Configuration assignment of stereogenic centers in a β-pinene derivative by 1H NMR and molecular modeling

Article abstract of DOI:10.1016/j.molstruc.2005.09.001

The absolute configuration of three contiguous newly generated stereocenters in (1R,2R,3S,5S,1′R)-3-(1′-(4-methoxyphenyl)ethyl)-6, 6-dimethylbicyclo [3.1.1] heptan-2-ol (6), stereoselectively prepared from β-pinene in four steps, was established on the ba

Full text of DOI:10.1016/j.molstruc.2005.09.001

Journal of Molecular Structure 783 (2006) 157–160
www.elsevier.com/locate/molstruc
Configuration assignment of stereogenic centers in a b-pinene
1
derivative by H NMR and molecular modeling
a
Katia S.P. Perry , Jorge L.O. Domingos , Ayres G. Dias , Sergio Pinheiro ,
b
c
d
´
Antonio J.R. da Silva a, Paulo R.R. Costa b,
*
a
´ ˆ ´ ´ ˆ ´
Laboratorio de Ressonancia Magnetica Nuclear,Nucleo de Pesquisas de Produtos Naturais, Centro de Ciencias da Saude, bloco H,
´
Ilha da Cidade Universitaria, Universidade Federal do Rio de Janeiro, 21941-590, Rio de Janeiro, RJ, Brasil
´ ´ ˆ ´ ˆ ´
Laboratorio de Quımica Bioorganica (LQB), Nucleo de Pesquisas de Produtos Naturais, Centro de Ciencias da Saude, bloco H,
b
´
Ilha da Cidade Universitaria, Universidade Federal do Rio de Janeiro, 21941-590, Rio de Janeiro, RJ, Brasil
c
´
Instituto de Quımica, Universidade do Estado do Rio de Janeiro, RJ, Brasil
d
´
Instituto de Quımica, Universidade Federal Fluminense, RJ, Brasil
Received 20 June 2005; revised 1 September 2005; accepted 6 September 2005
Available online 17 October 2005
Abstract
The absolute configuration of three contiguous newly generated stereocenters in (1R,2R,3S,5S,10R)-3-(10-(4-methoxyphenyl)ethyl)-6,
6-dimethylbicyclo [3.1.1] heptan-2-ol (6), stereoselectively prepared from b-pinene in four steps, was established on the basis of 1H NMR data
and molecular modeling.
q 2005 Elsevier B.V. All rights reserved.
1
Keywords: b-Pinene; Configuration assignment; H NMR; Molecular Modeling; NOE
1. Introduction
As part of a program aiming the stereoselective synthesis of
new b-pinene derivatives, we decided to prepare alcohols type
3 bearing alkyl groups at the benzylic position, since data
obtained by molecular modeling (vide infra) suggested that the
presence of these groups would impose conformational
constraints for the rotation of C–C benzylic bond. The enone
2 was used as starting material for this purpose and the methyl
group was chosen to check this assumption.
Naturally occurring a- and b-pinene have been explored as
chiral building-blocks in the total synthesis of biologically
active compounds [1] and their derivatives have met great
success in asymmetric synthesis [2] being employed as chiral
auxiliaries [3], reagents [4] and ligands [5]. We have
previously reported the use of the (-)-b-pinene derivative 3
(Scheme 1) as a chiral auxiliary in asymmetric Friedel–Crafts
reaction (up to 84% d.e.) [6] and in the reduction of b-keto
esters (up to 40% d.e.) [7]. This auxiliary was stereoselec-
tively prepared from enone 2, through hydrogenation of the
carbon–carbon double bond followed by reduction of the
carbonyl group in the resulting ketone by LiAlH4. Both
reactions occurred with total stereoselectivity, being the
hydrogen atoms delivered at the opposite side of the methyl
group (C8) at the b-pinene moiety (less hindered side). The
stereochemistry at C2 and C3 was established by NOE
measurements [8].
2. Results and discussion
The conjugate addition of dimethyl cuprate to 2 led to
ketone 5, being the two newly generated stereogenic centers, at
the benzylic carbon (C10) and C3, formed with total
stereoselectivity, Scheme 2. A possible explanation for the
observed stereoselection is to assume the attack of the methyl
group taking place at the less hindered face of the carbon–
carbon double bond in 2, leading to the lithium enolate
intermediate 4, having a R configuration at C10. The second
stereogenic center at C3 is formed as the protonation of 4
occurs, during the work-up, the proton being delivered at the
opposite side of the methyl group C8, leading to the ketone 5.
Similarly, [8] the reduction of the carbonyl group in 5 is
stereocontrolled by C8 methyl group and the substituent at C3,
leading to alcohol 6, Scheme 2.
*
Corresponding author. Tel.: C55 2125626793; fax: C55 2125626512.
E-mail address: lqb@nppn.ufrj.br (P.R.R. Costa).
0022-2860/$ - see front matter q 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2005.09.001

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K.S.P. Perry et al. / Journal of Molecular Structure 783 (2006) 157–160
Scheme 1. Stereoselective synthesis of the alcohol 3 from b-pinene. Conditions: (i) and (ii)—Ref. [8].
In order to know more about the conformational behavior
more hindered axial position, has the major population
contribution to the conformational equilibrium. These
findings suggested that alcohol 6 has low conformational
mobility stimulating us to use NOE measurements in order to
determine the configuration at the benzylic carbon, as well as
at C2 and C3.
of alcohols 3 and 6, we have accomplished a theoretical study
(Scheme 3) using molecular mechanics and ab initio
calculations (Section 3.1) The results obtained clearly show
that the bicycle system is relatively rigid and the confor-
mational freedom of the alicyclic part of the molecule is
controlled mainly by steric interactions with C8 methyl
group. Only the small hydrogen atom is tolerated at the axial
position, near to C8 [9]. Thus, for 3, two conformers emerged
from the calculations, the less populated one having the aryl
group in a stacked position while in the more populated one,
the aryl group occupies the anti position, less sterically
hindered. The comparison of these data with those obtained
for 6 shows that the methyl group at the benzylic position
imposes severe conformational constraints to the structure
and one conformer, in which the hydrogen is placed at the
The structure of the alcohol 3 was previously studied
through NOE experiments [8]. Attempts to determine the
relationship between the benzylic hydrogens and H3 through
the measurement of the coupling constant failed due to signal
overlap.
In the case of 6, NOE experiments also strongly supported
the proposed structure. Irradiation at H2 led to an enhancement
of 18% at H3, confirming the cis-relationship between these
hydrogen atoms (Fig. 1) while the axial position for H10 was
suggested by the 2% increment observed at this hydrogen after
Scheme 2. Stereoselective synthesis of the alcohol 6 from enone 2. Conditions: (i) Me2CuLi, Et2O, K78 8C to rt; (ii) NH4Cl, 83%; (iii) LiAlH4, THF, 95%.
Scheme 3. Conformational analysis of the alcohols 3 and 6.

K.S.P. Perry et al. / Journal of Molecular Structure 783 (2006) 157–160
159
Fig. 1. NOE in alcohol 6 and in the corresponding cinammate 7. The distances between hydrogens were estimated by molecular modeling.
irradiating the C8 methyl group signal. Finally, the stacked
position of the methyl group at the benzylic position was
supported by an enhancement of 5.1% observed when H2 is
irradiated. These data are in good agreement with the calculated
distances between these hydrogen atoms. However, since in 6
the signal for C10 methyl group overlaps with three other
signals, this alcohol was transformed into the corresponding
cinnamate 7. In this derivative, the overlap was removed and the
configuration at the benzylic carbon could be confirmed by the
observed enhancement at H2 (2.9%) when the Me group was
irradiated. In both compounds 6 and 7, the vicinal coupling
constant value for hydrogens H3 and H10 is 11.4 Hz, which is in
full agreement with an anti configuration for the two hydrogens.
In conclusion, the stereogenic centers in alcohol 6, prepared
in two steps from enone 2, could be assigned through NOE
experiments and coupling constant measurements. This
structure is in agreement with the expected stereochemical
outcome of the reactions and the conformational analysis
obtained by molecular modeling calculations.
using standard Varian software (NOEDIFF). 1% deuterated
chloroform solutions (degassed by freeze–thaw cycles) at 298 K
were used for the measurements. A pre-saturation time of 4 s was
used and the free induction decays were processed with a line
broadening of 2 Hz to minimize artifacts during subtraction.
3.3. Synthesis
3.3.1. Materials and methods
The reactions were performed under N2 atmosphere in flame
dried glassware. THF and Et2O were distilled from sodium–
benzophenone under N2. LiAlH4, CuBr.Me2S, methyllithium
(1.4 M solution in Et2O) and n-butyllithium (2.5 M solution in
hexanes) were commercially available (Aldrich, Fluka or
Merck) and were used as purchased. The compounds 2 and 3
were prepared as described in Ref. [3c].
(1) (1R,3S,5S,10R)-3-(10-(4-methoxyphenyl)ethyl)-6,6-
dimethylbicyclo [3.1.1] heptan-2-one (5):
A solution of methyllithium (1.00 mmol) was added in a
suspension of CuBr$Me2S (0.29 g—1.14 mmol) in dry diethyl
ether (3 mL), under N2 and cooled at 0 8C. The resulting
mixture is stirred and cooled at K78 8C, and then a solution of
(E,1R,5S)-3-(4-methoxybenzylidene)-6,6-dimethylbicyclo
[3.1.1] heptan-2-one (2) (0.30 g—1.17 mmol) in Et2O
(1.20 mL) was added. After stirring for 1 h, a solution of
NH4Cl (10 mL) was added, and the resulting mixture was
extracted with CH2Cl2 (3!10 mL). The organic layers were
dried with anhydrous Na2SO4, and the solvent was removed in
vacuo. The ketone 5 was obtained in 83% of yield (0.26 g) after
purification by flash chromatography (eluent—EtOAc-hexane:
5:95). 1H NMR, CDCl3: 7.30–6.70 (m, 4H), 3.80 (s, 3H), 3.39
(q, JZ6.9 Hz, 1H), 2.80 (m, 1H), 2.53 (t, JZ5.3 Hz, 1H),
2.44–2.30 (m, 1H), 2.18–2.08 (m, 1H), 1.95 (ddd, JZ13.3 Hz;
10.2 Hz; 4.7 Hz, 1H), 1.71 (d, JZ10.7 Hz, 1H), 1.50–1.38 (m,
4H), 1.20 (s, 3H), 0.35 (s, 1H)
3. Experimental
3.1. Computational procedures
3.1.1. Molecular modeling studies
The molecules were constructed using the graphical interface
of the Spartan Pro v.1.0 package. They were optimised at the
molecular mechanics level using the MMFF force field. The
optimised geometries were submitted to a Monte Carlo
conformational search at the same level, with 500 steps. The
different conformations obtained, differing from the most stable
one by no more than 3 kcal molK1, were fully optimised at the
MM/MMFF level. Their energies were calculated through
single-point calculations at the ab initio HF/6-31G* level.
Relative populations for each set of conformers (Scheme 3)
were estimated using the Boltzmann distribution law.
(2) (1R,2R,3S,5S,10R)-3-(10-(4-methoxyphenyl)ethyl)-6,6-
dimethylbicyclo [3.1.1] heptan-2-ol (6):
3.2. NMR experiments
NMR spectra were recorded on a Varian Gemini-200
1
spectrometer operating at 200 MHz for H and at 50 MHz for
13C. Steady-state NOE difference experiments were performed
To a solution of the ketone 5 (0.25 g—0.92 mmol) in THF
(4.60 mL) at 0 8C, LiAlH4 (0.06 g—1.56 mmol) was added

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K.S.P. Perry et al. / Journal of Molecular Structure 783 (2006) 157–160
and the resulting mixture was stirred during 2.5 h at room
temperature. Then, after cooling the mixture to 0 8C, 0.30 mL
of an aqueous solution of NaOH (10%) and 0.50 mL of water
were added (a vigorous release of H2 was observed). The
material was filtered through a Celite pad, and the solvent was
removed to stereoselectively obtain the alcohol 6 in 95% of
Acknowledgements
To FINEP-PADCT, CNPq and FUJB for financial support.
To Francisco A. Santos for 1H NMR and 13C NMR spectra. To
CNPq for financial support and fellowships to the authors.
1
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47.82, 40.72, 39.94, 39.17, 38.07, 30.48, 27.33, 24.69, 22.66,
21.82
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