Organocatalytic asymmetric transfer hydrogenation in aqueous media using resin-supported peptide having a polyleucine tether

Article abstract of DOI:10.1021/ol800031p

A resin-supported N-terminal prolyl peptide having a β-turn motif and hydrophobic polyleucine chain effectively catalyzed the asymmetric transfer hydrogenation under aqueous conditions. The polyleucine tether provides a hydrophobic cavity in aqueous media that brought about a remarkable acceleration of the reaction. In addition, the polyleucine chain also turned out to be essential for high enantioselectivity.

Full text of DOI:10.1021/ol800031p

ORGANIC
LETTERS
2008
Vol. 10, No. 10
2035-2037
Organocatalytic Asymmetric Transfer
Hydrogenation in Aqueous Media Using
Resin-Supported Peptide Having a
Polyleucine Tether
Kengo Akagawa, Hajime Akabane, Seiji Sakamoto, and Kazuaki Kudo*
Institute of Industrial Science, UniVersity of Tokyo, 4-6-1 Komaba, Meguro-ku,
Tokyo 153-8505, Japan
kkudo@iis.u-tokyo.ac.jp
Received March 5, 2008
ABSTRACT
A resin-supported N-terminal prolyl peptide having a ꢀ-turn motif and hydrophobic polyleucine chain effectively catalyzed the asymmetric
transfer hydrogenation under aqueous conditions. The polyleucine tether provides a hydrophobic cavity in aqueous media that brought about
a remarkable acceleration of the reaction. In addition, the polyleucine chain also turned out to be essential for high enantioselectivity.
In the body of living organisms, various reactions are cat-
alyzed under aqueous conditions by naturally refined en-
zymes having inner hydrophobic catalytic active sites and
outer hydrophilic peripheries. The hydrophobic cavities of
enzymes play essential roles in accelerating reactions through
the capture of organic substrates as well as in achieving
highly stereoselective reactions.
catalytic active site. So far, several well-designed asymmetric
organocatalysts focusing on surfactant type,2 dendrimer type,3
and solid support type4 catalysts have been reported mainly for
aldol or Michael reactions.
Among a great many reports on organocatalytic reac-
tions, asymmetric transfer hydrogenation of unsaturated
aldehydes using NADH-like Hantzsch ester5 is of interest
because this reaction seems to mimic biochemical reduc-
tions. The reaction is considered to proceed through the
iminium ion formation between the secondary ammonium
On the other hand, an increasing attention has been paid to
asymmetric organocatalysts in recent years.1 Although the
majority of the organocatalytic reactions have been performed
in organic solvents, such reactions in water or aqueous media
are of interest because of their relevance to reactions in living
cells. In order to perform reactions in water or aqueous media,
it would be effective to construct a hydrophobic space where
organic substrates and reagents are concentrated near the
(2) (a) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka,
F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128, 734. (b) Hayashi, Y.;
Aratake, S.; Okano, T.; Takahashi, J.; Sumiya, T.; Shoji, M. Angew. Chem.,
Int. Ed. 2006, 45, 5527. (c) Luo, S.; Mi, X.; Liu, S.; Xu, H.; Cheng, J.-P.
Chem. Commun. 2006, 3687.
(3) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8,
4417.
(1) For reviews, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2001, 40, 3726. (b) List, B. Tetrahedron 2002, 58, 5573. (c) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (d) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (e) Alma¸i, D.;
Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007, 18, 299. (f)
Pellissier, H. Tetrahedron 2007, 63, 9267.
(4) (a) Akagawa, K.; Sakamoto, S.; Kudo, K. Tetrahedron Lett. 2005,
46, 8185. (b) Font, D.; Jimeno, C.; Perica`s, M. A. Org. Lett. 2006, 8, 4653.
(c) Giacalone, F.; Gruttadauria, M.; Marculescu, A. M.; Noto, R. Tetra-
hedron Lett. 2007, 48, 255. (d) Alza, E.; Cambeiro, X. C.; Jimeno, C.;
Perica`s, M. A. Org. Lett. 2007, 9, 3717.
10.1021/ol800031p CCC: $40.75
Published on Web 04/12/2008
2008 American Chemical Society

catalyst and the substrate aldehydes. Although a number
of variants have appeared for the organocatalytic reduction
with Hantzsch ester,5–7 a successful emulation of nature’s
efficiency and selectivity in an aqueous environment has not
been realized yet.
Table 1. Transfer Hydrogenation in Aqueous Media
We have developed an N-terminal prolyl peptide catalyst
supported by polyethyleneglycol grafted on polystyrene (PEG-
PS) resin8 for an aqueous aldol reaction.4a PEG-PS-supported
peptide catalysts can be easily prepared through conventional
solid-phase peptide synthesis and can be readily removed from
a reaction mixture by filtration. Such a supported peptide is an
attractive candidate for an efficient asymmetric organocatalyst
that works in aqueous media since it is easy to control hy-
drophobicity and stereostructure simply by changing peptide
sequences. Herein we report on a novel PEG-PS-supported
hydrophobic peptide catalyst for the asymmetric transfer
hydrogenation in aqueous media.
Initially, we checked the efficiency of the proline-based
catalysts for the reduction of (E)-3-phenylbut-2-enal with
Hantzsch ester 1 in THF/H2O ) 2/1 (v/v) (Table 1). Both
proline TFA salt (entry 1) and its PEG-PS-supported variant
(entry 2) showed almost no activity under this aqueous
condition. Since a simple proline salt is known to show some
level of catalytic activity in toluene (47% conversion after
5 h),5c the present result indicates water has an inhibitory
effect for the proline-catalyzed reduction. For the purpose
of generating a hydrophobic environment around the prolyl
residue, a polyleucine chain was introduced between the
proline and the solid support.9 The catalyst having 25.4
leucine residues on average considerably enhanced the
reaction (entry 3). More interestingly, when the proportion
a
Estimated by H NMR of the crude mixture. b Determined by chiral
1
HPLC analysis of the corresponding alcohol after NaBH4 reduction in EtOH.
of water increased from THF/H2O ) 2/1 to 1/2, the reaction
proceeded 3 times faster (entry 6), presumably because of
the intensified hydrophobic interaction between the aldehyde,
Hantzsch ester, and the catalyst. The length of polyleucine
chain and the reaction rate were positively correlated up to
about 25 leucine residues (entries 4-6). The reaction also
proceeded smoothly in the presence of a nonsupported
N-terminal prolyl polyleucine catalyst (entry 7). However,
in this case, the 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. Therefore,
in the following experiments, we used PEG-PS resin-
supported hydrophobic peptides.10,11
We optimized a terminal peptide sequence from the aspect
of enantioselectivity (Table 2). Peptides including the D-Pro-
Aib (Aib: 2-aminoisobutyric acid) sequence are known to form
a ꢀ-turn structure in organic solvents through an intramolecular
hydrogen bond.12 Miller et al. showed that this ꢀ-turn motif
can be successfully applied to the design of peptide-based
asymmetric organocatalysts that work in nonpolar solvents.13
We anticipated that the D-Pro-Aib sequence combined with a
hydrophobic polyleucine chain could also provide the rigid
ꢀ-turn structure necessary to control facial selectivity even in
aqueous media. Introducing the D-Pro-Aib sequence between
the terminal L-prolyl group and the polyleucine tether turned
out to be quite effective for enhancing selectivity despite the
low reaction rate (entry 1). Furthermore, incorporation of one
(5) (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.
(g) Martin, N. J. A.; Ozores, L.; List, B. J. Am. Chem. Soc. 2007, 129,
8976
.
(6) Other examples for catalytic asymmetric reduction using Hantzsch
esters: (a) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, 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
.
(7) Examples for 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,
(10) In the Julia´-Colonna epoxidation, resin-supported polyleucine was
also used to facilitate efficient handling of the catalyst. Itsuno, S.; Sakakura,
M. J. Org. Chem. 1990, 55, 6047
.
G.-L.; Co´rdova, A. Tetrahedron Lett. 2006, 47, 7417
.
(11) When (R)-2-(tert-butyl)-3-methyl-4-imidazolidinone salt (ref 5c)
was used as a catalyst under aqueous condisions, the conversion and the
enantioselectivity were modest (in THF/H2O ) 2/1, 42% conversion and
60% ee; in THF/H2O ) 1/2, 44% conversion and 59% ee).
(12) Copeland, G. T.; Jarvo, E. R.; Miller, S. J. J. Org. Chem. 1998,
63, 6784.
(8) PEG-PS resin is widely used in solid-phase peptide synthesis and is
compatible with a variety of solvents, including water, by virtue of its
amphiphilic nature. Bayer, E. Angew. Chem., Int. Ed. Engl. 1991, 30, 113.
(9) The synthesis of the polyleucine tether was straightforward based
on an established chemistry of the N-carboxyanhydride (NCA) polymeri-
zation. Leucine is suitable for this purpose because of its high hydrophobicity
and high reactivity of its NCA. Simple polyleucine has been used as a
catalyst for Julia´-Colonna epoxidation. For a review, see: Porter, M. J.;
Roberts, S. M.; Skidmore, J. Bioorg. Med. Chem. 1999, 7, 2145.
(13) (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.
2036
Org. Lett., Vol. 10, No. 10, 2008

Table 2. Optimization of Terminal Peptide Sequence
Table 3. Substrate Scope
a
Estimated by H NMR of the crude mixture. b Determined by chiral
1
HPLC analysis of the corresponding alcohol after NaBH4 reduction in EtOH.
or two Trp residue(s) into the peptide at the point next to Aib
afforded even higher enantioselectivity (entries 2 and 3), while
the insertion of three Trp brought about no additional improve-
ment (entry 4). Concerning the reaction catalyzed by the peptide
4, increasing the ratio of water from THF/H2O ) 2/1 to 1/2
brought about a remarkable acceleration of the reaction without
loss of enantioselectivity (entry 5). Further increase in the ratio
of water did not improve the reaction rate because of the limited
solubility of Hantzsch ester 1 to water. A control experiment
with the catalyst having no polyleucine tether resulted in only
low reaction rate and a significant decrease in selectivity (entry
6). This indicates that the polyleucine chain provides an efficient
hydrophobic cavity and allows the terminal peptide sequence
to fold into a desirable secondary structure. This necessity of
the hydrophobic moiety is in a sharp contrast to the results
reported by Uozumi et al. in which the simple PEG-PS support
behaved as an efficient hydrophobic sink for organic substrates
in palladium-catalyzed reactions under aqueous conditions.14
Some typical unsaturated aldehydes were examined as
hydride acceptors (Table 3). Reactions were performed in
the presence of 20 mol % of catalyst 4 TFA salt with 1.2
equiv of Hantzsch ester 1 in THF/H2O ) 1/2. Aldehydes
2a-e having aromatic groups of various sizes and electronic
natures gave good yields and high levels of enantioselectivity
(entries 1-5). The aldehyde 2f possessing an ortho chloro
group was hardly reduced to 3f probably because of the steric
hindrance (entry 6). Aliphatic aldehyde 2g also showed
excellent enantioselectivity even though the yield was
moderate (entry 7).15 The absolute configurations of the
major products 3a and 3g were determined in comparison
with the authentic samples obtained by the reported
method.5c,d Considering the mechanistic similarity in all
cases, which is based on the known mechanism through the
a Isolated yields. b Unless otherwise noted, determined by chiral HPLC
analysis of the corresponding alcohol after NaBH4 reduction. c Determined
by 1H NMR in the presence of Eu(hfc)3 as the chiral shift reagent after
NaBH4 reduction. d Determined by 1H NMR after NaBH4 reduction and
derivatization of the corresponding alcohol to the Mosher ester with
(-)-MTPA-Cl. e E/Z mixture of 2g was used as a starting material (E/Z )
2/1). Reaction time was 10 h. f After NaBH4 reduction, ee of the
corresponding alcohol was determined according to the literature (see
Supporting Information).
formation of the iminium ion,5c all products were considered
to have the same stereostructure.
In summary, we have developed a novel resin-supported
peptide catalyst for the asymmetric transfer hydrogena-
tion.16 With this catalyst, we attained the first highly
enantioselective reaction in aqueous media. The hydro-
phobic leucine chain was essential for both reaction rate
and selectivity, which imitates the performance of enzymes
in the cell. Currently, the generality of the present catalyst
design for the reactions in aqueous conditions is under
investigation in our laboratory.
Acknowledgment. This work was supported by the Global
COE Program for Chemistry Innovation.
Supporting Information Available: Synthesis of peptide
catalysts and experimental details. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) Nakai, Y.; Uozumi, Y. Org. Lett. 2005, 7, 291 and references
therein.
OL800031P
(15) E/Z mixture (E/Z ) 2/1) of 2g was used as a starting material, whereas
2a-f were only E isomers. Regardless, the high ee value of 3g was obtained.
This suggests that the enantioconvergence described by List et al. and
MacMillan et al. occurred in this case as well (see refs 5b and 5c).
(16) A full account of this survey including more detailed data and the
structural insight into the peptide catalyst will be forthcoming.
Org. Lett., Vol. 10, No. 10, 2008
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