An experimental/theoretical approach to determine the optical purity and the absolute configuration of endo- and exo-norborn-5-en-2-ol using mandelate derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.08.056

The O-acetylmandelates and mandelates of endo- and exo-norborn-5-en-2-ol were prepared, both as a mixture and also as separate diastereomers. ¹H NMR spectroscopy of these derivatives was efficiently used to determine the enantiomeric ratios and

Full text of DOI:10.1016/j.tetlet.2009.08.056

Tetrahedron Letters 50 (2009) 6121–6125
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An experimental/theoretical approach to determine the optical purity
and the absolute configuration of endo- and exo-norborn-5-en-2-ol
using mandelate derivatives
*
Pablo L. Pisano, Ariel M. Sarotti, Silvina C. Pellegrinet
Instituto de Química Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, Rosario 2000, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
The O-acetylmandelates and mandelates of endo- and exo-norborn-5-en-2-ol were prepared, both as a
mixture and also as separate diastereomers. 1H NMR spectroscopy of these derivatives was efficiently
used to determine the enantiomeric ratios and to predict the absolute configuration of the alcohols. The-
oretical calculations were performed to locate the predominant conformations of the mandelate deriva-
tives and GIAO 1H NMR Boltzmann-weighted average chemical shifts were computed, correctly
Received 22 June 2009
Revised 7 August 2009
Accepted 18 August 2009
Available online 21 August 2009
reproducing the experimental d and
Dd values.
Ó 2009 Elsevier Ltd. All rights reserved.
Bicyclo[2.2.1]heptane systems are interesting from the struc-
tural and synthetic points of view due to their occurrence as natu-
ral products and their utility as versatile building blocks for the
synthesis of diverse chemical structures.1 Chiral norborn-5-en-2-
ol (bicyclo[2.2.1]hept-5-en-2-ol) (1) has been prepared in a num-
ber of ways, including the asymmetric hydroboration of norborna-
diene2 and various chemical and enzymatic resolutions.3 However,
no general method has been developed to determine its enantio-
meric purity and to assign its absolute configuration. In most cases,
the optical purity has been estimated based on optical rota-
tions.2b,3a,b,g,h However, the values found in the literature are vari-
as separate diastereoisomers, as a means to develop a direct meth-
od to determine their enantiomeric ratios and to assign their abso-
lute configurations.
Due to the key role played by enantiomerically pure compounds
in different fields of chemistry, many efforts have been devoted to
the development of simple and reliable methods for the determi-
nation of the optical purities and the absolute configurations.
Among the existing methods available, 1H NMR spectroscopy has
emerged as one of the most useful and widely used techniques
for this purpose.7 We have focused our attention on the use of
readily available mandelic acid and its O-substituted analogues
as chiral derivatising agents (CDA).8 The cheap and easily prepared
mandelates and their O-acetyl analogues have been found to be
best suited than the expensive, although more frequently used,
O-methylmandelates to assess the enantiomeric excesses and
absolute configurations of secondary alcohols.8d For this reason,
we decided to prepare the mandelates and the O-acetyl analogues
derived from endo and exo-norborn-5-en-2-ol (1) and analyse their
NMR spectra in detail. Reaction of commercially available racemic
norborn-5-en-2-ol (endo/exo 75:25) with (S)-O-acetylmandelic
acid,9 DCC and catalytic DMAP in dichloromethane gave the mix-
ture of diastereomeric O-acetylmandelates 2 in quantitative yield
(Scheme 1). By integration of the 1H NMR spectrum, we corrobo-
rated that the 75:25 endo/exo and 1:1 R/S ratios were maintained.
We were delighted to note that the signals of the bridgehead pro-
tons attached to C1 of the four diastereomers were well resolved
(Fig. 1, spectrum a). In addition, the signals of C3–H were clearly
separated, and the same was observed for the olefinic protons at-
tached to C6 for the endo isomer. Subsequent selective hydrolysis
of the acetate group gave the mixture of mandelates 3 without
apparent epimerisation. The spectra of the mandelates showed
able and, moreover, the exo isomer has a very small [a]D, which can
lead to inaccurate results.4 Other techniques such as chiral GC of
the acetates,3e chiral HPLC of the 3,5-dinitrobenzoates,3f and 1H
NMR using the chiral shift reagent Eu(hfc)3 as well as 19F NMR of
the Mosher esters3c,d have been applied to determine the enantio-
meric excess of the endo isomer. In 1968, Sandman and Mislow
synthesised the O-methylmandelates of racemic norborn-5-en-2-
ol (endo/exo 13:87) as a means to determine the optical purity of
norborn-5-en-2-one.5 The signals for the methoxymethine protons
of the endo isomer were resolved, appearing at 4.59 and 4.55 ppm
(60 MHz, benzene). In a related and more recent Letter, Guan and
Li investigated the preparation and the optical properties of opti-
cally pure 1-methyl-7-oxabicyclo[2.2.1]heptan-2-one via resolu-
tion of the reductive products with (+)-mandelic acid, followed
by saponification and oxidation.6
Our interest in the asymmetric synthesis of cyclohexenols has
led us to examine the properties of the mandelate derivatives of
endo- and exo-norborn-5-en-2-ol (1), both as a mixture and also
* Corresponding author. Tel./fax: +54 341 4370477.
D
ds(D
d = dR À dS) which were even higher than those of the
E-mail address: pellegrinet@iquir-conicet.gov.ar (S.C. Pellegrinet).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.056

6122
P. L. Pisano et al. / Tetrahedron Letters 50 (2009) 6121–6125
OAc
CO2H
7
1
9
S
R
S
6
2
OAc
AcO
S
S
O
O
5
4
3
(S)-(+)-O-acetylmandelic acid
O
O
2N-S
(2 eq)
2N-R
DCC (2 eq), DMAP (0.2 eq)
CH2Cl2, rt, 1h
OH
( )-1
endo/exo
75:25
99%
S
S
O
O
R
S
OAc AcO
O
O
2X-S
2X-R
R
S
OH
HO
S
S
S
O
O
O
3N-R
O
3N-S
K2CO3 aq. (0.05 eq)
MeOH, rt, 1h
81%
S
O
O
R
S
OH HO
O
O
3X-S
3X-R
Scheme 1.
OR
H
O
H
RO
Ph
S
=
L1
L2
L1
O
5
Ph
L2
H
H
δL2 < δL1
6
6
6
6
5
5
5
7
7
7
7
1
1
1
4
4
4
4
1
RO
OR
H
Ph
H
Ph
3
3
3
3
Ph
H
Ph
H
OR
2X-
3X-
OR
and
S
2N-
3N-
R
and
R
2N-
3N-
S and
S
2X-
3X-
S
R
and
R
H-1
XR
H-9
(b)
H-3x
X
XR
H-3x
H-6
H-3n
H-9
H-2
N
NR
H-3n
H-4
H-1 H-1
NR NS
N
N
H-6
NS
N
X
X
H-2
X
S R
H-1
XS
S
R
OH
S R
H-9
N
(a)
H-1
XR
H-9
H-3x
XR
X
H-3x
H-6
NR
X
H-3n
H-4
N
H-6 H-2
H-1H-1
NR NS
N
H-2
X
S R
H-1
XS
NS
N
S
R
6.0
5.5
5.0
4.5
4.0
3.5
(ppm)
3.0
2.5
2.0
1.5
1.0
Figure 1. Models proposed to assign the absolute configuration and partial 1H NMR spectra of O-acetylmandelates 2 (spectrum a) and mandelates 3 (spectrum b) at 300 MHz
in CDCl3.

P. L. Pisano et al. / Tetrahedron Letters 50 (2009) 6121–6125
6123
O-acetylmandelate analogues (Fig. 1, spectrum b). According to the
model proposed to explain the NMR spectra of secondary O-meth-
ylmandelates,8a,c the most stable conformation in solution is the
synperiplanar (sp) conformation, in which the methine proton,
the carbonyl and the methoxy group are all syn and coplanar. As
a consequence of the anisotropic magnetic field created by the
phenyl ring, the groups L1 and L2 of the alcohol moiety can be
either shielded or deshielded. Based on this model, we predicted
the absolute configuration of the diastereomers of O-acetylmande-
lates 2 and mandelates 3 as shown in Figure 1. For example, the
protons attached to C1 and C6 were predicted to be more shielded
in the endo and exo isomers having the S absolute configuration at
C2 (2N-S and 2X-S: spectrum a, 3N-S and 3X-S: spectrum b). On
the other hand, C3–H were predicted to be more shielded in the
diastereoisomers having the R stereochemistry at C2.
In order to confirm the absolute configurations, we decided to
synthesise the mandelate derivatives of the separate endo and
exo epimers. After chromatographic separation on silica gel (pen-
tane/diethyl ether), the sequence shown in Scheme 1 was repeated
individually for endo and exo-norborn-5-en-2-ol (1N and 1X,
respectively) without difficulty. A 1:1 mixture of the endo-O-acet-
ylmandelates was enriched in the 2R diastereomer by column
chromatography on silica gel (hexane/ethyl acetate) and hydroly-
sed to endo-norborn-5-en-2-ol (1N) with lithium hydroxide
(Scheme 2). The optical rotation of the 66:34 R/S mixture thus
obtained confirmed that the absolute configuration of the endo
isomer was correctly assigned by NMR of the mandelate deriva-
tives.4 The exo isomer was subjected to the same protocol and
the optical rotation of the product of hydrolysis of a 67:33 R/S
mixture of 2X corroborated the absolute configuration of 1X.
a large number of geometries were generated using the conforma-
tional search module of Hyperchem10 with the MM+ method. Se-
lected structures were then successively reoptimised at the RHF/
AM1, RHF/3-21G and B3LYP/6-31G* levels of theory using GAUSSIAN
03.11 Normal coordinate analyses were used to confirm the nature
of the stationary points and to evaluate the thermochemical prop-
erties at 1 atm and 298.15 K. For all significantly populated con-
formers of each stereoisomer, free energies in solution were
computed on the structures optimised in the gas phase at the
B3LYP/6-311++G** level of theory with the Polarisable Continuum
Model (PCM) as implemented in GAUSSIAN 03 using chloroform as
the solvent.12
Figure 2 gathers the optimised geometries of the major con-
formers for each compound (for all conformers, see the Supple-
mentary data). In agreement with the empirical model,8a,c all
global minima correspond to conformations in which the methine
proton, the carbonyl and the acetate or hydroxy group are synperi-
planar.13 For each compound, we found two synperiplanar con-
formers of similar energies, having H–C2–O–C8 torsion angles of
ca. 40° and À40°. In addition, conformers having syn or antiperipla-
nar arrangements of the acetate and the carbonyl oxygen were lo-
cated for O-acetylmandelates 2N and 2X, but the anti counterparts
were considerably less stable and account for 15–30% of the popu-
lation. On the other hand, the free hydroxy group in mandelates 3N
and 3X is H-bonded to the carbonyl oxygen, so the hydroxyl and
the carbonyl are synperiplanar. The conformational preferences to-
wards the synperiplanar conformers are maintained in solution.
NOE experiments support these theoretical results since they con-
firmed the proximity of the aromatic protons and H-6 of 2N-S, H-6
and H-1 of 3N-S and H-3n of 3N-R. In addition, irradiation of the
aromatic protons enhanced the signals of H-3n of 2X-R, H-1 of
2X-S and H-1 of 3X-S. We also carried out NMR experiments at
low temperature (À40 °C) for O-acetylmandelates 2N and noticed
However, since the [a] was very small we converted the alcohol
D
into its acetate 4X, which has a higher value of optical rotation.
Although the experimental value was slightly lower than expected,
the negative sign of the optical rotation provided further support to
the proposed stereochemistry. The same was repeated with a
33:67 R/S mixture of the O-acetylmandelate 2X, giving consistent
results. The spectra of the O-acetylmandelates and the mandelates
of separate endo and exo-norborn-5-en-2-ol are shown in the Sup-
plementary data.
that the
Dd for H-6 was increased in 0.12 ppm, which suggests that
conformational equilibria are important for these compounds and
affect the chemical shifts significantly. For O-acetylmandelates 2X,
H-6 and H-3x become 0.02 and 0.04 ppm more shielded for the dia-
stereomers having the S and R configurations at C-2, respectively.
Finally, we performed GIAO NMR calculations at the B3LYP/6-
*
To validate these experiments, we performed theoretical calcu-
lations for the endo and exo-O-acetylmandelates (2N and 2X) and
mandelates (3N and 3X). Conformational searches were run to lo-
cate the minimum energy conformers of all the structures. Initially,
31G level of theory for all significantly populated conformers of
each diastereoisomer and compared the calculated Boltzmann-
weighted average 1H NMR chemical shifts obtained using relative
free energies in the gas phase with the experimental values
LiOH.H2O
MeOH, rt, 1h
2N
R/S 66:34
OH
85%
1N
[α]D +45.5 (c 0.50, CHCl3)
Lit.5 [α]D -73.4 (c 2.62, CHCl3) for (
)-1N, ee 45.2%
S
LiOH.H2O
MeOH, rt, 1h
Ac2O, Py, DMAP
CHCl3
2X
R/S 67:33
OH
OAc
89%
77%
1X
[α]D -2.8 (c 0.77, CHCl3)
4X
[α]D -6.9 (c 0.81, CHCl3)
LiOH.H2O
MeOH, rt, 1h
Ac2O, Py, DMAP
OH
OAc
CHCl3
2X
R/S 33:67
83%
79%
1X
4X
[α]D +8.5 (c 0.83,CHCl3)
[α]D +2.5 (c 0.76, CHCl3)
Lit.2a [α]D +5.8 (c 8.7, CHCl3), for ee 48%
Lit.2a [α]D +22.9 (neat), for ee 48%
Scheme 2.

6124
P. L. Pisano et al. / Tetrahedron Letters 50 (2009) 6121–6125
(Table 1).14,15 Gratifyingly, the experimental d and
correctly reproduced.
D
d values were
chemical shifts of the derivatives obtained with CDAs might be
crucial.
These computational results support the stereochemical assign-
ment predicted by 1H NMR spectroscopy based on the empirical
model. In our case, this was unequivocally confirmed by optical
rotation measurements. However, this might not always be possi-
ble. When the optical rotations of the enantiomerically pure sec-
ondary alcohols are not known, the theoretical prediction of the
In summary, the O-acetylmandelates and the mandelate deriv-
atives have been efficiently used to determine the optical purity
and to predict the absolute configuration of endo- and exo-nor-
born-5-en-2-ol. The conformational, stereochemical and NMR
properties of these derivatives have been studied using an experi-
mental/theoretical approach. In accordance with the empirical
model proposed for secondary O-methylmandelates, all major con-
formers are synperiplanar. GIAO 1H NMR Boltzmann-weighted
average chemical shifts correctly reproduced the experimental d
and
Dd values. Preliminary studies show that this protocol can
be successfully applied to determine the enantiomeric ratios and
to predict the absolute configurations of other bicyclic and mono-
cyclic secondary cyclohexenols. These results will be reported in
due course.
Acknowledgements
We thank CONICET, Universidad Nacional de Rosario and AN-
PCyT for financial support, and Manuel González Sierra for NMR
assistance. P.L.P. thanks ANPCyT for the award of a fellowship.
A.M.S. thanks CONICET for the award of a fellowship.
Supplementary data
Supplementary data (experimental procedures, spectroscopic,
analytic and computational data and NMR spectra for all new com-
pounds) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2009.08.056.
References and notes
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*
Figure 2. B3LYP/6-31G optimised geometries of the major conformers for O-
acetylmandelates 2 and mandelates 3.
estimated from the work of Sandman and Mislow (Ref. 5, [
CHCl3, ee 45.2%). The optical rotation of optically pure (1R,2S)-exo-norborn-5-
en-2-ol has been estimated from the work of Mislow and Berger (Ref. 2a, [
a
]
D
À73.4, c 2.62,
a
]
D
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Experimental and calculated 1H NMR d and
D
d values (in ppm) for selected nuclei
H-3x H-6
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H-3n
Calcd. Exp.
Exp. Calcd. Exp.
Calcd. Exp. Calcd.
2N dR
3.19 3.12
3.02 2.90
0.17 0.22
0.75
0.99
1.03
1.20
2.03
2.10
1.99 5.95 6.20
2.12 5.47 5.73
dS
D
d
À0.24 À0.17 À0.07 À0.13 0.48 0.47
2X dR
2.93 2.83
2.71 2.52
0.22 0.31
1.62
1.70
1.63
1.71
1.17
1.47
1.44 5.93 6.02
1.68 5.89 5.87
dS
D
d
À0.08 À0.08 À0.30 À0.24 0.04 0.15
3N dR
3.19 3.01
3.00 2.81
0.19 0.21
0.68
0.99
0.89
1.27
2.04
2.13
2.09 5.92 6.29
2.22 5.40 5.76
dS
D
d
À0.31 À0.38 À0.09 À0.13 0.52 0.53
3X dR
2.94 2.83
2.68 2.54
0.26 0.29
1.62
1.72
1.64
1.78
1.11
1.47
1.28 5.95 6.00
1.68 5.90 5.92
dS
D
d
À0.10 À0.14 À0.36 À0.40 0.05 0.08
D
d = dR À dS.

P. L. Pisano et al. / Tetrahedron Letters 50 (2009) 6121–6125
6125
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phase and in solution. Although all methods correctly reproduced the
experimental d and
Dd values, best results were obtained with the B3LYP/6-
31G* level of theory using relative free energies in the gas phase.
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