Asymmetric transfer hydrogenation in aqueous media catalyzed by resin-supported peptide having a polyleucine tether

Article abstract of DOI:10.1016/j.tetasy.2009.02.036

A resin-supported N-terminal prolyl peptide having a β-turn motif and a polyleucine tether has been developed for the organocatalytic asymmetric transfer hydrogenation under aqueous conditions. Polyleucine accelerated the reaction in a highly enantioselective manner by providing a hydrophobic microenvironment around the prolyl residue. The investigation of catalyst structures indicates that the l-form of polyleucine is essential for both reaction efficiency and enantioselectivity.

Full text of DOI:10.1016/j.tetasy.2009.02.036

Tetrahedron: Asymmetry 20 (2009) 461–466
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric transfer hydrogenation in aqueous media catalyzed
by resin-supported peptide having a polyleucine tether
*
Kengo Akagawa, Hajime Akabane, Seiji Sakamoto, Kazuaki Kudo
Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A resin-supported N-terminal prolyl peptide having a b-turn motif and a polyleucine tether has been
developed for the organocatalytic asymmetric transfer hydrogenation under aqueous conditions. Polyleu-
cine accelerated the reaction in a highly enantioselective manner by providing a hydrophobic microen-
Received 7 January 2009
Accepted 2 February 2009
Available online 25 March 2009
vironment around the prolyl residue. The investigation of catalyst structures indicates that the
of polyleucine is essential for both reaction efficiency and enantioselectivity.
L-form
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
There are several reports on the organocatalytic asymmetric
transfer hydrogenation of
a,b-unsaturated aldehydes using
Biochemical transformations are catalyzed by enzymes. The
structural feature of most enzymes is that they have a hydrophobic
cavity which enables a stereoselective reaction with high efficiency
under aqueous conditions in living cells. Such an inner hydropho-
bic pocket is realized by an outer higher-order structure of an
appropriately folded peptide chain.
NADH-like Hantzsch esters as a reductant.9 The reaction proceeds
through the formation of an iminium ion intermediate between a
substrate enal and a secondary amine catalyst followed by hydride
transfer from the Hantzsch ester. To date, all the reported reduc-
tions of this type have been performed in organic solvents.9–11 Re-
cently, we have demonstrated the first example of an asymmetric
transfer hydrogenation in aqueous media by employing a resin-
supported peptide catalyst.12 The catalyst consists of a terminal
Recently, increasing attention has been paid to the research
area of organocatalysts.1 Small peptides, which can be considered
as simplified enzymes, have also been used for organocatalytic
reactions. After the proline-catalyzed intermolecular asymmetric
aldol reaction was reported by List,2 both N-terminal prolyl-3 and
N-terminal primary amino4 peptides have been explored to im-
prove catalytic activity. Most of the reported peptide catalysts have
relatively simple structures, typically consisting of a few residues,
and there are only a limited number of examples of well-designed
peptide catalysts incorporated with a secondary structure such as
five-residue peptide Pro-D-Pro-Aib-Trp-Trp, which is important
for high asymmetric induction, and hydrophobic polyleucine chain,
which accelerates the reaction by gathering substrates and sup-
ports the structure of the terminal sequence. Herein, we report a
full account of that work.
2. Results and discussion
an
a
-helix for asymmetric organocatalytic reactions.5
On the other hand, organocatalytic reactions in water or aque-
The efficiency of the reduction of (E)-3-phenylbut-2-enal with
Hantzsch ester 1 in THF/H2O = 2/1 (v/v) was examined using pro-
line-based catalysts (Table 1). Although simple proline salt is re-
ported to moderately promote the reaction in toluene (47%
conversion after 5 h),9c the salt showed almost no catalytic activity
under the present aqueous conditions (entry 1). This indicates that
water has an inhibitory effect for the proline-catalyzed reduction.
We thought that attaching a hydrophobic moiety to the catalyst
would circumvent this problem. Polyethyleneglycol grafted on
cross-linked polystyrene (PEG-PS) resin13 has been claimed to be
an effective solid-support for palladium-catalysts that work under
aqueous conditions.14 Therefore, PEG-PS-supported proline salt
was tested, however, it did not provide any enhancement for the
reaction (entry 2). In order to generate a hydrophobic microenvi-
ronment proximate to the prolyl residue, a polyleucine chain was
introduced between the proline and the resin. Resin-bound
polyleucine can be easily prepared through the ring-opening
ous media are of interest because such systems are relevant to
enzymatic reactions under physiological conditions. As for the cat-
alysts in aqueous reactions, those having a highly hydrophobic
moiety seem promising. They are expected to construct a hydro-
phobic environment where organic substrates and reagents are
concentrated near a catalytically active site in an aqueous environ-
ment. So far, surfactant type,6 dendrimer type,3h,7 and solid-sup-
ported type3e,8 catalysts have been reported mainly for
asymmetric aldol and Michael reactions under aqueous conditions.
A peptide can be an attractive candidate for such a class of catalysts
provided that a catalytically active site is supported appropriately
by a hydrophobic peptide segment.
* Corresponding author. Tel.: +81 3 5452 6357; fax: +81 3 5452 6359.
E-mail address: kkudo@iis.u-tokyo.ac.jp (K. Kudo).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.036

462
K. Akagawa et al. / Tetrahedron: Asymmetry 20 (2009) 461–466
Table 1
Table 2
Transfer hydrogenation in aqueous media
Effect of the length of polyleucine chain
Entry
n
Conversiona (%)
eeb (%)
1
7.5
21
40
46
63
60
7
19
24
24
25
2
3
4
5
14.8
20.2
25.4
42.2
Entry
Catalysta
Proline
Solvent
Conversionb (%)
eec (%)
n.d.
1
2
THF/H2O = 2/1
THF/H2O = 2/1
3
3
n.d.
a
Estimated by 1H NMR of the crude mixture.
Determined by chiral HPLC analysis of the corresponding alcohol after NaBH4
b
3
4
5
6
THF/H2O = 2/1
THF/H2O = 2/1
THF/H2O = 2/1
THF/H2O = 1/2
THF/H2O = 1/2
3
n.d.
27
reduction in EtOH.
21
1
Hantzsch ester, and the catalyst.16 The reaction proceeded
smoothly even in the absence of the solid support (entry 7). How-
ever, in this case, removal of the catalyst from the reaction mixture
was laborious because the aggregating nature of the hydrophobic
catalyst led to the formation of a gel. This observation demon-
strates the superiority of the PEG-PS-immobilized catalyst.17 Fur-
thermore, there are additional merits for the resin-supported
peptide catalyst: (1) a purification process in catalyst preparation
can be omitted, (2) a catalyst can be readily removed from a reac-
tion mixture by filtration, and (3) fine-tuning of a peptide catalyst
could be accomplished through well-established solid-phase pep-
tide synthesis.18
The effect of a polyleucine chain was investigated in relation
with the reaction rate (Table 2). The length of the polyleucine
tether and the reaction efficiency were positively correlated up
to about 25 leucine residues (entries 1–4), but further extension
of the chain did not improve the reaction rate any more (entry 5).
Next, terminal peptide sequences were surveyed from the as-
pect of stereoselectivity (Table 3). Enantioselectivity in this reac-
tion is governed by the geometry of the iminium ion
intermediate and by the facial selectivity of the nucleophilic attack
by Hantzsch ester 1. The latter factor should be controlled by the
steric constraints of a peptide chain next to the prolyl group. Inser-
tion of an amino acid having a bulky side chain such as Phe, Tyr, or
n.d.
24
63
70
7
Pro-(Leu)28.8–NH-n-Butyl
21
a
The symbol
denotes PEG-PS resin.
Estimated by 1H NMR of the crude mixture.
b
c
Determined by chiral HPLC analysis of the corresponding alcohol after NaBH4
reduction in EtOH.
polymerization of leucine-N-carboxyanhydride (NCA) initiated by
a terminal amino group on PEG-PS resin.15 The catalyst having
25.4 leucine residues on average successfully promoted the reac-
tion (entry 4), while the catalyst having only two leucine residues
did not show any improvement (entry 3). Deca-phenylalanine was
also tried as a hydrophobic segment for the prolyl catalyst. In this
case, the reaction hardly proceeded in spite of its high hydropho-
bicity (entry 5). This indicates that the steric hinderance of the
deca-phenylalanine moiety severely prevented the reaction and
that a hydrophobic part is required so as not to hinder the terminal
active site. It is noteworthy that the reaction was considerably
accelerated when the ratio of water in the solvent system was in-
creased from THF/H2O = 2/1 to 1/2 (entry 6), presumably because
of an intensified hydrophobic interaction among the aldehyde,
Table 3
Optimization of terminal peptide sequence
Entry
Peptide
Conversiona (%)
eeb (%)
Abs. config.c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Pro-Phe
Pro-Tyr
Pro-Trp
68
22
53
35
20
30
45
26
35
19
21
34
36
4
33
45
45
60
47
32
29
41
29
48
20
55
62
77
87
91
89
R
R
R
S
R
S
R
S
S
D
-Pro-Trp
Pro- -Trp
-Pro- -Trp
Pro-Trp- -Leu
-Pro-Trp- -Leu
-Pro-Trp-Trp
-Pro-Trp- -Trp
D
D
D
D
D
D
D
D
D
S
Pro-Pro
Pro- -Pro-Trp
-Pro-Pro-Trp
R
R
S
R
R
R
R
D
D
Pro-
Pro-
Pro-
Pro-
D
D
D
D
-Pro-Aib
-Pro-Aib-Trp
-Pro-Aib-Trp-Trp (6)
-Pro-Aib-Trp-Trp-Trp
7
13
12
a
Estimated by 1H NMR of the crude mixture.
Determined by chiral HPLC analysis of the corresponding alcohol after NaBH4 reduction in EtOH.
Absolute configuration of the major product.
b
c

K. Akagawa et al. / Tetrahedron: Asymmetry 20 (2009) 461–466
463
Trp between the proline and the polyleucine tether brought about
somewhat enhanced selectivity (entries 1–3). Exchanging -Pro
with -Pro in Pro-Trp sequence afforded improved enantioselectiv-
ity along with the reversal of the absolute configuration of the ma-
jor product (entry 4). In contrast, the displacement of -Trp by
Trp in Pro-Trp sequence did not show a significant improvement
(entry 5). Although -Pro-Trp and Pro- -Trp are antipodal to each
hyde 2g showed excellent enantioselectivity (entry 8) even though
the substrate was used as a mixture of diastereomers (E/Z = 2/1).22
Such an enantioconvergence has been also observed by other
groups, and the reactions were considered to proceed through E/
Z isomerization of enals prior to the face selective hydrogenation
of the E-enals.9b,c This might be the case for the present result.
The reuse of solid-supported catalyst 6 recovered by filtration after
the reaction resulted in a somewhat decreased isolated yield,
although the enantioselectivity was maintained (entry 3).23
L
D
L
D-
D
D
other, the absolute values of ee’s in entries 4 and 5 are quite differ-
ent. Such a difference was also observed between the catalyst hav-
ing Pro-Trp (entry 3) and
D-Pro-D-Trp (entry 6) termini. These
results mean that while enantioselectivity depends mainly on the
structure of the terminal sequence, the polyleucine moiety partic-
ipates in the stereochemical course of this catalytic reaction to
some extent. To achieve higher enantioselectivity, various combi-
Table 5
Substrate scope
nations of the L/D forms of Pro/Trp/Leu were examined. However,
such an approach did not provide a significant enhancement in
selectivity (entries 7–13).19
Entry
1
R
Yielda (%)
75
eeb (%)
Then,
introduced into the N-terminal of the polyleucine moiety. A pep-
tide including a -Pro-Aib sequence is known to form a b-turn
D-Pro-Aib (Aib: 2-aminoisobutyric acid), a turn motif, was
a
90 (R)c
D
structure in organic solvents through an intramolecular hydrogen
bond.20 Miller et al. showed that this b-turn motif can be success-
fully applied to the design of peptide-based asymmetric catalysts
2
b
71
94
working in nonpolar solvents.21 We anticipated that a
D
-Pro-Aib se-
quence combined with hydrophobic polyleucine chain should also
provide b-turn structure even in aqueous media. Inserting -Pro-
Aib between the terminal -prolyl group and polyleucine tether
3
4
b
c
(reuse of catalyst)
65
76
95
D
L
95d
turned out to be quite effective for enhancing the selectivity (entry
14). Furthermore, the incorporation of one or two Trp residue(s)
into the peptide at the C-terminal site of Aib afforded even higher
enantioselectivity (entries 15 and 16), while the insertion of three
tryptophans did not bring about an additional improvement (entry
17).
By using highly enantioselective catalyst 6, the effect of the con-
tent of water in the solvent system was examined (Table 4). By
increasing the ratio of water up to THF/H2O = 1/2, the reaction
was accelerated without loss of enantioselectivity (entries 1–3).
The reactions in even more water-rich solvents did not give a bet-
ter result probably because of the limited solubility of Hantzsch es-
ter 1 in water (entries 4 and 5).
Some typical unsaturated aldehydes were examined in this
aqueous reaction system (Table 5). Reactions were performed in
the presence of 20 mol % of catalyst 6 TFA salt with 1.2 equiv of
Hantzsch ester 1 in THF/H2O = 1/2. Aldehydes 2a–e having aro-
matic groups of various sizes and electronic natures gave good
yields and high levels of enantioselectivity (entries 1, 2, 4–6). Alde-
hyde 2f possessing an ortho chloro group was hardly converted to
3f probably because of steric hindrance (entry 7). Aliphatic alde-
5
d
e
72
69
95e
93e
6
7
f
<1
53
n.d.
8f
g
96g (S)e
a
Isolated yield.
b
Unless otherwise noted, determined by chiral HPLC analysis of the corre-
sponding alcohol after NaBH4 reduction.
c
Absolute configuration of the major product.
Determined by 1H NMR in the presence of Eu(hfc)3 as the chiral shift reagent
d
after NaBH4 reduction.
Determined by 1H NMR after NaBH4 reduction and derivatization of the cor-
e
responding alcohol to the Mosher ester with (À)-MTPA–Cl.
f
E/Z mixture of 2g was used as a starting material (E/Z = 2/1). Reaction time was
10 h.
g
After NaBH4 reduction, ee of the corresponding alcohol was determined
Table 4
according to the literature.
Effect of the ratio of water
To clarify the roles of the polyleucine tether in the catalytic pro-
cess under aqueous conditions, the optimized catalyst 6, a catalyst
without a polyleucine chain 7, and a catalyst having an antipode
peptide at the terminal active site 8 were tested for the reduction
in THF and in THF/H2O = 1/2, respectively (Table 6). Catalyst 6
showed high efficiency and selectivity both in THF and in aqueous
media (entries 1 and 4). This indicates that the polyleucine tether
works appropriately in aqueous media through providing a hydro-
phobic environment for the efficient reaction and keeping the ste-
reostructure of the terminal peptide similar to that in THF.24
Catalyst 7 showed the moderate reaction rate and high enantiose-
lectivity in THF (entry 2). However, significant decreases in reactiv-
ity and selectivity were observed in THF/H2O = 1/2 (entry 5).
Entry
Solvent
Conversiona (%)
eeb (%)
1
2
3
4
5
THF/H2O = 2/1
THF/H2O = 1/1
THF/H2O = 1/2
THF/H2O = 1/4
H2O
13
48
75c
74
29
91
91
91
89
82
a
Estimated by 1H NMR of the crude mixture.
Determined by chiral HPLC analysis of the corresponding alcohol after NaBH4
b
reduction in EtOH.
c
Isolated yield of 3 was 50%.

464
K. Akagawa et al. / Tetrahedron: Asymmetry 20 (2009) 461–466
Without a polyleucine tether, the inhibitory effect of water could
not be suppressed, and the structure of the catalytically active site
was considered to be disturbed in aqueous media because the
intramolecular hydrogen bond to retain a rigid b-turn structure
can be weakened by water molecules. With catalyst 8, only low
reactivity and selectivity were attained both in THF and in aqueous
media (entries 3 and 6). Theoretically, to realize highly enantiose-
lective and efficient reaction, one stereotopic face of the intermedi-
ate iminium ion should be shielded by peptide residues and the
other face be open to the attack of Hantzsch ester 1. In this case,
the polyleucine chain might cover the stereotopic face needed to
be accessible by the reducing agent, leading to the low conversion
accompanied by decreased selectivity.
Table 6
Effect of catalyst structure and solvent
Figure 1. IR spectra of resin-supported peptide catalysts in CH2Cl2. (a) Pro-
(Leu)25.4-PEG-PS, (b) Pro-
(Leu)25.4-PEG-PS.
D-Pro-Aib-Trp-Trp-PEG-PS, and (c) Pro-D-Pro-Aib-Trp-Trp-
Entry
Catalyst
Solvent
Conversiona (%)
eeb (%)
Abs. config.c
1
2
3
4
5
6
6
7
8
6
7
8
THF
THF
THF
THF/H2O = 1/2
THF/H2O = 1/2
THF/H2O = 1/2
89
51
24
75
17
20
88
86
59
91
64
52
R
R
S
R
R
S
a
Estimated by 1H NMR of the crude mixture.
Determined by chiral HPLC analysis of the corresponding alcohol after NaBH4
b
reduction in EtOH.
c
Absolute configuration of the major product.
Figure 2. IR spectra of resin-supported peptide catalysts in CH2Cl2/DMSO = 9/1. (a)
Pro-(Leu)25.4-PEG-PS, (b) Pro-
Trp-(Leu)25.4-PEG-PS.
D-Pro-Aib-Trp-Trp-PEG-PS, and (c) Pro-D-Pro-Aib-Trp-
To obtain insights into the structures of the peptide catalysts, IR
spectra of 4, 6, and 7 were measured. The N–H stretch region of re-
sin-supported peptides swollen in CH2Cl2 and in CH2Cl2/DMSO = 9/
1 is shown in Figures 1 and 2, respectively. Polyleucine-tethered
prolyl catalyst 4 in CH2Cl2 showed a band at around 3300 cmÀ1
arising from an N–H stretch involved in typical amide-to-amide
hydrogen bonds (Fig. 1a).25 This is consistent with the fact that
lute configuration of the major product obtained with catalyst 6
can be accounted for by a stereochemical model of the iminium
intermediate formed between a catalyst and an
a,b-unsaturated
aldehyde, which is considered to adopt an E-configuration.9 Han-
tzsch ester 1 approaches to activated aldehyde 2a from the less
hindered Si face because the b-turn peptide residues effectively
shields the Re face (Fig. 3). The IR spectra of catalyst 8 were almost
identical with the ones of catalyst 6 both in CH2Cl2 and in CH2Cl2/
DMSO = 9/1, suggesting that catalyst 8 also has a strong b-turn
polyleucine forms a stable
a-helix through strong intramolecular
hydrogen bonds.26 Catalyst 7 having the terminal peptide without
polyleucine gave a slightly higher energy band which can be as-
signed to an N–H stretch involved in a b-turn hydrogen bond
(Fig. 1b).25 The spectrum of polyleucine-tethered peptide catalyst
6 also shifted to higher energy compared to that of 4 (Fig. 1c),
implying that the terminal peptide of 6 formed a b-turn which is
supported by an
model of the intermediate formed with the catalyst having the ter-
minal peptide and -Leu residues shows that both the sides of the
a-helix structure of polyleucine. However, the
D
supported by an
a-helix structure of polyleucine. Adding 10%
aldehyde are shielded by the peptide residues (Fig. 4). This explains
the low reactivity and selectivity when catalyst 8 was used for the
reaction (entries 3 and 6 in Table 6).
DMSO, a strong hydrogen bond breaker, decreased the absorbance
of 7 to the baseline level (Fig. 2b). In this solvent system, the struc-
ture of the independent b-turn peptide was considered to be dis-
rupted, whereas the band around 3300 cmÀ1 of 4 attributed to a
rigid
a-helix was maintained (Fig. 2a). Interestingly, the shape of
3. Conclusion
the band of 6 in CH2Cl2/DMSO = 9/1 was almost identical with
the one in CH2Cl2 (Fig. 2c). These observations indicate that the ter-
minal b-turn peptide combined with polyleucine chain has stron-
ger structural rigidity than the one having no adjacent
polyleucine tether. This coincides with the results in enantioselec-
tivity of the reactions using catalysts 6 and 7 under aqueous and
non-aqueous conditions (entries 1, 2, 4, and 5 in Table 6). The abso-
In conclusion, the asymmetric transfer hydrogenation in aque-
ous media was attained using the resin-supported peptide catalyst
having a polyleucine tether. Polyleucine played essential roles for
both reaction efficiency and stereoselectivity by providing a hydro-
phobic microenvironment at the reaction center and maintaining
the terminal peptide structure. This study demonstrates that sup-

K. Akagawa et al. / Tetrahedron: Asymmetry 20 (2009) 461–466
465
intermediate formed between 2a and Pro-
D
-Pro-Aib-(Trp)2-(
L
- or
D-Leu)6-NH2 was calculated by the MM2 method. As an initial
structure, the oligoleucine part of this intermediate was assumed
to have an
a-helix structure according to the present IR data and
the previous reports on oligoleucine derivatives.26
Acknowledgment
This work was supported in part by Global COE Program, Chem-
istry Innovation through Cooperation of Science and Engineering,
MEXT, Japan.
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Eur. J. Org. Chem. 2007, 4688; (e) Gruttadauria, M.; Giacalone, F.; Marculescu, A.
M.; Noto, R. Adv. Synth. Catal. 2008, 350, 1397.
9. (a) Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. Angew. Chem., Int. Ed. 2004,
43, 6660; (b) Yang, J. W.; Hechavarria Fonseca, M. T.; Vignola, N.; List, B. Angew.
Chem., Int. Ed. 2005, 44, 108; (c) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2005, 127, 32; (d) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006,
45, 4193; (e) Tuttle, J. B.; Ouellet, S. G.; MacMillan, D. W. C. J. Am. Chem. Soc.
2006, 128, 12662; (f) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368.
10. Other examples of catalytic asymmetric reductions using Hantzsch esters: (a)
Rueping, M.; Sugiono, E.; Azap, C.; Theissman, T.; Bolte, M. Org. Lett. 2005, 7,
3781; (b) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed. 2005, 44,
7424; (c) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc.
2006, 128, 84; (d) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem.,
Int. Ed. 2006, 45, 3683; (e) Rueping, M.; Antonchick, A. P.; Theissmann, T.
Angew. Chem., Int. Ed. 2006, 45, 6751; (f) Hoffmann, S.; Nicoletti, M.; List, B. J.
Am. Chem. Soc. 2006, 128, 13074; (g) Li, G.; Liang, Y.; Antilla, J. C. J. Am. Chem.
Soc. 2007, 129, 5830; (h) Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed.
2007, 46, 4562; (i) Kang, Q.; Zhao, Z.-A.; You, S.-L. Adv. Synth. Catal. 2007, 349,
1657; (j) Martin, N. J. A.; Ozores, L.; List, B. J. Am. Chem. Soc. 2007, 129, 8976; (k)
Guo, Q.-S.; Du, D.-M.; Xu, J. Angew. Chem., Int. Ed. 2008, 47, 759; (l) Metallinos,
C.; Barrett, F. B.; Xu, S. Synlett 2008, 720; (m) Rueping, M.; Theissmann, T.; Raja,
S.; Bats, J. W. Adv. Synth. Catal. 2008, 350, 1001.
Figure 4. Plausible structure of the iminium intermediate formed between 2a and
Pro- -Pro-Aib-(Trp)2-( -Leu)6-NH2.
D
D
porting a catalytically active peptide with a hydrophobic peptide
segment can be a powerful strategy for developing a newly de-
signed biomimetic catalyst. Currently, applications of the present
catalyst for other organocatalytic reactions in aqueous media and
an asymmetric reduction in complete water system27 are under
investigation in our laboratory.
4. Experimental
Preparation of peptide catalysts and general procedure for the
asymmetric transfer hydrogenation were previously reported.12
IR spectra of catalysts were recorded on a JASCO FT/IR-4100 spec-
trometer after resins were swollen in CH2Cl2 or in CH2Cl2/
DMSO = 9/1 on NaCl plates. A plausible structure of the iminium
11. Examples of reductions using Hantzsch esters incorporated in sequential
reactions: (a) Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. J. Am. Chem. Soc.
2005, 127, 15036; (b) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2005, 127, 15051; (c) Zhao, G.-L.; Córdova, A. Tetrahedron Lett.
2006, 47, 7417; (d) Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2008,
47, 5836.

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K. Akagawa et al. / Tetrahedron: Asymmetry 20 (2009) 461–466
12. Akagawa, K.; Akabane, H.; Sakamoto, S.; Kudo, K. Org. Lett. 2008, 10, 2035.
13. PEG-PS resin is compatible with a variety of solvents, including water, by
virtue of its amphiphilic nature: Bayer, E. Angew. Chem., Int. Ed. 1991, 30,
113.
21. (a) Miller, S. J. Acc. Chem. Res. 2004, 37, 601; (b) Blank, J. T.; Miller, S. J.
Biopolymers 2006, 84, 38; (c) Linton, B. R.; Reutershan, M. H.; Aderman, C. M.;
Richardson, E. A.; Brownell, K. R.; Ashley, C. W.; Evans, C. A.; Miller, S. J.
Tetrahedron Lett. 2007, 48, 1993.
14. Nakai, Y.; Uozumi, Y. Org. Lett. 2005, 7, 291. and references cited therein.
15. To construct a hydrophobic polymer, leucine is a suitable amino-acid monomer
because it is highly hydrophobic and its NCA has high reactivity. Simple
polyleucine has been used as a catalyst for the Juliá-Colonna epoxidation. For a
review, see: Porter, M. J.; Roberts, S. M.; Skidmore, J. Bioorg. Med. Chem. 1999, 7,
2145.
16. When (R)-2-(tert-butyl)-3-methyl-4-imidazolidinone salt (ref 9c) was used as
a catalyst, the conversion and enantioselectivity were moderate under aqueous
conditions and the remarkable acceleration of the reaction by increasing the
ratio of water was not observed (in THF/H2O = 2/1, 42% conversion and 60% ee;
in THF/H2O = 1/2, 44% conversion and 59% ee).
22. Substrates 2a–f were only the E isomers.
23. The further reuse of the catalyst drastically decreased the isolated yield (34%
yield, 95% ee in the second reuse).
24. To prove that each supported peptide functions independently but not
cooperatively with an adjacent peptide, catalyst 6 with a higher density of
peptides in the PEG-PS resin was also examined. The high-density catalyst was
synthesized using TentaGel S-NH2 (Fluka) with 0.46 mmol/g amine loading,
while in other experiments TentaGel with 0.26 mmol/g amine loading was
used as
a PEG-PS resin. If some peptide chains worked collaboratively,
increasing the density of peptides would have enhanced the reaction rate in
spite of the same amount of the total peptides. But such an enhancement was
not observed with the high-density catalyst (71% conversion and 91% ee in
THF/H2O = 1/2).
17. Resin supported polyleucine was also used in the Juliá-Colonna epoxidation for
an operational advantage and a straightforward reuse of the catalyst: Itsuno,
S.; Sakakura, M. J. Org. Chem. 1990, 55, 6047.
25. Haque, T. S.; Little, J. C.; Gellman, S. H. J. Am. Chem. Soc. 1996, 118, 6975.
26. (a) Ostroy, S. E.; Lotan, N.; Ingwall, R. T.; Scheraga, H. A. Biopolymers 1970, 9,
749; (b) Flood, R. W.; Geller, T. P.; Petty, S. A.; Roberts, S. M.; Skidmore, J.; Volk,
M. Org. Lett. 2001, 3, 683; (c) Kelly, D. R.; Bui, T. T. T.; Caroff, E.; Drake, A. F.;
Roberts, S. M. Tetrahedron Lett. 2004, 45, 3885.
27. Recently, a non-asymmetric reduction under aqueous conditions using the
analogue of Hantzsch ester 1, 1,4-dihydropyridine-3,5-dicarboxylic acid, which
can avoid the problem of insolubility of 1 in water, was reported; Brogan, A. P.;
Dickerson, T. J.; Janda, K. D. Chem. Commun. 2007, 4952.
18. Fields, G. B.; Noble, R. L. Int. J. Pept. Protein Res. 1990, 35, 161.
19. Other organic cosolvents were examined instead of THF in the case of using the
catalyst of entry 4, but the enantioselectivity was not improved (59% ee in
DFM/H2O, 55% ee in CH3CN/H2O). Changing an acid which forms an
ammonium salt with terminal proline from TFA to (+)- or (À)-
camphorsulfonic acid (CSA) in the catalyst of entry 4 also did not improve
selectivity (53% ee with (+)-CSA, 52% ee with (À)-CSA).
20. Copeland, G. T.; Jarvo, E. R.; Miller, S. J. J. Org. Chem. 1998, 63, 6784.