A facile and efficient method for the kinetic separation of commercially available cis- and trans-limonene epoxide

Article abstract of DOI:10.1016/S0957-4166(02)00646-8

cis- and trans-Diastereomers of (R)-(+)-limonene oxide can be purified by simple kinetic separation of the commercially available (1:1) diastereomeric mixture of limonene oxides. Nucleophilic amines, such as pyrrolidine and piperidine, selectively open the epoxide ring of the trans-isomer, leaving the cis-limonene oxide largely unreacted. The unreacted cis-(R)-limonene oxide is recovered in up to 88% yield. On the other hand, less nucleophilic amines, such as triazole or pyrazole, selectively catalyze hydrolysis of the cis-limonene oxide to 1,2-limonene diol leaving the trans-limonene oxide largely unreacted. The unreacted trans-limonene oxide is recovered in up to 80% of the theoretical yield by a simple workup procedure. The cis- and trans-diastereomers of (R)-(+)-limonene oxide thus isolated were found to be >98% pure by both GC and NMR analyses. Thus, depending on the choice of amine, either cis- or trans-limonene oxide may be obtained in high diastereomeric purity by this simple and environmentally friendly method.

Full text of DOI:10.1016/S0957-4166(02)00646-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2359–2363
A facile and efficient method for the kinetic separation of
†
commercially available cis- and trans-limonene epoxide
a
a
b
b
b
Derek Steiner, Lacie Ivison, Christian T. Goralski, Robert B. Appell, Jasna R. Gojkovic and
a,
Bakthan Singaram *
a
Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
b
The Dow Chemical Company, Pharmaceutical Services, 1710 Building, Midland, MI 48674, USA
Received 4 September 2002; accepted 26 September 2002
Abstract—cis- and trans-Diastereomers of (R)-(+)-limonene oxide can be purified by simple kinetic separation of the commercially
available (1:1) diastereomeric mixture of limonene oxides. Nucleophilic amines, such as pyrrolidine and piperidine, selectively open
the epoxide ring of the trans-isomer, leaving the cis-limonene oxide largely unreacted. The unreacted cis-(R)-limonene oxide is
recovered in up to 88% yield. On the other hand, less nucleophilic amines, such as triazole or pyrazole, selectively catalyze
hydrolysis of the cis-limonene oxide to 1,2-limonene diol leaving the trans-limonene oxide largely unreacted. The unreacted
trans-limonene oxide is recovered in up to 80% of the theoretical yield by a simple workup procedure. The cis- and
trans-diastereomers of (R)-(+)-limonene oxide thus isolated were found to be >98% pure by both GC and NMR analyses. Thus,
depending on the choice of amine, either cis- or trans-limonene oxide may be obtained in high diastereomeric purity by this simple
and environmentally friendly method. © 2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
fractional distillation. However, the result was ineffi-
cient, producing only small amounts of the desired
1
0
Enantiomerically pure epoxides are synthetically useful
for the construction of many chiral non-racemic com-
pounds. Both (+)- and (−)-limonene oxide are com-
mercially available and relatively inexpensive, but they
are marketed as a 1:1 mixture of the cis- and trans-
epoxides. Bacteria, enzymes and yeasts have been
used for enantioselective bioconversion of limonene
oxide, allowing preferential isolation of one isomer.
products. Due to the difficulty involved in the separa-
tion of limonene oxide diastereomers by physical
means, synthetic routes to pure limonene oxide have
been attempted by many research groups. It has been
reported that diastereomerically pure cis- and trans-
1
–5
6
,7
11
isomers of (R)-(+)-limonene oxide can be synthesized
in moderate yield from the corresponding quaternary
ammonium salts derived from limonene amino
8,9
12,13
Separation of the diastereomers was also attempted by
alcohols.
Scheme 1. Kinetic separation of cis- and trans-limonene oxides.
*
Corresponding author. Tel.: 831-459-3154; fax: 831-459-2935; e-mail: singaram@chemistry.ucsc.edu
This paper is cordially dedicated to Professor Herbert C. Brown on the occasion of his 90th birthday.
†
0
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00646-8

2
360
D. Steiner et al. / Tetrahedron: Asymmetry 13 (2002) 2359–2363
The inherent difficulty associated with physical separa-
tion and the inefficiency of synthetic approaches
prompted us to study the kinetic separation of the
commercially available 1:1 mixture of limonene oxide
for the preparation of pure cis- and trans-isomers. The
isolation of trans-limonene oxide 1 by kinetic resolution
The selectivity observed in these reactions (Scheme 1)
can be explained by the inherent conformational differ-
ences between cis- and trans-limonene oxide. Due to
the large A value, the isopropenyl group prefers the
equatorial orientation in both the cis- and trans-iso-
mers. For the trans-isomer 1, an S 2-type reaction with
N
14
was first reported using HClO in water at pH 4.5.
a nucleophilic amine can be envisioned to occur at the
less hindered C-2-carbon through a thermodynamically
stable chair-like transition state (Scheme 2A). In con-
4
Due to the hazards involved in working with perchloric
acid, safer and more efficient methods were explored.
For example, trans-(+)-limonene oxide 1 was isolated in
trast, for S 2-type attack at the C-2-carbon atom to
N
2
4% yield by treating a 1:1 mixture of (R)-(+)-limonene
occur, the cis-isomer would have to attain the unfavor-
able, energetically demanding ‘boat-like’ transition
state. Consequently, the cis-isomer 2 is left largely
15
oxide with NaHSO at a low pH. More recently, a
3
molybdenum catalyst has been shown to selectively
hydrolyze cis-limonene oxide 2 to form a diol. trans-
Limonene oxide was left unreacted, however no iso-
19,20
unreacted (Scheme 2B).
1
6
lated yield was reported. Similarly, HgCl was used,
The epoxide ring opening reaction was carried out
using a wide variety of amines, producing structurally
2
with a pH 7 buffer, to selectively hydrolyze 2, facilitat-
17
18
ing the isolation of the trans-isomer 1 in 40% yield.
interesting b-amino alcohols. cis-Limonene oxide 2 is
isolated as a by-product in these reactions. For exam-
ple, the reaction of (R)-(+)-limonene oxide with pyrro-
lidine gave a mixture of the b-amino alcohol 3 and
unreacted cis-limonene oxide 2, from which 2 was
isolated in 88% theoretical yield with >98% purity
(Table 1).
2
. Results and discussion
In all of the aforementioned kinetic separations, only
the trans-diastereomer of limonene oxide can be
obtained. Recently, we reported the reaction of sec-
ondary amines with a 1:1 mixture of cis-2 and trans-
limonene oxide 1 as an efficient and easily scalable
reaction for the synthesis of limonene based b-amino-
alcohols. This reaction and related methods using less
nucleophilic amines, such as pyrazole and triazole, have
led to the discovery of a new and useful method for the
kinetic resolution of cis- and trans-limonene oxide. We
report herein a simple and environmentally friendly
method to isolate either diastereomer of limonene oxide
with >98% purity in high yield (Scheme 1).
When we attempted to extend this reaction to non-
nucleophilic amines, such as triazole and pyrazole, we
observed an unexpected result. The reactions involving
non-nucleophilic amines catalyzed the selective hydroly-
sis of cis-limonene oxide, leaving trans- limonene oxide
1 unreacted. This unexpected result can be rationalized
as follows: Triazole and pyrazole activate the epoxide
ring by protonation, allowing water to selectively react
with cis-limonene oxide 2 at the C-1-carbon atom,
through a chair-like transition state, to form the trans-
1
8
Scheme 2. Selective opening of trans-limonene oxide with pyrrolidine.
Table 1. Isolation of cis-limonene oxide of high purity by aminolysis-mediated kinetic resolution
Amino alcohol yielda (%)
%2 yield (purity)b
a
Entry
Amine
Time (h)
1
2
Pyrrolidine
Piperidine
24
48
85
89
84 (98)
80 (98)
a
Isolated yield after distillation.
b
Determined by 1H NMR integration. Reactions run at 100°C in an open reflux condenser with constant stirring.

D. Steiner et al. / Tetrahedron: Asymmetry 13 (2002) 2359–2363
2361
Scheme 3. Selective opening of cis-limonene oxide with pyrazole–water.
diaxial limonene diol 4 (Scheme 3A). It should be pointed
of pyrazole and 30, 10, 1, and 0 equiv. of added water.
The results of the three experiments using 30 equiv. of
water are shown in Fig. 1. The graphs clearly show that
in all three cases, the cis-(R)-limonene oxide is com-
pletely consumed after 4–5 h of reaction time. With 2
equiv. of pyrazole, nearly equal quantities of diols and
amines are produced, and trans-(R)-limonene oxide
out that the reaction approaches an S 1 type mechanism
N
based on the electronic state of the C-1-carbon atom, but
still retains the S 2 characteristics and gives inversion of
N
configuration at the C-1 center. This is in agreement with
the results observed previously in the reaction of cis-
2
1
limonene oxide with sodium acetate. In contrast, trans-
limonene oxide is slow to react with water due to the
conformation of the ring and the stereoelectronics of the
system; the C-1-carbon atom forcing water to react at the
C-2-carbon atom sluggishly (Scheme 3B). The unreacted
trans-limonene oxide can be easily separated from the
diol by a simple extraction with cold pentane.
2
2
remains as less than 30 area percent of the mixture.
With 0.24 equiv. of pyrazole the major products are the
diols, and approximately 43 area percent of the mixture
is the trans-(R)-(+)-limonene oxide.
3
. Conclusion
The amount of water used in the reaction is critical, and
determines the rate of the reaction and the product ratio.
Initially reactions were run with a 1:1 stoichiometric ratio
of pyrazole and epoxide with 0.8 equiv. of water. After
In summary, we have shown a simple and environmen-
tally friendly way to isolate both the cis- and trans-
diastereomers of (R)-(+)-limonene oxide in high yield
and high diastereomeric purity. The method disclosed
herein is inexpensive and uses readily available limonene
oxide and a wide variety of secondary amines. Our
method is not only useful for the isolation of both
diastereomers of limonene oxide, but also for the syn-
thesis of pure b-amino alcohols and trans-limonene-1,2-
diol.
2
weeks at reflux temperature, a mixture of pyrazole-
derived limonene amino alcohol regioisomers were iso-
lated as the major product, with very little trans-limonene
oxide. In order to make water the reactive nucleophile
in this reaction, a large excess was subsequently used with
a catalytic amount of pyrazole. Thus, the reaction of a
1
:1 mixture of limonene oxide with 0.15 equiv. of
pyrazole and 30 equiv. of water afforded a 77% yield of
98% pure trans-limonene oxide 1 after 6 h at 100°C
>
along with the trans-diol 4. A similar result was obtained
using triazole as the acid catalyst, resulting in 73% yield
of 1 in >98% purity (Table 2).
4. Experimental
Reactions were carried out in oven-dried glassware
under an inert atmosphere. cis/trans-(+)-Limonene
oxide and amines were supplied by the Aldrich Chemical
Company and used as received. H and C NMR
spectra were recorded on a Varian 500 MHz system.
Optical rotations were recorded on a Jasco DIP-371
These observations were further verified by a more
detailed study of the reaction stoichiometry with pyra-
zole. Using a 12-station Bohdan automated synthesizer,
reactions were run at 95°C using 2.0, 1.0, and 0.24 equiv.
1
13
Table 2. Isolation of trans-limonene oxide of high purity by hydrolysis-mediated kinetic resolution
Water:amine (equiv.)a
Time (h)
Diol 4 yield (%)
b
%1 yield (purity)c
b
Entry
Amine
1
2
3
4
5
None
30:0
7
6
24
5
100
55
85
71
71
61 (96)
27
48 (98)
77 (98)
73 (97)
Pyrazole
Pyrazole
Pyrazole
Triazole
30:1.5
9:0.05
30:0.15
30:0.15
5.5
a
One equiv. of limonene oxide is used in all reactions.
Isolated yield after distillation.
b
c
Determined by 1H NMR integration.

2
362
D. Steiner et al. / Tetrahedron: Asymmetry 13 (2002) 2359–2363
1
00°C, and stirred under reflux for 24 h. The contents
of the round-bottom were transferred to a separatory
funnel with pentane (50 mL). The organic solution was
extracted with deionized water (2×50 mL). The pentane
layer was dried with anhydrous magnesium sulfate and
gravity filtered into a 100 mL, round-bottom flask. The
pentane was removed in vacuo (rotary evaporator). The
cis-(R)-(+)-limonene oxide was then distilled at reduced
pressure, bp 68°C (18 Torr) giving product (5.49 g).
2
3
h =+44° (neat), d 0.931 (Fluka), HRMS calcd for
D
+
1
C H O(M ) m/z 153.12739, found 153.12666,
H
10
17
NMR (500 MHz, CDCl ): l 1.32 (s, 3H), 1.55 (m, 2H),
3
1
3
.71 (s, 3H), 1.74 (m, 2H), 1.86 (m, 2H), 2.14 (m, 1H),
.07 (t, 1H), 4.70 (d, 2H). C NMR (125 MHz, CDCl3)
13
l 21.145, 24.334, 25.998, 28.689, 30.805, 36.280, 57.371,
6
0.576, 109.121, 149.017.
4
.2. (1R,2R,4S)-1-Methyl-4-(1-methylethenyl)-2-
18
(
1-pyrrolidino)cyclohexanol
2
3
Bp 128–131°C (3.0 Torr), h =−34.9 (c, 4.0, methanol),
D
+
HRMS calcd for C H NO (M ) m/z 224.20226, found
14
26
2
1
24.20089, IR (neat): 3460.5, 2873.4, 2795.2, 1640.9,
455, 1368.8, 1123.8, 1089.5 cm , H NMR (250 MHz,
−1 1
DMSO-d ): l=1.25 (s, 3H), 1.37–1.68 (m, 9H), 1.68 (s,
6
3
2
H), 1.90 (m, 1H), 2.25 (m, 1H), 2.54 (m, 2H), 2.68 (m,
H), 3.94 (m, 1H), 4.79 (s, 2H). C NMR (62.5 MHz,
13
DMSO-d ) l=21.59, 23.50, 24.01, 25.73, 26.98, 29.29,
6
3
6.14, 52.80, 66.47, 71.88, 109.56, 148.86.
4
.3. General procedure for preparation of trans-(R)-
(
+)-limonene oxide, 1
A 50 mL, round-bottom flask equipped with a magnetic
stir bar and a reflux condenser was charged with (R)-
(
0
+)-limonene oxide (4.57 g, 0.03 mol), pyrazole (0.34 g,
.005 mol), and deionized water (16.2 mL). The mixture
was heated to 100°C (reflux) and heated under reflux
for 5 h. The reaction mixture was placed in a water
bath heated to approximately 80°C. The mixture was
then transferred to a separatory funnel and extracted
with warm (80°C) deionized water (2×30 mL) to
remove the diol. The aqueous layer was then placed in
a refrigerator wherein the diol precipitated upon cool-
ing. Excess pentane was then added to the open separa-
tory funnel containing the organic layer and a slurry of
white solid formed immediately. The mixture was vac-
uum filtered to remove the solid and further solid
formed upon evaporative cooling from the vacuum.
The mixture was filtered for a second time removing the
remainder of 1,2-limonene diol. The pentane remained
clear and was dried over anhydrous magnesium sulfate
and gravity filtered into a 100 mL, round-bottom flask.
The pentane was removed in vacuo (rotary evaporator)
Figure 1. Reaction profiles of the reaction of (R)-(+)-
limonene oxide with 30 equiv. of water in the presence of 2.0,
1.0, and 0.24 equiv. of pyrazole (capillary GC area%).
polarimeter diluted in spectral grade methanol. High
resolution mass spec. was done on a PerSeptive Biosys-
tems, Mariner TOF mass spectrometer using positive
ionization.
2
3
leaving trans-R-(+)-limonene oxide (2.01 g). h =+82°
D
7
+
4.1. General procedure for cis-(+)-limonene oxide, 2
(neat), d 0.930 (Fluka), HRMS calcd for C H O(M )
10 17
1
m/z 153.12739, found 153.12666, H NMR (500 MHz,
Pyrrolidine (8.35 mL, 0.10 mol), (R)-(+)-limonene oxide
16.4 mL, 0.10 mol), and deionized water (1.5 mL, 0.08
CDCl ): l=1.31 (s, 3H), 1.39 (m, 2H), 1.69 (s, 3H),
3
(
1.69–1.72 (m, 2H), 1.84–1.88 (m, 2H), 2.06 (m, 1H),
13
mol) were added to a 50 mL round-bottom flask
equipped with a magnetic stir bar and a reflux con-
denser. The reaction mixture was heated to reflux,
2.98 (d, 1H), 4.66 (s, 2H). C NMR (125 MHz, CDCl3)
l=20.274, 23.163, 24.412, 29.949, 30.836, 40.806,
57.574, 59.331, 109.167, 149.204.

D. Steiner et al. / Tetrahedron: Asymmetry 13 (2002) 2359–2363
2363
4
.4. (1S,2S,4R)-Limonene-1,2-diol
11. The cis and trans designation refers to the relative orien-
tation between the 1-methyl and 4-isopropenyl groups of
limonene oxide.
1
1
H NMR (500 MHz, CDCl ): H NMR (500 MHz,
3
CDCl ): l=1.26 (s, 3H), 1.51–1.68 (m, 4H), 1.73 (s,
12. Kuczynski, H.; Piatkowski, K. Roczniki Chem. 1959, 33,
299.
13. Newhall, W. F. J. Org. Chem. 1964, 29, 185.
14. Leffingwell, J. C.; Shackelford, R. E.; R. J. Reynolds
Tobacco Co., 1969, French Patent No. 2002595,
19691031.
3
3
2
2
1
H), 1.93 (m, 2H), 2.27 (m, 1H), 3.63 (d, 1H), 4.73 (s,
1
3
H). C NMR (125 MHz, CDCl ) l=21.161, 26.294,
3
6.760, 33.791, 34.118, 37.555, 71.417, 74.030, 109.089,
49.391. Correlates to previously reported preparation,
Ref. 23.
15. Jones, J.; dos Santos, A. G.; de Lima Castro, F. Synth.
Commun. 1996, 26, 2651.
Acknowledgements
16. Cole-Hamilton, D. J.; Salles, L.; Nixon, A. F.; Russell,
N. C.; Clarke, R.; Pogorzelec, P. Tetrahedron: Asymmetry
1999, 10, 1471.
The authors would like to thank the Dow Chemical
Company for financial and research support.
17. Van der Warf, M. J.; Jongejan, H.; Franssen, M. C. R.
Tetrahedron Lett. 2001, 42, 5521.
1
8. (a) Singaram, B.; Chrisman, W.; Camara, J. N.; Mar-
cellini, K.; Goralski, C. T.; Hasha, D. L.; Rudolf, P. R.;
Nicholson, L. W.; Borodychuk, K. K. Tetrahedron Lett.
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2
19. Similar lack of reactivity of cis-(R)-(+)-limonene oxide
with nucleophilic reagents has been reported for
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diastereomeric amino alcohols, the major product being
(1S,2S,5R)-2-methyl-5-(1-methylethenyl)-2-(1-pyrrolidin-
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. Currently, (R)-(+)-limonene sells for $0.77–$1.10/Kg in
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. Fluka sells pure trans-limonene oxide and cis-limonene
oxide, 5 g for $213 each.
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22. Two diastereomeric diols and two diastereomeric amino
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alcohol product arises from reaction of the trans-
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. Van der Werf, M. J.; Orru, R. V. A.; Overcamp, K. M.;
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