4
Tetrahedron Letters
room temperature was treated. Additionally, the Fmoc
deprotection and coupling with Fmoc-Gly-OH by
DIPC/HOBt/DIPEA in DMF were carried out. Finally, the Fmoc
deprotection followed by cleavage from resin with TFA gave the
crude tripeptide, which was one major product of Gly-Phe-Gly
(
(
9) by HPLC analysis. Ant-containing peptides, Gly-Ant-Gly
11) and Ant-Gly, were not observed by HPLC analysis.
Next, we demonstrated the glycine-2-chlorotrityl resin with
Fmoc-Phe-OH (6) (3 eq.), Fmoc-Ala-OH (2) (0.5 eq.), H-Ant-
OH (7) (0.5 eq.), DIPC (3 eq.), HOBt (3 eq.), DIPEA (4 eq.) in
DMF for 2h at room temperature was treated. After the
elongation of Gly and cleavage from resin, the corresponding
crude tripeptides, which were two major products of Gly-Phe-
Gly (9) and Gly-Ala-Gly (10), were detected by HPLC analysis.
Nevertheless 3 equivalents of Fmoc-Phe-OH (6) and 0.5
equivalent of Fmoc-Ala-OH (2) as the second coupling reaction
were used in Fmoc-SPPS, approximately 2:1 mixture of Gly-Phe-
Gly (9) and Gly-Ala-Gly (10) was appeared. It means that
coupling of Fmoc-Ala-OH (2) proceed quickly and therefore
contamination of Fmoc-Ala-OH (2) is extremely risky. In
contrast, Ant-containing peptides, Gly-Ant-Gly (11) and Ant-
Gly, were not observed by HPLC analysis in spite of the mixing
of H-Ant-OH (7) into the reaction mixture. Even if there is the
impurity of H-Ant-OH (7) and/or the corresponding Fmoc-Ant-
OH, it is possible to decrease the by-product formation (Scheme
Scheme 5. Synthesis of tripeptides Gly-Phe-Gly (9) to compere
reactivity of Phe, Ala and Ant. Conversions (%) were estimated
from HPLC.
In conclusion, we investigated the availability of Fmoc-
OPhth (3) to avoid formation of Fmoc-βAla-OH (2) by the
Lossen rearrangement. Fmoc-OPhth (3) was synthesized from
cheap phthalic anhydride in 3 steps. Fmoc protection of amino
acids by Fmoc-OPhth (3) was carried out in good yields. In
contrast, the reaction times of Fmoc formation were similar to
those of Fmoc-OSu (1); therefore, we recommend Fmoc-OPhth
5).
(
3) as the reagent for Fmoc protection as Fmoc-Ala-OH (2) is
contamined by Fmoc-OSu (1).
8
9
.
.
Lapatsanis, L.; Milias, G.; Froussios, K.; Kolovos, M. Synthesis 1983,
71-673.
Obkircher, M.; Stahelin, C.; Dick, F. J. Pep. Sci. 2008, 14, 763-766.
Acknowledgments
6
This work was supported in part by a Grant-in-Aid from the
Japan Society for the Promotion of the Science (240145) to H.K.
Y.T. is grateful to the Japan Society for the Promotion of Science
Fellowships for young scientists (00465).
10. Isidro-Llobet, A.; Just-Baringo, X.; Ewenson, A.; Alvarez, M.; Albericio,
F. Biopolymers (Pep. Sci.) 2007, 88, 733-737.
1
1. Rao, B. L. M.; Nowshuddin, S.; Jha, A.; Divi, M. K.; Rao, M. N. A.
Tehrahedron Lett. 2016, 57, 4220-4223.
1
1
1
1
2. Warner-Lambert pharmaceutical company, BG Patent, 898, 692, 1962.
3. Nowshuddin, S.; Reddy, A. R. Tetrahedron: Asymmetry 2011, 22, 22-25.
4. Kikuchi, M.; Konno, H. Tetrahedron Lett. 2011, 52, 3872-3875.
5. Kikuchi, M.; Konno, H. Org. Lett. 2014, 16, 4324-4327.
References and notes
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Supplementary Material
Supplementary material that may be helpful in the review process should
be prepared and provided as a separate electronic file. That file can then be
transformed into PDF format and submitted along with the manuscript and
graphic files to the appropriate editorial office.
3
4
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3
953.
Henklein, P.; Heyne, H. U.; Halatsch, W. R.; Niedrich, H. Synthesis
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1
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Schon, I.; Kisfaludy, L. Synthesis 1986, 303-305.
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376.
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Sigler, G. F.; Fuller, W. D.; Chaturvedi, N. C.; Goodman, M.; Verlander,
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