The use of Mosher derivatives for the determination of the absolute configuration of substituted isoxazolidines

Article abstract of DOI:10.1016/j.tetasy.2013.01.016

Isoxazolidines serve as intermediates in the synthesis of natural products. In addition, they can display significant biological activity, much of which derives from their ability to act as nucleoside analogues. As a result, considerable effort has been applied toward the asymmetric synthesis of isoxazolidines. However, a rapid and straightforward method for determination of the absolute configuration of isoxazolidines has not yet been reported. Herein we report the application of Mosher derivatives for the determination of the absolute configuration of substituted isoxazolidines. The Mosher derivatives exhibit conformational behavior similar to the Mosher derivatives of cyclic secondary amines. Interpretation of the chemical shift anisotropy, with these conformational biases in mind, can be used for the assignment of the absolute configuration of substituted isoxazolidines.

Full text of DOI:10.1016/j.tetasy.2013.01.016

Tetrahedron: Asymmetry 24 (2013) 223–228
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Tetrahedron: Asymmetry
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The use of Mosher derivatives for the determination of the absolute
configuration of substituted isoxazolidines
⇑
Wentian Wang, Ryan T. Cassell, Kathleen S. Rein
Department of Chemistry and Biochemistry, 11200 SW 8th St, Florida International University, Miami, FL 33199, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 December 2012
Accepted 23 January 2013
Isoxazolidines serve as intermediates in the synthesis of natural products. In addition, they can display
significant biological activity, much of which derives from their ability to act as nucleoside analogues.
As a result, considerable effort has been applied toward the asymmetric synthesis of isoxazolidines. How-
ever, a rapid and straightforward method for determination of the absolute configuration of isoxazoli-
dines has not yet been reported. Herein we report the application of Mosher derivatives for the
determination of the absolute configuration of substituted isoxazolidines. The Mosher derivatives exhibit
conformational behavior similar to the Mosher derivatives of cyclic secondary amines. Interpretation of
the chemical shift anisotropy, with these conformational biases in mind, can be used for the assignment
of the absolute configuration of substituted isoxazolidines.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
the amides (Fig. 1) is such that the a-protons of the amine, the car-
bonyl oxygen, and the trifluoromethyl groups are coplanar and
syn.25,26 Chemical shift differences result from the different aniso-
tropic effects experienced by the two diastereomeric derivatives. In
the (S)-MTPA amide, the protons of the R1 group will be shielded
relative to the (R)-MTPA derivative (Fig. 1). In this conformation,
Isoxazolidines have proven to be particularly useful synthetic
intermediates for a variety of natural products,1–4 and serve as bio-
logically active compounds, such as antifungal,5 anti-tuberculosis,6
antiviral,7 and cytotoxic8 agents. As highly desirable synthetic tar-
gets, substantial effort has been invested toward the asymmetric
synthesis of isoxazolidines. The 1,3-dipolar cycloaddition of nitro-
nes with alkenes is a powerful approach, which provides isoxazoli-
dine cycloadducts with predictable regioselectivity and excellent
control of relative stereochemistry.9 The introduction of chiral nitro-
nes,10,11 chiral dipolarophiles,12–14 and chiral Lewis acid catalysts15–
18 provides isoxazolidine cycloadducts with high enantioselectivity.
Other approaches include a stereoselective Pd-catalyzed ring-clos-
ing carbonylative amidation,19 and Pd-catalyzed carboetherification
of N-butenylhydroxylamines.20 The determination of the absolute
configuration of substituted isoxazolidines has involved one of
two approaches: X-ray crystallography12,13,18,21,22 or conversion of
the isoxazolidine into a compoundfor whichthe signof specificrota-
tion is known.14
the
a
-CF3 group experiences anisotropic deshielding by the amide
-CF3 group is forced out of
carbonyl. However, if R1 is bulky, the
a
coplanarity with the carbonyl oxygen and consequently, will no
longer experience this deshielding effect. As a result, the chemical
shift for the 19F signal of the (S)-MTPA amide will be lower com-
pared with the (R)-MTPA amide.27
MeO
Ph
Ph
R2
R1
H
N
OMe
CF3
R2
R1
H
N
(S)
CF3
(R)
H
O
H
O
Figure 1. (S)-MTPA amide and (R)-MTPA amide.
The use of Mosher’s amide derivatives for determination of the
absolute configuration of amines has been applied principally to
primary amines. A comparative analysis of the 1H and/or the 19F
NMR spectra of the analyte, which has been derivatized with each
With respect to cyclic amines, the use of Mosher derivatives has
been largely limited to the determination of enantiomeric ratio,
with only a handful of reports describing the use of Mosher deriv-
atives for the assignment of absolute configuration. Among the
latter, a few have applied an empirical model similar to that used
for primary amines. Instead, these reports involve the acquisition
of an X-ray crystal structure of the derivative,28–31 analysis of
NOESY spectra,32,33 or comparison with derivatives of known con-
figuration34,35 and Vidal et al.36 reported the assignment of the
absolute configuration of 2-substituted pyrrolidines based on the
enantiomer of
a-methoxy-a-(trifluoromethyl)phenylacetic acid
(MTPA), using an empirical model can be used to reliably predict
the absolute configuration.23,24 The dominant conformation of
⇑
Corresponding author. Tel.: +1 305 348 6682; fax: +1 305 348 3772.
E-mail address: reink@fiu.edu (K.S. Rein).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.01.016

224
W. Wang et al. / Tetrahedron: Asymmetry 24 (2013) 223–228
ring conformation of the Mosher derivatives. Mosher amide deriv-
atives of cyclic amines can exist as two slowly interconverting and
unequally populated diastereomeric amide rotamers, which are of-
ten observed as two distinct species in the 1H and 19F NMR spectra
configuration of isoxazolidines using the Mosher derivatives. We
reasoned that these derivatives would behave in a fashion similar
to the Mosher derivatives of cyclic amines.
(Fig. 2).36–40 Similar to the acyclic amine derivatives, the
a-CF3 is
2. Results and discussion
biased toward an eclipsed arrangement with the amide C@O. This
bias, combined with the planar geometry imposed by the amide
group, positions the phenyl group on opposite sides of the mean
plane of the ring in the two rotamers. The chemical shift differ-
ences of the ring substituents enforced by shielding of the substit-
N-Benzylidene-1,1-diphenylmethanamine oxide 1 and oxazo-
lidinone 2 were prepared according to published methods18,45
and the 1,3-dipolar cycloaddition was performed using
Ti(i-OPr)2Cl2 as the catalyst. The dipolarophile may approach in
an endo fashion resulting in the trans relative configuration be-
tween substituents at the 3- and 4-positions of the isoxazolidine
ring. Alternatively, an exo approach will provide the cis-relative
configuration. The exo/endo selectivity dictating the relative config-
uration of the newly formed carbon–carbon bond is influenced by
uents on the same face of the ring as the a-phenyl group allow the
reliable assignment of the absolute configuration either when the
derivative appears as two discreet rotamers or as an average of
two conformations. This reasoning has been applied to the
assignment of the absolute configuration of the solenopsins,41
a
suite of piperidine derivatives, as well as several pyrrolidine
the coordination of the dipolarophile to
a Lewis acid cata-
derivatives.39,42,43
lyst.13,14,17,46 As anticipated on the basis of earlier studies, using
Ti(i-OPr)2Cl2 as the catalyst favored the exo approach, providing a
3:1 mixture of exo to endo cycloadducts after 9 days, as determined
by 1H NMR spectroscopy. After chromatographic separation, the exo
cycloadduct 3 was obtained in 58% yield (Scheme 1). Two diastereo-
topic exo adducts may be produced, resulting from an attack on the
diastereotopic faces of the dipolarophile 2. The 1H NMR spectra of
the purified exo adduct 3 suggested the formation of a single diaste-
reomer. Oxazolidinone chiral auxiliaries provide high diastereofa-
cial discrimination in a wide variety of reactions including 1,3-
dipolar cycloadditions.13,14,17,21,47–49 Based on these earlier studies,
it can be reliably predicted that the cycloadduct resulting from the
(S)-MTPA amide
A and D shielded
C
D
A
B
n
n
N
O
OMe
Ph
Ph
MeO
N
O
A
C
B
D
CF3
F3C
n = 0, 1
(R)-MTPA amide
C -Si face approach is preferred since it arises from attack of the nit-
a
B and C shielded
C
A
B
n
rone on the dipolarophile from the face opposite the directing
group. Therefore, product 3 can be predicted to have (3S,4S,5R)-
absolute configurations in the isoxazolidine ring (Scheme 1).13,21,48
After deprotection using Et3SiH, the cycloadduct was converted into
the (R)-MTPA amide derivative by treatment with (S)-MTPA-Cl
(Scheme 1). Two peaks were observed in the 19F NMR spectra of 5
in CDCl3, with a ratio of 1 to 2 (Fig. 3A). There are two possible
explanations for this observation. The first possibility is that there
are two different diastereomers. The other explanation is that a sin-
gle isomer exists as two slowly interconverting rotamers, consis-
tent with the coexistence of syn- and anti-rotamers of the MTPA
derivatives of cyclic amines, such as piperidines and pyrrol-
idines.36–40
n
D
MeO
Ph
N
O
N
O
Ph
OMe
C
A
D
B
F3C
CF3
Figure 2. Two diastereomeric amide rotamers of cyclic (S)-MTPA and (R)-MTPA
amides.
A single example of the use of Mosher derivatives of isoxazoli-
dines to determine the enantiomer ratio has been reported.44 How-
ever, the use of Mosher derivatives for the assignment of the
absolute configuration of chiral isoxazolidines has not been
described. As part of our interest in the synthesis of isoxazolidines,
we wished to develop a model for the determination of the absolute
With the acquisition of the 19F NMR spectrum in acetone-d6, the
peak ratio changed to 1 to 4 (Fig. 3B). Since the diastereomer ratio
Ph
Ph
O
O
TiCl2(i-OPr)2
dry CH2Cl2
Et3SiH
TFA
N
HN
O
N
O
Ox
Ox
Ph
+
Ph
4Å M.S.
CH2Cl2
reflux
81%
Ox
Ph
Ph
rt
O
O
Ph
9 d
1
2
3
4
58%
H3CO
Ph
CF3
Cl
O
O
O
CF3
O
(
)
H3CO
Ph
S
Ox
N
Ox =
N
O
O
(R)
O
pyridine
CCl4
rt
Ph
5
Scheme 1. 1,3-Dipolar cycloaddition of nitrone 1 with chiral dipolarophile 2, deprotection and preparation of (R)-MTPA amide [because of a change in priority, the (S)-MTPA-
Cl becomes the (R)-MTPA amide].

W. Wang et al. / Tetrahedron: Asymmetry 24 (2013) 223–228
225
out of plane atom and the oxazolidinone group is in a pseudo-
equatorial position. As observed with the piperidine and pyrroli-
dine MTPA amides, and supported by our 19F NMR spectra, these
calculations predict the existence of two major families of rota-
mers (E and Z) with the E-rotamers being favored over the Z rota-
mers (Fig. 4). The E- and Z-forms are assigned, in our case, on the
basis of the relationship between the C@O and the N–O bonds.
Within three of these four groups [Z- and E-rotamers of the (R)-
and (S)-derivatives], the lowest energy conformer has the trifluoro-
methyl group eclipsed with the amide carbonyl. The single excep-
tion is the E-rotamer of the (R)-MTPA derivative, in which the
methoxy group eclipsed by the amide carbonyl is favored by
1.43 kcal/mol.
(R)-MTPA
Ph CF3
amide
O
MeO
O
F3C
O
N
N
O
MeO
Ph
Ox
Ox
Ph
Ph
O
O
Major (E)
Minor (Z)
(S)-MTPA
amide
Ph OMe
F3C
O
O
F3C
Ph
O
N
N
O
OMe
Ox
Ox
Ph
Ph
O
O
Major (E)
Minor (Z)
Figure 4. Conformational preferences of (S)- and (R)-MTPA amides of 4.
On the basis of these computational results, the relative chem-
ical shifts of diagnostic signals in the 19F, 1H NMR of (R)- and (S)-
MTPA amides may be predicted, resulting in the assignment of
the absolute configuration. The diagnostic peaks (Fig. 5C) in the
1H NMR were assigned on the basis of 1H COSY experiments.
According to our calculations, the MTPA-phenyl group of the E-
rotamers of both (R)- and (S)-MTPA amides is on the same side of
Figure 3. 19F NMR spectra of MTPA amides of 4; (A) 19F NMR spectra of (R)-MTPA
amide acquired in CDCl3; (B) 19F NMR spectra of (R)-MTPA amide acquired in d6-
acetone; (C) 19F NMR spectra of (R)-MTPA amide (red) and racemic MTPA amides
(blue) acquired in CDCl3.
the isoxazolidine ring. This results from the preference for the
a-
OCH3 of the E-rotamer of the (R)-MTPA amide to adopt an eclipsed
arrangement with the C@O double bond, whereas the E-rotamer of
the (S)-MTPA amide adopts the more typical conformation in which
would not be solvent dependent, we concluded that the two peaks
represented slowly equilibrating amide rotamers. Furthermore,
partial coalescence of the two peaks was observed when the 19F
NMR was acquired at 45 °C in CDCl3. This observation, that there
were only two equilibrating rotamers, also suggested the presence
of a single exo-diastereomer. The deprotected exo adduct 4 was
also derivatized with racemic Mosher’s acid chloride for compari-
son of the 19F and 1H NMR spectra. The 19F NMR spectra of the
Mosher derivative prepared from racemic MTPA showed four
peaks, two of which were coincident with those observed in the
(R)-MTPA amide obtained from the reaction of 4 with (S)-MTPA-
Cl (Fig. 3C) and two new peaks belonging to the (S)-MTPA amide
produced by the reaction of 4 with (R)-MTPA-Cl.
In order to better understand the conformational properties of
the Mosher derivatives of these isoxazolidines, a Monte Carlo con-
formational search of both (R)- and (S)-Mosher derivatives of 4
using the AMBER force field with the programs MacroModel
(v. 6.5) and Batchmin (v. 6.5)50 was performed. Within a 25 kJ/
mol energetic window, the isoxazolidine ring adopts a single enve-
lope conformation in which C-4, bearing the largest group, is the
the a-CF3 is eclipsed with the C@O double bond. Due to the prefer-
ence for different conformations, the protons on the isoxazolidine
ring in both the (R)- and (S)-derivatives experience similar aniso-
tropic shielding effects of the phenyl group. It is therefore not infor-
mative to examine the relative chemical shifts of the ring protons of
the E-rotamers in order to determine the absolute configuration.
However, the chemical shifts of methoxy and trifluoromethyl
groups may be affected by the phenyl substitutent of the isoxazoli-
dine ring. The predicted and observed chemical shifts for the
and the OCH3 for the E-rotamers of the (R)- and (S)-derivatives are
shown in Table 1. In the E-rotamer of the (R)-MTPA amide, the
a-CF3
a-
CF3 is shielded by the phenyl of the isoxazolidine and the methoxy
group experiences anisotropic deshielding by the amide carbonyl.
These groups on the (S)-MTPA amide E-rotamer experience opposite
effects. The a-CF3 group experiences anisotropic deshielding by the
amide carbonyl and the methoxy group is shielded by the phenyl of
the isoxazolidine. This analysis suggests that the chemical shift for
the 19F
a-CF3 signal of the (R)-MTPA amide must be lower when
compared with the (S)-MTPA amide and the chemical shift of the
methoxy protons of the (R)-MTPA amide must be higher than in

226
W. Wang et al. / Tetrahedron: Asymmetry 24 (2013) 223–228
Figure 5. 1H NMR spectra of the MTPA amides of 4; (A) 1H NMR spectrum of the (R)-MTPA amide of 4; (B) 1H NMR spectra of the product of racemic MTPA amides; (C)
Superimposed 1H NMR spectra of (R)-MTPA amide (red) and racemic (blue) MTPA amides of 4.
Table 1
acyclic amides and so a similar analysis may be applied. In the
(R)-MTPA derivative of the Z-rotamer, Hb and Hc of the isoxazoli-
dine ring are shielded by the MTPA-phenyl group, whereas in the
(S)-MTPA derivative, only Ha is shielded by the MTPA-phenyl (Ta-
ble 2). In addition, because the bulky MTPA-phenyl and isoxazoli-
dine-phenyl are on the same side of the isoxazolidine ring in the Z-
Analysis of the anisotropic effects of the C@O and isoxazolidine-Ph on the CF3 and
OCH3 groups of the major E-rotamers of MTPA amides of 4
Ph OMe
Ph CF3
F3C
MeO
(R)
(S)
O
O
rotamer of the (S)-MTPA amide, the a-CF3 will therefore be shifted
away from co-planarity with the C@O, and will not be subjected to
N
N
O
O
Ox
Ox
the anisotropic deshielding of the C@O group to the same degree as
the (R)-MTPA amide. The chemical shift for the 19F
a
-CF3 signal of
the (S)-MTPA amide must be lower when compared with the (R)-
MTPA amide, that is, the relative chemical shifts of the -CF3
Ph
Ph
O
O
a
(R)-MTPA amide
(S)-MTPA amide
groups of the Z-rotamers should be opposite to those of the E-rota-
mers. These predictions were observed in 1H NMR spectra (Fig. 5C)
and 19F NMR spectra (Fig. 3C) If the exo-cycloadduct 3 arose from
CF3
OCH3
CF3
Deshielded
Not affected Not affected Shielded
OCH3
C@O
Isoxazolidine-Ph
Not affected Deshielded
Shielded
Not affected
attack of the dipole on the C -Re face, the relative chemical shift
d ppm (expected) Lower
d ppm (observed) À71.9
Higher
3.67
Higher
À71.4
Lower
3.52
a
differences of
a-CF3 and Ha, Hb, and Hc of the Z rotamers should
be the opposite of what is observed.
3. Conclusion
the (S)-MTPA. We observed these results in the 19F NMR spectra
(Fig. 3C) and 1H NMR spectra (Fig. 5C and summarized in Table 1).
In conclusion we have demonstrated the application of Mosher
derivatives of isoxazolidines for the assignment of absolute config-
urations. Similar to secondary cyclic amines, isoxazolidine deriva-
tives can exist as a pair of slowly equilibrating rotamers. As a
result, the assignment of configuration can be performed using
either rotamer by interpretation of chemical shift anisotropy in a
manner similar to that of secondary cyclic amines.
If exo cycloadduct 3 arose from attack of the dipole on the C -Re face,
the relative chemical shift differences of a-CF3 and methoxy groups
of the E rotamers should be opposite of what is observed. This dem-
onstrated that 3 has (3S,4S,5R)-absolute configurations in the isoxa-
zolidine ring.
a
The conformational bias and chemical shift differences of the a-
CF3 and methoxy groups are strongly influenced by the isoxazoli-
dine phenyl substituent. In the absence of this substituent, it is
not clear that this analysis would be generally applicable to isoxaz-
olidines. However, inspection of the minor Z-rotamers of the (R)-
and (S)-MTPA isoxazolidine amides is perhaps more informative
and generally applicable. The conformation of the Z-rotamers of
both the (R)- and (S)-MTPA derivatives is more similar to that of
4. Experimental
4.1. General
Unless otherwise noted, reagents purchased from Sigma–
Aldrich or Acros chemical companies were used without further

W. Wang et al. / Tetrahedron: Asymmetry 24 (2013) 223–228
227
Table 2
Analysis of the anisotropic effects of the C@O and
a-Ph on the CF3 and isoxazolidine protons of the minor (Z) rotamers of MTPA amides of 4
O
O
O
O
(S)
F3C
Ph
F3C (R)
N
N
MeO
Ph
OMe
Ph
Ox
Ox
Ph
O
O
(R)-MTPA amide
(S)-MTPA amide
Ha
Hb
Hc
CF3
Ha
Hb
Hc
CF3
a-Ph
Shielded
Shielded
Shielded
C@O
d ppm (expected)
d ppm (observed)
De-shielded
Higher
À69.5
Higher
5.17
Lower
3.48
Lower
5.39
Lower
2.96
Higher
4.68
Higher
5.61
Lower
À70.1
purification. Radial chromatography was performed on a chro-
matotron (Harrison Research Corp.) using plates coated with silica
gel 60 PF254 containing gypsum. NMR spectra were recorded on a
Bruker Avance spectrometer (400 MHz for proton). 1H NMR spectra
were referenced internally to the residual proton resonance in
CDCl3 (d = 7.26 ppm), or with tetramethylsilane (TMS, d = 0.00
ppm) as the internal standard. Chemical shifts are reported as parts
per million (ppm) in the d scale downfield from TMS. 13C NMR
spectra were recorded with continuous proton decoupling. Chem-
ical shifts are reported in ppm from TMS with the solvent as the
internal reference (CDCl3, d = 77.0 ppm).
until the solution became slightly basic. The solution was extracted
with CH2Cl2 (3 Â 30 ml) and the combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. Radial chromatography (2:1 hexane/EtOAc then 1:1 hexane/
EtOAc) provided the N-unsubstituted isoxazolidine 4. White solid;
81% yield (0.0479 g); mp 120–123 °C; 1H NMR (CDCl3, 400 MHz) d
7.24 (m, 5H), 4.99 (d, 1H, J = 9.6 Hz), 4.70 (dq, 1H, J = 6.0 Hz,
J = 8.0 Hz), 4.32 (dd, 1H, J = 9.6, 8.0 Hz), 4.19 (m, 1H), 4.12 (t, 1H,
J = 8.8 Hz), 4.01 (dd, 1H, J = 8.8, 2.4 Hz), 1.59 (m, 1H), 1.39 (d, 3H,
J = 6.0 Hz), 0.64 (d, 3H, J = 6.8 Hz), 0.00 (d, 3H, J = 6.8 Hz); 13C
NMR (CDCl3, 100 MHz) d 171.0, 153.5, 135.0, 128.7, 128.6, 128.5
128.3, 83.0, 68.5, 63.1, 59.0, 58.5, 28.3, 18.6, 18.0, 13.7. HR-MS
4.2. Synthesis of 3 and 4 and preparation of Mosher derivatives
(ESI/APCI) calcd for:
319.1662.
C
17H23N2O4 (MH+): 319.1652, found:
4.2.1. (S)-3-((3S,4S,5R)-2-Benzhydryl-5-methyl-3-phenylisoxazo-
lidine-4-carbonyl)-4-isopropyloxazolidin-2-one 3
4.2.2.1. Preparation of Mosher derivatives.
To a 25 ml flask
To a 100 ml flame-dried flask were added N-benzylidene-ben-
zhydrylamine N-oxide (0.2834 g, 0.99 mmol), (S,E)-3-but-2-enoyl-
4-isopropyloxazolidin-2-one (0.2356 g, 1.20 mmol), powered 4 Å
molecular sieve (215.6 mg), and dry CH2Cl2 (5 ml). The flask was
then flushed with N2 gas and sealed by a rubber septum, which
was fitted with a nitrogen balloon. Next, TiCl2(i-OPr)2 (2 M in CH2Cl2,
0.12 ml) was added via syringe. The resulting suspension was stirred
at room temperature for 9 days. A mixture of 20% methanol and 80%
CH2Cl2 (25 ml) was added and the cloudy solution was then filtered
through one layer of Celite (top) and one layer of silica gel (bottom),
followed by a wash of the solids with CH2Cl2 (20 ml), after which the
solvent was evaporated in vacuo. Radial chromatography (5:1 hex-
ane/EtOAc) afforded the pure exo adduct 3 as a white solid
(0.2770 g, 58% yield). Mp 82–85 °C; 1H NMR (CDCl3, 400 MHz) d
7.37–7.01 (m, 15H), 4.97 (m, 1H), 4.86 (s, 1H), 4.56 (d, 1H,
J = 10.8 Hz), 4.16–3.97 (m, 4H), 1.53 (m, 1H), 1.27 (d, 3H,
J = 6.0 Hz), 0.61 (d, 3H, J = 6.8 Hz), À0.01 (d, 3H, J = 6.8 Hz); 13C
NMR (CDCl3, 100 MHz) d 169.3, 153.4, 141.0, 140.3, 130.0, 129.1,
128.4, 128.0, 127.9, 127.7, 127.6, 127.1, 126.8, 75.2, 72.7, 70.3,
63.3, 59.8, 58.6, 28.3, 18.1, 13.9. HR-MS (ESI/APCI) calcd for:
equipped with a magnetic stirrer bar were added N-unsubstituted
isoxazolidine 4 (0.15 mmol), CCl4 (1 ml), pyridine (6 drops), and
Mosher acid chloride (0.18 mmol). The reaction mixture was stir-
red for 24 h and then concentrated under reduced pressure. The
residue was dissolved in CH2Cl2 (25 ml) and washed with H2O
(3 Â 25 ml) and a saturated NaHCO3 solution (3 Â 25 ml) to re-
move excess Mosher acid chloride. The organic layer was dried
over Na2SO4, filtered, and concentrated under reduced pressure
to give the crude Mosher amide.
4.2.3. (S)-4-Isopropyl-3-((3S,4S,5R)-5-methyl-3-phenyl-2-((R)-
3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl)isoxazolidine-4-
carbonyl)oxazolidin-2-one, (R)-Mosher amide 5
Purified by radial chromatography (2:1 hexane/EtOAc); 55%
yield. Mp 235–238 °C. 1H NMR (CDCl3, 400 MHz) Major rotamer
(E) d 7.63–7.14 (m, 10H), 5.87 (br, 1H), 4.33 (br, 1H), 4.00 (br,
2H), 3.91 (1H), 3.67 (br, 3H), 2.71 (br, 1H), 1.35 (1H), 1.09 (br,
3H), 0.52 (d, 3H, J = 7.2 Hz), 0.15 (br, 3H); Minor rotamer (Z) d
7.63–7.14 (m, 10H), 5.39 (br, 1H), 5.17 (br, 1H), 4.00 (4H), 3.67
(br, 1H), 3.48 (br, 1H), 2.71 (1H), 1.35 (1H), 1.19 (3H), 0.52 (3H),
0.15 (3H). 19F NMR (CDCl3, 376 MHz) Major rotamer (E) d À71.9;
Minor rotamer (Z) d À69.5. 13C NMR (CDCl3, 100 MHz) d 166.6,
160.1, 153.4, 135.1, 134.0, 132.7, 129.9, 128.7, 128.6, 128.2,
127.5, 126.7, 84.4, 84.1, 63.8, 58.7, 57.8, 56.0, 28.4, 18.0, 17.0, 14.5.
C
30H33N2O4 (MH+): 485.2435, found: 485.2444.
4.2.2. (S)-4-Isopropyl-3-((3S,4S,5R)-5-methyl-3-phenylisoxazoli-
dine-4-carbonyl)oxazolidin-2-one 4
A 100 ml flask was charged with (S)-3-((3S,4S,5R)-2-benzhy-
dryl-5-methyl-3-phenylisoxazolidine-4-carbonyl)-4-isopropylox-
azolidin-2-one 3 (0.0896 g, 0.19 mmol), dry CH2Cl2 (8 ml), TFA
(2 ml), and triethylsilane (0.0596 g, 0.51 mmol). The flask was
flushed with N2 and equipped with a reflux condenser fitted with
a rubber septum and a balloon. The reaction mixture was refluxed
for 3 h and then cooled to room temperature. The flask was placed
into an ice bath after which saturated NaHCO3 was added dropwise
4.3. Computational methods
Monte Carlo conformational sampling, minimization and struc-
ture comparisons were performed of both Mosher derivatives of 4
using the AMBER force field with the programs MacroModel (v.
6.5) and Batchmin (v. 6.5). Dihedral angles were varied randomly
within a range of 0 to 180°. A ring closure distance of 2.0

228
W. Wang et al. / Tetrahedron: Asymmetry 24 (2013) 223–228
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