800
N. Yamagata et al. / Tetrahedron Letters 52 (2011) 798–801
Figure 3. X-ray diffraction structure of R3,7R-2, as viewed from positions (A) perpendicular to and (B) along the helical axis. The chloroform molecule has been omitted. The
linker is shown in green.
Table 3
dominant conformation of the linear peptide R3,7R-1 was a (P)
Asymmetric epoxidation of (E)-chalcone using the N-terminal free peptides H-S3,7S-1,
H-S3,7R-1, H-R3,7S-1, H-R3,7R-1, H-S3,7S-2, H-S3,7R-2, H-R3,7S-2, and H-R3,7R-2
310-helix. Through the cyclization of R3,7R-1 into R3,7R-2, its
dominant conformation was changed to a (P) -helical struc-
a
ture. In addition, its N-terminal free peptide was successfully
used as a catalyst for the enantioselective epoxidation of (E)-
chalcone. The design of further stabilized short helical peptides
and their application to asymmetric reactions is currently
underway.
Peptide (5 mol %)
UHP (1.1 Eq.)
DBU (5.6 Eq.)
O
O
O
S
Ph
Ph
Ph
Ph
THF, 0º to rt, 24h
R
(E)-chalcone (3)
(2
R
,3
S
)-4
Acknowledgments
Entry
Peptide
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
H-S3,7S-1
H-S3,7S-2
H-S3,7R-1
H-S3,7R-2
H-R3,7S-1
H-R3,7S-2
H-R3,7R-1
H-R3,7R-2
90
89
91
89
82
86
93
89
58
65
57
64
35
37
30
69
This work was supported, in part, by a Grant-in-Aid for Young
Scientists (B) (21790018) from the Ministry of Education, Science,
Sports, and Culture of Japan and a Grant-in-Aid for Scientific Re-
search (C) (22590114) from the Japan Society for the Promotion
of Science.
References and notes
1. (a) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C.; Broxterman, Q. B.;
Kaptein, B. J. Incl. Phenom. Macrocycl. Chem. 2005, 51, 121–136; (b) Kaul, R.;
Balaram, P. Bioorg. Med. Chem. 1999, 7, 105–117; (c) Gellman, S. H. Acc. Chem.
Res. 1998, 31, 173–180; (d) Wysong, C. L.; Yokum, T. S.; MacLaughlin, M. L.;
Hammer, R. P. CHEMTECH 1997, 27, 26–33.
Next, we used the N-terminal free peptides17 H-S3,7S-1, H-S3,7R-
1, H-R3,7S-1, H-R3,7R-1, H-S3,7S-2, H-S3,7R-2, H-R3,7S-2, and H-
R3,7R-2 as catalysts for the enantioselective epoxidation of (E)-
chalcone (3).18 The epoxidation of 3 (0.3 mmol) using 5 mol % of
peptides was carried out in THF (2 mL) containing urea-H2O2
(UHP, 0.33 mmol) and DBU (1.68 mmol) under aerobic conditions
with the temperature gradually increasing from 0 °C to room tem-
perature over 24 h.19 In all cases, the epoxidation proceeded
smoothly to afford the product (2R,3S)-4 in high yield (Table 3).
The use of the linear and cyclic H-S3,7S- and H-S3,7R-peptides affor-
ded the epoxide (2R,3S)-4 with moderate enantiomeric excess (en-
tries 1, 2, 3, and 4), but that involving H-R3,7S-peptides gave
(2R,3S)-4 in a poor enantiomeric excess (entries 5 and 6). On the
other hand, the enantioselectivity of (2R,3S)-4 was improved by
2. (a) Crisma, M.; Formaggio, F.; Moretto, A.; Toniolo, C. Biopolymers (Pept. Sci.)
2006, 84, 3–12; (b) Royo, S.; Borggraeve, W. M. D.; Peggion, C.; Formaggio, F.;
Crisma, M.; Jiménez, A. I.; Cativiela, C.; Toniolo, C. J. Am. Chem. Soc. 2005, 127,
2036–2037; (c) Dehner, A.; Planker, E.; Gemmecker, G.; Broxterman, Q. B.;
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Kurihara, M.; Suemune, H. Angew. Chem., Int. Ed. 2004, 43, 5360–5363.
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Kaptein, B. Biopolymers (Pept. Sci.) 2004, 76, 162–176; (b) Karle, I. L. Biopolymers
(Pept. Sci.) 2001, 60, 351–365; (c) Venkatraman, J.; Shankaramma, S. C.;
Balaram, P. Chem. Rev. 2001, 101, 3131–3152; (d) Demizu, Y.; Yamagata, N.;
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the use of a stabilizing H-R3,7R-2
a-helical peptide (entries 7 and
8). Whether linear or cyclic peptides (entries 1–6) were used barely
affected the enantiomeric excess of (2R,3S)-4. However, in the case
of H-R3,7R-peptides, the enantiomeric product excess was strongly
affected by cyclization (entries 7 and 8); that is, the linear R3,7R-1
peptide forming the 310-helix gave a poor enantiomeric excess, but
the cyclic R3,7R-2 peptide forming the
a-helix gave a moderate
enantiomeric excess. Since the R3,7R-2 peptide has a much stron-
ger tendency to form
a-helix than the other peptides, it worked
more as an effective catalyst.18b,20
5. Glenn, M. P.; Pattenden, L. K.; Reid, R. C.; Tyssen, D. P.; Tyndall, J. D. A.; Birch, C.
J.; Fairlie, D. P. J. Med. Chem. 2002, 45, 371–381.
6. The length of the cross-linked subunit was designed by reference to the
following report: Blackwell, H. E.; Sadowsky, J. D.; Howard, R. J.; Sampson, J. N.;
Chao, J. A.; Steinmetz, W. E.; O’Leary, D. J.; Grubbs, R. H. J. Org. Chem. 2001, 66,
5291–5302.
In summary, we have synthesized four linear heptapeptides,
S3,7S-1, S3,7R-1, R3,7S-1, and R3,7R-1, and four cyclic peptides,
S3,7S-2, S3,7R-2, R3,7S-2, and R3,7R-2, containing Aib as a helical
promoter and serine derivatives as a cross-linking system. The