(2S,4R,5R)-2-Benzhydryl-5-benzylaminotetrahydropyran-4-ol
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15 4969
with saturated NaHCO3 and brine and then dried over
anhydrous Na2SO4. Evaporation of the solvent gave a light
brown solid residue. The crude products were purified by flash
chromatography on silica gel (hexane/ethyl ether ) 9:1) to give
8a (0.08 g, 50%) ([R]D ) (-)60, c ) 1, MeOH) and 8b (0.065 g,
41%) ([R]D ) (-)76, c ) 1, MeOH). For (1S,4S,6R)-4-benzhy-
dryl-3,7-dioxa-bicyclo[4.1.0]heptane 8a, 1H NMR (CDCl3, 400
MHz): 1.71 (m, 1H, H-5), 1.89 (m, 1H, H-5), 3.27 (t, J ) 4.0
Hz, 1H, H-1), 3.34 (m,1H, H-6), 3.82 (d, J ) 9.6 Hz, 1H, Ph2-
CH), 3.95 (d, J ) 13.6 Hz, 1H, H-2ax), 4.14 (dt, J ) 2.4 Hz,
10.0 Hz, H-4), 4.22 (dd, J ) 4.0 Hz, 13.6 Hz, 1H, H-2eq), 7.16-
7.36 (m, 10H, aromatic-CH). For (1R,4S,6S)-4-benzhydryl-3,7-
dioxabicyclo[4.1.0]heptane 8b, 1H NMR (CDCl3, 400 MHz):
1.71 (td, J ) 4.0 Hz, 15.6 Hz, 1H, H-5eq), 1.82 (dd, J ) 10.4
Hz, 15.2 Hz, 1H, H-5ax), 3.06 (d, J ) 4.0 Hz, 1H, H-1), 3.29 (t,
J ) 4.0 Hz, 1H, H-6), 3.82 (d, J ) 13.6 Hz, 1H, H-2), 3.86 (d,
J ) 9.2 Hz, 1H, Ph2CH), 3.93 (dt, J ) 4.0 Hz, 9.2 Hz, 1H, H-4),
4.19 (d, J ) 13.6 Hz, 1H, H-2), 7.16-7.36 (m, 10H, aromatic-
CH).
13.2 Hz, 1H, PhCH2), 3.72-3.96 (m, 5H, H-4, 2H-6, Ph2CH,
PhCH2), 4.49 (dt, J ) 2.4 Hz, 10.0 Hz, 1H, H-2), 6.80-7.40
(m, 14H, aromatic-CH). The free base was converted into the
oxalate: mp 222-223 °C. Anal. [C25H26NFO2‚(COOH)2 ] C, H,
N.
Synthesis of (2R,4S,5S)-2-Benzhydryl-5-(4-fluoroben-
zylamino)tetrahydropyran-4-ol (+)-9b. Compound 8c (0.02
g, 0.08 mmol) was reacted with p-fluorobenzylamine (0.19 g,
1.50 mmol) in ethanol (procedure E) to yield (+)-9b (0.03 g,
94%) ([R]D ) (+)77.6, c ) 1, MeOH). 1H NMR (CDCl3, 400
MHz): 1.43 (td, J ) 3.2 Hz, 14.4 Hz, 1H, H-3eq), 1.68-1.78
(m, 3H, H-3ax, NH, OH), 2.43 (m, 1H, H-5), 3.68 (d, J ) 13.2
Hz, 1H, PhCH2), 3.74-4.00 (m, 5H, H-4, 2H-6, Ph2CH, PhCH2),
4.50 (dt, J ) 2.4 Hz, 10.4 Hz, 1H, H-2), 6.80-7.40 (m, 14H,
aromatic-CH). The free base was converted into the oxalate:
mp 223-225 °C. Anal. [C25H26NFO2‚(COOH)2‚0.25H2O] C, H,
N.
Synthesis of (2S,4R,5R)-2-Benzhydryl-5-[2-(4-fluoro-
phenyl)ethylamino]tetrahydropyran-4-ol (-)9c. Com-
pound 8a (0.03 g, 0.09 mmol) was reacted with 2-(4-fluorophen-
yl)ethylamine (0.26 g, 1.88 mmol) in ethanol (procedure E) to
Synthesis of (1R,4R,6S)-4-Benzhydryl-3,7-dioxabicyclo-
[4.1.0]heptane (8c) and (1S,4R,6R)-4-Benzhydryl-3,7-
dioxabicyclo[4.1.0]heptane (8d). Compound 7b (0.20 g, 0.79
mmol) was reacted with mCPBA (0.27 g, 70%, 1.58 mmol)
(procedure D) to yield the corresponding 8c (0.11 g, 52%) ([R]D
) (+)60.4, c ) 1, MeOH) and 8d (0.086 g, 41%) ([R]D ) (+)78,
c ) 1, MeOH). For (1R,4R,6S)-4-benzhydryl-3,7-dioxa-bicyclo-
1
yield (-)-9c (0.04 g, 98%) ([R]D ) (-)62.9, c ) 1, MeOH). H
NMR (CDCl3, 400 MHz): 1.40 (td, J ) 3.2 Hz, 14.0 Hz, 1H,
H-3eq), 1.63 (dt, J ) 3.2 Hz, 12.0 Hz, 1H, H-3ax), 1.84 (s, 2H,
NH, OH), 2.43 (m, 1H, H-5), 2.73-2.92 (m, 4H, (F)PhCH2CH2),
3.70 (dd, J ) 2.0 Hz, 11.6 Hz, 1H, H-6), 3.86-3.98 (m, 3H,
H-4, H-6, Ph2CH), 4.49 (dt, J ) 2.4 Hz, 10.0 Hz, 1H, H-2),
6.80-7.40 (m, 14H, aromatic-CH). The free base was converted
into the oxalate: mp 205-207 °C. Anal. [C26H28NFO2‚(COOH)2
0.25H2O] C, H, N.
1
[4.1.0]heptane 8c, H NMR (CDCl3, 400 MHz): 1.71 (m, 1H,
H-5eq), 1.89 (m, 1H, H-5qx), 3.27 (t, J ) 4.0 Hz, 1H, H-1),
3.34 (m,1H, H-6), 3.82 (d, J ) 9.6 Hz, 1H, Ph2CH), 3.95 (d, J
) 14.0 Hz, 1H, H-2ax), 4.14 (dt, J ) 2.4 Hz, 10.2 Hz, H-4),
4.22 (dd, J ) 4.0 Hz, 12.8 Hz, 1H, H-2eq), 7.16-7.36 (m, 10H,
aromatic-CH). For (1S,4R,6R)-4-benzhydryl-3,7-dioxabicyclo-
Synthesis of (2R,4S,5S)-2-Benzhydryl-5-[2-(4-fluoro-
phenyl)ethylamino]tetrahydropyran-4-ol (+)-9c. Com-
pound 8c (0.02 g, 0.08 mmol) was reacted with 2-(4-fluorophen-
yl)ethylamine (0.21 g, 1.50 mmol) in ethanol (procedure E) to
1
[4.1.0]heptane 8d, H NMR (CDCl3, 400 MHz): 1.71 (td, J )
4.0 Hz, 15.6 Hz, 1H, H-5eq), 1.82 (dd, J ) 10.4 Hz, 15.2 Hz,
1H, H-5ax), 3.06 (d, J ) 4.0 Hz, 1H, H-1), 3.28 (t, J ) 4.0 Hz,
1H, H-6), 3.82 (d, J ) 12.8 Hz, 1H, H-2), 3.86 (d, J ) 10.0 Hz,
1H, Ph2CH), 3.93 (dt, J ) 3.6 Hz, 10.0 Hz, 1H, H-4), 4.19 (d,
J ) 12.8 Hz, 1H, H-2), 7.16-7.36 (m, 10H, aromatic-CH).
1
yield (+)-9c (0.03 g, 98%) ([R]D ) (+)63.4, c ) 1, MeOH). H
NMR (CDCl3, 400 MHz): 1.40 (td, J ) 3.2 Hz, 14.4 Hz, 1H,
H-3eq), 1.63 (dt, J ) 3.2 Hz, 12.0 Hz, 1H, H-3ax), 1.70 (s, 2H,
NH, OH), 2.43 (m, 1H, H-5), 2.73-2.92 (m, 4H, (F)PhCH2CH2),
3.70 (dd, J ) 2.0 Hz, 11.6 Hz, 1H, H-6), 3.86-3.98 (m, 3H,
H-4, H-6, Ph2CH), 4.49 (dt, J ) 2.4 Hz, 10.0 Hz, 1H, H-2),
6.80-7.40 (m, 14H, aromatic-CH). The free base was converted
into the oxalate: mp 203-205 °C. Anal. [C26H28NFO2‚(COOH)2‚
0.5H2O] C, H, N.
Procedure E. Synthesis of (2S,4R,5R)-2-Benzhydryl-
5-(4-methoxybenzylamino)tetrahydropyran-4-ol (-)-9a.
A mixture of 8a (0.03 g, 0.10 mmol) and p-methoxybenzyl-
amine (0.28 g, 2.03 mmol) in ethanol (1 mL) was refluxed
under N2 overnight. The solvent was removed and the residue
was purified by flash chromatography on silica gel (hexane/
ethyl acetate/Et3N ) 6:4:0.2) to give (-)-9a (0.03 g, 73%) ([R]D
Synthesis of (2S,4R,5R)-2-Benzhydryl-5-benzylami-
notetrahydropyran-4-ol (-)-9d. Compound 8a (0.03 g, 0.09
mmol) was reacted with benzylamine (0.20 g, 1.88 mmol) in
ethanol (procedure E) to yield (-)-9d (0.03 g, 86%) ([R]D ) (-)-
54.0, c ) 1, MeOH). 1H NMR (CDCl3, 400 MHz): 1.43 (m,1H,
H-3eq), 1.69 (s, 2H, NH, OH), 1.74 (dt, J ) 2.8 Hz, 10.8 Hz,
1H, H-3ax), 2.45 (m, 1H, H-5), 3.73 (d, J ) 13.2 Hz, 1H, Ph-
CH2), 3.79 (dd, J ) 2.0 Hz, 12.0 Hz, 1H, H-6), 3.86-4.02 (m,
4H, H-4, H-6, Ph2CH, Ph-CH2), 4.50 (dt, J ) 2.4 Hz, 10.0 Hz,
1H, H-2), 7.00-7.40 (m, 15H, aromatic-CH). The free base was
converted into the oxalate: mp 250-252 °C. Anal. [C25H27NO2‚
(COOH)2‚0.5H2O] C, H, N.
Synthesis of (2R,4S,5S)-2-Benzhydryl-5-benzylami-
notetrahydropyran-4-ol (+)-9d. Compound 8c (0.02 g, 0.08
mmol) was reacted with benzylamine (0.18 g, 1.64 mmol) in
ethanol (procedure E) to yield (+)-9d (0.03 g, 81%) ([R]D ) (+)-
53.7, c ) 1, MeOH). 1H NMR (CDCl3, 400 MHz): 1.43 (m, 1H,
H-3eq), 1.68 (s, 2H, NH, OH), 1.74 (dt, J ) 2.4 Hz, 12.0 Hz,
1H, H-3ax), 2.54 (m, 1H, H-5), 3.73 (d, J ) 13.6 Hz, 1H, Ph-
CH2), 3.79 (m, 1H, H-6), 3.86-4.02 (m, 4H, H-4, H-6, Ph2CH,
Ph-CH2), 4.50 (dt, J ) 2.4 Hz, 9.6 Hz, 1H, H-2), 7.00-7.40 (m,
15H, aromatic-CH). The free base was converted into the
oxalate: mp 249-251 °C. Anal. [C25H27NO2‚(COOH)2 0.25H2O]
C, H, N.
1
) (-)71.9, c ) 1, MeOH). H NMR (CDCl3, 400 MHz): 1.42
(m, 1H, H-3eq) 1.70 (dt, J ) 3.2 Hz, 12.0 Hz, 1H, H-3ax), 1.72
(s, 2H, NH, OH), 2.44 (m, 1H, H-5), 3.66 (d, J ) 12.8 Hz, Ph-
CH2), 3.74-3.84 (m, 5H, H-6, -OCH3, Ph-CH2), 3.90 (dd, J )
2.4 Hz, 12.0 Hz, 1H, H-6), 3.92-3.98 (m, 2H, H-4, Ph2CH),
4.50 (dt, J ) 2.4 Hz, 9.6 Hz, 1H, H-2), 6.80-7.40 (m, 14H,
aromatic-CH). The free base was converted into the oxalate:
mp 230-232 °C. Anal. [C26H29NO3‚(COOH)2] C, H, N.
Synthesis of (2R,4S,5S)-2-Benzhydryl-5-(4-methoxy-
benzylamino)tetrahydropyran-4-ol (+)-9a. Compound 8c
(0.02 g, 0.075 mmol) was reacted with p-methoxybenzylamine
(0.21 g, 1.50 mmol) in ethanol (procedure E) to yield (+)-9a
(0.02 g, 80%) ([R]D ) (+)72.8, c ) 1, MeOH). The 1H NMR was
identical to that of (-)-9a; 1H NMR (CD3OD, 400 MHz): 1.43
(td, J ) 2.8 Hz, 14.4 Hz, 1H, H-3eq), 1.67 (dt, J ) 2.8 Hz, 12.0
Hz, 1H, H-3ax), 2.44 (m, 1H, H-5), 3.65 (d, J ) 12.8 Hz, Ph-
CH2), 3.70-3.80 (m, 5H, H-6, -OCH3, Ph-CH2), 3.87 (dd, J )
2.4 Hz, 12 Hz, 1H, H-6), 3.91 (m, 1H, H-4), 3.95 (d, J ) 9.2
Hz, Ph2CH), 4.51 (dt, J ) 2.4 Hz, 9.6 Hz, 1H, H-2), 6.80-7.40
(m, 14H, aromatic-CH). The free base was converted into the
oxalate: mp 230-232 °C. Anal. [C26H29NO3‚(COOH)2‚0.5H2O]
C, H, N.
Synthesis of (2S,4R,5R)-2-Benzhydryl-5-(4-fluoroben-
zylamino)tetrahydropyran-4-ol (-)-9b. Compound 8a (0.03
g, 0.09 mmol) was reacted with p-fluorobenzylamine (0.24 g,
1.88 mmol) in ethanol (procedure E) to yield (-)-9b (0.03 g,
86%) ([R]D ) (-)77.2, c ) 1, MeOH). 1H NMR (CDCl3, 400
MHz): 1.40 (m, 1H, H-3eq), 1.71 (dt, J ) 3.2 Hz, 12.0 Hz, 1H,
H-3ax), 1.78 (bs, 2H, NH, OH), 2.41 (m, 1H, H-5), 3.66 (d, J )
Synthesis of (3S,4R,6S)-6-Benzhydryl-4-(4-methoxy-
benzylamino)tetrahydropyran-3-ol (-)-9g. Compound 8b
(0.02 g, 0.08 mmol) was reacted with p-methoxybenzylamine
(0.22 g, 1.58 mmol) (procedure E) to yield (-)-9g (0.02 g, 63%)
1
([R]D ) (-)63.75, c ) 1, MeOH). H NMR (CDCl3, 400 MHz):
1.37 (m, 1H, H-5eq), 1.81 (dt, J ) 4.0 Hz, 12.0 Hz, 1H, H-5ax),
2.95 (m, 1H, H-4), 3.46 (m, 1H, H-3), 3.63 (m, 2H, PhCH2),