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M. D. Rozwadowska, A. Tomczak / Tetrahedron: Asymmetry 20 (2009) 2048–2051
4.1.1. (1S,2S)-(+)-2-N,N-Dibenzylamino-1-(4-nitrophenyl)-1,3-
propanediol 4
ment with D2O). 13C NMR (CDCl3) d: 141.9, 138.8, 137.5, 129.3,
128.9, 128.6, 127.4, 93.3, 77.4, 77.0, 76.6, 70.6, 64.9, 58.9, 54.4. EI
MS, m/z (%): 241 (14), 240 (75), 232 (2), 231 (2), 181 (6), 91
(100). Anal. Calcd for C23H24NO2I (473): C, 58.34; H, 5.11; N,
2.96. Found: C, 58.36; H, 4.64; N, 2.76. HR MS m/z: 472.07700.
Calcd for [M+À1]: 472.07736.
To a mixture of (1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-pro-
panediol
3 (R = NO2) (2.12 g, 10 mmol) and K2CO3 (4.13 g,
30 mmol) in acetonitrile (40 ml) benzyl bromide (2.36 ml,
20 mmol) was added and the mixture was stirred at reflux for
8 h, then left at room temperature for 16 h. Water (50 ml) was
added to this mixture and stirring was continued for 30 min. The
crystalline precipitate was filtered off, washed with water
(50 ml), and dried in air to afford TLC-pure 4, 3.55 g (85%). Mp
4.1.4. (1S,2S)-(+)-2-N,N-Dibenzylamino-1-(4-methoxyphenyl)-
1,3-propanediol 7
An ampule equipped with magnetic stirring bar was filled with
iodide 6 (1.42 g, 3 mmol), CuI (28 mg, 0.15 mmol), 3,4,7,8-tetra-
methyl-1,10-phenanthroline (72 mg, 0.3 mmol), and Cs2CO3
(1.17 g, 3.5 mmol) in anhydrous methanol (3 ml). After being
sealed it was placed in oil bath at 90 °C for 24 h, then cooled to
room temperature, opened and the solution was decanted from
inorganic material, which was washed several times with metha-
nol. The organic solution was filtered through a pad of Celite, after
which water (12 ml) was added to the filtrate, methanol evapo-
rated and the water solution was extracted with ethyl ether until
the Dragendorff test was negative. The ethereal solution was dried
and concentrated to give 1.1 g of oily residue, from which 0.66 g
(58%) of pure 7 was obtained by column chromatography separa-
tion [silica gel (1:15), hexane/ethyl acetate (85:15)]. Mp 119–
154.5–156.5 °C (from ethanol) [lit.18 mp 156–158 °C], [
a]D = +73.5
(c 1.05, methanol). 1H NMR (CDCl3) d: 8.10–8.01 (m, 2H), 7.39–
7.25 (m 12H), 4.77 (s, 1H, disappears on treatment with D2O),
4.70 (d, J = 9.6 Hz, 1H), 4.10 (d, J = 13.1 Hz, 2H), 3.75–3.66 (m,
4H), 2.82 (ddd, J = 4.1, 6.5, 9.6 Hz, 1H), 1.50 (s, 1H, disappears on
treatment with D2O). 13C NMR (CDCl3) d: 150.0, 147.4, 138.5,
129.7, 128.8, 128.6, 127.8, 127.5, 123.5, 77.4, 77.0, 76.6, 69.8,
64.9, 58.5, 54.5. EI MS m/z (%): 361 (1), 240 (55), 181 (5), 150 (2),
148 (2), 91 (100). Anal. Calcd for C23H24N2O4 (329): C, 70.38; H,
6.17; N, 7.14. Found: C, 70.37; H, 5.94; N, 7.15.
4.1.2. (1S,2S)-(+)-2-N,N-Dibenzylamino-1-(4-aminophenyl)-1,3-
propanediol 5
A mixture of nitro compounds 4 (5.25 g, 13.4 mmol) and
SnCl2ÁH2O (15.12 g, 67 mmol) in ethanol (100 ml) was heated at
60 °C for 1 h with stirring. Next NaBH4 (255 mg, 67 mmol) in eth-
anol (80 ml) was introduced dropwise over 10 min and the mixture
was kept at 60 °C for another 1 h. After being cooled to ca. 10 °C
water (100 ml) was added followed by neutralization with 15%
NaOH. Ethanol was evaporated and the residue was extracted with
ethyl ether until the Dragendorff test was negative (ca. 500 ml).
The ether solution was dried and concentrated to give a white solid
(4.8 g, 92%), which was digested with ethyl ether to give pure
120 °C (from ethanol), [a]
D = +88.9 (c 1.01, methanol). 1H NMR
(CDCl3) d: 7.34–7.25 (m, 10H), 7.09–7.04 (m, 2H), 6.82–6.77 (m,
2H), 4.54 (d, J = 9.8 Hz, 1H), 4.11 (s, 1H, disappears upon treatment
with D2O), 4.05 (d, J = 12.9 Hz, 2H), 3.76 (d, J = 12.9 Hz, 2H), 3.75 (s,
3H), 3.63 (dd, J = 7.6, 11.5 Hz, 1H), 3.45 (dd, J = 4.4, 11.5 Hz, 1H),
2.92 (ddd, J = 4.4, 7.7, 9.8 Hz, 1H), 1.69 (s, 1H, disappears upon
treatment with D2O). 13C NMR (CDCl3) d: 159.3, 139.8, 133.9,
129.3, 128.5, 128.1, 127.3, 112.9, 77.4, 77.0, 76.6, 71.3, 65.1, 59.0,
55.2, 54.3. EI MS m/z (%): 376 (0.2), 241 (13), 240 (77), 181 (6),
1
147 (5), 135 (3), 91 (100). Anal. Calcd for C24H27NO3 (377)Á 4H2O:
amine 5 (3.51 g, 73%), mp 136.5–138.5 °C. [
a
]D = +94.7 (c 1.03,
C, 75.46; H, 7.12; N, 3.67. Found: C, 75.63; H, 6.90; N, 3.54.
methanol). 1H NMR (CDCl3) d: 7.37–7.23 (m, 10H), 6.04–6.89 (m,
2H), 6.56 (m, 2H), 4.47 (d, J = 9.9 Hz, 1H), 4.02 (d, J = 13.2 Hz,
2H, + 1H which disappears upon treatment with D2O), 3.75 (d,
J = 13.2 Hz, 2H), 3.60 (s, 1H, disappears upon treatment with
D2O), 3.54 (dd, J = 7.5, 11.5 Hz, 2H), 3.40 (dd, J = 4.4, 11.5 Hz, 2H),
2.90 (ddd, J = 4.4, 7.5, 9.7 Hz, 1H), 1.87 (br s, 1H, disappears on
treatment with D2O). 13C NMR (CDCl3) d: 146.2, 139.1, 131.5,
129.3, 128.5, 127.9, 127.2, 115.1, 77.4, 77.0, 76.6, 71.7, 65.0, 59.0,
54.3. EI MS m/z (%): 363 (0.2), 240 (58), 223 (6), 181 (5), 120 (4),
4.1.5. (1S,2S)-(+)-2-Amino-1-(4-methoxyphenyl)-1,3-
propanediol 8
To a solution of dibenzylated amine 7 (480 mg, 1.27 mmol) in
dry methanol (12 ml), 20% Pd(OH)2–C (254 mg) was added and
the mixture was hydrogenated under 5 atm hydrogen for 9 h.
The catalyst was removed by filtration through Celite, washed with
methanol and the filtrate was concentrated under reduced pres-
sure to afford a crystalline solid (250 mg, 91%), which was digested
with ethyl ether to give pure amino diol 8 (210 mg, 76 %), contain-
ing 0.5 molecules of water of crystallization. Mp 127.5–130 °C,
1
91 (100). Anal. Calcd for C23H26N2O2 (362)Á 4H2O: C, 75.28; H,
7.15; N, 7.63. Found: C, 75.77; H, 7.18; N, 7.48.
[
a
]
D = +32.5 (c 1.15, 2 M HCl) [lit.16 for ent-8, mp 132–134 °C (from
methanol/ethyl ether), [
4.1.3. (1S,2S)-(+)-2-N,N-Dibenzylamino-1-(4-iodophenyl)-1,3-
propanediol 6
a
]
D = À28.3 (c 1.06, 2 M HCl)].
1H NMR (CDCl3) d: 7.29–7.24 (m, 2H), 6.92–6.87 (m, 2H), 4.46
(d, J = 7.1 Hz, 1H), 3.77 (s, 3H), 3.42 (dd, J = 4.4, 10,7 Hz, 1H), 3.27
(dd, J = 6.5, 10.7, 1H), 2.88 (ddd, J = 4.4, 6.6, 6.9 Hz, 1H). 13C NMR
(CDCl3) d: 160.7, 136.0, 128.8, 114.8, 75.4, 64.0, 59.9, 55.7. EI MS
m/z (%): 180 (10), 162 (6), 160 (18), 149 (47), 148 (7), 137 (35),
134 (60), 121 (43), 118 (9), 117 (10), 109 (35), 107(12), 106 (14),
105 (8), 94 (42), 79 (33), 78 (24), 77 (67), 75 (9), 60 (99). Anal Calcd
for C10H15NO3 (197)Á1/2H2O: C, 58.02; H, 7.29; N, 6.76. Found: C,
58.18; H, 6.96; N, 6.51.
To a suspension of amine 5 (1.09 g, 3 mmol) and p-TsOHÁH2O
(1.72 g, 9 mmol) in acetonitrile (12 ml), a solution of NaNO2
(414 mg, 6 mmol) and KI (1.25 g, 7.5 mmol) in water (1.8 ml) was
added dropwise. The reaction mixture was stirred for 10 min at
10 °C, then at room temperature for 2 h. Water (500 ml) was added
and stirring was continued for 30 min, after which the mixture was
neutralized with 10% NaHCO3, followed by the addition of satd
Na2S2O3 (3 ml) and extracted with ethyl ether, until the Drag-
endorff test was negative. The organic phase was dried and con-
centrated to give iodide 6 as a yellowish foam (1.2 g, 84%), which
was purified by column chromatography [silica gel (1:10), hex-
ane/ethyl acetate (9:1)] to afforded pure 6 (0.99 g, 70%), mp
4.1.6. (1S,2S)-(+)-2-tButoxycarbonylamino-1-(4-
methoxyphenyl)-1,3-propanediol 9
Amino diol 8 (197 mg, 1 mmol) and Boc2O (327 mg, 1.5 mmol)
were placed in an agate mortar and ground from time to time,
while monitoring the progress of the reaction by TLC. After 3 h,
the mixture was dissolved in ethyl ether, transferred into separato-
ry funnel and washed with 1% HCl. The ether solution was dried
and concentrated to give crude product, which was purified by col-
umn chromatography [silica gel (1:15), hexane/ethyl acetate
108.5–110 °C (from methanol), [a]
D = +65.1 (c 1.1, methanol). 1H
NMR (CDCl3) d: 7.60–7.56 (m, 2H), 7.38–7.27 (m, 10H), 6.89–6.86
(m, 2H), 4.52 (d, J = 9.8 Hz, 1H), 4.42 (s, 1H, disappears upon treat-
ment with D2O), 4.06 (d, J = 12.9 Hz, 2H), 3.75 (d, J = 12.9 Hz, 2H),
3.62 (dd, J = 7.6, 11.5 Hz, 1H), 3.50 (dd, J = 3.8, 11.5 Hz, 1H), 2.83
(ddd, J = 3.8, 7.6, 9.8 Hz 1H), 1.54 (br s, 1H, disappears upon treat-