Kinetic resolution of racemic epoxides using a chiral diamine catalyst

Article abstract of DOI:10.1016/j.tetlet.2005.05.017

The kinetic resolution of a variety of racemic epoxides has been performed using a chiral bicyclic diamine ligand. Using 5 mol % of catalyst very high selectivity could be achieved; both epoxide and the corresponding allylic alcohol could be obtained in up to 99% ee.

Full text of DOI:10.1016/j.tetlet.2005.05.017

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4805–4807
Kinetic resolution of racemic epoxides using a chiral
diamine catalyst
Arnaud Gayet and Pher G. Andersson*
Department of Organic Chemistry, Uppsala University, PO Box 599, BMC, 751 24Uppsala, Sweden
Received 16 March 2005; revised 27 April 2005; accepted 5 May 2005
Abstract—The kinetic resolution of a variety of racemic epoxides has been performed using a chiral bicyclic diamine ligand. Using
5 mol % of catalyst very high selectivity could be achieved; both epoxide and the corresponding allylic alcohol could be obtained in
up to 99% ee.
Ó 2005 Elsevier Ltd. All rights reserved.
The use of enzymes for the kinetic resolution of racemic
NH
substrates, to afford enantiopure compounds in high ee
and good yields has long been a popular strategy in syn-
thesis.1 It is only recently that the widespread application
of non-enzymatic chiral catalysts for kinetic resolution2
(or dynamic kinetic resolution3) has gained popularity
within the synthetic community.4 In a typical kinetic reso-
lution, the two enantiomers of a racemic substrate react
at different rates allowing partial separation. Depending
on whether one is interested in recovering the unreacted
starting material in high enantiomeric excess or the prod-
uct (if chiral), the reaction must be stopped shortly after
or before 50% conversion is reached.
N
Figure 1. Chiral diamine 1.
Our group recently showed that the diamine 1 (Fig. 1)
could be used as a very efficient ligand for the kinetic
resolution of racemic epoxides.6 Using 1, the chiral
non-racemic epoxide and the corresponding allylic alco-
hol were both isolated in up to 99% ee. A limitation of
this ligand was a low substrate tolerance, as only a-
substituted and b-disubstituted epoxides could be suc-
cessfully resolved. Epoxides having other substitution
patterns, either did not react or led to racemic mixtures.
The first kinetic resolution method applied to the resolu-
tion of a racemic epoxide was described by Asami et al.5
Using a chiral lithium amide they performed the kinetic
resolution of cis-3-alkylcyclohexene oxides. However, a
stoichiometric amount of the chiral base was necessary
in order to obtain both the alcohol and the unreacted
epoxide in good enantiomeric excess (Scheme 1).
The bicyclic diamine 27 featuring a dimethylpyrrolidine
has proven to be superior to 18,9 having a simple pyrrol-
idine ring, in the rearrangement of meso-epoxides, both
in terms of activity and selectivity. Therefore, diamine 2
was tested in the kinetic resolution of a racemic epoxide
in order to increase the scope of the reaction (Fig. 2).
The reactions were performed as previously described6
using 5 mol % of the chiral diamine and LDA as stoichio-
metric base. The result are summarised in Table 1.
HO
O
O
O
chiral Li-amide
+
+
Scheme 1. Lithium amide mediated kinetic resolution of racemic
epoxides.
NH
N
Keywords: Kinetic resolution; Epoxide rearrangement; Allylic alcohol;
Chiral diamine.
*
Corresponding author. Tel.: +46 18 471 3801; fax: +46 18 471
3818; e-mail: phera@kemi.uu.se
Figure 2. Chiral diamine 2.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.017

4806
A. Gayet, P. G. Andersson / Tetrahedron Letters 46 (2005) 4805–4807
Table 1. Kinetic resolution of racemic epoxides
2 (5 mol%)
LDA (1.2 equiv.)
DBU (5 equiv.)
racemic epoxide
epoxide + allylic alcohol
THF 0°C
Entry
16
Epoxidea
Conv. (%)b
ee (%)c epoxide
72
Alcohold
ee (%)c alcohol
99
t-Bu OH
t-Bu
O
46
32
t-Bu
t-Bu OH
t-Bu OH
26
nd
nd
96
96
O
t-Bu
36
34
O
n-Bu OH
n-Bu
O
4
41
56
49
42
96
51
94
85
95
HO
OH
O
O
56
6
O
HO
7
8
cis
trans
62
70
99
99
55
40
Ph
O
Ph
HO
9
10
cis
60
65
99
21
90
20
trans
HO
O
11
12
cis
trans
80
30
99
5
64
16
n-Bu
n-Bu
HO
O
13
trans
32
nde
94
t-Bu
t-Bu
a cis and trans refers to the relative stereochemistry between the epoxide and the substituent.
b Determined by GC. Based on epoxide consumption relative to an internal standard.
c Determined by chiral GC.
d Absolute configuration tentatively assigned on the basis of the selectivity model published earlier.9
e Not determined. The enantiomers could not be successfully separated by chiral GC.
Diamine 2 displays an equal or higher selectivity than its
non-substituted equivalent 1 for a large range of sub-
strates (Table 1). Using this chiral base, racemic cyclic
a-tert-butyl epoxides can be converted to the corre-
sponding allylic alcohols in up to 99% ee when the reac-
tion is stopped before 50% conversion (entries 1–3).
Decreasing the size of the a-substituent did not affect
the selectivity, with 1-ethylcyclohept-2-en-1-ol being
produced in 95% ee from the corresponding epoxide
after 49% conversion (entry 6). A b-spiro epoxide was
also resolved with high stereoselectivity, the starting
material and the alcohol were obtained in 96 and 85%
eeÕs, respectively, after 56% conversion.
to kinetic resolutions (entries 7 and 8). Diamine 2 was
also able to resolve b-monosubstituted cyclic epoxides,
but in this case the size of the substituent and its relative
position to the epoxide had a tremendous effect on the
selectivity. cis-Epoxides proved to be excellent candi-
dates for kinetic resolution irrespective of the size of
the b-substituents (entries 9 and 11), while only trans-
epoxides having a very large b-substituent can be suc-
cessfully resolved. trans-b-tert-Butyl cyclohexene oxide
produced the corresponding allylic alcohol in 94% ee
after 32% conversion. Replacement of the tert-butyl
group by an isopropyl group resulted in a dramatic loss
of selectivity, with the epoxide and the alcohol obtained
in 21% and 20% ee, respectively, after 65% conversion
(entry 10).
More interesting, are the cases of cyclohexene oxides
having two different substituents at the b-position. In
the case of b-disubstituted cyclohexene oxides both the
cis- and trans-epoxides could be successfully subjected
Further reduction in the size of the b-substituent re-
sulted in very poor selectivity; the use of an n-butyl

A. Gayet, P. G. Andersson / Tetrahedron Letters 46 (2005) 4805–4807
4807
substituent produced the epoxide in 5% ee and the allylic
alcohol in 16% ee after 30% conversion (entry 12).
References and notes
1. For recent reviews on the use of enzymes and whole cells
for kinetic resolution, see: (a) Davis, B. G.; Boyer, V. Nat.
Prod. Rep. 2001, 18, 618–640; (b) Groger, H. Adv. Synth.
Catal. 2001, 343, 547–558; (c) Roberts, S. M. J. Chem. Soc.,
Perkin Trans. 1 2001, 1475–1499; (d) Reetz, M. T. Angew.
Chem., Int. Ed. 2001, 40, 284–310; (e) Carrea, G.; Riva, S.
Angew. Chem., Int. Ed. 2000, 39, 2226–2254.
It is also worth noting that a-hydrogen abstraction in
the exo-cyclic position observed using the diamine 1
has been greatly diminished using the second generation
amine 2. This is probably due to better selectivity and a
shorter reaction time.
2. For an excellent introduction into the principles of kinetic
resolution for asymmetric synthesis, see: Kagan, H. B.;
Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
3. For excellent treatises on the principles and application of
dynamic kinetic resolution for stereoselective synthesis, see:
(a) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem.
Soc. Jpn. 1995, 68, 36–55; (b) Ward, R. S. Tetrahedron:
Asymmetry 1995, 6, 1475–1490.
4. For general reviews on kinetic resolution using non-
enzymatic catalysts, see: (a) Robinson, D. E. J. E.; Bull,
S. D. Tetrahedron: Asymmetry 2003, 14, 1407–1446; (b)
Keith, M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal.
2001, 343, 5–26; (c) Cook, G. R. Curr. Org. Chem. 2000, 4,
869–886; (d) Hoveyda, A. H.; Didiuk, M. T. Curr. Org.
Chem. 1998, 2, 489.
In conclusion we have demonstrated that the dimethyl-
pyrrolidine diamine 2 in combination with LDA as a
stoichiometric base is a very selective catalyst for the ki-
netic resolution of racemic epoxides. Using 5 mol % of
catalyst, both epoxide and allylic alcohol can be
obtained in up to 99% ee when the reaction is stopped
shortly before or after 50% conversion is reached. Using
2 we were able to increase the scope of the reaction to b-
mono-substituted cyclohexene oxides, which so far have
proven to be problematic substrates.
Acknowledgements
5. Asami, M.; Sato, S.; Honda, K.; Inoue, S. Heterocycles
2000, 52, 1029–1032.
6. Gayet, A.; Bertilsson, S.; Andersson, P. G. Org. Lett. 2002,
4, 3777–3779.
This workwas supported by grants from The Swedish
Research Council and COST Chemical Action D24.
7. Bertilsson, S. K.; So¨dergren, M. J.; Andersson, P. G.
J. Org. Chem. 2002, 67, 1567–1573.
Supplementary data
8. So¨dergren, M. J.; Andersson, P. G. J. Am. Chem. Soc. 1998,
120, 10760–10761.
9. So¨dergren, M. J.; Bertilsson, S. K.; Andersson, P. G. J. Am.
Chem. Soc. 2000, 122, 6610–6618.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2005.
05.017.