 2014 Wiley Periodicals, Inc. KEY WORDS: enantiomers; diterpene-derived thiourea; maleimide; Michael reaction; succinimide INTRODUCTION

Substituted maleimides are important structural scaffolds and other precursors of some biologically interesting substances. The chiral α-substituted succinimides are prevalent in a variety of natural products and some clinical drug candidates.1–5 Since the report of Komura and co-workers in 1987, on the isolation of andrimid as a new and highly specific antibiotic,2 a great deal of effort has been dedicated to the discovery and synthesis of chiral succinimides. Notably, organocatalytic versions using maleimides as substrates for the synthesis of chiral succinimides have been actively pursued recently.6–16 Maleimides are an important class of substrates, which have successfully been used in asymmetric organocatalytic transformations such as asymmetric cycloadditions, Michael reactions, and asymmetric cascade reactions.7–16 Asymmetric organocatalytic functionalization of maleimides provides easy access to chiral-substituted succinimide derivatives. Michael addition is one of the most efficient and powerful atom-economical carbon-carbon bond-forming reactions in synthetic chemistry.17–20 In particular, the asymmetric Michael addition of maleimide represents a potentially attractive approach, which opens up efficient direct entries to substituted succinimides from simple precursors.7–16 Both enantiomers of a chiral compound are often useful and versatile in terms of pharmaceutical industry and organic synthesis.21,22 However, the efficient preparation of both enantiomers of a chiral compound still represents a daunting task, and to the best of our knowledge, effective double asymmetric induction on metal-free organocatalytic reactions have rarely been reported to date.23–26 Thus, the development of an effective organocatalytic method to prepare both enantiomers of substituted succinimides individually is a highly desirable goal. Thiourea-based catalysts are considered powerful and efficient catalysts for various types of asymmetric reactions, and great progress has been achieved in this field.27–30 Nevertheless, the skeleton structures to construct thiourea catalysts are very limited, and there is still great demand for novel bifunctional thiourea catalysts for this purpose. Recently, we found that, similar to the cinchona alkaloids, the incorporation of a chiral © 2014 Wiley Periodicals, Inc.

diterpene moiety (isosteviol) into the thiourea catalysts led to impressive results in asymmetric reactions.31–37 Inspired by the excellent chiral structural skeleton of isosteviol, we designed and synthesized a new class of primary amine-thiourea bifunctional catalysts 3a and 3b. With these novel catalysts in hand, the effects of the thiourea catalysts were investigated. Although there is still much to investigate in terms of the role of the chiral terpene moiety in the stereocontrol that is exerted by the bifunctional thiourea catalysts, we believe that this excellent structural backbone is necessary. Based on this, excellent results are expected when the catalyst is varied by moving the thiourea moiety from 16-position to 4-position (Fig. 1). We now report a highly efficient asymmetric Michael addition of aldehydes to maleimides promoted by new diterpenederived primary amine thioureas. Both enantiomers were finished with high to excellent yields (up to 98%) and enantioselectivities (up to 99%) and this catalytic system can be used in large-scale reactions with the enantioselectivity being maintained at the same level. EXPERIMENTAL All chemicals were used as received unless otherwise noted. Reagent 1 grade solvents were redistilled prior to use. H nuclear magnetic 13 resonance (NMR) and C NMR spectra were collected on a Bruker DPX 400 NMR spectrometer with tetramethylsilane (TMS) as internal reference. Infrared (IR) spectra were determined on a Thermo Nicolet IR200 unit. High-resolution mass spectra (HRMS) were obtained on a Waters Micromass Q-Tof Micro instrument using the electrospray ionization (ESI) technique. Chromatography was performed on silica gel (200–300 mesh). Melting points were determined using the aXT5 apparatus and are uncorrected. Optical rotations were determined on a Perkin Elmer 341 polarimeter. Enantiomeric excess was determined by chiral HPLC at room temperature using Labtech 2006 pump equipped with Labtech UV600 ultra detector with Chiral columns.

*Correspondence to: J.-C. Tao, College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China. E-mail: [email protected] Received for publication 13 July 2013; Accepted 17 November 2013 DOI: 10.1002/chir.22279 Published online 14 January 2014 in Wiley Online Library (wileyonlinelibrary.com).

122

SONG ET AL.

General Procedure for the Michael Addition The aldehyde (4, 0.40 mmol) was added to a mixture of catalyst 3 (1 mol%) and corresponding maleimide 5 (0.20 mmol) in toluene (1.0 mL). The reaction mixture was stirred at ambient temperature for the needed time. After maleimide was consumed by thin-layer chromatography (TLC) analysis, the reaction mixture was subjected to TLC on silica gel (ethyl acetate/petroleum ether) to afford the pure Michael product. The enantiomeric excess (ee) of the products was determined by chiral HPLC analysis using Chiral columns. Fig. 1. Design of novel diterpene-derived thiourea.

Synthesis of Catalyst Synthesis of isosteviolisothiocyanate (2). Ethanol (5 mL) was added to isosteviol amine (1, 1.28 g, 4.4 mmol), CS2 (3.34 g, 44 mmol), and Et3N (0.44 g, 4.4 mmol) were added while stirring, resulting in the precipitation of the dithiocarbamate. The reaction mixture was stirred for 30 min at room temperature and then cooled in an ice bath. Boc2O (0.95 g, 4.4 mmol), dissolved in ethanol (1 mL), was added followed by the immediate addition of a catalytic amount of DMAP (2 mol %) in ethanol (1 mL). The reaction mixture was kept in the ice bath for 5 min and was then allowed to reach room temperature stirring for a further 5 min and evaporated thoroughly in vacuo. After purification the isosteviol isothiocyanate 2 was obtained as a white solid. o -1 Yield: 89%; ½α20 D = -96.6 (c 1.0, CH2Cl2); Mp.: 125.2-126.5 C; IR (KBr, cm ): 1 2926, 2849, 2263, 2107, 1735, 1449, 1374, 1251, 1188, 975, 911; H NMR (400 MHz, CDCl3, TMS): δ 2.66 (dd, J = 18.4, 3.6 Hz, 1H), 1.86-1.89 (m, 1H), 1.78 (m, 1H), 1.74 (m, 1H), 1.68-1.70 (m, 2H), 1.63-1.65 (m, 3H), 1.50-1.53 (m, 2H), 1.47 (s, 2H), 1.38 (s, 3H), 1.31-1.35 (m, 3H), 1.13-1.22 (m, 4H, 13 0.98-1.00(m, 1H), 0.95 (s, 3H), 0.91 (s, 3H); C NMR (100 MHz, CDCl3): δ 221.9, 130.2, 61.9, 59.1, 55.2, 54.6, 54.4, 48.8, 48.7, 40.5, 40.2, 39.1, 38.1, 37.4, 37.0, 30.4, 19.9, 19.8, 17.9, 13.8

Synthesis of isosteviolthiourea (3). Isosteviolisothiocyanate (2, 0.99 g, 3 mmol) was added over a period of 0.5 h to a stirred solution of (R, R)- or (S,S)-1,2-diaminocyclohexane (0.41 g, 3.6 mmol) in dry dichloromethane (25 mL). The reaction mixture was stirred for a further 12 h at room temperature. The solvent was removed under reduced pressure and the crude product was purified using column chromatography eluting with CHCl3/MeOH = 50:1. Isosteviol thiourea 3 was obtained as a white solid. 3a: Yield: 72%; ½α20 D = -34.2 (c 1.0, CH2Cl2); Mp.:136.2-137.4oC; IR (KBr, -1 cm ): 3380, 3223, 3042, 2930, 2853, 1733, 1631, 1533, 1451, 1364, 1 1320, 969; H NMR (400 MHz, CDCl3, TMS): δ 4.73 (s, 2H), 3.0 (s, 1H), 2.67 (m, 1H), 2.10 (m, 2H), 1.76-1.86(m, 5H), 1.67-1.71 (m, 4H), 1.57-1.59 (m, 7H), 1.41-1.44 (m, 5H), 1.29-1.31 (m, 2H), 1.23-1.26 (m, 3H), 1.09-1.14 (m, 5H), 0.99 (s, 3H), 0.90-0.93 (m, 1H); 13 C NMR (100 MHz, CDCl3): δ 223.1, 180.8, 58.4, 57.9, 55.6, 55.1, 54.2, 48.8, 41.0, 39.2, 37.7, 37.2, 32.0, 31.1, 26.9, 24.5, 24.3, 19.8, + 19.1, 17.6, 15.2; HRMS (ESI, m/z) calcd. for C26H43N3OS [M+H] 446.3205. Found: 446.3206. o 3b: Yield: 75%; ½α20 D = -65.8 (c 1.0, CH2Cl2); Mp.:144.2-145.1 C; IR -1 (KBr, cm ): 3363, 3228, 3046, 2931, 2851, 1736, 1629, 1536, 1452, 1369, 1 1315, 1280, 1247, 975; H NMR (400 MHz, CDCl3, ppm): δ 6.21 (s, 1H), 4.42 (s, 1H), 3.54 (s, 1H), 3.15-3.19 (m, 1H), 2.68-2.73(m, 1H), 2.09-2.28 (m, 2H), 1.75-1.87 (m, 5H), 1.63-1.70 (m, 4H), 1.57-1.59 (m, 8H), 1.391.43 (m, 4H), 1.25-1.34 (m, 4H), 1.22 (s, 3H), 1.02-1.08 (m, 5H), 0.98 13 (s, 3H), 0.89-0.92 (m, 1H); C NMR (100 MHz, CDCl3): δ 223.1, 180.8, 58.5, 57.9, 55.6, 55.2, 54.2, 48.8, 41.0, 39.2, 37.7, 37.2, 32.0, 31.1, 27.0, 24.4, 24.3, 19.8, 19.1, 17.6, 15.2; HRMS (ESI, m/z) calcd. for C26H43N3OS + [M+H] 446.3205. Found: 446.3203. Chirality DOI 10.1002/chir

Characterization of Michael Addition Products 2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-methylpropanal (6a). 35 1 H NMR (400 MHz, CDCl3, TMS): δ 1.27 (s, 3H), 1.31 (s, 3H), 2.61 (dd, J = 5.6, 18.2 Hz, 1H), 2.96 (dd, J = 9.6, 18.4 Hz, 1H), 3.14 (dd, J = 5.6, 9.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 13 7.2 Hz, 2H), 9.50 (s, 1H); C NMR (100 MHz, CDCl 3, TMS): δ 19.6, 20.3, 31.8, 45.0, 48.5, 126.5, 128.7, 129.2, 131.8, 174.8, 176.9, 202.8; IR (KBr, -1 cm ): ν 499, 563, 627, 666, 703, 755, 814, 885, 1164, 1189, 1395, 1454 ,1471, 1490, 1500, 1705, 1773, 2730, 2822, 2932, 2989, 3459; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 25.1 min (major), 31.8 min (minor). 2-(1-(4-Fluorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal 35 1 (6b). H NMR (400 MHz, CDCl3, TMS): δ 1.29 (s, 3H), 1.36(s, 3H), 2.61 (dd, J = 5.6, 18.4 Hz, 1H), 2.98 (dd, J = 9.6, 18.4 Hz, 1H), 3.12 (dd, J = 13 5.6, 9.6 Hz, 1H), 7.16 (m, 2H), 7.27 (m, 2H), 9.49 (s, 1H); C NMR (100 MHz, CDCl3, TMS): δ 19.9, 20.5, 31.9, 44.9, 48.7, 116.2, 127.7, 128.4, -1 163.5, 174.7, 176.9, 202.8; IR (KBr, cm ): ν 468, 532, 669, 760, 841, 1198, 1222, 1392, 1508, 1703, 1728, 1780, 2977, 3081, 3121, 3464; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 24.2 min (major), 41.0 min (minor). 2-(1-(3-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal 35 1 (6c). H NMR (400 MHz, CDCl3, TMS): δ 1.26 (s, 3H), 1.33(s, 3H), 2.60 (dd, J = 5.6, 18.4 Hz, 1H), 2.96 (dd, J = 9.6, 18.4 Hz, 1H), 3.12 (dd, J = 5.6, 9.6 Hz, 1H), 7.21 (d, J = 6.8 Hz, 1H), 7.33-7.42 (m, 3H), 9.48 (s, 13 1H); C NMR (100 MHz, CDCl3, TMS): δ 19.7, 20.4, 31.8, 44.9, 48.6, 124.8, 126.8, 128.8, 130.1, 133.0, 134.5, 174.4, 176.6, 202.8; IR (KBr, cm 1 ): ν 481, 582, 624, 683, 731, 791, 808, 873, 964, 1073, 1155, 1193, 1386, 1430, 1477, 1585, 1705, 1778, 2850, 2919, 2969, 3467; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 22.5 min (major), 27.5 min (minor). 2-(1-(4-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal 35 1 (6d). H NMR (400 MHz, CDCl3, TMS): δ 1.28 (s, 3H), 1.35(s, 3H), 2.61 (dd, J = 5.2, 18.4 Hz, 1H), 2.96 (dd, J = 9.6, 18.4 Hz, 1H), 3.11 (dd, J = 5.6, 9.6 13 Hz, 1H), 7.24 (m, 2H), 7.43 (m, 2H), 9.49 (s, 1H); C NMR (100 MHz, CDCl3, TMS): δ 19.9, 20.5, 32.0, 45.0, 48.7, 127.8, 129.4, 130.3, 134.5, -1 174.5, 176.7, 202.7; IR (KBr, cm ): ν 510, 730, 773, 838, 1090, 1167, 1200, 1398, 1493, 1702, 1720, 1773, 2969, 3456; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 25.2 min (major), 45.9 min (minor). 2-(1-(3-Bromophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal 35 1 (6e). H NMR (400 MHz, CDCl3, TMS): δ 1.29 (s, 3H), 1.36(s, 3H), 2.62 (dd, J = 5.6, 18.4 Hz, 1H), 2.98 (dd, J = 9.6, 18.4 Hz, 1H), 3.11 (dd, J = 5.6, 9.6 Hz, 1H), 7.24-7.27 (m, 1H), 7.32-7.36 (t, J = 8.0 Hz, 1H), 13 7.47-7.48 (t, J = 2.0 Hz, 1H), 7.52-7.55 (m, 1H), 9.49 (s, 1H); C NMR (100 MHz, CDCl3, TMS): δ 19.9, 20.5, 32.0, 45.0, 48.7, 122.5, 125.3, 129.6, 130.4, -1 131.8, 133.0, 174.7, 176.6, 202.7; IR (KBr, cm ): ν 621, 661, 681, 721, 785, 814, 886, 1066, 1180, 1383, 1425, 1475, 1573, 1706, 1778, 2850, 2919, 2963, 3466; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 24.5 min (major), 30.2 min (minor).

THIOUREA CATALYZED ENANTIOSELECTIVE MICHAEL ADDITION

2-(1-(4-Bromophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal 35 1 (6f). H NMR (400 MHz, CDCl3, TMS): δ 1.28 (s, 3H), 1.36 (s, 3H), 2.61 (dd, J = 5.6, 18.0 Hz, 1H), 2.97 (dd, J = 9.6, 18.4 Hz, 1H), 3.11 (dd, J = 5.6, 9.6 Hz, 1H), 7.17-7.21 (m, 2H), 7.58-7.61 (m, 2H), 9.48 (s, 1H); 13 C NMR (100 MHz, CDCl3, TMS): δ 19.9, 20.5, 32.0, 45.0, 48.7, 122.6, -1 128.1, 130.8, 132.4, 174.4, 176.6, 202.7; IR (KBr, cm ): ν 570, 720, 769, 828, 887, 1015, 1067, 1168, 1200, 1399, 1489, 1698, 1719, 1770, 2849, 2922, 2966, 3093, 3450; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 32.4 min (major), 55.3 min (minor). 2-Methyl-2-(1-(3-nitrophenyl)-2,5-dioxopyrrolidin-3-yl)propanal 35 1 (6g). H NMR (400 MHz, CDCl3, TMS): δ 1.32 (s, 3H), 1.42(s, 3H), 2.67 (dd, J = 5.6, 18.4 Hz, 1H), 2.03 (dd, J = 9.6, 18.4 Hz, 1H), 3.13 (dd, J = 5.6, 9.6 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.71 (dt, J = 1.6, 8.0 Hz, 1H), 13 8.25-8.28 (m, 2H), 9.48 (s, 1H); C NMR (100 MHz, CDCl3, TMS): δ 20.3, 20.7, 32.1, 45.0, 49.0, 121.9, 123.3, 129.9, 132.5, 132.9, 148.5, -1 174.0, 176.4, 202.7; IR (KBr, cm ): ν 581, 679, 731, 782, 820, 1193, 1350, 1395, 1481, 1529, 1587, 1712, 1780, 2733, 2833, 2874, 2937, 2970, 3097, 3473; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 31.7 min (major), 38.3 min (minor). 2-Methyl-2-(1-(4-nitrophenyl)-2,5-dioxopyrrolidin-3-yl)propanal 35 1 H NMR (400 MHz, CDCl3, TMS): δ 1.32 (s, 3H), 1.43(s, 3H), (6h). 2.67 (dd, J = 5.6, 18.0 Hz, 1H), 3.02 (dd, J = 9.6, 18.0 Hz, 1H), 3.11 (dd, J = 5.6, 9.6 Hz, 1H), 7.58 (dt, J = 2.4, 9.2 Hz, 2H), 8.34 (dt, J = 1.6, 9.2 Hz, 13 2H), 9.47 (s, 1H); C NMR (100 MHz, CDCl3, TMS): δ 20.4, 20.8, 32.2, 45.0, 49.0, 124.4, 127.1, 137.4, 147.1, 173.9, 176.2, 202.7; IR (KBr, -1 cm ): ν 585, 644, 689, 718, 752, 782, 852, 1171, 1200, 1292, 1347, 1396, 1494, 1524, 1593, 1611, 1709, 1778, 2860, 2968, 3116, 3473; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 50.5 min (major), 64.8min (minor). 35 1

H 2-(2,5-Dioxo-1-(p-tolyl)pyrrolidin-3-yl)-2-methylpropanal (6i). NMR (400 MHz, CDCl3, TMS): δ 1.28 (s, 3H), 1.31(s, 3H), 2.38 (s, 3H), 2.60 (dd, J = 5.2, 18.4 Hz, 1H), 2.96 (dd, J = 9.6, 18.4 Hz, 1H), 3.16 (dd, J = 5.6, 13 9.6 Hz, 1H), 7.14 (m, 2H), 7.26 (m, 2H), 9.52 (s, 1H); C NMR (100 MHz, CDCl3, TMS): δ 19.6, 20.3, 21.2, 31.8, 45.0, 48.5, 126.3, -1 129.1, 129.9, 138.8, 174.9, 177.0, 202.8; IR (KBr, cm ): ν 510, 669, 754, 782, 822, 1167, 1202, 1397, 1512, 1708, 1732, 1779, 2929, 2964, 3465; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 24.9 min (major), 30.3 min (minor). 2-(1-(2,6-Dimethylphenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal 35 1 H NMR (400 MHz, CDCl3, TMS): δ 1.30 (s, 3H), 1.35(s, 3H), 2.08 (6j). (s, 3H), 2.18 (s, 3H), 2.70 (dd, J = 6.4, 18.4 Hz, 1H), 3.01 (dd, J = 9.6, 18.4 Hz, 1H), 3.23 (dd, J = 6.4, 9.6 Hz, 1H), 7.12-7.15 (m, 2H), 7.21-7.26 (m, 13 1H), 9.53 (s, 1H); C NMR (100 MHz, CDCl3, TMS): δ 17.8, 18.0, 19.8, 20.5, 32.0, 45.5, 48.1, 128.5, 128.7, 129.5, 130.2, 135.5, 136.1, -1 174.5, 176.6, 202.7; IR (KBr, cm ): ν 492, 665, 724, 746, 784, 864, 909, 1028, 1070, 1193, 1284, 1381, 1474, 1704, 1732, 1780, 2710, 2809, 2926, 2979, 3469; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 20.0 min (major), 26.8 min (minor). 2-(1-(2-Methoxyphenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal 35 1 (6k). H NMR (400 MHz, CDCl3, TMS): δ 1.28 (s, 3H), 1.30(s, 3H), 2.60 (dd, J = 5.6, 18.4 Hz, 1H), 2.98 (dd, J = 8.0, 18.0 Hz, 1H), 3.21 (dd, J = 5.2, 9.6 Hz, 1H), 3.78 (s, 3H), 6.99-7.05 (m, 2H), 7.12 (q, J = 8.0 Hz, 13 1H), 7.39 (t, J = 8.0 Hz, 1H), 9.59 (s, 1H); C NMR (100 MHz, CDCl3, TMS): δ 19.5, 20.3, 31.6, 45.2, 48.1, 55.7, 112.1, 120.6, 120.9, 129.1, 130.9, -1 154.6, 174.8, 176.7, 202.9; IR (KBr, cm ): ν 472, 567, 623, 669, 756, 865, 1023, 1044, 1114, 1191, 1254, 1284, 1303, 1389, 1465, 1505, 1601, 1709, 1781, 2847, 2930, 2975, 3475; HPLC: AE.LICHROM-AM2-5 (Hexanes/i-

123

PrOH = 80/20, flow rate = 0.6 mL/min, λ = 220 nm): tR = 59.8 min (major), 74.2 min (minor). 35 1

H 2-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal (6l). NMR (400 MHz, CDCl3, TMS): δ 1.15 (d, 6H), 2.45 (dd, J = 5.6, 18.4 Hz, 1H), 2.81 (dd, J = 9.2, 18.4 Hz, 1H), 3.03 (dd, J = 5.6, 9.2 Hz, 1H), 7.24-7.37 13 (m, 5H), 9.48 (s, 1H); C NMR (100 MHz, CDCl3, TMS): δ 19.0, 21.0, 31.4, 42.4, 44.9, 48.0, 128.0, 128.6, 128.7, 135.7, 175.4, 177.5, 202.7; IR -1 (KBr, cm ): ν 668, 708, 895, 1084, 1171, 1345, 1400, 1431, 1456, 1497, 1701, 1729, 1774, 2932, 2968, 3446; HPLC: Chiralpak AD-H (Hexanes/i-PrOH = 80/20, flow rate = 0.6 mL/min, λ = 220 nm): tR = 13.2 min (major), 28.1 min (minor). 1-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)cyclohexanecarbaldehyde 35 1 (7a). H NMR (CDCl 3, 400 MHz) δ 1.54-1.63 (m, 7H), 1.85 (d, J=8.8 Hz, 1H), 1.96 (s, 2H), 2.64-2.68 (m, 1H), 2.86 (dd, J=9.6, 16.0 Hz, 1H), 3.21 (m, 1H), 7.27-7.29 (m, 2H), 7.39-7.48 (m, 3H), 9.53 (s, 13 1H); C NMR (100 MHz, CDCl 3, TMS) δ 21.2, 21.4, 25.1, 28.1, 28.6, 31.6, 42.7, 52.2, 126.6, 128.7, 129.2, 131.9, 174.8, 177.1, 204.6; IR -1 (KBr, cm ): ν 627, 658, 699, 762, 1159, 1186, 1214, 1397, 1499, 1705, 1772, 2857, 2933, 3447; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 30.2 min (major), 38.9 min (minor). 1-(1-(4-Fluorophenyl)-2,5-dioxopyrrolidin-3-yl)cyclohexanecarbaldehyde 35 1 (7b). H NMR (CDCl3, 400 MHz) δ 1.54-1.68 (m, 7H), 1.83-1.86 (m, 1H), 1.90-1.97 (m, 2H), 2.01-2.08 (m, 1H), 2.66 (dd, J = 6.0, 18.0 Hz, 1H), 2.87 (dd, J = 9.6, 18.0 Hz, 1H), 3.22 (dd, J = 6.0, 9.6 Hz, 1H), 7.12-7.18 (m, 2H), 7.25-7.31 13 (m, 2H), 9.51 (s, 1H); C NMR (100 MHz, CDCl3, TMS) δ 21.1, 21.3, 25.1, 28.2, 28.5, 31.6, 42.2, 52.4, 116.1, 116.3, 127.8, 127.9, 128.5, 174.7, 177.1, 204.5; IR -1 (KBr, cm ): ν 528, 594, 654, 754, 772, 843, 878, 948, 1095, 1181, 1220, 1296, 1394, 1449, 1511, 1600, 1704, 1775, 2854, 2945, 3076, 3465; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 33.7 min (major), 58.2 min (minor). 1-(2,5-Dioxo-1-(p-tolyl)pyrrolidin-3-yl)cyclohexanecarbaldehyde 35 1 (7i). H NMR (CDCl3, 400 MHz) δ 1.49-1.63 (m, 7H), 1.83-1.89 (m, 1H), 1.94-1.95 (m, 2H), 2.37 (s, 3H), 2.66 (dd, J = 6.0, 18.4 Hz, 1H), 2.86 (dd, J = 9.6, 18.0 Hz, 1H), 3.20 (dd, J = 6.0, 9.6 Hz, 1H), 7.12-7.16 (m, 2H), 13 7.25-7.27 (m, 2H), 9.55 (s, 1H); C NMR (100 MHz, CDCl3, TMS) δ 21.2, 21.3, 21.5, 25.1, 28.1, 28.7, 31.5, 52.1, 126.3, 126.4, 129.2, 129.8, -1 138.7, 175.0, 177.1, 204.6; IR (KBr, cm ): ν 510, 671, 744, 818, 934, 1103, 1204, 1397, 1447, 1512, 1708, 1773, 2860, 2930, 3455; HPLC: Chiralcel OD-H (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 31.9 min (major), 36.7 min (minor). 1-(1-(2-Methoxyphenyl)-2,5-dioxo-pyrrolidin-3-yl)cyclohexane35 1 carbaldehyde (7k). H NMR (CDCl3, 400 MHz) δ 1.45-1.70 (m, 7H), 1.85-2.01 (m, 3H), 2.66 (dd, J = 5.6, 18.0 Hz, 1H), 2.85 (dd, J = 9.6, 18.0 Hz, 1H), 3.18 (dd, J = 5.6, 9.2 Hz, 1H), 3.78 (s, 3H), 6.99-7.05 (m, 2H), 13 7.13 (dd, J = 8.0, 29.6 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 9.55 (s, 1H); C NMR (100 MHz, CDCl3, TMS) δ 21.3, 22.3, 25.2, 28.1, 28.6, 29.7, 31.7, 52.0, 55.8, 112.0, 120.6, 120.9, 129.1, 130.8, 154.6, 174.8, 176.3, 204.7; IR -1 (KBr, cm ): ν 471, 623, 675, 755, 1020, 1195, 1256, 1286, 1394, 1461, 1509, 1602, 1704, 1775, 2853, 2927, 3402; HPLC: AE.LICHROM-AM2-5 (Hexanes/i-PrOH = 75/25, flow rate = 0.6 mL/min, λ = 220 nm): tR = 58.4 min (major), 79.3 min (minor). 1-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)cyclohexanecarbaldehyde 35 1 (7l). H NMR (CDCl 3, 400 MHz) δ 1.38-1.53 (m, 7H), 1.73-1.76 (m, 2H), 1.87-1.92 (m, 1H), 2.50 (dd, J = 5.6, 18.0 Hz, 1H), 2.68 (dd, J = 9.2, 18.0 Hz, 1H), 3.03 (dd, J = 6.0, 8.8 Hz, 1H), 4.62 (dd, J = 14.4, 13 24.0 Hz, 2H), 7.24-7.36 (m, 5H), 9.49 (s, 1H); C NMR (100 MHz, CDCl 3 , TMS) δ 21.3, 21.5, 25.0, 27.7, 28.7, 31.1, 42.3, 51.4, 127.8, -1 128.5, 135.7, 175.4, 177.5, 204.6; IR (KBr, cm ): ν 706, 927, 1083, Chirality DOI 10.1002/chir

124

SONG ET AL.

1169, 1343, 1399, 1431, 1454, 1697, 1773, 2854, 2934, 3450; HPLC: Chiralpak AD-H (Hexanes/i-PrOH = 80/20, flow rate = 0.6 mL/min, λ = 220 nm): t R = 14.1 min (major), 22.6 min (minor). 35

1

H NMR 2-(2,5-dioxo-1-phenylpyrrolidin-3-yl)hexanal (8a). (400 MHz, CDCl3, TMS): δ 1.30 (t, J = 5.6 Hz, 3H), 1.26-1.34 (m, 4H), 1.60-1.66 (m, 2H), 2.63 (dd, J = 5.6, 18.4 Hz, 1H), 2.99 (dd, J = 9.6, 18.4 Hz, 1H), 3.16 (dd, J = 5.6, 9.6 Hz, 1H), 3.34 (dd, J = 8.8, 18.4 Hz, 1H), 13 7.27-7.33 (m, 2H), 7.38-7.51 (m, 3H), 9.52 (s, 1H); C NMR (100 MHz, CDCl3, TMS): δ 14.1, 22.7, 29.3, 29.7, 31.9, 37.1, 48.6, 126.4, 126.5, -1 128.8, 129.0, 129.2, 129.3, 172.2, 174.8, 202.7; IR (KBr, cm ): ν 753, 1199, 1229, 1379, 1401, 1459, 1501, 1719, 1746, 2853, 2923, 2956, 3489; HPLC: Chiralpak AD-H (Hexanes/i-PrOH = 80/20, flow rate = 0.5 mL/min, λ = 210 nm): major diastereomer: tR = 31.6 min (minor), 47.0 min (major); minor diastereomer: tR = 38.6 min (major), 45.1 min (minor).

General Procedure for Large-Scale Michael Addition Isobutyraldehyde (4a, 0.2 mol) was added to a mixture of catalyst 3 (1 mol%) and corresponding maleimide 5 (0.1 mol) in toluene (250 mL). The reaction mixture was stirred at ambient temperature for 12 h. After maleimide was consumed by TLC analysis, the solvent was removed under reduced pressure and the crude product was purified using column chromatography eluting with ethyl acetate/petroleum ether. The ee of the products was determined by chiral HPLC analysis using Chiral columns.

TABLE 1. Solvent optimization

a

RESULTS AND DISCUSSION

With the novel diterpene-derived bifunctional thioureas 3a and 3b in hand, we investigated the catalytic activities for asymmetric Michael addition with isobutyraldehyde 4a as the donor aldehyde and N-phenylmaleimide 5a as the acceptor substrate in chloroform at ambient temperature using thiourea 3a as an organocatalyst (Table 1, entry 1). The results indicated that the thiourea 3a can efficiently catalyze this transformation with 82% yield and 87% ee (Scheme 1). We then simply examined the effects of other solvents on the reaction. Aprotic solvents such as toluene, 1,2-dichloroethane, THF, and CHCl3 gave high to excellent yields (81–97%) and enantioselectivities (82–95%, Table 1, entries 1–4). Changing the solvent to protic solvent such as CH3OH, both the yield and enantioselectivity were remarkably decreased (Table 1, entry 5). In addition, the use of H2O only gave the adduct moderate enantioselectivity (Table 1, entry 6). This was probably due to the disbenefit of hydrogen bonding interactions between substrates and the protic solvents, which disturbed the efficient aggregation surrounding the thiourea catalyst. Having confirmed toluene as the optimum solvent for the reaction, other factors were thoroughly investigated. Adjusting the reaction temperature demonstrated a slight influence on the yield and the enantioselectivity of the reaction. Reducing the catalyst loading from 15 mol% to 1 mol% did not affect the yield but the enantioselectivity increased obviously (Table 2, entries 1–4) , while almost perfect stereocontrol was realized by employing 1 mol% (Table 2, entry 4). When the catalyst was further lowered TABLE 2. Screening of the catalyst loading

Entry 1 2 3 4 5 6 7 8

b

c

Solvent

Yield (%)

ee (%)

CHCl3 THF 1,2-Dichloroethane Toluene CH3OH H2O Ethyl acetate Acetonitrile

82 81 95 97 45 74 80 68

87 82 91 95 12 42 84 51

a

Experimental conditions (unless stated otherwise): Isobutyraldehyde (4a, 0.40 mmol), N-phenylmaleimide (5a, 0.20 mmol), and 10 mol% catalyst 3a in 1.0 mL solvent at ambient temperature. b Isolated yield. c Determined by chiral HPLC analysis.

Entry 1 2 3 4 5

b

c

X (mol%)

Time (h)

Yield (%)

ee (%)

15 10 5 1 0.5

1 2 3 10 48

98 97 96 95 83

92 95 97 99 99

a

Experimental conditions (unless stated otherwise): Isobutyraldehyde (4a, 0.40 mmol), N-phenylmaleimide (5a, 0.20 mmol), X mol% catalyst 3a in 1.0 mL toluene at ambient temperature. b Isolated yield. c Determined by chiral HPLC analysis.

Scheme 1. Synthetic routes of thioureas 3. Chirality DOI 10.1002/chir

a

125

THIOUREA CATALYZED ENANTIOSELECTIVE MICHAEL ADDITION

TABLE 3. Substrate studies

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

a

b

c

R

Cat

Product

Yield (%)

ee (%)

C6H5(5a) 4-F-C6H4(5b) 3-Cl-C6H4(5c) 4-Cl-C6H4(5d) 3-Br-C6H4(5e) 4-Br-C6H4(5f) 3-NO2-C6H4 (5g) 4-NO2-C6H4 (5h) 4-CH3-C6H4 (5i) 2,6-(CH3)2C6H3(5j) 2-CH3O-C6H4 (6k) Bn(5l) H(5m)

3a/3b 3a/3b 3a/3b 3a/3b 3a/3b 3a/3b 3a/3b

6a/6a’ 6b/6b’ 6c/6c’ 6d/6d’ 6e/6e’ 6f/6f’ 6g/6g’

95/96 93/95 85/86 70/75 70/72 86/84 62/62

99/99 94/98 98/97 97/98 99/98 97/99 98/94

3a/3b

6h/6h

70/71

92/98

3a/3b

6i/6i’

95/96

99/99

3a/3b

6j/6j’

78/58

97/93

3a/3b

6k/6k’

93/92

99/99

3a/3b 3a/3b

6l/6l’ -/-

94/95 trace/ trace

91/98 d -/-

a

Experimental conditions (unless stated otherwise): Aldehyde (4a, 0.40 mmol), maleimide (5, 0.20 mmol), 1mol% catalyst 3a in 1.0 mL toluene at ambient temperature for 10–72 h. b Isolated yield. c Determined by chiral HPLC analysis. d Not determined.

to 0.5 mol%, the yield was slightly lower, but the reaction time was prolonged to 48 h. Thus, the optimized catalyst loading was chosen as 1 mol% (Table 2, entry 5). To investigate the scope of this reaction, a wide range of maleimides bearing different N-substituents was subjected to the new diterpene-derived bifunctional thiourea-catalyzed Michael reaction under the optimized conditions. The results are collected in Table 3. As shown in Table 3, the reaction has a broad substrate scope with respect to the maleimides. The yield varied as the substituent on the N-phenly moiety of the maleimides, but the enantioselectivity was to some degree independent of the substituent. All the maleimides gave the desired Michael adducts in good to high yields (62–96%) and excellent enantioselectivities (92–99%) regardless of the electronic and sterical properties of the substituents (Table 3, entries 1–11). For the N-alkyl substituted maleimide 5l, the conjugate addition also produced excellent both in terms of yield and enantioselectivity (Table 3, entry 12). In the case of maleimide 5m, only a trace amount of the product was obtained; both thiourea 3a and 3b were inefficient (Table 3, entry 13). This is probably due to the influence of the H-bonding interaction by the active N-H of maleimide 5m. To further demonstrate the scope of this organocatalytic Michael reaction, cyclohexanecarboxaldehyde 4b was also evaluated for the reaction with various maleimides (Table 4, entries 1–5). These reactions proceeded smoothly and the corresponding Michael adducts were obtained with high yields (79–90%) and enantioselectivities (92–99%). When n-hexalaldehyde 4c was used as a donor, two stereogenic carbon centers were formed in this reaction with good yield and ee values (Table 4, entries 6, 7). We further performed large-scale asymmetric Michael reactions with 100 mmol of N-phenylmaleimide 5a and 2 equiv. of isobutyraldehyde 4a (Scheme 2). The same catalyst loading of 1 mol% as in the experimental scale was used. Using the same procedure, both the yield and enantioselectivity were maintained at the same level for large-scale reactions, which offers a great possibility for application in industry.

TABLE 4. Substrate studies

Entry 1 2 3 4 5 6 7

R1

R2

-CH2(CH2)3CH2- (4b) -CH2(CH2)3CH2- (4b) -CH2(CH2)3CH2- (4b) -CH2(CH2)3CH2- (4b) -CH2(CH2)3CH2- (4b) H n-C4H10(4c) H n-C4H10(4c)

a

b

c

d

R

Cat

Product

Yield (%)

dr

ee (%)

C6H5(5a) 4-F-C6H4(5b) 4-CH3-C6H4(5i) 2-CH3O-C6H4(5k) Bn(5l) C6H5(5a) C6H5(5a)

3a/3b 3a/3b 3a/3b 3a/3b 3a/3b 3a 3b

7a/7a’ 7b/7b’ 7i/7i’ 7k/7k’ 7l/7l’ 8a 8a’

85/90 87/86 79/87 79/83 87/79 84 75

— — — — — 2.2/1 2.7/1

95/99 92/99 98/99 98/99 99/95 85/60 90/99

a

Experimental conditions (unless stated otherwise): Aldehyde (4b-4c, 0.40 mmol), maleimide (5, 0.20 mmol) and 1mol% catalyst 3 in 1.0 mL toluene at ambient temperature for 6–36 h. Isolated yield. 1 c Determined by H NMR analysis. d Determined by chiral HPLC analysis. b

Chirality DOI 10.1002/chir

126

SONG ET AL.

Scheme 2. Large-scale asymmetric Michael addition.

The fact that the conversion of the configuration of 1,2diaminocyclohexane moiety from (R,R) to (S,S) exhibited an opposite sense of asymmetric induction indicates that the stereochemical control of the reaction is mainly provided by the 1,2-diaminocyclohexane moiety of thiourea. It also suggests that the catalytic activities of the isosteviol-derived thioureas depend not only on the remaining chiral scaffold moiety of thiourea, but also on the suitable matching of the configuration of the 1,2-diaminocyclohexane moiety with the remaining chiral scaffold moiety. The (R,R) configuration of 1,2-diaminocyclohexane moiety or the (S,S) configuration can well match the isosteviol scaffold of 3 due to its excellent structural backbone and well-defined stereocenters, resulting in excellent enantioselectivities. It was realized that the two chiral moieties of thiourea are mutually reinforcing for the high efficacy of catalyst, and the thiourea bridged isosteviolprimary amines were found to be ideal catalysts for the doubly stereocontrolled organocatalytic process. In addition, the results obtained by using the novel C4-derived iosteviolthiourea are even better than that of the C16-derivative, indicating that the conjugation of the thiourea moiety with the chiral backbone of isosteviol on C4 position is more suitable for matching of the thiourea moiety with the remaining chiral scaffold moiety. CONCLUSIONS

In summary, we have demonstrated the performance of novel diterpene-derived bifunctional thiourea catalysts and the excellence of the structural backbone of isosteviol, which has been successfully applied to the doubly stereocontrolled Michael addition of aldehydes to maleimides for the synthesis of substituted succinimides. With only 1 mol% catalyst loading, both enantiomers can be obtained individually in high to excellent yield (up to 98%) and enantioselectivity (up to 99%) when a special chiral diterpene-derived bifunctional thiourea was used as catalyst. Furthermore, this novel catalytic system can be efficiently used in large-scale reactions, with the enantioselectivity being maintained at the same level, which offers a great possibility for application in industry. ACKNOWLEDGMENTS

Contract grant sponsor: National Natural Science Foundation of China; Contract grant numbers: 20772113. Contract grant sponsor: Doctoral Foundation of Xinxiang Medical University. LITERATURE CITED 1. Crider AM, Kolczynski TM, Yates KM. Synthesis and anticancer activity of nitrosourea derivatives of phensuximide. J Med Chem 1980;23:324–326. Chirality DOI 10.1002/chir

2. Fredenhagen A, Tamura SY, Kenny PTM, Komura H, Naya Y, Nakanishi K, Nishiyama K, Sugiura M, Kita H. Andrimid, a new peptide antibiotic produced by an intracellular bacterial symbiont isolated from a brown planthopper. J Am Chem Soc 1987;109:4409–4411. 3. Freiberg C, Brunner NA, Schiffer G, Lampe T, Pohlmann M, Habich D, Ziegelbauer K. Identification and characterization of the first class of potent bacterial acetyl-coa carboxylase inhibitors with antibacterial activity. J Biol Chem 2004;279:26066–26073. 4. Freiberg C, Fischer HP Brunner NA. Discovering the mechanism of action of novel antibacterial agents through transcriptional profiling of conditional mutants. Antimicrob Agents Chemother 2005;49:749–759. 5. Uddin J, Ueda K, Siwu ERO, Kita M, Uemura D. Cytotoxic labdane alkaloids from an ascidian Lissoclinum sp.: Isolation, structure elucidation, and structure-activity relationship. Bioorg Med Chem 2006;14:6954–6961. 6. Chauhan P, Kaur J, Chimni SS. Asymmetric organocatalytic addition reactions of maleimides: a promising approach towards the synthesis of chiral succinimide derivatives. Chem Asian J 2013;8:328–346. 7. Bosco M, Carlone A, Cavalli A, Locatelli M, Mazzanti A, Ricci P, Sambri L, Melchiorre P. Organocatalytic asymmetric conjugate addition of 1,3dicarbonyl compounds to maleimides. Angew Chem Int Ed 2006;45:4966–4970. 8. Ye W, Jiang Z, Zhao Y, Goh SLM, Leow D, Soh YT, Tan C-H. Chiral bicyclic guanidine as a versatile Brønsted base catalyst for the enantioselective Michael reactions of dithiomalonates and β-keto thioesters. Adv Synth Catal 2007;349:2454–2458. 9. Jiang Z, Ye W, Yang Y, Tan C-H. Rate Acceleration of triethylaminemediated guanidine-catalyzed enantioselective Michael reaction. Adv Synth Catal 2008;350:2345–2351. 10. Jiang Z, Pan Y, Zhao Y, Ma T, Lee R, Yang Y, Huang K-W, Wong MW, Tan C-H. Synthesis of a chiral quaternary carbon center bearing a fluorine atom: enantio- and diastereoselective guanidine-catalyzed addition of fluorocarbon nucleophiles. Angew Chem Int Ed 2009;48:3627–3631. 11. Bai J-F, Peng L, Wang L-L, Wang L-X, Xu X-Y. Chiral primary amine thiourea promoted highly enantioselective Michael reactions of isobutylaldehyde with maleimides. Tetrahedron 2010;66:8928–8932. 12. Miura T, Nishida S, Masuda A, Tada N, Itoh A. Asymmetric Michael additions of aldehydes to maleimides using a recyclable fluorous thiourea organocatalyst. Tetrahedron Lett 2011;52:4158–4160 13. Deng H-P, Wang D, Wei Y, Shi M. Chiral multifunctional thioureaphosphine catalyzed asymmetric [3+2] annulation of Morita-Baylis-Hillman carbonates with maleimides. Beilstein J Org Chem 2012;8:1098–1104. 14. Mazzanti A, Calbet T, Font-Bardia M, Moyano A, Rios R. Organocatalytic enantioselective pyrazol-3-one addition to maleimides: Reactivity and stereochemical course. Org Biomol Chem 2012;10:1645–1652. 15. Kokotos CG. An asymmetric Michael addition of α,α-disubstituted aldehydes to maleimides leading to a one-pot enantioselective synthesis of lactones catalyzed by amino acids. Org Lett 2013;15:2406–2409. 16. Avila A, Chinchilla R, Gόmez-Bengoa E, Nájera C. Enantioselective synthesis of succinimides by Michael addition of aldehydes to maleimides organocatalyzed by chiral primary amine-guanidines. Eur J Org Chem 2013;23:5085–5092. 17. Berner OM, Tedeschi L, Enders D. Asymmetric Michael additions to nitroalkenes. Eur J Org Chem 2002;12:1877–1895. 18. Christoffers J, Baro A. Construction of quaternary stereocenters: new perspectives through enantioselective Michael reactions. Angew Chem Int Ed 2003;42:1688–1690. 19. Tsogoeva SB. Recent advances in asymmetric organocatalytic 1,4conjugate additions. Eur J Org Chem 2007;72:1701–1716. 20. Sulzer-Mosse S, Alexakis A. Chiral amines as organocatalysts for asymmetric conjugate addition to nitroolefins and vinyl sulfones via enamine activation. Chem Commun 2007;43:3123–3135. 21. Burke MD, Schreiber SL. A planning strategy for diversity-oriented synthesis. Angew Chem Int Ed 2004;43:46–58. 22. Zanoni G, Castronovo F, Franzini M, Vidari G, Giannini E. Toggling enantioselective catalysis—a promising paradigm in the development of more efficient and versatile enantioselective synthetic methodologies. Chem Soc Rev 2003;32:115–129. 23. Jiang X-X, Zhang Y-F, Chan ASC, Wang R. Highly enantioselective synthesis of γ-nitro heteroaromatic ketones in a doubly stereocontrolled manner catalyzed by bifunctional thiourea catalysts based on dehydroabietic

THIOUREA CATALYZED ENANTIOSELECTIVE MICHAEL ADDITION

24.

25.

26.

27. 28. 29. 30. 31.

amine: A doubly stereocontrolled approach to pyrrolidine carboxylic acids. Org Lett 2009;11:153–156. Chen J-R, Cao Y-J, Zou Y-Q, Tan F, Fu L, Zhu X-Y, Xiao W-J. Novel thiourea-amine bifunctional catalysts for asymmetric conjugate addition of ketones/aldehydes to nitroalkenes: Rational structural combination for high catalytic efficiency. Org Biomol Chem 2010;8:1275–1279. Chen J-R, Zou Y-Q, Fu L, Ren F, Tan F, Xiao W-J. Highly enantioselective Michael addition of aldehydes to nitroolefins catalyzed by primary amine thiourea organocatalysts. Tetrahedron 2010;66:5367–5372. Durmaz M, Sirit A. Calixarene-based highly efficient primary aminethiourea organocatalysts for asymmetric Michael addition of aldehydes to nitrostyrenes. Supramol Chem 2013;25:292–301. Taylor MS, Jacobsen EN. Asymmetric catalysis by chiral hydrogen-bond donors. Angew Chem Int Ed 2006;45:1520–1543. Doyle AG, Jacobsen EN. Small-molecule H-bond donors in asymmetric catalysis. Chem Rev 2007;107:5713–5743. Connon SJ. Asymmetric catalysis with bifunctional cinchona alkaloid-based urea and thiourea organocatalysts. Chem Commun 2008;22:2499–2510. Zhang Z-G, Schreiner PR. (Thio)urea organocatalysis-What can be learnt from anion recognition. Chem Soc Rev 2009;38:1187–1198. An Y-J, Zhang Y-X, Wu Y, Liu Z-M, Pi C, Tao J-C. Simple amphiphilic isosteviol-proline conjugates as chiral catalysts for the direct asymmetric

32.

33.

34.

35.

36.

37.

127

aldol reaction in the presence of water. Tetrahedron Asymmetry 2010;21:688–694. An Y-J, Wang C-C, Xu Y-Z, Wang W-J, Tao J-C. Highly enantioselective α-aminoxylation reactions catalyzed by isosteviol-proline conjugates in buffered aqueous media. Catal Lett 2011;141:1123–1129. An Y-J, Qin Q, Wang C-C, Tao J-C. Isosteviol-amino Acid Conjugates as Highly efficient organocatalysts for the asymmetric one-pot threecomponent Mannich reactions. Chin J Chem 2011;29:1511–1517. Ma Z-W, Liu Y-X, Zhang W-J, Tao Y, Zhu Y, Tao J-C, Tang M-S. Highly enantioselective Michael additions of isobutyraldehyde to nitroalkenes promoted by amphiphilic bifunctional primary amine-thioureas in organic or aqueous medium. Eur J Org Chem 2011;33:6747–6754. Ma Z-W, Liu Y-X, Li P-L, Ren H, Zhu Y, Tao J-C. A highly efficient largescale asymmetric Michael addition of isobutyraldehyde to maleimides promoted by a novel multifunctional thiourea. Tetrahedron Asymmetry 2011;22:1740–1748. Ma Z-W, Liu Y-X, Huo L-J, Gao X, Tao J-C. Doubly stereocontrolled asymmetric Michael addition of acetylacetone to nitroolefins promoted by an isosteviol-derived bifunctional thiourea. Tetrahedron Asymmetry 2012;23:443–448. Ma Z-W, Wu Y, Sun B, Du H-L, Shi W-M, Tao J-C. Thiourea-catalyzed asymmetric conjugate addition of α-substituted cyanoacetates to maleimides. Tetrahedron Asymmetry 2013;24:7–13.

Chirality DOI 10.1002/chir