Enantioselective deprotonation of ketones using a novel heterodimer chiral amide base

Article abstract of DOI:10.1016/j.tetasy.2003.12.012

A novel heterodimer chiral base system has been prepared and reacted with a series of prochiral ketones in the presence of TMSCl to give efficient formation of the corresponding enol ethers in an enantiomeric excess up to 85%.

Full text of DOI:10.1016/j.tetasy.2003.12.012

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 577–579
Enantioselective deprotonation of ketones using a
novel heterodimer chiral amide base
Mohamed Amedjkouh*
Organic Chemistry, Department of Chemistry, G€oteborg University, SE-412 96 G€oteborg, Sweden
Received 6 November 2003; accepted 3 December 2003
Abstract—A novel heterodimer chiral base system has been prepared and reacted with a series of prochiral ketones in the presence
of TMSCl to give efficient formation of the corresponding enol ethers in an enantiomeric excess up to 85%.
Ó 2003 Elsevier Ltd. All rights reserved.
Chiral lithium amides are being developed as useful
reagents for the preparation of nonracemic com-
pounds.1 They have been exploited for enantioselective
deprotonation reactions such as epoxides and ketones.
These reactions are synthetically important since the
chiral products are useful intermediates in organic
synthesis.2 Because enolates are interesting carbon
nucleophiles, their generation enantioselectively is
becoming widely used in order to prepare enantiomeri-
cally enriched building blocks for synthesis.
N
Ph
N
N
N
N
X
N
F3C
X
X
1 X = H
3 X = Li
2 X = H
4 X = Li
6 X = H
5 X = Li
N
N
Li
Li
Li
N
N
N
Ph
N
Ph
F3C
N
N
Li
F3C
S
S
9 S = THF
11 S = MIm
10 S = THF
12 S = DBU
Koga has devised an approach to the catalytic asym-
metric deprotonation of 4-substituted cyclohexanones
based on the regeneration of the catalytic chiral lithium
base by an achiral lithium amide. However the use of
additives in excess such DABCO and HMPA was nec-
Figure 1.
bases can be employed as alternatives to their more
widely used lithium homodimers or monomer counter-
parts in catalytic deprotonation of meso-epoxides.6 It
has been previously reported that addition of organo-
lithiums to enolizable ketones is often problematic and
adduct yields tend to be low.7 This drawback could be
used advantageously in deprotonation reactions pro-
moted by heterodimers.
essary to achieve the optimum enantioselectivity.3
A
very desirable situation would be a way of regenerating
the chiral lithium amide base from the amine without a
competitive racemic reaction and need of excess addi-
tives especially cancerogenic HMPA.
In our search for such bases we have used 1-methylim-
idazole 1 and DBU 2 as precursors.4 The latter undergo
carbon deprotonation by n-BuLi to yield the carbenoid
compound 2-lithio-1-methylimidazole 1 and 3-lithio-
DBU 4, respectively (Fig. 1).4;5
Thus, we envisioned that an enantioselective deproto-
nating reagent could be built from chiral lithium amide 5
and bulky bases 3 or 4. Based on these considerations,
herein, we report the first use of such heterodimeric
complexes as reagents in the enantioselective deproto-
nation of conformationally locked ketones.
Studies within our laboratories have shown how hetero-
dimers built from chiral lithium amides and such bulk
In THF, we have shown by NMR spectroscopy that 3
and 4 have basicities comparable to LDA.4 The
deprotonating ability of bases 3 and 4 has been studied
using cyclohexene oxide as a substrate. In contrast to
* Tel.: +46-31-7722895; fax: +46-31-7723840; e-mail: mamou@chem.
gu.se
0957-4166/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.12.012

578
M. Amedjkouh / Tetrahedron: Asymmetry 15 (2004) 577–579
Ph
Ph
HO
Ph
NH2
c, d
a, b
N
N
N
NH
F3C
7
8
6
Scheme 1. Reagents and conditions: (a) 3 equiv Et3N, 1.5 equiv MsCl, THF, 0 °C, 60 min; (b) 2 equiv Et3N, 20 equiv NH3/H2O, rt, 16 h; (c) 1.5 equiv
CF3CO2Et, EtOH, rt, 16 h; (d) LiAlH4, THF, 0 °C and then reflux, 4 h.
LDA, compounds 3 and 4 did not measurably yield any
deprotonation of the epoxide. This is presumably due to
the fact that proton transfers to carbon are usually
slower than those to a more electronegative atom like
nitrogen. These properties indicated that 3 and 4 would
be useful as bulk bases in catalytic asymmetric depro-
tonations.
fied as the heterodimer 11, in which one lithium was
solvated by 1 that resulted from protonation of 3.
However, only a small amount of heterodimer was
observed when a THF solution of chiral amide 5 was
titrated with 1. Indeed, upon addition of 1 equiv of 1 to
6
a solution of 5, the Li spectrum showed only a down-
6
field shift of the Li resonance from d 1.05 to d 1.49,
Chiral diamine (1R,2S)-N-(2,2,2)-trifluoroethyl-1-phe-
nyl-2-pyrrolidinylpropanamine 6 was prepared as out-
lined in Scheme 1. The design of 6 was based on its
similarity with KogaÕs diamine and would be more
effective as chiral base. Thus (1R,2S)-7, generated from
(1R,2S)-norephedrine,8 was subjected to mesylation in
THF followed by reaction with aqueous ammonia
to give (1R,2S)-1-phenyl-2-pyrrolidinylpropanamine 8.
The latter underwent trifluoroacetylation followed
by reduction with LAH to give the corresponding
diamine 6.
presumably as a consequence of Li-solvation by 1, along
with signals from the heterodimer in a 9:1 ratio,
respectively. Further addition of 1 up to 2 equiv resulted
in a shift of the largest peak at d 1.85. These observa-
tions suggest that 5 is not a strong enough base to
deprotonate 1.
The stereoselectivities of the new chiral base 5 in
deprotonation were studied using 4-t-Bu-cyclohexanone
13a as a substrate. The results are summarized in Table
1.9 In the first place we evaluated the chiral lithium
amide 5 using the Ôin situ quench protocolÕ.10 Using
chiral base 5 in a stoichiometric amount, the silylenol
ether (R)-14a was obtained in 79% yield and 85%
enantiomeric excess. Similarly but under the Ôexternal
quench protocolÕ conditions the silylenol ether could be
obtained in 98% conversion and 75% ee (Scheme 2).
By analogy with previously reported work,4 lithium
amide 5 was supposed to build heterobimers of type 9–
12 in the presence of bases 3 or 4 in solution in THF.
Multinuclear NMR analysis of THF solutions of chiral
base 5 revealed the existence of the chiral amide 5 as a
6
homodimer with a single Li resonance at d 1.05. Fur-
thermore, when 6 was titrated with up to 0.5 equiv of 3
We then turned our attention to the heterodimer 9 and
we were delighted to find that the stoichiometric reac-
tion resulted in 89% conversion with 63% ee, under
external quench conditions. Under these conditions, the
reaction also yielded a substantial amount of alkylation
product, by competing addition of 3 to the ketone. We
6
in solution in THF a new set of two Li signals in a 1:1
ratio appeared at d 2.15 and d 2.40. These results indi-
cate the presence of a new complex with two different
1
lithiums. Similarly H and 13C show that 6 had been
deprotonated to provide 5. The new species was identi-
Table 1. Enantioselective deprotonation of ketone to give silylenol under different conditions
Entry
R
Bulk base (equiv)
Quench
Time
Conversion (%)a
Ee (%)a
1
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
None
None
IQ
70 min
70 min
70 min
70 min
90 min
60 min
70 min
3 h min
3 h min
2 h min
60 min
2 h
79
98
98
98
93
91
78
98
97
73
79
82
85
75
63
63
66
46
48
34
33
8
2
EQ
EQ
EQb
EQc
EQd
EQ
EQ
EQc
EQd
EQc
EQ
3
3 (1.0)
3 (1.0)
3 (1.0)
4 (1.0)
BuLi (1.0)
None
4
5
6
7
8
9
Me
Me
4 (1.0)
4 (1.0)
3 (0.2)
3 (0.2)
10
11
12
t-Bu
t-Bu
47
35
a The yield and ee were determined by chiral GC-analysis: Chirasil-DEX CB column. Configuration assignment based on comparison with literature
data.
b TMSCl was added 3 min after addition of ketone.
c 1 equiv Methylimidazole was added in excess.
d 1 equiv DBU was added in excess.

M. Amedjkouh / Tetrahedron: Asymmetry 15 (2004) 577–579
579
References and notes
OTMS
O
R
Chiral amide
TMS-Cl
1. For reviews see: (a) Jones, S. J. Chem. Soc., Perkin Trans.
1 2002, 1; (b) Eames, J. Eur. J. Org. Chem. 2002, 393; (c)
OÕBrien, P. J. Chem. Soc., Perkin Trans. 1 2001, 95; (d)
OÕBrien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439; (e)
Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron
1996, 52, 14361; (f) Cox, P. J.; Simpkins, N. S. Tetra-
hedron: Asymmetry 1991, 2, 1.
°
THF, -78 C
°
THF, -78 C
R
13a: R = tBu
13b: R = Me
(R)-14a, R = tBu
(R)-14b: R = Me
Scheme 2.
2. (a) Hodgson, D. M.; Gibbs, A. R. Synlett 1997, 657; (b)
Hodgson, D. M.; Witherington, J.; Moloney, B. A.
J. Chem. Soc., Perkin Trans. 1 1994, 3373; (c) Asami,
M.; Takahashi, J.; Inoue, S. Tetrahedron: Asymmetry
1994, 5, 1649; (d) Kasai, T.; Watanabe, H.; Mori, K.
Biorg. Med. Chem. 1993, 1, 67; (e) Mori, K.; Murata, N.
Liebigs Ann. Chem. 1995, 2089; (f) Bhuniya, D.; Datta-
Gupta, A.; Singh, V. K. J. Org. Chem. 1996, 61, 6108; (g)
Asami, M.; Inoue, S. Tetrahedron 1995, 51, 11725; (h) de
Sousa, S. E.; OÕBrien, P.; Pilgrim, C. D. Tetrahedron Lett.
2001, 42, 8081.
3. (a) Yamashita, T.; Sato, D.; Kiyoto, T.; Kumar, A.; Koga,
K. Tetrahedron 1997, 53, 16987; (b) Yamashita, T.; Sato,
D.; Kiyoto, T.; Kumar, A.; Koga, K. Tetrahedron Lett.
1996, 37, 8195.
4. (a) Amedjkouh, M.; Pettersen, D.; Nilsson Lill, S. O.;
€
Davidsson, O; Ahlberg, P. Chem. Eur. J. 2001, 7, 4368–
wondered whether an early external quench would
influence the reaction outcome. This was not the case
since addition of TMSCl 3 min after that of the ketone
resulted in a similar 63% ee despite a conversion of 97%
(entry 4), and less alkylation adduct was produced. In
contrast using one equivalent excess of 1 gave improved
enantioselectivity up to 66% ee (entry 5) and no alkyl-
ation product formation.
The ee decreased to 46% when 4 is used as achiral base
(entry 6). Furthermore, and more interestingly, the
reaction in the presence of 1 equiv excess of BuLi the
reaction resulted in an enantioselectivity of 48% ee with
78% conversion and no alkylated byproduct. It is rea-
sonable to suggest a heterodimer built from 5 and BuLi
to be the reactive species. This constitutes the first
example of such use of BuLi in a mixed aggregate for
deprotonation reactions.
4377; (b) Nilsson Lill, S. O.; Pettersen, D.; Amedjkouh,
M.; Ahlberg, P. J. Chem. Soc., Perkin Trans. 1 2001, 3054;
(c) Pettersen, D.; Amedjkouh, M.; Nilsson Lill, S. O.;
Ahlberg, P. J. Chem. Soc., Perkin Trans. 2 2002, 1397–
1405; (d) Matsumura, N.; Nishiguchi, H.; Okada, M.;
Yoneda, S. Heterocycles 1985, 885.
The above-mentioned slow proton transfer to carbon
rather than to nitrogen, prompted us to explore the
potential of the mixed dimer in catalytic enantioselective
reaction. Thus, control reactions were run to evaluate
competitive reactivity of 3 towards ketone in absence of
chiral lithium amide. It was found that the alkylation
was the main reaction resulting in addition of 3 to
ketone as shown with both NMR and mass spectro-
scopy. The reaction proceeded with 82% conversion and
with only 8% deprotonation occurred after 70 min.
Similarly, reaction with only 4 gave deprotonation
product in only 3% after 2 h.
5. Hilf, C.; Bosold, F.; Harms, K.; Marsch, M.; Boche, G.
Chem. Ber. 1997, 130, 1213.
6. Pettersen, D.; Amedjkouh, M.; Ahlberg, P. Tetrahedron
2002, 58, 4669–4673.
ꢀ
7. Lecomte, V.; Stephan, E.; Le Bideau, F.; Jaouen, G.
Tetrahedron 2003, 59, 2169–2176.
ꢀ
8. Pettersen, D.; Amedjkouh, M.; Nilsson Lill, S. O.; Dahlen,
K.; Ahlberg, P. J. Chem. Soc., Perkin Trans. 2 2001, 1654.
9. Typical procedure for the enantioselective deprotonation
(entry 1, internal quench): A round bottomed flask was
charged with a solution of 6 (29 lL, 0.1 mmol) in dry THF
(2 mL) under nitrogen atmosphere. The solution was
cooled to )78 °C and n-BuLi (2.26 M in hexane, 45 lL,
0.1 mmol) was added dropwise. The reaction mixture was
left for 15 min at room temperature. The reaction mixture
was rapidly cooled to )78 °C and chlorotrimethylsilane
(0.5 mL, 0.5 mmol) was added dropwise (in the case of
external quench, TMSCl was added 3 min prior to
addition of triethylamine). After the reaction mixture
had been stirred for 2 min at this temperature a solution
of 4-tert-butylcyclohexanone (1 M in THF, 100 lL,
0.1 mmol) was added dropwise over 5 min. After 70 min
triethylamine (2 mL) was added, followed by a saturated
solution of NH4CL (2.5 mL). The reaction mixture was
warmed to room temperature, extracted with diethyl ether
and the organic phase washed with water. The combined
aqueous phase was extracted with diethyl ether (10 mL),
and the organic phase was dried over Na2SO4. The
reaction conversion and the enantiomeric ratio was
determined by GC analysis Chirasil-DEX CB capillary
column, carrier gas He (2 mL/min), 80 °C (1 min)–130 °C;
temperature gradient: 1.5 °C/min, tR ¼ 25:8 min (S)-14a,
tR ¼ 26:1 min (R)-14a.
In entry 11, the lithium amide is used in sub-stoichio-
metric amounts and the initial concentration of 3 is five
times that of 5 and no excess of 1. This resulted in a
lower ee of 35% (entry 12). In the presence of 1 equiv
excess of 1 the ee increased up to 47% (entry 11). The
low enantioselectivity under catalytic conditions is pos-
sibly due to a competing non-enantioselective reaction
of 3 with the ketone. This demonstrates the important
solvation effect and its influence on the enantioselectivity
and reactivity.
In conclusion, having prepared a new chiral base derived
from norephedrine, synthetically useful silylenol ethers
were prepared in up to 85% ee. We have demonstrated
for the first time the use of heterodimer built from
a chiral base and a bulk base for such a reaction,
including BuLi. Although a lower ee was obtained,
attempts to run the reaction under catalytic and external
quench conditions show the potential for this method-
ology.
10. Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25,
495–498.