Absolute configuration determination of 2-(2-oxo-3-indolyl)acetamide derivatives

Article abstract of DOI:10.1016/j.tetasy.2009.09.017

We describe a reliable method for determining the absolute configuration of 2-(2-oxo-3-indolyl)acetamides based on analysis of the ¹H NMR spectra of their phenylethylamide diastereomers. The conformational preferences for two diastereomeric ami

Full text of DOI:10.1016/j.tetasy.2009.09.017

Tetrahedron: Asymmetry 20 (2009) 2374–2389
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Absolute configuration determination of
2-(2-oxo-3-indolyl)acetamide derivatives
a
a
Oscar R. Suárez-Castillo a, , Myriam Meléndez-Rodríguez , Luis Enrique Castelán-Duarte ,
*
Maricruz Sánchez-Zavala a, Ernesto Rivera-Becerril b, 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, México, D. F., 07000 Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe a reliable method for determining the absolute configuration of 2-(2-oxo-3-indolyl)aceta-
mides based on analysis of the 1H NMR spectra of their phenylethylamide diastereomers. The conforma-
tional preferences for two diastereomeric amides were calculated by DFT, which matched well with the
experimental results. X-ray diffraction analysis allowed us to validate the method.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 24 August 2009
Accepted 22 September 2009
Available online 29 October 2009
1. Introduction
uct synthesis and biological important targets, herein we show
that inexpensive enantiomerically pure phenylethylamine (FEA)
The oxindole ring system is a very important structural unit
found in many natural products and biologically active com-
pounds.1 In particular, 1,3,3-trisubtituted oxindole derivatives 1
have been widely applied in the total synthesis of terrestrial and
marine natural products containing the furo- and pyrroloindole
skeletons 22 (Fig. 1). The reduction of oxindoles 1 containing acid,
ester, or amide functionalities on a C3 chain is the frequently used
strategy to synthesize the corresponding systems 2. Many oxindole
derivatives 1 are often found in Nature as optically active com-
pounds in which a key problem is to find a suitable and easy meth-
od to assign their absolute configuration. NMR spectroscopy is a
widely used method for the absolute configuration assignment of
monofunctional and polyfunctional compounds, such as alcohols,
amines, and carboxylic acids, when using Chiral Derivatizing
Agents (CDAs), which contain an aryl ring that selectively directs
its anisotropic cone toward a substituent on the asymmetric unit
of the substrate, thereby reflecting their spatial relationship with
respect to the aryl ring and absolute configuration.3 Although pre-
could be used as a reliable reagent to determine the absolute con-
figuration of C3-chiral oxindoles of type 1. To pursue this achieve-
ment, we used molecular mechanics and DFT calculations to
predict the conformational preferences of two diastereomeric
amides and compared these data with those obtained by 1H NMR
spectroscopy. This absolute configuration assignment methodol-
ogy was confirmed by X-ray diffraction analysis.
2. Results and discussion
To investigate the utility of (R)-phenylethylamine [(R)-FEA] as a
CDA for the absolute configuration assignment of the C3 stereogen-
ic center in 2-oxo-3-indolylacetic acid derivatives 9a–e containing
a variety of alkyl groups at the N1 and C3 positions, diastereomeric
amides 11a–e were synthesized according to Scheme 1. Thus,
treatment of 3 with KOH/TBAB/THF and subsequent alkylation
with MeI, EtBr, or BnBr gave N-alkylindoles 4a–c in 92%, 90%, or
87% yield, respectively, which were oxidized with DMSO/HCl6 at
room temperature to afford the corresponding 2-(2-oxo-3-indo-
lyl)acetic acid derivatives 5a–c (68–71%) together with methyl 2-
(2-oxo-3-indolyl)acetate derivatives 6a–c (21–25%). Methyl ester-
ification of oxindoles 5a–c with MeOH/H+ at reflux6 afforded esters
6a–c (83–86% overall yield from 4a–c). Subsequent C3 alkylation of
6a–c and 8 with the corresponding alkyl halide MeI, EtBr, or BnBr
using K2CO3/acetone gave N1,C3-dialkyloxindole derivatives 7a–e
(86–91% yields).7 Alkaline hydrolysis of esters 7a–e (NaOH/H2O/
MeOH) followed by acidification with HCl/H2O gave carboxylic
acids 9a–e (85–89% yields).
dictions of absolute configuration of
a-chiral carboxylic acids by
this means are very well documented, the absolute configuration
assignment of chiral b-branched carboxylic acids has scarcely been
investigated.4 Among several CDAs available for the configura-
tional assignment of a- and b-branched carboxylic acids, 1-aryleth-
ylamines are the most widely used reagents due to the
conformational properties of the resulting RC(@O)NHCH–(Me)Ar
substructural unit.4a,b,5 As 2-(2-oxo-3-indolyl)acetic acid deriva-
tives 1 represent a very important structural unit in natural prod-
With racemic samples of 9a–e now being readily available,
* Corresponding author. Tel.: +52 771 71 72000x2206; fax: +52 771 71
72000x6502.
amide derivatization with (R)-a-FEA 10 [(R)-10] was carried out
by activation of carboxylic acids 9 with ClCO2Et and Et3N8 followed
E-mail address: osuarez@uaeh.edu.mx (O.R. Suárez-Castillo).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.09.017

O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
2375
R2
R2
4
5
R3
R3
3a
R4
Y
3
6
O
X
7a
2
7
N
N
R1
2
R1
1
R1 = H, Me, Bn,
X = O, NH, NMe, NHCH(Me)Ph
Y = O, H
R2 = H, Me, CH2OH,
R3 = H, OMe, Br
,
R4 = OH, CH2OH, CH2NMe2, CH2NO2,
NHCbz, CH2COMe, CO2H, CO2Me,
CO2Et, CHO, CN, CONHMe
Figure 1.
by reaction with the amine to give equimolar diastereomeric mix-
tures of (3R,11R)-11a–e (41–43%) and (3S,11R)-11a–e (40–42%), as
evidenced by 1H NMR of the reaction crudes, which indicated that
no kinetic resolution occurred in any case. The diastereomeric
amides (3R,11R)-11a–e and (3S,11R)-11a–e were easily separated
by column chromatography due to their different Rf values (Table
1) to afford enantiomerically pure isomers (de >99% as determined
by 1H NMR).
Using conformational arguments, the structures in Figure 4
(3R,11R)-11a (A) and (3S,11R)-11a (B) always have anti-periplanar
(ap) (C@O)–(N–H)–(C–H) arrays (v
and h angles).5 These ap confor-
mations were supported by X-ray crystallographic analyses and
DFT calculations of both diastereomers of 11a. As shown in Figure
4, free rotation around the C8–C@O bond generates the three main
conformers I–III. In conformer II, the shift of the N1-Me protons of
the (3R,11R)-11a diastereomer and the C3-Me protons of the
(3S,11R)-11a diastereomer should always be upfield as a result of
the anisotropic shielding of the phenyl ring. Therefore conformer
II is the predominant rotamer of diastereomeric amides 11a.
The above-mentioned methodology of 1H NMR configuration
assignment was extended to include 2-oxindole carboxylic amides
with substituents other than a methyl group at N1 and C3 posi-
tions, including the substrates shown in Table 2; the results con-
Interpretation of the 1H NMR spectra of the two resulting sets of
diastereomers (3R,11R)-11a–e and (3S,11R)-11a–e, combined with
the evaluation of their representative low energy conformations,
allowed absolute configuration assignment at the C3 stereogenic
center of the chiral oxindole unit substrate. Thus, both diastereo-
meric amides 11a were used as representative models for this goal.
The 1H NMR spectra allowed discrimination of the amides
(3R,11R)-11a and (3S,11R)-11a since these compounds showed
firm the applicability of the methodology. The
D
dRS values
large enough chemical shift differences (
D
d
RS = dR ꢀ dS, where the
obtained for amides 11b–e have the same sign for the N1–CH2–R
and C3–CH2–R groups and for the C8 AB system, as those obtained
for 11a, which suggests that amides 11a–e adopt similar confor-
R and S descriptors refer to the stereogenic C3 configuration in
the oxindole moiety4c) for diagnostic signals N1-Me, C3-Me, and
H8A (Table 2). Essentially, these
D
d
RS values arise from the diamag-
mations at the C3–C8–C(@O)–N(H)–C11 fragment (u, /,
v, and h
netic influence of the aromatic (R)-FEA moiety on the NMR signals
of N1-Me and C3-Me groups in the (3R)- and (3S)-stereogenic cen-
ters of the oxindole skeleton. As shown in Figure 2 the signals due
to N1-Me anisochronous protons, which are far from the C3 stere-
ogenic Cb-center, show a higher chemical shift difference [and sign
angles). As shown in Table 2, the +
D
dRS magnitude values (0.03–
0.07) for the C3–CH2–R group in oxindole-amides 11a–e are com-
parable to those reported for other types of amides containing FEA
as a CDA and a methyl group at the b-position.4a,b However, the
ꢀ
D
dRS magnitude values (0.09–0.23) for the N1–CH2–R group are
(ꢀ
D
d
RS)] than those of the closer C3-Me group (+
D
d
RS) (Fig. 2, Table
longer than the Dd values reported for the substituents at positions
2). Also, considering the polarity of diastereoisomeric amides 11a
(Table 1), it is shown that the N1-Me group signal of the less polar
(3R,11R)-11a appears at lower frequency than that of the more po-
lar (3S,11R)-11a (Fig. 2), while the C3-Me signal for the more polar
(3S,11R)-11a appears at lower frequency than that of the less polar
(3R,11R)-11a.
other than the b position in b-branched substituted carboxylic
acids,4a,b suggesting that in our case, FEA is a more reliable reagent
to assign the absolute configuration of chiral amides 11a–e.
Further evidence to explain the
Dd
RS values observed in Figure 2
and Table 2 was provided when a systematic molecular modeling
protocol with Monte Carlo searching10–12 and geometry optimiza-
tion using DFT calculations at the B3LYP/6–31G(d),5,12,13 and
B3LYP/DGDZVP14,15 levels of theory was applied to amides
(3R,11R)-11a and (3S,11R)-11a.16 According to the conformer con-
tribution,17,18 only 5 conformers arose as relevant components
(99.3%) for amide (3R,11R)-11a and only 4 conformers (99.7%) for
The assumption that the aromatic (R)-FEA moiety influences the
chemical shifts of N1-Me and C3-Me groups in 11a–e is reinforced
when considering the d values (range 3.17–3.29 ppm)2b–f,9 for the
N-Me group signals in several derivatives of type 1 without an aro-
matic moiety at the C -phenyethylacetamide unit at C3. The ob-
a
served signs for
D
dRS between both diastereomers of 11a could
amide (3S,11R)-11a, which are shown in Figures 5 and 6,
be accounted for by using the representation proposed in Figure
3, where the substituent arrangement around C3 in (3R,11R)-11a
shows that the dominating conformation of the amide should be
that in which the orientation of the magnetic anisotropy imposed
by the phenyl group of the (R)-FEA moiety should spend enough
time to shield the protons of the N1-Me group, whereas those in
the C3-Me group remain unaffected. In the (3S,11R)-11a derivative,
the C3-Me group is protected while the N1-Me group is unaffected
(Fig. 3). Therefore, the N1-Me group will be more shielded in
(3R,11R)-11a than in (3S,11R)-11a, while the C3-Me group will
be more shielded in (3S,11R)-11a than in (3R,11R)-11a.
respectively.
It is worth noting that an anti-disposition between C11–H and
N10–H was invariably detected as the most stable conformer irre-
spective of the diastereomeric amide studied showing h values be-
tween ꢀ135.7° and 172.6° for the (3R,11R)-11a conformers and
between ꢀ137.2° and 168.5° for the (3S,11R)-11a conformers. This
result implies that the Z-conformer at the C@O–NCH moiety is al-
a
ways significantly preferred over the E-conformer and leaves the
free conformation around the u and / angles (Fig. 4) as the dominat-
ing process in both diastereomers. Conformers 11aA and 11aB are
depicted as the most populated in the conformational equilibria

2376
O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
1). KOH, TBAB
CO2Me
CO2Me
CO2H
THF
DMSO
HCl
2). MeI, EtBr
or BnBr
O
N
H
N
R
N
R
4a: R = Me
4b: R = Et
4c: R = Bn
5a: R = Me
5b: R = Et
5c: R = Bn
3
TsOH
MeOH
+
MeI
K2CO3
R2
MeI, EtBr
or BnBr
CO2Me
CO2Me
CO2Me
acetone
for 7a
K2CO3
acetone
for 7b-e
O
O
O
N
H
N
N
R
R1
7a: R1 = R2 = Me
8
6a: R = Me
6b: R = Et
6c: R = Bn
7b: R1 = Me, R2 = Et
7c: R1 = Me, R2 = Bn
7d: R1 = Et, R2 = Me
7e: R1 = Bn, R2 = Me
1. NaOH/H2O
MeOH
2. H+/H2O
9a: R1 = R2 = Me
R2
8
4
5
9b: R1 = Me, R2 = Et
9c: R1 = Me, R2 = Bn
9d: R1 = Et, R2 = Me
9e: R1 = Bn, R2 = Me
CO2H
3a
3
2
6
O
7a
7
N
R1
1. Et3N, ClCO2Et
2. (R)-α-FEA (10) [(R)-10]
3. cc separation
H
N
H
N
11
R2
9
R2
4
8
5
3a
6
3
O
O
+
O
2
O
7a
7
N
N
R1
R1
(3R,11R)-11a: R1 = R2 = Me
(3S,11R)-11a: R1 = R2 = Me
(3R,11R)-11b: R1 = Me, R2 = Et
(3R,11R)-11c: R1 = Me, R2 = Bn
(3R,11R)-11d: R1 = Et, R2 = Me
(3R,11R)-11e: R1 = Bn, R2 = Me
(3S,11R)-11b: R1 = Me, R2 = Et
(3S,11R)-11c: R1 = Me, R2 = Bn
(3S,11R)-11d: R1 = Et, R2 = Me
(3S,11R)-11e: R1 = Bn, R2 = Me
Scheme 1. Synthesis of diastereomeric amides 11a–e.
for both diastereomeric amides (3R,11R)-11a (64.9% and 20.4%)
(Fig. 5) and (3S,11R)-11a (69.2% and 17.6%) (Fig. 6), while the
remaining conformers are minor contributors. It is interesting to
note that for (3R,11R)-11a, the global minimum structure 11aA
has the CDA phenyl ring pointing toward the N1-Me group in exact
coincidence with conformer II presented in Figure 4, trace A. Regard-
ing (3S,11R)-11a, the global minimum structure 11aA has the CDA
phenyl group oriented in close proximity to the C3-Me group and
also in coincidence with conformer II as shown in Figure 4, trace B.
In both cases, the global minimum of both amides corresponded
very well with those predicted in Figure 4 and with the experimental
results. Thus, computational results reinforce the assignment of the
absolute configuration in (3R,11R)-11a and (3S,11R)-11a.
From the minimum energy conformational analysis of (3R,11R)-
11a, a hydrogen bond between the amide hydrogen and the car-
bonyl oxygen atom would be expected, but a detailed analysis of
the geometry of this fragment revealed that such a hydrogen bond
is only allowed for conformer (3R,11R)-11aB (Fig. 5). In the case of
amide (3S,11R)-11a such a hydrogen bond is formed for the most
Table 1
Rfa values of diastereomeric amides 11a–e
Compound
(3R,11R)-Diastereomer Rf
(3S,11R)-Diastereomer Rf
11a
11b
11c
11d
11e
0.34
0.38
0.48
0.44
0.58
0.18
0.28
0.32
0.24
0.40
a
Determined by TLC (Silica gel F254 coated aluminum sheets 0.25 mm thickness)
using EtOAc/hexane (1:2, v/v).

O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
2377
Table 2
Significant
D
dRS values for (3R,11R)-11a–e and (3S,11R)-11a–e, and
D
dSR for (3S,11S)-11a,f and (3R,11S)-11a,f
0.07
0.06
0.03
0.06
Me -0.02
0.01
-0.03
0.06
0.01
0
-0.03
-0.01
-0.02
-0.01
(R)-FEA
(R)-FEA
(R)-FEA
A)a
O
O
O
O
O
O
N
N
N
-0.05
-0.05
-0.05
Me
Me
Me
-0.16
-0.19
-0.19
11a
11c
11b
0.07
Me
0.07
Me
-0.02
-0.02
-0.04
-0.05
-0.02
-0.01
-0.02
(R)-FEA
(R)-FEA
O
O
O
O
N
N
-0.03
-0.07
-0.09, -0.15
-0.09, -0.23
11d
11e
0.07
0.02
0.06
0.06
0.02
0.05 -0.01
0
-0.03
Me -0.02
-0.02
-0.02
(S)-FEA
B)a
(S)-FEA
O
O
O
O
N
N
-0.05
-0.08
-0.05
-0.13, -0.27
Me
-0.16
11f
11a
-0.04
-0.02
a DdRS Values (dR ꢀ dS) were calculated by subtracting the proton chemical shifts of (3S)-oxyndole-(11R)-FEA from those of (3R)-oxyndole-(11R)-FEA (A) while
(dS ꢀ dR) were calculated by subtracting the proton chemical shifts of (3R)-oxyndole-(11S)-FEA from those of (3S)-oxyndole-(11S)-FEA (B).4c
D
dSR values
abundant (3S,11R)-11aA conformer (Fig. 6). Thus, we envisioned
that the solvent polarity, apart from intramolecular interactions,
should govern the orientation of the substituents in amides 11a–
e. Therefore, we next examined the 1H NMR spectra of amides
(3R,11R)-11a and (3S,11R)-11a, using Cl2CDCDCl2, CD3OD, DMSO-
d6, CD3CN, and acetone-d6 (Table 3). The d values of diagnostic sig-
nals in both diastereomeric amides in Cl2CDCDCl2 are consistent
with trends observed in CDCl3, although d decreased smoothly.
However, in solvents more polar than CDCl3 no significant differ-
ences in d for the N1-Me and C3-Me protons were observed be-
tween both (3R,11R)-11a and (3S,11R)-11a diastereomers. An
additional point of interest in Table 3 is related to the chemical
shifts for protons H8. The chemical shifts of these AB system vary
notably between amides (3R,11R)-11a and (3S,11R)-11a when the
spectra were obtained in CD3OD and CD3CN (Table 3), and the
same trend was observed between amides (3R,11R)-11c–e and
(3S,11R)-11c–e (Table 4). In the case of amides 11a,c–e the differ-
The reliability of our methodology for the absolute configura-
tion assignment of 2-(2-oxo-3-indolyl)acetamide derivatives
11a–e by 1H NMR was supported by X-ray diffraction analysis of
amides (3R,11R)-11a, (3S,11R)-11a, (3S,11R)-11b, (3S,11R)-11c,
(3R,11R)-11d, and (3S,11R)-11d whose absolute configuration
structures are shown in Figure 7. Thus, these results validate the
method for the assignment of the absolute configuration of oxin-
dole carboxylic amides 11a–e by 1H NMR using (R)-FEA as a CDA.
As Nature usually produces only one chiral enantiomer or dia-
stereomer, it was important to use (S)-FEA [(S)-10] as a CDA to re-
solve a mixture of ( )-9a and to study its effect on the chemical
shifts for N1-Me and C3-Me signals in order to establish the abso-
lute configuration of chiral acid derivatives of type 9 using both
FEA enantiomers. As expected, preferential shielding of the N1-
Me group was observed in the diastereomer (3S,11S)-11a
(D
d
SR = ꢀ0.16), whereas preferential shielding of the C3-Me group
was observed in the (3R,11S)-11a one (Dd
SR = 0.06) (Table 2).
ence in chemical shift for the H8A and H8B signals (
D
d) was always
Amides (3R,11S)-11a and (3S,11S)-11a gave suitable crystals for
X-ray diffraction analysis and the corresponding absolute configu-
ration structures are shown in Figure 8. According to the aforemen-
tioned methodology, it is now possible to establish the absolute
configuration of reported amides8 (3S,11S)-11f and (3R,11S)-11f
(Table 2). In the less polar (3S,11S)-11f diastereomer (Rf = 0.60,
EtOAc/hexane, 1:1 v/v), the N1–CH2–R group appears at lower fre-
quency than that of the more polar (3R,11S)-11f (Rf = 0.27, EtOAc/
higher in amides (3S,11R)-11a,c–e than in the (3R,11R)-11a,c–e
stereoisomer (Tables 3 and 4). Furthermore, in amides 11a–e the
average chemical shift for H8A and H8B was always higher in
(3S,11R)-11a–e than in (3R,11R)-11a–e. Thus, we can initially pre-
dict the relative configuration of each amide 11 by inspection of
the chemical shift difference for the C8 AB protons when measured
in CD3OD or in CD3CN.

2378
O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
Figure 2. Partial 1H NMR spectra illustrating the
D
dRS for N1-Me, H8A, and C3-Me in (3R,11R)-11a and (3S,11R)-11a.
O
Me
H
N
Me
3 O
N
N
H
Me
11
O
MRe
R
O
N
Me
Me
(3R,11R)-11a
Shielding on N-Me
H
N
Me
Me
O
3
H
R
S
N
H
11
O
Me
O
O
Me
N
N
Me
Me
(3S,11R)-11a
Shielding on C3-Me
N1-Me: ΔδRS < 0
C3-Me: ΔδRS > 0
Figure 3. N1-Me and C3-Me anisotropic shielding in amides (3R,11R)-11a and (3S,11R)-11a.
hexane, 1:1 v/v) compound. On the contrary, the C3–CH2–R signal
for the more polar (3R,11S)-11f appears at lower frequency than
that of the less polar (3S,11S)-11f.
commercially available enantiomer of FEA (R)-10 or (S)-10 and
subsequent 1H NMR analysis of their corresponding amides 11.
A
general assumption might be made for the configuration
assignment as follows: (3R,11R)- and (3S,11S)- stereoisomers of
amides of type 11 will present the N1–CH2–R proton signal at
3. Conclusion
a lower frequency value (ꢀ
D
dRS or ꢀ
Dd
SR) and the C3–CH2–R
proton signal at a higher frequency value (+D Dd
dRS or + SR) when
In conclusion, we have demonstrated that the absolute con-
figuration assignment of 2-(2-oxo-3-indolyl)acetic acid deriva-
compared to their corresponding (3S,11R)- and (3R,11S)-
diastereomers.
tives
9 could be achieved by its derivatization with either

O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
2379
O
H
O
H
χ
ϕ
Me
H
Me
Me
Me
N
H
N
O
H
R
N
H
O
H
N
Me
Me
θ
Me
R O
φ
O
A
B
H
H
N
H
H
H
N
Me
Me
II
I
III
O
H
O
H
Me
Me
H
N11
H
O
H
Me
H
Me
8
N
H
R
N
H
9
Me
Me
3
H
S
Me
O
O
O
N
H
N
H
N
Me
H
Me
II
I
III
Figure 4. Preferred conformations of amides (3R,11R)-11a (A) and (3S,11R)-11a (B).
(1 ꢁ 10 mL), saturated solution of NaHCO3 (1 ꢁ 10 mL), brine
(1 ꢁ 10 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuum. Resultant crudes 4a–c were purified by flash col-
umn chromatography on silica gel with EtOAc/hexane 1:10 for 4a
and 4b and 1:8 for 4c.
4. Experimental
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 ob-
tained on a JEOL Eclipse 400 spectrometer and the 300 and
75 MHz 1H and 13C NMR spectra were obtained on a Varian Mer-
cury-300 spectrometer using CDCl3, DMSO-d6, Cl2CDCDCl2, CD3OD,
CD3CN, or acetone-d6 as the solvents and TMS as the internal refer-
ence. For complete assignments 2D NMR, HMQC, HSQC, HETCOR,
and HMBC spectra were used. Data are reported as follows: chemical
shift in ppm from TMS, integration, multiplicity (s = singlet, d = dou-
blet, t = triplet, q = quartet, quintet, m = multiplet, br = broad), cou-
pling 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 carrier gas (1 mL/min), pro-
gramed from 70 °C to 250 °C at a rate of 30 °C/min, with the injector
temperature at 200 °C. MS analyses were obtained in the electron
impact (EI) mode at an ionizing voltage of 70 eV on a Hewlett Pack-
ard 5989-A spectrometer. High-resolution (HR) mass spectra were
measured on a JEOL JMS-SX 102A mass spectrometer at Instituto
de Química, UNAM-México and at the UCR Mass Spectrometry Facil-
ity, University of California, Riverside. Microanalytical determina-
4.3. Methyl 2-(1-methyl-1H-3-indol-3-yl)acetate 4a
Prepared from 3 as a yellow oil (1.98 g, 92%).19 1H NMR
(300 MHz, CDCl3): d 7.58 (1H, br d, J = 7.7 Hz, H4), 7.27 (1H, br d,
J = 8.0 Hz, H7), 7.21 (1H, td, J = 7.4, 1.1 Hz, H6), 7.11 (1H, td,
J = 7.4, 1.5 Hz, H5), 7.00 (1H, s, H2), 3.75 (2H, s, H8), 3.70 (3H, s,
H11), 3.67 (3H, s, H10); 13C NMR (75 MHz, CDCl3): d 172.5 (C9),
136.8 (C7a), 127.6 (C2), 127.5 (C3a), 121.7 (C6), 119.1 (C5), 118.8
(C4), 109.2 (C7), 106.6 (C3), 51.8 (C10), 32.5 (C11), 31.0 (C8).
4.4. Methyl 2-(1-ethyl-1H-3-indol-3-yl)acetate 4b
Prepared from 3 as a yellow oil (2.06 g, 90%). 1H NMR (300 MHz,
CDCl3): d 7.59 (1H, ddd, J = 7.8, 1.4, 0.8 Hz, H4), 7.29 (1H, dt, J = 8.3,
1.1 Hz, H7), 7.20 (1H, ddd, J = 8.1, 6.9, 1.1 Hz, H6), 7.10 (1H, ddd,
J = 8.0, 6.9, 1.4 Hz, H5), 7.07 (1H, br s, H2), 4.08 (2H, q, J = 7.3 Hz,
H11), 3.75 (2H, d, J = 0.8 Hz, H8), 3.67 (3H, s, H10), 1.41 (3H, t,
J = 7.3 Hz, H12); 13C NMR (75 MHz, CDCl3): d 172.5 (C9), 135.8
(C7a), 127.7 (C3a), 125.9 (C2), 121.5 (C6), 119.0 (C5), 118.9 (C4),
109.3 (C7), 106.7 (C3), 51.8 (C10), 40.7 (C11), 31.0 (C8), 15.3 (C12);
IR (CHCl3) mmax 3056, 2953, 2920, 2850, 1730, 1613, 1467 cmꢀ1
;
tions were performed on
a Perkin–Elmer 2400 series PCII
EIMS m/z (relative intensity) 217 (M+, 41), 158 (100), 130 (10). FAB-
HRMS m/z calcd for C13H15NO2: 217.1103, found: 217.1099.
apparatus. Optical rotation measurements were performed on a Per-
kin–Elmer 341 polarimeter. Analytical thin-layer chromatography
(TLC) was done 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.
4.5. Methyl 2-(1-benzyl-1H-3-indol-3-yl)acetate 4c
Prepared from 3 as a yellow oil (2.56 g, 87%). 1H NMR (300 MHz,
CDCl3): d 7.61 (1H, br d, J = 6.8 Hz, H4), 7.27–7.17 (4H, m, H7, H14–
H16), 7.15 (1H, td, J = 7.0, 1.5 Hz, H6), 7.10 (1H, br t, J = 7.3 Hz, H5),
7.07 (2H, dd, J = 6.6, 2.2 Hz, H13, H17), 7.06 (1H, br s, H2), 5.19 (2H,
s, H11), 3.75 (2H, s, H8), 3.65 (3H, s, H10); 13C NMR (75 MHz,
CDCl3): d 172.3 (C9), 137.3 (C12), 136.4 (C7a), 128.6 (C14,C16),
127.8 (C3a), 127.5 (C15), 127.0 (C2), 126.7 (C13,C17), 121.9 (C6),
119.3 (C5), 119.0 (C4), 109.7 (C7), 107.4 (C3), 51.8 (C10), 49.8
(C11), 31.0 (C8); IR (CHCl3) mmax 3059, 3030, 2950, 2918, 1736,
1615, 1467 cmꢀ1; EIMS m/z (relative intensity) 279 (M+, 65), 221
(100), 91 (38). Anal. Calcd for C18H17NO2: C, 77.40; H, 6.13; N,
5.01. Found: C, 77.05; H, 6.19; N, 5.41.
4.2. General procedure for the preparation of N-alkyl indoles
4a–c
To a solution of indole-3-acetic acid methyl ester 3 (2 g,
10.6 mmol) in dry THF (20 mL) were added the appropriate alkyl
halide (MeI, 2.6 mL, EtBr, 3.2 mL, or BnBr, 5.0 mL, 42 mmol), TBAB
(212 mg, 0.66 mmol), and KOH (2.35 g, 42 mmol). The mixture was
stirred at room temperature over 8 h and filtered off through a Cel-
ite pad. The solvent was removed under reduced pressure and the
residue was dissolved in CH2Cl2 (30 mL), washed with H2O

2380
O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
Figure 5. Optimized geometries, calculated energies (E/kcal/mol), relative energy differences (Erel/kcal/mol) and populations (p in %) for (3R,11R)-11aA–E conformers
obtained at the DFT B3LYP/DGDZVP level of theory.
4.6. General procedure for the preparation of oxindoles 5a–c
and 6a–c from 4a–c
layers were washed with brine (2 ꢁ 30 mL), dried over anhy-
drous Na2SO4, filtrated, and evaporated to dryness in vacuum.
The resultant crude products 5a–c were purified by flash chro-
matography on silica gel using EtOAc/hexane 3:2 for 5a and 5b
and 1:1 for 5c.
To a solution of the appropriate indoles 4a–c (0.02 mol) in
DMSO (7 mL, 10 mmol) was added an aqueous solution (36%) of
HCl (46 mL, 0.54 mol) and the solution was stirred at room temper-
ature for 2.5 h. The mixture was diluted with water (100 mL), neu-
tralized with a saturated solution of NaHCO3, and extracted with
EtOAc (6 ꢁ 70 mL). The organic layer was washed with brine
(2 ꢁ 100 mL), dried over anhydrous Na2SO4, filtered, and evapo-
rated to dryness in vacuum. The resultant crude products 6a–c
were purified by flash column chromatography on silica gel eluting
with EtOAc/hexane 1:3.
4.7. General procedure for the esterification of oxindoles 5a–c
To a solution of the appropriate oxindoles 5a–c (13.2 mmol) in
MeOH (30 mL) was added p-toluenesulfonic acid (100 mg) and
heated at reflux for 4 h. After cooling to room temperature the
MeOH was evaporated under reduced pressure and the residue
was dissolved in EtOAc (30 mL). The organic phase was washed
The aqueous phase was acidified to pH 1 with aqueous HCl
and extracted with EtOAc (4 ꢁ 30 mL). The combined organic
with
a
saturated solution of NaHCO3 (3 ꢁ 20 mL), brine
(3 ꢁ 20 mL), dried over Na2SO4 and evaporated to dryness in vac-

O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
2381
Figure 6. Optimized geometries, calculated energies (E/kcal/mol), relative energy differences (Erel/kcal/mol) and population (p in %) for (3S,11R)-11aA–D conformers obtained
at the DFT B3LYP/DGDZVP level of theory.
Table 3
Diagnostic chemical shifts (d)a for N1-Me, C3-Me, and CH2 groups and
D
d values for the AB system in (3R,11R)-11a and (3S,11R)-11a using various solvents
Solvent
Chemical shift, d (ppm)
(3S,11R)-11a
(3R,11R)-11a
N1-Me
C3-Me
H8A, H8B
D
d
N1-Me
C3-Me
H8A, H8B
Dd
CDCl3
Cl2CDCDCl2
CD3OD
DMSO-d6
CD3CN
(CD3)2CO
3.06
3.01
3.22
3.06
3.12
3.13
1.42
1.32
1.36
1.20
1.30
1.30
2.77, 2.64
2.71, 2.53
2.84
2.76, 2.61
2.75
0.13
0.18
0
0.15
0
3.22
3.12
3.21
3.05
3.12
3.18
1.36
1.28
1.35
1.20
1.28
1.32
2.80, 2.66
2.76, 2.54
2.91, 2.88
2.81, 2.68
2.81, 2.77
2.86, 2.79
0.14
0.22
0.03
0.13
0.04
0.07
2.79, 2.70
0.09
a
Room temperature measurements at 300 MHz.
uum. The resultant crude products 6a–c were purified by flash
column chromatography on silica gel eluting with EtOAc/hexane
1:3.
Table 4
Chemical shift (d, ppm) and
D
d (ppm) values for H8 of (3R,11R)-11b–e and (3S,11R)-
Chemical shift, d (ppm)
11b–e in CD3OD and CD3CNa
Compound
CD3OD
H8A, H8B
2.83
CD3CN
H8A, H8B
4.8. 2-(1-Methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetic acid 5a
D
d
D
d
Prepared from 4a as colorless crystals (2.91 g, 71%), mp:
167–168 °C (EtOAc/hexane). Lit.20 168–170 °C. 1H NMR
(400 MHz, DMSO-d6): d 11.0 (1H, br s, H10), 7.31 (1H, br d,
J = 7.3 Hz, H4), 7.30 (1H, br t, J = 8.1 Hz, H6), 7.04 (1H, br t,
J = 7.4 Hz, H5), 7.00 (1H, br d, J = 7.7 Hz, H7), 3.72 (1H, dd,
J = 6.6, 5.1 Hz, H3), 3.15 (3H, s, H11), 2.97 (1H, dd, J = 17.1,
4.6 Hz, H8A), 2.77 (1H, dd, J = 17.2, 6.9 Hz, H8B); 13C NMR
(100 MHz, DMSO-d6): d 177.4 (C2), 173.2 (C9), 145.4 (C7a),
(3R,11R)-11b
(3S,11R)-11b
(3R,11R)-11c
(3S,11R)-11c
(3R,11R)-11d
(3S,11R)-11d
(3R,11R)-11e
(3S,11R)-11e
0
0
0.02
0.05
0
0.03
0
0.04
2.71
0
2.88
2.77, 2.75
2.86, 2.84
2.93, 2.86
2.71
2.77, 2.74
2.80
0.02
0.02
0.07
0
0.03
0
3.00, 2.98
3.06, 3.01
2.83
2.88, 2.85
2.90
2.96, 2.92
2.87, 2.82
0.05
a
Room temperature measurements at 300 MHz.

2382
O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
(3R,11R)-11a
(3S,11R)-11a
(3S,11R)-11b
(3S,11R)-11c
(3R,11R)-11d
(3S,11R)-11d
Figure 7. X-ray diffraction structures of (3R,11R)-11a, (3S,11R)-11a, (3S,11R)-11b, (3S,11R)-11c, (3R,11R)-11d, and (3S,11R)-11d.
129.6 (C3a), 128.9 (C6), 124.4 (C4), 122.9 (C5), 109.3 (C7), 42.4
(C3), 35.2 (C8), 27.1 (C11); IR (KBr) mmax 3440, 2923, 2889,
2595, 2525, 1725, 1671, 1611, 1200, 1177 cmꢀ1; EIMS m/z (rel-
ative intensity) 205 (M+, 47), 159 (100).
4.9. 2-(1-Ethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetic acid 5b
Prepared from 4b as colorless crystals (3.10 g, 71%), mp: 182–
184 °C (EtOAc/hexane). 1H NMR (400 MHz, DMSO-d6): d 12.00

O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
2383
(3S,11S)-11a
(3R,11S)-11a
Figure 8. X-ray diffraction structures of (3S,11S)-11a and (3R,11S)-11a.
(1H, br s, H10), 7.31 (1H, d, J = 7.3 Hz, H4), 7.28 (1H, t, J = 8.0 Hz,
H6), 7.02 (1H, d, J = 7.3 Hz, H7), 7.01 (1H, t, J = 8.0 Hz, H5), 3.75–
3.61 (3H, m, H3 y H11), 2.94 (1H, dd, J = 16.9, 4.4 Hz, H8A), 2.76
(1H, dd, J = 16.9, 6.6 Hz, H8B), 1.12 (3H, t, J = 7.3 Hz, H12); 13C
NMR (100 MHz, DMSO-d6): d 176.2 (C2), 172.2 (C9), 143.5 (C7a),
128.8 (C3a), 128.0 (C6), 123.6 (C4), 121.8 (C5), 108.4 (C7), 41.4
(C3), 34.2 (C8,C11), 12.5 (C12); IR (KBr) mmax 3434, 3030, 2970,
2927, 1728, 1654, 1609, 1467 cmꢀ1; EIMS m/z (relative intensity)
219 (M+, 35), 173 (100), 160 (28), 159 (62), 158 (92). Anal. Calcd
for C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.56; H,
5.98; N, 6.34.
4.12. Methyl (1-ethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate 6b
Prepared from 4b (1.03 g, 22%) and from 5b (2.56 g, 83%) as a
yellow oil. 1H NMR (400 MHz, CDCl3): d 7.28 (1H, t, J = 7.7 Hz,
H6), 7.25 (1H, d, J = 7.7 Hz, H4), 7.02 (1H, t, J = 7.3 Hz, H5), 6.87
(1H, d, J = 7.7 Hz, H7), 3.85–3.71 (3H, m, H3, H11), 3.67 (3H, s,
H10), 3.08 (1H, dd, J = 16.8, 4.4 Hz, H8A), 2.80 (1H, dd, J = 16.9,
8.1 Hz, H8B), 1.27 (3H, t, J = 7.3 Hz, H12); 13C NMR (100 MHz,
CDCl3): d 176.3 (C2), 171.5 (C9), 143.4 (C7a), 128.4 (C3a), 128.3
(C6), 124.0 (C4), 122.3 (C5), 108.3 (C7), 52.0 (C10), 41.8 (C3),
34.8 (C11), 34.7 (C8), 12.6 (C12); IR (CHCl3) mmax 3056, 2977,
2953, 2935, 1739, 1715, 1614, 1468 cmꢀ1; EIMS m/z (relative
intensity) 233 (M+, 64), 174 (54), 173 (100), 158 (56). FABHRMS
m/z calcd for C13H15NO3: 233.1052, found: 233.1050.
4.10. 2-(1-Benzyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetic acid 5c
Prepared from 4c as colorless crystals (3.85 g, 68%), mp: 126–
127 °C (EtOAc). 1H NMR (300 MHz, CDCl3): d 10.69 (1H, br s,
H10), 7.32–7.20 (6H, m, H4, H13–H17), 7.16 (1H, br t, J = 7.6 Hz,
H6), 7.00 (1H, td, J = 7.5, 0.9 Hz, H5), 6.71 (1H, br d, J = 7.8 Hz,
H7), 4.99, 4.85 (2H, AB system, J = 15.7 Hz, H11), 3.87 (1H, dd,
J = 7.5, 4.7 Hz, H3), 3.16 (1H, dd, J = 17.3, 4.7 Hz, H8A), 2.95 (1H,
dd, J = 17.3, 7.5 Hz, H8B); 13C NMR (75 MHz, CDCl3): d 177.0 (C2),
176.1 (C9), 143.2 (C7a), 135.5 (C12), 128.7 (C14,C16), 128.3 (C6),
127.7 (C15), 127.6 (C3a), 127.2 (C13,C17), 123.8 (C4), 122.7 (C5),
109.3 (C7), 43.9 (C11), 41.6 (C3), 34.5 (C8); IR (CHCl3) mmax 3061,
3031, 2928, 1712, 1614, 1490, 1467 cmꢀ1; EIMS m/z (relative
intensity) 281 (M+, 69), 235 (94), 91 (100). FABHRMS m/z calcd
for C17H14NO3 (MꢀH+): 280.0974, found: 280.097.
4.13. Methyl 2-(1-benzyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-
acetate 6c
Prepared from 4c (1.48 g, 25%) and from 5c (3.35 g, 86%) as a
white solid, mp: 107–108 °C (Et2O/hexane). 1H NMR (400 MHz,
CDCl3): d 7.36–7.22 (5H, m, H13–H17), 7.24 (1H, br d, J = 7.0 Hz,
H4), 7.15 (1H, br t, J = 7.7 Hz, H6), 6.98 (1H, br t, J = 7.3 Hz, H5),
6.72 (1H, br d, J = 7.7 Hz, H7), 4.93, 4.91 (2H, AB system,
J = 15.8 Hz, H11), 3.87 (1H, dd, J = 8.0, 4.7 Hz, H3), 3.65 (3H, s,
H10), 3.13 (1H, dd, J = 16.8, 4.7 Hz, H8A), 2.88 (1H, dd, J = 16.8,
8.0 Hz, H8B); 13C NMR (100 MHz, CDCl3): d 176.8 (C2), 171.5
(C9), 143.6 (C7a), 135.9 (C12), 128.8 (C14,C16), 128.3 (C6), 128.2
(C3a), 127.7 (C15), 127.4 (C13,C17), 123.9 (C4), 122.6 (C5), 109.2
(C7), 52.0 (C10), 44.0 (C11), 42.0 (C3), 34.8 (C8); IR (CHCl3) mmax
3032, 2951, 1737, 1712, 1614, 1489, 1467, 1211 cmꢀ1; EIMS m/z
(relative intensity) 295 (M+, 100), 235 (74), 158 (12), 91 (79). Anal.
Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.11; H,
5.70; N, 4.76.
4.11. Methyl (1-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate
6a21
Prepared from 4a (0.92 g, 21%) and from 5a (2.46 g, 85%) as a
white solid, mp: 70–72 °C (Et2O/hexane). 1H NMR (400 MHz,
CDCl3): d 7.30 (1H, br t, J = 7.4 Hz, H6), 7.28 (1H, br d, J = 6.6 Hz,
H4), 7.05 (1H, br t, J = 7.3 Hz, H5), 6.87 (1H, br d, J = 8.0 Hz, H7),
3.77 (1H, dd, J = 8.1, 4.4 Hz, H3), 3.70 (3H, s, H10), 3.23 (3H, s,
H11), 3.09 (1H, dd, J = 16.9, 4.4 Hz, H8A), 2.78 (1H, dd, J = 16.8,
8.0 Hz, H8B); 13C NMR (100 MHz, CDCl3): d 175.8 (C2), 170.9
(C9), 143.7 (C7a), 127.7 (C6), 127.6 (C3a), 123.1 (C4), 121.8 (C5),
107.5 (C7), 51.3 (C10), 41.1 (C3), 34.0 (C8), 25.6 (C11); IR (CHCl3)
4.14. General procedure for the preparation of N1,C3
dialkylated oxindoles 7a–e
To
a solution of the appropriate oxindoles 6a–c or 8
(4.57 mmol) in acetone (20 mL) was added K2CO3 (4.70 g,
34 mmol) and the mixture was stirred at room temperature for
30 min. The mixture was treated with the appropriate alkyl halide
MeI (4.6 mL, 73.2 mmol for 6b,c and 8), EtBr (5.5 mL, 73.2 mmol for
6a), or BnBr (8.7 mL, 73.2 mmol for 6a) and heated at reflux for 8 h.
m
max 3056, 2953, 1737, 1712, 1614 cmꢀ1; EIMS m/z (relative inten-
sity) 219 (M+, 59), 159 (100). Anal. Calcd for C12H13NO3: C, 65.75;
H, 5.94; N, 6.39. Found: C, 65.72; H, 6.01; N, 6.32.

2384
O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
After cooling to room temperature, additional MeI was added
(4.6 mL) for 6b,c and 8, and additional EtBr was added (5.5 mL)
for 6a. The mixtures were heated at reflux for further 8 h. After
cooling to room temperature, the acetone was evaporated under
reduced pressure and the mixture was diluted with water
(40 mL) and EtOAc (25 mL). The aqueous phase was extracted with
EtOAc (2 ꢁ 25 mL) and the combined organic layers were washed
with brine (2 ꢁ 25 mL), dried over Na2SO4, filtrated, and evapo-
rated to dryness in vacuum. Crudes 7a–d were purified by flash
column chromatography on silica gel with EtOAc/hexane 1:3 for
7a, 1:4 for 7b,c, and 1:5 for 7d,e.
(100), 146 (19), 130 (17). FABHRMS m/z calcd for C14H17NO3:
247.1208, found: 247.1213.
4.19. Methyl 2-(1-benzyl-3-methyl-2-oxo-2,3-dihydro-1H-
indol-3-yl)acetate 7e
Prepared from 6c as a yellow oil (1.24 g, 88%). 1H NMR
(300 MHz, CDCl3): d 7.36 7.40–7.22 (5H, m, H13–H17), 7.20 (1H,
br dd, J = 7.4, 1.1 Hz, H4), 7.15 (1H, td, J = 7.8, 1.3 Hz, H6), 7.00
(1H, td, J = 7.5, 1.0 Hz, H5), 6.74 (1H, br d, J = 7.7 Hz, H7), 4.97,
4.94 (2H, AB system, J = 15.8 Hz, H11), 3.42 (3H, s, H10), 3.10,
2.91 (2H, AB system, J = 16.3 Hz, H8), 1.44 (3H, s, H18); 13C NMR
(75 MHz, CDCl3): d 179.9 (C2), 170.2 (C9), 142.5 (C7a), 136.0
(C12), 132.8 (C3a), 128.6 (C14,C16), 128.0 (C6), 127.4 (C15),
127.3 (C13,C17), 122.4 (C5), 122.2 (C4), 109.1 (C7), 51.5 (C10),
45.5 (C3), 43.9 (C11), 41.2 (C8), 24.8 (C18); IR (CHCl3) mmax 3059,
3032, 2952, 2927, 1740, 1714, 1613 cmꢀ1; EIMS m/z (relative
intensity) 309 (M+, 96), 250 (15), 236 (22), 208 (30), 207 (100),
130 (25), 91 (66). FABHRMS m/z calcd for C19H19NO3: 309.1365,
found: 309.1366.
4.15. Methyl 2-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-
yl)acetate 7a
Prepared from 8 as a yellow oil (0.92 g, 86%).7
4.16. Methyl 2-(1-methyl-3-ethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-
acetate 7b
Prepared from 6a as a yellow oil (1.01 g, 89%). 1H NMR
(400 MHz, CDCl3): d 7.27 (1H, br t, J = 7.7 Hz, H6), 7.16 (1H, br d,
J = 7.3 Hz, H4), 7.04 (1H, br t, J = 7.4 Hz, H5), 6.86 (1H, br d,
J = 7.3 Hz, H7), 3.41 (3H, s, H10), 3.25 (3H, s, H11), 3.00, 2.87 (2H,
AB system, J = 16.2 Hz, H8), 1.88 (1H, dq, J = 13.2, 7.3 Hz, H12A),
1.80 (1H, dq, J = 13.2, 7.3 Hz, H12B), 0.58 (3H, t, J = 7.3 Hz, H13);
13C NMR (100 MHz, CDCl3): d 179.1 (C2), 170.2 (C9), 144.5 (C7a),
130.8 (C3a), 128.1 (C6), 122.4 (C4), 122.2 (C5), 107.8 (C7), 51.4
(C10), 50.1 (C3), 40.8 (C8), 31.0 (C12), 26.1 (C11), 8.0 (C13); IR
4.20. General procedure for the preparation of 2-oxindoleacetic
acids 9a–e
To a solution of the appropriate oxindoles 7a–e (3.24 mmol) in
MeOH (12 mL) was added a solution of aqueous NaOH (15%,
3.4 mL) and the mixture was stirred at 50 °C for 1.5 h. After cooling
to 0 °C, the mixture was treated with an aqueous solution of HCl
(1 M) to pH 1 and extracted with EtOAc (3 ꢁ 30 mL). The combined
organic layers were washed with brine (3 ꢁ 20 mL), dried over
Na2SO4, filtrated, and evaporated to dryness in vacuum. The resul-
tant crude products 9a–e were purified by flash chromatography
on silica gel using EtOAc/hexane 2:1 for 9a,b,d and 3:2 for 9c,e.
(CHCl3) m
max 3055, 2966, 2936, 1740, 1715, 1614, 1494 cmꢀ1; EIMS
m/z (relative intensity) 247 (M+, 100), 232 (20), 219 (20), 176 (46),
159 (54), 130 (21). FABHRMS m/z calcd for C14H17NO3: 247.1208,
found: 247.1209.
4.17. Methyl 2-(1-methyl-3-benzyl-2-oxo-2,3-dihydro-1H-
4.21. 2-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetic
indol-3-yl)acetate 7c
acid 9a
Prepared from 6a as colorless crystals (1.21 g, 86%), mp: 105–
107 °C (EtOAc/hexane). 1H NMR (400 MHz, CDCl3): d 7.18 (1H, td,
J = 7.7, 1.5 Hz, H6), 7.11–7.02 (4H, m, H4, H15–H17), 6.99 (1H, td,
J = 7.3, 0.7 Hz, H5), 6.80 (2H, dd, J = 8.0, 1.4 Hz, H14, H18), 6.59
(1H, d, J = 7.7 Hz, H7), 3.43 (3H, s, H10), 3.16, 2.96 (2H, AB system,
J = 16.7 Hz, H8), 3.03 (2H, s, H12), 2.99 (3H, s, H11); 13C NMR
(100 MHz, CDCl3): d 178.5 (C2), 170.2 (C9), 144.2 (C7a), 134.9
(C13), 130.3 (C3a), 130.1 (C14,C18), 128.3 (C6), 127.6 (C15,C17),
126.8 (C16), 123.3 (C4), 122.0 (C5), 107.9 (C7), 51.7 (C10), 51.3
(C3), 44.0 (C12), 40.3 (C8), 26.1 (C11); IR (CHCl3) mmax 3057,
3030, 2952, 1740, 1713, 1614 cmꢀ1; EIMS m/z (relative intensity)
309 (M+, 69), 233 (32), 218 (34), 176 (100), 91 (32). Anal. Calcd
for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C, 73.69; H,
6.26; N, 4.56.
Prepared from 7a as colorless crystals (0.62 g, 88%), mp: 181–
182 °C (EtOAc/hexane). Lit.2b 179–180.5 °C.
4.22. 2-(1-Methyl-3-ethyl-2-oxo-2,3-dihydro-1H-indol-3-
yl)acetic acid 9b
Prepared from 7b as a brown solid (0.64 g, 85%), mp: 109–
110 °C (EtOAc/hexane). 1H NMR (400 MHz, CDCl3): d 9.64 (1H, br
s, H10), 7.26 (1H, td, J = 7.7, 1.4 Hz, H6), 7.13 (1H, br d, J = 7.3 Hz,
H4), 7.04 (1H, t, J = 7.5, H5), 6.82 (1H, br d, J = 7.7 Hz, H7), 3.17
(3H, s, H11), 2.94, 2.78 (2H, AB system, J = 16.3 Hz, H8), 1.84 (1H,
dq, J = 13.7, 7.3 Hz, H12A), 1.76 (1H, dq, J = 13.7, 7.3 Hz, H12B),
0.54 (3H, t, J = 7.5 Hz, H13); 13C NMR (100 MHz, CDCl3): d 179.8
(C2), 174.3 (C9), 144.3 (C7a), 130.9 (C3a), 128.4 (C6), 122.8 (C4),
122.7 (C5), 108.3 (C7), 50.3 (C3), 40.9 (C8), 31.0 (C12), 26.4
(C11), 8.1 (C13); IR (KBr) mmax 3432, 2985, 2931, 1737, 1722,
1674, 1610 cmꢀ1; EIMS m/z (relative intensity) 233 (M+, 100),
188 (36), 174 (22), 160 (80), 159 (40), 146 (43), 130 (26). Anal.
Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.65;
H, 6.51; N, 5.86.
4.18. Methyl 2-(1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-indol-
3-yl)acetate 7d
Prepared from 6b as a yellow oil (1.03 g, 91%). 1H NMR
(300 MHz, CDCl3): d 7.26 (1H, td, J = 7.7, 1.4 Hz, H6), 7.20 (1H, dd,
J = 7.4, 0.6 Hz, H4), 7.02 (1H, td, J = 7.4, 1.1 Hz, H5), 6.88 (1H, br
d, J = 7.7 Hz, H7), 3.86 (1H, dq, J = 14.1, 7.1 Hz, H11A), 3.74 (1H,
dq, J = 14.1, 7.1 Hz, H11B), 3.44 (3H, s, H10), 3.02, 2.85 (2H, AB sys-
tem, J = 16.2 Hz, H8), 1.37 (3H, s, H13), 1.29 (3H, t, J = 7.3 Hz, H12);
13C NMR (75 MHz, CDCl3): d 179.4 (C2), 170.1 (C9), 142.5 (C7a),
133.0 (C3a), 128.0 (C6), 122.3 (C4), 122.1 (C5), 108.2 (C7), 51.4
(C10), 45.3 (C3), 41.3 (C8), 34.6 (C11), 24.3 (C13), 12.3 (C12); IR
(CHCl3) mmax 3055, 2976, 2952, 1741, 1713, 1613 cmꢀ1; EIMS m/z
(relative intensity) 247 (M+, 97), 232 (20), 204 (28), 188 (19), 174
4.23. 2-(1-Methyl-3-benzyl-2-oxo-2,3-dihydro-1H-indol-3-
yl)acetic acid 9c
Prepared from 7c as colorless crystals (0.85 g, 89%), mp: 90–
91 °C (Et2O/hexane). 1H NMR (300 MHz, CDCl3): d 9.52 (1H, br s,
H10), 7.16 (1H, td, J = 7.8, 0.9 Hz, H6), 7.10 (1H, br d, J = 7.3 Hz,
H4), 7.07–6.98 (4H, m, H5, H15–H17), 6.73 (2H, br dd, J = 8.0,
1.8 Hz, H14, H18), 6.54 (1H, br d, J = 7.8 Hz, H7), 3.11, 2.89 (2H,

O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
2385
AB system, J = 16.5 Hz, H8), 2.99 (2H, br s, H12), 2.89 (3H, s, H11);
13C NMR (75 MHz, CDCl3): d 178.8 (C2), 174.0 (C9), 143.7 (C7a),
134.5 (C13), 129.8 (C3a,C14,C18), 128.2 (C6), 127.4 (C15,C17),
126.7 (C16), 123.1 (C4), 122.2 (C5), 108.0 (C7), 51.0 (C3), 43.7
(C12), 40.0 (C8), 26.0 (C11); IR (KBr) mmax 3436, 3033, 2919,
1733, 1665 cmꢀ1. EIMS m/z (relative intensity) 295 (M+, 26), 277
(25), 262 (18), 237 (20), 221 (18), 105 (17), 91 (100), 44 (50). Anal.
Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C, 72.85; H,
5.82; N, 4.61.
(400 MHz, CDCl3): d 7.29–7.19 (5H, m, H4, H6, H15–H17), 7.15
(2H, br d, J = 7.7 Hz, H14, H18), 7.05 (1H, td, J = 7.5, 1.0 Hz, H5),
6.79 (1H, br d, J = 7.7 Hz, H7), 6.64 (1H, br d, J = 8.0 Hz, H10), 4.96
(1H, q, J = 7.3 Hz, H11), 3.06 (3H, s, H19), 2.77, 2.64 (2H, AB system,
J = 14.3 Hz, H8), 1.42 (3H, s, H20), 1.33 (3H, d, J = 7.0 Hz, H12); 13C
NMR (100 MHz, CDCl3): d 180.3 (C2), 167.8 (C9), 143.0 (C13), 142.6
(C7a), 132.9 (C3a), 128.4 (C15,C17), 128.0 (C6), 127.0 (C16), 126.1
(C14,C18), 122.8 (C4), 122.7 (C5), 108.2 (C7), 48.2 (C11), 46.3 (C3),
43.8 (C8), 26.1 (C19), 23.7 (C20), 21.4 (C12); IR (CHCl3) mmax 3300,
3059, 2970, 2927, 1701, 1652, 1614, 1542, 1471 cmꢀ1. EIMS m/z
(relative intensity) 322 (M+, 17), 174 (31), 160 (21), 130 (10), 120
(100). Anal. Calcd for C20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found:
C, 74.23; H, 6.93; N, 8.49.
4.24. 2-(1-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-
yl)acetic acid 9d
Prepared from 7d as a brown solid (0.66 g, 87%), mp: 250 °C de-
comp. (EtOAc/hexane). 1H NMR (300 MHz, CDCl3): d 10.53 (1H, br
s, H10), 7.25 (1H, td, J = 7.7, 1.4 Hz, H6), 7.16 (1H, dd, J = 7.4, 0.8 Hz,
H4), 7.02 (1H, td, J = 7.7, 1.1 Hz, H5), 6.84 (1H, br d, J = 7.7 Hz, H7),
3.83 (1H, dq, J = 14.3, 7.2 Hz, H11A), 3.63 (1H, dq, J = 14.3, 7.2 Hz,
H11B), 2.97, 2.78 (2H, AB system, J = 16.7 Hz, H8), 1.31 (3H, s,
H13), 1.18 (3H, t, J = 7.4 Hz, H12); 13C NMR (75 MHz, CDCl3): d
179.7 (C2), 174.7 (C9), 142.2 (C7a), 132.9 (C3a), 128.1 (C6), 122.4
(C5), 122.3 (C4), 108.4 (C7), 45.1 (C3), 41.2 (C8), 34.6 (C11), 24.0
(C13), 11.9 (C12); IR (CHCl3) mmax 3056, 2978, 2935, 2876, 1712,
1612 cmꢀ1; EIMS m/z (relative intensity) 233 (M+, 100), 188 (53),
174 (48), 146 (25), 130 (16). Anal. Calcd for C13H15NO3: C, 66.94;
H, 6.48; N, 6.00. Found: C, 66.73; H, 6.56; N, 5.72.
4.28. (3S,10R)-N-(10-Phenylethyl)-2-(1,3-dimethyl-2-oxo-2,3-
dihydro-1H-indol-3-yl) acetamide (3S,11R-11a)
Prepared from 9a as colorless crystals (0.32 g, 42%), mp: 126–
127 °C (EtOH). ½a D20
ꢂ
¼ þ160:2 (c 1, EtOH). 1H NMR (400 MHz,
CDCl3): d 7.35–7.18 (5H, m, H4, H6, H15–H17), 7.14 (2H, d,
J = 7.3 Hz, H14, H18), 7.07 (1H, td, J = 7.5, 0.8 Hz, H5), 6.84 (1H, d,
J = 8.0 Hz, H7), 6.67 (1H, br d, J = 6.2 Hz, H10), 4.93 (1H, q,
J = 7.0 Hz, H11), 3.22 (3H, s, H19), 2.80, 2.66 (2H, AB system,
J = 14.6 Hz, H8), 1.36 (3H, s, H20), 1.33 (3H, d, J = 7.0 Hz, H12);
13C NMR (100 MHz, CDCl3): d 180.5 (C2), 167.9 (C9), 142.9 (C13),
142.7 (C7a), 133.0 (C3a), 128.4 (C15,C17), 128.1 (C6), 127.0
(C16), 126.0 (C14,C18), 122.7 (C5), 122.6 (C4), 108.2 (C7), 48.4
(C11), 46.3 (C3), 43.9 (C8), 26.3 (C19), 23.6 (C20), 21.6 (C12); IR
(CHCl3) mmax 3301, 3059, 2970, 2928, 1704, 1651, 1614,
1471 cmꢀ1; EIMS m/z (relative intensity) 322 (M+, 17), 174 (10),
130 (11), 120 (100), 105 (11). FABHRMS m/z calcd for C20H23N2O2
(M+H+): 323.1760, found: 323.1760.
4.25. 2-(1-Benzyl-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-
yl)acetic acid 9e
Prepared from 7e as colorless crystals (0.84 g, 88%), mp: 154–
155 °C (EtOAc/hexane). 1H NMR (300 MHz, CDCl3): d 9.59 (1H, br
s, H10), 7.30- 7.22 (5H, m, H13–H17), 7.17 (1H, dd, J = 7.3, 0.7 Hz,
H4), 7.12 (1H, td, J = 7.7, 1.2 Hz, H6), 6.99 (1H, td, J = 7.5, 1.0 Hz,
H5), 6.67 (1H, br d, J = 7.5 Hz, H7), 4.98, 4.83 (2H, AB system,
J = 15.8 Hz, H11), 3.08, 2.88 (2H, AB system, J = 16.8 Hz, H8), 1.40
(3H, s, H18); 13C NMR (75 MHz, CDCl3): d 180.0 (C2), 175.0 (C9),
142.3 (C7a), 135.7 (C12), 132.6 (C3a), 128.7 (C14,C16), 128.1
(C6), 127.5 (C15), 127.1 (C13,C17), 122.6 (C5), 122.2 (C4), 109.5
(C7), 45.3 (C3), 43.9 (C11), 40.9 (C8), 24.9 (C18); IR (KBr) mmax
3420, 3208, 3058, 2971, 2925, 2909, 1742, 1677, 1614, 1494,
1469 cmꢀ1; EIMS m/z (relative intensity) 295 (M+, 100), 236 (17),
222 (20), 207 (25), 130 (15), 91 (49). Anal. Calcd for C18H17NO3:
C, 73.20; H, 5.80; N, 4.74. Found: C, 72.88; H, 5.63; N, 4.64.
4.29. (3S,10S)-N-(10-Phenylethyl)-2-(1,3-dimethyl-2-oxo-2,3-
dihydro-1H-indol-3-yl) acetamide (3S,11S-11a)
Prepared from 9a as colorless crystals (0.31 g, 41%), mp: 157–
158 °C (EtOH). ½a D20
ꢂ
¼ ꢀ87:9 (c 1, EtOH). 1H NMR (300 MHz,
CDCl3): d 7.29–7.19 (5H, m, H4, H6, H15–H17), 7.15 (2H, br d,
J = 7.2 Hz, H14, H18), 7.05 (1H, td, J = 7.5, 0.7 Hz, H5), 6.79 (1H,
br d, J = 7.5 Hz, H7), 6.68 (1H, br d, J = 7.6 Hz, H10), 4.94 (1H, br
q, J = 7.2 Hz, H11), 3.06 (3H, s, H19), 2.77, 2.64 (2H, AB system,
J = 14.3 Hz, H8), 1.42 (3H, s, H20), 1.32 (3H, d, J = 6.9 Hz, H12);
13C NMR (75 MHz, CDCl3): d 180.3 (C2), 167.8 (C9), 143.0 (C13),
142.6 (C7a), 132.9 (C3a), 128.4 (C15,C17), 128.0 (C6), 127.0
(C16), 126.0 (C14,C18), 122.8 (C4), 122.6 (C5), 108.2 (C7), 48.2
(C11), 46.3 (C3), 43.8 (C8), 26.1 (C19), 23.7 (C20), 21.4 (C12). IR
(CHCl3) mmax 3301, 3059, 3029, 2970, 2927, 2870, 1702, 1651,
1614 cmꢀ1; EIMS m/z (relative intensity) 322 (M+, 16), 174 (28),
160 (21), 130 (9), 120 (100). Anal. Calcd for C20H22N2O2: C,
74.51; H, 6.88; N, 8.69. Found: C, 74.10; H, 6.89; N, 8.59.
4.26. General procedure for the preparation of diastereomeric
amides 11a–e
A
cooled solution (0 °C) of the appropriate acids 9a–e
(2.36 mmol) in THF (20 mL) was treated dropwise with Et3N
(0.32 mL, 2.3 mmol). The mixture was stirred for 15 min and
ClCO2Et (0.32 mL, 3.3 mmol) was added dropwise and stirred for
additional 1 h. After cooling to ꢀ60 °C, (R)- or (S)-FEA (0.64 mL,
5.0 mmol) was added dropwise and the reaction mixture was stir-
red for 1 h. After warming to room temperature, EtOAc was added
(20 mL) and the organic layer was washed with brine (2 ꢁ 20 mL),
dried over anhydrous Na2SO4, filtered, and evaporated to dryness
in vacuum. The crude products 11a–e were purified by flash col-
umn chromatography on silica gel with EtOAc/hexane 2:3 for
11a, 11b, and 11d, and with EtOAc/hexane 1:2 for 11c and 11e.
4.30. (3R,10S)-N-(10-Phenylethyl)-2-(1,3-dimethyl-2-oxo-2,3-
dihydro-1H-indol-3-yl) acetamide (3R,11S-11a)
Prepared from 9a as colorless crystals (0.32 g, 42%), mp: 126–
127 °C (EtOAc/hexane).
½
a 2D0
ꢂ
¼ ꢀ159:5 (c 1, EtOH). 1H NMR
(300 MHz, CDCl3): d 7.32–7.20 (5H, m, H4, H6, H15–H17), 7.15
(2H, d, J = 7.5 Hz, H14, H18), 7.07 (1H, td, J = 7.5, 0.9 Hz, H5), 6.84
(1H, br d, J = 7.6 Hz, H7), 6.64 (1H, br d, J = 7.8 Hz, H10), 4.94 (1H,
q, J = 7.2 Hz, H11), 3.22 (3H, s, H19), 2.80, 2.66 (2H, AB system,
J = 14.6 Hz, H8), 1.36 (3H, s, H20), 1.33 (3H, d, J = 6.9 Hz, H12);
13C NMR (75 MHz, CDCl3): d 180.5 (C2), 167.9 (C9), 142.9 (C13),
142.8 (C7a), 133.1 (C3a), 128.4 (C15,C17), 128.1 (C6), 127.0
(C16), 126.0 (C14,C18), 122.8 (C5), 122.7 (C4), 108.2 (C7), 48.4
(C11), 46.3 (C3), 44.0 (C8), 26.3 (C19), 23.6 (C20), 21.6 (C12); IR
4.27. (3R,10R)-N-(10-Phenylethyl)-2-(1,3-dimethyl-2-oxo-2,3-
dihydro-1H-indol-3-yl) acetamide (3R,11R-11a)
Prepared from 9a as colorless crystals (0.32 g, 42%), mp: 157–
159 °C (EtOAc/hexane).
½
a 2D0
ꢂ
¼ þ87:3 (c 1, EtOH). 1H NMR

2386
O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
(CHCl3)
m
max 3300, 3059, 2969, 2925, 1702, 1652, 1614 cmꢀ1; EIMS
4.34. (3S,10R)-N-(10-Phenylethyl)-2-(1-methyl-3-benzyl-2-oxo-
2,3-dihydro-1H-indol-3-yl)acetamide (3S,11R-11c)
m/z (relative intensity) 322 (M+, 17), 174 (25), 160 (18), 120 (100).
FABHRMS m/z calcd for C20H23N2O2 (M+H+): 323.1760, found:
323.1753.
Prepared from 9c as colorless crystals (0.40 g, 42%), mp: 182–
183 °C (CH2Cl2/hexane).
½
a 2D0
ꢂ
¼ þ177:7 (c 1, EtOH). 1H NMR
4.31. (3R,10R)-N-(10-Phenylethyl)-2-(1-methyl-3-ethyl-2-oxo-
2,3-dihydro-1H-indol-3-yl)acetamide (3R,11R-11b)
(300 MHz, CDCl3): d 7.30–6.98 (11H, m, H4–H6, H14–H18, H23–
H25), 6.74 (2H, br dd, J = 7.7, 1.3 Hz, H22, H26), 6.64 (1H, br d,
J = 8.1 Hz, H10), 6.56 (1H, d, J = 7.8 Hz, H7), 4.94 (1H, q, J = 7.0 Hz,
H11), 3.06, 3.03 (2H, AB system, J = 12.9 Hz, H20), 2.95 (3H, s,
H19), 2.95, 2.76 (2H, AB system, J = 14.5 Hz, H8), 1.32 (3H, d,
J = 6.9 Hz, H12); 13C NMR (75 MHz, CDCl3): d 179.0 (C2), 167.7
(C9), 143.3 (C7a), 142.9 (C13), 134.8 (C21), 130.1 (C3a), 129.8
(C22, C26), 128.4 (C15,C17), 128.2 (C6), 127.4 (C23,C25), 127.0
(C16), 126.6 (C24), 126.0 (C14,C18), 123.7 (C4), 122.2 (C5), 107.9
(C7), 52.1 (C3), 48.3 (C11), 43.4 (C20), 42.7 (C8), 25.9 (C19), 21.5
(C12); IR (CHCl3) mmax cmꢀ1 3288, 3061, 3030, 2959, 2925, 2854,
1702, 1648; EIMS m/z (relative intensity) 398 (M+, 17), 277 (14),
236 (100), 160 (67), 120 (34), 105 (37). FABHRMS m/z calcd for
C26H27N2O2 (M+H+): 399.2073, found: 399.2072.
Prepared from 9b as colorless crystals (Et2O/hexane) (0.34 g,
43%), mp: 131–132 °C (Et2O/hexane). ½a D20
¼ þ73:0 (c 1, EtOH).
ꢂ
1H NMR (300 MHz, CDCl3): d 7.34–7.18 (5H, m, H4, H6, H15–
H17), 7.12 (2H, br dd, J = 8.3, 1.6 Hz, H14, H18), 7.06 (1H, td,
J = 7.5, 1.0 Hz, H5), 6.78 (1H, br d, J = 7.9 Hz, H7), 6.50 (1H, br d,
J = 7.0 Hz, H10), 4.92 (1H, br q, J = 7.3 Hz, H11), 3.03 (3H, s, H19),
2.79, 2.64 (2H, AB system, J = 14.2 Hz, H8), 1.92 (1H, dq, J = 13.6,
7.3 Hz, H20A), 1.85 (1H, dq, J = 13.6, 7.3 Hz, H20B), 1.30 (3H, br d,
J = 7.0 Hz, H12), 0.57 (3H, t, J = 7.4 Hz, H21); 13C NMR (75 MHz,
CDCl3): d 179.7 (C2), 167.8 (C9), 143.6 (C7a), 143.0 (C13), 130.7
(C3a), 128.4 (C15,C17), 128.0 (C6), 127.0 (C16), 126.1 (C14,C18),
123.1 (C4), 122.6 (C5), 108.0 (C7), 51.3 (C3), 48.1 (C11), 43.3
(C8), 30.7 (C20), 25.9 (C19), 21.3 (C12), 8.1 (C21); IR (CHCl3) mmax
3303, 3059, 3030, 2969, 2932, 2878, 1699, 1648 cmꢀ1; EIMS m/z
(relative intensity) 336 (M+, 20), 321 (8), 200 (21), 188 (28), 146
(21), 120 (100), 105 (16). FABHRMS m/z calcd for C21H25N2O2
(M+H+): 337.1916, found: 337.1909.
4.35. (3R,10R)-N-(10-Phenylethyl)-2-(1-ethyl-3-methyl-2-oxo-
2,3-dihydro-1H-indol-3-yl)acetamide (3R,11R-11d)
Prepared from 9d as colorless crystals (0.33 g, 41%), mp: 126–
127 °C (Et2O/hexane). ½a D20
ꢂ
¼ þ74:8 (c 1, EtOH). 1H NMR (300 MHz,
CDCl3): d 7.31–7.19 (5H, m, H4, H6, H15–H17), 7.17 (2H, br dd,
J = 7.2, 2.2 Hz, H14, H18), 7.04 (1H, td, J = 7.6, 1.0 Hz, H5), 6.83 (1H,
dd, J = 8.5, 1.2 Hz, H7), 6.68 (1H, br d, J = 7.3 Hz, H10), 4.98 (1H, q,
J = 7.0 Hz, H11), 3.73 (1H, dq, J = 14.1, 7.2 Hz, H19A), 3.58 (1H, dq,
J = 14.2, 7.2 Hz, H19B), 2.76, 2.63 (2H, AB system, J = 14.4 Hz, H8),
1.43 (3H, s, H21), 1.35 (3H, d, J = 6.9 Hz, H12), 1.20 (3H, t,
J = 7.2 Hz, H20); 13C NMR (75 MHz, CDCl3): d 180.0 (C2), 167.9
(C9), 143.1 (C13), 141.7 (C7a), 133.3 (C3a), 128.4 (C15,C17), 128.0
(C6), 127.0 (C16), 126.1 (C14,C18), 123.1 (C4), 122.6 (C5), 108.4
(C7), 48.4 (C11), 46.2 (C3), 43.8 (C8), 34.6 (C19), 23.6 (C21), 21.5
(C12), 12.5 (C20); IR (CHCl3) mmax 3310, 3059, 3030, 2973, 2928,
1698, 1652 cmꢀ1; EIMS m/z (relative intensity) 336 (M+, 23), 188
(33), 174 (21), 128 (11), 120 (100). Anal. Calcd for C21H24N2O2: C,
74.97; H, 7.19; N, 8.33. Found: C, 74.90; H, 7.18; N, 8.20.
4.32. (3S,10R)-N-(10-Phenylethyl)-2-(1-methyl-3-ethyl-2-oxo-
2,3-dihydro-1H-indol-3-yl)acetamide [(3S,11R-11b)]
Prepared from 9b as colorless crystals (0.33 g, 42%), mp: 111–
112 °C (Et2O/hexane).
½
a 2D0
ꢂ
¼ þ143:1 (c 1, EtOH). 1H NMR
(300 MHz, CDCl3): d 7.34–7.17 (5H, m, H4, H6, H15–H17), 7.12
(2H, br dd, J = 8.0, 1.8 Hz, H14, H18), 7.07 (1H, td, J = 7.5, 1.0 Hz,
H5), 6.83 (1H, br d, J = 7.8 Hz, H7), 6.47 (1H, br d, J = 7.8 Hz, H10),
4.91 (1H, q, J = 7.0 Hz, H11), 3.22 (3H, s, H19), 2.82, 2.65 (2H, AB sys-
tem, J = 14.4 Hz, H8), 1.89 (1H, dq, J = 13.5, 7.3 Hz, H20A), 1.79 (1H,
dq, J = 13.5, 7.3 Hz, H20B), 1.30 (3H, d, J = 6.9 Hz, H12), 0.56 (3H, t,
J = 7.3 Hz, H21); 13C NMR (75 MHz, CDCl3): d 179.8 (C2), 167.8
(C9), 143.7 (C7a), 142.9 (C13), 130.9 (C3a), 128.4 (C15,C17), 128.1
(C6), 127.0 (C16), 126.0 (C14,C18), 123.0 (C4), 122.6 (C5), 108.0
(C7), 51.2 (C3), 48.3 (C11), 43.5 (C8), 30.6 (C20), 26.1 (C19), 21.5
(C12), 8.1 (C21); IR (CHCl3) mmax 3307, 3058, 3029, 2968, 2932,
1702, 1651 cmꢀ1; EIMS m/z (relative intensity) 336 (M+, 24), 321
(10) 200 (24), 188 (33), 146 (21), 120 (100). FABHRMS m/z calcd
for C21H25N2O2 (M+H+): 337.1916, found: 337.1912.
4.36. (3S,10R)-N-(10-Phenylethyl)-2-(1-ethyl-3-methyl-2-oxo-
2,3-dihydro-1H-indol-3-yl)acetamide (3S,11R-11d)
Prepared from 9d as colorless crystals (0.33 g, 41%), mp: 152–
153 °C (Et2O/hexane).
½
a 2D0
ꢂ
¼ þ145:8 (c 1, EtOH). 1H NMR
(300 MHz, CDCl3): d 7.32–7.20 (5H, m, H4, H6, H15–H17), 7.17
(2H, br dd, J = 7.3, 1.8 Hz, H14, H18), 7.06 (1H, td, J = 7.4, 0.9 Hz,
H5), 6.86 (1H, br d, J = 7.6 Hz, H7), 6.71 (1H, br d, J = 7.6 Hz, H10),
4.96 (1H, q, J = 7.0 Hz, H11), 3.82 (1H, dq, J = 14.1, 7.3 Hz, H19A),
3.73 (1H, dq, J = 14.1, 7.3 Hz, H19B), 2.78, 2.65 (2H, AB system,
J = 14.6 Hz, H8), 1.36 (3H, s, H21), 1.35 (3H, d, J = 7.9 Hz, H12),
1.27 (3H, t, J = 7.2 Hz, H20); 13C NMR (75 MHz, CDCl3): d 180.1
(C2), 167.9 (C9), 143.0 (C13), 141.8 (C7a), 133.4 (C3a), 128.4
(C15,C17), 128.0 (C6), 127.0 (C16), 126.1 (C14,C18), 123.0 (C4),
122.5 (C5), 108.4 (C7), 48.5 (C11), 46.2 (C3), 43.9 (C8), 34.7
(C19), 23.6 (C21), 21.7 (C12), 12.6 (C20); IR (CHCl3) mmax 3307,
3057, 3030, 2968, 2932, 2878, 1704, 1651 cmꢀ1; EIMS m/z (relative
intensity) 336 (M+, 24), 321 (10), 200 (23), 188 (33), 146 (22), 120
(100), 105 (16). Anal. Calcd for C21H24N2O2: C, 74.97; H, 7.19; N,
8.33. Found: C, 74.74; H, 7.31; N, 8.27.
4.33. (3R,10R)-N-(10-Phenylethyl)-2-(1-methyl-3-benzyl-2-oxo-
2,3-dihydro-1H-indol-3-yl)acetamide (3R,11R-11c)
Prepared from 9c as a white solid (0.39 g, 41%), mp: 137–138 °C
(EtOAc/hexane). ½a D20
ꢂ
¼ þ29:1 (c 1, EtOH). 1H NMR (300 MHz,
CDCl3): d 7.28–7.14 (5H, m, H4, H6, H16, H23, H25), 7.11 (2H, br
dd, J = 7.8, 1.8 Hz, H14, H18), 7.08–6.99 (5H, m, H5, H15, H17,
H21, H24), 6.77 (2H, br dd, J = 7.8, 1.7 Hz, H22, H26), 6.51 (1H, br
d, J = 7.8 Hz, H7), 6.41 (1H, br d, J = 7.6 Hz, H10), 4.96 (1H, q,
J = 7.0 Hz, H11), 3.13, 3.09 (2H, AB system, J = 12.9 Hz, H20), 2.96,
2.76 (2H, AB system, J = 14.3 Hz, H8), 2.76 (3H, s, H19), 1.35 (3H,
d, J = 6.9 Hz, H12); 13C NMR (75 MHz, CDCl3): d 179.0 (C2), 167.7
(C9), 143.2 (C7a), 143.0 (C13), 134.9 (C21), 130.0 (C3a), 129.9
(C22, C26), 128.5 (C15,C17), 128.2 (C6), 127.4 (C23,C25), 127.1
(C16), 126.7 (C24), 126.1 (C14,C18), 123.9 (C4), 122.4 (C5), 108.0
(C7), 52.4 (C3), 48.3 (C11), 43.8 (C20), 42.8 (C8), 25.7 (C19), 21.4
(C12); IR (CHCl3) mmax 3301, 3060, 3030, 2972, 2927, 1698,
1649 cmꢀ1; EIMS m/z (relative intensity) 398 (M+, 14), 321 (13),
276 (29), 236 (100), 160 (55), 105 (32). FABHRMS m/z calcd for
C26H27N2O2 (M+H+): 399.2073, found: 399.2066.
4.37. (3R,10R)-N-(10-Phenylethyl)-2-(1-benzyl-3-methyl-2-oxo-
2,3-dihydro-1H-indol-3-yl)acetamide (3R,11R-11e)
Prepared from 9e as a yellow solid on standing (0.39 g, 41%),
mp: 64–65 °C. ½a 2D0
ꢂ
¼ þ66:7 (c 1, EtOH). 1H NMR (300 MHz, CDCl3):

O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
2387
Table 5
Crystal data for (3R,11R)-11a, (3S,11R)-11a, (3S, 11R)-11b, and (3S, 11R)-11c
(3R,11R)-11a
(3S,11R)-11a
(3S,11R)-11b
(3S,11R)-11c
Empirical formula
Formula weight
Crystal size (mm)
Wavelength (Å)
C20H22N2O2
322.40
C20H22N2O2H2O
322.40 + 18.02
0.38 ꢁ 0.28 ꢁ 0.70
0.71073
C21H24N2O2
336.42
C26H26N2O2
398.49
0.30 ꢁ 0.26 ꢁ 0.22
0.38 ꢁ 0.34 ꢁ 0.34
0.30 ꢁ 0.12 ꢁ 0.10
1.54184
1.54184
0.71073
Crystal system, space group
Orthorhombic, P212121
Orthorhombic, P212121
Orthorhombic, P212121
Tetragonal, P43212
Unit cell dimensions
a (Å)
b (Å)
8.4402(8)
10.323(3)
21.631(2)
1884.7(5)
4, 1, 1.136
12.7641(6)
16.7665(9)
17.6059(8)
3767.8(3)
4, 2, 1.168
12.421(3)
16.391(3)
18.089(3)
3682.9(13)
4, 2, 1.213
10.235(1)
10.235(1)
45.036(9)
4717.9(13)
8, 1, 1.122
c (Å)
Volume (Å3)
Z, Z0, Calculated density (mg/
mm3)
Absorption coefficient
0.587
0.077
0.621
0.071
(mmꢀ1
)
F(0 0 0)
688
1416
1440
1696
Theta range for data
4.09–59.93
4.28–72.22
4.89–60.01
2.96–27.47
collection (°)
Limiting indices
0 6 h 6 9, 0 6 k 6 11,
2 6 l 6 23
1462/1445
ꢀ15 6 h 6 15, ꢀ17 6 k 6 20,
ꢀ21 6 l 6 21
0 6 h 6 13, 0 6 k 6 18,
2 6 l 6 20
2774/2661
ꢀ13 6 h 6 12, ꢀ13 6 k 6 12,
ꢀ57 6 l 6 49
Reflections collected/unique
25,267/7417 [R(int) = 0.0645]
21,984/5214 [R(int) = 0.0001]
[R(int) = 0.0001]
88.7%
[R(int) = 0.0001]
86.4%
Completeness to
99.7%
96.9%
theta = 59.93
Data/restraints/parameters
1365/0/226
1.108
3212/0/459
0.773
2522/0/467
1.029
2314/0/276
0.990
Goodness-of-fit on F2
Final R indices [I > 2
R indices (all data)
Largest diff. peak and hole
CCDC Nos.
r
(I)
R1 = 3.2%, wR2 = 9.5%
R1 = 3.4%, wR2 = 9.6%
0.112 and ꢀ0.092 e Aꢀ3
750097
R1 = 3.7%, wR2 = 6.4%
R1 = 12.4%, wR2 = 7.9%
0.108 and ꢀ0.118 e Åꢀ3
750098
R1 = 3.2%, wR2 = 8.7%
R1 = 3.5%, wR2 = 8.9%
0.093 and ꢀ0.110 e Aꢀ3
750200
R1 = 5.5%, wR2 = 10.3%
R1 = 17.6%, wR2 = 12.8%
0.123 and ꢀ0.091 e Aꢀ3
750201
d 7.34–7.22 (9H, m, H4, H15–H17, H21–H25), 7.20 (2H, br dd,
J = 7.2, 1.9 Hz, H14, H18), 7.14 (1H, td, J = 7.5, 0.8 Hz, H6), 7.00
(1H, br t, J = 7.3 Hz, H5), 6.67 (1H, br d, J = 7.8 Hz, H7), 6.55 (1H,
br d, J = 7.9 Hz, H10), 4.99 (1H, q, J = 8.0 Hz, H11), 4.97, 4.57 (2H,
AB system, J = 15.9 Hz, H19), 2.82, 2.70 (2H, AB system,
J = 14.5 Hz, H8), 1.50 (3H, s, H26), 1.33 (3H, d, J = 6.9 Hz, H12);
13C NMR (75 MHz, CDCl3): d 180.6 (C2), 167.9 (C9), 143.1 (C13),
141.8 (C7a), 135.7 (C20), 133.1 (C3a), 128.7 (C22,C24), 128.5
(C15,C17), 128.0 (C6), 127.5 (C23), 127.1 (C16), 127.1 (C21,C25),
126.2 (C14,C18), 122.9 (C4), 122.8 (C5), 109.3 (C7), 48.4 (C11),
46.3 (C3), 43.9 (C8), 43.6 (C19), 23.9 (C26), 21.5 (C12); IR (CHCl3)
mmax 3318, 3061, 3030, 2970, 2927, 2870, 1702, 1649 cmꢀ1; EIMS
m/z (relative intensity) 398 (M+, 20), 250 (24), 120 (100), 91 (56).
FABHRMS m/z calcd for C26H26N2O2: 398.1993, found: 398.1994.
Table 6
Crystal data for (3R,11R)-11d, (3S,11R)-11d, (3S,11S)-11a, (3R,11S)-11a
(3R,11R)-11d
(3S,11R)-11d
(3S,11S)-11a
(3R,11S)-11a
Empirical formula
Formula weight
Crystal size (mm)
Wavelength (Å)
C21H24N2O2
336.42
C21H24N2O2
336.42
C20H22N2O2
322.40
C20H22N2O2ꢃH2O
322.40 + 18.02
0.36 ꢁ 0.32 ꢁ 0.63
0.71073
0.42 ꢁ 0.40 ꢁ 0.36
0.40 ꢁ 0.34 ꢁ 0.34
0.40 ꢁ 0.34 ꢁ 0.30
1.54184
1.54184
1.54184
Crystal system, space group
Orthorhombic, P212121
Orthorhombic, P212121
Orthorhombic, P212121
Orthorhombic, P212121
Unit cell dimensions
a (Å)
b (Å)
8.639(1)
10.179(4)
18.122(9)
20.578(4)
3796(3)
8.439(1)
12.7741(7)
16.7934(8)
17.6281(9)
3781.6(3)
4, 2, 1.164
10.190(5)
22.383(3)
1970.4(11)
4, 1, 1.134
10.325(3)
21.636(2)
1885.2(6)
4, 1, 1.136
c (Å)
Volume (Å3)
Z, Z0, Calculated density (mg/
mm3)
4, 2, 1.177
Absorption coefficient (mmꢀ1
F(0 0 0)
)
0.580
720
0.602
1440
0.587
688
0.077
1416
Theta range for data collection
3.95–59.91
4.30–60.00
4.09–59.91
2.31–25.98
(°)
Limiting indices
0 6 h 6 9, 0 6 k 6 11,
2 6 l 6 24
0 6 h 6 11, 0 6 k 6 20,
2 6 l 6 22
0 6 h 6 9, 0 6 k 6 11,
2 6 l 6 23
ꢀ15 6 h 6 15, 0 6 k 6 20,
0 6 l 6 21
Reflections collected/unique
Completeness to theta = 59.93
Data/restraints/parameters
Goodness-of-fit on F2
1589/1514 [R(int) = 0.0001]
89.1%
1350/0/234
2804/2790 [R(int) = 0.0001]
87.5%
2464/0/467
1462/1441 [R(int) = 0.0001]
88.4%
1392/0/226
25,278/7400 [R(int) = 0.0001]
99.7%
3732/0/465
0.993
1.039
1.098
0.828
Final R indices [I > 2
R indices (all data)
Largest diff. peak and hole
CCDC Nos.
r
(I)
R1 = 5.8%, wR2 = 16.8%
R1 = 6.4%, wR2 = 17.3%
0.219 and ꢀ0.228 e Aꢀ3
950202
R1 = 3.2%, wR2 = 8.4%
R1 = 3.9%, wR2 = 8.7%
0.096 and ꢀ0.100 e Aꢀ3
950203
R1 = 5.0%, wR2 = 14.8%
R1 = 5.2%, wR2 = 15.5%
0.144 and ꢀ0.146 e Aꢀ3
750099
R1 = 3.8%, wR2 = 8.0%
R1 = 9.0%, wR2 = 9.5%
0.133 and ꢀ0.162 e Aꢀ3
750100

2388
O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
4.38. (3S,10R)-N-(10-Phenylethyl)-2-(1-benzyl-3-methyl-2-oxo-
2,3-dihydro-1H-indol-3-yl) acetamide (3S,11R-11e)
M.; Walker, D. H.; Kuyper, L. F. J. Med. Chem. 2001, 44, 4339–4358; (k)
Woodard, C. L.; Li, Z.; Katchcart, A. K.; Terrell, J.; Gerena, L.; Lopez-Sanchez, M.;
Kyle, D. E.; Bhattacharjee, A. K.; Nichols, D. A.; Ellis, W.; Prigge, S. T.; Geyer, J. A.;
Waters, N. C. J. Med. Chem. 2003, 46, 3877–3882; (l) Tokunaga, T.; Hume, W. E.;
Umezome, T.; Okazaki, K.; Ueki, Y.; Kumagai, K.; Hourai, S.; Nagamine, J.; Seki,
H.; Taiji, M.; Noguchi, H.; Nagata, R. J. Med. Chem. 2001, 44, 4641–4649; (m)
Emura, T.; Esaki, T.; Tachibana, K.; Shimizu, M. J. Org. Chem. 2006, 71, 8559–
8564.
Prepared from 9e as a white solid (0.38 g, 40%), mp: 125–126 °C.
½
a 2D0
ꢂ
¼ þ146:3 (c 1, EtOH). 1H NMR (300 MHz, CDCl3): d 7.31–7.18
(9H, m, H4, H15–H17, H21–H25), 7.14 (2H, br dd, J = 7.8, 1.8 Hz,
H14, H18), 7.14 (1H, td, J = 7.8, 1,3 Hz, H6), 7.01 (1H, td, J = 7.6,
1.0 Hz, H5), 6.69 (1H, br d, J = 7.5 Hz, H7), 6.57 (1H, br d,
J = 7.8 Hz, H10), 5.06, 4.80 (2H, AB system, J = 15.8 Hz, H19), 4.97
(1H, q, J = 7.0 Hz, H11), 2.85, 2.71 (2H, AB system, J = 14.5 Hz,
H8), 1.43 (3H, s, H26), 1.35 (3H, d, J = 6.9 Hz, H12); 13C NMR
(75 MHz, CDCl3): d 180.6 (C2), 167.9 (C9), 143.0 (C13), 141.9
(C7a), 135.7 (C20), 133.1 (C3a), 128.7 (C22,C24), 128.4 (C15,C17),
128.0 (C6), 127.5 (C23), 127.1 (C21,C25), 127.0 (C16), 126.1
(C14,C18), 122.8 (C4), 122.7 (C5), 109.3 (C7), 48.5 (C11), 46.3
(C3), 43.9 (C8), 43.7 (C19), 24.0 (C26), 21.6 (C12); IR (CHCl3) mmax
3316, 3060, 3029, 3005, 2971, 2927, 1702, 1656 cmꢀ1; EIMS m/z
(relative intensity) 398 (M+, 36), 250 (30), 120 (100), 105 (11), 91
(48), 77 (11). FABHRMS m/z calcd for C26H27N2O2 (M+H+):
399.2073, found: 399.2064.
2. (a) Morales-Ríos, M. S.; Suárez-Castillo, O. R.; Joseph-Nathan, P. Trends
Heterocycl. Chem. 1999, 6, 111–124. and references cited therein; (b) Horne,
S.; Taylor, N.; Collins, S.; Rodrigo, R. J. Chem. Soc., Perkin Trans. 1 1991, 3047–
3051; (c) Yu, Q.-s.; Luo, W.-m.; Li, Y.-q. Heterocycles 1993, 36, 1279–1285; (d)
Pallavicini, M.; Valoti, E.; Villa, L.; Resta, I. Tetrahedron: Asymmetry 1994, 5,
363–370; (e) Pei, X.-F.; Bi, S. Heterocycles 1994, 39, 357–360; (f) Matsuura, T.;
Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500–6503; (g) Morales-
Ríos, M. S.; Suárez-Castillo, O. R. Nat. Prod. Commun. 2008, 3, 629–642. and
references cited therein.
3. Seco, J. M.; Quiñoá, E.; Riguera, R. Chem. Rev. 2004, 104, 17–117. and references
cited therein.
4. (a) Hoye, T. R.; Koltun, D. O. J. Am. Chem. Soc. 1998, 120, 4638–4643; (b) Hoye, T.
R.; Hamad, A.-S. S.; Koltun, D. O.; Tennakoon, M. A. Tetrahedron Lett. 2000, 41,
2289–2293; (c) Yabuuchi, T.; Kusumi, T. J. Org. Chem. 2000, 65, 397–404.
5. Avalos, M.; Babiano, R.; Barneto, J. L.; Cintas, P.; Clemente, F. R.; Jiménez, J. L.;
Palacios, C. J. Org. Chem. 2003, 68, 1834–1842.
6. 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.
7. Osman, F. H.; El-Samahy, F. A. Phosphorus, Sulfur Silicon 1998, 134/135, 437–
446.
8. Morales-Ríos, M. S.; Rivera-Becerril, E.; Joseph-Nathan, P. Tetrahedron:
Asymmetry 2005, 16, 2493–2499.
9. (a) Morales-Ríos, M. S.; Bucio, M. A.; Joseph-Nathan, P. Tetrahedron Lett. 1994,
35, 881–882; (b) Luo, Y.-l.; Yu, Q.-s.; Chrisey, L.; Brossi, A. Heterocycles 1990, 31,
283–287; (c) Akai, S.; Tsujino, T.; Akiyama, E.; Tanimoto, K.; Naka, T.; Kita, Y. J.
Org. Chem. 2004, 69, 2478–2486; (d) Yamazaki, S.; Yamamoto, M.; Morikawa, S.
Heterocycles 2006, 67, 269–289.
4.39. X-ray diffraction analyses
The studies for (3S,11R)-11a, (3R,11S)-11a, and (3S, 11R)-11c
were carried out on a Bruker Smart 6000 CCD diffractometer using
Mo Ka radiation (k = 0.7073 Å). A total of 1321 frames were col-
lected at a scan width of 0.3° and an exposure time of 10 s/frame.
These data were processed with the SAINT software package, pro-
vided by the diffractometer manufacturer, by using a narrow-
frame integration algorithm. An empirical absorption correction
was applied. Data collections for (3R,11R)-11a, (3S,11S)-11a,
(3S,11R)-11b, (3R,11R)-11d, and (3S,11R)-11d were done on a Bru-
10. Chang, G.; Guida, W. C.; Still, W. C. J. Am. Chem. Soc. 1989, 111, 4379–4386.
11. (a) Halgren, T. J. Comput. Chem. 1996, 17, 490–519; (b) Halgren, T. J. Comput.
Chem. 1996, 17, 520–552; (c) Halgren, T. J. Comput. Chem. 1996, 17, 553–586;
(d) Halgren, T.; Nachbar, R. B. J. Comput. Chem. 1996, 17, 587–615; (e) Halgren,
T. J. Comput. Chem. 1996, 17, 616–641.
12. As implemented in the computer package Spartan004, Windows
v 1.0.1;
Wavefunction Inc. Irvine, CA, USA, 2004.
13. Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital
Theory; Wiley: New York, 1986.
ker-Nonius CAD4 diffractometer using Cu
Ka
radiation
(k = 1.54184 Å). The structures for (3S,11R)-11b and (3S,11R)-11c
were solved by direct methods using the SHELXS-9722 program while
the remaining compounds were solved using the SIR200423 soft-
ware. Both programs are included in the WINGX v1.6 package.24
The structural refinement was 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. Data for (3S,11R)-11b show a
disordered methyl group.25 Atomic coordinates, bond lengths,
bond angles and anisotropic thermal parameters are in deposit at
the Cambridge Crystallographic Data Center. Tables 5 and 6 sum-
marize the relevant data of the X-ray procedures.
14. (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.
15. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, Jr., J. A.; 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.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.;
Gaussian, Inc.: Wallingford CT, 2004.
Acknowledgments
16. Monte Carlo searching protocol was applied to amides (3R,11R)-11a and
(3S,11R)-11a using the MMFF94 molecular mechanics force field method as
implemented in the SPARTAN04 program. This protocol gave 14 conformers
within 8.5 kcal/mol from the global minimum energy conformation for both
diastereomeric amides. These structures were submitted to geometry
optimization using DFT calculations at the B3LYP/6-31G(d) level of theory
from which 9 conformers account for 99.8% in the case of amide (3R,11R)-11a,
while 8 conformers (99.9%) account for amide (3S,11R)-11a, within 3.0 and
2.0 kcal/mol from the global minimum energy conformation, respectively.
Further DFT geometry optimizations were carried out at the B3LYP/DGDZVP
level of theory as implemented in the Gaussian 03 W program, giving rise to
corresponding molecular model sets of 8 and 6 conformers for (3R,11R)-11a
and (3S,11R)-11a amides, respectively, whose populations were estimated
from the thermochemical parameters in the conformational equilibrium.
17. Cerda-García-Rojas, C. M.; Catalán, C. A. N.; Muro, A. C.; Joseph-Nathan, P. J. Nat.
Prod. 2008, 71, 967–971.
We are pleased to acknowledge the financial support from SEP-
PROMEP (Mexico) grant UAEHGO-PTC-244 and CONACYT (Mexico)
grants 83723 and 58994.
References
1. (a) Kinashi, H.; Suzuki, Y.; Takeuchi, S.; Kawarada, A. Agric. Biol. Chem. 1976, 40,
2465–2470; (b) Suzuki, Y.; Kinashi, H.; Takeuchi, S.; Kawarada, A.
Phytochemistry 1977, 16, 635–637; (c) Ohmoto, T.; Yamaguchi, K.; Ikeda, K.
Chem. Pharm. Bull. 1988, 36, 578–581; (d) Dekker, T. G.; Fourie, T. G.; Matthee,
E.; Snyckers, F. O. Phytochemistry 1987, 26, 1845–1846; (e) Monde, K.; Sasaki,
K.; Shirata, A.; Takasugi, M. Phytochemistry 1991, 30, 2915–2917; (f)
Ubaidullaev, K. A.; Shakirov, R.; Yunosov, S. Y. Khim. Prir. Soedin 1976, 12,
553–554; (g) Zhang, H.-p.; Kamano, Y.; Ichiharra, Y.; Kizu, H.; Komiyama, K.;
Itokawa, H.; Itokawa, H.; Pettit, G. R. Tetrahedron 1995, 51, 5523–5528; (h)
Fréchard, A.; Fabre, N.; Péan, C.; Montaut, S.; Fauvel, M.-T.; Rollin, P.; Fourasté,
I. Tetrahedron Lett. 2001, 42, 9015–9017; (i) Zhou, L.; Yang, J.-S.; Wu, X.; Zou, J.-
H.; Xu, X.-D.; Tu, G.-Z. Heterocycles 2005, 65, 1409–1414; (j) Bramson, H. N.;
Corona, J.; Davis, S. T.; Dickerson, S. H.; Edelstein, M.; Frye, S. V.; Gampe, R. T.;
Harris, J. P. A.; Hassell, A.; Holmes, W. D.; Hunter, R. N.; Lackey, K. E.; Lovejoy,
B.; Luzzio, M. J.; Montana, V.; Rocque, W. J.; Rusnak, D.; Shewchuk, L.; Veal, J.
18. Relative populations were calculated according to
D
G =
D
H ꢀ T
DS and
D
G = ꢀRT ln
K
equations. For conformational equilibria of (3R,11R)-11a
equations K1,2 = n2/n1, K2,3 = n3/n2, K3,4 = n4/n3, K4,5 = n5/n4, K5,6 = n6/n5,
K6,7 = n7/n6, K7,8 = n8/n7, and n1 + n2 + n3 + n4 + n5 + n6 + n7 + n8 = 1 were used
while for (3S,11R)-11a equations K1,2 = n2/n1, K2,3 = n3/n2, K3,4 = n4/n3, K4,5 = n5/
n4, K5,6 = n6/n5, and n1 + n2 + n3 + n4 + n5 + n6 = 1 were used, where Ki,j stands for
equilibrium constants and ni stands for the molar fraction.
19. Hilton, S. T.; Ho, T. C. T.; Pljevaljcic, G.; Jones, K. Org. Lett. 2000, 2, 2639–2641.

O. R. Suárez-Castillo et al. / Tetrahedron: Asymmetry 20 (2009) 2374–2389
2389
20. Amat-Guerri, F.; Martínez-Utrilla, R.; López-González, M. M. C. J. Photochem.
Photobiol., A 1990, 50, 361–375.
21. Bowman, W. R.; Heaney, H.; Jordan, B. M. Tetrahedron Lett. 1988, 29, 6657–6660.
22. Sheldrick, G. M.. Programsfor Crystal Structure Analysis. In Institütfür Anorganische
Chemie der Universität; University of Göttingen: Göttingen, Germany, 1988.
23. Burla, M. C.; Caliandro, R.; Camalli, M.; Carrozzini, B.; Cascarano, G. L.; De Caro,
L.; Giacovazzo, C.; Polidori, G.; Spagna, R. J. Appl. Crystallogr. 2005, 38, 381–388.
24. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837–838.
25. Stomberg, R.; Langer, V.; Hauteville, M. Acta Crystallogr., Sect. E 2002, 58,
o1116–o1118.