CHIRALITY 26:801–805 (2014)
Direct Asymmetric anti-Mannich-Type Reactions Catalyzed by Cinchona Alkaloid Derivatives YING JIN,1 DI CHEN,2 AND XIU RONG ZHANG1* Department of Pharmacy, Jilin Medical College, Jilin, China 2 Department of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China 1
ABSTRACT A series of cinchona alkaloid derivatives were used to catalyze the asymmetric antiMannich-type reaction of 3-methyl-2-oxindole with N-tosyl aryl aldimines. The resulting anti-3, 3-disubstituted 2-oxindole products were obtained in good yields (up to 92%) with high diastereoand enantioselectivities (anti/syn up to 97:3 and 91% ee). Chirality 26:801–805, 2014. © 2014 Wiley Periodicals, Inc.
KEY WORDS: cinchona alkaloid derivatives; asymmetric; anti-Mannich reaction; anti-3,3disubstituted 2-oxindole INTRODUCTION
The direct Mannich-type reaction is a highly effective carbon–carbon bond-forming method that is especially useful for the preparation of β-amino carbonyl derivatives.1–4 During the course of the last two decades, significant research efforts have been devoted to the development of highly stereoselective (i.e., diastereo- and enantioselective) Mannich reactions because of the importance of the asymmetric Mannich products in organic synthesis. Although syn-selective catalytic asymmetric Mannich reactions have been well established,5–16 methods for the stereoselective anti-Mannich reactions are relatively scarce,17–24 and there is therefore an urgent need for the development of effective stereoselective anti-Mannich catalysts to overcome the challenges of asymmetric synthesis (Scheme 1). Compounds possessing the C3-quaternary oxindole structure have been found in a number of natural and pharmaceutical molecules,25–27 and have frequently been used as synthetic intermediates for the construction of indole alkaloids.28–31 A variety of different stereoselective strategies and methodologies have been applied to the synthesis of optically active 3,3-disubstituted oxindoles,32–35 and the application of prochiral 3-substititued oxindoles as nucleophiles represents a particularly straightforward approach to the introduction of a C3-quaternary center. In 2009, Cheng et al.36 reported the development of a stereoselective method for the synthesis 3,3-disubstituted 2-oxindoles with high levels of diastereo- (anti/syn up to 95:5) and enantioselectivity (up to 89% ee) via the organocatalytic anti-Mannich-type reaction of N-unprotected 3-substituted 2-oxindoles with aromatic N-tosyl-aldimines in the presence of a cinchona alkaloid catalyst. Herein, we report the results of our recent study involving the use of a series of cinchona alkaloid derivatives (1a–g, Fig. 1) to effect the same transformation. The cinchona alkaloid derivatives investigated in the current study were prepared by making modifications to the 9-OH, 6′-OH and terminal vinyl groups of quinine and quinidine. Pleasingly, with a catalyst loading in the range of 3–5 mol%, the quinidine derivative 1c bearing a 6′-hydroxy-quinoline ring and tertbutyldiphenylsilyl group (TBDPS) at its C9 position induced the anti-Mannich reaction of 3-methyl-2-oxindole with aromatic N-tosyl-aldimine to give the anti (R,R)-products with high levels of stereoselectivity (anti/syn up to 97:3 and 91% enantiomeric excess [ee]). © 2014 Wiley Periodicals, Inc.
EXPERIMENTAL SECTION Instruments and Materials 1
H NMR spectra were recorded on 500 MHz spectrometer using CDCl3 as a solvent. The chemical shifts are reported in ppm with the residual CHCl3 signal being used as a reference (7.26 ppm). The splitting patterns of the signals were reported as s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; m, multiplet; and bs, broad signal. The 13 C NMR spectra were recorded on a 125 MHz instrument using CDCl3 as a solvent. The chemical shifts are reported in ppm with the residual CHCl3 signal being used as a reference (77.0 ppm). High-resolution mass spectra (HRMS) were measured on a mass spectrometer equipped with an electrospray ionization (ESI) source in the positive-ion mode. The ee values of the products were determined by chiral high-performance liquid chromatography (HPLC) using Daicel Chiralpak AD-H and Chiralcel OD-H columns. The melting points are uncorrected. The reactions were monitored by thin layer chromatography (TLC). Purifications by column chromatography were conducted over silica gel (200–300 mesh). The aromatic imines were prepared according to literature procedures.36,37 Catalysts 1a–g were synthesized according to literature procedures.38
General Procedure for Asymmetric Mannich Reaction Catalyst 1c (0.01 mmol) was added to a mixture of 3-methyl-2-oxindole (30 mg, 0.2 mmol) and the corresponding imine (0.2 mmol) in toluene (1.0 mL) at 0°C, and the resulting mixture was stirred for 36 h at 0°C for a period of time. The crude mixture was then loaded directly onto a column packed with silica gel and eluted with a mixture of hexane/EtOAc (7:1 – v/v) to give the desired product 3a–l as waxy oil. (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-phenyl-methyl]-3-methyl1 indolin-2-one 3a: H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 7.5 Hz, 1H), 7.28-7.18 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 7.03-6.98 (m, 3H), 6.87 (t, J = 8.0 Hz, 2H), 6.68 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 7.5 Hz, 2H), 5.53 (d, J = 9.0 Hz, 1H), 4.46 (d, J = 9.0 Hz, 1H), 2.29 (s, 3H), 1.62 (s, 3H); HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 0.8 mL/min, 235 nm), tR: 34.2 min (anti, minor), 55.6 min (syn, minor), 85.4 min (syn, major), 90.2 min (anti, major).
Contract grant sponsor: National Natural Science Foundation of China; Contract grant number: 21102055. Contract grant sponsor: Natural Science Foundation of Jilin province; Contract grant number: 201015237. *Correspondence to: X. Zhang, Department of Pharmacy, Jilin Medical College, Jilin 132013, China. E-mail: [email protected] Received for publication 26 April 2014; Accepted 13 June 2014 DOI: 10.1002/chir.22358 Published online 18 July 2014 in Wiley Online Library (wileyonlinelibrary.com).
802
JIN ET AL.
Scheme 1. Stereoselective anti-Mannich reactions.
(R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(2-methyl-phenyl) methyl]1 3-methyl-indolin-2-one 3b: H NMR (500 MHz, CDCl3) δ 7.61-7.54 (m, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.27-7.23 (m, 1H), 7.09-7.03 (m, 2H), 7.02 (d, J = 8.0 Hz, 2H), 6.99-6.95 (m, 1H), 6.83 (d, J = 7.0 Hz, 1H), 6.75 (d, J = 7.5 Hz, 2H), 6.41 (d, J = 8.0 Hz, 1H), 5.76 (d, J = 7.0 Hz, 1H), 4.80 (d, J = 7.5 Hz, 1H), 2.31 13 (s, 3H), 1.89 (s, 3H), 1.58 (s, 3H); C NMR (125 MHz, CDCl3) δ 180.0, 143.5, 143.0, 140.3, 139.0, 136.6, 134.8, 130.6, 129.9, 129.0(×2), 128.7, 127.5, 127.0(×2), 125.3, 124.5, 122.6, 109.7, 56.5, 52.2, 21.4, 19.8, 19.4; HRMS (ESI +): m/z calcd. for C24H25N2O3S [M+H]: 421.1586, found: 421.1580. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 0.8 mL/min, 235 nm), tR: 26.4 min (anti, minor), 35.6 min (anti, minor). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(2-fluorophenyl) methyl]1 3-methyl- indolin-2-one 3c: H NMR (500 MHz, CDCl3) δ 8.22 (s, 1H), 7.47 (d, J = 8.0 Hz, 3H), 7.35 (d, J = 7.5 Hz, 1H), 7.11-7.04 (m, 2H), 6.99 (d, J =8.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 2H), 6.85-6.81 (m, 3H), 6.64 (d, J = 7.5 13 Hz, 1H), 5.51 (d, J = 9.5 Hz,1H), 2.24 (s, 3H), 1.65 (s, 3H); C NMR (125 MHz, CDCl3) δ 181.0, 143.0, 140.1, 137.3, 136.1, 130.4, 129.3, 129.0, 128.8 (×2), 128.3, 127.6, 126.6 (×2), 124.2, 123.5, 122.4, 114.4, 109.6, 54.9, 51.7, 21.2, 20.3. (ESI+): m/z calcd. for C23H22FN2O3S [M+H]: 425.1335, found: 425.1339. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 0-30 min: 1 ml/min, after 30min: 0.8 ml/min, 235 nm), tR: 36.9 min (anti, minor), 44.3 min (syn, major), 50.0 min (syn, minor), 70.9 min (anti, major). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(2-chloro- phenyl) methyl]1 3-methyl- indolin-2-one 3d: H NMR (500 MHz, CDCl3) δ 8.22 (s, 1H), 7.47 (d, J = 8.0 Hz, 3H), 7.35 (d, J = 7.5 Hz, 1H), 7.11-7.04 (m, 2H), 6.99 (d, J = 8.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 2H), 6.85-6.81 (m, 3H), 6.64 (d, J = 7.5 Hz, 1H), 5.51 (d, J = 9.5 Hz,1H), 2.24 (s, 3H), 1.65 (s, 3H); HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 0.8 mL/min, 235 nm), tR: 54.0 min (anti, minor), 57.2 min (anti, major), 71.2 min (syn, minor), 84.0 min (syn, major). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(2-trifluoro-methylphenyl) 1 methyl]-3-methyl-indolin-2-one 3e: H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 9.0 Hz, 1H), 7.40-7.36 (m, 3H), 7.30 (d, J = 7.5 Hz, 1H), 7.27-7.23 (m, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 2H), 7.26 (d, J = 7.5 Hz, 1H), 7.15 (t, J =8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 5.38 (s, 1H), 13 2.24 (s, 3H), 1.34 (s, 3H); C NMR (125 MHz, CDCl3) δ 181.0, 142.5, 141.3, 137.8, 135.6, 131.0, 130.6, 129.1, 128.5 (×2), 128.4, 128.2, 127.5 (×2), 126.8, 126.3, 123.8, 121.9, 121.5, 109.4, 56.8, 52.2, 19.9, 19.7; HRMS (ESI+): m/z calcd. for C24H22F3N2O3S [M+H]: 475.1303, found: 475.1308. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 0.8 mL/min, 235 nm),
tR: 36.7 min (anti, minor), 46.8 min (anti, major), 70.0 min (syn, major), 88.8 min (syn, minor). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(3-fluorophenyl) methyl]1 3-methyl- indolin-2-one 3f: H NMR (500 MHz, CDCl3) δ 7.58-7.53 (m, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 6.0 Hz, 1H), 7.26-7.24 (m, 1H), 7.12-7.08 (m, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.89-6.84 (m, 1H), 6.73 (d, J = 8.0 Hz, 2H), 6.34 (d, J = 7.5 Hz, 1H), 6.22 (d, J = 10 Hz, 1H), 5.76 13 (d, J = 9.0 Hz, 1H), 4.45 (d, J = 9.0 Hz, 1H), 2.30 (s, 3H), 1.60 (s, 3H); C NMR (125 MHz, CDCl3) δ 179.5, 143.4, 140.2, 138.5, 138.4, 136.3, 130.3, 129.1(×2), 129.0, 128.9, 127.1(×2), 126.6, 124.2, 123.0, 122.7, 114.4, 109.8, 62.3, 52.7, 21.2, 20.3; HRMS (ESI+): m/z calcd. for C23H22FN2O3S [M+H]: 425.1335, found: 425.1341. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 0.8 mL/min, 235 nm), tR: 26.0 min (anti, minor), 47.5 min (syn, minor), 56.6 min (anti, major), 60.2 min (syn, minor). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(3-methyl- phenyl) methyl]1 3-methyl- indolin-2-one 3g: H NMR (500 MHz, CDCl3) δ 7.48 (bs, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 7.5 Hz, 1H), 7.26-7.22 (m, 1H), 7.12-7.08 (m, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.81-6.78 (m, 1H), 6.76-6.72 (m, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.24-6.19 (m, 2H), 5.61 (d, J = 9.0 Hz, 1H), 4.39 (d, J = 9.0 13 Hz, 1H), 2.28 (s, 3H), 1.96 (s, 3H), 1.63 (s, 3H); C NMR (125 MHz, CDCl3) δ 179.8, 142.9, 140.3, 136.8, 136.4, 135.8, 130.7, 129.6, 128.9 (×2), 128.6, 128.2, 127.4, 127.2 (×2), 124.4, 123.9, 122.5, 109.6, 62.8, 52.9, 21.2, 20.8, 20.4; HRMS (ESI+): m/z calcd. for C24H25N2O3S [M+H]: 421.1586, found: 421.1583. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 95:5, 0-110 min:1 ml/min, after 110 min: 1.2 ml/min, 235 nm), tR: 53.9 min (anti, minor), 84.3 min (syn, major), 89.2 min (syn, minor), 153.0 min (anti, major). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(4-fluorophenyl) methyl]1 3-methyl-indolin-2-one 3h: H NMR (500 MHz, CDCl3) for anti, δ 7.44 (d, J = 8.0 Hz, 2H), 7.34-7.30 (m, 2H), 7.24 (d, J = 7.5 Hz, 1H), 7.12-7.08 (m, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 7.5 Hz, 1H), 6.60-6.55 (m, 2H), 6.50-6.46 (m, 2H), 5.60 (d, J = 8.5 Hz, 1H), 4.46 (d, J = 9.0 Hz, 13 1H), 2.31 (s, 3H), 1.61 (s, 3H); C NMR (125 MHz, CDCl3) for anti,δ 179.4, 143.3, 140.2, 136.4, 131.8, 130.2, 129.6, 129.1(×2), 129.0, 128.9, 128.8, 127.1(×2), 126.3, 124.3, 122.7, 114.4, 109.7, 62.0, 52.9, 21.2, 20.1; HRMS (ESI+): m/z calcd. for C23H22FN2O3S [M+H]: 425.1335, found: 425.1339. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 95:5, 1.0 mL/min, 235 nm), tR: 71.7 min (anti, minor), 85.0 min (syn, minor), 157.1 min (syn, major), 174.2 min (anti, major). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(4-chlorophenyl) methyl]-31 methyl-indolin-2-one 3i: H NMR (500 MHz, CDCl3) δ 7.93 (s, 1H), 7.457.42 (m, 3H), 7.26-7.22 (m, 1H), 7.13-7.09 (m, 1H), 7.00 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 7.5 Hz, 1H), 6.46 (d, J = 8.5 Hz, 2H), 6.18 13 (d, J = 9.0 Hz, 1H), 4.48 (d, J = 9.5 Hz, 1H), 2.30 (s, 3H), 1.62 (s, 3H); C NMR (125 MHz, CDCl3) δ 179.9, 143.4, 140.2, 136.3, 134.4, 133.4, 130.2, 129.1(×2), 128.8(×3), 127.5(×2), 127.1(×2), 124.4, 122.8, 109.7, 62.3, 53.0, 21.3, 20.4; HRMS (ESI+): m/z calcd. for C23H22ClN2O3S [M+H]: 441.1040, found: 441.1045. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 0.8 mL/min, 235 nm), tR:54.7 min (anti, minor), 72.5 min (anti, major), 86.7 min (syn, minor), 97.1 min (syn, major).
Fig. 1. Cinchona alkaloid derivatives screened as organocatalysts in the current study (1a–g). Chirality DOI 10.1002/chir
803
DIRECT ASYMMETRIC ANTI-MANNICH-TYPE REACTIONS
(R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(4-methyl-phenyl) methyl]1 3-methyl-indolin-2-one 3j: H NMR (500 MHz, CDCl3) δ 7.54 (s, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 7.0 Hz, 1H), 7.25-7.21 (m, 1H), 7.12-7.08 (m, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 8.0 Hz, 2H), 6.38 (d, J = 8.0 Hz, 2H), 5.70 (d, J =9.0 Hz, 1H), 4.42 (d, J = 9.0 Hz, 1H), 13 2.29 (s, 3H), 2.15 (s, 3H), 1.61 (s, 3H); C NMR (125 MHz, CDCl3) δ179.9, 142.9, 140.3, 137.2, 136.5, 132.9, 130.8, 129.0 (×2), 128.6, 128.1 (×2), 127.2 (×2), 127.1 (×2), 124.4, 122.5, 109.7, 62.6, 53.0, 21.2, 20.8, 20.4; HRMS (ESI +): m/z calcd. for C24H25N2O3S [M+H]: 421.1586, found: 421.1592. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 95:5, 0-160 min: 1 ml/min, after 160 min:1.2 ml/min, 235 nm), tR:119.2 min (anti, minor), 132.7 min (syn, major), 146.7 min (anti, major), 204.3 min (syn, minor). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(4-isopropyl-phenyl) methyl]1 3-methyl-indolin-2-one 3k: H NMR (500 MHz, CDCl3) δ 7.40-7.37 (m, 3H), 7.32 (d, J = 8.5 Hz, 1H), 7.26-7.22 (m, 1H), 7.13-7.10 (m, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.71-6.67 (m, 3H), 6.37 (d, J = 8.5 Hz, 2H), 5.64 (d, J = 9.5 Hz, 1H), 4.45 (d, J = 9.5 Hz, 1H), 2.71-2.67 (m, 1H), 2.26 (s, 3H), 1.63 13 (s, 3H), 1.10 (d, J = 1.5 Hz, 3H), 1.09 (d, J = 1.5 Hz, 3H); C NMR (125 MHz, CDCl3) δ 179.7, 148.1, 142.7, 140.3, 136.5, 133.2, 130.8, 129.6, 128.9 (×2), 128.6, 127.2. 127.1, 126.3, 125.4 (×2), 124.3, 122.6, 109.6, 62.6, 52.9, 33.4, 23.7, 23.6, 21.2, 20.5; (ESI+): m/z calcd. for C26H29N2O3S [M+H]: 449.1899, found: 449.1894. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 1.0 mL/min, 235 nm), tR: 22.5 min (anti, major), 28.9 min (anti, minor), 53.6 min (syn, minor), 64.1 min (syn, minor). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(4-tert-butyl-phenyl) methyl]1 3-methyl-indolin-2-one 3l: H NMR (500 MHz, CDCl3) δ 7.48 (bs, 1H), 7.42 (d, J = 7.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.27-7.23 (m, 1H), 7.157.11 (m, 1H), 6.91 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 7.5Hz, 1H), 6.40 (d, J =8.5 Hz, 2H), 5.85 (d, J = 8.0 Hz, 1H), 4.46 (d, J = 9.0 13 Hz, 1H), 2.24 (s, 3H), 1.62 (s, 3H), 1.16 (s, 9H); C NMR (125 MHz, CDCl3) δ 179.9, 150.3, 142.6, 140.3, 136.5, 132.9, 130.9, 129.6, 128.9 (×2), 128.6, 127.1, 126.9, 126.3, 124.3, 124.2 (×2), 122.6, 109.7, 62.6, 52.9, 34.2, 31.1 (×3), 21.2, 20.7; (ESI+): m/z calcd. for C27H31N2O3S [M+H]: 463.2055, found: 463.2058. HPLC (Daicel chiralcel OD-H, Vhex:ViPrOH = 97:3, 0-220 min: 0.4 ml/min, after 220 min: 1 ml/min, 235 nm), tR: 113.7 min (anti, major), 141.7 min (syn, major), 182.1 min (syn, minor), 235.5 min (anti, minor).
RESULTS AND DISCUSSION
Based on the optimized conditions reported by Cheng et al.,36 we selected CHCl3 as the best solvent to investigate the catalytic activities of the cinchona alkaloid catalysts 1a–g towards the Mannich reaction of 3-methyl-2-oxindole with N-tosyl benzaldimine (Table 1). All of the catalysts smoothly catalyzed the reaction to provide the desired product in good yields (61–92%). Catalysts 1a and 1b, which were derived from quinidine following demethylation of the 6′-OMe moiety, exhibited poor diastereo- and enantioselectivities (Table 1, entries 2 and 3). Catalyst 1c, which was derived from 1a following the introduction of a bulky TBDPS group at the C9 position, gave an excellent yield of the desired product with high diastereoselectivity (82:18) and improved enantioselectivity (Table 1, entry 4). The pseudoenantiomeric quinine derivative 1d gave results similar to those of 1c, but with the opposite configuration as determined by chiral HPLC analysis (Table 1, entry 5). To confirm the configuration of the product, we repeated the reaction using quinidine (QD) as the catalyst according to the literature procedure,36 and obtained the same anti-(S,S) enantiomer as the major product (Table 1, entry1). In contrast to the use of QD as a catalyst, the quinidine derivative 1c induced the reaction to give the opposite enantiomer (anti-R,R) as the major product based on the HPLC analysis (Table 1, entry 4 vs. entry 1). These results indicated that cinchona alkaloid-derived catalysts bearing a free hydroxyl group at the 9- or 6′-position exhibited a contrasting level of stereoinduction in this Mannich reaction. The use of
TABLE 1. Asymmetric Mannich reaction of 3-methyl-2a oxindole with N-tosyl benzaldimine
Entry 1 2 3 4 5 6 7 8
b
Catalyst
Yield (%)
anti/syn
QD 1a 1b 1c 1d 1e 1f 1g
68 67 61 92 88 81 79 82
49:51 55:45 59:41 82:18 78:22 58:42 55:45 53:47
c
c
anti ee (%) 22 10 13 -60 56 9 0 -10
a All of the reactions were performed with the N-tosyl benzaldimine (0.20 mmol), catalyst (0.02 mmol), and 3-methyl-2-oxindole (0.20 mmol) in 1 ml of CHCl3 at rt for 36 h. b Isolated yield. c Determined by HPLC analysis (Chiralcel AD-H).
cinchona alkaloid derivatives containing a sulfide ether (1e–g) was also investigated in this reaction, but the observed stereoselectivities induced by these catalysts were very low (Table 1, entries 6-8). To optimize the stereoselectivity of the transformation, we investigated a variety of different reaction variables, including the solvent, catalyst loading, and temperature. The results of these optimization experiments are shown in Table 2. The solvent was found to have a significant impact on the stereoselectivity of the reaction. In contrast to Cheng et al.’s procedure,36 where CHCl3 was reported as the optimal solvent for the reaction, we found that toluene provided the best results in terms of the yield and stereoselectivity of the transformation. It is worth noting that toluene is less toxic than chloroform. The screening of different amounts of catalyst showed that a 5 mol% loading was optimal in terms of the stereoselectivity (Table 2, entry 10). Attempts to reduce the loading of the catalyst to 3 mol% led to a slight decrease in asymmetric induction (Table 2, entry 11), whereas further increasing the catalyst loading to 10 or 15 mol% did not provide any improvement in the stereoselectivity (Table 2, entries 5 and 8 vs. entry 9). The temperature of the reaction was found to have a moderate impact on the level of asymmetric induction. When the reaction temperature was lowered from room temperature to 0°C, the stereoselectivity increased slightly (Table 2, entry 10 vs. entry 9). Further reducing the temperature to 20°C, however, led a reduction in the yield and stereoselectivity of the reaction (Table 2, entry 7 vs. entry 6). Based on these experiments, the optimized conditions were determined to be toluene as the solvent with a 5 mol% loading of catalyst 1c at 0°C. In order to investigate the practical characteristic of the screened catalytic system, we also tested a large-scale experiment (2.0 mmol, Table 2, entry 12) using the same procedure. The stereoselectivity was maintained at the same level, which indicated this asymmetric Mannich reaction in the screened catalytic system could be developed as a potential method to synthesize the substituted 2-oxindoles in large scale. Chirality DOI 10.1002/chir
804
JIN ET AL.
TABLE 2. Screening of the reaction conditions for the asyma metric Mannich reaction Entry
Solvent
T (°C)
Cat. loading (mmol%)
Yield b (%)
anti/ c syn
ee c (%)
1 2 3 4 5 6 7 8 9 10 11 d 12
CHCl3 CHCl3 THF CH2Cl2 PhMe PhMe PhMe PhMe PhMe PhMe PhMe PhMe
rt 0 rt rt rt 0 -20 rt rt 0 0 0
10% 10% 10% 10% 10% 10% 10% 15% 5% 5% 3% 5%
92 81 80 73 95 92 69 96 93 92 86 88
82:18 89:11 88:12 84:16 94:6 93:7 93:7 94:6 91:9 97:3 93:7 95:5
60 74 74 60 74 82 72 77 79 83 81 81
a
All of the reactions were performed with the N-Tosyl benzaldimine (0.20 mmol), catalyst 1c, and 3-methyl-2-oxindole (0.20 mmol) in 2 ml solvent for 24 h. b Isolated yield. c Determined by HPLC analysis (Chiralcel AD-H). d The reaction was run in large scale (2.0 mmo1).
With the optimized conditions in hand, we proceeded to evaluate the scope and general applicability of this enantioselective Mannich reaction using a variety of different aromatic aldimines (Table 3). All of the aldimines tested in the current study reacted smoothly to give the corresponding products in good yields with moderate to high stereoselectivities. Interestingly, the stereoselectivities were significantly affected by the type and position of the substituents on the phenyl ring. For example, the meta- and parasubstituted substrates reacted smoothly under the optimized conditions to give the corresponding anti products with high diastereoselectivities (Table 3, entries 6–12), whereas the TABLE 3. Scope of the enantioselective Mannich reaction of a aromatic aldimines
Entry 1 2 3 4 5 6 7 8 9 10 11 12
b
R
Yield (%)
anti/syn
3a H 3b 2-CH3 3c 2-F 3d 2-Cl 3e 2-CF3 3f 3-F 3g 3-CH3 3h 4-F 3i 4-Cl 3j 4-CH3 3k 4-iPr 3l 4-tBu
92 90 74 90 78 81 88 71 79 83 90 92
97:3 67:33 65:35 55:45 65:35 82:18 94:6 93:7 94:6 97:3 94:6 97:3
a
c
ee (%)
c
83 91 56 60 72 70 78 67 65 59 89 83
All of the reactions were performed with the aldimine (0.20 mmol), catalyst 1c (0.02 mmol), and 3-methyl-2-oxindole (0.20 mmol) in 2 ml toluene for 24 h. Isolated yield. c Determined by HPLC analysis (Chiralcel AD-H). b
Chirality DOI 10.1002/chir
corresponding ortho-substituted substrates gave much lower levels of diastereoselectivity (Table, 3, entries 2–5). Furthermore, electron-donating groups at the para-position appeared to favor higher enantioselectivities. When the para-methyl group was changed to an isopropyl or tert-butyl group, the ee value increased significantly (Table 3, entries 11 and 12 vs. entry 10). Of all of the different substrates listed above, the Mannich of the ortho-methyl aromatic aldimine afforded the highest enantioselectivity (entry 2, 91% ee), whereas the product of the ortho-fluoro aromatic aldimine gave the lowest enantioselectivity (56% ee). CONCLUSION
We have demonstrated that the cinchona alkaloid derivative 1c promoted the asymmetric anti-Mannich reaction of 3-methyl-2-oxindole with N-tosyl aryl aldimines with catalyst loadings in the range of 3–5 mol%, which were significantly lower than the previously reported catalyst loading of 10 mol %. Furthermore, we used our optimized conditions to expand upon the substrate scope of this transformation. Further investigations aimed at clarifying the exact catalytic mechanism of this process are currently under way in our laboratory. LITERATURE CITED 1. Kobayashi S, Ishitani H. Catalytic enantioselective addition to imines. Chem Rev 1999;99:1069–1094. 2. Kobayashi S, Mori Y, Fossey JS, Salter MM. Catalytic enantioselective formation of C C bonds by addition to imines and hydrazones: a ten-year update. Chem Rev 2011;111:2626–2704. 3. Marques MMB. asymmetric catalysis C-C coupling enantioselectivity homogeneous catalysis Mannich reaction. Angew Chem Int Ed 2006;45:348–352. 4. Li WH, Song BA, Bhadury PS, Li L, Wang ZC, Zhang XY, Hu DY, Chen Z, Zhang YP, Bai S, Wu J, Yang S. Chiral cinchona alkaloid-derived thiourea catalyst for enantioselective synthesis of novel β-amino esters by Mannich reaction. Chirality 2012, 24, 223–231. 5. Trost B, Terrell LR. A direct catalytic asymmetric Mannich-type reaction to syn-amino alcohols. J Am Chem Soc 2003;125:338–339. 6. Westermann B, Neuhaus C. Dihydroxyacetone in amino acid catalyzed Mannich-type reactions. Angew Chem Int Ed 2005;44:4077–4079. 7. Enders D, Grondal C, Vrettou M, Raabe G. Asymmetric synthesis of selectively protected amino sugars and derivatives by a direct organocatalytic Mannich reaction. Angew Chem Int Ed 2005;44:4079–4083. 8. Okada A, Shibuguchi T, Ohshima T, Masu H, Yamaguchi K, Shibasaki M. Enantio- and diastereoselective catalytic Mannich-type reaction of a glycine Schiff base using a chiral two-center phase-transfer catalyst. Angew Chem Int Ed 2005;44:4564–4567. 9. Lou S, Taoka BM, Ting A, Schaus S. Asymmetric Mannich reactions of β-keto esters with acyl imines catalyzed by cinchona alkaloids. J Am Chem Soc 2005;127:11256–11257. 10. Kobayashi S, Matsubara R, Nakamura Y, Kitagawa H, Sugiura M. Catalytic, asymmetric Mannich-type reactions of N-acylimino esters: reactivity, diastereo- and enantioselectivity, and application to synthesis of n-acylated amino acid derivatives. J Am Chem Soc 2003;125:2507–2515. 11. Ooi T, Kameda M, Fujii J, Maruoka K. Catalytic asymmetric synthesis of a nitrogen analogue of dialkyl tartrate by direct Mannich reaction under phase-transfer conditions. Org Lett 2004;6:2397–2399. 12. Notz W, Tanaka F, Watanabe S, Chowdari NS, Turner JM, Thayumanuvan R, Barbas CF III. The direct organocatalytic asymmetric Mannich reaction: unmodified aldehydes as nucleophiles. J Org Chem 2003;68:9624–9634. 13. Zhuang W, Saaby S, Jorgensen KA. Direct organocatalytic enantioselective Mannich reactions of ketimines: an approach to optically active quaternary α-amino acid derivatives. Angew Chem Int Ed 2004;43:4476–4478. 14. Notz W, Watanabe S, Chowdari N S, Zhong G, Betancort JM, Tanaka F, Barbas CFIII. The scope of the direct proline-catalyzed asymmetric addition of ketones to imines. Adv Synth Catal 2004;346:1131–1140. 15. Wang W, Wang J, Li H. Catalysis of highly stereoselective Mannich-type reactions of ketones with α-imino esters by a pyrrolidine-sulfonamide. Synthesis of unnatural α-amino acids. Tetrahedron Lett 2004;45:7243–7246.
DIRECT ASYMMETRIC ANTI-MANNICH-TYPE REACTIONS 16. Akiyama T, Itoh J, Yokota K, Fuchibe K. Enantioselective Mannich-type reaction catalyzed by a chiral Brønsted acid. Angew Chem Int Ed 2004;43:1566–1568. 17. Zhang H, Mitsumori S, Utsumi N, Imai M, Garcia-Delgado N, Mifsud M, Albertshofer K, Cheong PH-Y, Houk KN, Tanaka F, Barbas CFIII. Catalysis of 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives in enantioselective anti-Mannich-type reactions: importance of the 3-acid group on pyrrolidine for stereocontrol. J Am Chem Soc 2008;130:875–886. 18. Yoshida T, Morimoto H, Kumagai N, Matsunaga S, Shibasaki M. Non-C2symmetric, chirally economical, and readily tunable linked-binols: design and application in a direct catalytic asymmetric Mannich-type reaction. Angew Chem Int Ed 2005;44:3470-–3474. 19. Kano T, Yamaguchi Y, Maruoka K. A designer axially chiral amino sulfonamide as an efficient organocatalyst for direct asymmetric Mannich reactions of N-Boc-protected imines. Angew Chem Int Ed 2009;48:1838–1840 20. Pouliquen M, Blanchet J, Lasne M-C, Rouden J. 3-Trifluoromethanesulfonamidopyrrolidine: a general organocatalyst for anti-selective Mannich reactions. Org Lett 2008;10:1029–1032 21. Zhang H, Chuan Y, Li Z, Peng Y. 4-Aminothiourea prolinol tertbutyldiphenylsilyl ether: a chiral secondary amine-thiourea as organocatalyst for enantioselective anti-Mannich reactions. Adv Synth Catal 2009;351:2288–2294 22. Gómez-Bengoa E, Maestro M, Mielgo A, Otazo I, Palomo C, Velilla I. A 4-hydroxypyrrolidine-catalyzed Mannich reaction of aldehydes: control of anti-selectivity by hydrogen bonding assisted by Brønsted acids. Chem Eur J 2010;16:5333–5342 23. Martín-Rapún R, Fan X, Sayalero S, Bahramnejad M, Cuevas F, Pericàs MA. Highly active organocatalysts for asymmetric anti-Mannich reactions. Chem Eur J 2011;17:8780–8783. 24. Martín-Rapún R, Sayalero S, Pericàs MA. Asymmetric anti-Mannich reactions in continuous flow. Green Chem 2013;15:3295–3301. 25. Albrecht BK, Williams RM. A concise formal total synthesis of TMC-95A/ B proteasome inhibitors. Org Lett 2003;5:197–200. 26. Reisman SE, Ready JM, Weiss MM, Hasuoka A, Hirata M, Tamaki K, Ovaska TV, Smith CJ, Wood JL. Evolution of a synthetic strategy: total synthesis of (±)-Welwitindolinone A isonitrile. J Am Chem Soc 2008;130:2087–2100. 27. Abadi AH, Abou-Seri SM, Abdel-Rahman DE, Klein C, Lozach O, Meijer L. Synthesis of 3-substituted-2-oxoindole analogues and their evaluation
28.
29.
30.
31.
32. 33.
34.
35.
36.
37.
38.
805
as kinase inhibitors, anticancer and antiangiogenic agents. Eur J Med Chem 2006;41:296–305. Ponglux D, Wongseripipatana S, Aimi N, Nishimura M, Ishikawa M, Sada H, Haginiwa J, Sakai SI. Structure and synthesis of two new types of oxindole alkaloids found from Uncaria salaccensis. Chem Pharm Bull 1990;38:573–575. Lee KK, Zhou BN, Kingston DGI, Vaisberg AJ, Hammond GB. Bioactive indole alkaloids from the bark of Uncaria guianensis. Planta Med 1999;65:759–760 Cui CB, Akeya H, Osada H. Novel mammalian cell cycle inhibitors, spirotryprostatins A and B, produced by Aspergillus fumigatus, which inhibit mammalian cell cycle at G2/M phase. Tetrahedron 1996;52: 12651–12666. Edmondson S, Danishefsky SJ, Sepp-Lorenzino L, Rosen N. Total synthesis of Spirotryprostatin A, leading to the discovery of some biologically promising analogues. J Am Chem Soc 1999;121:2147–2155. Tian X, Jiang K, Peng J, Du W, Chen YC. Organocatalytic stereoselective Mannich reaction of 3-substituted oxindoles. Org Lett 2008;10:3583–3586. Ashimori A, Bachand B, Calter MA, Govek SP, Overman LE, Poon DJ. Catalytic asymmetric synthesis of quaternary carbon centers. Exploratory studies of intramolecular Heck reactions of (z)-α,β-unsaturated anilides and mechanistic investigations of asymmetric Heck reactions proceeding via neutral intermediates. J Am Chem Soc 1998;120:6488–6499. Overman LE, Watson DA. Diastereoselection in the formation of spirocyclic oxindoles by the intramolecular Heck reaction. J Org Chem 2006;71:2587–2599. Pinto A, Jia Y, Neuville L, Zhu J. Palladium-catalyzed enantioselective domino Heck–cyanation sequence: development and application to the total synthesis of esermethole and physostigmine. Chem Eur J 2007; 13:961–967. Cheng L, Liu L, Jia H, Wang D, Chen Y-J. Enantioselective organocatalytic anti-Mannich-type reaction of N-unprotected 3-substituted 2-oxindoles with aromatic N-Ts-aldimines. J Org Chem 2009;74:4650–4653. Jia YX, Xie JH, Duan HF, Wang LX, Zhou QL. Asymmetric Friedel Crafts addition of indoles to N-sulfonyl aldimines: a simple approach to optically active 3-indolyl-methanamine derivatives. Org Lett 2006;8:1621–1624. Zhang TY, He W, Zhao XY, Jin Y. Asymmetric oxaziridination catalyzed by cinchona alkaloid derivatives containing sulfide. Tetrahedron 2013;69:7416–7422.
Chirality DOI 10.1002/chir
Direct Asymmetric anti-Mannich-Type Reactions Catalyzed by Cinchona Alkaloid Derivatives YING JIN,1 DI CHEN,2 AND XIU RONG ZHANG1* Department of Pharmacy, Jilin Medical College, Jilin, China 2 Department of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China 1
ABSTRACT A series of cinchona alkaloid derivatives were used to catalyze the asymmetric antiMannich-type reaction of 3-methyl-2-oxindole with N-tosyl aryl aldimines. The resulting anti-3, 3-disubstituted 2-oxindole products were obtained in good yields (up to 92%) with high diastereoand enantioselectivities (anti/syn up to 97:3 and 91% ee). Chirality 26:801–805, 2014. © 2014 Wiley Periodicals, Inc.
KEY WORDS: cinchona alkaloid derivatives; asymmetric; anti-Mannich reaction; anti-3,3disubstituted 2-oxindole INTRODUCTION
The direct Mannich-type reaction is a highly effective carbon–carbon bond-forming method that is especially useful for the preparation of β-amino carbonyl derivatives.1–4 During the course of the last two decades, significant research efforts have been devoted to the development of highly stereoselective (i.e., diastereo- and enantioselective) Mannich reactions because of the importance of the asymmetric Mannich products in organic synthesis. Although syn-selective catalytic asymmetric Mannich reactions have been well established,5–16 methods for the stereoselective anti-Mannich reactions are relatively scarce,17–24 and there is therefore an urgent need for the development of effective stereoselective anti-Mannich catalysts to overcome the challenges of asymmetric synthesis (Scheme 1). Compounds possessing the C3-quaternary oxindole structure have been found in a number of natural and pharmaceutical molecules,25–27 and have frequently been used as synthetic intermediates for the construction of indole alkaloids.28–31 A variety of different stereoselective strategies and methodologies have been applied to the synthesis of optically active 3,3-disubstituted oxindoles,32–35 and the application of prochiral 3-substititued oxindoles as nucleophiles represents a particularly straightforward approach to the introduction of a C3-quaternary center. In 2009, Cheng et al.36 reported the development of a stereoselective method for the synthesis 3,3-disubstituted 2-oxindoles with high levels of diastereo- (anti/syn up to 95:5) and enantioselectivity (up to 89% ee) via the organocatalytic anti-Mannich-type reaction of N-unprotected 3-substituted 2-oxindoles with aromatic N-tosyl-aldimines in the presence of a cinchona alkaloid catalyst. Herein, we report the results of our recent study involving the use of a series of cinchona alkaloid derivatives (1a–g, Fig. 1) to effect the same transformation. The cinchona alkaloid derivatives investigated in the current study were prepared by making modifications to the 9-OH, 6′-OH and terminal vinyl groups of quinine and quinidine. Pleasingly, with a catalyst loading in the range of 3–5 mol%, the quinidine derivative 1c bearing a 6′-hydroxy-quinoline ring and tertbutyldiphenylsilyl group (TBDPS) at its C9 position induced the anti-Mannich reaction of 3-methyl-2-oxindole with aromatic N-tosyl-aldimine to give the anti (R,R)-products with high levels of stereoselectivity (anti/syn up to 97:3 and 91% enantiomeric excess [ee]). © 2014 Wiley Periodicals, Inc.
EXPERIMENTAL SECTION Instruments and Materials 1
H NMR spectra were recorded on 500 MHz spectrometer using CDCl3 as a solvent. The chemical shifts are reported in ppm with the residual CHCl3 signal being used as a reference (7.26 ppm). The splitting patterns of the signals were reported as s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; m, multiplet; and bs, broad signal. The 13 C NMR spectra were recorded on a 125 MHz instrument using CDCl3 as a solvent. The chemical shifts are reported in ppm with the residual CHCl3 signal being used as a reference (77.0 ppm). High-resolution mass spectra (HRMS) were measured on a mass spectrometer equipped with an electrospray ionization (ESI) source in the positive-ion mode. The ee values of the products were determined by chiral high-performance liquid chromatography (HPLC) using Daicel Chiralpak AD-H and Chiralcel OD-H columns. The melting points are uncorrected. The reactions were monitored by thin layer chromatography (TLC). Purifications by column chromatography were conducted over silica gel (200–300 mesh). The aromatic imines were prepared according to literature procedures.36,37 Catalysts 1a–g were synthesized according to literature procedures.38
General Procedure for Asymmetric Mannich Reaction Catalyst 1c (0.01 mmol) was added to a mixture of 3-methyl-2-oxindole (30 mg, 0.2 mmol) and the corresponding imine (0.2 mmol) in toluene (1.0 mL) at 0°C, and the resulting mixture was stirred for 36 h at 0°C for a period of time. The crude mixture was then loaded directly onto a column packed with silica gel and eluted with a mixture of hexane/EtOAc (7:1 – v/v) to give the desired product 3a–l as waxy oil. (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-phenyl-methyl]-3-methyl1 indolin-2-one 3a: H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 7.5 Hz, 1H), 7.28-7.18 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 7.03-6.98 (m, 3H), 6.87 (t, J = 8.0 Hz, 2H), 6.68 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 7.5 Hz, 2H), 5.53 (d, J = 9.0 Hz, 1H), 4.46 (d, J = 9.0 Hz, 1H), 2.29 (s, 3H), 1.62 (s, 3H); HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 0.8 mL/min, 235 nm), tR: 34.2 min (anti, minor), 55.6 min (syn, minor), 85.4 min (syn, major), 90.2 min (anti, major).
Contract grant sponsor: National Natural Science Foundation of China; Contract grant number: 21102055. Contract grant sponsor: Natural Science Foundation of Jilin province; Contract grant number: 201015237. *Correspondence to: X. Zhang, Department of Pharmacy, Jilin Medical College, Jilin 132013, China. E-mail: [email protected] Received for publication 26 April 2014; Accepted 13 June 2014 DOI: 10.1002/chir.22358 Published online 18 July 2014 in Wiley Online Library (wileyonlinelibrary.com).
802
JIN ET AL.
Scheme 1. Stereoselective anti-Mannich reactions.
(R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(2-methyl-phenyl) methyl]1 3-methyl-indolin-2-one 3b: H NMR (500 MHz, CDCl3) δ 7.61-7.54 (m, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.27-7.23 (m, 1H), 7.09-7.03 (m, 2H), 7.02 (d, J = 8.0 Hz, 2H), 6.99-6.95 (m, 1H), 6.83 (d, J = 7.0 Hz, 1H), 6.75 (d, J = 7.5 Hz, 2H), 6.41 (d, J = 8.0 Hz, 1H), 5.76 (d, J = 7.0 Hz, 1H), 4.80 (d, J = 7.5 Hz, 1H), 2.31 13 (s, 3H), 1.89 (s, 3H), 1.58 (s, 3H); C NMR (125 MHz, CDCl3) δ 180.0, 143.5, 143.0, 140.3, 139.0, 136.6, 134.8, 130.6, 129.9, 129.0(×2), 128.7, 127.5, 127.0(×2), 125.3, 124.5, 122.6, 109.7, 56.5, 52.2, 21.4, 19.8, 19.4; HRMS (ESI +): m/z calcd. for C24H25N2O3S [M+H]: 421.1586, found: 421.1580. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 0.8 mL/min, 235 nm), tR: 26.4 min (anti, minor), 35.6 min (anti, minor). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(2-fluorophenyl) methyl]1 3-methyl- indolin-2-one 3c: H NMR (500 MHz, CDCl3) δ 8.22 (s, 1H), 7.47 (d, J = 8.0 Hz, 3H), 7.35 (d, J = 7.5 Hz, 1H), 7.11-7.04 (m, 2H), 6.99 (d, J =8.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 2H), 6.85-6.81 (m, 3H), 6.64 (d, J = 7.5 13 Hz, 1H), 5.51 (d, J = 9.5 Hz,1H), 2.24 (s, 3H), 1.65 (s, 3H); C NMR (125 MHz, CDCl3) δ 181.0, 143.0, 140.1, 137.3, 136.1, 130.4, 129.3, 129.0, 128.8 (×2), 128.3, 127.6, 126.6 (×2), 124.2, 123.5, 122.4, 114.4, 109.6, 54.9, 51.7, 21.2, 20.3. (ESI+): m/z calcd. for C23H22FN2O3S [M+H]: 425.1335, found: 425.1339. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 0-30 min: 1 ml/min, after 30min: 0.8 ml/min, 235 nm), tR: 36.9 min (anti, minor), 44.3 min (syn, major), 50.0 min (syn, minor), 70.9 min (anti, major). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(2-chloro- phenyl) methyl]1 3-methyl- indolin-2-one 3d: H NMR (500 MHz, CDCl3) δ 8.22 (s, 1H), 7.47 (d, J = 8.0 Hz, 3H), 7.35 (d, J = 7.5 Hz, 1H), 7.11-7.04 (m, 2H), 6.99 (d, J = 8.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 2H), 6.85-6.81 (m, 3H), 6.64 (d, J = 7.5 Hz, 1H), 5.51 (d, J = 9.5 Hz,1H), 2.24 (s, 3H), 1.65 (s, 3H); HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 0.8 mL/min, 235 nm), tR: 54.0 min (anti, minor), 57.2 min (anti, major), 71.2 min (syn, minor), 84.0 min (syn, major). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(2-trifluoro-methylphenyl) 1 methyl]-3-methyl-indolin-2-one 3e: H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 9.0 Hz, 1H), 7.40-7.36 (m, 3H), 7.30 (d, J = 7.5 Hz, 1H), 7.27-7.23 (m, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 2H), 7.26 (d, J = 7.5 Hz, 1H), 7.15 (t, J =8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 5.38 (s, 1H), 13 2.24 (s, 3H), 1.34 (s, 3H); C NMR (125 MHz, CDCl3) δ 181.0, 142.5, 141.3, 137.8, 135.6, 131.0, 130.6, 129.1, 128.5 (×2), 128.4, 128.2, 127.5 (×2), 126.8, 126.3, 123.8, 121.9, 121.5, 109.4, 56.8, 52.2, 19.9, 19.7; HRMS (ESI+): m/z calcd. for C24H22F3N2O3S [M+H]: 475.1303, found: 475.1308. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 0.8 mL/min, 235 nm),
tR: 36.7 min (anti, minor), 46.8 min (anti, major), 70.0 min (syn, major), 88.8 min (syn, minor). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(3-fluorophenyl) methyl]1 3-methyl- indolin-2-one 3f: H NMR (500 MHz, CDCl3) δ 7.58-7.53 (m, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 6.0 Hz, 1H), 7.26-7.24 (m, 1H), 7.12-7.08 (m, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.89-6.84 (m, 1H), 6.73 (d, J = 8.0 Hz, 2H), 6.34 (d, J = 7.5 Hz, 1H), 6.22 (d, J = 10 Hz, 1H), 5.76 13 (d, J = 9.0 Hz, 1H), 4.45 (d, J = 9.0 Hz, 1H), 2.30 (s, 3H), 1.60 (s, 3H); C NMR (125 MHz, CDCl3) δ 179.5, 143.4, 140.2, 138.5, 138.4, 136.3, 130.3, 129.1(×2), 129.0, 128.9, 127.1(×2), 126.6, 124.2, 123.0, 122.7, 114.4, 109.8, 62.3, 52.7, 21.2, 20.3; HRMS (ESI+): m/z calcd. for C23H22FN2O3S [M+H]: 425.1335, found: 425.1341. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 0.8 mL/min, 235 nm), tR: 26.0 min (anti, minor), 47.5 min (syn, minor), 56.6 min (anti, major), 60.2 min (syn, minor). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(3-methyl- phenyl) methyl]1 3-methyl- indolin-2-one 3g: H NMR (500 MHz, CDCl3) δ 7.48 (bs, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 7.5 Hz, 1H), 7.26-7.22 (m, 1H), 7.12-7.08 (m, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.81-6.78 (m, 1H), 6.76-6.72 (m, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.24-6.19 (m, 2H), 5.61 (d, J = 9.0 Hz, 1H), 4.39 (d, J = 9.0 13 Hz, 1H), 2.28 (s, 3H), 1.96 (s, 3H), 1.63 (s, 3H); C NMR (125 MHz, CDCl3) δ 179.8, 142.9, 140.3, 136.8, 136.4, 135.8, 130.7, 129.6, 128.9 (×2), 128.6, 128.2, 127.4, 127.2 (×2), 124.4, 123.9, 122.5, 109.6, 62.8, 52.9, 21.2, 20.8, 20.4; HRMS (ESI+): m/z calcd. for C24H25N2O3S [M+H]: 421.1586, found: 421.1583. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 95:5, 0-110 min:1 ml/min, after 110 min: 1.2 ml/min, 235 nm), tR: 53.9 min (anti, minor), 84.3 min (syn, major), 89.2 min (syn, minor), 153.0 min (anti, major). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(4-fluorophenyl) methyl]1 3-methyl-indolin-2-one 3h: H NMR (500 MHz, CDCl3) for anti, δ 7.44 (d, J = 8.0 Hz, 2H), 7.34-7.30 (m, 2H), 7.24 (d, J = 7.5 Hz, 1H), 7.12-7.08 (m, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 7.5 Hz, 1H), 6.60-6.55 (m, 2H), 6.50-6.46 (m, 2H), 5.60 (d, J = 8.5 Hz, 1H), 4.46 (d, J = 9.0 Hz, 13 1H), 2.31 (s, 3H), 1.61 (s, 3H); C NMR (125 MHz, CDCl3) for anti,δ 179.4, 143.3, 140.2, 136.4, 131.8, 130.2, 129.6, 129.1(×2), 129.0, 128.9, 128.8, 127.1(×2), 126.3, 124.3, 122.7, 114.4, 109.7, 62.0, 52.9, 21.2, 20.1; HRMS (ESI+): m/z calcd. for C23H22FN2O3S [M+H]: 425.1335, found: 425.1339. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 95:5, 1.0 mL/min, 235 nm), tR: 71.7 min (anti, minor), 85.0 min (syn, minor), 157.1 min (syn, major), 174.2 min (anti, major). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(4-chlorophenyl) methyl]-31 methyl-indolin-2-one 3i: H NMR (500 MHz, CDCl3) δ 7.93 (s, 1H), 7.457.42 (m, 3H), 7.26-7.22 (m, 1H), 7.13-7.09 (m, 1H), 7.00 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 7.5 Hz, 1H), 6.46 (d, J = 8.5 Hz, 2H), 6.18 13 (d, J = 9.0 Hz, 1H), 4.48 (d, J = 9.5 Hz, 1H), 2.30 (s, 3H), 1.62 (s, 3H); C NMR (125 MHz, CDCl3) δ 179.9, 143.4, 140.2, 136.3, 134.4, 133.4, 130.2, 129.1(×2), 128.8(×3), 127.5(×2), 127.1(×2), 124.4, 122.8, 109.7, 62.3, 53.0, 21.3, 20.4; HRMS (ESI+): m/z calcd. for C23H22ClN2O3S [M+H]: 441.1040, found: 441.1045. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 0.8 mL/min, 235 nm), tR:54.7 min (anti, minor), 72.5 min (anti, major), 86.7 min (syn, minor), 97.1 min (syn, major).
Fig. 1. Cinchona alkaloid derivatives screened as organocatalysts in the current study (1a–g). Chirality DOI 10.1002/chir
803
DIRECT ASYMMETRIC ANTI-MANNICH-TYPE REACTIONS
(R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(4-methyl-phenyl) methyl]1 3-methyl-indolin-2-one 3j: H NMR (500 MHz, CDCl3) δ 7.54 (s, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 7.0 Hz, 1H), 7.25-7.21 (m, 1H), 7.12-7.08 (m, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 8.0 Hz, 2H), 6.38 (d, J = 8.0 Hz, 2H), 5.70 (d, J =9.0 Hz, 1H), 4.42 (d, J = 9.0 Hz, 1H), 13 2.29 (s, 3H), 2.15 (s, 3H), 1.61 (s, 3H); C NMR (125 MHz, CDCl3) δ179.9, 142.9, 140.3, 137.2, 136.5, 132.9, 130.8, 129.0 (×2), 128.6, 128.1 (×2), 127.2 (×2), 127.1 (×2), 124.4, 122.5, 109.7, 62.6, 53.0, 21.2, 20.8, 20.4; HRMS (ESI +): m/z calcd. for C24H25N2O3S [M+H]: 421.1586, found: 421.1592. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 95:5, 0-160 min: 1 ml/min, after 160 min:1.2 ml/min, 235 nm), tR:119.2 min (anti, minor), 132.7 min (syn, major), 146.7 min (anti, major), 204.3 min (syn, minor). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(4-isopropyl-phenyl) methyl]1 3-methyl-indolin-2-one 3k: H NMR (500 MHz, CDCl3) δ 7.40-7.37 (m, 3H), 7.32 (d, J = 8.5 Hz, 1H), 7.26-7.22 (m, 1H), 7.13-7.10 (m, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.71-6.67 (m, 3H), 6.37 (d, J = 8.5 Hz, 2H), 5.64 (d, J = 9.5 Hz, 1H), 4.45 (d, J = 9.5 Hz, 1H), 2.71-2.67 (m, 1H), 2.26 (s, 3H), 1.63 13 (s, 3H), 1.10 (d, J = 1.5 Hz, 3H), 1.09 (d, J = 1.5 Hz, 3H); C NMR (125 MHz, CDCl3) δ 179.7, 148.1, 142.7, 140.3, 136.5, 133.2, 130.8, 129.6, 128.9 (×2), 128.6, 127.2. 127.1, 126.3, 125.4 (×2), 124.3, 122.6, 109.6, 62.6, 52.9, 33.4, 23.7, 23.6, 21.2, 20.5; (ESI+): m/z calcd. for C26H29N2O3S [M+H]: 449.1899, found: 449.1894. HPLC (Daicel Chiralpak AD-H, Vhex:ViPrOH = 90:10, 1.0 mL/min, 235 nm), tR: 22.5 min (anti, major), 28.9 min (anti, minor), 53.6 min (syn, minor), 64.1 min (syn, minor). (R)-3-[(R)-1-(p-methylbenzenesulfonylamino)-1-(4-tert-butyl-phenyl) methyl]1 3-methyl-indolin-2-one 3l: H NMR (500 MHz, CDCl3) δ 7.48 (bs, 1H), 7.42 (d, J = 7.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.27-7.23 (m, 1H), 7.157.11 (m, 1H), 6.91 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 7.5Hz, 1H), 6.40 (d, J =8.5 Hz, 2H), 5.85 (d, J = 8.0 Hz, 1H), 4.46 (d, J = 9.0 13 Hz, 1H), 2.24 (s, 3H), 1.62 (s, 3H), 1.16 (s, 9H); C NMR (125 MHz, CDCl3) δ 179.9, 150.3, 142.6, 140.3, 136.5, 132.9, 130.9, 129.6, 128.9 (×2), 128.6, 127.1, 126.9, 126.3, 124.3, 124.2 (×2), 122.6, 109.7, 62.6, 52.9, 34.2, 31.1 (×3), 21.2, 20.7; (ESI+): m/z calcd. for C27H31N2O3S [M+H]: 463.2055, found: 463.2058. HPLC (Daicel chiralcel OD-H, Vhex:ViPrOH = 97:3, 0-220 min: 0.4 ml/min, after 220 min: 1 ml/min, 235 nm), tR: 113.7 min (anti, major), 141.7 min (syn, major), 182.1 min (syn, minor), 235.5 min (anti, minor).
RESULTS AND DISCUSSION
Based on the optimized conditions reported by Cheng et al.,36 we selected CHCl3 as the best solvent to investigate the catalytic activities of the cinchona alkaloid catalysts 1a–g towards the Mannich reaction of 3-methyl-2-oxindole with N-tosyl benzaldimine (Table 1). All of the catalysts smoothly catalyzed the reaction to provide the desired product in good yields (61–92%). Catalysts 1a and 1b, which were derived from quinidine following demethylation of the 6′-OMe moiety, exhibited poor diastereo- and enantioselectivities (Table 1, entries 2 and 3). Catalyst 1c, which was derived from 1a following the introduction of a bulky TBDPS group at the C9 position, gave an excellent yield of the desired product with high diastereoselectivity (82:18) and improved enantioselectivity (Table 1, entry 4). The pseudoenantiomeric quinine derivative 1d gave results similar to those of 1c, but with the opposite configuration as determined by chiral HPLC analysis (Table 1, entry 5). To confirm the configuration of the product, we repeated the reaction using quinidine (QD) as the catalyst according to the literature procedure,36 and obtained the same anti-(S,S) enantiomer as the major product (Table 1, entry1). In contrast to the use of QD as a catalyst, the quinidine derivative 1c induced the reaction to give the opposite enantiomer (anti-R,R) as the major product based on the HPLC analysis (Table 1, entry 4 vs. entry 1). These results indicated that cinchona alkaloid-derived catalysts bearing a free hydroxyl group at the 9- or 6′-position exhibited a contrasting level of stereoinduction in this Mannich reaction. The use of
TABLE 1. Asymmetric Mannich reaction of 3-methyl-2a oxindole with N-tosyl benzaldimine
Entry 1 2 3 4 5 6 7 8
b
Catalyst
Yield (%)
anti/syn
QD 1a 1b 1c 1d 1e 1f 1g
68 67 61 92 88 81 79 82
49:51 55:45 59:41 82:18 78:22 58:42 55:45 53:47
c
c
anti ee (%) 22 10 13 -60 56 9 0 -10
a All of the reactions were performed with the N-tosyl benzaldimine (0.20 mmol), catalyst (0.02 mmol), and 3-methyl-2-oxindole (0.20 mmol) in 1 ml of CHCl3 at rt for 36 h. b Isolated yield. c Determined by HPLC analysis (Chiralcel AD-H).
cinchona alkaloid derivatives containing a sulfide ether (1e–g) was also investigated in this reaction, but the observed stereoselectivities induced by these catalysts were very low (Table 1, entries 6-8). To optimize the stereoselectivity of the transformation, we investigated a variety of different reaction variables, including the solvent, catalyst loading, and temperature. The results of these optimization experiments are shown in Table 2. The solvent was found to have a significant impact on the stereoselectivity of the reaction. In contrast to Cheng et al.’s procedure,36 where CHCl3 was reported as the optimal solvent for the reaction, we found that toluene provided the best results in terms of the yield and stereoselectivity of the transformation. It is worth noting that toluene is less toxic than chloroform. The screening of different amounts of catalyst showed that a 5 mol% loading was optimal in terms of the stereoselectivity (Table 2, entry 10). Attempts to reduce the loading of the catalyst to 3 mol% led to a slight decrease in asymmetric induction (Table 2, entry 11), whereas further increasing the catalyst loading to 10 or 15 mol% did not provide any improvement in the stereoselectivity (Table 2, entries 5 and 8 vs. entry 9). The temperature of the reaction was found to have a moderate impact on the level of asymmetric induction. When the reaction temperature was lowered from room temperature to 0°C, the stereoselectivity increased slightly (Table 2, entry 10 vs. entry 9). Further reducing the temperature to 20°C, however, led a reduction in the yield and stereoselectivity of the reaction (Table 2, entry 7 vs. entry 6). Based on these experiments, the optimized conditions were determined to be toluene as the solvent with a 5 mol% loading of catalyst 1c at 0°C. In order to investigate the practical characteristic of the screened catalytic system, we also tested a large-scale experiment (2.0 mmol, Table 2, entry 12) using the same procedure. The stereoselectivity was maintained at the same level, which indicated this asymmetric Mannich reaction in the screened catalytic system could be developed as a potential method to synthesize the substituted 2-oxindoles in large scale. Chirality DOI 10.1002/chir
804
JIN ET AL.
TABLE 2. Screening of the reaction conditions for the asyma metric Mannich reaction Entry
Solvent
T (°C)
Cat. loading (mmol%)
Yield b (%)
anti/ c syn
ee c (%)
1 2 3 4 5 6 7 8 9 10 11 d 12
CHCl3 CHCl3 THF CH2Cl2 PhMe PhMe PhMe PhMe PhMe PhMe PhMe PhMe
rt 0 rt rt rt 0 -20 rt rt 0 0 0
10% 10% 10% 10% 10% 10% 10% 15% 5% 5% 3% 5%
92 81 80 73 95 92 69 96 93 92 86 88
82:18 89:11 88:12 84:16 94:6 93:7 93:7 94:6 91:9 97:3 93:7 95:5
60 74 74 60 74 82 72 77 79 83 81 81
a
All of the reactions were performed with the N-Tosyl benzaldimine (0.20 mmol), catalyst 1c, and 3-methyl-2-oxindole (0.20 mmol) in 2 ml solvent for 24 h. b Isolated yield. c Determined by HPLC analysis (Chiralcel AD-H). d The reaction was run in large scale (2.0 mmo1).
With the optimized conditions in hand, we proceeded to evaluate the scope and general applicability of this enantioselective Mannich reaction using a variety of different aromatic aldimines (Table 3). All of the aldimines tested in the current study reacted smoothly to give the corresponding products in good yields with moderate to high stereoselectivities. Interestingly, the stereoselectivities were significantly affected by the type and position of the substituents on the phenyl ring. For example, the meta- and parasubstituted substrates reacted smoothly under the optimized conditions to give the corresponding anti products with high diastereoselectivities (Table 3, entries 6–12), whereas the TABLE 3. Scope of the enantioselective Mannich reaction of a aromatic aldimines
Entry 1 2 3 4 5 6 7 8 9 10 11 12
b
R
Yield (%)
anti/syn
3a H 3b 2-CH3 3c 2-F 3d 2-Cl 3e 2-CF3 3f 3-F 3g 3-CH3 3h 4-F 3i 4-Cl 3j 4-CH3 3k 4-iPr 3l 4-tBu
92 90 74 90 78 81 88 71 79 83 90 92
97:3 67:33 65:35 55:45 65:35 82:18 94:6 93:7 94:6 97:3 94:6 97:3
a
c
ee (%)
c
83 91 56 60 72 70 78 67 65 59 89 83
All of the reactions were performed with the aldimine (0.20 mmol), catalyst 1c (0.02 mmol), and 3-methyl-2-oxindole (0.20 mmol) in 2 ml toluene for 24 h. Isolated yield. c Determined by HPLC analysis (Chiralcel AD-H). b
Chirality DOI 10.1002/chir
corresponding ortho-substituted substrates gave much lower levels of diastereoselectivity (Table, 3, entries 2–5). Furthermore, electron-donating groups at the para-position appeared to favor higher enantioselectivities. When the para-methyl group was changed to an isopropyl or tert-butyl group, the ee value increased significantly (Table 3, entries 11 and 12 vs. entry 10). Of all of the different substrates listed above, the Mannich of the ortho-methyl aromatic aldimine afforded the highest enantioselectivity (entry 2, 91% ee), whereas the product of the ortho-fluoro aromatic aldimine gave the lowest enantioselectivity (56% ee). CONCLUSION
We have demonstrated that the cinchona alkaloid derivative 1c promoted the asymmetric anti-Mannich reaction of 3-methyl-2-oxindole with N-tosyl aryl aldimines with catalyst loadings in the range of 3–5 mol%, which were significantly lower than the previously reported catalyst loading of 10 mol %. Furthermore, we used our optimized conditions to expand upon the substrate scope of this transformation. Further investigations aimed at clarifying the exact catalytic mechanism of this process are currently under way in our laboratory. LITERATURE CITED 1. Kobayashi S, Ishitani H. Catalytic enantioselective addition to imines. Chem Rev 1999;99:1069–1094. 2. Kobayashi S, Mori Y, Fossey JS, Salter MM. Catalytic enantioselective formation of C C bonds by addition to imines and hydrazones: a ten-year update. Chem Rev 2011;111:2626–2704. 3. Marques MMB. asymmetric catalysis C-C coupling enantioselectivity homogeneous catalysis Mannich reaction. Angew Chem Int Ed 2006;45:348–352. 4. Li WH, Song BA, Bhadury PS, Li L, Wang ZC, Zhang XY, Hu DY, Chen Z, Zhang YP, Bai S, Wu J, Yang S. Chiral cinchona alkaloid-derived thiourea catalyst for enantioselective synthesis of novel β-amino esters by Mannich reaction. Chirality 2012, 24, 223–231. 5. Trost B, Terrell LR. A direct catalytic asymmetric Mannich-type reaction to syn-amino alcohols. J Am Chem Soc 2003;125:338–339. 6. Westermann B, Neuhaus C. Dihydroxyacetone in amino acid catalyzed Mannich-type reactions. Angew Chem Int Ed 2005;44:4077–4079. 7. Enders D, Grondal C, Vrettou M, Raabe G. Asymmetric synthesis of selectively protected amino sugars and derivatives by a direct organocatalytic Mannich reaction. Angew Chem Int Ed 2005;44:4079–4083. 8. Okada A, Shibuguchi T, Ohshima T, Masu H, Yamaguchi K, Shibasaki M. Enantio- and diastereoselective catalytic Mannich-type reaction of a glycine Schiff base using a chiral two-center phase-transfer catalyst. Angew Chem Int Ed 2005;44:4564–4567. 9. Lou S, Taoka BM, Ting A, Schaus S. Asymmetric Mannich reactions of β-keto esters with acyl imines catalyzed by cinchona alkaloids. J Am Chem Soc 2005;127:11256–11257. 10. Kobayashi S, Matsubara R, Nakamura Y, Kitagawa H, Sugiura M. Catalytic, asymmetric Mannich-type reactions of N-acylimino esters: reactivity, diastereo- and enantioselectivity, and application to synthesis of n-acylated amino acid derivatives. J Am Chem Soc 2003;125:2507–2515. 11. Ooi T, Kameda M, Fujii J, Maruoka K. Catalytic asymmetric synthesis of a nitrogen analogue of dialkyl tartrate by direct Mannich reaction under phase-transfer conditions. Org Lett 2004;6:2397–2399. 12. Notz W, Tanaka F, Watanabe S, Chowdari NS, Turner JM, Thayumanuvan R, Barbas CF III. The direct organocatalytic asymmetric Mannich reaction: unmodified aldehydes as nucleophiles. J Org Chem 2003;68:9624–9634. 13. Zhuang W, Saaby S, Jorgensen KA. Direct organocatalytic enantioselective Mannich reactions of ketimines: an approach to optically active quaternary α-amino acid derivatives. Angew Chem Int Ed 2004;43:4476–4478. 14. Notz W, Watanabe S, Chowdari N S, Zhong G, Betancort JM, Tanaka F, Barbas CFIII. The scope of the direct proline-catalyzed asymmetric addition of ketones to imines. Adv Synth Catal 2004;346:1131–1140. 15. Wang W, Wang J, Li H. Catalysis of highly stereoselective Mannich-type reactions of ketones with α-imino esters by a pyrrolidine-sulfonamide. Synthesis of unnatural α-amino acids. Tetrahedron Lett 2004;45:7243–7246.
DIRECT ASYMMETRIC ANTI-MANNICH-TYPE REACTIONS 16. Akiyama T, Itoh J, Yokota K, Fuchibe K. Enantioselective Mannich-type reaction catalyzed by a chiral Brønsted acid. Angew Chem Int Ed 2004;43:1566–1568. 17. Zhang H, Mitsumori S, Utsumi N, Imai M, Garcia-Delgado N, Mifsud M, Albertshofer K, Cheong PH-Y, Houk KN, Tanaka F, Barbas CFIII. Catalysis of 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives in enantioselective anti-Mannich-type reactions: importance of the 3-acid group on pyrrolidine for stereocontrol. J Am Chem Soc 2008;130:875–886. 18. Yoshida T, Morimoto H, Kumagai N, Matsunaga S, Shibasaki M. Non-C2symmetric, chirally economical, and readily tunable linked-binols: design and application in a direct catalytic asymmetric Mannich-type reaction. Angew Chem Int Ed 2005;44:3470-–3474. 19. Kano T, Yamaguchi Y, Maruoka K. A designer axially chiral amino sulfonamide as an efficient organocatalyst for direct asymmetric Mannich reactions of N-Boc-protected imines. Angew Chem Int Ed 2009;48:1838–1840 20. Pouliquen M, Blanchet J, Lasne M-C, Rouden J. 3-Trifluoromethanesulfonamidopyrrolidine: a general organocatalyst for anti-selective Mannich reactions. Org Lett 2008;10:1029–1032 21. Zhang H, Chuan Y, Li Z, Peng Y. 4-Aminothiourea prolinol tertbutyldiphenylsilyl ether: a chiral secondary amine-thiourea as organocatalyst for enantioselective anti-Mannich reactions. Adv Synth Catal 2009;351:2288–2294 22. Gómez-Bengoa E, Maestro M, Mielgo A, Otazo I, Palomo C, Velilla I. A 4-hydroxypyrrolidine-catalyzed Mannich reaction of aldehydes: control of anti-selectivity by hydrogen bonding assisted by Brønsted acids. Chem Eur J 2010;16:5333–5342 23. Martín-Rapún R, Fan X, Sayalero S, Bahramnejad M, Cuevas F, Pericàs MA. Highly active organocatalysts for asymmetric anti-Mannich reactions. Chem Eur J 2011;17:8780–8783. 24. Martín-Rapún R, Sayalero S, Pericàs MA. Asymmetric anti-Mannich reactions in continuous flow. Green Chem 2013;15:3295–3301. 25. Albrecht BK, Williams RM. A concise formal total synthesis of TMC-95A/ B proteasome inhibitors. Org Lett 2003;5:197–200. 26. Reisman SE, Ready JM, Weiss MM, Hasuoka A, Hirata M, Tamaki K, Ovaska TV, Smith CJ, Wood JL. Evolution of a synthetic strategy: total synthesis of (±)-Welwitindolinone A isonitrile. J Am Chem Soc 2008;130:2087–2100. 27. Abadi AH, Abou-Seri SM, Abdel-Rahman DE, Klein C, Lozach O, Meijer L. Synthesis of 3-substituted-2-oxoindole analogues and their evaluation
28.
29.
30.
31.
32. 33.
34.
35.
36.
37.
38.
805
as kinase inhibitors, anticancer and antiangiogenic agents. Eur J Med Chem 2006;41:296–305. Ponglux D, Wongseripipatana S, Aimi N, Nishimura M, Ishikawa M, Sada H, Haginiwa J, Sakai SI. Structure and synthesis of two new types of oxindole alkaloids found from Uncaria salaccensis. Chem Pharm Bull 1990;38:573–575. Lee KK, Zhou BN, Kingston DGI, Vaisberg AJ, Hammond GB. Bioactive indole alkaloids from the bark of Uncaria guianensis. Planta Med 1999;65:759–760 Cui CB, Akeya H, Osada H. Novel mammalian cell cycle inhibitors, spirotryprostatins A and B, produced by Aspergillus fumigatus, which inhibit mammalian cell cycle at G2/M phase. Tetrahedron 1996;52: 12651–12666. Edmondson S, Danishefsky SJ, Sepp-Lorenzino L, Rosen N. Total synthesis of Spirotryprostatin A, leading to the discovery of some biologically promising analogues. J Am Chem Soc 1999;121:2147–2155. Tian X, Jiang K, Peng J, Du W, Chen YC. Organocatalytic stereoselective Mannich reaction of 3-substituted oxindoles. Org Lett 2008;10:3583–3586. Ashimori A, Bachand B, Calter MA, Govek SP, Overman LE, Poon DJ. Catalytic asymmetric synthesis of quaternary carbon centers. Exploratory studies of intramolecular Heck reactions of (z)-α,β-unsaturated anilides and mechanistic investigations of asymmetric Heck reactions proceeding via neutral intermediates. J Am Chem Soc 1998;120:6488–6499. Overman LE, Watson DA. Diastereoselection in the formation of spirocyclic oxindoles by the intramolecular Heck reaction. J Org Chem 2006;71:2587–2599. Pinto A, Jia Y, Neuville L, Zhu J. Palladium-catalyzed enantioselective domino Heck–cyanation sequence: development and application to the total synthesis of esermethole and physostigmine. Chem Eur J 2007; 13:961–967. Cheng L, Liu L, Jia H, Wang D, Chen Y-J. Enantioselective organocatalytic anti-Mannich-type reaction of N-unprotected 3-substituted 2-oxindoles with aromatic N-Ts-aldimines. J Org Chem 2009;74:4650–4653. Jia YX, Xie JH, Duan HF, Wang LX, Zhou QL. Asymmetric Friedel Crafts addition of indoles to N-sulfonyl aldimines: a simple approach to optically active 3-indolyl-methanamine derivatives. Org Lett 2006;8:1621–1624. Zhang TY, He W, Zhao XY, Jin Y. Asymmetric oxaziridination catalyzed by cinchona alkaloid derivatives containing sulfide. Tetrahedron 2013;69:7416–7422.
Chirality DOI 10.1002/chir
