Absolute configuration assignment of 3-oxindolylacetyl-4- phenyloxazolidinone derivatives

Article abstract of DOI:10.1016/j.tetasy.2011.11.018

The straightforward determination of the absolute configuration of 2-oxo-3-indolylacetic acid derivatives 5a-e, based on analysis of the ¹H NMR spectra of their oxindolylacetyl-phenyloxazolidinones 6a-e, is described. The conformational prefere

Full text of DOI:10.1016/j.tetasy.2011.11.018

Tetrahedron: Asymmetry 22 (2011) 2085–2098
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Tetrahedron: Asymmetry
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Absolute configuration assignment of 3-oxindolylacetyl-4-phenyloxazolidinone
derivatives
Oscar R. Suárez-Castillo a, , Myriam Meléndez-Rodríguez a, Luis E. Castelán-Duarte a,
⇑
Erick A. Zúñiga-Estrada a, Julián Cruz-Borbolla a, Martha S. Morales-Ríos b, Pedro Joseph-Nathan b
a Área Académica de Química, Universidad Autónoma del Estado de Hidalgo, Mineral de la Reforma, Hidalgo 42184, Mexico
b Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado 14-740, Mexico DF, 07000, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
The straightforward determination of the absolute configuration of 2-oxo-3-indolylacetic acid derivatives
5a–e, based on analysis of the 1H NMR spectra of their oxindolylacetyl-phenyloxazolidinones 6a–e, is
described. The conformational preferences for two diastereomeric amides were calculated by DFT, which
matched well with the experimental results, while X-ray diffraction analysis allowed us to validate the
methodology. Independent absolute configuration evidence was also obtained by vibrational circular
dichroism.
Received 21 October 2011
Accepted 30 November 2011
Available online 20 January 2012
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
used for the synthesis of indole derivatives, enolate alkylations, Mi-
chael additions, b-lactams, alkene acylation, cyclopropanations,
Substituted oxindole derivatives 1 (Fig. 1) are of considerable
interest since they are natural products as well as starting materi-
als or intermediate compounds in the total synthesis of terrestrial
and marine natural products containing the furo- and pyrroloin-
dole skeletons 2.1,2 Due to the optical activity of oxindole
derivatives such as 1, suitable and easy methods to assign their
absolute configuration are required. As part of an ongoing effort
to develop improved chiral derivatizing agents (CDAs) for deter-
mining the absolute configuration of oxindole derivatives, we have
recently demonstrated that 1H NMR spectroscopy could be a useful
tool for establishing these assignments in chiral 2-(2-oxo-3-indo-
lyl)acetetamide derivatives 3 (Fig. 2) using enantiomerically pure
phenylethylamine (FEA) as a CDA.3 Experimental data and DFT
calculations demonstrated that the phenyl ring of FEA shields
the N1–R1 group in the (3R,11R)-3 derivatives, whereas, in the
(3S,11R)-3 diastereomers, the shielded group is C3–R2. Thus,
Wittig olefination, and Diels–Alder reactions,4 their use as a CDA
has scarcely been explored. Pirkle and Simmons have achieved
the absolute configuration assignment of primary amines by 1H
NMR via the formation of allophanate derivatives in which the aryl
ring causes specific shielding on the substituents of the amine5a
moiety, while Pridgen and De Brosse have carried out the relative
stereochemical assignments of some N-[a-hetero-b-hydroxy(acet-
oxy)-b-(substituted-phenyl)-10-oxopropyl]-2-oxazolidinones.5b
2. Results and discussion
In order to evaluate the utility of (S)-phenyloxazolidinone 4 as a
CDA for the absolute configuration assignment of the C3 stereogenic
center in 2-oxo-3-indolylacetic acid derivatives 5a–e,2i,l,3,6
containing a variety of substituents at the N1 and C3 positions, dia-
stereomeric oxindolylacetyl-phenyloxazolidinones 6a–e were syn-
thesized according to Scheme 1. Oxindolylacetic acid derivatives
5c,d have been used as intermediates in the total synthesis of natural
products.2i,l,6a,b A derivatization of racemic carboxylic acids 5a–e
into oxazolidinones was carried out by the activation of 5a–e with
dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide (EDC) and 4-dimethylaminopyridine (DMAP),7
followed by the reaction with phenyloxazolidinone (S)-4 to give
equimolar diastereomeric mixtures of (3R,14S)-6a–e and (3S,14S)-
6a–e, as evidenced by 1H NMR analysis of the reaction crudes, which
indicated that no kinetic resolution occurred.8 Diastereomeric phen-
yloxazolidinones (3R,14S)-6a–e and (3S,14S)-6a–e were easily
separated by column chromatography (Table 1) to afford pure iso-
mers with de >99% as determined by 1H NMR measurements.
the
D
dRS parameter allows us to assign the absolute configuration
in diastereomers 3 as shown in Figure 2.
Herein we report that (R)- or (S)-phenyl-2-oxazolidinone 4 could
be a reliable CDA for the absolute configuration assignment of chiral
2-(2-oxo-3-indolyl)acetic acid derivatives regardless of the substit-
uents at the N1- or C3-positions (Scheme 1). One advantage of the
present methodology is that once the absolute configuration at C3
in the oxindolyl moiety has been achieved, the CDA could be recov-
ered after hydrolysis of the corresponding oxazolidinone. Although
aryloxazolidinones are versatile chiral auxiliaries and have been
⇑
Corresponding author. Tel.: +52 771 71 72000x2206; fax: +52 771 71
72000x6502.
E-mail address: osuarez@uaeh.edu.mx (O.R. Suárez-Castillo).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.11.018

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O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 22 (2011) 2085–2098
R2
3a
R2
4
The assumption that aromatic moieties in (S)-oxazolidinyl and
5
R4
oxindolyl fragments influence each other, thus affecting their
chemical shifts at H4–H7 and H16–H20 in 6a–e is reinforced when
considering the d values for the aromatic hydrogen signals in phen-
yloxazolidinone 4 and oxindole derivatives 7 and 82i,10 (Fig. 4). The
chemical shifts for the aromatic hydrogens in these compounds are
more similar to those of the less polar oxazolidinone (3S,14R)-6a
diastereomer, which did not show the mutual aromatic ring aniso-
tropic effect.
R3
6
Y
R3
3
X
O
7a
2
7
N
N
R1
R1
1
2
R1 = H, Me, Bn,
X = O, NH, NMe, NHCH(Me)Ph
Y = O, H
The observed
Dd
RS signs for both 6a diastereomers could be ac-
R2 = H, Me, CH2OH, OH,
3 = H, OMe, Br
4 = OH, CH2OH, CH2NMe2, CH2NO2,
counted for by using the representation proposed in Figure 5,
where the substituent arrangement around C3 and C14 in
(3S,14S)-6a shows that the dominating conformation of the oxazo-
lidinone should be that in which the orientation of the magnetic
anisotropy imposed by both phenyl groups of the (S)-oxazolidinyl
and oxindolyl moieties spends enough time to shield the H4–H7
and H16–H20 signals, whereas H8A is deshielded by the C11
carbonyl group (Fig. 5, A). In the (3R,14S)-6a diastereomer, the
H4–H7, H16–H20, and H8A signals are not affected by both aro-
matic rings, nor by the C11 carbonyl group (Fig. 5, B). Therefore,
the H4–H7 and H16–H20 signals will be more shielded in
(3S,14S)-6a than in (3R,14S)-6a, while the H8A signal should be
more shielded in (3R,14S)-6a than in (3S,14S)-6a.
R
R
NHCbz, CH2COMe, CO2H, CO2Me,
CO2Et, CHO, CN, CONHMe
O
O
N
O
Figure 1.
It has been demonstrated that, in general, N-acyl oxazolidinones
such as 9 are more stable in their s-trans conformation. The zero-
point calculated energy difference of the s-cis and s-trans confor-
mations ranged between 4.30 and 11.92 kcal/mol (Scheme 2).11
Therefore structures (3S,14S)-6a (A) and (3R,14S)-6a (B) in Figure 6
should mainly adopt an s-trans array of the C9@O and C11@O car-
bonyl groups from which the remaining substituents at C8 and C14
protrude. This rigidity could stem from the oxazolidinone ring and
from the dipole–dipole repulsion of the two C9@O and C11@O
carbonyl groups.5,12 Furthermore, it has been found that in
N-acyloxazolidinones of type 9, the barrier to rotation around the
O@C–R2 single bond is lower than that of the (R2)O@C–N bond.
Thus, the free rotation around the C8–C9@O bond generates three
main conformers I–III for both diastereomers of 6a. Conformer I
should be the most populated in both diastereomers due to the
lower steric effects between the oxindolyl and phenyloxazolidinyl
rings. As shown in conformer I for (3S,14S)-6a (A) the mutual
anisotropic shielding of both phenyl rings is present and
consequently an upfield shift of the H4–H7 and H16–H20 signals
should always occur. On the other side, in conformer I such an
interaction was not observed for (3R,14S)-6a (B).
The 1H NMR spectra allowed discrimination of oxazolidinones
(3R,14S)-6a–e and (3S,14S)-6a–e since these compounds showed
large enough chemical shift differences (
D
d
RS = dR ꢀ dS, where the
R and S descriptors refer to the stereogenic C3 configuration in
the oxindole moiety3,9) for the H4–H7, H16–H20 and H8A signals
(Table 2). These significant chemical shift nonequivalences arise
from the mutual diamagnetic influence of the aromatic (S)-oxazo-
lidinone and the oxindole moieties on the NMR signals of their own
hydrogen atoms. Diastereomeric oxazolidinones 6a were used as
representative models to evidence this fact. As shown in Figure 3
with C and D, the signals due to H4–H7 and H16–H20 showed low-
er chemical shift values for the (3S,14S)-6a isomer than for the
(3R,14S)-6a diastereomer (
remarkable
dRS shifts occurred only for the C8AB system, for
which the chemical shift value for H8A is higher in (3S,14S)-6a
than in (3R,14S)-6a, showing
dRS <0 for HA (Fig. 3, A and B,
Dd
RS >0, Table 2). In the aliphatic region,
D
D
Table 2). It is worth noting that the chemical shift for the N1-Me
and C3-Me groups are almost the same in both diastereoisomers,
suggesting at first glance that substituents in those positions do
not influence the mutual anisotropic effect of the aromatic rings.
Considering the polarity of the diastereoisomeric oxazolidinon-
es5 6a (Table 1), it is shown that the H4–H7 and H16–H20 signals
of the more polar (3S,14S)-6a appear at lower frequency values
than those of the less polar (3R,14S)-6a (Fig. 3), while the H8A sig-
nal for the less polar (3R,14S)-6a appears at lower frequency values
than that of the more polar (3S,14S)-6a.
The aforementioned 1H NMR configuration assignment meth-
odology was extended to oxazolidinones with substituents other
than a methyl group at the N1 and C3 positions, including the sub-
strates shown in Table 2; the results confirm the applicability of
the methodology. The
D
dRS values obtained for oxazolidinones
6b–e have the same sign for the H4–H7, H16–H20, and H8A signals
and suggest that oxazolidinones 6b–e adopt similar conformations
H
H
11
R2
R2
4
N
N
8
5
9
3a
Me
Me
O
3
6
O
O
O
N
7a
2
7
N
R1
(3R,11R)-3
R1
R1 and/or R2 = Me, Et, Bn
(3S,11R)-3
ΔδRS R1 = δR1(R) − δR1(S) < 0
ΔδRS R2 = δR2(R) − δR2(S) > 0
Figure 2.

O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 22 (2011) 2085–2098
2087
O
O
13
11
N
R2
4
3a
8
5
9
R2
3
14
CO2H
3
6
O
O
7a
2
1. DCC or EDC, 4-DMAP
7
N
O
N
R1
R1
O
2.
H
(3R,14S)-6a-e
5a-e
N
O
+
a: R1 = R2 = Me
b: R1 = Me, R2 = Bn
O
14
O
(S)-4
R2
3
N
3. column chromatography separation
c: R1 = R2
=
O
O
N
d: R1 = Bn, R2
=
R1
e: R1 = Ph, R2 = Me
(3S,14S)-6a-e
Scheme 1.
Table 1
Rfa values of diastereomeric oxazolidinones 6a–e
fraction. It is worth noting that the s-trans arrays of the C9@O
and C11@O carbonyl groups were always detected as the most sta-
ble conformations, irrespective of the diastereomeric oxazolidi-
none 6a studied. With these results, it becomes evident that the
free rotation around the C8–C9@O single bond (Fig. 6) is the dom-
inating process in both diastereomers. Conformers (3S,14S)-6aA,
6aC, 6aE. and 6aG (Fig. 7) and (3R,14S)-6aA–D (Fig. 8) are depicted
as the most populated in the conformational equilibria for oxazo-
lidinones 6a. It is interesting to note that for oxazolidinone
(3S,14S)-6a, the global minimum structure 6aA (81.4%) has the
phenyl rings pointing toward each other, in exact coincidence with
conformer I presented in Figure 6, trace A. Regarding oxazolidinone
(3R,14S)-6a, three of the most abundant conformers (6aA, 6aB and
6aD 94.7%) show both aromatic rings far from each other, thus
eliminating the mutual anisotropic effect. The global minimum
(3S,14S)-6aA and (3R,14S)-6aB conformers corresponded very well
with those predicted in Figure 6 and with the experimental results.
Thus, computational results reinforce the assignment of the abso-
lute configuration in (3S,14S)-6a and (3R,14S)-6a.
Compound
(3R,14S)-Diastereomer Rf
(3S,14S)-Diastereomer Rf
6a
6b
6c
6d
6e
0.49
0.74
0.72
0.56
0.71
0.23
0.53
0.55
0.28
0.51
a
Determined by TLC (Silica gel F254 coated aluminum sheets 0.25 mm thickness)
using EtOAc/hexanes (1:1, v/v).
at the C8–(C9@O)–N10–C11@O fragment regardless of the substit-
uents at the N1- and C3-positions.
Molecular modeling protocols with Monte Carlo searching13
and geometry optimization using DFT calculations at the B3LYP/
6-31G(d),14 B3LYP/DGDZVP,15 and B3PW91/DGDZVP216 levels of
theory were applied to oxazolidinones (3S,14S)-6a and (3R,14S)-
6a in order to find further evidence to explain the
D
dRS values ob-
served in Figure 6 and Table 2. The Monte Carlo search protocol
The reliability of our methodology for the absolute configura-
tion assignment of oxazolidinones 6a–e by 1H NMR was supported
by X-ray diffraction analysis of oxazolidinones (3S,14S)-6a,
(3S,14S)-6d, (3R,14S)-6e and (3S,14S)-6e, whose structures are
shown in Figure 9 (Table 4). These results validate the assignment
of the absolute configuration of oxazolidinones 6a–e by 1H NMR
using (S)-phenyloxazolidinone 4 as a CDA.
Similarly, when (R)-phenyloxazolidinone (R)-4 was used as a
CDA to resolve the ( )-5a oxazolidinone mixture, (3S,14R)-6a and
(3R,14R)-6a were obtained in a 90% yield (Scheme 3). As expected,
the 1H NMR spectra showed preferential shielding of the H4–H7
and H16–H20 signals and deshielding of the H8A signal for diaste-
reomer (3R,14R)-6a (Table 2), whereas preferential shielding of the
H8A signal and deshielding of H4–H7 and H16–H20 signals were
observed for oxazolidinone (3S,14R)-6a (Table 2). Oxazolidinone
(3R,14R)-6a gave crystals suitable for X-ray diffraction analysis
and the corresponding structure is shown in Figure 9 (Table 4).
With this result in hand, we were able to assign the absolute
configuration of the reported oxazolidinones (3R,14R)-10 and
(3S,14R)-10, which have been used as intermediates in the total
synthesis of (ꢀ)- and (+)-debromoflustramine A 11, respectively
(Scheme 4).20 The relative configuration in (3R,14R)-10 and
(3S,14R)-10 was tentatively assigned by their transformation to
using the MMFF9417 molecular mechanics force field method, as
18
implemented in the SPARTAN04 program, afforded 8 conformers
for oxazolidinone (3S,14S)-6a (6aA–H) and 9 conformers for
(3R,14S)-6a (6aA–I) within 4.1 and 7.6 kcal/mol gaps, respectively
(Table 3). These structures were submitted to geometry optimiza-
tion using DFT calculations at the B3LYP/6-31G(d) level of theory
from which 6 conformers for oxazolidinone (3S,14S)-6a (6aA–C,
6aE–G) and 7 conformers for oxazolidinone (3R,14S)-6a (6aA–E,
6aH,I) accounted for 100% within 2.5 and 4.3 kcal/mol gaps,
respectively. Further successive DFT geometry optimizations were
carried out at the B3LYP/DGDZVP and B3PW91/DGDZVP2 levels of
theory, respectively, as implemented in the GAUSSIAN 03W19 program,
giving 4 conformers for both (3S,14S)-6a (6aA, 6aC, 6aE, 6aG) and
(3R,14S)-6a (6aA–D) oxazolidinones, which are shown in Figures 7
and 8, respectively, while their relative energies are shown in
Table 3. The population of each conformational species was esti-
mated using the thermochemical parameters in the conforma-
tional equilibrium using the
D
G =
D
H ꢀ T
D
S and
D
G = ꢀRTlnK
equations (Table 3).3 For conformational equilibria of both
(3S,14S)-6a and (3R,14S)-6a diastereomers, equations K1,2 = n2/n1,
K2,3 = n3/n2, K3,4 = n4/n3, and n1 + n2 + n3 + n4 = 1 were used, where
Ki,j stands for the equilibria constants and ni stands for the molar

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O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 22 (2011) 2085–2098
Table 2
Significant
D
dRS values for (3R,14S)-6a–e–(3S,14S)-6a–e and (3R,14R)-10–(3S,14R)-1020 and
D
dSR values for (3S,14R)-6a–(3R,14R)-6aa
O
O
O
O
O
-0.12
O
N
0.02
-0.17
0.08
Me
-0.11
0.02
0.02
0.12
N
N
0.03
0.32
0.03
O
0.35
O
O
O
N
O
O
N
0.11
Me
N
0.12
6a
Me
0.03
6b
6c
O
O
O
O
-0.12
0.02
N
-0.22
0.12
Me
N
N
0.02
O
O
0.03
O
0.14
O
N
0.12
6e
6d
O
O
O
O
-0.15
0.14
-0.12
0.02
N
N
Me
0.02
0.06
0.32
0.45
O
O
O
O
N
N
0.12
0.16
Me
6a
10
a
D
dRS Values (dR ꢀ dS) were obtained by subtracting the 1H chemical shifts of (3S)-oxyndolyl–(14S)-oxazolidinone from those of (3R)-oxyndolyl–(14S)-oxazolidinone A
while
D
d
SR values (dS ꢀ dR) were obtained by subtracting the 1H chemical shifts of (3R)-oxyndolyl–(14R)-oxazolidinone from those of (3S)-oxyndolyl-(14R)-oxazolidinone B.3,9
(ꢀ)-11 and (+)-11, respectively. The stereochemistry of (ꢀ)-11 was
elucidated by comparing specific rotations of known pyrrolo[2,3-
b]indole compounds, for example, (ꢀ)-flustramines and (ꢀ)-physo-
stigmine, although this is not necessarily a completely safe com-
parison methodology as evidenced recently.21 According to the
aforementioned methodology, for the (3R,14R)-10 diastereomer,
the H4–H7 and H16–H20 signals are deshielded whereas the
H8A signal is shielded.20 On the contrary, in diastereomer
(3S,14R)-10 the H4–H7 and H16–H20 signals are shielded while
H8A is deshielded. Thus, considering our NMR methodology, the
absolute configurations of the reported oxazolidinones (3R,14R)-
10 and (3S,14R)-10 are those shown in Scheme 4. It is worth noting
that although the absolute configuration at C3 in (3R,14R)-6a and
(3S,14R)-10 are opposite, due to proper application of the Cahn-In-
gold-Prelog sequence rule,22 the spatial relationship of the methyl -
methyl and -dimethylallyl groups with respect to the phenyl ring
at C14 is the same in these compounds, allowing mutual aniso-
tropic effect of both aryl rings.
Boltzmann-averaged to generate the calculated spectrum which
was plotted using Lorentzian bandshapes and bandwidths of
6 cmꢀ1. The calculated IR and VCD spectra of (3S,14S)-6a and
(3R,14S)-6a showed good agreement with those obtained exper-
imentally (Figs. 10 and 11). In order to avoid bias when assess-
ing the degree of agreement between computed and
experimental spectra by visual inspection, quantitative evalua-
tion of this concordance was achieved by applying a recently
developed confidence level algorithm (BioTools Co., Jupiter, FL
33458, USA) which calculates the integrated overlap of the
experimental and theoretical data as a function of a relative
shift.23 Application of this procedure allowed us to obtain the
anharmonicity factor (anH = 0.975), and the VCD spectral similar-
ity for the correct (SE = 75.4%) and the incorrect enantiomer
(SꢀE = 20.4%) with a 100% confidence level for the absolute con-
figuration determination of (3S,14S)-6a oxazolidinone, while for
the (3R,14S)-6a diastereomer anH = 0.972, SE = 83.4%, and
SꢀE = 13.4% with a 100% confidence level for the absolute config-
To further substantiate our assignments, the absolute config-
urations of (3S,14S)-6a and (3R,14S)-6a were independently
determined using vibrational circular dichroism (VCD) spectros-
copy. Thus, for both diastereomers the vibrational frequencies
and IR and VCD intensities were calculated at the B3PW91/
DGDZVP216 level of theory. The calculations involve the genera-
tion of weighted-averaged vibrational plots including conformers
6aA, 6aC, 6aE, and 6aG for (3S,14S)-6a oxazolidinone and
conformers 6aA–D for diastereomer (3R,14S)-6a. The VCD
frequencies of these major conformers were calculated and
uration determination were obtained. These results undoubtedly
allow us to conclude that 1H NMR is a reliable method for the
absolute configuration assignment of oxindoles such as
(3S,14S)-6a and (3R,14S)-6a.
3. Conclusions
We have demonstrated that the absolute configuration assign-
ment of 2-(2-oxo-3-indolyl)acetic acid derivatives 5 could be
achieved by its derivatization with either commercially available

O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 22 (2011) 2085–2098
2089
Figure 3.
enantiomer of 4-phenyl-2-oxazolidinone (S)-4 or (R)-4 followed by
1H NMR analysis of the corresponding oxazolidinones 6. A general
assumption could be made for the configuration assignment as fol-
lows: (3S,14S)- or (3R,14R)-stereoisomers of oxazolidinones of type
6 will present the H4–H7 and H16–H20 signals at lower frequency
values (+
D
dRS or +
D
d
SR) and the H8A signal at a higher frequency
Dd
SR) when compared to their corresponding
value (ꢀ
D
dRS or ꢀ
(3R,14S)- and (3S,14R)-diastereomers. The results were indepen-
dently confirmed by X-ray diffraction analysis, VCD
measurements, and calculations.

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O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 22 (2011) 2085–2098
R2
O
O
O
O
3.01
3.02
H
7.16
R2
N
O
N
O
7.19
O
Me 2.89
2.89
N
O
7.03
7.27
6.99
7.22
CO2H
CO2H
R1
R1
O
O
s-cis-9
s-trans-9
N
N
6.78
6.86
R1 = H, Me, Bn, Ph, etc.
7.26-7.40
Me
R
2 = Me, Et, Pr, i-Pr, t-Bu, etc.
4
7
Scheme 2.
8
Figure 4. Aromatic 1H chemical shifts (in ppm) for 4, 7 and 8 in CDCl3.
chromatography was done using Silica Gel 60 (230–400 mesh)
from Aldrich.
4. Experimental
4.2. General procedure for the preparation of diastereomeric
amides 6a–e
4.1. General experimental procedures
Melting points were determined on a Büchi B-540 apparatus. IR
spectra were recorded on a Perkin–Elmer 2000 FT-IR spectropho-
tometer. The 400 and 100 MHz 1H and 13C NMR spectra were
obtained on JEOL Eclipse +400 and on Varian VNMRS 400 spec-
trometers, while the 300 and 75 MHz 1H and 13C NMR spectra were
obtained on a Varian Mercury-300 spectrometer using CDCl3 as
solvent and TMS as the internal reference. For complete assign-
ments gHMQC, gHSQC, and gHMBC spectra were measured. Data
are reported as follows: chemical shift in ppm from TMS, integra-
tion, multiplicity (s = singlet, d = doublet, t = triplet, sp = septet,
AB = AB system, m = multiplet, br = broad), coupling constant
(Hz), and assignment. GC/MS analyses were conducted on a Varian
CP 3800 GC equipped with a Varian Saturn 2000 selective mass
detector and a 30 m, 0.25 mm i.d., 0.25 mm CP-SIL capillary
column, using helium as a carrier gas (1 mL/min), programed from
70 °C to 250 °C at a rate of 30 °C/min, with the injector temperature
at 200 °C. MS were obtained in the electron impact (EI) mode at an
ionizing voltage of 70 eV on a Hewlett Packard 5989-A spectrome-
ter. High-resolution (HR) mass spectra were measured on a JEOL
JMS-SX 102A mass spectrometer at the Instituto de Química,
UNAM-México. Optical rotation measurements were performed
A solution of the appropriate acids 5a–d (3.20 mmol), 5e
(0.36 mmol), (S)-(+)-4-phenyl-2-oxazolidinone (S)-4 (0.52 g,
3.2 mmol for 5a–d and 0.06 g, 0.36 mmol for 5e), 4-DMAP (0.17 g,
1.4 mmol for 5a–d and 0.017 g, 0.14 mmol for 5e) and DCC
(0.76 g, 3.68 mmol) in CH2Cl2 (20 mL) for 5a–d or EDCꢁHCl (0.08 g,
0.43 mmol) in toluene (20 mL) for 5e was stirred for 24 h at rt
and then at reflux for 2.5 h for 5a–d and at reflux for 2 h for 5e. After
cooling to room temperature, the reaction mixture was filtered and
the solvent evaporated. The residue 6e was diluted with CH2Cl2
(40 mL) and washed with water (2 ꢂ 10 mL), an aqueous solution
of HCl (1 M, 2 ꢂ 10 mL) and a saturated aqueous solution of NaH-
CO3 (2 ꢂ 20 mL), dried over Na2SO4, filtered, and evaporated. The
residues 6a–e were purified by flash column chromatography on
silica gel with EtOAc/hexanes 2:3 for 6a and 6b, with EtOAc/hex-
anes 1:2 for 6c–6d and with EtOAc/hexanes 2:1 for 6e.
4.2.1. (S)-3-(2-((R)-1,3-Dimethyl-2-oxoindolin-3-yl)acetyl)-4-
phenyloxazolidin-2-one (3R,14S)-6a
Prepared from 5a as a white solid (0.23 g, 45%), mp: 197–198 °C
(MeOH). ½a 2D0
ꢃ
¼ þ118:7 (c 0.81, CHCl3). 1H NMR (400 MHz, CDCl3):
d 7.35–7.27 (3H, m, H17–H19), 7.26 (1H, td, J = 7.7, 1.1 Hz, H6),
7.13 (3H, m, H4, H16, H20), 7.00 (1H, td, J = 7.6, 1.0 Hz, H5), 6.83
(1H, d, J = 7.7 Hz, H7), 5.16 (1H, dd, J = 8.8, 3.3 Hz, H14), 4.52 (1H,
t, J = 8.8 Hz, H13A), 4.14 (1H, dd, J = 8.8, 3.3 Hz, H13B), 3.90 and
3.37 (2H, AB, J = 17.4 Hz, H8), 3.16 (3H, s, H21), 1.39 (3H, s, H22);
on
chromatography (TLC) was done on silica gel F254 coated aluminum
sheets (0.25 mm thickness) with fluorescent indicator.
a
Perkin–Elmer 341 polarimeter. Analytical thin-layer
a
Visualization was accomplished with UV light (254 nm). Flash
O
O
H
N
O
Me
3
Me
14
H
8
B
3
O
N
14
O
O
O
2
N
N
O
Me
Me
(3R,14S)-6a
O
O
O
N
H
N
O
4
Me
3
14
Me
O
5
H
16
17
8
2
A
3
14
O
6
20
19
O
N
O
N
Me
7
+
+
18
+
+
+
+
+
Me
+
+
+
+
+
(3S,14S)-6a
Figure 5.

O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 22 (2011) 2085–2098
2091
Me
N
Me
N
O
O
O
O
H
H
O
I
I
N
N
Me
Me
H
H
O
H
H
O
O
O
O
H
H
H
N
H
Me
Me
O
N
N
II
II
H
O
H
O
O
O
O
N
Me
Me
O
H
O
H
9
H
Me
8
9
O
H
N
8
14
10
N
14
10
H
O
11
Me
III
III
N
11
H
O
O
O
Me
O
N
Me
A
B
Figure 6. Preferred conformations of (3S,14S)-6a (A) and (3R,14S)-6a (B) phenyloxazolidinones.
13C NMR (100 MHz, CDCl3): d 179.6 (C2), 168.7 (C9), 153.8 (C11),
143.6 (C7a), 138.4 (C15), 133.2 (C3a), 129.1 (2C, C17, C19), 128.5
(C18), 127.9 (C6), 125.5 (2C, C16, C20), 122.1 (C5), 121.7 (C4),
108.1 (C7), 70.0 (C13), 57.1 (C14), 45.4 (C3), 42.0 (C8), 26.3
(C21), 24.6 (C22); IR (KBr) mmax 3053, 3034, 2972, 2926, 1787,
1719, 1613, 1495, 1472, 1454 cmꢀ1; EIMS m/z (relative intensity)
364 ([M]+, 100), 186 (30), 174 (48), 160 (46); FABHRMS m/z calcd
for C21H20N2O4 ([M]+): 364.1423, found: 364.1416.
100), 186 (22), 174 (18), 160 (16); FABHRMS m/z calcd for
21H20N2O4 ([M]+): 364.1423, found: 364.1415.
C
4.2.3. (S)-3-(2-((R)-1,3-Dimethyl-2-oxoindolin-3-yl)acetyl)-4-
phenyloxazolidin-2-one (3S,14R)-6a
Prepared from 5a and (R)-(ꢀ)-4-phenyl-2-oxazolidinone (R)-4
as colorless crystals (0.23 g, 45%), mp: 198–199 °C (MeOH).
½
a 2D0
ꢃ
¼ ꢀ120:0 (c 0.69, CHCl3). Spectroscopic data are identical with
those of its (3R,14S)-6a enantiomer.
4.2.2. (S)-3-(2-((S)-1,3-Dimethyl-2-oxoindolin-3-yl)acetyl)-4-
phenyloxazolidin-2-one (3S,14S)-6a
4.2.4. (R)-3-(2-((R)-1,3-Dimethyl-2-oxoindolin-3-yl)acetyl)-4-
phenyloxazolidin-2-one (3R,14R)-6a
Prepared from 5a as colorless crystals (0.23 g, 45%), mp: 172–
173 °C (CH2Cl2).
½
a 2D0
ꢃ
¼ þ184:3 (c 1.08, CHCl3). 1H NMR
Prepared from 5a and (R)-(ꢀ)-4-phenyl-2-oxazolidinone
(300 MHz, CDCl3): d 7.22–7.10 (5H, m, H4, H6, H17–H19), 6.98
(1H, td, J = 7.5, 0.8 Hz, H5), 6.81 (2H, m, H16, H20), 6.71 (1H, dd,
J = 8.2, 0.7 Hz, H7), 5.22 (1H, br dd, J = 8.5, 3.5 Hz, H14), 4.52 (1H,
br t, J = 8.7 Hz, H13A), 4.05 (1H, m, H13B), 4.02 and 3.35 (2H, AB,
J = 17.1 Hz, H8), 3.13 (3H, s, H21), 1.38 (3H, s, H22); 13C NMR
(75 MHz, CDCl3): d 179.9 (C2), 168.6 (C9), 153.6 (C11), 143.5
(C7a), 138.2 (C15), 132.8 (C3a), 128.8 (2C, C17, C19), 128.0 (C18),
127.9 (C6), 125.0 (2C, C16, C20), 122.0 (C5), 121.8 (C4), 108.1
(C7), 69.9 (C13), 57.0 (C14), 45.6 (C3), 41.7 (C8), 26.2 (C21), 24.6
(C22); IR (film) mmax 3057, 3009, 2969, 2928, 1779, 1710, 1614,
1495, 1472, 1453 cmꢀ1; EIMS m/z (relative intensity) 364 ([M]+,
(R)-4 as colorless crystals (0.23 g, 45%), mp: 172–173 °C (CH2Cl2).
½
a 2D0
ꢃ
¼ ꢀ183:5 (c 0.68, CHCl3). Spectroscopic data are identical with
those of its (3S,14S)-6a enantiomer.
4.2.5. (S)-3-(2-((R)-3-Benzyl-1-methyl-2-oxoindolin-3-
yl)acetyl)-4-phenyloxazolidin-2-one (3R,14S)-6b
Prepared from 5b as white crystals (0.26 g, 42%), mp:
190–191 °C (CH2Cl2/MeOH). ½a D20
ꢃ
¼ þ138:9 (c 1.82, CHCl3). 1H
NMR (300 MHz, CDCl3):
d
7.37–7.00 (10H, m, H4, H6,
H16–H20, H25–H27), 6.97 (1H, td, J = 7.4, 1.0 Hz, H5), 6.78

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O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 22 (2011) 2085–2098
Table 3
Thermochemical analysis for oxazolidinones (3S,14S)-6a and (3R,14S)-6a
a
c
e
g
Conformer
D
EMMFF
%MMFFb
D
EDFT
%DFTd
D
GOPT
%OPTf
D
GOPT
%OPTh
(3S,14S)-6a
6aA
6aB
6aC
6aD
6aE
6aF
6aG
6aH
0
57.0
26.3
10.5
4.4
1.0
0.4
0.79
0
0.20
—
0.54
1.98
2.45
—
10.8
41.1
29.5
—
16.5
1.5
0
—
1.40
—
0.76
—
74.3
—
6.6
—
18.9
—
0.2
—
0
—
2.20
—
0.91
—
81.4
—
1.8
—
16.7
—
0.1
—
0.46
1.00
1.52
2.40
3.01
3.04
4.09
0.3
0.1
0.7
—
3.39
—
4.15
—
(3R,14S)-6a
6aA
6aB
6aC
6aD
6aE
6aF
6aG
6aH
0
96.3321
1.4079
0.7427
0.7207
0.3639
0.3160
0.0724
0.0441
0.0003
0
63.77
17.54
5.71
11.79
1.05
—
—
0.05
0.09
0.48
0
0.75
0.76
2.24
—
—
—
3.66
23.1
48.4
13.6
13.6
1.1
—
—
—
0.1
1.04
0
1.50
0.87
—
—
—
—
—
12.4
67.0
5.3
15.3
—
—
—
—
—
2.50
2.88
2.90
3.31
3.39
4.26
4.56
7.59
0.76
1.43
1.00
2.43
—
—
4.27
3.88
6aI
a
b
c
Molecular mechanics energies relative to (3S,14S)-6aA with EMMFF = ꢀ16.613 kcal/mol or relative to (3R,14S)-6aA with EMMFF = ꢀ17.878 kcal/mol.
Population in % calculated from the MMFF energies according to
EMMFF ꢄ ꢀRTlnK.
D
Single point B3LYP/6-31G(d) energies relative to (3S,14S)-6aB with E6-31G(d) ꢄ ꢀRTlnK = ꢀ767280.695 kcal/mol or relative to (3R,14S)-6aA with E6-
31G(d) ꢄ ꢀRTlnK = ꢀ767281.432 kcal/mol.
d
Population in % calculated from B3LYP/6-31G(d) energies according to
D
E6-31G(d) ꢄ ꢀRTlnK.
e
Gibbs free energies relative to (3S,14S)-6aA with GB3LYP/DGDZVP = ꢀ767160.601 kcal/mol or relative to (3R,14S)-6aB with GB3LYP/DGDZVP = ꢀ767160.701 kcal/mol.
f
g
h
Population in % calculated from B3LYP/DGDZVP energies according to
Gibbs free energies relative to (3S,14S)-6aA with GB3PW91/DGDZVP2 = ꢀ766949.457 kcal/mol or relative to (3R,14S)-6aB with GB3PW91/DGDZVP2 = ꢀ766949.517 kcal/mol.
Population in % calculated from B3PW91/DGDZVP2 energies according to
G = ꢀRTlnK.
D
G = ꢀRTlnK.
D
Figure 7. Optimized geometries for (3S,14S)-6aA, 6aC, 6aE and 6aG conformers using DFT calculations at the B3PW91/DGDZVP2 level of theory.
(2H, dd, J = 7.8, 1.7 Hz, H24, H28), 6.54 (1H, br d, J = 7.6 Hz, H7),
5.18 (1H, dd, J = 8.6, 3.5 Hz, H14), 4.53 (1H, dd, J = 8.7 Hz, H13A),
4.15 (1H, dd, J = 8.8, 3.5 Hz, H13B), 4.03 and 3.53 (2H, AB,
J = 17.4 Hz, H8), 3.07 (2H, s, H22), 2.87 (3H, s, H21); 13C NMR
(75 MHz, CDCl3): d 178.2 (C2), 168.6 (C9), 153.9 (C11), 144.2
(C7a), 138.4 (C15), 134.7 (C23), 130.4 (C3a), 130.0 (2C, C24,

O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 22 (2011) 2085–2098
2093
Figure 8. Optimized geometries for (3R,14S)-6aA–D conformers using DFT calculations at the B3PW91/DGDZVP2 level of theory.
C28), 129.1 (C17, C19), 128.6 (C18), 128.1 (C6), 127.4 (2C, C25,
C27), 126.6 (C26), 125.5 (2C, C16, C20), 122.7 (C4), 121.7 (C5),
107.8 (C7), 70.1 (C13), 57.1 (C14), 51.2 (C3), 44.1 (C22), 41.0
(C8), 25.9 (C21); IR (film) mmax 3060, 3031, 2921, 1780, 1708,
4.81 (1H, tm, J = 7.7 Hz, H27), 4.51 (1H, br t, J = 8.8 Hz, H13A),
4.33 (1H, dd, J = 15.8, 6.6 Hz, H21A), 4.18–4.10 (2H, m, H13B,
H21B), 3.93 and 3.40 (2H, AB, J = 17.6 Hz, H8), 2.49 (1H, dd,
J = 13.6, 7.4 Hz, H26A), 2.44 (1H, dd, J = 13.7, 7.5 Hz, H26B), 1.74
(3H, s, H24), 1.65 (3H, s, H25), 1.57 (3H, s, H29), 1.47 (3H, s,
H30); 13C NMR (100 MHz, CDCl3): d 178.4 (C2), 168.7 (C9), 153.8
(C11), 143.5 (C7a), 138.5 (C15), 136.1 (C28), 135.7 (C23), 131.6
(C3a), 128.5 (2C, C17, C19) 127.7 (C18), 127.7 (C6), 125.6 (2C,
C16, C20), 122.2 (C4), 121.6 (C5), 118.8 (C22), 116.9 (C27), 108.3
(C7), 70.0 (C13), 57.1 (C14), 49.6 (C3), 40.8 (C8), 37.9 (C21), 36.7
(C26), 25.8 (C29), 25.8 (C25), 18.0 (C24), 17.9 (C30); IR (KBr) mmax
3036, 2965, 2919, 2855, 1793, 1724, 1611, 1489, 1467,
1436 cmꢀ1; EIMS m/z (relative intensity) 472 ([M]+, 7), 404 (100),
267 (57), 242 (77), 215 (32), 185 (54), 172 (34), 158 (24), 145
(19), 69 (22), 41 (34); FABHRMS m/z calcd for C29H32N2O4 (M+):
472.2362, found: 472.2361.
1613, 1495, 1471, 1455 cmꢀ1
;
EIMS m/z (relative intensity)
440 ([M]+, 13), 186 (100), 91 (10); FABHRMS m/z calcd for
27H24N2O4 ([M]+): 440.1736, found: 440.1744.
C
4.2.6. (S)-3-(2-((S)-3-Benzyl-1-methyl-2-oxoindolin-3-yl)-
acetyl)-4-phenyloxazolidin-2-one (3S,14S)-6b
Prepared from 5b as white crystals (0.26 g, 42%), mp: 168–
169 °C (EtOAc/hexane). ½a D20
ꢃ
¼ þ183:7 (c 1.26, CHCl3). 1H NMR
(300 MHz, CDCl3): d 7.15–7.00 (8H, m, H4, H6, H17–H19, H25–
H27), 6.94 (1H, br t, J = 7.4 Hz, H5), 6.81–6.74 (4H, m, H16, H20,
H24, H28), 6.42 (1H, br d, J = 7.6 Hz, H7), 5.20 (1H, br dd, J = 8.4,
3.3 Hz, H14), 4.50 (1H, br t, J = 8.0 Hz, H13A), 4.14 and 3.51 (2H,
AB, J = 17.2 Hz, H8), 4.03 (1H, br dd, J = 8.8, 3.5 Hz, H13B), 3.06
(2H, s, H22), 2.84 (3H, s, H21); 13C NMR (75 MHz, CDCl3): d 178.4
(C2), 168.5 (C9), 153.7 (C11), 144.0 (C7a), 138.1 (C15), 134.6
(C23), 130.0 (C3a), 129.9 (2C, C24, C28) 128.7 (2C, C17, C19),
127.9 (2C, C6, C18), 127.3 (2C, C25, C27), 126.5 (C26), 124.9 (C16,
C20), 122.6 (C4), 121.5 (C5), 107.7 (C7), 69.9 (C13), 57.0 (C14),
51.3 (C3), 44.2 (C22), 40.8 (C8), 25.8 (C21); IR (film) mmax 3060,
3030, 2918, 1780, 1709, 1614, 1495, 1471, 1455 cmꢀ1; EIMS m/z
(relative intensity) 440 ([M]+, 13), 186 (100), 91 (10); FABHRMS
m/z calcd for C27H24N2O4 ([M]+): 440.1736, found: 440.1737.
4.2.8. (S)-3-(2-((S)-1,3-Bis(3-methylbut-2-enyl)-2-oxoindolin-3-
yl)acetyl)-4-phenyloxazolidin-2-one (3S,14S)-6c
Prepared from 5c as a colorless oil (0.28 g, 42%). ½a D20
¼ þ91:0 (c
ꢃ
1.01, CHCl3). 1H NMR (300 MHz, CDCl3): d 7.18 (1H, ddd, J = 7.3, 1.2,
0.5 Hz, H4), 7.17–7.10 (4H, m, H6, H17–H19), 6.93 (1H, td, J = 7.5,
1.0 Hz, H5), 6.79 (2H, m, H16, H20), 6.63 (1H, ddd, J = 7.7, 1.0,
0.5 Hz, H7), 5.23 (1H, dd, J = 8.6, 3.6 Hz, H14), 4.97 (1H, tsp,
J = 6.5, 1.4 Hz, H22), 4.82 (1H, tsp, J = 7.6, 1.4 Hz, H27), 4.55 (1H,
dd, J = 8.7 Hz, H13A), 4.38 (1H, br dd, J = 15.8, 6.2 Hz, H21A), 4.10
(1H, br dd, J = 15.5, 6.3 Hz, H21B), 4.07 (1H, dd, J = 8.4, 4.1 Hz,
H13B), 4.10 and 3.32 (2H, AB, J = 16.9 Hz, H8), 2.50 (1H, dd,
J = 13.7, 7.3 Hz, H26A), 2.47 (1H, dd, J = 13.7, 7.7 Hz, H26B), 1.76
(3H, d, J = 0.9 Hz, H24), 1.65 (3H, d, J = 0.9 Hz, H25), 1.56 (3H, d,
J = 1.0 Hz, H29), 1.46 (3H, d, J = 1.2 Hz, H30); 13C NMR (75 MHz,
CDCl3): d 178.6 (C2), 168.7 (C9), 153.7 (C11), 143.5 (C7a), 138.3
(C15), 136.0 (C28), 135.4 (C23), 131.0 (C3a), 128.8 (2C, C17, C19)
127.9 (C18), 127.7 (C6), 125.0 (2C, C16, C20), 122.5 (C4), 121.6
(C5), 119.0 (C22), 116.9 (C27), 108.5 (C7), 69.9 (C13), 57.2 (C14),
4.2.7. (S)-3-(2-((R)-1,3-Bis(3-methylbut-2-enyl)-2-oxoindolin-3-
yl)acetyl)-4-phenyloxazolidin-2-one (3R,14S)-6c
Prepared from 5c as a white solid (0.28 g, 42%), mp: 122–123 °C
(Et2O/hexane). ½a D20
ꢃ
¼ þ90:0 (c 1.34, CHCl3). 1H NMR (400 MHz,
CDCl3): d 7.35–7.25 (3H, m, H17–H19), 7.20 (1H, br t, J = 7.7 Hz,
H6), 7.14 (2H, br d, J = 8.0 Hz, H16, H20), 7.11 (1H, dd, J = 7.3,
0.7 Hz, H4), 6.96 (1H, t, J = 7.5, H5), 6.74 (1H, br d, J = 7.7 Hz, H7),
5.15 (1H, dd, J = 8.6, 3.5 Hz, H14), 5.02 (1H, tm, J = 6.6 Hz, H22),

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O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 22 (2011) 2085–2098
(3R,14R)-6a
(3S,14S)-6a
(3R,14S)-6e
(3S,14S)-6d
(3S,14S)-6e
Figure 9. X-ray diffraction structures of (3S,14S)-6a, (3R,14R)-6a, (3S,14S)-6d, (3R,14S)-6e and (3S,14S)-6e.
50.0 (C3), 40.8 (C8), 38.0 (C21), 36.8 (C26), 25.8 (C29), 25.5 (C25),
J = 7.6 Hz, H7), 5.12 (1H, dd, J = 8.6, 3.6 Hz, H14), 4.88 and 4.77
(2H, AB, J = 15.9 Hz, H21), 4.84 (1H, tsp, J = 7.8, 1.4 Hz, H29), 4.46
(1H, br t, J = 8.7 Hz, H13A), 4.11 (1H, dd, J = 8.9, 3.7 Hz, H13B),
3.95 and 3.49 (2H, AB, J = 17.7 Hz, H8), 2.53 (2H, d, J = 7.6 Hz,
H28), 1.58 (3H, d, J = 0.7 Hz, H31), 1.50 (3H, d, J = 1.0 Hz, H32);
13C NMR (75 MHz, CDCl3): d 179.0 (C2), 168.7 (C9), 153.8 (C11),
143.4 (C7a), 138.4 (C15), 136.3 (C30), 136.0 (C22), 131.4 (C3a),
129.0 (2C, C17, C19), 128.5 (C18), 128.4 (2C, C24, C26), 127.7
(C6), 127.2 (2C, C23, C27), 127.1 (C25), 125.6 (2C, C16, C20),
122.1 (C4), 121.8 (C5), 116.9 (C29), 108.8 (C7), 69.9 (C13), 57.1
(C14), 49.7 (C3), 43.7 (C21), 41.2 (C8), 36.9 (C28), 25.8 (C31),
17.9 (C32); IR (film) mmax 3061, 3031, 2972, 2917, 2857, 1780,
1710, 1614, 1490, 1466, 1456 cmꢀ1; EIMS m/z (relative intensity)
18.0 (C24), 17.9 (C30); IR (film) mmax 3057, 3033, 2917, 2856, 1781,
1709, 1611, 1489, 1467, 1456 cmꢀ1; EIMS m/z (relative intensity)
472 ([M]+, 8), 404 (100), 267 (49), 241 (51), 185 (16), 172 (14),
158 (12), 145 (13); FABHRMS m/z calcd for C29H32N2O4 (M+):
472.2362, found: 472.2361.
4.2.9. (S)-3-(2-((R)-1-Benzyl-3-(3-methylbut-2-enyl)-2-oxoind
olin-3-yl)acetyl)-4-phenyloxazolidin-2-one (3R,14S)-6d
Prepared from 5d as a yellow solid (0.30 g, 43%), mp: 74–75 °C.
½
a 2D0
ꢃ
¼ þ119:8 (c 1.09, CHCl3). 1H NMR (300 MHz, CDCl3): d 7.37–
7.10 (11H, m, H4, H16–H20, H23–H27), 7.08 (1H, td, J = 7.8,
1.3 Hz, H6), 6.93 (1H, td, J = 7.5, 0.9 Hz, H5), 6.60 (1H, br d,

O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 22 (2011) 2085–2098
2095
Table 4
Crystal data for (3S,14S)-6a, (3R,14R)-6a, (3S,14S)-6d, (3R,14S)-6e and (3S,14S)-6e
(3S,14S)-6a
21H20N2O4
(3R,14R)-6a
(3S,14S)-6d
(3R,14S)-6e
(3S,14S)-6e
Empirical formula
Formula weight
Crystal size (mm)
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions (Å)
a
C
C21H20N2O4
364.39
C31H30N2O4
494.57
C26H22N2O4
426.46
C26H22N2O4
426.46
364.39
0.40 ꢂ 0.38 ꢂ 0.20
0.36 ꢂ 0.28 ꢂ 0.16
0.38 ꢂ 0.32 ꢂ 0.32
0.13 ꢂ 0.35 ꢂ 0.6
0.35 ꢂ 0.33 ꢂ 0.12
1.54184
1.54184
1.54184
0.71073
1.54184
Orthorhombic
P212121
Orthorhombic
P212121
Monoclinic
P21
Orthorhombic
P212121
Orthorhombic
P21212
6.874(1)
13.117(3)
20.458(4)
90
1844.7(6)
4, 1.312
6.862(5)
13.123(2)
20.484(1)
90
1844.0(1)
4, 1.312
7.1305(9)
11.015(1)
16.860(4)
93.8(1)
1321.3(4)
2, 1.243
6.8409(1)
11.8744(2)
25.5360(4)
90
2074.33(6)
4, 1.366
21.7953(6)
15.0159(3)
6.5806(2)
90
2153.7(1)
4, 1.315
b
c
b (°)
Volume (Å3)
Z, Calculated density
(mg/mm3)
Absorption coefficient
0.751
0.751
0.661
0.093
0.727
(mmꢀ1
)
F(000)
768
768
524
896
896
h Range for data
4.32–59.87
4.32–59.97
2.53–59.95
1.59–26.26
3.57–73.74
collection (°)
Limiting indices
0 6 h 6 7, 0 6 k 6 14,
2 6 l 6 22
1477 [R(int) = 0.0001]
1411
87.9
1356/0/248
0 6 h 6 7, 0 6 k 6 14,
ꢀ2 6 l 6 22
1497 [R(int) = 0.0001]
1422
88.2
1294/0/248
ꢀ8 6 h 6 7, 0 6 k 6 12,
0 6 l 6 18
2223 [R(int) = 0.0001]
2064
88.4
1956/0/342
ꢀ8 6 h 6 8, 0 6 k 6 14,
0 6 l 6 31
16,832 [R(int) = 0.0001]
4109
98.6
3927/0/295
ꢀ26 6 h 6 26, ꢀ18 6 k 6 18,
ꢀ6 6 l 6 7
19,893 [R(int) = 0.0255]
4261
Collected reflections
Unique reflections
Completeness to h (%)
Data/restraints/
98.6
3656/0/294
parameters
Goodness-of-fit on F2
1.058
1.060
1.048
1.033
1.085
Final R indices [I > 2
r(I)] R1 = 3.4, wR2 = 8.9
R1 = 3.5, wR2 = 9.2
R1 = 3.1, wR2 = 8.9
R1 = 2.7, wR2 = 6.1
R1 = 3.8, wR2 = 8.6
(%)
R indices (all data) (%)
Largest diff. peak and
hole (e Å3)
R1 = 3.4, wR2 = 9.6
0.111 and ꢀ0.092
R1 = 4.0, wR2 = 9.5
0.108 and ꢀ0.118
R1 = 3.3, wR2 = 9.0
0.097 and ꢀ0.083
R1 = 2.9, wR2 = 6.3
0.156 and ꢀ0.146
R1 = 4.8, wR2 = 9.2
0.138 and ꢀ0.180
CCDC No.
858993
858994
858995
858996
858997
O
O
13
11
N
4
Me
3a
8
5
9
14
3
6
O
O
7a
2
7
N
Me
Me
3
CO2H
(3S,14R)-6a
1. DCC, 4-DMAP
+
O
N
O
2.
O
14
O
H
Me
N
O
N
Me
3
( )-5a
O
O
N
Me
(R)-4
3. column chromatography separation
(3R,14R)-6a
Scheme 3.
494 ([M]+, 1), 428 (28), 426 (100), 290 (35), 264 (34), 263 (20), 236
(19), 91 (34); FABHRMS m/z calcd for C31H30N2O4 ([M]+): 494.2206,
found: 494.2197.
dd, J = 8.6, 3.7 Hz, H14), 5.06 and 4.64 (2H, AB, J = 16.0 Hz, H21),
4.84 (1H, tsp, J = 7.6, 1.4 Hz, H29), 4.57 (1H, t, J = 8.7 Hz, H13A),
4.17 and 3.37 (2H, AB, J = 16.7 Hz, H8), 4.09 (1H, dd, J = 8.8,
3.7 Hz, H13B), 2.55 (2H, d, J = 7.6 Hz, H28), 1.57 (3H, d, J = 0.9 Hz,
H31), 1.49 (3H, d, J = 1.2 Hz, H32); 13C NMR (75 MHz, CDCl3): d
179.2 (C2), 168.8 (C9), 153.7 (C11), 143.4 (C7a), 138.2 (C15),
136.3 (C30), 136.0 (C22), 130.8 (C3a), 128.8 (C17, C19), 128.5
(C24, C26), 128.0 (C18), 127.8 (C6), 127.1 (C25), 127.0 (C23, C27),
125.0 (C16, C20), 122.5 (C4), 121.8 (C5), 116.9 (C29), 109.0 (C7),
69.9 (C13), 57.2 (C14), 50.2 (C3), 43.7 (C21), 40.6 (C8), 37.0
(C28), 25.8 (C31), 18.0 (C32); IR (film) mmax 3060, 3034, 2919,
4.2.10. (S)-3-(2-((S)-1-Benzyl-3-(3-methylbut-2-enyl)-2-oxoind
olin-3-yl)acetyl)-4-phenyoxazolidin-2-one (3S,14S)-6d
Prepared from 5d as white crystals (0.30 g, 43%), mp: 173–
174 °C (EtOAc/hexane). ½a D20
ꢃ
¼ þ63:7 (c 1.75, CHCl3). 1H NMR
(300 MHz, CDCl3): d 7.24–7.09 (9H, m, H4, H17–H19, H23–H27),
7.05 (1H, td, J = 7.8, 1.3 Hz, H6), 6.93 (1H, td, J = 7.5, 1.0 Hz, H5),
6.79 (2H, m, H16, H20), 6.48 (1H, br d, J = 7.5 Hz, H7), 5.26 (1H,

2096
O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 22 (2011) 2085–2098
O
11
O
13
N
4
8
5
9
14
3a
3
6
O
N
O
7a
N
2
7
N
Me
H
(-)-debromoflustramine A 11
(3R,14R)-10
O
O
N
14
3
O
N
O
N
N
H
Me
(+)-debromoflustramine A 11
(3S,14R)-10
Scheme 4.
Figure 11. Comparison of the B3PW91/DGDZVP2 calculated (center) VCD spectrum
of (3R,14S)-6a and the experimental VCD spectra of (3R,14S)-6a (top) and its
enantiomer (3S,14R)-6a (bottom).
1780, 1712, 1489, 1467, 1456 cmꢀ1; EIMS m/z (relative intensity)
494 ([M]+, 7), 426 (100), 290 (32), 289 (33), 263 (36), 262 (20),
235 (44), 91 (51); FABHRMS m/z calcd for C31H30N2O4 ([M]+):
494.2206, found: 494.2206.
4.2.11. (S)-3-(2-((R)-3-Methyl-2-oxo-1-phenylindolin-3-yl)-
acetyl)-4-phenyloxazolidin-2-one (3R,14S)-6e
Prepared from 5e as white crystals (0.021 g, 14%), mp: 168–
169 °C (MeOH).
½
a 2D0
ꢃ
¼ þ166:3 (c 2.0, CHCl3). 1H NMR
(400 MHz, CDCl3): d 7.43 (2H, br t, J = 7.4 Hz, H23, H25), 7.39–
7.28 (4H, m, H17–H19, H24), 7.27–7.13 (5H, H4, H16, H20,
H22, H26), 7.17 (1H, td, J = 7.8, 1.1 Hz, H6), 7.04 (1H, td, J = 7.4,
0.8 Hz, H5), 6.76 (1H, br d, J = 7.8 Hz, H7), 5.22 (1H, dd, J = 8.6,
3.9 Hz, H14), 4.57 (1H, t, J = 8.8 Hz, H13A), 4.20 (1H, dd, J = 9.0,
3.9 Hz, H13B), 3.93 and 3.52 (2H, AB, J = 17.6 Hz, H8), 1.50 (3H,
s, H27); 13C NMR (100 MHz, CDCl3): d 179.7 (C2), 169.2 (C9),
154.2 (C11), 144.2 (C7a), 138.7 (C15), 135.2 (C21), 133.5 (C3a),
129.8 (2C, C23, C25), 129.4 (2C, C17, C19), 128.9 (C18), 128.2
(C6, C24), 127.2 (2C, C22, C26), 126.1 (2C, C16, C20), 122.9
Figure 10. Comparison of the B3PW91/DGDZVP2 calculated (center) VCD spectrum
of (3S,14S)-6a and the experimental VCD spectra of (3S,14S)-6a (top) and its
enantiomer (3R,14R)-6a (bottom).

O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 22 (2011) 2085–2098
2097
(C5), 122.3 (C4), 109.6 (C7), 70.4 (C13), 57.7 (C14) 45.8 (C3), 43.4
References
(C8), 25.1 (C27); IR (KBr) mmax 3032, 2970, 2926, 1779, 1713,
1612, 1501, 1482, 1384, 1363 cmꢀ1; EIMS m/z (relative intensity)
426 ([M]+, 100), 249 (11), 237 (49), 223 (14), 77 (8), 51 (5); FAB-
HRMS m/z calcd for
427.1660.
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Sakaguchi, K.-e.; Sekiguchi, H.; Sakamoto, M. Tetrahedron Lett. 1996, 37, 7525–
7528; (i) Morales-Ríos, M. S.; Rivera-Becerril, E.; Joseph-Nathan, P. Tetrahedron:
Asymmetry 2005, 16, 2493–2499; (j) Suárez-Castillo, O. R.; Sánchez-Zavala, M.;
Meléndez-Rodríguez, M.; Castelán-Duarte, L. E.; Morales-Ríos, M. S.; Joseph-
Nathan, P. Tetrahedron 2006, 62, 3040–3051; (k) Suárez-Castillo, O. R.; Sánchez-
Zavala, M.; Meléndez-Rodríguez, M.; Aquino-Torres, E.; Morales-Ríos, M. S.;
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M.; Kamimura, D.; Ohzono, M.; Ogawa, A. Chem. Commun. 2006, 420–422.
3. Suárez-Castillo, O. R.; Meléndez-Rodríguez, M.; Castelán-Duarte, L. E.; Sánchez-
Zavala, M.; Rivera-Becerril, E.; Morales-Ríos, M. S.; Joseph-Nathan, P.
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C
26H23N2O4 ([M+1]+): 427.1658, found:
4.2.12. (S)-3-(2-((S)-3-Methyl-2-oxo-1-phenylindolin-3-yl)-
acetyl)-4-phenyloxazolidin-2-one (3S,14S)-6e
Prepared from 5e as white crystals (0.023 g, 15%), mp: 181–
182 °C (MeOH). ½a D20
ꢃ
¼ þ200:0 (c 2.0, CHCl3). 1H NMR (400 MHz,
CDCl3): d 7.45 (2H, br t, J = 7.7 Hz, H23, H25), 7.35 (1H, br t,
J = 7.5 Hz, H24), 7.30–7.25 (3H, m, H4, H22, H26), 7.18–7.15 (3H,
m, H17–H19), 7.11 (1H, td, J = 7.7, 1.4 Hz, H6), 7.02 (1H, td,
J = 7.4, 0.7 Hz, H5), 6.85 (2H, m, H16, H20), 6.62 (1H, br d,
J = 7.8 Hz, H7), 5.28 (1H, dd, J = 8.6, 3.5 Hz, H14), 4.59 (1H, t,
J = 8.6 Hz, H13A), 4.12 (1H, dd, J = 9.0, 3.6 Hz, H13B), 4.16 and
3.39 (2H, AB, J = 16.9 Hz, H8), 1.51 (3H, s, H27); 13C NMR
(100 MHz, CDCl3): d 179.8 (C2), 169.0 (C9), 154.1 (C11), 144.1
(C7a), 138.6 (C15), 135.1 (C21), 132.8 (C3a), 129.7 (2C, C23, C25),
129.2 (2C, C17,19), 128.4 (C18), 128.2, 128.1 (2C, C6, C24), 127.1
(2C, C22, C26), 125.5 (2C, C16, C20), 122.9 (C5), 122.6 (C4), 109.8
(C7), 70.3 (C13), 57.6 (C14) 46.2 (C3), 42.6 (C8), 25.1 (C27); IR
(KBr) mmax 2919, 1779, 1716, 1612, 1596, 1502, 1482, 1467, 1455,
1384, 1363, 1330, 1303, 1204 cmꢀ1; EIMS m/z (relative intensity)
426 ([M]+, 100), 249 (8), 237 (39), 223 (8), 77 (8), 51 (7); FABHRMS
m/z calcd for C26H23N2O4 ([M+1]+): 427.1658, found: 427.1654.
4. (a) Kouko, T.; Matsumura, K.; Kawasaki, T. Tetrahedron 2005, 61, 2309–2318;
(b) Boteju, L. W.; Wegner, K.; Qian, X.; Hruby, J. V. Tetrahedron 1994, 50, 2391–
2404; (c) Davies, S. G.; Sanganee, H. J. Tetrahedron: Asymmetry 1995, 6, 671–
674; (d) Palomo, C.; Aizpurua, J. M.; Mielgo, A.; Linden, A. J. Org. Chem. 1996, 61,
9186–9195; (e) Hosokawa, T.; Yamanaka, T.; Itotani, M.; Murahashi, S.-I. J. Org.
Chem. 1995, 60, 6159–6167; (f) Akiba, T.; Tamura, O.; Hashimoto, M.;
Kobayashi, Y.; Katoh, T.; Nakatani, K.; Kamada, M.; Hayakawa, I.; Terashima,
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Castonguay, L.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett.
1995, 36, 7619–7622.
4.3. VCD measurements
VCD spectra were measured using a BioTools BOMEM ChiralIR
spectrophotometer equipped with a dual photoelastic modulation.
Samples of diastereomers (3S,14S)-6a, (3R,14S)-6a, (3R,14R)-6a,
5. (a) Pirkle, W. H.; Simmons, K. A. J. Org. Chem. 1983, 48, 2520–2527; (b) Pridgen,
L. N.; De Brosse, C. J. Org. Chem. 1997, 62, 216–220.
and (3S,14R)-6a were dissolved in 150
lL of CDCl3, placed in a
6. (a) Morales-Ríos, M. S.; Rivera-Becerril, E.; González-Juárez, D. E.; García-
Vázquez, J. B.; Trujillo-Serrato, J. J.; Hernández-Barragán, A.; Joseph-Nathan, P.
Nat. Prod. Commun. 2011, 6, 457–464; (b) Lakshmaiah, G.; Kawabata, T.; Shang,
M.; Fuji, K. J. Org. Chem. 1999, 64, 1699–1704; (c) Miyamoto, H.; Okawa, Y.;
Nakazaki, A.; Kobayashi, S. Tetrahedron Lett. 2007, 48, 1805–1808; (d) Walker,
G. N.; Alkalay, D.; Smith, R. T. J. Org. Chem. 1965, 30, 2973–2983.
7. (a) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M. J.
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Nomura, K.; Yoshii, E. J. Org. Chem. 1992, 57, 2888–2902.
BaF2 cell with a path length of 100
l
m and data were acquired at
a resolution of 4 cmꢀ1 during 4 h. For (3S,14S)-6a, (3R,14R)-6a
and (3S,14R)-6a 5.0 mg were used, while for (3R,14S)-6a, 5.2 mg
were measured. Baseline corrections were done either by subtract-
ing the individual spectra of (3S,14S)-6a, (3R,14S)-6a, (3R,14R)-6a,
and (3S,14R)-6a from the solvent or from a 5 mg samples of their
respective racemic mixture in 150 lL of CDCl3.
8. Yabuuchi, T.; Kusumi, T. J. Org. Chem. 2000, 65, 397–404.
9. Shaye, N. A.; Eames, J. Tetrahedron Lett. 2010, 51, 5892–5895.
10. (a) Osman, F. H.; El-Samahy, F. A. Phosphorus, Sulfur Silicon 1998, 134/135,
437ꢀ446; (b) Aldrich/ACD Library of FT NMR Spectra Pro. Advanced Chemistry
Development, Inc. and Aldrich Chemical Company, Inc. V. 1.00, 1998.
11. Taaning, R. H.; Lindsay, K. B.; Schiøtt, B.; Daasbjerg, K.; Skrydstrup, T. J. Am.
Chem. Soc. 2009, 131, 10253–10262.
12. Kitoh, S.; Senda, H.; Kunimoto, K.-K.; Maeda, S.; Kuwae, A.; Hanai, K. Cryst. Res.
Technol. 2004, 39, 375–381.
13. Chang, G.; Guida, W. C.; Still, W. C. J. Am. Chem. Soc. 1989, 111, 4379–4386.
14. Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital
Theory; Wiley: New York, 1986.
15. (a) Godbout, N.; Salahub, D. R.; Andzelm, J.; Wimmer, E. Can. J. Chem. 1992, 70,
560–571; (b) Andzelm, J.; Wimmer, E. J. Chem. Phys. 1992, 96, 1280–1303.
16. (a) Cheeseman, J. R.; Trucks, G. W.; Keith, T. A.; Frisch, M. J. J. Chem. Phys. 1996,
104, 5497–5509; (b) Cerda-García-Rojas, C. M.; Catalán, C. A. N.; Muro, A. C.;
Joseph-Nathan, P. J. Nat. Prod. 2008, 71, 967–971.
17. (a) Halgren, T. A. J. Comput. Chem. 1996, 17, 490–519; (b) Halgren, T. A. J.
Comput. Chem. 1996, 17, 520–552; (c) Halgren, T. A. J. Comput. Chem. 1996, 17,
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(e) Halgren, T. A. J. Comput. Chem. 1996, 17, 616–641.
4.4. X-ray diffraction analyses
Data collections for (3S,14S)-6a, (3R,14R)-6a and (3S,14S)-6d
were carried out on a Bruker-Nonius CAD4 diffractometer while
those for (3R,14S)-6e and (3S,14S)-6e were done on a Agilent Tech-
nologies Gemini A CCD diffractometer using Cu/K
a radiation
(k = 1.54184 Å). The structures were solved by direct methods
using the SHELXS-9724 program included in the WINGX v1.6 pack-
age.25 Structural refinements were carried out by full-matrix least
squares on F2. The non-hydrogen atoms were treated anisotropi-
cally, and the hydrogen atoms, included in the structure factor cal-
culation, were refined isotropically. Atomic coordinates, bond
lengths, bond angles, and anisotropic thermal parameters are in
deposit at the Cambridge Crystallographic Data Center. Table 4
summarizes the relevant data.
18. As implemented in the computer package SPARTAN04, Windows
Wavefunction Inc.: Irvine, CA, USA, 2004.
v 1.0.1;
19. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
Acknowledgments
We are pleased to acknowledge the financial support from
CONACYT (Mexico) grants 83723 and 84453. L.E.C.D. and E.A.Z.E.
thank CONACYT for fellowships 186031, 58994 (for L.E.C.D.) and
237631 (for E.Z.E.).

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