Chiral cyclohexene block from R-(-)-carvone

Article abstract of DOI:10.1134/S1070428012020054

The oxidation with SeO2 of a methyl group linked to an sp2-hybridized carbon in the product of the intramolecular iodoetherifi cation of cis-carveol afforded (1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]- oct-3-en-4-carbaldehyde and [(1R,5R,7S)-7-i

Full text of DOI:10.1134/S1070428012020054

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 2, pp. 180−183. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © F.A. Gimalova, G.M. Khalikova, S.A. Torosyan, D.Z. Akhmetshina, M.S. Miftakhov, 2012, published in Zhurnal Organicheskoi Khimii,
2012, Vol. 48, No. 2, pp. 194−196.
Chiral Cyclohexene Block from R-(–)-Carvone
F. A. Gimalovaa, G. M. Khalikovab, S. A. Torosyana, D. Z. Akhmetshinab,
and M. S. Miftakhova
aInstitute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, Ufa, 450054 Russia
e-mail: bioreg@anrb.ru
bBashkir State University, Ufa, Russia
Received May 20, 2011
Abstract—The oxidation with SeO2 of a methyl group linked to an sp2-hybridized carbon in the product of the
intramolecular iodoetherification of cis-carveol afforded (1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]-
oct-3-en-4-carbaldehyde and [(1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]oct-3-en-4-yl]methanol that
were oxidized to methyl (1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]oct-3-en-4-carboxylate. The latter
by the Zn-promoted opening of the γ-oxide ring was converted into the target chiral block, methyl (4R,6R)-6-
hydroxy-4-(prop-1-en-2-yl)cyclohex-1-encarboxylate.
DOI: 10.1134/S1070428012020054
Commercially available and cheap R-(–)-carvone
is extensively used in the targeted synthesis as a chiral
matrix [1]. In this study aiming at the preparation of the
functionalized α,β-unsaturated cyclohexenecarbonic
blocks oxidation was studied with the help of SeO2 of
cis-carveol I [2] and its bicyclic derivative II [3].
The reactions were carried out by boiling in toluene
equimolar amounts of the substrate and the reagent. In
HO
O
NaBH4_CeCl3
MeOH, 0oC
I2, NaHCO3
O
MeCN
I
II
I
OH
Carvone
O
OH
HO
Zn, EtOH, Δ
+
SeO2
O
O
PhMe, D
I
I
~2 : 1
VII
III
IV
KCN, MnO2,
AcOH, MeOH
(1) H2CrO4
(2) CH2N2
CO2Me
CO2Me
HO
Zn, EtOH, Δ
O
I
V
VI
180

CHIRAL CYCLOHEXENE BLOCK FROM R-(–)-CARVONE
181
the case of cis-carveol a complex mixture of compounds
was obtained, but the reaction of compound II with SeO2
proceeded cleanly and gave aldehyde III and primary
alcohol IV. Both these products were isolated in the
individual state by column chromatography on SiO2.
In the final stage aldehyde III was by Corey method
[4] converted into methyl ester V. The same compound
was obtained from alcohol IV by the oxidation with
Jones reagent followed by the methylation of the acid
obtained with diazomethane. The Zn-promoted opening
of the γ-oxide ring to generate the isopropenyl function
was first carried out on iodoalcohol IV and then on ester
V in order to prepare compound VI, the key substance in
the synthesis of analogs of the antiviral drug Tamiflu [5].
EtOAc–petroleum ether, 1 : 2). Yield 0.28 g (~45%) of
compound III and and 0.1 g (~15%) of compound IV.
(1R,5R,7S)-7-Iodomethyl-7-methyl-6-oxabi-
cyclo[3.2.1]oct-3-en-4-carbaldehyde (III). Colorless
20
crystals, mp 98–99°С, [α]D –89.3° (с 1.685, CHCl3).
IR spectrum, cm–1: 2953, 2924, 2870, 2851, 2357, 1670,
1657, 1629, 1448, 1420, 1373, 1184, 1157, 1132, 1037,
1028, 1001, 957, 935, 906, 830, 787, 719, 607, 595.
1Н NMR spectrum (CDCl3), δ, ppm: 1.42 s (3Н, СН3),
1.76 d (1Н, Н8, J 11.3 Hz), 2.38–2.48 m (2Н, СН, Н8),
2.60 d.t (1Н, Н2, J 3.4 and 21.5 Hz), 2.92 d.d (1Н, Н2,
J 3.6 and 21.5 Hz), 3.01 d (1Н, CH2I, J 9.9 Hz), 3.26 d
(1Н, СН2I, J 9.9 Hz), 4.97 d (1H, ОСН, J 4.9 Hz), 6.67 s
(1Н, =СН), 9.35 s (1Н, СНО). 13С NMR spectrum
(CDCl3), δ, ppm: 12.82 (CH2I), 27.37 (СH3), 31.14 (C8),
34.20 (С2), 41.00 (С1), 68.50 (С5), 84.94 (С7), 146.19
(С4), 149.28 (С3), 190.44 (CНO). Mass spectrum, m/z
(Irel, %): 292 [M]+ (6), 277 [M – СН3]+ (18), 185 (5), 169
(7), 151 (74), 107 (100), 79 (80), 77 (29), 43 (25). Found
[M]+ 291.992. С10Н13IО2. Calculated M 291.996.
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer IR
Prestige-21 Shimadzu from thin films. 1Н and 13С NMR
spectra were registered on a spectrometer Bruker AM-
300 at operating frequencies 300.13 and 75.47 MHz
respectively, internal reference TMS. The optical rotation
was measured on a Perkin Elmer-341instrument. Mass
spectra were taken on an instrument Thermo Finnigan
MAT 95XP, ionizing electrons energy 70 eV. The
temperature of the ionization chamber 200°С, sample
admission at 5–270°С, heating rate 22 deg/min. The
reaction progress was monitored by TLC on Sorbfil
plates (Russia), development by the ethanol solution of
anisaldehyde acidified with sulfuric acid with subsequent
heating at 120–150°С. The synthesized products were
isolated by column chromatography on silica gel (30–60 g
of sorbent per 1 g of substance), as eluents freshly distilled
solvents were used.
[(1R,5R,7S)-7-Iodomethyl-7-methyl-6-oxabi-
cyclo-[3.2.1]oct-3-en-4-yl]methanol (IV). Oily
substance, [α]D20 –40.6° (с 2.452, CHCl3). IR spectrum,
cm–1: 3408, 3396, 2970, 2947, 1448, 1419, 1373, 1290,
1224, 1201, 1153, 1136, 1086, 1037, 1025, 1003, 957,
943, 905, 823, 785, 597. 1Н NMR spectrum (CDCl3), δ,
ppm: 1.47 s (3Н, СН3), 1.96 d (1Н, Н8, J 10.61 Hz), 2.37
t (1Н, Н2, J 4.60 Hz), 2.41–2.44 m (2Н, СН, СН2), 2.59–
2.66 m (1Н, СН2), 3.26 d (1Н, СН2I, J 9.8 Hz), 3.38 d
(1Н, СН2I, J 9.6 Hz), 4.08 с (2H, ОСН2), 4.39 d (1Н,
ОСН, J 4.9 Hz), 5.57 br.s (1Н, =СН). 13С NMR spectrum
(CDCl3), δ, ppm: 13.88 (CH2I), 27.85 (СH3), 29.52 (C8),
35.03 (С2), 41.03 (С1), 64.80 (OСH2), 73.89 (С5), 84.41
(С7), 122.63 (С3), 143.27 (С4). Mass spectrum, m/z (Irel,
%): 294 [M]+ (25), 261 [M – СН3OH]+ (20), 185 (3),
169 (18), 153 [M – СН2I]+ (35), 149 (20), 135 (40), 110
(19), 93 (35), 91 (100), 79 (90), 77 (30), 57 (18), 43 (35).
Found [M]+ 294.008. С10Н15IО2. Calculated M 294.0116.
Reaction of compound II with SeO2. To the boiling
solution of 0.5 g (3.30 mmol) of compound II in 15 ml
of anhydrous toluene under argon was added by small
portions 0.75 g (6.60 mmol) of SeO2 within 60 min. The
reaction mixture was boiled for 1.5 h, cooled to room tem-
perature, and filtered. Then the red-brown solution was
cooled to 0°С, and m-chloroperbenzoic acid was added
till the solution became light-yellow (~0.6 g). The reaction
mixture was stirred for 5 min at 0°С, then it was poured
into K2CO3 and extracted first with toluene (2 × 20 ml),
and afterwards with CHCl3 (3 × 20 ml). The combined
organic extracts were washed with the saturated K2CO3
solution, dried with MgSO4, and evaporated. The residue
was subjected to column chromatography on SiO2 (eluent
Methyl [(1R,5R,7S)-7-iodomethyl-7-methyl-6-
oxabicyclo[3.2.1]oct-3-en-4-carboxylate (V). а. To a
solution of 0.1 g (0.34 mmol) of aldehyde III in 20 ml of
methanol at room temperature was added while stirring
in one portion 0.085 g (1.30 mmol) of KCN, 0.59 g
(6.8 mmol) of MnO2, 0.03 g (0.51 mmol) of AcOH. The
reaction mixture was filtered, methanol was distilled off,
the residue was dissolved in CHCl3, washed with brine,
dried with MgSO4, and evaporated. The residue was
subjected to column chromatography on SiO2 (eluent
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GIMALOVA et al.
182
EtOAc–petroleum ether, 1 : 5). Yield 0.04 g (47%) of
ester V. Besides 0.02 g of initial aldehyde was recovered.
by flash-chromatography on a column packed with SiO2
(eluent EtOAc–petroleum ether, 1:5). Yield 0.010 g
(67%). Colorless crystals, mp 152–153°С, [α]D20 –85.0°
(с 0.574, CHCl3). IR spectrum, cm–1: 3527, 3466, 2947,
2924, 2856, 1715, 1701, 1689, 1647, 1437, 1400, 1375,
1358, 1294, 1259, 1207, 1118, 1090, 1047, 929, 894,
810, 764, 696, 613. 1Н NMR spectrum (CDCl3), δ, ppm:
1.55 d.d (1Н, Н5, J 2.6, 12.5 Hz), 1.76 s (3Н, СН3),
2.17–2.30 m (4Н, СН, СН2), 3.78 s (3Н, СО2Mе), 3.88 d
(1Н, ОН, J 1.92 Hz), 4.66 m (1Н, ОСН), 4.78 m (2Н,
=СН2), 7.05 m (1Н, =СН). 13С NMR spectrum (CDCl3),
δ, ppm: 20.36 (СH3), 31.60 (C5), 35.49 (С3), 39.38 (С4),
51.78 (OСН3), 66.73 (С6), 109.96 (=СН2), 132.55 (С1'),
141.85 (С2), 147.68 (С1), 167.53 (CO2). Mass spectrum,
m/z (Irel, %): 195 [M – H]+ (2), 178 [M – H2O]+ (70), 165
(18), 164 (52), 163 (16), 153 (15), 152 (20), 137 (40),
128 (54), 119 (65), 100 (40), 96 (100), 91 (32), 84 (20),
79 (25), 68 (58), 67 (20), 59 (10), 53 (14). Found [M]+
196.10. С11Н16IО3. Calculated M 196.11.
b. To a solution of 0.08 g (0.27 mmol) of compound
IV in 10 ml of acetone at 0°С while stirring was added
dropwise 0.53 ml (1.37 mmol) of 2.67 M solution of Jones
reagent.After a complete consumption of the initial com-
pound (TLC monitoring) to the reaction mixture i-PrOH
was added dropwise till the reaction mixture got green.
Acetone was distilled off, the residue was dissolved in
EtOAc, the precipitate was filtered off. The filtrate was
washed with brine, dried with MgSO4, and evaporated
to obtain 0.060 g (75%) of (1R,5R,7S)-7-iodomethyl-7-
methyl-6-oxabicyclo[3.2.1]oct-3-en-4-carboxylic acid.
1Н NMR spectrum (CDCl3), δ, ppm: 1.48 s (3Н, СН3),
1.87 d (1Н, Н8, J 10.7 Hz), 2.47 m (2Н, СН, Н8), 2.55 d
(1Н, Н2, J 21.1 Hz), 2.88 d.d (1Н, Н2, J 3.5, 21.1 Hz), 3.09
d (1Н, СН2I, J 10.2 Hz), 3.34 d (1Н, СН2I, J 9.9 Hz), 5.01
d (1Н, ОСН, J 2.8 Hz), 6.72 s (1Н, =СН), 10.53 br.s (1Н,
СО2Н). The reaction product without further purification
was brought into the next methylation stage.
(1R,5R)-2-Hydroxymethyl-5-isopropenyl-
cyclohex-2-en-1-ol (VII) was obtained similarly to
compound VI from 0.32 g (1.09 mmol) of compound
IV at the addition of 0.715 g (10.94 mmol) of activated
zinc. After the treatment the residue was purified by
flash-chromatography on a column packed with SiO2
(eluent EtOAc–petroleum ether, 1 : 5). Yield 0.18 g
(86%), [α]D20 –5.1° (с 0.751, CHCl3). IR spectrum, cm–1:
3392, 3373, 3356, 3080, 2966, 2937, 2920, 2879, 2862,
1645, 1448, 1437, 1375, 1273, 1201, 1153, 1095, 1076,
1060, 1020, 999, 945, 920, 891, 817. 1Н NMR spectrum,
δ, ppm: 1.53–1.65 m (1Н, Н6), 1.75 s (3Н, СН3), 2.04–
2.34 m (5Н, СН, СН2, ОН), 2.51 m (1Н, ОН), 4.24 s (2Н,
ОСН2), 4.53 m (1Н, ОСН), 4.76 s (2Н, =СН2), 5.77 m
(1Н, =СН). 13С NMR spectrum, δ, ppm: 20.36 (СH3),
30.72 (C6), 37.22 (С4), 40.07 (С5), 65.48 (СН2O), 70.45
(С1), 109.61 (=СН2), 129.20 (С3), 136.89 (С1'), 148.12
(С2). Found, %: С 71.88; Н 9.86. C10H16O2. Calculated,
%: С 71.39; Н 9.59.
To a solution of 0.06 g (0.19 mmol) of acid in 5 ml of
ethyl ether was added at room temperature while stirring
an ethereal solution of diazomethane till the appearance
of the stable light-yellow color of the solution. Excess
CH2N2 was removed by adding several drops of АсОН.
The reaction mixture was washed with brine, dried with
MgSO4, and evaporated to obtain 0.06 g (93%) of ester V.
Compound V. Oily substance, [α]D20 –63.4° (с 1.395,
CHCl3). IR spectrum, cm–1: 2970, 2924, 1772, 1705,
1697, 1454, 1443, 1375, 1250, 1247, 1080, 1026, 1001,
962, 930, 910, 800, 759, 600. 1Н NMR spectrum (CDCl3),
δ, ppm: 1.52 s (3Н, СН3), 1.92 d (1Н, Н8, J 10.7 Hz),
2.49 d (1Н, Н8, J 10.7 Hz), 2.48 m (1Н, СН), 2.58 d (1Н,
Н2, J 20.8 Hz), 2.88 d.d (1Н, Н2, J 20.8, 4.4 Hz), 3.16 d
(1Н, СН2I, J 9.9 Hz), 3.38 d (1Н, СН2I, J 9.9 Hz), 3.80 s
(3Н, СО2Mе), 5.08 d (1Н, ОСН, J 4.2 Hz), 6.88 m (1Н,
=СН). 13С NMR spectrum (CDCl3), δ, ppm: 13.04 (CH2I),
27.37 (СH3), 30.45 (C8), 34.54 (С2), 40.43 (С1), 51.83
(CO2Me), 71.78 (С5), 84.97 (С7), 136.21 (С4), 143.02
(С3), 165.69 (CO2). Found, %: С 40.88; Н 4.87; I 40.06.
C11H15IO3. Calculated, %: С 41.01; Н 4.69; I 39.39.
ACKNOWLEDGMENTS
Methyl (4R,6R)-6-hydroxy-4-(prop-1-en-2-yl)-
cyclohex-1-enecarboxylate (VI). To 0.027 g (0.09 mmol)
of compound V in anhydrous ethanol was added 0.055 g
(0.87 mmol) of activated zinc. The reaction mixture was
boiled at stirring for 5 h, then it was cooled to room tem-
perature, filtered, the precipitate was washed with ethanol.
The filtrate was evaporated and the residue was purified
The study was performed under the financial support
of the program of the Russian Foundation for Basic
Research-Povolzhie (grant 11-03-97013 р_а) and of
the Federal target program “Scientific and scientific-
pedagogical staff of the innovation Russia” for 2009–
2013 (State contract no. 14.740.11.0367).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 2 2012

CHIRAL CYCLOHEXENE BLOCK FROM R-(–)-CARVONE
183
E.Yu., and Miftakhov, M.S., Mendeleev Commun., 2010,
vol. 20, p. 77.
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