Phase-transfer-catalyzed enantioselective alkylation of α-benzoyloxy-β-keto ester

Article abstract of DOI:10.1055/s-0028-1087814

Highly enantioselective alkylation of tert-butyl 2-benzoyloxy-3- oxobutanoate could be realized by the use of N-spiro chiral quaternary ammonium salt as phase-transfer catalyst, as a complementary approach to the asymmetric hydroxylation of α-alkyl-β-keto

Full text of DOI:10.1055/s-0028-1087814

CLUSTER
661
Phase-Transfer-Catalyzed Enantioselective Alkylation of a-Benzoyloxy-
b-Keto Ester
E
a
nantioselective
a
Alkylatio
k
n
of
a
-
Benzo
u
yloxy-
b
-Ket
y
o
E
ste
r
a Hashimoto,a Keigo Sasaki,a Kazuhiro Fukumoto,a Yuichi Murase,a Takashi Ooi,b Keiji Maruoka*a
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
Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Chikusa, Nagoya 464-8603, Japan
b
Received 10 October 2008
Asymmetric benzylation of tert-butyl 2-benzoyloxy-3-
oxobutanoate (2a) catalyzed by 1 mol% N-spiro chiral
quaternary ammonium bromide 1a in the presence of 25%
aqueous KOH was initially investigated in relation to our
extensive researches on the use of 1 for various asymmet-
ric phase-transfer catalysis.5 Ester 2a was chosen as a suit-
able substrate due to its ready availability and ease of
deprotection after the reaction.6 Gratifyingly, asymmetric
benzylation proceeded smoothly at 0 °C to provide the
alkylated compound 3a in 72% yield with 79% ee
(Table 1, entry 1). Further experiments using different
catalysts revealed the efficiency of (S,S)-1c, with which
the benzylated product was obtained in highest ee among
the catalysts screened (entries 2–4). Anticipating the in-
crease of the enantioselectivity, the reaction was then per-
formed at lower temperature. When the reaction was
performed under the influence of (S,S)-1c and 25% aque-
ous KOH at –20 °C, 3a could be obtained with 90% ee
(entry 5). We observed some amounts of hydrolyzed side
products 4 and 5 (Figure 1) derived from 3a in these reac-
tions. To avoid such undesired processes, the reaction was
then conducted under the influence of powdered KOH
(1.5 equiv), while minimizing the amount of water present
in the reaction mixture (entry 6). As a result, the benzylat-
ed compound was obtained in 91% yield without affecting
the enantiomeric excess. Use of Cs2CO3 as base resulted
in poor reactivity, leading to moderate conversion after
prolonged reaction time (entry 7). Although further in-
crease of the enantioselectivity could be achieved by con-
ducting the reaction at –40 °C at the expense of the
reaction time and the amount of base (entry 8), the reac-
tion conditions employed in entry 6 was utilized for the
further investigation, having the practical aspect in mind.
Abstract: Highly enantioselective alkylation of tert-butyl 2-ben-
zoyloxy-3-oxobutanoate could be realized by the use of N-spiro
chiral quaternary ammonium salt as phase-transfer catalyst, as a
complementary approach to the asymmetric hydroxylation of a-
alkyl-b-keto esters.
Key words: phase-transfer catalysis, alkylations, asymmetric catal-
ysis, esters, alkyl halides
Asymmetric hydroxylation of a-alkyl-b-keto esters re-
cently appeared as a unique tool to provide functionalized
chiral tert-alcohol (Scheme 1, eq. 1).1,2 Despite the attrac-
tiveness of this reaction, especially as a key intermediate
for the preparation of 2,3-dihydroxycarboxylic acids con-
taining a quaternary stereocenter, they generally suffer
from the poor reactivity or enantioselectivity in the reac-
tion of acyclic a-alkyl-b-keto esters irrespective of the
catalyst employed. In this context, we planned to access
these molecules in an optically enriched form relying on
the well-established phase-transfer catalysis.3 Thus, hy-
droxy group is initially incorporated into the a-position of
the unfunctionalized b-keto ester as a prochiral molecule
and the subsquent alkylation of this substrate under phase-
transfer conditions is set as a crucial asymmetric induction
step (Scheme 1, eq. 2).4 The additional advantage of such
a strategy is that a variety of chiral compounds are easily
available just by changing the alkylating reagent (R3 in
Scheme 1), while anticipating the similar level of enantio-
selectity. Herein, we wish to report asymmetric alkylation
of a-benzoyloxy-b-keto ester catalyzed by N-spiro
chiral quaternary ammonium bromide 1 under liquid–
solid phase-transfer conditions.
O
O
[O]
CO2R2
O
CO2R2
(1)
R1
R1
asymmetric
hydroxylation
CO2t-Bu
Ph
CO2t-Bu
R3 OH
R3
Ph
Me
O
HO
OH
CO2R2
R1
4
5
O
O
R3X
CO2R2
OPG
CO2R2
Figure 1
(2)
R1
R1
asymmetric
alkylation
R3 OPG
With the optimized conditions in hand, the scope and lim-
itation of this asymmetric alkylation of a-benzoyloxy-b-
keto ester was surveyed as shown in Table 2. Use of sub-
stituted benzyl bromides was initially evaluated. Irrespec-
tive of the electronic property of the aromatic rings,
Scheme 1 Two distinctive approaches for the syntheses of a-alkyl-
a-hydroxy-b-keto esters
SYNLETT 2009, No. 4, pp 0661–0663
x
x.
x
x.
2
0
0
9
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087814; Art ID: Y01308ST
© Georg Thieme Verlag Stuttgart · New York

662
T. Hashimoto et al.
CLUSTER
Table 1 Asymmetric Alkylation of tert-Butyl 2-Benzoyloxy-3-
Oxobutanoate7 and Benzyl Bromide – Optimization of the Reaction
Conditionsa
Table 2 Asymmetric Alkylation of a-Benzoyloxy-b-Keto Esters
and Alkyl Halides Catalyzed by (S,S)-1ca
O
O
(S,S)-1c (1 mol%)
O
O
BnBr
KOH (1.5 equiv)
CO2t-Bu
CO2t-Bu
R1Br
R2
R2
+
(S,S)-1 (1 mol%)
CO2t-Bu
OBz
CO2t-Bu
Ph
toluene, –20 °C
BzO R1
Me
Me
2
3
OBz
toluene, base
BzO
2a
Ar
3a
Entry R1Br
R2
Time
(h)
Yield
(%)b
ee
(%)c
1a Ar = 3,4,5-F3C6H2
1b Ar = 2-naphthyl
+
Br–
F
N
1
Me (2a) 10
3b 86
92
1c Ar = 3,5-(F3C)2C6H3
1d Ar = 3,5-Ph2C6H3
Br
Br
Ar
Br
(S,S)-1
2
Me
Me
Me
10
4
3c 91
3d 79
3e 92
91
89
88
Entry Catalyst Base
Temp
(°C)
Time Yield ee
(h)
(%)b
72
72
76
83
79
91
49
95
(%)c
79
60
85
62
90
90
89
94
3
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1c
1c
1c
1c
25% KOHd
0
0
9
Br
25% KOH
25% KOH
25% KOH
25% KOH
KOHe
9
MeO
4
7
0
10
9
Br
0
5
Me
Me
Me
20
9
3f 85
3g 90
3h 88
91
91
90
Br
–20
–20
–20
–40
12
12
96
98
6d
Br
Br
7
8
9
Ph
Br
f
Cs2CO3
KOHg
Me
10
3i 89
3j 41
87
83
a Performed with tert-butyl 2-benzoyloxy-3-oxobutanoate (2a, 0.20
mmol) and benzyl bromide (0.24 mmol) in the presence of 1 mol% of
catalyst (S,S)-1 in toluene (2.0 mL) under the given reaction condi-
tions.
9
Me
Me
20
24
Br
Br
b Isolated yield.
10
3k 29
3l 88
61
79
c Determined by chiral HPLC analysis.
d Aqueous KOH (0.50 mL).
e Powdered KOH (0.30 mmol).
11
12
Et (2b)
Pr (2c)
4
12
f Powdered Cs2CO3 (1.0 mmol).
3m 40 73
Br
g Powdered KOH (1.0 mmol).
a Performed with 2 (0.2 mmol) and R1Br (0.24 mmol) in the presence
of 1 mol% of catalyst (S,S)-1c and powdered KOH (0.3 mmol) in tol-
uene (2 mL) at –20 °C.
alkylated compounds were obtained in good yields with
the selectivity ranging from 88% to 92% ee (entries 1–4).
Allylic substrates were also suitable for this reaction fur-
nishing the products in good yields and enantioselectivi-
ties (entries 5–9). Curiously, the reaction with propargyl
bromide led to the significant drop of enantiomeric excess
(entry 10). Our focus was then moved to the employment
of other a-benzoyloxy-b-keto esters as nucleophiles.
Asymmetric benzylation of 2-benzoyloxy-3-oxopen-
tanoate 2b furnished the alkylated compound in 88% yield
with slightly diminished ee of 79%. Use of a-benzoyloxy-
b-keto ester 2c bearing propyl group as R2 resulted in the
further decrease of the enantioselectivity.
b Isolated yield.
c Determined by chiral HPLC analysis or GC analysis.
d Crotyl bromide used as a 5:1 E/Z mixture.
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.
References and Notes
(1) For general reviews, see: (a) Christoffers, J.; Baro, A.;
Werner, T. Adv. Synth. Catal. 2004, 346, 143.
(b) Shibasaki, M.; Kanai, M. Chem. Rev. 2008, 108, 2853.
(2) (a) Toullec, P. Y.; Bonaccorsi, C.; Mezzetti, A.; Togni, A.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5810.
In conclusion, we succeeded in obtaining various a-alkyl-
a-hydroxy-b-keto esters with uniformly high enantiose-
lectivities by employing the phase-transfer catalyzed
asymmetric alkylation of tert-butyl 2-benzoyloxy-3-oxo-
butanoate as a key asymmetric induction step.
(b) Bonaccorsi, C.; Althaus, M.; Becker, C.; Togni, A.;
Mezzetti, A. Pure Appl. Chem. 2006, 78, 391. (c) Acocella,
M. R.; Mancheno, O. G.; Bella, M.; Jørgensen, K. A. J. Org.
Synlett 2009, No. 4, 661–663 © Thieme Stuttgart · New York

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Enantioselective Alkylation of a-Benzoyloxy-b-Keto Ester
663
Chem. 2004, 69, 8165. (d) Ishimaru, T.; Shibata, N.; Nagai,
J.; Nakamura, S.; Toru, T.; Kanemasa, S. J. Am. Chem. Soc.
2006, 128, 16488.
mmol, 2.2 mg) and 2a (0.20 mmol, 55.7 mg) in toluene (2
mL) was added benzyl bromide (0.24 mmol, 28.5 mL) and
the mixture was cooled to –20 °C. After adding freshly
powdered KOH (0.3 mmol, 19.8 mg) 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-benzoyloxy-2-benzyl-3-oxobutanoate as a
colorless oil [91% (67.6 mg), 90% ee]. Enantiomeric purity
was determined by HPLC analysis [(Daicel Chiralpak AD-
H, hexane–2-PrOH (100:1), flow rate = 0.5 mL/min, tR =
22.3 min(major) and 25.0 min(minor)].
(3) For recent reviews, see: (a) Hashimoto, T.; Maruoka, K.
Chem. Rev. 2007, 107, 5656. (b) Ooi, T.; Maruoka, K.
Angew. Chem. Int. Ed. 2007, 46, 4222. (c) Ooi, T.;
Maruoka, K. Aldrichimica Acta 2007, 40, 77. (d) Maruoka,
K.; Ooi, T.; Kano, T. Chem. Commun. 2007, 1487.
(e) Maruoka, K. Chimia 2007, 61, 263. (f) Maruoka, K.
Org. Process Res. Dev. 2008, 12, 679.
(4) For the phase-transfer-catalyzed asymmetric hydroxylation
of oxindoles by molecular oxygen, see: Sano, D.; Nagata,
K.; Itoh, T. Org. Lett. 2008, 10, 1593.
(5) (a) Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi, M.; Takeuchi,
M.; Maruoka, K. Angew. Chem. Int. Ed. 2003, 42, 3796.
(b) Ooi, T.; Miki, T.; Maruoka, K. Org. Lett. 2005, 7, 191.
(c) Ooi, T.; Miki, T.; Fukumoto, K.; Maruoka, K. Adv. Synth.
Catal. 2006, 348, 1539.
(6) Scheid, G.; Kuit, W.; Ruijter, E.; Orru, R. V. A.; Henke, E.;
Bornsheuer, U.; Wessjohann, L. A. Eur. J. Org. Chem. 2004,
1063.
1H NMR (400 MHz, CDCl3): d = 8.00 (2 H, d, J = 7.3 Hz,
ArH), 7.61 (1 H, t, J = 7.6 Hz, ArH), 7.46 (2 H, app t, J = 7.8
Hz, ArH), 7.21–7.22 (3 H, m, ArH), 7.12 (2 H, m, ArH), 3.65
(2 H, s, PhCH2), 2.25 (3 H, s, COCH3), 1.40 (9 H, s, t-Bu).
13C NMR (100 MHz, CDCl3): d = 202.2, 165.3, 165.2, 134.4,
133.5, 130.2, 129.8, 129.3, 128.5, 128.3, 127.1, 89.0, 83.4,
38.8, 27.6, 27.4. IR (neat): 2978, 2932, 1755, 1721, 1279,
1152, 1107, 1094, 1069, 1026 912, 845, 733, 700 cm–1. ESI-
HRMS: m/z calcd for C22H24O5: 391.1516 [M + Na]+; found:
391.1516 [M + Na]+. [a]D28 –46.5 (c 1.0, CHCl3; 90% ee).
(7) Typical Procedure for the Catalytic Asymmetric
Alkylation of tert-Butyl 2-Benzoyloxy-3-oxobutanoate
under Phase-Transfer Conditions
To a solution of phase-transfer catalyst (S,S)-1c (0.002
Synlett 2009, No. 4, 661–663 © Thieme Stuttgart · New York

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