FACULTAD DE FARMACIA

DEPARTAMENTO DE FARMACOLOGA Y QUMICA TERAPUTICA

SNTESIS ESTEREOSELECTIVA DE cis-DECAHIDROQUINOLINAS:

INTERMEDIOS AVANZADOS PARA EL ACCESO A LAS LEPADINAS

MARISA MENA CERVIGN

2006

7.

EXPERIMENTAL

281

Experimental

Experimental
General. All reactions were carried out under an argon atmosphere with dry, freshly
distilled solvents under anhydrous conditions. Analytical TLC was performed on SiO2
(silica gel 60 F254, Merck) or Al2O3 (ALOX N/UV254, Polygram), and the spots were
located with iodoplatinate reagent. Chromatography refers to flash chromatography
and was carried out on SiO2 (silica gel 60, SDS, 230-240 mesh ASTM) or Al2O3
(aluminium oxide 90, Merck). Drying of organic extracts during workup of reactions
was performed over anhydrous Na2SO4. Optical rotations were recorded with a
Perkin-Elmer 241 polarimeter. 1H and

13

C NMR spectra were recorded with a Varian

Gemini 200 or 300 instrument. Chemical shifts are reported in ppm downfield () from
1

Me4Si. All new compounds were determined to be >95% pure by

H NMR

spectroscopy.

CHAPTER 2. (R)-1-CHLORO-5-METHOXYMETHOXY-OCTANE (C)

1.4 eq. MCPBA

Cl

R-salen

Cl

CH2Cl2

43%

1.3 h from 5 C to rt

6-Chloro-hex-1-ene

1,2-epoxy-6-chlorohexane

83%

OH
O

EtMgBr, CuI

Cl

82%

Cl
B
(R)-O-methyl-mandelic acid
DCC
DMAP

OMOM

MOMCl, DIPEA
98%

Ph
OMe

Cl

Cl
C

C3H7

(1S)-1,2-epoxy-6-chlorohexane
To a solution of (+)-1,2-epoxy-6-chlorohexane (888 mg, 6.6 mmol), which was
prepared from 6-Chloro-hex-1-ene (MCPBA, DCM) by the procedure previously
reported41, the catalyst ((R,R)-Salen, 20 mg, 0.005 eq.) and AcOH (36 L, 0.025 eq.)
at 0 C, H2O (66 L, 0.55 eq.) was added in one portion. After 16 h, (1S)-1,2-epoxy283

Captulo 7
6-chlorohexane (382 mg, 2.83 mmol, 43%) was isolated by distillation under reduced
pressure (67 C, 0.1 atm). The enantiomeric purity of the recovered epoxide was
determined by optical rotation.
Colourless oil. []25D +8 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3): 1.40-1.70 (m,
4H), 1.70-1.95 (m, 2H), 2.50 (dd, J = 4.9, 2.7 Hz, 1H), 2.76 (dd, J = 5.0, 3.8 Hz, 1H),
2.86-2.98 (m, 1H), 3.56 (t, J = 6.6 Hz, 2H);

13

C NMR (50 MHz, CDCl3): 23.4 (CH2),

31.7 (CH2), 32.2 (CH2), 44.8 (CH2), 46.9 (CH2), 52.0 (CH).
(4R)-8-Chloro-octan-4-ol (B)
A mixture of CuI (11 mg, 0.06 mmol) in Et2O (8 mL) was cooled to -78 C and treated
with EtMgBr (3.4 mL, 3.4 mmol) 1 M in THF. After 15 min, (1S)-1,2-epoxy-6chlorohexane (382 mg, 2.84 mmol) in Et2O (1 mL) was added, and the mixture was
brought to r.t. overnight. The mixture was hydrolyzed with HCl (2 mL) and extracted
with Et2O (3 x 50 mL). The resulting organic layer was washed with brine (20 mL),
dried over Na2SO4 and concentrated to an oil which was purified by chromatography
(SiO2, 9:1 hexane/AcOEt) to give B as a colourless oil (432 mg, 82%). Rf = 0.15
(SiO2, 9:1 hexane/AcOEt); 1H NMR (200 MHz, CDCl3) 0.93 (t, J = 7.1 Hz, 3H), 1.21.7 (m, 6H), 1.7-1.9 (m, 2H), 3.55 (t, J = 6.6 Hz, 2H), 3.50-3.70 (masked, 1H);

13

NMR (50 MHz, CDCl3): 14.1 (CH3), 18.8 (CH2), 23.0 (CH2), 32.2 (CH2), 32.6 (CH2),
36.6 (CH2), 39.7 (CH2), 45.0 (CH2), 71.4 (CH).
(D)
DMAP (2 mg, 0.013 mmol) was added all at once over a mixture of B (21 mg, 0.13
mmol), (R)-O-methylmandelic acid (22 mg, 0.13 mmol) and DCC (30 mg, 0.14 mmol)
in CH2Cl2 (1 mL). The reaction mixture was stirred at rt overnight.

Then, the

dicyclohexylurea was removed by filtration and the filter cake was washed with
hexane (3 x 10 mL) and the combined filtrates were washed with HCl (2 x 10 mL),
Na2CO3 (2 x 10 mL) and brine (2 x 10 mL), dried over Na2SO4 and concentrated to
an oil which was purified by chromatography (SiO2, 9:1 hexane/AcOEt) to give D as a
single diastereoisomer (37 mg, 90%). Colourless oil. Rf = 0.26 (SiO2, 9:1
hexane/AcOEt); 1H NMR (200 MHz, CDCl3) 0.72 (t, J = 7.0 Hz, 3H), 1.2-1.6 (m, 6H),
1.75-1.85 (m, 2H), 3.42 (s, 3H, OMe), 3.46 (t, J = 6.6 Hz, 2H), 4.75 (s, 1H, CHOMe),
4.86-4.99 (m, 1H).

284

Experimental

(4R)-1-chloro-5-methoxymethoxy-octane (C)
To a solution of B (381 mg, 2.33 mmol) in CH2Cl2 (8 mL) was added
diisopropylamine (8.1 mL, 46.6 mmol) followed by MOMCl (1.8 mL, 23.3 mmol). The
resulting mixture was stirred at rt overnight. The reaction was quenched with H2O.
The aqueous layer was extracted with CH2Cl2 (2 x 10 mL). The combined organic
layers were dried over Na2SO4 and concentrated to an oil which was purified by
chromatography (SiO2, 9:1 hexane/AcOEt) to give C as a colourless oil (474 mg,
98%). Rf = 0.46 (SiO2, 9:1 hexane/AcOEt); 1 H NMR (200 MHz, CDCl3): 0.92 (t, J =
7.0 Hz, 3H), 1.2-1.6 (m, 6H), 1.75-1.85 (m, 2H), 3,38 (s, 3H), 3.54 (t, J = 6.6 Hz, 2H),
3.50-3.60 (masked, 1H), 4.65 (s, 2H);

13

C NMR (50 MHz, CDCl3): 14.3 (CH3), 18.5

(CH2), 22.7 (CH2), 32.7 (CH2), 33.6 (CH2), 36.5 (CH2), 45.0 (CH2), 55.5 (CH3), 77.0
(CH), 95.4 (CH2).

285

Captulo 7

CHAPTER 4. (2S,3S)-3-AMINO-1-(4-METHOXYPHENYL)BUTAN-2-OL (5a)

CO2H
O

HO

(S) CO2H

(+)-DIPCl / Et3N
THF
8.5 h
HO
from -20 C to 25 C

5 eq. MeI / 4 eq. K2CO3

DMF
15 h 25 C

OH
I

92%
O
CO2Me
OH

MeO
II

5 eq. NH(OMe)Me.HCl
10 eq. iPrMgCl 2 M THF
THF
4.5 h
from -20 C to 25 C

OH

MeO
III

O
N

TBSCl / Imidazole
DMF
24 h 25 C

MeO

O
MeMgBr 3 M THF

OTBS

THF
4h
from 0 C to 25 C

IV
67 % from I

(S)

4 eq. NaBH4 / 0.15 eq. CeCl3

MeOH
1.5 h -20 C

OH
(R)

OTBS

MeO
V

2 eq. MsCl / 2 eq.Et3N

CH2Cl2

OTBS

MeO

15 h 25 C

VI

95%

81 % from IV
e.d. 84 %

(S)

N3
(S) (S)

OMs
(R)

H2 / Pd-C

3 eq. NaN3
MeO

OTBS
VII

NH2
(S) (S)

MeO

OTBS
IX

DMF
72%

OTBS

MeO

EtOH
90%

VIII

(S)

HCl 5% v/v
MeOH
1h rt
80%

MeO

NH2
(S)

OH
5a

(S)--(4-hydroxyphenyl)lactic acid [L-Hpla] (I)

A solution of -(4-hydroxyphenyl)pyruvic acid (Aldrich, 901 mg, 5 mmol) in THF (18
mL) was treated with Et3N (0.7 mL, 5 mmol) at -20 C. After 30 min at this
temperature, a solution of (+)-DIPCl (1.9 g, 6 mmol) in THF (6 mL) was added, and
the resulting solution was stirred at rt for 8 h. The reaction mixture was quenched
286

Experimental
with 2 N aqueous NaOH (10 mL) and H2O (5 mL). The aqueous layer was washed
with tert-butylmethylether (2 x 20 mL) and the organic layer with H2O (2 x 30 mL).
The combined aqueous phases were acidified with HCl 2 N to pH 1 and extracted
with AcOEt (4 x 50 mL), dried and concentrated to give L-Hpla I (846 mg, 92 %) as a
white solid. The spectroscopic data were identical to its enantiomer previously
reported30. Rf = 0.40 (SiO2, 1:1 AcOEt/MeOH); m.p. 162-164 C. []25D 10.7 (c 0.56,
CHCl3); 1H NMR (200 MHz, CDCl3) 2.90 (dd, J = 14.0, 8.0 Hz, 1H, H-3), 3.4 (br s,
1H, OH), 4.34 (dd, J = 7.8, 4.4 Hz, 1H, H-2), 6.75 (d, J = 8.4 Hz, 2H, H-6, H-8), 7.10
(d, J = 8.8 Hz, 2H, H-5, H-9);

13

C NMR (50 MHz, CDCl3): 40.7 (C-3), 73.0 (C-2),

116.0 (C-6, C-8), 129.5 (C-4), 131.5 (C-5, C-9), 157.0 (C-7), 177.5 (C-1).

(2S)-2-Hydroxy-3-(4-methoxy-phenyl)-propionic acid methyl ester (II)

K2CO3 (558 mg, 4 mmol) was added to a solution of hydroxy acid I (182 mg, 1 mmol)
in DMF anh. (1 mL). After the mixture had been stirred for 15 min at rt, MeI (0.32 mL,
5 mmol) was added drowise and the mixture was stirred overnight. The mixture was
quenched with H2O (20 mL) and extracted with AcOEt (3 x 20 mL). The dried organic
extracts were concentrated to give II (210 mg) as a brown oil wich was used without
further purification. The NMR data were identical to the racemic compound previously
reported79. Rf = 0.23 (SiO2, CH2Cl2); 1H NMR (200 MHz, CDCl3) 2.40 (br s, 1H),
2.91 (dd, J = 14.0, 6.6 Hz, 1H), 3.06 (dd, J = 14.0, 4.4 Hz, 1H), 3.76 (s, 3H), 3.78 (s,
3H), 4.42 (dd, J = 6.6, 4.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H);
13

C NMR (50 MHz, CDCl3): 39.6 (CH2), 52.4 (CH3), 55.2 (CH3), 71.4 (CH), 113.9

(CH), 128.2 (C), 130.5 (CH), 158.6 (C), 174.5 (C).

(2S)-2-Hydroxy-N-methoxy-3-(4-methoxy-phenyl)-N-methyl-propionamide (III)
To a solution of ester II (210 mg, 1 mmol) in THF (15 mL) cooled to -20 C under
argon atmosphere Me(MeO)NH.HCl (542 mg, 5 mmol) was added and then over 30
min a solution of iPrMgCl 2.0 M in THF (5 mL, 10 mmol) was added dropwise
maintaining the temperature at -20 C. The mixture was stirred 2 h at -20 C and 2.5
h from

-20 C to rt. The mixture was quenched with saturated aqueous NH4Cl

solution (50 mL). The organic layer was dried and concentrated to afford the
corresponding Weinreb amide III (240 mg) as a yellow oil, which was used without fur
79

Rho, H; Ko, B. Synth. Commun. 1999, 29, 2875.

287

Captulo 7

ther purification: Rf = 0.29 (SiO2, CH2Cl2/MeOH 99:1). 1H NMR (200 MHz, CDCl3):
1.60 (br s, 1H), 2.81 (dd, J = 13.8, 7.2 Hz, 1H), 3.01 (dd, J = 13.9, 3.8 Hz, 1H), 3.72
(s, 3H), 3.77 (s, 3H), 3.78 (s, 3H), 4.55-4.65 (m, 1H), 6.83 (d, J = 8.7 Hz, 2H), 7.14
(d, J = 8.4 Hz, 2H); 13C NMR (50 MHz, CDCl3): 29.7 (CH3), 40.1 (CH2), 55.2 (CH3),
61.4 (CH3), 69.8 (CH), 113.8 (CH), 129.2 (C), 130.4 (CH), 158.4 (C), 168.6 (C).
(2S)-2-(tert-Butyl-dimethyl-silanyloxy)-N-methoxy-3-(4-methoxy-phenyl)-Nmethyl-propionamide (IV)
To a solution of Weinreb amide III (231 mg, 0.97 mmol) in DMF (3 mL) at rt under
argon atmosphere imidazol (344 mg, 4.8 mmol) was added and then over the
resulting mixture a solution of TBSCl (330 mg, 2.1 mmol) in DMF (2 mL) was added.
The mixture was stirred for 18 h and then diluted with Et2O (20 mL). The organic
layer was washed with H2O (10 mL), HCl 1 N (10 mL), NaHCO3 (10 mL) and brine
(10 mL), dried and concentrated to an oil which was purified by chromatography
(SiO2, CH2Cl2) to afford the corresponding Weinreb amide IV (229 mg, 67% from I)
as a yellow oil. Rf = 0.23 (SiO2, CH2Cl2). 1H NMR (200 MHz, CDCl3): 0.14 (s, 3H),
0.10 (s, 3H), 0.81 (s, 9H), 2.76 (dd, J = 13.5, 8.7 Hz, 1H), 2.98 (dd, J = 13.4, 4.4 Hz,
1H), 3.19 (s, 3H), 3.62 (s, 3H), 3.79 (s, 3H), 4.58-4.63 (m, 1H), 6.82 (d, J = 8.4 Hz,
2H), 7.14 (d, J = 9.0 Hz, 2H);

13

C NMR (50 MHz, CDCl3): 5.3 (CH3), 5.2 (CH3),

18.3 (C), 25.7 (CH3), 29.7 (CH3), 40.3 (CH2), 55.3 (CH3), 61.5 (CH3), 71.9 (CH),
113.6 (CH), 130.1 (C), 130.7 (CH), 158.3 (C), 168.5 (C).

(3S)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(4-methoxy-phenyl)-butan-2-one (V)
To a solution of Weinreb amide V (222 mg, 0.63 mmol) in THF (8 mL) cooled to 0 C
under argon atmosphere MeMgBr 3 M in Et2O (1 mL, 3.1 mmol) was added
dropwise. The reaction mixture was stirred for 4 h at 0 C and then it was quenched
with saturated aqueous NH4Cl solution (5 mL). The organic layer was dried and
concentrated to an oil which was purified by chromatography (SiO2, CH2Cl2) to afford
the corresponding ketone V (194 mg) which was used without further purification.
The crude product was cromatographed (SiO2, CH2Cl2) to provide the pure ketone V
to measure the optical rotation. Rf = 0.5 (SiO2, CH2Cl2); []25D 39.5 (c 1.2, CHCl3);
H NMR (200 MHz, CDCl3): 0.25 (s, 3H), 0.09 (s, 3H), 0.86 (s, 9H), 2.10 (s, 3H),

2.74 (dd, J = 13.6, 8.0 Hz, 1H), 2.86 (dd, J = 13.6, 4.4 Hz, 1H), 3.79 (s, 3H), 4.12 (dd,
288

Experimental
J = 7.6, 4.4 Hz, 1H), 6.81 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.6 Hz, 2H); 13C NMR (50
MHz, CDCl3): 5.4 (CH3), 5.3 (CH3), 18.0 (C), 25.6 (CH3), 25.7 (CH3), 40.4 (CH2),
55.3 (CH3), 80.3 (CH), 113.7 (CH), 129.0 (C), 130.8 (CH), 158.4 (C), 212.2 (C). Anal.
Calcd for C17H28O3Si: C 66.19, H 9.15. Found: C 66.47, H 9.34.
(2R,3S)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(4-methoxy-phenyl)-butan-2-ol (VI)
To a solution of ketone V (110 mg, 0.36 mmol) in MeOH (4 mL) at rt CeCl3 (14 mg,
0.05 mmol) was added. The resulting mixture was stirred for 20 min and then cooled
to -20 C. NaBH4 (56 mg, 1.43 mmol) was added and the reaction mixture was
stirred for 1 h at -20 C. After that it was quenched with H2O (4 mL) and extracted
with CH2Cl2 (3 x 10 mL). The resulting organic layer was dried and concentrated to
give a mixture of alcohols VI and epi-VI in a 92:8 ratio according to the NMR
spectrum. Purification by chromatography (SiO2, CH2Cl2) gave VI (89 mg, 81% from
IV) as a colourless oil. Rf = 0.35 (SiO2, CH2Cl2); []25D 5.8 (c 1.2, CHCl3); 1 H NMR
(300 MHz, CDCl3): 0.06 (s, 3H), 0.06 (s, 3H), 0.91 (s, 9H), 1.11 (d, J = 6.3 Hz,
3H), 2.66 (dd, J = 13.4, 5.5 Hz, 1H), 2.89 (dd, J = 13.8, 7.5 Hz, 1H), 3.53-3-66 (m,
2H), 3.79 (s, 3H), 6.82 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H);

13

C NMR (75

MHz, CDCl3): 4.6 (CH3), 4.5 (CH3), 18.1 (C), 20.3 (CH3), 25.9 (CH3), 39.4 (CH2),
55.2 (CH3), 67.8 (CH), 77.5 (CH), 113.7 (CH), 130.3 (C), 130.6 (CH), 158.1 (C). Anal.
Calcd for C17H30O3Si: C 65.73, H 9.74. Found: C 65.76, H 9.71.
(2R,3S)-Methanesulfonic acid 2-(tert-butyl-dimethyl-silanyloxy)-3-(4-methoxyphenyl)-1-methyl-propyl ester (VII)
To a solution of VI (68 mg, 0.22 mmol) in CH2Cl2 (2 mL) cooled to -20 C and under
argon atmosphere MsCl (0.035 mL, 0.44 mmol) and Et3N (0.061 mL, 0.44 mmol)
were added. The resulting solution was stirred from 0 C to rt for 15 h. The reaction
mixture was washed with NaHCO3 (2 mL), HCl 1 N (2 mL), dried and concentrated to
an oil which was purified by chromatography (SiO2, CH2Cl2) to give VII (81 mg, 95%)
as a colourless oil. Rf = 0.57 (SiO2, CH2Cl2); []25D 14.9 (c 1.1, CHCl3); 1H NMR
(300 MHz, CDCl3): 0.38 (s, 3H), 0.03 (s, 3H), 0.85 (s, 9H), 1.44 (d, J = 6.6 Hz,
3H), 2.56 (dd, J = 13.6, 8.8 Hz, 1H), 2.90 (dd, J = 13.6, 4.4 Hz, 1H), 3.04 (s, 3H),
3.80 (s, 3H), 3.95 (dt, J = 8.8, 4.4 Hz, 1H), 4.71 (qd, J = 6.6, 4.4 Hz, 1H), 6.84 (d, J =
8.4 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H);

13

C NMR (75 MHz, CDCl3): 4.74 (CH3),

289

Captulo 7
4.66 (CH3), 15.0 (CH3), 17.9 (C), 25.8 (CH3), 36.6 (CH3), 38.7 (CH2), 55.3 (CH3),
74.8 (CH), 79.7 (CH), 113.6 (CH), 130.2 (C), 130.7 (CH), 158.2 (C). Anal. Calcd for
C18H32O5SSi: C 55.63, H 8.30, S 8.25. Found: C 55.93, H 8.60, S 7.95.
(1S,2S)-[2-Azido-1-(4-methoxy-benzyl)-propoxy]-tert-butyl-dimethyl-silane (VIII)
To a solution of VII (70 mg, 0.18 mmol) in DMF (1.5 mL) under argon atmosphere Na
N3 (40 mg, 0.54 mmol) was added. The mixture was heated at 60 C for 6 h. Then, 3
equivalents more of NaN3 (40 mg, 0.54 mmol) were added and the mixture was
stirred for 24 h. After cooling, the mixture was poured in water (5 mL) and extracted
with Et2O (3 x 15 mL). The resulting organic layer was dried and concentrated to an
oil which was purified by chromatography (SiO2, CH2Cl2) to give VIII (43 mg, 72%) as
a colourless oil. Rf = 0.86 (SiO2, CH2Cl2); []25D 18.6 (c 1.0, CHCl3); 1H NMR (300
MHz, CDCl3): 0.13 (s, 3H), 0.09 (s, 3H), 0.93 (s, 9H), 1.29 (d, J = 6.9 Hz, 3H), 2.70
(dd, J = 13.6, 6.8 Hz, 1H), 2.80 (dd, J = 13.6, 6.8 Hz, 1H), 3.80 (s, 3H), 3.44 (qd, J =
6.9, 4.4 Hz, 1H), 3.95 (td, J = 6.8, 4.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7.14 (d, J =
8.4 Hz, 2H);

13

C NMR (75 MHz, CDCl3): 4.9 (CH3), 4.7 (CH3), 13.7 (CH3), 18.1

(C), 25.9 (CH3), 39.0 (CH2), 55.3 (CH3), 60.4 (CH), 76.3 (CH), 113.7 (CH), 130.0 (C),
130.5 (CH), 158.2 (C).

(2S,3S)-3-(tert-Butyl-dimethyl-silanyloxy)-4-(4-methoxyphenyl)-2-butanamine
(IX)
A suspension of VIII (43 mg, 0.13 mmol) and Pd/C (23 mg) in MeOH (1 mL) was
stirred at room temperature under hydrogen atmosphere overnight. The catalyst was
removed by filtration through Celite and the filtrate was concentrated to give an oil
which was purified by chromatography (Al2O3, CH2Cl2 saturated with NH3) to give IX
(36 mg, 90%) as a colourless oil. Rf = 0.45 (Al2O3, CH2Cl2 saturated with NH3); []25D
18.6 (c 1.2, CHCl3); 1 H NMR (300 MHz, CDCl3): 0.30 (s, 3H), 0.06 (s, 3H), 0.84
(s, 9H), 1.11 (d, J = 6.6 Hz, 3H), 2.20-2.40 (br s, 2H), 2.65 (d, J = 6.6 Hz, 2H), 2.903.00 (m, 1H), 3.70-3.80 (m, 1H), 3.79 (s, 3H), 6.81 (d, J = 8.4 Hz, 2H), 7.08 (d, J =
8.4 Hz, 2H);

13

C NMR (75 MHz, CDCl3): 4.9 (CH3), 4.65 (CH3), 17.9 (CH3), 18.1

(C), 25.9 (CH3), 37.5 (CH2), 50.7 (CH), 55.3 (CH3), 77.9 (CH), 113.6 (CH), 130.5
(CH), 131.0 (C), 158.0 (C). Anal. Calcd for C17H31NO2Si: C 65.97, H 10.10, N 4.53.
Found: C 65.78, H 10.21, N 4.26.

290

Experimental

(2S,3S)-3-Amino-1-(4-methoxyphenyl)butan-2-ol (5a)
To a solution of IX (30 mg, 0.1 mmol) in MeOH (1 mL) was added concentrated HCl
(0.05 mL, resulting in a 5% v/v solution in MeOH). The resulting solution was stirred
for 1 h at rt and then saturated aqueous NaHCO3 (10 mL) was added. The product
was extracted with Et2O (3 x 15 mL), dried and concentrated to an oil which was
purified by chromatography (Al2O3, CH2Cl2 saturated with NH3/MeOH 9:1) to give 5a
(15 mg, 80%) as a colourless oil. Rf = 0.3 (Al2O3, CH2Cl2 saturated with NH3/MeOH
9:1); []25D 15.0 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): 1.12 (d, J = 6.6 Hz,
3H), 2.56 (dd, J = 14.0, 8.6 Hz, 1H), 2.74-2.86 (m, 2H), 3.40-3.46 (m, 1H), 3.78 (s,
3H), 6.84 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H);

13

C NMR (75 MHz, CDCl3):

20.5 (CH3), 39.6 (CH2), 50.3 (CH), 54.7 (CH2), 55.2 (CH3), 76.4 (CH), 113.7 (CH),
130.1 (C), 130.2 (CH), 158.0 (C).

291

Captulo 7

CHAPTER 4. (2R,3S)-3-AMINO-1-(4-METHOXYPHENYL)BUTAN-2-OL (epi-5a)

(S)

OH

BocHN

SF3
N

(S)

CH2Cl2

2) 2 eq.
O

BocHN

MgCl
MeO

NHBoc
(S)

0.25 M THF

NHBoc
(R) (S)

NaBH4
MeOH

OH

MeO

MeO

76%

76%

80%
O

THF
5 h from -15 C to rt

HN(OMe)Me

iPrMgCl 2 M THF

1) 1.05 eq
(S)

BocHN

iPrNEt, 0 C

NH2
(R) (S)

TFA
CH2Cl2
79%

MeO

OH
epi-5a

(3S)-3-(
-Boc)-amino-1-(4-methoxyphenyl)butan-2-one (B)
A solution of N-Boc-L-alanine Weinreb amide (176 mg, 0.8 mmol), which was
prepared from N-Boc-L-alanine ([bis(2-methoxyethyl)amino]sulfur trifluoride, DIPEA,
HN(OMe)Me, DCM) by the procedure previously reported72, in dry THF (5 mL) under
argon atmosphere was cooled to -15 C and iPrMgCl 2 M in THF (0.4 mL, 0.8 mmol)
was added dropwise to afford a clear solution. Then 2-methoxybenzylmagnesium
chloride 0.25 M in THF (6 mL, 1.5 mmol) was added dropwise. The reaction mixture
was allowed to warm to rt over 30 min. After 5 h aged at rt, the reaction was
complete. The mixture was cooled over an ice bath and aqueous HCl 1 N (5 mL)
was added slowly, followed by AcOEt (5 mL). The aqueous layer was cut and the
organic layer washed with H2O (5 mL), dried and concentrated to an oil, which was
purified by chromatography (SiO2, CH2Cl2) to give B as a colourless oil (170 mg,
76%). Rf = 0.16 (SiO2, CH2Cl2); []25D +21.4 (c 1.1, CHCl3); 1H NMR (200 MHz,
CDCl3): 1.31 ( d, J = 7.4 Hz, 3H), 1.44 (s, 9H), 3.77 (d, J = 10.2 Hz, 2H), 3.79 (s,
3H), 4.4 (m, 1H), 5.2 (br s, 1H), 6.86 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H); 13C
292

Experimental
NMR (50 MHz, CDCl3): 17.9 (CH3), 28.4 (CH3), 45.4 (CH2), 54.5 (CH), 55.3 (CH3),
79.2 (C), 114.1 (CH), 125.2 (C), 130.4 (CH), 155.5 (C), 158.3 (C).
(2R,3S)-3-(
-Boc)-amino-1-(4-methoxyphenyl)butan-2-ol (C)
To a solution of ketone B (130 mg, 0.4 mmol) in MeOH (4 mL) cooled to -50 C
NaBH4 (30 mg, 0.74 mmol) was added and the reaction mixture was stirred for 1 h at
-50 C. After that it was quenched with brine (4 mL) and extracted with CH2Cl2 (3 x 10
mL). The resulting organic layer was dried and concentrated to give an oil which was
purified by chromatography (SiO2, CH2Cl2) to give C (100 mg, 76%) as a white solid.
mp = 88-92 C. Rf = 0.02 (SiO2, CH2Cl2); []25D 19.8 (c 1.0, CHCl3); 1 H NMR (300
MHz, CDCl3): 1.16 ( d, J = 6.9 Hz, 3H), 1.43 (s, 9H), 2.4 (br s, 1H), 2.50-2.75 (m,
2H), 3.60-3.80 (masked, 1H), 3.79 (s, 3H), 4.9 (br s, 1H), 6.84 (d, J = 9.0 Hz, 2H),
7.13 (d, J = 8.4 Hz, 2H);

13

C NMR (50 MHz, CDCl3): 14.5 (CH3), 28.4 (CH3), 39.3

(CH2), 50.2 (CH), 55.2 (CH3), 75.3 (CH), 79.3 (C), 114.0 (CH), 130.1 (CH), 130.2 (C),
155.6 (C), 158.2 (C). Anal. Calcd for C16H25NO4: C 65.06, H 8.53, N 4.74. Found: C
65.26, H 8.46, N 4.66.

(2R,3S)-3-Amino-1-(4-methoxyphenyl)butan-2-ol (epi-5a)
To a solution of C (95 mg, 0.32 mmol) in CH2Cl2 (3 mL) cooled to 0 C under argon
atmosphere trifluoroacetic acid (Aldrich, 1.2 mL, 16 mmol) was added and the
mixture was stirred for 45 min at 0 C. The mixture was diluted with CH2Cl2 (10 mL)
and the organic layer was washed with NaHCO3 (10 mL). The aqueous layer was
extracted with CHCl3/MeOH 8:2 (2 x 10 mL). The combined organic layers were dried
over Na2SO4 and concentrated to an oil which was purified by chromatography
(Al2O3, CH2Cl2 saturated with NH3/MeOH 9:1) to give epi-5a as a colourless oil (50
mg, 79%). Rf = 0.25 (Al2O3, CH2Cl2 saturated with NH3/MeOH 9:1); []25D +15.7 (c
0.5, CHCl3); 1H NMR (300 MHz, CDCl3) 1.07 (d, J = 6.6 Hz, 3H), 1.97 (br s, 3H),
2.50-2.80 (m, 2H), 2.82-3.00 (m, 1H), 3.55-3.65 (m, 1H), 3.77 (s, 3H), 6.83 (d, J = 8.8
Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H);

13

C NMR (75 MHz, CDCl3): 17.4 (CH3), 38.3

(CH2), 50.1 (CH), 55.3 (CH3), 76.1 (CH), 114.0 (CH), 130.2 (CH), 130.3 (C), 158.1
(C).

293