Peptide-catalyzed regio- and enantioselective reduction of α,β,γ,δ-unsaturated aldehydes

Article abstract of DOI:10.1002/anie.201305004

A resin-supported peptide catalyst (see box in the scheme) was used in the title reaction. The inherent regioselectivity was overcome by the peptide catalyst to promote the 1,6-selective reaction prior to 1,4-reduction. High stereoconvergence was also achieved when using a mixture of geometric isomers of the starting aldehydes. Ach=1-amino-1-cyclohexanecarboxylic acid. Copyright

Full text of DOI:10.1002/anie.201305004

Angewandte
Chemie
DOI: 10.1002/anie.201305004
Peptide Catalysis
Peptide-Catalyzed Regio- and Enantioselective Reduction of a,b,g,d-
Unsaturated Aldehydes**
Kengo Akagawa, Jun Sen, and Kazuaki Kudo*
Regiochemistry of organic reactions is generally governed by
the intrinsic reactivity of each functional group in a substrate,
and this sometimes renders the synthetic route of a target
compound complicated. Catalytic regioselective reactions
have great potential for realizing straightforward synthesis.
However, compared to stereoselective ones, there have been
much less reports on regioselective catalysts.[1–4] One of the
major subjects in the catalytic regioselective reactions is the
nucleophilic addition to a,b,g,d-unsaturated carbonyl com-
pounds.[5] While transition metal catalysts have mainly been
employed for the regioselective reactions with such sub-
strates,[6] only a few examples with organocatalysts have been
reported.[7,8] Because organocatalysis has potential advan-
tages, such as mild reaction conditions and wide applicability
for various reactions,[9] exploring novel regioselective organo-
catalysts is highly desirable.
Considering the fact that enzymes catalyze reactions with
high regioselectivity,[10] their simplified forms, peptides, are
attractive candidates for regioselective catalysts.[11] So far,
Miller and co-workers[3] and Kawabata and co-workers[4] have
developed peptide or peptide-related catalysts for regiose-
lective reactions such as derivatization of polyols and
epoxidation of polyenes. Meanwhile, our group has reported
a resin-supported peptide catalyst (Figure 1) for enantiose-
peptide while avoiding problems with solubility.[17] Because of
the formation of a secondary structure, the peptide catalyst
can be expected to create a larger reaction site effective for
controlling regioselectivity than low-molecular-weight cata-
lysts. Herein, we report the first regio- and enantioselective
transfer hydrogenation of a,b,g,d-unsaturated aldehydes with
a resin-supported peptide catalyst.
For organocatalytic regioselective reduction using
a
Hantzsch ester, a,b,g,d-unsaturated aldehyde 1 with
a methyl group at the b-position was chosen as a starting
material (Table 1). Because of the presence of the stereogenic
center in the reduced products 3 and 5, the catalytic ability for
enantioselectivity as well as for regioselectivity can be
evaluated. The reaction is considered to proceed through
the formation of the iminium intermediate with an amine
catalyst. Compounds 3 and 4 are the products of 1,4- and 1,6-
reduction, respectively. Only compound 4 can be reduced
further to afford fully hydrogenated product 5. To check the
intrinsic regiochemistry in the reaction of this substrate, we
first tried the reaction with simple secondary amine catalysts,
pyrrolidine and morpholine, in chloroform. In both cases,
compound 3 was mainly obtained with low conversion
(Table 1, entries 1 and 2). These results are consistent with
the report by Hayashi et al. for an amine-catalyzed Michael
addition of nucleophiles to a,b,g,d-unsaturated aldehydes, in
which 1,4-addition predominantly took place.[18] On the basis
of an ab initio calculation, they concluded that such regiose-
lectivity originates from the electronic nature of the iminium
intermediate, i.e., a larger p-orbital coefficient of the LUMO
and a more positive charge at the b-position. Melchiorre and
co-workers[19] and Jørgensen and co-workers[20] attained 1,6-
addition to a,b,g,d-unsaturated carbonyl compounds through
the iminium activation. In those cases, however, the use of
cyclic substrates for the Michael acceptors or finely designed
nucleophiles is essential to suppress 1,4-addition. This type of
regioselectivity is considered to be controlled by the sub-
strate, and not regulated by a catalyst. When imidazolidinone
8 was used as a catalyst, the distribution of the products
changed (Table 1, entry 3). This result implies a possibility for
the controlled selective formation of compound 5 by a cata-
lyst. In terms of stereochemistry, both products 3 and 5 were
nearly racemic, although this catalyst is known to effectively
promote asymmetric reduction of a,b-unsaturated aldehy-
des.[13b] We then tried the reaction with peptide catalysts. The
use of peptide catalyst 9 enhanced 1,6-selectivity to give
compound 5 as a major product with good enantioselectivity
(Table 1, entry 5). The combination of the terminal five
residues including the turn motif and the polyleucine part was
essential for regio- and enantioselectivity (Table 1, entries 5–
7). Replacing a-helical polyleucine with a 310-helical unit,
Figure 1. Resin-supported peptide catalyst. Aib=a-aminoisobutyric
acid.
lective transfer hydrogenation of a,b-unsaturated aldehydes
with a Hantzsch ester.[12–14] The peptide consists of a turn
motif[15] and a helical part, and the whole peptide chain is
attached to a polyethylene glycol grafted polystyrene resin.
This catalyst can be easily prepared through the polymeri-
zation with leucine N-carboxyanhydride followed by the
standard Fmoc solid-phase peptide synthesis.[16] The amphi-
philic nature of the resin facilitates the use of the hydrophobic
[*] Dr. K. Akagawa, J. Sen, Prof. Dr. K. Kudo
Institute of Industrial Science, University of Tokyo
4-6-1 Komaba, Meguro-ku, Tokyo 153-8505 (Japan)
E-mail: kkudo@iis.u-tokyo.ac.jp
[**] This work was supported by JSPS KAKENHI Grant Number
23750171 (to K.A.) and 23550116 (to K.K.), and by MEXT KAKENHI
Grant number 24105506 (to K.K.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305004.
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Table 1: Catalyst screening for regio- and enantioselective reduction of
an a,b,g,d-unsaturated aldehyde.
for the first step of the reduction as the catalyst 9 (entry 11).
Next, the electronic nature of the indole rings of the
tryptophan residues was modified. The use of tryptophan
residues with an electron-donating methoxy group afforded
product 5 in excellent enantioselectivity with a significant
decrease in conversion (Table 1, entry 12). In contrast,
introducing an electron-withdrawing nitro group to the
tryptophan residues promoted the reaction, but the regio-
and enantioselectivity were slightly lowered (Table 1,
entry 13). To overcome the low-efficiency problem of catalyst
15, the Aib residue in the turn motif was replaced by Ach
according to our previous experience for peptide-catalyzed
asymmetric epoxidation.[22] In the present case as well,
a remarkable acceleration of the reaction occurred (Table 1,
entry 14). Furthermore, changing the polyleucine part to
hexaleucine[23] gave a slightly better result (Table 1, entry 15),
and we regarded peptide 18 as the optimum catalyst. After
screening the reaction conditions, a highly regio- and
enantioselective reduction of a,b,g,d-unsaturated aldehyde
1 was achieved (Table 1, entry 16). The detailed mechanism
accounting for the regioselectivity of the peptide-catalyzed
reaction is not clear to date. Considering the poor regiose-
lectivity with catalyst 13 lacking one tryptophan and some-
what lowered 1,6-selectivity with catalyst 16 possessing the
electron-withdrawing groups on the tryptophan residues, the
electron-rich nature of the tryptophan residues seems to be
important for increasing the regioselectivity through the
interaction with the iminium intermediate.
Entry Catalyst T [8C] Conversion[a] [%] 3/4/5[a]
ee [%] of 5 (3)
1[b]
2[b]
3[b]
4
5
6
7
8
9
10
11
12
13
14
15
16[c]
6
7
8
8
9
10
11
12
9
13
14
15
16
17
18
18
20
20
20
20
20
20
20
20
30
30
30
30
30
30
30
10
12
26
79
93
52
51
19
56
86
97
99
32
95
95
98
99
76:0:24
73:8:19
59:9:32
59:0:41
11:36:53 88 (51)
41:28:31 29 (15)
14:66:20 62 (40)
23:19:58 86 (54)
15:10:75 86 (46)
35:1:64
15:0:85
16:50:34 97 (76)
19:5:76
13:8:79
13:0:87
10:0:90
–
–
1 (2)
3 (1)
78 (61)
90 (69)
82 (44)
93 (68)
96 (58)
99 (78)
[a] Determined from 1H NMR spectra of the crude mixture. [b] The
reaction was performed in CHCl3 for 3 h. [c] The reaction was performed
in 1,2-dimethoxyethane (DME) for 48 h.
Next, the substrate scope for this type of reaction was
examined (Table 2). Regardless of the kinds of substituents
on the benzene ring, the reduction proceeded regioselectively
to give compound 5 as a major product with excellent
enantioselectivity (Table 2, entries 2 and 5–8). The substrates
with 2-naphthyl and 3-thienyl groups showed similar regio-
and enantioselectivity (Table 2, entries 9 and 10). Alkyl
Table 2: Peptide-catalyzed regio- and enantioselective reduction of
a,b,g,d-unsaturated aldehydes.
(Leu-Leu-Aib)2,[21] also decreased 1,6-selectivity (Table 1,
entry 8). Notably, a subtle difference in the helical structure
influences the regioselectivity of the reaction, although this
part is somewhat distant from the catalytically active prolyl
group. This demonstrates the importance of the whole
peptide secondary structure for regioselective reduction.
The reaction in the presence of catalyst 9 at slightly higher
temperature gave product 5 in moderate ratio and enantio-
selectivity (Table 1, entry 9). Then, we set out further screen-
ing for the peptide sequences. In the peptide chain, trypto-
phan residues are most likely to affect the regio- and
enantioselectivity, since this part is considered to be allocated
near the iminium intermediate, when the d-Pro-Aib unit[15]
formed a turn structure.[12b] First, the effect of the number of
tryptophan residues between Aib and polyleucine was inves-
tigated. The catalyst with one tryptophan residue lowered the
1,6-selectivity (Table 1, entry 10), whereas the catalyst with
three tryptophan residues showed the same regioselectivity
Entry
R
5
t [h] 3/5[a]
Yield [%] of 5[b] ee [%] of 5
1
2
C6H5
5a 48
10:90
10:90
9:91
6:94
10:90
8:92
10:90
9:91
10:90
10:90
<1 : >99 55
<1 : >99 65
<1 : >99 67
79
75
71
70
79
74
71
65
71
64
99
97
97
97
97
98
98
98
98
98
99
97
97
4-NO2C6H4 5b 36
4-NO2C6H4 5b 36
4-NO2C6H4 5b 36
4-ClC6H4
3-ClC6H4
4-BrC6H4
4-MeOC6H4 5 f 60
2-naphthyl 5g 36
3-thienyl
nBu
3[c]
4[d]
5
5c 36
5d 36
5e 36
6
7
8
9
10
11
12
13
5h 48
5i 36
5j 36
c-Hex
C6H5-(CH2)2 5k 36
[a] Determined from 1H NMR spectra of the crude mixture. [b] Yields of
isolated products. [c] The mixture of (2E,4E)/(2Z,4E) (67:33) was used as
a starting material. [d] The mixture of (2E,4E)/(2E,4Z)/(2Z,4E)/(2Z,4Z)
(27:45:8:20) was used as a starting material.
2
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Table 3: Regio- and stereoselectivity of the reaction with d-substituted
substrates.
substituents at the d-position enhanced the 1,6-selectivity in
the first reduction step (Table 2, entries 11–13). The amine-
catalyzed asymmetric transfer hydrogenation of a,b-unsatu-
rated aldehydes with a Hantzsch ester is known to be
stereoconvergent; despite the different geometry of a starting
material, the same enantiomer can be obtained.[13,24] In the
present reaction, such a phenomenon was also observed. A
2E/2Z mixture of substrate 1b afforded the products with the
same regio- and enantioselectivity (Table 2, entry 3) as the
reaction using a single isomer of 1b (entry 2). Even when
a mixture of four geometric isomers was used, the reaction
still proceeded in a highly regio- and enantioselective manner
(Table 2, entry 4). This is practically advantageous, because
geometric isomers are usually generated in the synthesis of
this type of substrate.
Entry 22
Conversion 23/24/25 d.r.
ee [%]
[%]
of 25 of 25
1
2
3
4
22a (R1 =Me, R2 =H)
87
31:0:69
9:1:90
–
87
(2E,4E)
22b (R1 =Me, R2 =Me) 97
(2E,4E)
57:43 93, 95
53:47 90, 95
As a demonstration, fragrance compounds, Citralis and
Phenoxanol, were synthesized according to Scheme 1. The
2E/2Z mixture of 1a obtained by a Heck reaction[25] was
22b (R1 =Me, R2 =Me) 70
(2Z,4E)/(2Z,4Z) (87:13)
11:3:86
22c (R1 =Et, R2 =Me)
(2Z,4E)/(2Z,4Z) (60:40)
80
14:11:75 55:45 93, 81
also 1,6-selective in the first step of the reduction, in spite of
steric congestion at the d-position (Table 3, entry 1). In the
case of substrate 22b with b,d-dimethyl substituents, the 1,6-
selective reduction predominantly proceeded, and after the
subsequent 1,4-reduction, the fully hydrogenated compound
25b was obtained as a major product (Table 3, entry 2).
Although 25b was a mixture of two diastereomers, the
enantioselectivity for each compound was high (see the
Supporting Information for a hydrogenation experiment,
which suggests that the low diastereoselectivity is caused by
the initial 1,6-reduction step). For this type of substrate, good
stereoconvergence was observed as well, while the reactivity
is low with 2Z isomers (Table 3, entry 3). Substrate 22c with
an ethyl substituent at the d-position showed a comparable
1,6-selectivity for the first reduction step (Table 3, entry 4).
In conclusion, a new peptide catalyst suitable for regio-
and enantioselective reduction of a,b,g,d-unsaturated alde-
hydes was developed. It was applicable for the stereoconver-
gent synthesis using a mixture of geometric isomers. In this
study, a high regioselectivity was attained by catalyst control,
not by intrinsic reactivity of a substrate. Further application of
peptide catalysts for other regioselective reactions can be
expected.
Scheme 1. Short asymmetric synthesis of fragrance compounds.
applied to the peptide-catalyzed reduction to afford Citralis
with high enantiomeric excess,[26] which could be easily
derivatized to Phenoxanol. Compared to the reports for the
synthesis of these compounds,[27] the present regio- and
enantioselective reaction offers a simpler synthetic pathway.
In the case of b-ethylated substrate 19, the inherent
reactivity resulted in a preferred 1,4-selectivity (Scheme 2),
which was demonstrated by the fact that catalyst 8 exclusively
Experimental Section
1,2-Dimethoxyethane (0.5 mL) was added at 108C to a round-bottom
flask containing aldehyde
1 (0.05 mmol), Hantzsch ester 2
Scheme 2. Reduction of a b-ethyl-substituted substrate.
(0.15 mmol), and resin-supported peptide 18 (57 mg, 0.01 mmol of
the terminal prolyl group). The mixture was stirred with a magnetic
stirrer at 200 rpm for the given time. Then, the peptide catalyst was
filtered off and washed with chloroform. After removal of the solvent,
the residue was purified by preparative TLC using hexanes/ethyl
acetate (4:1) as eluent to afford product 5. For compound 5b,
preparative TLC was performed with hexanes/ethyl acetate (2:1) as
eluent.
afforded the 1,4-reduced product 20. The use of peptide
catalyst 18 overturned the regioselectivity of the reaction, and
gave compound 21 in a moderate yield with high enantiose-
lectivity.
Finally, d-substituted substrates were tested in the pep-
tide-catalyzed reduction (Table 3). The reaction with sub-
strate 22a having only one methyl group at the d-position was
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Received: June 11, 2013
Published online: && &&, &&&&
Keywords: asymmetric synthesis · heterogeneous catalysis ·
.
peptides · reduction · regioselectivity
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4
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Peptide Catalysis
K. Akagawa, J. Sen,
K. Kudo*
&&&& — &&&&
Peptide-Catalyzed Regio- and
Enantioselective Reduction of a,b,g,d-
Unsaturated Aldehydes
A resin-supported peptide catalyst (see
box in the scheme) was used in the title
reaction. The inherent regioselectivity
was overcome by the peptide catalyst to
promote the 1,6-selective reaction prior
to 1,4-reduction. High stereoconvergence
was also achieved when using a mixture
of geometric isomers of the starting
aldehydes. Ach=1-amino-1-cyclohexane-
carboxylic acid.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!