Journal of Medicinal Chemistry
Article
4.29 (dd, J = 2.5, 5.5 Hz, 1H), 4.18 (td, J = 2.4, 6.4 Hz, 1H), 3.98−
3.89 (m, 2H), 3.42 (dd, J = 3.7, 7.8 Hz, 1H), 1.49 (d, J = 6.6 Hz, 3H),
1.33 (s, 3H), 1.32 (s, 3H), 1.10 (s, 9H) ppm; 13C NMR (125 MHz,
162.7 (d, JCF = 245.7 Hz), 146.6, 134.1 (d, JCF = 3.4 Hz), 131.8 (q, JCF
= 33.3 Hz), 130.0 (d, JCF = 8.2 Hz), 126.6 (q, JCF = 2.9 Hz), 123.5 (q,
J
CF = 273.0 Hz), 121.6 (sept, JCF = 3.6 Hz), 115.3 (d, JCF = 21.3 Hz),
CDCl3): 162.5 (d, JCF = 244.8 Hz), 145.9, 135.8(2C), 133.9 (d, JCF
3.2 Hz), 133.7, 133.6, 132.1 (q, JCF = 33.5 Hz), 130.0, 129.7 (d, JCF
=
=
110.5, 101.6, 79.7, 79.4, 76.4, 74.0, 73.6, 73.1, 62.4, 27.9, 26.5, 22.9
ppm. [α]D20: +28.5 (c1, chloroform). HRMS (EI): calcd for
C26H27F7O6: [M]+ 568.1792, found 568.1789 (0.5 ppm).
8.3 Hz), 127.9 (2C), 126.9 (q, JCF = 2.4 Hz), 123.5 (q, JCF = 272.9
Hz), 121.9 (sept, JCF = 4.0 Hz), 115.3 (d, JCF = 21.4 Hz), 109.4, 95.0,
76.3, 76.1, 73.5, 72.6, 71.5, 68.9, 63.4, 28.3, 27.0, 26.6, 24.5, 22.8, 19.5
ppm. [α]D20: +87.8 (c1, chloroform). HRMS: calcd for
C42H45O6F7SiNa: [M + Na]+ 829.2771, found 829.2811 (4.1 ppm).
(R)-{1-[3,5-Bis-(trifluoromethyl)phenyl]ethyl} 6-O-tert-Butyldi-
phenylsilyl-2-O-p-fluorobenzyl-3,4-O-isopropylidene-β-D-galacto-
(R)-{1-[3,5-Bis-(trifluoromethyl)phenyl]ethyl} 2-O-p-Fluoroben-
zyl-α-D-galactopyranoside (13α). To a solution of 0.50 g of 12α
(0.88 mmol) in methanol (20.00 mL) at room temperature, a
catalytic amount of CSA was added. After stirring overnight, the
solvent was evaporated under reduced pressure. The residue obtained
was purified by flash chromatography (EtOAc) to obtain 0.46 g of
13α (0.87 mmol, 99% yield) as a white solid; Rf = 0.51 (EtOAc);
1
pyranoside (11β). H NMR (500 MHz, CDCl3): δ 7.85 (bs, 1H),
1
7.79−7.74 (m, 3H), 7.66−7.61 (m, 4H), 7.43−7.32 (m, 7H), 7.05−
7.00 (m, 2H), 4.97 (q, J = 6.5 Hz, 1H), 4.82 (s, 2H), 4.46 (d, J = 8.0
Hz, 1H), 4.25 (dd, J = 1.7, 5.5 Hz, 1H), 4.17 (dd, J = 5.8, 6.7 Hz,
1H), 3.87 (dd, J = 6.0, 8.5 Hz, 1H), 3.77−3.71 (m, 2H), 3.42 (t, J =
7.5 Hz, 1H), 1.50 (d, J = 6.5 Hz, 3H), 1.36 (s, 3H), 1.33 (s, 3H), 1.02
(s, 9H) ppm; 13C NMR (125 MHz, CDCl3): δ 162.6 (d, JCF = 245.2
Hz), 148.4, 146.3, 135.8, 135.7, 134.1 (d, JCF = 3.1 Hz), 133.6, 133.4,
131.9 (q, JCF = 33.1 Hz), 131.5, 129.9 (d, JCF = 8.2 Hz), 129.9, 127.9,
127.8, 125.8 (q, JCF = 2.2 Hz), 123.5 (q, JCF = 272.3 Hz), 121.4 (sept,
m.p.: 147−149 °C; H NMR (500 MHz, CDCl3): δ 7.89 (bs, 2H),
7.84 (bs, 1H), 7.17−7.14 (m, 2H), 6.98−6.94 (m, 2H), 4.92 (q, J =
6.5 Hz, 1H), 4.79 (d, J = 3.5 Hz, 1H), 4.53 (d, J = 11.9 Hz, 1H), 4.34
(d, J = 11.8 Hz, 1H), 4.16−4.10 (m, 2H), 4.02−3.88 (m, 3H), 3.69
(dd, J = 3.5, 9.8 Hz, 1H), 2.79 (bs, 1H), 2.34 (d, J = 2.6 Hz, 1H), 2.30
(dd, J = 3.6, 7.1 Hz, 1H), 3.07 (d, J = 6.7 Hz, 3H) ppm; 13C NMR
(125 MHz, CDCl3): δ 162.8 (d, JCF = 246.9 Hz), 145.8, 133.4 (d, JCF
= 3.0 Hz), 132.2 (q, JCF = 33.4 Hz), 129.9 (d, JCF = 8.2 Hz), 126.9 (q,
JCF = 3.8 Hz), 123.4 (q, JCF = 271.8 Hz), 122.0 (sept, JCF = 3.8 Hz),
115.7 (d, JCF = 21.3 Hz), 95.1, 75.9, 73.4, 72.2, 70.9, 69.9, 69.1, 63.5,
24.5 ppm. [α]D20: +121.5 (c1, chloroform). HRMS: calcd for
C23H23O6F7Na: [M + Na]+ 551.1281, found 551.1264 (−3.0 ppm).
(R)-{1-[3,5-Bis-(trifluoromethyl)phenyl]ethyl} 2-O-p-Fluoroben-
zyl-β-D-galactopyranoside (13β). To a solution of 0.50 g of 12β
(0.88 mmol) in methanol (200.00 mL) at room temperature, a
catalytic amount of CSA was added. After stirring overnight, the
solvent was evaporated under reduced pressure. The residue obtained
was purified by flash chromatography (EtOAc) to obtain 0.45 g of
13β (0.85 mmol, 97% yield) as a white solid; Rf = 0.47 (EtOAc);
J
CF = 3.8 Hz), 115.3 (d, JCF = 21.5 Hz), 110.1, 100.8, 79.7, 79.3, 75.0,
20
73.6, 73.4, 73.1, 62.6, 28.0, 26.9, 26.4, 25.8, 22.3, 19.3 ppm. [α]D
:
+21.2 (c1, chloroform). HRMS: calcd for C42H45O6F7SiNa: [M +
Na]+ 829.2771, found 829.2809 (4.5 ppm).
(R)-{1-[3,5-Bis-(trifluoromethyl)phenyl]ethyl} 2-O-p-Fluoroben-
zyl-3,4-O-isopropylidene-α-D-galactopyranoside (12α). To a sol-
ution of 0.70 g of 11α (0.87 mmol) in THF (20 mL) at room
temperature under an argon atmosphere, 4.34 mL (4.34 mmol) of 1
M tetrabutylammonium fluoride solution was added dropwise. After
stirring for 1 h, the reaction mixture was diluted with ether and
quenched with saturated NaCl aqueous solution. The aqueous phase
was extracted with ethyl acetate (3 × 40 mL), and the combined
organic phases were dried with anhydrous Na2SO4. The solvent was
evaporated under reduced pressure and the reaction crude was
purified by flash chromatography (EtOAc/hexane, 1:4) to obtain 0.40
g of 12α (0.70 mmol, 80% yield) as a yellow syrup; Rf = 0.13
(EtOAc/hexane, 1:4); 1H NMR (500 MHz, CDCl3): δ 7.91 (bs, 2H),
7.83 (bs, 1H), 7.20−7.17 (m, 2H), 6.96−6.92 (m, 2H), 4.92 (q, J =
6.7 Hz, 1H), 4.64 (d, J = 3.6 Hz, 1H), 4.62 (d, J = 12.5 Hz, 1H), 4.58
(d, J = 12.4 Hz, 1H), 4.47 (dd, J = 5.6, 7.9 Hz, 1H), 4.30 (dd, J = 2.7,
5.6 Hz, 1H), 4.19−4.16 (m, 1H), 3.97 (dd, J = 6.0, 11.8 Hz, 1H), 3.87
(dd, J = 3.9, 11.8 Hz, 1H), 3.42 (dd, J = 3.6, 8.0 Hz, 1H), 2.25 (dd, J
= 3.2, 9.3 Hz, 1H), 1.52 (d, J = 6.7 Hz, 3H), 1.35 (s, 3H), 1.33 (s,
3H) ppm; 13C NMR (125 MHz, CDCl3): δ 162.6 (d, JCF = 245.6
Hz), 145.7, 133.7 (d, JCF = 3.4 Hz), 132.1 (q, JCF = 33.3 Hz), 129.7
(d, JCF = 8.2 Hz), 126.9 (q, JCF = 3.3 Hz), 123.5 (q, JCF = 272.8 Hz),
122.0 (sept, JCF = 3.6 Hz), 115.3 (d, JCF = 21.7 Hz), 109.7, 95.3, 76.3,
75.7, 74.7, 73.1, 71.5, 68.1, 62.9, 28.2, 26.6, 24.5 ppm. [α]D20: +105.5
(c1, chloroform). HRMS (EI): calcd for C26H27F7O6: [M]+ 568.1792,
found 568.1790 (0.5 ppm).
(R)-{1-[3,5-Bis-(trifluoromethyl)phenyl]ethyl} 2-O-p-Fluoroben-
zyl-3,4-O-isopropylidene-β-D-galactopyranoside (12β). To a sol-
ution of 0.70 g of 11β (0.87 mmol) in THF (20 mL) at room
temperature under an argon atmosphere, 4.34 mL (4.34 mmol) of 1
M tetrabutylammonium fluoride solution was added dropwise. After
stirring for 1 h, the reaction mixture was diluted with ether and
quenched with saturated NaCl aqueous solution. The aqueous phase
was extracted with ethyl acetate (3 × 40 mL), and the combined
organic phases were dried with anhydrous Na2SO4. The solvent was
evaporated under reduced pressure and the reaction crude was
purified by flash chromatography (EtOAc/hexane, 1:4) to obtain 0.37
g of 12β (0.65 mmol, 75% yield) as a yellow syrup; Rf = 0.07 (EtOAc/
hexane, 1:4); 1H NMR (500 MHz, CDCl3): δ 7.75 (bs, 2H), 7.70 (bs,
1H), 7.29−7.26 (m, 2H), 6.95−6.92 (m, 2H), 4.88 (q, J = 6.5 Hz,
1H), 4.72 (bs, 2H), 4.39 (d, J = 7.9 Hz, 1H), 4.09 (dd, J = 5.8, 6.7 Hz,
1H), 4.02−4.00 (m, 1H), 3.71−3.66 (m, 1H), 3.63−3.58, (m, 2H),
3.34 (dd, J = 7.0, 7.8 Hz, 1H), 1.59 (bs, 1H), 1.44 (d, J = 6.5 Hz, 3H),
1.28 (s, 3H), 1.22 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ
1
m.p.: 143−145 °C; H NMR (500 MHz, CDCl3): δ 7.85 (bs, 2H),
7.80 (bs, 1H), 7.38−7.35 (m, 2H), 7.08−7.05 (m, 2H), 4.99 (q, J =
6.4 Hz, 1H), 4.97 (d, J = 11.5 Hz, 1H), 4.74 (d, J = 11.5 Hz, 1H),
4.56 (d, J = 7.3 Hz, 1H), 3.98 (dd, J = 3.6, 5.9 Hz, 1H), 3.79 (dd, J =
3.9, 12.6 Hz, 1H), 3.71 (dd, J = 3.4, 8.0 Hz, 2H), 3.63−3.56 (m, 2H),
3.44−3.42 (m, 1H), 1.57 (d, J = 6.5 Hz, 3H) ppm; 13C NMR (125
MHz, CDCl3): δ 162.8 (d, JCF = 246.5 Hz), 146.5, 134.2 (d, JCF = 3.6
Hz), 131.7 (q, JCF = 33.4 Hz), 129.9 (d, JCF = 8.2 Hz), 126.6 (q, JCF
=
3.0 Hz), 123.4 (q, JCF = 272.7 Hz), 121.6 (sept, JCF = 3.7 Hz), 115.7
(d, JCF = 21.2 Hz), 102.7, 79.2, 76.8, 74.3, 73.4, 69.5, 62.7, 22.9 ppm.
[α]D20: +25.3 (c1, chloroform). HRMS: calcd for C23H23F7O6: [M +
Na]+ 551.1281, found 551.1262 (−3.0 ppm).
(R)-{1-[3,5-Bis-(trifluoromethyl)phenyl]ethyl} (R)-(4,6-O-Benzyli-
dene)-2-O-p-fluorobenzyl-α-D-galactopyranoside (14α). To a sol-
ution of 100.00 mg of 13α (0.19 mmol) in DMF (15.00 mL) and 0.32
mL of dimethoxymethyl benzene (0.21 mmol) under an argon
atmosphere, a catalytic amount of CSA was added. After stirring for 1
h in vacuo at 40 °C, the reaction mixture was quenched with a
saturated NaHCO3 aqueous solution. The aqueous phase was
extracted with dichloromethane (3 × 40 mL), and the combined
organic phases were dried with anhydrous Na2SO4. The solvent was
evaporated under reduced pressure and the reaction crude was
purified by flash chromatography (EtOAc/hexane, 1:4) to obtain
100.00 mg of 14α (0.18 mmol, 95% yield) as a white solid; Rf = 0.48
1
(EtOAc); m.p.: 158−159 °C. H NMR (500 MHz, CDCl3): δ 7.90
(bs, 2H), 7.84 (bs, 1H), 7.47−7.43 (m, 2H), 7.38−7.35 (m, 3H),
7.16−7.13 (m, 2H), 6.95−6.90 (m, 2H), 5.57 (s, 1H), 4.92 (q, J = 6.6
Hz, 1H), 4.81 (d, J = 3.5 Hz, 1H), 4.52 (d, J = 3.0 Hz, 2H), 4.35−
4.34 (m, 1H), 4.32 (dd, J = 1.4, 12.6 Hz, 1H), 4.25 (dd, J = 3.7, 10.0
Hz, 1H), 4.15−4.12 (m, 1H), 3.84 (bs, 1H), 3.75 (dd, J = 3.6, 10.0
Hz, 1H), 1.53 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (125 MHz,
CDCl3): δ 162.6 (d, JCF = 246.1 Hz), 145.6, 137.6, 133.7 (d, JCF = 3.0
Hz), 132.1 (q, JCF = 33.6 Hz), 129.7 (d, JCF = 8.2 Hz), 129.5, 128.5,
127.0 (d, JCF = 2.7 Hz), 126.4, 123.4 (q, JCF = 272.1 Hz), 122.0 (sept,
JCF = 4.0 Hz), 115.4 (d, JCF = 21.8 Hz), 101.5, 96.0, 76.3, 76.1, 73.3,
72.7, 69.5, 68.8, 63.3, 24.4 ppm. [α]D20: +94.6 (c1, chloroform).
HRMS: calcd for C30H27O6F7Na: [M + Na]+ 639.1594, found
639.1565 (−4.5 ppm).
10363
J. Med. Chem. 2021, 64, 10350−10370