H.-M. Xu et al. / Tetrahedron Letters 54 (2013) 1380–1383
1383
Removal of the Boc group of 6 using TFA was coupled with 7 using
HATU and DIPEA as a coupling reagent,16 leading to the dipeptide 8
(95% yield). Compound 8 was N-deprotected and coupled with 9 to
afford tripeptide 10 (85% yield). The corresponding building block
the National Basic Research Program of China (2009CB522300 and
2013CB127505), the National New Drug Innovation Major Project
of China (2011ZX09307-002-02), the Foundation of Chinese
Academy of Sciences (Hundred Talents Program), and the
Natural Science Foundation of Yunnan Province (2012GA003 and
2011FZ206).
9 was prepared from
benzyl bromide followed by the reaction with 1H-pyrrole-2-car-
bonyl chloride. Sequential addition of N-Boc-(S)-Abu or N-Boc-
L-allo-threonine by protection with Boc2O and
L
-
allo-Thr under standard procedures (HATU/DIPEA as coupling
reagent) and cleavage of silyl ether of the hydroxyl group with
TBAF delivered tetrapeptide 11 or 12. The cyclization is a key step
in the synthesis of cyclic peptides. After the Boc group and benzyl
in tetrapeptide 11 were respectively removed, the free amine/free
acid linear tetrapeptide 3 was dissolved in DMF slowly dropwise to
HATU/DIPEA in CH2Cl2. The crude product was purified by prepara-
tive HPLC and provided the pure cyclic peptide 1 in 31% yield.
Tetrapeptide 12 has an identical sequence to 11, but the major
difference came from the last residue (11 R = H, 12 R = OH). There-
fore, protection of two hydroxyl groups by TBDMSCI in 12 afforded
the corresponding compound 13, followed by the deprotection of
Boc protecting group with TFA and then reduced by hydrogenation
with Pd/C to give the linear tetrapeptide 14. The resulting peptide
was cyclized in the presence of HATU/DIPEA to give 15. Treatment
of cyclic peptide 15 with TBAF to cleave silyl ether of the hydroxyl
group and purification by preparative HPLC provided the pure cyc-
lic peptide 2. The yield of 4 steps was 19% (from 13 to 2). Synthetic
Supplementary data
Supplementary data (detailed isolation procedures, Marfey’s
reaction, 1D and 2D NMR spectra, MS, IR, UV, CD, [a] of com-
pounds 1 and 2, synthetic intermediates are supplied) associated
with this article can be found, in the online version, at http://
files and InChiKeys of the most important compounds described
in this article.
D
References and notes
1. National Pharmacopoeia Committee of China, Ch. P, Chinese Medical Science
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271–273.
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10. (a) Saviano, G.; Benedetti, E.; Cozzolino, R.; Capua, A. D.; Laccetti, P.; Palladino,
P.; Zanotti, G.; Amodeo, P.; Tancredi, T.; Rossi, F. Biopolymers 2004, 76, 477–
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1 and 2 were identical to the natural 1 and 2 in all respects ([a]D,
MS, 1H, 13C NMR, COSY, HMQC, HMBC, NOESY spectra, and HPLC
analysis, see Supplementary data).
To the best of our knowledge, tataricins A (1) and B (2) repre-
sent a new type of cyclotetrapeptide backbone with a 4 2,4Pro side
chain in nature. Therefore, the possible biosynthetic pathway of 1
and 2 should be quite different from other common Compositae-
type cyclopeptides. In general, linear peptidyl backbone of
Compositae-type cyclopeptides could be generated by Nonriboso-
mal Peptide Synthetase (NRPS).17 After the hydrolyzation,
common Compositae-type cyclopeptides could be reached by
immediate cyclization and chlorination. The hydrolyzed linear
peptide might be further modified by elimination, carbonyl transf-
eration, and cyclization, which could lead to compounds 1 and 2
(Scheme 2).
Biological activity of 1 and 2 was tested for cytotoxicity against
BGC-823 and Hela cells as well as immunosuppressive9 activity.
Unfortunately, 1 and 2 are inactive.
In summary, we have isolated two rare cyclotetrapeptides, that
is, tataricins A (1) and B (2), from the traditional Chinese medicine
A. tataricus. Their structures and absolute configurations were
unambiguously determined using a combination of spectroscopic
11. (a) Fan, J. T.; Chen, Y. S.; Xu, W. Y.; Du, L. C.; Zeng, G. Z.; Zhang, Y. M.; Su, J.; Li,
Y.; Tan, N. H. Tetrahedron Lett. 2010, 51, 6810–6813; (b) Fan, J. T.; Su, J.; Peng, Y.
M.; Li, Y.; Li, J.; Zhou, Y. B.; Zeng, G. Z.; Yan, H.; Tan, N. H. Bioorg. Med. Chem.
2010, 18, 8226–8234; (c) Han, J.; Ji, C. J.; He, W. J.; Shen, Y.; Leng, Y.; Xu, W. Y.;
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12. Tataricin A (1): white powder; ½a D15:0
ꢀ26.1 (c 0.13, C5H5N); UV (MeOH) kmax
ꢁ
(log
e
) 204 (4.26), 268 (4.20); CD (c 0.098, MeOH) k (4e) 227 (ꢀ7.48), 271
(0.89); IR (KBr) m ;
max 3424, 1660, 1533, 1410, 1305, 1149, 1075, 752, 578 cmꢀ1
1H NMR (600 MHz, DMSO-d6) and 13C NMR (150 MHz, DMSO-d6), see Table 1;
HRESIMS m/z 514.2295 [M+H]+ (calcd for C25H32N5O7, 514.2301).
13. Tataricin B (2): white powder; ½a D13:8
ꢀ5.3 (c 0.15, C5H5N); UV (MeOH) kmax
ꢁ
(log
e
) 207 (4.15), 267 (4.17); CD (c 0.098, MeOH) k (4e) 227 (ꢀ6.92), 271
(0.58); IR (KBr) mmax 3426, 2930, 1725, 1679, 1548, 1289, 1127, 1076,
data, the advanced Marfey’s method, and
a total synthesis.
749 cmꢀ1 1H NMR (600 MHz, DMSO-d6) and 13C NMR (150 MHz, DMSO-d6),
;
Compounds 1 and 2 possess a unique cyclotetrapeptide backbone
and a 4 2,4Pro side chain, which add a new skeleton to the diverse
group of Compositae-type cyclopeptides. Additionally, the efficient
synthesis of 1 and 2 should allow for the preparation of various
analogues of this kind of cyclic peptide.
see Table 1; HREIMS m/z 529.2179 [M]+ (calcd for C25H31N5O8, 529.2173).
14. (a) Fujii, K.; Ikai, Y.; Mayumi, T.; Oka, H.; Suzuki, M.; Harada, K. Anal. Chem.
1997, 69, 3346–3352; (b) Fujii, K.; Ikai, Y.; Oka, H.; Suzuki, M.; Harada, K. Anal.
Chem. 1997, 69, 5146–5151.
15. (a) Brady, S. F.; Varga, S. L.; Freidinger, R. M.; Schwenk, D. A.; Mendlowski, M.;
Holly, F. W.; Veber, D. F. J. Org. Chem. 1979, 44, 3101–3105; (b) Tang, Y. C.; Xie,
H. B.; Tian, G. L.; Ye, Y. H. J. Pept. Res. 2002, 60, 95–103.
16. Davies, J. S. J. Pept. Sci. 2003, 9, 471–501.
17. Xu, W. Y.; Li, L. L.; Du, L. C.; Tan, N. H. Acta Biochim. Biophys. Sin. 2011, 43,
757–762.
Acknowledgments
This work was supported by the National Natural Science Foun-
dation of China (U1032602, 91013002, 21102152, and 30725048),