SUPPORTING INFORMATIONSynthesis, Antioxidant and Molecular Docking Studies of (−)-Catechin Derivatives

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Journal of the Korean Chemical Society 2021, Vol. 65, No. 2

Printed in the Republic of Korea

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SUPPORTING INFORMATION

Synthesis, Antioxidant and Molecular Docking Studies of ( −)-Catechin Derivatives

Deepak Kumar^†,‡, Raj Kumar^§,#, R. Ramajayam^¶, Keun Woo Lee^§, and Dong-Soo Shin^†,*

†Department of Chemistry, Changwon National University, Changwon, GN, 51140, S. Korea.

*E-mail: [email protected]

‡Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Solan, H.P-173 229.

§Division of Applied Life Science (BK21 Plus), Systems and Synthetic Agrobiotech Center, Plant Molecular Biology and Biotechnology Research Center, Research Institute of Natural Science, Gyeongsang National University, Jinju, GN, 52828, Korea.

#Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan, Himachal Pradesh, 173234, India.

¶Pharmacy Department, DIT University, Dehradun, Uttrakhand, 248009, India.

(Received January 12, 2021; Accepted January 14, 2021)

Characterization of the final compound (1a-1l) (2S,3R)-2-(3,4-Dihydroxyphenyl)-3-(9-hydroxynonyl- oxy)chroman-5,7-diol (1a): Semi solid, Yield 83% (0.093 g), [α]D25–52.4 (c 1.0, MeOH). ¹H NMR (CD3OD, 400 MHz): δ 6.88 (s, 1H), 6.84-6.74 (m, 2H), 5.96 (d, 2H, J = 3.28 Hz), 4.68 (d, 1H, J = 7.83 Hz), 3.73-3.68 (m, 1H), 3.58 (t, 2H, J = 6.56 Hz), 3.47-3.39 (m, 1H), 3.21-3.13 (m, 1H), 2.98(dd, 1H, J = 5.30, 16.16Hz), 2.57 (dd, 1H, J = 8.58, 16.16Hz), 1.58-1.49 (m, 2H), 1.43-1.03(m, 12H).

13C NMR (CD₃OD, 100 MHz): δ 160.0, 159.8, 159.4, 148.3, 148.3, 135.1, 123.0, 118.7, 117.9, 103.7, 99.2, 98.6, 83.92, 79.5, 73.6, 66.2, 36.2, 33.4, 33.2, 33.0, 32.6, 29.4, 29.2. ESI-MS (m/z): 455 [M+Na]⁺.

(2S,3R)-2-(3,4-Dihydroxyphenyl)-3-(9-methoxy nonyl- oxy)chroman-5,7-diol (1b): Semi solid, Yield 83% (0.060 g), [α]D25 –59.9 (c 1.0, MeOH). ¹H NMR (CD3OD, 400 MHz): δ 6.82 (d, 1H, J = 1.76 Hz), 6.76-6.68 (m, 2H), 5.92 (d, 1H, J = 2.27Hz), 5.85 (d, 1H, J = 2.27 Hz), 4.62 (d, 1H, J = 7.32 Hz), 3.69-3.63 (m, 1H), 3.48-3.40 (m, 1H), 3.37 (t, 2H, J = 6.56 Hz), 3.31 (s, 3H), 3.21-3.15 (m, 1H), 2.86 (dd, 1H, J = 5.33, 15.91 Hz), 2.50(dd, 1H, J = 1.80, 16.16 Hz), 1.58-1.49 (m, 2H), 1.42-1.10 (m, 12H).¹³C NMR (CD₃OD, 100 MHz) δ 157.8, 157.5, 157.0, 146.1, 146.1, 132.6, 119.9, 116.1, 115.2, 100.8, 96.4, 95.6, 81.2, 77.1, 74.0, 70.7,58.6, 30.8, 30.6, 30.5, 30.4, 30.3, 27.1, 27.0, 26.2. ESI-MS (m/z):

469 [M+Na]⁺.

(2S,3R)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychro- man-3-yl-oxy)nonylacetate (1c): Semi solid, Yield 82%

(0.055 g), [α]_D²⁵ –46.9 (c 1.0, MeOH). ¹H NMR (CD₃OD, 400 MHz): δ 6.82 (d, 1H, J = 1.76 Hz), 6.77-6.68 (m, 2H), 5.92 (d, 1H, J = 2.27Hz), 5.85 (d, 1H, J = 2.27 Hz), 4.62 (d, 1H, J = 7.32 Hz), 4.04 (t, 2H, J = 6.56 Hz), 3.70-3.63

(m, 1H), 3.49-3.38 (m, 1H), 3.23-3.14 (m, 1H), 2.87 (dd, 1H, J = 5.30, 16.16 Hz), 2.51 (dd, 1H, J = 7.83, 15.91Hz), 2.01 (s, 3H), 1.65-1.55 (m, 2H), 1.43-1.10 (m, 12H). ¹³C NMR (CD3OD, 100 MHz): δ 173.2, 157.8, 157.6, 156.9, 146.1, 132.6, 119.9, 116.0, 115.3, 100.8, 96.4, 95.6, 81.3, 77.2, 70.6, 65.8, 30.8, 30.5, 30.4, 30.2, 29.7, 27.2, 26.9, 26.2, 20.8. ESI-MS (m/z): 475 [M+H]⁺.

(2S,3R)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychro- man-3-yl)oxy)nonyl benzoate (1d): Semi solid, Yield 84% (0.061 g), [α]_D²⁵ –24.4 (c 1.0, MeOH). ¹H NMR (CD₃OD, 400 MHz): δ 7.93-7.83 (m, 2H), 7.51-7.46 (m, 1H), 7.39- 7.34 (m, 2H), 6.72 (d, 1H, J = 1.76 Hz), 6.66-6.58 (m, 2H), 5.83 (d, 1H, J = 2.27 Hz), 5.75 (d, 1H, J = 2.27 Hz),4.51 (d, 1H, J = 7.57 Hz), 4.21 (t, 2H, J = 6.56 Hz), 3.59-3.51 (m, 1H), 3.38-3.30 (m, 1H), 3.11-3.04 (m, 1H), 2.76 (dd, 1H, J = 5.30, 16.16 Hz), 2.40 (dd, 1H, J = 8.08, 16.16 Hz), 1.72-1.62 (m, 2H), 1.38-0.98 (m, 12H). ¹³C NMR (CD₃OD, 100 MHz): δ 168.2, 157.9, 157.5, 157.0, 146.1, 134.1, 132.5, 131.7, 119.9, 116.0, 115.2, 100.7, 96.4, 95.6, 81.2, 77.1, 70.7, 66.3, 30.8, 30.4, 30.2, 30.2, 29.7, 27.1, 26.9, 26.2.

ESI-MS (m/z): 560 [M+Na]⁺.

(2S,3R)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychro- man-3-yl-oxy nonyl oxy)-1-morpholinoethanone (1e):

Semi solid, Yield 75% (0.046 g), [α]_D²⁵ –27.5 (c 1.0, MeOH).

1H NMR (CD3OD, 400 MHz): δ 6.85 (d, 1H, J = 2.02 Hz), 6.79-6.70 (m, 2H), 5.96 (d, 1H, J = 2.27 Hz), 5.90 (d, 1H, J = 2.27 Hz), 4.65 (d, 1H, J = 7.57 Hz), 4.15 (s, 2H), 3.74- 3.64 (m, 5H), 3.61-3.56 (m, 2H), 3.53-3.41 (m, 5H), 3.23- 3.16 (m, 1H), 2.91 (dd, 1H, J = 5.30, 16.16 Hz), 2.54 (dd, 1H, J = 8.08, 16.16 Hz), 1.65-1.55 (m, 2H), 1.36-1.08 (m, 12H). ¹³C NMR (CD₃OD, 100 MHz): δ 170.0, 157.3, 157.1, 156.5, 145.7, 132.1, 119.6, 115.7, 114.9, 100.5,

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Journal of the Korean Chemical Society 2 Deepak Kumar, Raj Kumar, R. Ramajayam, Keun Woo Lee, and Dong-Soo Shin

96.2, 80.9, 76.7, 76.7, 72.4, 70.5, 67.5, 61.3, 46.4, 43.3, 30.4, 30.2, 30.0, 29.9, 26.7, 26.6, 26.0, 20.9. ESI-MS (m/z):

582 [M+Na]⁺.

(2S,3R)-2-(3,4-Dihydroxyphenyl)-5,7dihydroxychro- man-3-yl) oxy-nonyl-oxy-1-(4-phenylpiperazin-1(-yl)ethanone (1f): Semi solid, Yield 79%, (0.046 g), [α]_D²⁵ –26.4 (c 1.0, MeOH). ¹H NMR (CD₃OD, 400 MHz): δ 7.25-7.20 (m, 2H), 6.98-6.93 (m, 2H), 6.88-6.83 (m, 1H) 6.70 (t, 3H, J = 2.01 Hz), 5.96 (d, 1H, J = 2.27 Hz), 5.85 (d, 1H, J = 2.27 Hz), 4.62 (d, 1H, J = 2.02 Hz), 4.20 (s, 2H), 3.74-3.69 (m, 1H), 3.67-3.61 (m, 2H), 3.61-3.55 (m, 1H), 3.54-3.39 (m, 4H), 3.22-3.10 (m, 3H), 2.85 (dd, 1H, J = 2.52, 16.16 Hz), 2.65-2.58 (m, 2H), 2.50 (dd, 1H, J = 8.58, 16.16 Hz), 1.67-1.55 (m, 2H), 1.42-1.09 (m, 12H).¹³C NMR (CD₃OD, 100 MHz) δ 168.0, 158.7, 157.8, 149.0, 131.7, 129.2, 129.5, 128.5, 120.6, 120.5, 116.6, 115.1, 114.2, 102.5, 94.5, 93.7, 80.1, 75.5, 70.8, 70.2, 70.1, 49.8, 45.1, 29.8, 29.7, 29.6, 29.5, 26.1, 25.9.ESI-MS (m/z): 635 [M+H]⁺.

(2S,3R)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychro- man-3-yl)oxy)nonyl)oxy)-1-(4-(4-fluorophenyl)piperazin-1-yl)ethanone (1g): Semi solid, Yield 77% (0.046 g), [α]_D²⁵ –25.5 (c 1.0, MeOH). ¹H NMR (CD₃OD, 400 MHz):

δ 6.89-6.88 (m, 2H), 6.87-6.86 (m, 2H), 6.72 (d, 1H, J = 2.02 Hz), 6.66-6.68 (m, 2H), 5.92 (d, 1H, J = 2.27 Hz), 5.82 (d, 1H, J = 2.27 Hz), 4.61 (d, 1H, J = 7.57 Hz), 4.20 (s, 2H), 3.74-3.69 (m, 1H), 3.67-3.61 (m, 2H), 3.61-3.55 (m, 1H), 3.54-3.39 (m, 4H), 3.22-3.10 (m, 3H), 2.85 (dd, 1H, J = 2.52, 16.16 Hz), 2.65-2.58 (m, 2H), 2.50 (dd, 1H, J

= 8.58, 16.16 Hz), 1.67-1.55 (m, 2H), 1.42-1.09 (m, 12H).¹³C NMR (CD₃OD, 100 MHz) δ 168.9, 158.7, 157.9, 154.0, 152.6, 152.0, 148.2, 148.1, 148.1, 135.6, 134.9, 132.5, 130.5, 130.2, 125.6, 117.6, 116.3, 114.8, 102.6, 94.6, 78.7, 77.8, 75.8, 71.4, 59.4, 52.9, 52.1, 36.7, 36.4, 36.3, 34.6, 30.1, 25.1.ESI-MS (m/z): 653 [M+H]⁺.

(2S,3R)-2-(3,4-Dihydroxyphenyl)-5,7dihydroxychro- man-3 yl-oxy nonyl oxy)-1-(4-(2-fluorophenyl piperazin-1 yl) propan-1-one (1h): Semi solid, Yield 77% (0.054 g), [α]_D²⁵ –22.4 (c 1.0, MeOH). ¹H NMR (CD₃OD, 400 MHz) δ 7.26-7.20 (m, 2H), 7.00-6.93 (m, 1H), 6.87-6.82 (m, 1H), 6.81 (d, 1H, J = 2.02 Hz), 6.76-6.67 (m, 2H), 5.92 (d, 1H, J = 2.27 Hz), 5.84 (d, 1H, J = 2.27 Hz), 4.61 (d, 1H, J

= 7.32 Hz), 3.77-3.68 (m, 6H), 3.67-3.61 (m, 2H), 3.50- 3.38 (m, 3H), 3.20-3.09 (m, 4H), 2.86 (dd, 1H, J = 5.30, 16.16 Hz), 2.69 (t, 2H, J = 6.06 Hz), 2.49 (dd, 1H, J = 5.30, 16.16 Hz), 1.57-1.49 (m,2H) 1.38-1.08 (m, 12H).¹³C NMR (CD3OD, 100 MHz) δ 168.9, 158.7, 157.9, 154.0, 152.6, 152.0, 148.2, 148.1, 148.1, 135.6, 134.9, 132.5, 130.5, 130.2, 125.6, 117.6, 116.3, 114.8, 102.6, 94.6, 78.7, 77.8, 75.8, 71.4, 59.4, 52.9, 52.1, 36.7, 36.4, 36.3, 34.6, 30.1, 25.1.

(2S,3R)-2-(3,4-Dihydroxyphenyl)-5,7dihydroxychro- man-3yl-nonyl-oxy-1-(2-trifluoromethyl phenyl)piperazin- 1-yl)propanone (1i): Semi solid, Yield 83% (0.093 g), [α]_D²⁵ –14.9 (c 1.0, MeOH). ¹H NMR (CD₃OD, 400 MHz): δ 7.45-7.36 (m, 1H), 7.23-7.16 (m, 2H), 7.13-7.07 (m, 1H), 6.81 (d, 1H, J = 2.02 Hz), 6.76-6.67 (m, 2H), 5.92 (d, 1H, J

= 2.27 Hz), 5.84 (d, 1H, J = 2.27 Hz), 5.85 (d, 1H, J = 2.27 Hz), 4.61 (d, 1H, J = 7.32 Hz),, 3.79-3.61 (m, 7H), 3.49- 3.39 (m, 3H), 3.28-3.12 (m, 5H), 2.86 (dd, 1H, J = 5.30, 16.16 Hz), 2.69 (t, 2H, J = 6.06 Hz), 2.48 (dd, 1H, J = 7.83, 16.16 Hz), 1.58-1.48(m,2H) 1.39-1.02 (m, 12H).¹³C NMR (CD₃OD, 100 MHz) δ 171.0, 157.8, 157.5, 152.6, 146.2, 145.4, 131.4, 130.9, 127.8, 126.6, 123.9, 121.9, 120.6, 117.1, 116.4, 116.0, 112.0, 109.4, 104.7, 95.5, 79.5, 79.2, 78.9, 72.3, 69.2, 59.0, 50.1, 45.3, 34.4, 30.7, 30.5, 30.3, 30.2, 27.2, 26.9, 26.2. ESI-MS (m/z): 740 [M+Na]⁺.

(2S,3R)-3-9-(3-Chloro-5-(trifluoromethyl)pyridin-2- yl)oxy)nonyl-oxy)-2-(3,4-dihydroxyphenyl)-chroman- 5,7-diol (1j): Semi solid, Yield 80% (0.085 g), [α]_D²⁵ –29.9 (c 1.0, MeOH). ¹H NMR (CD3OD, 400 MHz): δ 8.25-8.23 (m, 1H), 7.94-7.92 (m, 1H), 6.73 (d, 1H, J = 2.27 Hz), 6.66-6.58 (m, 2 H), 5.83 (d, 1H, J = 2.27 Hz), 5.75 (d, 1H, J = 2.27 Hz), 4.52 (d, 1H, J = 7.32 Hz), 4.33 (d, 2H, J = 7.32 Hz), 3.60-3.51 (m, 1H) 3.37-3.28 (m, 1H), 3.12-3.03 (m, 1H), 2.77 (dd, 1H, J = 5.30, 16.16 Hz), 2.40 (dd, 1H, J

= 8.08, 16.16 Hz), 1.75-1.65 (m,2H) 1.46-0.99 (m, 12H).

13C NMR (CD3OD, 100 MHz): δ 162.8, 157.8, 157.5, 156.9, 146.1, 146.1, 143.7, 136.4, 132.5, 126.1, 123.4, 121.8, 119.9, 116.0, 115.2, 100.7, 96.4, 81.2, 77.1, 70.7, 69.2, 30.8, 30.7, 30.5, 30.2, 29.7, 27.2, 26.3, 20.9. ESI-MS (m/z):

634 [M+Na]⁺.

(2S,3R)-3-(9-(5-Aminopyridin-2-yl)oxy-nonyl-oxy)- 2-(3,4dihydroxyphenyl) chroman-5,7-diol (1k): Semi solid, Yield 73% (0.085 g), [α]D25 –44.4 (c 1.0, MeOH).

1H NMR (CD₃OD, 400 MHz) δ 8.30-8.28 (m, 1H), 7.96 (dd, 1H, J = 2.27 ,9.09 Hz), 6.72 (d, 1H, J = 2.02 Hz), 6.66-6.58 (m, 3H), 5.82 (d, 1H, J = 2.27 Hz), 5.74(d, 1H, J

= 7.33 Hz), 4.54 (d, 1H, J = 7.32 Hz ), 4.36 (t 1H, J = 6.56 Hz) 3.60-3.53 (m, 1H), 3.46-3.41 (m, 1H) 3.39-3.32 (m, 1H), 3.12-3.05 (m, 1H), 2.76 (dd, 1H, J =5.05, 15.95 Hz), 2.40 (dd, 1H, J =7.83, 15.91 Hz), 1.76-1.16 (m, 2H), 1.48- 0.97 (m, 12H).¹³C NMR (CD₃OD, 100 MHz) δ 157.7, 156.9, 155.9, 154.0, 145.9, 143.0, 137.0, 131.9, 131.9, 126.8, 120.8, 119.5, 115.0, 111.1, 101.7, 95.8, 81.0, 79.8, 70.6, 69.8, 30.8, 30.7, 30.5, 30.1, 29.6, 27.2, 26.2, 20.7. ESI-MS (m/z): 547 [M+Na]⁺.

(2S,3R)-5-(Benzyloxy)-2-(3,4-dihydroxyphenyl)-7 hydroxy chroman-3-yl)oxy)nonyl 3-phenylpropanoate (1l): Semi solid, Yield 46% (0.080 g), [α]_D²⁵ –20.9 (c 1.0, MeOH).

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Synthesis, Antioxidant and Molecular Docking Studies of (−)-Catechin Derivatives 3

2021, Vol. 65, No. 2

1H NMR (CD3OD, 400 MHz) δ 7.30-7.12 (m, 5H), 6.82 (d, 1H, J = 2.02 Hz), 6.76-6.67 (m, 2H), 5.92 (d, 1H, J = 2.27 Hz), 5.84 (d, 1H, J = 2.27 Hz), 4.61 (d, 1H, J = 7.57 Hz), 4.03 (t, 2H, J = 6.31 Hz), 3.69-3.62 (m, 1H), 3.41 (t, 2H, J = 6.31), 2.9 (m, 3H), 2.60 (m, 2H), 2.50 (dd, 1H, J = 8.08, 16.16 Hz), 1.60-1.48 (m, 2H) 1.42-1.06 (m, 12H).¹³C

NMR (CD3OD, 100 MHz) δ 175.3, 157.8, 157.6, 146.2, 146.1, 141.9, 129.4, 129.3, 127.2, 119.9, 116.0, 115.2, 107.6, 96.4, 95.6, 81.3, 73.8, 71.9, 65.7, 36.8, 32.0, 30.7, 30.5, 30.4, 29.7, 27.1, 26.9, 26.2, 23.7. ESI-MS (m/z): 587 [M+Na]⁺.