Cooperative use of VCD and XRD for the determination of tetrahydrobenzoisoquinolines absolute configuration: A reliable proof of memory of chirality and retention of configuration in enediyne rearrangements

Article abstract of DOI:10.1002/chir.22221

The absolute configurations (AC) of azaheterocylic compounds resulting from the cascade rearrangement of enediynes involving only light atoms were unambiguously assigned by the joint use of vibrational circular dichroism (VCD) and copper radiation single

Full text of DOI:10.1002/chir.22221

CHIRALITY 25:832–839 (2013)
Cooperative Use of VCD and XRD for the Determination of
Tetrahydrobenzoisoquinolines Absolute Configuration: A Reliable
Proof of Memory of Chirality and Retention of Configuration in
Enediyne Rearrangements
2
1
2
1
SHOVAN MONDAL,1† JEAN-VALÈRE NAUBRON, DAMIEN CAMPOLO, MICHEL GIORGI, MICHÉLE P. BERTRAND,
*
1
*
AND MALEK NECHAB
1Aix-Marseille Université, CNRS ICR UMR7273, Marseille, France
2Aix-Marseille Université, Spectropole, Fédération de Chimie, Marseille, France
ABSTRACT
The absolute configurations (AC) of azaheterocylic compounds resulting from
the cascade rearrangement of enediynes involving only light atoms were unambiguously
assigned by the joint use of vibrational circular dichroism (VCD) and copper radiation single
crystal X-ray diffraction (XRD). These AC determinations proved that the rearrangements of
enediynes proceeded with memory of chirality and retention of configuration. Chirality
25:832–839, 2013. © 2013 Wiley Periodicals, Inc.
KEY WORDS: VCD; X-ray diffraction; enediynes; memory of chirality; absolute configurations;
heterocycles
INTRODUCTION
The postulated mechanism was supported by the determina-
tion by XRD of the AC of one compound in the series, i.e.,
2a, from our preliminary study.18
Tetrahydroisoquinolines (THIQ) constitute an important
class of compounds which possess a broad array of biological
activities.1,2 This ring system is present in many naturally
occurring alkaloids. The seven-membered analogs, i.e.,
benzazepines, are also encountered in several medicinal
products.3–5 These two classes of compounds are chiral, and
reliable determination of the absolute configuration (AC) is
of prime importance for new drugs to be approved.
During the past decades powerful methods for absolute
configuration assignment such as X-ray crystallography, cir-
cular dichroism, Raman optical activity (ROA), nuclear mag-
netic resonance (NMR) analysis of diastereoisomeric
derivatives, and chemical correlations have been devel-
oped.6–12 Meanwhile, vibrational circular dichroism (VCD),
which couples vibrational modes to chirality elements, has
grown into a powerful tool.6,10,13,14 This last approach has
seen improvements that enable the determination of absolute
configuration from neat liquid, oil, and solution samples. It
requires neither derivatization of the sample nor growth of a
pure single crystal.
Recently, our group has been involved in the development
of cascade rearrangement of enediynes giving access to
THIQ and benzazepines derivatives.15,16 The memory of
chirality (MOC) strategy was used to prepare enantiopure
heterocycles including constraint heterocyclic α-amino esters
bearing two contiguous quaternary stereocenters.17
The determination of absolute configuration by XRD
depends on the measurement of small intensity differences
between related pairs of reflections. These differences are
greater and the determination is thus facilitated when heavy
elements are present. As shown in Scheme 1, XRD analyses
of molecules possessing a sulfur atom allowed the AC of the
tetracyclic products to be determined and, consequently,
the chiral memory effect to be validated.15 However, the
elucidation of the AC of azaheterocycles including only light
elements was required to confirm the assumed mechanism
in the rearrangements of a new series of starting materials.
© 2013 Wiley Periodicals, Inc.
By using the copper (Cu) X-ray wavelength to maximize
the all-important anomalous scattering signal, it is effectively
possible to assign the absolute configuration of light
atom-containing samples. However, this technique is not
widespread yet.19–21 In the case of such compounds XRD
has its limitation and the reliability of the results is entirely
dependent on the quality of the data produced.6 Even though
chiroptical spectroscopic methods have become highly
popular, it has been demonstrated that it is important to use
more than one method for determining the structure of chiral
molecules.22 Therefore, in our problem pertinent information
concerning chirality had to be inferred from the cooperative
use of both XRD and VCD.23
We report herein how the combination of both techniques
was used to demonstrate that the rearrangement of
enediynes, including only light atoms, proceeded as assumed
with retention of configuration.
MATERIALS AND METHODS
The synthesis of products 2a-c from substrates 1a-c used in this study
has been described previously.18
General procedure for the synthesis of 2. (CH2O)n (27 mg,
0.89 mmol), CuI (34 mg, 0.18 mmol), 1,4-dioxane (1 mL), enediyne (S)-
1a (100 mg, 0.36 mmol) and dicyclohexylamine (0.13 mL, 0.64 mmol)
were added sequentially into an oven-dried reaction tube equipped with
Additional Supporting Information may be found in the online version of this
article.
*Correspondence to: M. P. Bertrand or M. Nechab, Aix-Marseille Université,
CNRS ICR UMR7273, 13397 Marseille Cedex 20, France. E-mail: michele.
bertrand@univ-amu.fr or malek.nechab@univ-amu.fr
†Present address for S. Mondal: Department of Chemistry, Visva Bharati,
Santiniketan, Birbhum, West Bengal, India, 731235.
Received for publication 24 April 2013; Accepted 11 June 2013
DOI: 10.1002/chir.22221
Published online 13 August 2013 in Wiley Online Library
(wileyonlinelibrary.com).

COOPERATIVE USE OF VCD AND XRD
833
a reflux condenser under an argon atmosphere. The resulting mixture
was stirred at reflux for 2 h. Solvent was evaporated under vacuum. The
residue was redissolved in DCM, filtered, and the filtrate was concen-
trated and purified by column chromatography on silica gel using 1:1
ethyl acetate:pentane as eluent to afford the cyclized product (R)-2a
(85 mg, 81%, ee = 95%). The enantiomeric excesses (ee) of compounds
2a-c were determined by chiral HPLC shown in Fig 1.
Spectroscopic and Computational Details
Diffraction data were measured at 150 K on an Agilent Xcalibur Sap-
phire3 Gemini diffractometer using the Cu(Kα) radiation (λ = 1.5418 Å).
Data were collected, reduced, and corrected from absorption (empirical
correction using spherical harmonics) with CrysAlisPro (Agilent
Technologies). Structures were solved with Superflip24 and refined with
Crystals.25 H-atoms were introduced at geometrical positions and refined
as riding atoms, with C-H = 0.91-0.98 Å, Uiso(H) = 1.5Ueq(C) for methyl
groups and 1.2Ueq(C) for all other H atoms.
Scheme 1. X-ray evidence for memory of chirality in the cascade
rearrangement of enediyne bearing a tosyl group.
Fig. 1. Chiral HPLC analyses of 2a-c.
Chirality DOI 10.1002/chir

834
MONDAL ET AL.
Crystal data for 2a (CCDC 858572)18: C18H17NO3, M = 295.33, ortho-
a) leads via Crabbé homologation to an enyne-allene which
spontaneously undergoes Myers-Saito cyclization to afford
biradical A (step b). Subsequent 1,5-hydrogen shift gives rise
to the rearranged biradical B (step c) which eventually leads
to product 2 through intramolecular coupling of the two reac-
tive radical centers (step d).32
The substrates were selected to fulfill several criteria.
Hydrogen abstraction from a chiral captodative position offers
several advantages, such as enhancing the rate of step b.
Moreover, since only one conformation of the side chain en-
ables the transfer of the hydrogen atom from the stereogenic
center, this transfer generates the captodative radical center
in intermediate B in a dynamic chiral conformation.
Radical coupling reactions are diffusion-limited processes.
In the case of intermediate B the rate of recombination is con-
trolled by rotational barriers around bonds α and β. As shown
in Scheme 3, a 180° rotation around bond β would result in
the complete loss of enantioselectivity. A high level of chiral-
ity transfer (from 96% to 95% ee) is observed in the recombina-
tion of biradical B. Therefore, this reaction is likely to
proceed via rotation around bond α without any competitive
racemization. This implies that kα is far superior to kβ at least
by two orders of magnitude. Typical rotational barriers
rhombic, a = 5.89431(12) Å, b = 8.01643(17) Å, c = 30.0923(6) Å, α = 90°,
β = 90°, γ = 90°, V = 1421.90(5) Å3, T = 150 K, space group P212121, Z = 4,
μ(Cu Kα) = 0.764 mm-1, 12,903 reflections measured, 2,544 independent
reflections (Rint = 0.051). The final R1 values were 0.0317 (I > 2(I)). The fi-
nal wR(F2) values were 0.0803 (I > 2(I)). The final R1 values were 0.0324
(all data). The final wR(F2) values were 0.0809 (all data). The goodness of
fit on F2 was 0.9910. Flack parameter = 0.029(18).
Crystal data for 2b (CCDC 912598).
C21H17NO2, M = 315.36, tetragonal,
a = 10.30133(6) Å, b = 10.30133(6) Å, c = 14.93272(14) Å, α = 90°, β = 90°,
γ = 90°, V = 1584.62(2) Å3, T = 150 K, space group P43, Z = 4, μ(Cu Kα) =
0.677 mm-1, 23,946 reflections measured, 2,839 independent reflections
(Rint = 0.050). The final R1 values were 0.0381 (I > 2(I)). The final wR
(F2) values were 0.0912 (I > 2(I)). The final R1 values were 0.0384 (all
data). The final wR(F2) values were 0.0916 (all data). The goodness of
fit on F2 was 1.0080. Flack parameter = 0.021(21).
All VCD measurements were done on Bruker PMA 50 accessory coupled
to a Vertex70 Fourier transform infrared spectrometer. A photoelastic
modulator (Hinds PEM 90) set at l/4 retardation was used to modulate
the handedness of the circular polarized light at 50 kHz. Demodulation
was performed by a lock-in amplifier (SR830 DSP). An optical low-pass filter
(<1,800 cm-1) before the photoelastic modulator was used to enhance the
signal/noise ratio. For all compounds, solutions with
a
0.1mol.L-1
concentration were prepared by dilution of solid sample in CD2Cl2.
The geometry optimizations, vibrational frequencies, IR absorption, and
VCD intensities of each conformation were calculated using Density
Functional Theory (DFT) with B3LYP functional with the 6-311 + G (d,p) ba-
sis set. Solvent effects (CH2Cl2) were introduced using the polarizable
continuum model IEF-PCM combined with cavities SMD parameters.26,27
Systematic search of conformational minima was carried out at the
B3LYP/6-311 + G (d,p) level of theory. Vibrational frequencies were calcu-
lated at the same level to ensure that the optimized geometries were minima
on the potential energy surface (no imaginary frequency). Frequencies
were scaled by a factor of 0.985. IR absorption and VCD spectra were
constructed from calculated dipole and rotational strengths assuming
Lorentzian band shape with a half-width, at half maximum, of 8 cm-1.
The populations of significant conformers were estimated using a
Boltzmann statistic.
RESULTS AND DISCUSSION
The rearrangement of enyne-allene to highly reactive (σ,π)
biradicals is known as Myers-Saito cycloaromatization.28–30
We took advantage of the production of these reactive species
to design routes to highly functionalized enantiopure hetero-
cycles bearing a single tetrasubstituted stereogenic center
(Scheme 2). The latter were reached through a polar-radical
cascade involving five elementary steps.31 The first step (step
Scheme 3. Origin of facial stereocontrol in the recombination of intermedi-
ate B.
Scheme 2. Cascade rearrangement of enediyne 1a with memory of chirality.
Chirality DOI 10.1002/chir
Fig. 2. Structure and ee of 2a, 2b, and 2c and the corresponding substrates.

COOPERATIVE USE OF VCD AND XRD
835
Fig. 3. ORTEP diagram of compound 2a (ref. 18) and 2b.
around C-C bonds like bond α are close to 7.5 kcal/mol.33
Conversely, rotation around bond β should be much slower,
as is it is restricted by the extended delocalization of the sin-
gle electron, the cyclic frame, and steric hindrance. Rotation
around β should decrease as rotation around bond α pro-
ceeds, which might explain the partial racemization of inter-
mediate B during the recombination step. The increased
flexibility of the lateral functional chain in the biradical
resulting from the rearrangement of homopropargylic analog
1c supports this rationale as a larger erosion of the ee is reg-
istered (Fig. 2).
The drawings in Scheme 3 are kind of caricatures since,
once admitted that rotation around bond α is much faster than
rotation around bond β, one should imagine the rotations
around bond α and γ necessary to the recombination not to
proceed stepwise, through conformers Bconf1-2, but rather to
be coupled.
The transient chirality of the intermediate radical should be
preserved during the time scale of the recombination step
and the whole rearrangement should proceed with memory
of chirality (MOC). MOC is intended here as defined by Fuji
and Kawabata as “an asymmetric transformation in which the
chirality of the starting material is preserved in the
conformationally labile intermediate during the transforma-
tion whereas no other permanently chiral center is present
in the molecule”.34
The measurements of the enantiomeric excess of product
2a confirmed the nearly total transfer of chirality of the
starting material, which validated the mechanistic hypothesis.
A similar conclusion applied to the rearrangement of 1b (99%
ee) which led to 2b in 90% ee (Fig. 2). Due to the increased
flexibility in the biradical intermediate resulting from the
homopropargylic oxazolidinone 1c, the latter led to lower en-
antiomeric excess in the formation of 2c (80 %) from (-)-1c
(99% ee, Fig. 2).
In order to ascertain the assumed retention of configura-
tion a reliable determination of the AC of the stereogenic
center in the products was needed. Good quality single
crystals of compound 2a were successfully grown in acetoni-
trile by slow evaporation, which enabled structure determina-
tion by X-ray diffraction. Copper radiation was used in order
to enhance, as far as possible, the anomalous signal from
the light atoms constituting the molecule and it finally turned
out to be accurate enough to discriminate between the two
enantiomers.
The Flack parameter was refined to a value of 0.029 (18)
with 1,023 Bijvoet pairs. The standard uncertainty is slightly
higher than the currently admitted criteria,35 but the Flack
parameter was confirmed by the values extracted from the
TABLE 1. Gibbs energies and Boltzmann populations
calculated for conformations of 2a, 2b and 2c
A1 (55 %)
A2 (24 %)
ΔG°298K(a)
Boltzmann pop.
(b)
2a
A1
A2
A3
A4
A5
A6
2b
B1
B2
B3
2c
C1
C2
C3
0.0
0.5
0.9
1.3
2.4
2.7
0.55
0.24
0.13
0.06
0.01
0.01
A3 (13 %)
A4 (6 %)
0.0
0.3
0.6
0.5
0.3
0.2
0.0
0.8
4.5
0.8
0.2
0.0
A5 (1 %)
A6 (1 %)
Fig. 4. Stable conformers of (R)-2a, calculated at the SMD-
IEFPCM_B3LYP/6-311 + G(d,p) theoretical level.
ain kcal.mol-1. bBoltzmann statistic calculation.
Chirality DOI 10.1002/chir

836
MONDAL ET AL.
X-ray experimental data: the Flack parameter was equal to
0.02 (21) (1,358 Bijvoet pairs), the Hooft parameter was equal
to 0.091 (76), and the P2(true), P3(true) and P3(false) proba-
bilities were equal to 1.0, 0.99 and 0.28x10-30, respectively.
Both crystal structures were successfully determined and
gave absolute configurations in good agreement with those
previously obtained for the product derived from sulfur
containing substrates (Scheme 1). They supported the
proposed mechanism.15
B1 (52 %)
B2 (31 %)
In the case of 2c, good quality single crystals necessary for
X-ray analysis could not be obtained. VCD spectra were
necessary to assign its absolute configuration.
The stereochemical assignment of all compounds 2 was
therefore approached from the comparison of the experimen-
tal VCD spectra of one (or both) of each couple of enantio-
mers to the calculated spectra of one enantiomer, using
DFT–calculated VCD spectra. The AC of compounds 2a
and 2b were investigated using VCD to corroborate the con-
clusions drawn from X-ray data. The VCD methodology alone
was then applied to the determination of the AC of 2c.
Calculated spectra of 2a-c were obtained by averaging
individual spectra of their significant conformations (i.e.,
those having a Boltzmann population superior to 5%). The
conformational search performed with 2a and 2b showed
that for the latter four and three conformations were signifi-
cantly populated, respectively (see Table 1). The correspond-
ing geometries are given in Figures 4 and 5.
The two pseudo-planar conformations A1 and A2 (Fig. 4)
which together account for 80% of the total population of
(R)-2a are quite similar to the conformation of the molecule
in the solid state where the heteroatom-containing ring, fused
with the pyroglutamic five-membered ring, adopts a half-chair
conformation. Conformers A1 and A2 differ by the relative ori-
entation of the two carbonyl groups and therefore by their
B3 (18 %)
Fig. 5. Stable conformers of (R)-2b, calculated at the SMD-
IEFPCM_B3LYP/6-311 + G(d,p) theoretical level.
Bayesian statistics on Bijvoet differences.36 The Hooft
Parameter was equal to 0.054 (95) and, more pertinent, the
probabilities relative to the choice of the right enantiomer
(P2(true) and P3(true)) or the false enantiomer (P3(false))
were equal to 1.0, 0.99 and 0.35x10-,21 respectively. Therefore,
these results clearly argued for the assignment of (R)-config-
uration to the stereogenic center in compound (-)-2a (Figs. 2
and 3).
The absolute configuration of (–)-2b derived from phenyl
oxazolidine 1b was determined by the same methodology.
The (R)-configuration (Figs. 2 and 3) was deduced from
(a) 0
(b) 27,28
1500
200
100
0
-10
26
8
25
1600
-20
17,18
19
10
1640
1000
9
11
29
16
23
20,21
29,30
28
2
4
10,11
17,18
500
9
12-15
8
3
24
23
22
30
26
22
5-7
20
25
26
19
27
16
24
2-4
1
25
14,15
12
13
-100
5-7
0
1
27,28
21
1500
10
200
0
18
17
8
11
9
14
16
23
19
6
4
2
1000
500
0
29,30
21
15,16
17
10,9
15
5
3
26
20
25
22
2-4
12
7
13
12
30
8
14
18
20
11
23
5-7
-200
13
24
21
1
19
26
25
1
1800
1600
1400
1200 1050
1800
1600
1400
1200 1050
⎯ν (
⎯ν (
Fig. 6. VCD (a) and IR absorption (b) spectra of (–)-2a measured in CD2Cl2 (in green), and calculated for (R)- 2a (in blue). Calculated rotational and dipole
strengths are also drawn (in light blue). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Chirality DOI 10.1002/chir

COOPERATIVE USE OF VCD AND XRD
837
200
100
0
400
16-17
0
(a)
(b)
-10
18
7
13
-20 23
15
300
22
12
8
6
3
1640
1600
20
9-8
200
100
21
14
13
19
23
4-5
22
18
10
5
10
11
1
20-21
19
4
9
14
11
7
-100
-200
6
2
3
1
23
22
15-17
0
18
400
13
400
200
0
16
7
8
300
200
100
0
15
12
3
6
20
17-18
19
21
11-12
14
23
21
20
5
11
10
4
22
17
8
19
5
9
14
15
7
-200
-400
13
3
10
9
22
4
23
6
2
16
1600
1400
1200
1600
1400
1200
⎯ν (
⎯ν (
Fig. 7. VCD (a) and IR absorption (b) spectra measured for (–)-2b (in green) and (+)-2b (in dashed red) in CD2Cl2, and calculated for (R)-2b (in blue). [Color
figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
dipole moment. Apparently, only the most polar structure A2
is present in the crystal lattice. The closely related
conformers A3 and A4 differ also by their dipole moment.
The more highly energetic boat conformers A5 and A6 do
not contribute significantly to the spectroscopic properties.
The phenyl group in 2b replaces the carbomethoxy group in
2a. Similar conformations were found for both compounds.
However, their relative energies are different. It is worth noting
that the half-chair conformers B1 and B3 (Fig. 5) are similar to
conformers A3-A4 and A1-A2, respectively, and that in this case
the contribution of the boat conformer B2 reaches 30%.
For each compound, IR and VCD spectra of enantiomers
were recorded in CD2Cl2 and compared to calculated spectra
of the (R)-2a and (R)-2b enantiomers. Comparisons of
calculated to experimental spectra are shown in Figures 6
and 7. For the individual spectra of enantiomers about
12,000 scans were averaged at 4 cm-1 resolution (correspond-
ing to three hours measurement time). The baselines of the
VCD spectra of 2b were corrected using the half-subtraction
of the raw spectra of the two enantiomers (a similar protocol
was applied to 2c). Since only one enantiomer was isolated
for 2a, the baseline of its VCD spectra was corrected using
simple subtraction of the spectrum of the racemic mixture.
Calculated IR absorption and VCD spectra were constructed
from calculated dipole and rotational strengths assuming
Lorentzian band shape with a half-width, at half maximum,
of 8 cm-1.
Despite a lesser agreement between the measured VCD
spectrum for (–)-2a (green line in Fig. 6a) and the spectrum
calculated for (R)-2a (blue line in Fig. 6a), the absolute con-
figuration could also be elucidated. Noticeable bands 26, 25,
20, 21, 13, 12, 11, 10, 9, 8, and 7 showed the same sign as com-
pared to the calculated bands indicating that the absolute
configuration of (–)-2a is (R).
Among all plotted bands, negative bands 25, 26 in the VCD
spectrum of 2a and bands 22, 23 in the VCD spectrum of 2b
have attracted our attention. They appear in a zone with quasi
Good agreements were observed between the experimen-
tal and calculated spectra (Figs. 6 and 7). The VCD and IR
spectra of (-)-2b (green line in Fig. 7a,b) matched the spectra
calculated for (R)-2b (blue line in Fig. 7a,b). The best coinci-
dence was observed for bands 12 to 23 (see Supplementary
Material).
Fig. 8. Stable conformers of (R)-2c, calculated at the SMD-
IEFPCM_B3LYP/6-311 + G(d,p) theoretical level.
Chirality DOI 10.1002/chir

838
MONDAL ET AL.
25
(a)
(b)
24
5
0
20
400
21
-5
12
200
0
1640
1600
300
200
100
0
12
13
19
3
1
17,18
15
9
2
6,7
4
25
24
23
3
17,18
10,11
21
23
22
15
16
22
16
5
14
8
9
24
4
10,11
14
8
1
19
25
2
5
6,7
-200
500
13
21
20
20
22
400
300
200
100
0
12
15
9
18
17
24
26
4
3
25
19
21
2,3
1
0
17,18
15
12
19
8
13
10,11
9
5
16
14
22
23
6,7
8
2
23
16
11
1
6,7
13
14
10
4
5
24
20
25
-500
1600
1400
⎯ν (
1200
1600
1400
1200
⎯ν (
Fig. 9. VCD (a) and IR absorption (b) spectra measured for (–)-2c (in green) and (+)-2c (in red dashed-line) in CD2Cl2, and calculated spectra for (R)- 2c
(in blue). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
no superimposition of other vibrational modes and, most of
all, they have the same sign and relative intensity in the spec-
tra of both compounds which present the same configuration
at the stereogenic center.
Characteristic bands that appear systematically on the VCD
spectra of a family of compounds are of great interest for the
elucidation of their AC. However, the use of such bands as
probes must be cautious as VCD spectra are highly sensitive
to slight structural changes (for detailed examination of these
vibrational modes, see Supplementary Material).
Since no crystal could be obtained for 2c, its absolute con-
figuration was determined using VCD only. Notwithstanding
the increased flexibility of the nitrogen atom containing ring,
only two significantly populated conformations were found
from the theoretical calculations (Fig. 8). The good agree-
ment between the experimental spectra of (–)-2c (green line
in Fig. 9a) and the calculated spectra (R)-2c (blue line in
Fig. 9a) allowed the unambiguous elucidation of its
absolute configuration.
ACKNOWLEDGMENTS
This research was funded by Aix-Marseille University, CNRS
and ANR JCJC2010-MOCER2. S.M. thanks Aix-Marseille
Université for his postdoctoral grant. We also thank Arie
van der Lee for x-ray analyses.
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