Scheme 5 Reagents and conditions: (a) PyBOP1, CH2Cl2, DIPEA (81%); (b) (i) LiOH, THF, MeOH, H2O (2 : 2 : 1), (ii) 10, DCC, DMAP, HOAt,
CH2Cl2 (69% over 2 steps); (c) Pd(OAc)2 (10 mol%), PPh3, THF, morpholine (93%); (d) AgNO3, pyridine, MeOH, 30 min, 0 uC, then HSCH2CH2OH
(10 equiv.), rt (75%); (e) Method A. DCC (1.2 equiv.), THF (0.01 M), 1 h, then DMAP (1.2 equiv.), 16 h (52%); Method B. PyBOP1 (1.2 equiv.), DIPEA
(2.0 equiv.), THF (0.01 M), 16 h (47%).
12 J.-Y. Lu and H.-D. Arndt, J. Org. Chem., 2007, 72, 4205.
respectively. The spectroscopic data for the macrocycle 2 show,
13 D. Taddei, C. Poriel and C. J. Moody, Arkivoc, 2007, Part xi, 56.
inter alia, a signal at 182.8 ppm in its 13C NMR spectrum
14 T. Belhadj, A. Nowicki and C. J. Moody, Synlett, 2006, 3033.
15 M. Iwakawa, Y. Kobayashi, S. Ikuta and J. Yoshimura, Chem. Lett.,
1982, 1975.
characteristic of a thiolactone (cf. the thiolactone carbon in
nosiheptide at 181.3 ppm8). Hence, the synthesis of the macrocyclic
thiodepsipeptide model southern hemisphere for nosiheptide was
completed in an overall yield of 9.6% with a longest linear
sequence of 13 steps.
16 C. Shin, Y. Nakamura, Y. Yamada, Y. Yonezawa, K. Umemura and
J. Yoshimura, Bull. Chem. Soc. Jpn., 1995, 68, 3151.
17 K. Umemura, T. Tate, M. Yamaura, J. Yoshimura, Y. Yonezawa and
C. Shin, Synthesis, 1995, 1423.
In conclusion, the strategy of successive amide, ester and
thioester bond formation between orthogonally protected
dicarboxylate, hydroxy-acid and amino-thiol fragments has proved
to be a viable and robust route towards the lower 20-membered
macrocyclic array of nosiheptide 1. The methodology establishes,
for the first time, that macrocyclic thiodepsipeptides can be
accessed by formation of the thioester bond in the macrocycliza-
tion step, and paves the way for a synthesis of nosiheptide itself.
18 K. Koerber-Ple´ and G. Massiot, Synlett, 1994, 759.
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20 D. J. Bentley, J. Fairhurst, P. T. Gallagher, A. K. Manteuffel,
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21 The synthesis of the 1-hydroxyindole fragment of the closely related
antibiotics, the nocathiacins, has also been reported: K. C. Nicolaou,
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23 R. A. Hughes, S. P. Thompson, L. Alcaraz and C. J. Moody, J. Am.
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