Dramatic rate enhancement of asymmetric phase-transfer-catalyzed alkylations

Article abstract of DOI:10.1002/anie.200462035

The intervention of crown ethers or achiral quaternary ammonium salts as achiral phase-transfer catalysts (PTCs, see scheme) in a chiral PTC system leads to dramatic rate enhancements in the asymmetric alkylation of glycine derivatives.

Full text of DOI:10.1002/anie.200462035

Angewandte
Chemie
Phase-Transfer Catalysis
Dramatic Rate Enhancement of Asymmetric
Phase-Transfer-Catalyzed Alkylations**
Seiji Shirakawa, Kenichiro Yamamoto,
Masanori Kitamura, Takashi Ooi, and Keiji Maruoka*
The synthesis of optically active organic molecules from
prochiral substrates by using chiral catalysts under phase-
transfer conditions is one of the most exciting topics in
practical organic synthesis because of its operational simplic-
ity, mild reaction conditions, and environmental conscious-
ness.[1] Hence, numerous efforts have been devoted to the
elaboration of effective chiral quaternary ammonium salts,
[*] Dr. S. Shirakawa, K. Yamamoto, Dr. M. Kitamura, Dr. T. Ooi,
Prof. K. Maruoka
Department of Chemistry
Graduate School of Science
Kyoto University
Sakyo, Kyoto, 606-8502 (Japan)
Fax: (+81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[**] This work was partially supported by a grant-in-aid for scientific
research from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan. S.S. and M.K. are grateful to the Japanese
Society for the Promotion of Science for Young Scientists for
research fellowships.
Angew. Chem. Int. Ed. 2005, 44, 625 –628
DOI: 10.1002/anie.200462035
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
625

Communications
and considerable progress has recently made it possible
to successfully perform various asymmetric bond-form-
ing reactions under mild phase-transfer conditions.[2]
However, one intrinsic yet critical problem associated
with this type of reaction is insufficient catalytic
efficiency, which often necessitates the use of a relatively
large amount of catalyst (1–10 mol%). As part of our
program for the truly practical asymmetric synthesis of
a-amino acids utilizing designed C2-symmetric chiral
quaternary ammonium bromide 1,[3] we required a new
approach to fully induce its potential catalytic activity in
the asymmetric phase-transfer alkylation of the tert-
butyl glycinate Schiff base 4 to adequately reduce the
catalyst loading. Our strategy to this end is the develop-
ment of
a dual mode of phase-transfer catalysis
(Scheme 1).
Owing to the highly lipophilic nature of 1, the
reaction would proceed through the interfacial mecha-
nism initiated by the direct interfacial deprotonation of
4 by an alkaline metal hydroxide such as potassium
hydroxide.[4] On the basis of this plausible mechanistic
profile, we envisioned that the addition of an achiral
cocatalyst which is capable of extracting KOH into the
organic phase would substantially accelerate the other-
wise slow deprotonation process. This process should
result in a significant rate enhancement without dimin-
ishing the enantioselectivity if the subsequent enolate
exchange with 1 is extremely fast. Verification of this
hypothesis is illustrated by the novel binary phase-transfer
catalyst systems with the chiral phase-transfer catalyst 1 and
the crown ether 2 as an ideal achiral cocatalyst, taking
advantage of its well-known ability of extracting metal cations
(Scheme 2). This conceptually new approach allowed the
Scheme 2. Proposed mechanism of the binary phase-transfer system.
Q*Br=chiral PTC 1.
reaction to be implemented with as low as 0.05 mol% each of
1 and 2 to give the corresponding alkylation product 5 in
excellent yield and enantioselectivity.
First, we investigated the effect of achiral phase-transfer
catalysts as additives on the chemical yield and enantioselec-
tivity in the phase-transfer benzylation of benzophenone
derivative 4 under the influence of the chiral phase-transfer
catalyst 1. Thus, treatment of the protected glycine derivative
4 with benzyl bromide (1.2 equiv) and 50% aqueous KOH/
toluene (volume ratio 2:3) with 0.10 mol% of chiral catalyst 1
at 08C for 3 h resulted in the formation of phenylalanine
derivative 5 (R = CH2Ph) in only 8% yield with 94% ee
(entry 1 in Table 1). In marked contrast, however, addition of
18-crown-6 2c (0.10 mol%) as the achiral phase-transfer
catalyst under similar conditions gave rise to 5 in 98% yield
with 98% ee (entry 4 in Table 1). Without the chiral phase-
transfer catalyst 1, 18-crown-6 (0.10 mol%) did not show any
acceleration effect (entry 5 in Table 1) which suggests a low
reactivity of the potassium enolate/18-crown-6 complex.
Analogues of 18-crown-6, 2d and 2e, showed similar reac-
tivity and enantioselectivity (entries 6 and 7 in Table 1).
Other examples including various achiral phase-transfer
catalysts are also included in Table 1. Several characteristic
features of the present benzylation follow: 1) 18-Crown-6 and
its analogues 2c–e as additives led to high chemical yields
with high enantioselectivities compared to when other crown
ethers 2a–b of smaller cavity sizes were used (entries 2–3 in
Table 1).[5] 2) Tetrabutyl- and tetraoctylammonium bromide
3b–c as achiral phase-transfer catalysts gave relatively high
yields with high enantioselectivities (entries 9 and 11 in
Table 1). As tetrabutylammonium bromide itself gave a
similarly high chemical yield (84%) in the phase-transfer-
catalyzed benzylation of 4 (entry 10 in Table 1), the chiral
Scheme 1. Catalytic asymmetric alkylation of 4 with binary phase-trans-
fer system. PTC=phase-transfer catalyst.
626
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Chemie
Table 1: Catalytic enantioselective phase-transfer benzylation of 4 with
Table 2: Catalytic enantioselective phase-transfer alkylation of 4 with
chiral PTC 1 and achiral 18-crown-6 2c.[a]
chiral and achiral phase-transfer catalysts (PTCs).[a]
Entry
Chiral PTC
Achiral PTC
Yield[b] [%]
ee[c] [%] (config)[d]
Entry RX
1 [mol%] 2c [mol%] t [h] Yield[b] [%] ee [%][c]
(config)[d]
1
2
3
4
1
1
1
1
none
2a
2b
2c
8
94 (S)
96 (S)
96 (S)
98 (S)
16
29
98
3
1
2
3
4
PhCH2Br 0.1
none
0.1
none
0.05
3
3
3
3
8
98
4
94 (S)
98 (S)
92 (S)
98 (S)
0.1
0.05
0.05
5
none
2c
90
6
7
8
9
10
11
12
13
1
1
1
1
2d
2e
3a
3b
3b
3c
92
96
17
80
84
90
9
97 (S)
96 (S)
97 (S)
96 (S)
5
6
0.05
0.05
none
0.05
5
5
2
97
93 (S)
91 (S)
none
7
8
9
0.2
0.1
0.1
0.1
none
0.1
1.5 93
91 (S)
86 (S)
85 (S)
1
1
1
96 (S)
91 (S)
91 (S)
2
2
13
87
3d
3e
13
96 (S)[e]
95 (S)[e]
94 (S)[e]
91 (S)[e,f]
[a] Unless otherwise specified, the reaction was carried out with 1.2 equiv
of PhCH2Br in the presence of 0.1 mol% of 1 and 0.1 mol% of 2 or 3 in
50% aq KOH/toluene (v/v 2:3) at 08C for 3 h under argon atmosphere.
[b] Isolated yield. [c] Enatiopurity of 5 was determined by HPLC analysis
of the alkylated imine by using a chiral column (DAICEL Chiralcel OD or
OD-H) with hexane/propan-2-ol (v/v 100:1) as solvent. [d] The absolute
configuration of 5 was determined by comparison of the HPLC retention
time with that of the authentic sample independently synthesized by the
reported procedure.[3a]
10
11
12
13
EtI
1.0
1.0
0.5
0.5
none
5
5
9
70
0.5
0.5
0.5
20 63
86
3
[a] Unless otherwise specified, the reaction was carried out with 1.2 equiv
of RX in 50% aq KOH/toluene (v/v 2:3) under the given reaction
conditions under argon. [b] Isolated yield. [c] The enantiopurity of 5 was
determined by HPLC analysis of the alkylated imine by using a chiral
column (DAICEL Chiralcel OD or OD-H) with hexane/propan-2-ol as
solvent. [d] The absolute configuration of
5 was determined by
comparison of the HPLC retention time with that of the authentic
sample independently synthesized by the reported procedure.[3a]
[e] 5.0 equiv of EtI employed. [f] Reaction under ultrasonic irradiation.
catalyst 1 must induce extremely facile enolate exchange with
tetrabutylammonium enolate.[6] However, polar tetramethyl-
ammonium bromide 3a and pyridinium salts 3d–e were not
effective for the system (entries 8, 12, and 13 in Table 1).
3) The enantioselectivity of 5 was lowered by increasing or
decreasing the amount of achiral catalyst 2 or 3.
was then stirred vigorously at 08C for 3 h and then poured into water
and extracted with ether. The organic extracts were washed with brine
and dried over Na2SO4. Evaporation of solvents and purification of
the residual oil by column chromatography on silica gel (1:10 ether/
hexane) gave the corresponding benzylation product 5 (104 mg,
0.27 mmol, 90% yield, 98% ee). The enantiomeric excess was
determined by HPLC analysis (Daicel Chiralcel OD, 100:1 hexane/
propan-2-ol, flow rate: 0.5 mLminÀ1, retention times: 14.8 min (R)
and 28.2 min (S)). The absolute configuration was determined by
comparison of the HPLC retention time with that of the authentic
sample independently synthesized by the reported procedure.[3a]
We further found that the amounts of chiral catalyst 1 and
18-crown-6 2c as achiral catalyst could both be reduced to
0.05 mol% without losses in yields or enantioselectivity of the
products as shown in Table 2 (entry 4). The present catalytic
system is also applicable to other alkyl halides, and some
selected results are summarized in Table 2. By the addition of
a catalytic amount of 18-crown-6 2c, the reaction rate is
dramatically accelerated (6.7–49-times faster than in the
absence of 2c under the same reaction conditions). The
satisfactory yield and enantioselectivity of product 5 results
by the use of only 0.05–0.10 mol% of chiral catalyst 1 and 2c,
except when less-reactive alkyl halides such as EtI are used.
Combination of ultrasonic irradiation with this catalytic
system further accelerated the rate of the alkylation
(entry 13 in Table 2).[7]
Received: September 18, 2004
Published online: December 13, 2004
Keywords: alkylation · amino acids · crown compounds ·
.
enantioselectivity · phase-transfer catalysis
In conclusion, we have demonstrated a dramatic rate
enhancement by combination of an achiral phase-transfer
catalyst with a chiral phase-transfer catalyst. The present
catalyst system provides powerful options in asymmetric
reactions for practical organic synthesis.
[1] Reviews: a) M. J. OꢀDonnell in Catalytic Asymmetric Synthesis,
2nd ed., (Ed.: I. Ojima), Wiley-VCH, New York, 2000, chap. 10;
b) T. Shioiri in Handbook of Phase-Transfer Catalysis (Eds.: Y.
Sasson, R. Neumann), Blackie Academic
& Professional,
London, 1997, chap. 14; c) M. J. OꢀDonnell in Phases—The
Sachem Phase-Transfer Catalysis Review 1998, 4, 5; M. J. OꢀDon-
nell in Phases—The Sachem Phase-Transfer Catalysis Review
1999, 5, 5; d) T. Shioiri, S. Arai in Stimulating Concepts in
Chemistry (Eds.: F. Vogtle, J. F. Stoddart, M. Shibasaki), Wiley-
VCH, Weinheim, 2000, p. 123; e) M. J. OꢀDonnell, Aldrichimica
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3013; g) M. J. OꢀDonnell, Acc. Chem. Res. 2004, 37, 506; h) B.
Lygo, B. I. Andrews, Acc. Chem. Res. 2004, 37, 518; i) T. Ooi, K.
Maruoka, Acc. Chem. Res. 2004, 37, 526.
Experimental Section
General procedure for catalytic enantioselective alkylation of 4 with
catalyst 1 and 2c: Benzyl bromide (0.36 mmol) was added dropwise to
a mixture of 4 (0.30 mmol), chiral catalyst 1 (0.15 mmol, 0.05 mol%),
and 18-crown-6 2c (0.15 mmol, 0.05 mol%) in toluene (3.0 mL) and
50% aqueous KOH solution (2.0 mL) at 08C. The reaction mixture
Angew. Chem. Int. Ed. 2005, 44, 625 –628
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Communications
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[4] For a discussion of mechanisms in normal chiral phase-transfer
catalyst systems, see: a) K. B. Lipkowitz, M. W. Cavanaugh, B.
Baker, M. J. OꢀDonnell, J. Org. Chem. 1991, 56, 5181; b) M. J.
OꢀDonnell, S. Wu, J. C. Huffman, Tetrahedron 1994, 50, 4507.
[5] 18-Crown-6 derivatives are known to make the most-stable host–
guest complex with potassium ions and hence they accelerate the
phase-transfer reaction with potassium hydroxide compared with
other crown ethers that have a different ring size. For reviews, see:
a) E. V. Dehmlow, S. S. Dehmlow, Phase Transfer Catalysis,
3rd ed., VCH, Weinheim, 1993; b) C. M. Starks, C. L. Liotta, M.
Halpern, Phase-Transfer Catalysis, Chapman & Hall, New York,
1994; c) Handbook of Phase-Transfer Catalysis (Eds.: Y. Sasson,
R. Neumann), Blackie Academic & Professional, London, 1997;
d) Phase-Transfer Catalysis, ACS Symposium Series 659 (Ed.:
M. E. Halpern), American Chemical Society, Washington DC,
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[3] a) T. Ooi, M. Kameda, K. Maruoka, J. Am. Chem. Soc. 1999, 121,
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[6] A similar acceleration effect with some loss of enantioselectivity
was observed by adding tetrahexylammonium bromide (1 mol%)
in the phase-transfer catalyzed asymmetric cyclopropanation
reaction. See: S. Arai, K. Nakayama, T. Ishida, T. Shioiri,
Tetrahedron Lett. 1999, 40, 4215.
[7] T. Ooi, E. Tayama, K. Doda, M. Takeuchi, K. Maruoka, Synlett
2002, 1500.
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