Chlorogenic Acid DeriVatiVes: R-Glucosidase Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19 6193
(C-7′), 149.5 (C-3′), 168.8 (C-9′), 175.4 (C-7). ESI-MS (negative):
393.3 ([M - H]-, 100%).
1,7-(6-Undecanone) Chlorogenic Acid Ketal (6). After acid
hydrolysis of 26 and purification on ODS, 6 was obtained from
90% MeOH eluted part (yield: 72.6%) of an ODS column as an
amorphous powder, [R]D +20.9 (c 0.2, MeOH). 1H NMR (CDCl3)
δ 0.87 (m, 6H, -(CH2)5CH3), 1.28 (m, 16H, -CH2(CH2)4CH3),
1.80 (m, 4H, -CH2(CH2)4CH3), 1.93 (t, J ) 12.5 Hz, 1H, H-6a),
2.10 (dd, J ) 3.0, 15.0 Hz, 1H, H-2a), 2.25 (br d, J ) 15.0, 1H,
H-2b), 2.34 (br dd, J ) 2.5, 12.5 Hz, 1H, H-6b), 3.74 (dd, J ) 3.5,
9.5 Hz, 1H, H-4), 4.27 (br s, H-3), 5.37 (m, 1H, H-5), 6.11 (d, J )
15.5 Hz, 1H, H-8′), 6.80 (d, J ) 8.5 Hz, 1H, H-5′), 6.83 (br d, J
) 8.5 Hz, 1H, H-6′), 6.98 (br s, J ) 2.0 Hz, 1H, H-2′), 7.48 (d, J
) 15.5 Hz, 1H, H-7′). 13C NMR (CDCl3, 300 MHz) δ 14.1
(-(CH2)5CH3), 22.6 and 23.4 and 29.2 and 31.6 and 37.4 and 38.1
and 38.9 (-(CH2)5CH3 and C-2, C-6), 69.6 (C-3), 70.1 (C-5), 73.5
(C-4), 79.6 (C-1), 114.2 and 114.5 and 114.9 and 115.5 (C-2′, C-1′′,
C-8′, and C-5′), 122.4 (C-6′), 126.9 (C-1′), 143.9 (C-3′), 146.0 (C-
7′), 146.7 (C-4′), 167.4 (C-9′), 172.7 (C-7). ESI-MS (negative):
533.4 ([M - H]-, 100%)
1,7-(3-Pentanone) Ketal (2). The title compound was obtained
from 70% MeOH eluted part of an ODS column after acid
hydrolysis of 22 (yield: 71.5%). 2: crystalline powder; [R]D +4.4
1
(c 0.5, MeOH); mp 103-105 °C. H NMR (CDCl3 + CD3OD) δ
0.97 (m, 6H, -CH2CH3), 1.84 (m, 5H, -CH2CH3 and H-6a), 2.08
(br d, J ) 14.0 Hz, 1H, H-2a), 2.20 (br d, J ) 14.0 Hz, 1H, H-2b),
2.34 (br d, J ) 12.0 Hz, 1H, H-6b), 3.73 (br d, J ) 6.5 Hz, 1H,
H-4), 4.26 (br s, 1H, H-3), 5.35 (m, 1H, H-5), 6.17 (d, J ) 15.5
Hz, 1H, H-8′), 6.80 (br s, 1H, H-5′), 6.84 (d, J ) 7.5 Hz, 1H,
H-6′), 7.01 (br s, 1H, H-2′), 7.53 (d, J ) 15.5 Hz, 1H, H-7′). 13C
NMR (CDCl3-CD3OD) δ 7.3 (-CH2CH3), 31.0 (-CH2CH3), 31.1
(-CH2CH3), 37.2 (C-2), 37.7 (C-6), 69.4 (C-4), 69.6 (C-3), 72.7
(C-5), 79.5 (C-1), 113.7 (C-2′), 114.0 (C-8′) 115.2 (C-5′), 115.3
(C-1′′), 122.2 (C-6′), 126.4 (C-1′), 144.6 (C-4′), 146.2 (C-7′), 147.5
(C-3′), 167.7 (C-9′), 173.4 (C-7). ESI-MS (negative): 421.3 ([M
- H]-, 100%).
1,7-(4-Heptanone) Ketal (3). After acid hydrolysis of 23 and
purification on ODS, Cr3 was obtained from 50-60% MeOH
eluted part (yield: 81.0%). 3: crystalline powder: [R]D +9.9 (c 0.06,
MeOH); mp 180-182 °C. 1H NMR (CD3OD) δ 0.98 (m, 6H,
-CH2CH2CH3), 1.46 (m, 4H) and 1.79 (m, 5H) (-CH2CH2CH3),
1.86 (dd, J ) 11.0, 13.5 Hz, 1H, H-6a), 2.05 (dd, J ) 3.0, 15.0
Hz, 1H, H-2a), 2.14 (m, 1H, H-2b), 2.29 (m, 1H, H-6b), 3.73 (dd,
J ) 3.5, 9.0 Hz, 1H, H-4), 4.22 (dd, J ) 3.5, 6.5 Hz, 1H, H-3),
5.31 (m, 1H, H-5), 6.28 (d, J ) 15.5 Hz, 1H, H- H-8′), 6.78 (d, J
) 8.5 Hz, 1H, H-5′), 6.92 (dd, J ) 2.0, 8.5 Hz, 1H, H-6′), 7.05 (d,
J ) 2.0 Hz, 1H, H-2′), 7.59 (d, J ) 15.5 Hz, 1H, H-7′).13C NMR
(CD3OD) δ 14.3 and 14.4(-CH2CH2CH3), 17.7 and 17.8
(-CH2CH2CH3), 39.0 (-C-2 and C-6), 41.9 and 42.2
(-CH2CH2CH3), 70.4 (C-3), 71.0 (C-5), 73.4 (C-4), 80.7 (C-1),
115.0 and 115.2 (C-2′, 8′, 1′′), 116.5 (C-5′), 123.0 (C-6′), 127.8
(C-1′), 146.8 (C-4′), 147.2 (C-7′), 149.6 (C-3′), 168.8 (C-9′), 175.6
(C-7). ESI-MS (negative): 449.2 ([M - H]-, 100%).
1,7-(5-Nonanone) Chlorogenic Acid Ketal (4). After acid
hydrolysis of 24 and purification on ODS, 4 was obtained from 60%
MeOH eluted part (yield: 81.2%) as a crystalline powder, [R]D +17.8
(c 0.4, MeOH); mp 194-195 °C. 1H NMR (CD3OD) δ 0.97 (m, 6H,
-CH2CH2CH2CH3), 1.41 (m, 8H) and 1.87 (m, 5H) (-CH2CH2-
CH2CH3, and H-6a), 2.08 (dd, J ) 3.0, 15.0 Hz, 1H, H-2a), 2.16 (m,
1H, H-2b), 2.32 (m, 1H, H-6b), 2.29 (m, 1H, H-2b), 3.73 (dd, J )
3.5, 9.0 Hz, 1H, H-4), 4.23 (dd, J ) 3.5, 6.5 Hz, 1H, H-3), 5.34 (m,
1H, H-5), 6.30 (d, J ) 15.5 Hz, 1H, H-8′), 6.80 (d, J ) 8.5 Hz, 1H,
H-5′), 6.97 (dd, J ) 2.0, 8.5 Hz, 1H, H-6′), 7.07 (d, J ) 2.0 Hz, 1H,
H-2′), 7.62 (d, J ) 15.5 Hz, 1H, H-7′).13C NMR (CD3OD) δ 14.3
(-CH2CH2CH2CH3), 23.6 (-CH2CH2CH2CH3), 26.5 and 26.6
(-CH2CH2CH2CH3), 39.1 (C-2, 6), 39.5 and 39.7 (-CH2CH2-
CH2CH3), 70.4 (C-3), 70.9 (C-5), 73.4 (C-4), 80.7 (C-1), 115.0 (C-
2′), 115.2 (C-1′′ and C-8′), 116.5 (C-5′), 123.0 (C-6′), 127.8 (C-1′),
146.8 (C-3′), 147.2 (C-7′), 149.6 (C-4′), 168.7 (C-9′), 175.6 (C-7).
ESI-MS (negative): 477.3 ([M - H]-, 100%).
1,7-(6-Undecanone) Chlorogenic Acid Ketal (5). After acid
hydrolysis of 25 and purification on ODS, 5 was obtained from
80% MeOH eluted part (yield: 76.3%) of an ODS column as a
crystalline powder, [R]D +22.2 (c 0.6, MeOH); mp 171-172 °C.
1H NMR (CDCl3 + CD3OD 1:1) δ 0.91 (m, 6H, -CH2CH2-
CH2CH2CH3), 1.32 (m, 8H, -CH2CH2CH2CH2CH3), 1.42 (m, 4H,
-CH2CH2CH2CH2CH3), 1.83 (m, 4H, -CH2CH2CH2CH2CH3),
1.93 (dd, J ) 11.0, 13.0 Hz, 1H, H-6a), 2.09 (dd, J ) 3.0, 15.0
Hz, 1H, H-2a), 2.20 (m, 1H, H-2b), 2.34 (m, 1H, H-6b), 3.72 (dd,
J ) 3.5, 9.5 Hz, 1H, H-4), 4.24 (m, H-3), 5.34 (m, 1H, H-5), 6.26
(d, J ) 15.5 Hz, 1H, H-8′), 6.82 (d, J ) 8.5 Hz, 1H, H-5′), 6.93
(dd, J ) 2.0, 8.5 Hz, 1H, H-6′), 7.06 (d, J ) 2.0 Hz, 1H, H-2′),
7.62 (d, J ) 15.5 Hz, 1H, H-7′). 13C NMR (CDCl3 + CD3OD 1:1)
δ 13.4 (-CH2CH2CH2CH2CH3), 22.0 and 22.5 and 22.6 and 31.2
and 37.2 and 37.6 and 38.4 and 38.5 (-CH2CH2CH2CH2CH3 and
C-2, C-6), 69.1 (C-3), 69.2 (C-5), 72.3 (C-4), 79.2 (C-1), 113.6
and 114.4 and 115.0 (C-2′,1′′, C-8′, and C-5′), 121.8 (C-6′), 126.2
(C-1′), 144.7 (C-3′), 145.9 (C-7′), 147.5 (C-4′), 167.3 (C-9′), 173.7
(C-7). ESI-MS (negative): 505.4 ([M - H]-, 100%).
1,7-(8-Pentadecanone) Chlorogenic Acid Ketal (7). After acid
hydrolysis of 27 and purification on a silica gel column, 7 was
obtained from CHCl3-MeOH 9:1 eluted part (yield: 40.1%, and
41.0% of 27 was recovered) as a wax; [R]D +20.8 (c 0.3, MeOH).
1H NMR (CDCl3) δ 0.84 (t, J ) 6.5 Hz, 3H) and 0.89 (t, J ) 7.0
Hz, 3H) (-(CH2)6CH3), 1.26 (m, 16H, -(CH2)2(CH2)4CH3), 1.37
(m, 4H, -CH2CH2(CH2)4CH3), 1.78 (m, 4H, -CH2(CH2)5CH3),
1.93 (br t, J ) 12.5 Hz, 1H, H-6a), 2.10 (br d, J ) 14.5 Hz, 1H,
H-2a), 2.23 (br d, J ) 14.5 Hz, 1H, H-2b), 2.30 (br d, 1H, J )
12.5 Hz, H-6b), 3.75 (br d, J ) 14.0 Hz, 1H, H-4), 4.28 (br s,
H-3), 5.38 (m, 1H, H-5), 6.06 (d, J ) 15.5 Hz, 1H, H-8′), 6.78 (br
s, 2H, H-2′,6′), 6.95 (br s, 1H, H-5′), 7.44 (d, J ) 15.5 Hz, 1H,
H-7′). 13C NMR (CDCl3) δ 14.0 (-(CH2)6CH3), 22.6 and 23.3 and
29.0 and 29.4 and 31.6 and 38.8 (-(CH2)6CH3), 37.3 (C-2), 38.0
(C-6), 69.3 (C-5), 70.1 (C-3), 73.4 (C-4), 79.4 (C-1), 113.8 (C-8′),
114.5 (C-5′), 114.7 (C-1′′), 115.4 (C-2′), 122.3 (C-6′), 126.6 (C-
1′), 144.0 (C-3′), 146.0 (C-7′), 146.9 (C-4′), 167.4 (C-9′), 172.5
(C-7). APCI-MS (negative): 561.5.4 ([M - H]-, 100%).
1,7-(9-Heptadecanone) Chlorogenic Acid Ketal (8). After acid
hydrolysis of 28 in 95% MeOH and purification on a silica gel column,
8 was obtained from CHCl3-MeOH 9:1 eluted part (yield: 80.3%) as
a wax; [R]D +24.1 (c 0.3, MeOH). 1H NMR (CDCl3) δ 0.84 (t, J )
6.5 Hz, 3H) and 0.89 (t, J ) 7.0 Hz, 3H) (-(CH2)7CH3), 1.26 (m,
20H, -(CH2)2(CH2)5CH3), 1.36 (m, 4H, -CH2CH2(CH2)5CH3), 1.78
(m, 4H, -CH2(CH2)6CH3), 1.94 (br t, J ) 12.5 Hz, 1H, H-6a), 2.11
(dd, J ) 2.5, 14.5 Hz, 1H, H-2a), 2.25 (br d, J ) 14.5 Hz, 1H, H-2b),
2.31 (br d, 1H, J ) 12.5 Hz, H-6b), 3.75 (dd, J ) 3.0, 10.5 Hz, 1H,
H-4), 4.29 (br s, H-3), 5.38 (m, 1H, H-5), 6.06 (d, J ) 16.0 Hz, 1H,
H-8′), 6.78 (br s, 2H, H-2′,6′), 6.95 (br s, 1H, H-5′), 7.45 (d, J ) 16.0
Hz, 1H, H-7′). 13C NMR (CDCl3, 300 MHz) δ 14.2 (-(CH2)7CH3),
22.7 and 23.4 and 29.2 and 29.4 and 29.5 and 31.9 and 38.9
(-(CH2)7CH3), 37.4 (C-2), 38.1 (C-6), 69.5 (C-5), 70.2 (C-3), 73.5
(C-4), 79.5 (C-1), 114.0 (C-8′), 114.6 (C-5′), 114.9 (C-1′′), 115.5 (C-
2′), 122.4 (C-6′), 126.8 (C-1′), 144.0 (C-3′), 146.1 (C-7′), 146.8 (C-
4′), 167.5 (C-9′), 172.7 (C-7). APCI-MS (negative): 589.5 ([M - H]-,
100%).
1,7-Pelargonaldehyde-chlorogenic Acid Acetal (33-34). A
mixture of the isomers 33 and 34 (78.7%) was obtained from 70%
MeOH eluted part of an ODS column after acid treatment of 35-38.
This mixture was purified using preparative HPLC eluted with
70-80% MeOH in 60 min to obtain 33 at 27 min and 34 at 29
min, respectively. 33, crystalline powder; [R]D -14.3 (c 0.1,
1
CH3OH); mp 115-117 °C. H NMR (CD3OD) δ 0.90 [t, J ) 6.5
Hz, 3H, -(CH2)7CH3], 1.38 (m, 10H) and 1.47 (m, 2H) and 1.80
[m, 2H, -(CH2)7CH3], 1.85 (overlapped, H-2a), 1.96 (dd, J ) 13.0,
11.0 Hz, 1H, H-6a), 2.20 (m, 1H, H-6b), 2.30 (m, 1H, H-2b), 3.72
(dd, J ) 3.5, 9.5 Hz, 1H, H-4), 4.21 (m, H-3), 5.36 (m, 1H, H-5),
5.69 (t, J ) 4.5 Hz, 1H, H-1′′), 6.29 (d, J ) 15.5 Hz, 1H, H-8′),
6.78 (d, J ) 8.5 Hz, 1H, H-5′), 6.95 (dd, J ) 2.0, 8.5 Hz, 1H,
H-6′), 7.05 (d, J ) 2.0 Hz, 1H, H-2′), 7.60 (d, J ) 15.5 Hz, 1H,
H-7′). 13C NMR (CD3OD) δ 14.4 [-(CH2)7CH3], 23.7 and 30.3
and 30.4 and 30.6 and 33.0 and 34.0 and 35.2 and 38.3
[-(CH2)7CH3 and C-2, C-6], 70.6 (C-3), 70.7 (C-5), 73.8 (C-4),