5154 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21
Chelliah et al.
MHz, CDCl3) 4.73-4.66 (m, 1H), 4.01 (dd, J ) 3.7, 11.7 Hz, 1H),
3.87 (dd, J ) 4.0, 11.4 Hz, 1H), 3.48 (dt, J ) 2.0, 11.9 Hz, 1H),
3.09 (t, J ) 11.0 Hz, 1H), 2.76-2.70 (m, 1H), 2.63-2.52 (m, 2H),
1.81 (ddd, J ) 2.0, 6.0, 13.4 Hz, 1H), 1.77-1.73 (m, 1H), 1.65
(dq, J ) 3.1, 11.1 Hz, 1H), 1.33 (d, J ) 5.9 Hz, 3H), 1.47-1.24
(m, 2H), 1.08 (q, J ) 13.0 Hz, 1H); MS 255.1 (MH+).
(1R,3aR,4aS,8aS,9S,9aS)-Decahydro-1-methyl-3-oxo-3H-pyr-
ano[3,4-f]isobenzofuran-9-carboxaldehyde (25a). 1H NMR (400
MHz, CDCl3) 9.79 (d, J ) 2.2 Hz, 1H), 4.64-4.57 (m, 1H), 3.99
(dd, J ) 4.4, 11.7 Hz, 1H), 3.87 (dd, J ) 4.0, 11.4 Hz, 1H), 3.48
(dt, J ) 2.2, 12.3 Hz, 1H), 3.12 (t, J ) 11.0 Hz, 1H), 2.78-2.60
(m, 3H), 1.85-1.73 (m, 3H), 1.47-1.38 (m, 1H), 1.34 (d, J ) 5.9
Hz, 3H), 1.29-1.22 (m, 1H), 1.10 (q, J ) 12.9 Hz, 1H).
124.54, 124.51, 121.21, 116.24, 116.02, 76.65, 71.99, 68.42, 48.20,
44.78, 41.42, 39.59, 38.81, 31.18, 26.33, 22.18; [R]20D ) +23.9 (c
10.6 mg/mL, MeOH); HRMS calcd for C25H26FNO3 (MH+),
408.1975; found, 408.1989; Anal. (C25H26FNO3‚HCl‚0.5H2O) C,
H, N.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(E)-2-[5-(2,3-Difluorophenyl)-2-
pyridinyl]ethenyl]-decahydro-1-methyl-3H-furo[3,4-g][2]-
1
benzopyran-3-one (27d). H NMR (400 MHz, CDCl3) 8.71 (s,
1H), 7.83 (d, J ) 8.1 Hz, 1H), 7.27 (d, J ) 8.8 Hz, 1H), 7.23-
7.14 (m, 3H), 6.65-6.54 (m, 2H), 4.79-4.72 (m, 1H), 3.98 (dd, J
) 4.1, 11.4 Hz, 1H), 3.86 (dd, J ) 3.3, 11.4 Hz, 1H), 3.40 (t, J )
12.1 Hz, 1H), 3.06 (t, J ) 10.6 Hz, 1H), 2.77-2.70 (m, 1H), 2.48-
2.37 (m, 2H), 1.83 (dd, J ) 6.3, 11.4 Hz, 1H), 1.67 (d, J ) 12.5
Hz, 1H),1.44 (d, J ) 5.9 Hz, 3H), 1.48-1.38 (m, 2H), 1.28-1.01
(1R,3aR,4aS,8aS,9S,9aS)-Decahydro-1-methyl-9-[(e)-2-[5-[3-
(trifluoromethyl)phenyl]-2-pyridinyl]ethenyl]-3H-furo[3,4-g][2]-
benzopyran-3-one (27a). To a solution of [5-(3-trifluoromethyl-
phenyl)-pyridin-2-ylmethyl]-phosphonic acid diethyl ester (200 mg,
0.536 mmol) in 2 mL of THF at 0 °C was added a 2.5 M solution
of BuLi in hexanes (0.21 mL, 0.537 mmol), and this mixture was
stirred for 10 min. To this was added Ti(Oi-Pr)4 (0.16 mL, 0.538
mmol) followed by a solution of aldehyde 25a in 1 mL of THF
(68 mg, 0.285 mmol). The mixture was stirred for 2 h, poured into
20 mL of aq sodium potassium tartrate, and extracted with
dichloromethane (3 × 15 mL). The combined organic layer was
washed with brine, dried over MgSO4, filtered, concentrated, and
chromatographed using 50% ethyl acetate in hexanes to provide
(m, 2H); [R]20 ) +12.2 (c 8 mg/mL, MeOH); HRMS calcd for
D
C25H26F2NO3 (MH+), 426.1881; found, 426.1881; Anal. (C25H25F2-
NO3‚HCl‚0.4H2O) C, H, N.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(E)-2-[5-(3-Chlorophenyl)-2-py-
ridinyl]ethenyl]-decahydro-1-methyl-3H-furo[3,4-g][2]benzopyran-
1
3-one (27e). H NMR (400 MHz, CDCl3) 8.75 (d, J ) 1.5 Hz,
1H), 7.81 (dd, J ) 2.2, 8.1 Hz, 1H), 7.55-7.54 (m, 1H), 7.47-
7.35 (m, 3H), 7.25 (d, J ) 8.1 Hz, 1H), 6.63-6.52 (m, 2H), 4.80-
4.72 (m, 1H), 3.99 (dd, J ) 3.7, 11.7, 1H), 3.87 (dd, J ) 3.7, 11.0
Hz, 1H), 3.40 (dt, J ) 2.0, 11.9 Hz, 1H), 3.06 (t, J ) 10.9 Hz,
1H), 2.77-2.71 (m, 1H), 2.47-2.36 (m, 2H), 1.84 (ddd, J ) 2.2,
6.6, 13.2 Hz, 1H), 1.68 (d, J ) 12.5 Hz, 1H), 1.44 (d, J ) 5.9 Hz,
3H), 1.48-1.38 (m, 2H), 1.28-1.07 (m, 2H); 13C NMR (100
MHz, CDCl3) 177.27, 153.51, 139.09, 135.06, 134.83, 133.62,
131.10, 130.20, 127.94, 126.79, 124.83, 121.63, 72.04, 68.45, 48.26,
1
105 mg of product. H NMR (400 MHz, CDCl3) 8.78 (d, J ) 2.2
Hz, 1H), 7.86 (dd J ) 8.1, 2.2 Hz, 1H), 7.80 (s, 1H), 7.75 (d, J )
8.1 Hz, 1H), 7.65-7.57 (m, 2H,), 7.28 (d, J ) 8.1 Hz, 1H), 6.64-
6.55 (m, 2H), 4.79-4.72 (m, 1H), 3.98 (dd, J ) 3.7, 11.7 Hz, 1H),
3.86 (dd, J ) 3.3, 11.4 Hz, 1H), 3.40 (dt, J ) 2.0, 12.1 Hz, 1H),
3.06 (t, J ) 11.0 Hz, 1H), 2.77-2.70 (m, 1H), 1.83 (dq, J ) 1.9,
7.0 Hz, 1H), 1.67 (d, J ) 11.7 Hz, 1H), 1.44 (d, J ) 5.9 Hz, 3H),
1.48-1.39 (m, 2H), 1.28-1.07 (m, 2H); 13C NMR (100 MHz,
CDCl3) 177.20, 153.75, 147.89, 147.80, 138.16, 135.25, 134.88,
133.53, 131.07, 129.94, 129.47, 124.57, 123.48, 121.63, 76.63,
72.02, 68.43, 48.29, 44.87, 41.50, 39.64, 38.87, 31.24, 26.37, 22.17;
[R]20D ) +25.7 (c 10 mg/mL, MeOH); HRMS calcd for C26H27F3-
NO3 (MH+), 458.1943; found, 458.1941; Anal. (C26H26F3NO3‚HCl‚
0.6H2O) C, H, N.
44.87, 41.47, 39.65, 38.86, 31.23, 26.38, 22.20; [R]20 ) -8.2 (c
D
1.7 mg/mL, MeOH); HRMS calcd for C25H27ClNO3 (MH+),
424.1679; found, 424.1686; Anal. (C25H26ClNO3‚HCl‚0.8H2O) C,
H, N.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(E)-2-[5-(2-Chlorophenyl)-2-py-
ridinyl]ethenyl]-decahydro-1-methyl-3H-furo[3,4-g][2]benzopyran-
1
3-one (27f). H NMR (400 MHz, CDCl3) 8.63 (d, J ) 2.2 Hz,
1H), 7.70 (dd, J ) 2.9, 8.1 Hz, 1H), 7.52-7.49 (m, 1H), 7.37-
7.31 (m, 3H), 7.26 (d, J ) 7.3 Hz, 1H), 6.64-6.55 (m, 2H), 4.81-
4.74 (m, 1H), 4.00 (dd, J ) 3.7, 11.7 Hz, 1H), 3.88 (dd, J ) 3.7,
11.0 Hz, 1H), 3.41 (dt, J ) 2.0, 12.1 Hz, 1H), 3.07 (d, J ) 10.7
Hz, 1H), 2.78-2.72 (m, 1H), 2.47-2.38 (m, 2H), 1.85 (ddd, J )
2.2, 6.6, 13.4 Hz, 1H), 1.70 (d, J ) 13.2 Hz, 1H), 1.47 (d, J ) 5.9
Hz, 3H), 1.49-1.39 (m, 2H), 1.30-1.08 (m, 2H); 13C NMR (100
MHz, CDCl3) 177.24, 153.22, 149.67, 137.31, 136.49, 134.82,
133.43, 132.48, 131.37, 130.93, 130.02, 129.20, 127.01, 120.79,
76.67, 72.04, 68.45, 48.27, 44.88, 41.48, 39.65, 38.90, 31.24, 26.40,
The following compounds were prepared using a procedure
similar to the preparation of 27a using appropriate phosphonate
reagents.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(E)-2-[5-(3-Fluorophenyl)-2-py-
ridinyl]ethenyl]-decahydro-1-methyl-3H-furo[3,4-g][2]benzopyran-
1
3-one (27b). H NMR (400 MHz, CDCl3) 8.75 (d, J ) 1.5 Hz,
22.25; [R]20 ) +16.9 (c 6 mg/mL, MeOH); HRMS calcd for
1H), 7.80 (dd, J ) 2.9, 8.1 Hz, 1H), 7.45-7.39 (m, 1H), 7.34 (d,
J ) 7.3 Hz, 1H), 7.09-7.05 (m, 1H), 6.61-6.51 (m, 2H), 4.78-
4.71 (m, 1H), 3.97 (dd, J ) 3.6, 11. 7 Hz, 1H), 3.85 (dd, J ) 3.3,
11.4 Hz, 1H), 3.39 (t, J ) 11.7 Hz, 1H), 3.05 (t, J ) 10.6 Hz, 1H),
2.76-2.69 (m, 1H), 2.45-2.36 (m, 1H), 1.84-1.79 (m, 1H), 1.66
(d, J ) 13.2 Hz, 1H), 1.43 (d, J ) 5.9 Hz, 3H), 1.47-1.37 (m,
2H), 1.27-1.06 (m, 2H); 13C NMR (100 MHz, CDCl3) 177.21,
164.17, 161.72, 153.56, 147.87, 147.76, 139.53, 139.46, 134.93,
134.72, 133.68, 131.17, 130.52, 130.44, 122.33, 122.30, 121.54,
114.85, 114.65, 113.70, 113.48, 71.99, 68.42, 48.24, 44.84, 41.42,
39.63, 38.86, 31.21, 26.35, 22.18, 22.13; [R]20D ) +25.9 (c 8 mg/
mL, MeOH); HRMS calcd for C25H26FNO3 (MH+), 408.1975;
found, 408.1982; Anal. (C25H26FNO3‚HCl‚0.5H2O) C, H, N.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(E)-2-[5-(2-Fluorophenyl)-2-py-
ridinyl]ethenyl]-decahydro-1-methyl-3H-furo[3,4-g][2]benzopyran-
D
C25H27ClNO3 (MH+), 424.1679; found, 424.1684; Anal. (C25H26-
ClNO3‚HCl‚0.7H2O) C, H, N.
(1R,3aR,4aS,8aS,9S,9aS)-9-[(E)-2-[5-(2,3-Dichlorophenyl)-2-
pyridinyl]ethenyl]-decahydro-1-methyl-3H-furo[3,4-g][2]-
1
benzopyran-3-one (27g). H NMR (400 MHz, CDCl3) 8.60 (d, J
) 2.2 Hz, 1H), 7.74 (dd, J ) 2.2, 8.1 Hz, 1H), 7.53 (dd, J ) 1.9,
7.7 Hz, 1H), 7.31-7.22 (m, 3H), 6.67-6.56 (m, 1H), 4.81-4.74
(m, 1H), 4.00 (dd, J ) 4.1, 11.4 Hz, 1H), 3.88 (dd, J ) 3.7, 11.7
Hz, 1H), 3.40 (dt, J ) 2.2, 11.7 Hz, 1H), 3.07 (t, J ) 10.7 Hz,
1H), 2.78-2.72 (m, 1H), 2.49-2.38 (m, 2H), 1.84 (ddd, J ) 2.2,
6.6, 13.6 Hz, 1H), 1.70 (d, J ) 13.2 Hz, 1H), 1.47 (d, J ) 5.9 Hz,
3H), 1.44-1.37 (m, 2H), 1.30-1.05 (m, 2H); 13C NMR (100 MHz,
CDCl3) 177.24, 153.58, 149.48, 138.80, 137.25, 135.22, 133.80,
133.34, 131.25, 131.13, 130.08, 129.09, 127.35, 120.85, 76.65,
72.06, 68.46, 48.28, 44.91, 41.50, 39.66, 38.90, 31.25, 26.40, 22.26;
[R]20D ) +15.5 (c 5 mg/mL, MeOH); HRMS calcd for C25H26Cl2-
NO3, 458.1290; found, 458.1299; Anal. (C25H25Cl2NO3‚HCl‚
1.5H2O) C, H, N.
3-Formyl-5,6-dihydro-1(2H)-pyridinecarboxylic Acid, Ethyl
Ester (19b). To a solution of 5,6-dihydro-2H-pyridine-1,3-dicar-
boxylic acid 1-ethyl ester 3-methyl ester37 (35.4 g, 166 mmol) in
CH2Cl2 (600 mL) at -78 °C was slowly added a solution of 1 M
DIBAL (365 mL, 365 mmol, 2.2 equiv) in CH2Cl2, and the mixture
was stirred for 1.5 h. The reaction was quenched by the addition
1
3-one (27c). H NMR (400 MHz, CDCl3) 8.74 (s, 1H), 7.85 (d, J
) 8.1, Hz, 1H), 7.44 (dt, J ) 1.7, 7.7 Hz, 1H), 7.41-7.35 (m,
1H), 7.28-7.17 (m, 4H), 6.64-6.55 (m, 2H), 4.80-4.74 (m, 1H),
4.00 (dd, J ) 3.7, 11.7 Hz, 1H), 3.88 (dd, J ) 4.1, 11.4 Hz, 1H),
3.41 (dt, J ) 2.0, 12.1 Hz, 1H), 3.07 (t, J ) 10.7 Hz, 1H), 2.78-
2.72 (m, 1H), 2.40-2.38 (m, 2H), 1.85 (ddd, J ) 2.6, 6.3, 13.2
Hz, 1H), 1.70 (d, J ) 13. 2 Hz, 1H), 1.46 (d, J ) 5.9 Hz, 3H),
1.49-1.36 (m, 2H), 1.29-1.08 (m, 2H); 13C NMR (100 MHz,
CDCl3) 177.26, 160.75, 158.29, 153.16, 149.14, 136.70, 136.67,
134.82, 131.24, 129.98, 129.95, 129.74, 129.67, 125.18, 125.05,