Enantioselective alkylation of α-fluoro-β-keto esters by asymmetric phase-transfer catalysis

Article abstract of DOI:10.1055/s-0028-1087813

Highly enantioselective alkylation of tert-butyl α-fluoro-β-keto esters can be effected by the use of N-spiro chiral quaternary ammonium salt as chiral phase-transfer catalyst, as a complementary approach to the asymmetric fluorination of α-alkyl-β-keto e

Full text of DOI:10.1055/s-0028-1087813

664
CLUSTER
Enantioselective Alkylation of a-Fluoro-b-Keto Esters by Asymmetric
Phase-Transfer Catalysis
Enantioselective
Alkylation
o
a
f
a
-
Fluoro-
b-Keto
E
ster
g
s
hua Ding, Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Fax +81(75)7534041; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Received 8 October 2008
O
O
O
O
O
O
Abstract: Highly enantioselective alkylation of tert-butyl a-fluoro-
b-keto esters can be effected by the use of N-spiro chiral quaternary
ammonium salt as chiral phase-transfer catalyst, as a complementa-
ry approach to the asymmetric fluorination of a-alkyl-b-keto esters.
R1
OR2
OR2
*
asymmetric
fluorination
R1
OR2
(1)
*
*
O
O
R3
R3
F
R1
OR2
O
O
R3X
Key words: phase-transfer catalysis, alkylations, asymmetric catal-
ysis, esters, alkyl halides
R1
R1
OR2
(2)
*
asymmetric
alkylation
F
R3
F
Scheme 1 Two distinctive approaches for the syntheses of a-alkyl-
a-fluoro-b-keto esters
The recent significant expansion in the use of organofluo-
rine compounds has attracted the attention in various sci-
entific fields including organic, agricultural, medicinal,
and material chemistry.1 Among these, one of the most
fascinating aspects of organofluorine chemistry is the
asymmetric synthesis of fluorinated molecules.2 Accord-
ingly, various asymmetric approaches have been devel-
oped for this purpose. For example, there are two
possibilities of preparing optically active organofluorine
compounds as shown in Scheme 1. Asymmetric fluorina-
tion of carbonyl substrates such as b-keto esters is a well-
known approach for obtaining optically active organo-
fluorine compounds (Scheme 1, eq. 1).3 Alternatively,
asymmetric alkylation of a-fluorocarbonyl substrates
would give similar organofluorine compounds
(Scheme 1, eq. 2). The advantage of the latter strategy is
the ready availability of various organofluorine com-
pounds in optically active forms by changing the alkylat-
ing agent (R3 in Scheme 1). In addition, the use of
asymmetric phase-transfer catalysis would be most pref-
erable from the practical viewpoint.4 Here, we wish to re-
port asymmetric alkylation of a-fluoro-b-keto esters
catalyzed by N-spiro chiral quaternary ammonium bro-
mide (S,S)-1 under phase-transfer conditions.
examined by asymmetric benzylation of tert-butyl 2-fluo-
ro-3-oxo-3-phenylpropanoate (2b) in toluene with 1
mol% of (S,S)-1 (Figure 1) under similar phase-transfer
conditions to furnish 3b, and among these, the use of 10%
aqueous CsOH was found to be most preferable in terms
of both reactivity and selectivity (entry 5 vs. 2–4).
We also examined the effect of temperature and solvent
by asymmetric benzylation of tert-butyl 2-fluoro-3-oxo-
3-phenylpropanoate (2b) in toluene with 10% aqueous
CsOH catalyzed by 1 mol% of (S,S)-1 under similar
phase-transfer conditions as shown in Table 2. In toluene
solvent, the use of lower temperature enhanced the enan-
tioselectivity (entry 2 vs. 1). The use of aromatic solvents
such as toluene, o-xylene, and mesitylene generally gave
Table 1 Asymmetric Alkylation of Ethyl or tert-Butyl 2-Fluoro-3-
oxo-3-phenylpropanoates 2 and Benzyl Bromide – Effect of Basea
O
O
O
O
(S,S)-1
(1 mol%)
*
+
BnBr
Ph
OR
Ph
OR
toluene
base, r.t.
F
Bn
F
2a R = Et
2b R = t-Bu
3a R = Et
3b R = t-Bu
Asymmetric benzylation of ethyl 2-fluoro-3-oxo-3-phe-
nylpropanoate (2a) in toluene catalyzed by 1 mol% N-
spiro chiral quaternary ammonium bromide (S,S)-1 in the
presence of 33% aqueous K2CO3 was initially carried out
in consideration of our extensive researches on the use of
(S,S)-1 for various asymmetric phase-transfer alkyla-
tions.5,6 However, the observed enantioselectivity of the
product 3a was found to be moderate (48% ee in entry 1
of Table 1). Switching the ethyl ester 2a to the corre-
sponding tert-butyl ester 2b enhanced the enantioselectiv-
ity (78% ee in entry 2). Then, the effect of base was
Entry
R
Base
Time
(h)
Yield
(%)b
ee
(%)c
1
2
3
4
5
Et
33% K2CO3
33% K2CO3
50% Cs2CO3
50% K3PO4
10% CsOH
12
12
24
24
2
93
77
86
66
64
48
78
77
69
77
t-Bu
t-Bu
t-Bu
t-Bu
a The asymmetric alkylation of ethyl 2-fluoro-3-oxo-3-phenylpro-
panoate (2a, 0.10 mmol) with benzyl bromide (0.12 mmol) and aq
base (1.0 mL) in the presence of 1 mol% of catalyst (S,S)-1 in toluene
(2.0 mL) at r.t. under the given reaction time.
SYNLETT 2009, No. 4, pp 0664–0666
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Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087813; Art ID: Y01408ST
© Georg Thieme Verlag Stuttgart · New York
b Isolated yield.
c Determined by chiral HPLC analysis.

CLUSTER
Enantioselective Alkylation of a-Fluoro-b-Keto Ester
665
Table 3 Asymmetric Alkylation of a-Fluoro-b-Keto Esters 2b and
2c with Several Alkyl Halides Catalyzed by (S,S)-1a
3,4,5-F3-C6H2
Br
O
O
(S,S)-1
O
O
(1 mol%)
N
R2X
*
+
R1
Ot-Bu
R1
Ot-Bu
10% CsOH
mesitylene
0 °C
F
R2
F
3
2b R = Ph
2c R = Me
3,4,5-F3-C6H2
(S,S)-1
Entry R1
R2X
Time Yield ee
(h)
Figure 1
(%)b
(%)c
1
2
Ph
Ph
BnBr
16
82
85
Table 2 Asymmetric Alkylation of tert-Butyl 2-Fluoro-3-oxo-3-
phenylpropanoate (2b) and Benzyl Bromide – Effect of Temperature
and Solventa
F
12
36
87
81
88
81
Br
O
O
O
O
(S,S)-1
(1 mol%)
*
+
BnBr
3
Ph
Ph
Ot-Bu
Ph
Ot-Bu
10% CsOH
Br
F
Bn
F
4
5
Ph
Ph
15
36
89
80
86
78
2b
3b
Ph
Br
Temp (°C) Time (h) Yield (%)b ee (%)c
MeI
Entry Solvent
1
2
3
4
5
6
7d
toluene
r.t.
0
2
7
64
56
81
62
50
86
82
77
84
85
80
82
85
85
6
Ph
36
68
65
Br
toluene
F
7
8
Me
Me
8
8
79
85
80
68
o-xylene
TBME
0
7
Br
0
7
Ph
Br
CPME
0
7
a The asymmetric alkylation of tert-butyl 2-fluoro-3-oxo-3-phenyl-
propanoate (2b) or tert-butyl 2-fluoro-3-oxobutanoate (2c, 0.10
mmol) with alkyl halide (0.12 mmol) and 10% aq CsOH (0.2 mmol)
in the presence of 1 mol% of catalyst (S,S)-1 in mesitylene (2.0 mL)
at 0 °C under the given reaction time.
mesitylene
mesitylene
0
7
0
16
a The asymmetric alkylation of tert-butyl 2-fluoro-3-oxo-3-phenyl-
propanoate (2b, 0.10 mmol) with benzyl bromide (0.12 mmol) and
10% aq CsOH (1.0 mL) in the presence of 1 mol% of catalyst (S,S)-1
in solvent (2.0 mL) at r.t. or 0 °C under the given reaction time.
b Isolated yield.
b Isolated yield.
c Determined by chiral HPLC analysis.
c Determined by chiral HPLC analysis.
(S,S)-1 (1 mol%)
Na2CO3 (1 equiv)
O
O
O
O
O
d Use of 10% aq CsOH (2 equiv).
*
+
Ot-Bu
Ph
Ot-Bu
O
Ph
mesitylene
–20 °C, 24 h
0 °C, 10 h
F
F
2b
better enantioselectivity than ethereal solvents such as
tert-butyl methyl ether (TBME) and cyclopentyl methyl
ether (CPME).
4
99% yield, 86% ee
Scheme 2
With the optimized conditions in hand, the scope and lim-
itation of this asymmetric alkylation of a-fluoro-b-keto
esters was summarized as shown in Table 3.7 In addition
to substituted benzyl bromide, various alkyl halides such
as allylic and simple alkyl halides can be employable (en-
tries 1–5). Unfortunately, asymmetric alkylation with pro-
pargyl bromide led to the eminent loss of
enantioselectivity (entry 6). Use of another a-fluoro-b-
keto ester such as tert-butyl 2-fluoro-3-oxobutanoate (2c)
as nucleophile also exhibited similar reactivity and enan-
tioselectivity (entries 7 and 8).
to afford the corresponding conjugate adduct 4 in 99%
yield with high enantioselectivity.
In conclusion, we succeeded in obtaining various a-alkyl-
a-fluoro-b-keto esters with high enantioselectivity by us-
ing the phase-transfer-catalyzed asymmetric alkylation of
tert-butyl 2-fluoro-3-oxo-3-phenylpropanoate and tert-
butyl 2-fluoro-3-oxobutanoate as a key asymmetric in-
duction step.
This approach is also applicable to the asymmetric conju-
gate addition of tert-butyl 2-fluoro-3-oxo-3-phenylpro-
panoate (2b) to methyl vinyl ketone with Na2CO3 in the
presence of a catalytic amount (1 mol%) of (S,S)-1 in mes-
itylene at –20 °C for 24 hours and then at 0 °C for 10 hours
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
Synlett 2009, No. 4, 664–666 © Thieme Stuttgart · New York

666
C. Ding, K. Maruoka
CLUSTER
(5) (a) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am.
Chem. Soc. 2000, 122, 5228. (b) Ooi, T.; Kameda, M.;
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S.-s.; Lee, Y.-J.; Lee, J.; Kang, M. J.; Jeong, B.-S.; Lee,
J.-H.; Yoo, M.-S.; Kim, M.-J.; Choi, S.-h.; Ku, J.-M.; Park,
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(7) Typical Procedure for the Catalytic Asymmetric
Alkylation of tert-Butyl 2-Fluoro-3-oxo-3-phenyl-
propanoate (2b) under Phase-Transfer Conditions
To a solution of phase-transfer catalyst (S,S)-1 (0.001 mmol,
0.9 mg) and 2b (0.10 mmol, 23.6 mg) in mesitylene (2 mL)
was added benzyl bromide (0.12 mmol, 14.0 mL), and the
mixture was cooled to 0 °C. After adding 10% aq CsOH (0.3
mL, ca. 0.2 mmol) to this mixture, the reaction mixture was
vigorously stirred until the completion of the reaction. The
mixture was then poured into sat. aq NH4Cl and extracted
with EtOAc. The organic layer was dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column
chromatography on SiO2 to give tert-butyl 2-benzyl-2-
fluoro-3-oxo-3-phenylpropanoate (3b) as a colorless oil
[82% (26.8 mg), 85% ee]. Enantiomeric purity was
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determined by HPLC analysis [Daicel Chiralpak OD,
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MHz, CDCl3): d = 7.99–8.02 (2 H, m, ArH), 7.53–7.58 (1 H,
m, ArH), 7.41–7.44 (2 H, m, ArH), 7.25–7.30 (5 H, m, ArH),
3.46–3.68 (2 H, m, PhCH2), 1.29 (9 H, s, t-Bu).
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