Catalytic asymmetric phase-transfer reactions using tartrate-derived asymmetric two-center organocatalysts

Article abstract of DOI:10.1016/j.tet.2004.05.120

A new highly versatile asymmetric two-center catalyst, tartrate-derived diammonium salt (TaDiAS), was designed and a catalyst library containing more than 70 new two-center catalysts was constructed. A variety of (S,S)- and (R,R)-TaDiAS were easily synthesized from diethyl L- and D-tartrate, respectively, using common and inexpensive reagents under operationally simple reaction conditions. TaDiAS was used in phase-transfer alkylations and Michael additions to afford various optically active α-amino acid equivalents in up to 93% yield. Moreover, dramatic counter anion effects were observed in phase-transfer catalysis (PTC) for the first time, making it possible to further improve reactivity and selectivity. These findings validate the usefulness of three-dimensional fine-tuning of the catalyst (acetal, Ar, and counter anion) for optimization. Recovery and reuse of the catalyst was also possible using simple procedures. The present asymmetric PTC was successfully applied to enantioselective syntheses of serine protease inhibitor aeruginosin 298-A and its analogues.

Full text of DOI:10.1016/j.tet.2004.05.120

Tetrahedron 60 (2004) 7743–7754
Catalytic asymmetric phase-transfer reactions using
tartrate-derived asymmetric two-center organocatalysts
*
Takashi Ohshima, Tomoyuki Shibuguchi, Yuhei Fukuta and Masakatsu Shibasaki
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 26 April 2004; revised 25 May 2004; accepted 26 May 2004
Available online 26 June 2004
Dedicated to Professor Dieter Seebach in recognition of his receipt of the Tetrahedron Prize
Abstract—A new highly versatile asymmetric two-center catalyst, tartrate-derived diammonium salt (TaDiAS), was designed and a catalyst
library containing more than 70 new two-center catalysts was constructed. A variety of (S,S)- and (R,R)-TaDiAS were easily synthesized
from diethyl L- and D-tartrate, respectively, using common and inexpensive reagents under operationally simple reaction conditions. TaDiAS
was used in phase-transfer alkylations and Michael additions to afford various optically active a-amino acid equivalents in up to 93% yield.
Moreover, dramatic counter anion effects were observed in phase-transfer catalysis (PTC) for the first time, making it possible to further
improve reactivity and selectivity. These findings validate the usefulness of three-dimensional fine-tuning of the catalyst (acetal, Ar, and
counter anion) for optimization. Recovery and reuse of the catalyst was also possible using simple procedures. The present asymmetric PTC
was successfully applied to enantioselective syntheses of serine protease inhibitor aeruginosin 298-A and its analogues.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
mono-alkylation of the Schiff base of tert-butyl glycinate
1 (Scheme 1) using similar Cinchona alkaloid-derived
catalysts.5a Later, Corey et al.6 and Lygo et al.7 inde-
pendently greatly improved this catalyst system by
changing the N-alkyl moiety from N-benzyl to N-anthra-
cenylmethyl.8 Although many types of phase-transfer
catalysts have been used as chiral catalysts in PTC,
Cinchona alkaloid derivatives provide greater enantio-
selectivity for a wider range of reactions than do other
catalysts. Several efficiently designed chiral phase-transfer
catalysts such as N-spiro binaphtyl derivatives9 were
recently developed.10 The major drawback of these catalysts
is the difficulty in modifying the catalyst structure for
further improvement of selectivity and reactivity or further
application to other types of catalytic asymmetric reaction
systems.3
In contrast to the natural subtle balance between metal-free
and metal-mediated conditions, asymmetric catalysis has
been advanced mainly by the development of chiral metal
complexes.1 In recent years, asymmetric organocatalysis
has become of great interest as a new catalytic method to
introduce chirality into a molecule.2 Among them, phase-
transfer catalysis (PTC) is one of the most important and
useful methods in synthetic organic chemistry because of its
preparative advantages, such as simple reaction procedures,
mild conditions, inexpensive and environmentally friendly
reagents, and the ease in scaling-up the reaction.3 An
asymmetric version of PTC utilizing chiral phase-transfer
catalysts is a highly attractive method in terms of atom
economy; however, it has not been as extensively studied as
metal-mediated asymmetric catalysis. The first efficient
asymmetric PTC was reported in 1984 by the Merck group,
where cinchonidine-derived quaternary ammonium
salt catalyzed methylation of 6,7-dichloro-5-methoxy-2-
phenyl-1-indanone
with
92%
enantioselectivity
(1 example).4 In 1989, O’Donnell and co-workers
developed a very useful method for the syntheses of
a-alkyl-a-amino acids by asymmetric phase-transfer
Scheme 1. Syntheses of a-alkyl-a-amino esters 2 by asymmetric phase-
transfer mono-alkylation of the Schiff base of tert-butyl glycinate 1.
Keywords: Phase-transfer catalysis; Asymmetric two-center catalyst;
Alkylation; Michael addition; Aeruginosin 298-A; Serine protease
inhibitor.
To address this issue, we developed a new versatile
asymmetric phase-transfer catalyst. The design of our new
asymmetric catalyst was based on a two-center catalyst and
structural diversity. Herein, we describe our efforts towards
*
Corresponding author. Tel.: þ81-3-5684-0651; fax: þ81-3-5684-5206;
e-mail address: mshibasa@mol.f.u-tokyo.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.120

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T. Ohshima et al. / Tetrahedron 60 (2004) 7743–7754
the development of a novel two-center catalyst: tartrate-
derived diammonium salt (TaDiAS 3) (Fig. 1)11 and present
a brief introduction of its application for the syntheses of
serine protease inhibitor aeruginosin 298-A and its
analogues.12
catalyst screening of N-substituents. Thus, we hypothesized
that the combination of two large N-substituents and one
small N-substituent like TaDiAS 3 would be best for the
phase-transfer alkylation of 1.
Figure 3. Other candidates for the two-center catalyst.
Figure 1. Structure of a new two-center asymmetric organocatalyst,
TaDiAS 3.
Scheme 2 summarizes the synthesis of (S,S)-TaDiAS 3 from
diethyl L-tartrate. Several synthetic processes were
examined, and the present five-step synthesis, which needs
only common and inexpensive reagents under operationally
simple reaction conditions, was selected. The ketone
(R1COR2) was first converted to the corresponding
dimethoxy acetal, which was then directly reacted with
diethyl tartrate to afford an acetal compound (mixture of
ethyl and methyl esters). Introduction of ammonia gas to a
methanol solution of the acetal compound gave diamide 7 in
50–77% yield (two steps) after purification by recrystal-
lization. Reduction of the diamide moiety of 7 to diamine
with LiAlH4 following arylmethylation provided di-tert-
amine 8 in 56–70% yield (two steps). Finally, treatment
with iodomethane furnished the synthesis of diammonium
salt TaDiAS 3 (X2¼I2) (57–95% yield). A potentially
large-scale reaction, starting from 0.1 mol (20.6 g) of
diethyl tartrate, can also be performed with the same
efficiency; thus, this process is suitable for industrial-scale
reactions.18 Using this synthetic process, a variety of
catalysts with versatility on the acetal moiety and aromatic
part (more than 70) were produced.
2. Results and discussion
2.1. Design and synthesis of TaDiAS11
We developed a wide variety of metal-mediated asymmetric
two-center catalyses based on a multifunctional catalyst
concept.13 To extend this concept to asymmetric organo-
catalysis, we introduced two ammonium salt moieties in the
catalyst, keeping an appropriate distance (two-center
organocatalyst), where the substrate can be fixed in a chiral
environment by two cationic moieties. To achieve ideal
complexation of the two-center catalyst and the substrate
(glycine Schiff base 1), we selected a 1,4-diammonium salt,
rather than a 1,2-diammonium salt or a 1,3-diammonium
salt, based on the spatial environment created by two
cationic moieties and several preliminary investigations.
Thus, we designed a new two-center catalyst, TaDiAS 3,
both enantiomers of which can be synthesized from
commercially available and relatively inexpensive14 L- or
D-tartrate. Preliminary molecular mechanics simulations
using the Monte Carlo method on Cerius2 (Accelrys Inc.)15
supported our hypothesis (Fig. 2). Although a naked enolate
is thought to form E-enolate preferentially,6a we expect that
the two-center catalyst TaDiAS 3 might form a tight
complex with the Z-enolate of ketimine 1 through several
hydrogen bonds (see Section 2.7).
Scheme 2. Preparation of TaDiAS 3 (X2¼I2) from diethyl tartrate.
Figure 2. The results of molecular mechanics simulations (right).
2.2. Catalytic asymmetric phase-transfer alkylation11,12a
As in the success of TADDOLs, many chiral catalysts and
chiral ligands were synthesized from tartaric acid, which
provides a proper C2 symmetric framework and structural
diversity.16,17 TaDiAS 3 (Fig. 1) has remarkable structural
diversity because a wide variety of catalysts can be easily
synthesized by changing acetal moieties (R1 and R2),
aromatic parts (Ar), and counter anions (X2), making it
possible to three-dimensionally fine-tune the catalyst (vide
infra).
We then examined a variety of TaDiAS 3 in phase-transfer
alkylation under screening conditions and selected results
are shown in Table 1.19 This condition is very convenient
for high throughput screening of catalysts because the
reaction can be performed with a common disposable test
tube and a rubber septum without any special care to avoid
contamination by moisture or air. Moreover, the reaction
was usually complete in 1–4 h at 4 8C (ice-cold water bath).
Although the reactions were performed under an argon
atmosphere to prevent partial decomposition of 1 under
Other candidates, such as 4, 5, and 6 (Fig. 3), produced
unsatisfactory results (,10% ee) during preliminary

T. Ohshima et al. / Tetrahedron 60 (2004) 7743–7754
7745
Table 1. Catalytic asymmetric phase-transfer alkylations: catalyst screening under screening conditions
Entry
R1
R2
Ar
–C6H5
–C6H5
–C6H5
–C6H5
–C6H4-4-OMe
–C6H4-4-OMe
–C6H5
(S,S)-TaDiAS 3
Time (h)
Yield (%)a
ee (%)b
1c
2
3
4
5
6
7
8
Me
Me
Et
Pr
Bu
Me
Me
Et
Pr
Bu
i-Bu
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
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
3.0
1.5
1.5
2.5
67
87
94
92
91
87
92
90
92
94
91
89
92
89
87
84
92
91
93
89
92
47
47
37
40
38
39
38
48
57
57
54
52
63
67
62
49
70
71
67
68
60
i-Bu
–(CH2)5–
t-Bu
i-Pr
H
–C6H5
9
Me
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-OMe
–C6H4-4-OEt
–C6H4-4-OPr
–C6H4-4-OMe
10
11
12
13
14
15
16
17
18d
19
20
21
Bu
i-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
C14H29
3j
3k
3l
3m
3n
3o
3p
3p
3q
3r
3s
a
Isolated yield.
Determined by HPLC analysis.
The reaction was performed under aerobic conditions.
The reaction mixture was completely degassed by the freeze-pump-thaw cycle.
b
c
d
aerobic conditions (Table 1, entry 1),9d simple replacement
of the reaction atmosphere with flowing argon was enough
to obtain high yield (entry 2) and degassed conditions were
not necessary (entry 18). Starting from the original TaDiAS
3a, the effect of an acetal moiety was examined.20 On the
contrary to our expectation, better phase-transfer alkylation
was obtained when un-C2-symmetric catalysts (R1–R2)
were used. Among them, tert-butyl methyl acetal had the
highest selectivity (entry 12). Keeping the acetal moiety as a
tert-butyl methyl acetal, the effect of the aromatic part was
examined (entries 12–20). Screening of the aromatic part
revealed that TaDiAS 3p (Ar¼4-methoxyphenyl) gave the
best result (92% yield and 70% ee, entry 17). In all entries,
when (S,S)-TaDiAS 3 was used as a catalyst, the absolute
configurations were R.21
cesium hydroxide, all phase-transfer alkylations of 1 with
benzyl, allyl, and propargyl reagents proceeded at 270 8C
in good to high enantiomeric excess. In addition, the
reaction with 4-bromo- and 4-fluorobenzyl bromide, allyl
bromide, propargyl bromide, and so on, afforded the
corresponding protected synthetic a-amino acids, which
can be a versatile intermediate of various synthetic a-amino
acids.
Using the best catalyst 3p, the reaction conditions were
further optimized to improve selectivity. Because lower
temperature conditions cannot be applied to liquid–liquid
phase-transfer reactions, liquid–solid phase-transfer
reactions were investigated. Although the reactivity signifi-
cantly dropped when NaOH (pellet) or KOH (pellet) was
used as a base in organic solvent (toluene/CH2Cl2¼7/3) due
to a dramatic decrease in the surface area (v phase),
powdered CsOH·H2O had higher reactivity than the liquid–
liquid phase-transfer reaction conditions shown in Table 1.
As expected, this liquid–solid phase-transfer system
worked even at 270 8C with improved enantioselectivity
(from 70 to 93% ee). Under the optimized conditions, we
examined the scope and limitations of different electrophiles
(Scheme 3). When 10 mol% of TaDiAS 3p was used with
Scheme 3. Catalytic asymmetric phase-transfer alkylation of various
electrophiles under optimized conditions.

7746
T. Ohshima et al. / Tetrahedron 60 (2004) 7743–7754
In a similar way, optically active a,a-disubstituted a-amino
acids can be synthesized using aldimine 9 as a substrate
instead of ketimine 1 (Scheme 4). Because of the low
reactivity of aldimine 9, the reaction can be performed
under screening conditions (4 8C, shown in Table 1), but not
in the optimized conditions (270 8C, shown in Scheme 3).
Therefore, even when using the best catalyst, TaDiAS 3p,
the obtained enantioselectivities were good to moderate
(58–74% ee). Later, this low reactivity was improved by
changing a counter anion of the catalyst (vide infra).
very rapidly, even in the absence of a phase-transfer
catalyst. K2CO3 had very low reactivity, but Cs2CO3 was
the best base to use in this reaction. Catalyst screening for
phase-transfer Michael additions of 1 to 12a were then
performed under the screening conditions described in
Table 2.22 In contrast to the above-mentioned phase-transfer
alkylation, C2-symmetric catalysts gave better results
(entries 1–13) than un-C2-symmetric catalysts (entries 14
and 15) in Michael additions. In this reaction, 4-methyl-
phenyl was the best aromatic substituent and 3t
(R1¼R2¼Pr), 3aa (R1¼R2¼Bu), and 3bb (R1¼R2¼i-Bu)
gave the highest enantiomeric excess (64% ee). Surpris-
ingly, using (S,S)-TaDiAS 3, the obtained Michael product
12a had an S configuration in all entries.21
The scope and limitations of the phase-transfer Michael
addition were examined using the best catalyst 3t under
optimized conditions shown in Scheme 5. At lower
temperature (230 8C), the enantiomeric excess of the
Michael adduct 12a was improved from 64% ee (Table 2,
entry 5) to 75% ee. Further improvement of the enantio-
selectivity was obtained using ethyl acrylate as an electro-
phile (1!12b, 82% ee). Using more reactive methyl vinyl
ketone as an electrophile gave unsatisfactory selectivity,
even at low temperature (33% ee, not optimized).
2.4. Counter anion effects12a
Scheme 4. Catalytic asymmetric phase-transfer alkylation using aldimine 9
to synthesize a,a-disubstituted a-amino ester 10 under screening
conditions.
Although the phase-transfer Michael addition, in principle,
requires only a catalytic amount of base, most reported
phase-transfer Michael additions were performed in the
presence of excess base.3 In the case of our catalyst system
for the Michael addition, a decrease in Cs2CO3 from 10 to
0.5 equiv. resulted in lower selectivity (57% ee, Table 3,
entry 2); reactivity, however, was maintained. At this stage,
we expected that the counter anion of the catalyst 3 would
2.3. Catalytic asymmetric phase-transfer Michael
addition11
Next, catalytic asymmetric phase-transfer Michael addition
of 1 to methyl acrylate (11a) was investigated. With a strong
base such as KOH or CsOH, the Michael addition proceeded
Table 2. Catalytic asymmetric phase-transfer Michael addition: catalyst screening under screening conditions
Entry
R1
R2
Ar
–C6H5
–C6H5
–C6H5
–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-Me
–C6H4-4-Me
–C6H4-4-Me
–C6H4-4-Me
(S,S)-TaDiAS 3
Time (h)
Yield (%)a
ee (%)b
1c
2
3
4
5
6
7
8
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
3a
3a
3b
3c
20
12
19
12
9
11
12
12
9
70
91
78
92
94
87
87
89
93
89
93
89
88
89
67
37
39
49
59
64
59
62
47
54
58
57
64
64
23
40
3t
3u
3v
3w
3x
3y
3z
3aa
3bb
3cc
3l
9
10
11
12
13
14
15
8
12
14
12
20
20
Me
a
Isolated yield.
Determined by HPLC analysis.
The reaction was performed under aerobic conditions.
b
c

T. Ohshima et al. / Tetrahedron 60 (2004) 7743–7754
7747
Scheme 6. Catalytic asymmetric phase-transfer Michael addition using the
tetrafluoroborate catalyst 3dd under optimized conditions.
Even in phase-transfer alkylation with excess hydroxide,
there was a moderate counter anion effect (Table 4). The
tetrafluoroborate catalyst 3ii, which was directly syn-
thesized from di-tert-amine intermediate 8 (R1¼t-Bu,
R2¼Me, Ar¼C6H4-4-OMe) using Meerwein reagent
(Me3OBF4), had higher reactivity than the iodide catalyst
3p.
Scheme 5. Catalytic asymmetric phase-transfer Michael addition of several
electrophiles under optimized conditions.
Table 3. Counter anion (X2) effects in catalytic asymmetric phase-transfer
Michael addition promoted by TaDiAS 3 under screening conditionsa
Table 4. Counter anion (X2) effects in catalytic asymmetric phase-transfer
alkylation promoted by TaDiAS 3 under screening conditionsa
Entry
X2
Y (equiv.)
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
I2: 3t
10
0.5
10
0.5
0.1
0.1
0.5
0.5
0.5
0.5
9
10
94
84
86
85
85
85
89
87
85
43
64
57
69
69
69
69
68
54
52
43
I2: 3t
Entry
X2
Time (h)
Yield (%)b
ee (%)c
BF24 : 3dd
BF24 : 3dd
BF24 : 3dd
BF24 : 3dd
ClO24 : 3ee
TfO2: 3ff
PF26 : 3gg
SbF26 : 3hh
0.5
0.5
1.0
2.0
1.0
1.0
1.0
35
1
2
3
4
5
I2: 3p
2
1
1
1
1
92
91
87
88
86
70
70
63
55
53
BF24 : 3ii
ClO24 : 3jj
TfO2: 3kk
PF26 : 3ll
5
6d
7
8
9
10
a
In all entries, R1¼t-Bu, R2¼Me, and Ar¼C6H4-4-OMe.
b
c
Isolated yield.
Determined by HPLC analysis.
a
In all entries, R1¼R2¼Pr and Ar¼C6H4-4-Me.
b
c
d
Isolated yield.
Determined by HPLC analysis.
One mole percent of catalyst was used.
Tetrafluoroborate catalyst 3ii successfully promoted the
alkylation of aldimine 9, even at low temperature (270 8C),
to afford a,a-disubstituted a-amino ester 10a (83 and 89%
ee) and 10c (76 and 88% ee) (Scheme 7, see also Scheme 4).
The alkylation of 1 to 2g also slightly improved (85% yield,
93% ee compared with 79% yield, 91% ee using the iodide
affect the reactivity in the catalytic base system. Thus, we
examined counter anion effects of catalyst 3 in the present
Michael addition system. A variety of new types of TaDiAS
3dd–hh with hard counter anions such as tetrafluoroborate
instead of iodide were synthesized by counter anion
exchange using the corresponding silver salts. Those
phase-transfer catalysts 3dd–hh have lower polarity on
silica-gel thin-layer chromatography and higher solubility in
organic solvent than the iodide catalyst 3t. As shown in
Table 3, hard counter anions dramatically accelerated the
phase-transfer Michael addition even in the case of a
catalytic amount of Cs2CO3. Among the examined counter
anions, tetrafluoroborate catalyst 3dd had the highest
reactivity with improved enantioselectivity (69% ee, entry
4). Moreover, only 1 mol% of the catalyst 3dd gave the
same result (entry 6) as that using 10 mol% of 3dd (entry 3–
5). The counter anion effects were also observed under
optimized conditions (230 8C)23 to provide 12d in 81% ee,
the optical purity of which was further enriched to .99% ee
by recrystallization (43% yield) (Scheme 6). To the best of
our knowledge, this is the first example of such dramatic
counter anion effects in PTC. These results clearly
demonstrate that three-dimensional fine-tuning of the
catalyst 3 can be realized by changing acetal moieties (R1
and R2), aromatic parts (Ar), and counter anions (X2).
Scheme 7. Catalytic asymmetric phase-transfer alkylation using the
tetrafluoroborate catalyst 3ii under optimized conditions.

7748
T. Ohshima et al. / Tetrahedron 60 (2004) 7743–7754
catalyst 3p shown in Scheme 3). These results indicate that,
even in the presence of excess hydroxide or enolate, one of
the original counter anions remained unchanged in the
catalyst.
2.5. Catalyst recovery and reuse12a
In contrast to commonly used Cinchona alkaloid-derived
catalysts,3–9 TaDiAS 3 is extremely stable under strongly
basic conditions. In spite of the existence of b-hydrogens to
the ammonium cation, catalyst decomposition, such as that
due to Hoffman elimination, has not been observed under
phase-transfer reaction conditions. As a result, TaDiAS 3
can be recovered from the reaction mixture in a high
recovery yield. After quenching the reaction with water and
diethyl ether, the catalyst appeared as a white solid between
two layers. After stirring vigorously for 5–10 min, this
white solid stuck to the glass wall. Thus, the solid was easily
separated from the product by simple decantation (Fig. 4).
The residual solid was dissolved with 30% MeOH in
CH2Cl2 and filtered through a paper filter to remove
inorganic salts, resulting in recovered catalyst after solvent
evaporation.
Scheme 8. Reuse of the recovered catalyst 3p under screening conditions.
2.6. Synthetic application12
With the practical asymmetric PTC using TaDiAS 3 with
broad substrate generality in hand, we next examined the
synthetic application of this asymmetric PTC to produce
complex natural products. In addition, its easy accessibility
to a variety of optically active natural and unnatural
a-amino acids makes it possible to supply very valuable
product libraries. First, we chose aeruginosin 298-A (Fig. 5,
14a) as a target compound based on its unique serine
protease inhibitor activity and the existence of nonstandard
amino acids such as 2-carboxy-6-hydroxyoctahydroindole
(Choi) in the molecule.25a,26 To gain insight into the
structure-activity relations, we developed a highly versatile
synthetic method of aeruginosin 298-A as well as its
analogues. We used the above-mentioned catalytic asym-
metric phase-transfer alkylation for the synthesis of the
D-Leu, L-Choi, and L-Algol portions and catalytic asym-
metric epoxidation of a,b-unsaturated imidazolide, which
was previously developed by our group,27 for the synthesis
of the (R)-3-(4-hydroxyphenyl)lactic acid (D-Hpla) portion.
Because most of the aeruginosin families contain a D-Hpla
portion, an L-Choi portion, and a guanidine unit,25 we
synthesized a variety of analogues by altering the second
amino acid portion from the N-terminus (R6) and arginine
portion (R7, R8 as well as their enantiomers).
Figure 4. General procedure for recovery of the catalyst 3.
We then investigated catalyst recovery with several
combinations of counter anions and electrophiles after the
standard phase-transfer alkylation of 1 to 2a. As shown in
Table 5, when the iodide catalyst 3p was used, 3p was
recovered in approximately 90% yield as a white powder.24
On the other hand, when the tetrafluoroborate catalyst 3ii
was used, complete (entry 3) or partial (entry 4) counter
anion exchange proceeded with a lower recovery yield
(approximately 80%). These findings suggest that the order
of stability of counter anions in the catalyst should be
I2.BF24 .Br2 and the reason for the counter anion effect in
the alkylation shown in Scheme 7 might be due to the
remaining BF24 in the catalyst complex during the reaction.
The recovered catalyst 3p (Table 5, entry 2) was reused in
the same phase-transfer alkylation without further purifi-
cation, and had the same catalyst efficiency (94% yield, 71%
ee, Scheme 8). Thus, the catalyst can be recovered and
reused using simple deposition and decantation techniques,
as shown in Figure 4.
Table 5. Recovery of the catalyst 3 with several combinations of counter
anions and electrophiles
Entry
X2
Electrophile
X2 of the recovered catalyst
Figure 5. Structure of aeruginosin 298-A (14a) and its analogues.
1
2
3
4
I2: 3p
PhCH2I
I2, I2
I2: 3p
PhCH2Br
PhCH2I
PhCH2Br
I2, I2
Synthesis of the unusual bicyclic amino acid L-Choi portion
was achieved by catalytic asymmetric phase-transfer
alkylation of 1 to (S)-2l with electrophile 1512a using
BF24 : 3ii
BF24 : 3ii
I2, I2
BF24 , BF24 or Br2

T. Ohshima et al. / Tetrahedron 60 (2004) 7743–7754
7749
10 mol% of (R,R)-TaDiAS 3p and the following acid
treatment, resulting in bicyclic amino ester 17 in high yield
through five one-pot reactions (deprotection of the benzo-
phenone imine and acetal, transesterification, migration of
the C–C double bond to form enone, and 1,4-addition of the
resulting amine to enone) (Scheme 9). After benzylation, the
bicyclic amino ester 18 was obtained as a diastereomixture
(84%, 18a:18b¼1:2). The undesired minor isomer 18b was
transformed to the desired 18a under acidic conditions
(78%, 18a:18b¼8:1) and 18a was successfully converted to
19 (71% in 2 steps) following Bonjoch’s procedure.26a
(R8¼Me) was also synthesized from (S)-10c (Scheme 7,
76 and 88% ee).
The syntheses of aeruginosin 298-A and its analogues are
summarized in Scheme 11. D-Leu and several derivatives,
corresponding to the second amino acid portion from the
N-terminus, were synthesized from (R)-2h (91% ee, for
aeruginosin 298-A), 2d (92% ee, for analogue), and 2e
(.99% ee after recrystallization, for analogue) (Scheme 3).
The D-Hpla portion 23, which was directly used for
coupling with the above-mentioned second amino acid
portions, was prepared in 95% yield and 94% ee based on
catalytic asymmetric epoxidation of a,b-unsaturated
imidazolide 22 using 10 mol% of La-(S)-BINOL-Ph3P¼O
(1:1:3) complex. With all the component amino acids and
their derivatives in hand, each peptide portion of aerugino-
sin 298-A and its six analogues was assembled. Using a
peptide coupling of epoxy peroxy ester 23 and a subsequent
regioselective one-pot epoxide-opening reaction (for
D-Hpla-D-Leu) and normal peptide coupling protocols (for
other couplings), enantioselective syntheses of aeruginosin
298-A (14a) and its six analogues were accomplished.
Furthermore, inhibitory activity studies against the serine
protease trypsin were examined. The biological activity
studies of the newly synthesized aeruginosin analogues
suggest that conformation of the Argol portion, especially
the guanidine side-chain, is extremely important for the
inhibitory activity. Access to additional derivatives and
closer investigation are now possible through molecular
design and chemical synthesis.
Scheme 9. Synthesis of the L-Choi portion 19.
Synthesis of the L-Argol portion began from (S)-2g, which
was prepared by the phase-transfer alkylation of the
ketimine 1 using the tetrafluoroborate catalyst (R,R)-3ii
shown in Scheme 7 (85 and 93% ee). Then, (S)-2g was
converted to (S)-21a (R8¼H) through introduction of the
guanidine moiety (Scheme 10). In a similar way, the
enantiomer (R)-21a was prepared using (S,S)-3ii as a
catalyst. Moreover, the a-methyl analogue (S)-21b
Scheme 11. Syntheses of aeruginosin 298-A (14a) and its analogues.
2.7. Preliminary mechanistic studies
As demonstrated above using molecular mechanics
Scheme 10. Synthesis of the L-Argol portion 21.

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T. Ohshima et al. / Tetrahedron 60 (2004) 7743–7754
simulations (Fig. 2), the existence of two cationic moieties
in the catalyst is essential for obtaining high enantio-
selectivity. Monocationic catalyst 24 (10 mol%) had much
lower reactivity and selectivity than dicationic catalyst 3dd
(5 mol %) in the phase-transfer Michael addition
(Scheme 12). Although bis- and tris-Cinchona alkaloid
ammonium salt catalysts were reported,28 similar reactivity
and selectivity were observed, compared with standard
Cinchona alkaloid catalysts, even with the same catalyst
loading. These results suggest that, as expected, substrate 1
is fixed in a chiral environment by two cationic moieties.
Figure 6. Results of optimization by molecular orbital calculations.
addition, remains unclear. Further intensive studies aimed at
determining the reaction mechanism are ongoing.
3. Conclusion
Scheme 12. Catalytic asymmetric phase-transfer Michael addition using
dicationic catalyst 3dd and monocationic catalyst 24 under screening
conditions.
In conclusion, we designed a new versatile asymmetric two-
center catalyst TaDiAS 3 and constructed a catalyst library.
A variety of (S,S)- and (R,R)-TaDiAS 3 catalysts were easily
synthesized from diethyl L- and D-tartrate, respectively,
using only common and inexpensive reagents under
operationally simple reaction conditions. They were applied
in phase-transfer alkylations and Michael additions and,
Based on molecular orbital calculations by Reetz et al. the
positive charge of tetraalkylammonium cation (R4Nþ) was
expected to be delocalized on the a-carbon and hydrogen
atoms;29a that is, not delocalized on the nitrogen atom.
Moreover, the presence of hydrogen bonds between the
a-methylene units of the tetrabutylammonium cations and
enolate oxygen atoms, making the anions and cations
interact in a highly ordered manner, was revealed by several
X-ray structural analyses.29b,c The magnitude of the
stabilizing interaction of an aliphatic C–H bond attached
to an ammonium nitrogen and a carbonyl oxygen (R3Nþ–
C–H· · ·OvC) was evaluated by Houk et al. using ab initio
calculations.29d Because TaDiAS 3 has two-ammonium
cation moieties in the molecule, we expect that it might
form a tight complex with the Z-enolate of ketimine 1.30 To
test our hypothesis, we performed more precise calculations
of the ion pairs of the counter anion-free dicationic catalyst
of (S,S)-TaDiAS and the Z-enolate of 1. Starting from the
structure shown in Figure 2, one of the acetal moiety
substituents was changed to t-Bu from Me. After molecular
mechanics optimization, the obtained structure was further
optimized by ab initio calculation at the HF/3-21G level
followed by B3LYP hybrid density functional methods
using a 3-21G basis set with Gaussian 98. This calculation
suggests that the Z-enolate of 1 is fixed with the catalyst 3
through several hydrogen bonds between the a-methylene
or methyne unit of the ammonium cation units and the
enolate oxygen atom and imine nitrogen atom of 1 (Fig. 6).
The precise reaction mechanism, especially the reason for
opposite facial selectivity between alkylation and Michael
Figure 7. Summary of phase-transfer alkylation and Michael addition of 1
using TaDiAS 3.

T. Ohshima et al. / Tetrahedron 60 (2004) 7743–7754
7751
starting from the initial catalyst 3aa, the enantiomeric
excess of both alkylated products and Michael adducts was
greatly improved (up to 94% ee and 82% ee, respectively)
by screening the acetal moiety and the aromatic moiety in
the catalyst 3. Moreover, dramatic counter anion effects in
PTC were observed for the first time, making it possible to
further improve reactivity and selectivity. The results were
summarized in Figure 7. These findings validate the
usefulness of three-dimensional fine-tuning of the catalyst
3 (acetal, Ar, and counter anion) for optimization. Recovery
using simple operations and reuse of the catalyst 3 were also
performed. The present asymmetric PTC was successfully
applied to the enantioselective syntheses of serine protease
inhibitor aeruginosin 298-A and its analogues. Further
studies on catalyst tuning, reaction mechanisms, application
to other phase-transfer reactions, their industrial application,
and the development of new types of bifunctional
organocatalysts are in progress.
bubbling. Bubbling was continued for 2 h and then the
solvent was evaporated to give crude 7p, which was further
purified by recrystallization from methanol (11.2 g,
0.049 mol, 61% from diethyl L-tartrate) as a white crystal.
Mp 235–238 8C; [a]D23¼þ2.7 (c 1.02, CH3OH); FT-IR
1
(KBr) nmax 3460, 3295, 2979, 1665, 1087 cm21; H NMR
(500 MHz, DMSO-d6) d 7.52 (br-s, 2H; CONH2), 7.43 (br-s
2H; CONH2), 4.46 (d, J¼8.0 Hz, 1H; OCH), 4.18 (d,
J¼8.0 Hz, 1H; OCH), 1.28 (s, 3H; Me), 0.96 (s, 9H; t-Bu);
13C NMR (125 MHz, DMSO-d6) d 171.4 (CONH2), 169.9
(CONH2), 116.5 (t-BuCMe), 78.2 (OCH), 77.1 (OCH), 38.4
(C(CH3)3), 25.0 (C(CH3)3), 19.5 (Me); MS [ESI(þ)] m/z
253 (MþNaþ). Anal. calcd for C10H18N2O4: C 52.16, H
7.88, N 12.17. Found: C 52.12, H 7.78, N 12.14.
4.2.2. Synthesis of (4S,5S)-2-tert-butyl-N,N,N0,N0-tetra-
kis[(4-methoxyphenyl)methyl]-2-methyl-1,3-dioxolane-
4,5-dimethanamine (8p). Diamide 7p (3.45 g, 15 mmol)
was placed in a Soxhlet thimble and extracted into a
refluxing suspension of lithium aluminum hydride (2.0 g,
52.5 mmol) in anhydrous THF (200 mL). Refluxing was
continued for 20 h and the suspension was cooled to room
temperature. Water (2.0 mL) was added dropwise to the
mixture, followed by 4 N aqueous NaOH (2.0 mL) and
water (6.2 mL). The mixture was filtered, the resulting solid
was washed with THF, and the combined filtrates were
concentrated to afford the crude diamine (2.99 g, ca. 99%)
as a pale brown oil. A solution of the diamine (2.62 g,
13 mmol) and i-Pr2NEt (13.6 mL, 78 mmol) in CH3CN
(30 mL) was treated with 4-methoxybenzyl chloride
(8.8 mL, 65 mmol) and TBAI (480 mg, 1.3 mmol) at 0 8C.
After the starting material was completely consumed, the
reaction was quenched by the addition of Et3N (10 mL).
After additional stirring for 1 h, water was added and the
mixture was extracted with ether (10 mL£3), washed with
brine (10 mL£3), and dried over Na2SO4. After evapor-
ation, the crude mixture was purified by flash column
chromatography (silica gel, 10–30% EtOAc in hexane) to
give 8p (7.27 g, 82%) as a colorless oil; Rf¼0.41 (silica gel,
EtOAc–hexane 1:3); [a]2D3¼25.8 (c 0.97, CHCl3); FT-IR
4. Experimental
4.1. General
Infrared (IR) spectra were recorded on a JASCO FT/IR 410
Fourier transform infrared spectrophotometer. NMR spectra
were recorded on a JEOL JNM-LA500 spectrometer,
1
operating at 500 MHz for H NMR and 125.65 MHz for
13C NMR. Optical rotations were measured on a JASCO
P-1010 polarimeter. ESI mass spectra (for LC-MS) were
measured on a Waters micromass ZQ. EI mass spectra (for
HR-MS) were measured on a JEOL JMS-MS/700V in
positive ion mode. Column chromatography was performed
with silica gel Merck 60 (230–400 mesh ASTM). The
enantiomeric excess was determined by HPLC analysis.
HPLC was performed on JASCO HPLC systems consisting
of the following: pump, 880-PU or PU-980; detector, 875-
UV or UV-970, measured at 254 or 280 nm; column,
DAICEL CHIRALPAK AD, AS, AS-H, or OD; mobile
phase, hexane-2-propanol or EtOH–2-propanol; flow rate,
0.4–1.0 mL/min. Reactions were performed in dry solvents
under an argon atmosphere, unless otherwise stated.
(neat) nmax 2955, 2061, 1883, 1610, 1248, 1087, 821 cm21
;
1H NMR (500 MHz, CDCl3) d 7.25 (d, J¼9.0 Hz, 4H; Ar-
H), 7.20 (d, J¼9.0 Hz, 4H; Ar-H), 6.82 (d, J¼9.0 Hz, 8H;
Ar-H), 3.84–3.73 (m, 1H; OCH), 3.76 (s, 12H; OCH3), 3.61
(d, J¼13.5 Hz, 2H; ArCH2N), 3.60 (d, J¼13.5 Hz, 2H;
ArCH2N), 3.58–3.54 (m, 1H; OCH), 3.47 (d, J¼13.5 Hz,
2H; ArCH2N), 3.43 (d, J¼13.5 Hz, 2H; ArCH2N), 2.56 (m,
2H; OCHCH2N), 2.54 (dd, J¼13.5, 3.5 Hz, 1H; OCHCH2N),
2.48 (dd, J¼13.5, 7.0 Hz, 1H; OCHCH2N), 1.20 (s, 3H; Me),
0.92 (s, 9H; t-Bu); 13C NMR (125 MHz, CDCl3) d 158.9
(Ar-O), 131.9 (Ar), 130.4 (Ar), 114.5(t-BuCMe), 113.9
(Ar), 80.0 (OCH), 78.6 (OCH), 56.2 (OCH3), 58.1
(ArCH2N), 55.6 (ArCH2N), 54.7 (OCH3), 39.2(C(CH3)3),
25.6 (C(CH3)3), 21.2 (Me); MS [ESI(þ)] m/z 683 [MþHþ];
HR-MS [FAB(þ)] calcd for C42H55N2Oþ6 [MþHþ]:
683.4060. Found: 683.4074.
4.2. General procedure for the synthesis of TaDiAS 3
4.2.1. Synthesis of (4S,5S)-2-tert-butyl-2-methyl-1,3-
dioxolane-4,5-dicarboxamide (7p). A mixture of 3,3-
dimethyl-2-butanone (12.5 mL, 0.10 mol), methyl ortho-
formate (16.4 mL, 0.15 mol), p-toluenesulfonic acid mono-
hydrate (95 mg, 5 mmol), and methanol (50 mL) was gently
heated while the methyl formate produced in the reaction
was distilled off through a short Vigreux column. To the
cooled reaction mixture, diethyl L-tartrate (13.7 mL,
0.08 mol) and toluene (30 mL) were added and brought to
reflux for 24 h. The cooled reaction mixture was basified by
the addition of potassium carbonate (5 g) and stirred at room
temperature for 1 h. After evaporation of the reaction
mixture, the residue was purified by flash column chroma-
tography (silica gel, 20% EtOAc in hexane) to afford a
mixture of methyl and ethyl ester, which was used for the
next reaction without further purification. A solution of the
esters (17.5 g) in methanol (100 mL) was cooled to 4 8C
(ice-water bath) and then NH3 gas was introduced by
4.2.3. Synthesis of (4S,5S)-2-tert-Butyl-N,N,N0,N0-tetra-
kis[(4-methoxyphenyl)methyl]-N,N022-trimethyl-1,3-
dioxolane-4,5-dimethanammonium diiodide ((S,S)-3p).
Methyl iodide (11.2 mL, 180 mmol) was added to 8p
(5.92 g, 9.0 mmol) at room temperature. After stirring for
18 h, the mixture was evaporated and purified by flash

7752
T. Ohshima et al. / Tetrahedron 60 (2004) 7743–7754
column chromatography (silica gel, EtOAc to 20% MeOH
in EtOAc) to give (S,S)-3p (7.74 g, 8.0 mmol, 89%) as a
yellow solid. Mp 132–135 8C; Rf¼0.35 (silica gel, 10%
MeOH in EtOAc); [a]D23¼263 (c 1.05, CDCl3); FT-IR
AgBF4 (428 mg, 2.2 mmol) was added to a solution of 3p
(913 mg, 1 mmol) in CH2Cl2 (5 mL). The mixture was
stirred at room temperature for 2 h, and filtrated to remove
the AgI. The solvent was evaporated and the residue was
purified by flash column chromatography (silica gel, 50–
100% EtOAc in hexane) to give 3ii (846 mg, 0.95 mmol,
95%). Mp 171–173.5 8C; Rf¼0.72 (silica gel, EtOAc);
[a]2D3¼233.2 (c 1.11, CHCl3); FT-IR (KBr) nmax 2972,
(KBr) nmax 3448, 2961, 1611, 1464, 1182, 1027, 841 cm21
;
1H NMR (500 MHz, CDCl3) d 7.66 (d, J¼8.5 Hz, 2H;
Ar-H), 7.60 (d, J¼8.5 Hz, 2H; Ar-H), 7.54 (d, J¼8.5 Hz,
2H; Ar-H), 7.47 (d, J¼8.5 Hz, 2H; Ar-H), 6.93 (d,
J¼8.5 Hz, 6H; Ar-H), 6.89 (d, J¼8.5 Hz, 2H; Ar-H), 5.94
(m, 1H; OCH), 5.49 (d, J¼13.0 Hz, 1H; NCHaHbAr), 5.40
(d, J¼12.5 Hz, 1H; NCHcHdAr), 5.18 (d, J¼14.5 Hz, 1H;
OCHCHaHbN), 5.06 (d, J¼12.5 Hz, 1H; NCHeHfAr), 4.78
(d, J¼12.5 Hz, 1H; NCHgHhAr), 4.76 (d, J¼12.5 Hz, 1H;
OCHCHcHdN), 4.71 (d, J¼13.0 Hz, 1H; NCHaHbAr), 4.67
(d, J¼13.0 Hz, 1H; NCHeHfAr) 4.64 (d, J¼12.5 Hz, 1H;
NCHgHhAr), 4.56 (m, 1H; OCH), 4.31 (d, J¼12.5 Hz, 1H;
NCHcHdAr), 4.10 (dd, J¼12.5 Hz, 10.0 Hz, 1H; OCHCHc-
HdN), 3.80 (s, 6H; OCH3), 3.78 (s, 3H; OCH3), 3.73 (s, 3H;
OCH3), 3.49 (dd, J¼14.5, 6.0 Hz, 1H; OCHCHaHbN), 2.94
(s, 3H; NCH3), 2.91 (s, 3H, NCH3), 1.83 (s, 3H; Me), 0.96
(s, 9H; t-Bu); 13C NMR (125 MHz, CDCl3) d 161.7, 161.6,
135.5, 135.4, 135.2, and 135.1 (Ar), 119.3 (t-BuCMe),
118,7, 118.6, 118.4, 118.0, 115.6, 115.0, and 114.9 (Ar),
74.6 (OCH), 73.2 (OCH), 66.2, 65.8, 65.2, and 65.0 (4 C;
ArCH2N), 62.1 (OCHCH2Nþ), 60.6 (OCHCH2Nþ), 55.8
(OCH3), 47.6 (NþCH3), 46.1 (NþCH3), 39.2 (C(CH3)3),
25.7 (C(CH3)3), 22.7 (Me); MS [ESI(þ)] m/z 989
[MþNaþ], 839 [M2I2], 591 [M22I2-CH2Ar]. Anal.
calcd for C44H62I2N2O7 (MþH2O): C 53.66, H 6.35, N
2.84. Found: C 53.66, H 6.40, N 3.04.
1
2841, 1613, 1518, 1468, 1029, 843, 762 cm21; H NMR
(500 MHz, CDCl3) d 7.47–7.37 (m, 8H; Ar-H), 6.96 (d,
J¼9.0 Hz, 2H; Ar), 6.95 (d, J¼9.0 Hz, 2H; Ar), 6.90 (d,
J¼8.5 Hz, 4H; Ar), 4.88 (m, 1H; OCH), 4.76 (d, J¼14.0 Hz,
1H; NCHaHbAr), 4.73 (d, J¼14.0 Hz, 1H; NCHcHdAr),
4.58 (d, J¼13.0 Hz, 2H; NCHeHfAr, NCHgHhAr), 4.41–
4.32 (m, 4H; NCHaHbAr, NCHcHdAr, NCHeHfAr, NCHg-
HhAr), 4.30 (m, 1H; OCH), 3.82 (s, 6H; OMe), 3.80 (s, 3H;
OMe), 3.78 (s, 3H; OMe), 3.76 (m, 2H; OCHCH2N), 3.63
(m, 2H; OCHCH2N), 2.81 (s, 6H; NMe), 1.49 (s, 3H; Me),
0.90 (s, 9H; t-Bu); 13C NMR (126 MHz, CDCl3) d 161.7,
161.6, 135.0, 134.9, 134.8, and 134.7 (Ar), 119.0
(t-BuCMe), 118.4, 118.3, 118.2, 118.0, 115.1, 115.0,
114.94, and 114.91 (Ar), 74.0 (OCH), 72.6 (OCH), 67.6,
67.2, 66.6, and 66.2 (4 C; ArCH2N), 62.3(CHCH2N), 61.6
(CHCH2N), 55.5 (OCH3), 46.5 (NCH3), 45.6 (NCH3), 38.8
(C(CH3)3), 25.3 (C(CH3)3), 20.6 (Me); MS [ESI(þ)] m/z
909 [MþNaþ], 799 [M2BF24 ]; HR-MS [FAB (þ)] calcd
for C44H60F4N2O6Bþ (M2BF24 ): 799.4475. Found:
799.4469.
4.2.6. (4S,5S)-N,N0-Dimethyl-N,N,N0,N0-tetrakis[(4-
methylphenyl)methyl]-2,2-dipropyl-1,3-dioxolane-4,5-
dimethanammonium bistetrafuluoroborate ((S,S)-3dd).
A white solid. Mp 201–204 8C; Rf¼0.68 (silica gel,
EtOAc); [a]2D2¼232.4 (c 0.98, CHCl3); FT-IR (KBr) nmax
4.2.4. (4S,5S)-N,N0-Dimethyl-N,N,N0,N0-tetrakis[(4-
methylphenyl)methyl]-2,2-dipropyl-1,3-dioxolane-4,5-
dimethanammonium diiodide ((S,S)-3t). A yellow pale
solid. Mp 112–115 8C; Rf¼0.41 (silica gel, EtOAc);
[a]2D2¼256.3 (c 1.02, CHCl3); FT-IR (KBr) nmax 2958,
1614, 1464, 1105, 805 cm21; 1H NMR (500 MHz, CDCl3) d
7.56 (d, J¼7.5 Hz, 4H; Ar-H), 7.49 (d, J¼7.5 Hz, 4H; Ar-H),
7.24–7.28 (m, 8H), 5.29 (m, 2H; OCH), 5.23 (d, J¼12.5 Hz,
2H; ArCH2N), 5.18 (d, J¼12.5 Hz, 2H; ArCH2N), 5.09 (d,
J¼14.0 Hz, 2H, OCHCH2N), 4.73 (d, J¼12.5 Hz, 2H;
ArCH2N), 4.40 (d, J¼12.5 Hz, 2H; ArCH2N), 3.85 (m, 2H;
OCHCH2N), 2.97 (s, 6H, NCH3), 2.39 (s, 6H; Ar-CH3), 2.35
(s, 6H; Ar-CH3), 1.89 (m, 2H, Pr), 1.81 (m, 2H; Pr), 1.33 (m,
4H; Pr), 0.95 (t, J¼7.0 Hz, 6H; Pr); 13C NMR (125 MHz,
CDCl3) d 141.2 and 141.1 (Ar), 133.4 and 133.2 (Ar), 130.1
and130.0(Ar), 123.3and123.1(Ar), 116.7(PrCPr), 73.0(2C;
OCH), 66.0 (2 C; ArCH2N), 65.1 (2 C; ArCH2N), 61.4 (2 C;
CHCH2N), 46.4 (NCH3), 39.7 (Pr), 21.2 (Ar-CH3), 17.5 (Pr),
14.0 (Pr); MS [ESI(þ)] m/z 789 [M2I2], 557 [M22I2-
CH2Ar]. Anal. calcd for C45H64N2O3 (MþH2O): C 57.82, H
6.90, N 3.00. Found: C 57.77, H 6.86, N 3.04.
1
2963, 1617, 1475, 1074, 790 cm21; H NMR (500 MHz,
CDCl3) d 7.41 (d, J¼8.0 Hz, 4H; Ar-H), 7.36 (d, J¼8.0 Hz,
4H; Ar-H), 7.28–7.23 (m, 8H; Ar-H), 4.80 (d, J¼13.0 Hz,
2H; ArCH2N), 4.77 (d, J¼12.0 Hz, 2H; ArCH2N), 4.70 (d,
J¼7.0 Hz, 2H; OCH), 4.40 (d, J¼12.0 Hz, 2H; ArCH2N),
4.30 (d, J¼13.0 Hz, 2H; ArCH2N), 3.96 (d, J¼13.5 Hz, 2H;
OCHCH2N), 3.78 (dd, J¼13.5, 8.0 Hz, 2H; OCHCH2N),
2.40 (s, 6H; Ar-CH3), 2.83 (s, 6H; NCH3), 2.37 (s, 6H;
Ar-CH3), 1.70 (m, 4H, Pr), 1.27 (m, 4H; Pr), 0.91 (t,
J¼7.5 Hz, 6H; Pr); 13C NMR (125 MHz, CDCl3) d 141.5,
130.3, 123.5, and 123.3 (Ar), 117.0 (PrCPr), 73.0 (OCH),
67.5 (2C; ArCH2N), 66.6 (2C; ArCH2N), 62.5 (OCHCH2N),
46.1 (NCH3), 14.2 (Pr), 39.5 (Pr), 21.4 (Ar-CH3), 17.6 (Pr);
MS [ESI(þ)] m/z 749 [M2BF24 ], 557 [M22BF42-CH2Ar].
Anal. calcd for C45H62B2F8N2O2: C 64.60, H 7.47, N 3.35.
Found: C 64.49, H 7.37, N 3.31.
4.3. General procedure for the catalytic asymmetric
phase-transfer alkylation using TaDiAS 3p under
optimized conditions
4.2.5. Synthesis of (4S,5S)-2-tert-butyl-N,N,N0,N0-tetra-
kis[(4-methoxyphenyl)methyl]-N,N0-2-trimethyl-1,3-
dioxolane-4,5-dimethanammonium bistetrafluoroborate
((S,S)-3ii). Trimethyloxonium tetrafluoroborate (4.44 g,
30 mmol) was added to a solution of 8p (6.32 g, 10 mmol)
in CH2Cl2 (100 mL) at room temperature. The mixture was
stirred for 6 h and concentrated. The residue was
recrystallized from ethyl acetate and hexane to give 3ii as
a white solid (7.26 g, 8.7 mmol, 87%). Alternatively, 3ii can
be synthesized from 3p using the following procedure.
A solution of 4-(triisopropylsilanyloxy)benzyl bromide
(approximately 0.2 M in toluene, 7.0 mL, 3.5 mmol,
5.0 equiv.) was added to a mixture of N-(diphenyl-
methylene)glycine tert-butyl ester (1) (207 mg,
0.70 mmol) and phase-transfer catalyst (S,S)-TaDiAS 3p
(67 mg, 0.070 mmol, 10 mol%) in CH2Cl2 (3.0 mL, total
0.07 M) at 270 8C. Finally, CsOH·H2O (1.18 g, 7.0 mmol,
10 equiv.) was added directly to the reaction mixture at the

T. Ohshima et al. / Tetrahedron 60 (2004) 7743–7754
7753
same temperature. After stirring for 72 h at the same
References and notes
temperature, the reaction was quenched by the addition of
water followed by diethyl ether. After vigorous stirring at
room temperature, both organic and aqueous layers were
transferred to a separation funnel by simple decantation.
The organic layer was separated and washed with brine. The
combined aqueous layers were re-extracted with diethyl
ether and the combined organic layers were dried over
Na2SO4. After concentration in vacuo, the residue was
purified by flash column chromatography (silica gel
deactivated with Et3N, hexane only to 5% EtOAc in
hexane) to give (R)-2d (343.2 mg, 88%) as a colorless oil
and the remaining excess electrophile was recovered
(820 mg, 85%). The catalyst was also recovered (60 mg,
90%) using the procedure shown in Figure 4. Spectro-
scopic data of the alkylated products 2 were reported in
Refs. 5, 6, 9, 12.
1. For general reviews of asymmetric catalyses using chiral metal
complexes, see: (a). In Catalytic Asymmetric Synthesis; 2nd
ed. Ojima, I., Ed.; Wiley: New York, 2000. (b) In
Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: New York, 1999.
(c) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994.
2. For recent general reviews of asymmetric organocatalysis, see:
(a) Drauz, K.; Kleeman, A.; Martens, J. Angew. Chem., Int. Ed.
Engl. 1982, 21, 584. (b) Dalko, P. I.; Moisan, L. Angew.
¨
Chem., Int. Ed. 2001, 40, 3726. (c) Groger, H.; Wilken, J.
Angew. Chem., Int. Ed. 2001, 40, 529. (d) Jarvo, E. R.; Miller,
S. J. Tetrahedron 2002, 58, 2481. (e) List, B. Tetrahedron
2002, 58, 5573.
3. For general reviews of asymmetric PTC, see: (a) O’Donnell,
M. J. In Catalytic Asymmetric Synthesis; 2nd ed.; Ojima, I.,
Ed.; Wiley: New York, 2000. (b) Shioiri, T.; Arai, S. In
The ketimine (R)-2d was treated with 0.5 N aqueous citric
acid solution (1.5 mL) in THF (6.2 mL) for 90 min at room
temperature. The mixture was quenched with water and the
aqueous phase was basified with solid NaHCO3, extracted
with CH2Cl2 (three times), and dried over Na2SO4. After
concentration in vacuo, the residue was purified by flash
column chromatography (silica gel, 40–60% EtOAc in
hexane) to give the corresponding a-amino ester (198 mg,
82%). Alternatively, transformation of (R)-2d to the
a-amino ester was promoted by 5 mol % of Pd–C in
MeOH under a hydrogen atmosphere (1 atm) (91% yield).
¨
Stimulating Concepts in Chemistry; Vogtle, F., Stoddart, J. F.,
Shibasaki, M., Eds.; Wiley: New York, 2000. (c) Nelson, A.
Angew. Chem., Int. Ed. 1999, 38, 1583. (d) O’Donnell, M. J.
Aldrichimica Acta 2001, 34, 3. (e) Maruoka, K.; Ooi, T. Chem.
Rev. 2003, 103, 3013.
4. Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem.
Soc. 1984, 106, 446.
5. (a) O’Donnell, M. J.; Bennett, 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, 56, 5181.
(c) O’Donnell, M. J.; Wu, S. Tetrahedron: Asymmetry. 1992,
3, 591. (d) O’Donnell, M. J.; Wu, S.; Huffman, J. C.
Tetrahedron 1994, 50, 4507. (e) O’Donnell, M. J.; Delgado,
F.; Hostettler, C.; Schwesinger, R. Tetrahedron Lett. 1998, 39,
8775. (f) O’Donnell, M. J.; Delgado, F.; Pottorf, R. S.
Tetrahedron 1999, 55, 6347.
4.4. General procedure for the catalytic asymmetric
phase-transfer Michael addition using TaDiAS 3dd
under optimized conditions
Benzyl acrylate (11d, 20.3 mL, 0.23 mmol) was added to the
solution of 1 (44.2 mg, 0.15 mmol) and phase-transfer
catalyst (S,S)-TaDiAS 3dd (12.5 mg, 0.015 mmol) in
chlorobenzene (1.0 mL). The reaction mixture was stirred
at 230 8C for 20 min, and then Cs2CO3 (24.4 mg,
0.075 mmol) was added. The mixture was stirred vigorously
at the same temperature for 10 h. The reaction was
quenched by the addition of water and extracted with
Et2O (10 mL£3). The combined organic layers were
washed with brine (20 mL), dried over Na2SO4, and
concentrated. The residue was purified by flash column
chromatography (silica gel, 10% EtOAc in hexane) to
give (S)-12d (46.2 mg, 84%) as a colorless oil. Spectro-
scopic data of the alkylated products 2 were reported in
Ref. 21.
6. (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997,
119, 12414. (b) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron
Lett. 1998, 39, 5347. (c) Corey, E. J.; Bo, Y.; Busch-Peterson,
J. J. Am. Chem. Soc. 1998, 120, 13000.
7. (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38,
8595. (b) Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron
Lett. 1999, 40, 1385. (c) Lygo, B. Tetrahedron Lett. 1999, 40,
1389. (d) Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron
Lett. 1999, 40, 8671.
8. For selected examples of other important contributions in this
field, see: (a) Arai, S.; Shioiri, T. Tetrahedron Lett. 1998, 39,
2145. (b) Arai, S.; Hamaguchi, S.; Shioiri, T. Tetrahedron
Lett. 1998, 39, 2997. (c) Arai, S.; Tsuge, H.; Shioiri, T.
Tetrahedron Lett. 1998, 39, 7563. (d) Arai, S.; Shioiri, T.
Tetrahedron 2002, 58, 1407. (e) Arai, S.; Tsuge, H.; Oku, M.;
Miura, M.; Shioiri, T. Tetrahedron 2002, 58, 1623, and
references therein.
Acknowledgements
9. (a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999,
121, 6519. (b) Ooi, T.; Kameda, M.; Tannai, H.; Maruoka, K.
Tetrahedron Lett. 2000, 41, 8339. (c) Ooi, T.; Takeuchi, M.;
Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228.
(d) Ooi, T.; Takeuchi, M.; Ohara, D.; Maruoka, K. Synlett
2001, 7, 1185. (e) Ooi, T.; Kameda, M.; Maruoka, K. J. Am.
Chem. Soc. 2003, 125, 5139.
This work was supported by RFTF, Grant-in-Aid for
Encouragements for Young Scientists (A), and Grant-in-
Aid for Specially Promoted Research from Japan Society
for the Promotion of Science (JSPS). We thank Miss
Y. Akachi for the development of TaDiAS, Mrs
V. Gnanadesikan and T. Nemoto for the synthesis of
aeruginosins, and Prof. T. Okino and Mr T. Kisugi
(Hokkaido University) for biological studies of
aeruginosins.
10. For other examples, see (a) Belokon, Y. N.; Kochetkov, K. A.;
Churkina, T. D.; Ikonnikov, N. S.; Chesnokov, A. A.;
Larionov, O. V.; Singh, I.; Parmar, V. S.; Vyskocil, S.;
Kagan, H. B. J. Org. Chem. 2000, 65, 7041. (b) Belokon, Y. N.;

7754
T. Ohshima et al. / Tetrahedron 60 (2004) 7743–7754
Kochetkov, K. A.; Churkina, T. D.; Ikonnikov, N. S.;
20. When dimethyl acetal (R1¼R2¼Me) was used for catalyst
synthesis, a mixture of diammonium salt and monoammonium
salt was obtained due to low reactivity in the methylation step.
Therefore, screening of the aromatic moiety was difficult with
dimethyl acetal. Changing the acetal moiety solved this low
reactivity problem.
Larionov, O. V.; Harutyunyan, S. R.; Vyskocil, S.; North,
M.; Kagan, H. B. Angew. Chem., Int. Ed. 2001, 40, 1948.
(c) Kita, T.; Georgieva, A.; Hashimoto, Y.; Nakata, T.;
Nagasawa, K. Angew. Chem., Int. Ed. 2002, 41, 2832. (d) Arai,
S.; Tsuji, R.; Nishida, A. Tetrahedron Lett. 2002, 43, 9535.
(e) Mase, N.; Ohno, T.; Hoshikawa, N.; Ohishi, K.; Morimoto,
H.; Yoda, H.; Takabe, K. Tetrahedron Lett. 2003, 44, 4073.
21. Absolute configurations of the products 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. 6a.
11. Shibuguchi, T.; Fukuta, Y.; Akachi, Y.; Sekine, A.; Ohshima,
T.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 9539.
12. (a) Ohshima, T.; Gnanadesikan, V.; Shibuguchi, T.; Fukuta,
Y.; Nemoto, T.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125,
11206. see also Supporting Information. (b) Fukuta, Y.;
Ohshima, T.; Gnanadesikan, V.; Shibuguchi, T.; Nemoto, T.;
Kisugi, T.; Okino, T.; Shibasaki, M. Proc. Natl. Acad. Sci.,
USA 2004, 101, 5433.
22. In the case of phase-transfer Michael additions, halobenzenes
had better selectivity than other aromatic solvents, such as
benzene and toluene. Although 1,2,4-trichlorobenzene gave
the best selectivity, we eventually selected chlorobenzene
based on the reactivity.
23. Because of the relatively high melting point of chlorobenzene
(245 8C), 230 8C should be the lowest temperature used in
this system. Other solvents, such as toluene, had worse
selectivity.
13. For recent reviews, see: (a) Shibasaki, M. In Stimulating
¨
Concepts in Chemistry; Vogtle, F., Stoddart, J. F., Shibasaki,
M., Eds.; Wiley: New York, 2000. (b) Shibasaki, M.;
Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
24. Based on LC-ESI Mass, 1H NMR, and TLC analysis. See also
14. For example, (Sigma-Aldrich Co., St. Louis, MO), L-tartaric
acid: 100 g, 4100 yen (ca. $ 33), diethyl L-tartrate: 100 g, 8600
yen (ca. $ 70), quinine: 100 g, 78000 yen (ca. $ 640), and (R)-
BINOL: 100 g, 783000 yen (ca. $ 6420).
15. Computational simulation was performed with Cerius2
(Accelrys Inc., San Diego, CA, and Cambridge, UK). The
conformation depicted in Figure 2 was obtained using a
random conformational search, the so-called Monte Carlo
method, followed by a molecular mechanics minimization
calculation (Universal Force Field v.1.02, see: Rappe, A. K.;
Casewit, C. J.; Colwell, K. S.; Goddard, W.A., III; Skiff, W. M.
J. Am. Chem. Soc. 1992, 114, 10024).
Section 4.
25. (a) Murakami, M.; Okita, Y.; Matsuda, H.; Okino, T.;
Yamaguchi, K. Tetrahedron Lett. 1994, 35, 3129. (b) Matsuda,
H.; Okino, T.; Murakami, M.; Yamaguchi, K. Tetrahedron
1996, 52, 14501.
26. For previous syntheses of aeruginosin 298-A, see: (a) Valls,
´
N.; Lopez-Canet, M.; Vallribera, M.; Bonjoch, J. J. Am. Chem.
Soc. 2000, 122, 11248. (b) Wipf, P.; Methot, J.-L. Org. Lett.
2000, 2, 4213.
27. (a) Nemoto, T.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc.
2001, 123, 9474. (b) Nemoto, T.; Tosaki, S.-y.; Ohshima, T.;
Shibasaki, M. Chirality 2003, 15, 306. (c) Ohshima, T.;
Nemoto, T.; Tosaki, S.-y.; Kakei, H.; Gnanadesikan, V.;
Shibasaki, M. Tetrahedron 2003, 59, 10485.
16. For a general review of TADDOL, see: Seebach, D.; Beck,
A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 40, 92.
17. Although TADDOL promotes asymmetric phase-transfer
alkylation of aldimine, it is not effective for alkylation of
ketimine. See Ref. 10a.
18. Both enantiomers of TaDiAS 3p (R1¼t-Bu, R2¼Me,
Ar¼C6H4-4-OMe, X2¼I2) and 3dd (R1¼R2¼Pr, Ar¼C6H4-
4-Me, X2¼BF24 ) are now commercially available from Wako
Pure Chemical Industries, Ltd., Japan (fax: þ81-120-052-806;
e-mail: labchem-tec@wako-chem.co.jp) [Catalog No. 201-
16141 for (R,R)-3p, 208-16151 for (S,S)-3p, 205-16161 for
(R,R)-3dd, and 202-16171 for (S,S)-3dd].
28. (a) Baba, N.; Oda, J.; Kawaguchi, M. Agric. Biol. Chem. 1986,
50, 3113. (b) Jew, S.; Jeong, B.-S.; Yoo, M.-S.; Huh, H.; Park,
H. Chem. Commun. 2001, 1244. (c) Park, H.; Jeong, B.-S.;
Yoo, M.-S.; Park, M.; Huh, H.; Jew, S. Tetrahedron Lett. 2001,
42, 4645. (d) Park, H.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.;
Park, M.; Lee, Y.-J.; Kim, M.-J.; Jew, S. Angew. Chem., Int.
Ed. 2002, 41, 3036.
29. (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1988, 27, 994.
(b) Reetz, M. T.; Hu¨tte, S.; Goddard, R. J. Am. Chem. Soc.
1993, 115, 9339. (c) Reetz, M. T.; Hu¨tte, S.; Goddard, R.;
Robyr, C. Chem. Eur. J. 1996, 2, 382. (d) Cannizzaro, C. E.;
Houk, K. N. J. Am. Chem. Soc. 2002, 124, 7163.
19. For the purpose of catalyst screening, the described reaction
conditions were selected based on reaction time. In pre-
liminary studies, toluene gave the best selectivity and CH2Cl2
gave the best reactivity in phase-transfer alkylations. Finally,
addition of CH2Cl2 to toluene (toluene/CH2Cl2 ¼7:3)
enhanced reactivity efficiently without loss of selectivity.
30. Nagasawa et al. and Takabe et al. also proposed the Z-enolate
complex with a chiral ammonium cation. See Ref. 10c,e.