Peptide-catalyzed diastereo- and enantioselective cyclopropanation of aromatic α,β-unsaturated aldehydes

Article abstract of DOI:10.1021/ol402227y

Highly diastereo- and enantioselective cyclopropanation of aromatic α,β-unsaturated aldehydes was achieved using a resin-supported peptide catalyst under aqueous conditions. In the peptide sequence, the residue possessing an oxygen atom with the appropriate length of the side chain was essential for attaining good diastereoselectivity.

Full text of DOI:10.1021/ol402227y

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Peptide-Catalyzed Diastereo- and
Enantioselective Cyclopropanation of
Aromatic r,β-Unsaturated Aldehydes
Kengo Akagawa, Shota Takigawa, Iman Sho Nagamine, Ryota Umezawa, 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 August 5, 2013
ABSTRACT
Highly diastereo- and enantioselective cyclopropanation of aromatic r,β-unsaturated aldehydes was achieved using a resin-supported peptide
catalyst under aqueous conditions. In the peptide sequence, the residue possessing an oxygen atom with the appropriate length of the side chain
was essential for attaining good diastereoselectivity.
Cyclopropane structures are widely found in natural
products and pharmaceuticals,1 and also the key inter-
mediates for further chemical transformations.2 Thus, a
variety of the synthetic methods for stereoselective con-
struction of cyclopropane rings have been developed.3
Compared to the procedures using auxiliaries or a stoi-
chiometric amount of chiral reagents, controlling the
stereochemistry of cyclopropanation in a catalytic manner
is advantageous for the synthesis of optically active
cyclopropanes. In addition to metal-catalyzed asymmetric
reactions,4 muchattention has beenpaid to organocatalytic
cyclopropanation over the past decade.5,6 After pioneering
works by Aggarwal et al.7 and Gaunt et al.8 using chiral
sulfides and cinchona alkaloid-derived catalysts, respec-
tively, MacMillan et al. achieved enantioselective cyclopro-
panation of R,β-unsaturated aldehydes with sulfur ylides in
the presence of an amine catalyst to afford 1,2,3-trisubsti-
tued cyclopropanes 1 (Scheme 1).9 Since such trisubstituted
cyclopropanes possess three stereogenic centers, deliberate
control of diastereoselectivity as well as for enantioselec-
tivity is requisite, and developing a new catalytic system
suitable for this purpose is a challenging subject. In 2011,
Ye et al. reported the stereoselective synthesis of diaste-
reomerically complementary cyclopropane 2 catalyzed
by a diphenylprolinol silyl ether, in which a wide scope
of R,β-unsaturated aldehydes was demonstrated.10 On
the other hand, the applicability of cyclopropanation for
obtaining diastereomers 1 with aromatic R,β-unsaturated
aldehydes is still limited. For example, although the reaction
with cinnamaldehyde is reported to give product 1 with
(1) For reviews, see: (a) Donaldson, W. A. Tetrahedron 2001, 57,
8589–8627. (b) Chen, D. Y.-K.; Pouwer, R. H.; Richard, J.-A. Chem.
Soc. Rev. 2012, 41, 4631–4642. (c) Pietruszka, J. Chem. Rev. 2003, 103,
1051–1070. (d) Brackmann, F.; de Meijere, A. Chem. Rev. 2007, 107,
4493–4537.
(2) For reviews, see: (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003,
103, 1151–1196. (b) Wessjohann, L. A.; Brandt, W. Chem. Rev. 2003,
103, 1625–1647. For selected examples, see: (c) Sohn, S. S.; Bode, J. W.
Angew. Chem., Int. Ed. 2006, 45, 6021–6024. (d) Bode, J. W.; Sohn, S. S.
J. Am. Chem. Soc. 2007, 129, 13798–13799. (e) Li, G.-Q.; Dai, L.-X.;
You, S.-L. Org. Lett. 2009, 11, 1623–1625. (f) Lv, H.; Mo, J.; Fang, X.;
Chi, Y. R. Org. Lett. 2011, 13, 5366–5369.
(4) For recent selected examples, see: (a) Kakei, H.; Sone, T.;
Sohtome, Y.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007,
129, 13410–13411. (b) Zhu, S.;Perman, J. A.; Zhang, X. P. Angew. Chem.,
Int. Ed. 2008, 47, 8460–8463. (c) Sherrill, W. M.; Rubin, M. J. Am. Chem.
Soc. 2008, 130, 13804–13809. (d) Phan, D. H. T.; Kou, K. G. M.; Dong,
V. M. J. Am. Chem. Soc. 2010, 132, 16354–16355. (e) Gao, L.; Hwang,
G.-S.; Ryu, D. H. J. Am. Chem. Soc. 2011, 133, 20708–20711.
(3) For reviews, see: (a) Lebel, H.; Marcoux, J.-F.; Molinaro, C.;
Charette, A. B. Chem. Rev. 2003, 103, 977–1050. (b) Pellissier, H.
Tetrahedron 2008, 64, 7041–7095.
r
10.1021/ol402227y
XXXX American Chemical Society

89% ee,9a enantioselectivity decreases to 79% ee with
4-methoxycinnamaldehyde,2e and there is no example
for other substituents on the aromatic ring.11 This type
of reaction was also extended to N-heterocyclic carbene-
catalyzed oxidative cyclopropanation of R,β-unsaturated
aldehydes12 and the use of β,γ-unsaturated R-ketoesters13
or R,β-unsaturated ketones14 as substrates. However, the
reactions with substituted aromatic groups have the draw-
back that either the yield or stereoselectivity is only low to
moderate. In this context, we set out to develop a catalyst
for asymmetric cyclopropanation with aromatic R,β-
unsaturated aldehydes to afford products 1 with high yield
and stereoselectivity.
Scheme 1. Organo-catalyzed Cyclopropanation of
R,β-Unsaturated Aldehydes
(5) For selected examples, see: (a) Vignola, N.; List, B. J. Am. Chem.
Soc. 2004, 126, 450–451. (b) Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.;
Liao, W.-W.; Li, K.; Tang, Y.; Wu, Y.-D.; Dai, L.-X. J. Am. Chem. Soc.
2006, 128, 9730–9740. (c) McCooey, S. H.; McCabe, T.; Connon, S. J. J.
Org. Chem. 2006, 71, 7494–7497. (d) Kojima, S.; Suzuki, M.; Watanabe,
A.; Ohkata, K. Tetrahedron Lett. 2006, 47, 9061–9065. (e) Xie, H.; Zu,
L.; Li, H.; Wang, J.; Wang, W. J. Am. Chem. Soc. 2007, 129, 10886–
10984. (f) Fan, R.; Ye, Y.; Li, W.; Wang, L. Adv. Synth. Catal. 2008, 350,
Figure 1. Resin-supported peptide catalyst.
In recent years, we have focused on resin-supported
peptide catalysts as secondary amine organocatalysts
(Figure 1).15,16 The peptide consisting of a β-turn motif,
D-Pro-Aib (Aib = 2-aminoisobutyric acid),17 and a helical
part is a versatile catalyst promoting various asymmetric
organocatalytic reactions especially in aqueous media. The
turn structure formed by the terminal five residues is
essential for controlling enantioselectivity, and the hydro-
phobic helical part enhances reactions and stabilizes the
whole peptide structure under aqueous conditions.15a We
envisioned that this type of catalyst might be also effective
for regulating the diastereoselectivity of the reaction be-
cause of the highly customizable property of peptides by
modifying sequences with various kinds of amino acids.
Herein, we report the diastereo- and enantioselective cy-
clopropanation of aromatic R,β-unsaturated aldehydes
with a resin-supported peptide catalyst.
ꢀ
2488–2492. (g) Ibrahem, I.; Zhao, G.-L.; Rios, R.; Vesely, J.; Sunden,
ꢀ
H.; Dziedzic, P.; Cordova, A. Chem.;Eur. J. 2008, 14, 7867–7879. (h)
Wascholowski, V.; Hansen, H. M.; Longbottom, D. A.; Ley, S. V.
Synthesis 2008, 1269–1275. (i) Vesely, J.; Zhao, G.-L.; Bartoszewicz, A.;
ꢀ
Cordova, A. Tetrahedron Lett. 2008, 49, 4209–4212. (j) Marini, F.;
Sternativo, S.; Del Verme, F.; Testaferri, L.; Tiecco, M. Adv. Synth.
Catal. 2009, 351, 1801–1806. (k) Lv, J.; Zhang, J.; Lin, Z.; Wang, Y.
ꢀ
Chem.;Eur. J. 2009, 15, 972–979. (l) Companyo, X.; Alba, A.-N.;
ꢀ
Cardenas, F.; Moyano, A.; Rios, R. Eur. J. Org. Chem. 2009, 3075–3080.
(m) Zhang, J.-M.; Hu, Z.-P.; Dong, L.-T.; Xuan, Y.-N.; Lou, C.-L.;
Yan, M. Tetrahedron: Asymmetry 2009, 20, 355–361. (n) Terrasson, V.;
van der Lee, A.; de Figueiredo, R. M.; Campagne, J. M. Chem.;Eur. J.
2010, 16, 7875–7880. (o) Pesciaioli, F.; Righi, P.; Mazzanti, A.; Bartoli,
G.; Bencivenni, G. Chem.;Eur. J. 2011, 17, 2842–2845. (p) Russo, A.;
Meninno, S.; Tedesco, C.; Lattanzi, A. Eur. J. Org. Chem. 2011, 5096–
ꢀ
5103. (q) Rueping, M.; Sunden, H.; Hubener, L.; Sugiono, E. Chem.
Commun. 2012, 48, 2201–2203. (r) Del Fiandra, C.; Piras, L.; Fini, F.;
Disetti, P.; Moccia, M.; Adamo, M. F. A. Chem. Commun. 2012, 48,
3863–3865. (s) Dou, X.; Lu, Y. Chem.;Eur. J. 2012, 18, 8315–8319. (u)
Das, U.; Tsai, Y.-L.; Lin, W. Org. Biomol. Chem. 2013, 11, 44–47. (v)
Raveendran, A. E.; Paul, R. R.; Suresh, E.; Nair, V. Org. Biomol. Chem.
2010, 8, 901–905.
€
(6) For reviews of organocatalysis, see: (a) Erkkila, A.; Majander, I.;
Cyclopropanation of 4-nitrocinnamaldehyde with a sul-
fur ylide waschosenasa modelreaction (Table 1). Initially,
we checked the general tendency of this reaction with some
typical amine catalysts in chloroform for 24 h. When the
reaction was performed with indoline-2-carboxylic acid 4
which was employed in MacMillan’s report,9 three diaster-
eomers were generated with low reaction efficiency (Table 1,
entry 1). Although diastereomer 1 was produced selectively
to some extent, the enantioselectivity was quite low. With
L-proline as a catalyst, enhancement of the reaction rate
and enantioselectivity was observed with lowered diastereo-
selectivity (Table 1, entry 2). A versatile secondary amine
catalyst, diphenylprolinol silyl ether 6,18 promoted the
Pihko, P. M. Chem. Rev. 2007, 107, 5416–5470. (b) Mukherjee, S.; Yang,
J. W.; Hoffman, S.; List, B. Chem. Rev. 2007, 107, 5471–5569. (c)
Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638–4660.
(d) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem.,
Int. Ed. 2008, 47, 6138–6171. (e) Bertelsen, S.; Jørgensen, K. A. Chem.
Soc. Rev. 2009, 38, 2178–2189.
(7) (a) Aggarwal, V. K.; Smith, H. W.; Jones, R. V. H.; Fieldhouse, R.
Chem. Commun. 1997, 1785–1786. (b) Aggarwal, V. K.; Alonso, E.;
Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem., Int. Ed.
2001, 40, 1433–1436.
(8) (a) Papageorgiou, C. D.; de Dios, M. A. C.; Ley, S. V.; Gaunt,
M. J. Angew. Chem., Int. Ed. 2004, 43, 4641–4644. (b) Johansson,
C. C. C.; Bremeyer, N.; Ley, S. V.; Owen, D. R.; Smith, S. C.; Gaunt,
M. J. Angew. Chem., Int. Ed. 2006, 45, 6024–6028.
(9) (a) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005,
127, 3240–3241. (b) Lakhdar, S.; Appel, R.; Mayr, H. Angew. Chem., Int.
Ed. 2009, 48, 5034–5037.
(10) Li, W.; Li, X.; Ye, T.; Wu, W.; Liang, X.; Ye, J. Tetrahedron Lett.
2011, 52, 2715–2718.
(11) (a) Hartikka, A.; Arvidsson, P. I. J. Org. Chem. 2007, 72, 5874–
(15) (a) Akagawa, K.; Suzuki, R.; Kudo, K. Adv. Synth. Catal. 2012,
354, 1280–1286. (b) Akagawa, K.; Umezawa, R.; Kudo, K. Beilstein J.
Org. Chem. 2012, 8, 1333–1337. (c) Akagawa, K.; Kudo, K. Angew.
Chem., Int. Ed. 2012, 51, 12786–12789.
(16) For reviews of peptide catalysts, see: (a) Miller, S. J. Acc. Chem.
Res. 2004, 37, 601–610. (b) Davie, E. A. C.; Mennen, S. M.; Xu, Y.;
Miller, S. J. Chem. Rev. 2007, 107, 5759–5812. (c) Wennemers, H. Chem.
Commun. 2011, 47, 12036–12041.
ꢀ
ꢀ
5877. (b) Hartikka, A.; Slosarczyk, A. T.; Arvidsson, P. I. Tetrahedron:
Asymmetry 2007, 18, 1403–1409. (c) Zhao, Y.-H.; Zhao, G.; Cao, W.-G.
Tetrahedron: Asymmetry 2007, 18, 2462–2467. (d) Zhao, Y.-H.; Zheng,
C.-W.; Zhao, G.; Cao, W.-G. Tetrahedron: Asymmetry 2008, 19, 701–
708.
(12) Biswas, A.; De Sarkar, S.; Tebben, L.; Studer, A. Chem. Commun.
2012, 48, 5190–5192.
(13) Cheng, Y.; An, J.; Lu, L.-Q.; Luo, L.; Wang, Z.-Y.; Chen, J.-R.;
(17) (a) Haque, T. S.; Little, J. C.; Gellman, S. H. J. Am. Chem. Soc.
1996, 118, 6975–6985. (b) Blank, J. T.; Miller, S. J. Biopolymers 2006, 84,
38–47.
Xiao, W.-J. J. Org. Chem. 2011, 76, 281–284.
(14) Wang, J.; Liu, X.; Dong, S.; Lin, L.; Feng, X. J. Org. Chem. 2013,
78, 6322–6327.
(18) Mielgo, A.; Palomo, C. Chem.;Asian J. 2008, 3, 922–948.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Cyclopropanation of an R,β-Unsaturated Aromatic
Aldehyde
Table 3. Substrate Scope for Diastereoselective Asymmetric
Cyclopropanation of R,β-Unsaturated Aromatic Aldehydesa
conversion
(%)a
ee (%)
entry
cat.
1/2/3a
of 1 (2)
1
4
5
6
7
7
18
84
51
98
97
71:11:18
37:15:48
67:11:22
35:56:9
65:28:7
27 (3)
2
À45 (À65)
75 (61)
3
4
5b
89 (98)
95 (96)
a Determined by 1H NMR spectroscopy of crude mixture. b Reaction
was performed in THF/H2O (1:2) for 3 h using 1.2 equiv each of
dimethylphenacylsulfonium bromide and sodium bicarbonate.
Table 2. Screening of Peptide Sequences
conversion
(%)
ee (%)
entry
AA1
AA2
Ser
1/2/3
of 1
a Unless otherwise noted, the reaction was performed in 0.05 mmol
scale. b The reaction was performed in 0.4 mmol scale with 10 mol % of
peptide catalyst 8 and 1.0 equiv each of dimethylphenacylsulfonium
bromide and sodium bicarbonate.
1
Ser
Thr
Hse
Hse
Hse
Ala
Trp
Trp
Trp
Trp
Trp
Trp
Trp
97
81
80
76
51
80
84
87
92
92
82
95
93
83:11:6
83:8:9
90
89
95
81
81
96
99
97
99
96
96
95
94
2
Thr
3
Hse
85:9:6
4
Ala
74:13:13
63:18:19
88:9:3
5
Trp
6
Hse
reaction with moderate efficiency and stereoselectivity
(Table 1, entry 3). Compared to these cases, a better reaction
efficiency and enantioselectivity were attained by using pep-
tide catalyst 7 despite the low diastereoselectivity (Table 1,
entry 4). With this peptide catalyst, the reaction rate was
dramatically increased under aqueous conditions; the reaction
almost completed in 3 h to afford diastereomer 1 as a major
product with good enantioselectivity (Table 1, entry 5).19
7
Hse
89:9:2
8
Ser
84:12:4
93:5:2
9
Ser(Me)
Nva
Hse(Me)
Met
10
11
12
13
80:14:6
85:11:4
81:13:6
79:13:8
Nle
(19) For cyclopropanation of R,β-unsaturated aldehydes using water
as reaction media, see: (a) Uria, U.; Vicario, J. L.; Badıa, D.; Carrillo, L.;
Reyes, E.; Pesquera, A. Synthesis 2010, 701–713. For a review of
organocatalytic reactions under aqueous conditions, see: Gruttadauria,
M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33–57.
Org. Lett., Vol. XX, No. XX, XXXX
C

Performing the reaction in aqueous media has another
merit in the fact that a water-soluble sulfonium salt can be
used and is converted to the ylide in situ by adding an
inorganic base such as sodium bicarbonate; hence, the use
of a generally unstable sulfur ylide can be avoided.
is supported by the result that the use of a bulky amino
acid residue causing large steric repulsion decreases the
diastereoselectivity (Table 1, entry 5), compared to the
cases with less bulky side chains at the AA2 position
(Table 2, entries 10 and 13).
Next, in order to achieve high diastereoselectivity for
this reaction, the peptide sequence was optimized
(Table 2). When the D-Pro-Aib moiety in peptide catalyst
7 takes a turn structure, the Trp-Trp part is likely to be
located around the substrate aldehyde attached to the
terminalprolyl group asaniminium intermediate.20 There-
fore, we considered that this part largely affected the
stereoselectivity of the reaction and replaced the Trp-Trp
with other amino acid residues. First, this position was
scanned withthepairwiseuseofamino acids, and wefound
that those possessing hydroxyl groups gave promising
results with respect to diastereoselectivity (Table 2, entries
1 to 3). To determine which of the two consecutive amino
acids is critical for the stereoselectivity, one of the homo-
serines in the catalyst used in entry 3 was altered to alanine
ortryptophan(Table 2, entries 4, 5 vsentries 6, 7). Itturned
out that the hydroxy-substituted amino acid at the fifth
residue (AA2) was crucial for good diastereoselectivity.
Then, by fixing the fourth residue (AA1) with tryptophan,
further optimization for the fifth position was conducted.
While introducing serine instead of homoserine somewhat
decreased the diastereoselectivity (Table 2, entry 8), the
use of the methyl ether of serine improved the selectivity
(Table 2, entry 9). The methyl ether of homoserine was not
as good as that of serine (Table 2, entry 11). These data
indicate that both the position of the oxygen atom and
the length of the side chain affect the diastereochemical
outcome of the reaction. With other residues having
no oxygen atom such as norvaline, methionine, and
norleucine, the diastereoselectivity was lowered in all cases
(Table 2, entries 10, 12, and 13). Although the role of the
oxygen functionality is not clear at present, it is presumed
that an attracting interaction between the oxygen atom on
the amino acid side chain and the sulfonium moiety in the
reaction intermediate might increase the selectivity for
the three-membered-ring-closing step.21 This hypothesis
Finally, the substrate scope for the diastereo- and
enantioselective cyclopropanation of aromatic R,β-
unsaturated aldehydes using the optimum peptide catalyst
8 was investigated (Table 3). Regardless of the nature of
the substituents on the phenyl ring, the reaction proceeded
with high diastereoselectivity to afford products 1 in good
yield and excellent enantioselectivity (Table 3, entries 1
to 7, and 13). The substrates with naphthyl and thienyl
groups were also applicable for this reaction system
(Table 3, entries 14 and 15). These results demonstrate
the high generality of the peptide-catalyzed cyclopropana-
tion of aromatic substrates for the stereoselective synthesis
of diastereomer 1.22 Because a resin-supported catalyst
has the advantage of high reusability, the reaction with the
catalyst 8 recovered by filtration was examined (Table 3,
entries 8 to 12). A significant decrease in the catalytic
ability was not observed until the fifth reuse of the catalyst.
In conclusion, highly diastereo- and enantioselective
cyclopropanation of aromatic R,β-unsaturated aldehydes
was realized with a resin-supported peptide catalyst. In-
troducing the amino acid residue having an oxygen atom
at theappropriate positioninthe sidechain withthe proper
length was important for the diastereoselectivity. This
study shows the high potential and customizability of
peptide catalysts, and further application for other stereo-
selective reactions can be expected.
Acknowledgment. This work was supported by JSPS
KAKENHI Grant Number 23550116 (to K.K.) and by
MEXT KAKENHI Grant number 24105506 (to K.K.).
Supporting Information Available. Experimental pro-
cedure and spectroscopic data for products. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(22) The reaction with an aliphatic aldehyde resulted in low diaster-
eoselectivity. For example, the use of 3-cyclohexylacrylaldehyde as a
substrate gave a mixture (ca. 1:1) of products 1 and 2.
(20) Akagawa, K.; Akabane, H.; Sakamoto, S.; Kudo, K. Tetrahedron:
Asymmetry 2009, 20, 461–466.
(21) Allwood, B. L.; Crosby, J.; Pears, D. A.; Stoddart, J. F.;
Williams, D. J. Angew. Chem., Int. Ed. 1984, 23, 977–979.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX