S. Llabrés et al. / European Journal of Medicinal Chemistry 81 (2014) 35e46
41
(CH), 128.6 (CH), 137.3 (C), 137.4 (C), 148.3 (C), 149.1 (C), 206.8 (C]
O) ppm. IR (film): nmax: 1708, 1512, 1262, 1137 cmꢀ1 HRMS (ESI):
calc. for C23H23Oþ3 ([M þ H]þ): 347.1642; found: 347.1651.
(film): nmax: 3436, 2923, 2872, 1508, 1264 cmꢀ1 HRMS (ESI): calc.
for C28H36NO3Sþ ([M þ H]þ): 466.2410; found: 466.2419.
4.1.6. (R)-1-(3,4-Bis(benzyloxy)phenyl)propan-2-amine, (R)-6a
In a 250 mL round bottomed flask, a solution of 4a (1.73 g,
3.82 mmol) in MeOH (15 mL) was placed. 4 M HCl in dioxane
(15 mL) was added dropwise at room temperature. The reaction
was stirred overnight. The solution was extracted with 0.1 M HCl
(20 mL ꢃ 5). The aqueous phase was treated with 1 M NaOH
(20 mL) and extracted with EtOAc (15 mL ꢃ 5). The organic phases
where dried (MgSO4) and evaporated to afford (R)-6a (1.25 g, 94%
yield) as a colourless oil.
4.1.3. (R,RS)-N-[1-(3,4-Dibenzyloxyphenyl)propan-2-yl]-tert-
butylsulfinamide, (R,RS)-4a
In a 2 necked 250 mL round bottomed flask was dissolved (R)-
(þ)-tert-butylsulfinamide (0.49 g, 4.0 mmol, 2 equiv) in anhydrous
THF (11 mL). To this solution was added Ti(OEt)4 (4.2 mL,
20.2 mmol, 10 equiv) and 3 (0.7 g, 2.0 mmol) in anhydrous THF
(13 mL). The brown solution was heated to reflux and monitored by
TLC. After 5 h the reaction was allowed to cool to room tempera-
ture. The reaction was then cooled down to ꢀ20 ꢁC, NaBH4 (76 mg,
2.0 mmol, 1 equiv) was added and the reaction was stirred 3 h
at ꢀ20 ꢁC and overnight at room temperature. The solution was
then filtered through celite and the solvent evaporated under
reduced pressure. The crude showed a 14:1 diastereomeric ratio by
NMR. Column chromatography (SiO2, hexane/ethyl acetate) affor-
ded (R,RS)-4a (0.80, 95% yield) as a white solid.
[a
]
¼ ꢀ4.7 (c 0.7, MeOH). 1H NMR (400 MHz, MeOD):
¼ 1.1 (m,
d
D
3H, CH3), 2.70 (dd, J ¼ 7.8, 13.7 Hz, 1H, CH2), 2.85 (dd, J ¼ 6.2,
13.6 Hz, 1H, CH2), 3.43 (m, 1H, CH), 5.12 (s, 2H, CH2), 5.14 (s, 2H,
CH2), 6.78 (dd, J ¼ 4.0, 8.1 Hz, 1H, CH), 6.91 (d, J ¼ 1.6 Hz, 1H, CH),
7.01 (d, J ¼ 8.2 Hz, 1H, CH), 7.26e7.37 (m, 6H, CH), 7.41e7.46 (m, 4H,
CH) ppm. 13C NMR (100 MHz, MeOD):
d
¼ 18.3 (CH3), 41.3 (CH2),
50.3 (CH), 72.4 (CH2), 72.5 (CH2), 116.8 (CH), 117.7 (CH), 123.5 (CH),
128.67 (CH), 128.74 (CH), 128.92 (CH), 128.95 (CH), 129.45 (CH),
129.47(CH), 130.6 (C), 138.69 (C), 138.74 (C), 149.7 (C), 150.4 (C)
ppm. IR (film): nmax: 3045, 2923,1508,1258 cmꢀ1. HRMS (ESI): Calc.
for C23H26O2Nþ ([M þ H]þ): 348.1958; found: 348.1957. Calc. for
M.p.: 91.3e92.6 ꢁC [
CDCl3):
J ¼ 6.6, 13.5 Hz, 2H, CH2), 3.19 (d, J ¼ 4.5 Hz, 1H, NH), 3.58 (m, 1H,
CH), 5.14 (m, 4H, CH2), 6.71 (dd, J ¼ 1.9, 8.1 Hz, 1H, CH), 6.82 (d,
J ¼ 1.9 Hz, 1H, CH), 6.87 (d, J ¼ 8.1 Hz, 1H, CH), 7.27e7.39 (m, 6H,
CH), 7.41e7.46 (m, 4H, CH) ppm. 13C NMR (100 MHz, CDCl3):
a
]
D ꢀ53.6 (c 0.7, MeOH). 1H NMR (400 MHz,
d
¼ 1.12 (d, J ¼ 6.3 Hz, 3H, CH3), 1.15 (s, 9H, CH3), 2.72 (qd,
C
23H25O2NNaþ ([M þ Na]þ): 370.1778; found: 370.1778.
d
¼ 20.7 (CH3), 22.7 (CH3), 44.2 (CH2), 51.5 (CH), 55.5 (C), 71.48
(CH2), 71.59 (CH2), 115.5 (CH), 116.7 (CH), 112.7 (CH), 127.46 (CH),
127.53 (CH), 127.88 (CH), 127.91(CH), 128.58 (CH), 128.59 (CH),
130.92 (C), 137.4 (C), 137.5 (C), 147.9 (C), 149.1 (C) ppm. IR (film):
nmax: 3025, 3033, 2969, 1508, 1271 cmꢀ1. HRMS (ESI): Calc. for
C
C
4.1.7. (S)-1-(3,4-Bis(benzyloxy)phenyl)propan-2-amine, (S)-6a
The procedure described for (R)-6a starting from (S)-4a (1.52 g,
3.36 mmol) and using 4 M HCl in dioxane (15 mL) afforded 0.97 g
(83% yield) of (S)-6a. [
data were identical to (R)-6a.
a
]
¼ D3.1 (c 0.7, MeOH). The spectroscopic
D
27H33NO3SNaþ ([M þ Na]þ): 474.2073; found: 474.2071. Calc for
54H67N2O6Sþ2 ([2 M þ H]þ): 903.4435; found: 903.4424. EA. Calc.
for C27H33NO3S: C, 71.81: H, 7.37; N, 3.10; S, 7.10. found: C, 71.83; H,
7.45; N, 3.36, S, 7.02.
4.1.8. (R)-Ethyl [1-(3,4-dibenzyloxyphenyl)propan-2-yl]carbamate,
(R)-7a
In a 100 mL round bottomed flask 6a (1.25 g, 3.58 mmol), 4-
(dimethylamino)pyridine (DMAP) (4.38 mg, 0.04 mmol, 0.01 equiv)
and triethylamine (2 mL, 14.33 mmol, 4 equiv) were solved in THF
(25 mL). The stirred solution was cooled to 0 ꢁC and a solution of
ethyl chloroformate (0.7 mL, 7.17 mmol, 2 equiv) was slowly added.
The mixture was stirred 6 h at room temperature. The residue was
dissolved in ether (60 mL) and washed with water (20 mL). The
aqueous phase was extracted with diethyl ether (2 ꢃ 25 mL) and
the combined organic phases were washed with water (10 mL), 1 N
HCl (20 mL) and brine (10 mL), dried (MgSO4) and evaporated to
obtain a white solid. Crystallization from hot heptane (20 mL) was
afforded (R)-7a (1.14 g, 76% yield) as a white solid. The enantiomeric
purity was 99% ee by HPLC.
4.1.4. (S,SS)-N-[1-(3,4-Dibenzyloxyphenyl)propan-2-yl]-tert-
butylsulfinamide, (S,SS)-4a
The procedure described for (R,RS)-4a, starting from 3 (2.9 g,
8.36 mmol), Ti(OEt)4 (17.4 mL, 83.7 mmol,10 equiv) and (S)-(-)-tert-
butylsulfinamide: (2.0 g, 16.8 mmol, 2 equiv), afforded 3.4 g (90%
yield) of (S,SS)-4a. M.p. 90.1e90.4 ꢁC. [
spectroscopic data were identical to (R,RS)-4a.
a
]
D ꢀ51.0 (c 0.7, MeOH). The
4.1.5. (R,RS)-N-[1-(3,4-dibenzyloxyphenyl)propan-2-yl]-N-methyl-
tert-butylsulfinamide, (R,RS)-5a
In a 10 mL round bottomed flask, NaH (4 mg, 0.17 mmol, 2 equiv)
was suspended in anhydrous DMF (1.5 mL). A solution of 4a (34 mg,
0.075 mmol) in anhydrous DMF (3.5 mL) was added and the reac-
M.p. 102.9e104.6. [
(400 MHz, CDCl3):
a
]
¼ ꢀ7.2 (c ¼ 0.7, MeOH). 1H NMR
D
tion stirred 20 min at room temperature. MeI (28
m
L, 0.45 mmol,
d
¼ 1.03 (d, J ¼ 6.6 Hz, 3H, CH3), 1.22 (t, J ¼ 7.1 Hz,
6 equiv) was added via syringe and the reaction was monitored by
TLC. When the starting material was consumed, water (10 mL) and
EtOAc (10 mL) were added. Phases were separated and the organic
phase was dried (MgSO4) and evaporated to give a yellow oil.
Column chromatography (SiO2, hexanes/ethyl acetate) afforded
(R,RS)-5a (33 mg, 99% yield) as a yellow oil.
3H, CH3), 2.57 (dd, J ¼ 7.2,13.5 Hz,1H, CH2), 2.73 (dd, J ¼ 5.0,13.2 Hz,
1H, CH2), 3.88 (bs, 1H, NH), 4.09 (m, 2H, CH2), 4.43 (bs, 1H, CH), 5.13
(s, 2H, CH2), 5.14 (s, 2H, CH2), 6.68 (dd, J ¼ 1.9, 8.1 Hz, 1H, CH), 6.77
(s, 1H, CH), 6.86 (d, J ¼ 8.1 Hz, 1H, CH), 7.27e7.39 (m, 6H, CH), 7.41e
7.46 (m, 4H, CH) ppm. 13C NMR (100 MHz, CDCl3):
d
¼ 14.6 (CH3),
20.0 (CH3), 42.2 (CH2), 47.7 (CH), 60.5 (CH2), 71.2 (CH2), 71.3 (CH2),
115.0 (CH), 116.5 (CH), 122.4 (CH), 127.2 (CH), 127.3 (CH), 127.6 (CH),
127.7 (CH), 128.4 (CH), 131.3 (C), 137.2 (C), 137.4 (C), 147.6 (C), 148.6
1H NMR (400 MHz, CDCl3):
d
¼ 1.06 (d, J ¼ 6.7 Hz, 3H, CH3), 1.14
(s, 9H, CH3), 2.56 (s, 3H, CH3), 2.57 (m, 1H, CH2), 2.88 (dd, J ¼ 4.8,
13.3 Hz, 1H, CH2), 3.38 (m, 1H, CH), 5.13 (s, 2H, CH2), 5.16 (s, 2H,
CH2), 6.67 (dd, J ¼ 2.0, 8.1 Hz, 1H, CH), 6.74 (d, J ¼ 2.0 Hz, 1H, CH),
6.86 (d, J ¼ 8.2 Hz, 1H, CH) 7.28e7.39 (m, 6H, CH), 7.41e7.46 (m, 4H,
(C), 155.8 (C]O). IR (film): nmax: 3340, 2971, 1682, 1537, 1513 cmꢀ1
.
HRMS (ESI): calc. for C26H30O4Nþ ([M þ H]þ): 420.21693; found:
420.21723. Calc. for C26H29O4NNaþ ([M þ Na]þ): 442.19888; found:
442.19913. Analysis. Calc. for C26H29NO4: C, 74.84; H, 6.97; N, 3.34;
Found: C, 74.71; H, 7.02; N, 3.75. HPLC: CHIRALCEL AS, 80%
CH) ppm. 13C NMR (100 MHz, CDCl3):
d
¼ 17.6 (CH3), 23.7 (CH3),
26.5 (CH3), 41.1 (CH2), 58.2 (CH), 60.7 (C), 71.6 (CH2), 115.4 (CH),
116.8 (CH), 122.4 (CH), 127.48 (CH), 127.54 (CH), 127.9 (CH),
128.6(CH), 132.5 (C), 137.5 (C), 137.6 (C), 147.8 (C), 149.0 (C) ppm. IR
heptane-20% IPA, 0.5 mL/min,
t(R) ¼ 17.0 min. Optical purity 99% ee.
l
¼ 254 nm, t(S) ¼ 14.8 min,