Synthesis and stereochemical assignment of geraniol- and nerol-derived Cygerol enantiomers

Article abstract of DOI:10.1016/j.tetasy.2017.10.024

The enantiomers (up to 99% ee) of both geraniol- and nerol-derived 2-cyclohexyl-5,9-dimethyldeca-4,8-dienoic acid, the active ingredient of the wound healing medication Cygerol, were prepared via a low-temperature alkylation, basic hydrolysis, derivatization with (S)-4-benzyloxazolidin-2-one and chromatographic separation steps. The absolute configuration of stereocenters in the antipodes having an (E)- or (Z)-geometry of the internal double bond was determined based on characteristic ¹H NMR signals of the corresponding (S)-4-benzyloxazolidin-2-one-derived imides and on conversion to the known diethyl (S)-2-cyclohexylsuccinate and (S)-2-cyclohexylbutane-1,4-diol with reported specific rotations.

Full text of DOI:10.1016/j.tetasy.2017.10.024

Tetrahedron: Asymmetry 28 (2017) 1834–1841
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and stereochemical assignment of geraniol- and
nerol-derived Cygerol enantiomers
⇑
Anna A. Sukhanova, Ilya A. Puchkin, Andrei A. Vasil’ev, Sergei G. Zlotin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantiomers (up to 99% ee) of both geraniol- and nerol-derived 2-cyclohexyl-5,9-dimethyldeca-4,8-
dienoic acid, the active ingredient of the wound healing medication Cygerol, were prepared via a
low-temperature alkylation, basic hydrolysis, derivatization with (S)-4-benzyloxazolidin-2-one and
chromatographic separation steps. The absolute configuration of stereocenters in the antipodes having
an (E)- or (Z)-geometry of the internal double bond was determined based on characteristic 1H NMR sig-
nals of the corresponding (S)-4-benzyloxazolidin-2-one-derived imides and on conversion to the known
diethyl (S)-2-cyclohexylsuccinate and (S)-2-cyclohexylbutane-1,4-diol with reported specific rotations.
Ó 2017 Elsevier Ltd. All rights reserved.
Received 21 October 2017
Accepted 25 October 2017
Available online 14 November 2017
1. Introduction
Known data
CO2H
∗
(E,Z)-2-Cyclohexyl-5,9-dimethyldeca-4,8-dienoic acid 1 is the
active ingredient of Cygerol, an efficient medication used for
wound healing, including surgical wounds, radiation or trophic
ulcers and burns.1 Being structurally similar to natural isoprenoids,
in particular to vitamins of group A, compound 1 exhibits antibac-
terial activity and has an extremely low toxicity.1d Furthermore,
isoprenoid acids turned out 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.2 Cygerol has been manufactured in Russia for
over thirty years at the end of the 20th century represented a mix-
ture of racemic E- and Z-isomers 1a and 1b in ꢀ3:1 ratio
(Scheme 1). According to current guidelines governing the devel-
opment of new chiral drugs enacted in 1992 in the USA3 and in
1993 in the EU,4 each medication can be produced as a racemate
only after experimental evidences are obtained that neither of
the enantiomers exhibits undesirable side effects. Therefore, the
asymmetric synthesis of enantiomerically pure medications has
attracted considerable attention over the past decades.5 Recently,
we achieved a resolution of racemic Cygerol to enantiomerically
enriched mixtures of 1a and 1b via a diastereoselective esterifica-
tion with (S)- or (R)-BINOL.6 However, these mixtures have not
been separated to individual components and their absolute con-
figurations have not been established so far. Herein, we reported
1
7
9
3
5
This
CO2H
∗
research
4
2
8
10
6
(S)- or (R)-1a
(S)- or (R)-1b
CO2H
∗
Cygerol
(1a/1b ~3:1)
Scheme 1. Research strategy.
the first synthesis of both enantiomers of compounds 1a and 1b
and experimental determination of their absolute configuration.
2. Results and discussion
At first, we synthesized the unknown individual isomers rac-1a
and rac-1b with E- or Z- configuration of the internal C4 = C5 double
bond, respectively. The conventional synthesis of Cygerol is based
on the alkylation of diethyl 2-cyclohexylmalonate with linalool-
derived mixture of geranyl and neryl chlorides followed by basic
hydrolysis and thermal decarboxylation reactions.1 To attain geo-
metrically pure alkylation products, we used geraniol and nerol-
derived chlorides with strictly defined E- or Z-configuration of
the key double bond as reactants. Furthermore, to avoid the ther-
mal decarboxylation step which might cause E/Z isomerization,7
2-cyclohexylacetate 2 was applied as a suitable substrate. The
alkylation of 2 with geranyl (neryl) chlorides and prenyl bromide
⇑
Corresponding author. Fax: +7 499 135 5328.
E-mail address: zlotin@ioc.ac.ru (S.G. Zlotin).
https://doi.org/10.1016/j.tetasy.2017.10.024
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.

A. A. Sukhanova et al. / Tetrahedron: Asymmetry 28 (2017) 1834–1841
1835
proceeded under mild conditions (LDA/THF/À78 °C) yielding the
corresponding esters 3a, 3b and 4 in moderate to high yields
(Scheme 2). The obtained compounds were converted into the cor-
responding racemic acids rac-1a, rac-1b and rac-5 via prolonged
refluxing with alkali in EtOH. The severe hydrolysis conditions
did not affect the E/Z isomerization. Indeed, the diagnostic dC6
(39.9 and 32.0 ppm) and dMe (16.0–16.1 and 23.5 ppm) values in
the 13C NMR spectra of compounds 1a/3a and 1b/3b corresponded
to those for geranyl (dC6 39.5, dMe 16.1) and neryl (d6C 31.9, dMe 23.4)
chlorides8 thus proving the E-configuration for 1a/3a and Z-config-
uration for 1b/3b.
Then, we attempted preparation of scalemic acids 1a and 1b via
diastereoselective esterification of rac-1a and rac-1b with (R)-
BINOL. However, equimolar mixtures (R,S)-6a/(R,R)-6a and (R,S)-
6b/(R,R)-6b were produced in these reactions under conditions
reported for kinetic resolution of the mixed sample rac-1a/rac-1b
(ꢀ3:1)6 (Scheme 3). We succeeded in separation of the (R,S)-6b/
(R,R)-6b mixture to the corresponding diastereomers (R,S)-6b (dr
90:10) and (R,R)-6b (dr 95:5) by column chromatography on silica
gel. Alkaline re-esterification/hydrolysis of (R,S)-6b and (R,R)-6b
with LiOHÁH2O/MeOH led to corresponding enantiomerically
enriched acids (S)-1b or (R)-1b. Unfortunately, the ee values of
the acids (HPLC data for the 2,4-dinitrophenyl esters) did not
exceed 64–67%, which indicated partial racemization over the re-
esterification/hydrolysis step (see Section 4 and SI). Numerous
attempts to isolate geraniol-derived diastereomers (R,S)-6a and
(R,R)-6a under various conditions were unsuccessful.
Therefore, we examined another approach to scalemic acids 1a
and 1b which was based on the use of enantiomerically pure oxa-
zolidin-2-ones, in particular, the available compound (S)-7, as a
chiral auxiliary. Chromatographic9–12 or kinetic13–15 resolution of
diastereomeric imides containing a chiral oxazolidin-2-one group
has been reported.9–13 However, to the best of our knowledge, this
auxiliary has never been applied for efficient resolution of
a-sub-
stituted linear isoprenoid acid enantiomers. The reactions of acid
chlorides rac-1a-Cl and rac-1b-Cl with (S)-oxazolidin-2-one 7
afforded equimolar mixtures of diastereomeric geraniol- or nerol-
derived imides (S,S)-8a/(S,R)-8a and (S,S)-8b/(S,R)-8b. Both 8a
and 8b could be readily separated to the corresponding diastere-
omers by column chromatography (Scheme 4). Moreover, we
O
GerCl
60%
Cy
Cy
rac-1a
rac-1b
OEt
3a
1. KOH/EtOH
rfx, 25 h
Ger
Ner
2. HCl
O
O
93-95%
NerCl
52%
LDA/THF
-78oC
Cy
OEt
3b
OEt
2
1. KOH/EtOH
rfx, 8 h
O
O
PreBr
83%
2. HCl
Cy
Cy
OH
OEt
96%
Pre
rac-5
Pre
4
Cy:
Ger:
Pre:
Ner:
Scheme 2. Synthesis of racemic geranyl, neryl and prenyl substituted cyclohexylacetic acids.
O
Ger
*
rac-1a
O
Cy
OH
DCC,
OH
OH
DMAP
6a
6a
(R,S)- /(R,R)- (~1:1), Yield 88%
DCM
O
O
Ner
O
Ner
rac-1b
O
(R)-BINOL
Cy
OH
Cy
OH
6b
(R,S)- , 40%, dr 90:10
(R,R)-6b, 39%, dr 95:5
1. LiOH*H2O/MeOH
2. KOH/EtOH
70%
72%
O
O
Ner
HO
Ner
HO
Cy
Cy
(S)-1b (64% ee)
(R)-1b (67% ee)
Scheme 3. (R)-BINOL-based approach to (S)-1b and (R)-1b.

1836
A. A. Sukhanova et al. / Tetrahedron: Asymmetry 28 (2017) 1834–1841
Table 1
managed to convert each diastereomer to corresponding chiral
acids (S)-1a, (R)-1a, (S)-1b or (R)-1b without racemization (HPLC
data for the 2,4-dinitrophenyl esters) under the action of the
LiOH/H2O2/THF hydrolytic system.16
Characteristic signals in the 1H NMR spectra of (S,S)- or (S,R)-isomers of 8a, 8b and 9
Compound
dCH
(a-CH), ppm
dCH (CH2Ph), ppm
(S,S)-Isomer (S,R)-Isomer
(S,S)-Isomer
(S,R)-Isomer
To determine the absolute configuration of acids 1a and 1b, we
synthesized compound 9 which was a prenyl analog of 8a and 8b,
using both non-selective and stereoselective pathways (Scheme 5).
The mixture of (S,S)-9/(S,R)-9 (ꢀ1:1) was obtained by the reaction
of (S)-7 with 2-cyclohexyl-5-methylhex-4-enoic acid chloride rac-
5-Cl. Stereoselective synthesis of (S,S)-9 (dr 98:2) was based on the
anti-selective LDA-induced alkylation of imide (S)-10 (readily
attainable from (S)-7 and cyclohexylacetyl chloride) with prenyl
bromide (the Evans reaction17).
The Evans procedure appeared inapplicable to the stereoselec-
tive synthesis of (S,S)-8a and (S,S)-8b from (S)-10 and geranyl- or
neryl chlorides or bromides apparently due to inhibiting impact
of the bulky geranyl (neryl) groups on the alkylation reaction. Nev-
ertheless, some characteristic spectral features of (S,S)-9 allowed
tentative stereochemical assignment for both diastereomers of
8a
8b
9
3.85–3.93
3.85–3.92
3.86–3.91
3.78–3.85
3.76–3.83
3.75–3.82
3.30
3.24
3.22
3.36
3.39
3.35
with the signals of (S,S)-9. The corresponding protons in the
(S,S)- and (S,R)-isomers of 8a and 8b resonated within the same
non-overlapping areas (see Table 1 and Supporting Information)
testifying 9 having similar absolute configurations of stereocenters
in the respective imides 8a and 8b and, consequently, acids 1a and
1b (see Schemes 4 and 5).
The reliability of the made assignments was unambiguously
confirmed by conversion of isoprenoid acids (S)-1a and (S)-1b to
known diethyl 2-cyclohexylsuccinate 13 with reported polarime-
try parameters18 via the esterification/ozonolysis/functional group
transformation reaction sequence (Scheme 6). At first, the syn-
thetic scheme was verified on a racemic sample of 1a aiming also
to access racemic dibenzoate 15 suitable for chiral HPLC analysis19
(see Supporting Information).
On moving to scalemic substances, in both (S)-1a and (S)-1b
cases dextrorotatory samples of diethyl 2-cyclohexylsuccinate 13
were obtained, which evidenced to their (S)-configuration.18 To
determine the enantiomeric purity of diester 13, it was reduced
to 2-cyclohexylbutane-1,4-diol 14 and then converted to diben-
zoate 15. Crude diol 14 derived from (S)-3b was levorotatory
(though its rotation was lower than reported in the literature),
which was an additional affirmation of the (S)-configuration.20
The HPLC analyses of scalemic dibenzoates 15 showed that their
enantiomeric excesses were somewhat reduced over the derivati-
zation outlined on Scheme 6, namely, (S)-1a of 80% ee turned into
(S)-15 with 68% ee, while (S)-1b of 99% ee turned into (S)-15 with
84% ee. Most probably, the esterification and/or oxidation stages
may be responsible for the racemization, since during rapid
hydride reduction of diester (S)-13 and benzoylation of diol (S)-
14 it seems unlikely to occur. The remaining two ‘cygerols’ were
obviously (R)-enantiomers.
compounds 8a and 8b. Indeed, signals of the
a-CH proton and a
CH2 proton of the Bn group are located in the 1H NMR spectra of
(S,S)-9 at 3.86–3.91 ppm (m, 1H) and 3.22 ppm (dd, 1H), respec-
tively (see Scheme 5). In the 1H NMR spectra of the mixed sample
(S,S)-9/(S,R)-9 the corresponding signals of (S,R)-9 were located at
3.75–3.82 ppm (m, 1H) and 3.35 ppm (dd, 1H), respectively, along
1a
(S)- , 80% ee
1a
(R)- , 97% ee
LiOH/H2O2
THF
Bn
Bn
(S)
(S)
1. BuLi, THF
1a
Ger
Ger
H
H
2. rac- -Cl
O
N
+
O
N
(
)
R
( )
S
Cy
Cy
O
O
O
O
Bn
NH
(S,S)-8a
(S,R)-8a
34%, dr 91:9
30%, dr 99:1
O
Bn
Bn
7
O
(S)
(S)
1. BuLi, THF
1b
Ner
Ner
H
H
2. rac- -Cl
O
N
O
N
+
(R) Cy
( )
S Cy
O
O
O
O
(S,S)-8b
18%, dr 99:1
8b
(S,R)-
15%, dr 92:8
3. Conclusion
LiOH/H2O2
THF
The first synthesis of E- and Z-isomers of 2-cyclohexyl-5,9-
dimethyldeca-4,8-dienoic acid, which is the active ingredient of
wound-curing medication Cygerol, was achieved via a low-temper-
ature alkylation of ethyl 2-cyclohexylacetate with geranyl or neryl
chlorides, respectively, followed by basic hydrolysis of the
resulting esters. The racemic E- and Z-isomers were converted into
readily separable diastereomeric imides bearing the (S)-4-benzy-
loxazolidin-2-one unit which were hydrolyzed to corresponding
(S)- and (R)-antipodes of high enantiomeric purity (up to 99% ee).
The absolute configuration of the antipodes was determined basing
on characteristic signals in the 1H NMR of corresponding (S)-4-ben-
zyloxazolidin-2-one imides and on facile conversion to known
diethyl (S)-2-cyclohexylsuccinate and (S)-2-cyclohexylbutane-
1,4-diol with reported specific rotations.
(S)-1b, 99% ee
1b
(R)- , 85% ee
Scheme 4. (S)-Oxazolidin-2-one-based approach to acids (S)-1a, (R)-1a, (S)-1b and
(R)-1b.
Bn
NH
7
Bn
(
)
S
(S)
5
rac- -Cl
O
O
N
*
BuLi, THF
86%
Cy
O
O
O
(S,S)-9/(S,R)-9 (1:1)
C(O)Cl
n-BuLi, THF,
-78oC, 86%
Cy
Ph
H
3.22 ppm
(dd, 1H)
4. Experimental
4.1. General
Bn
H
(S)
(S)
3.86-3.91 ppm
(m, 1H)
Cy
PreBr, LDA
H
O
N
O
N
THF, -78oC
30%
(S)
Cy
O
O
O
O
Commercially available reagents were used without further
purification. The solvents were purified by standard procedures.
Reactions were monitored by thin layer chromatography using
9
(S,S)- , dr 98:2
10
(S)-
Scheme 5. Non-selective and stereoselective pathways to imide 9.

A. A. Sukhanova et al. / Tetrahedron: Asymmetry 28 (2017) 1834–1841
1837
Cy
CO2Et
(S)-1a, 80% ee
1) O3, CH2Cl2, -78 °C
2) Me2S
EtOH, DCC, DMAP
3a
(S)-
or
CH2Cl2, 0-5 °C, 18 h
or
(S)-1b, 99% ee
Cy
CO2Et
3b
(S)-
NaClO2, H2O2,
Cy
CO2Et
CO2Et
Cy
OH
Cy
NaH2PO4
LiAlH4
THF
EtOH, DCC, DMAP
CH2Cl2, 0-5 °C, 18 h
CO2Et
O
CO2Et
MeCN,
O
0-5 °C, 1 h
11
(S)-
12
(S)-
(S)-13
Cy
Cy
PhCO2H, DCC, DMAP
CH2Cl2, 0-5 °C, 18 h
OC(O)Ph
OC(O)Ph
OH
OH
Cy = cyclohexyl
68% ee from (S)-1a
84% ee from (S)-1b
(S)-14
(S)-15
Scheme 6. Transformation of (S)-1a and (S)-1b to known compounds (S)-13–(S)-15.
silica plates and stained with UV or potassium permanganate.
Chromatographic purification was performed on silica gel (Acros
0.06–0.2). The 1H and 13C NMR spectra were recorded using Bruker
AM-300 instrument [300.13 MHz (1H), 75.47 MHz (13C), respec-
tively] in CDCl3. The high-resolution mass spectra (HRMS) were
measured using a Bruker microTOF II spectrometer with electro-
spray ionization (ESI). The IR spectra were recorded using a Spe-
(C@O); 1H NMR (300 MHz, CDCl3): d 5.10–5.08 (m, 2H), 4.12 (q, J
= 6.0 Hz, 2H), 2.30–1.97 (m, 6H), 1.84–1.49 (m, 6H), 1.69 (s, 3H),
1.61 (s, 6H), 1.30–0.93 (m, 6H), 1.26 (t, J = 6.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 175.4, 136.6, 131.2, 124.2, 121.6, 59.7, 52.3,
39.9, 39.7, 30.9, 30.7, 28.0, 26.7, 26.4, 26.3, 26.3, 25.6, 17.6, 16.0,
14.4; HRMS (ESI) m/z calcd for C20H34NaO+2: 329.2451; found [M
+Na]+ 329.2450.
cord M82 spectrometer. Specific optical rotations
[
a]
were
D
measured on a Jasco P-2000 instrument at 589 nm. Enantiomeric
ratios of the products were determined by HPLC (Stayer, 250
mm  4.6 mm Chiralpak AD-H or OD-H column, n-hexane/i-PrOH,
40 °C) and were re-calculated to ee’s. Solvents of ‘For chromatogra-
phy’ grade were purchased and used for HPLC-analysis as they are.
4.2.1.2. Ethyl (Z)-2-cyclohexyl-5,9-dimethyldeca-4,8-dienoate
rac-3b.
Colorless liquid, 0.69 g (52%); IR (CHCl3, cmÀ1): 1735
(C@O); 1H NMR (300 MHz, CDCl3): d 5.13–5.04 (m, 2H), 4.15 (q, J
= 6.0 Hz, 2H), 2.28–1.95 (m, 6H), 1.84–1.49 (m, 6H), 1.71 (s, 3H),
1.68 (s, 3H), 1.63 (s, 3H), 1.35–0.85 (m, 6H), 1.25 (t, J = 6.0 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 175.6, 136.9, 131.7, 124.4,
122.4, 59.9, 52.6, 40.0, 32.0, 31.0, 30.8, 27.9, 26.6, 26.5, 26.4, 26.4,
25.8, 23.5, 17.7, 14.5.
4.2. Preparation of racemic carboxylic acids rac-1a, rac-1b and
rac-5
4.2.1. Synthesis of racemic carboxylic acid ethyl esters rac-3a,
rac-3b and rac-4 (General procedure)
4.2.1.3. Ethyl 2-cyclohexyl-5-methylhex-4-enoate rac-4. Color-
less liquid, 0.86 g (83%); IR (CHCl3, cmÀ1): 1724 (C@O); 1H NMR
(300 MHz, CDCl3): d 5.08–5.03 (m, 1H), 4.13 (q, J = 6.0 Hz, 2H),
2.28–2.12 (m, 3H), 1.84–1.50 (m, 5H), 1.68 (s, 3H), 1.61 (s, 3H),
1.35–0.92 (m, 6H), 1.25 (t, J = 6.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 175.5, 133.0, 121.7, 59.7, 52.3, 39.9, 30.9, 30.7, 28.1,
26.4, 26.3, 26.3, 25.7, 17.7, 14.3; Elemental Analysis calcd for
Lithium diisopropylamide (LDA) was prepared by treating a stir-
red solution of diisopropylamine (0.53 g, 5.2 mmol) in dry THF (25
mL) with 2.5 M n-butyllithium in hexane (2.1 mL, 5.2 mmol) under
argon at À78 °C. The resulting solution was warmed to À30 °C and
then recooled to À78 °C. Ethyl cyclohexylacetate 2 (0.74 g, 4.35
mmol) in dry THF (2 mL) was added dropwise to this solution via
syringe over a 10 min. The mixture was stirred at À78 °C for 0.5
h. Then the corresponding allylic halide (5.2 mmol) in dry THF (2
mL) was syringed, and the mixture was stirred without external
cooling until it reached ambient temperature. Diethyl ether (30
mL) was added and the mixture was washed successively with 1
N HCl (2 Â 10 mL), brine (2 Â 10 mL) and water (2 Â 10 mL). The
organic layer was dried over anhydrous sodium sulfate and the sol-
vent was evaporated under reduced pressure (40 Torr). The residue
was purified by column chromatography (silica gel, n-hexane/
CH2Cl2 20:1 to 5:1) to afford the corresponding racemic ester.
C15H26O2: C 75.58, H 10.99. Found C 75.54, H 11.00.
4.2.2. Hydrolysis of racemic carboxylic acid ethyl esters (General
procedure)
The esters rac-3a, rac-3b and rac-4 were converted to corres-
pording carboxylic acids rac-1a, rac-1b and rac-5 by refluxing with
3 eq KOH in 96%-EtOH for 8–25 h (see ref.6).
4.2.2.1. (E)-2-Cyclohexyl-5,9-dimethyldeca-4,8-dienoic acid rac-
1a.
Colorless viscous oil, yield 95%; IR (CHCl3, cmÀ1): 1705
(C@O); 1H NMR (300 MHz, CDCl3): d 10.60 (br.s, 1H), 5.15–5.07
(m, 2H), 2.33–2.17 (m, 3H), 2.08–2.00 (m, 4H), 1.85–1.55 (m,
5H), 1.69 (s, 3H), 1.61 (s, 6H), 1.33–0.98 (m, 6H); 13C NMR (75
MHz, CDCl3): d 182.2, 137.3, 131.4, 124.3, 121.4, 52.3, 39.9, 39.8,
4.2.1.1. Ethyl (E)-2-cyclohexyl-5,9-dimethyldeca-4,8-dienoate
rac-3a.
Colorless liquid, 0.80 g (60%); IR (CHCl3, cmÀ1): 1740

1838
A. A. Sukhanova et al. / Tetrahedron: Asymmetry 28 (2017) 1834–1841
30.9, 30.7, 27.8, 26.7, 26.4, 26.4, 26.4, 25.7, 17.7, 16.1; HRMS (ESI)
4.3.3. (R)-1-(2-Hydroxynaphthalen-1-yl)naphthalen-2-yl (Z,2R)-
2-cyclohexyl-5,9-dimethyldeca-4,8-dienoate (R,R)-6b
m/z calcd for C18H31O+2: 279.2318; found [M+H]+ 279.2316.
Colorless oil, yield 526 mg (39%). [a]
28 = +68.8 (c 0.38, CHCl3); IR
D
4.2.2.2. (Z)-2-Cyclohexyl-5,9-dimethyldeca-4,8-dienoic acid rac-
(CHCl3, cmÀ1): 1741 (C@O), 1236 (C-O); 1H NMR (300 MHz, CDCl3):
d 8.07 (d, J = 10.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 7.7 Hz,
1H), 7.85 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.41–7.19 (m,
6H), 7.08 (d, J = 8.8 Hz, 1H), 5.45 (br.s, 1H), 5.08–5.02 (m, 2H),
2.20–1.91 (m, 6H), 1.79–1.23 (m, 6H), 1.74 (s, 3H), 1.66 (s, 3H),
1.58 (s, 3H), 0.95–0.89 (m, 4H), 0.54–0.35 (m, 2H); 13C NMR (75
MHz, CDCl3): d 175.4, 152.1, 148.3, 137.4, 133.7, 133.6, 132.3,
131.7, 130.8, 130.4, 129.2, 128.3, 128.0, 127.4, 126.7, 126.3,
125.8, 124.6, 124.2, 123.6, 122.0, 121.9, 118.6, 114.8, 52.0, 39.6,
32.0, 30.0, 29.8, 27.9, 26.5, 26.2, 26.2, 26.1, 25.7, 23.6, 17.7; Accord-
ing to HPLC (AD-H, n-hexane/i-PrOH 95:5, 0.7 mL minÀ1, 220 nm;
tmajor = 12.9 min; tminor = 19.7 min), diastereomeric purity of the
product was 90% de.
1b.
Colorless viscous oil, yield 93%; IR (CHCl3, cmÀ1): 1720
(C@O); 1H NMR (300 MHz, CDCl3): d 10.10 (br.s, 1H), 5.14–5.09
(m, 2H), 2.31–2.15 (m, 3H), 2.11–1.97 (m, 4H), 1.84–1.54 (m,
5H), 1.66 (s, 6H), 1.61 (s, 3H), 1.32–0.98 (m, 6H); 13C NMR (75
MHz, CDCl3): d 182.2, 137.3, 131.7, 124.4, 122.0, 52.5, 39.8, 32.0,
30.9, 30.6, 27.6, 26.6, 26.4, 26.4, 26.4, 25.8, 23.5, 17.7.
4.2.2.3.
5.
2-Cyclohexyl-5-methylhex-4-enoic
acid
rac-
Colorless liquid, yield 96%; 1H NMR (300 MHz, CDCl3): d
10.41 (br.s, 1H), 5.13–5.09 (m, 1H), 2.28–2.16 (m, 3H), 1.85–1.54
(m, 5H), 1.70 (s, 3H), 1.63 (s, 3H), 1.37–0.92 (m, 6H) (see Ref. 6).
4.3. Synthesis of (R)-BINOL esters 6a and 6b (General procedure)
BINOL esters (R,S)-6b and (R,R)-6b were converted to enan-
tiomerically enriched Z-2-cyclohexyl-5,9-dimethyldeca-4,8-die-
noic acids (S)-1b or (R)-1b by the re-esterification/ hydrolysis
reaction (see ref.6) in 70–72% yield. Enantiomeric purity of the pre-
pared acids was 64% ee and 67% ee respectively (determined by
HPLC analysis of the corresponding 2,4-dinitrophenyl esters, see
Supporting information).
The mixture of rac-2-cyclohexyl-5,9-dimethyldeca-4,8-dienoic
acid 1a or 1b (700 mg, 2.5 mmol), (R)-BINOL (721 mg, 2.5 mmol),
DCC (518 mg, 2.5 mmol) and DMAP (28 mg, 0.23 mmol) in CH2Cl2
(25 mL) was stirred at ambient temperature for 2 h (TLC-monitor-
ing). A precipitate was filtered off, the filtrate was washed succes-
sively with 10% HCl (2 Â 4 mL), water (2 Â 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, n-hexane/toluene 10:1) to afford the corre-
sponding BINOL ester 6a or 6b as a mixture of (R,S)- and (R,R)-
diastereomers (1:1). The mixture of nerol-derived 6b isomers
was separated to individual components by column chromatogra-
phy (silica gel, n-hexane/toluene 30:1).
4.4. Synthesis of (S)-4-benzyloxazolidin-2-one based imides 8a,
8b and 9
4.4.1. (S)-4-Benzyloxazolidin-2-one (S)-7
L
-Phenylalanine was converted into (S)-7 by a modified three-
step literature procedure21a,21b in 76% overall yield (see
Supporting information). Colorless crystals; mp—86–87 °C
(lit.21c—86–88 °C); [
a
]
D
28 = À63.2 (c 1, CHCl3); 1H NMR (300 MHz,
4.3.1. (R)-1-(2-Hydroxynaphthalen-1-yl)naphthalen-2-yl (E,2RS)-
2-cyclohexyl-5,9-dimethyldeca-4,8-dienoate (R,S)-6a/(R,R)-6a
Colorless oil, yield 1.20 g (88%). 1H NMR (300 MHz, CDCl3): d
8.06 (d, J = 8.9 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.9 Hz,
1H), 7.84 (d, J = 7.9 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.37–7.19 (m,
6H), 7.07 (d, J = 8.2 Hz, 1H), 5.43 (br.s, 0.5H), 5.33 (br.s, 0.5H),
5.15–4.98 (m, 2H), 2.18–1.94 (m, 6H), 1.77–1.17 (m, 6H), 1.73 (s,
1.5H), 1.71 (s, 1.5H), 1.66 (s, 1.5H), 1.64 (s, 1.5H), 1.58 (s, 1.5H),
1.56 (s, 1.5H), 0.97–0.37 (m, 6H); 13C NMR (75 MHz, CDCl3): d
175.4, 174.9, 152.1, 152.0, 148.3, 137.3, 137.1, 133.8, 133.8,
133.7, 133.6, 132.3, 132.3, 131.6, 131.5, 130.9, 130.8, 130.4,
129.2, 129.1, 128.3, 128.3, 128.1, 128.0, 127.5, 127.4, 126.7,
126.3, 126.3, 125.8, 125.8, 124.8, 124.6, 124.3, 123.7, 123.6,
123.4, 121.9, 121.3, 121.3, 118.6, 118.5, 114.8, 114.6, 52.2, 51.8,
39.9, 39.9, 39.7, 39.6, 30.3, 30.1, 30.0, 29.8, 28.1, 27.9, 26.8, 26.8,
26.3, 26.3, 26.3, 26.1, 26.1, 25.8, 25.8, 17.8, 16.2, 16.1.
CDCl3): d 7.38–7.26 (m, 3H), 7.21–7.18 (m, 2H), 6.04 (br.s, 1H),
4.44 (t, J = 8.0 Hz, 1H), 4.19–4.07 (m, 2H), 2.92–2.88 (m, 2H).21c
4.4.2. Non-selective imidation reactions (General procedure)
Racemic carboxylic acids rac-1a, rac-1b and rac-5 were con-
verted to corresponding acyl chlorides rac-1a-Cl, rac-1b-Cl and
rac-5-Cl on treatment with oxalyl chloride (3 equiv.) by known
procedure6 and used without further purification. A solution of
crude acyl chloride rac-1a-Cl, rac-1b-Cl or rac-5-Cl (4 mmol) in
THF (2 mL) was slowly added to prepared in advance (1.5 h earlier)
solution of n-BuLi (2.5 M in n-hexane, 1.6 mL) and (S)-4-benzylox-
azolidin-2-one 7 (600 mg, 3.4 mmol) in THF (20 mL) at À78 °C. The
reaction mixture was stirred overnight at ambient temperature
and quenched with a saturated aqueous solution of NH4Cl (20
mL). The organic layer was separated and the aqueous one was
extracted with diethyl ether (3 Â 20 mL). The combined organic
phase was washed with brine (3 Â 10 mL) and dried over anhy-
drous sodium sulfate. The solvent was evaporated under reduced
pressure (40 Torr) to afford the corresponding imides 8a, 8b or 9
as mixtures of (S,S)- and (S,R)-diastereomers (1:1). Geraniol 8a
and nerol-derived 8b imides were separated to individual diastere-
omers by column chromatography on silica gel (n-hexane/EtOAc
20:1–40:1).
4.3.2. (R)-1-(2-Hydroxynaphthalen-1-yl)naphthalen-2-yl (Z,2S)-
2-cyclohexyl-5,9-dimethyldeca-4,8-dienoate (R,S)-6b
Colorless oil, yield 550 mg (40%). [a]
28 = +23.9 (c 0.37, CHCl3); IR
D
(CHCl3, cmÀ1): 1740 (C@O), 1235 (C-O); 1H NMR (300 MHz, CDCl3):
d 8.08 (d, J = 10.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 7.7 Hz,
1H), 7.84 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.37–7.16 (m,
6H), 7.08 (d, J = 8.8 Hz, 1H), 5.36 (br.s, 1H), 5.08–4.93 (m, 2H),
2.20–1.90 (m, 6H), 1.74–1.18 (m, 6H), 1.69 (s, 6H), 1.60 (s, 3H),
0.98–0.55 (m, 6H); 13C NMR (75 MHz, CDCl3): d 174.9, 151.9,
148.3, 137.3, 133.8, 133.7, 132.2, 130.8, 130.4, 129.2, 128.3,
128.0, 127.4, 126.7, 126.3, 125.8, 124.3, 123.6, 123.5, 121.9,
121.9, 118.5, 114.8, 52.4, 39.6, 32.1, 30.3, 30.1, 27.7, 26.3, 26.2,
4.4.2.1.
(S)-4-benzyloxazolidin-2-one (S,S)-8a.
505 mg (34%). [
20 = +20.7 (c 1.33, CHCl3); IR (CHCl3, cmÀ1):
3-((S,E)-2-Cyclohexyl-5,9-dimethyldeca-4,8-dienoyl)-
Colorless oil, yield
a]
D
1778 (C@O) and 1697 (C@O); 1H NMR (300 MHz, CDCl3): d 7.37–
7.22 (m, 5H), 5.21–5.07 (m, 2H), 4.72–4.67 (m, 1H), 4.18–4.10
(m, 2H), 3.93–3.85 (m, 1H), 3.30 (dd, J1 = 13.0 Hz, J2 = 2.6 Hz, 1H),
2.61 (dd, J1 = 13.1 Hz, J2 = 10.1 Hz, 1H), 2.51–2.31 (m, 2H), 2.04–
1.97 (m, 4H), 1.88–1.74 (m, 5H), 1.68 (s, 3H), 1.65 (s, 3H), 1.59 (s,
3H), 1.32–0.92 (m, 6H); 13C NMR (75 MHz, CDCl3): d 176.5,
153.3, 137.2, 135.7, 131.5, 129.4, 129.0, 127.3, 124.2, 121.1, 65.7,
26.1, 25.8, 23.5, 17.7; HRMS (ESI) m/z calcd for
547.3213; found [M+H]+ 547.3207. According to HPLC (AD-H, n-
hexane/i-PrOH 95:5, 0.7 mL minÀ1
220 nm; tminor = 12.8 min;
tmajor = 19.5 min), diastereomeric purity of the product was 80% de.
C
38H43O+3:
,

A. A. Sukhanova et al. / Tetrahedron: Asymmetry 28 (2017) 1834–1841
1839
55.5, 48.1, 40.4, 39.9, 38.0, 31.2, 29.9, 28.3, 26.7, 26.4, 25.7, 17.7,
16.2; HRMS (ESI) m/z calcd for C28H40NO+3: 438.3002; found [M
+H]+ 438.3000; According to HPLC (OD-H, n-hexane/i-PrOH 95:5,
0.7 mL minÀ1, 220 nm; tminor = 7.3 min; tmajor = 8.9 min), diastere-
omeric purity of the product was 82% de.
mmol) in THF (15 mL) at À78 °C. After stirring for 1.5 h, a solution
of 2-cyclohexylacetyl chloride (1.35 g, 8.46 mmol) in THF (2 mL)
was added. The mixture was stirred for 2.5 h at À78 °C and then
overnight without external cooling. The reaction was quenched
with a saturated solution of ammonium chloride (30 mL). The
organic layer was separated and the aqueous one was extracted
with diethyl ether (3 Â 20 mL). The combined organic phase was
washed with brine (3 Â 15 mL), dried with anhydrous sodium sul-
fate and the solvent was evaporated under reduced pressure (40
Torr). The crude residue was purified by chromatography on a col-
umn of silica (n-hexane/EtOAc 5:1) to afford 1.47 g (86%) of (S)-4-
benzyl-3-(2-cyclohexylacetyl)oxazolidin-2-one (S)-10 as colorless
4.4.2.2.
(S)-4-benzyloxazolidin-2-one (S,R)-8a.
450 mg (30%). [
20 = +10.4 (c 0.80, CHCl3); IR (CHCl3, cmÀ1):
3-((R,E)-2-Cyclohexyl-5,9-dimethyldeca-4,8-dienoyl)-
Colorless oil, yield
a]
D
1778 (C@O) and 1693 (C@O); 1H NMR (300 MHz, CDCl3): d 7.35–
7.24 (m, 5H), 5.11–5.07 (m, 2H), 4.73–4.64 (m, 1H), 4.17–4.06
(m, 2H), 3.85–3.78 (m, 1H), 3.36 (dd, J1 = 13.2 Hz, J2 = 3.1 Hz, 1H),
2.70 (dd, J1 = 13.2 Hz, J2 = 10.2 Hz, 1H), 2.45–2.31 (m, 2H), 2.01–
1.95 (m, 4H), 1.80–1.70 (m, 5H), 1.67 (s, 3H), 1.62 (s, 3H), 1.58 (s,
3H), 1.35–0.84 (m, 6H); 13C NMR (75 MHz, CDCl3): d 176.4,
153.3, 137.4, 135.6, 131.5, 129.5, 129.0, 127.4, 124.2, 121.2, 65.7,
55.7, 48.2, 40.5, 39.9, 38.4, 31.3, 29.7, 27.8, 27.0, 26.5, 26.5, 25.7,
17.7, 16.2; According to HPLC (OD-H, n-hexane/i-PrOH 95:5, 0.7
crystals. mp 95–96 °C; [a]
28 = +20.8 (c 1.67, CHCl3); IR (CHCl3,
D
cmÀ1): 1781 (C@O) and 1698 (C@O); 1H NMR (300 MHz, CDCl3):
d 7.38–7.22 (m, 5H), 4.73–4.66 (m, 1H), 4.24–4.15 (m, 2H), 3.33
(dd, J1 = 13.3 Hz, J2 = 2.9 Hz, 1H), 2.95–2.73 (m, 3H), 1.95–1.88
(m, 1H), 1.82–1.60 (m, 4H), 1.38–0.99 (m, 6H); 13C NMR (75
MHz, CDCl3): d 172.6, 153.5, 135.4, 129.4, 129.0, 127.3, 66.1,
55.2, 42.7, 38.0, 34.3, 33.2, 33.1, 33.0, 26.2, 26.2, 26.1, 26.0; HRMS
(ESI) m/z calcd for C18H24NO3+: 302.1751; found [M+H]+ 302.1760.
The LDA reagent was prepared by treating a stirred solution of
diisopropylamine (81 mg, 0.80 mmol) in dry THF (5 mL) with 2.5
M n-butyllithium in hexane (0.32 mL, 0.80 mmol) under argon at
À78 °C. The resulting solution was warmed to À30 °C and then
re-cooled to À78 °C. Oxazolidin-2-one (S)-10 (200 mg, 0.67 mmol)
in dry THF (3 mL) was syringed dropwise to this solution within 10
min and the mixture was stirred at À78 °C to À50 °C for 0.5 h.
Then, prenyl bromide (120 mg, 0.81 mmol) in dry THF (1 mL)
was injected and the reaction mixture was stirred overnight with-
out external cooling. The reaction was quenched with a saturated
solution of ammonium chloride (15 mL). The organic layer was
separated and the aqueous one was extracted with diethyl ether
(3 Â 15 mL). The combined organic phase was washed with brine
(3 Â 10 mL), dried over anhydrous sodium sulfate and the solvent
was evaporated under reduced pressure (40 Torr). The crude resi-
due was purified by column chromatography, (silica gel, n-hex-
ane/EtOAc 15:1 to 3:1) to afford 75 mg (30%) of 3-((S)-2-
cyclohexyl-5-methylhex-4-enoyl)-(S)-4-benzyloxazolidin-2-one
mL minÀ1
omeric purity of the product was 97% de.
, 220 nm; tmajor = 7.4 min; tminor = 9.0 min), diastere-
4.4.2.3.
3-((S,Z)-2-Cyclohexyl-5,9-dimethyldeca-4,8-dienoyl)-
(S)-4-benzyloxazolidin-2-one (S,S)-8b.
Colorless oil, yield
270 mg (18%). [a]
28 = +22.7 (c 0.40, CHCl3); IR (CHCl3, cmÀ1):
D
1778 (C@O) and 1693 (C@O); 1H NMR (300 MHz, CDCl3): d 7.37–
7.22 (m, 5H), 5.19–5.15 (m, 2H), 4.74–4.71 (m, 1H), 4.19–4.11
(m, 2H), 3.92–3.85 (m, 1H), 3.24 (dd, J1 = 13.4 Hz, J2 = 2.9 Hz, 1H),
2.66 (dd, J1 = 13.4 Hz, J2 = 10.3 Hz, 1H), 2.51–2.30 (m, 2H), 2.19–
1.94 (m, 4H), 1.88–1.52 (m, 5H), 1.70 (s, 6H), 1.63 (s, 3H), 1.31–
0.89 (m, 6H); 13C NMR (75 MHz, CDCl3): d 176.4, 153.3, 137.3,
135.6, 131.6, 129.5, 128.9, 127.3, 124.3, 122.0, 65.6, 55.4, 48.2,
40.4, 37.9, 32.0, 31.2, 29.8, 28.1, 26.6, 26.4, 25.7, 23.6, 17.7; Accord-
ing to HPLC (OD-H, n-hexane/i-PrOH 99:1, 0.7 mL minÀ1, 220 nm;
tminor = 14.2 min; tmajor = 17.3 min), diastereomeric purity of the
product was 98% de.
4.4.2.4.
(S)-4-benzyloxazolidin-2-one (S,R)-8b.
225 mg (15%). [
20 = +16.1 (c 0.67, CHCl3); IR (CHCl3, cmÀ1):
3-((R,Z)-2-Cyclohexyl-5,9-dimethyldeca-4,8-dienoyl)-
Colorless oil, yield
a]
(S,S)-9 as colorless crystals. mp 70–72 °C; [a]
28 = +41.9 (c 0.94,
D
D
1778 (C@O) and 1693 (C@O); 1H NMR (300 MHz, CDCl3): d 7.40–
7.27 (m, 5H), 5.17–5.07 (m, 2H), 4.73–4.68 (m, 1H), 4.16–4.11
(m, 2H), 3.83–3.76 (m, 1H), 3.39 (dd, J1 = 13.2 Hz, J2 = 2.9 Hz, 1H),
2.73 (dd, J1 = 13.2 Hz, J2 = 10.2 Hz, 1H), 2.49–2.33 (m, 2H), 2.15–
2.00 (m, 4H), 1.88–1.59 (m, 5H), 1.74 (s, 3H), 1.69 (s, 3H), 1.67 (s,
3H), 1.31–0.91 (m, 6H); 13C NMR (75 MHz, CDCl3): d 176.1,
153.2, 137.3, 135.6, 131.6, 129.4, 128.9, 127.3, 124.3, 122.0, 65.8,
55.6, 48.4, 40.3, 38.3, 31.9, 31.2, 29.5, 27.3, 26.6, 26.5, 26.4, 26.3,
25.7, 23.5, 17.7; According to HPLC (OD-H, n-hexane/i-PrOH 99:1,
CHCl3); IR (CHCl3, cmÀ1): 1778 (C@O) and 1693 (C@O); 1H NMR
(300 MHz, CDCl3): d 7.36–7.22 (m, 5H), 5.19–5.14 (m, 1H), 4.71–
4.67 (m, 1H), 4.18–4.05 (m, 2H), 3.91–3.86 (m, 1H), 3.22 (dd, J1 =
13.4 Hz, J2 = 2.7 Hz, 1H), 2.63 (dd, J1 = 13.3 Hz, J2 = 9.8 Hz, 1H),
2.49–2.45 (m, 1H), 2.32–2.17 (m, 2H), 1.88–1.72 (m, 4H), 1.68 (s,
3H), 1.64 (s, 3H), 1.43–0.92 (m, 6H); 13C NMR (75 MHz, CDCl3): d
176.5, 153.3, 135.7, 133.6, 129.4, 129.0, 127.3, 121.5, 65.6, 55.4,
48.1, 40.4, 37.9, 33.1, 31.3, 29.9, 28.5, 26.4, 26.1, 25.9, 17.8; HRMS
(ESI) m/z calcd for C23H32NO3+: 370.2377; found [M+H]+ 370.2367;
0.7 mL minÀ1
diastereomeric purity of the product was 84% de.
,
220 nm;
tmajor = 14.0 min;
tminor = 17.2 min),
According to HPLC (AD-H, n-hexane/i-PrOH 95:5, 0.7 mL minÀ1
,
220 nm; tmajor = 7.2 min; tminor = 9.1 min), diastereomeric purity
of the product was 96% de.
4.4.2.5. 3-(2-Cyclohexyl-5-methylhex-4-enoyl)-(S)-4-benzyloxa-
zolidin-2-one (S,S)-9/(S,R)-9. Colorless crystals, mp 67–71 °C,
4.5. Synthesis and characterization of geraniol- 1a and nerol-
derived 1b Cygerol enantiomers
yield 1.08 g (86%); 1H NMR (300 MHz, CDCl3): d 7.37–7.23 (m, 5H),
5.17–5.06 (m, 1H), 4.73–4.65 (m, 1H), 4.18–4.08 (m, 2H), 3.93–3.75
(m, 1H), 3.35 (dd, J1 = 13.2 Hz, J2 = 2.7 Hz, 0.5H), 3.22 (dd, J1 = 13.2
Hz, J2 = 2.7 Hz, 0.5H), 2.74–2.60 (m, 1H), 2.53–2.29 (m, 3H), 1.94–
1.52 (m, 10H), 1.42–0.90 (m, 6H); 13C NMR (75 MHz, CDCl3): d
176.5, 176.2, 153.3, 135.6, 135.6, 133.6, 129.4, 128.9, 127.3,
121.4, 121.3, 65.8, 65.6, 55.6, 55.4, 48.2, 48.0, 40.4, 40.3, 38.3,
37.8, 31.2, 29.8, 29.5, 28.5, 27.6, 26.4, 25.9, 25.8, 17.8, 17.7.
4.5.1. Hydrolytic cleavage of imides (S,S)-8a, (S,R)-8a, (S,S)-8b
and (S,R)-8b (General procedure)
The 30% aqueous H2O2 (0.5 mL) and LiOHÁH2O (50 mg, 1.2
mmol) were successively added to a stirred solution of the corre-
sponding diastereomer 8a or 8b (200 mg, 0.46 mmol) in the THF
(4 mL)/H2O (1.2 mL) solvent system. The resulting mixture was
stirred overnight at ambient temperature. Then, Na2SO3 (5 mg)
was added to the mixture. The organic co-solvent was evaporated
under reduced pressure (40 Torr). The aqueous residue treated
with 2 N NaOH to adjust to pH 12–13 value and then extracted
with CH2Cl2 (5 Â 5 mL). The aqueous layer was acidified with HCl
4.4.3. Stereoselective synthesis of 3-((S)-2-cyclohexyl-5-methyl-
hex-4-enoyl)-(S)-4-benzyloxazolidin-2-one (S,S)-9
Butyllithium (3.4 mL, 2.5 M in hexanes, 8.46 mmol) was added
to a stirred solution of (S)-4-benzyloxazolidin-2-one 7 (1 g, 5.65

1840
A. A. Sukhanova et al. / Tetrahedron: Asymmetry 28 (2017) 1834–1841
to pH 1. The product was extracted with EtOAc (5 Â 5 mL) and the
combined organic layers were dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure (40 Torr) and the
residue was purified by flash chromatography (silica gel, n-hex-
ane/EtOAc 5:1) to afford corresponding acid 1.
4.5.2.4. 2,4-Dinitrophenyl (R,Z)-2-cyclohexyl-5,9-dimethyldeca-
4,8-dienoate (R)-1b-DNPE.
Colorless oil; [
a
]
D
28 = À2.7 (c 1.06,
CHCl3); According to HPLC (AD-H, n-hexane/i-PrOH 99:1, 0.7 mL
minÀ1, 254 nm; tminor = 18.9 min; tmajor = 23.1 min), enantiomeric
purity of the product was 85% ee.
4.5.1.1. (S,E)-2-Cyclohexyl-5,9-dimethyldeca-4,8-dienoic acid
4.6. Assignment of absolute configuration to geraniol- and
nerol-based enantiomers
(S)-1a.
Viscous oil, yield 127 mg (99%); [
a]
D
22 = À3.7 (c 1.00,
CHCl3).
4.6.1. Synthesis of diethyl 2-cyclohexylsuccinate rac-13 and (S)-
13 (General procedure)
4.5.1.2. (R,E)-2-Cyclohexyl-5,9-dimethyldeca-4,8-dienoic acid
(R)-1a.
Viscous oil, yield 115 mg (90%); [
a
]
D
22 = +4.4 (c 0.30,
An O3–O2 mixture was bubbled through a solution of technical
grade cygerol ethyl ester 3 (racemate, E/Z ꢀ3:1, 260 mg, 0.85
mmol) in dichloromethane (10 mL) at À78 °C at a speed of ca.
0.7 mmol minÀ1. When the blue color of the solution persisted
(in ca. 10 min), excess ozone was removed by bubbling pure oxy-
gen. The mixture was allowed to reach room temperature, and
then dimethyl sulfide (0.3 mL) was added. In 30 min, the volatiles
were removed in vacuo, and the residue was co-evaporated with
toluene. The non-volatile residue was diluted with MeCN (9 mL).
Then a solution of NaH2PO4Á2H2O (94 mg) in water (1.5 mL),
hydrogen peroxide (30% aq., 0.2 mL) and finally sodium chlorite
(tech., 300 mg) were successively added to the flask at ꢀ0 °C (ice
bath) and the mixture was stirred for 1 h. Acetonitrile was
removed on a rotary evaporator, the residue was mixed with brine
(5 mL) and extracted with ethyl acetate (4 Â 5 mL). The combined
extracts were dried over anhydrous Na2SO4 and concentrated in
vacuo to afford crude monoester 12 (181 mg). The latter (without
identification) was dissolved in CH2Cl2 (3 mL) and anhydrous etha-
CHCl3).
4.5.1.3. (S,Z)-2-Cyclohexyl-5,9-dimethyldeca-4,8-dienoic acid
(S)-1b.
CHCl3).
Viscous oil, yield 120 mg (94%); [
a]
22 = À3.5 (c 0.30,
D
4.5.1.4. (R,Z)-2-Cyclohexyl-5,9-dimethyldeca-4,8-dienoic acid
(R)-1b.
Viscous oil, yield 123 mg (96%); [a]
22 = +3.1 (c 0.35,
D
CHCl3).
4.5.2. Derivatization of 1a and 1b enantiomers for HPLC analysis
(General procedure)
2,4-Dinitrophenol (7 mg, 0.036 mmol), DCC (9 mg, 0.044 mmol)
and DMAP (cat.) were added to a stirred solution of the corre-
sponding enantiomer of 1a or 1b (10 mg, 0.036 mmol) in CH2Cl2
(0.5 mL). The mixture was stirred at ambient temperature for 2.5
h (TLC-monitoring). A precipitate was filtered off. The filtrate was
evaporated under reduced pressure (40 Torr, 40 °C) and the residue
was purified by column chromatography (SiO2, n-hexane/EtOAc
10:1) to afford the corresponding dinitrophenyl ester 1-DNPE in
quantitative yield.
nol (280
lL) was added. Then DMAP (15 mg) and DCC (386 mg)
were successively added to the solution at ꢀ0 °C (ice bath), and
the mixture was stirred for 2 h. GC MS analysis showed the pres-
ence of the target product 13, some minor impurities and nothing
of ethyl levulinate, a probable product arising from levulinic alde-
hyde. (Note. Levulinic aldehyde is the secondary ozonolysis pro-
duct of cygerol ester. Possibly, it is removed in the course of
evaporation, or is degraded during oxidation, or final water-soluble
levulinic acid is not extracted with ethyl acetate.) Dichloromethane
was removed by evaporation, the residue was suspended in little
toluene and placed on a top of column with silica gel. Elution with
light petroleum and then with light petroleum/EtOAc (95:5)
afforded 137 mg (63%) of diester rac-13. 1H NMR (300 MHz,
CDCl3): d 4.13 (m, 2H), 4.10 (q, J = 7.3 Hz, 2H), 2.73–2.62 (m, 2H),
2.41 (dt, J1 = 12.5, J2 = 8.8 Hz, 1H), 1.74–1.49 (m, 6H), 1.28–0.89
(m, 5H), 1.24 (t, J = 7.3 Hz, 3H), 1.22 (t, J = 7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 174.3, 172.4, 60.4, 60.2, 47.0, 39.9, 33.5, 30.5,
30.1, 26.3, 26.2, 26.1, 14.2, 14.1; GC MS (m/z): [MÀOEt]+ 211. The
NMR spectra are close to reported data.18
4.5.2.1. 2,4-Dinitrophenyl (S,E)-2-cyclohexyl-5,9-dimethyldeca-
4,8-dienoate (S)-1a-DNPE.
Colorless oil; [
a
]
28 = À5.0 (c 0.10,
D
CHCl3); IR (CHCl3, cmÀ1): 1773 (C@O), 1603, 1542; 1H NMR (300
MHz, CDCl3): d 8.90 (d, J = 2.7 Hz, 1H), 8.49 (dd, J1 = 9.0 Hz, J2 =
2.7 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 5.23–5.08 (m, 2H), 2.62–2.42
(m, 3H), 2.11–1.91 (m, 4H), 1.82–1.59 (m, 5H), 1.68 (s, 3H), 1.65
(s, 3H), 1.62 (s, 3H), 1.43–0.90 (m, 6H); 13C NMR (75 MHz, CDCl3):
d 171.9, 148.4, 144.6, 142.2, 137.9, 131.5, 128.3, 126.3, 123.9,
121.3, 120.5, 51.9, 39.7, 39.6, 30.9, 30.3, 27.5, 26.5, 26.2, 25.6,
17.6, 16.1; HRMS (ESI) m/z calcd for C24H32NaN2O+6: 467.2153;
found [M+Na]+ 467.2148; According to HPLC (AD-H, n-hexane/i-
PrOH 99:1, 0.7 mL minÀ1, 254 nm; tmajor = 18.0 min; tminor = 19.5
min), enantiomeric purity of the product was 80% ee.
4.5.2.2. 2,4-Dinitrophenyl (R,E)-2-cyclohexyl-5,9-dimethyldeca-
Enantiomerically enriched diethyl (S)-2-cyclohexylsuccinate
(S)-13 was obtained similarly from both (S)-3a and (S)-3b. The
(S)-3a-derived sample of (S)-13 (80% ee for the preceding acid
4,8-dienoate (R)-1a-DNPE.
Colorless oil; [a]
28 = +8.6 (c 0.94,
D
CHCl3); According to HPLC (AD-H, n-hexane/i-PrOH 99:1, 0.7 mL
minÀ1, 254 nm; tminor = 17.8 min; tmajor = 19.2 min), enantiomeric
purity of the product was 97% ee.
(S)-1a) had [
derived sample of (S)-13 (99% ee for the preceding acid (S)-1b)
had [
25 = +10.2 (c 1.0, 1,2-dichloroethane). Literature data:18
21 = +14.9 (c 2.3, CHCl3) for (S)-13; [
a]
25 = +4.6 (c 1.0, 1,2-dichloroethane). The (S)-3b-
D
a
]
D
4.5.2.3. 2,4-Dinitrophenyl (S,Z)-2-cyclohexyl-5,9-dimethyldeca-
[a]
a]
21 = –10.6 for (R)-13.
D
D
4,8-dienoate (S)-1b-DNPE.
Colorless oil; [a]
28 = +2.8 (c 0.14,
D
CHCl3); IR (CHCl3, cmÀ1): 1771 (C@O), 1610, 1542; 1H NMR (300
MHz, CDCl3): d 8.90 (d, J = 2.6 Hz, 1H), 8.49 (dd, J1 = 9.0 Hz, J2 =
2.6 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 5.22–5.10 (m, 2H), 2.62–2.41
(m, 3H), 2.15–1.99 (m, 4H), 1.90–1.62 (m, 5H), 1.76 (s, 3H), 1.70
(s, 3H), 1.62 (s, 3H), 1.39–0.88 (m, 6H); 13C NMR (75 MHz, CDCl3):
d 172.1, 148.6, 144.8, 142.4, 138.2, 131.9, 128.5, 126.5, 124.1,
121.5, 121.4, 52.3, 39.8, 32.1, 31.1, 30.5, 27.5, 26.5, 26.3, 25.8,
23.6, 17.7; According to HPLC (AD-H, n-hexane/i-PrOH 99:1, 0.7
4.6.2. Synthesis of 2-cyclohexylbutane-1,4-diol rac-14 and (S)-
14
Diethyl 2-cyclohexylsuccinate rac-13 was converted to 2-cyclo-
hexylbutane-1,4-diol rac-14 by modified literature procedure22a
(see Supporting information). Yield 86%, viscous oil; 1H NMR
(300 MHz, CDCl3): d 4.03 (br.s, 2H), 3.74 (m, 1H), 3.67–3.48 (m,
3H), 1.81–1.51 (m, 7H), 1.50–1.30 (m, 2H), 1.30–1.10 (m, 3H),
1.09–0.90 (m, 2H); 13C NMR (75 MHz, CDCl3): d 64.7, 61.7, 45.0,
40.1, 33.4, 30.1, 30.0, 26.7, 26.6, 26.5. The 1H NMR and 13C NMR
spectra are in agreement with reported data.22
mL minÀ1
tiomeric purity of the product was 99% ee.
, 254 nm; tmajor = 18.4 min; tminor = 22.9 min), enan-

A. A. Sukhanova et al. / Tetrahedron: Asymmetry 28 (2017) 1834–1841
1841
1970, 73, 34814r; (c) Bondar, L. S.; Okunev, R. A. A.s. 333162 USSR; Chem. Abstr.,
1972, 77, 100910e; (d) Nichols, J.; Bulbenko, G. F. Ger. Offen. DE 2,335,067;
Chem. Abstr., 1976, 80, 146380x.
Enantiomerically enriched 2-cyclohexylbutane-1,4-diol (S)-14
was obtained similarly from (S)-13. The (S)-3a-derived sample of
crude material had [
a]
25 = À5.5 (c 0.4, EtOH). Literature data:20
D
2. Smirnov, B. B.; Kryshtal, G. V.; Konopljannikov, A. G.; Zlotin, S. G.; Zhdankina, G.
M. RF Patent 2301667; Chem. Abstr., 2007, 147, 110262.
3. Food & Drug Administration, Chirality 1992, 4, 338–340.
[
a]
D
20 = À17.5 (c 0.49, EtOH).
4. Subramanian, G. In Chiral Separation Techniques.
A Practical Approach;
4.6.3. Synthesis of 2-cyclohexylbutane-1,4-diyl dibenzoate rac-
15 and (S)-15
Subramanian, G., Ed.; Wiley-VCH: Weinheim, 2006.
5. (a) Faigl, F.; Fogassy, E.; Nogradi, M.; Palovics, E.; Schindler, J. Tetrahedron:
Asymmetry 2008, 19, 519–536; (b) Ahmed, M.; Kelly, T.; Ghanem, A.
Tetrahedron 2012, 68, 6781–6802; (c) Borissov, A.; Davies, T. Q.; Ellis, S. R.;
Fleming, T. A.; Richardson, M. S. W.; Dixon, D. J. Chem. Soc. Rev. 2016, 45, 5474–
5540.
6. Zlotin, S. G.; Kryshtal, G. V.; Zhdankina, G. M.; Sukhanova, A. A.; Kucherenko, A.
S.; Smirnov, B. B.; Tartakovsky, V. A. Mendeleev Commun. 2014, 24, 257–259.
7. (a) Gensler, W. J. Chem. Rev. 1957, 57, 191–280; (b) Dugave, C.; Demange, L.
Chem. Rev. 2003, 103, 2475–2532.
8. Nowotny, S.; Tucker, C. E.; Jubert, C.; Knochel, P. J. Org. Chem. 1995, 60, 2762–
2772.
9. Butora, G.; Morriello, G. J.; Kothandaraman, S.; Guiadeen, D.; Pasternak, A.;
Parsons, W. H.; MacCoss, M.; Vicario, P. P.; Cascieri, M. A.; Yang, L. Bioorg. Med.
Chem. Lett. 2006, 16, 4715–4722.
Compounds rac-15 and (S)-15 were prepared from correspond-
ing diols rac-14 and (S)-14 by modified literature procedure19a (see
Supporting information). Yield 86%, viscous oil; 1H NMR (300 MHz,
CDCl3): d 8.03 (br.d, J = 7.3 Hz, 4H), 7.60–7.50 (m, 2H), 7.49–7.38
(m, 4H), 4.51–4.42 (m, 3H), 4.31 (dd, J1 = 11.4, J2 = 6.0 Hz, 1H),
2.10–1.85 (m. 3H), 1.85–1.64 (m, 5H), 1.57 (m, 1H), 1.39–1.05
(m, 5H); 13C NMR (75 MHz, CDCl3): d 166.5, 166.4, 132.8, 132.7,
130.3, 129.5, 128.3, 128.2, 65.9, 63.7, 40.2, 39.5, 30.3, 29.8, 28.3,
26.7, 26.6, 26.5. The NMR data for 15 have not been available so far.
The (S)-3b-derived sample of (S)-15 (99% ee for the preceding
10. Miyachi, H.; Nomura, M.; Tanase, T.; Suzuki, M.; Murakami, K.; Awano, K.
Bioorg. Med. Chem. Lett. 2002, 12, 333–335.
acid (S)-1b) was characterized by specific rotation [
a
]
28 = À10.3
D
(c 0.77, CHCl3) and enantiomeric purity values (84% ee, AD-H, n-
11. Kim, D. H.; Chung, S. Tetrahedron: Asymmetry 1999, 10, 3769–3776.
12. Hutchinson, J. H.; Riendeau, D.; Brideau, C.; Chan, C.; Falgueyret, J.-P.; Guay, J.;
Jones, T. R.; Lepine, C.; Macdonald, D. J. Med. Chem. 1994, 37, 1153–1164.
13. Chavda, S.; Coulbeck, E.; Eames, J. Tetrahedron Lett. 2008, 49, 7398–7402.
14. Al Shaye, N.; Benoit, D. M.; Chavda, S.; Coulbeck, E.; Dingjan, M.; Eames, J.;
Yohannes, Y. Tetrahedron: Asymmetry 2011, 22, 413–438.
hexane/i-PrOH 95:5, 0.7 mL minÀ1
, 220 nm; tminor = 20.6 min;
tmajor = 23.0 min). The (S)-3a-derived sample of (S)-15 (80% ee for
the preceding acid (S)-1a) had 68% ee (AD-H, n-hexane/i-PrOH
95:5, 0.7 mL minÀ1, 220 nm; tminor = 21.0 min; tmajor = 23.2 min).
15. Chavda, S.; Coulbeck, E.; Coumbarides, G. S.; Dingjan, M.; Eames, J.; Ghilagaber,
S.; Yohannes, Y. Tetrahedron: Asymmetry 2006, 17, 3386–3399.
16. Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141–6144.
17. (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737–
1739; (b) Heravi, M. M.; Zadsirjan, V.; Farajpour, B. RSC Adv. 2016, 6, 30498–
30551.
Acknowledgement
This research was supported by the Russian Science Foundation
(project no. 14-50-00126).
18. Stack, J. G.; Curran, D. P.; Geib, S. V.; Rebek, J.; Ballester, P. J. Am. Chem. Soc.
1992, 114, 7007–7018.
19. (a) Zhang, P.; Brozek, L. A.; Morken, J. P. J. Am. Chem. Soc. 2010, 132, 10686–
10688; (b) Yasuda, Y.; Ohmiya, H.; Sawamura, M. Angew. Chem., Int. Ed. 2016,
55, 10816–10820.
A. Supplementary data
20. Krause, H.; Sailer, C. J. Organomet. Chem. 1992, 423, 271–279.
21. (a) Veeresa, G.; Datta, A. Tetrahedron 1998, 54, 15673–15678; (b) Matsunaga,
H.; Ishizuka, T.; Kunieda, T. Tetrahedron 1997, 53, 1275–1294; (c) Dey, S.;
Gadakh, S. K.; Ahuja, B. B.; Kamble, S. P.; Sudalai, A. Tetrahedron Lett. 2016, 57,
684–687.
22. (a) Ballini, R.; Bosica, G.; Damiani, M.; Righi, P. Tetrahedron 1999, 55, 13451–
13456; (b) Parfenova, L. V.; Kovyazin, P. V.; Tyumkina, T. V.; Berestova, T. V.;
Khalilov, L. M.; Dzhemilev, U. M. J. Organomet. Chem. 2013, 723, 19–25.
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetasy.2017.10.024.
References
1. (a) Bondar, L. S.; Okunev, R. A. Brit. Pat. GB 1,173,419; Chem. Abstr., 1970, 72,
54770f; (b) Bondar, L. S.; Okunev, R. A. Ger. Offen. DE 1,801,868; Chem. Abstr.,