Kinetic resolution of racemic (cyclohexyl)(geranyl)acetic acid

Article abstract of DOI:10.1016/j.mencom.2014.09.002

A kinetic resolution of racemic (cyclohexyl)(geranyl)acetic acid, the active ingredient of wound-curing medication Cygerol, to (S)- and (R)-enantiomers was achieved by diastereoselective esterification with (S)- or (R)-BINOL.

Full text of DOI:10.1016/j.mencom.2014.09.002

Mendeleev
Communications
Mendeleev Commun., 2014, 24, 257–259
Kinetic resolution of racemic (cyclohexyl)(geranyl)acetic acid
Sergei G. Zlotin,* Galina V. Kryshtal, Galina M. Zhdankina, Anna A. Sukhanova,
Alexander S. Kucherenko, Boris B. Smirnov and Vladimir A. Tartakovsky
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5328; e-mail: zlotin@ioc.ac.ru
DOI: 10.1016/j.mencom.2014.09.002
A kinetic resolution of racemic (cyclohexyl)(geranyl)acetic acid, the active ingredient of wound-curing medication Cygerol, to
(S)- and (R)-enantiomers was achieved by diastereoselective esterification with (S)- or (R)-BINOL.
(Cyclohexyl)(geranyl)acetic acid 1 is the active substance of
Cygerol® that was manufactured in Russia and used for curing
of wounds, in particular surgery wounds, radiation or trophic
ulcers and burns.1–7 Being structurally similar to natural iso-
prenoids, in particular to vitamins of group A, compound 1
exhibits antibacterial activity and has an extremely low toxicity.
Furthermore, isoprenoid acids turned to be promising as tracking
drugs for cell therapy of various human diseases and injuries
of vital organs and tissues with mesenchymal stem cell (MSC)
and MSC-derived cardiomyoblasts.8 Molecule of 1 contains a
stereocenter, however, just racemic form of 1 is known so far.
Taking into account that biological activities of enantiomers
may be different9 we decided to prepare both enantiomers of
compound 1. Diastereoselective crystallization of rac-1 deriva-
tives (esters, amides, etc.) is not applicable in this case as most of
them are liquids6 due to the presence of long-chained geranyl
group. Therefore, we have selected a kinetic resolution method
assuming that enantiomers of 1 should react with chiral alcohols
with different rates. This method is commonly used for the
resolution of dicarboxylic acids via diastereoselective reaction
of cyclic meso-anhydrides with chiral alcohols.10 However, a few
examples of diastereoselective esterification of prochiral mono-
carboxylic acids have been reported up to now, enantiomeric
excesses of the products having been commonly modest.11
We synthesized racemic compound 1 by a modified synthetic
scheme1,4–6 that included alkylation of diethyl cyclohexyl-
malonate 2 with geranyl chloride 3 followed by a one-pot
hydrolysis–decarboxylation sequence starting from compound 4
(Scheme 1). We managed to improve the yield of diester 4 from
656 to 86% with respect to consumed starting compounds 2 and
3 by carrying out the alkylation in the phase-transfer catalytic
system KOH–DMF–BnNEt3Cl instead of Na–toluene,1 NaH–
DMF6 or NaOEt–EtOH6 systems. Furthermore, a change of the
solvent at the hydrolysis step (EtOH instead of water) allowed
us to significantly accelerate the reaction which simplified the
procedure.
For a kinetic resolution of rac-1 we have chosen (S)- and
(R)-BINOLs as we expected that the presence of bulky C2-sym-
metric binaphthyl fragment in these chiral auxiliaries12 would
enhance diastereoselectivity of the esterification reaction. First of
a
ll, we studied the model reaction between rac-1 and rac-BINOL in
the presence of DCC–DMAP at ambient temperature (Scheme 2).
We were pleased to find out that even in the presence of 2 equiv.
of acid rac-1 only monoester 5 was formed within 2 h from the
reaction start. The absence of the double-esterification product
may be attributed to a shielding of the hydroxyl group in com-
pound 5 by the geranyl and cyclohexyl fragments. This finding
was unexpected and useful for a success of kinetic resolution as
stereochemical outcomes of the first and second esterification
steps might be different.
Next, we carried out the esterification of rac-1 with (S)-BINOL
under the same conditions to obtain compound 5a in 75% yield
and with dr 90:10 (HPLC data, see Scheme 2). Ester 5a was
hydrolyzed to acid 1a by LiOH∙H2O in the THF–H2O solvent
O
DCC /
Ger
DMAP
HO
HO
O
+
rac-1
DCM, room
temperature,
2 h
Cy HO
Yield 75%
5 (from rac-BINOL)
or 5a (dr 90:10)
[from (S)-BINOL]
or 5b (dr 87:13)
rac-BINOL or
(S)-BINOL or
(R)-BINOL
Ger Cl
3
CO2Et
CO2Et
CO2Et
KOH / BnNEt3Cl
(5 mol%)
[from (R)-BINOL]
CO2Ph
Ger
Cy
Ger
CO2Et
DMF, 90 °C
Cy
Cy
MeOH, 50 °C
LiOH∙H2O
2
4
Yield 80–85%
7a (80% ee) or
7b (75% ee)
LiOH∙H2O
THF / H2O
Yield 56% (86%
with respect to
consumed 2 and 3)
i, (COCl)2, benzene,
room temperature
ii, PhOH, DCM,
(S)-BINOL or
(R)-BINOL
Yield 92%
Me
Me
Me
+
room temperature
i, KOH/EtOH, reflux, 2 h
ii, neat, 150 °C, 2 h
CO2H
*
CO2H
CO2Me
KOH
Cy
Ger
Cy
Ger
EtOH, 60 °C
rac-1
Yield 85%
Yield 85–87%
Cy = cyclohexyl
Ger = geranyl
6a or 6b
1a or 1b
Scheme 1
Scheme 2
© 2014 Mendeleev Communications. All rights reserved.
– 257 –

Mendeleev Commun., 2014, 24, 257–259
Pre Br
system. Unfortunately, the liberated acid 1a and (S)-BINOL were
8
found to have similar retention times and our attempts to separate
them by column chromatography on silica gel failed. Therefore,
we included a step of LiOH-promoted trans-esterification of
compound 5a with MeOH followed by hydrolysis of methyl
ester 6a with KOH–EtOH system. Products 6a and 1 could be
easily purified by column chromatography. Since acid 1a does
not contain a chromophoric group, we converted it to suitable for
UV detection phenyl ester 7a. The ee value of the latter (HPLC data,
Chiralcel AD-H) and consequently of original acid 1a was 80%.†
Our efforts to isolate antipode 1b that remained unchanged
during the esterification of rac-1 with (S)-BINOL were unsuc-
cessful as chromatographic characteristics of these compounds are
similar. However, we synthesized enantiomer 1b via a diastereo-
selective reaction of rac-1 with (R)-BINOL followed by LiOH-
promoted trans-esterification of (R)-BINOL ester 5b (dr 87:13)
and basic hydrolysis of methyl ester 6b to target acid 1b (see
Scheme 2). According to HPLC data for corresponding phenyl
ester 7b, the enantiomeric excess of product 1b was 75%. Un-
fortunately, we were not able to determine absolute configura-
tions of oily enantiomers 1a and 1b because the results of their
CD-analysis were not interpretable.
CO2Et
CO2Et
CO2Et
KOH / BnNEt3Cl
(5 mol%)
Cy
Pre
CO2Et
DMF, 90 °C
Yield 65%
Cy
2
9
(S)-BINOL
DCC/DMAP
i, KOH / EtOH, reflux, 2 h
ii, neat, 150 °C, 2 h
CO2H
Pre
Cy
Yield 81%
DCM, room
temperature, 2 h
10
O
O
Cy
Pre
O
O
O
Pre
Pre
+
HO
Cy
Cy
O
11
Yield 80%, dr 60:40
12
Yield 15%
Cy = cyclohexyl
Pre = Me2C=CHCH2
Scheme 3
†
The presence of the long-chained geranyl group in compound
rac-1 appeared to be a principal stereocontrolling factor for a
successful kinetic resolution of rac-1. Indeed, similarly prepared
from diethyl cyclohexylmalonate 2 and prenyl bromide 8 com-
pound 10 bearing the prenyl group instead of the geranyl unit at
the stereogenic carbon atom exhibited much worse diastereo-
selectivity in the reaction with (S)-BINOL to afford correspond-
ing ester 11 (dr 60:40) along with the exhaustive esterification
product 12 (Scheme 3).
In summary, we have prepared for the first time enantio-
merically enriched samples of 2-cyclohexyl-2-geranylacetic
acids 1a and 1b. Further biological studies will show whether
pharmacological properties of enantiomers are influenced by
their optical configurations.
2-Cyclohexyl-5,9-dimethyldeca-4,8-dienoic acid 2'-hydroxy[1,1']bi-
naphthalen-2-yl esters 5, 5a, 5b (general procedure). The mixture of
rac-1 (195 mg, 0.7 mmol), rac-, (S)- or (R)-BINOL (100 mg, 0.35 mmol),
DCC (144 mg, 0.7 mmol) and DMAP (8.0 mg) in CH2Cl2 (7.0 ml) was
stirred at ambient temperature for 2 h (TLC monitoring). A precipitate was
filtered off, the filtrate was washed successively with 10% HCl (2×4 ml),
w
ater (2×5 ml) and dried over anhydrous MgSO4. The solvent was evaporated
under reduced pressure (40 Torr, 40°C) and the residue was purified by
column chromatography (SiO2, hexane–toluene, 1:1) to afford the BINOL
ester 5, 5a, or 5b as colourless oils, 140 mg, yield 75%. 1H NMR (CDCl3)
d: 0.80–1.10 (m, 4H), 1.15–1.80 (m, 8H), 1.85–2.25 (m, 6H), 4.90–5.20
(m, 2H, 2HC=), 5.40 (m, 1H, OH), 7.05 (d, 1H, J 8.8 Hz), 7.19–7.41 (m,
7H, Ar), 7.50 (t, 1H, J 7.7 Hz), 7.80 (d, 1H, J 8.0 Hz), 7.88 (d, 1H, J 7.7 Hz),
7.95 (d, 1H, J 8.0 Hz), 8.10 (d, 1H, J 10.0 Hz). 13C NMR (CDCl3) d: 16.1,
16.2, 26.3, 26.8, 27.9, 29.8, 30.1, 30.3, 39.5, 52.2, 133.7 (Ar), 133.8 (Ar),
137.2 (Ar), 137.4 (Ar), 148.3 (Ar), 152.1 (Ar), 174.9 (C=O). ESI-HRMS,
m/z: 547.3207 [M+H]+ (calc. for C38H42O3, m/z: 547.3213). HPLC data
(Chiralpak AD-H, hexane–PriOH, 7:3, 30°C, 0.7 ml min–1, 254 nm):
5a, t1 = 5.67 min (minor), t2 = 6.10 (major), dr 90:10; 5b, t1 = 7.70 min
(major), t2 = 8.45 (minor), dr 87:13.
This work was supported by the Presidium of the Russian
Academy of Sciences (Basic research program ‘The Basic Sciences
for Medicine’).
Methyl (cyclohexyl)(geranyl)acetates 6a or 6b. Solid LiOH∙H2O
(13 mg, 3.0 mmol) was added to a solution of 5a or 5b (415 mg, 0.76 mmol)
in MeOH (2 ml). The mixture was stirred at 50°C for 7 h (TLC monitoring)
and acidified with TFA (0.35 mg). The solvent was evaporated under
reduced pressure (40 Torr, 40°C) and the residue was purified by column
chromatography (SiO2, hexane–toluene, 3:1) to afford the corresponding
methyl esters 6a or 6b. Colourless oils, 189 or 178 mg, yield 85 or 80%,
respectively, nD20 1.4793, Rf 0.65. 1H NMR (CDCl3) d: 0.90–1.31 (m, 6H,
3CH2), 1.60 (s, 6H, 2Me), 1.68 (s, 3H, Me), 1.90–2.10 (m, 4H, 2CH2),
2.16–2.30 (m, 3H, CH, CH2), 3.63 (s, 3H, Me), 5.05–5.15 (m, 2H, 2HC=).
13C NMR (CDCl3) d: 15.9, 17.7, 25.9, 26.3, 26.4, 26.7, 28.1, 30.8, 30.9,
39.9, 51.0, 52.2, 121.7, 124.3, 131.3, 136.9, 176.0. Chiral auxiliaries
(S)-BINOL (196 mg, 90%) or (R)-BINOL (184 mg, 85%) were recovered
by column chromatography as colourless solids, mp 206–208°C (lit.,13
mp 206–210°C), Rf = 0.25.
(Cyclohexyl)(geranyl)acetic acids 1a or 1b. The solution of KOH
(100 mg, 1.8 mmol) in EtOH (2 ml) was added to a solution of 6a or 6b
(175 mg, 0.6 mmol) in the same solvent (2 ml) and the reaction mixture
was stirred at 60°C for 20 h (TLC monitoring). The solvent was evaporated
under reduced pressure (40 Torr, 40°C) and water (2 ml) was added to the
residue. The resulting mixture was acidified to pH ~2 with 15% HCl and
extracted with diethyl ether (3×2 ml). The combined organic extract was
dried over anhydrous MgSO4 and the solvent was evaporated under
reduced pressure (40 Torr, 40°C) to afford the corresponding acid 1a,
[a]D25 = +3.89 (c 0.36, MeOH), or 1b, [a]D25 = −3.1 (c 0.48, MeOH) as
colourless oils, 145 mg (87%) or 142 mg (85%), respectively.
Online Supplementary Materials
Supplementary data associated with this article (synthetic details
and characteristics of the compounds obtained) can be found in
the online version at doi:10.1016/j.mencom.2014.09.002.
Phenyl (cyclohexyl)(geranyl)acetates 7a or 7b. Oxalyl chloride (0.19 ml,
2.2 mmol) was added to a solution of 1a or 1b (278 mg, 1.0 mmol) in
dry benzene (1.0 ml) and the reaction mixture was stirred at ambient
temperature for 2 h. The solvent was evaporated under reduced pressure
(40 Torr, 40°C), then THF (1.0 ml) and Et3N (1.0 mmol) were successively
added to the residue. The resulting solution was gradually added to a
solution of PhOH (94 mg, 1.0 mmol) in THF (1.0 ml) at 0°C and the
mixture was stirred at ambient temperature for 5 h. The precipitate was
filtered off and washed with THF (2×1 ml). The combined extracts were
concentrated under reduced pressure (40 Torr, 40°C) and the residue was
purified by column chromatography (SiO2, hexane–toluene, 9:1) to afford
the products 7a [a]D25 = +4.80 (c 0.1, CH2Cl2), or 7b [a]D25 = −4.30 (c 0.1,
CH2Cl2). Colourless oils, 326 mg, yield 92%, nD20 1.5112. 1H NMR (CDCl3)
d: 1.00–1.41 (m, 5H, CH, 2CH2), 1.60 (s, 6H, 2Me), 1.68 (s, 3H, Me),
1.55–1.98 (m, 5H, CH, 2CH2), 2.00–2.18 (m, 4H, 2CH2), 2.33–2.50
(m, 3H, CH, CH2), 5.08–5.18 (m, 2H, 2HC=), 7.00–7.43 (m, 5H, Ar).
13C NMR (CDCl3) d: 16.1, 17.7, 25.7, 26.3, 26.4, 26.7, 28.2, 30.7, 31.0,
40.1, 52.3, 121.8, 122.0, 124.2, 125.6, 129.3 (Ar), 131.5 (Ar), 137.3 (Ar),
150.9 (Ar), 174.0 (C=O). EI-MS, m/z: 354 [M]+. HPLC data (Chiralpak
AD-H, hexane–PriOH, 7:3, 30°C, 0.7 ml min–1, 254 nm): 7a, tR (major) =
= 4.83 min, ee 80%; 7b, tR (major) = 6.45 min, ee 75%.
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Mendeleev Commun., 2014, 24, 257–259
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