Journal of Medicinal Chemistry
Article
Triethylamine (0.22 mL, 10%) was added to the cyclic carbonate
(100 mg, 0.22 mmol) in MeOH (2.2 mL). After 12 h, the solvent was
concentrated and the residue was purified via column chromatography
(SiO2, 10:1, CH2Cl2:acetone) to afford inseparable diastereomers 13a
(see following experimental section for diastereoselectivities) as a
colorless amorphous solids. Compounds 13b−m were synthesized
using this procedure.
1H), 3.60 (s, 3H), 3.34 (dd, 1H, J = 1.9, 9.1 Hz), 3.28 (m, 2H), 2.75
(dt, 4H, J = 7.3, 14.5 Hz), 1.88 (s, 3H), 1.37 (s, 3H), 1.22 (s, 3H). 13
C
NMR (125 MHz, CDCl3) δ 170.1, 155.4, 143.5, 142.0, 134.3, 131.0,
130.9, 129.8, 129.4, 128.5, 127.6, 127.4, 118.2, 115.7, 97.9, 84.6, 78.4,
71.5, 68.7, 62.1, 40.8, 32.1, 29.2, 23.6, 23.1. HRMS m/z [M + Na+] for
C24H30ClNO6Na: calcd, 486.1659; found, 486.1642.
N-(2-(5-(((3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetra-
hydro-2H-pyran-2-yl)oxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-
ethyl)acetamide (13f). Colorless amorphous solid (52% yield over 2
N-(2-(5-(((3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetra-
hydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide
1
1
steps). H NMR (500 MHz, CDCl3) δ 7.64 (d, 1H, J = 7.7 Hz), 7.55
(13a). Colorless amorphous solid (63% yield over 2 steps). H NMR
(t, 2H, J = 7.6 Hz), 7.49 (m, 1H), 7.23 (d, 1H, J = 8.5 Hz), 7.06 (dd,
1H, J = 2.7, 8.4 Hz), 6.89 (d, 1H, J = 2.7 Hz), 5.56 (d, 1H, J = 2.2 Hz),
5.31 (s, 1H), 4.19 (m, 2H), 3.60 (s, 3H), 3.34 (d, 1H, J = 9.1 Hz), 3.29
(dd, 2H, J = 7.0, 13.3 Hz), 2.72 (t, 2H, J = 7.3 Hz), 2.69 (s, 1H), 2.64
(s, 1H), 1.87 (s, 3H), 1.37 (s, 3H), 1.22 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 170.1, 155.4, 142.1, 141.9, 132.6, 131.0, 130.7 (q, J = 31.5
Hz), 129.4, 129.0, 125.9 (q, J = 3.6, 7.2 Hz), 125.3, 124.2 (q, J = 3.6,
7.2 Hz), 123.1, 118.0, 115.8, 97.9, 84.4, 77.4, 71.4, 68.7, 62.0, 40.6,
32.1, 29.8, 29.2, 23.4, 23.0. HRMS m/z [M + Na+] for
C25H30F3NO6Na: 520.1923; found, 520.1932. This material was
determined to be 97.2% pure (retention time = 7.631) by HPLC
(Phenomenex Luna C-18, 5 μm, 10 mm × 250 mm column eluting
with 30% CH3CN, 70% H2O, flow rate 5.0 mL/min).
(500 MHz, CDCl3) δ 7.41−7.28 (m, 3H), 7.28−7.18 (dt, J = 5.9, 3.2
Hz, 2H), 7.13 (m, 1H), 6.97 (m, 1H), 6.92−6.78 (dd, J = 7.6, 2.7 Hz,
1H), 5.55−5.47 (dd, J = 7.7, 2.7 Hz, 1H), 5.39 (m, 1H), 4.14 (m, 2H),
3.58−3.46 (m, 3H), 3.34−3.15 (m, 4H), 3.03 (d, J = 5.5 Hz, 1H),
2.77−2.65 (m, 2H), 1.84−1.76 (m, 3H), 1.31 (d, J = 4.9 Hz, 3H),
1.21−1.10 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 170.3, 155.4,
143.5, 141.4, 130.8, 129.5, 129.2, 128.5, 127.4, 118.2, 115.2, 98.1, 84.5,
78.4, 71.5, 68.8, 62.0, 40.8, 32.1, 29.2, 23.4, 23.1. HRMS m/z [M +
H+] for C24H32NO6: calcd, 430.2224; found, 430.2227.
N-(2-(5-(((3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetra-
hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-
acetamide (13b). Colorless amorphous solid (51% yield over 2 steps).
1H NMR (500 MHz, CDCl3) δ 7.39 (dd, 1H, J = 7.9, 13.9 Hz), 7.22
N-(2-(5-(((3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetra-
hydro-2H-pyran-2-yl)oxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-
ethyl)acetamide (13g). Colorless amorphous solid (49% yield over 2
(d, 1H, J = 8.5 Hz), 7.07 (dd, 2H, J = 7.5, 10.5 Hz), 7.02 (dd, 1H, J =
2.8, 8.4 Hz), 6.99 (m, 1H), 6.91 (d, 1H, J = 2.7 Hz), 5.34 (d, 1H, J =
1.3 Hz), 5.28 (s, 1H), 4.20 (d, 1H, J = 2.2 Hz), 3.80 (m, 1H), 3.63 (s,
3H), 3.30 (d, 1H), 3.28 (m, 2H), 2.75 (t, 2H, J = 7.2 Hz), 2.63 (m,
2H, J = 15.9 Hz), 1.87 (s, 3H), 1.41 (s, 3H), 1.28 (s, 3H). 13C NMR
(125 MHz, CDCl3) δ 169.9, 163.5−161.6 (d, J = 251 Hz) 155.0, 143.2
(d, J = 7.8 Hz), 142.1 (d, J = 1.8 Hz), 130.9, 130.1, 130.0 (d, J = 8.8
Hz), 124.8 (d, J = 2.8 Hz), 118.0, 116.0 (d, J = 8.8 Hz), 115.4, 114.3
(d, J = 21.6 Hz), 93.8, 84.2, 76.0, 71.3, 71.1, 62.0, 40.4, 32.0, 28.6, 23.3,
18.5. HRMS m/z: [M + H+] for C24H31FNO6: calcd, 448.2180; found,
448.2174. This material was determined to be 95.6% pure (retention
time = 6.401) by HPLC (Phenomenex Luna C-18, 5 μm, 10 mm ×
250 mm column eluting with 30% CH3CN, 70% H2O, flow rate 5.0
mL/min).
N-(2-(5-(((3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetra-
hydro-2H-pyran-2-yl)oxy)-4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-
acetamide (13c). Colorless amorphous solid (57% yield over 2 steps).
1H NMR (500 MHz, CDCl3) δ 7.25 (dd, 2H, J = 5.4, 8.6 Hz), 7.18 (d,
1H, J = 8.5 Hz), 7.10 (t, 2H, J = 8.7 Hz), 7.01 (dd, 1H, J = 2.7, 8.5
Hz), 6.87 (d, 1H, J = 2.7 Hz), 5.54 (d, 1H, J = 2.2 Hz), 5.37 (t, 1H, J =
5.2 Hz), 4.20 (dd, 1H, J = 3.3, 9.1 Hz), 4.15 (m, 1H), 3.59 (s, 3H),
3.33 (d, 1H, J = 9.1 Hz), 3.26 (q, 2H, J = 6.9 Hz), 2.97 (s, 1H), 2.81
(s, 1H), 2.72 (t, 2H, J = 7.3), 1.87 (s, 3H), 1.36 (s, 3H), 1.22 (s, 3H).
13C NMR (125 MHz, CDCl3) δ 170.2, 163.2−161.3 (d, J = 250 Hz),
155.3, 142.3, 137.2 (d, J = 3.2 Hz), 130.8, 130.8, 130.7, 129.5, 118.1,
115.4, 115.3, 115.3, 97.9, 84.4, 78.3, 71.4, 68.7, 62.0, 40.6, 32.1, 29.1,
23.4, 23.1. HRMS m/z [M + Na+] for C24H30FNO6: calcd, 470.1955;
found, 470.1958.
N-(2-(2′-Chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-di-
methyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)-
acetamide (13d). Colorless amorphous solid (62% yield over 2 steps).
1H NMR (500 MHz, CDCl3) δ 7.46 (m, 1H), 7.31 (m, 2H), 7.21 (m,
2H), 7.03 (m, 1H), 6.86 (dd, 1H, J = 2.7, 13.2 Hz), 5.55 (m, 1H), 5.42
(s, 1H), 4.20 (dt, 1H, J = 3.0, 9.1 Hz), 4.14 (m, 1H), 3.59 (s, 3H), 3.33
(dd, 1H, J = 2.5, 9.1 Hz), 3.26 (ddt, 2H, J = 4.8, 6.8, 9.3 Hz), 3.11 (s,
1H), 2.93 (s, 1H), 2.58 (tq, 2H, J = 7.1, 14.2 Hz), 1.86 (s, 3H), 1.35
(d, 3H, J = 2.4 Hz), 1.20 (t, 3H, J = 5.8 Hz). 13C NMR (125 MHz,
CDCl3) δ 170.2, 155.2, 140.6, 140.5, 139.8, 133.4, 131.4, 130.5, 129.8,
126.9, 118.1, 117.9, 116.05, 97.9, 84.5, 78.4, 71.5, 71.4, 68.7, 62.1, 62.0,
40.2, 40.2, 32.1, 32.1, 29.3, 29.2, 23.5, 23.1, 23.0. HRMS m/z [M +
Na+] for C24H30ClNO6Na: 486.1659; found, 486.1652.
N-(2-(3′-Chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-di-
methyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)-
acetamide (13e). Colorless amorphous solid (55% yield over 2 steps).
1H NMR (500 MHz, CDCl3) δ 7.35 (m, 2H), 7.28 (m, 1H), 7.18 (m,
1
steps). H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.6 Hz, 2H), 7.43
(d, J = 7.9 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.09−7.03 (dd, J = 8.6,
2.7 Hz, 1H), 6.90 (d, J = 2.7 Hz, 1H), 5.55 (d, J = 2.3 Hz, 1H), 5.33
(m, 1H), 4.26−4.11 (m, 2H), 3.60 (s, 3H), 3.36−3.25 (m, 3H), 2.74
(t, J = 7.4 Hz, 2H), 2.56 (br s, 2OH), 1.88 (s, 3H), 1.37 (s, 3H), 1.22
(s, 3H). 13C NMR (125 MHz, MeOD) δ 173.1, 156.8, 146.9, 143.2,
132.1, 130.9, 130.7, 130.5, 130.2, 126.3, 126.2, 124.7, 118.5, 116.8,
100.1, 85.3, 79.5, 72.8, 69.5, 62.1, 41.7, 32.9, 29.2, 23.6, 22.5. HRMS
m/z [M + Na+] for C25H30F3NO6Na: 520.1923; found, 520.1934.
N-(2-(5-(((3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetra-
hydro-2H-pyran-2-yl)oxy)-2′-(methylthio)-[1,1′-biphenyl]-2-yl)-
ethyl)acetamide (13h). Colorless amorphous solid (63% yield over 2
1
steps). H NMR (400 MHz, CDCl3) δ 7.36 (t, 1H, J = 7.0 Hz), 7.27
(m, 3H), 7.09 (m, 1H), 7.01 (m, 1H), 6.87 (s, 1H), 5.64 (s, 1H), 5.54
(m, 1H), 4.16 (m, 2H), 3.32 (d, 2H, J = 8.8 Hz), 3.27 (m, 2H), 3.06
(s, 1H), 2.56 (t, 2H, J = 6.2 Hz), 2.36 (d, 3H, J = 7.6 Hz), 1.83 (s,
3H), 1.33 (s, 3H), 1.20 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
170.3, 155.1, 155.0, 141.0, 138.9, 130.5, 130.1, 129.8, 128.4, 124.6,
124.2, 118.3, 116.2, 115.9, 97.9, 84.5, 78.3, 71.5, 68.7, 62.0, 53.6, 40.1,
31.7, 29.3, 23.3, 15.3, 15.2. HRMS m/z [M + Na+] for
C25H33NO6SNa: calcd, 498.1926; found, 498.1925. This material
was determined to be 95% pure (retention time = 7.465) by HPLC
(Phenomenex Luna C-18, 5 μm, 10 mm × 250 mm column eluting
with 30% CH3CN, 70% H2O, flow rate 5.0 mL/min).
N-(2-(5-(((3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetra-
hydro-2H-pyran-2-yl)oxy)-2′-methoxy-[1,1′-biphenyl]-2-yl)ethyl)-
acetamide (13i). Colorless amorphous solid (41% yield over 2 steps).
1H NMR (500 MHz, CDCl3) δ 7.36 (ddd, 1H, J = 1.8, 7.6, 8.2 Hz),
7.18 (d, 1H, J = 8.3 Hz), 7.12 (t, 1H, J = 5.8 Hz), 7.02 (m, 3H), 6.87
(dd, 1H, J = 2.3, 11.3 Hz), 5.54 (s, 1H), 5.39 (s, 1H), 4.21 (dt, 1H, J =
3.3, 9.0 Hz), 4.15 (m, 1H), 3.77 (d, 3H, J = 6.9 Hz), 3.60 (s, 3H), 3.33
(d, 1H, J = 8.7 Hz), 3.29 (m, 2H), 2.73 (s, 1H), 2.66 (s, 1H), 2.60 (dd,
2H, J = 6.5, 12.8 Hz), 1.84 (s, 3H), 1.37 (s, 3H), 1.24 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 170.0, 156.4, 155.2, 139.9, 131.2, 130.8,
130.2, 130.0, 129.2, 120.9, 118.6, 118.3, 115.7, 115.2, 111.4, 111.2,
98.0, 97.9, 84.5, 78.2, 71.4, 68.7, 62.0, 55.9, 55.9, 40.3, 31.9, 30.2, 29.3,
29.2, 23.4, 23.1. HRMS m/z [M + H+] for C25H34NO7: calcd,
460.2335; found, 460.2336. This material was determined to be 96.1%
pure (retention time = 5.057) by HPLC (Phenomenex Luna C-18, 5
μm, 10 mm × 250 mm column eluting with 30% CH3CN, 70% H2O,
flow rate 5.0 mL/min).
N-(2-(5-(((3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetra-
hydro-2H-pyran-2-yl)oxy)-3′-methoxy-[1,1′-biphenyl]-2-yl)ethyl)-
acetamide (13j). Colorless amorphous solid (53% yield over 2 steps).
1H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 7.9 Hz, 1H), 7.17 (d, J =
2H), 7.03 (dd, 1H, J = 2.7, 8.5 Hz), 6.87 (d, 1H, J = 2.7 Hz), 5.55 (t,
1H, J = 2.5 Hz), 5.34 (m, 1H), 4.21 (dd, 1H, J = 3.1, 9.1 Hz), 4.16 (m,
5808
dx.doi.org/10.1021/jm300544c | J. Med. Chem. 2012, 55, 5797−5812