CrIII(salen) catalysed asymmetric ring opening of monocyclic terpene-epoxides

Article abstract of DOI:10.1016/S0040-4039(03)01052-9

The racemic Cr^III(salen) complex was found to be an efficient catalyst for the asymmetric ring opening (ARO) with TMSN₃ of cyclic 1,2-epoxy-terpenes bearing C₄-substituents.

Full text of DOI:10.1016/S0040-4039(03)01052-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4715–4717
CrIII(salen) catalysed asymmetric ring opening of monocyclic
terpene-epoxides
Bart M. L. Dioos and Pierre A. Jacobs*
Centre for Surface Chemistry and Catalysis, K.U.Leuven, Kasteelpark Arenberg 23, 3001 Heverlee, Belgium
Received 10 April 2003; revised 22 April 2003; accepted 23 April 2003
Abstract—The racemic CrIII(salen) complex was found to be an efficient catalyst for the asymmetric ring opening (ARO) with
TMSN3 of cyclic 1,2-epoxy-terpenes bearing C4-substituents. © 2003 Elsevier Science Ltd. All rights reserved.
The chiral CrIII(salen) complex 1 (Fig. 1) proved to be
affects the selectivity of the resolution: if the reaction
an efficient catalyst for the enantioselective ring open-
ing of epoxides with trimethylsilylazide (TMSN3). The
reaction was first examined with terminal epoxides1 as
substrates, but also meso-epoxides2, 1,2-3 and 2,2-
disubstituted4 epoxides have been successfully subjected
to the asymmetric ring opening reaction with TMSN3.
In a search for other and more complex substrates for
the ARO reaction, a range of trisubstituted epoxides, in
particular epoxides of monocyclic terpenes were
screened.
mixture is heated (in order to speed up the reaction) the
selectivity diminishes. If the reaction mixture is cooled,
the selectivity slightly improves, but the reaction slows
down significantly. A reaction temperature of about
20°C (rt) proved to be a good compromise.
Diethyl ether was used as solvent, since it offered
superior results compared to other ethereal solvents like
Terpenes are widely distributed in nature, in particular
as essential oils in higher plants. Epoxy-terpenes often
serve as starting materials for the synthesis of fra-
grances, flavours, herbicides, fungicides and biologically
or therapeutically active substances.5 In this perspective
enantiopure epoxy-terpenes are valuable building
blocks.6
Figure 1. The chromiumIII(salen) complex.
Starting from the corresponding terpenes, the epoxy-
terpenes (Fig. 2) were synthesised by epoxidation with
m-chloroperbenzoic acid7 (m-CPBA) or with an H2O2–
phosphorous–tungsten phase transfer system.8 Both
types of epoxidations are rapid and result in high
epoxide yields.
(−)-Carvomenthene epoxide
4 was synthesised by
hydrogenation of (−)-limonene 1,2-epoxide 2 using
Raney nickel as catalyst.9
The ARO reactions were performed at room tempera-
ture and at atmospheric pressure. The temperature
* Corresponding author. Tel: (+32) 16 321610; fax: (+32) 16 321998;
e-mail: pierre.jacobs@agr.kuleuven.ac.be
Figure 2. The epoxy-terpene substrates.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01052-9

4716
B. M. L. Dioos, P. A. Jacobs / Tetrahedron Letters 44 (2003) 4715–4717
THF or TBME.10 Though it can be expected that some
of these reactions can be performed without solvent,
most of these substrates however need to be dissolved
in a solvent because of their relatively high melting
point (Mp >20°C).
into an equatorial position. Consequently blocking the
approach of the CrꢀN3 species from one side, and
thereby allowing only a specific coordination of the
epoxide with the catalytic complex resulting in a
diastereoselective ARO reaction. Furthermore, the
selectivity of the ARO for all tested substrates was the
same, the cis-diastereomers were selectively trans-
formed and all remaining epoxides were trans-epoxides
(Fig. 4).
Although a slight excess of TMSN3, (0.55 equiv.)
suffices, a larger excess of 0.7 to 1.0 equiv. is used to
shorten the reaction time. Since the trisubstituted epox-
ides are not easily accessible for coordination with the
catalytic complex due to steric effects, a fairly high
catalyst/substrate ratio was required in order to reduce
the reaction time. A catalyst/substrate ratio of 5 mol%
was preferred.
The CrIII(salen) catalyst merely acts as an activating
agent for the azide-transfer, not as a stereogenic envi-
ronment for the ARO.
The selectivity of the ARO reactions can be tuned for
both epoxide and product by adjusting the amount of
TMSN3. All ARO reactions in Table 1 (except entry 1)
were optimised for the recuperation of the optically
pure epoxides. Therefore larger amounts of TMSN3
(0.7 or 1.0 equiv.) were added. The reaction can also be
adapted for the synthesis of ring-opened products,
hence 0.5 equiv. of TMSN3 should be added and con-
siderably longer reaction times are required (entry 1).
First of all, it is important to stipulate that the Jacob-
sen kinetic resolution of internal epoxides has not been
demonstrated.12 This was confirmed by the ARO of
1-methyl-1,2-epoxy-cyclohexene, for which an enan-
tiomeric excess of barely 5% was reached (Fig. 3).
Regarding the catalytic results summarised in Table 1,
a racemic CrIII(salen) catalyst13 was used and for all
substrates, D.E. values of over 85% were obtained at
conversions of 42–62%.14
Both trans-epoxide and ring-opened product can be
isolated from the reaction mixture by rotatory evapora-
tion followed by a column chromatography work-up.
The obtained azido products can be transformed into
the corresponding amino alcohols by a desilylation/
reduction sequence.16
Therefore, the selectivity for the asymmetric ring open-
ing of the epoxy-terpenes is not due to the chiral
properties of the CrIII(salen) catalyst, but is caused by
the presence of the C4-substituent. It is likely that the
C4-substituent forces the substrate molecules into the
most stable conformation, orienting the substituents
Figure 4. cis- And trans-diastereomers of (−)-limonene 1,2-
Figure 3. ARO of 1-methyl-1,2-epoxy-cyclohexene.
epoxide.15
Table 1. Catalytic results of asymmetric ring opening of cyclic 1,2-epoxy-terpenes
Entry
Substrate
TMSN3
(equiv.)
Reaction time Conversion
Initial D.E.a
(%)
Final D.E.a
(%)
Remaining
epoxide
Product D.E.a
(%)
(h)
(%)
1
2
3
4
5
6
7
2
2
3
4
5
6
7
0.5
0.7
1.0
1.0
0.7
0.7
0.7
182
42
48
25
19.5
50
56
56
55
53
42
62
13
9
85
92
88
90
92
96
94
trans
trans
trans
trans
trans
trans
trans
83
36
27
52
17
14
20
18
20
N.d.b
N.d.
N.d.
9
23
a D.E.: diastereomeric excess.11
b N.d.: not determined.

B. M. L. Dioos, P. A. Jacobs / Tetrahedron Letters 44 (2003) 4715–4717
4717
The technique here proposed is thus a practical strategy
for the synthesis of both optically pure trans-1,2-epoxy-
terpenes and the corresponding cis-azido-products that
can serve as chiral auxiliaries or be derivatised to
biologically active compounds.6
11. All diastereomeric excesses were determined by chiral GC
on a Chrompack-CHIRASIL-DEX CB column (0.32
mm×0.25 mm×25 m) using FID detection. The D.E.’s
listed in Table 1 correspond to the composition of the
reaction mixture and consequently do not reflect to the
isolated products.
12. Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth.
Catal. 2001, 343, 5–26.
Acknowledgements
13. Initially some introductory experiments using (R,R)-
CrIII(salen) proved the capacities of the complex for ARO
reactions of terpene-epoxides. In later experiments, the
(S,S)-CrIII(salen) exhibited identical selectivity and reac-
tivity. Therefore the final experiments (listed in Table 1)
were carried out with a racemic CrIII(salen) catalyst.
14. As a representative procedure, the experimental details
and work-up for the ARO of (−) limonene 1,2-epoxide
are described:
This work is done in the frame of an IAP-programme
sponsored by the Ministry of Science Policy, Belgium.
B.M.L.D. acknowledges a grant from K.U.Leuven.
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In a glass vial with a magnetic stirrer, the CrIII(salen)
complex (5 mol%) was dissolved in diethyl ether (5 ml).
Toluene was added as internal standard. (−)-Limonene
1,2-epoxide (1.5 mmol) was added and the solution was
allowed to stir for 10 min before adding 0.7 equiv. of
TMSN3. The glass vial was then sealed and the reaction
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(43% yield on epoxide, 89% D.E.) and azido product
(36% yield, 90% D.E.) were recovered (not listed in Table
1). During the chromatographic work-up, desilylation of
the azido compound already occurred due to the mild
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