Journal of Medicinal Chemistry
ARTICLE
2.52 (s, 3H), 2.50 (s, 3H), 2.34ꢀ2.26 (pq, 1H), 1.99ꢀ1.90 (m, 1H),
1.82ꢀ1.65 (m, 3H). Anal. (C15H19NO3) C, H, N.
(1S,20S)-1-(10-Boc-20-pyrrolidinyl)-2-(o-hydroxy-p-phenyl-
phenoxy)ethanol [(S,S)-29]. Obtained as an oil in 93% yield from
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(1R,20S)-1-(10-methyl-20-pyrrolidinyl)-2-(o-hydroxy-p-bro-
mophenoxy)ethanol [(R,S)-28]. Obtained as an oil in quantitative
yield by treatment of (R,S)-19 with CF3COOH (4 mol) in DCM at
room temperature for 30 min: [α]D25 = ꢀ15.4 (c 1, MeOH). 1H NMR
(CDCl3) δ 7.05 (d, 1H, J=2.20 Hz), 6.85 (dd, 1H, J = 2.20 and 8.53 Hz),
6.77 (d, 1H, J = 8.53 Hz), 4.76 (bs, 2H), 4.03ꢀ3.91 (m, 2H),
3.85ꢀ3.80 (pq, 1H), 3.17ꢀ3.12 (m, 1H), 2.77ꢀ2.71 (m, 1H), 2.48
(s, 3H), 2.45ꢀ2.39 (m, 1H), 2.04ꢀ1.68 (m, 4H).
(S,S)-20 as described for (R,S)-29: [α]D = ꢀ7.8 (c 1, CHCl3). H
NMR (CDCl3) δ 7.55 (d, 2H, J = 7.15 Hz), 7.40 (t, 2H, J = 7.15 Hz),
7.34ꢀ7.20 (m, 2H), 7.08ꢀ7.01 (m, 1H), 6.98ꢀ6.93 (m, 1H), 5.08 (bs,
1H), 4.20ꢀ4.06 (m, 3H), 4.00ꢀ3.90 (m, 1H), 3.61ꢀ3.42 (m, 1H),
3.33ꢀ3.21 (m, 1H), 2.08ꢀ1.68 (m, 4H), 1.47 (s, 9H).
(2R,20S)-2-(10-Boc-20-pyrrolidinyl)-7-phenyl-1,4-benzodiox-
ane [(R,S)-30]. Obtained as an oil in 72% from (S,S)-29 as described for
(S,S)-30: [α]D25 = ꢀ44.1 (c 1, CHCl3). 1H NMR (CDCl3) δ 7.53 (d, 2H,
J = 7.43 Hz), 7.40 (t, 2H, J = 7.43 Hz), 7.32ꢀ7.21 (m, 1H), 7.20ꢀ7.15
(m, 1H), 7.14ꢀ7.02 (m, 1H), 6.93 (d, 1H, J = 8.25 Hz), 4.50ꢀ4.18 (m,
3H), 4.06ꢀ3.90 (m, 1H), 3.65ꢀ3.39 (m, 2H), 2.20ꢀ2.00 (m, 3H),
1.98ꢀ1.86 (m, 1H), 1.47 (s, 4.5H), 1.57 (s, 4.5H).
(2S,20S)-2-(10-Methyl-20-pyrrolidinyl)-7-bromo-1,4-benzo-
dioxane [(S,S)-5]. Obtained as an oil in 69% yield by treatment of (R,
S)-28 with PMe3 (1.5 mol) and DEAD (1.1 mol) in THF at room
temperature for 24 h and chromatography on silica gel (EtOAc/TEA
98:2): [α]D25 = ꢀ133.7 (c 0.5, MeOH). 1H NMR (CDCl3) δ 7.08 (d,
1H, J = 2.20 Hz), 6.91 (dd, 1H, J = 2.2 and 8.53 Hz), 6.72 (d, 1H, J =
8.53 Hz), 4.27 (dd, 1H J = 1.93 and 11.00 Hz), 4.06 (ddd, 1H, J = 1.93
Hz, 4.40 and 7.98 Hz), 3.97 (dd, 1H, J = 7.98 and 11.00 Hz), 3.12ꢀ3.06
(m, 1H), 2.50ꢀ2.46 (m, 1H), 2.41(s, 3H), 2.30ꢀ2.24 (m, 1H),
1.88ꢀ1.75 (m, 4H). Anal. (C13H16BrNO2) C, H, N.
(2R,20S)- 2-(10-Methyl-20-pyrrolidinyl)-7-phenyl-1,4-ben-
zodioxane [(R,S)-6]. Obtained as an oil in 80% yield from (R,S)-30
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as described for (S,S)-6: [α]D = ꢀ29.4 (c 1, CHCl3). 1H NMR
(CDCl3) δ 7.53 (d, 2H, J = 7.15 Hz), 7.40 (t, 2H, J = 7.15 Hz), 7.30 (d,
1H, J = 7.15 Hz), 7.15 (d, 1H, J = 2.20 Hz), 7.08 (dd, 1H, J = 8.53 and
2.20 Hz), 6.92 (d, 1H, J = 8.53 Hz), 4.33 (dd, 1H, J = 2.20 and 11.27
Hz), 4.19 (dt, 1H, J = 2.20 and 7.42 Hz), 4.06 (dd, 1H, J = 7.42 and
11.27 Hz), 3.15ꢀ3.09 (m, 1H), 2.71ꢀ2.64 (m, 1H), 2.52 (s, 3H, CH3),
2.39ꢀ2.23 (m, 1H), 2.20ꢀ1.92 (m, 1H), 1.84ꢀ1.64 (m, 3H). Anal.
(C19H21NO2) C, H, N.
(1S,20S)-1-(10-Methyl-20-pyrrolidinyl)-2-(o-hydroxy-p-bro-
mophenoxy)ethanol [(S,S)-28]. Obtained as an oil in quantitative
yield by treatment of (S,S)-19 with CF3COOH (4 mol) in DCM at
room temperature for 30 min: [α]D25 = ꢀ5.8 (c 1, MeOH). 1H NMR
(CDCl3) δ 7.06 (d, 1H, J = 2.2 Hz), 6.87 (dd, 1H, J = 2.2 and 8.53 Hz),
6.73 (d, 1H, J = 8.53 Hz), 6.30 (bs, 2H), 4.13ꢀ4.08 (m, 1H),
4.05ꢀ4.00 (m, 1H), 3.84ꢀ3.78 (m, 1H), 3.15ꢀ3.11 (m, 1H), 2.40 (s,
3H), 2.38ꢀ2.28 (m, 2H), 1.86ꢀ1.76 (m, 4H).
(1R,20S)-1-(10-Boc-20-pyrrolidinyl)-2-(o,p-dibenzyloxyphe-
noxy)ethyl mesylate [(R,S)-31]. Obtained as a white solid in 55%
yield from (R,S)-21 by treatment with equimolar mesyl chloride and
trimethylamine in DCM at room temperature for 5 h and subsequent
chromatography on silica gel (cyclohexane/EtOAc 7:3): mp 97.3 °C;
(2R,20S)-2-(10-Methyl-20-pyrrolidinyl)-7-bromo-1,4-ben-
zodioxane [(R,S)-5]. Obtained as an oil in 69% yield from (S,S)-28
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[α]D = ꢀ61.4 (c 1, CHCl3). H NMR (CDCl3) δ 7.30ꢀ7.50 (m,
10H), 6.77 (d, 1H, J = 8.81 Hz), 6.66 (d, 1H, J = 2.75 Hz), 6.47 (dd, 1H,
J = 8.81 and 2.75 Hz), 5.10ꢀ5.30 (m, 1H), 4.91ꢀ5.00 (m, 4H),
3.99ꢀ4.11 (m, 3H), 3.36ꢀ3.50 (m, 2H), 2.82 (bs, 3H), 1.78ꢀ2.10 (m,
4H), 1.47 (s, 7H), 1.42 (s, 2H).
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as described for (S,S)-5: [α]D = ꢀ2.8 (c 1, MeOH). 1H NMR
(CDCl3) δ 7.03 (d, 1H, J = 2.20 Hz), 6.91 (dd, 1H, J = 2.20 and 8.52
Hz), 6.74 (d, 1H, J = 8.52 Hz), 4.31 (dd, 1H, J = 2.20 and 11.28 Hz),
4.11 (dt, 1H, J = 2.20 and 7.15 Hz), 3.96 (dd, 1H, J = 7.15 and 11.28
Hz), 3.12ꢀ3.06 (m, 1H), 2.65ꢀ2.57 (m, 1H), 2.47 (s, 3H),
2.33ꢀ2.24 (pq, 1H), 1.97ꢀ1.72 (m, 4H). Anal. (C13H16BrNO2)
C, H, N.
(1R,20S)-1-(10-Boc-20-pyrrolidinyl)-2-(o,p-dihydroxyphenox-
y)ethyl mesylate [(R,S)-32]. Obtained as an oil in 87% yield by
hydrogenolysis (H2 5 atm, 10% Pd(C)) of (R,S)-31 in methanol for 16
h: [α]D25 = ꢀ49.4 (c 1, MeOH). 1H NMR (CDCl3) δ 6.59 (m, 1H), 6.49
(d, 1H, J = 2.75 Hz), 6.27 (m, 1H), 5.34 (m, 1H), 4.15ꢀ3.90 (m, 4H),
3.46ꢀ3.28 (m, 3H), 3.05 (s, 3H), 1.84ꢀ2.04 (m, 4H), 1.48 (s, 9H).
(2S,20S)-2-(10-Boc-20-pyrrolidinyl)-7-hydroxy-1,4-benzodiox-
ane [(S,S)-33]. Obtained as a white solid in 77% yield by treatment of
(R,S)-32 with equimolar K2CO3 in boiling DME for 6 h and subsequent
chromatography on silica gel (cyclohexane/EtOAc 6:4): mp 166.5 °C;
[α]D25 = ꢀ174.4 (c 1, MeOH). 1H NMR (CDCl3) δ 6.71 (d, 1H, J = 8.53
Hz), 6.40 (d, 1H, J = 2.75 Hz), 6.33 (d, 1H, J = 8.53 Hz), 5.10ꢀ4.90 (bs,
1H), 4.24 (dd, 1H, J = 11.55 and 2.20 Hz), 4.20ꢀ3.85 (m, 3H), 3.30ꢀ3.55
(m, 2H), 2.30ꢀ2.15 (m, 1H), 2.05ꢀ1.85 (m, 3H), 1.47 (s, 9H).
(2S,20S)-2-(20-Pyrrolidinyl)-7-hydroxy-1,4-benzodioxane
[(S,S)-7a]. Obtained as a white solid in 48% yield by treatment of (S,S)-
33 with CF3COOH in DCM at room temperature for 2 h and successive
crystallization from diisopropyl ether: mp 205.5 °C; [α]D25 = ꢀ76.4 (c
1, MeOH). 1H NMR (DMSO-d6) δ 8.89 (s, 1H), 6.58ꢀ6.61 (d, 1H, J =
8.25 Hz), 6.20 (d, 1H, J = 3.05 Hz), 6.16 (m, 1H), 4.21 (dd, 1H, J =
11.28 and 1.93 Hz), 3.83 (dd, 1H, J = 11.28 and 7.15 Hz), 3.70 (t, 1H,
J = 7.15 Hz), 3.04ꢀ3.08 (m, 1H), 2.71ꢀ2.82 (m, 2H), 2.53 (bs, 1H),
1.83ꢀ1.56 (m, 4H). Anal. (C12H15NO3) C, H, N.
(1R,20S)-1-(10-Boc-20-pyrrolidinyl)-2-(o-hydroxy-p-phenyl-
phenoxy)ethanol [(R,S)-29]. Obtained as an oil in 85% yield by
hydrogenolysis (H2 1 atm, 10% Pd(C)) of (R,S)-20 in methanol for 48
h: [α]D25 = ꢀ34.1 (c 1, CHCl3). 1H NMR (CDCl3) δ 7.92 (bs, 1H),
7.55 (d, 2H, J = 7.15 Hz), 7.40 (t, 2H, J = 7.15 Hz), 7.31 (d, 1H, J = 7.15
Hz), 7.20 (d, 1H, J = 1.93 Hz), 7.02 (dd, 1H, J = 1.93 and 8.26 Hz), 6.98
(d, 1H, J = 8.26 Hz), 6.23 (bs, 1H), 4.14ꢀ4.07 (m, 1H), 4.06ꢀ3.99 (m,
1H), 3.90ꢀ3.80 (m, 1H), 3.61ꢀ3.49 (m, 1H), 3.38ꢀ3.27 (m, 1H),
2.13ꢀ2.05 (m, 1H), 2.00ꢀ1.65 (m, 3H,), 1.50 (s, 9H).
(2S,20S)-2-(10-Boc-20-pyrrolidinyl)-7-phenyl-1,4-benzodiox-
ane [(S,S)-30]. Obtained as an oil in 60% yield by treatment of (R,S)-29
with PMe3 (2.2 mol) and DEAD (2.2 mol) in THF under microwave
irradiation at 100 °C and 300 W for 10 min and chromatography on silica
gel (cyclohexane/EtOAc 7:3): [α]D25 = ꢀ126.4 (c 1, CHCl3). 1H NMR
(CDCl3) δ 7.54 (d, 2H, J = 7.7 Hz), 7.40 (t, 2H, J = 7.7 Hz), 7.34ꢀ7.22
(m, 1H), 7.19ꢀ7.05 (m, 2H), 6.94 (d, 1H, J = 8.25 Hz), 4.35 (d, 1H, J =
11.27 Hz), 4.25ꢀ3.90 (m, 3H), 3.62ꢀ3.35 (m, 2H), 2.36ꢀ2.20 (m,
1H), 2.10ꢀ1.80 (m, 3H), 1.43 (s, 4.5H), 1.42 (s, 4.5H).
(2S,20S)-2-(10-Methyl-20-pyrrolidinyl)-7-phenyl-1,4-benzodiox-
ane [(S,S)-6]. Obtained as an oil in 70% yield by treatment of (S,S)-30 with
LiAlH4 (2 mol) in boiling THF for 1 h: [α]D25 = ꢀ83.4 (c 1, CHCl3). 1H
NMR (CDCl3) δ7.55 (d, 2H, J= 7.15 Hz), 7.41 (t, 2H, J= 7.15 Hz), 7.31 (d,
1H, J = 7.15 Hz), 7.24 (d, 1H, J = 2.20 Hz), 7.10 (dd, 1H, J = 8.52 and 2.20
Hz), 6.95 (d, 1H, J = 8.52 Hz), 4.31 (dd, 1H, J = 1.92 and 11.27 Hz), 4.17
(ddd, 1H, J = 1.92 Hz, 4.40 and 8.00 Hz), 4.06 (dd, 1H, J = 8.00 and 11.27
Hz), 3.18ꢀ3.13 (m, 1H), 2.58ꢀ2.52 (m, 1H), 2.46 (s, 3H), 2.33ꢀ2.25 (m,
1H), 2.03ꢀ1.77 (m, 4H). Anal. (C19H21NO2) C, H, N.
(2S,20S)-2-(10-Methyl-20-pyrrolidinyl)-7-hydroxy-1,4-ben-
zodioxane [(S,S)-7]. Obtained as a white solid in 96% yield by
treatment of (S,S)-7a with H2 (1 atm)/10% Pd(C) in methanol in the
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presence of formalin for 16 h: mp 161.3 °C; [α]D = ꢀ95.0 (c 1,
CHCl3). 1H NMR (DMSO-d6) δ 8.91 (s, 1H), 6.61 (d, 1H, J = 8.52
Hz), 6.21 (m, 1H), 6.16 (d, 1H, J = 2.75 Hz), 4.20 (dd, 1H, J = 11.28 and
1.92 Hz), 3.92ꢀ3.97 (ddd, 1H, J = 7.70 Hz, 4.67 and 1.92 Hz),
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dx.doi.org/10.1021/jm200937t |J. Med. Chem. 2011, 54, 7588–7601