Formal synthesis of (-)-flustramine B and its absolute configuration assignment by vibrational circular dichroism exciton chirality

Article abstract of DOI:10.1016/j.tetasy.2015.05.009

Abstract A formal synthesis of the natural product (-)-flustramine B (3) is described, together with an easy and reliable approach for the absolute configuration assignment of a series of (3R,14S)- and (3S,14S)-oxindolylacetylphenyloxazolidinones 4, 6, 13

Full text of DOI:10.1016/j.tetasy.2015.05.009

Tetrahedron: Asymmetry 26 (2015) 710–720
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Formal synthesis of (ꢀ)-flustramine B and its absolute configuration
assignment by vibrational circular dichroism exciton chirality
a,
Reyna E. Cordero-Rivera a, Myriam Meléndez-Rodríguez a, , Oscar R. Suárez-Castillo
⇑
⇑
,
Claudia I. Bautista-Hernández a, Nayely Trejo-Carbajal a, Julián Cruz-Borbolla a, Luis E. Castelán-Duarte 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, 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:
A formal synthesis of the natural product (ꢀ)-flustramine B (3) is described, together with an easy and
reliable approach for the absolute configuration assignment of a series of (3R,14S)- and (3S,14S)-oxin-
dolylacetylphenyloxazolidinones 4, 6, 13a–c, and amides (+)- and (ꢀ)-14 by evaluation of the vibrational
circular dichroism bisignated couplet resulting from the interaction of the C2 and C9 carbonyl groups. The
absolute configuration assignment was validated by 1H NMR spectra and X-ray diffraction, and therefore
(ꢀ)-flustramine B 3 was established as (3aS,8aR)-3.
Received 20 April 2015
Accepted 18 May 2015
Available online 9 June 2015
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
R2
4
R2
5
R4
3a
Oxindole derivatives 1 (Fig. 1) are important compounds of con-
siderable interest as starting materials or intermediates for the
total synthesis of terrestrial and marine alkaloids containing furo-
and pyrroloindole skeletons 2,1 such as (ꢀ)-flustramine B 3 iso-
lated from the bryozoa Flustra foliacea (L.),2a,b which has shown
skeletal and smooth muscle relaxant activity.2c Although (ꢀ)-3
has been synthesized in enantiomerically pure form, its absolute
configuration and that of related compounds have been assigned
only by chemical correlation using diverse synthetical
approaches.3 Due to the optical activity of oxindole, furoindole,
and pyrroloindole derivatives such as 1, 2, and 3, suitable and fast
methods to assign their absolute configuration are required. We
have recently shown that 1H NMR spectroscopy is a useful tool
for establishing the absolute configuration of chiral 2-(2-oxo-3-in-
dolyl)acetic acid derivatives, such as 4, using (S)-phenyl-2-oxazo-
lidinone 5 as the chiral derivatizing agent (CDA) (Fig. 2).4 The
R3
6
R3
Y
3
X
O
7a
2
7
N
N
R1
R1
1
2
X = O, NH, NMe, NHCH(Me)Ph
Y = O, H
R1 = H, Me, Bn,
R2 = H, Me, CH2OH, OH,
R3 = H, OMe, Br
,
R
4 = OH, CH2OH, CH2NMe2, CH2NO2,
NHCbz, CH2COMe, CO2H, CO2Me,
CO2Et, CHO, CN, CONHMe
Br
N
O
O
N
Me
H
systematic variation of
(3S,14S)-4 presents the H4-H7 and H16-H20 signals at lower fre-
quency values (+
RS) and the H8A signal at a higher frequency
value (ꢀ
RS) than the corresponding (3R,14S)-4 diastereomer. It
D
dRS values allowed the assumption that
O
Me
N
O
N
H
D
d
D
d
3
(-)-flustramine B
was evidenced that the chemical shift nonequivalences arising
from the mutual diamagnetic influence of the aromatic (S)-oxazo-
lidinone and oxindole moieties on the 1H NMR signals is present in
Figure 1. Synthetic and natural oxindole 1, furoindole
2 and pyrroloindole 3
derivatives.
(3S,14S)-4, but not in the (3R,14S)-4 diastereomer, as shown in
Figure 2. The absolute configuration of (3R,14S)- and (3S,14S)-4
was independently determined using the time consuming protocol
⇑
Corresponding authors. Tel.: +52 771 71 72000x2206; fax: +52 771 71
72000x6502.
E-mail address: osuarez@uaeh.edu.mx (O.R. Suárez-Castillo).
http://dx.doi.org/10.1016/j.tetasy.2015.05.009
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

R. E. Cordero-Rivera et al. / Tetrahedron: Asymmetry 26 (2015) 710–720
711
indole and oxindole derivatives,4,7 we herein report that the abso-
lute configuration of (3R,14S)- and (3S,14S)-6-bromooxindoly-
lacetylphenyloxazolidinones 4, 6, 13a–c, and (3R)- and (3S)-
amides 14, an intermediate in the formal synthesis of flus-
tramine,3b can be assigned solely by VCD exciton chirality
(VCDEC)8 considering the bisignate couplets that originate from
the through-space interaction of the C2 and C9 amide carbonyl
groups. The absolute configuration in both diastereomers was also
assigned when comparing specific VCD bands in the (3R,14S)- and
(3S,14S)-4, 6, 13a–c series.
O
H
O
17
Me
O
N
H
H
N
16
4
O
Me
18
5
3
14
H
8
O
3
6
N 14
19
Me
+
+
20
O
+
+
+
7
N
Me
13
+
+
+
O
+
O
+
+
+
4
(3R,14S)-
(3S,14S)-4
ΔδRS
ΔδRS
> 0 for H4-H7, H16-H20
< 0 for H8
2. Results and discussion
Figure 2. Mutual anisotropic effect of the aromatic rings of (3S,14S)-4.
Compounds (3R,14S)- and (3S,14S)-bromooxindolylacetyl-
phenyloxazolidinones 6 were synthesized according to Schemes
1 and 2. Thus, 6-bromoindole malonate 79 was treated with
t-BuNH2/LiBr/MeOH/H2O to obtain 2-(6-bromoindolyl)acetic acid
8 in 96% yield. Acid 8 was converted, in 49% overall yield, into ester
needed to compare experimental vibrational circular dichroism
(VCD) spectra with those calculated using density functional the-
ory, which showed good agreement.5
In continuation of our studies aimed at the synthesis of flus-
tramines6 and the determination of the absolute configuration of
CO2Me
CO2Me
CO2H
CO2H
t-BuNH2
HCl
DMSO
Br
Br
Br
O
LiBr
N
N
H
N
H
MeOH/H2O
CO2Me
7
8
9
p-TsOH
MeOH
CO2H
CO2Me
CO2Me
K2CO3
NaOH
H2O
MeOH
Br
Br
Br
O
O
O
N
N
N
H
Br
acetone
10
12
11
Scheme 1. Synthesis of ( )-6-bromooxoindolinacetic acid 12.
O
11
O
13
4
OH
4
N
8
8
5
9
5
9
14
3a
3a
6
6
LiOH
H2O2
3
3
O
O
Br
Br
O
O
7a
2
7a
2
7
7
N
N
1. DCC, 4-DMAP
(-)-(3 R,14S)-6
(+)-(R)-12
( )-12
O
2.
H
N
O
O
O
OH
N
14
(S)-5
LiOH
H2O2
O
3
Br
O
Br
O
3. column chromatograpy
separation
O
N
N
(+)-(3S,14S)-6
(-)-(S)-12
Scheme 2. Resolution of ( )-6-bromooxoindolinacetic acid 12 with (S)-phenyl-2-oxazolidinone 5.

712
R. E. Cordero-Rivera et al. / Tetrahedron: Asymmetry 26 (2015) 710–720
Figure 3.
the oxindole moiety).
D
d
RS values for the aromatic H5, H7, H16-H20 and H8 atoms of (3R,14S)- and (3S,14S)-6 (
D
d
RS = dR ꢀ dS, where the R and S descriptors refer to the C3 configuration at
10 by oxidation with HCl/DMSO to give oxindole 9 followed by
esterification. Dialkylation of 10 with prenyl bromide using
K2CO3/acetone gave N1,C3-diprenyloxindol 11 in 92% yield, which
was saponified with NaOH/H2O/MeOH followed by acidification
with HCl/H2O to obtain 12 in 97% yield (Scheme 1).
Derivatization of a racemic sample of 12 into oxazolidinones 6
was carried out with dicyclohexylcarbodiimide (DCC) and
4-dimethylaminopyridine (4-DMAP),4 followed by reaction with
phenyloxazolidinone (S)-5 to give an equimolar diastereomeric
mixture of (3R,14S)- and (3S,14S)-6, as was evidenced by 1H
NMR analysis of the reaction crudes. Phenyloxazolidinones
(3R,14S)- and (3S,14S)-6 were easily separated by column chro-
matography to afford pure isomers with >99% diastereomeric
excess as determined by 1H NMR measurements.

R. E. Cordero-Rivera et al. / Tetrahedron: Asymmetry 26 (2015) 710–720
713
Figure 4. Comparison of the VCD spectra of (3R,14S)-4, 13a–c, and 6.
Figure 5. Comparison of the VCD spectra of (3S,14S)-4, 13a–c, and 6.
The 1H NMR spectra comparison of (3R,14S)- and (3S,14S)-6
showed positive
D
dRS values (
D
d
RS = dR ꢀ dS, where the R and S
With the precedent of the absolute configuration of (3R,14S)-
and (3S,14S)-6 assigned, according to our own experience by 1H
NMR spectroscopy, we next assessed the applicability of VCD as
descriptors refer to the C3 configuration at the oxindole moiety)
for the aromatic H5, H7, H16-H20 and H8B signals as a conse-
quence of the orientation of the magnetic anisotropy imposed by
both phenyl groups of the (S)-oxazolidinyl and oxindolyl moieties,
a
confident method to assign the absolute configuration of
as is depicted in Figure 3. On the contrary, negative
D
dRS shifts
diastereomers 6 and other structurally related compounds. The
assignment of the absolute configuration using vibrational spec-
troscopy is not a simple task since normal vibrational modes
may contain complex combinations of individual molecular con-
formation. Thus, although time consuming, the conformational
analysis, geometry optimization at different levels of theory, and
VCD spectra calculation is essential. Therefore, in search of a faster
methodology to assign the absolute configuration of oxindole
occurred for H4 and H8A. The
D
dRS values have the same sign dis-
tribution for H5, H7, H16-H20 and H8B as those obtained for
(3R,14S)- and (3S,14S)-4, which suggests that diastereomers with
the same configuration, such as (3R,14S)-6 and (3R,14S)-4, and
(3S,14S)-6 and (3S,14S)-4, adopt similar conformations at the
C8A(C9@O)AN10AC11@O fragment.4 In Figure 3, colours are used
to identify the same proton signals of both diastereoisomers.

714
R. E. Cordero-Rivera et al. / Tetrahedron: Asymmetry 26 (2015) 710–720
Table 1
concluding that dihedral angles close to 0° and 180°, or a larger
interchromophoric distance could attenuate the coupling.
negative-lower to positive-higher wave numbers signal twist
generated by the interaction of the electric transition moments
of the C2 and C9 carbonyl groups in (3R,14S)-4, 6, 13a–c was
VCDEC couplets for (3R,14S)- and (3S,14S)-4, 13a–c, 6
A
Compound
M
D
e1
(
v
(cmꢀ1))a
D
e2
(
v
(cmꢀ1))a
Ab
(3R,14S)-4
(3R,14S)-6
(3R,14S)-13a
(3R,14S)-13b
(3R,14S)-13c
(3S,14S)-4
0.095
0.078
0.068
0.045
0.046
0.091
0.088
0.091
0.052
0.041
ꢀ0.074 (1701)
ꢀ0.122 (1706)
ꢀ0.020 (1714)
ꢀ0.064 (1701)
ꢀ0.172 (1703)
0.128 (1699)
0.247 (1703)
0.096(1708)c
0.067 (1701)
0.129 (1699)
0.032 (1722)
0.042 (1724)
0.081 (1724)
0.077 (1718)
0.026 (1716)
ꢀ0.065 (1722)
ꢀ0.192 (1720)
—
ꢀ0.106
ꢀ0.164
ꢀ0.101
ꢀ0.141
ꢀ0.198
0.193
0.438
—
observed, while
a positive-lower to negative-higher wave
numbers signal twist was observed for (3S,14S)-4, 6 and 13a–c.
According to the model proposed by Monde and Taniguchi,8a
(3R,14S)-4, 6, 13a–c should display
a
counterclockwise
(3S,14S)-6
(ꢀ180° < h < 0°, negative twist) chromophoric orientation of the
C2 and C9 carbonyl groups (Fig. 6A), while diastereomers
(3S,14S)-4, 6, 13a–c should present a clockwise (0° < h < +180°,
positive twist) disposition (Fig. 6B) as a consequence of their C3
absolute configuration. It is worth noting that for (3S,14S)-13a
(3S,14S)-13a
(3S,14S)-13b
(3S,14S)-13c
ꢀ0.095 (1718)
0.162
0.326
ꢀ0.197 (1718)
a
b
c
In Mꢀ1 cmꢀ1
.
D
e1
ꢀ De2.
only a positive monosignate signal was detected at 1708 cmꢀ1
,
For (3S,14S)-13a only a positive monosignate signal was detected.
which could evidence that no coupling between the C2 and C9
carbonyl groups would exist. However, its position coincides
derivatives, the experimental VCD spectra of oxindoly-
lacetylphenyloxazolidinones 13a–c were acquired and compared
with those of 4 and 6 (Figs. 4 and 5). As can be seen, a great simi-
larity of oxazolidinones (3R,14S)- and (3S,14S)-6 with their respec-
tive analogues 4, 13a–c is evident, since the achiral alkyl groups at
C3 have no relevant contributions to the VCD spectra.10
with that of the first negative Cotton effect signal (1714 cmꢀ1
)
for the (3R,14S)-13a diastereoisomer (Fig. 7), indicating that even
for (3S,14S)-13a the absolute configuration could be assigned by
comparison at the 1650ꢀ1750 cmꢀ1 VCD spectral region.
Furthermore, it has been demonstrated that when no through-
space interaction between two carbonyl groups in chiral
compounds is possible, the VCD signals are 20–25 times less
intense.8a
The VCD spectra of (3R,14S)- and (3S,14S)-4, 6, 13a–c shown in
Figures 4 and 5 evidence some particular features attributed to each
family. For example, (3R,14S)-4, 6, 13a–c show common VCD bands
in the 1087–1110, 1103–1130, 1230–1247, 1311–1328, 1382,
1456–1458, 1604–1614, 1701–1714, and 1716–1724 cmꢀ1 ranges
(Fig. 4), while for the (3S,14S)-4, 6, 13a–c diastereomers the com-
mon VCD bands appear in the 1085–1114, 1103–1128, 1301–
1328, 1382–1384, 1456–1458, 1604–1616, 1699–1708, and
1718–1722 cmꢀ1 ranges (Fig. 5). The VCD bands in the 1085–
1130, 1604–1616, and 1699–1724 cmꢀ1 ranges are very sensitive
to the absolute configuration in both (3R,14S)- and (3S,14S)-
oxazolidinone 4, 6, 13a–c series, as similar absorption bands are
shown, but with an opposite sign. The negative sign of the band
at 1604–1616 cmꢀ1 and the negative/positive combination from
low to high wave numbers at 1085–1130 cmꢀ1 account for the
(3R)-configuration, whereas the opposite situation corresponds to
the (3S)-configuration.
O
O
O
O
N
N
Me
N
Me
N
O
O
O
O
(3R,14S)-13a
(3S,14S)-13a
O
O
O
O
N
N
Both (3R,14S)- and (3S,14S)-4, 6, 13a–c diastereomeric series
show strong sharp bisignate VCDEC signals around 1699–1714
and 1716–1724 cmꢀ1 which evidence the through-space coupling
of the C2 and C9 carbonyl groups.8a As shown in Figures 4 and 5,
and in Table 1, these bisignate VCDEC signals are, in general,
more intense in the (3S,14S)-(A values from 0.162 to 0.438)
series than in the (3R,14S)-4, 6, 13a–c (A values from ꢀ0.101 to
ꢀ0.198) series. Accordingly, Monde et al.8a studied the influence
of carbonyl groups’ spatial arrangement on the amplitude A,
O
O
O
O
N
N
Me
Me
(3R,14S)-13b
(3S,14S)-13b
O
O
O
O
N
N
O
O
O
O
N
N
13c
13c
(3R,14S)-
(3S,14S)-
NHMe
NHMe
O
Br
O
Br
O
O
N
N
14
(-)-( S)-
(+)-(R)-14
Figure 6. Twist sense for the electric transition moments of the C2 (orange arrows)
and C9 (yellow arrows) carbonyl groups in (3R,14S)- and (3S,14S)-6.

R. E. Cordero-Rivera et al. / Tetrahedron: Asymmetry 26 (2015) 710–720
715
(3S,14S)-6 based on the bisignate VCDEC couplets originated by
the two amide carbonyl groups in 4, 6, and 13a–c.
Subsequently, hydrolysis of (3R,14S)- and (3S,14S)-6 with
16
LiOH/H2O2 afforded the corresponding (+)-(R)- and (ꢀ)-(S)-acids
12, in 74% and 72% yield, respectively (Scheme 2) which were
transformed into (+)-(R)-(54%) and (ꢀ)-(S)-amides 14 (51%)
through the mixed anhydrides after treatment with pentafluo-
rophenol, 1-ethyl-3-(3-dimethylamino propyl)carbodiimide (EDC)
and methylamine.16 We were able to obtain single crystals of (S)-
14 which provided the X-ray structure shown in Figure 10 (top).
The absolute configuration structure was established by taking
advantage of the heavy atom at C6 by evaluation of the Flack17a
[ꢀ0.002(7), (R)-enantiomer 1.015(16)] and the Hooft17b
parameters [0.006(2), (R)-enantiomer 1.008(2)]. As can also be
seen in Figure 9 (bottom), in the solid state a clockwise twist is
evident for the (ꢀ)-(3S)-14 isomer with a C2@O, C9@O distance
of 3.2 Å.
The VCD spectra of (3R)- and (3S)-14 are shown in Figure 11
with their respective bisignate couplets. A counterclockwise twist
of the C2 and C9 carbonyl groups is evident in (3R)-14 (Fig. 11,
top) while a clockwise twist is evident for (3S)-14 (Fig. 11, bottom).
This result confirms that the additional carbonyl at the phenylox-
azolidinone moiety (C14) in (3R,14S)- and (3S,14S)-4, 6, 13a–c does
not perturb the twist sign of the C2 and C9 carbonyl groups.
Since the synthesis of the natural product (ꢀ)-flustramine B 3
has been carried out from (ꢀ)-(S)-14,3b and taking into account
the well known cis-configuration of the C3a/C8a ring fusion,2 the
absolute configuration follows as (3aS,8aR)-3.
Figure 7. VCD spectral region of the bisignate couplet for compounds (3R,14S)-13a
(red trace) and (3S,14S)-13a (blue trace) showing that the positive monosignate
signal (1708 cmꢀ1) in (3S,14S)-13a coincides with the negative first Cotton effect
(1714 cmꢀ1) for the (3R,14S)-13a.
In addition to the bisignate signal in the VCD spectra of (3R,14S)-
and (3S,14S)-4, 6, 13a–c shown in Figures 4 and 5, a third signal
in the 1774–1784 cmꢀ1 range appeared. This signal is due to the
C11 carbonyl group and although its phase sign is not systematic
in each group of spectra, it does not perturb the sense of sign vari-
ation for the bisignate signal in each group. Although it has been
demonstrated that the presence of three carbonyl groups could gen-
erate a strong bisignate VCD signal,8c this does not occur in the
(3R,14S)- and (3S,14S)-4, 6, 13a–c series because of the distinct
absorption of the C11 carbonyl group.
3. Conclusions
We have demonstrated that the absolute configuration of oxin-
dole derivatives 4, 6, 13a–c, and 14 can easily be assigned by con-
sidering the twist of their VCDEC bisignate couplet and other
characteristic signals. A general assumption for the absolute con-
figuration assignment is: (3R)-oxindole derivatives 4, 6, 13a–c,
14 show a positive twist of the C2 and C9 carbonyl groups, while
(3S)-4, 6, 13a–c, 14 show a negative twist. This approach could
be useful for the absolute configuration assignment of natural
and synthetic furo- and pyrroloindoles, as shown for (ꢀ)-
(3aS,8aR)-flustramina B 3.
In order to evaluate the preferred orientation of the C2 and C9
carbonyl groups, a conformational search and geometry optimiza-
tion for (3R,14S)- and (3S,14S)-6 was carried out. Thus, a molecular
modeling protocol with Monte Carlo searching11 using the
MMFF9412 molecular mechanics force field method, as imple-
mented in the Spartan0813 program, gave 116 conformers for
(3R,14S)-6 and 128 conformers for (3S,14S)-6 within the first
10 kcal/mol energy window. With the aim to avoid the possibility
of overlooking relevant conformers, all conformers were submitted
to single-point energy calculations at the DFT B3LYP/6-31G(d)14
level of theory to afford 106 conformers for (3R,14S)-6 and 118
conformers for the (3S,14S)-6 appearing in 9.49 kcal/mol and
9.64 kcal/mol energy gaps, respectively. The meaningful 50 con-
formers for (3R,14S)-6 and 82 conformers for (3S,14S)-6 found in
the initial 5.0 kcal/mol gap, contributing in both cases to 99.9% of
the total conformational population, were optimized at the
B3LYP/DGDZVP15 level of theory to provide 45 conformers for
(3R,14S)-6 and 65 conformers for (3S,14S)-6 in the 5.63 kcal/mol
for both diastereoisomers. As can be seen in Figures 8 and 9, the
most stable 23 conformers (79.1% of the total population) for
(3R,14S)-6 (Fig. 8, A, C) and 33 conformers (81.4% of the total pop-
ulation) for (3S,14S)-6 (Fig. 9, A, C) show the O@C2AC3AC8AC9@O
fragment almost in the same spatial disposition. It is evident that
the large number of conformers is due to the conformational free-
dom of the flexible prenyl groups at the N1 and C3 positions. The
chromophoric orientation of the C2 and C9 carbonyl groups is bet-
ter appreciated, for the most stable conformer in each group, when
the prenyl and phenyloxazolidinone groups are omitted for clarity.
A counterclockwise twist of these groups appears for (3R,14S)-6
(Fig. 8, B, D) while a clockwise twist is evident for the (3S,14S)-6
isomer (Fig. 9, B, D). The distances between the two carbonyl
groups are in the 3.2–3.3 Å range. Thus, computational results rein-
force the absolute configuration assignment in (3R,14S)- and
4. Experimental
4.1. General
The melting point was determined on a Büchi B-545 apparatus.
IR spectra were recorded on a Perkin–Elmer 2000 FT-IR spec-
trophotometer. The 400 and 100 MHz 1H and 13C NMR spectra
were obtained on a Varian VNMRS 400 spectrometers using
CDCl3 as the solvent and TMS as the internal reference. For com-
plete assignments gHSQC and gHMBC spectra were measured.
Data are reported as follows: chemical shift in ppm from TMS, inte-
gration, multiplicity (s = singlet, d = doublet, t = triplet, sext = sex-
tet, sept = septet, m = multiplet, br = broad), coupling constant
(Hz), and assignment. GC/MS analyses were conducted on a
Varian CP 3800 GC equipped with a Varian Saturn 2000 selective
mass detector and a 30 m, 0.25 mm i. d., 0.25 mm CP-SIL capillary
column, using helium as the carrier gas (1 mL/min), programed
from 70 °C to 250 °C at a rate of 30 °C/min, with the injector tem-
perature at 200 °C. Optical rotation measurements were performed
on a Perkin–Elmer 341 polarimeter. Microanalytical determina-
tions were performed on a Perkin Elmer 2400 Series CHNS/O appa-
ratus. Analytical thin-layer chromatography (TLC) was carried out
on silica gel F254 coated aluminum sheets (0.25 mm thickness)

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R. E. Cordero-Rivera et al. / Tetrahedron: Asymmetry 26 (2015) 710–720
8
9
3
8
3
9
2
2
θ
(-180° < θ < 0°)
C2=O --- C9=O distance ~ 3.2 Å
17 conformers
p = 72.9 %
B
A
3
8
8
3
9
2
9
2
θ
(-180° < θ < 0°)
C2=O --- C9=O distance ~ 3.2 Å
6 conformers
p = 6.2 %
D
C
Figure 8. DFT B3LYP/DGDZVP optimized geometries for (3R,14S)-6 showing the preferred orientation of the C2 and C9 carbonyl groups in the most stable conformers (A, C).
Prenyl and phenyloxazolidinone groups in B, D were omitted for clarity.
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.
4.3. Preparation of methyl 2-(6-bromo-2-oxoindolin-3-
yl)acetate 10
To a solution of acid 8 (0.30 g, 1.18 mmol) in DMSO (5 mL,
10 mmol) was added an aqueous solution (36%) of HCl (5 mL)
and the mixture was stirred for 12 h at room temperature, diluted
with water (15 mL), neutralized with a saturated solution of
NaHCO3, and extracted with EtOAc (5 ꢁ 20 mL). The organic layer
was washed with brine (3 ꢁ 15 mL), dried over anhydrous
Na2SO4, filtered, and evaporated to dryness in vacuum. The residue
containing acid 9 was dissolved in MeOH (5 mL) and p-toluenesul-
fonic acid (0.010 g, 0.05 mmol) was added, and the mixture heated
at reflux for 2.5 h. After cooling to room temperature, MeOH was
evaporated under reduced pressure and the residue was dissolved
in EtOAc (50 mL). The organic phase was washed with a saturated
solution of NaHCO3 (2 ꢁ 20 mL), brine (2 ꢁ 15 mL), dried over
Na2SO4, and evaporated to dryness in vacuum. The resultant crude
product was purified by flash column chromatography on silica gel
4.2. Preparation of 2-(6-bromo-1H-indol-3-yl)acetic acid 8
To a solution of 7 (0.32 g, 0.83 mmol) in MeOH (2.5 mL) was
added t-BuNH2 (0.88 mL, 8.37 mmol) and LiBr (0.22 g, 2.53 mmol
dissolved in 5 mL of H2O), and the mixture was stirred at reflux
for 3.5 h. After cooling to room temperature, the volatiles were
evaporated under reduced pressure and the residue was diluted
with EtOAc (50 mL), washed with a saturated solution of NaHCO3
(5 ꢁ 20 mL) and brine (2 ꢁ 15 mL). The combined aqueous solu-
tions were acidified to pH ca. 1 with a 1 M aqueous solution of
HCl and extracted with EtOAc (5 ꢁ 20 mL). The organic phase
was dried over anhydrous Na2SO4, filtered, and evaporated to dry-
ness in vacuum to give acid 8 as a pale yellow oil (0.20 g, 95%). The
spectroscopic data of 8 were consistent with those reported.18

R. E. Cordero-Rivera et al. / Tetrahedron: Asymmetry 26 (2015) 710–720
717
9
8
8
3
3
2
9
2
θ
(0° < θ < +180°)
C2=O --- C9=O distance ~ 3.2 Å
21 conformers
p = 75.8 %
B
A
9
8
3
3
8
2
9
2
θ
(0° < θ < +180°)
C2=O --- C9=O distance ~ 3.3 Å
12 conformers
p = 5.6 %
D
C
Figure 9. DFT B3LYP/DGDZVP optimized geometries for (3S,14S)-6 showing the preferred orientation of the C2 and C9 carbonyl groups in the most stable conformers (A, C).
Prenyl and phenyloxazolidinone groups in B, D were omitted for clarity.
eluting with EtOAc/hexanes 1:3 to give ester 10 as white crystals
(0.16 g, 66%). The spectroscopic data of 10 match those reported.6d
4.5. Preparation of 2-(6-bromo-1,3-bis(3-methylbut-2-enyl)-2-
oxoindolin-3-yl)acetic acid 12
4.4. Preparation of methyl 2-(6-bromo-1,3-bis(3-methylbut-2-
enyl)-2-oxoindolin-3-yl)acetate 11
To a solution of ester 11 (0.32 g, 0.76 mmol) in MeOH (16 mL)
was added an aqueous solution (15%) of NaOH (8 mL) and the mix-
ture stirred for 40 min at 50–60 °C. After cooling in an ice/water
bath, the mixture was acidified to pH 1 with a 1 M HCl aqueous
solution and extracted with EtOAc (3 ꢁ 20 mL). The combined
organic phases were washed with brine (3 ꢁ 20 mL), dried over
anhydrous Na2SO4, and evaporated under reduced pressure to give
11 as a pale yellow oil (0.30 g, 97%). Although 11 is known,3b it is
spectroscopically not yet characterized. Thus, NMR data follow:
1H NMR (400 MHz, CDCl3): d 7.14 (1H, dd, J = 7.9, 1.7 Hz, H5),
7.00 (1H, d, J = 7.9 Hz, H4), 6.90 (1H, d, J = 1.7 Hz, H7), 5.03 (1H,
tsept, J = 6.6, 1.3 Hz, H16), 4.74 (1H, tsept, J = 7.7, 1.3 Hz, H11),
4.36 (1H, dd, J = 15.7, 6.6 Hz, H15A), 4.17 (1H, dd, J = 15.7, 6.6 Hz,
H15B), 3.04 and 2.80 (2H, AB system, J = 16.7 Hz, H8), 2.42 (2H,
d, J = 7.7 Hz, H10), 1.81 (3H, br s, Me18), 1.72 (3H, br s, Me19),
1.57 (3H, br s, Me13), 1.45 (3H, br s, Me14); 13C NMR (100 MHz,
To a solution of 10 (0.26 g, 0.92 mmol) in acetone (12 mL) was
added K2CO3 (0.92 g, 6.67 mmol) and the mixture stirred for
30 min at room temperature. Then, 4-bromo-2-methyl-2-butene
(0.38 g, 2.55 mmol) was added and the resulting mixture was stir-
red for 2.5 h at reflux. After cooling to room temperature, the vola-
tiles were evaporated under reduced pressure. The residue was
diluted with water and extracted with EtOAc (2 ꢁ 30 mL). The
organic phase was dried over anhydrous Na2SO4, filtered, and the
solvent was evaporated under reduced pressure. The crude product
was purified by flash chromatography on silica gel eluting with
EtOAc/hexanes (1:5) to obtain ester 11 as a pale yellow oil
(0.35 g, 91%). The spectroscopic data of 11 were consistent with
those reported.19

718
R. E. Cordero-Rivera et al. / Tetrahedron: Asymmetry 26 (2015) 710–720
9
2
θ
Figure 11. VCD spectra of (3R)-14 (top) and (3S)-14 (bottom) showing the carbonyl
groups bisignate couplet in the 1632–1753 cmꢀ1 region.
(0° < θ < +180°)
d, J = 7.8 Hz, H4), 6.86 (1H, d, J = 1.7 Hz, H7), 5.21 (1H, dd, J = 8.7,
3.7 Hz, H14), 4.98 (1H, tsept, J = 6.6, 1.4 Hz, H22), 4.78 (1H, tsept,
J = 7.7, 1.4 Hz, H27), 4.57 (1H, t, J = 8.8 Hz, H13A), 4.29 (1H, br dd,
J = 15.9, 6.7 Hz, H21A), 4.19 (1H, dd, J = 8.8, 3.7 Hz, H13B), 4.12
(1H, br dd, J = 15.9, 6.4 Hz, H21B), 3.89 and 3.43 (2H, AB system,
J = 17.9 Hz, H8), 2.46 (1H, dd, J = 13.5, 6.9 Hz, H26A), 2.41 (1H,
dd, J = 13.5, 7.9 Hz, H26B), 1.73 (3H, d, J = 0.9 Hz, Me24), 1.67
(3H, d, J = 1.2 Hz, Me25), 1.58 (3H, d, J = 0.9 Hz, Me29), 1.48 (3H,
d, J = 1.1 Hz, Me30); 13C NMR (100 MHz, CDCl3): d 178.5 (C2),
168.8 (C9), 154.0 (C11), 145.1 (C7a), 138.5 (C15), 136.8 (C28),
136.6 (C23), 130.8 (C3a), 129.3 (C17, C19), 128.7 (C18), 125.7
(C16, C20), 124.5 (C5), 123.6 (C4), 121.5 (C6), 118.3 (C22), 116.6
(C27), 112.1 (C7), 70.3 (C13), 57.3 (C14), 49.5 (C3), 41.1 (C8),
38.2 (C21), 36.8 (C26), 26.0 (C29), 25.8 (C25), 18.2 (C24), 18.1
(C30); IR (KBr) mmax 2970, 2915, 2857, 1782, 1712, 1605, 1488,
1439, 1382, 1322, 1248, 1199 cmꢀ1; EIMS m/z (relative intensity)
C2=O --- C9=O distance ~ 3.2 Å
Figure 10. X-ray diffraction structure of (3S)-14 (top). Twist direction of the C2 and
C9 carbonyl groups in the solid state (bottom).
CDCl3): d179.0 (C2), 174.0 (C9), 144.7 (C7a), 137.1 (C17), 137.0
(C12), 130.1 (C3a), 125.1 (C5), 124.2 (C4), 121.8 (C6), 117.9 (C16),
116.4 (C11), 112.3 (C7), 49.5 (C3), 39.8 (C8), 38.4 (C15), 36.3
(C10), 26.0 (C13), 25.8 (C19), 18.3 (C18), 18.1 (C14); IR (KBr) mmax
3434, 2972, 2927, 1716, 1605, 1488, 1434, 1378, 1176 cmꢀ1
.
4.6. General procedure for the preparation of diastereomeric
imides 6
þ
ꢃ
550/552 (½Mꢂ
5.7/5.3), 483/485 (98/86), 387/389 (49/58),
To a solution of acid 12 (0.25 g, 0.62 mmol) in CH2Cl2 (15 mL)
were added 4-DMAP (0.16 g, 1.31 mmol), DCC (0.15 g, 0.73 mmol)
and (S)-(+)-4-phenyloxazolidinone 5 (0.10 g, 0.61 mmol). The reac-
tion mixture was stirred at room temperature for 24 h, filtered, and
the solvent evaporated in vacuum. The residue containing the
(3R,14S)- and (3S,14S)-6 diastereomeric pair was purified by flash
column chromatography on silica gel using EtOAc/hexanes 1:2.
345/347 (56/44), 321 (73.4), 319 (100), 292 (83), 265 (39), 263
(52), 252 (69), 250 (80), 164 (66), 133 (44), 104 (89), 105 (37),
91 (35), 69 (27), 41 (45), 39 (45). Anal. Calcd for C29H31BrN2O4;
C, 63.16; H, 5.67; N, 5.08. Found: C, 62.69; H, 5.80; N, 5.54.
4.6.2. (S)-3-(2-((S)-6-Bromo-1,3-bis(3-methylbut-2-enyl)-2-
oxoindolin-3-yl)acetyl)-4-phenyloxazolidin-2-one (3S,14S)-6
Prepared from 12 as yellow oil (0.11 g, 32%). [a]
20 = +92.6 (c
D
4.6.1. (S)-3-(2-((R)-6-Bromo-1,3-bis(3-methylbut-2-enyl)-2-
oxoindolin-3-yl)acetyl)-4-phenyloxazolidin-2-one (3R,14S)-6
Prepared from 12 as white solid (0.12 g, 35%), mp: 146–147 °C
1.20, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.25–7.19 (3H, over-
lapped, H17-H19), 7.06 (1H, dd, J = 7.9, 1.7 Hz, H5), 7.02 (1H, d,
J = 8.0 Hz, H4), 6.82 (2H, dm, J = 7.9 Hz, H16, H20), 6.71 (1H, br d,
J = 1.6 Hz, H7), 5.23 (1H, dd, J = 8.6, 3.6 Hz, H14), 4.91 (1H, tsept,
J = 6.4, 1.4 Hz, H22), 4.77 (1H, tsept, J = 7.6, 1.4 Hz, H27), 4.59
(EtOAc/hexanes). [
a
]
20 = ꢀ9.2 (c 1.20, CHCl3). 1H NMR (400 MHz,
D
CDCl3): d 7.36–7.27 (3H, overlapped, H17-H19), 7.15 (2H, dm,
J = 7.9 Hz, H16, H20), 7.09 (1H, dd, J = 7.8, 1.7 Hz, H5), 6.96 (1H,

R. E. Cordero-Rivera et al. / Tetrahedron: Asymmetry 26 (2015) 710–720
719
(1H, t, J = 8.9 Hz, H13A), 4.33 (1H, br dd, J = 15.8, 6.4 Hz, H21A),
4.14 (1H, dd, J = 8.9, 3.5 Hz, H13B), 4.06 (1H, br dd, J = 15.8,
6.4 Hz, H21B), 4.11 and 3.27 (2H, AB system, J = 16.7 Hz, H8),
2.47 (1H, dd, J = 13.8, 7.4 Hz, H26A), 2.42 (1H, dd, J = 13.8, 8.0 Hz,
H26B), 1.76 (3H, d, J = 0.8 Hz, Me24), 1.67 (3H, d, J = 1.1 Hz,
Me25), 1.57 (3H, br s, Me29), 1.47 (3H, d, J = 0.8 Hz, Me30); 13C
NMR (100 MHz, CDCl3): d 178.7 (C2), 168.7 (C9), 153.9 (C11),
145.1 (C7a), 138.3 (C15), 136.7 (C28), 136.3 (C23), 130.0 (C3a),
129.0 (C17, C19), 128.4 (C18), 125.3 (C16, C20), 124.5 (C5), 124.0
(C4), 121.6 (C6), 118.4 (C22), 116.6 (C27), 112.1 (C7), 70.1 (C13),
57.4 (C14), 50.1 (C3), 40.4 (C8), 38.2 (C21), 36.7 (C26), 26.0
(C29), 25.7 (C25), 18.3 (C24), 18.1 (C30); IR (KBr) mmax 2972,
CCDC, 12 Union Road, Cambridge CB2 IEZ, UK. Fax: +44 (0)1223
336033 or e-mail: deposit@ccdc.cam.ac.uk.
Acknowledgments
We are pleased to acknowledge the financial support from
CONACYT (Mexico) grants 183481, 152994 and 132048. R.E.C.R.
and C.I.B.H. thank CONACYT for fellowships 330632 and 237689,
respectively.
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ꢃ
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4.7. Preparation of (+)- and (ꢀ)-2-(6-bromo-1,3-bis(3-methylbut-
2-enyl)-2-oxoindolin-3-yl)acetic acids (+)-12 and (ꢀ)-12
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(3 ꢁ 15 mL). The organic phase was washed with brine
(2 ꢁ 15 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography using AcOEt–hexanes 1:2 to give (+)-12 as a pale
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yellow oil (0.060 g, 74%), [
pale yellow oil (0.058 g, 72%), [
a
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20 = +18.3 (c 1, CHCl3), or (ꢀ)-12 as a
D
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4.8. VCD measurements
IR and VCD spectra were measured using a BioTools ChiralIR
spectrophotometer equipped with dual photoelastic modulation.
Samples of (3R,14S)- and (3S,14S)-4, 6, 13a–c, and 14 were
dissolved in 150
l
L of CDCl3, placed in a BaF2 cell with a path
length of 100
l
m and data were acquired at a resolution of
4 cmꢀ1 during 4–20 h. Baseline corrections were done by subtract-
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was monitored by 1H NMR immediately prior and after VCD
measurements.
4.9. X-ray diffraction analyses
Data for (3S)-14 were acquired on an Agilent Technologies
Gemini A CCD diffractometer using Mo Ka radiation (k = 0.7073 Å).
Crystal data were C21H27BrN2O2 M = 419.35, orthorhombic, space
group P212121 a = 9.1141(3) Å, b = 10.1139(2) Å, c = 24.0163(7) Å,
V = 2213.80(11) Å3,
Z = 4,
1.872 mmꢀ1, total reflections = 96675, unique reflections 5967
(Rint 0.0001%), observed reflections 4230, final R indices [I > 2 (I)]
q
= 1.26 mg/mm3,
l
(Mo
Ka) =
r
R1 = 3.9%, wR2 = 8.3%. The structure was solved by direct methods
using the SHELXS-9720 program, included in the WINGX v1.621
package, and refined by full-matrix least squares on F2. The non-hy-
drogen atoms were treated anisotropically, and the hydrogen atoms,
included in the structure factor calculation were refined isotropi-
cally. Crystallographic data (excluding structure factors) have been
deposited at the Cambridge Crystallographic Data Centre. Copies
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