On the structure and chiroptical properties of (S)-4-isopropyl-oxazolidin-2-one

Article abstract of DOI:10.1016/j.tetasy.2008.03.032

The specific rotation of (S)-4-isopropyl-oxazolidin-2-one is extremely solvent dependent. In chloroform it is dextrorotatory {[α]_D²⁶ = + 15.5 (c 5.2, CHCl₃)}, whereas in ethanol it is levorotatory {[α]_D²⁶ = - 16.1 (c 5.2, EtOH)}.

Full text of DOI:10.1016/j.tetasy.2008.03.032

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 1068–1077
On the structure and chiroptical properties of
(S)-4-isopropyl-oxazolidin-2-one
David Benoit,a Elliot Coulbeck,b Jason Eamesb,* and Majid Motevallic
aNachwuchsgruppe Theorie im SFB 569, Albert-Einstein-Allee 11, University of Ulm, D-89081 ULM, Germany
bDepartment of Chemistry, University of Hull, Cottingham Road, Kingston Upon Hull HU6 7RX, UK
cSchool of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, UK
Received 6 March 2008; accepted 31 March 2008
Abstract—The specific rotation of (S)-4-isopropyl-oxazolidin-2-one is extremely solvent dependent. In chloroform it is dextrorotatory
26
26
f½aꢀD ¼ þ15:5 ðc 5:2; CHCl3Þg, whereas in ethanol it is levorotatory f½aꢀD ¼ ꢁ16:1 ðc 5:2; EtOHÞg.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
respectively, with excellent levels of diastereocontrol
(Scheme 1).
Over the last few years, we have been interested in the par-
allel kinetic resolution of profen-based active esters,1 such
as rac-3, using a combination of quasi-enantiomeric Evans’
oxazolidin-2-ones (S)-1 and (S)-22 to give oxazolidin-2-one
adducts (S,S)-syn-4 and (R,S)-syn-5 in 49% and 60% yields,
In recent years, we have extended this methodology to-
wards the resolution of oxazolidin-2-ones, such as rac-1,3
using a combination of complementary quasi-enantiomeric
active esters, such as (R)-3 and (S)-6 to give the related
oxazolidin-2-one adducts (R,R)-syn-4 and (S,S)-syn-7 in
55% and 59% yields, respectively, with excellent levels of
diastereocontrol (Scheme 2).
O
O
1. n-BuLi
THF, -78 oC
HN
EtO2C
O
HN
O
2.
Ph
CO2C6F5
(2 equiv.)
CH3
2. Results and discussion
i-Pr
H
rac-3
By using our standard protocol,1–3 we were interested in
(S)-1
(S)-2
the kinetic resolution of 4-isopropyl-oxazolidin-2-one rac-
2
using a novel active ester, pentafluorophenyl 2-
O
O
O
O
(4-isobutylphenyl)propionate (S)-9 [derived from the
DCC coupling of 2-(4-isobutylphenyl)propionic acid (S)-8
and pentafluorophenol in 92% yield—Scheme 3]. The treat-
ment of an excess of oxazolidin-2-one rac-2 (5 equiv) in
THF at ꢁ78 °C with n-BuLi, followed by the addition of
the active ester (S)-9, gave two separable diastereoisomeric
adducts (S,R)-syn- and (S,S)-anti-10 in a combined 79%
yield with a high level of diastereoselectivity (ratio: syn-
:anti- 88:12) as shown in Scheme 4.4 The remaining 4-iso-
Ph
Ph
N
O
N
O
Me
H
H
Me
EtO2C
i-Pr
(R,S)-syn-: (S,S)-anti-5
(S,S)-syn-: (R,S)-anti-4
95:5; 60%
95:5; 49%
Scheme 1. Parallel kinetic resolution of active ester rac-3 using quasi-
enantiomeric oxazolidin-2-ones (S)-1 and (S)-2.
propyl-oxazolidin-2-one 2, which was presumed to have
25
an (S)-configuration f½aꢀD ¼ þ2:6 ðc 4:8; CHCl3Þg was
re-isolated in 64% yield with ꢂ16% ee.5 The enantiomeric
*
Corresponding author. Tel.: +44 1482 466401; fax: +44 1482 466410;
e-mail: j.eames@hull.ac.uk
excess was determined by use of a chiral shift NMR
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.032

D. Benoit et al. / Tetrahedron: Asymmetry 19 (2008) 1068–1077
1069
O
O
Ph
Me
N
O
O
H
1. n-BuLi
THF, -78 oC
EtO2C
HN
EtO2C
O
2.
Ph
Me
(R)-3
CO2C6F5
(R,R)-syn-:(S,R)-anti-4; 95:5; 55%
H
(2 equiv.)
rac-1
MeO
O
O
MeO
N
O
CO2C6F5
Me
H
Me
H
(S)-6
EtO2C
(S,S)-syn-:(R,S)-anti-7; 95:5; 59%
Scheme 2. Parallel kinetic resolution of oxazolidin-2-one (rac)-1 using quasi-enantiomeric active esters (R)-3 and (S)-6.
and solvent dependence on the sign of (specific) rotation
(Table 1).
i-Bu
i-Bu
C6F5OH
DCC
CO2H
CO2C6F5
CH2Cl2
In an attempt to solve this uncertainty, we chose to check
the synthesis of both enantiomers of 4-isopropyl-oxazoli-
din-2-ones (R)- and (S)-2 by treatment of the correspond-
ing 2-amino-3-methyl-butanol (R)- and (S)-11 with
Me
H
Me
H
(S)-8
(S)-9; 92%
Scheme 3. Synthesis of pentafluorophenyl 2-(4-isobutylphenyl)propionate
(S)-9.
diethylcarbonate (Scheme 6). The addition of 2-amino-3-
26
methyl-butanol (R)-11 {½aꢀD ¼ ꢁ23:2 ðc 3:7; CHCl3Þ;
26
20
½aꢀD ¼ ꢁ15:0 ðc 4:2; EtOHÞ;
lit.14
½aꢀD ¼ ꢁ16:6 ðc
0:09; EtOHÞ} {formed by LiAlH4 reduction of (ꢁ)-(R)-va-
26
26
line; ½aꢀD ¼ ꢁ23:3 (c 2.8, 2 M HCl); lit.27 ½aꢀD ¼ ꢁ27:5 (c
reagent, tris[3-(trifluoromethylhydroxymethylene)-d-campho-
rato] europium(III). Simple hydrolysis of these separable
oxazolidin-2-ones (S,R)-syn-and (S,S)-anti-10 using LiOH/
5.0, 5 M HCl)} to diethylcarbonate, gave the levorotatory
26
4-isopropyl-oxazolidin-2-one (R)-2 {½aꢀD ¼ ꢁ13:1 (c 4.2,
6
H2O2 in THF/H2O (3:1) gave the corresponding enantio-
CHCl3)} in 90% yield (Scheme 6). In comparison, the treat-
26
merically pure 4-isopropyl-oxazolidin-2-ones (R)- and (S)-
2,1,2 and the recovered 2-(4-isobutylphenyl)propionic acid
(S)-8 in high yields (Scheme 5). In an attempt to confirm
the configurations of these 4-isopropyl-oxazolidin-2-ones
(R)- and (S)-2 [and their parent adducts (S,R)-syn- and
(S,S)-anti-10], we chose to simply compare their specific
rotations with known literature values. However, closer
examination of the literature revealed what appeared to
be some ambiguity in their assignment of configuration
ment of 2-amino 3-methyl-butanol (S)-11 {½aꢀD ¼ þ20:8 (c
20
5.8, CHCl3); ½aꢀD ¼ þ15:6 (c 3.8, EtOH); lit.28
20
½aꢀD ¼ þ18:5 (c 7.83, EtOH)} {formed by LiAlH4 reduc-
26
tion of (+)-(S)-valine; ½aꢀD ¼ þ24:0 (c 2.4, 2 M HCl);
20
lit.27 ½aꢀD ¼ þ28:0 (c 8.0, 6 M HCl)} with diethylcarbonate,
gave the dextrorotatory 4-isopropyl-oxazolidin-2-one (S)-2
20
f½aꢀD ¼ þ15:6 ðc 3:0; CHCl3Þg in 80% yield (Scheme 6).
These oxazolidin-2-ones were determined to be enantio-
merically pure (>96% ee) by using a chiral shift NMR
i-Bu
O
O
N
O
Me
H
O
O
i-Pr
1. n-BuLi (5 equiv.),
(S,R)-syn-10; 70%
THF, -78oC
HN
O
HN
O
2. (S)-9
i-Bu
O
O
i-Pr
i-Pr
(S)-2; 16% e.e.
rac-2
(5 equiv.)
(3.2 equiv. recovered
N
O
which equates to 64% yield)
Me
H
i-Pr
(S,S)-anti-10; 9%
(S,R)-syn-: (S,S)-anti- 88:12
Scheme 4. Kinetic resolution of 4-isopropyl-oxazolidin-2-one (rac)-2 using active ester (S)-9.

1070
D. Benoit et al. / Tetrahedron: Asymmetry 19 (2008) 1068–1077
i-Bu
i-Bu
O
O
O
i-Bu
LiOH
H2O2
N
O
O
HN
i-Pr
O
CO2H
CH2Cl2
Me
Me
H
Me
H
i-Pr
(S,R)-syn-10
(S)-8; 59%
(R)-2; 71%
O
O
O
i-Bu
LiOH
H2O2
N
HN
i-Pr
O
CO2H
CH2Cl2
H
Me
H
i-Pr
(S,S)-anti-10
(S)-8; 73%
(S)-2; 84%
Scheme 5. Hydrolysis of adducts (S,R)-syn- and (S,S)-anti-10.
Table 1. Literature values for the specific rotation of 4-isopropyl-
oxazolidin-2-one 27
O
HN
O
Sign
Specific rotation
k
c
T (°C)
Solvent
H2N
OH
OH
EtOCO2Et
EtOCO2Et
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(R)-2
(R)-2
(R)-2
(R)-2
(R)-2
(R)-2
(R)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(R)-2
+
+
+
+
+
+
ꢁ
ꢁ
ꢁ
+
+
+
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+13.38
+16.89
—
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
—
D
D
6.8
—
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
i-Pr
i-Pr
0.17 25
+14.810
+12.011
+5.312
7.0
—
25
—
20
—
(-)-(R)-11
(R)-2; 90%
15.0
—
7.0
—
O
+14.013
ꢁ5.112
HN
O
H2N
ꢁ15.514
ꢁ14.013
+17.515
+19.316
+17.018
+17.517
ꢁ18.018
ꢁ17.019
ꢁ17.517
ꢁ16.620
ꢁ20.021
ꢁ16.522
ꢁ16.623
ꢁ18.524
ꢁ18.025
ꢁ18.026
ꢁ18.027
ꢁ18.027
0.07 25
7.0
20
—
22
20
20
20
30
20
—
20
20
i-Pr
i-Pr
—
(S)-2; 80%
(+)-(S)-11
1.0
6.0
6.0
6.0
6.0
6.0
Scheme 6. Synthesis of 4-isopropyl-oxazolidin-2-ones (R)- and (S)-2.
i-Bu
—
O
O
O
1. n-BuLi,
THF, -78oC
1.0
6.0
N
O
HN
i-Pr
O
1.02 25
2. (S)-9
Me
H
6.0
1.0
1.6
1.0
1.0
25
20
—
20
20
i-Pr
(S,R)-syn-10; 59%; >98 % d.e.
(R)-2
i-Bu
O
O
O
1. n-BuLi,
THF, -78oC
HN
i-Pr
O
N
O
2. (S)-9
reagent, tris[3-(trifluoromethylhydroxymethylene)-d-campho-
rato] europium(III).5
Me
H
i-Pr
(S,S)-anti-10; 64%; >98 % d.e.
(S)-2
With this information in hand, we next determined the con-
figurational assignment of their parent adducts (S,R)-syn-
and (S,S)-anti-10 by the addition of the corresponding lith-
iated oxazolidin-2-one to a stirred solution of pentafluor-
ophenyl 2-(4-isobutylphenyl)propionate (S)-9 in THF at
ꢁ78 °C (Scheme 7). The deprotonation of the oxazolidin-
2-ones (R)- and (S)-2 in THF at ꢁ78 °C using n-BuLi, fol-
lowed by the addition of active ester (S)-9, gave the corre-
sponding diastereoisomerically pure oxazolidin-2-one
adducts (S,R)-syn-and (S,S)-anti-10 in 59% and 64% yields,
respectively (Scheme 7). The levels of diastereocontrol were
Scheme 7. Stereospecific synthesis of oxazolidin-2-one adducts (S,R)-syn-
and (S,S)-anti-10.
Slightly puzzled by the ambiguity within the literature, we
next chose to investigate the role of the solvent (structural
nature and polarity) on the magnitude and the sign of the
specific rotation for 4-isopropyl-oxazolidin-2-one (S)-2
(Table 2). From this particular study, it was evident that
the specific rotation of this oxazolidin-2-one 2 was extre-
mely solvent dependent. By using protic solvents, such as
methanol, 4-isopropyloxazolidin-2-one (S)-2 was found to
1
determined to be >98% de by H NMR spectroscopy (at
400 MHz).

D. Benoit et al. / Tetrahedron: Asymmetry 19 (2008) 1068–1077
1071
Table 2. The specific rotations of 4-isopropyl-oxazolidin-2-one 2 in
different solvents at 26 °C
Table 3. The specific rotations of 4-isopropyl-oxazolidin-2-one (S)-2 at
different concentrations at 26 °C
Entry
Sign
Specific
rotation
k
C
Solvent
Entry
Sign
Specific
rotation
k
c
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(R)-2
(R)-2
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
+
+
+
+
+
+
+
+
ꢁ
ꢁ21.9
ꢁ20.2
ꢁ17.4
ꢁ13.2
ꢁ11.7
ꢁ9.2
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
2.8
4.2
2.6
5.0
4.6
2.8
6.2
3.2
5.2
3.4
2.8
4.4
2.6
3.0
2.4
2.8
4.2
MeOH
DMSO
EtOH
1
2
3
4
5
6
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
+
+
+
ꢁ
ꢁ
ꢁ
+10.0
+15.6
+16.5
ꢁ16.0
ꢁ15.7
ꢁ14.6
D
D
D
D
D
D
0.6
3.0
10.4
0.7
4.4
11.0
CHCl3
CHCl3
CHCl3
EtOH
EtOH
EtOH
DMF
MeCN
i-PrOH
Acetone
1,4-Dioxane
THF
EtOAc
CCl4
EtOCO2Et
CH2Cl2
CHCl3
Et2O
ꢁ4.6
+0.25
+0.3
+2.8
+5.1
+6.8
Table 4. The specific rotations of 4-isopropyl-oxazolidin-2-one 2 in
varying amounts of chloroform and ethanol at 26 °C
Entry Oxazoldin- Sign Specific
k
c
Solvent
+9.7
2-one
rotation
+15.6
+25.1
+15.0
ꢁ13.1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
+
+
+
+15.5
+14.3
+2.9
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
5.2 CHCl3
6.2 CHCl3/EtOH (99:1)
5.2 CHCl3/EtOH (90:10)
6.2 CHCl3/EtOH (85:15)
6.4 CHCl3/EtOH (80:20)
6.2 CHCl3/EtOH (70:30)
7.0 CHCl3/EtOH (60:40)
6.8 CHCl3/EtOH (50:50)
5.8 CHCl3/EtOH (40:60)
6.0 CHCl3/EtOH (25:75)
7.0 CHCl3/EtOH (30:70)
6.0 CHCl3/EtOH (20:80)
6.0 CHCl3/EtOH (15:85)
5.8 CHCl3/EtOH (10:90)
6.2 CHCl3/EtOH (1:99)
5.2 EtOH
EtOH
CHCl3
0.0
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ1.8
ꢁ5.1
26
be levorotatory {½aꢀD ¼ ꢁ21:9 (c 2.8, MeOH)}, whereas in
ꢁ7.2
ꢁ9.8
aprotic solvents, such as diethyl ether, it was found to be
26
ꢁ12.7
ꢁ13.9
ꢁ13.6
ꢁ14.3
ꢁ14.4
ꢁ16.1
ꢁ16.1
ꢁ16.1
dextrorotatory f½aꢀD ¼ þ25:1 ðc 2:4; Et2OÞg for a simi-
larly concentrated sample (Table 2: entries 1 vs 15). Inter-
estingly, changing the solvent from methanol, to ethanol
and then isopropanol, the magnitude of the specific rota-
26
tion f½aꢀD g decreased from ꢁ21.9 (c 2.8, MeOH) to ꢁ9.2
(c 2.8, i-PrOH) presumably due to changes in polarity
and intermolecular hydrogen bonding (Table 2: entries 1,
3 and 6). By comparison, changing the solvent from aprotic
carbon tetrachloride to dichloromethane and then to chlo-
roform increased the magnitude of the specific rotation
26
Table 5. The specific rotations of 4-isopropyl-oxazolidin-2-one 2 with
varying enantiomeric excesses at 26 °C
f½aꢀD g from +5.1 (c 2.8, CCl4) to +15.6 (c 3.0, CHCl3)
(Table 2: entries 11, 13 and 14). Whereas, using a polar
aprotic solvent, such as DMSO, DMF and acetonitrile,
4-isopropyl-oxazolidin-2-one (S)-2 was levorotatory
Entry
Oxazoldin-2-one
Sign
Specific
rotation
k
c
Solvent
26
26
{½aꢀD ¼ ꢁ20:2 (c 4.2, DMSO); ½aꢀD ¼ ꢁ13:2 (c 5.0,
1
2
3
4
5
6
7
8
9
(S)-2; >98% ee
(S)-2; >98% ee
(S)-2; 50% ee
(S)-2; 50% ee
rac-2; 0% ee
+
ꢁ
+
ꢁ
+14.9
ꢁ15.8
+8.1
ꢁ7.5
0.0
D
D
D
D
D
D
D
D
D
D
4.2
5.0
3.8
4.2
3.8
4.8
4.6
3.6
4.6
4.2
CHCl3
EtOH
CHCl3
EtOH
CHCl3
EtOH
EtOH
CHCl3
EtOH
CHCl3
26
DMF) and ½aꢀD ¼ ꢁ11:7 (c 4.6, MeCN)} (Table 2: entries
2, 4 and 5). Re-evaluation of the original literature in Table
1 is now clearer; 4-isopropyl-oxazolidin-2-one (S)-2 is dex-
26
trorotatory f½aꢀD ¼ þ15:6 ðc 3:0; CHCl3Þg in chloroform,
26
rac-2; 0% ee
0.0
but levorotatory {½aꢀD ¼ ꢁ17:4 (c 2.4, EtOH)} in ethanol
(Table 2: entries 3 and 14).29 The reverse has also been
shown to be true for its enantiomeric 4-isopropyl-oxazoli-
(R)-2; 50% ee
(R)-2; 50% ee
(R)-2; >98% ee
(R)-2; >98% ee
+
ꢁ
+
ꢁ
+8.1
ꢁ7.6
+16.1
ꢁ13.1
din-2-one (R)-2 (Table 2: entries 16 and 17).3 The magni-
10
26
tude of these specific rotations f½aꢀD g were also shown to
be concentration dependent; for higher concentrations of
(S)-2 in chloroform, the magnitude increased from +10.0
(for c 0.6, CHCl3) to +16.5 (for c 10.4, CHCl3) (Table 3:
entries 1–3), whereas in ethanol, the magnitude decreased
from ꢁ16.0 (for c 0.7, EtOH) to ꢁ14.6 (for c 11.0, CHCl3)
(Table 3: entries 4–6). Interestingly, the position of null
excess and its specific rotation. In an attempt to obtain a
better understanding of these scalemic oxazolidin-2-ones
2, we next chose to measure their melting points (Table
6). The scalemic oxazoldin-2-ones (S)-2; 50% ee and (R)-
2; 50% ee have identical melting points (64–68 °C) which
were lower than their corresponding enantiomerically pure
4-isopropyl-oxazolidin-2-ones (S)- and (R)-2; >98% ee (mp
67–70 °C) due to their colligative behaviour. However, the
racemic oxazolidin-2-one (rac)-2 had a higher melting (73–
76 °C) than the enantiomerically pure oxazolidin-2-ones
(S)- and (R)-2; >98% ee (mp 67–70 °C). This change is
particularly interesting as the crystalline 4-isopropyl-oxazo-
rotation corresponded to a solution of chloroform and eth-
26
anol in a ratio of 85:15; ½aꢀD ¼ 0:0 (c 6.2, CHCl3/EtOH
85:15) (Table 4: entry 4).
We next probed this solvent effect using scalemic mixtures
of oxazolidin-2-one 2 - formed by pre-mixing its (S)- and
(R)-enantiomers (Table 5). From this study, there appeared
to be a near-linear relationship between the enantiomeric

1072
D. Benoit et al. / Tetrahedron: Asymmetry 19 (2008) 1068–1077
Table 6. The melting points of 4-isopropyl-oxazolidin-2-one 2 with
varying enantiomeric excesses
Entry
Oxazolidin-2-one
Mp (°C)
1
2
3
4
5
(S)-2; >98% ee
(S)-2; 50% ee
rac-2; 0% ee
(R)-2; 50% ee
(R)-2; >98% ee
67–70
64–68
73–76
64–68
67–70
lidin-2-one (rac)-2 appeared to be more thermally stable
than either the (R)- or (S)-oxazolidin-2-one 2. Single crystal
X-ray diffraction of oxazolidin-2-ones (rac)- and (S)-2 gave
two related oxazolidin-2-one structures (as shown in
Schemes 8 and 9). However, closer inspection of their crys-
tallographic packing arrangements revealed two funda-
mentally different packing arrangements (Schemes 10 and
11). The racemic oxazolidin-2-one 2 appeared as a hydro-
gen bonded meso-dimer (as shown in Schemes 10 and
12), whereby, the (S)-enantiomer (of 2) recognised the
(R)-enantiomer (of 2), whereas, the related enantiomeri-
cally pure (S)-oxazolidin-2-one 2 prefers to form a hydro-
gen bonded ‘head-to-tail’ polymer as shown in Scheme 11.
Scheme 10. A view along the B-axis of the unit cell of oxazolidin-2-one
(rac)-2, showing the intermolecular C@Oꢃ ꢃ ꢃH–N hydrogen bonding.
We performed the density functional perturbation theory
(DFPT) calculations in order to investigate the possible
origin of this difference in stability. This DFPT approach
enables the change in electronic density generated in one
molecule in response to the presence of another to be mod-
elled. This particular methodology has also already been
applied successfully to investigate the water dimer and
crystalline silicon.31 The computed total interaction energy
Scheme 11. Intermolecular C@Oꢃ ꢃ ꢃH–N hydrogen bonding present in the
unit cell of oxazolidin-2-one (S)-2 [where (S)-2 is hydrogen bonded to
another molecule of (S)-2 in a ‘head-to-tail’ arrangement].
Scheme 8. Molecular structure of oxazolidin-2-one (rac)-2, showing the
atom labelling scheme. Displacement ellipsoids are drawn at 25%
probability level and the H atoms have been omitted.
Scheme 9. Molecular structure of oxazolidin-2-one (S)-2, showing the
atom labelling scheme. Displacement ellipsoids are drawn at 25%
probability level and the H atoms have been omitted.
Scheme 12. Intermolecular C@Oꢃ ꢃ ꢃH–N hydrogen bonding present in the
unit cell of oxazolidin-2-one (rac)-2 [where (S)-2 is hydrogen bonded to
(R)-2 and vice versa].

D. Benoit et al. / Tetrahedron: Asymmetry 19 (2008) 1068–1077
1073
Scheme 13. Isosurface plots of the correction to the electronic density of the monomers upon formation of hydrogen bonds for the oxazolidin-2-one (S)-2
crystal (left) and the racemic oxazolidin-2-one (rac)-2 crystal (right). The blue zones correspond to regions where the electronic density is reduced and the
purple zones to regions where the density in increased, compared to the non-interacting molecules. Note that the blue and purple zones enclose the same
displaced charge in both cases.
per unit cell is ꢁ23.5 kcal/mol for oxazolidin-2-one (S)-2
and ꢁ29.7 kcal/mol for the oxazolidin-2-one (rac)-2, or
ꢁ5.88 kcal/mol and ꢁ7.43 kcal/mol per molecule, respec-
tively, showing that the racemate crystal is energetically
favoured. For both structures, we observed a significant
displacement of the p electrons around to the amide bond
(see correction-density plots in Scheme 13). This mecha-
nism enables the molecules to shift their electronic density
from the electron-rich nitrogen atom to the adjacent elec-
tron-deficient carbon, thus pushing the carbonyl oxygen
to become more negative, whilst the amide proton becomes
more positive. Interestingly, the cyclic arrangement
observed for the racemate crystal seems to enhance the
co-operative participation of the p electrons of the C@O
bond, an effect that is barely seen in the S-only crystal.
For the racemic crystal, this enables the carbonyl oxygen
to accumulate more electron density, in response to the
charge displacement created in the (H–)N–C(@O) bond,
thus increasing the binding affinity with the amide proton
of the neighbouring oxazolidin-2-one. This enhancement
suggests that in the racemic case, there is a genuine commu-
nication between the hydrogen bond donating part of the
oxazolidin-2-one and the hydrogen bond accepting part.
In the case of the (S)-only crystal, the two parts of the
molecule that participate in the hydrogen bonding are
nearly independent and are much less reinforced by each
others electronic re-arrangement.
Assigning the enantiomeric purity and configuration of
these oxazolidin-2-ones (R)- and (S)-2 proved problematic
as the specific rotation was found to be solvent and concen-
tration dependent; in chloroform it was shown to be dex-
26
trorotatory f½aꢀD ¼ þ15:5 ðc 5:2; CHCl3Þg, whereas in
26
ethanol it was levorotatory f½aꢀD ¼ ꢁ16:1 ðc 5:2;
EtOHÞg. Due to this unusual behaviour where, both spe-
cific rotations were of similar magnitude but opposite sign
(for the rotation of the plane of plane polarised light), it is
understandable that some literature assignments were
incorrectly assigned,27 and therefore stereochemically mis-
leading when considering its nomenclature.13 This type of
solvent dependence on the sign of the specific rotation
has been reported.32–35 In certain cases, changes in the spe-
cific rotation occur through conformational effects due to
H-bonding36–38 and (de)-protonation processes have been
reported.39,40 The role of aggregates41,42 and counter-ions43
have also been shown to play a significant role. The nearest
analogy to our study is that reported by Fueno44 and Furs-
toss.45 Fueno44 has shown that the sign of the specific rota-
tion for a conformationally rigid heterocycle, propylene
oxide, can be changed from dextrorotatory (using hydro-
carbon and organic solvents) to levorotatory when using
water as the solvent. Whereas, Furstoss45 has reported sim-
ilar findings for a-methylstyrene when using either chloro-
form or acetone as the solvent.
4. Experimental
4.1. General
3. Conclusion
In conclusion, we have reported the kinetic resolution of
racemic 4-isopropyl-oxazolidin-2-one 2 using pentafluoro-
phenyl 2-(4-isobutylphenyl)propionate (S)-9 as the resolv-
ing component to give access to both enantiomers of the
parent oxazolidin-2-ones (R)- and (S)-2 in good yield.
All solvents were distilled before use. All reactions were
carried out under a nitrogen using oven-dried glassware.
Flash column chromatography was carried out using Merck
Kieselgel 60 (230–400 mesh). Thin layer chromatography

1074
D. Benoit et al. / Tetrahedron: Asymmetry 19 (2008) 1068–1077
(TLC) was carried out on commercially available pre-
coated plates (Merck Kieselgel 60F254 silica). Proton and
2 (0.17 g, 1.34 mmol) in THF (10 mL) at ꢁ78 °C. After
stirring for 1 h, a solution of (+)-pentafluorophenyl 2-
(4-isobutylphenyl)propionate (S)-9 (0.10 g, 0.27 mmol) in
THF (1 mL) was added. The resulting mixture was stirred
for 2 h at ꢁ78 °C. The reaction was quenched with water
(10 mL). The organic layer was extracted with dichloro-
methane (3 ꢄ 10 mL), dried over MgSO4 and evaporated
under reduced pressure to give two diastereoisomeric
oxazolidin-2-one (S,R)-syn- and (S,S)-anti-10 [syn-:anti-
carbon NMR spectra were recorded on
a Bruker
400 MHz Fourier transform spectrometers using an
internal deuterium lock. Chemical shifts are quoted in parts
per million downfield from tetramethylsilane. Carbon
NMR spectra were recorded with broad proton decoupling.
Infrared spectra were recorded on a Shimadzu 8300 FTIR
spectrometer. Optical rotation was measured using an
automatic AA-10 Optical Activity Ltd polarimeter with a
cell of path length 2.5 cm. The samples (ꢂ20–30 mg) were
prepared using 0.5 mL of the specified solvent.
1
88:12—determined by 400 MHz H NMR spectroscopy].
The crude mixture was purified by flash column chroma-
tography on silica gel eluting with light petroleum
(bp 40–60 °C)/diethyl ether (7:3) to give 3-[2-(4-iso-
butylphenyl)propionyl]-4-isopropyl-oxazolidin-2-one (S,S)-
4.2. Pentafluorophenyl 2-(4-isobutylphenyl)propionate (S)-9
anti-10 (7 mg, 9%) as a colourless oil; Rf [light petroleum
22
2-(4-Isobutylphenyl)propionic acid (S)-8 (2.03 g, 9.84
(bp 40–60 °C)/diethyl ether (1:1)] 0.77; ½aꢀD ¼ þ123:7 (c
20
mmol) f½aꢀD ¼ þ54:2 ðc 3:8; CHCl3Þg was added to a
1.2, CHCl3); mmax(CHCl3) cmꢁ1 1776 (C@O) and 1692
(C@O); dH (400 MHz; CDCl3) 7.23 (2H, d, J 8.2,
2 ꢄ CH; Ar), 7.07 (2H, d, J 8.2, 2 ꢄ CH; Ar), 5.11 (1H,
q, J 7.2, ArCHCH3), 4.37–4.32 (1H, dt, J 7.2 and 3.8, i-
PrCHN), 4.15–4.07 (2H, m, CH2O), 2.46–2.39 (2H, m,
CH2Ar), 1.87–1.77 (1H, m, CH(CH3)2), 1.49 (3H, d, J
7.2, ArCHCH3) and 0.92–8.86 (12H, m, 2 ꢄ CH(CH3)2);
dC (100.6 MHz; CDCl3) 174.9 (NC@O), 153.6 (OC@O),
140.6 (i-C; Ar), 137.5 (i-C; Ar), 129.3 and 127.8
(2 ꢄ CH; Ar), 63.1 (CH2O), 59.0 (i-PrCHN), 45.1
(CH(CH3)2), 42.6 (ArCHCH3), 30.2 (CH2), 28.6
(CH(CH3)2), 22.7 (CHA3 CHCH3B; i-BuC6H4–), 22.4
(CHACHCHB; i-BuC6H4–), 19.7 (CHACHCHB; oxazoli-
stirred solution of N,N0-dicyclohexylcarbodiimide (DCC)
(2.23 g, 10.82 mmol) in dichloromethane (10 mL). The
resulting solution was stirred for 10 min. A solution of
pentafluorophenol (1.81 g, 9.81 mmol) in dichloromethane
(10 mL) was slowly added, and the resulting solution was
stirred for 12 h. The resulting precipitate (N,N0-dicyclo-
hexylurea) was filtered off (using suction filtration). Brine
(10 mL) was added and the solution was extracted with
dichloromethane (3 ꢄ 50 mL) and dried over MgSO4.
The combined organic layers were evaporated under re-
duced pressure. The crude residue was purified by flash col-
umn chromatography on silica gel eluting with light
petroleum (bp 40–60 °C)/diethyl ether (9:1) to give penta-
fluorophenyl 2-(4-isobutylphenyl)propionate (S)-9 (3.55 g,
3
3
3
3
din-2-one), 18.0 (CH3ACHCHB3 ; oxazolidin-2-one) and
14.7 (ArCHCH3) (Found MH+, 318.2062; C19H28NO3 re-
quires 318.2064); 3-[20-(4-isobutylphenyl)propionyl]-4-iso-
propyl-oxazolidin-2-one (2S,4R)-syn-10 (60 mg, 70%) as
92%) as a colourless liquid; Rf [light petroleum (bp 40–
26
60 °C)/diethyl ether (9:1)] 0.63; ½aꢀD ¼ þ91:7 (c 29.6,
26
CHCl3) {for (R)-9; ½aꢀD ¼ ꢁ91:4 (c 5.0, CHCl3)};
a colourless oil; Rf [light petroleum (bp 40–60 °C)/
22
m
max(CHCl3) cmꢁ1 1782 (C@O); dH (400 MHz; CDCl3)
diethyl ether (1:1)] 0.55; ½aꢀD ¼ þ32:7 (c 3.6, CHCl3)
22
7.26 (2H, dt, J 8.2 and 2.2, 2 ꢄ CH; Ar), 7.14 (2H, dt, J
8.2 and 2.2, 2 ꢄ CH; Ar), 4.04 (1H, q, J 7.2, ArCHCH3),
2.46 (2H, d, J 7.2, CH2Ar), 1.92–1.80 (1H, m, CH(CH3)2),
1.62 (3H, d, J 7.2, ArCHCH3), 0.99 (3H, d, J 6.7,
CHA3 CHCHB3 ) and 0.88 (3H, d, J 6.7, CHA3 CHCH3B); dC
(100 MHz; CDCl3) 170.3 (OC@O), 140.8 (i-C; Ar), 141.2
(142.92 and 139.42, 2C, ddt, 1JC,F = 251.3 Hz,
2JC,F = 11.9 Hz and 3JC,F = 4.2 Hz, C(2)–F), 138.9
(140.18 and 137.66, 1C, dtt, 1JC,F = 253.2 Hz,
2JC,F = 13.8 Hz and 3JC,F = 3.8 Hz, C(4)–F), 137.3
(138.61 and 136.08, 2C, dtdd, 1JC,F = 254.7 Hz,
{for (2R,4S)-syn-10; ½aꢀD ¼ ꢁ33:0 (c 1.2, CHCl3)};
m
max(CHCl3) cmꢁ1 1778 (C@O) and 1699 (C@O); dH
(400 MHz; CDCl3) 7.23 (2H, d, J 8.2, 2 ꢄ CH; Ar), 7.03
(2H, d, J 8.2, 2 ꢄ CH; Ar), 5.11 (1H, q, J 6.9,
ArCHCH3), 4.50–4.44 (1H, dt, J 8.80 and 3.48, i-
PrCHN), 4.21 (1H, t, J 8.6, CHAHBO), 4.07 (1H, dd, J
8.6 and 3.5, CHAHBO), 2.40 (2H, d, J 7.2, CH2), 2.19–
2.07 (1H, m, CH(CH3)2; oxazolidin-2-one), 1.87–1.75
(1H, m, CH(CH3)2; i-BuC6H4–), 1.44 (3H, d, J 6.9,
ArCHCH3), 0.85 (3H, d, J 6.7, CH3; CHA3 CHCH3B;
i-BuC6H4–), 0.84 (3H, d, J 6.7, CH3; CHA3 CHCH3B;
i-BuC6H4–), 0.76 (3H, d, J 6.9, CHA3 CHCH3B; oxazolidin-
2-one) and 0.38 (3H, d, J 6.9, CHA3 CHCH3B; oxazolidin-
2-one); dC (100.6 MHz; CDCl3) 174.8 (NC@O), 153.5
(OC@O), 140.6 (i-C; Ar), 137.6 (i-C; Ar), 129.3 and
127.8 (2 ꢄ CH; Ar), 62.8 (CH2O), 58.0 (i-PrCHN), 45.0
(CH(CH3)2), 42.9 (ArCHCH3), 30.2 (CH2Ar), 27.8
3
4
2JC,F = 14.5 Hz, JC,F = 5.3 and JC,F = 3.0 Hz, C(3)–F),
135.5 (i-C; Ar), 129.1 and 126.7 (2 ꢄ CH; Ar), 124.7 (1C,
2
4
3
tdt, JC,F = 14.2 Hz, JC,F = 4.6 Hz and JC,F = 2.3 Hz, i-
CO; OC6F5), 44.5 (CH2Ar), 44.4 (ArCHCH3), 29.7
(CH(CH3)2), 21.9 (CH(CH3)2) and 18.0 (ArCHCH3); dF
3
(378 MHz; CDCl3) ꢁ152.6 (2 F, d, JF,F 18.5, Fortho),
3
B
ꢁ158.1 (1F, t, JF,F 20.8, Fpara) and ꢁ162.4 (2 F, dd,
(CH(CH3)2; oxazolidin-2-one), 22.7 (CHA3 CHCH3 ; i-
3JF,F 20.8 and 18.5, Fmeta) (Found M+, 372.1144;
BuC6H4–), 22.3 (CHA3 CHCH3B; i-BuC6H4–), 18.5
(CH3ACHCH3B; oxazolidin-2-one), 17.7 (CH3ACHCHB3 ;
oxazolidin-2-one) and 14.0 (ArCHCH3) (Found M+,
317.1979; C19H27NO3 requires M+, 317.1985); and 4-iso-
propyl-oxazolidin-2-one (S)-2 (0.11 g, 64%) as a white so-
C19H17F5O2 requires M+, 372.1143).
4.3. Kinetic resolution of racemic 4-isopropyl oxazolidin-2-
one rac-2 using pentafluorophenyl 2-(4-isobutylphenyl) pro-
pionate (S)-9
lid; Rf [diethyl ether] 0.30; mp 64–66 °C (ꢂ16% ee);
22
{½aꢀD ¼ þ2:6 (c 4.8, CHCl3) (which equates to ꢂ16% ee
n-BuLi (0.54 mL, 2.5 M in hexane, 1.34 mmol) was added
to a stirred solution of 4-isopropyl oxazolidin-2-one (rac)-
by specific rotation and ꢂ16% ee using a chiral shift
reagent)}.5

D. Benoit et al. / Tetrahedron: Asymmetry 19 (2008) 1068–1077
1075
4.4. Synthesis of 4-isopropyl-oxazolidin-2-one (S)-2
4.7. Stereospecific coupling of 4-isopropyloxazolidin-2-one
(R)-2 with pentafluorophenyl 4-isobutylphenylpropionate
(S)-9
Potassium carbonate (0.28 g, 2.02 mmol) was added to a
stirred solution of L-valinol (2.0 g, 20.7 mmol) in diethyl-
carbonate (4.76 g, 4.88 mL, 40.33 mmol) in a 50 mL round
bottom flask. A short-path distillation apparatus was con-
nected to this flask and the resulting solution was heated to
130 °C for 3 h. The residue was purified by aqueous extrac-
tion into dichloromethane (3 ꢄ 50 mL) using brine (50 mL)
to give the oxazolidin-2-one (S)-2 (2.01 g, 80%) as a white
crystalline solid; Rf [diethyl ether] 0.30; mp 67–70 °C;
Under the same conditions as described above, n-BuLi
(0.40 mL, 2.5 M in hexane, 1.00 mmol), 4-isopropyl-oxaz-
olidin-2-one (R)-2 (0.117 g, 0.91 mmol) and pentafluoro-
phenyl 2-(4-isobutylphenyl)propionate (+)-(S)-9 (0.34 g,
0.91 mmol), gave after purification by column chromatog-
raphy on silica gel eluting with light petroleum (bp 40–
60 °C)/diethyl ether (7:3) the oxazolidin-2-one (2S,4R)-
22
22
½aꢀD ¼ þ15:6 (c 3.0, CHCl3)] and ½aꢀD ¼ ꢁ17:4 (c 2.4,
EtOH)]; mmax(CHCl3) cmꢁ1 3263 (N–H) and 1751 (C@O);
dH (400 MHz; CDCl3) 6.78 (1H, br s, NH), 4.37 (1H, t, J
8.6, CHAHBO), 4.04 (1H, dd, J 8.6 and 6.4, CHAHBO),
3.55 (1H, br dt, J 8.6 and 6.4, CHN), 1.65 (1H, appears
as an octet, J 6.8, CH(CH3)2), 0.90 (3H, d, J 6.6,
CHA3 CHCHB3 ) and 0.83 (3H, d, J 6.8, CHA3 CHCH3B); dC
(100 MHz; CDCl3) 160.2 (C@O), 68.6 (CH2O), 58.4 (i-
PrCHN), 32.7 (CH(CH3)2), 18.0 and 17.7 (2 ꢄ CH3;
CH(CH3)2) (Found MH+, 130.0880; C6H12NO2 requires
MH+, 130.0868).
syn-10 (0.171 g, 59%) as a colourless oil; Rf [light petroleum
22
(bp 40–60 °C)/diethyl ether (1:1)] 0.33; ½aꢀD ¼ þ31:5 (c 8.4,
22
CHCl3) {for (2R,4S)-syn-10; ½aꢀD ¼ ꢁ33:0 (c 1.2, CHCl3)}
(Found M+, 317.1979; C19H27NO3 requires M+, 317.1985);
which was spectroscopically identical to that obtained
previously.
4.8. X-ray crystallographic data and structure determination
For 4-isopropyl-oxazolidin-2-one rac-2: the intensity data
were collected on an Enraf Nonius CAD-4 diffractometer
˚
using Mo Ka radiation (k 0.71069 A) with an x-2h scan
at 160 K. The unit cell parameters were determined by
least-squares refinement on diffractometer angles
9.277 6 h 6 13.361° for 25 automatically centred
reflections.46
4.5. Synthesis of 4-isopropyl-oxazolidin-2-one (R)-2
Under the same conditions as described above, D-valinol
(2.0 g, 20.17 mmol) and potassium carbonate (0.28 g,
2.02 mmol) in diethylcarbonate (4.76 g, 4.88 mL,
40.33 mmol) gave the oxazolidin-2-one (R)-2 (2.34 g,
4.9. Crystallographic data for 4-isopropyl-oxazolidin-2-one
rac-2
90%) as a white crystalline solid; Rf [diethyl ether] 0.30;
22
mp 67–70 °C; ½aꢀD ¼ ꢁ13:1 (c 4.2, CHCl3)] and
C6H11NO2, Mr 129.16, monoclinic, space group P21/n,
22
½aꢀD ¼ þ15:0 (c 2.8, EtOH)] (Found MH+, 130.0880;
a = 12.223(9) A, b = 10.177(9) A, c = 5.777(7) A, a = 90°,
˚
˚
˚
C6H12NO2 requires MH+, 130.0868), which was spectro-
b = 93.75(7)°, c = 90°, V = 717.1(12) A , Z = 4, Dca
3
˚
scopically identical to that obtained previously.
1.196 Mg mꢁ3, l = 0.090 mmꢁ1, F(000) = 280. Data were
collected using a crystal of size 0.40 ꢄ 0.20 ꢄ 0.10 mm3.
A
total of 1429 reflections were collected for
4.6. Stereospecific coupling of 4-isopropyloxazolidin-2-one
(S)-2 with pentafluorophenyl 4-isobutylphenylpropionate
(S)-9
2.61° < h < 24.99°
and
ꢁ6 6 h 6 14,
ꢁ4 6 k 6 12,
0 6 l 6 6. There were 1245 independent reflections
[Rint = 0.0120] with full-matrix least squares on F2 used
in the refinement. The final R indices were [I > 2r(I)]
R1 = 0.0696, wR2 = 0.1796; (all data) R1 = 0.1320,
n-BuLi (0.41 mL, 2.5 M in hexane, 1.02 mmol) was added
to a stirred solution of 4-isopropyl-oxazolidin-2-one (S)-2
(0.12 g, 0.93 mmol) in THF (10 mL) at ꢁ78 °C. After stir-
ring for 1 h, a solution of pentafluorophenyl 2-(4-isobutyl-
phenyl)propionate (+)-(S)-9 (0.34 g, 0.93 mmol) in THF
(1 mL) was added. The resulting mixture was stirred for
2 h at ꢁ78 °C. The reaction was quenched with water
(10 mL). The organic layer was extracted with dichloro-
methane (3 ꢄ 10 mL), dried over MgSO4 and evaporated
under reduced pressure to give the diastereoisomerically
pure oxazolidin-2-ones (S,S)-anti-10 [syn-:anti- > 98:2—
determined by 400 MHz 1H NMR spectroscopy]. The
crude mixture was purified by flash column chromatogra-
phy on silica gel eluting with light petroleum (bp
40–60 °C)/diethyl ether (7:3) to give 3-[20-(4-isobutyl-
phenyl)propionyl]-4-isopropyl-oxazolidin-2-one (2S,4S)-
anti-10 (0.19 mg, 64%) as a colourless oil; Rf [light petro-
wR2 = 0.2138. The laꢁrg3est difference peak and hole were
˚
0.427 and ꢁ0.224 e A
.
4.10. X-ray crystallographic data and structure
determination
For 4-isopropyl-oxazolidin-2-one rac-2: the intensity data
were collected on an Enraf Nonius CAD-4 diffractometer
using Mo Ka radiation (k 0.71073 A) with an x-2h scan
at 160 K. The unit cell parameters were determined by
˚
least-squares refinement on diffractometer angles
2.64 6 h 6 24.95°
for
25
automatically
centred
reflections.46
4.11. Crystallographic data for 4-isopropyl-oxazolidin-2-one
(S)-2
leum
(bp
40–60 °C)/diethyl
ether
(1:1)]
0.64;
22
½aꢀD ¼ þ108:9 (c 9.7, CHCl3) (Found MH+, 318.2062;
C19H28NO3 requires 318.2064); which was spectroscopi-
cally identical to that obtained previously.
C6H11NO2, Mr 129.16, orthorhombic, space group
˚
˚
˚
P212121, a = 5.607(3) A, b = 10.149(5) A, c = 11.907(8) A,
3
˚
a = 90°, b = 90°, c = 90°, V = 677.6(7) A , Z = 4, Dca

1076
D. Benoit et al. / Tetrahedron: Asymmetry 19 (2008) 1068–1077
1.266 Mg mꢁ3, l = 0.095 mmꢁ1, F(000) = 280. Data were
collected using a crystal of size 1.13 ꢄ 0.38 ꢄ 0.30 mm3.
(d) Boyd, E.; Chavda, S.; Eames, J.; Yohannes, Y. Tetrahe-
dron: Asymmetry 2007, 18, 476–482; (e) Coumbarides, G. S.;
Dingjan, M.; Eames, J.; Flinn, A.; Northen, J. Chirality 2007,
19, 321–328; (f) Chavda, S.; Coumbarides, G. S.; Dingjan, M.;
Eames, J.; Flinn, A.; Northen, J. Chirality 2007, 19, 313–320.
2. Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.;
Northen, J.; Yohannes, Y. Tetrahedron Lett. 2005, 46, 2897–
2902.
3. Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.;
Motevalli, M.; Northen, J.; Yohannes, Y. Synlett 2006, 101–
105.
4. Using 2 equiv of 4-isopropyl-oxazolidin-2-one rac-2 gave the
corresponding oxazolidin-2-ones (S,R)-syn- and (S,S)-anti-10
(ratio: 81:19) with reduced diastereoselection.
5. Determined by the splitting (ꢂ1.6 Hz) at 4.06 ppm {measured
at 400 MHz using a chiral shift NMR reagent, tris[3-
(trifluoromethylhydroxymethylene)-d-camphorato] europium
(III)}.
6. Kanomata, N.; Tadashi, N. J. Am. Chem. Soc. 2000, 122,
4563–4568, and references therein.
7. For additional reports into the use of 4-isopropyl-oxazolidin-
2-one, see: (a) Doyle, M. P.; Dorow, R. L.; Terpstra, J. W.;
Rodenhouse, R. A. J. Org. Chem. 1985, 50, 1663–1666; (b)
Gawley, R. E.; Hart, G. C.; Bartolotti, L. J. J. Org. Chem.
1989, 54, 175–181; (c) Evans, D. A.; Dow, R. L.; Shih, T. L.;
Takacs, J. M.; Zahler, R. J. Am. Chem. Soc. 1990, 112, 5290–
5313; (d) Davies, S. G.; Mortlock, A. A. Tetrahedron:
Asymmetry 1991, 2, 1001–1004; (e) Davies, S. G.; Doisneau,
G. J.-M.; Prodger, J. C.; Sanganee, H. J. Tetrahedron Lett.
1994, 35, 2362–2372; (f) Huwe, C. M.; Blechert, S. Tetrahe-
dron Lett. 1994, 35, 9533–9536; (g) Shafer, C. M.; Molinski,
T. F. J. Org. Chem. 1996, 61, 2044–2050; (h) Sudharshan, M.;
Hultin, P. G. Synlett 1997, 171–172; (i) Kanomata, N.;
Nakata, T. J. Am. Chem. Soc. 2000, 122, 4563–4568; (j)
Casadei, M. A.; Feroci, M.; Inesi, A.; Rossi, L.; Sotgiu, G. J.
Org. Chem. 2000, 65, 4759–4761; (k) Chiarotto, I.; Feroci, M.
Tetrahedron Lett. 2001, 42, 2453–3451; (l) Palomo, C.;
Oiarbide, M.; Dias, F.; Ortiz, A.; Linden, A. J. Am. Chem.
Soc. 2001, 123, 5602–5603; (m) Feroci, M.; Gennaro, A.;
Inesi, A.; Orsini, M.; Palombi, L. Tetrahedron Lett. 2002, 43,
5863–5865; (n) Kanomata, N.; Marutama, S.; Tomono, K.;
Anada, S. Tetrahedron Lett. 2003, 44, 3599–3603; (o) Kano-
mata, N.; Maruyama, S.; Tomono, K.; Anada, S. Tetrahe-
dron Lett. 2003, 44, 3599–3603.
A
total of 1465 reflections were collected for
2.64° < h < 24.95°
and
ꢁ6 6 h 6 6,
ꢁ12 6 k 6 12,
ꢁ14 6 l 6 14. There were 1186 independent reflections
[Rint = 0.0127] with full-matrix least squares on F2 used
in the refinement. The final R indices were [I > 2r(I)]
R1 = 0.0389, wR2 = 0.1024; (all data) R1 = 0.0401,
wR2 = 0.1034. The laꢁrg3est difference peak and hole were
˚
0.296 and ꢁ0.227 e A
.
All data were corrected for absorption by semi-empirical
methods (w scan)47 and for Lorentz-polarisation effects
by XCAD4.48 The structure was solved by direct method
using SHELXS-97,49 and refined anisotropically (non-hydro-
gen atoms) by full-matrix least-squares on F2 using the
SHELXL-97 program.49 The H atoms were calculated geo-
metrically and refined with a riding model. The program
ORTEP-3550 was used for drawing the molecules. WINGX651
was used to prepare material for publication. The data
relating to the single crystal X-ray structures of (S)- and
(rac)-2 have been deposited at the Cambridge Crystallo-
graphic Database {CCDC reference numbers 679810 [for
(S)-2] and 679811 [for rac-2]}.
4.12. Computational method
The theoretical modelling was performed using density
functional theory as implemented in the CPMD ab initio
pseudopotential plane-wave package.52 We used the gradi-
ent-corrected Perdew-Burke-Ernzerhof (PBE) exchange
and correlation functional,53 a plane-wave cut-off energy
of 100Ry, and Goedecker norm-conserving pseudopoten-
tials54,55 for each atom in the system. The atomic coordi-
nates and cell parameters for both racemic and S-only
crystals were taken from the X-ray structure without fur-
ther optimisation. The density functional perturbation the-
ory calculations were performed using
a
parallel
implementation of the method described in Ref. 30. All cal-
culations were performed on a cluster of Apple X-Serve
computers at Queen Mary, University of London.
8. Guerlavais, V.; Carroll, P. J.; Joullie, M. M. Tetrahedron:
Asymmetry 2002, 13, 675–680.
9. Nerz-Stormes, M.; Thornton, E. R. J. Org. Chem. 1991, 56,
2489–2498.
10. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127–2129.
Acknowledgements
11. Pettit, G. R.; Burkett, D. D.; Williams, M. D. J. Chem. Soc.,
Perkin Trans. 1 1996, 853–858.
12. Ishizuka, T.; Kimura, K.; Isibuchi, S.; Kunieda, T. Chem.
Lett. 1992, 991–994.
13. Lancaster Chemical catalogue, 2002–2003, p 1106; the name
contradicts the sign of rotation for both compounds.
14. Kleschick, W. A.; Reed, M. W.; Bordner, J. J. Org. Chem.
1987, 52, 3168–3169.
We are grateful to the EPSRC (to E.C.) for a studentship
and the EPSRC National Mass Spectrometry Service
(Swansea) for accurate mass determinations. We would
also like to thank Yonas Yohannes for crystallising a sam-
ple of racemic 4-isopropyl-oxazolidin-2-one.
15. Matsunaga, H.; Ishizuka, T.; Kunieda, T. Tetrahedron 1997,
53, 1275–1294.
References
16. Suzuki, M.; Yamazaki, T.; Ohta, H.; Shima, K.; Ohi, K.;
Nishiyama, S.; Sugai, T. Synlett 2000, 189–192.
17. Chiral compounds and reference catalogue, Oxford Asym-
metry, 1997, p 34.
18. Sigma Aldrich Limited, Chemical catalogue, 2005–2006, p
1472.
1. (a) Coumbarides, G. S.; Eames, J.; Flinn, A.; Northen, J.;
Yohannes, Y. Tetrahedron Lett. 2005, 46, 849–853; (b)
Chavda, S.; Coulbeck, E.; Coumbarides, G. S.; Dingjan, M.;
Eames, J.; Ghilagaber, S.; Yohannes, Y. Tetrahedron: Asym-
metry 2006, 17, 3386–3399; (c) Boyd, E.; Chavda, S.;
Coulbeck, E.; Coumbarides, G. S.; Dingjan, M.; Eames, J.;
Flinn, A.; Krishnamurthy, A. K.; Namutebi, M.; Northen, J.;
Yohannes, Y. Tetrahedron: Asymmetry 2006, 17, 3406–3422;
19. Wu, Y.; Shen, X. Tetrahedron: Asymmetry 2000, 11, 4359–
4363.

D. Benoit et al. / Tetrahedron: Asymmetry 19 (2008) 1068–1077
1077
20. Evans, D. A.; Mathre, D. J. J. Org. Chem. 1985, 50, 1830–
1835.
31. Benoit, D. M.; Sebastiani, D.; Parrinello, M. Phys. Rev. Lett.
2001, 87, 226401.
21. Knolker, H.-J.; Braxmeier, T. Tetrahedron Lett. 1998, 39,
9407–9410.
32. Hargreaves, M. K.; Richardson, P. J. J. Chem. Soc. 1957,
2260–2271.
22. Burns, B.; King, N. P.; Tye, H.; Studley, J. R.; Gamble, M.;
Wills, M. J. Chem. Soc., Perkin Trans. 1 1998, 1027–1038.
23. Pridgeb, L. N.; Prol, J. J. Org. Chem. 1989, 54, 3232–3233.
24. Wuts, P. G. M.; Pruitt, L. E. Synthesis 1989, 622–623.
25. Alouane, N.; Boutier, A.; Baron, C.; Vrancken, E.; Mange-
ney, P. Synthesis 2006, 885–889.
33. Mori, K. Tetrahedron: Asymmetry 2005, 16, 685–692.
34. (a) Fischer, A. T.; Compton, R. N.; Pagni, R. M. J. Phys.
Chem. A 2006, 110, 7067–7071; (b) Schlundt, H. J. Phys.
Chem. 1903, 7, 194–204.
35. Mukhopadhyay, P.; Zuber, G.; Wipf, P.; Beratan, D. N.
Angew. Chem., Int. Ed. 2007, 46, 6450–6452.
26. Correa, A.; Denis, J.-N.; Greene, A. E. Synth. Commun. 1991,
21, 1–9.
27. ACROS, Chemical catalogue, 2006–2007, p 1133; both
enantiomers of oxazolidin-2-one 2 have the same sign and
specific rotation.
36. Ko, K.-Y.; Eliel, E. L. J. Org. Chem. 1986, 51, 5353–5362.
37. Eliel, E. L.; Brunet, E. J. Org. Chem. 1991, 56, 1668–1670.
38. Suga, T.; Ohta, S.; Aoki, T.; Hirata, T. Chem. Lett. 1985,
1331–1334.
39. Levene, P. A.; Bass, L. W.; Rothen, A.; Steiger, R. E. J. Biol.
Chem. 1929, 81, 687–695.
40. Idelson, M.; Blout, E. R. J. Am. Chem. Soc. 1958, 80, 4631–
4634.
41. Krow, G.; Hill, R. K. Chem. Commun. 1968, 430–431.
42. Goldsmith, M.-R.; Jayasuriya, N.; Beratan, D. N.; Wipf, P. J.
Am. Chem. Soc. 2003, 125, 15696–15697.
43. Rossi, S.; Le Nostro, P.; Lagi, M.; Ninham, B. W.; Baglioni,
P. J. Phys. Chem. B 2007, 111, 10510–10519.
44. Kumata, Y.; Furukawa, J.; Fueno, T. Bull. Chem. Soc. Jpn.
1970, 43, 3920–3921.
45. Archelas, A.; Furstoss, R. J. Org. Chem. 1999, 64, 6112–6114.
46. Enraf-Nonius CAD-4/PC Software: Version 1.5c; Enraf-
Nonius: Delft, The Netherlands, 1994.
47. North, A. C. T.; Phillips, D. C.; Mathews, F. S. Acta
Crystallogr., Sect. A 1968, 42, 351–359.
48. Harms, K.; Wocadlo, S. XCAD4—CAD4 Data Reduction;
University of Marburg: Marburg, Germany, 1995.
49. Sheldrick, G. M. SHELX-97. Program for solution and Refine-
ment of Crystal Structures; University of Go¨ttingen: Ger-
many, 1997.
50. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
51. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837–838.
52. CPMD, Copyright IBM Corp 1990–2004, Copyright MPI fur
¨
Festko¨rperforschung Stuttgart, 1997–2001.
53. Perdew, J. P.; Burke, K.; Ernzerhof, M. Phys. Rev. Lett. 1996,
77, 3865–3868.
54. Goedecker, G.; Teter, M.; Hutter, J. Phys. Rev. B 1996, 54,
1703–1710.
28. Meyers, A. I.; Poindexter, G. S.; Brich, Z. J. Org. Chem.
1978, 43, 892–898.
29. Interestingly, by 1H NMR spectroscopy there appears to be a
subtle chemical shift difference for oxazolidin-2-one (S)-2
when performed in CDCl3 and MeOH-d4 (using 20 mg of
substrate with 0.75 mL of the corresponding D-labelled
solvent). dH (400 MHz; CDCl3) 6.78 (1H, br s, NH), 4.37
(1H, t, J 8.6, CHAHBO), 4.04 (1H, dd, J 8.6 and 6.4,
CHAHBO), 3.55 (1H, br dt, J 8.6 and 6.4, CHN), 1.65 (1H,
appears as an octet, J 6.8, CH(CH3)2), 0.90 (3H, d, J 6.6,
CHA3 CHCHB3 ) and 0.83 (3H, d, J 6.8, CHA3 CHCH3B); dH
(400 MHz; MeOH-d4) 4.37 (1H, t, J 8.8, CHAHBO), 4.07 (1H,
dd, J 8.8 and 6.1, CHAHBO), 3.55 (1H, ddd, J 8.8, 6.2 and
6.1, CHN), 1.64 (1H, appears as an octet, J 6.6, CH(CH3)2),
0.88 (3H, d, J 6.6, CH3ACHCHB3 ) and 0.84 (3H, d, J 6.7,
CHA3 CHCHB3 ). The NH proton was absent from the 1H
NMR spectrum due to deuterium exchange with MeOH-d4.
30. This solvent effect has also been shown to occur for 4-
phenylmethyl oxazolidin-2-one (derived from phenylalanine):
26
26
(R)-enantiomer ½aꢀD ¼ þ35:0 (c 5.4, CHCl3) and ½aꢀD ¼ ꢁ3:9
26
(c 4.4, EtOH), whereas, (S)-enantiomer ½aꢀD ¼ ꢁ37:3 (c 5.0,
26
CHCl3); ½aꢀD ¼ þ4:8 (c 4.0, EtOH). The specific rotation
appears to be concentration dependent (R)-enantiomer
26
½aꢀD ¼ þ68:7 (c 1.2, CHCl3) and (S)-enantiomer
26
½aꢀD ¼ ꢁ57:3 (c 1.2, CHCl3). Whereas, for related oxazoli-
din-2-ones such as 4-phenyl-oxazolidin-2-one {(R)-enantio-
26
26
mer ½aꢀD ¼ ꢁ40:9 (c 3.0, CHCl3) and ½aꢀD ¼ ꢁ55:5 (c 3.8,
EtOH),} and 4-methyl-5-phenyl-oxazolidin-2-one {(4R,5S)-
26
26
enantiomer ½aꢀD ¼ þ156:8 (c 4.0, CHCl3) and ½aꢀD ¼ þ107:3
55. Hartwigsen, C.; Goedecker, S.; Hutter, J. Phys. Rev. B 1998,
58, 3641–3662.
(c 3.4, EtOH)} no change of sign occurred.