3694
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6. (a) Terada, M.; Ishih, A.; Tungtrongchitr, A.; Sano, M.;
sulfate, the filtrate was concentrated in vacuo and the
residue purified by silica gel chromatography to give the
MePhe or (R)-PhLac-containing enniatins.
Shomura, T. Jpn. J. Parasitol. 1993, 42, 199; (b) Kachi, S.;
Terada, M.; Hashimoto, H. Jpn. J. Pharmacol. 1998, 77,
235; (c) Jeschke, P.; Harder, A.; von Samson-Himmelstj-
erna, G.; Etzel, W.; Gau, W.; Thielking, G.; Bonse, G.
Pest Manag. Sci. 2002, 58, 1205, and references therein.
7. (a) Zahner, H.; Taubert, A.; Harder, A.; von Samson-
Himmelstjerna, G. Acta Trop. 2001, 80, 19; (b) Willson, J.;
Amliwala, K.; Davis, A.; Cook, A.; Cuttle, M. F.; Kriek,
N.; Hopper, N. A.; O’Connor, V.; Harder, A.; Walker, R.
J.; Holden-Dye, L. Curr. Biol. 2004, 14, 1374.
18. Cyclo(N-methyl-(S)-isoleucinyl-(R)-2-hydroxy-isovaleryl-N-
methyl-(S)-isoleucyl-(R)-2-hydroxy-isovaleroyl-N-methyl-
(S)-phenylalanyl-(R)-2-hydroxy-isovaleroyl) 6 (yield: 39%):
13C NMR (100 MHz, CDCl3) d 2· 10.6, 15.7, 15.9, 2·
18.2, 4· 18.3, 18.6, 19.0 (CH3), 25.0, 25.2, 29.4, 29.7, 30.3,
35.0 (CH), 31.4, 31.8, 36.0 (NCH3), 59.6, 60.5, 62.6 (CH–
N), 74.8, 75.2 (CH–O), 169.3, 170.3, 170.4 (CO–O), 169.1,
169.2, 169.7 (CO–N). EI-MS: m/e 715 (M+, 27).
8. (a) Charles, S. D.; Altreuther, G.; Reinemeyer, C. R.;
Buch, J.; Settje, T.; Cruthers, L.; Kok, D. J.; Bowmann,
D. D.; Kazakos, K. R.; Jenkins, D. J.; Schein, E. Parasitol.
Res. 2005, 97, S33; (b) Reinemeyer, C. R.; Charles, S. D.;
Buch, J.; Settje, T.; Altreuther, G.; Cruthers, L.; McCall,
J. W.; Young, D. R.; Epe, C. Parasitol. Res. 2005, 97, S41;
(c) Altreuther, G.; Borgsteede, F. H. M.; Buch, J.; Charles,
S. D.; Cruthers, L.; Epe, C.; Young, D. R.; Krieger, K. J.
Parasitol. Res. 2005, 97, S51; (d) Altreuther, G.; Buch, J.;
Charles, S. D.; Davis, W. L.; Krieger, K. J.; Radeloff, I.
Parasitol. Res. 2005, 97, S58.
9. (a) Jeschke, P.; Benet-Buchholz, J.; Harder, A.; Etzel, W.;
Schindler, M.; Thielking, G. Bioorg. Med. Chem. Lett.
2003, 13, 3285; (b) Jeschke, P.; Benet-Buchholz, J.;
Harder, A.; Etzel, W.; Schindler, M.; Gau, W.; Weiss,
H.-Ch. Bioorg. Med. Chem. Lett. 2006, 16, 4410.
10. (a) Hamill, R. L.; Higgens, C. E.; Boaz, H. E.; Gorman,
M. Tetrahedron Lett. 1969, 4255; (b) Suzuki, A.; Kanaoka,
M.; Isogai, A.; Murakoshi, S.; Ichinoe, M.; Tamura, S.
Tetrahedron Lett. 1977, 2167; (c) Fukuda, T.; Arai, M.;
Tomoda, H.; Omura, S. J. Antibiot. 2004, 57, 117.
11. Ohyama, M.; Ohishi, M. Okada, Y.; Koyama, M.; Sumi,
S.; Murai, Y.; Takagi, M.; Okada, T.; Sakanaka, O.;
Yoneta, T.; Iinuma, K.; Shibahara, K. PCT Int. Appl., WO
9419334, 1994 (Meiji Seika Kaisha, Ltd, Tokyo, Japan).
12. Jeschke. P.; Scherkenbeck, J.; Haberkorn, A.; Harder, A.;
Mencke, N. DE 4412492, 1995 (Bayer A.-G., Germany).
13. All depsipeptide intermediates gave satisfactory spectral
and/or accurate EI-mass data.
14. Jeschke, P.; Etzel, W.; Harder, A.; Schindler, M.; Go¨hrt,
A.; Pleiss, U.; Kleinkauf, H.; Zocher, R.; Thielking, G.;
Gau, W.; Bonse, G. In Bioorganic Chemistry: Highlights
and New Aspects; Diederichsen, U., Lindhorst, T. K.,
Westermann, B., Wessjohan, L. A., Eds.; Wiley-VCH:
Weinheim, 1999; p 207.
15. (a) Kunz, H.; Lerchen, H. G. Angew. Chem. 1984, 96, 798;
(b) Sefler, A. M.; Kozlowski, M. C.; Guo, T.; Bartlett, P.
A. J. Org. Chem. 1997, 62, 93; (c) Krause, M.; Lindemann,
A.; Glinski, M.; Hornbogen, T.; Bonse, G.; Jeschke, P.;
Thielking, G.; Gau, W.; Kleinkauf, H.; Zocher, R.
J. Antibiot. 2001, 54, 797.
19. Synthesis of cyclo(N-methyl-(S)-isoleucyl-(R)-lactyl-N-
methyl-(S)-isoleucyl-(R)-lactyl-N-methyl-(S)-phenylala-
nyl-(R)-lactyl) 8. DIEA (0.24 g, 1.92 mmol) and BOP-Cl
(0.235 g, 0.92 mmol) were added at 0 ꢂC to a solution of
N-methyl-(S)-isoleucyl-(R)-lactyl-N-methyl-(S)-isoleu-
cyl-(R)-lactyl-N-methyl-(S)-phenylalanyl-(R)-lactic acid
(0.50 g, 0.769 mmol) in CH2Cl2 (DCM) (500 mL) and
the mixture was stirred for 24 h at room temperature.
Then a further amount of DIEA (0.24 g, 1.92 mmol) and
BOP-Cl (0.235 g, 0.92 mmol) was added at 0 ꢂC and
stirring continued for 24 h at room temperature. The
reaction solution was washed twice with water, and the
organic phase separated off and dried over Na2SO4. The
filtrate was concentrated in vacuo and the residue purified
by silica gel chromatography (cyclohexane/ethyl acetate,
2:1) to give cyclo(N-methyl-(S)-isoleucyl-(R)-lactyl-N-
methyl-(S)-isoleucyl-(R)-lactyl-N-methyl-(S)-phenylala-
nyl-(R)-lactyl) (1.3 g, 67%). 13C NMR (100 MHz, CDCl3)
d 2· 10.6, 15.3, 16.2 (CH3), 24.4, 24.5 (CH2), 32.2, 34.2
(CH), 31.0, 31.3, 36.0 (NCH3), 34.8 (CH2-phenyl), 60.0,
60.1, 64.4 (CH–N), 66.3, 65.6, 67.8 (CH–O), 126.6, 128.5,
129.4, 137.7 (C-phenyl), 169.8, 169.6, 170.2 (CO–O),
168.9, 169.0, 169.6 (CO–N). EI-MS: m/e 631 (M+, 23).
20. Cyclo(N-methyl-(S)-isoleucinyl-(R)-lactyl-N-methyl-(S)-
isoleucyl-(R)-phenyllactyl-N-methyl-(S)-isoleucyl-(R)-lac-
tyl) 10 (yield: 52–63%): 13C NMR (100 MHz, CDCl3) d 2·
16.4, 21.7, 21.8, 22.9 (CH3), 2· 22.8, 23.0, 24.6, 2· 24.9,
37.6 (CH2), 36.8, 2· 37.4 (CH), 31.0, 31.7, 32.8 (NCH3),
55.3, 54.6, 56.5 (CH–N), 67.0, 67.1, 70.2 (CH–O), 126.9,
128.4, 129.6, 135.5 (arom-C), 170.3, 170.5, 170.6 (CO–O),
168.8, 2· 169.7 (CO–N). EI-MS: m/e 673 (M+, 41).
21. Weckwerth, W.; Miyamoto, K.; Iinuma, K.; Krause, M.;
Glinski, M.; Storm, T.; Bonse, G.; Kleinkauf, H.; Zocher,
R. J. Biol. Chem. 2000, 275, 17909.
22. Cyclo(N-methyl-(S)-alanyl-(R)-lactyl-N-methyl-(S)-isoleu-
cyl-(R)-phenyllactyl-N-methyl-(S)-alanyl-(R)-lactyl) 12
(yield: 42%): 13C NMR (100 MHz, CDCl3) d 10.7, 13.7,
15.4, 16.0, 16.3, 16.4 (CH3), 23.8, 37.7 (CH2), 31.7 (CH),
29.7, 29.8, 30.1 (NCH3), 53.7, 54.0, 59.9 (CH–N), 67.6,
68.7, 71.2 (CH–O), 127.2, 128.4, 129.3, 135.3 (arom-C),
169.3, 170.9, 171.5 (CO–O), 168.2, 168.9, 171.2 (CO–N).
EI-MS: m/e 589 (M+, 26).
23. General procedure for hydrogenation of MePhe or (R)-
PhLac-containing enniatins. Enniatin (0.8 mmol) was
hydrogenated at 50 ꢂC in water (8.4 mL) in presence of
0.1 g PtO2 as catalyst for 18 h at 4–5 bar (autoclave). Then
the reaction solution was filtered, the filtrate concentrated
in vacuo and the residue purified by silica gel chromatog-
raphy (cyclohexan/ethyl acetate, 2:1) to give the Chm-
substituted enniatins.
16. Schmidt, U.; Lieberknecht, A.; Griesser, H.; Utz, R.;
Beuttler, T.; Bartkowiak, F. Synthesis 1986, 361.
17. General method for macrocyclization of the N-terminal
protected hexadepsipeptide pentafluorophenyl esters. N-
terminal protected linear hexadepsipeptide pentafluoro-
phenyl ester (1.08 mmol) in 50 ml of absolute dioxan was
injected uniformely during the course of 6 h at an internal
temperature of 95 ꢂC into a rapidly stirred suspension of
1.5 g of 10% Pd–C in 550 ml of absolute dioxan containing
12 ml ethanol and 4-pyrrolidino-pyridine (1.08 mmol).
During this process, hydrogen was passed through the
reaction solution. Stirring was continued for a further 4 h at
95 ꢂC, and for 12 h at room temperature. Then the reaction
solution was filtered and the filtrate was concentrated in
vacuo. The oily residue was taken up in chloroform and
washed twice with 5% citric acid, NaHCO3 solution and
twice with water. The organic phase was dried over sodium
Cyclo(N-methyl-(S)-isoleucinyl-(R)-lactyl-N-methyl-(S)-
isoleucyl-(R)-lactyl-N-methyl-(S)-cyclohexylmethylala-
nyl-(R)-lactyl) 9 (yield: 100%): 13C NMR (100 MHz,
CDCl3)d 10.6, 10.8, 2· 15.7, 16.2, 16.5, 16.9, (CH3), 24,4,
24.7 (CH2), 33.3, 34.2 (CH), 31.1, 32.5, 32.6 (NCH3), 26.0,
26.1, 26.3, 32.5, 33.5, 35.8 (Chm), 56.2, 60.1, 61.9 (CH–N),
66.6, 66.8, 67.3 (CH–O), 169.9, 170.0, 170.6 (CO–O), 168.9,
169. 3, 169.5 (CO–N). EI-MS: m/e 637 (M+, 25).