Crystallization of bisulfite derivatives of enantiomerically enriched verbenone

Article abstract of DOI:10.1134/S1070428017100190

After separation of crystalline bisulfite derivatives of enantiomerically enriched (1S)- and (1R)-verbenones, steam distillation of the filtrates afforded (1S)- and (1R)-verbenones whose optical purity was higher by 30 and 20%, respectively, than that of

Full text of DOI:10.1134/S1070428017100190

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 10, pp. 1598–1600. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © V.N. Kovalenko, A.S. Prat’ko, K.N. Prokhorevich, 2017, published in Zhurnal Organicheskoi Khimii, 2017, Vol. 53, No. 10,
pp. 1562–1564.
SHORT
COMMUNICATIONS
Crystallization of Bisulfite Derivatives of Enantiomerically
Enriched Verbenone
a, b
b
c
V. N. Kovalenko ,* A. S. Prat’ko , and K. N. Prokhorevich
a
Belarusian State University, pr. Nezavisimosti 4, Minsk, 220030 Belarus
*
e-mail: kovalenkovn@rambler.ru
b
Tank Belarusian State Pedagogical University, Sovetskaya ul. 18, Minsk, 220050 Belarus
c
Belarusian Military Academy, pr. Nezavisimosti 220, Minsk, 220057 Belarus
Received April 21, 2017
Abstract—After separation of crystalline bisulfite derivatives of enantiomerically enriched (1S)- and (1R)-ver-
benones, steam distillation of the filtrates afforded (1S)- and (1R)-verbenones whose optical purity was higher
by 30 and 20%, respectively, than that of the initial enantiomers.
DOI: 10.1134/S1070428017100190
Verbenone 1 and some related terpene compounds
exist in nature as mixtures of optical isomers. The
optical purity varies over a wide range, and the natural
compound may be both dextro- and levorotatory,
depending on the place of its origin.
[α] = –273° for optically pure (1S)-(–)-verbenone}
D
and dextrorotatory (1R)-(+)-verbenone (1R)-1 with
50% ee, which was obtained by oxidation of
(+)-α-pinene [2].
The bisulfite derivatives were synthesized by stir-
ring a mixture of verbenone with an aqueous solution
of a Na SO /NaHSO mixture until it became homo-
An efficient method for the isolation and purifica-
tion of verbenone is based on its conversion to water-
soluble bisulfite derivative which is then decomposed
by steam distillation from alkaline medium [1]. It is
known that under appropriate conditions bisulfite
derivatives of carbonyl compounds can be isolated in
the crystalline form. As a rule, crystallization of enan-
tiomerically enriched compounds is accompanied by
redistribution of enantiomers between the phases.
2
3
3
geneous. The solution was cooled, and the crystalline
bisulfite derivative and concomitant inorganic salts
were filtered off. The crystalline bisulfite derivative
was decomposed by treatment with aqueous sodium
carbonate, and verbenone was isolated by steam dis-
tillation. Likewise, verbenone was isolated from the
mother liquor by steam distillation after treatment with
an aqueous solution of sodium carbonate.
We have synthesized crystalline bisulfite deriva-
tives of enantiomerically enriched verbenone isomers
and studied distribution of the enantiomers between
the mother liquor and crystalline bisulfite derivative.
As substrates we used (1S)-(–)-verbenone [(1S)-1,
The optical purity of verbenone before and after
preparation of bisulfite derivatives was monitored by
the Mosher method. For this purpose, (1S)- and
(1R)-enantiomers of 1 were reduced with lithium
tetrahydridoaluminate to (1S)- and (1R)-cis-verbenols
Sigma–Aldrich] with 54% ee and [α] = –147.1° {cf.
D
Scheme 1.
Ph
O
MeO
F3C
Cl
(3)
Me
Me
LiAlH4
pyridine
Me
Me
H
Mosher ester
Me
O
Me
OH
Verbenone (1S)-1
Verbenol (1S)-2
1
598

CRYSTALLIZATION OF BISULFITE DERIVATIVES
1599
Scheme 2.
Me
Me
Me
(
(
1) NaHSO , crystallization
3
2) Na CO , ∆
2
3
Verbenone (±)-1
+
Verbenone (1R)-1
O
26%
62%, >70% ee
(
from crystals)
(from filtrate)
Verbenone (1R)-1
0% ee
5
(
(
1) NaHSO , crystallization
3
2) Na CO , ∆
2
3
Verbenone (1S)-1
4% ee
Verbenone (1S)-1
+
Verbenone (1S)-1
5
6
7%, 40% ee
20%, >85% ee
(from filtrate)
(
from crystals)
(
(
1S)-2 and (1R)-2 which were acylated with
S)-Mosher’s acid chloride (3) [3] (Scheme 1). The
derivative for preparative purposes is expedient only
when crystalline racemate seeds are available and
conditions are created for its preferential crystallization
from the solution.
ratio of (1S)-2 and (1R)-2 was determined from the
intensities of signals of the geminal methyl groups in
the H NMR spectra. The enantiomeric purity of
a commercial sample of (1S)-1 (Sigma–Aldrich),
determined by the Mosher method, coincided with that
calculated from its optical rotation value (54% ee),
which confirmed reliability this method.
1
Crystalline bisulfite derivative of (1R)-(+)-verbe-
none and isolation of racemic verbenone therefrom.
Sulfur dioxide was passed through a mixture of 37.8 g
(
0.3 mol) of sodium sulfite and 115 mL of water until
a weight gain of 20 g was attained and the solution
turned slightly yellowish. Sodium hydrogen carbonate,
2 g, and (1R)-(+)-verbenone, 1.3 g (8.2 mmol), were
added to 20 mL of the resulting solution, and the
mixture was stirred for 24 h at room temperature until
it became homogeneous, cooled to 3°C, and kept for
24 h at that temperature. The precipitate was filtered
off and washed with a small amount of a saturated
The ee value of (1S)-1 decreased from 54 to 40%
after its conversion to bisulfite derivative and isolation
from the crystalline fraction. A sample of (1R)-(+)-
verbenone [(1R)-1, 50% ee] was converted to racemic
crystalline bisulfite derivative: the methyl proton
signals of the (S)-Mosher esters with the corresponding
(
1S)- and (1R)-enantiomers of cis-verbenol 2 had equal
intensities.
Thus, it was impossible to isolate enantiomerically
solution of Na
SO . The crystals of bisulfite derivative
2
3
were added to 50 mL of a 10% solution of sodium
carbonate, and the mixture was steam-distilled to
separate racemic verbenone (±)-1. The distillate was
saturated with sodium chloride and extracted with
diethyl ether (3×10 mL). The combined extracts were
dried over anhydrous sodium sulfate and evaporated
under reduced pressure. The residue, 0.34 g (26%),
was pure racemic verbenone (±)-1 (according to the
pure crystalline bisulfite derivatives and improve in
this way the optical purity of commercially available
verbenone. We revealed a clear tendency for precipita-
tion of racemic bisulfite derivatives, especially when
the initial substrate had lower ee value and the amount
of the crystalline fraction was low. Therefore, it
became possible to increase the optical purity of verbe-
none by separation of racemic crystalline bisulfite
derivative and isolation of verbenone from the mother
liquor. After separation of racemic verbenone (±)-1
from a sample of (1R)-1 with 50% ee, from the mother
liquor we isolated (1R)-1 in 62% yield with >70% ee.
Likewise, from a sample of (1S)-1 with 54% ee we
isolated 1S-(–)-verbenone in 20% yield with an ee
value of higher than 85%; i.e., the optical purity was
improved by 31% (Scheme 2).
1
H NMR data).
Enantiomerically enriched (1R)-(+)-verbenone
from the mother liquor. After separation of the crys-
talline bisulfite derivative of (1R)-1, the mother liquor
was added to 50 mL of a 15% aqueous solution of
sodium carbonate, and the mixture was steam-distilled.
The distillate was saturated with sodium chloride and
extracted with diethyl ether (3 × 10 mL), and the
combined extracts were dried over anhydrous Na SO
2
4
We believe that the use of the described procedure
for enhancement of the optical purity of verbenone by
crystallization and separation of its racemic bisulfite
and evaporated under reduced pressure. The residue,
0.80 g (62%) was (1R)-(+)-verbenone with >70% ee
1
( H NMR).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 10 2017

1
600
KOVALENKO et al.
NaHCO and NaCl, dried over anhydrous Na SO , and
3 2 4
Crystalline bisulfite derivative of 1S-(–)-verbe-
none was obtained as described above for (1R)-1 from
.3 g (8.2 mmol) of (1S)-1 and was then decomposed
evaporated under reduced pressure. The residue was
1
1
analyzed by H NMR. The intensities of the methyl
to isolate 0.87 g (67%) of (1S)-1 with 40% ee.
proton signals at δ 0.72 (1R) and 0.84 ppm (1S), as
well as at δ 1.26 (1R) and 1.34 ppm (1S), were
compared [3].
Enantiomerically enriched 1S-(–)-verbenone was
isolated from the mother liquor as described above for
1
(
1R)-1. Yield 0.26 g (20%), >85% ee.
The H NMR spectra were recorded on a Bruker
Avance 500 spectrometer at 500 MHz using CDCl as
3
Determination of the optical purity of (1R)-(+)-
solvent. The solvents used were dried according to
standard procedures and distilled.
and 1S-(–)-verbenone. A suspension of 0.1 g
2.6 mmol) of LiAlH in 4 mL of THF was cooled with
(
4
This study was performed under financial support
by the Belarusian Republican Foundation for Basic
Research (project no. Kh16MV-007) and by the State
Program of Scientific Research for 2016–2018 (project
no. 2.31).
ice water, and 200 mg (1.3 mmol) of (1R)-1 or (1S)-1
was added with stirring. The mixture was stirred for
1
0
h at room temperature and treated in succession with
.1 mL of water, 0.1 mL of 20% aqueous sodium hy-
droxide, and 0.2 mL of water. The mixture was
filtered, and the filtrate was dried over anhydrous
Na SO and evaporated under reduced pressure.
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2
4
A 10-mg portion of the residue was dissolved in
1
2
3
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. Sivik, M.R., Stanton, K.J., and Paquette, L.A., Org.
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. Mori, K., Mizumachi, N., and Matsui, M., Agric. Biol.
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0
3
.5 mL of methylene chloride, 0.1 mL of pyridine and
5 mg (0.14 mmol) of (S)-Mosher’s acid chloride were
1
added, and the mixture was kept for 18 h at room
temperature. It was then diluted with 5 mL of diethyl
ether, washed in succession with saturated solutions of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 10 2017