Development of new asymmetric two-center catalysts in phase-transfer reactions

Article abstract of DOI:10.1016/S0040-4039(02)02416-4

A new asymmetric two-center phase-transfer catalyst was designed and a catalyst library containing more than 40 new two-center catalysts was constructed. The catalysts were applied in phase-transfer alkylations and Michael additions to afford the correspo

Full text of DOI:10.1016/S0040-4039(02)02416-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9539–9543
Development of new asymmetric two-center catalysts in
phase-transfer reactions
Tomoyuki Shibuguchi, Yuhei Fukuta, Yoko Akachi, Akihiro Sekine, Takashi Ohshima and
Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 2 October 2002; revised 24 October 2002; accepted 25 October 2002
Abstract—A new asymmetric two-center phase-transfer catalyst was designed and a catalyst library containing more than 40 new
two-center catalysts was constructed. The catalysts were applied in phase-transfer alkylations and Michael additions to afford the
corresponding products in up to 93% ee and 82% ee, respectively. © 2002 Elsevier Science Ltd. All rights reserved.
Phase-transfer catalysis (PTC) is one of the most
important and useful methods in synthetic organic reac-
tions because of its simple reaction procedure, mild
conditions, inexpensive and environmentally friendly
reagents, and the ease in scaling-up the reaction.1 An
asymmetric version of PTC utilizing chiral phase-trans-
fer catalysts, however, has not been extensively studied
as compared to general asymmetric catalysis. The pio-
neering studies of O’Donnell and co-workers in 1989
led to the development of a highly practical enantiose-
lective alkylation of a prochiral protected glycine
derivative using Cinchona alkaloid ammonium salts to
produce chiral a-amino acids.2 Later, Corey3 and Lygo4
independently greatly improved this catalyst system.5
Although many types of phase-transfer catalysts have
been used as chiral catalysts in PTC, Cinchona alkaloid
derivatives give more impressive enantioselectivity for a
range of reactions than do other catalysts, with few
exceptions.6 The major drawback of these catalysts is
the difficulty in modifying the catalyst structure to
further improve selectivity or reactivity. To address this
issue, we developed a new versatile asymmetric phase-
transfer catalyst. In the course of our development of
new asymmetric catalyses using bifunctional com-
plexes,7 we designed a new asymmetric two-center
phase-transfer catalyst 1, in which the substrate could
be activated and fixed in a chiral environment by a
two-cationic moiety (Fig. 1). We report the design and
synthesis of a variety of new asymmetric two-center
catalysts 1 and their application in phase-transfer alkyl-
ations and Michael additions. The newly constructed
catalyst library is very effective for screening for the
best catalyst. Using the same catalyst, the alkylations
and the Michael additions have opposite enantiofacial
selectivity.
To design a two-center catalyst, we first performed
molecular mechanics simulation using the Monte Carlo
method. The results suggested that the Schiff base of
tert-butyl glycinate 2 is fixed between both ammonium
cations, as we expected (Fig. 1).8 We then started
syntheses of a variety of catalysts 1. From the view-
point of catalyst accessibility and versatility, our cata-
lysts
1
have
a
great advantage, because both
enantiomers can be easily synthesized from commer-
cially available and relatively inexpensive9
L
- or D-tar-
trate with a variety of ketal moieties (R1 and R2) and
aromatic parts (Ar).10 Scheme 1 summarizes the five-
step preparation of the catalysts 1 using only common
and inexpensive reagents. Dimethyl ketal derivative 4aa
(R1=R2=Me, Ar=Ph) had low reactivity in the
methylation step (step e), resulting in the formation of
Keywords: phase-transfer catalysis; asymmetric two-center catalyst;
alkylation; Michael addition.
* Corresponding author. Tel.: +81-3-5684-0651; fax: +81-3-5684-5206;
e-mail: mshibasa@mol.f.u-tokyo.ac.jp
Figure 1. Structure of new two-center asymmetric catalysts 1
(left) and the result of molecular mechanics simulation (right).
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02416-4

9540
T. Shibuguchi et al. / Tetrahedron Letters 43 (2002) 9539–9543
bis-ammonium salt 1aa promoted the reaction approxi-
mately twice as fast as the mono-ammonium salt 5aa
with higher enantiomeric excess (42% ee compared with
12% ee). Although bis- and tris-Cinchona alkaloid
ammonium salt catalysts were reported,11 similar reac-
tivity and selectivity were observed, compared with
ordinal Cinchona alkaloid catalysts even with the same
catalyst loading. Thus, our finding indicated that the
two-cationic moiety simultaneously activated and fixed
the substrate 2 in the chiral environment.
We then examined a variety of catalysts 1 (>40) in
phase-transfer alkylations and Michael additions for
catalyst screening.12 Selected results are shown in
Tables 1 and 2, respectively. All reactions were per-
formed under an argon atmosphere13 due to the partial
decomposition of 2 under aerobic conditions (entries 1
and 2, in Tables 1 and 2).6d First, we examined the
effect of a ketal moiety. In the case of alkylations,
better results were obtained when un-C2-symmetric cat-
alysts were used as a catalyst (Table 1, entries 8–12 and
20). Among them, tert-butyl methyl ketal had the
highest selectivity (entry 12). Screening of the aromatic
part revealed that 1kf (Ar=4-methoxyphenyl) was the
best catalyst for the alkylation (92% yield and 70% ee,
entry 17). In all entries, the absolute configurations
were R.14 On the other hand, C2-symmetric catalysts
gave better results in Michael additions (Table 2,
entries 1–13). In this reaction, 4-methylphenyl was the
best aromatic substituent and 1cb (entry 5), 1db (entry
Scheme 1. Reagents and conditions: (a) ketone (1.2 equiv.),
HC(OMe)3 (1.5 equiv.), cat. TsOH·H2O, MeOH, 70°C, then
diethyl L-tartrate, toluene, 110°C; (b) NH3 gas, MeOH, 4°C;
(c) LAH (3.5 mol equiv.), THF, rt to reflux; (d) ArCH2Cl (7.0
mol equiv.), i-Pr2NEt (7.2 mol equiv.), MeCN, rt; (e) MeI (40
mol equiv.), rt.
a mixture of mono-ammonium salt 5aa and the desired
bis-ammonium salt 1aa, even after refluxing. In con-
trast, other ketal derivatives (Tables 1 and 2) were
smoothly converted to bis-ammonium salts 1 in reason-
able yields (57–89%).
As a preliminary study, we evaluated 1aa and 5aa for
phase-transfer alkylation of 2 with benzyl bromide. The
Table 1. Catalytic asymmetric phase-transfer alkylations
Entry
R1
R2
Ar
1
Time (h)
Yield (%)a
Ee (%)b
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Me
Me
Et
Pr
Bu
i-Bu
Me
Me
Et
Pr
Bu
i-Bu
-C6H5
-C6H5
-C6H5
-C6H5
-C6H4-4-OMe
-C6H4-4-OMe
-C6H5
1aa
1aa
1ba
1ca
1df
1ef
1fa
1ga
1hf
1if
4.0
2.0
2.0
2.5
4.0
4.0
2.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.5
2.5
67
87
94
92
91
87
92
90
92
94
91
89
92
89
87
84
92
93
89
92
47
47
37
40
38
39
38
48
57
57
54
52
63
67
62
49
70
67
68
60
-(CH2)5-
t-Bu
i-Pr
Bu
H
-C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
-C6H4-4-OMe
-C6H4-4-OMe
-C6H4-4-OMe
-C6H5
-C6H4-4-Me
-C6H4-4-i-Pr
-C6H4-4-t-Bu
2-Naphthyl
-C6H4-4-OMe
-C6H4-4-OEt
-C6H4-4-OPr
-C6H4-4-OMe
i-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
1jf
1ka
1kb
1kc
1kd
1ke
1kf
1kg
1kh
1lf
C14H29
a Isolated yield.
b Determined by HPLC analysis.
c The reaction was performed under aerobic conditions.

T. Shibuguchi et al. / Tetrahedron Letters 43 (2002) 9539–9543
9541
12), and 1eb (entry 13) gave the highest enantiomeric
excess (64% ee). The obtained Michael products 7 had
an S configuration in all entries.14
6) afforded the corresponding protected unnatural a-
amino acids 10–12, which can be a versatile intermedi-
ate of various unnatural a-amino acids, in 91% ee. The
enantiomeric excess of Michael adducts was also
improved (75% ee, entry 1, Table 4 compared with 64%
ee, entry 5, Table 2) when the reaction was performed
at −30°C.15 Further improvement of the enantiomeric
excess of the Michael product was obtained using ethyl
acrylate as an electrophile (82% ee, entry 2). Moreover,
all alkylations gave the R-configuration and all Michael
additions gave the S-configuration. These results sug-
gested that the bis-ammonium cation moiety in cata-
lysts 1 functions as a bifunctional catalyst that activates
and fixes nucleophiles as well as electrophiles in
Michael additions.
Using the best catalyst (1kf for alkylations, 1cb for
Michael additions), we examined the scope and limita-
tions of different electrophiles under optimized condi-
tions (Tables 3 and 4). When 10 mol% of 1kf was used
with cesium hydroxide, all phase-transfer alkylations of
2 with benzyl (entries 1–4), allyl (entries 5–7) and
propargyl (entry 8) reagents proceeded at −70°C and
gave higher enantiomeric excess (93% ee, entry 1, Table
3 compared with 70% ee, entry 17, Table 1). In addi-
tion, the reaction with 4-bromobenzyl bromide (entry
4), allyl bromide (entry 5) and methallyl bromide (entry
Table 2. Catalytic asymmetric phase-transfer Michael additions
Entry
R1
R2
Ar
1
Time (h)
Yield (%)a
Ee (%)b
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Me
Me
Et
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Bu
i-Bu
t-Bu
t-Bu
Me
Me
Et
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Bu
i-Bu
H
-C6H5
-C6H5
-C6H5
-C6H5
1aa
1aa
1ba
1ca
1cb
1cc
1cd
1ce
1cf
1cg
1ch
1db
1eb
1gb
1kb
20
12
19
12
9
11
12
12
9
70
91
78
92
94
87
87
89
93
89
87
89
88
89
67
37
39
49
59
64
59
62
47
54
58
57
64
64
23
40
-C6H4-4-Me
-C6H4-4-i-Pr
-C6H4-4-t-Bu
2-Naphthyl
-C6H4-4-OMe
-C6H4-4-OEt
-C6H4-4-OPr
-C6H4-4-Me
-C6H4-4-Me
-C6H4-4-Me
-C6H4-4-Me
8
12
14
12
20
20
Me
a Isolated yield.
b Determined by HPLC analysis.
c The reaction was performed under aerobic conditions.
Table 3. Catalytic asymmetric phase-transfer alkylations
Entry
Electrophile
Product
Time (h)
Yield (%)a
Ee (%)b
1
2
3
4
5
6
7
8
Benzyl bromide
6
8
9
10
11
12
13
14
60
72
72
72
22
72
72
60
87
85
81
71
79
82
92
73
93 (R)
90 (R)
89 (R)
91 (R)
91 (R)
91 (R)
80 (R)
81 (R)
4-Methylbenzyl bromide
4-t-Butylbenzyl bromide
4-Bromobenzyl bromide
Allyl bromide
Methallyl bromide
Cinnamyl bromide
Propargyl bromide
a Isolated yield.
b Determined by HPLC analysis.

9542
T. Shibuguchi et al. / Tetrahedron Letters 43 (2002) 9539–9543
Table 4. Catalytic asymmetric phase-transfer Michael additions
Entry
Electrophile
Product
Time (h)
Yield (%)a
Ee (%)b
1
2
3
Methyl acrylate
Ethyl acrylate
Butyl acrylate
7
15
16
20
26
22
86
88
79
75(S)
82(S)
78(S)
a Isolated yield.
b Determined by HPLC analysis.
In conclusion, we designed a new versatile asymmetric
two-center catalyst and constructed a catalyst library.
More than 40 catalysts 1 were easily synthesized from
3. (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc.
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Tetrahedron Lett. 1998, 39, 2997; (c) Arai, S.; Tsuge, H.;
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Shioiri, T. Tetrahedron 2002, 58, 1407; (d) Arai, S.;
Tsuge, H.; Oku, M.; Miura, M.; Shioiri, T. Tetrahedron
2002, 58, 1623 and references cited therein.
6. (a) Ooi, T.; Kaneda, M.; Maruoka, K. J. Am. Chem. Soc.
1999, 121, 6519; (b) Ooi, T.; Takeuchi, M.; Kaneda, M.;
Maruoka, K. Tetrahedron Lett. 2000, 41, 8339; (c) Ooi,
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Belokon, Y. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Larionov, O. V.; Harutyunyan, S. R.;
Vyskocil, S.; North, M.; Kagan, H. B. Angew. Chem., Int.
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diethyl L
-tartrate16 and applied in phase-transfer alkyla-
tions and Michael additions. Starting from the initial
catalyst 1aa, the enantiomeric excess of both alkylated
products and Michael adducts was greatly improved
(up to 93% ee and 82% ee, respectively) by screening
the ketal moiety and the aromatic moiety in the catalyst
1. These findings validate the usefulness of catalyst
tuning for optimization. Moreover, comparing absolute
configurations of alkylated products and Michael
adducts led us to consider the possibility that the
two-center catalysts act as bifunctional catalysts in
Michael additions. Further studies on catalyst tuning,
reaction mechanisms, application to other phase-trans-
fer reactions by rational design of the catalyst based on
mechanistic studies, and the development of new types
of bifunctional organocatalysts are currently in
progress.
Acknowledgements
This work was supported by RFTF and Encourage-
ment of Young Scientists (A) of Japan Society for the
Promotion of Science.
7. For recent reviews, see: (a) Shibasaki, M. Stimulating
Concepts in Chemistry; Vo¨gtle, F.; Stoddart, J. F.;
Shibasaki, M., Eds.; John Wiley & Sons: New York,
2000; (b) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002,
102, 2187.
References
1. For general reviews of asymmetric PTC, see: (a) O’Don-
nell, M. J. Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; John Wiley & Sons: New York, 2000; (b)
Shioiri, T.; Arai, S. Stimulating Concepts in Chemistry;
Vo¨gtle, F.; Stoddart, J. F.; Shibasaki, M., Eds.; John
Wiley & Sons: New York, 2000; (c) Nelson, A. Angew.
Chem., Int. Ed. Engl. 1999, 38, 1583.
2. (a) O’Donnell, M. J.; Benett, W. D.; Wu, S. J. Am. Chem.
Soc. 1989, 111, 2353; (b) Lipkowitz, K. B.; Cavanaugh,
M. W.; Baker, B.; O’Donnell, M. J. J. Org. Chem. 1991,
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Asymmetry 1992, 3, 591; (d) O’Donnell, M. J.; Wu, S.;
Huffman, J. C. Tetrahedron 1994, 50, 4507; (e) O’Don-
nell, M. J.; Delgado, F.; Hostettller, C.; Schwesinger, R.
Tetrahedron Lett. 1998, 39, 8775; (f) O’Donnell, M. J.;
Delgado, F.; Pottorf, R. Tetrahedron 1999, 55, 6347.
8. Computational simulation was performed with Cerius2
(Accelrys Inc., San Diego, CA and Cambridge, UK). The
conformation depicted in Fig. 1 was obtained using a
random conformational search, the so-called Monte
Carlo method, followed by a molecular mechanics mini-
mization calculation (Universal Force Field v.1.02, see:
Rappe, A. K.; Casewit, C. J.; Colwell, K. S.; Goddard,
W. A.; Skiff, W. M. J. Am. Chem. Soc. 1992, 114, 10024).
9. For example, (Sigma-Aldrich Co., St. Louis, MO),
L
-tar-
taric acid: 100 g, 4100 yen (ca. 33 US$), diethyl
L
-tar-
trate: 100 g, 8600 yen (ca. 70 US$), quinine: 100 g, 78000
yen (ca. 640 US$) and (R)-BINOL: 100 g, 783000 yen
(ca. 6420 US$).

T. Shibuguchi et al. / Tetrahedron Letters 43 (2002) 9539–9543
9543
10. In preliminary studies, N,N,N%N%-tetraalkyl-N,N%-diben-
zyl type bis-ammonium salts were not effective catalysts
in terms of enantioselectivity.
CH2Cl2 to toluene (toluene/CH2Cl2=7:3) enhanced reac-
tivity efficiently without any loss of selectivity. In the case
of phase-transfer Michael additions, halobenzenes
showed better selectivity than do other aromatic solvents,
such as benzene and toluene. Although 1,2,4-
trichlorobenzene gave the best selectivity, we eventually
selected chlorobenzene based on reactivity.
13. Degassed conditions did not improve the results. Thus,
the reaction atmosphere was simply replaced with flowing
argon.
14. Absolute configurations of the products shown in Tables
1–4 were determined based on the previous reports, see:
Ishikawa, T.; Araki, Y.; Kumamoto, T.; Seki, H.;
Fukuda, K.; Isobe, T. Chem. Commun. 2001, 245. See
also Ref. 3a.
15. Because of the relatively high melting point of chloroben-
zene (−45°C), −30°C should be the lowest temperature
used in this system. Other solvents, such as toluene, had
worse selectivity.
11. (a) Baba, N.; Oda, J.; Kawaguchi, M. Agric. Biol. Chem.
1986, 50, 3113; (b) Jew, S.-s.; Jeong, B.-S.; Yoo, M.-S.;
Huh, H.; Park, H.-g. Chem. Commun. 2001, 1244; (c)
Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Park, M.-k.; Huh,
H.; Jew, S.-s. Tetrahedron Lett. 2001, 42, 4645; (d) Park,
H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-k.;
Lee, Y.-J.; Kim, M.-J.; Jew, S.-s. Angew. Chem., Int. Ed.
Engl. 2002, 41, 3036.
12. For the purpose of catalyst screening, the described reac-
tion conditions were selected based on reaction time. In
preliminary studies, we found that toluene gave the best
selectivity and CH2Cl2 gave the best reactivity in phase-
transfer alkylations. Finally, we found that addition of
16. Recently, spiro-type phase-transfer catalyst derived from
L
-tartrate was synthesized by Arai, S., Tsuji, R. and
Nishida, A. (private communication).