Eleuthesides and their analogs: I. Synthesis of the base compound from levoglucosenone adduct with piperylene

Article abstract of DOI:10.1134/S1070428010080063

The Diels-Alder adduct of levoglucosenone and piperylene was converted into the corresponding oxime, and second-order Beckmann rearrangement of the latter, followed by treatment with a base, gave (1S,2R,6R)-6-(2-hydroxyethyl)-2- methylcyclohex-3-ene-1-car

Full text of DOI:10.1134/S1070428010080063

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 8, pp. 1151–1156. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © Yu.A. Kondrova, O.Yu. Krasnoslobodtseva, L.V. Spirikhin, F.A. Valeev, 2010, published in Zhurnal Organicheskoi Khimii, 2010,
Vol. 46, No. 8, pp. 1152–1157.
Eleuthesides and Their Analogs: I. Synthesis of the Base
Compound from Levoglucosenone Adduct with Piperylene
Yu. A. Kondrova, O. Yu. Krasnoslobodtseva, L. V. Spirikhin, and F. A. Valeev
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: sinvmet@anrb.ru
Received July 14, 2009
Abstract—The Diels–Alder adduct of levoglucosenone and piperylene was converted into the corresponding
oxime, and second-order Beckmann rearrangement of the latter, followed by treatment with a base, gave
(1S,2R,6R)-6-(2-hydroxyethyl)-2-methylcyclohex-3-ene-1-carbaldehyde which was used in the synthesis of
eleutheside analog. Conditions were found for opening of oxirane ring with formation of primary alcohol and
simultaneous reduction of cyano group to aldehyde by the action of Red-Al–H2O.
DOI: 10.1134/S1070428010080063
Eleutherobin isolated in 1994 from soft corals
turned out to be the second compound (after taxol)
capable of stabilizing microtrubules [1, 2]. Eleuthero-
bin together with sarcodictyins and valdivones gave
rise to a new class of structurally related compounds,
eleuthesides [3]. The structure of eleuthesides is char-
acterized by the presence of 4,7-oxaeunicellane-like
tricyclic skeleton consisting of a menthene ring fused
to ten-membered ring with an epoxy bridge. A com-
bination of unusual structure and unique biological
properties of eleuthesides stimulated studies on their
chemical synthesis [4–6].
eleutheside core. Following this approach, strategically
independent methods were developed for the synthesis
of eleutherobin and sarcodictyins from (+)-carvone
and (–)-α-phellandrene [4, 5]. We previously described
a formal synthesis from structurally more complex
sesquiterpene alcohol, (+)-δ-cadinol [7].
The set of available initial compounds for the syn-
thesis of eleuthesides can be extended, and the synthe-
sis may be simplified provided that pharmacophoric
fragment of eleuthesides is known. With a view to
elucidate the effect of substituents in the A ring on
cytotoxicity, we made efforts to develop procedures for
the preparation of eleutheside analogs modified at the
menthene fragment. For this purpose, appropriate start-
ing compounds may be Diels–Alder adducts of levo-
glucosenone with butadiene [8], piperylene [9], iso-
prene [10], and cyclopentadiene [11], as well as some
new adducts synthesized by us previously [12].
In order to develop a general scheme for the syn-
thesis of eleuthesides on the basis of Diels–Alder ad-
ducts, as model compound we selected adduct I ob-
tained from levoglucosenone and piperylene. Cleavage
of the carbohydrate fragment in I to build up side
chains was performed by the second-order Beckmann
rearrangement [13]. Oxime II was prepared by treat-
ment of adduct I with hydroxylamine hydrochloride in
pyridine. The structure of oxime II follows from the
fact that the α-carbon atom in the syn position with
respect to the oxime group is shielded to a stronger
An evident synthetic approach to eleuthesides is
based on the use of initial compounds possessing
a menthene ring and having other functional groups
necessary for subsequent transformations leading to
O
O
Me
A
H
Me
C
N
B
O
N
OR'
H
Me
R
Me
Me
O
OAc
Eleutherobin: R =
, R′ = Me;
OH
O
OH
Sarcodictyins: A, R = COOMe, R′ = H; B, R = COOEt, R′ = H.
1151

KONDROVA et al.
1152
Scheme 1.
Cl
O
Cl
O
H
H
H
H
KOH
NH2OH·HCl
SOCl2
O
EtOH–H2O
O
O
H
OH
O
CN
CN
CN
Me
O
Me
NOH
Me
Me
OH
I
II
III
IV
OEt
OH
Me
OH
KOH
EtOH–H2O
(i-Bu)2AlH (a)
or LiAlH4 (b)
H
Me
OH
CN
CN
CN
Me
Me
Me
Me
V
VII
VIII
Red-Al, alcohol
or H2O
O
OH
MeONa
LiAlH4m AlCl3
CN
CHO
Me
VI
IX
Br
MgBr2
OH
CN
Me
X
extent by the hydroxy group, and its signal appears in
a stronger field in the 13C NMR spectrum [14]. The C9
signal in the 13C NMR spectrum of oxime II is dis-
placed upfield by 9.63 ppm as compared to the corre-
sponding signal of initial ketone I, while the C7 signal
is displaced by only 2.03 ppm [9], indicating cis orien-
tation of the hydroxy group and C9. By treatment of
oxime II with thionyl chloride we obtained formate III
which was subjected to alkaline hydrolysis with potas-
sium hydroxide in aqueous ethanol. The reaction of
chlorohydrin IV thus formed with sodium methoxide
gave epoxy nitrile VI (Scheme 1). A small amount of
compound VI can also be formed in the course of
hydrolysis of III; prolonged stirring of the reaction
mixture (which is necessary to ensure complete con-
version of chloro nitrile) was accompanied by nucleo-
philic replacement of the chlorine atom in IV with
formation of ethoxy derivative V.
LiAlH4 and (i-Bu)2AlH always led to the formation of
hydroxy nitrile VII, and in the second case compound
VIII was also obtained as a result of opening of the
oxirane ring in VI by intermediate organoaluminum
compound [15]. In the reaction of compound VI with
MgBr2 we isolated bromohydrin X having a secondary
hydroxy group.
Radically different results were obtained in the
reaction of compound VI with freshly prepared Red-Al
[sodium bis(2-methoxyethoxy)hydridoaluminate] [16]
and that stored for a long time (its surface was coated
with a thin crust). In the first case, the only product
was secondary alcohol VII, whereas in the second case
opening of the oxirane ring with formation of primary
alcohol was accompanied by reduction of the cyano
group to aldehyde. Here, the major product was hy-
droxy aldehyde IX, while the yield of hydroxy nitrile
VII was as low as 9%.
We tried to effect selective cleavage of the oxirane
ring in VI to obtain primary alcohol via reduction with
some hydride reagents. The reactions of VI with
We examined the effect of addition of some alco-
hols, water, and Lewis acids to Red-Al on the results
of its reaction with epoxy nitrile VI (see table). In the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 8 2010

ELEUTHESIDES AND THEIR ANALOGS: I.
1153
Reactions of (1R,2R,6S)-[(2S)-oxiran-2-yl]-2-methylcyclohex-3-ene-1-carbonitrile (VI) with magnesium bromide and
hydride reagents
Amount of the reagent
(equiv)
Solvent,
Reaction time,
min
Reagent
Product
VII
VII; VIII
IV
Yield, %
temperature
(i-Bu)2AlH
(i-Bu)2AlH
LiAlH4, AlCl3
.02.5
3
1.1; 0.3
.01.2
Et2O, –40°C
Et2O, –78°C
Et2O
30
30
2 days
40
92
86, 7
13
LiAlH4
Et2O
VII
38
MgBr2 [17]
3
3
3
3
3
3
3
3
Et2O
60
40
40
40
40
40
40
40
IX
VII
VII, X
79
76
Red-Al
THF, 0°C
THF, 0°C
THF, 0°C
THF, 0°C
THF, 0°C
THF, 0°C
THF, 0°C
Red-Ala
9, 65
Inseparable mixture
Red-Al–AlCl3 (8:1)
Red-Al–ethylene glycol (8:1)
Red-Al–ethanol (9:1)
Red-Al–propan-2-ol (8:1)
Red-Al–water (15:1)
X
X
X
X
74
68
43
80
a
After prolonged storage.
reactions of VI with Red-Al in the presence of water or
alcohols regioselective formation of hydroxy aldehyde
IX was observed in all cases. The best results were
obtained at a Red-Al–water ratio of 15:1. Presumably,
radical change of the reaction direction in the presence
of such a small amount of water is related to formation
of a supramolecular structure in which Red-Al coor-
dinates both oxygen and nitrogen atoms in such a way
that the active hydrogen atom appears inside the com-
plex, so that attack by hydride ion on the nearest
secondary carbon atom in the oxirane ring and on the
cyano group becomes possible.
Commercial Red-Al (a 70% solution in toluene; from
Lancaster) and (i-Bu)2AlH (a 73% solution in toluene)
were used.
(1S,2S,6R,7R,9R)-6-Methyl-10,12-dioxatricyclo-
[7.2.1.02,7]dodec-4-en-8-one syn-oxime (II). Hy-
droxylamine hydrochloride, 3.70 g (53.2 mmol), was
added under stirring to a solution of 2.00 g
(10.0 mmol) of Diels–Alder adduct I in 34.5 ml of pyr-
idine. The mixture was stirred for 30 min, ethyl acetate
was added, and the mixture was washed with water
and dried over MgSO4. Yield 1.560 g (73%). Colorless
crystals, mp 103°C, [α]D20 = +65.9° (c = 1.0, CHCl3),
Rf 0.48 (petroleum ether–ethyl acetate, 3:1). IR spec-
trum, ν, cm–1: 3380, 2940, 2870, 1730, 1440, 1120,
930, 680. 1H NMR spectrum, δ, ppm: 1.24 d (3H, CH3,
J = 7.5 Hz), 2.06 m (1H, 3-H), 2.24 m (1H, 2-H),
2.40–2.58 m (2H, 3-H, 6-H), 3.07 t (1H, 7-H, J =
4.7 Hz), 3.91 d.d (1H, exo-11-H, J = 7.3, 4.7 Hz),
4.10 d (1H, endo-11-H, J = 7.3 Hz), 4.38 d.d (1H, 1-H,
J = 4.7, 2.1 Hz), 5.50 d (1H, 5-H, J = 10.0 Hz),
5.62 d.d (1H, 4-H, J = 10.0, 3.4 Hz), 6.52 s (1H, 9-H),
8.22 s (1H, NOH). 13C NMR spectrum, δC, ppm: 17.82
(CH3), 23.83 (C3), 31.77 (C6), 37.17 (C2), 42.14 (C7),
67.81 (C11), 77.12 (C1), 93.03 (C9), 124.40 (C4),
129.68 (C5), 155.08 (C8). Mass spectrum: m/z 164
(Irel 100%) [M]+. Found, %: C 63.32; H 7.15; N 6.49.
C11H15NO3. Calculated, %: C 63.14; H 7.23; N 6.69.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Bruker AM-300 spectrometer at 300 and 75.47 MHz,
respectively, using CDCl3 as solvent, unless otherwise
stated. The melting points were measured on
an S 30A/G Kofler melting point apparatus (DDR).
Analytical thin-layer chromatography was performed
on Sorbfil plates (PTSKh-AF-A, Sorbpolimer close
corporation, Krasnodar). The elemental compositions
were determined on an Evro-2000 CHNS(O) analyzer.
The IR spectra were recorded on UR-20 and Specord
M-80 instruments from neat substances (films) or
samples dispersed in mineral oil. The mass spectra
were obtained on a Hewlett–Packard GC–MS system
consisting of an HP 6890 gas chromatograph and an
HP 5973 mass-selective detector. The optical rotations
were measured on a Perkin–Elmer-341 polarimeter.
(1S)-2-Chloro-1-[(1S,5R,6R)-6-cyano-5-methyl-
cyclohex-3-en-1-yl]ethyl formate (III). A solution of
1.18 ml of thionyl chloride in 5.0 ml of methylene
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 8 2010

KONDROVA et al.
1154
chloride was added dropwise to a solution of 1.25 g
(6 mmol) of oxime II in 25 ml of methylene chloride,
cooled to 0°C. The mixture was stirred for 1 h at 0°C
(TLC), 10.0 ml of a saturated aqueous solution of
sodium chloride was added, the organic phase was
separated, and the aqueous phase was extracted with
methylene chloride (3×10 ml). The extracts were com-
bined with the organic phase, dried over MgSO4, and
evaporated to isolate 1.07 g (80%) of compound III as
colorless crystals with mp 91°C, [α]D20 = 65.0° (c = 1.0,
CHCl3), Rf 0.36 (petroleum ether–ethyl acetate, 3:1).
IR spectrum, ν, cm–1: 2950, 1730, 1190, 770, 690.
1H NMR spectrum, δ, ppm: 1.22 d (3H, CH3, J =
7.3 Hz), 2.10 m (2H, 2-H, 5-H), 2.46 m (1H, 2-H),
2.55 m (1H, 5-H), 3.08 d.d (1H, 6-H, J = 4.1, 3.2 Hz),
3.68 d.d (1H, ClCH2, J = 12.8, 3.2 Hz), 3.94 d.d (1H,
ClCH2, J = 12.8, 3.2 Hz), 5.14 d.t (1H, CHO, J = 9.6,
3.2 Hz), 5.48 d (1H, 4-H, J = 10.1 Hz), 5.73 m (1H,
3-H), 8.17 s (1H, OCHO). 13C NMR spectrum, δC,
ppm: 18.79 (CH3), 24.05 (C2), 32.35 (C5), 33.71 (C1),
36.70 (C6), 43.46 (ClCH2), 73.06 (CHO), 117.72 (CN),
124.64 (C3), 129.90 (C4), 159.77 (OCHO). Found, %:
C 59.12; H 6.04; Cl 15.66; N 6.23. C11H14ClNO2. Cal-
culated, %: C 58.03; H 6.20; Cl 15.57; N 6.15.
0.5 ml of water and 1.0 ml of ethanol was added to
0.150 g (1.4 mmol) of compound III. After 3 days
(TLC), the mixture was neutralized to pH 7 by adding
10% hydrochloric acid and extracted with ethyl acetate
(3×2 ml). The extracts were combined, washed with
a saturated solution of sodium chloride, and dried over
MgSO4, the solvent was distilled off, and the residue
was subjected to chromatography. Yield 0.045 g
(33%), oily substance, [α]D20 = –48.12° (c = 1.0,
CHCl3), Rf 0.23 (petroleum ether–ethyl acetate, 3:1).
1H NMR spectrum, δ, ppm: 1.23 d (3H, CH3, J =
7.2 Hz), 1.19 t (3H, CH3, J = 6.9 Hz), 1.93–2.02 m
(3H, 5-H, 6-H), 2.49 m (1H, 3-H), 2.68 br.s (1H, OH),
3.36 d.d (1H, CH2OEt), J = 9.5, 6.7 Hz), 3.43 m (1H,
4-H), 3.48–3.60 m (2H, CH2OEt, CHOH), 3.71 m
(1H, OCH2Me), 5.43 d (1H, 2-H, J = 10.2 Hz),
5.69 d.d.d (1H, 1-H, J = 10.2, 6.8, 3.1 Hz). 13C NMR
spectrum, δC, ppm: 15.03 (CH3), 18.92 (CH3), 24.44
(C6), 24.46 (C3), 32.17 (C4), 34.08 (C5), 66.85 (OCH2),
71.43 (CHOH), 71.92 (CH2OEt), 118.74 (CN), 125.32
(C1), 130.07 (C2). Found, %: C 69.01; H 9.14; N 6.55.
C12H19NO2. Calculated, %: C 68.87; H 9.15; N 6.69.
(1R,2R,6S)-[(2S)-Oxiran-2-yl]-2-methylcyclohex-
3-ene-1-carbonitrile (VI). A solution of 0.807 g
(3.8 mmol) of chlorohydrin IV in 6.0 ml of chloroform
was cooled to 0°C, a solution of sodium methoxide
prepared from 0.167 g (4.0 mmol) of metallic sodium
and 3.8 ml of methanol was added, and the mixture
was stirred for 30 min (TLC), treated with water, and
extracted with ethyl acetate (3×5 ml). The combined
extracts were dried over MgSO4, the solvent was
distilled off, and the residue was subjected to chroma-
tography on silica gel. Yield 0.573 g (87%), colorless
crystals, mp 28°C, [α]D20 = –119.0° (c = 1.0, CHCl3),
(1R,2R,6S)-6-[(1S)-2-Chloro-1-hydroxyethyl]-2-
methylcyclohex-3-ene-1-carbonitrile (IV). A solution
of 0.30 g of potassium hydroxide in a mixture of 1 ml
of water and 2 ml of ethanol was added to 0.320 g
(1.4 mmol) of formate III. The mixture was stirred for
1 h (TLC), neutralized to pH 7 by adding 10% hydro-
chloric acid, and extracted with ethyl acetate (3×3 ml).
The extracts were combined, washed with a saturated
solution of sodium chloride, and dried over MgSO4,
the solvent was distilled off, and the residue was sub-
jected to chromatography. Yield 0.227 g (81%), oily
substance, [α]D20 = –56.65° (c = 1.0, CHCl3), Rf 0.23
1
Rf 0.28 (petroleum ether–ethyl acetate, 3:1). H NMR
spectrum, δ, ppm: 1.20 d (3H, CH3, J = 7.3 Hz),
1.58 d.d.d.d (1H, 6-H, J = 10.9, 4.3, 6.5, 2.7 Hz),
2.03 m (1H, 5-H), 2.22 m (1H, 5-H), 2.49 m (1H, 2-H),
2.61 d.d (1H, CH2O, J = 4.9, 2.7 Hz), 2.88 d.d (1H,
CH2O, J = 4.9, 4.0 Hz), 3.01 d.d.d (1H, CHO, J = 6.5,
4.0, 2.7 Hz), 3.18 d.d (1H, 1-H, J = 4.3, 4.0 Hz), 5.45 d
(1H, 3-H, J = 10.1 Hz), 5.72 d.d.d (1H, 4-H, J = 10.1,
4.8, 2.5 Hz). 13C NMR spectrum, δC, ppm: 18.66
(CH3), 23.94 (C5), 32.07 (C2), 35.44 (C6), 39.94 (C1),
46.85 (CH2O), 53.20 (CHO), 118.17 (CN), 125.02
(C4), 129.83 (C3). Found, %: C 73.29; H 8.22; N 8.38.
C10H13NO. Calculated, %: C 73.59; H 8.03; N 8.58.
1
(petroleum ether–ethyl acetate, 3:1). H NMR spec-
trum, δ, ppm: 1.21 d (3H, CH3, J = 7.3 Hz), 2.03 m
(3H, 5-H, 6-H), 2.50 m (1H, 2-H), 3.20–3.43 br.s (1H,
OH), 3.43 d (1H, 1-H, J = 5.0 Hz), 3.58 d.d (1H,
ClCH2, J = 11.9, 6.1 Hz), 3.80 m (2H, ClCH2, CHOH),
5.48 d (1H, 3-H, J = 9.9 Hz), 5.72 d.d.d (1H, 4-H, J =
9.9, 7.1, 2.7 Hz). 13C NMR spectrum, δC, ppm: 18.91
(CH3), 24.44 (C5), 29.64 (C2), 34.05 (C6), 39.62 (C1),
48.54 (ClCH2), 72.09 (CHOH), 118.62 (CN), 124.92
(C4), 130.14 (C3). Found, %: C 60.31; H 6.98;
Cl 17.92; N 7.15. C10H14ClNO. Calculated, %:
C 60.15; H 7.07; Cl 17.76; N 7.01.
Reactions of epoxy nitrile VI with hydrides (gen-
eral procedure). a. The corresponding reducing agent
was added under argon to a solution of 0.163 g
(1 mmol) of epoxy nitrile VI in 10 ml of appropriate
(1R,2R,6S)-6-[(1S)-2-Ethoxy-1-hydroxyethyl]-2-
methylcyclohex-3-ene-1-carbonitrile (V). A solution
of 0.140 g of potassium hydroxide in a mixture of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 8 2010

ELEUTHESIDES AND THEIR ANALOGS: I.
1155
1
solvent at a required temperature (see table). In the
reactions with Red-Al the reducing agent was prelim-
inarily mixed with the corresponding amount of alco-
hol or water. When the reaction was complete (TLC),
the reaction mixture was allowed to warm up to room
temperature [in the reaction with (i-Bu)2AlH the
mixture was preliminarily treated with 3 ml of ethyl
acetate at –40°C to remove the residual reducing
agent], hydrolyzed with water, treated with 6% hydro-
chloric acid until precipitate dissolved completely, and
extracted with ethyl acetate (3×10 ml). The extracts
were combined and dried over MgSO4, the solvent was
distilled off on a rotary evaporator, and the residue was
subjected to chromatography on silica gel.
b. A solution of epoxy nitrile VI in 3 ml of anhy-
drous diethyl ether was added over a period of 15 min
with stirring at room temperature under argon to a so-
lution of LiAlH4 in 5.0 ml of anhydrous diethyl ether
containing or not some amount of AlCl3. When the
reaction was complete (TLC), the mixture was treated
with water and then with 3% hydrochloric acid until
the precipitate dissolved completely. The organic phase
was separated, the aqueous phase was extracted with
ethyl acetate (3×10 ml), the extracts were combined
with the organic phase and dried over MgSO4, the
solvent was distilled off on a rotary evaporator, and the
residue was subjected to chromatography on silica gel.
3400, 2940, 2880, 1080, 970, 920. H NMR spectrum,
δ, ppm: 1.25 d (6H, CH3, J = 7.3 Hz), 1.96–2.12 m
(6H, 5-H, 6-H), 2.52 m (2H, 2-H), 3.47 d (2H, 1-H, J =
4.8 Hz), 3.60 d.d (2H, CHOH, J = 11.2, 5.6 Hz), 3.82 d
(2H, CH2CH2, J = 11.3 Hz), 3.84 m (2H, CH2CH2),
5.50 d (2H, 3-H, J = 10.0 Hz), 5.72 d.d (2H, 4-H, J =
10.0, 2.6 Hz). 13C NMR spectrum, δC, ppm: 18.90
(CH3), 24.44 (C5), 32.20 (C1), 34.06 (C6), 39.68 (C2),
48.56 (CH2CH2), 72.11 (CHOH), 118.57 (CN), 124.90
(C4), 132.29 (C3). Mass spectrum, m/z (Irel, %): 164 (7)
[M/2]+, 152 (82) [HOCHC6H7CH3CN]+, 120 (25)
[C6H7CH3CN]+), 119 (35) [C6H6CH3CN]+, 107 (30)
[C6H19O]+, 93 (85) [120 – HCN]+, 72 (100) [C5H6O]+,
59 (60) [C3H7O]+. Found, %: C 73.27; H 8.66; N 8.29.
C20H28N2O2. Calculated, %: C 73.14; H 8.59; N 8.53.
(1S,2R,6R)-6-(2-Hydroxyethyl)-2-methylcyclo-
hex-3-ene-1-carbaldehyde (IX) was synthesized ac-
cording to method a. Colorless crystals, mp 85.7°C,
[α]D20 = –105.2° (c = 1.0, CHCl3), Rf 0.3 (petroleum
ether–ethyl acetate, 3:1). IR spectrum, ν, cm–1: 3400,
1
2970, 1640, 1700, 1370, 1070, 920. H NMR spec-
trum, δ, ppm: 1.07 d (3H, CH3, J = 7.3 Hz), 1.40–
1.65 m (2H, 6-CH2), 1.7–1.9 m (2H, 2-H, 6-H), 2.36 m
2
3
(1H, 5-H), 2.50 d.d.d.d (1H, 5-H, J = 18.5, J = 6.8,
4
3.0, J = 1.5 Hz), 3.21 m (1H, 1-H), 3.85 d.d (1H,
CH2OH, J = 11.3, 7.9 Hz), 3.92 d.d (1H, CH2OH, J =
11.3, 6.0 Hz), 5.51 m (2H, 3-H, 4-H), 8.80 s (1H,
CHO). 13C NMR spectrum, δC, ppm: 19.25 (CH3),
19.81 (C1), 20.46 (C5), 25.11 (C6), 29.66 (C2), 38.53
(6-CH2), 57.81 (HOCH2), 122.94 (C4), 129.95 (C3),
201.74 (CHO). Found, %: C 71.22; H 9.58. C10H16O2.
Calculated, %: C 71.39; H 9.59.
(1R,2R,6S)-6-[(1R)-1-Hydroxyethyl]-2-methyl-
cyclohex-3-ene-1-carbonitrile (VII) was synthesized
according to methods a and b. Oily substance, [α]D20
=
–81.59° (c = 1.0, CHCl3), Rf 0.5 (petroleum ether–
ethyl acetate, 3:1). IR spectrum, ν, cm–1: 3400, 3025,
2980, 2890, 2240, 1470, 1390, 1310, 1250, 1100,
(1R,2R,6S)-6-[(1S)-2-Bromo-1-hydroxyethyl]-2-
methylcyclohex-3-ene-1-carbonitrile (X). Bromine,
1.3 ml (50 mmol), was added at 0°C under argon to
1.250 g (50 mmol) of magnesium turnings in 50 ml of
diethyl ether. When the formation of MgBr2 was com-
plete, the mixture was allowed to warm up to room
temperature, and a solution of 0.80 g (6.0 mmol) of
epoxy nitrile VI in 7.0 ml of diethyl ether was added.
The mixture was stirred until the reaction was com-
plete (TLC), treated with water, and extracted with
ethyl acetate (3×20 ml). The extract was dried over
MgSO4, the solvent was distilled off, and the residue
was subjected to chromatography. Yield 0.940 g
(79%), colorless crystals, mp 85°C, [α]D20 = –73.4° (c =
1.19, CHCl3), Rf 0.08 (benzene). IR spectrum, ν, cm–1:
1
1010, 950, 890, 760. H NMR spectrum, δ, ppm:
1.22 d (3H, CH3, J = 7.2 Hz), 1.28 d (3H, CHCH3, J =
6.2 Hz), 1.73 d.d.d.d (1H, 6-H, J = 9.5, 9.5, 5.5,
2.7 Hz), 1.94 m (1H, 5-H), 2.06 m (1H, 5-H), 2.48 m
(1H, 2-H), 3.46 d.d (1H, 1-H, J = 4.1, 3.8 Hz), 3.75 d.q
(1H, CHOH, J = 9.5, 6.2 Hz), 5.45 d (1H, 3-H, J =
10.1 Hz), 5.73 m (1H, 4-H). 13C NMR spectrum, δC,
ppm: 18.89 (CH3), 21.52 (CH3), 25.05 (C5), 32.25 (C1),
34.14 (C6), 43.61 (C2), 68.91 (CHOH), 119.0 (CN),
125.73 (C4), 129.80 (C3). Found, %: C 73.45; H 9.62;
N 7.76. C11H17NO. Calculated, %: C 73.70; H 9.56;
N 7.81.
6,6′-(1,4-Dihydroxybutan-1,4-diyl)bis-
[(1R,2R,6S)-2-methylcyclohex-3-ene-1-carbonitrile]
(VIII) was synthesized according to method a. Oily
substance, [α]D20 = –79.5° (c = 1.0, CHCl3), Rf 0.3 (pe-
troleum ether–ethyl acetate, 1:1). IR spectrum, cm–1:
1
3498, 2954, 2922, 2852, 1458. H NMR spectrum, δ,
ppm: 1.14 d (3H, CH3, J = 7.3 Hz), 1.95 m (2H, 5-H),
2.39 d (1H, 2-H, J = 7.3 Hz), 2.46 m (1H, 6-H), 3.38 d
(1H, 1-H, J = 4.0 Hz), 3.40 d.d (1H, CH2Br, J = 10.7,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 8 2010

KONDROVA et al.
1156
and Gennari, C., Tetrahedron Lett., 2003, vol. 44,
p. 7913; Ritter, N. and Metz, P., Synlett., 2003, no. 15,
p. 2422; Tolstikov, G.A., Kunakova, A.M., Tsypyshe-
va, I.P., and Valeev, F.A., Izv. Ross. Akad. Nauk, Ser.
Khim., 2001, p. 1618; Valeev, F.A., Tsypysheva, I.P.,
Kunakova, A.M., and Tolstikov, G.A., Dokl. Akad.
Nauk, 2002, vol. 382, p. 781.
5.8 Hz), 3.62 d.d (1H, CH2Br, J = 2.6 Hz), 5.40 d (1H,
3-H, J = 9.6 Hz), 5.72 m (1H, 4-H). 13C NMR spec-
trum, δC, ppm: 18.89 (CH3), 24.49 (C5), 32.30 (C2),
34.08 (C6), 40.61 (C1), 38.70 (CH2Br), 71.59 (CHOH),
118.64 (CN), 124.91 (C4), 130.12 (C3). Found, %:
C 49.31; H 5.82; Br 32.69; N 5.76. C10H14BrNO. Cal-
culated, %: C 49.20; H 5.78; Br 32.73; N 5.74.
This study was performed under financial support
by the Russian Foundation for Basic Research
(project nos. 08-03-97033-r_povolzh’e_a and NSh-
1725.2008.3).
7. Krasnoslobodtseva, O.Yu., Spirikhin, L.V., Tolsti-
kov, G.A., and Valeev, F.A., Bashkir. Khim. Zh., 2007,
vol. 14, p. 76.
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Akad. Nauk SSSR, Ser. Khim., 1996, p. 2584.
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