A scalable and expedient method of preparing diastereomerically and enantiomerically enriched pseudonorephedrine from norephedrine

Article abstract of DOI:10.1016/j.tetasy.2006.11.007

Norephedrine has been efficiently converted into the corresponding diastereomer pseudonorephedrine using a three step, one-pot reaction. The three step process involves treatment of norephedrine with di-tert-butyl dicarbonate (Boc₂O); cyclization by way of mesylate formation at the alcohol; and lithium hydroxide mediated hydrolysis of the oxazolidinone. The diastereomeric purity was determined by HPLC and the enantiomeric purity was determined by optical activity measurements and chiral stationary phase HPLC analysis of the pseudonorephedrine oxazolidinone derivatives.

Full text of DOI:10.1016/j.tetasy.2006.11.007

Tetrahedron: Asymmetry 17 (2006) 2884–2889
A scalable and expedient method of preparing diastereomerically
and enantiomerically enriched pseudonorephedrine
from norephedrineI
Jonathan A. Groeper, Shawn R. Hitchcock* and Gregory M. Ferrence
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
Received 30 August 2006; accepted 2 November 2006
Abstract—Norephedrine has been efficiently converted into the corresponding diastereomer pseudonorephedrine using a three step, one-
pot reaction. The three step process involves treatment of norephedrine with di-tert-butyl dicarbonate (Boc2O); cyclization by way of
mesylate formation at the alcohol; and lithium hydroxide mediated hydrolysis of the oxazolidinone. The diastereomeric purity was deter-
mined by HPLC and the enantiomeric purity was determined by optical activity measurements and chiral stationary phase HPLC anal-
ysis of the pseudonorephedrine oxazolidinone derivatives.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
it is a component from the extraction of the khat shrub
(Catha edulis) found in eastern Africa (e.g., Ethiopia) and
Saudi Arabia.3
The Ephedra alkaloids, norephedrine1 and pseudoephed-
rine2 have proven to be very useful starting materials in
the preparation of chiral auxiliaries for stoichiometric
applications,1a–g,2a–e and for the preparation of chiral
ligands for catalytic asymmetric synthesis.1h–l,2f–j Our
research group has recently become interested in the
development of chiral ligands based on the corresponding
diastereomer of norephedrine, namely pseudonorephedrine
(Fig. 1). Pseudonorephedrine is also known as either nor-
pseudoephedrine or cathine. The availability of pseudonor-
ephedrine from commercial sources is apparently limited as
The asymmetric synthesis of pseudonorephedrine has been
accomplished with varying degrees of success using a wide
range of methods. Most of these reported methods afford
moderate diastereoselectivities at best and often require
the use of chromatography, relatively expensive reagents,
halogenated solvents, and excessive amounts of time.
Many of the reported methods with higher diastereoselec-
tivities lack the scalability to produce pseudonorephedrine
on a useful academic or commercial level.
A previous report of a ‘convenient’ synthesis of pseudonor-
ephedrine involved an intermediate taken from the synthe-
sis of chloramphenicol.4a Through a sequence of seven
reactions, this process afforded pseudonorephedrine in an
overall yield of 26%. The authors report a specific rotation
value suggesting a high enantiomeric purity,4b but do not
address the enantiomeric ratio in a more rigorous fashion.
Lee et al. also prepared pseudonorephedrine by reaction of
organometallic reagents with enantiomerically enriched
aziridine-2-carboxaldehydes. The diastereomeric ratios ob-
tained ranged from 91:9 to 94:6 and required flash chroma-
tography to further enhance them.5 In addition to these
methods, Claremon et al. carried out the addition of meth-
yllithium to a chiral, non-racemic a-substituted hydrazone
to prepare pseudonorephedrine.6 However, this method
OH
NH2
Ph
CH3
(1S,2S)-pseudonorephedrine 1a
(1R,2R)-pseudonorephedrine 1b
(1R,2S)-norephedrine 2a
(1S,2R)-norephedrine 2b
Figure 1. Pseudonorephedrines 1a and b and norephedrines 2a and b.
q A patent application has been filed.
Corresponding author. Tel.: +1 309 438 7854; fax: +1 309 438 5538;
*
e-mail: hitchcock@ilstu.edu
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.007

J. A. Groeper et al. / Tetrahedron: Asymmetry 17 (2006) 2884–2889
Table 1. Synthesis of the pseudonorephedrine based oxazolidinone
2885
involved multiple steps as well as a kinetic resolution pro-
tocol to generate the key starting material.7 Cho et al. car-
ried out the reduction of racemic b-propiophenones by
using a double asymmetric induction protocol that in-
volved a partial kinetic resolution.8 This method afforded
diastereomeric ratios that strongly favored the formation
of norephedrine over pseudonorephedrine. Reddy et al.
prepared the related pseudoephedrine in a series of steps
including the reaction of an L-alanine derived oxazolidine
with phenylmagnesium bromide to afford an inseparable
mixture of diastereomers (95:5) favoring the pseudoephed-
rine related diastereomer.9
OH
OH
(Boc)2O, TEA
MsCl, TEA
temp. 2
time 2
NH2
NHBoc
Ph
Ph
solvent, rt
time 1
CH3
CH3
2a-(R,S)
2b-(S,R)
3a-(R,S)
3b-(S,R)
O
O
O
H
O
H
Ph
H
O
N
O
N
N
H
Ph
CH3
Ph
CH3
MsO
CH3
There have been other studies conducted that have afforded
moderate to good diastereoselectivities. Moran et al.10 have
prepared pseudonorephedrine by employing an enzymatic
reduction of an a-keto-O-methyloxime that required 30 g
of Baker’s yeast and 30 g of sucrose to convert 0.53 g of
substrate into 0.28 g of product. The diastereoselective
reduction of the resultant a-hydroxy-O-methyloxime prod-
uct with lithium aluminum hydride afforded pseudonor-
ephedrine with a diastereoselectivity of 4:1.10
4a-(R,S)
4b-(S,R)
5a-(S,S)
5b-(R,R)
6a-(R,S)
6b-(S,R)
Entry Solvent Time 1 Time 2 Temp 2a Yield dr (5:6)b
(h)
(h)
(%)
1
2
3
4
5
6
CH2Cl2
CH2Cl2
CH2Cl2
THF
THF
THF
2
2
2
2
2
2
3
2
16
2.5
3
3
40
40
25
47
49
48
82
55
70
89
90
84
n/a
95:5c
95:5c
97:3c
99:1d
99:1d
Agami et al.11a prepared a pseudonorephedrine based oxa-
zolidinone using a technique that involved the formation
and isolation of N-tert-butoxycarbonylnorephedrine.11b,c
This material was reacted with p-toluenesulfonyl chloride
to yield the corresponding O-tosylnorephedrine derivative,
which presumably underwent cyclization to give the oxazo-
lidinone in a highly stereoselective fashion.11 Davies and
Doisneau also obtained the oxazolidinone of pseudonor-
ephedrine by the n-BuLi induced epimerization of the C5-
phenyl position of a norephedrine derived oxazolidinone.12
Only the (1R,2S)-norephedrine pathway is shown.
a Temperatures are in degree Celsius (ꢁC).
b HPLC data were gathered on a Shimadzu SCL-10 AVP system (dr are
reported as anti:syn).
Crude dr determined by HPLC on a Dynamax-100 A column.
d Crude dr determined by chiral HPLC on a Chiracel-OD column.
c
˚
tion was complete within 2 h. At this point, methanesulfo-
nyl chloride and an additional equivalent of triethylamine
were added. This gave rise to the target pseudonorephe-
drine based oxazolidinones 5a and 5b. The putative inter-
mediates 4a and 4b were not observed by TLC analysis
Enantiomerically enriched (S,S)-pseudonorephedrine 1a
from natural sources is available in the United States at
an estimated cost of $16,800/g.13a Enantiomer 1b is not
readily available for purchase from commercial sources,13b
due to the fact that it is a minor Ephedra alkaloid in the
C. edulis plant.14 It is probable that the relative expense
and lack of an efficient synthetic process have hindered
research concerning the uses and effects of pseudonor-
ephedrine. In conjunction with our interest in developing
structurally novel catalytic systems, we sought to develop
a process that would afford either enantiomer of pseudo-
norephedrine with minimal time and expense, while
simultaneously affording high diastereoselectivity and
enantiomeric purity. Herein, we report a new process that
allows the formation of enantiomerically enriched pseudo-
norephedrine from norephedrine in high diastereomeric
purity and good overall yield in a process that is inexpen-
sive, expedient, and scalable.
1
or by H NMR spectroscopy, suggesting that rapid dis-
placement of the mesylate had occurred.11 This process
led to stereochemical inversion of the carbon bearing the
phenyl substituent leading to 5a and 5b in diastereomeric
ratios of P95:5 as determined by HPLC analysis.16 It is
believed that oxazolidinones 6a and 6b form as the result
of an SN1 type displacement.
Table 1 illustrates the reaction conditions, diastereoselec-
tivities, and yields that were obtained over the course of
our optimization studies. The formation of 5a was accom-
plished in both dichloromethane and THF solvent systems
in good yield, as well as high diastereoselectivity. The most
significant difference involved the cyclization process. If the
synthesis was carried out in THF, the cyclization process
required heating between 45 and 50 ꢁC for 3 h. In contrast,
the reaction conducted in methylene chloride underwent
cyclization at reflux temperature and required 2–3 h. It
was also determined that the reaction in methylene chloride
underwent cyclization at room temperature in 16 h. Both
processes afforded minimal diastereomeric scrambling in
the formation of desired pseudonorephedrine oxazolidi-
none and the product could be easily purified by trituration
with ethyl acetate. It should be noted that cyclization at-
tempts with norephedrine and either p-toluenesulfonyl
2. Results and discussion
The initial process that was pursued involved formation of
the pseudonorephedrine based oxazolidinone from nor-
ephedrine from a one-pot reaction. To this end, norephed-
rines 2a and 2b were reacted with di-tert-butyl dicarbonate
and triethylamine to afford amide derivatives 3a and 3b
(Table 1).15 TLC analysis suggested that the transforma-

2886
J. A. Groeper et al. / Tetrahedron: Asymmetry 17 (2006) 2884–2889
chloride or triflic anhydride were unsuccessful in both THF
and methylene chloride. We also pursued the use of methyl
chloroformate at the acylation stage and this process was
successful. However, the cyclization failed to progress in
a timely manner. The two reaction, one-pot, process
involving the Boc-protected norephedrine and cyclization
with methanesulfonyl chloride proved to be the best meth-
od. The ultimate formation of pseudonorephedrine was
completed through the hydrolysis of 5a and 5b, which
was accomplished in a LiOH/H2O solution and heating
(Table 2).17 Attempts at hydrolysis with Cs2CO3 and
K2CO3 proved not to be very successful.18 The stereochem-
ical integrity of the pseudonorephedrine from hydrolysis
mixture was determined by 1H NMR spectroscopy and
HPLC. In all cases, the stereochemical purity was directly
comparable to the enantiomeric and diastereomeric purity
of the starting oxazolidinone. The relative stereochemistry
of the product of the hydrolysis was confirmed by X-ray
crystallographic analysis (Fig. 2).
1a. Boc2O, TEA, THF
1b. MsCl, TEA
1c. LiOH, H2O
OH
OH
NH2
NH2
Ph
Ph
CH3
CH3
55-60%
>97 d.e., >99 e.e.
Scheme 1. One-pot synthesis of pseudonorephedrine.
chosen for the one-pot synthesis was THF as chromato-
graphic and H NMR spectroscopic analysis of the two
1
oxazolidinone syntheses indicated that the THF reaction
had fewer impurities. In addition, the miscibility of THF
and water rendered THF far less troublesome than methyl-
ene chloride. The cyclization of the norephedrine to form
the pseudonorephedrine oxazolidinone proceeded as ex-
pected. The success of the conversion of norephedrine to
pseudonorephedrine relied primarily on the lithium
hydroxide mediated hydrolysis of the oxazolidinone, which
involved temperatures of 80 ꢁC and higher. This required
the THF to be removed in order for the thermal require-
ment to be met. It was determined that the most efficient
way to remove THF was through the removal of the sol-
vent under aspirator vacuum, while the reaction vessel
was held at a temperature of 60 ꢁC.
Table 2. Hydrolysis of oxazolidinone
O
OH
H
LiOH
H2O
O
N
NH2
Ph
CH3
Ph
CH3
Once the THF was removed, the reaction was heated be-
tween 85 and 90 ꢁC to induce the hydrolysis process. The
extraction process that was developed for this reaction in-
volved initial acidification to remove any impurities such
as unreacted oxazolidinone. This allowed the pseudonor-
ephedrine to be efficiently isolated from the extraction
and readily purified by a simple trituration process. The
diastereoselectivity was not compromised through this
one-pot synthesis and the results were comparable as if
each of the three reactions had been performed alone.
The one-pot synthesis yielded between 55% and 60% of
the product, thus suggesting an average yield of 80–85%
for each of the three steps.
5a-(S,S)
1a-(S,S)
Entry
Base %
Time (min)
Tempa
Yield (%)
1
2
3
10
10
5
30
45
30
80
90
85
82
91
94
a Temperatures are in degree Celsius.
3. Conclusions
The one-pot synthesis of either enantiomer of pseudonor-
ephedrine in high diastereoselectivity and good yield devel-
oped in this work is superior to methods that have been
described in the chemical literature. Based on our estima-
tion, the cost of producing either enantiomer from nor-
ephedrine is under $10/g, significantly less expensive than
the commercially available (1S,2S)-pseudonorephedrine.13a
This process also allows for the production of (1R,2R)-
pseudonorephedrine,13b which is not readily available
through commercial sources. The reagents used in this pro-
cess are easily available and inexpensive. Relative to other
b-aminoalcohols that are used regularly, such as L-phenyl-
alaninol ($19.76/g), L-alaninol ($21.08/g), L-valinol ($14.56/
g), L-phenylglycinol ($18.96/g), L-leucinol ($12.52/g) and
L-tert-leucinol ($58.20/g), pseudonorephedrine is now
potentially less expensive than these commonly used sub-
strates.19 This method now provides a scalable process to
Figure 2. RASTEP drawing of (1S,2S)-pseudonorephedrine 1a X-ray
crystal structure.
It was at this time that we attempted to combine the cycli-
zation reaction and hydrolysis reaction into a one-pot pro-
cess to afford pseudonorephedrine (Scheme 1). The solvent

J. A. Groeper et al. / Tetrahedron: Asymmetry 17 (2006) 2884–2889
2887
generate these alkaloids in an inexpensive and time efficient
process on either an academic or potentially industrial
scale.
the heating mantle was replaced under the main vessel (a
nearly quantitative recovery of the THF and TEA was
achieved). The reaction was then heated to 85–90 ꢁC. The
reaction was allowed to proceed in open air with no con-
denser for one h after which time the heat was removed
and the solution was allowed to cool. After the reaction
had cooled, the water was acidified with 6 M HCl until
the solution turned clear. The pH tested and adjusted with
6 M NaOH to afford an approximate pH of 3–4. Extrac-
tion was performed by exposure of the water to chloroform
(4 · 100 mL). The water was then basified with 6 M NaOH
until the pH was approximately 8. The water was removed
by evaporation until the saturation point was reached
(approximately 25% original volume) and the pH was
tested and adjusted to afford a pH ꢁ 8. The water was then
exposed to ethyl acetate (6 · 200 mL), and the solvents
dried and removed. The resulting white solid was formed
and purification was performed by trituration with diethyl
ether, however, the initial washes with chloroform at pH 3–
4 removed most impurities. Progress of the reaction was
monitored by TLC (1:1 ethyl acetate–hexanes) with the
Boc-(1R,2S)-norephedrine 3 at Rf ꢁ 0.64 and the oxazolid-
inone (5) at Rf ꢁ 0.25.
4. Experimental
4.1. General information
(1S,2R)-Norephedrine (98% ee) and (1R,2S)-norephedrine
(99% ee) were purchased from Sigma–Aldrich. All reaction
vessels were flame dried and purged under a nitrogen atmo-
sphere. Tetrahydrofuran was distilled over lithium alumi-
˚
num hydride and stored over 4 A molecular sieves.
Triethylamine was distilled over calcium hydride. All
extractions were dried over anhydrous magnesium sulfate,
gravity filtered, and the solvents removed via rotary evap-
oration. Infrared data were acquired using a PerkinElmer
Spectrum BX FT-IR spectrophotomer on NaCl plates
and reported in reciprocal centimeters (cmꢀ1). A Varian
FT NMR spectrometer operating at 400 MHz for 1H
NMR and 100 MHz for 13C {1H} NMR with all spectra
recorded in CDCl3 and reported in parts per million
(d scale) with tetramethylsilane as an internal standard
1
1
(d = 0.00 ppm H, 77.0 ppm 13C) was used for H and 13C
spectroscopies. HPLC information was gathered on a
Shimadzu HPLC SCL-10AVP instrument with a UV–vis
4.2.1. (1S,2S)-2-Amino-1-phenyl-1-propanol 1a. White
granular crystals (12.02 g) were produced from 20 g of
(1R,2S)-norephedrine (60%). 1H NMR (CDCl3): d 0.96
(d, 3H, J = 6.64 Hz), 2.33 (s, 1H), 2.97 (quintet, 1H,
J = 6.45 Hz), 4.18 (d, 1H, J = 7.03 Hz), 7.25–7.23 (m,
5H). 13C {1H} NMR (CDCl3): d 20.2, 52.9, 78.6, 126.5,
˚
detector operating at 254 nm on either a Dynamax-100 A
(R008010C5) column or a Chiracel-OD (OD00CE-IE048)
chiral column, each with a flow rate of 1 mL/min. Optical
rotation data were collected on a JASCO P-1010 digital
polarimeter operating at 589 nm in a 100 mm cell. Melting
points were determined using a Laboratory Devices Mel-
Temp apparatus and are uncorrected.
127.4, 128.2, 142.7. FT-IR (Nujol): 1456, 1047, 752, 693.
28
Mp = 72–74 ꢁC. ½aꢂD ¼ þ31:8 (c 3.49, EtOH), lit.8,19
20
½aꢂD ¼ þ32:6 (c 3.5, EtOH). Elem. Calcd: C, 71.40; H,
8.50; N, 9.20. Found: C, 70.97; H, 8.90; N, 9.15.
4.2. General procedure for one-pot synthesis of
pseudonorephedrine
4.2.2. (1R,2R)-2-Amino-1-phenyl-1-propanol 1b. Granular
white crystals (1.792 g) were produced from 3 g of (1S,2R)-
norephedrine (60%). 1H NMR (CDCl3): d 0.95 (d, 3H,
J = 6.64 Hz), 3.02 (quintet, 1H, J = 6.44 Hz), 3.12 (s,
1H), 4.24 (d, 1H, J = 7.03 Hz), 7.23–7.33 (m, 5H). 13C
{1H} NMR (CDCl3): d 19.9, 52.9, 78.5, 126.6, 127.5,
THF was distilled directly into a 2 L three-neck reaction
vessel fitted with an addition funnel and thermometer
through a Claisen adapter. To this was added norephedrine
to provide a 0.3 M solution. Triethylamine (1.1 equiv) was
added via syringe through the Claisen adapter septum to
the solution and the vessel was immersed in an ice bath.
To this solution was added di-tert-butyl dicarbonate
(1.05 equiv) and the ice was removed after 5 min. The reac-
tion was allowed to proceed at ambient temperature for 2 h
when the reaction was cooled to 0 ꢁC in an ice bath. An
additional portion of TEA (1.1 equiv) was added and then
methanesulfonyl chloride (1.1 equiv) was added dropwise
through the addition funnel. The ice was removed after
5 min and the solution was heated to 48 ꢁC for 3 h to afford
a light orange solution. An aqueous 10% LiOH solution
equal to the original volume of THF was prepared and
added to the solution. The flask was fitted with a distilla-
tion arm, condenser, vacuum adapter, and a collection
flask with the entire apparatus sealed with vacuum grease.
The collection flask was immersed in an ice/NaCl water
bath. The main reactor was immersed in a 60 ꢁC water
bath. A gentle vacuum was applied by a water aspirator
for 45 min until the solvent was removed, after which the
vacuum apparatus and the water bath were removed and
128.3, 142.5. FT-IR (nujol): 1456, 1041, 749, 699.
28
Mp = 71–73 ꢁC. ½aꢂD ¼ ꢀ31:4 (c 3.49, EtOH), lit.8,20
20
½aꢂD ¼ ꢀ32:6 (c 3.5, EtOH). HRMS (M+1): calcd:
152.1078, found: 152.1075.
4.3. Preparation of (5S,4S)-4-methyl-5-phenyl-2-oxazolidi-
none 5a
Methylene chloride was added to (1R,2S)-norephedrine
(2 g, 12.1 mmol) to afford approximately a 0.3 M solution.
To this solution, was added triethylamine (1.85 mL,
13.31 mmol) and the reaction was cooled in an ice bath.
Upon sufficient cooling, di-tert-butyl dicarbonate (2.68 g,
12.3 mmol) was added and the ice removed after the
di-tert-butyl dicarbonate was dissolved (approximately
5 min). The reaction was allowed to proceed for 2 h at
ambient temperature. The reaction was again cooled in
an ice bath and an additional portion of triethylamine
(1.85 mL, 13.3 mmol) was added followed by an addition
of methanesulfonyl chloride (1.41 mL, 18.2 mmol) and
the ice was removed after 5 min. The reaction was then

2888
J. A. Groeper et al. / Tetrahedron: Asymmetry 17 (2006) 2884–2889
refluxed for 3 h at which time the reaction was allowed to
cool to room temperature. Oxazolidinone 5a was washed
with bicarbonate and brine solutions and the solvents re-
moved. The resulting orange crystals were triturated in
diethyl ether to afford 5a as granular white crystals
in 82% yield. 1H NMR (CDCl3): d 1.39 (d, 3H,
J = 6.25 Hz), 3.84 (quintet, 1H, J = 6.45 Hz), 5.04 (d,
1H, J = 7.42), 7.35–7.42 (m, 5H). 13C {1H} NMR (CDCl3):
d 19.8, 56.5, 85.3, 125.8, 128.7, 128.8, 137.6, 159.4. FT-IR
systems Cobra Cryostream. Data were collected at 173 K
using graphite-monochromated Mo Ka (k = 0.71073 A)
˚
radiation. A monoclinic unit cell with dimensions: a =
˚
˚
˚
5.4136(5) A; b = 7.5436(5) A; 10.234(1) A; b = 91.525(9)
was indexed from 25 reflections. Limiting indices for full
data collection were as follows: ꢀ7 6 h 6 7, ꢀ10 6 k 6
10, ꢀ13 6 l 6 13. A total of 4424 reflections were collected,
of which 1190 were unique, and 1144 were observed with
F 2o > 2rðF 2oÞ. Systematic absences were consistent with
either the P21 or P21/m space groups. As the crystal con-
tained an enantiomerically pure substance, the space group
was conclusively determined to be P21. Data reduction, psi-
scan absorption correction, solution, refinement, and data
analysis were performed using the WinGX software pack-
age.21 The structure was solved using the direct methods
program SIR-2004.22 The remaining atoms were located
using difference Fourier synthesis, and full-matrix least-
squares refinement on F2 that led to a convergence was per-
formed using SHELXL-97.23 All non-hydrogen atoms were
refined with anisotropic thermal parameters. Hydrogen
atoms attached to carbon atoms were assigned positions
based on the geometries of their attached carbon atoms
and were given isotropic thermal parameters 20% greater
than their parent carbon atoms.
(Nujol)—3275, 1704, 1456, 767, 700. Mp = 121–123 ꢁC
29
lit.12 117–119 ꢁC. ½aꢂD ¼ þ21:6 (c 2.3, CHCl3) lit.12
21
½aꢂD ¼ þ29:5 (c 2.3, CHCl3). HRMS (M+1) calcd:
178.0858, found: 178.0868.
4.4. Formation of (5S,4R)- and (5R,4S)-oxazolidinones
Racemic norephedrine was reacted with diethyl carbonate
and lithium hydride in hexanes to afford a white solid
whose 1H NMR matched the enantiomerically enriched
oxazolidinones. This racemic oxazolidinone was used for
HPLC studies on compounds 5a and 5b. Additionally, a
sample of (1R,2S)-norephedrine was converted to the cor-
responding (5R,4S)-oxazolidinone 6a in the same manner
and used for HPLC analysis of 5a only.
4.5. HPLC studies
Full-matrix least-squares refinement on F2 led to conver-
gence with R1 = 0.029 and wR2 = 0.083 for 1144 data with
F 2o > 2rðF 2oÞ. A final difference Fourier synthesis showed
Crude samples of the oxazolidinone were obtained either
after the extraction of the oxazolidinone or from samples
taken from the one-pot synthesis prior to the addition of
the aqueous LiOH solution. These were not extracted prior
to HPLC analysis, only the THF was removed under
vacuum.
ꢀ
3
˚
features in the range of +0.263 to ꢀ0.126 e /A and were
deemed of no chemical significance. The use of Mo radia-
tion precluded the collection of meaningful Friedel pairs,
so absolute stereochemistry is known strictly from the syn-
thetic method. The relative stereochemistry is conclusive as
determined by crystallography. A RASTEP drawing24 of
the refined structure is shown in Figure 2. Complete X-
ray structural data have been deposited at the Cambridge
Crystallographic Data Center, CCDC No. 617758.25 This
X-ray structure for 1a has previously been reported,
although, only unit cell parameters, space group, and final
R value were published.26
Crude HPLC (4S,5S)-oxazolidinone from 5a CH2Cl2 syn-
thesis (Dynamax-100 A) in a 1:1 hexanes–ethyl acetate sol-
vent system. tR1 = 10.0 min (5a), 95%; tR2 = 12.8 min, 5%
(6a). Sample spiked with (5R,4S)-oxazolidinone (6a)
(Dynamax-100): tR1 = 9.83 min, 32% (5a); tR2 = 12.17 min,
68% (6a).
˚
Crude chiral HPLC (4S,5S)-oxazolidinone 5a from one-
pot synthesis (Chiracel-OD) in a 9:1 hexanes–isopropanol
Acknowledgments
solvent system. tR1 = 11.25 min (5a), >99%; tR2
=
13.33 min, <1% (5b); racemic tR1 = 11.17 min (5a), 50%;
tR2 = 13.41 min, 50% (5b).
The authors would like to thank Professor Gin at the Uni-
versity of Illinois at Champaign-Urbana for the use of the
JASCO polarimeter. The authors also thank the Depart-
ment of Chemistry and the Dean’s Office of the College
of Arts & Sciences at Illinois State University for summer
support. G.M.F. thanks the donors of the American
Chemical Society Petroleum Research Fund for support
of the X-ray crystallographic analysis component of this
research.
Crude chiral HPLC (4R,5R)-oxazolidinone 5b from one-
pot synthesis (Chiracel-OD) in a 9:1 hexanes–isopropanol
solvent system. tR1 = 12.08 min (5a), 1%; tR2 = 13.83 min,
99% (5b), mixture of 5a and 5b in a 92:8 hexanes–isopropa-
nol solvent system: tR1 = 13.83 min, 51% (5a); tR2
16.83 min, 49% (5b).
=
4.6. X-ray crystal structure data for 1a
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