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The (S,R)-reboxetine enantiomer was also obtained using the
same procedure of diastereomer 6b in 51.7% yield.
and the organic phase was separated, dried over anhydrous
Na2SO4, filtered, and the solvent removed in vacuo to give the de-
sired diastereomeric mixture 6a+6b (95% yield, dr = 73:27). The
diastereomeric mixture was separated by column chromatography
on silica gel with petroleum ether/ethyl acetate.
3. Conclusion
We have shown that chiral non-racemic amide-stabilized sulfur
ylide 4 is a valuable starting material for the preparation of the
reboxetine skeleton. Using only six steps, (R,S)-reboxetine was ob-
tained in 35.6% overall yield whereas its enantiomer (S,R)-reboxe-
tine was prepared in 13.7% yield from the same precursor. This
new, versatile, and scalable access to both enantiomers opens the
route to the pharmacological investigation of these promising
compounds as well as the design of analogs.
4.1.3. (10S,2S,3S)-(ꢀ)-3-(2-Ethoxy-phenoxy)-2-hydroxy-3-
phenyl-N-(10-phenyl-ethyl)propionamide 6a
Major diastereoisomer. Mp = 116–118 °C; ½a D20
ꢂ
¼ ꢀ46:0 (c 1.0,
CH2Cl2); IR (film) 3393, 1652, 1498, 1248 cmꢀ1
.
1H NMR (400
MHz, CDCl3) d 1.14 (d, J = 7.2 Hz, 3H), 1.42 (t, J = 7.2 Hz, 3H), 4.02
(m, 2H), 4.44 (b, OH), 4.53 (d, J = 4.4 Hz, 1H), 4.99 (m, J = 7.1,
7.2 Hz, 1H), 5.37 (d, J = 4.4 Hz, 1H), 6.65–7.62 (m, 14H, NH); 13C
NMR (100 MHz, CDCl3) d 14.81, 21.39, 48.11, 64.49, 72.91, 83.15,
113.37, 118.60, 121.47, 123.14, 125.95, 125.96, 127.12, 127.61,
128.01, 128.19, 128.43, 128.44, 136.39, 142.72, 146.20, 149.65,
169.30. HRMS (FAB): Calcd for C25H27NO4: 405.1940. Found:
405.1931.
4. Experimental
4.1. General methods
Melting points are uncorrected. 1H NMR and 13NMR spectra
were acquired on Varian VX400 (400 MHz), chemical shifts were
given on the delta scale as parts per million (ppm) with tetrameth-
ylsilane (TMS) as an internal standard. IR spectra were recorded on
Nicolet FT-IR Magna 750. Mass spectra were recorded on JEOL JEM-
AX505HA at a voltage of 70 eV. Optical rotations were measured on
Perkin–Elmer 341 polarimeter at room temperature. Column chro-
matography was performed on silica gel (60, 0.063–0.2 mm/70–
230 mesh ASTM). All reagents and solvents were analytically pure.
4.1.4. (10S,2R,3R)-(ꢀ)-3-(2-Ethoxy-phenoxy)-2-hydroxy-3-
phenyl-N-(10-phenyl-ethyl)propionamide 6b
Minor diastereoisomer. Mp = 140–142 °C; ½a D20
ꢂ
¼ ꢀ26:5 (c 1.0,
CH2Cl2); IR (film) 3382, 1654, 1498, 1249 cmꢀ1
.
1H NMR
(400 MHz, CDCl3) d 1.35 (d, J = 6.8 Hz, 3H), 1.43 (t, J = 7.2 Hz, 3H),
4.08 (m, 2H), 4.31 (d, J = 3.2 Hz, OH), 4.60 (dd, J = 3.2, 4.4 Hz, 1H),
5.00 (dq, J = 7.1, 7.2 Hz, 1H), 5.41 (d, J = 4.8 Hz, 1H), 6.79–7.42 (m,
14H, NH); 13C NMR (100 MHz, CDCl3) d 14.79, 21.47, 47.85,
64.60, 72.96, 83.50, 113.44, 119.19, 121.59, 123.38, 125.92,
126.93, 127.68, 128.13, 128.16, 128.36, 136.22, 142.49, 146.20,
149.90, 169.21. HRMS (FAB): Calcd for C25H27NO4: 405.1940.
Found: 405.1933.
4.1.1. Synthesis of a diastereomeric mixture of (1S,2R/S,3S/R,)-3-
phenyloxirane-2-carboxylic acid (1-phenyl-ethyl)amides 5a and
5b
To a stirred suspension of potassium tert-butoxide (0.15 g,
1.25 mmol, 1.1 equiv) and sulfonium salt 4 (0.37 g, 1.24 mmol,
1 equiv) in anhydrous THF (30 mL) at ꢀ30 °C was added benzalde-
hyde (0.26 g, 2.48 mmol, 2 equiv). The resulting mixture was stir-
red for 15 h at ꢀ30 °C. The reaction was then quenched by the
successive addition of an aqueous brine solution (25 mL) and the
organic phase was separated, dried over anhydrous Na2SO4, fil-
tered, and the solvent was removed by evaporation. The resulting
diastereomeric mixture was purified via flash column chromatog-
raphy. The diastereomeric mixture of 5a and 5b was obtained as
a white solid in a quantitative yield and dr = 73:27. Spectroscopic
details of the diastereomeric mixture 5a and 5b; IR (film) 3277,
4.1.5. Representative procedure for the reduction of an amide
function with borane dimethyl sulfide complex (BMS)
4.1.5.1. (10S,2R,3S)-(ꢀ)-1-(2-Ethoxy-phenoxy)-1-phenyl-3-(10-
phenyl-ethylamino)-propan-2-ol 7a.
To a stirred solution of
6a (0.1 g, 0.246 mmol) in anhydrous THF (10 mL) at 0 °C was added
a solution of BMS (0.07 mL, 0.055 g, 0.724 mmol, 3 equiv). Then,
the reaction mixture was stirred at room temperature for 8 h.
The reaction was quenched with methanol (2 mL) and stirred for
1 h at room temperature. Finally, the solvents were evaporated un-
der reduced pressure. The product was purified via flash column
chromatography and the corresponding aminoalcohol 7a was ob-
tained as a white oil (0.072 g, 75% yield). ½a D20
ꢂ
¼ ꢀ23:4 (c 1.0,
1654, 1552, 1250 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.46 (d,
.
CH2Cl2); IR (film) 3431, 1498, 1251, 1042 cmꢀ1
.
1H NMR
J = 7.2 Hz, 3H), 1.47 (d, J = 7.2 Hz, 3H), 3.45 (d, J = 2 Hz, 1H), 3.50
(d, J = 2 Hz, 1H), 3.77 (d, J = 2 Hz, 1H), 3.90 (d, J = 1.6 Hz, 1H), 5.14
(m, J = 7.2 Hz, 2H), 6.73 (br, NH, 2H), 7.20–7.37 (m, 20H); 13C
NMR (100 MHz, CDCl3) d 21.66, 21.73, 48.24, 48.27, 58.78, 58.91,
125.73, 126.07, 126.12, 127.48, 128.52, 128.57, 128.65, 128.90,
128.61, 128.92, 134.88, 142.46, 142.68, 166.51.
(400 MHz, CDCl3) d 1.36 (d, J = 6.4 Hz, 3H), 1.42 (t, J = 7.6 Hz, 3H),
2.60 (dd, J = 4.2, 12.6 Hz, 1H), 2.71 (dd, J = 6.2, 10.2 Hz, 1H), 3.75
(q, J = 6.4 Hz, 2H), 3.91 (q, J = 6 Hz, 1H), 4.06 (q, J = 6.8 Hz, 2H),
5.10 (d, J = 4 Hz, 1H), 6.69–7.35 (m, 14H); 13C NMR (100 MHz,
CDCl3) d 14.94, 24.29, 47.76, 58.22, 64.37, 72.76, 85.16, 113.38,
117.27, 120.89, 122.16, 126.65, 126.81, 126.85, 127.77, 128.36,
138.18, 145.18, 147.63, 149.46. HRMS (FAB): Calcd for
C25H29NO3: 391.2147. Found: 391.2123.
4.1.2. Opening of epoxide function of diastereomeric mixture
5a and 5b
To a stirred suspension of Na° in anhydrous THF at room tem-
perature was added 2-ethoxyphenol (0.34 g, 2.48 mmol). The mix-
ture was then stirred until the total formation of the corresponding
sodium alkoxy salt (20–30 min). Later, the excess Na° was elimi-
nated by filtration, and the solvent was removed under reduced
pressure to give the 2-ethoxyphenoxy sodium salt. The resulting
4.1.5.2. (10S,2S,3R)-(ꢀ)-1-(2-Ethoxy-phenoxy)-1-phenyl-3-(1-ph
enyl-ethylamino)-propan-2-ol 7b.
The corresponding ami-
noalcohol was obtained as a white oil (0.075 g, 78% yield).
¼ ꢀ18:2 (c 1.0, CH2Cl2); IR (film) 3431, 1498, 1251,
1042 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.37 (m, 6H), 2.69 (dd,
½ ꢂ
a 2D0
.
J = 4.1, 12.2 Hz, 3H), 2.70 (dd, J = 4.2, 12.0 Hz, 1H), 3.25 (s, NH,
OH), 3.69 (q, J = 6.4 Hz, 1H), 3.96 (q, J = 6 Hz, 1H), 4.03 (q,
J = 6.6 Hz, 2H), 5.14 (d, J = 4.1 Hz, 1H), 6.639–7.331 (m, 14H); 13C
NMR (100 MHz, CDCl3) d 14.92, 24.27, 29.86, 47.56, 58.27, 62.38,
64.30, 72.86, 85.11, 113.30, 116.91, 120.85, 122.03, 126.37,
126.62, 126.84, 127.73, 128.39, 128.43, 138.25, 145.30, 147.73,
salt and
a catalytic amount of 18-crown-6-ether (0.13 g,
0.49 mmol, 20%) were placed in anhydrous CH3CN. The mixture
was stirred at room temperature for 30 min. A solution of diaste-
reomeric mixture 5a and 5b (0.33 g, 1.23 mmol) in CH3CN (5 mL)
was then added. The resulting mixture was refluxed for 16 h. The
reaction was quenched with an aqueous brine solution (15 mL)