Synthesis of IB-01211, a cyclic peptide containing 2,4-concatenated thia- and oxazoles, via Hantzsch macrocyclization

Article abstract of DOI:10.1021/ol063023c

(Chemical Equation Presented) An efficient and versatile convergent synthesis of IB-01211 based on a combination of peptide and heterocyclic chemistry is described. The key step in the synthesis is macrocyclization through intramolecular Hantzsch formatio

Full text of DOI:10.1021/ol063023c

ORGANIC
LETTERS
2007
Vol. 9, No. 5
809-811
Synthesis of IB-01211, a Cyclic Peptide
Containing 2,4-Concatenated Thia- and
Oxazoles, via Hantzsch
Macrocyclization†
Delia Herna´ndez,‡ Gemma Vilar,‡ Estela Riego,‡ Librada M. Can˜edo,§
|
Carmen Cuevas, Fernando Albericio,*,‡, and Mercedes A
Ä
lvarez*,‡,#
Barcelona Science Park Josep Samitier 1-5, E-08028 Barcelona, Spain
albericio@pcb.ub.es; malVarez@pcb.ub.es
Received December 14, 2006
ABSTRACT
An efficient and versatile convergent synthesis of IB-01211 based on a combination of peptide and heterocyclic chemistry is described. The
key step in the synthesis is macrocyclization through intramolecular Hantzsch formation of the thiazole ring. Dehydration of a free primary
alcohol to furnish the exocyclic methylidene present in the natural product was applied during the macrocyclization.
Naturally occurring, directly linked 2,4-azoles possess fas-
cinating structures and interesting biological activities.
Numerous bis- and trisoxazoles as well as a few oxazole-
thiazoles have been isolated from marine organisms, whereas
linked thiazole-containing natural products have generally
been obtained from marine microorganism cultures.1
Recently, a new cyclic peptide, IB-01211 (Figure 1), was
isolated from the marine microorganism strain ES7-008,
which is phylogenetically close to Thermoactinomyces
genus.2,3 This peptide is strongly cytotoxic to several tumor
cell lines.4 IB-01211, which has no precedent in natural
products, contains four oxazoles, one thiazole, and a tri-
peptide that includes a didehydroamino acid residue. Herein,
* To whom correspondence should be addressed. (F.A.) Tel: (+34) 93
403 7088. (M.A.) Tel: (+34) 93 403 7086. Fax: (+34) 93 403 7126.
† This work was supported by CICYT (BQU 2003-00089), Generalitat
de Catalunya, and Barcelona Science Park.
‡ Barcelona Science Park.
§ Present address: Instituto Biomar S.A., E-24231 Onzonilla, Leo´n, Spain.
| Present address: PharmaMar, E-28770 Colmenar Viejo, Madrid, Spain.
Department of Organic Chemistry, University of Barcelona, 08028
Barcelona, Spain.
# Laboratory of Organic Chemistry, Faculty of Pharmacy, University of
Barcelona, 08028 Barcelona, Spain.
(1) Reviews of the chemistry can be found in: (a) Roy, R. S.; Gehring,
A. M.; Milne, J. C.; Belshaw, P. J.; Walsh, C. T. Nat. Prod. Rep. 1999, 16,
249. (b) Yeh, V. S. C. Tetrahedron 2004, 60, 11995.
Figure 1. Structure of IB-01211 and synthons for its preparation.
10.1021/ol063023c CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/01/2007

an efficient and versatile synthesis of IB-01211 based on a
combination of peptide (dehydration of serine- and phen-
ylserine-containing peptides) and heterocyclic chemistry
(Hantzsch synthesis) is described.5-7 The key step in the
synthesis is a Hantzsch macrocyclization with concomitant
dehydration of the deprotected hydroxy group to render the
didehydro residue.
The synthesis of IB-01211 was designed, following a
biomimetic pathway, through the bond-disconnection de-
picted in Figure 1, which provided three key synthetic
precursors, the dipeptide 1 and the bis-oxazoles 2 and 3.
Several approaches to the target compound could be
followed depending on the order of precursor connection.
Reaction between 2 and 3 with formation of the central
thiazole could give a penta-azole, which could then be
reacted with 1 to achieve macrocyclization. Alternatively,
formation of two peptide bonds among 1, 3, and 2 could
afford a peptide-heterocycle useful for macrocyclization,
whereby concomitant formation of the thiazole ring would
occur at the last step of the synthesis. We opted for this last
approach, using a peptide-tetra-azole, for our synthesis of
IB-01211.
Peptides 1, 4 (precursor of 2), and 5 (precursor of 3) were
prepared in excellent yields from the appropriate amino acids
with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride (EDC‚HCl)/1-hydroxybenzotriazole (HOBt) in the
presence of diisopropylethylamine (DIEA) as coupling
reagent (see the Supporting Information). Hydroxyl groups
involved in oxazole formation were incorporated unprotected.
When needed, N-Boc, methyl ester, and O-t-Bu were used
as protecting groups. These groups were stable in the azole
ring-formation conditions.
followed by cyclization under basic conditions to give an
oxazoline. Finally, oxidation of the oxazoline furnished the
corresponding oxazole. The bis-oxazole 2 was obtained from
the tri-Ser peptide 4 by simultaneous construction of the two
azole rings, using a cyclization-oxidation procedure, fol-
lowed by final transformation of the methyl ester into the
thioamide. Activation of the hydroxy group using (diethyl-
amino)sulfur trifluoride (DAST) in CH2Cl2 at low temper-
ature8 followed by cyclization with K2CO3 afforded the bis-
oxazoline 6, which was oxidized with 1,8-azabicyclo[5.4.0]-
undec-7-ene (DBU)-CCl4 in a mixture of CH3CN and
pyridine (Pyr) to give the bis-oxazole 7.9 Last, reaction of 7
with NH4OH and treatment of the resulting amide 8 with
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-
disulfide (Lawesson’s reagent) provided 2 in 73% yield for
the two steps. To the best of our knowledge, this is the first
report of the one-pot formation of two concatenated oxazoles
by cyclodehydration-oxidation of amino acids.10 The pro-
cedure is faster and higher yielding than sequential formation
of the two rings.11
Preparation of the bis-oxazole 3 (Scheme 1) required more
development because the presence of a PhSer favored
â-elimination over cyclization. The DAST/K2CO3 protocol
for cyclization of Boc-Ser(t-Bu)-PhSer-OMe 5 afforded a
1:2 mixture12 of the desired oxazole 9 and the didehydro-
peptide 10.13 â-Elimination also occurred during the simul-
taneous formation of the two oxazoles when starting from
the tripeptide Boc-Ser(t-Bu)-Ser-PhSer-OMe and using the
DAST/K2CO3 protocol. However, 3 was obtained in 25%
yield via sequential formation of the two oxazole rings
starting from Boc-Ser(t-Bu)-PhSer-OMe 5 by changing the
base to pyridine instead of K2CO3 for cyclization of the
phenylazole ring.
The bis-oxazoles 2 and 3 were prepared from Ser- or
PhSer-containing peptides, respectively (Scheme 1). The
procedure began with activation of the hydroxy group
Cyclization-oxidation of 5 using DAST-Pyr and DBU-
CCl4 gave oxazole 9.8,14 Deprotection of the hydroxy and
amino groups of 9 with trifluoroacetic acid (TFA) and
formation of the amide bond with the bromopyruvic acid
dimethyl acetal15sthe precursor of the Hantzsch synthesiss
using EDC‚HCl/HOBt in CH2Cl2 gave 11, which was in turn
used for the subsequent oxazole-ring formation to afford bis-
(2) Romero, F.; Malet, L.; Can˜edo, M. L.; Cuevas, C.; Reyes, J. WO
2005/000880 A2, 2005.
(3) The same structure was proposed for mechercharmycin A, isolated
from a marine-derived Thermoactinomices sp., by: Kanoh, K.; Matsuo,
Y.; Adachi, K.; Imagawa, H.; Nishizawa, M.; Shizuri, Y. J. Antibiot. 2005,
58, 289.
(4) Can˜edo, M. L.; Mart´ınez, M.; Sa´nchez, J. M.; Ferna´ndez-Puentes, J.
L.; Malet, L.; Pe´rez, J.; Romero, F.; Garc´ıa, L. F. 4th European Conference
on Marine Natural Products, Paris, 2005, poster 54.
(8) Temperature control is crucial in this step because dehydration was
a severe side reaction favored by higher temperatures.
(9) Oxidation of the dioxazoline 6 with DBU-BrCCl3 furnished a 1:1
mixture of 7 and a partially oxidized compound. Other reagents such as
MnO2 in CH2Cl2, NiO2 in benzene at reflux, I2, and KHDMS also gave
mixtures of oxidized products. Further experiments were carried out to
investigate if CCl4 was required. Thus, DBU/CBr4 in CH3CN/Pyr, DBU/
CBr4 in CH3CN, and DBU/CBrCl3 in CH3CN were assayed, but in all cases
the partially oxidized system was the major product.
(10) This strategy was used only for the preparation of the tetrathiazoline/
thiazole of (-)-mirabazole by Akaji, K.; Kuriyama, N.; Kiso, Y. J. Org.
Chem. 1996, 61, 3350, and in the synthesis of tiangazole,which contains a
tetrathiazoline/oxazole system by: Wipf, P.; Venkatraman, S. Synlett 1997,
1.
(5) Recently, Pattenden and Deeley (Deeley, J.; Pattenden, G. Chem.
Commun. 2005, 797) and Takahashi et al. (Doi, T.; Yoshida, M.; Shin-ya,
K.; Takahashi, T. Org. Lett. 2006, 8, 4165) have published syntheses of
YM-216391 and telomestatin, respectively, which are other cyclopeptides
containing concatenated azoles. Telomestatin was described in a patent by
Yamada, S.; Shigeno, K.; Kitagawa, K.; Okajima, S.; Asao, T. (Taiho
Pharmaceutical Co. Ltd., SoseiCo. Ltd.) WO2002248153, 2002; Chem.
Abstr. 2002, 137, 47050.
(6) For a recent review, see: Riego, E.; Herna´ndez, D.; Albericio, F.;
AÄ lvarez, M. Synthesis 2005, 1907.
(7) (a) Raman, P.; Razavi, H.; Kelly, J. W. Org. Lett. 2000, 2, 3289. (b)
You, S.-L.; Razavi, H.; Kelly, J. W. Angew. Chem., Int. Ed. 2003, 42, 83.
(c) Charette, A. B.; Chua, P. J. Org. Chem. 1998, 63, 908. (d) DeRoy, P.
L.; Charette, A. B. Org. Lett. 2003, 5, 4163. (e) Knight, D. W.; Pattenden,
G.; Rippon, D. E. Synlett 1990, 36. (f) Chattopadhyay, S. K.; Kempson, J.;
McNeil, A.; Pattenden, G.; Reader, M.; Rippon, D. E.; Waite, D. J. Chem.
Soc., Perkin Trans. 1 2000, 2415. (g) Stankova, I. G.; Videnov, G. I.;
Golovinsky, E. V.; Jung, G. J. Peptide Sci. 1999, 5, 392. (h) Muir, J. C.;
Pattenden, G.; Thomas, R. M. Synthesis 1998, 613. (i) Phillips, A. J.; Uto,
Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2, 1165. (j)
Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc. 1999,
121, 4924.
(11) The global yield working on a 500 mg scale was 57%. However,
with 2 g of tripeptides, it decreased to 32%, which is still superior to the
28% obtained by sequential formation of the oxazole rings.
1
(12) The proportion of each compound was evaluated by H NMR by
the relative integration of the methyl ester singlets of 9 (3.92 ppm) and 10
(3.84 ppm). A sign of the formation of 10 was the upfield shift of the phenyl
protons as compared to those of 9, which occurs as a result of their
conjugation with the ester. For the ortho protons, the difference in chemical
shift is 0.5 ppm.
(13) Other reagents, such as the Burgess reagent, did not improve the
results.
810
Org. Lett., Vol. 9, No. 5, 2007

Scheme 1. Total Synthesis of IB-01211
oxazole 3. Compound 12 may be sequentially prepared in
reveals singlets at 6.06 and 6.70 ppm, due to the two
methylidene protons, and four singlets, corresponding to the
protons of the azole ringssall indicative of formation of IB-
01211. The IB-01211 obtained had the same spectroscopic
data and HPLC retention time as the natural product.16
The total synthesis of the cyclic peptide IB-01211, which
contains 2,4-concatenated thia- and oxazoles, using a con-
vergent strategy is described. This strategy combines peptide
chemistry approaches for the preparation of the backbone
and the formation of the oxazole structures by dehydration-
oxidation of Ser- containing peptides, and the Hantzsch
synthesis for the elaboration of the thiazole unit.
92% yield from 3 by methyl ester hydrolysis with LiOH,
followed by condensation with N-deprotected 1 using EDC‚
HCl/HOBt/DIEA as an activating reagent. Introduction of
the bis-oxazole 2, followed by selective N-deprotection of 2
with 25% TFA, and reaction of the resulting amine with the
acid from the saponification of 12, using the same conditions
as before, gave the peptide-heterocycle 13 in 94% yield.
As 13 has the open skeleton of the target natural compound,
it possesses the proper functionalities to obtain the latter:
the protected R-bromo ketone and the thioamide needed for
the thiazole ring formation and the protected alcohol precur-
sor of the exocyclic methylidene. Deprotection of 13 with
formic acid afforded a peptide-heterocycle with the free
hydroxyl and carbonyl group precursors of the exocyclic
double bond and the thiazole ring, respectively. Treatment
of a dilute solution of the resulting compound with NaHCO3
followed by addition of trifluoroacetic anhydride (TFAA)
and 2,6-lutidine gave IB-01211 in 11% yield (from 13).
Formation of the thiazole ring, macrocyclization, and dehy-
dration were achieved in a one pot-reaction as the last step
Acknowledgment. This study was partially supported by
CICYT (BQU 2003-00089), Generalitat de Catalunya, and
the Barcelona Science Park. We gratefully acknowledge
PharmaMar S.L. for performing the preliminary biological
tests. D.H. (Barcelona Science Park) thanks the Ministerio
de Educacio´n y Ciencia for a predoctoral fellowship, and
E.R. (Barcelona Science Park) thanks the Principado de
Asturias for a postdoctoral fellowship.
1
of the synthesis. The H NMR spectrum of the product
Supporting Information Available: Experimental de-
1
tails, characterization of products, and H and 13C NMR
(14) Alternatively, and to avoid the elimination side reaction, the
phenyloxazole was also obtained from a route that involves reaction of the
ketoamide formed by Swern oxidation, as described by: Wipf, P.; Miller,
C. P. J. Org. Chem. 1993, 58, 3604.
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL063023C
(16) Simultaneous injection of natural and synthetic compounds gave
only one peak at tr ) 14.2 min (A ) H2O + 0.045% TFA, B ) MeCN +
0.036% TFA, gradient ) 0-100% B in 15 min) and identical shape and
wavelength in the UV detector. A sample of IB01211 was kindly supplied
by the fermentation department of PharmaMar.
(15) Obtained by saponification of the methyl bromopyruvate dimethyl
acetal with LiOH as described by: Chari, R. V. J.; Kozarich, J. W. J. Org.
Chem. 1982, 47, 23.
Org. Lett., Vol. 9, No. 5, 2007
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