Total synthesis of ulongamide A, a cyclic depsipeptide isolated from marine cyanobacteria Lyngbya sp.

Article abstract of DOI:10.1016/j.tetlet.2006.11.117

A total synthesis of ulongamide A (1), a cytotoxic natural cyclic depsipeptide, was achieved by a convergent route involving coupling of the fragments 7 and 8 to the pentapeptide 24, and subsequent cyclization thereof after prior removal of the t-Boc protecting groups.

Full text of DOI:10.1016/j.tetlet.2006.11.117

Tetrahedron Letters 48 (2007) 603–607
Total synthesis of ulongamide A, a cyclic depsipeptide isolated
from marine cyanobacteria Lyngbya sp.
´
*
´
´
´
Cuauhtemoc Alvarado, Eduardo Dıaz and Angel Guzman
Instituto de Quı´mica, Universidad Nacional Auto´noma de Me´xico, Circuito Exterior s/n,
Ciudad Universitaria, Coyoacan, 04510 Me´xico, DF, Mexico
Received 26 October 2006; revised 16 November 2006; accepted 17 November 2006
Available online 12 December 2006
Abstract—A total synthesis of ulongamide A (1), a cytotoxic natural cyclic depsipeptide, was achieved by a convergent route involv-
ing coupling of the fragments 7 and 8 to the pentapeptide 24, and subsequent cyclization thereof after prior removal of the t-Boc
protecting groups.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
and L-phenylalanine. Compounds 5 and 6 were synthe-
sized in the manner described later in the text.
Cyanobacteria, or blue-green marine algae, are of con-
siderable interest because of the impressive number
and structural diversity of the metabolites which they
produce. A wide variety of biological activities is found
amongst these metabolites1 including extreme toxicity in
some instances.2 Depsipeptides, one class of compounds
produced by cyanobacteria, are of potential importance
in the therapy of cancer. For example, criptophycin-52,
a synthetic analog of criptophycin-1, isolated from Nosto-
ceae sp.,3,4 and dolastatine-10, a modified pentapeptide
isolated from a marine cyanobacterium,5 have been
tested as anticancer drugs. In 2002, six new depsipep-
tides designated as ulongamides A–F, were isolated by
Luesch et al.6 from Palauan collections of the marine
cyanobacterium Lyngbya sp., and found to possess
activity against some types of cancer. Herein, is
described the synthesis of ulongamide A (1), the first
member of this series of compounds.
A convergent strategy was used for the synthesis of 1.
The two starting materials required for this purpose
were 7 and 8 (Fig. 2). The depsitripeptide 7 was prepared
by sequential coupling of 4, 5, and 6. Dipeptide 8 was
likewise obtained from structural units 2 and 3.
2. Synthesis of depsitripeptide 7
The optically pure benzyl ester 4a of L-lactic acid was
prepared by well known literature methodology.8,9 The
unusual b-amino acid 5 was synthesized using a proce-
dure reported by Kimura et al.,10 in which the
(4R,5S)-oxazolidinone derivative 9 was N-acylated with
propionyl chloride 11, and the so produced N-propionyl
derivative 10 (Scheme 1) was subjected to low tempera-
ture aldolization with n-butanal. The essentially pure
(2R,3S)-aldol 12 thus obtained (78% from 9), was con-
verted into the azide 13 (43% yield), of inverted config-
uration, by a Mitsunobu11 reaction using hydrogen
azide. Cleavage of the chiral auxiliary from 13 with alka-
line hydrogen peroxide, followed by catalytic reduction
of the azido acid 14 provided the b-amino acid 5, which
was transformed into its t-Boc derivative 5a.
Luesch et. al.,6 also showed that ulongamide A (1) is a
cyclic depsipeptide formally derived from five structural
units, four of which are the amino acids 2, 3, 5, and 6,
the fifth being L-lactic acid 4 (Fig. 1). Amino acids 2
and 3 were obtained by N-methylation7 of L-valine
The (S)-thiazole carboxylic acid 6a was prepared follow-
ing the procedure described by Xia and Smith12 for the
(R)-enantiomer. To this end, L-alanine (15, Scheme 2)
was protected as the t-Boc derivative 16, and then
Keywords: Ulongamide A; Cyanobacteria; Cyclodepsipeptides.
*
Corresponding author. Tel.: +52 55 56 22 44 21; fax: +52 55 56 16 22
17; e-mail addresses: alvaradosanchezc@yahoo.com.mx; maudiaz@
servidor.unam.mx; angelgs@servidor.unam.mx
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.117

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C. Alvarado et al. / Tetrahedron Letters 48 (2007) 603–607
HN
S
N
O
N
O
O
HN
O
O
N
O
Ulongamide A 1
O
O
O
OH
OH
OH
NH
OH
NH
3
4
2
NH2
O
NH2
O
N
OH
OH
S
6
5
Figure 1. Ulongamide A and its structural components.
O
O
O
NH
O
O
O
N
OH
N
N
H
O
HN
O
S
O
8
7
Figure 2. Convergent way.
Ph
O
OH
O
N3
O
HN
O
Ph
Ph
Ph
c
O
a
b
N
N
N
9
O
10
O
13
12
O
O
O
+
O
O
d
Cl
11
O
NH2
O
N3
O
e
O
NH
O
f
OH
OH
OH
14
5
5a
Scheme 1. Synthetic route to 5a. Reagents and conditions: (a) n-BuLi, THF, ꢀ78 °C, 93%; (b) 1. DBBT, EDIPA, CH2Cl2, 0 °C, 2. n-butanal,
ꢀ78 °C, 84%; (c) DEAD, PPh3, HN3, toluene, 43%; (d) H2O2, LiOH, H2O; (e) H2/Pd–C, methanol, 88%; (f) (Boc)2O, Et3N, H2O/p-dioxane, 85%.
converted into the primary amide 17 by amination of the
mixed anhydride derived from ethyl chloroformate. Thio-
nation of 17 with Lawesson’s reagent and subsequent
reaction of the thioamide 18 with ethyl bromopyruvate
19 generated the hydroxythiazoline 20, which was con-
verted into the thiazole 21 by treatment with trifluoro-
acetic anhydride in the presence of 2,6-lutidine.
Saponification of 21 with aqueous sodium hydroxide
(3 equiv) at room temperature generated the protected
amino acid 6a.

C. Alvarado et al. / Tetrahedron Letters 48 (2007) 603–607
605
O
O
O
a
b
OH
OH
NHBoc
NH2
(Boc)2O
+
NH2
NHBoc
15
16
17
c
NHBoc
O
S
O
N
d
O
NH2
Br
O
+
OH
S
20
NHBoc
O
19
18
e
NHBoc
O
NHBoc
O
f
N
N
OH
O
S
S
21
6a
Scheme 2. Synthetic route to 6a. Reagents and conditions: (a) Et3N, p-dioxane/H2O (3:1), rt, 16–18 h, 87%; (b) 1. ethyl chloroformate, CH2Cl2,
ꢀ10 °C, 2. NH3/CH2Cl2, 90%; (c) Lawesson’s reagent, DME, 16–18 h, 85%; (d) KHCO3, DME, ꢀ15 °C; (e) (CF3CO)2O, lutidine, ꢀ15 °C, 77%; (f)
NaOH/H2O, 83%.
O
O
O
OH
4a
O
NH
O
a
O
+
O
O
O
22
O
NH
O
b
OH
5a
NH2
O
O
O
O
O
22a
O
NH
O
O
c
N
O
O
+
N
H
O
S
O
O
O
NH
N
7a
OH
S
d
6a
O
O
NH
O
O
N
OH
N
O
H
S
O
7
Scheme 3. Synthetic route to 7. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, 16–18 h, 70%; (b) TFA, CH2Cl2, 88%; (c) DCC/HOBt, CH2Cl2,
16–18 h, 67%; (d) H2/Pd–C, 87%.

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C. Alvarado et al. / Tetrahedron Letters 48 (2007) 603–607
O
O
OH
R
+
N
R
OR2
3a
H
O
NHR1
O
3b CH3
R1
R2
2a
2b
2c
Cbz
H
a
Cbz t-butyl ester
H
t-butyl ester
O
O
O
O
b, c
N
N
H
HN
O
N
O
8
O
23
O
Scheme 4. Synthetic route to 8. Reagents and conditions: (a) DCC/HOBt, CH2Cl2, 16–18 h, 87%; (b) CH3I, NaH, THF, 0 °C, 85%; (c) H2/Pd–C.
O
O
O
NH
O
O
O
O
N
OH
N
+
N
H
O
O
HN
O
S
O
8
a
7
O
NH
O
O
N
N
O
N
H
O
N
S
O
O
24
b, c
HN
O
S
N
N
O
O
HN
O
O
N
O
Ulongamide A 1
Scheme 5. Obtention of ulongamide A. Reagents and conditions: (a) BOP, Et3N, CH2Cl2, 55%; (b) TFA, CH2Cl2; (c) BOP, DMF, 80–90 °C, 60%.
With the requisite starting materials in hand, the synthe-
sis of the depsitripeptide 7 was completed by the follow-
ing sequence of reactions. Coupling of benzyl lactate
(4a, Scheme 3) with the b-amino acid 5a, mediated by
dicyclohexylcarbodiimide (DCC), provided the bis-
protected depsipeptide 22 (70% yield) from which the
t-Boc group was removed with trifluoroacetic acid,
giving the amino compound 22a. Coupling of 22a with
the thiazole carboxylic acid derivative 6a, by means
of DCC containing hydroxybenzotriazole (HOBt),
produced 7a which on hydrogenolysis generated depsi-
peptide 7 (58% yield over two steps).

C. Alvarado et al. / Tetrahedron Letters 48 (2007) 603–607
607
5. Pettit, G. R.; Kamano, Y.; Herald, C. L.; Tuinman, A. A.;
Boettner, F. E.; Kizu, H.; Schmidt, J. M.; Baczynskyj, L.;
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109, 6883–6885.
6. Luesch, H.; Williams, P. G.; Yoshida, W. Y.; Moore, R.
E.; Paul, V. J. J. Nat. Prod. 2002, 65, 996–1000.
7. (a) McDermott, J. R.; Benoiton, N. L. Can. J. Chem.
1973, 51, 2555–2561; (b) Coggins, J. R.; Benoiton, N. L.
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10. Kimura, J.; Takada, Y.; Inayoshi, T.; Nakao, Y.; Goetz,
G.; Yoshida, W. Y.; Scheuer, P. J. J. Org. Chem. 2002, 67,
1760–1767.
11. (a) Kurihara, T.; Nakajima, Y.; Mitsunobu, O. Tetra-
hedron Lett. 1976, 17, 2455–2458; (b) Schmidt, U.; Utz, R.
Angew. Chem., Int. Ed. Engl. 1984, 23, 725–726; (c)
Schmidt, U.; Gleich, P.; Griesser, H.; Utz, R. Synthesis
1986, 992–997; For a review see: Mitzunobu, O. Synthesis
1981, 1–28.
12. (a) Bredenkamp, M. W.; Holzapfel, C. W.; van Zyl, W. J.
Synth. Commun. 1990, 20, 2235–2249; (b) Aguilar, E.;
Meyers, A. I. Tetrahedron Lett. 1994, 35, 2473–2476; (c)
Xia, Z.; Smith, C. D. J. Org. Chem. 2001, 66, 3459–3466.
13. (a) Anderson, G. W.; Callahan, F. M. J. Am. Chem. Soc.
1960, 82, 3359–3363; (b) Bodanszky, M. The Practice of
Peptide Synthesis, 2nd ed.; Springer-Verlag: Berlin, 1993,
pp 38–40; (c) Ward, D. E.; Gai, Y.; Lazny, R.; Pedras, M.
S. C. J. Org. Chem. 2001, 66, 7832–7840; (d) Mc Dermot,
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(e) Tung, R.; Dhaon, M.; Rich, D. J. Org. Chem. 1986, 51,
3350–3354; (f) Galpin, I. J.; Mohammed, A. K.; Patel, A.;
Priestley, G. Tetrahedron. 1988, 44, 1763–1772.
3. Synthesis of dipeptide 8
N-Cbz-L-Phenylalanine 3a was selectively N-methylated
with methyl iodide (sodium hydride) giving 3b (Scheme
4). Cbz-L-valine 2a was converted into the t-butyl ester
2b with 2-methylpropene under acidic conditions, and
then hydrogenolyzed to L-valine t-butyl ester (2c).13
Compounds 2c and 3b were then coupled using the
DCC–HOBt mixture to afford the dipeptide 23. Sequen-
tial methylation of the valine amido NH of 23 with
methyl iodide in the presence of sodium hydride and
hydrogenolysis generated dipeptide 8.
4. Synthesis of depsipentapeptide 24, and cyclization
to ulongamide A14
The optimum conditions found for the coupling of 7 and
8 utilized BOP in dichloromethane solution. The penta-
peptide 24 (55% yield, Scheme 5) so obtained was depro-
tected with trifluoroacetic acid (TFA), and the crude
product, after removal of the TFA in vacuo and dilution
with DMF, was cyclized to ulongamide A (1, 60% yield)
with BOP. The spectral properties15 of synthetic ulonga-
mide A were fully concordant with those reported6 for
the natural product.
Acknowledgements
We thank DGAPA-UNAM (PAPIIT-IN210405) for its
generous financial support. We also thank CONACYT
for a doctoral grant to C. Alvarado, and we gratefully
acknowledge the helpful assistance of the spectroscopic
14. (a) Wenger, R. M. Helv. Chim. Acta 1984, 67, 502–525; (b)
Jones, J. The Chemical Synthesis of Peptides; Clarendon
Press: Oxford, 1994, pp 175–182.
15. Physical and spectroscopic constants of ulongamide A 1.
´
staff of the Instituto de Quımica (UNAM). The authors
25
White, amorphous solid, mp 85 °C.; ½aꢁD +12 (c 0.73,
acknowledge Dr. Joseph M. Muchowski for the revision
of the original manuscript.
MeOH); IR (film) mmax 3321, 2962, 2934, 2872, 1734,
1672, 1633, 1553, 1522, 1497, 1462, 1271, 1216, 1078, 1048;
1H NMR (500 MHz, CDCl3): d 8.94 (d, 1H, J = 10.5),
8.17 (d, 1H, J = 7.0), 8.04 (s, 1H), 7.29 (t, 2H), 7.24 (t,
1H), 7.17 (d, 2H), 6.08 (dd, 1H, J = 9.5, 5.5), 5.34 (q, 1H,
J = 6.5), 5.17 (q, 1H, J = 7.0), 4.51 (d, 1H, J = 11), 4.31
(m, 1H, J = 10.6, 9.0, 5.0, 2.5), 3.27 (dd, 1H, J = 9.5,
15.0), 3.21 (s, 3H), 3.16 (dd, 1H, J = 5.5, 15.0), 2.99 (s,
3H), 2.70 (dq, 1H, J = 7.0, 2.5), 2.33 (m, 1H), 1.46 (d, 3H,
J = 6.8), 1.43 (m, 4H), 1.33 (d, 3H, J = 6.8), 1.23 (d, 3H,
J = 7.2), 0.97 (t, 3H, J = 7.0), 0.85 (d, 3H, J = 6.4), 0.60
(d, 3H, J = 7.0); 13C NMR (125 MHz, CDCl3): d 14.0,
14.5, 16.2, 18.3, 19.3, 19.6, 24.5, 27.3, 29.0, 30.0, 35.4, 35.5,
45.0, 47.7, 50.7, 51.0, 66.4, 67.0, 122.0, 127.0, 128.5, 128.8,
136.0, 149.1, 160.8, 167.9, 169.6, 170.4, 171.9, 172.9;
HRFABMS m/z [M+H]+ 628.3179 (calcd for
C32H46N5O6S, 628.3169).
References and notes
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