Practical method for increasing optical purity of cis-verbenol

Article abstract of DOI:10.1002/chir.23119

R/S mixture of monoterpene alcohol cis-verbenol can be separated in preparative scale by its conversion into phthalic mono-ester and subsequent crystallization of its diastereomeric salts with (R)-α-methylbenzylamine and (S)-α-methylbenzylamine. Finally, basic methanolysis of the resolved phthalic mono-esters results (S)-cis-verbenol and (R)-cis-verbenol in high enantiomeric and diastereomeric purity.

Full text of DOI:10.1002/chir.23119

Received: 11 June 2019
DOI: 10.1002/chir.23119
Revised: 12 July 2019
Accepted: 18 July 2019
R E G U L A R A R T I C L E
Practical method for increasing optical purity of cis‐
verbenol
Vitaly Kovalenko1
| Aliaksei Krauchanka1 | Konstantin Prokhorevich2
1 Laboratory of Biotechnology and
Biochemistry, Department of Natural
Abstract
R/S mixture of monoterpene alcohol cis‐verbenol can be separated in
Sciences, Belarusian State Pedagogical
University, Minsk, Belarus
2 Department of Chemical Protection and
Ecology, Belarusian Military Academy,
Minsk, Belarus
preparative scale by its conversion into phthalic mono‐ester and subsequent
crystallization of its diastereomeric salts with (R)‐α‐methylbenzylamine and
(S)‐α‐methylbenzylamine. Finally, basic methanolysis of the resolved phthalic
mono‐esters results (S)‐cis‐verbenol and (R)‐cis‐verbenol in high enantiomeric
and diastereomeric purity.
Correspondence
Dr V. Kovalenko, Laboratory of
Biotechnology and Biochemistry,
Department of Natural Sciences,
Belarusian State Pedagogical University,
Minsk 220030, Sovetskaya st. 18, Belarus.
Email: kovalenkovn@rambler.ru
KEYWORDS
chiral resolution, crystallization, monoterpenoids, optical activity, phthalic mono‐esters, α‐
methylbenzylamine
Funding information
National Research Program
1 | INTRODUCTION
The co‐occurrence of (+) and (−) forms is fairly common
among the cyclic monoterpenes.1 Especially, for pinene,
and its metabolites, optical activity varies over a wide
range, and the natural compound may be both dextrorota-
tory and levorotatory depending on the source its origin.1-3
The same goes for the commercially available semisyn-
thetic verbenone and cis‐verbenol which are usually
marketed with a relatively low enantiomeric excess.4
Meanwhile, recent studies revealed that the increased opti-
cal purity of terpene compounds has profound influence
on their biological properties.5,6
Monoterpene alcohol cis‐verbenol 1 has traditionally
been used as flavoring ingredient,7 major component of
the insect pheromones,8,9 and building block for natural
product synthesis.10,11 Some new aspects of its biological
activity were disclosed in last years,12-14 although little
attention was paid to the contribution of individual enan-
tiomers. Herein, we present an efficient and scalable res-
olution method that results optically pure cis‐verbenol
from the mixtures of enantiomers. Our approach makes
available both chiral forms, as appropriate.
2 | MATERIALS AND METHODS
2.1 | General information
1H and 13C NMR spectra were recorded at 500 and
125 MHz, respectively, on a Bruker Avance 500 spectrom-
eter. Chemical shifts were referred to the signals of residual
1
CHCl3 (δ = 7.26 ppm in H NMR; δ = 77.0 ppm in 13C
NMR). Melting points were determined on a capillary
apparatus. Optical rotations were measured with a porta-
ble P‐161 polarimeter. Elemental analyses were performed
using Thermo Scientific TM Flash 2000 CHNS/O analyzer.
IR spectra were recorded on a Vertex 70 spectrometer. TLC
analysis was performed on Silica gel 60F254 plates. (1S)‐
(−)‐verbenone was purchased from Sigma‐Aldrich (prod-
uct number W506907). Solvents were dried by standard
methods and distilled prior to use.
Chirality. 2019;1–5.
wileyonlinelibrary.com/journal/chir
© 2019 Wiley Periodicals, Inc.
1

2
KOVALENKO ET AL.
130°C; [α]D = +22.7 (c = 2.5 in MeOH); 1H NMR
(500 MHz, CDCl3, δ): 7.98 (br. s, 3H, NH3+), 7.60
to 7.63 (m, 1H; ArH), 7.22 to 7.32 (m, 5H; ArH), 7.15 to
7.17 (m, 3H; ArH), 5.53 to 5.55 (m, 1H; ═CH), 5.35 to
5.37 (m, 1H; CH―O), 4.27 (q, J = 6.8 Hz, 1H; CHNH3+),
2.45 (ddd, J1 = 9.0, J2 and J3 ≈ 5.5 Hz, 1H), 2.32–5.36
(m, 1H), 1.98 (app. t, J = 5.5 Hz, 1H), 1.70 (br. s, 3H;
═CCH3), 1.51 (d, J = 6.8 Hz, 3H; CH3CHNH3+), 1.33
(d, J = 9.0 Hz, 1H), 1.31 (s, 3H; CH3), 1.07 (s, 3H; CH3);
13C NMR (125 MHz, CDCl3, δ): 174.6 (C), 167.5 (C),
149.4 (C), 140.6 (C), 140.4 (C), 130.9 (CH), 129.8 (C),
128.6 (2CH), 128.4 (CH), 127.9 (CH), 127.7 (2CH), 126.6
(2CH), 115.9 (CH), 75.8 (CH), 51.1 (CH), 47.6 (CH), 45.5
(CH), 39.7 (C), 35.5 (CH2), 26.7 (CH3), 22.8 (CH3), 22.7
(CH3), 21.6 (CH3); IR (KBr): ν = 3012, 2919, 1714, 1627,
1550, 1529 cm−1. Anal. calcd. for C26H31NO4: C 74.08, H
7.41; found: C 74.25, H 7.50.
20
2.2 | (S)‐Verbenol (S)‐1 (starting material)
(S)‐Verbenol (S)‐1, ee < 60%, cis/trans ratio 94.5/5.5, was
prepared by the reduction of (1S)‐(−)‐verbenone (S)‐2,
ee < 60%, (10.0 g, 66.6 mmol) with LiAlH4 in Et2O
according to Mori et al.15 The yield of the reduced mate-
rial was assumed as quantitative. The cis/trans ratio was
determined by comparing the intensity of the signals of
allylic protons in the 1H NMR spectrum, at 4.46 and
4.26 ppm, respectively. This product was used directly in
the next step without any purification.
2.3 | Salt of 2‐({[(1S,2S,5S)‐4,6,6‐
trimethylbicyclo[3.1.1]hept‐3‐en‐2‐yl]oxy}
carbonyl)benzoic acid and (1R)‐α‐phenyl‐
ethanamine (S)‐3•(R)‐4
Crude (S)‐verbenol (S)‐1 (about 10.13 g, 66.6 mmol)
was dissolved in anhydrous benzene (100 mL), then
triethylamine (15 mL, 108 mmol) and phthalic anhydride
(10.1 g, 68.2 mmol) were successively added to the stirred
solution at room temperature. The resulted mixture was
stirred at 40°C for 16 hours. After cooling in ice bath,
the mixture was treated with 20% solution of KHSO4
(150 mL) and ethyl acetate (100 mL). The two‐phase mix-
ture was transferred into a separatory funnel. The organic
layer was separated, and the aqueous layer was extracted
with ethyl acetate (2 × 50 mL). Combined organic phases
were washed with brine, dried under Na2SO4, and evapo-
rated in vacuum to give crude phthalic mono‐ester (S)‐3
as light gray solid. The residue was dissolved in acetone
(220 mL), and (R)‐α‐methylbenzylamine (R)‐4 (9.5 g,
78.4 mmol) was added dropwise. Rapid formation of
white precipitate was observed. The mixture was heated
under reflux to dissolve all solids. The transparent solu-
tion was allowed to cool gradually to room temperature
while white needle crystals were formed. Further, the
flask was put into a refrigerator (+4°C‐5°C) for 12 hours.
The crystalline material was collected by filtration,
washed with cooled acetone, and dried in vacuum. The
yield of the salt (S)‐3•(R)‐4: 16.5 g. Crystallization was
repeated second and third time using minimal volume
of acetone (about 180‐200 mL); some amounts of (R)‐α‐
methylbenzylamine (0.2‐0.3 mL) were additionally added
to the saturated hot solutions. Diastereomerically pure
salt (S)‐3•(R)‐4 was obtained in final yield 11.5 g (41%).
Mother liquors after second and third crystallizations
were combined, concentrated in vacuum; the residue
was recrystallized from acetone (about 30‐50 mL) three
times as described above giving additional amount of
diasteromerically pure salt (S)‐3•(R)‐4: 2.5 g (9%). Total
yield of the salt (S)‐3•(R)‐4: 14.0 g (50%); mp 127°C to
2.4 | Salt of 2‐({[(1R,2R,5R)‐4,6,6‐
trimethylbicyclo[3.1.1]hept‐3‐en‐2‐yl]oxy}
carbonyl)benzoic acid and (1S)‐1‐
phenylethanamine (R)‐3•(S)‐4
Mother liquor after first crystallization of the salt (S)‐3•(R)‐
4 was concentrated under reduced pressure. The residue
was treated with 20% solution of KHSO4 (100 mL) and
ethyl acetate (100 mL).The two‐phase mixture was trans-
ferred into a separatory funnel. The organic layer was
separated, and the aqueous layer was extracted with ethyl
acetate (2 × 50 mL). Combined organic phases were
washed with 20% solution of KHSO4, brine, dried over
Na2SO4, and evaporated in vacuum to give crude phthalic
half ester 3 as viscous oil. The residue was dissolved in ace-
tone (60 mL), and (1S)‐α‐methylbenzylamine (S)‐4 (3.64 g,
30.0 mmol) was added dropwise. Crystallization was
performed as described above for the salt (S)‐3•(R)‐4. The
yield of the salt (R)‐3•(S)‐4: 2.9 g. Three additional
crystallizations from acetone (about 20‐30 mL) resulted
diastereomerically pure product in yield 1.82 g (6.5%); mp
20
127°C to 130°C; [α]D = −22.8 (c = 2.5 in MeOH). IR
and NMR spectra were identical with those recorded for
opposite enantiomer (S)‐3•(R)‐4.
2.5 | (S)‐cis‐Verbenol (S)‐1, ee > 99%, dr
99:1
Salt of phthalic mono‐ester and α‐methylbenzylamine (S)‐
3•(R)‐4 (12.50 g, 29.65 mmol) was treated with 20% solu-
tion of KHSO4 (150 mL) and ethyl acetate (100 mL). The
mixture was transferred into a separatory funnel and vigor-
ously shaken. The organic and aqueous layers were sepa-
rated, and the aqueous layer was additionally extracted

KOVALENKO ET AL.
3
with ethyl acetate (2 × 50 mL). Combined organic phases
were washed with brine, dried over Na2SO4, and evapo-
rated in vacuum to give a white solid residue. The residue
was dissolved in methanol (70 mL). A freshly prepared
solution of sodium methoxide (180 mmol) in methanol
(60 mL) was added dropwise, while the mixture was coold
in ice bath. Then, the reaction was stirred under argon at rt
(25°C) for 4 days. The solvent was evaporated under
reduced pressure at 30°C. Water (100 mL) was added to
the residue, and the product was extracted with diethyl
ether (4 × 50 mL). Extracts were washed with brine and
passed through a short layer of silica (70‐230 mesh, 10 g).
Evaporation of diethyl ether in vacuum gave (S)‐
cis‐ verbenol (S)‐1 (4.02 g, 89%) which was sufficiently pure
by 1H NMR (see Supporting Information, p. S3); mp 68°C
Ester of (R)‐cis‐verbenol (R)‐1 with (S)‐(−)‐Mosher
acid: 1H NMR, (500 MHz, CDCl3, δ): Selected signal
0.725 (s, 3H; CH3), J 13C‐H = 125.3 Hz.
3 | RESULTS AND DISCUSSION
Model compound (S)‐1 was obtained by lithium alumi-
num hydride reduction of its cheaper precursor
verbenone (S)‐2 (Scheme 1). This standard procedure
gave cis‐verbenol (S)‐1 in almost quantitative yield and
1
in good diastereoselectivity.15 According to H NMR, the
reduced material contained a little over 5% of trans‐
verbenol. The enantiomeric ratio for cis‐verbenol was
1
worse than 80:20, according to H NMR of the Mosher
to 71°C; [α]D = +12.0 (c = 2.0 in MeOH), lit.:15 mp
ester, which is equivalent to ee < 60%. Further study
was focused on the purification and enantioenrichment
of cis‐verbenol.
20
71°C to 72°C; [α]D23 = +11.4 (c = 0.89% in MeOH).
Often, the resolution of enantiomers by crystalliza-
tion16,17 compares favorably with other separation tech-
niques due to better robustness and scalability, and high
purity of final products. Following our successful experi-
ence,18-22 we have chosen this approach toward verbenol.
The only known report on the enantioenrichment of cis‐
verbenol was published by Mori in 1976.15 His procedure
requires resolving material with a relatively high initial ee
and rarely used 3‐β‐acetoxyetienic acid as derivatizing
agent. An obvious alternative to the resolution could be
the direct synthesis of cis‐verbenol from enantiopure α‐
pinene23; however, its limited availability and high price
restrict this option.
2.6 | (R)‐cis‐Verbenol (R)‐1, ee > 98%, dr
99:1
(R)‐cis‐Verbenol (R)‐1 was prepared from the salt (R)‐
3•(S)‐4 (1.50 g, 3.56 mmol) in the same manner as
enantiopure (S)‐cis‐verbenol (S)‐1. The yield of (R)‐1:
20
0.49 g (90%); mp 69°C to 71°C; [α]D = −12.0 (c = 2.0
in MeOH), lit.:15 mp 71°C to 72°C; [α]D = −12.8
23
(c = 0.81% in MeOH).
In our approach, crude verbenol (S)‐1 was converted
into phthalic mono‐ester (S)‐3 by treatment with phthalic
anhydride. Installed carboxylic function24,25 served
to obtain the salts with chiral bases. It was fortunate
that cheapest (R)‐α‐methylbenzylamine and (S)‐α‐
methylbenzylamine gave diastereomeric products with a
completely different crystallization behavior (Scheme 1).
2.7 | Determination of enantiomer
composition of cis‐verbenol 1
The samples of cis‐verbenol were converted into (S)‐ (−)‐
Mosher acid esters.15 cis‐Verbenol (10 mg, 0.066 mmol)
was dissolved in dichloromethane (0.2 mL), whereupon
pyridine (0.06 mL) and (S)‐Mosher acid chloride (33 mg,
0.13 mmol) were added. The mixture was left at room tem-
perature for 24 hours and then diluted with ethyl acetate
(3 mL); the resulting solution was washed with saturated
solution of NaHCO3, brine, and dried over Na2SO4. After
evaporation of the solvents, the residue was analyzed
1
by H NMR. Enantiomeric excess (ee) of (S)‐ and (R)‐
cis‐ verbenol was determined by the integration of well‐
resolved peaks at 0.835 and 0.725 ppm in 1H NMR spectra
of unpurified Mosher esters. For more accurate assessment
of the percentage of minor diastereomer, its specific signal
was compared with the 13C satellites (0.55%) belonging to
major diastereomer.
Ester of (S)‐cis‐verbenol (S)‐1 with (S)‐(−)‐Mosher
acid: 1H NMR, (500 MHz, CDCl3, δ): Selected signal
0.835 (s, 3H; CH3), J 13C‐H = 125.2 Hz.
SCHEME 1 Preparation of phthalic mono‐ester (S)‐3 and
crystallization behavior of α‐methylbenzylamine salts

4
KOVALENKO ET AL.
Hence, there is a possibility for resolution of acid 3 using
these amines.
We investigated crystallization of the salt of mono‐ester
(S)‐3 with (R)‐(+)‐α‐methylbenzylamine (R)‐4 (Scheme 2).
Single crystallization from acetone provided a material
with a significantly higher ee (up to 93% according to mea-
surements), which continued to increase after second and
third runs. The overall yield of pure salt (S)‐3•(R)‐4 was
about 50% from verbenone (S)‐2. The mono‐ester (S)‐3
was released from the salt by treatment with aqueous
inorganic acid. Removal of the phthalate group using
MeONa solution in MeOH was then followed to afford suf-
ficiently pure (S)‐cis‐verbenol (S)‐1 with greater than 99%
ee. The ee values were established according to NMR of
cis‐verbenol Mosher ester (see Supporting Information).
We also managed to isolate minor (R)‐enantiomer of
cis‐verbenol (R)‐1 (Scheme 2). Mother liquor after first
crystallization contained a relatively higher proportion
of (R)‐3•(R)‐4 salt. Phthalic mono‐ester was released
from this mother liquor and mixed with (S)‐(−)‐α‐
methylbenzylamine (S)‐4 in acetone; four successive
crystallizations resulted salt (R)‐3•(S)‐4. (R)‐cis‐verbenol
(R)‐1 was obtained from the resolved mono‐ester (R)‐3
in the same manner as (S)‐1 and found to be of similar
enantiomeric purity but opposite optical rotation.
Alongside (S)‐ and (R)‐enantiomer separation, their
diastereomeric purity (cis/trans ratio) has been improved.
Repeated crystallizations enabled almost all trans‐
verbenol derivative to be removed from the salt. The cis/
trans ratio of the resolved material has reached up to
100:1, while the initial one was less than 95:5, according
to NMR (see Supporting Information).
SCHEME 3 Stereochemical outcome of the cleavage of phthalic
mono‐ester (S)‐3
hydroxyl group.26 Especially, removal of phthalic ester by
NaOH in MeOH causes “recurrence” of trans‐isomer
impurity (Scheme 3). According to our experiments,
this undesired process can be easily avoided by using
hydroxide‐free MeONa/MeOH solution, although longer
reaction time is required.
4 | CONCLUSION
We presented simple and efficient procedure for the reso-
lution or enantioenrichment of monoterpene alcohol cis‐
verbenol. The separation of enantiomers was achieved
through the crystallization of the salts of cis‐verbenol
phthalic mono‐ester with (S)‐α‐methylbenzylamine and
(R)‐α‐methylbenzylamine.
ACKNOWLEDGMENTS
This work was supported by the National Research
Program “Biologically Active Compounds” (Sections
2.31; 2.54).
However, conversion of the resolved phthalic mono‐
esters into cis‐verbenol appeared to be complicated by
a partial epimerization of stereocenter bearing allylic
ORCID
Vitaly Kovalenko https://orcid.org/0000-0003-3426-2300
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How to cite this article: Kovalenko V,
Krauchanka A, Prokhorevich K. Practical method
for increasing optical purity of cis‐verbenol.
Chirality. 2019;1–5. https://doi.org/10.1002/
chir.23119
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