1084
S. Hara et al. / Tetrahedron Letters 47 (2006) 1081–1085
Cl
a
b
16
MeO
O
O
NHFmoc
Me
Me
25
O
R1
Me
R2
S
H
S
Me
Me
O
HN
O
HN
N
N
c-e
Me
Me
Me
R
N
O
N
O
OMe
OMe
OTBS
OTBS
R3O2C
NHR4
HN
O
Me
O
Me
Me
O
O
Me
O
H
28a: R =
28b: R =
H
H
Me
H
f
26a: R1 = Me, R2 = H, R3 = Bn, R4 = Fmoc
26b: R1 = H, R2 = Me, R3 = Bn, R4 = Fmoc
halipeptin A
27a: R1 = Me, R2 = H, R3 = H, R4 = H
27b: R1 = H, R2 = Me, R3 = H, R4 = H
Scheme 3. Construction of halipeptin A. Reagents and conditions: (a) (COCl)2, CH2Cl2, 23 °C, 5 h; (b) 24, DIEA, CH2Cl2, 0–23 °C, 6.5 h, 89% from
15; (c) Et2NH–MeCN (1:1), 0–23 °C, 1.5 h, 97%; (d) H2, Pd-black, MeOH–buffer (10:1), 23 °C, 8 h, 40% and 35% of the epimer; (e) HATU, DIEA,
CH2Cl2, 23 °C, 24 h, 61% and 29% of the epimer; (f) 4 M HCl–dioxane, ether, 0–23 °C, 4 h, 35% and 50% of the epimer.
2. Monica, C. D.; Randazzo, A.; Bifulco, G.; Cimino, P.;
Aquino, M.; Izzo, I.; De Riccardis, F.; Gomez-Paloma, L.
Tetrahedron Lett. 2002, 43, 5707–5710.
3. Snider, B. B.; Duvall, J. R. Tetrahedron Lett. 2003, 44,
3067–3070.
4. Monica, C. D.; Maulucci, N.; De Riccardis, F.; Izzo, I.
Tetrahedron: Asymmetry 2003, 14, 3371–3378.
5. Izzo, I.; Avallone, E.; Corte, L. D.; Maulucci, N.; De
Riccardis, F. Tetrahedron: Asymmetry 2004, 15, 1181–1186.
6. Hara, S.; Makino, K.; Hamada, Y. Tetrahedron 2004, 60,
8031–8035.
during the cyclization. Final deprotection of the TBS
group in 28a was carried out using 4 M HCl–dioxane,
which caused again extensive epimerization at the a-
position of the thiazoline. Pure halipeptin A (1)17 was
obtained after chromatographic purification in 35%
yield. Interestingly, when [(R)-(ala)Thz]-epimer 27b was
subjected to macrolactamization under the same condi-
tions, the TBS ether of [(R)-(ala)Thz]-halipeptin A was
obtained in 73% yield without any epimerization at the
N-MeOHIle residue.
7. Yu, S.; Pan, X.; Lin, X.; Ma, D. Angew. Chem., Int. Ed.
2005, 44, 135–138.
8. Nicolaou, K. C.; Kim, D. W.; Schlawe, D.; Lizos, D. E.;
de Noronha, R. G.; Longbottom, D. A. Angew. Chem.,
Int. Ed. 2005, 44, 4925–4929.
9. Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2003, 125, 10808–10809.
10. Kiyooka, S.-I.; Kaneko, Y.; Komura, M.; Matsuo, H.;
Nakano, M. J. Org. Chem. 1991, 56, 2276–2278.
11. Abbreviations: DMP (Dess–Martin periodinane), DEAD
(diethyl azodicarboxylate), KHMDS (potassium hexa-
methylsilazide), EDCI (1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride), DMAP (4-(dimethyl-
amino)pyridine), DIEA (N,N-diisopropylethylamine),
BMTB (2-bromo-3-methyl-4-methylthiazolium bromide),
HATU (O-(7-azabenzotriazol-1yl)-N,N,N0,N0-tetramethyl-
uronium hexafluorophosphate).
In conclusion, we have succeeded in total synthesis of
halipeptin A through stereoselective construction of
the HTMMD fragment. Further studies on the synthesis
of halipeptins and the relatives for biological evaluation
are underway.
Acknowledgements
This work was financially supported in part by Grant-
in-Aid for Scientific Research on Priority Areas
(17035015) from The Ministry of Education, Culture,
Sports, Science, and Technology (MEXT). We are
grateful for a JSPS research fellowship for young scien-
tists (to S.H.).
12. Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000,
365–366.
13. Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 14, 4833–
4836.
References and notes
14. You, S.-L.; Razavi, H.; Kelly, J. W. Angew. Chem., Int.
Ed. 2003, 42, 83–85.
15. (a) Hamada, Y.; Kawai, A.; Kohno, Y.; Hara, O.; Shioiri,
T. J. Am. Chem. Soc. 1989, 111, 1524–1525; (b) Hamada,
1. Randazzo, A.; Bifulco, G.; Giannini, C.; Bucci, M.;
Debitus, C.; Cirino, G.; Gomez-Paloma, L. J. Am. Chem.
Soc. 2001, 123, 10870–10876.