Construction of an all-carbon quaternary stereocenter by the peptide-catalyzed asymmetric michael addition of nitromethane to β-disubstituted α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/anie.201206916

Pepping up Michael: An asymmetric Michael addition of nitromethane to β-disubstituted α,β-unsaturated aldehydes was realized by a resin-supported peptide catalyst. Whereas the use of a low-molecular-weight catalyst resulted in poor yields, the peptide effectively promoted the reaction in aqueous media with high enantioselectivity. Copyright

Full text of DOI:10.1002/anie.201206916

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DOI: 10.1002/anie.201206916
Peptide Catalysis
Construction of an All-Carbon Quaternary Stereocenter by the
Peptide-Catalyzed Asymmetric Michael Addition of Nitromethane to
b-Disubstituted a,b-Unsaturated Aldehydes**
Kengo Akagawa and Kazuaki Kudo*
Recently, considerable attention has been devoted to the
synthesis of chiral g-amino acid derivatives[1–3] because of
their biological activity in relation to g-aminobutyric acid
(GABA), a major inhibitory neurotransmitter in central
nervous system.[4] g-Amino acids are also of great value as
non-proteinogenic amino acid components involved in bio-
logically active short peptides such as pepstatin,[5] hapalosin,[6]
and dolastatin 10.[7] Among the diverse structural variants of
chiral g-amino acids, those with a substituent at the b-position
are an important class of pharmaceuticals, which includes
baclofen,[8] pregabalin,[9] and phenibut.[10] Whereas a variety
of methods have been developed for the synthesis of chiral
b-monosubstituted g-amino acids, there are only limited
examples for the preparation of b-disubstituted derivatives.[11]
Furthermore, the reported reaction scope is confined to those
having two alkyl groups on the b-carbon of g-amino acids, and
catalytic enantioselective construction of an all-carbon-sub-
stituted quaternary stereocenter at the b-position has not yet
been achieved.[12,13]
reaction center of the b-disubstituted substrate is sterically
À
congested for C C bond formation, it is supposed that side
reactions such as the 1,2-addition of nitromethane and an
aldol-type reaction of the products could accompany the
reaction to a considerable extent, thus resulting in a decrease
in the product yield. To suppress such side reactions and
promote the desired conjugate addition, a catalyst with high
potential for iminium activation is necessary.
Meanwhile, our group has developed resin-supported
peptide catalysts (Figure 1) for organocatalytic reactions.[17–19]
The specific feature of these catalysts is that the presence of
Figure 1. Resin-supported peptide catalyst.
One plausible route to obtain a g-amino acid with
a quaternary chiral center at the b-position is an enantiose-
lective Michael addition of nitromethane to a b-disubstituted
a,b-unsaturated aldehyde followed by the transformation of
functional groups (Scheme 1). However, although the
Michael addition of nitromethane to b-monosubstituted
substrates has been attained by chiral secondary amine
catalysts through an iminium activation,[14] the application
of such a catalytic system to a b-disubstituted a,b-unsaturated
aldehyde has not been realized thus far.[15,16] Because the
a helical segment, (AA)n, significantly enhances the reaction
rate and the enantioselectivity under aqueous conditions. In
some cases, this type of peptide catalyst was found to be
superior to a conventional low-molecular-weight catalyst. We
envisaged that, by employing the resin-supported peptide
catalyst in aqueous media, the enantioselective Michael
addition of nitromethane to b-disubstituted a,b-unsaturated
aldehydes could be performed.
Initially, the Michael addition of nitromethane to com-
pound 6a, which has methyl and phenyl groups at the
b-position, was examined (Table 1). With resin-supported
peptide 1, which consists of a catalytically active N-terminal
proline and polyleucine, the reaction proceeded smoothly in
water to afford the product with moderate enantioselectivity
(entry 1). The significant effect of the polyleucine portion of
the catalyst was indicated by the result obtained when using
d-prolyl polyleucine catalyst 2. In this case, the mismatched
chirality of the terminal prolyl group and the polyleucine
chain sharply lowered the reaction rate and enantioselectivity
(entry 2).[20] Catalyst 3, which possesses five terminal residues
and has been shown to be highly effective in asymmetric
induction for other reactions,[17a,b] gave good enantioselectiv-
ity (entry 3).[21] In our recent study, it was found that
replacement of the polyleucine unit with a (Leu-Leu-Aib)2
sequence (Aib = 2-aminoisobutyric acid) improved the cata-
lyst activity in an asymmetric Friedel–Crafts-type reaction in
water.[17c] The use of catalyst 4 for the present reaction also
Scheme 1. Proposal for the synthesis of g-amino acids with an all-
carbon quaternary center.
[*] Dr. K. Akagawa, 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 (23750171 to K.A. and
23550116 to K.K.), and by MEXT KAKENHI (24105506 to K.K.). The
authors thank Mr. Atsushi Okumura for experimental assistance.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206916.
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Table 1: Michael addition of nitromethane to b-disubstituted aldehyde.
Entry
Catalyst
Conversion [%]
ee [%]
Scheme 2. Stereoconvergence with the Z isomer as a starting material.
1
2
3
4
1
2
3
4
5
5
5
4
4
62
11
69
90
9
27
À72[a]
12
89
95
93
73
88
97
98
5
6[b]
7[b,c]
8[e]
9[e,f]
56 (12)[d]
98 (70)[d]
9
Scheme 3. Michael addition of nitromethane to citral.
[a] A minus sign denotes the R isomer as the major product. [b] Reaction
was performed in MeOH. [c] Benzoic acid (40 mol%) was added. [d] The
value in parentheses is the yield of isolated product. [e] The amount of
nitromethane was 10 molar equiv. [f] Reaction was performed in THF.
When 3-phenyl-2-hexanal (10), a more sterically demand-
ing substrate than 6a, was used, the yield of the desired
product was quite low, despite the high level of enantioin-
duction (Table 2, entry 1). The low yield was due to side
Table 2: Optimization of reaction conditions.
enhanced both the reaction rate and the enantioselectivity
(entry 4). When diphenylprolinol silyl ether 5 was employed
for the reaction as a control catalyst, the reaction gave low
conversion in water (entry 5), whereas in methanol it gave the
product with somewhat improved conversion, but with
lowered enantioselectivity (entry 6). When the reaction was
performed under the optimized conditions reported by Ha-
yashi et al. for the Michael addition of nitromethane to
b-monosubstituted substrates in the presence of benzoic
acid,[14g] moderate conversion was attained (entry 7). How-
ever, many by-products were observed and the yield of the
isolated desired product was only 12%. In the case of peptide
catalyst 4, the product could be isolated in 70% yield when an
increased amount of nitromethane was employed (entry 8).
The use of the peptide in water was important for catalyst
effectiveness. This was demonstrated by the result of the
reaction in an organic solvent, THF, which afforded the
product with poor conversion (entry 9).
Entry
Catalyst
Solvent[a]
Yield[b] [%]
ee [%]
1
2
3
4
5
6
4
4
4
4
4
4
4
9
H2O
13
22
20
5
40
<5
47
54
96
92
85
81
90
61
91
96
1,4-dioxane/H2O
CH3CN/H2O
DMF/H2O
MeOH/H2O
MeOH
7[c]
8[c]
MeOH/H2O
MeOH/H2O
[a] All solvent mixtures shown are 1:2 cosolvent/water. [b] Estimated by
1H NMR spectroscopy. [c] Reaction was performed at 08C for 24 h with 5
molar equiv of nitromethane.
Concerning the stereochemical relationship of 3-methyl-
cinnamaldehydes and the corresponding conjugate adducts,
MacMillan et al. and List et al. independently reported the
phenomenon of enantioconvergence in a hydride transfer
reaction from a Hantzsch ester.[22] In the present reaction,
such a phenomenon was also observed: the addition of
nitromethane to (Z)-6a predominantly afforded the S adduct,
which was the same configuration as the one obtained from
(E)-6a (Scheme 2). Encouraged by this result, citral, a readily
available mixture of the diastereomers geranial and neral, was
used for the reaction. The 1,4-adduct with nitromethane was
obtained in a higher enantiomeric ratio than the starting E/Z
ratio of citral (Scheme 3). This is one of the few examples in
which a good degree of enantioconvergence was obtained
with citral.[23]
reactions. Accordingly, further optimization of reaction con-
ditions was conducted with this substrate. It was found that
reaction in 1:2 MeOH/H2O gave the product in higher yield
than the other solvent systems tested, along with a slight
decrease in enantioselectivity (entry 5). A water-containing
solvent system was essential for the efficient reaction, which is
shown by the fact that use of MeOH alone as a solvent
brought about a sharp decrease in the yield (entry 6).
Additional optimization for conditions such as temperature,
reaction time, and the amount of nitromethane somewhat
improved the product yield (entry 7). Replacing the (Leu-
Leu-Aib)2 moiety of peptide catalyst 4 with a hexaleucine
chain further increased the yield of the product and enhanced
enantioselectivity (entry 8). Although the full effects of this
helical part are not clear at present, the improvement of the
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reaction outcome by fine-tuning the peptide sequences
demonstrates the potential of peptide catalysis.
The substrate scope was next investigated using 1:2
MeOH/H2O with peptide catalyst 9, (Table 3). The reaction
using aldehyde 6a gave the product in good yield and high
class of b-dialkylated g-amino acids bearing a cyclohexyl
group was obtained. These procedures offer the facile syn-
thesis of highly congested b-disubstituted g-amino acids.
In conclusion, the asymmetric Michael addition of nitro-
methane to b-disubstituted a,b-unsaturated aldehydes has
been realized using a resin-supported peptide catalyst. The
use of an aqueous solvent system was essential for effective
reaction, and the hydrophobic helical part of the peptide
significantly affected the reaction rate and enantioselectivity.
With the optimized peptide catalyst, which has a hexaleucine
chain, highly enantioenriched products with all-carbon-sub-
stituted quaternary centers were obtained. This reaction
could provide a simple means of synthesizing sterically
congested b-disubstituted g-amino acids. The present study
demonstrates the high potential of peptide catalysis for
organocatalytic reactions in which a conventional low-molec-
ular-weight catalyst is ineffective.
Table 3: Substrate scope for the peptide-catalyzed asymmetric Michael
addition of nitromethane to b-disubstituted aldehydes.
Entry
R1
R2
12
Yield [%][a]
ee [%]
1[b]
2[c]
3
C6H5
Me
Me
Me
Me
Me
Me
Me
Et
12a
12b
12c
12d
12e
12 f
12g
12h
12i
82
81
78
70
72
64
76
73
71
65
98
96
95
95
98
97
95
99
98
99
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3-ClC6H4
4-NO2C6H4
2-naphthyl
C6H5
4[d]
5
6
7
Experimental Section
8[b,e]
9[b]
10[b]
Water (334 mL) was slowly added to a round-bottom flask containing
a b-disubstituted a,b-unsaturated aldehyde (0.05 mmol), resin-sup-
ported Pro-d-Pro-Aib-(Trp)2-(Leu)6 (52 mg, 0.01 mmol of the termi-
nal prolyl group), and MeOH (167 mL). Nitromethane (0.5 mmol or
0.25 mmol) was added at room temperature or at 08C, and the
resulting mixture was stirred with magnetic stirrer at ca. 500 rpm for
the given time. The peptide catalyst was filtered off and washed with
chloroform. After removal of the solvent, the residue was purified by
preparative TLC (dichloromethane as eluent) to afford the product.
In cases where isolation was not enough, further purification by
preparative TLC with hexanes/ethyl acetate (2:1) was effective.
4-MeOC6H4
4-ClC6H4
Et
Et
12j
[a] Yield of isolated product. [b] Reaction was performed at 08C.
[c] Reaction time was 36 h. [d] Reaction time was 18 h. [e] The amount of
nitromethane used was 5 molar equiv.
enantioselectivity (entry 1).[24] Regardless of the electronic
nature of the substituents on the phenyl ring, the products
were obtained with high enantioselectivity (entries 2–7). The
yield of isolated product was decreased to some extent in the
case of a substrate with a strong electron-withdrawing group
(entry 6). The introduction of an ethyl substituent in place of
the methyl group at the b-position did not lower the
enantioselectivity, and the products could be obtained in
good to moderate yields with excellent ee values (entries 8–
10).
Received: August 27, 2012
Revised: October 5, 2012
Published online: November 9, 2012
Keywords: amino acids · asymmetric synthesis ·
.
heterogeneous catalysis · Michael addition · peptides
Finally, the 1,4-adducts of nitromethane were converted
into b-disubstituted
[1] For a review, see: M. OrdꢀÇez, C. Cativiela, Tetrahedron:
Asymmetry 2007, 18, 3 – 99.
g-amino acids (Scheme 4). Compound 12d could be derivat-
ized to the b-methylated analogue of baclofen by a simple
procedure: Pinnick oxidation followed by reduction in the
presence of Raney nickel. This is the first example of the
asymmetric synthesis of a b-disubstituted g-amino acid
possessing a b-aryl group. When the reduction was performed
with platinum(IV) oxide after the oxidation of 12a, a new
[2] For recent selected examples of the synthesis of g-amino acid
derivatives with organocatalysts, see: a) D. Enders, C. Wang,
J. W. Bats, Angew. Chem. 2008, 120, 7649 – 7653; Angew. Chem.
Int. Ed. 2008, 47, 7539 – 7542; b) Y. Chi, L. Guo, N. A. Kopf, S. H.
Gellman, J. Am. Chem. Soc. 2008, 130, 5608 – 5609; c) M.
Wiesner, J. D. Revell, S. Tonazzi, H. Wennemers, J. Am. Chem.
Soc. 2008, 130, 5610 – 5611; d) A. Baschieri, L. Bernardi, A.
Ricci, S. Suresh, M. F. A. Adamo, Angew. Chem. 2009, 121,
9506 – 9509; Angew. Chem. Int. Ed. 2009, 48, 9342 – 9345; e) S. E.
Park, E. H. Nam, H. B. Jang, J. S. Oh, S. Some, Y. S. Lee, C. E.
Song, Adv. Synth. Catal. 2010, 352, 2211 – 2217; f) H. Y. Bae, S.
Some, J. H. Lee, J.-Y. Kim, M. J. Song, S. Lee, Y. J. Zhang, C. E.
Song, Adv. Synth. Catal. 2011, 353, 3196 – 3202; g) L.-T. Shen, L.-
H. Sun, S. Ye, J. Am. Chem. Soc. 2011, 133, 15894 – 15897.
[3] For other selected recent examples for the synthesis of g-amino
acid derivatives, see: a) J. Deng, Z.-C. Duan, J.-D. Huang, X.-P.
Hu, D.-Y. Wang, S.-B. Yu, X.-F. Xu, Z. Zheng, Org. Lett. 2007, 9,
4825 – 4828; b) M. Furutachi, S. Mouri, S. Matsunaga, M.
Shibasaki, Chem. Asian J. 2010, 5, 2351 – 2354; c) Y. Zhu, S.
Khumsubdee, A. Schaefer, K. Burgess, J. Org. Chem. 2011, 76,
7449 – 7457; d) C. Shao, H.-J. Yu, N.-Y. Wu, P. Tian, R. Wang, C.-
G. Feng, G.-Q. Lin, Org. Lett. 2011, 13, 788 – 791.
Scheme 4. Derivatization of products into b-disubstituted g-amino
acids.
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[4] a) E. Roberts, Biochem. Pharmacol. 1974, 23, 2637 – 2649;
b) I. A. Sytinsky, A. T. Soldatenkov, Prog. Neurobiol. 1978, 10,
89 – 133.
[5] a) H. Umezawa, T. Aoyagi, H. Morishima, M. Matsuzaki, M.
Hamada, T. Takeuchi, J. Antibiot. 1970, 23, 259 – 262; b) D. H.
Rich, J. Med. Chem. 1985, 28, 263 – 273.
Wang, W. Wang, Adv. Synth. Catal. 2007, 349, 2660 – 2664; e) H.
Gotoh, H. Ishikawa, Y. Hayashi, Org. Lett. 2007, 9, 5307 – 5309;
f) S. K. Ghosh, Z. Zheng, B. Ni, Adv. Synth. Catal. 2010, 352,
2378 – 2382; g) Y. Hayashi, T. Itoh, H. Ishikawa, Angew. Chem.
2011, 123, 4006 – 4010; Angew. Chem. Int. Ed. 2011, 50, 3920 –
3924; h) O. V. Maltsev, A. O. Chizhov, S. G. Zlotin, Chem. Eur. J.
2011, 17, 6109 – 6117; i) Y. Hayashi, D. Okamura, S. Umemiya, T.
Uchimaru, ChemCatChem 2012, 4, 959 – 962.
[6] K. Stratmann, D. L. Burgoyne, R. E. Moore, G. M. L. Patterson,
J. Org. Chem. 1994, 59, 7219 – 7226.
[7] a) G. R. Pettit, Y. Kamano, C. L. Herald, A. A. Tuinman, F. E.
Boettner, H. Kizu, J. M. Schmidt, L. Baczynskyj, K. B. Tomer,
R. J. Bontems, J. Am. Chem. Soc. 1987, 109, 6883 – 6885.
[8] a) B. A. Sachais, J. N. Logue, M. S. Carey, Arch. Neurol. 1977, 34,
422; b) G. H. Fromm, C. F. Terrence, A. S. Chattha, J. D. Glass,
Arch. Neurol. 1980, 37, 768 – 771.
[9] a) P. Yuen, G. D. Kanter, C. P. Taylor, M. G. Vartanian, Bioorg.
Med. Chem. Lett. 1994, 4, 823 – 826; b) R. B. Silverman, Angew.
Chem. 2008, 120, 3552 – 3556; Angew. Chem. Int. Ed. 2008, 47,
3500 – 3504.
[15] Another possible approach to obtaining a chiral b-disubstituted
g-amino acid is the Michael addition of an aldehyde to a
b-disubstituted nitroolefin. Such a reaction has also not been
achieved, although the asymmetric Michael addition to
b-monosubstituted nitroolefins is well-established; see Ref. [2].
[16] The Michael addition of nitromethane to b-disubstituted a,b-
unsaturated ketones has been reported, see: a) C. E. T. Mitchell,
S. E. Brenner, S. V. Ley, Chem. Commun. 2005, 5346 – 5348; b) P.
Li, Y. Wang, X. Liang, J. Ye, Chem. Commun. 2008, 3302 – 3304;
´
c) P. Kwiatkowski, K. Dudzinski, D. Łyz˙wa, Org. Lett. 2011, 13,
[10] I. Lapin, CNS Drug Rev. 2001, 7, 471 – 481.
3624 – 3627.
[11] For selected examples, see: a) S. Shuto, N. Shibuya, S. Yamada,
T. Ohkura, R. Kimura, A. Matsuda, Chem. Pharm. Bull. 1999,
47, 1188 – 1192; b) D. Aguirre, C. Cativiela, M. D. Dꢁaz-de-
Villegas, J. A. Gꢂlvez, Tetrahedron 2006, 62, 8142 – 8146; c) F.
Felluga, F. Ghelfi, G. Pitacco, F. Roncaglia, E. Valentin, C. D.
Venneri, Tetrahedron: Asymmetry 2010, 21, 2183 – 2191.
[12] For reviews on synthetic methods for constructing quaternary
stereocenters, see: a) J. Christoffers, A. Baro, Adv. Synth. Catal.
2005, 347, 1473 – 1482; b) B. M. Trost, C. Jiang, Synthesis 2006,
369 – 396; c) M. Bella, T. Gasperi, Synthesis 2009, 1583 – 1614;
d) J. P. Das, I. Marek, Chem. Commun. 2011, 47, 4593 – 4623.
[13] For selected examples of the construction of quaternary
stereocenters with organocatalysts, see: a) T. Ooi, T. Miki, M.
Taniguchi, M. Shiraishi, M. Takeuchi, K. Maruoka, Angew.
Chem. 2003, 115, 3926 – 3928; Angew. Chem. Int. Ed. 2003, 42,
3796 – 3798; b) N. Mase, F. Tanaka, C. F. Barbas III, Angew.
Chem. 2004, 116, 2474 – 2477; Angew. Chem. Int. Ed. 2004, 43,
2420 – 2423; c) M. S. Kerr, T. Rovis, J. Am. Chem. Soc. 2004, 126,
8876 – 8877; d) N. S. Chowdari, J. T. Suri, C. F. Barbas III, Org.
Lett. 2004, 6, 2507 – 2510; e) J. F. Austin, S.-G. Kim, C. J. Sinz, W.-
J. Xiao, D. W. C. MacMillan, Proc. Natl. Acad. Sci. USA 2004,
101, 5482 – 5487; f) H. Li, Y. Wang, L. Tang, F. Wu, X. Liu, C.
Guo, B. M. Foxman, L. Deng, Angew. Chem. 2005, 117, 107 –
110; Angew. Chem. Int. Ed. 2005, 44, 105 – 108; g) T. Okino, Y.
Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am. Chem. Soc.
2005, 127, 119 – 125; h) K. Mori, T. Katoh, T. Suzuki, T. Noji, M.
Yamanaka, T. Akiyama, Angew. Chem. 2009, 121, 9832 – 9834;
Angew. Chem. Int. Ed. 2009, 48, 9652 – 9654; i) T. Kano, Y.
Tanaka, K. Osawa, T. Yurino, K. Maruoka, Chem. Commun.
2009, 1956 – 1958; j) E. Zhang, C.-A. Fan, Y.-Q. Tu, F.-M. Zhang,
Y.-L. Song, J. Am. Chem. Soc. 2009, 131, 14626 – 14627; k) Q.
Zhu, Y. Lu, Angew. Chem. 2010, 122, 7919 – 7922; Angew. Chem.
Int. Ed. 2010, 49, 7753 – 7756; l) Y. Inokoishi, N. Sasakura, K.
Nakano, Y. Ichikawa, H. Kotsuki, Org. Lett. 2010, 12, 1616 –
1619; m) Y.-H. Liao, X.-L. Liu, Z.-J. Wu, X.-L. Du, X.-M. Zhang,
W.-C. Yuan, Adv. Synth. Catal. 2011, 353, 1720 – 1728.
[17] a) K. Akagawa, H. Akabane, S. Sakamoto, K. Kudo, Org. Lett.
2008, 10, 2035 – 2037; b) K. Akagawa, T. Fujiwara, S. Sakamoto,
K. Kudo, Org. Lett. 2010, 12, 1804 – 1807; c) K. Akagawa, R.
Suzuki, K. Kudo, Adv. Synth. Catal. 2012, 354, 1280 – 1286.
[18] For reviews on peptide catalysts, see: a) E. A. C. Davie, S. M.
Mennen, Y. Xu, S. J. Miller, Chem. Rev. 2007, 107, 5759 – 5812;
b) H. Wennemers, Chem. Commun. 2011, 47, 12036 – 12041;
c) M. Freund, S. B. Tsogoeva in Catalytic Methods in Asymmetric
Synthesis: Advanced Materials, Techniques, and Applications
(Eds.: M. Gruttadauria, F. Giacalone), Wiley, Hoboken, 2011,
pp. 529 – 578.
[19] For reviews on supported organocatalysts, see: a) M. Benaglia,
A. Puglisi, F. Cozzi, Chem. Rev. 2003, 103, 3401 – 3429; b) M.
Gruttadauria, F. Giacalone, R. Noto, Chem. Soc. Rev. 2008, 37,
1666 – 1688.
[20] When simple resin-supported l-proline was used as a catalyst,
the enantioselectivity was 25% ee (R selective). Dramatic
changes in the ee values when combining l- or d-Pro with
poly-l-Leu suggest the importance of the a-helical structure of
polyleucine.
[21] The absolute configuration of the major product indicates Si-
face attack of nitromethane on the substrate, which is consistent
with the previously suggested model of the iminium intermedi-
ate in transfer hydrogenation; see: K. Akagawa, H. Akabane, S.
Sakamoto, K. Kudo, Tetrahedron: Asymmetry 2009, 20, 461 –
466.
[22] a) S. G. Ouellet, J. B. Tuttle, D. W. C. MacMillan, J. Am. Chem.
Soc. 2005, 127, 32 – 33; b) J. W. Yang, M. T. H. Fonseca, N.
Vignola, B. List, Angew. Chem. 2005, 117, 110 – 112; Angew.
Chem. Int. Ed. 2005, 44, 108 – 110.
[23] a) X. Wang, B. List, Angew. Chem. 2008, 120, 1135 – 1138;
Angew. Chem. Int. Ed. 2008, 47, 1119 – 1122; b) H. Maeda, S.
Yamada, H. Itoh, Y. Hori, Chem. Commun. 2012, 48, 1772 –
1774.
[24] When the catalyst recovered from the reaction was reused, the
conversion decreased to 33% after 24 h. Zlotin et al. reported
the mechanism for the deterioration of an amine catalyst by
oxidation in the Michael addition of nitromethane to an a,b-
unsaturated aldehyde (Ref. [14h]). In the present case, such
oxidation is considered to be the cause of deactivation in the
peptide catalyst.
[14] For selected examples, see: a) N. Halland, R. G. Hazell, K. A.
Jørgensen, J. Org. Chem. 2002, 67, 8331 – 8338; b) A. Prieto, N.
Halland, K. A. Jørgensen, Org. Lett. 2005, 7, 3897 – 3900; c) L.
Hojabri, A. Hartikka, F. M. Moghaddam, P. I. Arvidsson, Adv.
Synth. Catal. 2007, 349, 740 – 748; d) L. Zu, H. Xie, H. Li, J.
Angew. Chem. Int. Ed. 2012, 51, 12786 –12789
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