Stabilized α-helix-catalyzed enantioselective epoxidation of α,β-unsaturated ketones

Article abstract of DOI:10.1021/ol101435w

(Equation Presented). Chiral cyclic α-amino acid containing oligopeptide catalyzed highly enantioselective epoxidation of α,β-unsaturated ketones and the α-helical secondary structure of the peptide catalyst were revealed by X-ray crystallographic analysis.

Full text of DOI:10.1021/ol101435w

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3564-3566
Stabilized r-Helix-Catalyzed
Enantioselective Epoxidation of
r,ꢀ-Unsaturated Ketones
Masanobu Nagano,†,⊥ Mitsunobu Doi,‡ Masaaki Kurihara,§ Hiroshi Suemune,† and
Masakazu Tanaka*,†,|
Graduate School of Pharmaceutical Sciences, Kyushu UniVersity, 3-1-1 Maidashi,
Higashi-ku, Fukuoka 812-8582, Japan, DiVision of Organic Chemistry,
National Institute of Health Sciences, Tokyo 158-8501, Japan, Osaka UniVersity of
Pharmaceutical Sciences, Osaka 569-1094, Japan, and Graduate School of Biomedical
Sciences, Nagasaki UniVersity, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
matanaka@nagasaki-u.ac.jp
Received June 22, 2010
ABSTRACT
Chiral cyclic r-amino acid containing oligopeptide catalyzed highly enantioselective epoxidation of r,ꢀ-unsaturated ketones and the r-helical
secondary structure of the peptide catalyst were revealed by X-ray crystallographic analysis.
Poly L-R-amino acid catalyzed epoxidation of chalcone is
known as the Julia´-Colonna asymmetric reaction.1 Many
research endeavors of chemists have been devoted to disclosing
the reaction mechanisms, overcoming substrate limitations, and
developing a more efficient asymmetric reaction.2 In the
reaction, poly L-R-amino acids might form R-helical structures,
and at their R-helical N-terminal, three or four NH protons of
amide are important for asymmetric induction. To stabilize the
R-helical structure of the oligomer catalyst, polyethyleneglycol
and resin-attached L-Leu oligomers have been developed, and
thus the high molecular weight and insolubility of catalysts were
in part overcome.2,3 Also, R,R-disubstituted amino acids
(dAAs) were used to induce a helical structure, but dAA-
containing oligomers formed 310-helices, which did not give
an epoxide of high enantiomeric excess.2d,4 On the basis of
our studies of dAA peptides,5 we reasoned that cyclic amino
acid containing L-Leu-based peptides would form elaborate
R-helical structures5d and would catalyze the asymmetric
epoxidation of (E)-chalcone. Here we demonstrate the
† Kyushu University.
(2) (a) Porter, M. J.; Roberts, S. M.; Skidmore, J. Bioorg. Med. Chem.
1999, 7, 2145–2156. (b) Carrea, G.; Colonna, S.; Kelly, D. R.; Lazcano, A.;
Ottolina, G.; Roberts, S. M. Trends Biotechnol. 2005, 23, 507–513. (c) Kelly,
D. R.; Roberts, S. M. Biopolymers (Pept. Sci.) 2006, 84, 74–89. (d) Berkessel,
A.; Koch, B.; Toniolo, C.; Rainaldi, M.; Broxterman, Q. B.; Kaptein, B.
‡ Osaka University of Pharmaceutical Sciences.
§ National Institute of Health Sciences.
| Nagasaki University.
⊥ Research Fellow of the Japan Society for the Promotion of Science.
(1) (a) Julia´, S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed. 1980,
19, 929–931. (b) Julia´, S.; Guixer, J.; Masana, J.; Rocas, J.; Colonna, S.;
Annuziata, R.; Molinari, H. J. Chem. Soc., Perkin Trans. 1982, 1, 1317–
1324.
Biopolymers (Pept. Sci.) 2006, 84, 90–96, and references cited therein
.
(3) (a) Geller, T.; Roberts, S. M. J. Chem. Soc., Perkin Trans. I 1999,
1397–1398. (b) Kelly, D. R.; Bui, T. T. T.; Caroff, E.; Drake, A. F.; Roberts,
S. M. Tetrahedron Lett. 2004, 45, 3885–3888
.
10.1021/ol101435w  2010 American Chemical Society
Published on Web 07/06/2010

enantioselective epoxidation of R,ꢀ-unsaturated ketones and
the relationship between the secondary structure of catalysts
and the enantiomeric excesses of epoxides.
We synthesized chiral cyclic dAA-containing oligomers
Boc-{L-Leu-L-Leu-dAA}n-OMe {n ) 2 (1), 3 (2), and 4 (3);
dAA ) Aib (a), (R,R)-Ac5cdOM (b), (S,S)-Ac5cdOM (c),
(1R,3S)-Ac5cOM (d), (1S,3S)-Ac5cOM (e)} using solution-phase
methods (Figure 1).
X-ray crystallographic analysis revealed that the (1S,3S)-
Ac5cOM hexamer 1e assumed a mixture of (P) 310-/R-helix,
where intramolecular hydrogen bonds of iri+3-type are
formed on the N-terminal side (i ) 0, 1) and those of iri+4-
type are formed on the C-terminal side (i ) 1, 2). Three
crystallographic independent conformers, which are similar
in the peptide backbone, exist in asymmetric units. Contrary
to the 310-/R-helix of 1e, the (1S,3S)-nonamer 2e formed fully
developed right-handed R-helices, where iri+4-type hy-
drogen bonds were observed (Figure 2). Judging from the R
Figure 1. Structures of R,R-disubstituted amino acids and their
peptides.
First, asymmetric epoxidation of (E)-chalcone 7a using
25 mol % of oligomer was examined under conditions of
urea-H2O2 (1.1 equiv) and DBU (5.6 equiv) in THF at 0
°C to room temperature for 24 h.2,4a Selected results are
shown in Table 1. Although the reactions by hexamers 1a-e
Figure 2. 310-/R-helical structure of 1e (a) and R-helical structure
of 2e (b) by X-ray crystallographic analysis.
Table 1. Asymmetric Epoxidation of (E)-Chalcone 7a Using
Boc-Protected Oligomera
value (maxima: θ222/θ208) of the CD spectra in 2,2,2-
trifluoroethanol solution, Aib hexamer and nonamer (R )
0.4) form (P) 310-helices, whereas the cyclic dAA-containing
nonamer and dodecamer (R ) >0.7) assume (P) R-helices.6
In Boc-protected 310-helical peptides, intramolecular hy-
drogen bonds of iri+3-type are formed, and the two
N-terminal NH protons are not involved in intramolecular
hydrogen bonding. On the other hand, in R-helical peptides,
intramolecular hydrogen bonds of iri+4-type are formed,
and the first three N-terminal NH protons are free of
intramolecular hydrogen bonding. According to Roberts’
model,2b,c,7b the three N-terminal N(2)H, N(3)H, and N(4)H
entry
Boc-protected peptide
conversion % ee of 8a %
1
2
2a: Aib nonamer
91
86
86
76
98
84
96
99
92
99
6
20
12
16
82
6
24
40
28
83
2b: (R,R)-Ac5cdOM nonamer
2c: (S,S)-Ac5cdOM nonamer
2d: (1R,3S)-Ac5cOM nonamer
2e: (1S,3S)-Ac5cOM nonamer
3a: Aib dodecamer
3
4
5
6
7
3b: (R,R)-Ac5cdOM dodecamer
3c: (S,S)-Ac5cdOM dodecamer
3d: (1R,3S)-Ac5cOM dodecamer
3e: (1S,3S)-Ac5cOM dodecamer
8
9
10
a Epoxidation proceeded to give a racemic epoxide 8a in 50% conversion
yield without oligopeptides.
(4) (a) Takagi, R.; Shiraki, A.; Manabe, T.; Kojima, S.; Ohkata, K. Chem.
Lett. 2000, 366–367. (b) Licini, G.; Bonchio, M.; Broxterman, Q. B.;
Kaptein, B.; Moretto, A.; Toniolo, C.; Scrimin, P. Biopolymers (Pept. Sci.)
2006, 84, 97–104.
afforded epoxide 8a of low enantiomeric excesses (7-11%
ee) in 77-91% conversion yield (not shown), elongation of
the peptide chain improved enantiomeric excesses, except
for Aib-containing peptides. It should be noted that side-
chain chiral centers affected enantiomeric excesses, and those
by (1S,3S)-Ac5cOM-containing nonamer 2e and dodecamer
3e were 82-83% ee, which are in contrast to other cases.
(5) (a) Tanaka, M.; Demizu, Y.; Doi, M.; Kurihara, M.; Suemune, H.
Angew. Chem., Int. Ed. 2004, 43, 5360–5363. (b) Tanaka, M.; Anan, K.;
Demizu, Y.; Kurihara, M.; Doi, M.; Suemune, H. J. Am. Chem. Soc. 2005,
127, 11570–11571. (c) Tanaka, M. Chem. Pharm. Bull. 2007, 55, 349–
358, and references cited therein. (d) Demizu, Y.; Tanaka, M.; Nagano,
M.; Kurihara, M.; Doi, M.; Maruyama, T.; Suemune, H. Chem. Pharm.
Bull. 2007, 55, 840–842. (e) Nagano, M.; Tanaka, M.; Doi, M.; Demizu,
Y.; Kurihara, M.; Suemune, H. Org. Lett. 2009, 11, 1135–1137.
(6) See the Supporting Information.
Org. Lett., Vol. 12, No. 15, 2010
3565

protons are crucial for asymmetric induction, and the N(1)H
proton is less important.7 In Boc-protected R-helical peptides,
the N(4)H proton forms an intramolecular hydrogen bond
with the CdO of the protecting group, and thus, the N(4)H
proton may not be available for interaction with the chalcone
intermediate. Thus, we deprotected the Boc-protecting group
to remove the intramolecular hydrogen bond of N(4)H and
examined epoxidation using reduced 5 mol % of oligomers
4-6. The results are summarized in Table 2.
Ac5cdOM and (1S,3S)-Ac5cOM containing nonamers 5c,e and
dodecamers 6c,e afforded epoxides of >95% ee in good yield.
X-ray crystallographic analysis of (S,S)-Ac5cdOM dodecamer
6c shows an R-helical structure, along with disordered DMF
molecules (Figure 3). The disordered DMF molecules
connect to N(1)H and N(3)H protons by hydrogen bonds.7
The chalcone might bind to amide NH protons of the helical
peptide instead of DMF in the initial stage of the reaction.
The generality of asymmetric epoxidation of R,ꢀ-unsatur-
ated ketones 7a-h was examined using 5 mol % of R-helical
nonamer 5e (Table 3). Acyclic (E)-R,ꢀ-unsaturated ketones
Table 2. Asymmetric Epoxidation of (E)-Chalcone 7a Using
N-Terminal Free Oligomers 4-6
Table 3. Asymmetric Epoxidation of R,ꢀ-Unsaturated Ketones
Using N-Terminal Free Nonamer 5e2a,c
entry
N-terminal free peptide
conversion % ee of 8a %
1
4a: Aib hexamer
80
86
86
85
92
91
96
96
97
99
97
99
98
99
99
5
27
31
15
61
29
93
95
72
98
58
96
97
93
98
2
4b: (R,R)-Ac5cdOM hexamer
4c: (S,S)-Ac5cdOM hexamer
4d: (1R,3S)-Ac5cOM hexamer
4e: (1S,3S)-Ac5cOM hexamer
5a: Aib nonamer
entry
substrate
conversion % ee of 8 %
3
1
2
3
4
5
6
7
8
7a: R1 ) Ph, R2 ) Ph
99
43
52
67
99
99
96
94
8a: 98
8b: 96
8c: 97
8d: 97
8e: 98
8f: 97
8g: 96
8h: 97
4
7b: R1 ) Ph, R2 ) Me
5
7c: R1 ) Ph, R2 ) i-Pr
7d: R1 ) Ph, R2 ) t-Bu
7e: R1 ) Ph, R2 ) 2-furanyl
7f: R1 ) Me, R2 ) Ph
6
7
5b: (R,R)-Ac5cdOM nonamer
5c: (S,S)-Ac5cdOM nonamer
5d: (1R,3S)-Ac5cOM nonamer
5e: (1S,3S)-Ac5cOM nonamer
6a: Aib dodecamer
8
9
7g: R1 ) 4-Cl-Ph, R2 ) Ph
7h: R1 ) 4-MeO-Ph, R2 ) Ph
10
11
12
13
14
15
6b: (R,R)-Ac5cdOM dodecamer
6c: (S,S)-Ac5cdOM dodecamer
6d: (1R,3S)-Ac5cOM dodecamer
6e: (1S,3S)-Ac5cOM dodecamer
were suitable as substrates, and all substrates in Table 3 were
converted to epoxides of excellent enantiomeric excesses
(>95% ee), although the yields of 8b-d having an alkyl
substituent as R2 were moderate.
Except for hexamers having Aib and (R,R)-Ac5cdOM
,
In summary, we synthesized chiral cyclic amino acid
containing peptide catalysts for asymmetric epoxidation,
revealed the relationship between the helical structures and
enantiomeric excesses, and remodeled the peptide catalyst
by taking the hydrogen bonding pattern of helices into
consideration. Using 5 mol % of the N-terminal free (1S,3S)-
Ac5cOM nonamer 5e, highly enantioselective epoxidation of
R,ꢀ-unsaturated ketones has been completed. Other cyclic
amino acid containing oligomer-catalyzed asymmetric reac-
tions are currently underway in our group.8
N-terminal free peptides gave better enantiomeric excesses
than Boc-protected ones. In particular, the reaction by (S,S)-
Acknowledgment. This work was supported in part by a
Grant-in-Aid (B) from JSPS, by a Grant-in-Aid for Scientific
Research on Priority Areas (No. 20037054, “Chemistry of
Concerto Catalysis”) from MEXT, and also by a Grant-in-
Aid from the ASAHI GLASS Foundation.
Supporting Information Available: Experimental sec-
tion, spectroscopic data of new compounds, and crystal-
lographic details (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
OL101435W
(7) (a) Berkessel, A.; Gasch, N.; Glaubitz, K.; Koch, C. Org. Lett. 2001,
3, 3839–3842. (b) Kelly, D. R.; Roberts, S. M. Chem. Commun. 2004, 2018–
2020.
Figure 3. X-ray crystallographic analysis of H-{L-Leu-L-Leu-(S,S)-
Ac5cdOM}4-OMe 6c. (a) View perpendicular to the R-helical axis
and (b) along the R-helical axis.
(8) Maayan, G.; Ward, M. D.; Kirshenbaum, K. Proc. Natl. Acad. Sci.
U.S.A. 2009, 106, 13679–13684.
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