Enantioselective catalytic rearrangement of cyclohexene oxide with new homochiral bis-lithium amide bases

Article abstract of DOI:10.1016/j.tetasy.2004.02.030

Cyclohexene oxide can be rearranged with good levels of induction (up to 68% ee) with substoichiometric amounts of chiral bases derived from readily available diamines. The influence of the steric bulk of the amine substituents on the rearrangement enantioselectivity has also been studied.

Full text of DOI:10.1016/j.tetasy.2004.02.030

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1069–1072
Enantioselective catalytic rearrangement of cyclohexene oxide
with new homochiral bis-lithium amide bases
Olivier Equey and Alexandre Alexakis*
Dꢀepartement de Chimie Organique, Universitꢀe de Genꢁeve, 30 quai Ernest-Ansermet, 1211 Genꢁeve 4, Switzerland
Received 13 January 2004; revised 19 February 2004; accepted 24 February 2004
Abstract—Cyclohexene oxide can be rearranged with good levels of induction (up to 68% ee) with substoichiometric amounts of
chiral bases derived from readily available diamines. The influence of the steric bulk of the amine substituents on the rearrangement
enantioselectivity has also been studied.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
strong carbon base such as n-BuLi or MeLi was used
(entries 4–6).
The asymmetric base-mediated rearrangement of meso-
epoxides into optically active allylic alcohols is a reac-
tion of great interest since allylic alcohols are useful
intermediates for organic synthesis. This transformation
has been extensively studied during the last two decades1
and has been applied to the synthesis of a number of
commercially and biologically important substances,
such as carbovir,2 lasiol,3 faranal,4 leukotrienes5 and
prostaglandin precursors.6 The best results for the
asymmetric epoxide rearrangement have been obtained
Herein we report preliminary results obtained in the
catalytic enantioselective deprotonation of cyclohexene
oxide 1 using new homochiral bis-lithium amide bases.
The reactions have been carried out in THF rather than
in benzene because we observed a huge decrease of the
reactivity of the chiral amide in this solvent. We have
obtained similar results than with bis-amide (R,R)-2.
The main advantage of these new chiral bases is that
they can be prepared easily in only one or two steps. We
have varied the steric bulk of their substituents a to the
nitrogen in order to study their influence on enantio-
selectivity.
7
by Andersson etal., who have developed a chiral lith-
ium amide, which allows the isomerisation of several
epoxides with enantioselectivities up to 99% ee. They
also found that the presence of an additive such as DBU
was essential to achieve optimum enantioselectivities.
Our group has also investigated the enantioselective
deprotonation of meso-epoxides with bis-lithium amides
derived from C2 symmetric diamines.8 The bestresult
for the enantioselective deprotonation of cyclohexene
oxide 1 was been obtained with the bis-lithium amide
base (R,R)-2. This chiral base gave the allylic alcohol
(R)-3 in good yield (68%), with an enantiomeric excess
of 76% (Table 1, entry 1). Use of LDA to regenerate the
original bis-lithium amide (R,R)-2 gave the allylic alco-
hol (R)-3 with a significantly lower enantiomeric excess
(entry 2). The addition of DBU has not allowed to en-
hance the enantioselectivity of the rearrangement (entry
3). Surprisingly, efficientrecycling was observed when a
2. Results and discussion
The diamines 4–8 were prepared in two steps: first for-
mation of the diimine by condensation of 2 equiv of the
corresponding amine with an aq solution of glyoxal,10
and then reduction of the diimine with NaBH4 in MeOH
(Scheme 1).
We obtained 45% enantiomeric excess (ee) for the
asymmetric rearrangement of cyclohexene oxide 1 to
2-cyclohexen-1-ol 3 using MeLi (1 equiv) in the presence
of substoichiometric amounts (0.2 mol %) of base
Li-4 (Table 2, entry 1). Replacement of the methyl
groups in Li-4 by ethyl groups increased the ee from
45% to 59% (entry 2). We thought that replacement of
the phenyl groups in Li-4 by 1-methoxyphenyl groups
could enhance the stereocontrol of the deprotonation.
* Corresponding author. Tel.: +41-(0)22-37-96522; fax: +41-(0)22-37-
93215; e-mail: alexandre.alexakis@chiorg.unige.ch
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.02.030

1070
O. Equey, A. Alexakis / Tetrahedron: Asymmetry 15 (2004) 1069–1072
Table 1. Enantioselective rearrangement of cyclohexene oxide 1 with chiral base (R,R)-2
(R,R)-2
OH
O
NLi LiN
OMe MeO
achiral base
THF, 0 °C → rt
1
(R)-3
(R,R)-2
Entry
(R,R)-2
Achiral base
Additive
Time (h)
Yield (%)a
Ee (%)b
1
2
3
4
5
6
1.0 equiv
0.2 equiv
0.2 equiv
0.2 equiv
0.2 equiv
0.2 equiv
––
––
––
21
22
43
20
68
48
68
66
35
54
56
47
76 (R)
32 (R)
13 (R)
60 (R)
67 (R)
67 (R)
LDA (1.0 equiv)
LDA (1.0 equiv)
MeLi (1.0 equiv)
MeLi (1.0 equiv)c
DBU (6 equiv)
––
––
––
n-BuLi (1.0 equiv)c
a Isolated yield after flash chromatography.
b Enantiomeric excess determined by 31P NMR analysis.9
c Reaction carried out in benzene.
R
NH2
=
NH2
,
NH2 ,
NH2 ,
O
O
NaBH4 (2.5 éq.)
O
R
N
N R
R
NH2
R
NH HN R
2
HCO2H (cat.)
MgSO4, CH2Cl2
rt, 5 h
MeOH
rt, overnight
90-96 % yield
43-90 % yield
NH2
NH2
,
Scheme 1. Formation of 1,2-ethane-diamines 4–8.
Table 2. Enantioselective rearrangement of cyclohexene oxide 1 with chiral bases Li-4–8
Diamines 4-8 (0.2 eq.)
MeLi (1.4 eq.)
OH
O
or
THF, 0 °C → rt
OH
1
(R)-3
(S)-3
Entry
1
Chiral base
Time (h)
Yield (%)a
Ee (%)b
NH HN
21
80
45 (S)
Ph
Ph
Ph
(S,S)-4
2
3
23
80
71
59 (R)
56 (S)
NH HN
Ph
(R,R)-5
NH HN
4 days
O
O
(R,R)-6
NH HN
1-Naph
4
5
39
46
63
57
40 (S)
34 (S)
1-Naph
(S,S)-7
NH HN
2-Naph
2-Naph
(S,S)-8
a Isolated yield after flash chromatography.
b Enantiomeric excess determined by chiral-GC on HYDRODEX B-3P.

O. Equey, A. Alexakis / Tetrahedron: Asymmetry 15 (2004) 1069–1072
Br Br
100 °C, 10'
1071
R
NH HN R
R
NH2
2.5
30-94 % yield
R
NH2
=
NH2
,
NH2 ,
NH2
O
,
NH2,
NH2
NH2
,
NH2
,
Scheme 2. Formation of 1,3-propane-diamines 9–15.
Table 3. Enantioselective rearrangement of cyclohexene oxide 5 with chiral bases Li-9–15
Diamines 9-15 (0.2 eq.)
MeLi (1.4 eq.)
OH
O
or
THF, 0 °C → rt
OH
1
(R)-3
(S)-3
Entry
1
Chiral base
Time (h)
Yield (%)a
62
Ee (%)b
NH HN
(R,R)-9
72
63
57 (R)
Ph
Ph
Ph
2
3
60
57 (S)
10 (S)
NH HN
Ph
(S,S)-10
NH HN
4 days
29c
O
O
(R,R)-11
NH HN
1-Naph
4
5
45
49
68 (S)
8 (S)
1-Naph
(S,S)-12
6 days
36d
NH HN
(S,S)-13
6
7
40
42
67
63
16 (R)
39 (S)
NH HN
(S,S)-14
NH HN
(S,S)-15
a Isolated yield after flash chromatography.
b Enantiomeric excess determined by chiral-GC on HYDRODEX B-3P.
c Conversion: 55%.
dFormation of trans-2-methyl-cyclohexan-1-ol (11%).
Additional ligation in the bis-lithium amide should
increase the rigidity of the base. Unfortunately, the
presence of the methoxy groups did not improve the ee
obtained with Li-5 (entry 3). Replacement of the phenyl
groups in Li-1 by either 1-naphthyl or 2-naphthyl
groups was unsuccessful (entries 4 and 5). The ee’s
were slightly lower than those obtained with base Li-4
(40% and 34%, respectively). In the case of the bases

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O. Equey, A. Alexakis / Tetrahedron: Asymmetry 15 (2004) 1069–1072
derived from 1,2-diamino-ethane, replacement of the
methyl groups by ethyl groups was favourable in terms
of enantioselectivity for the asymmetric rearrangement
of cyclohexene oxide 1.
available diamines. Further developments are under
studies in order to increase the catalyst efficiency and
results will be reported in due course.
In order to see if such an improvement could also be
achieved with bases derived from 1,3-propane-diamine,
we have prepared the diamines 9–15. They have been
prepared in one step, by nucleophilic substitution of 1,3-
dibromo-propane with 2.5 equiv of the corresponding
amine (Scheme 2).11
Acknowledgements
We thank the Swiss National Science Foundation for
financial support(grantN ° 20-61891-00) and the BASF
company for generous gift of the starting amines.
The base Li-9 was firstevaluaetd. We obatined 57% ee
for the enantioselective deprotonation of cyclohexene
oxide 1 (Table 3, entry 1). In this case, replacement of
the methyl groups in Li-9 by ethyl groups had no effect
on the enantioselectivity of the rearrangement. We
obtained exactly the same ee (entry 2). Replacement of
the phenyl groups in Li-9 by 1-methoxy groups had a
very detrimental effect on enantioselectivity, as the ee
dropped to 10% (entry 3). Replacement of the phenyl
groups in Li-9 by 1-naphthyl groups increased the
enantiomeric excess from 57% to 68% (entry 4), which is
the best ee obtained to date with a homochiral bis-lith-
ium amide for the enantioselective deprotonation of
cyclohexene oxide 1.8 We have also tried to replace the
phenyl groups in Li-9 by tert-butyl groups. The base Li-
13 afforded 2-cyclohexen-1-ol 3 with only 8% ee and
36% yield (entry 5). The replacement of the phenyl
groups by alkyl groups had a detrimental effect on
enantioselectivity and on reactivity. Indeed, we observed
the formation of product of opening by MeLi (11%).
Finally, we have tested the bases Li-14 and Li-15, which
possessed a cyclic substituent in a of the nitrogen atoms.
We thought that such a unit would bring less flexibility
to our system, thus inducing better enantioselectivity.
However, in both cases, the ee’s were lower. The ee’s
dropped from 45% to 16% and 39%, respectively (entries
6 and 7). Thus, in the case of the bases derived from 1,3-
diamino-propane, replacement of the methyl groups by
1-naphthyl groups was favourable in term of enantio-
selectivity for the asymmetric rearrangement of cyclo-
hexene oxide 1.
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In conclusion, we have shown that fine tuning of the
substituents of the amine moiety improved the enantio-
selectivity for the base-mediated epoxide rearrangement
of cyclohexene oxide. We were able to rearrange cyclo-
hexene oxide 1 with ee up to 68% with really easily