(-)-(R)- and (+)-(S)-carvone in the synthesis of optically active acetylenic alcohols, ethers, and dichlorosilyl derivatives

Article abstract of DOI:10.1023/A:1022587918015

Reaction of butyllithium with acetylene and 1-hexyne gave the corresponding lithium acetylides which reacted with (-)-(R)- and (+)-(S) -carvone in a stereospecific fashion to give lithium (1-ethynyl- or 1-hexynyl)-5-isopropenyl-2-methyl-2-cyclohexenolates

Full text of DOI:10.1023/A:1022587918015

Russian Journal of Organic Chemistry, Vol. 38, No. 10, 2002, pp. 1440 1444. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 10, 2002,
pp. 1493 1497.
Original Russian Text Copyright
2002 by Dikusar, Kozlov, Moiseichuk.
( )-(R)- and (+)-(S)-Carvone in the Synthesis of Optically
Active Acetylenic Alcohols, Ethers, and Dichlorosilyl Derivatives
E. A. Dikusar, N. G. Kozlov, and K. L. Moiseichuk
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus,
ul. Surganova 13, Minsk, 220072 Belarus
e-mail: loc@ifoch.bas-net.by
Received October 27, 2000*
Abstract Reaction of butyllithium with acetylene and 1-hexyne gave the corresponding lithium acetylides
which reacted with ( )-(R)- and (+)-(S)-carvone in a stereospecific fashion to give lithium (1-ethynyl- or
1-hexynyl)-5-isopropenyl-2-methyl-2-cyclohexenolates. Hydrolysis of the latter gave individual optically
active tertiary terpene alcohols having both acetylenic and p-menthene fragment. Their treatment with methyl
iodide in the presence of hexamethylphosphoric triamide afforded the corresponding methyl ethers. The
reaction of 3-ethynyl-5-isopropenyl-3-methoxy-2-methylcyclohexene with butyllithium and trichloro(vinyl)-
silane yielded optically active dichlorosilyl-containing acetylenic compounds.
Syntheses of various p-menthene derivatives are
now extensively studied with the goal to examine
their reactivity and obtain biologically active com-
pounds from renewable wood-chemical raw materials.
2,6,6-Trimethylbicyclo[3.1.1]hept-2-ene ( -pinene) is
used most frequently in such syntheses; its concentra-
tion in the turpentine isolated from Pinus Silvestris L.
is 40 70% [1]. -Pinene has become the key starting
compound for the synthesis of a number of substances
exhibiting various kinds of biological activity: anti-
viral, antitumor, cytostatic, analgetic, etc. [2 4].
However, search for alternative natural sources for
preparation of drugs remains important. Terpene
derivatives having a triple bond do not occur in
nature, and they were not described in the literature
[5, 6]. On the other hand, many medicines contain
an acetylenic fragment; in particular, substituted
acetylenic alcohols exhibit a wide spectrum of bio-
logical activity [7].
According to our previous data [8, 9], such synthons
may be highly reactive lithium alcoholates of various
structures. These compounds can be generated in situ,
and their further transformations are not accompanied
by change of the stereochemical structure [10, 11].
We were the first to accomplish stereospecific syn-
thesis of lithium ( )-(R)- and (+)-(S)-1-ethynyl- and
1-(1-hexynyl)-5-isopropenyl-2-methyl-2-cyclohexen-
olates IVa, IVb, Va, and Vb from ( )-(R)-carvone
(IIIa) and (+)-(S)-carvone (IIIb) and lithium ace-
tylides IIa and IIb, generated by the action of butyl-
lithium on acetylene (Ia) or 1-hexyne (Ib) in tetra-
hydrofuran (Scheme 1). Lithium alcoholates IVa,
IVb, Va, and Vb were hydrolyzed with water (without
isolation) to obtain optically active tertiary alcohols
VIa, VIb, VIIa, and VIIb, respectively, in 78 90%
yield. Their molecules contain the acetylenic fragment
in the pseudoequatorial position, and the hydroxy
group, in the pseudoaxial position of the cyclohexene
ring which adopts a semichair conformation.
The goal of the present study was to obtain a multi-
purpose synthon ensuring selective preparation of
previously unknown tertiary acetylenic alcohols and
ethers with pharmacophoric p-menthene fragment
from optically active p-mentha-6,8-dien-2-one
(carvone). The latter compound is widely spread in
nature and is the major component of essential oils
from Anethum graveolens L. and Carum carui L.
____________
The structure of alcohols VIa, VIb, VIIa, and
VIIb was proved by IR and NMR spectroscopy. Their
IR spectra lack carbonyl absorption but contain bands
1
at 2220 and 3455 cm , typical of stretching vibra-
tions of C C bond and associated hydroxy group,
1
respectively. In the H NMR spectra of these com-
pounds we observed signals from protons of both
p-menthene fragment and side-chain substituent
(Table 1). The spectral patterns are typical of pure
*
Revised May 28, 2002.
1070-4280/02/3810-1440$27.00 2002 MAIK Nauka/Interperiodica

( )-(R)- AND (+)-(S)-CARVONE IN THE SYNTHESIS OF OPTICALLY . . .
1441
Scheme 1.
I, II, IV IX, R = H (a), (CH2)3Me (b); VI, VIII, R = H; VII, IX, R = Me.
isomers, indicating high stereoselectivity of the
process. The signal from the methyl group on C2 is
displaced downfield relative to the corresponding
signal of initial ketones IIIa and IIIb, while those
from the 6-H proton almost do not change their
position. This is possible as a result of 1,3-nonvalence
interaction between the methyl and hydroxy groups,
so that the latter should occupy pseudoaxial position.
These data are consistent with our previous conclusion
[8] that the addition of organolithium compounds to
carbonyl group is stereoselective: the attack occurs
from the least sterically hindered side of the molecule.
vibrations of the C O C fragment. Unlike the initial
compounds, the H NMR spectra of methyl ethers
1
VIIa, VIIb, IXa, and IXb contain a signal from the
methoxy protons at 3.3 ppm. Taking into account
that the orientation of substituents does not change
during the reaction [10, 11], ethers VII and IX were
assigned the structures with pseudoaxial orientation
of the methoxy group.
( )-(R)- and (+)-(S)-3-Ethynyl-5-isopropenyl-3-
methoxycyclohexenes VIIa and IXa react with butyl-
lithium, yielding the corresponding lithium acetylides.
Treatment of the latter with trichloro(vinyl)silane
leads to formation of optically active dichloro(vinyl)-
silyl-substituted derivatives Xa and Xb in 51 57%
yield. The IR spectra of Xa and Xb contain bands
typical of C CSiCl2CH CH2 group: 3075 ( C H),
2155 (C C), 1650 (C C), and 580 cm 1 (Si Cl).
Lithium derivatives IVa, IVb, Va, and Vb readily
react with methyl iodide in the presence of hexa-
methylphosphoric triamide (HMPA) to give the corre-
sponding methyl ethers VIIa, VIIb, IXa, and IXb in
72 83% yield. No reaction occurs in the absence of
HMPA. The resulting ethers show in the IR spectra
Compounds VI X are characterized by a high
optical purity. They attract interest as potential
1
an absorption band at 1090 cm due to stretching
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 10 2002

1442
DIKUSAR et al.
Table 1. 1H NMR spectra of compounds VI X
Comp.
no.
Chemical shifts , ppm
VIa
1.60 2.55 m (6H, CH, OH, 2CH2), 1.73 s and 1.84 s (6H, 2MeC C), 2.54 s (1H, C CH), 4.74 s (2H,
C CH2), 5.50 br.s (1H, MeCH C)
VIb
0.91 t [3H, Me(CH2)3], 1.20 2.70 m [10H, OH, CH, 2CH2, (CH2)2Me], 1.75 s and 1.85 s (6H, 2MeC C),
2.21 t (2H, CH2C C), 4.74 s (2H, C CH2), 5.44 br.s (1H, MeCH C)
VIIa
VIIb
VIIIa
VIIIb
IXa
1.73 s and 1.75 s (6H, 2MeC C), 1.83 2.65 m (5H, CH, 2CH2), 2.54 s (1H, C CH), 3.37 s (3H, MeO),
4.75 s (2H, C CH2), 5.57 br.s (1H, MeCH C)
0.91 t [3H, Me(CH2)3], 1.25 2.60 m [9H, CH, 2CH2, (CH2)2Me], 1.77 s (6H, 2MeC C), 2.24 t (2H,
CH2C C), 3.34 s (3H, MeO) 4.74 s (2H, C CH2), 5.52 br.s (1H, MeCH C)
1.56 2.54 m (6H, CH, OH, 2CH2), 1.74 s and 1.83 (6H, 2MeC C), 2.54 s (1H, C CH), 4.74 s (2H,
C CH2), 5.51 br.s (1H, MeCH C)
0.92 t [3H, Me(CH2)3], 1.20 2.75 m [10H, OH, CH, 2CH2, (CH2)2Me], 1.75 s and 1.82 s (6H, 2MeC C),
2.21 t (2H, CH2C C), 4.74 s (2H, C CH2), 5.46 br.s (1H, MeCH C)
1.76 s and 1.80 s (6H, 2MeC C), 1.85 2.70 m (5H, CH, 2CH2), 2.54 s (1H, C CH), 3.37 s (3H, MeO),
4.75 s (2H, C CH2), 5.58 br.s (1H, MeCH C)
IXb
0.92 t [3H, Me(CH2)3], 1.30 2.60 m [9H, CH, 2CH2, (CH2)2Me], 1.78 s (6H, 2MeC C), 2.25 t (2H,
CH2C C), 3.35 s (3H, MeO) 4.75 s (2H, C CH2), 5.53 br.s (1H, MeCH C)
Xa
1.75 s (3H, MeCH CH2), 2.03 s (3H, MeC CH), 1.70 2.70 m (5H, CH, 2CH2), 3.37 s (3H, MeO ),
4.60 br.s (1H, SiCH CH2), 4.77 s (2H, CC CH2), 5.62 br.s (1H, MeCCH C), 6.05 6.55 m (2H,
SiCH CH2)
Xb
1.80 s (3H, MeCH CH2), 2.03 s (3H, MeC CH), 1.70 2.70 m (5H, CH, 2CH2), 3.41 s (3H, MeO),
4.65 br.s (1H, SiCH CH2), 4.80 s (2H, CC CH2), 5.65 br.s (1H, MeCCH C), 6.05 6.45 m (2H,
SiCH CH2)
biologically active substances, and dichloro(vinyl)silyl
derivatives Xa and Xb can be used as monomers
for preparation of optically active chromatographic
hexane (Xb). The molecular weights were determined
by cryoscopy in benzene. Neutral Al2O3 of activity
grade II (according to Brockmann) was used for
column chromatography. Butyllithium was prepared
1
phases. The H NMR spectra of the obtained com-
pounds are given in Table 1, and Table 2 contains
their yields, physical constants, optical rotations, and
analytical data.
The UV spectra of the products contain the follow-
ing absorption bands, max, nm ( ): VI IX: 206 2
(5000 1000); X: 210 (6000), 242 (9000).
by the procedure described in [12]; ( )-(R)-carvone:
20
bp 227 230 C, d = 0.959, n2D0 = 1.4990, [ ]D20
=
20
20
20
61 ; (+)-(S)-carvone: bp 98 C (10 mm), d = 0.965,
n2D0 = 1.4970, [ ]2D0 = +54 .
Lithium ( )-(5R)- and (+)-(5S)-1-ethynyl-5-iso-
propenyl-2-methyl-2-cyclohexenolates IVa and Va.
Ketone IIIa or IIIb, 0.3 mol, was added in one
portion to a solution of 0.4 mol of lithium acetylide
(IIa) (a solution of 0.4 mol of butyllithium was added
dropwise over a period of 30 min at 70 C to 300 ml
of anhydrous tetrahydrofuran with simultaneous
bubbling of dry acetylene), and the mixture was
stirred for 4 h at 20 23 C and was left to stand for
18 h. The resulting solutions of lithium derivatives
IVa and Va were used in further syntheses.
EXPERIMENTAL
The IR spectra were measured on a Specord 75IR
spectrometer from samples prepared as thin films.
1
The H NMR spectra were recorded on a Tesla BS-
567A instrument in CDCl3 using tetramethylsilane as
internal reference. The UV spectra were obtained on
3
a Specord UV-Vis spectrophotometer from 10
M
solutions in methanol (VI IX) or hexane (Xb). The
optical rotations were measured on an SM-2 instru-
ment from 3.5% solutions in methanol (VI IX) or
Lithium ( )-(5R)- and (+)-(5S)-1-(1-hexynyl)-
5-isopropenyl-2-methyl-2-cyclohexenolates IVb and
Vb. A solution of 0.011 mol of butyllithium in hexane
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 10 2002

( )-(R)- AND (+)-(S)-CARVONE IN THE SYNTHESIS OF OPTICALLY . . .
Table 2. Yields, constants, and analytical data of compounds VI X
1443
Found, %
Calculated, %
M
Comp. Yield,
bp,
(p, mm)
C
20
d
n2D0
[ ]2D0
Formula
20
no.
%
C
H
C
H
found calcd.
VIa
VIb
87
78
76
76
90
78
83
72
57
51
53 54 (0.05) 1.0602 1.5075
92 93 (0.05) 0.9178 1.5015
99 100 (25) 1.0738 1.4945
79 80 (0.05) 0.9851 1.4900
66 67 (0.05) 1.0831 1.5070 +220 81.93 9.18 C12H16O
96 97 (0.05) 0.9213 1.4995 +116 82.85 10.47 C16H24O
120 121 (25) 1.0087 1.4945 +197 82.41 9.66 C13H18O
88 89 (0.05) 0.9613 1.4890 +208 82.94 10.77 C17H26O
225 81.91 9.22 C12H16O
108 82.81 10.44 C16H24O
206 82.34 9.71 C13H18O
189 83.03 10.69 C17H26O
81.77 9.15 171.4 176.3
82.70 10.41 226.4 232.4
82.06 9.53 181.9 190.3
82.87 10.64 240.3 246.4
81.77 9.15 170.8 176.3
82.70 10.41 224.7 232.4
82.06 9.53 184.1 190.3
82.87 10.64 239.0 246.4
VIIa
VIIb
VIIIa
VIIIb
IXa
IXb
Xaa
83 84 (0.05) 1.1677 1.5100
90 91 (0.05) 1.1552 1.5055 +133 5730 6.48 C15H20Cl2SiO 57.14 6.39 296.0 315.3
170 57.21 6.44 C15H20Cl2SiO 57.14 6.39 293.6 315.3
Xba
a
Found, %: Cl 22.20 (Xa), 22.03 (Xb); Si 8.79 (Xa), 8.61 (Xb). Calculated, %: Cl 22.49; Si 8.91.
was added over a period of 30 min to a solution of
0.013 mol of 1-hexyne in 20 ml of anhydrous tetra-
hydrofuran under vigorous stirring at 40 to 20 C
in a stream of argon. The mixture was stirred for 1 h,
0.01 mol of ketone IIIa or IIIb was added, and the
mixture was allowed to warm up to 20 23 C over
a period of 1 2 h, stirred for 3 4 h, and left to stand
for 18 h. The resulting solutions of compounds IVb
and Vb were used in further syntheses.
hexane as eluent. The products were additionally
purified by vacuum distillation.
( )-(5R)- and (+)-(5S)-3-(1-Hexynyl)-5-isopro-
penyl-3-methoxy-2-methylcyclohexenes VIIb and
IXb. Methyl iodide, 0.01 mol, and HMPA, 3 ml, were
added to a solution containing 0.01 mol of lithium
alcoholate IVb or Vb. The mixture was stirred for
3 h at 20 23 C and was left to stand for 18 h. It was
then diluted with 50 ml of hexane, and the organic
phase was washed with water and 30% aqueous
NaOH, dried over CaCl2, and evaporated. The residue
was kept under reduced pressure and subjected to
column chromatography on Al2O3 using hexane as
eluent. Compounds VIIb and IXb were additionally
purified by vacuum distillation.
( )-(5R)- and (+)-(5S)-3-[2-Dichloro(vinyl)silyl-
ethynyl]-5-isopropenyl-3-methoxy-2-methylcyclo-
hexenes Xa and Xb. A solution of 0.2 mol of butyl-
lithium in hexane was added over a period of 30 min
to a solution of 0.2 mol of methyl ether VIIa or
IXa in 100 ml of anhydrous tetrahydrofuran under
vigorous stirring at 40 to 20 C in a stream of argon.
The mixture was stirred for 1 h, transferred into
a dropping funnel, and added over a period of 1 h
under argon to a solution of 0.4 mol of trichloro-
(vinyl)silane in 100 ml of anhydrous tetrahydrofuran,
vigorously stirred at 0 to 5 C. The mixture was
stirred for 3 h at 20 23 C and was left to stand for
18 h. The solution was quickly separated from the
precipitate of LiCl (by decanting), and the solvent
was removed. The residue was distilled in a vacuum.
Compounds Xa and Xb readily undergo hydrolysis,
and they should be stored in sealed ampules.
( )-(5R)- and (+)-(5S)-1-Ethynyl and 1-(1-hex-
ynyl)-5-isopropenyl-2-methyl-2-cyclohexenols VIa,
VIb, VIIIa, and VIIIb. Water, 100 ml, was added to
a solution containing 0.01 mol of lithium alcoholate
IVa, IVb, Va, or Vb. The mixture was extracted with
hexane, the extract was dried over CaCl2, the solvent
was removed, and the residue was purified by vacuum
distillation.
( )-(5R)- and (+)-(5S)-3-Ethynyl-5-isopropenyl-
3-methoxy-2-methylcyclohexenes VIIa and IXa.
A solution of 0.3 mol of butyllithium in hexane was
added over a period of 30 min to a solution of 0.3 mol
of alcohol VIa or VIIIa in 200 ml of anhydrous
tetrahydrofuran under vigorous stirring at 40 to
20 C in a stream of argon. The mixture was stirred
for 1 h, 0.33 mol of methyl iodide and 100 ml of
HMPA were added, and the mixture was stirred for
3 h at 20 23 C and was left to stand for 18 h. The
mixture was then diluted with 200 ml of hexane, and
the organic phase was washed with water and 30%
aqueous NaOH, dried over CaCl2, and evaporated.
The residue was kept under reduced pressure and was
subjected to column chromatography on Al2O3 using
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 10 2002

1444
DIKUSAR et al.
7. Schulte, K. and Rucker, G., Prog. Drug. Res., 1970,
REFERENCES
vol. 14, pp. 387 563.
1. Nikitin, N.I., Khimiya drevesiny, (Wood Chemistry),
8. Koval’skaya, S.S., Kozlov, N.G., and Dikusar, E.A.,
Russ. J. Org. Chem., 2000, vol. 36, no. 3, pp. 379
385.
Moscow: Akad. Nauk SSSR, 1951.
2. FRG Patent no. 2437900, 1974; Chem. Abstr., 1975,
vol. 83, no. 114680.
9. Dikusar, E.A., Zhukovskaya, N.A., Moiseichuk, K.L.,
and Yuvchenko, A.P., Russ. J. Org. Chem., 2002,
vol. 38, no. 2, pp. 153 157.
3. Goryaev, M.I. and Poplavskaya, I.A., Puti sinteza
i izyskaniya protivoopukholevykh preparatov (Methods
of Synthesis and Design of Antitumor Medical Com-
positions), Moscow: Meditsina, 1967, no. 2, p. 385.
10. Yuvchenko, A.P., Dikusar, E.A., Moiseichuk, K.L.,
and Kozlov, N.G., Russ. J. Org. Chem., 1995,
vol. 31, no. 3, pp. 304 307.
4. Mais, D., Knapp, D., Halushka, P., Ballard, K., and
Hamanaka, N., Tetrahedron Lett., 1984, vol. 25,
no. 38, pp. 4207 4210.
11. Yuvchenko, A.P., Dikusar, E.A., Kozlov, N.G.,
Popova, L.A., and Moiseichuk, K.L., Russ. J. Org.
Chem., 1995, vol. 31, no. 4, pp. 498 503.
5. Pentegova, V.A., Dubovenko, Zh.V., Raldugin, V.A.,
and Shmidt, E.N., Terpenoidy khvoinykh rastenii
(Terpenoids from Coniferous Plants), Novosibirsk:
Nauka, 1987.
12. Talalaeva, T.V. and Kocheshkov, K.A., Metody
elementoorganicheskoi khimii. Litii, natrii, kalii,
rubidii, tsezii (Methods of Organometallic Chemistry.
Lithium, Sodium, Potassium, Rubidium, and
Cesium), Moscow: Nauka. 1971, book 1, pp. 99 107,
554 555.
6. Plemenkov, V.V., Vvedenie v khimiyu prirodnykh
soedinenii (An Introduction to the Chemistry of
Natural Compounds), Kazan’, 2001.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 10 2002