Chemistry
The EGCG derivatives (compounds
1–
5) were prepared according to Fig.
1. Compound
1 and
2 were prepared in 11–27% yield by the treatment of
d-glucopyranosyl bromide (2) [
18] and EGCG with potassium carbonate and potassium hydroxide solution (0.5 M in CH
3OH) as previously described [
19]. The preparation of
IV,
V and
VI were obtained as the major products in 11–45% yield by the reaction of EGCG with sodium hydride and propargyl bromide using a similar method as reported in the literature. To introduce the azido functionality for the click reaction,
d-glucose was readily converted to
d-glucosyl azide (3) according to known procedures [
18].
d-Glucosyl azide (3) was then reacted with the alkynes
IV,
V and
VI in the presence of copper (II) acetate and sodium ascorbate in
tert-butyl alcohol and water (1:1) at room temperature for 2 h to afford the EGCG glycosides compound
3–
5 in 56–78% yield. The derivatives were characterized by
1H-NMR,
13C-NMR, ESI–MS, and HRESI-MS, which were consistent with the proposed structures.
(2R,3R)-7-Hydroxy-5-(prop-2-yn-1-yloxy)-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate (IV)
Yield: 45%, 1H-NMR (CD3OD, 500 MHz) δ 6.90 (s, 2H, C2″-H, C6″-H), 6.50 (s, 2H, C2′-H, C6′-H), 5.96 (s, 2H, C6-H, C8-H), 5.53 (brs, 1H, C3-H), 4.97 (s, 1H, C2-H), 4.78 (d, 2H, J = 2.4 Hz, OCH2), 3.29 (t, 1H, J = 1.6 Hz, C≡CH), 2.96 (dd, 1H, J = 4.6 Hz, 12.0 Hz, C4-Ha), 2.85 (dd, 1H, J = 4.6 Hz, 12.0 Hz, C4-Hb); 13C-NMR (CD3OD, 125 MHz) δ 167.0 (C=O), 157.9 (C-7), 157.8 (C-9), 157.2 (C-5), 151.9 (C-3′, C-5′), 146.7 (C-3″, C-5″), 138.4 (C-4″), 133.8 (C-4′), 130.7 (C-1′), 127.1 (C-1″), 110.1 (C-2″, C-6″), 106.8 (C-2′, C-6′), 99.3 (C-10), 96.5 (C-8), 95.9 (C-6), 80.4 (C-2), 79.5 (C≡CH), 78.5 (C≡CH), 76.7 (C-3), 60.0 (OCH2), 26.8 (C-4); ESIMS: m/z 495 [M−H]–.
(2R,3R)-2-(3,5-Dihydroxy-4-(prop-2-yn-1-yloxy)phenyl)-5,7-dihydroxychroman-3-yl 3,5-dihydroxy-4-(prop-2-yn-1-yloxy)benzoate (V)
Yield: 27%, 1H-NMR (CD3OD, 500 MHz) δ 6.90 (s, 2H, C2″-H, C6″-H), 6.52 (s, 2H, C2′-H, C6′-H), 5.96 (s, 2H, C6-H, C8-H), 5.56 (brs, 1H, C3-H), 5.00 (s, 2H, C2-H), 4.77 (d, 2H, J = 2.4 Hz, OCH2), 4.67 (d, 2H, J = 2.4 Hz, OCH2), 3.30 (t, 2H, J = 1.6 Hz, 2 × C≡CH), 2.98 (dd, 1H, J = 4.6 Hz, 12.1 Hz, C4-Ha), 2.86 (dd, 1H, J = 4.6 Hz, 12.1 Hz, C4-Hb); 13C-NMR (CD3OD, 125 MHz) δ 167.0 (C=O), 157.9 (C-7), 157.8 (C-9), 157.0 (C-5), 151.9 (C-3′, C-5′), 151.8 (C-3″, C-5″), 139.4 (C-4″), 136.3 (C-4′), 134.6 (C-1′), 127.0 (C-1″), 110.1 (C-2″, C-6″), 106.8 (C-2′, C-6′), 99.3 (C-10), 96.6 (C-8), 95.9 (C-6), 80.4 (C-2), 80.0 (C≡CH), 78.2 (C≡CH), 76.7 (C≡CH), 76.4 (C≡CH), 70.2 (C-3), 60.2 (OCH2), 60.0 (OCH2), 26.8 (C-4); ESIMS: m/z 533 [M−H]−.
(2R,3R)-2-(3,5-Dihydroxy-4-(prop-2-yn-1-yloxy)phenyl)-7-hydroxy-5-(prop-2-yn-1-yloxy)chroman-3-yl 3,5-dihydroxy-4-(prop-2-yn-1-yloxy)benzoate (VI)
Yield: 11%, 1H-NMR (CD3OD, 500 MHz) δ 6.88 (s, 2H, C2″-H, C6″-H), 6.52 (s, 2H, C2′-H, C6′-H), 6.00 (s, 2H, C6-H, C8-H), 5.75 (brs, 1H, C3-H), 5.12 (s, 1H, C2-H), 4.79 (d, 6H, J = 2.4 Hz, 3 × OCH2), 3.29 (t, 3H, J = 1.6 Hz, 3 × C≡CH), 2.98 (dd, 1H, J = 4.6 Hz, 12.0 Hz, C4-Ha), 2.85 (dd, 1H, J = 4.6 Hz, 12.0 Hz, C4-Hb); 13C-NMR (CD3OD, 125 MHz) δ 166.7 (C=O), 158.2 (C-7), 158.0 (C-9), 156.2 (C-5), 152.1 (C-3′, C-5′), 151.8 (C-3″, C-5″), 149.2 (C-4″), 139.3 (C-4′), 126.2 (C-1′), 117.7 (C-1″), 110.4 (C-2″, C-6″), 110.0 (C-2′, C-6′), 98.9 (C-10), 97.2 (C-8), 95.7 (C-6), 80.0 (C-2), 77.4 (C≡CH), 76.7 (C≡CH), 76.7 (C≡CH), 76.7 (C≡CH), 76.7 (C≡CH), 76.3 (C≡CH), 68.2 (C-3), 60.0 (OCH2), 54.5 (OCH2), 23.7 (C-4); ESIMS: m/z 571 [M−H]−.
(2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,5-dihydroxy-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)benzoate (compound 1)
Yield: 17%, 1H-NMR (CD3OD, 500 MHz) δ 6.82 (s, 2H, C2″-H, C6″-H), 6.52 (s, 2H, C2′-H, C6′-H), 5.84 (d, 1H, J = 2.4 Hz, C6-H), 5.84 (d, 1H, J = 2.4 Hz, C8-H), 5.37 (brs, 1H, C3-H), 5.25–5.24 (m, 1H, C3‴-H), 5.03 (s, 1H, C2-H), 4.87 (d, 1H, J = 9.0 Hz, C1‴-H), 4.59-4.57 (m, 1H, C5‴-H), 3.60–3.58 (m, 2H, C6‴-H), 3.33–3.15 (m, 2H, C2‴-H, C4‴-H), 2.89–2.69 (m, 1H, C4-Ha), 2.58–2.49 (m, 1H, C4-Hb); 13C-NMR (CD3OD, 125 MHz) δ 164.7 (C=O), 156.7 (C-5), 156.5 (C-9), 155.3 (C-7), 150.3 (C-3′, 5′), 149.8 (C-3″, 5″), 137.1 (C-4″), 135.6 (C-4′), 132.6 (C-1″), 125.6 (C-1′), 108.6 (C-2″, 6″), 106.0 (C-1‴), 105.6 (C-2′, 6′), 95.7 (C-6), 94.2 (C-8), 92.0 (C-10), 77.3 (C-2), 77.2 (C-5‴), 76.4 (C-3‴), 75.1 (C-2‴), 73.6 (C-4‴), 69.3 (C-3), 60.4 (C-6‴); ESIMS: m/z 621 [M+H]+, HRESIMS: calcd for C28H28O16 [M−H]− 619.1305, found 619.1295.
(2R,3R)-2-(3,5-Dihydroxy-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)phenyl)-5,7-dihydroxychroman-3-yl 3,5-dihydroxy-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)benzoate (compound 2)
Yield: 20%, 1H-NMR (CD3OD, 500 MHz) δ 6.80 (s, 2H, C2″-H, C6″-H), 6.51 (s, 2H, C2′-H, C6′-H), 5.94 (d, 1H, J = 2.4 Hz, C6-H), 5.84 (d, 1H, J = 2.4 Hz, C8-H), 5.38 (brs, 1H, C3-H), 5.24–5.23 (m, 1H, C3‴-H), 5.14–5.13 (m, 1H, C3‴-H), 5.03 (s, 1H, C2-H), 4.70 (d, 1H, J = 9.0 Hz, C1‴-H), 4.61–4.60 (m, 1H, C5‴′-H), 4.56–4.55 (m, 1H, C5‴-H), 4.46 (d, 1H, J = 9.0 Hz, C1‴′-H), 3.61–3.57 (m, 4H, C6‴-H, C6‴′-H), 3.30–3.22 (m, 4H), 2.99–2.89 (m, 1H, C4-Ha), 2.70–2.66 (m, 1H, C4-Hb); 13C-NMR (CD3OD, 125 MHz) δ 164.7 (C=O), 156.7 (C-5), 156.5 (C-9), 155.3 (C-7), 150.3 (C-3′, 5′), 149.8 (C-3″, 5″), 137.1 (C-4″), 135.6 (C-4′), 132.6 (C-1″), 125.6 (C-1′), 108.6 (C-2″, 6″), 106.0 (C-1‴), 105.8 (C-2′, 6′), 104.6 (C-1‴), 95.7 (C-6), 94.3 (C-8), 92.1 (C-10), 77.2 (C-2), 77.1, 73.6, 76.1, 75.8, 75.7, 73.6, 69.4 (C-3), 61.2, 60.4, 25.6 (C-4); ESIMS: m/z 782 [M+H]+, HRESIMS: calcd for C34H38O21 [M−H]− 781.1833, found 781.1814.
(2R,3R)-7-Hydroxy-5-((1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-5-yl)methoxy)-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate (compound 3)
Yield: 78%, 1H-NMR (CD3OD, 500 MHz) δ 8.11 (s, 1H, CH–N), 6.91 (s, 2H, C2″-H, C6″-H), 6.53 (s, 1H, C2′-H), 6.52 (s, 1H, C6′-H), 5.96 (s, 1H, C6-H), 5.95 (s, 1H, C8-H), 5.58 (d, 1H, J = 7.6 Hz, C1‴-H), 5.21 (s, 1H, C3-H), 5.11 (s, 1H, C2-H), 4.78 (d, 2H, J = 2.4 Hz, OCH2), 3.89–3.86 (m, 2H), 3.72–3.69 (m, 1H), 3.57–3.53 (m, 2H), 3.51–3.48 (m, 1H), 2.99–2.87 (m, 1H, C4-Ha), 2.85–2.82 (m, 1H, C4-Hb); 13C-NMR (CD3OD, 125 MHz) δ 167.1 (C=O), 157.9 (C-5), 157.8 (C-7), 157.0 (C-9), 151.9 (C-3″), 151.9 (C-5″), 151.7 (C-3′), 151.6 (C-5′), 146.7 (CH=N), 139.4 (C-4″), 136.3 (C-4′), 127.0 (C-1′), 124.7 (C-1″), 110.4 (C-2″), 110.1 (C-6″), 106.9 (C-2′), 106.8 (C-6′), 99.3 (C-10), 96.6 (C-1‴), 95.9 (C-6), 89.6 (C-8), 81.1 (C-2), 78.4, 76.8, 74.1, 70.8, 70.2 (OCH2), 66.0 (C-3), 62.4 (C-6‴), 26.7 (C-4); ESIMS: m/z 702 [M+H]+, HRESIMS: calcd for C31H31N3O16H [M−H]− 700.1704, found 701.1636.
(2R,3R)-2-(3,5-Dihydroxy-4-((1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-5-yl)methoxy)phenyl)-5,7-dihydroxychroman-3-yl3,5-dihydroxy-4-((1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-5-yl)methoxy)benzoate (compound 4)
Yield: 70%, 1H-NMR (CD3OD, 500 MHz) δ 8.18 (s, 1H, CH–N), 8.12 (s, 1H, CH–N), 6.92 (s, 2H, C2″-H, C6″-H), 6.53 (s, 2H, C2′-H, C6′-H), 5.96 (s, 2H, C6-H, C8-H), 5.58 (d, 1H, J = 7.6 Hz, C1‴-H), 5.57 (d, 1H, J = 7.6 Hz, C1‴′-H), 5.22 (C3-H), 5.11 (C2-H), 5.00 (d, 2H, J = 2.4 Hz, 2 × OCH3), 3.91–3.85 (m, 4H), 3.71–3.68 (m, 2H), 3.57–3.48 (m, 6H), 2.97 (dd, 1H, J = 4.6 Hz, 12.0 Hz, C4-Ha), 2.94 (dd, 1H, J = 4.6 Hz, 12.0 Hz, C4-Hb); 13C-NMR (CD3OD, 125 MHz) δ 167.0 (C=O), 157.9 (C-7), 157.8 (C-9), 157.0 (C-5), 151.7 (C-3′, C-5′), 151.6 (C-3″, C-5″), 139.4 (C-4″), 136.3 (C-4′), 134.6 (C-1′), 127.0 (C-1″), 110.4 (C-2″, C-6″), 107.2 (C-2′, C-6′), 99.2 (C-10), 96.6 (C-8), 95.9 (C-6), 89.5 (C-1‴), 89.5 (C-1‴′), 81.1, 78.4, 78.3, 74.1, 74.0, 70.8, 70.8, 70.2 (OCH2), 66.0 (C-3), 62.4 (C-6‴), 62.4 (C-6‴′′), 26.8 (C-4); ESIMS: m/z 945 [M+H]+, HRESIMS: calcd for C40H44N6O21H [M−H]− 943.2487, found 944.2460.
(2R,3R)-2-(3,5-Dihydroxy-4-((1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-5-yl)methoxy)phenyl)-7-hydroxy-5-((1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-5-yl)methoxy)chroman-3-yl 3,5-dihydroxy-4-((1-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-5-yl)methoxy)benzoate (compound 5)
Yield: 56%, 1H-NMR (CD3OD, 500 MHz) δ 8.19 (s, 1H, CH–N), 8.13 (s, 1H, CH–N), 8.09 (s, 1H, CH–N), 6.98 (s, 2H, C2″-H, C6″-H), 6.57 (s, 2H, C2′-H, C6′-H), 5.97 (s, 2H, C6-H, C8-H), 5.64 (d, 1H, J = 7.6 Hz, C1‴-H), 5.59 (d, 1H, J = 7.6 Hz, C1‴′-H), 5.57 (d, 1H, J = 7.6 Hz, C1‴′′-H), 5.13 (C3-H), 5.12 (C2-H), 5.05 (d, 2H, J = 2.4 Hz, 3 × OCH3), 4.09–4.08 (m, 2H), 3.89–3.88 (m, 2H), 3.87–3.85 (m, 4H), 3.72–3.71 (m, 2H), 3.60–3.54 (m, 6H), 2.96 (dd, 1H, J = 4.6 Hz, 12.0 Hz, C4-Ha), 2.93 (dd, 1H, J = 4.6 Hz, 12.0 Hz, C4-Hb); 13C-NMR (CD3OD, 125 MHz) δ 166.9 (C=O), 158.0 (C-7), 157.9 (C-9), 156.9 (C-5), 151.9 (C-3′, C-5′), 151.7 (C-3″, C-5″), 140.7 (C-4″), 136.4 (C-4′), 134.8 (C-1′), 127.1 (C-1″), 112.7 (C-2″, C-6″), 107.4 (C-2′, C-6′), 99.1 (C-10), 96.3 (C-8), 95.8 (C-6), 89.6 (C-1‴), 89.6 (C-1‴″), 89.6 (C-1‴″″), 81.1, 78.4, 78.4, 78.1, 74.1, 74.0, 73.8, 70.8, 70.8 (OCH2), 66.2 (C-3), 62.4 (C-6‴), 62.3 (C-6‴″), 62.3 (C-6‴″), 26.4 (C-4); ESIMS: m/z 1186 [M−H]+, HRESIMS: calcd for C49H57N9O26H [M−H]− 1186.3342, found 1186.3376.