LETTER
The Synthesis of Novel Thiazole Containing Cyclic Peptides via Cyclooligomerisation Reactions
1725
O
R
S
O
R
O
R
S
N
H
S
S
N
N
N
N
H
N
H
R
O
O
R
S
S
N
N
N
N
NH
HN
R
NH
HN
O
R
NH
HN
O
N
H
N
N
N
S
O
R
O
R
S
S
S
R
O
9
14
R = i-Pr
R = CH2Ph
7
13
R = i-Pr
R = CH2Ph
R = i-Pr
8
15 R = CH2Ph
O
R
O
R
O
R
S
S
S
S
S
N
S
N
N
H
H
H
N
N
N
N
N
N
R
O
O
R
O
R
O
R
R
O
R
O
NH
HN
NH
HN
NH
HN
N
N
N
N
N
N
H
N
H
H
N
N
S
S
S
S
S
S
R
11
O
R
O
R
O
R = i-Pr
R = CH2Ph
10
16
R = i-Pr
R = CH2Ph
12
18
R = i-Pr
R = CH2Ph
17
Acknowledgement
(9) The following general cyclooligomerisation procedure is
described: Diisopropylethylamine (3 eq.) and FDPP (1.5 eq.)
were added to a suspension of 6 (2 mmol) in anhydrous aceto-
nitrile (42 mL) and the solution was stirred at ambient
temperature for 18 h before evaporating to dryness in vacuo.
The residue was partitioned between ethyl acetate (50 mL)
and aq. HCl (2 M, 50 mL) and the separated organic layer was
washed with aq. HCl (2 M, 50 mL). The combined aqueous
solutions were back extracted with ethyl acetate (50 mL) and
then the organic solutions were combined and washed
successively with aq. NaOH (1 M, 2 x 50 mL), H2O (50 mL)
and brine (50 mL). The solution was dried (MgSO4) and the
solvent was then removed under reduced pressure to leave a
mixture of cyclic peptide products which were separated by
column chromotography (silica gel) or by preparative HPLC
(Dynamax Silica Gel Cartridge Column, 30 cm x 10 mm
internal diameter).
We thank the EPSRC for a studentship (to JSH), and Astra Charn-
wood, SmithKline Beecham (CASE award to JSH) and Pfizer Ltd
for their support of this work.
References and Notes
(1) a) V. Admi, U. Afek and S. Carmeli, J. Nat. Prod., 1996, 59,
396; b) D. J. Freeman and G. Pattenden, Tetrahedron Lett.,
1998, 39, 3251.
(2) a) B. M. Degnan, C. J. Hawkins, M. F. Lavin, E. J. McCaffery,
D. L. Parry, A. L. van den Brenk and D. J. Watters, J. Med.
Chem., 1989, 32, 1349; b) F. J. Schmitz, M. B. Ksetbati, J. S.
Chang, J. L. Wang, M. B. Hossain, D. van der Helm, M. H.
Engel, A. Serban and J. A. Silfer, J. Org. Chem., 1989, 54,
3463; c) C. D. J. Boden and G. Pattenden, Tetrahedron Lett.,
1995, 36, 6153.
(3) a) Y. Hamamoto, M. Endo, M. Nagawaka, T. Nakanishi and
K. Mizukawa, J. Chem. Soc., Chem. Commun., 1983, 323;
b) Y. Hamada, S. Kato and T. Shioiri, Tetrahedron Lett., 1985,
26, 3223.
(4) For reviews on the isolation, structure and synthesis of the
Lissoclinum cyclic peptides see a) P. Wipf, in Alkaloids:
Chemical and Biological Perspectives, ed. S. W. Pelletier,
Elsevier, Amsterdam, 1998, vol 12., p. 187; b) P. Wipf, Chem.
Rev., 1995, 95, 2115.
(5) J. P. Michael and G. Pattenden, Angew. Chem., Int. Ed. Engl.,
1993, 32, 1.
(6) a) M. W. Bredenkamp, C. W. Holzapfel and W. J. Zyl, Synth.
Commun., 1990, 20, 2235; b) E. Aguilar and A. I. Meyers,
Tetrahedron Lett., 1994, 35, 2473; c) C. D. J. Boden, G.
Pattenden and T. Ye, Synlett, 1995, 417.
(7) C. J. Moody and M. C. Bagley, J. Chem. Soc., Perkin Trans.
1, 1998, 601.
(8) All new compounds gave satisfactory spectroscopic data
together with high resolution mass spectrometric and/or
microanalytical data.
(10) Spectroscopic data for 7: mp 258 - 260 °C (from Et2O); [a]298
D
+126.8 (c = 0.53, CHCl3); dH (360 MHz, CDCl3) 8.45 (3H, d,
J 9.3, 3 x NH), 8.1 (3H, s, 3 x CH=C), 5.4 (3H, dd, J 9.3 and
5.8, 3 x NHCH), 2.3 (3H, m, 3 x CH(CH3)2), 1.1 (9H, d, J 6.8,
3 x CH3), 1.0 (9H, d, J 6.8, 3 x CH3); dC (90 MHz, CDCl3)
168.6 (C=O), 159.7 (Cq), 149.1 (Cq), 123.4 (CH), 55.4 (CH),
35.3 (CH), 18.8 (CH3), 18.3 (CH3); m/z (ES) 569 (M+ Na)+;
Found C, 52.5; H, 5.6; N, 15.0 %. C24H30N6O3S3 requires C,
52.7; H, 5.5; N, 15.0 %.
Spectroscopic data for 8: mp 152 - 154 °C (from Et2O); [a]298
D
+204.6 (c = 0.57, CHCl3); dH (360 MHz, CDCl3) 8.0 (4H, s, 4
x CH=C), 7.85 (4H, d, J 9.1, 4 x NH), 5.2 (4H, dd, J 9.1 and
8.2, 4 x NHCH), 2.6 (4H, m, 4 x CH(CH3)2), 1.2 (12H, d, J 6.7,
4 x CH3), 1.0 (12H, d, J 6.6, 4 x CH3); dC (90 MHz, CDCl3)
169.3 (C=O), 160.3 (Cq), 148.9 (Cq), 124.2 (CH), 55.3 (CH),
32.6 (CH), 19.6 (CH3), 18.9 (CH3); m/z (ES) 751 (M + Na)+,
1479 (2M + Na)+; Found C, 50.9; H, 5.5; N, 14.6 %.
C32H40N8O4S4.0.5 H2O requires C, 50.9; H, 5.7; N, 14.8 %.
(11) V. F. Bystrov, V. T. Ivanov, S. L. Portnova, T. A. Balshova
and Y. A. Ovchinnikov, Tetrahedron, 1973, 29, 873.
Synlett 1999, No. 11, 1723–1726 ISSN 0936-5214 © Thieme Stuttgart · New York