Absolute configuration assignment of 3-indolylacetate esters

Article abstract of DOI:10.1016/j.tetasy.2012.08.005

Herein we describe a straightforward method for the determination of the absolute configuration of 3-indolyl(bromo)acetate 7, 3-indolyl(alkoxy)acetates 8a-f and 3-indolyl(amino)acetate 8g, based on ¹H NMR spectral analysis. The conformational preferences for two diastereomeric esters were calculated by DFT, which matched very well with the experimental results. X-ray diffraction analysis allowed us to validate the methodology, and independent absolute configuration evidence was obtained by vibrational circular dichroism.

Full text of DOI:10.1016/j.tetasy.2012.08.005

Tetrahedron: Asymmetry 23 (2012) 1279–1293
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Absolute configuration assignment of 3-indolylacetate esters
Rosa M. Vázquez-Arredondo a, Oscar R. Suárez-Castillo a, , Myriam Meléndez-Rodríguez a,
⇑
⇑
,
Maricruz Sánchez-Zavala a, Indira C. Cano-Escudero a, Claudia I. Bautista-Hernández a, Julián Cruz-Borbolla a,
Martha S. Morales-Ríos b, Pedro Joseph-Nathan b
a Área Académica de Química, Universidad Autónoma del Estado de Hidalgo, Mineral de la Reforma, Hidalgo 42184, Mexico
b Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado 14-740, México, DF 07000, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2012
Accepted 8 August 2012
Available online 14 September 2012
Herein we describe a straightforward method for the determination of the absolute configuration of 3-
indolyl(bromo)acetate 7, 3-indolyl(alkoxy)acetates 8a–f and 3-indolyl(amino)acetate 8g, based on 1H
NMR spectral analysis. The conformational preferences for two diastereomeric esters were calculated
by DFT, which matched very well with the experimental results. X-ray diffraction analysis allowed us
to validate the methodology, and independent absolute configuration evidence was obtained by vibra-
tional circular dichroism.
Ó 2012 Elsevier Ltd. All rights reserved.
R3
1. Introduction
CO2R2
X
Indole-3-acetic acid 1a, 2-(indole-3)-propionic acid 1f, and their
derivatives 1b–e and 1g,h are plant growth-regulators (auxins),
some of which have antiauxin activities (Fig. 1). Among these aux-
N
ins,
a-methoxy derivatives 1c and 1e increase the physiological
R1
effectiveness and strikingly translocate in plants,1 while the biolog-
ical activity of chlorinated auxins such as 1g is predominantly due
to the presence of chlorine atoms on the indole ring.2
( )- : R1 = R2 = R3 = X = H
1a
( )-1b: R1 = R2 = R3 = H, X = 5Cl, 6Cl
We previously reported3 a simple protocol for the synthesis of
3-indolyl(alkoxy)acetates 3 as potential plant growth-regulators,
via a two step process which included bromination and subsequent
alkoxylation of indole 2 in excellent yields (Scheme 1). In a contin-
uation of our studies aimed at the synthesis of indole auxins and
the determination of the absolute configuration of indole deriva-
tives,4 we herein report the synthesis of 3-indolyl(bromo)acetate
7, 3-indolyl(alkoxy)acetates 8a–f, and 3-indolyl(amino)acetate
8g, as well as their absolute configuration determination by 1H
NMR spectroscopic analysis and vibrational circular dichroism.
( )- : R1 = H, R2 = Me, R3 = OMe, X = H
1c
( )-1d: R1 = Ac, R2 = Me, R3 = H, X = H
( )- : R1 = Ac, R2 = Me, R3 = OMe, X = H
1e
(+)-1f: R1 = R2 = H, R3 = Me, X = H
(−)-1f: R1 = R2 = H, R3 = Me, X = H
(+)- : R = R2 = H, R3 = Me, X = 5Cl, 6Cl
1
1g
(−)-1g: R1 = R2 = H, R3 = Me, X = 5Cl, 6Cl
(+)- : R = R2 = H, R3 = Me, X = 5Cl, 7Cl
1
1h
(−)-1h: R1 = R2 = H, R3 = Me, X = 5Cl, 7Cl
Figure 1.
R2O
2. Results and discussion
CO2Me
CO2R1
1. NBS/AIBN
The general synthesis of 3-indolylacetate derivatives 7 and 8a–g
is shown in Scheme 2. Esterification of 1a with (1R,2S,5R)-(ꢀ)-
menthol or (R)-(ꢀ)-2-butanol, catalyzed by p-TsOH, afforded the
corresponding esters 4a and 4b in 93% and 83% yields, respectively.
Nitrogen protection of 4a,b was carried out with Me2CO3/DBU
CCl4
N
N
2. ROH
CO2Me
CO2Me
2
3
R1, R2 = Me, Et, i-Pr, t-Bu
⇑
Corresponding authors. Tel.: +52 771 71 72000x2206; fax: +52 771 71
72000x6502.
E-mail address: osuarez@uaeh.edu.mx (O.R. Suárez-Castillo).
Scheme 1.
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.08.005

1280
R. M. Vázquez-Arredondo et al. / Tetrahedron: Asymmetry 23 (2012) 1279–1293
Br
CO2R
CO2R1
CO2R1
Me2CO3/DBU
M.W.
NBS
AIBN
CCl4
or
Boc2O/DMPA
r.t.
N
H
N
N
CO2R2
CO2R2
1
: R1 = (-)-menthyl, R2 = Me
: R = (-)-menthyl, R2 = Me
4a
5a
6a
: R = menthyl
5b: R1 = (-)-sec-butyl, R2 = Me
6b: R1 = (-)-sec-butyl, R2 = Me
4b: R = sec-butyl
: R1 = (-)-menthyl, R2 = t-Bu
: R = (-)-mentyl, R2 = t-Bu
1
5c
6c
1. Br2 (8 eq)/CCl4
1. R3OH or MeNH2
2. Na2SO3/H2O
5a
for
3. HPLC separation
2. column chromatograpy
or HPLC separation
18
16
17
12
11
10
Br
O
9
R3
OR1
O
13
8
8
4
5
4
14
19
5
15
3a
3a
3
2
3
2
O
6
Br
R5
6
Br
R4
7a
7a
7
7
N
N
CO2Me
CO2R2
(8S,10R,11S,14R)-7
(8S)-8a-g
MeOH
+
+
Br
O
R3
OR1
O
O
Br
R5
Br
CO2Me
(8R,10R,11S,14R)-7
R4
N
N
CO2R2
(8R)-8a-g
: R1 = (10R,11S,14R)-menthyl, R2 = Me, R3 = OMe, R4 = R5 = H
8a
8b: R1 = (10R,11S,14R)-menthyl, R2 = Me, R3 = OEt, R4 = R5 = H
: R1 = (10R,11S,14R)-menthyl, R2 = Me, R3 = Oi-Pr, R4 = R5 = H
8c
8d: R1 = (R)-sec-butyl, R2 = Me, R3 = OMe, R4 = R5 = H
8e: R1 = (10R,11S,14R)-menthyl, R2 = t-butyl, R3 = OMe, R4 = R5 = H
1
: R = (10R,11S,14R)-menthyl, R2 = Me, R3 = OMe, R4 = R5 = Br
8f
8g: R1 = (10R,11S,14R)-menthyl, R2 = Me, R3 = NHMe, R4 = R5 = H
Scheme 2.
using microwave (MW) heating to obtain 5a and 5b in 77% and 70%
yields, respectively. Ester 4a was also treated with Boc2O/DMAP at
rt to afford 5c in quantitative yield. Treatment of 5a with NBS/
AIBN/CCl4 afforded the C8 brominated derivative 6a, which with-
out isolation was treated with MeOH at reflux to give a mixture
of 3-indolyl(alkoxy)acetate diastereomers (8S,10R,11S,14R)-8a
and (8R,10R,11S,14R)-8a in 45% yield. This mixture was separated
by column chromatography to afford the pure isomers in 17%
and 28% yields, respectively, with a diastereomeric excess >99%
as determined by 1H NMR measurements. In a similar way, the
preparation and treatment of 6b and 6c with several alcohols gave
the diastereoisomeric pairs (8S,10R,11S,14R)-8b–e and (8R,10R,
11S,14R)-8b–e, whose separation was carried out by HPLC. Diaste-
reomeric ratios for the 8b–8e pairs were about 1:1, as evidenced by
1H NMR analysis of the reaction crudes.
The reaction of 5a with an excess bromine5 afforded 3-
indolyl(bromo)acetates (8S,10R,11S,14R)-7 and (8R,10R,11S,14R)-
7, as a mixture which was stable enough to be separated by HPLC.

R. M. Vázquez-Arredondo et al. / Tetrahedron: Asymmetry 23 (2012) 1279–1293
1281
The mixture was treated with MeOH to provide diastereomeric es-
ters (8S,10R,11S,14R)-8f and (8R,10R,11S,14R)-8f, which were also
separated by HPLC. Treatment of 6a with MeNH2 at rt afforded the
3-indolyl(methylamino)acetates 8g as a diastereoisomeric mixture
which was easily separated by column chromatography to afford
(8S,10R,11S,14R)-8g and (8R,10R,11S,14R)-8g in 21% and 19%
yields, respectively. As is evident, the substitution reaction of bro-
mine in 6a by MeNH2 was faster than the acyl substitution of the
ester or carbamate functionalities.6
Figure 3, whereby the most stable conformation7a should contain
the methoxy group, the C8 carbon, the carboxyl ester group, and
the C10–H10 bond in, or almost, in a common plane with the
methoxy and the carbonyl groups in a syn-periplanar disposition.
In this conformation the indolyl moiety protrudes from C8 in
(8R,10R,11S,14R)-8a showing that the dominating conformation
should be that in which the orientation of the magnetic anisotropy
of the indolyl fragment should shield H16, H11, H10, H12a, H12e,
Me17, and Me18 of the menthyl fragment; conversely H15e,
H15a, H14, and Me19 should remain unaffected. In the
(8S,10R,11S,14R)-8a derivative, H15e, H15a, H14, and Me19 are
protected, while H16, H11, H10, H12a, H12e, Me17, and Me18
are unaffected (Fig. 3). Therefore, H16, H11, H10, H12a, H12e,
Me17, and Me18 will be more shielded to a lower frequency in
(8R,10R,11S,14R)-8a than in (8S,10R,11S,14R)-8a, while H15e,
H15a, H14, and Me19 will be more shielded in (8S,10R,11S,14R)-
8a than in (8R,10R,11S,14R)-8a.
Evaluation of the 1H NMR spectra owing to the sets of 3-indo-
lyl(alkoxy)acetates, 3-indolyl(bromo)acetate, and 3-indolyl(meth-
ylamino)acetate diastereomers combined with the evaluation of
their representative low energy conformers, allowed the assign-
ment of the absolute configuration at the C8 stereogenic center of
the chiral indole substrates. In order to achieve this goal, both 8a
diastereomeric esters were used as representative models. The 1H
NMR spectra allowed discrimination of the 3-indolyl(methoxy)ace-
tates (8S,10R,11S,14R)-8a and (8R,10R,11S,14R)-8a since these
compounds showed substantial chemical shift differences
Using conformational arguments, free rotation around the C8–
C@O bond in both 8a diastereomers should generate the two main
sp and ap conformers7c (Fig. 4). In the sp conformer, the methoxy
group, C8, the C9@O group, and the C10–H bond should be in the
same plane, with the methoxy and the C9@O groups in a syn-peri-
planar array. This arrangement was supported by X-ray crystallo-
graphic analysis and DFT calculations for the most stable
conformer of the (8R,10R,11S,14R)-8a diastereomer. In this confor-
mation H16, H11, H10, H12a, H12e, Me17, and Me18 in the
(8R,10R,11S,14R)-8a diastereomer and H15e, H15a, H14, and
Me19 in the (8S,10R,11S,14R)-8a diastereomer should always ap-
pear upfield due to the anisotropic shielding of the indolyl ring
(Fig. 4). In addition, in the ap conformer the methoxy group, C8,
the C9@O group, and the C10–H bond have the same coplanar
arrangement, but in this case, the methoxy and C9@O groups are
in an anti-periplanar relationship, and as a result, the indolyl ring
cannot efficiently transmit the shielding effect to the substituents
in the menthyl moiety as in the sp conformer. Therefore, conformer
sp should be the predominant rotamer of diastereomeric esters 8a.
Considering the polarity of diastereoisomeric esters 8a (Table 2),
it can be seen that H16, H11, H10, H12a, H12e, Me17, and Me18 of
less polar (8S,10R,11S,14R)-8a appear at higher frequencies
(Dd
RS = dR–dS, where the R and S descriptors refer to the stereogenic
C8 configuration at the indole moiety4) for the H10, H11, H12e,
H12a, H14, H15e, H15a, H16 atoms and the Me17, Me18, and
Me19 groups (Table 1). As can be seen in Table 1, there were no
chemical shift difference for the hydrogen atoms of the indole ring,
nor for the –OMe, –CO2Me groups or the H13a, H13e atoms.
Due to the structural resemblance of esters 8a with
-phenylacetic acid (MPA) and arylmethoxyacetic acids (AMAAs)
described by Riguera et al.,7 it was assumed that the dRS values
a-methoxy-
a
D
in compounds 8a arose from the anisotropic magnetic field
influence of the aromatic indole moiety on the NMR signals of
H10, H11, H12e, H12a, H14, H15e, H15a, H16, Me17, Me18, and
Me19 of the menthyl skeleton. Experimental evidence of this
assumption followed by comparison of the d 1H NMR values of
menthyl acetate8 with those of the menthyl fragment in stereoiso-
mers (8S,10R,11S,14R)-8a and (8R,10R,11S,14R)-8a (Fig. 2, Table 1)
supported this. As shown in Figure 2, the chemical shift values for
anisotropically unaffected hydrogen signals in diastereomers
(8S,10R,11S,14R)-8a and (8R,10R,11S,14R)-8a resembled the chem-
ical shift values of menthyl acetate.
The observed signs for
D
dRS between both diastereomers of 8a
(ꢀ
Dd
RS) than those of more polar (8R,10R,11S,14R)-8a, while
H15e, H15a, H14, and Me19 for more polar (8R,10R,11S,14R)-8a
could be accounted for by using the empirical model proposed in
Table 1
Chemical shifts (d) in ppm for menthyl acetate,a (8R,10R,11S,14R)-8a and (8S,10R,11S,14R)-8a
Proton signal
Menthyl acetate
(8R,10R,11S,14R)-8a
(8S,10R,11S,14R)-8a
D
dRSb
H2
H4
H5
H6
H7
H8
CO2Me
OMe
—
—
—
—
—
—
—
—
2.03
4.66
1.36
1.69
1.05
1.66
0.83
1.48
1.98
0.96
1.86
0.89
0.76
0.90
7.71
7.74
7.25
7.34
8.16
5.00
4.03
3.46
—
4.71
1.22
1.55
0.93
1.63
0.82
1.46
2.02
1.00
1.22
0.53
0.37
0.89
7.71
7.75
7.26
7.34
8.17
5.02
4.02
3.45
—
4.80
1.38
1.63
1.02
1.63
0.83
1.38
1.79
0.83
1.79
0.84
0.71
0.81
0
ꢀ0.01
ꢀ0.01
0
ꢀ0.01
ꢀ0.02
0.01
0.01
—
[Me12]
[H1] H10
[H2] H11
[H3e] H12e
[H3a] H12a
[H4e] H13e
[H4a] H13a
[H5] H14
[H6e] H15e
[H6a] H15a
[H7] H16
[Me8] Me17
[Me9] Me18
[Me10] Me19
ꢀ0.09
ꢀ0.16
ꢀ0.08
ꢀ0.09
0
ꢀ0.01
0.08
0.23
0.17
ꢀ0.57
ꢀ0.31
ꢀ0.34
0.08
a
Labels in brackets.
D
b
dRS values (dR–dS) were obtained by substracting the 1H chemical shifts of (8S,10R,11S,14R)-8a from those of (8R,10R,11S,14R)-8a.4

1282
R. M. Vázquez-Arredondo et al. / Tetrahedron: Asymmetry 23 (2012) 1279–1293
Figure 2. Partial 1H NMR spectra of (ꢀ)-menthyl acetate, (8S,10R,11S,14R)-8a and (8R,10R,11S,14R)-8a.
appear at higher frequencies (+
D
d
RS) than those of less polar
tain the substrates shown in Table 3. The Dd
RS values obtained for es-
(8S,10R,11S,14R)-8a.
ters 8b–g have the same sign of distribution for H10, H11, H12e,
H12a, H14, H15e, H15a, H16, Me17, Me18, and Me19 as those ob-
tained for 8a, which suggests that esters 7 and 8a–g quite probably
adopt the same conformationsat the MeO–C8–C9(@O)–O–C10–H10
The aforementioned 1H NMR methodology for the configuration
assignment was extended to include 3-indolyl(alkoxy)acetates, a 3-
indolyl(bromo)acetate and a 3-indolyl(amino)acetate, which con-

R. M. Vázquez-Arredondo et al. / Tetrahedron: Asymmetry 23 (2012) 1279–1293
1283
O
H
17
Me
H
10
a
MeO
19
O
4
7
15
9
14
Me
H
e
O
8
17Me
11
16
5
6
H
18
4
MeO
10
12
H
13
Me
15
3a
9
8
3
Me
14
H
O
e
H
16
H
3
3a
5
12
7a
13
2
11
H
18Me
H
a
2
N
N
6
7a
CO2Me
7
MeO2C
(8R,10R,11S,14R)-8a
8a
(8S,10R,11S,14R)-
Figure 3. Conformers of (8R,10R,11S,14R)-8a and (8S,10R,11S,14R)-8a showing the methoxy group, the C8 atom, the carboxyl ester group and the C10–H10 bond in a plane.
(8R,10R,11S,14R)-8a
sp conformer
MeO2C
N
O
O
H
H
H
H
a
a
Me
O
Me
Me
O
Me
10
H
MeO
8
H
9
Me
Me
H
OMe
H
H
H
H
H
e
e
ap conformer
N
ΔE
MeO2C
8a
(8S,10R,11S,14R)-
MeO2C
O
sp conformer
H
a
N
H
H
Me
O
O
Me
H
H
MeO
N
Me
O
a
OMe
8
Me
9
H
Me
e
H
Me
ap conformer
H
e
ΔE
CO2Me
Figure 4. Preferred conformations of (8R,10R,11S,14R)-8a and (8S,10R,11S,14R)-8a diastereomeric esters.
tively, in esters 8a is higher than those reported for MPA (ꢀ0.21,
ꢀ0.26 and 0.05) and menthyl 3-indolylpropionate2a and is compara-
Table 2
a
h
Retention time tR (min) and Rf values of diastereomeric esters 7 and 8a–g
ble to those of
a-(2-naphthyl)-a-methoxyacetic acid (2-NMA)
Compound
Diastereomer Rf or tR
(ꢀ0.41, ꢀ0.35, and 0.04).7b As is also shown in Table 3, changing
the methoxycarbonyl group for a t-butoxycarbonyl group had no
(8R,10R,11S,14R)-
(8S,10R,11S,14R)-
a,b,f
a,b,f
D
dRS values observed. However, changing
7
23.0 min
0.29h,i
16.0 min
24.0 min
20.0 min
0.28h,i
21.0 min
significant effect on the
the methoxy substituent at C8 with an ethoxy 8b, i-propoxy 8c or
a bromide 7 had a detrimental effect on the
RS values. It is interest-
ing to note that theintroductionof a bromineatom onthe indolering
8f produced a considerable increase in the
RS values, which were
-methoxyacetic acid
8a
8b
8c
8d
8e
8f
0.31h,i
a,c,g
a,c,g
a,d,g
a,c,g
19.0 min
28.0 min
D
d
a,c,g
a,d,g
23.0 min
0.33h,i
Dd
a,e,g
a,e,g
16.0 min
19.0 min
comparable to those of the
(1-NMA) derivatives.7b
a
-(1-naphthyl)-
a
8g
0.27h,j
0.32h,j
RS values observed in Figure 2
aValues obtained by HPLC using hexanes/EtOAc (130:1 v/vb), MeOH/H2O (43:7, v/v,c
13/7, v/vd) or MeCN/H2O (17:3, v/ve) with a semipreparative silica normal phase
columnf or with a C-18 reverse phase column.g
Further evidence to explain the
Dd
and Table 3 was provided when a systematic molecular modeling
protocol using a Monte Carlo searching9 and geometry optimization
by DFT calculations at the B3LYP/6-31G(d)10 and B3LYP/DGDZVP11
levels of theory were applied to diastereomeric esters
(8R,10R,11S,14R)-8a and (8S,10R,11S,14R)-8a. The Monte Carlo
search protocol using the MMFF9412 molecular mechanics force
field method, as implemented in the Spartan0413 program, afforded
hDetermined by TLC (silica gel F254 coated aluminum sheets 0.25 mm thickness)
recycling ten times with EtOAc/hexanes (45:1, v/v),i or recycling seven times with
EtOAc/hexanes (1:5, v/v)j.
fragment. As shown in Table 3, the magnitude of the
the Me17, Me18, and Me19 groups of ꢀ0.31, ꢀ0.34, and 0.08, respec-
Dd
RS values for

1284
R. M. Vázquez-Arredondo et al. / Tetrahedron: Asymmetry 23 (2012) 1279–1293
Table 3
Relevant
D
dRS values of diastereomeric esters (8R,10R,11S,14R)-7, 8a-g and (8S,10R,11S,14R)-7, 8a-ga
-0.34
-0.27
-0.25
-0.57
0
-0.31
-0.08
-0.09
-0.01
0. 01
-0.31
-0.28
-0.48
-0.07
-0.21
-0.08
0.01
-0.16
-0.12
-0.11
0
0. 01
0.02
-0.01
-0 .08
0
-0.08
-0.01
0.05
-0.01
O
O
O
-0.02
O
-0.09
0. 23
-0 .01
0. 04
O
-0.01
O
-0.01
0.08
0. 08
-0.02
-0.08
-0.01
0. 04
0.14
0. 03
0.13
0.22
0.18
0. 17
O
0. 02
O
O
0.05
0. 01
0.05
-0 .01
N
N
-0.01
N
0. 01
CO2Me
CO2Me0.01
CO2Me
8a
8b
8c
-0.29
-0.35
-0.15
-0.34
-0.52
-0.27
-0.6
-0.07
-0.82
-0.12
-0.42
-0.05
-0.13
-0.12
-0.05
-0.06
-0.01
-0.01
0.03
0.09
-0.05
-0.05
-0.03
0.01
0.02
0.03
-0.08
O
O
Br
-0.01
0.09
0.02
O
-0 .01
O
O
0. 03
0. 03
0. 04
0.14
0. 05
0. 01
0.12
0.21
0.32
0.28
0.14
O
O
O
Br
Br
0. 03
0.04
0.10
0.04
Br
Br
0.02
-0.02
-0.01
N
N
N
Boc0.01
CO2Me
CO2Me
8e
8f
7
-0.31
-0.58
-0.31
-0.23
-0.09
-0.09
-0.11
-0.02
-0.04
-0.13
O
0.03
NH
O
O
-0.07
0. 20
-0.02
0.15
-0.02
0.03
-0.01
-0.01
0. 22
O
O
0. 08
N
N
CO2Me
CO2Me
8g
8d
a
D
dRS values (dR–dS) were obtained by substracting the 1H chemical shifts of (8S,10R,11S,14R)-7, 8a–c, 8e–g from those of (8R,10R,11S,14R)-7, 8a–c, 8e–g or (8S,10R)-8d
from those of (8R,10R)-8d.4
91 conformers for diastereomer (8R,10R,11S,14R)-8a and 96
conformers for ester (8S,10R,11S,14R)-8a in 9.36 and 9.81 kcal/mol
energy gaps, respectively, from which 23 and 36 conformers, respec-
tively, accounted for 99.1% within 3.34 kcal/mol energy gaps. These
structures were submitted to geometry optimization using DFT cal-
culations at the B3LYP/6-31G(d) level of theory from which 22 con-
formers for esters (8R,10R,11S,14R)-8a and 34 conformers for ester
(8S,10R,11S,14R)-8a accounted for 99.99% within 4.5 and 3.8 kcal/
mol gaps, respectively. These conformers were further optimized
at the B3LYP/DGDZVP level of theory, as implemented in the GAUSSIAN
0914 program, to provide 15 conformers for (8R,10R,11S,14R)-8a and
21 conformers for (8S,10R,11S,14R)-8a which accounted for 98.87%
and 99.04% within 2.13 and 3.25 kcal/mol energy gaps, respectively.
The number of conformers was additionally reduced by eliminating
those contributing less than 1% to the conformational distribution to
provide 11 molecular models for (8R,10R,11S,14R)-8a (8aA–K)
(Table 4) and 12 molecular models for (8S,10R,11S,14R)-8a (8aA–
L) (Table 5), accounting for 96.25% and 95.06% of the conformational
distribution, respectively. Representative conformers for
(8R,10R,11S,14R)-8a and (8S,10R,11S,14R)-8a are shown in Figures
5 and 6, respectively. The population of each conformational species
was estimated using the thermochemical parameters of the
Table 4
Relative energies (kcal/mol) and conformational population (%) for the most stable
conformers of (8R,10R,11S,14R)-8a
a
b
c
b
d
e
Conformer
D
EMMFF
%
D
E6-31G(d)
%
D
GDGDZVP
%
8aA
8aB
8aC
8aD
8aE
8aF
8aG
8aH
8aI
0.00
0.36
0.84
1.05
1.18
1.79
2.19
2.21
2.62
2.83
3.13
41.61
22.73
10.12
7.09
5.69
2.01
1.04
1.01
0.50
0.35
0.21
0.00
0.31
1.06
0.68
1.85
1.88
0.16
1.81
2.31
0.29
0.18
19.61
11.72
3.26
6.24
0.87
0.82
14.95
0.92
0.40
11.98
14.43
0.00
0.24
0.08
0.43
0.70
0.70
0.17
0.78
0.71
0.35
0.48
15.38
11.21
13.84
8.17
4.82
4.82
12.45
4.34
4.82
9.07
7.35
8aJ
8aK
a
b
c
Relative to (8R,10R,11S,14R)-8aA with E = 120.195 kcal/mol.
Calculated according to
D
E ffi ꢀRT lnK.
Relative to (8R,10R,11S,14R)-8aA with E = ꢀ832090.874 kcal/mol.
Relative to (8R,10R,11S,14R)-8aA with G = ꢀ831907.778 kcal/mol.
d
e
Calculated according to
D
G = ꢀRT lnK.
reomers of 8a, with the former being the one that greatly causes the
indolyl moiety to be oriented either toward the H16, H11, H10,
H12a, H12e atoms, and the Me17 and Me18 groups, or toward
H15e, H15a, H14, and Me19. Thus, free rotation around the C8–
C9@O single bond in (8R,10R,11S,14R)-8a generates the most abun-
D
G =
D
H–TD
S and
D
G = ꢀRT lnK equations.4 Figures 5 and 6 show
that free rotation around the C8–C9@O, C8–C3, N1–CO2Me, and
(C8)–OMe single bonds are the dominating processes in both diaste-

R. M. Vázquez-Arredondo et al. / Tetrahedron: Asymmetry 23 (2012) 1279–1293
1285
Table 5
dant sp conformers 8aA–F, 8aH (62.58%) and the less abundant ap
conformers 8aG, 8aJ, and 8aK (28.87%). In the sp conformers, the
indolyl moiety is oriented toward the H16, H11, H10, H12a, H12e
atoms, and the Me17 and Me18 groups of the menthyl fragment,
while in the ap conformers, the indolyl group is oriented toward
H15e, H15a, H14, and Me19. Regarding diastereomer
(8S,10R,11S,14R)-8a, free rotation around the C8–C9@O single bond
generates the most abundant sp conformers 8aA,B, 8aD–F, and 8aH,I
(72.38%) and the less abundant ap conformers 8aC, 8aG, and 8aJ,K
(19.97%). In the sp conformers, the indolyl moiety is oriented toward
H15e, H15a, H14, and Me19 of the menthyl fragment, while in the ap
conformers, the indolyl group is oriented toward H16, H11, H10,
H12a, H12e, Me17, and Me18.
These results corresponded very well with those predicted in
Figure 3 and with the experimental results. Thus, the computa-
tional results reinforced the assignment of the absolute configura-
tion in (8R,10R,11S,14R)-8a and (8S,10R,11S,14R)-8a.
In order to further substantiate our assignments, the absolute
configurations of (8R,10R,11S,14R)-8a and (8S,10R,11S,14R)-8a
Relative energies (kcal/mol) and conformational population (%) for the most stable
conformers of (8S,10R,11S,14R)-8a
a
b
c
b
d
e
Conformer
D
EMMFF
%
D
E6-31G(d)
%
D
GDGDZPVP
%
8aA
8aB
8aC
8aD
8aE
8aF
8aG
8aH
8aI
0.00
0.02
0.34
0.87
0.89
1.06
1.18
1.79
1.83
1.91
2.02
2.44
22.70
21.90
12.71
5.24
5.07
3.79
3.08
1.10
1.04
0.91
0.75
0.37
0.00
0.25
0.76
1.02
1.86
0.67
1.28
2.44
1.63
0.54
1.93
2.13
22.37
14.61
6.25
4.01
0.97
7.28
2.59
0.36
1.43
9.00
0.86
0.61
1.21
0.00
1.02
1.03
1.43
1.39
0.81
2.04
0.88
2.13
2.12
1.64
5.09
42.00
6.99
6.99
3.71
3.71
10.66
1.29
9.59
1.16
1.16
2.70
8aJ
8aK
8aL
a
b
c
Relative to (8S,10R,11S,14R)-8aA with E = 121.246 kcal/mol.
Calculated according to
D
E ffi ꢀRT ln K.
Relative to (8S,10R,11S,14R)-8aA with E = ꢀ832090.831 kcal/mol.
d
e
Relative to (8S,10R,11S,14R)-8aB with G = ꢀ831908.673 kcal/mol.
Calculated according to
D
G = ꢀRT lnK.
sp-(8R,10R,11S,14R)-8aA
sp-(8R,10R,11S,14R)-8aB
sp-(8R,10R,11S,14R)-8aE
sp-(8R,10R,11S,14R)-8aH
sp-(8R,10R,11S,14R)-8aC
sp-(8R,10R,11S,14R)-8aF
sp-(8R,10R,11S,14R)-8aD
gauche-(8R,10R,11S,14R)-8aI
ap-(8R,10R,11S,14R)-8aG
ap-(8R,10R,11S,14R)-8aK
ap-(8R,10R,11S,14R)-8aJ
Figure 5. Optimized geometries for (8R,10R,11S,14R)-8aA-K conformers using DFT calculations at the B3LYP/DGDZVP level of theory.

1286
R. M. Vázquez-Arredondo et al. / Tetrahedron: Asymmetry 23 (2012) 1279–1293
sp-(8S,10R,11S,14R)-8aB
sp-(8S,10R,11S,14R)-8aA
ap-(8S,10R,11S,14R)-8aC
sp-(8S,10,11S,14R)-8aF
sp-(8S,10R,11S,14R)-8aD
sp-(8S,10,11S,14R)-8aE
sp-(8S,10R,11S,14R)-8aI
sp-(8S,10R,11,14R)-8aH
ap-(8S,10R,11S,1R)-8aG
gauche-(8S,10R,11S,14R)-8aL
ap-(8S,10R,11S,14R)-8aK
ap-(8S,10R,11S,14R)-8aJ
Figure 6. Optimized geometries for (8S,10R,11S,14R)-8aA-K conformers using DFT calculations at the B3LYP/DGDZVP level of theory.
were independently determined using vibrational circular
dichroism (VCD) spectroscopy. Thus for both diastereomers, the
vibrational frequencies and IR and VCD intensities were calculated
at the B3LYP/DGDZVP11 level of theory. The calculations involved
the generation of weighted-averaged vibrational plots including
8aA–K conformers for (8R,10R,11S,14R)-8a and 8aA–L conformers
for (8S,10R,11S,14R)-8a. The VCD frequencies of these major con-
formers were calculated and the Boltzmann averaged to generate
the calculated spectra, which were plotted using Lorentzian band-
shapes and bandwidths of 6 cmꢀ1. The calculated IR and VCD spectra
of (8R,10R,11S,14R)-8a and (8S,10R,11S,14R)-8a were in good agree-
ment with those obtained experimentally (Figs. 7 and 8). In order to
quantitatively evaluate the concordance between theoretical and
experimental data, a confidence level algorithm (BioTools Co., Jupi-
ter, FL 33458, USA) was applied to calculate the integrated overlap of
the experimental and theoretical data as a function of a relative
shift.15 This procedure allowed us to obtain the anharmonicity factor
(anH = 0.973), and the VCD spectral similarity for the correct
(SE = 82.4%) and incorrect enantiomer (SꢀE = 14.8%) with a 100%
confidence level for the absolute configuration determination of
(8R,10R,11S,14R)-8a, while for the (8S,10R,11S,14R)-8a diastereo-
mer, the values anH = 0.973, SE = 75.6%, and SꢀE = 22.0% with a
100% confidence level were obtained. These results were in agree-
ment with those obtained by 1H NMR analysis for the absolute con-
figuration assignment of diastereomeric esters (8R,10R,11S,14R)-8a
and (8S,10R,11S,14R)-8a.
Ester (8R,10R,11S,14R)-8a gave suitable crystals for X-ray dif-
fraction analysis and the corresponding absolute configuration
structure is shown in Figure 9. It is worth noting that in the solid
state, the preferred conformation shows the indolyl moiety ori-
ented toward H16, H11, H10, H12a, H12e, Me17, and Me18 in
excellent agreement with the most stable conformation 8aA
obtained at the B3LYP/DGDZVP level of theory. Thus, the X-ray
diffraction results obtained for (8R,10R,11S,14R)-8a validate the
1H NMR method for the absolute configuration assignment of
diastereomeric esters 7 and 8a-g.

R. M. Vázquez-Arredondo et al. / Tetrahedron: Asymmetry 23 (2012) 1279–1293
1287
Figure 7. Comparison of the experimental (top) and the DFT B3LYP/DGDZVP calculated (bottom) VCD spectra of (8R,10R,11S,14R)-8a.
an ionizing voltage of 70 eV on a Hewlett Packard 5989-A spectrom-
eter. High-resolution (HR) mass spectra were measured on a JEOL
JMS-SX 102A mass spectrometer at Instituto de Química, UNAM-
México. Microanalytical determinations were performed on a Per-
kin–Elmer 2400 series CHNS/O apparatus. Optical rotation measure-
3. Conclusion
We have demonstrated that the absolute configuration assign-
ment of 3-indolyl(alkoxy)acetates 8a–f, 3-indolyl(bromo)acetate
7, and 3-indolyl(amino)acetate 8g could be achieved by 1H NMR
analysis of their corresponding diastereoisomeric pairs. The
D
dRS
ments were performed on
a Perkin–Elmer 341 polarimeter.
Analytical thin-layer chromatography (TLC) was carried out on silica
gel F254 coated aluminumsheets (0.25 mm thickness) with a fluores-
cent indicator. Visualization was accomplished with UV light
(254 nm). Flash chromatography was carried out using silica gel
60 (230–400 mesh) from Aldrich. HPLC purification was carried
out on a Perkin Elmer Series 200 chromatographer using a UV-Vis
detector with a Varian Dynamax semipreparative Microsorb 100-5
silica normal phase column (id 10 mm, length 250 + 50 mm pre-col-
umn)or with a Varian Dynamax Microsorb100-5 C-18 reverse phase
column (id 10 mm, length 250 + 50 mm pre-column). Microwave
irradiation reactions were carried out on a CEM Mars 5 microwave
reactor working at 300 watts 15% equipped with an ESP-1500 Plus
Pressure Control System and a RTP-300 Plus Temperature Control
System. The reaction mixtures were deposited in HP-500 vessels
and the instrumental temperature settings were 120 °C for Me2CO3.
values found in these indolylacetate derivatives were greater than
those reported for MPA esters and comparable to those of 2-NMA es-
ters.7 The results were independently confirmed by X-ray diffraction
analysis and VCD measurements combined with DFT calculations.
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
obtained on JEOL Eclipse +400 and on Varian VNMRS 400 spectrom-
eters using CDCl3 as solvent and TMS as the internal reference. For
complete assignments gCOSY, gHMQC, gHSQC, and gHMBC spectra
were measured. Data are reported as follows: chemical shift in
ppm from TMS, integration, multiplicity (s = singlet, d = doublet,
t = triplet, sext = sextet, sept = septet, m = multiplet, br = broad),
coupling constant (Hz), and assignment. GC/MS analyses were con-
ducted on a Varian CP 3800 GC equipped with a Varian Saturn 2000
selectivemass detectorand a 30 m, 0.25 mmid, 0.25 mm CP-SILcap-
illary column, using helium as carrier gas (1 mL/min), programed
from 70 °C to 250 °C at a rate of 30 °C/min, with the injector temper-
ature at 200 °C. MSwere obtained in the electron impact(EI) mode at
4.2. Preparation of 2-(indol-3-yl)acetates 4a,4b
To a solution of indolylacetic acid 1a (1 g, 5.7 mmol) in toluene
(15 mL) were added 1.2 equiv of (ꢀ)-menthol or (ꢀ)-sec-butyl
alcohol and p-toluenesulfonic acid (0.01 equiv). The solution was
heated under reflux with a Dean-Stark tramp for 4 h. After cooling
to room temperature, the toluene was evaporated under reduced
pressure and the residue was dissolved in EtOAc (20 mL). The

1288
R. M. Vázquez-Arredondo et al. / Tetrahedron: Asymmetry 23 (2012) 1279–1293
Figure 8. Comparison of the experimental (top) and the DFT B3LYP/DGDZVP calculated (bottom) VCD spectra of (8S,10R,11S,14R)-8a.
organic phase was washed with a saturated solution of NaHCO3
(2 Â 20 mL) and brine (2 Â 20 mL), dried over Na2SO4, filtered,
and evaporated to dryness in vacuum. The resultant crude prod-
ucts were purified by flash column chromatography on silica gel
eluting with EtOAc/hexanes (1:4 v/v).
4.2.2. (R)-sec-Butyl 2-(1H-indol-3-yl)acetate 4b
Prepared from 1a as a yellow oil (1.18 g, 90%). ½a D20
¼ ꢀ13:3 (c
Š
0.6, EtOH). 1H NMR: d 8.16 1H, br s, NH), 7.60 (1H, dm, J = 7.8 Hz,
H4), 7.25 (1H, dm, J = 8.0 Hz, H7), 7.16 (1H, tm, J = 7.7 Hz, H6),
7.11 (1H, tm, J = 7.4 Hz, H5), 7.01 (1H, d, J = 2.4 Hz, H2), 4.87 (1H,
sext, J = 6.3 Hz, H10), 3.74 (2H, d, J = 0.9 Hz, H8), 1.56 (2H, m,
H12), 1.20 (3H, d, J = 6.3 Hz, Me11), 0.85 (3H, t, J = 7.5 Hz, Me13);
13C NMR: d 170.3 (C9), 135.4 (C7a), 126.6 (C3a), 122.6 (C2), 121.5
(C6), 118.9 (C5), 118.4 (C4), 110.9 (C7), 108.2 (C3), 73.0 (C10),
32.6 (C8), 29.8 (C12), 20.6 (Me11), 11.0 (Me13); IR (KBr) mmax
3355, 2973, 2933, 1721, 1491, 1306, 1073 cmꢀ1; EIMS m/z (relative
intensity) 231 ([M]+, 35), 130 (100), 77 (8).
4.2.1. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 2-(1H-indol-3-
yl)acetate 4a
Prepared from 1a as a white solid (1.72 g, 96%), mp: 82–84 °C
(EtOAc/hexanes) ½a D20
¼ ꢀ68:8 (c 1.6, EtOH). Although 15c is
Š
known,16 it was not spectroscopically fully characterized. Thus,
NMR data follows: 1H NMR: d 8.14 (1H, br s, NH), 7.58 (1H, d,
J = 7.7 Hz, H4), 7.24 (1H, d, J = 8.1 Hz, H7), 7.16 (1H, td, J = 7.0,
1.8 Hz, H6), 7.10 (1H, td, J = 7.9, 1.1 Hz, H5); 6.98 (1H, br s, H2),
4.72 (1H, td, J = 10.8, 4.3 Hz, H10), 3.74 (2H, s, H8), 1.98 (1H, dm,
J = 11.8 Hz, H15e), 1.78 (1H, sept d, J = 6.9, 2.2 Hz, H16), 1.65 (1H,
m, H13e), 1.63 (1H, m, H12e), 1.43 (1H, m, H14), 1.36 (1H, m,
H11), 1.01 (1H, m, H12a), 0.98 (1H, q, J = 11.3 Hz, H15a), 0.86
(3H, d, J = 6.6 Hz, Me19), 0.81 (4H, d, J = 7.0 Hz, H13a, Me17 or
Me18), 0.69 (3H, d, J = 6.9 Hz, Me17 or Me18); 13C NMR: d 172.0
(C9), 136.1 (C7a), 127.2 (C3a), 123.1 (C2), 122.0 (C6), 119.4 (C5),
118.8 (C4), 111.2 (C7), 108.4 (C3), 74.7 (C10), 47.1 (C11), 40.8
(C15), 34.2 (C13), 31.7 (C8), 31.4 (C14), 26.1 (C16), 23.4 (C12),
22.1 (Me19); 20.8 (Me17 or Me18), 16.3 (Me17 or Me18); IR (film)
mmax 3409, 2955, 2869, 1722, 1457, 1095 cmꢀ1; EIMS m/z (relative
intensity) 313 ([M]+, 21), 175 (13), 130 (100), 83 (12). Anal. Calcd
for C20H27NO2: C 76.64, H 8.68, N 4.47; Found: C 76.56, H 8.72, N
4.31.
4.3. General procedure for the preparation of indole carbamates
5a–c
Solutions of 4a (2 g, 6.38 mmol) and 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) (0.294 g, 1.93 mmol) in Me2CO3
(25 mL) or 4b (0.3 g, 1.30 mmol) and DBU (0.040 g, 0.26 mmol) in
Me2CO3 (15 mL) were stirred under microwave heating for 4 and
2.5 h, respectively. To a solution of 4a (2 g, 6.38 mmol) in MeCN
(25 mL) were added Boc2O (1.67 g, 7.65 mmol) and DMAP
(0.078 g, 0.64 mmol) and the mixture was stirred at room temper-
ature for 2 h. After cooling to room temperature, the volatiles were
evaporated and EtOAc (20 mL) was added to the reaction crudes.
The organic solution was washed with a saturated solution of NaH-
CO3 (2 Â 20 mL) and brine (2 Â 20 mL), dried over Na2SO4, filtered,
and concentrated in vacuo. The resultant crude products 5a–c were

R. M. Vázquez-Arredondo et al. / Tetrahedron: Asymmetry 23 (2012) 1279–1293
1289
purified by flash chromatography on silica gel using EtOAc/hex-
anes (1:15 v/v).
was shaken with a 10% aqueous solution of Na2SO3 (10 mL) for
24 h. The aqueous phase was separated and extracted with CH2Cl2
(2 Â 20 mL), and the combined organic layers were washed with
brine (2 Â 20 mL), dried over Na2SO4, filtered, and evaporated un-
der reduced pressure to give the crude reaction diastereoisomeric
mixture of (8S,10R,11S,14R)-7 and (8R,10R,11S,14R)-7, which was
purified by silica gel column chromatography eluting with
EtOAc/hexanes (1:30, v/v). The mixture of diastereomers
(8S,10R,11S,14R)-7 and (8R,10R,11S,14R)-7 was then separated by
HPLC with a semipreparative silica normal phase column, using
EtOAc/hexanes (1:130 v/v) at a flow rate of 4.0 mL/min.
4.3.1. Methyl 3-(2-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-
oxy)-2-oxoethyl)-1H-indole-1-carboxylate 5a
Prepared from 4a as white crystals (1.86 g, 78%), mp: 80–81 °C
(EtOAc/hexanes). ½a D20
Š
¼ ꢀ51:9 (c 1.5, EtOH). 1H NMR: d 8.16 (1H,
br d, J = 6.6 Hz, H7), 7.58 (1H, s, H2), 7.51 (1H, d, J = 8.4 Hz, H4),
7.33 (1H, td, J = 7.3, 1.1 Hz, H6), 7.24 (1H, td, J = 7.3, 1.1 Hz, H5),
4.41 (1H, td, J = 11.0, 4.4 Hz, H10), 3.99 (3H, s, NCO2Me), 3.68
(2H, s, H8), 1.99 (1H, dm, J = 12.1 Hz, H15e), 1.76 (1H, m, H16),
1.66 (1H, m, H13e), 1.62 (1H, m, H12e), 1.46 (1H, m, H14), 1.35
(1H, m, H11), 1.05 (1H, m, H12a), 0.97 (1H, m, H15a), 0.87 (3H,
d, J = 6.6 Hz, Me19), 0.85 (1H, m, H13a), 0.81 (3H, d, J = 6.9 Hz,
Me17 or Me18), 0.69 (3H, d, J = 6.9 Hz, Me17 or Me18); 13C NMR:
d 170.5 (C9), 151.4 (NCO2Me), 135.5 (C7a), 130.2 (C3a), 124.8
(C6), 123.9 (C2), 122.9 (C5), 119.4 (C4), 115.2 (C7), 114.5 (C3),
75.5 (C10), 53.7 (NCO2Me), 47.1 (C11), 40.9 (C15), 34.3 (C13),
31.5 (C14), 31.4 (C8), 26.3 (C12), 22.1 (C19), 20.7 (Me17 or
Me18), 16.3 (Me17 or Me18); IR (film) mmax 3408, 2954, 2868,
1720, 1457, 1170, 741 cmꢀ1; EIMS m/z (relative intensity) 313
([M]+, 13), 175 (14), 130 (100), 83 (58), 55 (55); Anal. Calcd for
C22H29NO4: C 71.13, H 7.87, N 3.77. Found: C 71.17, H 7.85, N 3.54.
4.4.1. Methyl 2,6-dibromo-3-((S)-1-bromo-2-((1R,2S,5R)-2-iso-
propyl-5-methylcyclo- hexyloxy)-2-oxoethyl)-1H-indole-1-
carboxylate (8S,10R,11S,14R)-7
HPLC tR: 23 min. ½a D20
Š
¼ ꢀ5:0 (c 0.5, EtOH). 1H NMR: d 8.26 (1H,
dd, J = 1.7, 0.4 Hz, H7), 7.77 (1H, dd, J = 8.6, 0.5 Hz, H4), 7.43 (1H,
dd, J = 8.6, 1.7 Hz, H5), 5.81 (1H, s, H8), 4.73 (1H, td, J = 10.9,
4.4 Hz, H10), 4.11 (3H, s, NCO2Me), 1.89 (1H, m, H15e), 1.88 (1H,
m, H16), 1.68 (1H, m, H13e), 1.65 (1H, m, H12e), 1.45 (1H, m,
H14), 1.39 (1H, m, H11), 1.04 (1H, m, H12a), 0.90 (1H, m, H15a),
0.87 (3H, d, J = 7.0 Hz, Me17 or Me18), 0.85 (3H, d, J = 6.5 Hz,
Me19), 0.85 (1H, m, H13a), 0.77 (3H, d, J = 7.0 Hz, Me17 or
Me18); 13C NMR: d 166.3 (C9), 150.5 (NCO2Me), 137.2 (C7a),
126.7 (C5), 125.4 (C3a), 122.2 (C4), 119.4 (C6), 118.9 (C3), 118.4
(C7), 111.8 (C2), 77.3 (C10), 54.5 (NCO2Me), 46.9 (C11), 40.5 (C8),
40.2 (C15), 34.0 (C13), 31.3 (C14), 26.2 (C16), 23.3 (C12), 21.9
(Me19), 20.7 (Me 17 or Me18), 16.3 (Me17 or Me18); IR (film) mmax
2956, 2924, 2870, 1750, 1465, 1302, 1106 cmꢀ1. EIMS m/z (relative
intensity) 530/528/526 ([M]+ꢀBr, 47/21/9), 348/346/344 (26/59/
22), 207/205 (29/24), 83/81 (100/78). FABHRMS m/z calcd for
4.3.2. (R)-Methyl 3-(2-sec-butoxy-2-oxoethyl)-1H-indole-1-carb-
oxylate 5b
Prepared from 4b as a yellow oil (0.34 g, 90%). ½a D20
¼ ꢀ18:3 (c
Š
1.2, EtOH). 1H NMR: d 8.16 1H, br d, J = 7.7 Hz, H7), 7.60 (1H, br
s, H2), 7.54 (1H, ddd, J = 7.8, 1.2, 0.8 Hz, H4), 7.33 (1H, ddd,
J = 8.4, 7.3, 1.2 Hz, H6), 7.25 (1H, ddd, J = 7.8, 7.3, 1.1 Hz, H5),
4.88 (1H, sext, J = 6.3 Hz, H10), 4.0 (3H, s, NCO2Me), 3.67 2H, d,
J = 0.6 Hz, H8), 1.55 (2H, m, H12), 1.20 (3H, d, J = 6.3 Hz, Me11),
0.85 (3H, t, J = 7.4 Hz, Me13); 13C NMR: d 170.5 (C9), 151.3
(NCO2Me), 135.4 (C7a), 130.1 (C3a), 124.7 (C6), 123.9 (C2), 122.9
(C5), 119.1 (C4), 115.1 (C7), 114.3 (C3), 73.0 (C10), 53.7 (NCO2Me),
C
22H26N1O4Br3 ([M]+): 606.9391, found: 606.9386.
4.4.2. Methyl 2,6-dibromo-3-((R)-1-bromo-2-((1R,2S,5R)-2-iso-
propyl-5-methylcyclo-hexyloxy)-2-oxoethyl)-1H-indole-1-
carboxylate (8R,10R,11S,14R)-7
31.4 (C8), 28.7 (C12), 19.3 (Me11), 9.6 (Me13); IR (film) mmax 2973,
2938, 1735, 1456, 1258, 1089 cmꢀ1; EIMS m/z (relative intensity)
HPLC tR: 21 min. ½a D20
Š
¼ ꢀ2:0 (c 0.6, EtOH). 1H NMR: d 8.25 (1H,
289 ([M]+, 30), 188 (100), 145 (14), 57 (4); Anal. Calcd for
dd, J = 1.7, 0.3 Hz, H7), 7.77 (1H, dd, J = 8.6, 0.3 Hz, H4), 7.43 (1H,
dd, J = 8.5, 1.8 Hz, H5), 5.81 (1H, s, H8), 4.68 (1H, td, J = 10.9,
4.4 Hz, H10), 4.11 (3H, s, NCO2Me), 2.03 (1H, m, H15e), 1.65 (1H,
m, H13e), 1.62 (1H, m, H12e), 1.46 (1H, sept d, J = 6.9, 2.8 Hz,
H16), 1.46 (1H, m, H14), 1.34 (1H, dddd, J = 12.3, 9.0, 3.3, 3.3 Hz,
H11), 1.01 (1H, q, J = 12.0 Hz, H15a), 0.97 (1H, m, H12a), 0.91
(3H, d, J = 6.6 Hz, Me19), 0.86 (1H, m, H13a), 0.70 (3H, d,
J = 7.0 Hz, Me17 or Me18), 0.50 (3H, d, J = 7.0 Hz, Me17 or Me18);
13C NMR: d 166.2 (C9), 150.5 (NCO2Me), 137.1 (C7a), 126.7 (C5),
125.3 (C3a), 122.1 (C4), 119.4 (C6), 118.8 (C2), 118.4 (C7), 111.8
(C3), 77.3 (C10), 54.5 (NCO2Me), 46.8 (C11), 40.9 (C8), 40.2 (C15),
34.0 (C13), 31.4 (C14), 26.0 (C16), 23.3 (C12), 22.0 (Me19), 20.5
(Me17 or Me18), 16.0 (Me17 or Me18). IR (fiml) mmax 2956, 2869,
1748, 1465, 1303, 1107 cmꢀ1. EIMS m/z (relative intensity) 530/
528/526 ([M]+–Br, 38/12/1), 348/346/344 (16/31/10), 207/205
(20/24), 83/81 (100/63). FABHRMS m/z calcd for C22H26N1O4Br3
([M]+): 606.9391, found: 606.9387.
C16H19NO4: C 66.42, H 6.62, N 4.84. Found: C 66.35, H 6.50, N 5.23.
4.3.3. tert-Butyl 3-(2-((1R,2S,5R)-2-isopropyl-5-methylcyclohex-
yloxy)-2-oxoethyl)-1H-indole-1-carboxylate 5c
Prepared from 4a as a yellow oil (2.61 g, 99%). ½a D20
¼ ꢀ40:8 (c
Š
1.2, EtOH). 1H NMR: d 8.14 (1H, br d, J = 6.6 Hz, H7), 7.56 (1H, br
s, H2), 7.52 (1H, ddd, J = 7.8, 1.1, 0.8 Hz, H4), 7.32 (1H, ddd, J = 8.4,
7.3, 1.2 Hz, H6), 7.23 (1H, td, J = 7.9, 1.1 Hz, H5), 4.72 (1H, td,
J = 10.9, 4.4 Hz, H10), 3.69 (2H, d, J = 1.0 Hz, H8), 1.99 (1H, m,
H15e), 1.77 (1H, sept d, J = 7.0, 2.7 Hz, H16), 1.70-1.61 (2H, m,
H12e, H13e), 1.66 (9H, s, NCO2C[Me]3) 1.46 (1H, m, H14), 1.36
(1H, dddd, J = 12.4, 10.9, 3.2, 3.2 Hz, H11), 1.02 (1H, qd, J = 14.0,
4.2 Hz, H12a), 0.97 (1H, q, J = 12.0 Hz, H15a), 0.88 (3H, d,
J = 6.6 Hz, Me19), 0.86 (1H, m, H13a), 0.82 (3H, d, J = 7.0 Hz, Me17
or Me18), 0.69 (3H, d, J = 6.96 Hz, Me17 or Me18); 13C NMR: d
169.5 (C9), 148.8 (NCO2C(Me)3), 134.9 (C7a), 129.7 (C3a), 124.1
(C2), 123.9 (C6), 122.2 (C5), 118.8 (C4), 115.0 (C7), 113.3 (C3),
83.9 (NCO2C(Me)3), 75.4 (C10), 48.1 (C11), 42.0 (C15), 35.5 (C13),
32.9 (C14), 32.7 (C8), 29.6 (NCO2C[Me]3), 27.6 (C16), 24.8 (C12),
23.5 (Me19), 22.3 (Me17 or Me18), 17.8 (Me17 or Me18); IR (film)
mmax 2955, 2870, 1734, 1454, 1308, 1084 cmꢀ1; EIMS m/z (relative
intensity) 313 ([M]+–CO2t-Bu, 18.0), 175 (18), 130 (100), 83 (13).
4.5. Preparation of diastereoisomeric esters 8a–g
To a solution of 5a (0.25 g, 0.67 mmol), 5b (0.25 g, 0.86 mmol),
or 5c (0.25 g, 0.60 mmol) in CCl4 (15 mL) were added 2.2 equiv of
NBS (0.26 g, 1.48 mmol for 5a, 0.34 g, 1.90 mmol for 5b, and
0.23 g, 1.33 mmol for 5c) and 0.04 equiv of AIBN (4 mg,
0.027 mmol for 5a, 6 mg, 0.034 mmol for 5b, and 4 mg,
0.034 mmol for 5c). The mixture was heated at reflux in a nitrogen
atmosphere for 2 h for 5a–c. After cooling to room temperature the
reaction mixture was washed with brine (2 Â 20 mL), dried over
Na2SO4, filtered, and evaporated under reduced pressure. The
4.4. Preparation of diastereoisomeric esters 7
To a solution of indole 5a (0.3 g, 0.80 mmol) in CCl4 (15 mL) was
added Br2 (560
lL, 10.89 mmol) in one portion and the resulting
mixture was stirred at room temperature for 24 h. The mixture

1290
R. M. Vázquez-Arredondo et al. / Tetrahedron: Asymmetry 23 (2012) 1279–1293
4.5.1. Methyl 3-((S)-2-((1R,2S,5R)-2-isopropyl-5-methylcyclo-
hexyloxy)-1-methoxy-2-oxoethyl)-1H-indole-1-carboxylate
(8S,10R,11S,14R)-8a
Prepared from 5a as a yellow oil (0.045 g, 17%). ½a D20
¼ ꢀ16:0 (c
Š
1.3, EtOH). 1H NMR: d 8.17 (1H, d, J = 7.7 Hz, H7), 7.75 (1H, d,
J = 7.7 Hz, H4), 7.71 (1H, s, H2), 7.34 (1H, t, J = 7.9 Hz, H6), 7.26
(1H, t, J = 7.5 Hz, H5), 5.02 (1H, s, H8), 4.80 (1H, td, J = 11.0,
4.4 Hz, H10), 4.02 (3H, s, NCO2Me), 3.45 (3H, s, OMe), 1.79 (2H,
m, H15e, H16), 1.63 (2H, m, H12e, H13e), 1.38 (2H, m, H11,
H14), 1.02 (1H, m, H12a), 0.84 (3H, d, J = 7.3 Hz, Me17 or Me18),
0.83 (2H, m, H13a, H15a), 0.81 (3H, d, J = 6.6 Hz, Me19), 0.71 (3H,
d, J = 6.9 Hz, Me17 or Me18); 13C NMR: d 169.9 (C9), 151.3
(NCO2Me), 135.7 (C7a), 128.3 (C3a), 125.1 (C6), 124.6 (C2), 123.2
(C5), 120.5 (C4), 117.1 (C3), 115.1 (C7), 76.6 (C8), 75.5 (C10),
57.3 (OMe), 53.9 (NCO2Me), 46.9 (C11), 40.4 (C15), 34.2 (C13),
31.4 (C14), 26.3 (C16), 23.3 (C12), 22.0 (Me19), 20.8 (Me17 or
Me18), 16.2 (Me17 or Me18); IR (CsI) mmax 3053, 2870, 2955,
1743, 1608, 1594, 1570, 1538, cmꢀ1; EIMS m/z (relative intensity)
401 ([M]+, 3), 218 (100), 159 (5); FABHRMS m/z calcd for
(8R,10R,11S,14R)-8a
C
23H31N1O5 ([M]+): 401.2202, found: 401.2195.
4.5.2. Methyl 3-((R)-2-((1R,2S,5R)-2-isopropyl-5-methylcyclo-
hexyloxy)-1-methoxy-2-oxoethyl)-1H-indole-1-carboxylate
(8R,10R,11S,14R)-8a
Prepared from 5a as white crystals (0.075 g, 28%). mp: 63–64 °C
(EtOAc/hexanes). ½a D20
Š
¼ ꢀ102:9 (c 1.6, EtOH). 1H NMR: d 8.16 (1H,
d, J = 7.7 Hz, H7), 7.74 (1H, d, J = 7.7 Hz, H4), 7.71 (1H, s, H2), 7.34
(1H, td, J = 7.9, 1.1 Hz, H6), 7.25 (1H, td, J = 7.5, 1.1 Hz, H5), 5.00
(1H, s, H8), 4.71 (1H, td, J = 10.8, 4.4 Hz, H10), 4.03 (3H, s, NCO2Me),
3.46 (3H, s, OMe), 2.02 (1H, m, H15e), 1.63 (1H, m, H13e), 1.55 (1H,
m, H12e), 1.46 (1H, m, H14), 1.22 (2H, m, H16, H11), 1.00 (1H, m,
H15e), 0.93 (1H, m, H12a), 0.89 (3H, d, J = 6.2 Hz, Me19), 0.82 (1H,
m, H13e), 0.53 (3H, d, J = 6.9 Hz, Me17 or Me18), 0.37 (3H, d,
J = 6.9 Hz, Me17 or Me18); 13C NMR: d 169.9 (C9), 151.3 (NCO2Me),
135.7 (C7a), 128.4 (C3a), 125.2 (C6), 124.8 (C2), 123.3 (C5), 120.6
(C4), 117.3 (C3), 115.1 (C7), 76.3 (C8), 75.6 (C10), 57.3 (OMe),
54.0 (NCO2Me), 47.1 (C11), 41.0 (C15), 34.2 (C13), 31.5 (C14),
25.6 (C16), 23.1 (C12), 22.1 (Me19), 20.5 (Me17 or Me18), 15.6
(Me17 or Me18); IR (CsI) mmax 3050, 3132, 2869, 2954, 1742,
1570, 1523, 1505 cmꢀ1; EIMS m/z (relative intensity) 401 ([M]+,
3), 218 (100), 158 (14), 116 (5), 55 (15); FABHRMS m/z calcd for
Figure 9. X-ray diffraction structure (top) and DFT B3LYP/DGDZVP minimum
energy conformer (bottom) of (8R,10R,11S,14R)-8a.
C
23H31N1O5 ([M]+): 401.2202, found: 401.2201.
crude products 6a–c were dissolved in 25 mL of the corresponding
alcohol (MeOH, EtOH, or i-PrOH) and the solution was stirred at
room temperature for 24 h (MeOH for 8a,d,e), 48 h (EtOH for 8b),
and 72 h (i-PrOH for 8c). The volatiles were evaporated in vacuo
and the crude products 8a–e were purified by flash column chro-
matography on silica gel eluting with EtOAc/hexanes (1:4 v/v).
The mixture of diastereomeric pairs (8S,10R,11S,14R)-8a,e and
(8R,10R,11S,14R)-8a,e was then repurified by successive column
chromatography on silica gel eluting with EtOAc/hexanes (1:45
v/v) while separation of the mixture of pairs of (8S,10R,11S,14R)-
8b–d and (8R,10R,11S,14R)-8b–d was carried out by HPLC with a
C-18 reverse phase column, using MeOH/H2O (43:7 v/v) for
(8S,10R,11S,14R)-8b,c and (8R,10R,11S,14R)-8b,c and MeOH/H2O
(13:7 v/v) for (8S,10R,11S,14R)-8d and (8R,10R,11S,14R)-8d at a
flow rate of 5.0 mL/min.
Alternatively, to a solution of crude 6a in THF (10 mL) was
added a solution of 2 M MeNH2/THF (10 equiv) and the mixture
was stirred at room temperature under a nitrogen atmosphere
for 1 h. The volatiles were evaporated in vacuo and the residue
was diluted with EtOAc (30 mL) and washed with brine
(2 Â 20 mL), dried over Na2SO4, filtered, and concentrated in vacuo.
The residue containing the mixture of diastereomeric amino esters
(8S,10R,11S,14R)-8g and (8R,10R,11S,14R)-8g was separated by
flash chromatography on silica gel using EtOAc/hexanes (1:5 v/v).
4.5.3. Methyl 3-((S)-1-ethoxy-2-((1R,2S,5R)-2-isopropyl-5-meth-
ylcyclohexyloxy)-2-oxoethyl)-1H-indole-1-carboxylate
(8S,10R,11S,14R)-8b
HPLC tR: 19 min. ½a D20
Š
¼ ꢀ18:9 (c 1.6, EtOH). 1H NMR: d 8.17
(1H, br d, J = 7.0 Hz, H7), 7.76 (1H, d, J = 7.8 Hz, H4), 7.70 (1H, br
s, H2), 7.35 (1H, td, J = 7.9, 1.2 Hz, H6), 7.26 (1H, td, J = 7.6,
1.1 Hz, H5), 5.12 (1H, d, J = 0.7 Hz, H8), 4.78 (1H, td, J = 10.7,
4.4 Hz, H10), 4.04 (3H, s, NCO2Me), 3.67 and 3.59 (2H, 2dq,
J = 9.0, 7.1 Hz, OCH2CH3), 1.82 (1H, m, H15e), 1.78 (1H, m, H16),
1.66 (1H, m, H13e), 1.62 (1H, m, H12e), 1.43 (1H, m, H14), 1.37
(1H, m, H11), 1.29 (3H, t, J = 7.0, OCH2CH3), 1.03 (1H, m, H12a),
0.91–0.84 (1H, m, H15a), 0.83 (3H, d, J = 6.9 Hz, Me17 or Me18),
0.81 (3H, d, J = 6.4 Hz, Me19), 0.79 (1H, m, H13a), 0.70 (3H, d,
J = 7.0 Hz, Me17 or Me18); 13C NMR: d 170.1 (C9), 151.3 (NCO2Me),
135.6 (C7a), 128.3 (C3a), 125.0 (C6), 124.3 (C2), 123.1 (C5), 120.4
(C4), 117.5 (C3), 115.0 (C7), 75.3 (C10), 74.9 (C8), 65.2 (CH2CH3),
53.9 (NCO2Me), 46.8 (C11), 40.3 (C15), 34.1 (C13), 31.3 (C14),
26.1 (C16), 23.2 (C12), 21.9 (Me19), 20.7 (Me17 or Me18), 16.1
(Me17 or Me18), 15.2 (CH2CH3); IR (film) mmax 2956, 2870, 1743,
1455, 1247, 1090 cmꢀ1; EIMS m/z (relative intensity) 415 ([M]+,
1), 205 (23), 232 (100), 158 (6), 117 (9); FABHRMS m/z calcd for
C
24H33N1O5 ([M]+): 415.2359, found: 415.2347.

R. M. Vázquez-Arredondo et al. / Tetrahedron: Asymmetry 23 (2012) 1279–1293
1291
4.5.4. Methyl 3-((R)-1-ethoxy-2-((1R,2S,5R)-2-isopropyl-5-meth-
ylcyclohexyloxy)-2-oxoethyl)-1H-indole-1-carboxylate
(8R,10R,11S,14R)-8b
22.2 (OCH2[CH3]2), 22.0 (OCH2[CH3]2), 21.9 (Me 19), 20.4 (Me17
or Me18), 15.5 (Me17 or Me18); IR (film) mmax 2957, 2870, 1743,
1455, 1309, 1097 cmꢀ1; EIMS m/z (relative intensity) 429 ([M]+,
2), 378 (48), 376 (100), 375 (50), 317 (14); FABHRMS m/z calcd
for C25H35N1O5 ([M]+): 429.2515, found: 429.2520.
HPLC tR: 16 min. ½a D20
Š
¼ ꢀ70:8 (c 1.2, EtOH). 1H NMR: d 8.16
(1H, br d, J = 7.7 Hz, H7), 7.76 (1H, ddd, J = 7.8, 1.2, 0.7 Hz, H4),
7.69 (1H, br s, H2), 7.36 (1H, ddd, J = 7.8, 7.8, 1.2 Hz, H6), 7.26
(1H, ddd, J = 8.5, 6.8, 0.8 Hz, H5), 5.10 (1H, d, J = 0.6 Hz, H8), 4.70
(1H, td, J = 10.8, 4.4 Hz, H10), 4.04 (3H, s, NCO2Me), 3.67 and 3.60
(2H, 2dq, J = 9.1, 7.1 Hz, OCH2CH3), 2.02 (1H, m, H15e), 1.64 (2H,
m, H13e, H16), 1.56 (1H, dq, J = 13.1, 3.2 H12e), 1.46 (1H, m,
H14), 1.28 (3H, t, J = 7.0 Hz, OCH2CH3), 1.25 (1H, m, H11), 0.99
(1H, q, J = 11.9 Hz, H15a), 0.94 (1H, m, H12a), 0.88 (3H, d,
J = 6.5 Hz, Me19), 0.82 (1H, m, H13a), 0.54 (3H, d, J = 6.9 Hz,
Me17 or Me18), 0.39 (3H, d, J = 6.8 Hz, Me17 or Me18); 13C NMR:
d 169.1 (C9), 150.3 (NCO2Me), 134.6 (C7a), 127.4 (C3a), 124.0
(C6), 123.4 (C2), 122.1 (C5), 119.4 (C4), 116.7 (C3), 113.9 (C7),
74.4 (C10), 73.6 (C8), 64.2 (CH2CH3), 52.9 (NCO2Me), 46.0 (C11),
39.8 (C15), 33.1 (C13), 30.4 (C14), 24.5 (C16), 21.9 (C12), 21.0
(Me19), 19.4 (Me17 or Me18), 14.5 (Me17 or Me18), 14.1
(CH2CH3); IR (film) mmax 2957, 2870, 1743, 1455, 1245,
1091 cmꢀ1; EIMS m/z (relative intensity) 415 ([M]+, 1), 232 (100),
205 (10); 117 (7); FABHRMS m/z calcd for C24H33N1O5 ([M]+):
415.2359, found: 415.2350.
4.5.7. Methyl 3-((S)-2-sec-butoxy-1-methoxy-2-oxoethyl)-1H-
indole-1-carboxylate (8S, 10R)-8d
HPLC tR: 23 min. ½a D20
Š
¼ þ41:3 (c 0.8, EtOH). 1H NMR: d 8.17
(1H, br d, J = 7.7 Hz, H7), 7.76 (1H, ddd, J = 7.9, 1.3, 0.8 Hz, H4),
7.72 (1H, br s, H2), 7.35 (1H, tm, J = 7.7 Hz, H6), 7.26 (1H, ddd,
J = 7.9, 7.2, 1.1 Hz, H5), 5.01 (1H, d, J = 0.8 Hz, H8), 4.94 (1H, sext,
J = 6.2 Hz, H10), 4.04 (3H, s, NCO2Me), 3.46 (3H, s, OMe), 1.58
(2H, m, H12), 1.08 (3H, d, J = 6.3 Hz, Me11), 0.87 (3H, t, J = 7.5 Hz,
Me13); 13C NMR: d 169.9 (C9), 151.3 (NCO2Me), 135.6 (C7a),
128.1 (C3a), 125.0 (C6), 124.6 (C2), 123.1 (C5), 120.4 (C4), 117.0
(C3), 115.1 (C7), 76.4 (C8), 73.7 (C10), 57.3 (OMe), 53.9 (NCO2Me),
28.7 (C12), 19.2 (Me11), 9.7 (Me13); IR (film) mmax 2925, 2877,
1741, 1607, 1196 cmꢀ1; EIMS m/z (relative intensity) 319 ([M]+,
2), 218 (100), 158 (9); FABHRMS m/z calcd for C17H21N1O5 ([M]+):
319.1420, found: 319.1419.
4.5.8. Methyl 3-((R)-2-sec-butoxy-1-methoxy-2-oxoethyl)-1H-
indole-1-carboxylate (8R,10R)-8d
4.5.5. Methyl 3-((S)-1-isopropoxy-2-((1R,2S,5R)-2-isopropyl-5-
methylcyclohexyloxy)-2-oxoethyl)-1H-indole-1-carboxylate
(8S,10R,11S,14R)-8c
HPLC tR: 20 min. ½a D20
Š
¼ ꢀ51:7 (c 1.2, EtOH). 1H NMR: d 8.17
(1H, br d, J = 7.1 Hz, H7), 7.76 (1H, ddd, J = 7.9, 1.2, 0.8 Hz, H4),
7.72 (1H, br s, H2), 7.35 (1H, ddd, J = 8.4, 7.2, 1.2 Hz, H6), 7.26
(1H, ddd, J = 7.9, 7.2, 1.1 Hz, H5), 5.00 (1H, d, J = 0.7 Hz, H8), 4.91
(1H, sext, J = 6.4 Hz, H10), 4.04 (3H, s, NCO2Me), 3.46 (1H, s,
OMe), 1.45 (2H, m, H12), 1.23 (3H, d, J = 6.3 Hz, Me11), 0.64 (3H,
t, J = 7.5 Hz, Me13); 13C NMR: d 169.9 (C9), 151.2 (NCO2Me),
135.6 (C7a), 128.1 (C3a), 125.0 (C6), 124.6 (C2), 123.1 (C5), 120.4
(C4), 117.1 (C3), 115.0 (C7), 76.3 (C8), 73.7 (C10), 57.3 (OMe),
53.9 (NCO2Me), 28.7 (C12), 19.5 (Me11), 9.7 (Me13); IR (film) mmax
2929, 2858, 1741, 1609, 1193 cmꢀ1; EIMS m/z (relative intensity)
319 ([M]+, 1), 218 (100), 158 (11); FABHRMS m/z calcd for
HPLC tR: 28 min. ½a D20
Š
¼ ꢀ14:8 (c 2.2, EtOH). 1H NMR: d 8.16 (1H,
br d, J = 7.0 Hz, H7), 7.76 (1H, ddd, J = 7.8, 1.1, 0.8 Hz, H4), 7.68 (1H,
br s, H2), 7.34 (1H, ddd, J = 7.8, 7.3, 1.12 Hz, H6), 7.26 (1H, ddd, J = 7.8,
7.1, 1.1 Hz, H5), 5.21 (1H, d, J = 0.9 Hz, H8), 4.76 (1H, td, J = 10.9,
4.4 Hz, H10), 4.03 (3H, s, NCO2Me), 3.76 (1H, sept, J = 6.1 Hz,
CH[CH3]2), 1.83 (1H, ddd, J = 12.0, 4.3, 1.8 Hz, H15e), 1.76 (1H, septd,
J = 7.1, 2.7 Hz, H16), 1.66 (1H, m, H13e), 1.63 (1H, m, H12e), 1.43 (1H,
m, H14), 1.37 (1H, m, H11), 1.28 (3H, d, J = 6.1 Hz, OCH(CH3)2), 1.24
(3H, d, J = 6.1, OCH(CH3)2), 1.02 (1H, m, H12a), 0.86 (1H, m, H15a),
0.83 (3H, d, J = 6.5 Hz, Me19), 0.81 (3H, d, J = 7.0 Hz, Me17 or
Me18), 0.83–0.76 (1H, m, H13a), 0.68 (3H, d, J = 7.0 Hz, Me17 or
Me18); 13C NMR: d 170.7 (C9), 151.3 (NCO2Me), 135.7 (C7a), 128.4
(C3a), 124.9 (C6), 124.1 (C2), 123.0 (C5), 120.4 (C4), 118.0 (C3),
115.0 (C7), 75.3 (C10), 72.7 (C8), 71.2 (OCH[CH3]2), 53.8 (NCO2Me),
46.9 (C11), 40.3 (C15), 34.1 (C13), 31.3 (C14), 26.1 (C16), 23.2
(C12), 22.4 (OCH2[CH3]2), 21.9 (OCH2[CH3]2), 21.8 (Me 19), 20.7
(Me17 or Me18), 16.0 (Me17 or Me18); IR (film) mmax 2957, 2869,
1743, 1455, 1245, 1092 cmꢀ1; EIMS m/z (relative intensity) 429
([M]+, 2), 246 (62), 232 (24), 204 (100), 144 (8), 117 (14).; FABHRMS
m/z calcd for C25H35NO5 ([M]+): 429.2515, found: 429.2523.
C
17H21N1O5 ([M]+): 319.1420, found: 319.1422.
4.5.9. tert-Butyl 3-((S)-2-((1R,2S,5R)-2-isopropyl-5-methylcyclo-
hexyloxy)-1-methoxy-2-oxoethyl)-1H-indole-1-carboxylate
(8S,10R,11S,14R)-8e
Prepared from 5c as a yellow oil (0.050 g, 19%). ½a D20
¼ ꢀ12:5
Š
(c = 1.2, EtOH). 1H NMR: d 8.12 (1H, br d, J = 8.0 Hz, H7), 7.70
(1H, dm, J = 7.8 Hz, H4), 7.63 (1H, br s, H2), 7.29 (1H, ddd, J = 8.4,
7.2, 1.3 Hz, H6), 7.21 (1H, td, J = 7.3, 1.1 Hz, H5), 5.01 (1H, d,
J = 0.7 Hz, H8), 4.78 (1H, td, J = 10.9, 4.4 Hz, H10), 3.44 (3H, s,
OMe), 1.84–1.77 (2H, m, H15e, H16), 1.71–1.60 (2H, m, H12e,
H13e), 1.66 (9H, br s, NCO2C[Me]3), 1.47-1.34 (2H, m, H11, H14),
1.02 (1H, m, H12a), 0.87 (1H, m H15a), 0.85 (3H, d, J = 6.9 Hz,
Me17 or Me18), 0.82 (3H, d, J = 6.5 Hz. Me19), 0.84–0.75 (1H, m,
H13a), 0.71 (3H, d, J = 6.9 Hz, Me17 or Me18); 13C NMR: d 168.8
(C9), 148.7 (NCO2C[Me]3), 135.1(C7a), 127.8 (C3a), 124.5 (C2),
124.4 (C6), 122.5 (C5), 120.0 (C4), 115.9 (C3), 115.0 (C7), 84.3
(NCO2C[Me]3), 77.0 (C8), 76.0 (C10), 58.1 (OMe), 47.9 (C11), 41.5
(C15), 35.4 (C13), 32.7 (C14), 29.6 (NCO2C[Me]3), 27.6 (C16), 24.7
(C12), 23.5 (Me19), 22.3 (Me17 or Me18), 17.8 (Me17 or Me18);
IR (film) mmax 2955, 2870, 1737, 1453, 1309, 1084 cmꢀ1; EIMS m/
z (relative intensity) 340 ([M]+–t-Boc, 1), 173 (23), 160 (100), 128
(20), 117 (12), 55 (12); FABHRMS m/z calcd for C26H37N1O5
([M]+): 443.2672, found: 443.2675.
4.5.6. Methyl 3-((R)-1-isopropoxy-2-((1R,2S,5R)-2-isopropyl-5-
methylcyclohexyloxy)-2-oxoethyl)-1H-indole-1-carboxylate
(8R,10R,11S,14R)-8c
HPLC tR: 24 min. ½a D20
Š
¼ ꢀ83:2 (c 2.5, EtOH). 1H NMR: d 8.15
(1H, br d, J = 7.5 Hz, H7), 7.75 (1H, ddd, J = 7.8, 1.2, 0.8 Hz, H4),
7.68 (1H, br s, H2), 7.34 (1H, ddd, J = 8.4, 7.3, 1.2 Hz, H6), 7.26
(1H, ddd, J = 8.4, 7.4, 1.2 Hz, H5), 5.20 (1H, d, J = 0.7 Hz, H8), 4.69
(1H, td, J = 10.9, 4.4 Hz, H10), 4.03 (3H, s, NCO2Me), 3.78 (1H, sept,
J = 6.1 Hz, OCH[CH3]2), 2.01 (1H, m, H15e), 1.64 (1H, m, H13e), 1.56
(1H, dq, J = 13.3, 3.2 Hz, H12e), 1.46 (1H, m, H14), 1.28 and 1.22
(6H, 2d, J = 6.1 Hz, OCH(CH3)2), 1.28–1.23 (2H, m H11, H16), 0.99
(1H, q, J = 11.7 Hz, H15a), 0.96 (1H, m, H12a), 0.88 (3H, d,
J = 6.5 Hz, Me19), 0.83 (1H, m, H13a), 0.56 (3H, d, J = 6.9 Hz,
Me17 or Me18), 0.40 (3H, d, J = 6.8 Hz, Me17 or Me18); 13C NMR:
d 170.6 (C9), 151.3 (NCO2Me), 135.6 (C7a), 128.4 (C3a), 125.0
(C6), 124.2 (C2), 123.1 (C5), 120.5 (C4), 118.2 (C3), 115.0 (C7),
75.3 (C10), 72.2 (C8), 70.9 (OCH[CH3]2), 53.9 (NCO2Me), 47.0
(C11), 40.8 (C15), 34.1 (C13), 31.4 (C14), 25.5 (C16), 22.9 (C12),
4.5.10. tert-Butyl 3-((R)-2-((1R,2S,5R)-2-isopropyl-5-methylcy
clohexyloxy)-1-methoxy-2-oxoethyl)-1H-indole-1-carboxylate
(8R,10R,11S,14R)-8e
Prepared from 5c as a yellow oil (0.075 g, 28%). ½a D20
¼ ꢀ88:75 (c
Š
0.8, EtOH). 1H NMR: d 8.14 (1H, br d, J = 7.7 Hz, H7), 7.72 (1H, ddd,

1292
R. M. Vázquez-Arredondo et al. / Tetrahedron: Asymmetry 23 (2012) 1279–1293
J = 7.9, 1.2, 0.8 Hz, H4), 7.67 (1H, br s, H2), 7.32 (1H, ddd, J = 8.5, 7.3,
1.3 Hz, H6), 7.24 (1H, ddd, J = 8.4, 7.3, 1.1 Hz, H5), 5.01 (1H, d,
J = 0.6 Hz, H8), 4.71 (1H, td, J = 10.9, 4.4 Hz, H10), 3.46 (3H, s,
OMe), 2.03 (1H, m, H15e), 1.66 (9H, br s, NCO2C[Me]3), 1.61 (1H,
m, H13e), 1.56 (1H, dq, J = 12.7, 3.4 Hz, H12e), 1.48 (1H, m, H14),
1.29–1.17 (2H, m, H11, H16), 1.01 (1H, q, J = 11.1 Hz, H15a), 0.92
(1H, m, H12a), 0.89 (3H, d, J = 6.5 Hz, Me19), 0.83 (1H, m, H13a),
0.53 (3H, d, J = 6.9 Hz, Me17 or Me18), 0.37 (3H, d, J = 6.9 Hz,
Me17 or Me18); 13C NMR: d 169.9 (C9), 149.4 (NCO2C(Me)3),
135.6 (C7a), 128.3 (C3a), 125.0 (C2), 124.8 (C6), 122.8 (C5), 120.2
(C4), 116.2 (C3), 115.0 (C7), 83.9 (NCO2C[Me]3), 76.2 (C8), 75.5
(C10), 57.2 (OMe), 47.0 (C11), 40.8 (C15), 34.1 (C13), 31.4 (C14),
28.1 (NCO2C[Me]3), 25.5 (C16), 22.9 (C12), 22.0 (Me19), 20.4
(Me17 or Me18), 15.4 (Me17 or Me18); IR (film) mmax 2955, 2871,
1737, 1453, 1091 cmꢀ1; EIMS m/z (relative intensity) 443 ([M]+,
0.1), 204 (10), 173 (12), 160 (100), 144 (13), 128 (13), 117 (8); FAB-
HRMS m/z calcd for C26H37N1O5 ([M]+): 443.2672, found: 443.2667.
and evaporated under reduced pressure. The volatiles were evapo-
rated in vacuo and the resultant crude product 8f was purified by
flash column chromatography on silica gel eluting with EtOAc/
hexanes (1:30 v/v). Next, the mixture of diastereomers
(8S,10R,11S,14R)-8f and (8R,10R,11S,14R)-8f was separated by
HPLC with a semipreparative C-18 reverse phase column, using
MeCN/H2O (17:3 v/v) at a flow rate of 5.0 mL/min.
4.6.1. Methyl 2,6-dibromo-3-((S)-2-((1R,2S,5R)-2-isopropyl-5-
methylcyclohexyloxy)-1-methoxy-2-oxoethyl)-1H-indole-1-
carboxylate (8S,10R,11S,14R)-8f
HPLC tR: 19 min. ½a D20
Š
¼ ꢀ96:1 (c 0.8, EtOH). 1H NMR: d 8.24
(1H, dd, J = 1.7, 0.4 Hz, H7), 7.68 (1H, dd, J = 8.4, 0.4 Hz, H4), 7.37
(1H, dd, J = 8.5, 1.7 Hz, H5), 5.14 (1H, s, H8), 4.74 (1H, td, J = 10.9,
4.4 Hz, H10), 4.12 (3H, s, NCO2Me), 3.38 (3H, s, OMe), 1.81 (1H,
sept d, J = 7.0, 2.6 Hz, H16), 1.69 (1H, m, H15e), 1.62 (2H, m,
H12e, H13e), 1.39 (1H, m, H14), 1.33 (1H, dddd, J = 12.6, 11.0,
3.1, 3.1 Hz, H11), 1.00 (1H, m, H12a), 0.85 (3H, d, J = 7.0 Hz, Me
17 or Me18), 0.78 (3H, d, J = 6.6 Hz, Me19), 0.74 (3H, d, J = 7.0 Hz,
Me17 or Me18), 0.72 (2H, m, H15a, H13a); 13C NMR: d 168.9
(C9), 150.7 (NCO2Me), 136.8 (C7a), 126.9 (C5), 125.5 (C3a), 121.3
(C4), 119.1 (C6), 118.8 (C3), 118.3 (C7), 112.3 (C2), 76.4 (C8),
75.7 (C10), 57.2 (OMe), 54.3 (NCO2Me), 46.7 (C11), 40.1 (C15),
34.0 (C13), 31.2 (C14), 26.3 (C16), 23.3 (C12), 21.9 (Me 19), 20.7
(Me17 or Me18), 16.4 (Me17 or Me18). IR (film) mmax 2927, 2870,
1749, 1455, 1350 cmꢀ1; EIMS m/z (relative intensity) 374/376/
378 ([M]+–CO2menthyl, 49/100/48), 319/317 (16/15), 274 (6), 55
(12); FABHRMS m/z calcd for C23H29N1O5Br2 ([M]+): 559.0392,
found: 559.0406.
4.5.11. Methyl 3-((S)-2-((1R,2S,5R)-2-isopropyl-5-methylcyclo-
hexyloxy)-1-(methylami no)-2-oxoethyl)-1H-indole-1-
carboxylate (8S,10R,11S,14R)-8g
Prepared from 5a as a yellow oil (0.056 g, 21%). ½a D20
¼ ꢀ10:9 (c
Š
1.3, EtOH). 1H NMR: d 8.17 (1H, br d, J = 6.4 Hz, H7), 7.71 (1H, ddd,
J = 7.8, 1.1, 0.7 Hz, H4), 7.61 (1H, br s, H2), 7.35 (1H, td, J = 7.3,
1.2 Hz, H6), 7.26 (1H, td, J = 7.3, 1.1 Hz, H5), 4.79 (1H, td, J = 10.9,
4.4 Hz, H10), 4.49 (1H, d, J = 0.9 Hz, H8), 4.03 (3H, s, NCO2Me),
2.48 (3H, s, NHMe), 1.93 (1H, br s, NH), 1.83 (2H, m, H15e, H16),
1.66 (2H, m, H12e, H13e), 1.44 (1H, m, H14), 1.36 (1H, m, H11),
1.04 (1H, m, H12a), 0.86 (3H, d, J = 7.1 Hz, Me17 or Me18), 0.82
(3H, d, J = 6.6 Hz, Me19), 0.79 (2H, m, H13a, H15a), 0.74 (3H, d,
J = 7.0 Hz, Me17 or Me18); 13C NMR: d 172.2 (C9), 151.3 (NCO2Me),
135.7 (C7a), 128.7 (C3a), 124.9 (C6), 123.4 (C2), 123.0 (C5), 119.8
(C4), 118.8 (C3), 115.1 (C7), 75.3 (C10), 60.2 (C8), 53.8 (NCO2Me),
46.8 (C11), 40.4 (C15), 34.6 (NHMe), 34.1 (C13), 31.3 (C14), 26.2
(C16), 23.2 (C12), 21.9 (Me19), 20.7 (Me17 or Me18), 16.1 (Me17
or Me18); IR (film) mmax 3345, 2955, 2928, 2870, 1739, 1456,
1378, 1252 cmꢀ1; EIMS m/z (relative intensity) 400 ([M]+, 1.0),
217 (100).
4.6.2. Methyl 2,6-dibromo-3-((R)-2-((1R,2S,5R)-2-isopropyl-5-
methylcyclohexyloxy)-1-methoxy-2-oxoethyl)-1H-indole-1-
carboxylate (8R,10R,11S,14R)-8f
HPLC tR: 16 min. ½a D20
Š
¼ ꢀ5:0 (c 0.8, EtOH). 1H NMR: d 8.22 (1H,
d, J = 1.4 Hz, H7), 7.67 (1H, dd, J = 8.4, 0.2 Hz, H4), 7.36 (1H, dd,
J = 8.5, 1.7 Hz, H5), 5.14 (1H, s, H8), 4.62 (1H, td, J = 10.9, 4.4 Hz,
H10), 4.12 (3H, s, NCO2Me), 3.41 (3H, s, OMe), 2.04 (1H, m,
H15e), 1.64 (1H, m, H13e), 1.52 (1H, dq, J = 13.2, 3.4 Hz, H12e),
1.43 (1H, m, H14), 1.20 (1H, td, J = 12.2, 3.1 Hz, H11), 0.99 (2H,
m, H15a, H16), 0.88 (3H, d, J = 6.5 Hz, Me19), 0.81 (2H, m, H12a,
H13a), 0.51 (3H, d, J = 7.0 Hz, Me17 or Me18), 0.22 (3H, d,
J = 7.0 Hz, Me17 or Me18); 13C NMR: d 168.9 (C9), 150.7 (NCO2Me),
136.7 (C7a), 126.8 (C5), 125.6 (C3a), 121.4 (C4), 119.1 (C6), 119.0
(C3), 118.1 (C7), 112.3 (C2), 76.3 (C8), 75.7 (C10), 57.2 (OMe),
54.3 (NCO2Me), 47.0 (C11), 40.6 (C15), 34.0 (C13), 31.3 (C14),
25.6 (C16), 23.0 (C12), 22.0 (Me19), 20.3 (Me17 or Me18), 15.5
(Me17 or Me18). IR (film) mmax 2954, 2829, 1748, 1551, 1456,
1419, 1029 cmꢀ1; FABHRMS m/z calcd for C23H29N1O5Br2 ([M]+):
559.0392, found: 559.0391.
4.5.12. Methyl 3-((R)-2-((1R,2S,5R)-2-isopropyl-5-methylcyclo
hexyloxy)-1-(methylami-no)-2-oxoethyl)-1H-indole-1-
carboxylate (8R,10R,11S,14R)-8g
Prepared from 5a as a yellow oil (0.052 g, 19%). ½a D20
¼ ꢀ87:0 (c
Š
1.2, EtOH). 1H NMR: d 8.17 (1H, br d, J = 7.2 Hz, H7), 7.69 (1H, d,
J = 7.7 Hz, H4), 7.61 (1H, br s, H2), 7.34 (1H, td, J = 7.7, 1.2 Hz,
H6), 7.25 (1H, td, J = 7.7, 1.1 Hz, H5), 4.72 (1H, td, J = 10.9, 4.4 Hz,
H10), 4.49 (1H, d, J = 0.7 Hz, H8), 4.03 (3H, s, NCO2Me), 2.48 (3H,
s, NHMe), 2.03 (1H, m, H15e), 1.64 (1H, m, H13e), 1.57 (1H, dq,
J = 13.1, 3.2 Hz, H12e), 1.47 (1H, m, H14), 1.25 (2H, m, H11, H16),
1.01 (1H, q, J = 11.7 Hz, H15a), 0.95 (1H, m, H12a), 0.90 (3H, d,
J = 6.6 Hz, Me19), 0.83 (1H, m, H13a), 0.55 (3H, d, J = 6.9 Hz,
Me17 or Me18), 0.43 (3H, d, J = 6.8 Hz, Me17 or Me18). 13C NMR:
d 172.2 (C9), 151.3 (NCO2Me), 135.6 (C7a), 128.8 (C3a), 124.9
(C6), 123.6 (C2), 123.0 (C5), 119.9 (C4), 118.9 (C3), 115.0 (C7),
75.4 (C10), 60.1 (C8), 53.8 (NCO2Me), 46.9 (C11), 40.9 (C15), 34.6
(NHMe), 34.1 (C13), 31.4 (C14), 25.5 (C16), 22.9 (C12), 22.0
(Me19), 20.4 (Me17 or Me18), 15.5 (Me17 or Me18); IR (film) mmax
3353, 2955, 2927, 2870, 1739, 1455, 1379, 1251 cmꢀ1; EIMS m/z
(relative intensity) 400 ([M]+, 1.0), 217 (100).
4.7. VCD Measurements
VCD spectra were measured on a BioTools BOMEM ChiralIR
spectrophotometer equipped with a dual photoelastic modulation.
Samples of 5.0 mg of (8S,10R,11S,14R)-8a and (8R,10R,11S,14R)-8a
diastereomers 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 res-
olution of 4 cmꢀ1 during 4 h. Baseline corrections were carried out
by subtracting the spectra from the solvent.
4.6. Preparation of diastereoisomeric esters 8f
4.8. Single crystal structural determination of (8R,10R,11S,14R)-
8a
A solution of both diastereoisomers of 7 (0.15 g, 0.25 mmol) in
MeOH (10 mL) was heated at reflux under a nitrogen atmosphere
for 2 h. After cooling to room temperature, the reaction mixture
was washed with brine (2 Â 10 mL), dried over Na2SO4, filtered,
Suitable crystals were obtained by slow evaporation of an
EtOAc/hexane solution.
A
crystal measuring 0.38 Â 0.32 Â
0.30 mm was mounted on a Enraf-Nonius CAD4 diffractometer

R. M. Vázquez-Arredondo et al. / Tetrahedron: Asymmetry 23 (2012) 1279–1293
1293
Tetrahedron: Asymmetry 2009, 20, 2374–2389; (b) Suárez-Castillo, O. R.;
Meléndez-Rodríguez, M.; Castelán-Duarte, L. E.; Zúñiga-Estrada, E.; Cruz-
Borbolla, J.; Morales-Ríos, M. S.; Joseph-Nathan, P. Tetrahedron: Asymmetry
2011, 22, 2085–2098.
and data collection was carried out using Cu/K
(k = 1.54184 Å). The crystal was orthorhombic, space group
a radiation
P212121, with cell dimensions a = 8.304(3), b = 11.377(1),
c = 24.120(3) Å, V = 2278(8) Å3,
q
calc = 1.17 g/cm3 for Z = 4,
5. Suárez-Castillo, O. R.; Meléndez-Rodríguez, M.; Beiza-Granados, L.; Cano-
Escudero, I. C.; Morales-Ríos, M. S.; Joseph-Nathan, P. Nat. Prod. Commun. 2011,
6, 451–456.
C23H31O5N1, MW = 401.49, and F(000) = 864 e. The total reflections
were 1835, the unique reflections were 1700, and the observed
reflections were 1481. The structure was solved by direct methods
using the SIR200417 program included in the WINGX v1.6 pack-
age.18 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. The final discrepancy indices,
refining 287 parameters, were R1 = 3.6%, wR2 = 9.4%, and the high-
est residual peak in the final difference Fourier map showed an
electron density of 0.09 e/Å3. Atomic coordinates, bond lengths,
bond angles, and anisotropic thermal parameters are in deposit
at the Cambridge Crystallographic Data Center.
6. (a) Suárez-Castillo, O. R.; Montiel-Ortega, L. A.; Meléndez-Rodríguez, M.;
Sánchez-Zavala, M. Tetrahedron Lett. 2007, 48, 17–20; (b) Suárez-Castillo, O. R.;
Sánchez-Zavala, M.; Meléndez-Rodríguez, M.; Aquino-Torres, E.; Morales-Ríos,
M. S.; Joseph-Nathan, P. Heterocycles 2007, 71, 1539–1551.
7. (a) Latypov, Sh. K.; Seco, J. M.; Quiñoá, E.; Riguera, R. J. Org. Chem. 1995, 60,
504–515; (b) Seco, J. M.; Latypov, Sh. K.; Quiñoá, E.; Riguera, R. Tetrahedron
1997, 53, 8541–8564; (c) Seco, J. M.; Quiñoá, E.; Riguera, R. Chem. Rev. 2004,
104, 17–117.
8. Kwan, E. E.; Huang, Sh. G. Eur. J. Org. Chem. 2008, 2671–2688.
9. Chang, G.; Guida, W. C.; Still, W. C. J. Am. Chem. Soc. 1989, 111, 4379–4386.
10. Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital
Theory; Wiley: New York, 1986.
11. (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.
12. (a) Halgren, T. A. J. Comput. Chem. 1996, 17, 490–519; (b) Halgren, T. A. J.
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Acknowledgments
13. As implemented in the computer package Spartan04, Windows
Wavefunction Inc.: Irvine, CA, USA, 2004.
v 1.0.1;
We are pleased to acknowledge the financial support from
CONACYT (Mexico) grant 132048. RMVA thanks 237609 and CIBH
thanks 237689 fellowships from CONACYT.
14. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
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