Absolute configuration assignment of oxindole derivatives by vibrational circular dichroism exciton coupling

Article abstract of DOI:10.1016/j.tetasy.2016.06.004

A convenient and reliable approach for the absolute configuration assignment of oxindole derivatives 2a–m by vibrational circular dichroism (VCD) measurements and evaluation of the VCD bisignated couplet resulting from the interaction of the C2 and C9 carbonyl groups is presented. The absolute configuration assignments were further tested by¹H NMR measurements and by X-ray diffraction analysis.

Full text of DOI:10.1016/j.tetasy.2016.06.004

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Absolute configuration assignment of oxindole derivatives
by vibrational circular dichroism exciton coupling
Claudia I. Bautista-Hernández a, Reyna E. Cordero-Rivera a, Erick A. Zúñiga-Estrada a,
Nayely Trejo-Carbajal a, Myriam Meléndez-Rodríguez a, , Oscar R. Suárez-Castillo a,
⇑
⇑
,
Maricruz Sánchez-Zavala 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 City 07000, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and reliable approach for the absolute configuration assignment of oxindole derivatives 2a–
m by vibrational circular dichroism (VCD) measurements and evaluation of the VCD bisignated couplet
resulting from the interaction of the C2 and C9 carbonyl groups is presented. The absolute configuration
assignments were further tested by 1H NMR measurements and by X-ray diffraction analysis.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 22 April 2016
Accepted 1 June 2016
Available online xxxx
R2
1. Introduction
4
5
R4
3a
R3
3
6
Chiral oxindole derivatives, mainly 1,3,3-trisubtituted 1 mole-
cules (Fig. 1), have been widely used in the total synthesis of chiral
or racemic terrestrial and marine natural products.1 For this pur-
pose, we recently assigned the absolute configuration of chiral 2-
(2-oxo-3-indolyl)acetic acid derivatives by 1H NMR spectroscopy
using enantiomerically pure (R)-phenylethylamine or (S)-phenyl-
2-oxazolidinone as chiral derivatizing agents.2 As shown for com-
pounds 2 and 3 (Fig. 2), experimental data demonstrated that the
phenyl ring of phenylethylamine shields the N1–Me group in
(3R,11R)-2 and the C3–Me group in (3S,11R)-2 diastereoisomers,2a
while (3S,14S)-3 presents the H4-H7 and H16-H20 signals at lower
frequency values and the H8A signal at higher values than the
corresponding signals for the (3R,14S)-3 diastereomer due to the
mutual diamagnetic influence of the aromatic (S)-oxazolidinone
O
7a
2
7
N
R1
1
R1 = H, Me, Bn,
R2 = H, Me, CH2OH, OH,
R3 = H, OMe, Br
,
R4 = OH, CH2OH, CH2NMe2, CH2NO2,
NHCO2Bn, CH2COMe, CO2H, CO2Me,
CO2Et, CHO, CN, CONHMe
O
O
O
Me
N
O
and oxindole moieties on the 1H NMR signals.2b Thus, the
D
dRS
N
H
parameter allowed us to assign the absolute configuration of
diastereoisomers 2 and 3 as shown in Figure 2. The absolute
configuration of (3S,14S)-3 and (3R,14S)-3 were independently
determined using a time consuming protocol needed to compare
the experimental vibrational circular dichroism (VCD) spectra
with those calculated using DFT, which showed good agreement.2b
In a continuation of our studies aimed at the determination of
the absolute configuration of oxindole derivatives,3 we herein
report that the absolute configuration of (3R)-2a–m and (3S)-2a–
Figure 1. Natural and synthetic oxindoles 1.
m can be assigned solely by VCD exciton coupling (VCDEC)4 by
considering the bisignate couplets that originate from the
through-space interaction of the C2 and C9 amide carbonyl groups.
We also demonstrate that the absolute configurations of (3R)-2a–
m and (3S)-2a–m can be assigned by this method independent of
the chiral derivatizing amine used, thus avoiding the need of hav-
ing an aromatic group that is capable of producing an efficient and
⇑
Corresponding authors. Tel.: +52 771 71 72000x2206; fax: +52 771 71
72000x6502.
E-mail address: osuarez@uaeh.edu.mx (O.R. Suárez-Castillo).
http://dx.doi.org/10.1016/j.tetasy.2016.06.004
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
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tetasy.2016.06.004

2
C. I. Bautista-Hernández et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
−
−
H
−
−
−
+
O
8
Me
N
Me
4
N
−
+
+
R
−
Me
3
−
5
−
−
N
Me
11
O
−
O
3
H
O
H
+
O
A
6
N
−
−
N
11
−
O
Me
7
−
+
+
N
Me
−
Me
H
Me
N
OH
−
1. Et3N, ClCO2Et/THF 0 °C
−
−
Me
−
(3R)-2f-k
2. RNH2(5f-k), -60 °C
O
O
(3R,11R)-2
(3S,11R)-2
3. chromatography
Me
H
N
ΔδRS < 0 for N1-Me
ΔδRS > 0 for C3-Me
Me
4
R
O
O
O
N
H
O
17
Me
Me
O
H
H
N
16
O
4
Me
18
5
14
3
H
2f k
(3S)- -
8
O
N
3
6
B
N
19
Me
+
14
+
20
O
+
+
+
7
N
O
13
+
+
+
+
O
H2N
+
H2N
+
Me
H2N
+
5h
5f
5g
(3R,14S)-3
(3S,14S)-3
H2N
OH
H2N
OH
ΔδRS > 0 for H4-H7, H16-H20
ΔδRS
H2N
< 0 for H8
Figure 2. Anisotropic effect of the aromatic rings in (R)-phenylethylamine (A) and
(S)-phenyl-2-oxazolidinone (B) on the oxindole moiety subsituents.
5i
Scheme 1. Synthesis of diastereoisomeric amides 2f–k.
5j
5k
space-oriented anisotropic effect to selectively affect substituents
in the substrate. This absolute configuration assignment methodol-
ogy was confirmed by single-crystal X-ray diffraction analysis.
and C3-Me groups. As shown in Figure 2A, the
D
dRS values would
arise from the diamagnetic influence of the aromatic (R)-naphthyl
moiety on the NMR signals of H7 and the N1-Me and C3-Me groups
in the (3R)- and (3S)-stereogenic centers of the oxindole skeleton
in 2f. It is worth noting that in diastereoisomers (3R)-2f and
(3S)-2f, the signals for the aromatic fragments are more scattered
than those of compounds (3R)-2a and (3S)-2a (Fig. 4). Furthermore,
2. Results and discussion
In order to investigate the utility of VCDEC for the absolute con-
figuration assignment in a series of 2-oxo-3-indolylacetic acid
derivatives 2a–e2a (Fig. 3) and 2f–m containing a variety of alkyl
groups at the N1 and C3 positions, and different chiral amine
fragments at the carboxyl group, their experimental VCD spectra
were acquired. For this goal, racemic carboxylic acids 4 were
derived into the corresponding amides 2f–k by activation with
Et3N and ClCO2Et,2a followed by reaction with different chiral
amines 5f–k (Scheme 1) to give equimolar diastereomeric
mixtures of (3R)-2f–k (28–46%) and (3S)-2f–k (29–43%), which
were easily separated by column chromatography to afford
enantiomerically pure isomers (de >99%) as determined by 1H
NMR.
the
D
dRS values for H7 (ꢀ0.24) and N1-Me (ꢀ0.44) are greater for
diastereoisomers 2f than in 2a (ꢀ0.06, ꢀ0.18) (Figs. 4 and 5), which
indicate a stronger aromatic magnetic cone projection of the naph-
thyl ring towards H7 and N1-Me than that of the phenyl ring.5 In
order to ensure that the
D
dRS values for H7, N1-Me and C3-Me
are mainly due to the anisotropic effect of the naphthyl aromatic
ring, the 1H NMR spectra of (3R)-2f and (3S)-2f were obtained in
CDCl3 at different concentrations (Fig. 6); we found that the chem-
ical shifts for H7 and N1-Me in (3R)-2f are more concentration
dependent than those of (3S)-2f, but the chemical shifts caused
by this effect are incomparable with those caused by the anisotro-
pic effect.
It is well known that 1H NMR spectroscopy is
a useful
H
H
R2
R2
method for the absolute configuration assignment of monofunc-
tional and polyfunctional compounds as long as the chiral
derivatizing agents have aromatic or carbonyl groups that selec-
tively produce an efficient and space-oriented anisotropic effect
on the substituent at the asymmetric unit of the substrate.6
Thus, although the 1H NMR spectra of diastereoisomers (3R)-
2g–k and (3S)-2g–k did not shown any systematic variation of
N
N
Me
Me
O
O
O
O
N
N
R1
R1
(3R)- : R1 = R2 = Me
(3S)- : R1 = R2 = Me
2a
2a
(3R)-2b: R1 = Et, R2 = Me
(3S)-2b: R1 = Et, R2 = Me
(3R)- : R1 = Me, R2 = Et
(3S)-
(3S)-
R
1 = Me, R2 = Et
R
1 = Bn, R2 = Me
D
dRS values for H7, N1-Me and C3-Me, we found a direct
2c
2c:
2d:
the
relationship between the chemical shifts difference for the AB
system at H8 ( dH8A-H8B) and the polarity in each diastereoiso-
mer with the configuration at C3 of amides 2a–k (Table 1).
We noticed that the values tended to be greater in
2d:
(3R)-
R
1 = Bn, R2 = Me
(3R)-2e: R1 = Me, R2 = Bn
(3S)-2e: R1 = Me, R2 = Bn
D
Figure 3. Formulas of (3R)-2a–e and (3S)-2a–e.
D
d
H8A–H8B
The 1H NMR spectra comparison of the less polar (3R)-2f and
the more polar (3S)-2f showed large enough chemical shift differ-
the more polar amides (3S)-2a–h than in the less polar (3R)-
2a–h ones,2a although this trend was reversed in amides 2i–k
as evidenced when these diastereoisomers where synthesized
from enantiomerically pure (3S)-4. Thus, the resolution of ( )-4
ences (
D
d
RS = dR ꢀ dS, where the R and S descriptors refer to the C3
configuration at the oxindole moiety) for the aromatic H7, N1-Me
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C. I. Bautista-Hernández et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Figure 4.
D
dRS values for H7 of (3R)- and (3S)-2a,2f.
with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 4-
dimethylaminopyridine (DMAP), followed by reaction with (R)-
4-phenyl-2-oxazolidinone 6, gave a diastereomeric mixture of
the less polar (3S,14R)-7 and the more polar (3R,14R)-7 in 22%
and 23% yields, respectively (Scheme 2), whose absolute
configurations were established after analysis of their 1H NMR
spectra.2b Subsequent hydrolysis of (3S,14R)-7 and (3R,14R)-7
with LiOH/H2O2 afforded the corresponding (3S)-4 and (3R)-4
acids in 90% and 85% yields, respectively (Scheme 2). Finally,
acid (S)-4 was transformed into the corresponding amides (3S)-
2i–k by activation with ClCO2Et and Et3N,2a followed by
reaction with chiral amines 5i–k (Scheme 3). TLC analysis
3
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C. I. Bautista-Hernández et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Figure 5.
D
dRS values for the N1-Me and C3-Me signals of (3R)- and (3S)-2a,2f.
showed that (3S)-2i–k correspond to the less polar amides when
compared with those obtained from racemic ( )-4 and thus, the
Therefore, we sought a more confident and general method for
the assignment of the absolute configuration of chiral 2-(2-oxo-
3-indolyl)acetic acid derivatives 2a–k that would not be restricted
to the presence of aromatic chiral derivatizing agents.6 Thus, the
experimental VCD spectra of 2a–k were acquired and compared
with each other (Figs. 7, 8, 10 and 11). We first analyzed the VCD
spectra of (3R)- and (3S)-2a–e in which the amide fragment is
the same, but the N1 and C3 substituents are different. As can be
Rf and
DdH8A-H8B values in Table 1 were justified.
As is evident for oxindoles 2a–f, 1H NMR spectroscopy is an easy
and reliable approach for the absolute configuration assignment of
chiral oxindoles, provided that the aromatic amines are used as
chiral derivatizing agent. However, when this condition is not ful-
filled, as in the case of 2g–k, this methodology does not work.
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5
(3R)-2f
(3S)-2f
Figure 6. Concentration dependence of the H7, N-Me and C3-Me chemical shift of (3R)- and (3S)-2f.
Table 1
dH8A-H8B and Rfa values of diastereoisomeric amides 2a–k
negative, while for (3S)-2a–d it is positive. Since there was no great
similarity in the 1550–950 cmꢀ1 range for (3R)-2a–e (Fig. 7) and
for (3S)-2a–e (Fig. 8), this indicated that although achiral, the dif-
ferent alkyl groups at the C3 and N1 positions make important
changes in this VCD region. In both (3R)- and (3S)-diastereomeric
series of 2a–e, there are intense bisignate VCDEC signals around
1626–1747 cmꢀ1 which indicate the through-space coupling of
the C2 and C9 carbonyl groups.3,7 As shown in Figures 7 and 8,
and in Table 2, these bisignate VCDEC signals are generally as
intense in both the (3R)- (A values from ꢀ0.039 to ꢀ0.101) and
the (3S)-2a–e (A values from 0.047 to 0.089) series. A negative-
lower to positive-higher wave numbers signal twist (negative Cot-
ton effect) generated by the interaction of the electric transition
moments of the C2 and C9 carbonyl groups in (3R)-2a–e was
observed, while a positive/negative combination from low to high
wave numbers signal twist (positive Cotton effect) was observed
for (3S)-2a–e. According to the model proposed by Monde and
D
Compound
(3R)-2a–k
(3S)-2a–k
Rf
D
dH8A–H8B
Rf
D
dH8A–H8B
2a
2b
2c
2d
2e
2f
2g
2h
2i
0.62
0.69
0.64
0.82
0.73
0.47
0.69
0.64
0.09
0.18
0.58
0.13
0.13
0.15
0.12
0.20
0.14
0.20
0.16
0.10
0.14
0.15
0.47
0.49
0.47
0.64
0.56
0.40
0.56
0.47
0.22
0.36
0.60
0.14
0.13
0.17
0.14
0.19
0.16
0.20
0.19
0.18
0.19
0.16
2j
2k
a
Determined by TLC (Silica gel F254 coated aluminum sheets 0.25 mm thickness)
using EtOAc.
seen, with the exception of the oxindole derivatives (3R)- and (3S)-
2e (Figs. 7 and 8), all other compounds presented the same sign for
the band around 1600 cmꢀ1. For amides (3R)-2a–d the sign is
Taniguchi,4a (3R)-2a–e should display
a
counterclockwise
(ꢀ180° < h < 0°, negative twist) chromophoric orientation of
the C2 and C9 carbonyl groups (Fig. 9A), while diastereoisomers
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O
O
Me
Me
N
(14R)
CO2H
LiOH, H2O2
(3S)
(3S)
O
1,4-dioxane
H2O
O
O
N
N
Me
Me
1. 4-DMAP, EDC.HCl
(R)-6, CH2Cl2
(3S,14R)-7
(3S)-4
(
)-4
2. chromatography
O
O
O
HN
O
Me
Me
N
(14R)
CO2H
LiOH, H2O2
(3R)
(3R)
O
O
1,4-dioxane
H2O
O
N
N
(R)-6
Me
Me
(3R,14R)-7
Scheme 2. Enantiomer separation of ( )-4.
(3R)-4
H
N
R*
(3S)-2a,f–k series since opposite signs are shown for these signals.
Furthermore, the VCD spectra of oxindole 2k, containing an amine
fragment with a stereogenic center in the b-position, were similar
to those of the (3R)- or (3S)-2a,f–j series. These results undoubt-
edly indicate the low influence of the amide fragment in the VCD
spectra of the oxindoles 2a,f–k series.
Me
Me
CO2H
(3S)
1. Et3N, ClCO2Et, 0 °C
5i k
O
O
O
2. RNH2
- , −60 °C
N
N
Me
Me
(3S)-2i-k
(3S)-4
It is important to note that when comparing the VCD spectra of
the (3R)-2a–e and (3R)-2f–k series (Figs. 7 and 10) or those of the
(3S)-2a–e and (3S)-2f–k series (Figs. 8 and 11), the plots are more
different when the substituents at the N1 and C3 positions are
changed, than when the chiral amine is changed. This was conclu-
sively demonstrated when the VCD spectra of the enantiomeric
esters 8 were obtained (Scheme 4, Fig. 12). It is evident that the
VCD spectrum of the ester (3R)-8 (Fig. 12A) seems more similar
to those of the (3R)-2a,f–k series than those to the (3R)-2b–e ser-
ies. Similarly, the VCD spectrum of ester (3S)-8 (Fig. 12B) seems
more like those of the (3S)-2a,f–k series than those of the (3S)-
2b–e series. We also observed in the VCD spectra shown in Figures
7 and 8 that a substituent change at the C3 position modifies the
spectra more than a change at the N1 position. For example the
VCD spectra of compounds (3R)-2a,b,d are more similar when
compared with the spectra of (3R)-2c,e (Fig. 7). The same applies
when comparing the VCD spectra of (3S)-2a,b,d with those of
(3S)-2c,e (Fig. 8). This observation was reaffirmed with the spectra
comparison of oxindoles (3R)-2f,l,m and (3S)-2f,l,m (Figs. 13 and
14, Scheme 5) in which the C3-Me substituted oxindoles are more
alike as compared with the C3-Et substituted counterparts.
Lastly, the reliability in the absolute configuration assignment
by means of evaluation of the bisignate VCDEC signals in the car-
bonyl region was supported by the X-ray diffraction analysis of
oxindoles (3R)-2f,g,h and (3S)-2j (Fig. 15). In the solid state a coun-
terclockwise twist of the chromophoric orientation of the C2 and
C9 carbonyl groups appears for (3R)-2f,g,h, while a clockwise twist
is evident for (3S)-2i. As shown in Figure 15, the chromophoric ori-
entation of these groups is better appreciated when the substituent
on the amide nitrogen is omitted.
H2N
H2N
OH
OH
H2N
5i
Scheme 3. Synthesis of enantiomerically pure amides (3S)-2i–k.
5j
5k
(3S)-2a–e should present a clockwise (0° < h < +180°, positive
twist) disposition (Fig. 9B) thus revealing their C3 absolute
configuration. Although for (3R)-2d only a negative monosignate
signal was detected at 1655 cmꢀ1 (Fig. 7), its position coincides
with that of the first negative Cotton effect signal (1655–
1665 cmꢀ1) for the (3R)-2a–c,e diastereoisomers (Fig. 7), thus
indicating that even for (3R)-2d, the absolute configuration could
be assigned at the 1655–1699 cmꢀ1 VCD spectroscopic region.
The applicability of the methodology was further evaluated
with the VCD spectroscopic comparison of oxindole derivatives
(3R)-2a,f–k and (3S)-2a,f–k containing methyl groups at the N1
and C3 positions, but with different amide residues (Figs. 10 and
11). Both series of spectra show the same sign for the band around
1600 cmꢀ1 as those shown for (3R)-2a–d and (3S)-2a–d. As
opposed to these latter, oxindoles (3R)-2f–k and (3S)-2f–k were
very similar in the 1550–950 cmꢀ1 region, which indicates that a
change of the amide fragment has less influence on the VCD spec-
tra than the substituents at N1 and C3 (Figs. 7 and 8). Meanwhile,
the VCDEC signals twist around 1626–1747 cmꢀ1 in (3R)-2f–k and
(3S)-2f–k is not altered due to the presence of the chiral amine, and
is consistent with those of (3R)-2a–e and (3S)-2a–e, but their
intensity A is smaller for (3R)-2f–k (ꢀ0.028 to ꢀ0.045, Table 2)
and similar for (3S)-2f–k (0.043–0.119). Just as for (3R)-2d, com-
pounds (3R)-2f,g,h and (3S)-2g present only negative or positive
monosignate signals but their position coincides with that of the
first or second negative or positive Cotton effect signal for the other
oxindoles in the series. The VCD spectra of (3R)- and (3S)-2a,f–k in
Figures 10 and 11 show common absorption bands in the
1466–1471, 1448–1460, 1379–1392, 1352–1356, 1240–1246,
1088–1098, 1059–1065, 1032–1036 cmꢀ1 ranges, which are also
very sensitive to the absolute configuration in both the (3R)- and
3. Conclusions
We have demonstrated that the stereochemistry of oxindole
derivatives 2a–m can easily be established by considering the sign
of their VCDEC bisignate couplet signals irrespective of the sub-
stituents at the N1 and C3 positions and on the chiral amide used.
A significant advantage of this methodology is that no aromatic
chiral derivatizing agent is necessary to establish the absolute con-
figuration in these oxindoles. The VCDEC technique seems reliable
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7
H
N
Me
O
O
N
Me
(3R)-2a
H
N
Me
O
O
N
Et
(3R)-2b
H
N
Et
O
O
N
Me
(3R)-2c
H
N
Me
N
O
O
(3R)-2d
H
N
O
O
N
Me
(3R)-2e
Figure 7. Comparison of the VCD spectra of (3R)-2a-e.
and could be of general value to assign the absolute configuration
of C3-chiral oxindole derivatives, thus avoiding the need for time
consuming DFT calculation protocols.
3800 GC equipped with a Varian Saturn 2000 selective mass detec-
tor and a 30 m, 0.25 mm i.d., 0.25 mm CP-SIL capillary column,
using helium as the carrier gas (1 mL/min), programmed 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 mass spectra (HRMS) were measured on a Bru-
4. Experimental
4.1. General
ker
micrOTOF-QII
mass
spectrometer.
Microanalytical
determinations were performed on a Perkin–Elmer 2400 Series
PCII. Optical rotation measurements were performed on a Per-
kin–Elmer 341 polarimeter. Analytical thin-layer chromatography
(TLC) was carried out on silica gel F254 coated aluminum sheets
(0.25 mm thickness) with a fluorescent indicator. Visualization
was accomplished with UV light (254 nm). Flash chromatography
was done using silica gel 60 (230–400 mesh) from Aldrich.9
Melting points were determined on a Büchi B-540 apparatus. IR
spectra were recorded on a Perkin–Elmer GX FT-IR spectropho-
tometer. The 400 and 100 MHz 1H and 13C NMR spectra were
obtained on a Varian VNMRS 400 spectrometer using DMSO-d6,
and CDCl3 as the solvents and TMS or the signal of the undeterated
solvents as the internal reference.8 Solutions of 35 mg/0.7 mL of
deuterated solvent were used to obtain the 1H and 13C NMR spec-
tra. For complete assignments, gCOSY, gHSQCAD, HSQCHT,
gHMBCAD and HMBCHT spectra were measured. Data are reported
as follows: chemical shift in ppm from TMS, integration, multiplic-
ity (s = singlet, d = doublet, t = triplet, q = quartet, sext = sextet,
sept = septet, m = multiplet, br = broad), coupling constant (Hz),
and assignment. GC/MS analyses were conducted on a Varian CP
4.2. Preparation of oxindoles (R)-4 and (S)-4
To a solution of (3S,14R)-7 or (3R,14R)-7 (0.25 g, 0.69 mmol) in
1,4-dioxane/H2O (8 mL/4 mL) was added a solution of LiOH (66 mg,
2.74 mmol) dissolved in an aqueous solution (29–32%) of H2O2
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C. I. Bautista-Hernández et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
H
N
Me
O
O
N
Me
(3S)-2a
H
N
Me
O
O
N
Et
2b
(3S)-
H
N
Et
O
O
N
Me
2c
(3S)-
H
N
Me
N
O
O
2d
(3S)-
H
N
O
O
N
Me
(3S)-2e
Figure 8. Comparison of the VCD spectra of (3S)-2a-e.
H8A
8
H8A
3
(2 ꢁ 15 mL). The organic phases were washed with brine
(2 ꢁ 15 mL), dried over anhydrous Na2SO4, filtered and concen-
trated under reduced pressure.
3a
3a
R
R
9
9
H8B
H8B
2
2
O
O
O
O
4.2.1. (R)-(ꢀ)-2-(1,3-Dimethyl-2-oxoindolin-3-yl)acetic acid (R)-
Θ
Θ
4
(0° < θ < +180°)
positive twist
(3S)-2a-e
(-180° < θ < 0°)
negative twist
(3R)-2a-e
Prepared from (3R,14R)-7 as a white solid (0.128 g, 85%), mp:
215–217 °C (EtOAc/hexanes). ½a D20
ꢂ
= ꢀ15.5 (c 1.0, EtOH). 1H NMR
(400 MHz, DMSO-d6): d 12.02 (1H, br s, OH), 7.34 (1H, ddd,
J = 7.2, 1.2, 0.5 Hz, H4), 7.24 (1H, td, J = 7.7, 1.3 Hz, H6), 7.00 (1H,
td, J = 7.7, 1.0 Hz, H5), 6.98 (1H, d, J = 7.7 Hz, H7), 3.12 (3H, s,
NMe), 2.92, 2.80 (2H, AB system, J = 16.6 Hz, H8), 1.22 (3H, s, C3-
Me). 13C NMR (100 MHz, DMSO-d6): d 179.2 (C2), 170.9 (C9),
143.4 (C7a), 133.2 (C3a), 127.6 (C6), 122.1 (C4), 121.7 (C5), 108.0
(C7), 44.7 (C3), 40.9 (C8), 26.0 (NMe), 24.3 (C3-Me). IR (KBr) mmax
3443, 2974, 2720, 2637, 2594, 1724, 1672, 1613, 1197 cmꢀ1. EIMS
m/z (relative intensity) 219 ([M]+, 100), 174 (53), 160 (38), 132
(21), 117 (13). HRMS (ESI) m/z calculated for C12H14NO3 [M+H]+:
220.0968, found: 220.0975.
A
B
Figure 9. Twist sense for the electric transition moments of the C2 and C9 carbonyl
groups in (3R)- and (3S)-2a–e.
(0.460 mL, 5.49 mmol) and the mixture was stirred at 0 °C for 18 h.
Next, an aqueous saturated solution of Na2SO3 (15 mL) was added
and the mixture was stirred at rt for 20 min, followed by extraction
with EtOAc (3 ꢁ 15 mL). The aqueous phase was treated with an
aqueous solution of HCl (1 M), followed by extraction with EtOAc
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9
H
N
Me
O
O
N
Me
2a
(3R)-
H
N
Me
O
O
N
Me
2f
(3R)-
H
N
Me
O
O
N
Me
2g
(3R)-
H
N
Me
O
O
N
Me
(3R)-2h
HO
H
N
Me
O
O
N
Me
(3R)-2i
H
N
OH
Me
O
O
N
Me
2j
(3R)-
H
N
Me
O
O
N
Me
2k
(3R)-
Figure 10. Comparison of the VCD spectra of (3R)-2a,f–k.
4.2.2. (S)-(+)-2-(1,3-Dimethyl-2-oxoindolin-3-yl)acetic acid (S)-4
Prepared from (3S,14R)-7 as a white solid (0.136 g, 90%), mp:
EIMS m/z (relative intensity) 219 ([M]+, 100), 174 (70), 160 (76),
132 (31), 117 (17). HRMS (ESI) m/z calcd for C12H14NO3 [M+H]+:
220.0968, found: 220.0974.
214–216 °C (EtOAc/hexanes). Lit.10 175.0–175.5 °C. ½a 2D0
ꢂ
= +15.0
(c 1.0, EtOH). 1H NMR (400 MHz, DMSO-d6): d 12.03 (1H, br s,
OH), 7.33 (1H, dd, J = 7.3, 0.7 Hz, H4), 7.24 (1H, td, J = 7.7, 1.2 Hz,
H6), 7.00 (1H, td, J = 7.7, 1.0 Hz, H5), 6.98 (1H, d, J = 7.7 Hz, H7);
3.12 (3H, s, NMe); 2.92, 2.79 (2H, AB system, J = 16.6 Hz, H8);
1.22 (3H, s, C3-Me). 13C NMR (100 MHz, DMSO-d6): d 179.2 (C2),
170.9 (C9), 143.4 (C7a), 133.2 (C3a), 127.5 (C6), 122.1 (C4), 121.6
(C5), 108.0 (C7), 44.7 (C3), 40.9 (C8), 26.0 (NMe), 24.3 (C3-Me). IR
4.3. General procedure for the esterification of oxindoles (R)-4
and (S)-4
To a solution of the appropriate acid (S)-4 or (R)-4 (0.075 g,
0.34 mmol) in MeOH (5 mL) was added concentrated H2SO4
(0.05 mL) and heated at reflux for 5 h. After cooling to the room
temperature, MeOH was evaporated under reduced pressure and
(KBr) mmax 2974, 2720, 2637, 2601, 1724, 1674, 1613, 1197 cmꢀ1
.
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C. I. Bautista-Hernández et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
H
N
Me
O
O
N
Me
2a
(3S)-
H
N
Me
O
O
N
Me
2f
(3S)-
H
N
Me
O
O
N
Me
2g
(3S)-
H
N
Me
O
O
N
Me
(3S)-2h
HO
H
N
Me
O
O
N
Me
(3S)-2i
H
N
OH
Me
O
O
N
Me
2j
(3S)-
H
N
Me
O
O
N
Me
2k
(3S)-
Figure 11. Comparison of the VCD spectra of (3S)-2a,f–k.
the residue was dissolved in EtOAc (15 mL). The organic phase was
washed with a saturated solution of NaHCO3 (2 ꢁ 10 mL), brine
(2 ꢁ 10 mL), dried over Na2SO4 and evaporated in vacuum.
J = 16.4 Hz, H8), 1.38 (3H, s, C3-Me). 13C NMR (CDCl3, 100 MHz):
d 179.9 (C2), 170.3 (C9), 143.6 (C7a), 132.9 (C3a), 128.2 (C6),
122.4 (C5), 122.2 (C4), 108.1 (C7), 51.6 (OMe), 45.5 (C3), 41.4
(C8), 26.4 (NMe), 24.2 (C3-Me). IR (film) mmax 3056, 2953, 2929,
1739, 1715, 1614, 1249, 1202 cmꢀ1. EIMS m/z (relative intensity)
233 ([M]+, 81), 174 (20), 160 (100), 132 (22).
4.3.1. Methyl (R)-2-(1,3-dimethyl-2-oxoindolin-3-yl)acetate (R)-
8
Prepared from (3R)-4 as a colorless oil2a,11 (0.079 g, 99%).
½
a 2D0
ꢂ
= ꢀ23.5 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.28
4.3.2. Methyl (S)-2-(1,3-dimethyl-2-oxoindolin-3-yl)acetate (S)-
(1H, td, J = 7.6, 1.3 Hz, H6), 7.20 (1H, ddd, J = 7.4, 1.2, 0.4 Hz, H4),
7.04 (1H, td, J = 7.5, 1.0 Hz, H5), 6.87 (1H, d, J = 7.8 Hz, H7), 3.45
(1H, s, OMe), 3.26 (3H, s, NMe), 3.01, 2.86 (2H, AB system,
8
Prepared from (3S)-4 as a pale yellow oil2a,11 (0.079 g, 99%).
½
a 2D0 = +23.3 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.28
ꢂ
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11
Table 2
(1H, td, J = 7.7, 1.2 Hz, H6), 7.20 (1H, dd, J = 7.4, 0.8 Hz, H4), 7.04
(1H, td, J = 7.5, 0.9 Hz, H5), 6.87 (1H, d, J = 7.8 Hz, H7), 3.46 (1H, s,
OMe), 3.26 (3H, s, NMe), 3.01, 2.86 (2H, AB system, J = 16.4 Hz,
H8), 1.38 (3H, s, C3-Me). 13C NMR (100 MHz, CDCl3), d 179.9
(C2), 170.3 (C9), 143.6 (C7a), 132.9 (C3a), 128.2 (C6), 122.4 (C5),
122.2 (C4), 108.1 (C7), 51.6 (OMe), 45.5 (C3), 41.4 (C8), 26.4
(NMe), 24.2 (C3-Me). IR (film) mmax 3056, 2967, 2953, 2930,
1739, 1715, 1614, 1204 cmꢀ1. EIMS m/z (relative intensity) 233
([M]+, 91), 174 (19), 160 (100), 132 (23). Anal. Calcd for
VCDEC couplets for (3R)- and (3S)-2a-k
a
a
Compound
M
D
e1
(m
[cmꢀ1])
D
e2
(
m
[cmꢀ1])
Ab
(3R)-2a
(3R)-2b
(3R)-2c
(3R)-2d
(3R)-2e
(3R)-2f
(3R)-2g
(3R)-2h
(3R)-2i
(3R)-2j
(3R)-2k
(3R)-2l
(3R)-2m
(3R)-8
(3S)-2a
(3S)-2b
(3S)-2c
(3S)-2d
(3S)-2e
(3S)-2f
(3S)-2g
(3S)-2h
(3S)-2i
(3S)-2j
(3S)-2k
(3S)-2l
(3S)-2m
(3S)-8
0.1055
0.1030
0.1248
0.0937
0.0987
0.1163
0.1531
0.1299
0.1096
0.0908
0.0790
0.1345
0.1087
0.1429
0.1199
0.1030
0.1149
0.1004
0.1138
0.1360
0.0729
0.1218
0.1264
0.1003
0.0940
0.1225
0.1121
0.1286
ꢀ0.025 (1655)
ꢀ0.027 (1662)
ꢀ0.022 (1663)
ꢀ0.024 (1655)c
ꢀ0.017 (1663)
ꢀ0.003 (1650)
ꢀ0.031 (1655)c
ꢀ0.037 (1655)c
ꢀ0.025 (1678)
ꢀ0.037 (1678)
ꢀ0.021 (1676)
ꢀ0.008 (1653)
ꢀ0.008 (1653)
ꢀ0.014 (1712)
0.035 (1666)
0.032 (1668)
0.040 (1668)
0.023 (1668)
0.028 (1668)
0.036 (1670)
0.007 (1653)
0.030 (1663)
0.029 (1653)
0.075 (1661)
0.031 (1664)
0.050 (1670)c
0.062 (1668)
0.015 (1716)
0.025 (1697)
0.012 (1699)
0.035 (1697)
—
0.084 (1697)
0.025 (1695)
—
ꢀ0.050
ꢀ0.039
ꢀ0.057
—
ꢀ0.101
ꢀ0.028
—
C13H15N1O3: C, 66.94; H, 6.48; N, 6.00. Found: C, 67.08; H, 6.09;
—
—
0.009 (1712)
0.020 (1711)
0.024 (1713)
0.021 (1699)
0.051 (1699)
0.010 (1738)
ꢀ0.012 (1709)
ꢀ0.036 (1709)
ꢀ0.024 (1705)
ꢀ0.028 (1709)
ꢀ0.061 (1709)
ꢀ0.027 (1709)
ꢀ0.051 (1711)
ꢀ0.013 (1705)
ꢀ0.053 (1690)
ꢀ0.044 (1701)
ꢀ0.018 (1701)
—
ꢀ0.034
ꢀ0.057
ꢀ0.045
ꢀ0.029
ꢀ0.059
ꢀ0.024
0.047
0.068
0.064
0.051
0.089
0.063
0.058
0.043
0.082
0.119
0.049
—
N, 5.90.
4.4. General procedure for the preparation of diastereomeric
amides 2f–m
A cooled solution (0 °C) of the appropriate acid 4 [(i) (0.15 g,
0.68 mmol) or (ii) (0.25 g, 1.14 mmol)], 9a [(iii) (0.25 g,
1.07 mmol)] or 9b [(iv) (0.25 g, 1.07 mmol)] in THF (20 mL)
was treated dropwise with Et3N (1 equiv). The mixture was stir-
red for 15 min after which ClCO2Et (1.4 equiv) was added drop-
wise and stirred for additional 1 h. After cooling to ꢀ60 °C,
one equiv of (R)-5f for i, iii and iv, (R)-5g for ii, (R)-5h for ii,
(1R,2R)-5i for i, (R)-5j for ii and (1S,2R,5S)-5k for i were added
and the reaction mixture stirred for 1 h. After warming to room
temperature, EtOAc was added (25 mL) and the organic layer
ꢀ0.024 (1703)
0.086
0.043
was washed with
a saturated aqueous solution of NH4Cl
ꢀ0.028 (1736)
(2 ꢁ 15 mL), brine (2 ꢁ 20 mL), dried over anhydrous Na2SO4, fil-
tered, and evaporated to dryness in vacuum. The crude products
were purified by flash column chromatography on silica gel
with EtOAc/hexanes 1:2 for 2f, EtOAc/hexanes 2:3 for 2h and
2k, EtOAc/hexanes 1:1 for 2g, 2l and 2m, and EtOAc for 2i
and 2j.
a
b
c
In Mꢀ1 cmꢀ1
.
D
e1
ꢀ
De2.
For (3R)-2d,g,h and (3S)-2l only monosignate signals were detected.
Me
Me
CO2H
CO2Me
H2SO4
MeOH
4.4.1. 2-((R)-1,3-Dimethyl-2-oxoindolin-3-yl)-N-((R)-1-(naphth-
alen-1-yl)ethyl)acetamide (3R)-2f
O
O
N
N
Prepared from 4 (i) as white crystals (0.115 g, 45%), mp:
Me
Me
221–223 °C (EtOAc/hexanes).
½
a 2D0 = +64.0 (c 1.0, CHCl3). 1H
ꢂ
(3S)-4
(3S)-8
NMR (400 MHz, CDCl3): d 7.83 (1H, br d, J = 8.2 Hz, H16), 7.82
(1H, m, H19), 7.75 (1H, br dd, J = 6.7, 2.7 Hz, H15), 7.45 (1H,
ddd, J = 8.2, 6.8, 1.1 Hz, H17), 7.40–7.42 (2H, overlapped, H13,
H14), 7.35 (1H, ddd, J = 8.4, 6.8, 1.4 Hz, H18), 7.24 (1H, ddd,
J = 7.4, 1.2, 0.5 Hz, H4), 7.21 (1H, td, J = 7.7, 1.2 Hz, H6), 7.04
(1H, td, J = 7.6, 1.0 Hz, H5), 6.59 (1H, d, J = 7.7 Hz, H7), 6.40
(1H, br d, J = 8.7 Hz, H10), 5.74 (1H, dq, J = 8.7, 6.8 Hz, H11),
2.78, 2.58 (2H, AB system, J = 14.0 Hz, H8), 2.77 (3H, s, NMe),
1.46 (3H, d, J = 6.8 Hz, H20), 1.37 (3H, s, C3-Me). 13C NMR
(100 MHz, CDCl3): d 179.3 (C2); 166.6 (C9), 141.6 (C7a), 137.1
(C12), 132.7 (C15a), 131.6 (C3a), 130.0 (C19a), 127.5 (C16),
127.1 (C15), 127.0 (C6), 125.6 (C18), 124.7 (C17), 124.2 (C14),
122.3 (C19), 121.8 (C4), 121.7 (C5), 121.4 (C13), 107.4 (C7),
45.6 (C3), 43.0 (C8), 42.8 (C11), 24.8 (NMe), 23.1 (C3-Me),
19.5 (C20). IR (KBr) mmax 3406, 3281, 3051, 2964, 2927, 1709,
Me
Me
CO2H
CO2Me
H2SO4
MeOH
O
O
N
N
Me
Me
(3R)-4
(3R)-8
Scheme 4. Synthesis of enantiomerically pure esters (3S)- and (3R)-8.
OMe
Me
1647, 1609, 1542 cmꢀ1
. EIMS m/z (relative intensity) 372
O
([M]+, 6), 212 (14), 174 (22), 170 (100), 160 (17), 154 (14).
Anal. Calcd for C24H24N2O2: C, 77.39; H, 6.49; N, 7.52. Found:
C, 77.21; H, 6.52; N, 7.20.
O
N
Me
(3R)-8
4.4.2. 2-((S)-1,3-Dimethyl-2-oxoindolin-3-yl)-N-((R)-1-(naphth-
alen-1-yl)ethyl)acetamide (3S)-2f
OMe
Me
O
Prepared from 4 (i) as white crystals (0.110 g, 43%), mp: 156–
O
a 2D0 = +34.7 (c 1.0, CHCl3). 1H NMR
ꢂ
N
Me
158 °C (EtOAc/hexanes).
½
(400 MHz, CDCl3): d 7.86–7.82 (2H, overlapped, H16, H19), 7.76
(1H, br dd, J = 7.0, 2.2 Hz, H15), 7.46 (1H, ddd, J = 8.0, 6.8, 1.2 Hz,
H17), 7.42–7.40 (2H, overlapped, H13, H14), 7.41 (1H, ddd,
J = 8.4, 6.9, 1.6 Hz, H18), 7.28 (1H, td, J = 7.7, 1.2 Hz, H6), 7.20
(1H, ddd, J = 7.4, 1.2, 0.4 Hz, H4), 7.06 (1H, td, J = 7.6, 1.0 Hz, H5),
8
(3S)-
Figure 12. VCD spectra of esters (3R)-8 (A) and (3S)-8 (B).
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12
C. I. Bautista-Hernández et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
H
N
Me
N
O
O
Me
2f
(3R)-
H
N
Me
O
O
N
Et
2l
(3R)-
H
N
Et
N
O
O
Me
(3R)-2m
Figure 13. Comparison of the VCD spectra of (3R)-2f,l,m.
H
N
Me
N
O
O
Me
2f
(3S)-
H
N
Me
O
O
N
Et
2l
(3S)-
H
N
Et
N
O
O
Me
(3S)-2m
Figure 14. Comparison of the VCD spectra of (3S)-2f,l,m.
6.83 (1H, d, J = 7.7 Hz, H7), 6.38 (1H, br d, J = 8.3 Hz, H10), 5.72 (1H,
dq, J = 8.2, 6.7 Hz, H11), 3.21 (3H, s, NMe), 2.81, 2.61 (2H, AB sys-
tem, J = 14.7 Hz, H8), 1.49 (3H, d, J = 6.8 Hz, H20), 1.32 (3H, s, C3-
Me). 13C NMR (100 MHz, CDCl3): d 180.4 (C2), 167.6 (C9), 142.9
(C7a), 138.0 (C12), 133.8 (C15a), 133.1 (C3a), 131.0 (C19a), 128.6
(C16), 128.2 (C15), 128.1 (C6), 126.5 (C18), 125.7 (C17), 125.2
(C14), 123.5 (C19), 122.7 (C4), 122.6 (C5), 122.5 (C13), 108.3
(C7), 46.3 (C3), 44.3 (C11), 43.9 (C8), 26.4 (NMe), 23.9 (C3-Me),
20.6 (C20). IR (KBr) mmax 3453, 3302, 3063, 2963, 2923, 1709,
1648, 1615, 1549 cmꢀ1. EIME m/z (relative intensity) 373 ([M
+H]+, 100), 372 (42), 354 (12), 195 (20), 170 (82), 154 (13), 130
(13). HRMS (ESI) m/z calcd for C24H25N2O2 [M+H]+: 373.1916,
found: 373.1909.
4.4.3. N-((R)-sec-Butyl)-2-((R)-1,3-dimethyl-2-oxoindolin-3-yl)
acetamide (3R)-2g
Prepared from 4 (ii) as white crystals (0.117 g, 37%), mp: 149–
151 °C (EtOAc/hexanes).
½
a 2D0 = +23.0 (c 1.0, CHCl3). 1H NMR
ꢂ
(400 MHz, CDCl3): d 7.22–7.18 (2H, overlapped, H4, H6), 7.00
(1H, tm, J = 7.6 Hz, H5), 6.78 (1H, d, J = 7.6 Hz, H7), 6.04 (1H, br d,
J = 7.8 Hz, H10), 3.65 (1H, dsext, J = 8.3, 6.7 Hz, H11), 3.16 (3H, s,
NMe), 2.71, 2.57 (2H, AB system, J = 14.5 Hz, H8), 1.35 (3H, s, C3-
Me), 1.25 (2H, q, J = 7.3 Hz, H12), 0.91 (3H, d, J = 6.7 Hz, H14),
0.71 (3H, t, J = 7.5 Hz, H13). 13C NMR (100 MHz, CDCl3): d 180.5
(C2), 168.1 (C9), 142.8 (C7a), 133.2 (C3a), 128.1 (C6), 122.8 (C4),
122.7 (C5), 108.2 (C7), 46.4 (C11, C3), 44.1 (C8), 29.5 (C12), 26.4
(NMe), 23.7 (C3-Me), 20.1 (C14), 10.2 (C13). IR (KBr) mmax 3439,
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13
H
R2
N
O
O
N
R1
R2
2l m
,
(3R)-
CO2H
1. Et3N, ClCO2Et, 0 °C
O
2. 5f, −60 ºC
N
R1
3. chromatography
H
R2
N
9a,b
O
O
N
R1
(3S)-2l,m
9a, 2l: R1 = Et, R2 = Me; 9b, 2m: R1 = Me, R2 = Et
Scheme 5. Synthesis of diastereoisomeric amides (3R)-2l,m and (3S)-2l,m.
3321, 2969, 2930, 2874, 1703, 1656, 1612, 1546 cmꢀ1. EIMS m/z
(relative intensity) 274 ([M]+, 25), 186 (17), 174 (100), 160 (38).
HRMS (ESI) m/z calcd for C16H23N2O2 [M+H]+: 275.1760, found:
275.1754.
4.4.6. N-((R)-1-Cyclohexylethyl)-2-((S)-1,3-dimethyl-2-oxoindo-
lin-3-yl)acetamide (3S)-2h
Prepared from 4 (ii) as a white solid (0.157 g, 42%), mp: 188–
190 °C (EtOAc/hexanes).
½
a 2D0
ꢂ
= ꢀ8.5 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): d 7.28 (1H, ddd, J = 7.3, 1.3, 0.7 Hz, H4), 7.27
(1H, ddd, J = 8.9, 7.7, 1.3 Hz, H6), 7.07 (1H, ddd, J = 7.8, 7.3,
1.0 Hz, H5), 6.85 (1H, ddd, J = 7.7, 0.8, 0.8 Hz, H7), 6.04 (1H, br d,
J = 8.9 Hz, H10), 3.66 (1H, dq, J = 8.8, 6.7 Hz, H11), 3.24 (3H, s,
NMe), 2.82, 2.63 (2H, AB system, J = 14.4 Hz, H8), 1.69–1.66 (2H,
overlapped, H14e, H16e), 1.62–1.53 (3H, overlapped, H13e, H15e,
H17e), 1.43 (3H, s, C3-Me), 1.21–1.01 (4H, overlapped, H12,
H14a, H15a, H16a), 0.91 (3H, d, J = 6.8 Hz, H18), 0.89–0.75 (2H,
overlapped, H13a, H17a). 13C NMR (100 MHz, CDCl3): d 180.5
(C2), 167.9 (C9), 142.9 (C7a), 133.1 (C3a), 128.1 (C6), 122.8 (C4),
122.7 (C5), 108.2 (C7), 49.1 (C11), 46.4 (C3), 44.4 (C8), 42.8
(C12), 28.8, 28.7 (C13, C17), 26.4 (NMe), 26.3 (C15), 26.1 (C14,
C16), 23.9 (C3-Me), 17.7 (C18). IR (KBr) mmax 3406, 3267, 2967,
2926, 2852, 1711, 1647, 1560 cmꢀ1. EIMS m/z (relative intensity)
329 ([M+H]+, 24), 245 (11), 219 (13), 202 (19), 174 (100), 160
(27). HRMS (ESI) m/z calcd for C20H29N2O2 [M+H]+: 329.2229,
found: 329.2224.
4.4.4. N-((R)-sec-Butyl)-2-((S)-1,3-dimethyl-2-oxoindolin-3-yl)
acetamide (3S)-2g
Prepared from 4 (ii) as white crystals (0.111 g, 35%), mp:
133–135 °C (EtOAc/hexanes).
½
a 2D0
ꢂ
= ꢀ37.0 (c 1.0, CHCl3). 1H
NMR (400 MHz, CDCl3): d 7.21 (1H, dd, J = 6.5, 1.3 Hz, H4),
7.20 (1H, ddd, J = 9.0, 7.7, 1.3 Hz, H6), 7.00 (1H, td, J = 7.4,
1.0 Hz, H5), 6.78 (1H, dd, J = 7.7, 0.9 Hz, H7), 6.03 (1H, br d,
J = 8.0 Hz, H10), 3.64 (1H, dsext, J = 8.3, 6.6 Hz, H11), 3.17 (3H,
s, NMe), 2.72, 2.56 (2H, AB system, J = 14.5 Hz, H8), 1.35 (3H,
s, C3-Me), 1.26 (2H, q, J = 7.4 Hz, H12), 0.89 (3H, d, J = 6.6 Hz,
H14), 0.72 (3H, t, J = 7.5 Hz, H13). 13C NMR (100 MHz, CDCl3):
d 180.0 (C2), 168.3 (C9), 143.0 (C7a), 133.3 (C3a), 128.3 (C6),
123.0 (C4), 122.9 (C5), 108.4 (C7), 46.3 (C11, C3), 44.4 (C8),
29.6 (C12), 26.5 (NMe), 23.9 (C3-Me), 20.4 (C14), 10.4 (C13).
IR (KBr) mmax 3322, 3058, 2967, 2937, 1710, 1702, 1659,
1540 cmꢀ1. EIMS m/z (relative intensity) 275 (100), 274 ([M]+,
61), 259 (22), 200 (13), 186 (37), 174 (79), 160 (38). HRMS
(ESI) m/z calcd for
C
16H23N2O2 [M+H]+: 275.1760, found:
4.4.7. 2-((R)-1,3-Dimethyl-2-oxoindolin-3-yl)-N-((1R,2R)-2-
hydroxycyclohexyl)acetami de (3R)-2i
275.1754.
Prepared from 4 (i) as a colorless oil (0.101 g, 47%). ½a D20
ꢂ
= +43.3
4.4.5. N-((R)-1-Cyclohexylethyl)-2-((R)-1,3-dimethyl-2-oxoindo-
lin-3-yl)acetamide (3R)-2h
(c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.31–7.27 (2H, over-
lapped, H4, H6), 7.10 (1H, td, J = 7.7, 0.9 Hz, H5), 6.87 (1H, dd,
J = 7.4, 1.0 Hz, H7), 6.61 (1H, br d, J = 7.0 Hz, H10), 3.49 (1H, m,
H11), 3.25 (3H, s, NMe), 3.22 (1H, m, H12), 2.81, 2.71 (2H, AB sys-
tem, J = 14.3 Hz, H8), 1.99 (1H, m, H13e), 1.80 (1H, m, H16e), 1.69–
1.63 (2H, overlapped, H14e, H15e), 1.44 (3H, s, C3-Me), 1.27–1.12
(4H, overlapped, H13a, H14a, H15a, H16a). 13C NMR (100 MHz,
CDCl3): d 180.8 (C2), 170.3 (C9), 142.8 (C7a), 133.2 (C3a), 128.2
(C6), 122.8 (C5), 122.7 (C4), 108.5 (C7), 74.3 (C12), 55.3 (C11),
46.4 (C3), 44.0 (C8), 34.1 (C13), 31.3 (C16), 26.4 (NMe), 24.5, 24.1
(C14, C15), 23.8 (C3-Me). IR (KBr) mmax 3433, 3092, 2932, 2858,
1697, 1647, 1554 cmꢀ1. EIMS m/z (relative intensity) 317 ([M
+H]+, 100), 299 (6), 202 (7), 174 (16). HRMS (ESI) m/z calcd for
Prepared from 4 (ii) as a white solid (0.170 g, 45%), mp: 161–
163 °C (EtOAc/hexanes).
½
a 2D0 = +48.5 (c 1.0, CHCl3). 1H NMR
ꢂ
(400 MHz, CDCl3): d 7.29 (1H, ddd, J = 7.4, 1.2, 0.6 Hz, H4), 7.27
(1H, td, J = 7.7, 1.2 Hz, H6), 7.07 (1H, td, J = 7.6, 1.0 Hz, H5), 6.85
(1H, d, J = 7.6 Hz, H7), 6.12 (1H, br d, J = 8.9 Hz, H10), 3.67 (1H,
dq, J = 8.8, 6.6 Hz, H11), 3.24 (3H, s, NMe), 2.81, 2.65 (2H, AB sys-
tem, J = 14.5 Hz, H8), 1.71–1.67 (2H, overlapped, H14e, H16e),
1.63–1.54 (3H, overlapped, H13e, H15e, H17e), 1.42 (3H, s, C3-
Me), 1.21–1.01 (4H, overlapped, H12, H14a, H15a, H16a), 0.94
(3H, d, J = 6.8 Hz, H18), 0.90–0.76 (2H, overlapped, H13a, H17a).
13C NMR (100 MHz, CDCl3): d 180.5 (C2), 168.1 (C9), 142.7
(C7a), 133.1 (C3a), 128.1 (C6), 122.9 (C4), 122.8 (C5), 108.2 (C7),
49.2 (C11), 46.4 (C3), 44.1 (C8), 42.8 (C12), 28.8, 28.7 (C13,
C17), 26.4 (NMe), 26.3 (C15), 26.2, 26.1 (C14, C16), 24.0 (C3-
Me), 17.6 (C18). IR (KBr) mmax 3397, 3317, 2961, 2925, 2851,
1709, 1659, 1547 cmꢀ1. EIMS m/z (relative intensity) 329 ([M
+H]+, 16), 245 (12), 219 (10), 202 (17), 174 (100), 160 (22), 146
(13). HRMS ESI m/z calcd for C20H29N2O2 [M+H]+: 329.2229,
found: 329.2224.
C
18H25N2O3 [M+H]+: 317.1860, found: 317.1873.
4.4.8. 2-((S)-1,3-Dimethyl-2-oxoindolin-3-yl)-N-((1R,2R)-2-
hydroxycyclohexyl)acetami de (3S)-2i
Prepared from 4 (i) as a colorless oil (0.094 g, 43%). ½a D20
= ꢀ24.5
ꢂ
(c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.30 (1H, td, J = 7.7,
1.3 Hz, H6), 7.28 (1H, ddd, J = 7.3, 1.2, 0.5 Hz, H4), 7.08 (1H, td,
J = 7.6, 1.0 Hz, H5), 6.87 (1H, d, J = 7.7 Hz, H7), 6.48 (1H, br d,
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14
C. I. Bautista-Hernández et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
4.4.9. 2-((R)-1,3-Dimethyl-2-oxoindolin-3-yl)-N-((R)-1-hydroxy-
3-phenylpropan-2-yl)acetamide (3R)-2j
Prepared from 4 (ii) as a white solid (0.136 g, 34%), mp: 88–
90 °C. ½a 2D0
ꢂ
= +45.8 (c 1.0, CHCl3). 1H NMR (400 MHz, DMSO-d6): d
7.66 (1H, br d, J = 8.2 Hz, H10), 7.23–7.12 (5H, overlapped, H4,
H6, H15, H16, H17), 7.04 (2H, dd, J = 8.3, 1.5 Hz, H18, H14), 6.94
(1H, td, J = 7.6, 1.0 Hz, H5), 6.92 (1H, dd, J = 7.4, 1.0 Hz, H7), 4.71
(1H, t, J = 5.5 Hz, OH), 3.64 (1H, m, H11), 3.22 (1H, dt, J = 10.7,
5.2 Hz, H19A), 3.17 (1H, dt, J = 10.7, 5.5 Hz, H19B), 3.10 (3H, s,
NMe), 2.71, 2.57 (2H, AB system, J = 15.0 Hz, H8), 2.61 (1H, dd,
J = 13.8, 6.1 Hz, H12A), 2.33 (1H, dd, J = 13.8, 7.7 Hz, H12B), 1.16
(3H, s, C3-Me). 13C NMR (100 MHz, DMSO-d6): d 180.5 (C2),
169.1 (C9), 144.3 (C7a), 140.0 (C13), 134.3 (C3a), 129.9 (C18,
C14), 129.0 (C17, C15), 128.3 (C6), 126.8 (C16), 123.5 (C4), 122.5
(C5), 108.9 (C7), 63.1 (C19), 53.0 (C11), 46.2 (C3), 43.3 (C8), 37.2
(C12), 27.0 (NMe), 25.1 (C3-Me). IR (KBr) mmax 3424, 2920, 2852,
1702, 1635, 1613, 1561 cmꢀ1. EIMS m/z (relative intensity) 353
([M+H]+, 100), 335 (11), 174 (12). HRMS (ESI) m/z calcd for
C21H25N2O3 [M+H]+: 353.1860, found: 353.1854.
(3R)-2f
(-180° < θ < 0°)
(3R)-2g
4.4.10. 2-((S)-1,3-Dimethyl-2-oxoindolin-3-yl)-N-((R)-1-hydroxy-
3-phenylpropan-2-yl)acetamide (3S)-2j
Prepared from 4 (ii) as a white solid (0.123 g, 31%), mp: 150–
152 °C. ½a 2D0
ꢂ
= +8.5 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d
(-180° < θ < 0°)
7.27 (1H, td, J = 7.7, 1.2 Hz, H6), 7.26 (1H, m, H4), 7.25–7.23 (2H,
overlapped, H15, H17), 7.18 (1H, m, H16), 7.16–7.14 (2H, over-
lapped, H18, H14), 7.06 (1H, td, J = 7.6, 1.0 Hz, H5), 6.85 (1H, d,
J = 7.8 Hz, H7), 6.50 (1H, br d, J = 8.0 Hz, H10), 4.04 (1H, m, H11),
3.49 (1H, dd, J = 11.2, 3.4 Hz, H19A), 3.39 (1H, dd, J = 11.2, 4.9 Hz,
H19B), 3.23 (1H, br s, OH), 3.21 (3H, s, NMe), 2.77 (1H, dd,
J = 13.8, 7.3 Hz, H12A), 2.71 (1H, dd, J = 13.7, 7.0 Hz, H12B), 2.76,
2.57 (2H, AB system, J = 14.3 Hz, H8), 1.42 (3H, s, C3-Me). 13C
NMR (100 MHz, CDCl3): d 180.5 (C2), 169.3 (C9), 142.7 (C7a),
137.8 (C13), 133.3 (C3a), 129.1 (C18, C14), 128.5 (C17, C15),
128.2 (C6), 126.4 (C16), 122.8 (C5), 122.7 (C4), 108.4 (C7), 63.3
(C19), 52.6 (C11), 46.3 (C3), 43.9 (C8), 36.7 (C12), 26.4 (NMe),
23.3 (C3-Me). IR (KBr) mmax 3425, 3373, 2935, 2913, 2866, 1706,
1646, 1536 cmꢀ1. EIMS m/z (relative intensity) 353 ([M+H]+, 100),
335 (28), 174 (37). Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86;
N, 7.95. Found: C, 71.55; H, 6.92; N, 8.34.
(3R)-2h
(-180° < θ < 0°)
4.4.11. 2-((R)-1,3-Dimethyl-2-oxoindolin-3-yl)-N-(((1S,2R,5S)-6,
6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)acetamide (3R)-2k
Prepared from 4 (i) as a white solid (0.067 g, 28%), mp: 145–
(3S)-2j
147 °C. ½a 2D0
ꢂ
= +14.5 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d
7.30–7.26 (2H, overlapped, H4, H6), 7.08 (1H, t, J = 7.8 Hz, H5),
6.85 (1H, dd, J = 7.3, 1.0 Hz, H7), 6.32 (1H, br s, H10), 3.24 (3H, s,
NMe), 3.11 (2H, dd, J = 7.8, 5.8 Hz, H11), 2.79, 2.64 (2H, AB system,
J = 14.6 Hz, H8), 2.30 (1H, m, H18A), 2.01 (1H, m, H12), 1.93–1.80
(4H, overlapped, H15, H16, H17e), 1.75 (1H, m, H13), 1.42 (3H, s,
C3-Me), 1.36 (1H, m, H17a), 1.14 (3H, s, H20), 0.96 (3H, s, H19),
0.82 (1H, d, J = 9.6 Hz, H18B). 13C NMR (100 MHz, CDCl3): d 180.6
(C2), 168.8 (C9), 142.7 (C7a), 133.2 (C3a), 128.1 (C6), 122.8 (C4,
C5), 108.3 (C7), 46.3 (C3), 45.1 (C11), 43.9 (C8), 43.6 (C13), 41.2
(C12,15), 38.6 (C14), 33.2 (C18), 27.9 (C20), 26.4 (NMe), 25.9
(C16), 23.7 (C3-Me), 23.1 (C19), 19.8 (C17). IR (KBr) mmax 3333,
2966, 2924, 2866, 1702, 1676, 1551 cmꢀ1. EIMS m/z (relative
intensity) 355 ([M+H]+, 16), 218 (26), 174 (100), 160 (40), 146
(16). Anal. Calcd for C22H30N2O2: C, 74.54; H, 8.53; N, 7.90. Found:
C, 74.36; H, 8.78; N, 8.32.
(0° < θ < +180°)
Figure 15. X-ray diffraction structures of (3R)-2f,g,h and (3S)-2j. The insert, on the
right, shows the twist direction of the C2 and C9 carbonyl groups in the solid state.
The substituent on the amide nitrogen is omitted for the sake of clarity.
J = 7.6 Hz, H10), 3.58–3.50 (2H, overlapped, H11, OH), 3.26 (1H, m,
H12), 3.24 (3H, s, NMe), 2.80, 2.62 (2H, AB system, J = 14.3 Hz, H8),
2.01 (1H, m, H13e), 1.82 (1H, m, H16e), 1.71–1.64 (2H, overlapped,
H14e, H15e), 1.47 (3H, s, C3-Me), 1.33–1.07 (4H, overlapped, H13a,
H14a, H15a, H16a). 13C NMR (100 MHz, CDCl3): d 180.6 (C2), 170.2
(C9), 142.6 (C7a), 133.3 (C3a), 128.3 (C6), 122.9 (C5), 122.8 (C4),
108.4 (C7), 74.6 (C12), 55.5 (C11), 46.3 (C3), 44.0 (C8), 33.9
(C13), 31.3 (C16), 26.4 (NMe), 24.5, 24.0 (C14, C15), 23.2 (C3-
Me). IR (film) mmax 3409, 3302, 2933, 2860, 1698, 1648,
1545 cmꢀ1. EIMS m/z (relative intensity) 317 ([M+H]+, 100), 299
(5), 202 (18), 174 (11). HRMS ESI m/z calcd for C18H25N2O3 [M
+H]+: 317.1860, found: 317.1855.
4.4.12. 2-((S)-1,3-Dimethyl-2-oxoindolin-3-yl)-N-(((1S,2R,5S)-6,
6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)acetamide (3S)-2k
Prepared from
4 (i) as a pale yellow oil (0.071 g, 29%).
½
a 2D0
ꢂ
= ꢀ34.8 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.28
(1H, dd, J = 7.5, 1.3 Hz, H4), 7.28 (1H, td, J = 7.9, 1.2 Hz, H6), 7.09
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C. I. Bautista-Hernández et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
15
(1H, td, J = 7.6, 1.0 Hz, H5), 6.86 (1H, dd, J = 8.0, 1.0 Hz, H7), 6.28
(1H, br t, J = 5.3 Hz, H10), 3.23 (3H, s, NMe), 3.15 (1H, ddd,
J = 13.3, 8.1, 5.9 Hz, H11A), 3.07 (1H, ddd, J = 13.3, 7.6, 5.7 Hz,
H11B), 2.80, 2.64 (2H, AB system, J = 14.5 Hz, H8), 2.29 (1H, m,
H18A), 2.00 (1H, m, H12), 1.93–1.80 (4H, overlapped, H15, H16,
H17e), 1.65 (1H, m, H13); 1.43 (3H, s, C3-Me), 1.36 (1H, m,
H17a), 1.09 (3H, s, H20), 0.95 (3H, s, H19), 0.82 (1H, d, J = 9.5 Hz,
H18B). 13C NMR (100 MHz, CDCl3): d 180.7 (C2), 168.9 (C9),
142.6 (C7a), 133.1 (C3a), 128.1 (C6), 123.0 (C5), 122.9 (C4), 108.3
(C7), 46.4 (C3), 45.0 (C11), 43.8 (C8), 43.4 (C13), 41.3 (C15), 41.2
(C12), 38.5 (C14), 33.2 (C18), 27.9 (C20), 26.4 (NMe), 25.9 (C16),
23.8 (C3-Me), 23.0 (C19), 19.8 (C17). IR (film) mmax 3317, 2924,
2868, 1705, 1651, 1550 cmꢀ1. EIMS m/z (relative intensity) 354
([M]+, 5), 218 (28), 174 (100), 160 (43), 146 (17). HRMS (ESI) m/z
calcd for C22H31N2O2 [M+H]+: 355.2380. Found: 355.2386.
7.82–7.79 (2H, overlapped, H16, H19), 7.74 (1H, m, H15), 7.44
(1H, ddd, J = 8.0, 6.8, 1.0 Hz, H17), 7.41–7.39 (2H, overlapped,
H13, H14), 7.33 (1H, ddd, J = 8.4, 6.8, 1.3 Hz, H18), 7.21 (1H, td,
J = 7.7, 1.3 Hz, H6), 7.20 (1H, m, H4), 7.04 (1H, td, J = 7.5, 1.0 Hz,
H5), 6.56 (1H, d, J = 7.6 Hz, H7), 6.29 (1H, br d, J = 8.8 Hz, H10),
5.71 (1H, dq, J = 8.7, 6.8 Hz, H11), 2.78, 2.58 (2H, AB system,
J = 14.0 Hz, H8), 2.74 (3H, s, NMe), 1.87 (1H, dq, J = 13.7, 7.4 Hz,
CH2CH3A), 1.77 (1H, dq, J = 13.5, 7.4 Hz, CH2CH3B), 1.42 (3H, d,
J = 6.8 Hz, H20), 0.53 (3H, t, J = 7.4 Hz, CH2CH3). 13C NMR
(100 MHz, CDCl3): d 179.9 (C2), 167.9 (C9), 143.8 (C7a), 138.5
(C12), 134.0 (C15a), 131.3 (C19a), 130.8 (C3a), 128.8 (C16), 128.4
(C15, C6), 126.9 (C18), 126.0 (C17), 125.4 (C14), 123.7 (C19),
123.4 (C4), 122.9 (C5), 122.7 (C13), 108.4 (C7), 51.8 (C3), 44.1
(C11), 43.7 (C8), 31.3 (CH2CH3), 25.9 (NMe), 20.7 (C20), 8.4 (CH2-
CH3). IR (KBr) mmax 3292, 3051, 2971, 2936, 1709, 1655, 1609,
1547 cmꢀ1. EIMS m/z (relative intensity) 386 ([M]+, 14), 188 (15),
170 (100), 146 (15). Anal. Calcd for C25H26N2O2: C, 77.69; H,
6.78; N, 7.25. Found: C, 77.73; H, 6.94; N, 6.80.
4.4.13. 2-((R)-1-Ethyl-3-methyl-2-oxoindolin-3-yl)-N-((R)-1-
(naphthalen-1-yl)ethyl)acetamide (3R)-2l
Prepared from 9a (iii) as a white solid (0.193 g, 47%), mp: 159–
161 °C. ½a 2D0
ꢂ
= +62.0 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d
4.4.16. 2-((S)-3-Ethyl-1-methyl-2-oxoindolin-3-yl)-N-((R)-1-
(naphthalen-1-yl)ethyl)acetamide (3S)-2m
7.89 (1H, d, J = 8.5 Hz, H19), 7.81 (1H, m, H16), 7.75 (1H, m, H15),
7.45 (1H, ddd, J = 8.0, 6.9, 1.2 Hz, H17), 7.42–7.40 (2H, overlapped,
H13, H14), 7.39 (1H, ddd, J = 8.3, 6.8, 1.4 Hz, H18), 7.25 (1H, dd,
J = 7.4, 0.7 Hz, H4), 7.23 (1H, td, J = 7.7, 1.2 Hz, H6), 7.02 (1H, td,
J = 7.7, 1.0 Hz, H5), 6.69 (1H, d, J = 7.8 Hz, H7), 6.53 (1H, br d,
J = 8.6 Hz, H10), 5.77 (1H, dq, J = 8.5, 6.8 Hz, H11), 3.55 (1H, dq,
J = 14.5, 7.3 Hz, CH2CH3A), 3.31 (1H, dc, J = 14.3, 7.2 Hz, CH2CH3B),
2.76, 2.58 (2H, AB system, J = 14.3 Hz, H8), 1.46 (3H, d, J = 6.8 Hz,
H20), 1.39 (3H, s, C3-Me), 1.10 (3H, t, J = 7.2 Hz, CH2CH3). 13C NMR
(100 MHz, CDCl3): d 180.2 (C2), 168.0 (C9), 142.0 (C7a), 138.5
(C12), 134.0 (C15a), 133.4 (C3a), 131.3 (C19a), 128.8 (C16), 128.4,
128.3 (C15, C6), 126.8 (C18), 126.0 (C17), 125.4 (C14), 123.7 (C19),
123.4 (C4), 122.8 (C5, C13), 108.8 (C7), 46.6 (C3), 44.3 (C11), 44.1
(C8), 34.7 (CH2CH3), 24.2 (C3-Me), 20.8 (C20), 12.7 (CH2CH3). IR
(KBr) mmax 3271, 3049, 2980, 2963, 2940, 1702, 1650, 1608,
1538 cmꢀ1. EIME m/z (relative intensity) 386 ([M]+, 17), 188 (19),
170 (100), 155 (16), 128 (18). Anal. Calcd for C25H26N2O2: C,
77.69; H, 6.78; N, 7.25. Found: C, 77.19; H, 6.85; N, 6.96.
Prepared from 9b (i
v
) as a white solid (0.186 g, 45%), mp: 164–
166 °C. ½a 2D0
ꢂ
= +30.3 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d
7.84–7.80 (2H, overlapped, H16, H19), 7.75 (1H, m, H15), 7.47
(1H, ddd, J = 8.1, 6.9, 1.2 Hz, H17), 7.43–7.38 (3H, overlapped,
H13, H14, H18), 7.29 (1H, td, J = 7.6, 1.3 Hz, H6), 7.15 (1H, ddd,
J = 7.5, 1.3, 0.5 Hz, H4), 7.06 (1H, td, J = 7.5, 0.9 Hz, H5), 6.81 (1H,
d, J = 7.8 Hz, H7), 6.30 (1H, br d, J = 8.3 Hz, H10), 5.67 (1H, dq,
J = 8.1, 6.8 Hz, H11), 3.21 (3H, s, NMe), 2.81, 2.61 (2H, AB system,
J = 14.6 Hz, H8), 1.83 (1H, dq, J = 13.6, 7.4 Hz, CH2CH3A), 1.74 (1H,
dq, J = 13.5, 7.4 Hz, CH2CH3B), 1.47 (3H, d, J = 6.8 Hz, H20), 0.53
(3H, t, J = 7.4 Hz, CH2CH3). 13C NMR (100 MHz, CDCl3): d 180.0
(C2), 167.9 (C9), 144.2 (C7a), 138.2 (C12), 134.0 (C15a), 131.3
(C19a, C3a), 128.9 (C16), 128.4 (C15, C6), 126.7 (C18), 126.0
(C17), 125.4 (C14), 123.7 (C19), 123.2 (C4), 122.9, 122.8 (C5,
C13), 108.3 (C7), 51.4 (C3), 44.6 (C11), 43.5 (C8), 31.2 (CH2CH3),
26.5 (NMe), 20.7 (C20), 8.4 (CH2CH3). IR (KBr) mmax 3269, 3051,
2971, 2932, 1703, 1650, 1545 cmꢀ1. EIMS m/z (relative intensity)
387 ([M+H]+, 21), 188 (12), 170 (100), 146 (17). Anal. Calcd for
4.4.14. 2-((S)-1-Ethyl-3-methyl-2-oxoindolin-3-yl)-N-((R)-1-
(naphthalen-1-yl)ethyl)acetamide (3S)-2l
C25H26N2O2: C, 77.69; H, 6.78; N, 7.25. Found: C, 77.63; H, 6.93;
N, 6.76.
Prepared from 9a (iii) as a white solid (0.186 g, 45%), mp: 152–
154 °C. ½a 2D0
ꢂ
= +13.3 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d
4.5. VCD measurements
7.89 (1H, d, J = 8.3 Hz, H19), 7.83 (1H, dm, J = 8.2 Hz, H16), 7.76
(1H, dd, J = 7.0, 2.3 Hz, H15), 7.47 (1H, ddd, J = 8.0, 6.8, 1.2 Hz,
H17), 7.45–7.38 (3H, overlapped, H13, H14, H18), 7.27 (1H, td,
J = 7.7, 1.2 Hz, H6), 7.21 (1H, ddd, J = 7.4, 1.2, 0.4 Hz, H4), 7.04 (1H,
td, J = 7.5, 0.9 Hz, H5), 6.85 (1H, d, J = 7.8 Hz, H7), 6.55 (1H, br d,
J = 8.2 Hz, H10), 5.74 (1H, dq, J = 8.1, 6.8 Hz, H11), 3.84 (1H, dq,
J = 14.5, 7.3 Hz, CH2CH3A), 3.69 (1H, dq, J = 14.3, 7.2 Hz, CH2CH3B),
2.78, 2.62 (2H, AB system, J = 14.8 Hz, H8), 1.50 (3H, d, J = 6.8 Hz,
H20), 1.31 (3H, s, C3-Me), 1.27 (3H, t, J = 7.2 Hz, CH2CH3). 13C NMR
(100 MHz, CDCl3): d 180.3 (C2), 168.0 (C9), 142.2 (C7a), 138.4
(C12); 134.1 (C15a), 133.7 (C3a), 131.2 (C19a), 128.9 (C16), 128.4,
128.3 (C15, C6), 126.7 (C18), 126.0 (C17), 125.5 (C14), 123.7 (C19),
123.2 (C4), 122.8 (C5, C13), 108.7 (C7), 46.5 (C3), 44.6 (C11), 44.0
(C8), 35.0 (CH2CH3), 24.2 (C3-Me), 20.9 (C20), 12.9 (CH2CH3). IR
IR and VCD spectra were measured using a BioTools ChiralIR
spectrophotometer equipped with dual photoelastic modulation.
Samples of (3R)-2a–m and (3S)-2a–m were dissolved in 150 lL
of CDCl3, placed in a BaF2 cell with a path length of 100 lm and
data were acquired at a resolution of 4 cmꢀ1 over 6 h. Baseline cor-
rections were done by subtracting the spectra from the solvent.
The stability of the samples was monitored by 1H NMR immedi-
ately prior and after VCD measurements.
4.6. X-ray diffraction analyses
Data for (3R)-2f–h, (3S)-2i were acquired on an Agilent Tech-
nologies Gemini A CCD diffractometer using Mo K
a radiation
(KBr) mmax 3259, 3051, 2975, 2935, 1703, 1653, 1612, 1548 cmꢀ1
.
(k = 0.7073 Å). The structures were solved by direct methods using
the SHELXS-9712 program included in the WINGX v1.6 package.13
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 3
summarizes the relevant data and the CCDC deposition numbers.
EIMS m/z (relative intensity) 387 ([M+H]+, 25), 188 (16), 170
(100), 155 (17), 128 (22). Anal. Calcd for C25H26N2O2: C, 77.69; H,
6.78; N, 7.25. Found: C, 77.29; H, 6.89; N, 7.26.
4.4.15. 2-((R)-3-Ethyl-1-methyl-2-oxoindolin-3-yl)-N-((R)-1-
(naphthalen-1-yl)ethyl)acetamide (3R)-2m
Prepared from 9b (i
v
) as a white solid (0.182 g, 44%), mp: 212–
214 °C. ½a 2D0
ꢂ
= +62.8 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d
Please cite this article in press as: Bautista-Hernández, C. I. ; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.
tetasy.2016.06.004

16
C. I. Bautista-Hernández et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 3
Crystal data for (3R)-2f, (3R)-2g, (3R)-2h and (3S)-2i
(3R)-2f
(3R)-2g
(3R)-2h
(3S)-2j
Empirical formula
Formula weight
Crystal size (mm)
Wavelength (Å)
Crystal system
Space group
C
24H24N2O2
C16H22N2O2
274.36
C20H28N2O2
328.44
C21H24N2O3
352.42
372.45
0.40 ꢁ 0.20 ꢁ 0.20
0.40 ꢁ 0.20 ꢁ 0.15
0.45 ꢁ 0.35 ꢁ 0.30
0.45 ꢁ 0.35 ꢁ 0.25
0.71073
0.71073
0.71073
0.71073
monoclinic
P21
orthorhombic
P212121
monoclinic
P21
orthorhombic
P212121
Unit cell dimensions
a (Å)
b (Å)
c (Å)
b (deg)
8.5281(4)
10.4698(4)
12.1072(5)
102.929(4)
1053.62(8)
2, 1.174
8.437(2)
10.331(2)
19.071(4)
90
1662.4(6)
4, 1.096
8.4199(3)
10.3450(2)
11.3849(3)
100.752(3)
974.26(5)
2, 1.120
6.922(1)
12.485(3)
22.139(4)
90
1913.4(7)
4, 1.223
Volume (Å3)
Z, calculated density (mg/
mm3)
Absorption coefficient
0.075
0.073
0.072
0.082
(mmꢀ1
)
F(000)
396
592
356
752
h range for data collection
(deg)
3.13–29.38
3.22–29.68
3.15–29.58
3.08–29.52
Limiting indices
ꢀ11 6 h 6 11, ꢀ14 6 k 6 12,
ꢀ11 6 h 6 11, ꢀ14 6 k 6 14,
ꢀ11 6 h 6 11, ꢀ14 6 k 6 14,
ꢀ9 6 h 6 9, 0 6 k 6 17,
0 6 l 6 16
12,668
ꢀ26 6 l 6 25
79,096
4545
ꢀ15 6 l 6 15
84,604
5225
0 6 l 6 30
65,279
5173
Collected reflections
Unique reflections
Completeness to h (%)
Data/
4926
92.1
3039/1/264
96.9
3378
97.7
4125
98.0
3826
restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2sigma
(I)] (%)
0.980
R1 = 3.8, wR2 = 6.0
1.032
R1 = 4.2, wR2 = 10.9
1.033
R1 = 3.9, wR2 = 9.1
1.028
R1 = 4.0, wR2 = 8.0
R indices (all data) (%)
R1 = 8.2, wR2 = 7.3
R1 = 6.6, wR2 = 12.3
0.162 and ꢀ0.126
R1 = 5.9, wR2 = 10.3
0.172 and ꢀ0.105
R1 = 7.1, wR2 = 9.7
0.133 and ꢀ0.119
Largest diff. peak and hole 0.104 and ꢀ0.112
(e Å3)
CCDC deposition No.
1468092
1468093
1468095
1468096
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Acknowledgments
We are pleased to acknowledge the financial support from
CONACYT (Mexico) grants 183481 and 132048. RECR and CIBH
thank CONACYT – Mexico for fellowships 267995 and 237689,
respectively.
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tetasy.2016.06.004