Asymmetric synthesis of (-)-pseudoephedrine from (2S,3S)-3-phenyloxiran-2-ylmethanol. Stereospecific interchange of amino and alcohol functions

Article abstract of DOI:10.1016/S0957-4166(01)00228-2

A ring-opening reaction of N-methylaziridines with Boc₂O/NaI has been applied to the asymmetric synthesis of pseudoephedrine. 3-Methylamino-3-phenyl-1,2-propanediol 1, derived from (2S,3S)-3-phenyloxiran-2-ylmethanol, was converted into the oxazolidin-2-one 4, a precursor of pseudoephedrine. The reaction occurs with a stereospecific interchange of amino and alcohol functions.

Full text of DOI:10.1016/S0957-4166(01)00228-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1369–1372
Asymmetric synthesis of (−)-pseudoephedrine from
(2S,3S)-3-phenyloxiran-2-ylmethanol. Stereospecific interchange
of amino and alcohol functions
Ma6 Luisa Testa, Chakib Hajji, Elena Zaballos-Garc´ıa, Ana Bele´n Garc´ıa-Segovia and
Jose´ Sepu´lveda-Arques*
Departamento Qu´ımica Orga´nica, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, Spain
Received 27 April 2001; accepted 16 May 2001
Abstract—A ring-opening reaction of N-methylaziridines with Boc2O/NaI has been applied to the asymmetric synthesis of
pseudoephedrine. 3-Methylamino-3-phenyl-1,2-propanediol 1, derived from (2S,3S)-3-phenyloxiran-2-ylmethanol, was converted
into the oxazolidin-2-one 4, a precursor of pseudoephedrine. The reaction occurs with a stereospecific interchange of amino and
alcohol functions. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
In a previous paper1 we reported the ring transforma-
tion of N-alkyl aziridines into oxazolidin-2-ones in one
step by reaction with di-tert-butyl dicarbonate and
sodium iodide in acetone. The proposed reaction mech-
anism supposed initial quaternization of the aziridine
nitrogen, ring opening by iodide and backside nucle-
ophilic attack by the carbonyl oxygen of the carbamate
on the halogenated carbon, followed by carbonylation
of the tert-butoxy group and elimination of 2-methyl-
propene (Scheme 1).
(E)-3-Phenyl-2-propen-1-ol ((E)-cinnamyl alcohol) was
converted by asymmetric epoxidation into (2S,3S)-3-
phenyloxiran-2-ylmethanol,2 which reacted regioselec-
tively with aqueous methylamine3 to yield (2R,3R)-
3-methylamino-3-phenyl-1,2-propanediol 1. The pri-
mary alcohol group was selectively silylated with tert-
butyldimethylsilyl chloride and the resulting 1-methyl-
amino-3-(dimethyl-tert-butylsilyloxy)-1-phenyl-2-pro-
panol 2 converted under Mitsunobu conditions4 into
the corresponding N-methylaziridine 3, which was
transformed without isolation into the oxazolidinone 4
by treatment with di-tert-butyl dicarbonate and sodium
iodide in acetone. As discussed previously, this rear-
rangement occurs by quaternization of the aziridine
nitrogen, ring opening by iodide in this case occurs at
Herein, we show how this ring transformation can be
used as the key reaction for the synthesis of (−)-pseu-
doephedrine or (+)-pseudoephedrine starting from
(2S,3S)-3-phenyloxiran-2-ylmethanol.
Scheme 1.
* Corresponding author. E-mail: jose.sepulveda@uv.es
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00228-2

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Ma6 L. Testa et al. / Tetrahedron: Asymmetry 12 (2001) 1369–1372
the most reactive benzylic position and nucleophilic
attack by the carbamate then occurs. Removal of the
silyl group of oxazolidinone 4 afforded the alcohol 5,
which was transformed into the tosyl derivative 6,
reduced with sodium borohydride-dimethylsulfoxide5 to
the oxazolidinone 76 and then subjected to alkaline
hydrolysis5 to afford the requisite product, (−)-pseu-
doephedrine (Scheme 2). The same sequence starting
with (E)-cinnamyl alcohol and Sharpless asymmetric
purification. Dichloromethane was distilled from cal-
cium chloride under argon. Analytical thin layer chro-
matography was performed on Merck precoated silica
gel (60 F254) plates and flash column chromatography
was accomplished on Merck Kieselgel 60 (230–240
mesh). Melting points were determined with a Kofler
hot-stage apparatus and are uncorrected. Optical rota-
tions were measured at room temperature in a Perkin–
Elmer 241 polarimeter. IR spectra were recorded on a
1
epoxidation using diethyl-
pseudoephedrine.
D
-tartrate would give (+)-
FT-IR spectrometer. H and 13C NMR spectra were
measured for CDCl3 solutions at 300 and 75.4 MHz,
respectively, using a Bruker AC-300 spectrometer and
chemical shifts were recorded relative to Me4Si. High-
resolution mass spectral data were obtained under EI
conditions at 70 eV with a VG Autospec spectrometer.
The transformation of the amino alcohol 2 to the
oxazolidinone 4 supposes a simultaneous and stereospe-
cific interchange of the amino and alcohol functions.
There is double inversion at both carbons in the trans-
formation of the epoxide into the aziridine,7 but rear-
rangement to the oxazolidinone occurs with retention
of configuration and transformation of 2 to 4 affords
the syn-amino alcohol configuration contained in the
pseudoephedrine.
4.2. (1R,2R)-3-(tert-Butyldimethylsilyloxy)-1-methyl-
amino-1-phenylpropan-2-ol 2
A
solution of (2R,3R)-3-methylamino-3-phenyl-1,2-
propanediol 13a (2.5 g, 13.8 mmol), tert-
butyldimethylsilyl chloride (2.21 g, 14.7 mmol),
imidazole (2.4 g, 34.7 mmol) in dichloromethane (25
mL) was stirred at room temperature for 1.5 h. The
reaction mixture was washed with water, dried
(Na2SO4) and evaporated. The residue was purified by
column chromatography on silica gel eluting with hex-
ane/ethyl acetate (1/1) to afford 2 (3.29 g, 81%) as an
oil. [h]2D0=−47.4 (c 3.80, CHCl3). IR (KBr): 3389 cm−1.
1H NMR: 0.12 (s, 3H), 0.19 (s, 3H), 1.00 (s, 9H), 2.37
(s, 3H), 2.91 (br, 1H), 3.31 (dd, 1H, J=10.2 and 4.7
Hz), 3.41 (dd, 1H, J=10.2 and 5.8 Hz), 3.69 (d, 1H,
J=4.4 Hz), 3.80 (m, 1H), 7.23 (m, 5H). 13C NMR: 5.6
(q), 17.9 (s), 25.7 (q), 33.6 (q), 63.8 (t), 66.2 (d), 72.8
(d), 127.3 (d), 127.9 (d), 128.3 (d), 138.0 (s). HRMS
(MH+) 296.2042. Calcd for C16H30NO2Si 296.2045.
Chemical shifts, coupling constants and the specific
rotation for oxazolidine 7 prepared using the synthetic
route we have presented are identical to those reported
in the literature for trans-3,4-dimethyl-5-phenyl-2-
oxazolidinone.6
3. Conclusion
In summary, we have presented an appropriate new
synthetic method for the preparation of pseu-
doephedrine based on an aziridine ring expansion
methodology.
4. Experimental
4.3. (2R,3S)-3-(tert-Butyldimethylsilyloxymethyl)-1-
methyl-2-phenylazirane 3
4.1. Materials and general methods
Unless otherwise specified, materials were purchased
from commercial suppliers and used without further
To a solution of (1R,3R)-3-(tert-butyldimethylsilyloxy)-
1-methylamino-1-phenyl-propan-2-ol 2 (1.44 g, 6.5
Scheme 2.

Ma6 L. Testa et al. / Tetrahedron: Asymmetry 12 (2001) 1369–1372
1371
1
mmol) and triphenylphosphine (2.5 g, 9.5 mmol) in dry
ether (35 mL) stirred under nitrogen in an ice bath, was
slowly added di-iso-propyl azodicarboxylate (1.7 mL,
9.5 mmol) via syringe. The ice bath was removed and
the mixture was stirred at room temperature for 24 h. A
crystalline precipitate (triphenylphosphine oxide/di-iso-
propyl hydrazinedicarboxylate complex) was filtered off
and washed with hexane/ether, 1:1 (30 mL). The filtrate
was evaporated under reduced pressure and the crude
product was used for the following reaction.
cm−1. H NMR: 2.38 (s, 3H), 2.71 (s, 3H), 3.61 (m, 1H,
J=6.1, 3.7 and 3.9 Hz), 4.08 (dd, 1H, J=11.1 and 3.7
Hz), 4.16 (dd, 1H, J=11.1 and 3.9 Hz), 5.05 (d, 1H,
J=6.2 Hz), 7.23–7.30 (m, 7H), 7.71 (d, 2H, J=8.3 Hz).
13C NMR: 22.1 (q), 29.8 (q), 64.2 (d), 66.6 (t), 76.6 (d),
125.4 (d), 127.8 (d), 128.9 (d), 129.0 (d), 130.1 (d), 131.8
(s), 137.4 (s), 145.6 (s), 157.1 (s). HRMS (M+) 361.0999.
Calcd for C18H19NO5S 361.0984.
4.7. (4R,5R)-3,4-Dimethyl-5-phenyl-1,3-oxazolan 2-one
7
4.4. (4R,5R)-4-(tert-Butyldimethylsilyloxymethyl)-3-
methyl-5-phenyl-1,3-oxazolan-2-one 4
Sodium borohydride (0.112 g, 3.0 mmol) was added to
a solution of the tosyl derivative 6 (0.5 g, 1.5 mmol) in
dimethylsulfoxide (8 mL). The mixture was heated to
150°C and kept at this temperature for 2 h. After
cooling at room temperature, the solution was diluted
with water (40 mL) and extracted with dichloromethane
(3×100 mL). The organic extracts were dried (Na2SO4),
filtered, and concentrated under reduced pressure to
afford a white solid that was identified as the oxazolidi-
none 7 (0.22 g, 76%). [h]2D0=−29.4 (c 3.46, CHCl3). Mp
Di-tert-butyl dicarbonate (1.4 g, 6.5 mmol) in acetone
(5 mL) was added to a mixture of the crude aziridine
derivative 3 (6.5 mmol) and sodium iodide (0.95 g, 6.5
mmol) and stirred under reflux for 4 h. After removing
the solvent, the residue was purified by column chro-
matography on silica gel eluting with hexane/ethyl ace-
tate (1/1) to afford 4 (1.35 g, 65%) as a white solid.
[h]2D0=+10.1 (c 0.91, CHCl3). Mp 70–72°C. IR (KBr):
1
1759 cm−1. H NMR: 0.01 (s, 6H), 0.81 (s, 9H), 2.81 (s,
45–46°C. IR (KBr): 1757 cm−1. H NMR: 1.26 (d, 3H,
1
3H), 2.91 (br, 1H), 3.44–3.48 (m, 1H), 3.67 (dd, 1H,
J=10.9 and 3.7 Hz), 3.76 (dd, 1H, J=10.9 and 4.5 Hz),
5.14 (d, 1H, J=5.4 Hz), 7.23–7.30 (m, 5H). 13C NMR:
5.6 (q), 17.9 (s), 25.5 (q), 29.2 (q), 61.2 (t), 66.2 (d), 76.7
(d), 125.3 (d), 128.5 (d), 128.7 (d), 138.9 (s), 157.8 (s).
HRMS (MH+) 322.1843. Calcd for C17H28NO3Si
322.1838.
J=6.2 Hz), 2.80 (s, 3H), 3.45 (m, 1H), 4.83 (d, 1H,
J=7.7 Hz), 7.28 (m, 5H). 13C NMR: 17.1 (q), 28.5 (q),
61.1 (d), 82.2 (d), 125.7 (d), 128.6 (d), 128.7 (d), 137.4
(s), 157.6 (s). HRMS (M+) 191.0941. Calcd for
C11H13NO2 191.0946.
4.8. (−)-Pseudoephedrine
4.5. (4R,5R)-4-Hydroxymethyl-3-methyl-5-phenyl-1,3-
A solution of oxazolidinone 6 (0.5 g, 2.6 mmol) in an
aqueous solution of KOH (20% KOH in water:ethanol,
1:1, 2.5 mL) was stirred under reflux for 2 h. The
mixture was cooled to room temperature, neutralized
with a saturated aqueous NH4Cl solution (25 mL) and
extracted with CH2Cl2 (2×20 mL). The organic extracts
were dried (MgSO4) and concentrated under reduced
pressure affording a white solid that was identified as
(−)-pseudoephedrine (0.35 g, 88%). Mp 119–120°C.
[h]2D0=−47.2 (c 1.0, CHCl3); 1H NMR: 0.79 (d, 3H,
J=6.0 Hz), 2.29 (s, 3H), 2.52 (dq, 1H, J=8.2 and 6.0
Hz), 2.96 (b, 1H), 4.08 (d, 1H, J=8.2 Hz), 7.24 (m,
5H). 13C NMR: 15.4 (q), 33.4 (q), 61.1 (d), 77.4 (d),
126.9 (d), 127.5 (d), 128.1 (d), 142.5 (s).
oxazolan-2-one 5
A mixture of 4-(tert-butyldimethylsilyloxymethyl)-3-
methyl-5-phenyl-1,3-oxazolan-2-one
4
(1.5 g, 4.7
mmol), potassium fluoride (0.8 g, 14.0 mmol) and
methanol (10 mL) was heated to reflux for 3 h. The
solvent was removed under reduced pressure and the
residue was purified by column chromatography on
silica gel, eluting with hexane/ethyl acetate (2/3),
affording 5 (0.8 g, 83%) as a white solid. [h]2D0=+12.2 (c
1.96, CHCl3). Mp 88–90°C. IR (KBr): 3418, 1746 cm−1.
1H NMR: 2.88 (s, 3H), 3.40 (m, 1H), 3.71 (dd, 1H,
J=12.4 and 3.5 Hz), 3.90 (dd, 1H, J=12.4 and 3.5 Hz),
5.37 (d, 1H, J=6.2 Hz), 7.34–7.39 (m, 5H). 13C NMR:
29.2 (q), 59.7 (d), 66.7 (t), 76.7 (d), 125.6 (d), 128.8 (d),
128.9 (d), 138.7 (s), 158.5 (s). HRMS (M+) 207.0890.
Calcd for C11H13NO3 207.0895.
Acknowledgements
4.6. (4R,5R)-4-(4-Methylphenylsulfonyloxymethyl)-3-
We are indebted to Direccio´n General de Investigacio´n
Cient´ıfico y Te´cnica, for project PB98-1451. Ma6 Luisa
Testa thanks Generalitat Valenciana for a Ph.D. Grant.
methyl-5-phenyl-1,3-oxazolan-2-one 6
To a solution of alcohol 5 (0.2 g, 0.96 mmol) in
pyridine (3 mL) was added p-toluenesulfonyl chloride
(0.7 g, 3.7 mmol) at 5°C. After 15 h of stirring, the
reaction mixture was quenched with 2 M aqueous HCl
(14 mL) and extracted with diethyl ether (3×15 mL), the
organic extracts were dried (Na2SO4), filtered, and con-
centrated under reduced pressure. The residue was
purified by column chromatography on silica gel, elut-
ing with hexane/ethyl acetate (3/2) gave 6 (0.25 g, 72%)
as an oil. [h]2D0=+20.6 (c 0.64, CHCl3). IR (KBr): 1761
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