Hydrogenation and conformational analysis of (1R,2R,6S)-3-methyl-6-(1- methylethenyl)cyclohex-3-ene-1,2-diol

Article abstract of DOI:10.1134/S1070428010120043

Hydrogenation of (1R,2R,6S)-3-methyl-6-(1-methylethenyl)cyclohex-3-ene-1,2- diol was studied. Nickel chloride-sodium tetrahydridoborate system turned out to selectively reduce the double bond in the isopropenyl group. The results of conformational analysis of (1R,2R,6S)-3-methyl-6-(1-methylethenyl)cyclohex-3- ene-1,2-diol and its partly and completely hydrogenated derivatives were in a good agreement with the NMR data. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S1070428010120043

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 12, pp. 1786–1789. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © O.V. Ardashov, A.M. Genaev, I.V. Il’ina, D.V. Korchagina, K.P. Volcho, N.F. Salakhutdinov, 2010, published in Zhurnal
Organicheskoi Khimii, 2010, Vol. 46, No. 12, pp. 1775–1778.
Hydrogenation and Conformational Analysis
of (1R,2R,6S)-3-Methyl-6-(1-methylethenyl)cyclohex-
3-ene-1,2-diol
O. V. Ardashov, A. M. Genaev, I. V. Il’ina, D. V. Korchagina,
K. P. Volcho, and N. F. Salakhutdinov
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
e-mail: volcho@nioch.nsc.ru
Received April 30, 2010
Abstract—Hydrogenation of (1R,2R,6S)-3-methyl-6-(1-methylethenyl)cyclohex-3-ene-1,2-diol was studied.
Nickel chloride–sodium tetrahydridoborate system turned out to selectively reduce the double bond in the
isopropenyl group. The results of conformational analysis of (1R,2R,6S)-3-methyl-6-(1-methylethenyl)cyclo-
hex-3-ene-1,2-diol and its partly and completely hydrogenated derivatives were in a good agreement with
the NMR data.
DOI: 10.1134/S1070428010120043
We recently found [1] that (1R,2R,6S)-3-methyl-6-
(1-methylethenyl)cyclohex-3-ene-1,2-diol (I) formed
by isomerization of (–)-cis-verbenol epoxide (II) over
montmorillonite clays (Scheme 1) [2] exhibits a strong
anticonvulsant activity. Therefore, synthesis of various
derivatives of compound I seems to be promising. The
goal of the present work was to develop a procedure
for selective hydrogenation of diene I to enediol III.
We have found that an efficient system for selective
hydrogenation of the exocyclic double bond in I may
be nickel(II) hydridoborate generated in situ from
NiCl2 and NaBH4. This system was successfully used
previously for reductive amination of aldehydes and
ketones [3], reduction of azides to amines [4] and
aromatic nitro compounds to anilines [5], and catalytic
hydrogenation of double bonds with molecular hydro-
gen [6].
Diol I was reduced on heating in boiling methanol
over a period of 5 h, and the yield of compound III
isolated and purified by column chromatography was
66%. Thus nickel borohydride turned out to be appro-
priate for the selective reduction of the exocyclic
double bond in compound I.
The reduction of compound I with hydrogen over
Raney nickel under pressure was characterized by poor
selectivity. Depending on the temperature and reaction
time, mixtures of unreacted compound I with partly
hydrogenated product III or of partly and completely
hydrogenated products III and IV were obtained, and
it was difficult to separate them. For example, the
reduction at 60°C (12 h, 100 atm) gave 63% of a mix-
ture of III and IV at a ratio of 1:0.4.
The structure of compounds III and IV was deter-
13
mined on the basis of the 1H and C NMR data. Un-
Scheme 1.
10
Me
Me
Me
Me
O
3
OH
OH
OH
OH
OH
OH
Clay
[H]
4
5
2
1
+
Me
Me
6
OH
7
8
9
H2C
Me
Me
Me
Me
Me
IV
II
I
III
1786

HYDROGENATION AND CONFORMATIONAL ANALYSIS OF (1R,2R,6S)-3-METHYL-...
1787
used computer programs as ChemDraw-Chem3D,
ChemSketch, and MarvinSketch make it possible to
quickly draw a two-dimensional structure and automat-
ically convert it into three-dimensional. However, this
is frequently insufficient, for the resulting conforma-
tion is not necessarily the most stable. As applied to
compound I, the above three programs (after additional
DFT optimization) gave three different structures, but
none of them corresponded to the global minimum on
the potential energy surface; only one program
(ChemSketch) correctly predicted equatorial orienta-
tion of the isopropenyl group.
Conformational analysis of compounds I, III, and
IV was performed in three steps. Initial sets of con-
formations were obtained by the molecular mechanics
method using several conformer generators. In the
second step, the conformer structures were optimized
in terms of semiempirical quantum-chemical methods.
Finally, the remaining structures were optimized at the
DFT level. After each step, doubles (i.e., structures
with equal or very similar geometric parameters) were
removed, so that the number of structures decreased
(especially strongly in the second step). For example,
conformer generators (Marvin, Vconf, and Tinker) pro-
posed in total 274 structures for diol I, 172 of which
were unique. After optimization in the second step
(RM1 MOPAC2009), only 54 structures remained, and
DFT optimization (PBE/L1, PRIRODA) left 28 struc-
tures. Ultimately, we obtained 35 and 38 conformers
for diols III and IV, respectively.
like compounds I and III, the 1-H and 2-H protons in
diol IV displayed a quite different vicinal coupling
constant (J1,2 = 8.5 Hz); in addition, coupling between
the 2-H and 3-H protons was observed (J2,3 = 8.5 Hz).
These data indicated axial orientation of the above
three protons. In keeping with the J1,6 value equal to
4.5 Hz, the 6-H proton occupies equatorial position,
and hence the bulky isopropyl group is axial. In order
to rationalize the observed pattern, detailed conforma-
tional analysis of compounds I, III, and IV was
performed.
Conformational analysis is very important from the
viewpoint of medicinal chemistry, for biological activ-
ity of structurally nonrigid organic molecules is largely
determined by their conformation [7]. Another impor-
tant field of application of conformational analysis is
prediction of steric structure and related spectral pa-
rameters, in particular spin–spin coupling constants in
NMR spectra. Most generally, conformational analysis
is performed with a view to find most stable conforma-
tions, though in some cases less favorable structures
should also be taken into account. Biologically active
conformation does not necessarily correspond to the
global minimum on the potential energy surface (PES),
and it can be characterized by a higher energy (ΔE ≤
40 kJ/mol) [8]. In addition, contributions of con-
formers having similar energy (which are capable of
undergoing fast interconversion) must be considered
while analyzing the NMR spectra.
The most populated energy levels of initial com-
pound I corresponded to conformers with equatorial
It should be noted that even search for most stable
conformation is not a trivial problem. Such widely
I-eq
I-ax
Most stable conformations of compounds I, III, and IV.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010
III
IV

ARDASHOV et al.
1788
isopropenyl group. The overall fraction of such con-
formers was 72%; it was estimated on the basis of the
calculated energies according to the Boltzmann distri-
bution at 25°C. In this case, the contribution of con-
formers with axial orientation of the isopropenyl group
was also significant (28%). Figure shows the most
stable conformations with equatorial and axial iso-
propenyl groups. According to the calculations, hydro-
genated derivatives of diol I are conformationally
homogeneous. The isopropyl group in almost all con-
formers of compound III (overall fraction 97%)
occupies equatorial position. In contrast, conformers of
completely hydrogenated compound IV with axial
orientation of the isopropyl group turned out to be
much more stable (overall fraction ~100%). In all
cases, the results of conformational analysis were con-
sistent with the structures of compounds I, II, and IV
determined on the basis of the NMR data.
was distilled off, 60 ml of 25% aqueous ammonia and
50 ml of ethyl acetate were added to the residue, and
the mixture was filtered through a layer of silica gel.
The organic phase was separated, the aqueous phase
was extracted with ethyl acetate (3×20 ml), and the
extracts were combined with the organic phase,
washed with 5% hydrochloric acid (3×20 ml) and
a saturated solution of NaCl–NaHCO3 (2 ×20 ml),
dried over Na2SO4, and evaporated. The residue,
0.154 g, was separated by column chromatography on
silica gel (60–200 μm, Macherey Nagel) using
hexane–ethyl acetate (gradient elution, 10 to 50% of
EtOAc) as eluent to isolate 0.135 g (0.79 mmol, 66%)
of diol III.
(1R,2R,6S)-6-Isopropyl-3-methylcyclohex-3-ene-
1,2-diol (III). [α]D22 = –89.4° (c = 2.67, CHCl3).
1H NMR spectrum, δ, ppm: 0.91 d and 0.96 d (C8H3,
C9H3, J8,7 = J9,7 = 6.8 Hz), 1.30 m (6-Hax), 1.62 d.q.q
(7-H, J7,6-ax = 10.0, J7,8 = J7,9 = 6.8 Hz), 1.76 d.d.d
EXPERIMENTAL
(C10H3, J10,5-ax = 2.2, J10,4 = J10,5-eq = 1.5 Hz), 1.78 m
2
1
The H and 13C NMR spectra were recorded on
(5-Hax), 2.08 d.d.d.q (5-Heq, J = 17.5, J5-eq,4 = J5-eq,6a
=
5.0, J5-eq,10 = 1.5 Hz), 3.71 d (2-Heq, J2-eq,1-eq 3.0 Hz),
3.90 br.d.d (1-Heq, J1-eq,2-eq = 3.0, J1-eq,6-ax = 1.5 Hz),
5.57 d.m (4-H, J4,5-eq = 5.0 Hz). 13C NMR spectrum,
δC, ppm: 70.76 d (C1), 72.61 d (C2), 131.58 s (C3),
125.77 d (C4), 25.32 t (C5), 38.88 d (C6), 28.59 d (C7),
20.72 q and 20.80 q (C8, C9), 21.05 q (C10). Found:
m/z 170.1302 [M]+. C10H18O2. Calculated: M 170.1301.
a Bruker DRX-500 spectrometer at 500.13 and
125.76 MHz, respectively, from solutions in CDCl3–
CCl4 (~1:1 by volume); the chemical shifts were deter-
mined relative to the residual proton and carbon
signals of the solvent (CHCl3, δ 7.24 ppm; CDCl3,
δC 76.90 ppm). Signals were assigned with the aid of
1H–1H double resonance techniques and two-dimen-
sional heteronuclear (13C–1H) correlation technique
Hydrogenation of (1R,2R,6S)-3-methyl-6-
(1-methylethenyl)cyclohex-3-ene-1,2-diol (I) with
hydrogen over Raney nickel. Raney nickel was pre-
pared according to the procedure described in [9] from
Al–Ni alloy containing 30–50% of Ni. A 400-ml high-
pressure reactor was charged with a solution of 0.670 g
(3.99 mmol) of compound I in 50 ml of ethanol, and
hydrogen was supplied to a pressure of 100 atm at
60°C over a period of 12 h. When the reaction was
complete, the catalyst was filtered off, the filtrate was
passed through a column charged with silica gel, and
the solvent was distilled off to isolate 0.436 g (63%) of
a mixture of compounds III and IV (1:0.4).
1
(C–H COSY, direct C–H coupling constants, JCH
=
135 Hz). The high-resolution mass spectra were ob-
tained on a DFS Thermo Scientific spectrometer (total
ion scanning in the a.m.u. range from 0 to 500; elec-
tron impact, 70 eV; direct sample admission into the
ion source). The specific rotations [α]D were deter-
mined on a polAAr 3005 polarimeter.
(1R,2R,6S)-3-Methyl-6-(1-methylethenyl)cyclohex-
3-ene-1,2-diol (I) was synthesized according to the
procedure described in [2]; [α]D31 = –49.1° (c = 2.6,
CHCl3).
Hydrogenation of (1R,2R,6S)-3-methyl-6-(1-
methylethenyl)cyclohex-3-ene-1,2-diol (I) with
nickel borohydride. Triethylamine, 1.0 ml
(7.22 mmol), was added to a solution of 2.18 g
(9.16 mmol) of NiCl2 ·6H2O in 10 ml of methanol,
a solution of 0.201 g (1.20 mmol) of compound I in
7 ml of methanol was added, 0.622 g (16.36 mmol) of
NaBH4 was then added in portions over a period of
2 min, and the mixture was heated for 5 h under reflux.
The mixture was diluted with 20 ml of water, methanol
(1R,2R,3S,6S)-3-Isopropyl-6-methylcyclohexane-
1
1,2-diol (IV). H NMR spectrum, δ, ppm: 0.86 d and
1.04 d (C8H3, C9H3, J8,7 = J9,7 = 6.8 Hz), 1.00 d (C10H3,
J10,3 = 6.5 Hz), 1.40 m (3-Hax), 1.47 m (4-Heq), [1.31]
and [1.69] (5-H), [1.56] (6-H), [1.75] (7-H), 3.27 d.d
(2-Hax, J2-ax,1-ax = 8.5, J2-ax,3-ax 8.5 Hz), 3.57 d.d (1-Hax,
J1-ax,2-ax = 8.5, J1-ax,6-eq 4.5 Hz). The values given in
brackets (positions of centers of multiplets) were taken
from two-dimensional 13C–1H correlation spectra
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

HYDROGENATION AND CONFORMATIONAL ANALYSIS OF (1R,2R,6S)-3-METHYL-...
1789
(direct 13C–1H coupling), for the corresponding signals
were not observed in the routine spectrum due to
3. Saxena, I., Borah, R., and Sarma, J.C., J. Chem. Soc.,
Perkin Trans. 1, 2000, p. 503.
4. Sarma, J.C. and Sharma, R.P., Chem. Ind. (London),
13
overlap by signals of the major component. C NMR
spectrum, δC, ppm: 77.71 d (C1), 76.14 d (C2), 37.71 d
(C3), 28.59 t (C4), 25.42 t (C5), 45.00 d (C6), 26.28 d
(C7), 23.40 q and 21.97 q (C8, C9), 18.29 q (C10).
Found: m/z 172.1456 [M]+. C10H20O2. Calculated:
M 172.1458.
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Conformational analysis of compounds I, III,
and IV. The initial set of conformers was generated by
the molecular mechanics method using ChemAxon
Marvin (conformers plugin) [10], VeraChem Vconf
[11] (Dreiding force field), and Scan program incor-
porated into Tinker software [12] (MM2 force field).
The structures were optimized first by the RM1
method [13] using MOPAC2009 [14] and then by DFT
(PBE functional [15], L1 basis set (Λ01 [16], an ana-
log of cc-pVDZ) using Priroda software [17]). Doubles
were removed after each optimization step with the aid
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and files containing Descartes coordinates of all
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