Asymmetric α-amination of aldehydes by a recyclable resin-supported peptide catalyst

Article abstract of DOI:10.1002/adsc.201200611

The asymmetric a-amination of aldehydes was performed using a resin-supported peptide catalyst. A tri- or tetrapeptide with an N-terminal D-Pro-Aib sequence efficiently catalyzed the reaction in a highly enantioselective manner. The supported catalyst could be easily recovered by filtration and reused at least ten times.

Full text of DOI:10.1002/adsc.201200611

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DOI: 10.1002/adsc.201200611
Asymmetric a-Amination of Aldehydes by a Recyclable Resin-
Supported Peptide Catalyst
Tatsuyoshi Tanaka,a,* Kengo Akagawa,b Masaru Mitsuda,a and Kazuaki Kudob,*
a
Kaneka Corporation, 1–8 Miyamae-machi, Takasago-cho, Takasago, Hyogo 676-8688, Japan
Fax : (+81)-79-445-2692; phone: (+81)-79-445-2847; e-mail: tatsuyoshi_tanaka@kn.kaneka.co.jp
Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan
b
Fax : (+81)-3-5452-6359; phone: (+81)-3-5452-6357; e-mail: kkudo@iis.u-tokyo.ac.jp
Received: July 12, 2012; Revised: November 1, 2012; Published online: January 16, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200611.
Abstract: The asymmetric a-amination of aldehydes
was performed using a resin-supported peptide cat-
alyst. A tri- or tetrapeptide with an N-terminal d-
Pro-Aib sequence efficiently catalyzed the reaction
in a highly enantioselective manner. The supported
catalyst could be easily recovered by filtration and
reused at least ten times.
catalyzed asymmetric a-amination. In contrast to
simple proline, the carboxyl group of the terminal
prolyl residue in a peptide is used for amide bond for-
mation. Since an amide proton is less acidic than a car-
boxylic acid,[5] the enantiocontrol by hydrogen bond-
ing shown in Figure 1 should be weakened. Therefore,
it is a challenging subject to establish a new strategy
for achieving high enantioselectivity with a peptide
catalyst.[6,7]
Keywords: enantioselective amination; peptide cat-
alysts; recyclable catalysts; resin-supported catalysts
On the other hand, our group has developed resin-
supported peptides for organocatalytic reactions.[8]
Supported peptides can be synthesized based on the
well-established solid phase method,[9] and immobili-
zation to a resin enables the easy recovery of catalysts
The organocatalyzed amination of aldehydes[1] is one from a reaction mixture and their reuse.[10] Herein, we
of the powerful methods for synthesizing chiral amino report a novel recyclable peptide catalyst that is effec-
alcohol or amino acid derivatives which are versatile tive for the asymmetric a-amination of aldehydes.
precursors for pharmaceuticals and natural products.
The asymmetric a-amination was examined with 3-
In 2002, Jørgensen et al.[1a] and List[1b] independently phenylpropanal and diisopropyl azodicarboxylate in
reported the asymmetric a-amination of aldehydes acetonitrile (Table 1). First, proline immobilized to
with azodicarboxylate in the presence of proline as the PEG-PS resin via an amide bond was tested as
a catalyst. This reaction proceeds via the enamine in- a catalyst. The reaction proceeded smoothly to afford
termediate derived from an aldehyde and proline.[2] the a-aminated product with moderate enantioselec-
The carboxyl group of proline has a role to activate tivity (entry 1). It should be noted that the sense of
the azodicarboxylate through hydrogen bonding, the chirality of the major product is the same as the
which simultaneously controls the enantioselectivity case of the reaction catalyzed by simple proline.[11]
of the reaction (Figure 1).[1a,b,d,3]
In relation with the proline catalyst, peptides with residue can serve as a weak hydrogen bonding donor.
This suggests that the amide proton next to the prolyl
a prolyl group at the N-terminus have been employed
Next, peptide sequences were screened to increase
for various kinds of organocatalytic reactions.[4] How- the enantioselectivity. Combining a terminal prolyl
ever, to date, there has been no report of a peptide- group with natural amino acids did not increase the
selectivity (examples are shown in entries 2 to 4). Pre-
viously, we have found that the peptide with the ter-
minal d-Pro residue followed by an a,a-disubstituted
amino acid was effective for an asymmetric epoxida-
tion of aldehydes.[8e] When the resin-supported dipep-
tide d-Pro-Aib (Aib=2-aminoisobutyric acid)[12] was
employed for the a-amination, the enantioselectivity
was improved to some extent (entry 5). Moreover, in-
Figure 1. Proposed reaction intermediate.
corporation of other amino acids next to the Aib resi-
294
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 294 – 296

Asymmetric a-Amination of Aldehydes by a Recyclable Resin-Supported Peptide Catalyst
Table 1. Screening of resin-supported peptide catalysts.
Table 2. Asymmetric a-amination of aldehydes with peptide
catalyst 1.
Entry
(AA)n
Yield [%][a]
ee [%]
Entry
R1
R2
Yield [%][a]
ee [%]
1
2
3
4
5
6
7
8
Pro
d-Pro-Phe
93
59
17
36
92
99
99
55
25
61
99
98
86
67
À61[b]
1
2
3
4
Bn
Bn
n-Bu
i-Pr
i-Pr
Bn
Bn
Bn
83
99
99
96
90
90
96
90
45
d-Pro-Phe-Phe
d-Pro-Trp-Phe
d-Pro-Aib
d-Pro-Aib-Ala
d-Pro-Aib-Phe
d-Pro-Aib-Trp
d-Pro-Ala-Phe
d-Pro-d-Ala-Phe
d-Pro-Aib-Ser-Ser (1)
TFA·1
57
52
72
88
89
88
63
42
[a]
Isolated yield.
9
Other substrates were tested for the asymmetric a-
amination with peptide catalyst 1 (Table 2). In addi-
tion to diisopropyl azodicarboxylate, a benzyl deriva-
tive could be employed for the a-amination of 3-phe-
nylpropanal in a highly enantioselective manner
(entry 2). Use of aliphatic aldehydes with a straight or
blanched carbon chain also gave the aminated prod-
ucts in excellent yield and enantioselectivity (entries 3
and 4).[13]
10
11
12[c]
13
14
91
83
Pro-Aib-Ser-Ser
Pro-d-Pro-Aib-Trp-Trp
À89[b]
60
[a]
Determined by HPLC.
[b]
The minus sign before the number means that the major
enantiomer was in (R)-configuration.
Reaction time was 2 h.
[c]
Finally, reusability of the catalyst was examined to
demonstrate the advantage of the resin-supported
due further enhanced the selectivity (entries 6 to 8). peptide (Table 3). The reactivity of N-free peptide
Replacing the Aib part with l- or d-alanine lowered
the catalytic ability (entries 9 and 10), which con-
Table 3. Reusability of a resin-supported peptide catalyst.
firmed the importance of employing the a,a-disubsti-
tuted amino acid at this position. Further optimization
afforded the d-Pro-Aib-Ser-Ser (1) sequence as a best
catalyst (entry 11). In the case that the TFA salt of
1 was used as a catalyst, the reaction proceeded
smoothly, although the enantioselectivity was some-
what decreased (entry 12).
Regardless of the kinds of amino acids next to the
Aib residue, the degree of enantioinduction was
almost at the same level (entries 6 to 8 and 11). It is
noteworthy that a product with the opposite absolute
configuration and a comparable degree of enantiose-
lectivity was obtained when only the N-terminal d-
prolyl group was replaced to its antipode (entry 13).
These results indicate that the enantioselectivity is
predominantly controlled by the (d or l)-Pro-Aib
part. From the observed selectivity for the major
enantiomer, the amide proton between the d-Pro and
Aib residues is considered to be involved in a transi-
tion state through hydrogen bonding. When Pro-d-
Pro-Aib-Trp-Trp, a b-turn peptide with no amide
proton adjacent to the N-terminal prolyl group, was
used as a catalyst, the sense of enantioselectivity was
inverted (entry 14). This might be because the enan-
tioselectivity was induced simply by steric hindrance
of the peptide chain.
Entry Catalyst
Time [h] Yield [%][a] ee [%]
1
2
3
4
5
6
1
2
2
2
3
3
5
2
2
2
2
2
2
2
2
2
3
4
99
99
99
73
99
57
98
98
99
99
88
90
99
98
99
84
92
91
91
90
91
92
89
83
84
88
86
87
91
90
92
92
92
91
1 (1st reuse)
1 (2nd reuse)
1 (3rd reuse)
1 (4th reuse)
1 (5th reuse)
7
8
9
TFA·1
TFA·1 (1st reuse)
TFA·1 (2nd reuse)
TFA·1 (3rd reuse)
TFA·1 (4th reuse)
TFA·1 (5th reuse)
TFA·1 (6th reuse)
TFA·1 (7th reuse)
TFA·1 (8th reuse)
TFA·1 (9th reuse)
TFA·1 (10th reuse)
10
11
12
13
14
15
16
17
[a]
Determied by HPLC.
Adv. Synth. Catal. 2013, 355, 294 – 296
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asc.wiley-vch.de
295

Tatsuyoshi Tanaka et al.
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catalyst 1 was lowered gradually up to the 4th reuse
(entries 1 to 5), and a serious decrease in yield was
observed in the 5th experiment even with a prolonged
reaction time (entry 6). In the case with the TFA salt
of 1, reusability of the catalyst remarkably improved,
and it could be recycled at least ten times with high
yield and enantioselectivity. Concerning the catalytic
activity, although the a-amination was completed
within 2 h until the 8th reuse, the reaction rate became
lower as the recycling times increased (entries 8 to
15). In the cases of the 9th and 10th experiments, pro-
longation of the reaction time was required to achieve
high yields (entries 16 and 17).
In conclusion, we have developed a recyclable
resin-supported peptide catalyst for the enantioselec-
tive a-amination of aldehydes. Although the peptide
catalyst lacked a carboxylic acid functionality, high
enantioselectivity was realized by optimizing the pep-
tide sequence. The present catalyst design is expected
to be applicable for other organocatalytic reactions.
[2] For a review of enamine catalysis, see: S. Mukherjee,
J. W. Yang, S. Hoffmann, B. List, Chem. Rev. 2007, 107,
5471.
[3] A. K. Sharma, R. B. Sunoj, Chem. Commun. 2011, 47,
5759.
[4] For reviews, see; a) E. A. C. Davie, S. M. Mennen, Y.
Xu, S. J. Miller, Chem. Rev. 2007, 107, 5759; b) H. Wen-
nemers, Chem. Commun. 2011, 47, 12036.
[5] The pKa values of proline and N-methylacetoamide in
DMSO are ~12 and ~26, respectively, see: a) S. Saito,
H. Yamamoto, Acc. Chem. Res. 2004, 37, 570; b) F. G.
Bordwell, J. A. Harrelson Jr, T. Y. Lynch, J. Org. Chem.
1990, 55, 3337.
[6] Wennemers et al. have successfully designed peptide
catalysts including a carboxyl group at the side chain of
a peptide residue; see: a) P. Krattiger, R. Kovasy, J. D.
Revell, S. Ivan, H. Wennemers, Org. Lett. 2005, 7, 1101;
b) M. Wiesner, J. D. Revell, S. Tonazzi, H. Wennemers,
J. Am. Chem. Soc. 2008, 130, 5610; c) M. Wiesner, J. D.
Revell, H. Wennemers, Angew. Chem. 2008, 120, 1897;
Angew. Chem. Int. Ed. 2008, 47, 1871; d) M. Wiesner,
G. Upert, G. Angelici, H. Wennemers, J. Am. Chem.
Soc. 2010, 132, 6.
[7] It is reported that the peptide catalyst with a hydroxy
group next to an N-terminal prolyl residue is effective
for an enantioselective aldol reaction, see: M. R. M.
Andreae, A. P. Davis, Tetrahedron: Asymmetry 2005,
16, 2487.
Experimental Section
General Procedure for the Asymmetric Amination of
Aldehydes (Table 2)
[8] a) K. Akagawa, S. Sakamoto, K. Kudo, Tetrahedron
Lett. 2005, 46, 8185; b) K. Akagawa, H. Akabane, S.
Sakamoto, K. Kudo, Org. Lett. 2008, 10, 2035; c) K.
Akagawa, T. Yamashita, S. Sakamoto, K. Kudo, Tetra-
hedron Lett. 2009, 50, 5602; d) K. Akagawa, T. Fuji-
wara, S. Sakamoto, K. Kudo, Org. Lett. 2010, 12, 1804;
e) K. Akagawa, K. Kudo, Adv. Synth. Catal. 2011, 353,
843; f) K. Akagawa, R. Suzuki, K. Kudo, Adv. Synth.
Catal. 2012, 354, 1280.
[9] G. B. Fields, R. L. Noble, Int. J. Pept. Protein Res. 1990,
35, 161.
[10] For a review of supported proline and proline deriva-
tives, see: M. Gruttadauria, F. Giacalone, R. Noto,
Chem. Soc. Rev. 2008, 37, 1666.
To a mixture of a substrate aldehyde (0.15 mmol) and the
resin-supported peptide (7.0 mmol of the terminal prolyl
group) in MeCN (0.86 mL), azodicarboxylate (0.073 mmol)
was added at room temperature. After the resulting mixture
had been stirred for 6 h, the catalyst was filtered off and
washed with THF. NaBH4 was added to the filtrate solution,
and the mixture was stirred for 1 h. The reaction was
quenched by addition of water, and the resulting solution
was extracted with CH2Cl2. The organic layer was dried over
anhydrous magnesium sulfate, and the solvent was removed
under reduced pressure. The crude product was chromato-
graphed on preparative TLC (silica gel, hexane/ethyl ace-
tate=7/3) to afford the product as an alcohol form.
In the examination of the reusability of the peptide cata-
lyst (Table 3), the catalyst recovered by filtration was dried
under vacuum, and used for the next reaction.
[11] Proline-catalyzed amination of 3-phenylpropanal with
dibenzyl azodicarboxylate in MeCN proceeded with
>95% ee, see, ref.[1b]
[12] Miller et al. developed the peptide catalysts containing
a
d-Pro-Aib sequence. For examples, see: a) S. J.
References
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Adv. Synth. Catal. 2013, 355, 294 – 296