Total synthesis of bistratamide G, a metabolite of the Philippines ascidian Lissoclinum bistratum, from dehydrotripeptides

Article abstract of DOI:10.1246/cl.2004.664

Total synthesis of triheterocyclic cyclopeptide bistratamide G, a metabolite from the Philippines ascidian Lissoclinum bistratum, was first achieved from two kinds of dehydrotripeptides.

Full text of DOI:10.1246/cl.2004.664

664
Chemistry Letters Vol.33, No.6 (2004)
Total Synthesis of Bistratamide G, a Metabolite of the Philippines
Ascidian Lissoclinum bistratum, from Dehydrotripeptides
Chung-gi Shin,ꢀ Chieko Abe, and Yasuchika Yonezawa
Laboratory of Organic Chemistry, Faculty of Engineering, Kanagawa University, Kanagawa-ku, Yokohama 221-8686
(Received March 5, 2004; CL-040251)
Total synthesis of triheterocyclic cyclopeptide bistratamide
G, a metabolite from the Philippines ascidian Lissoclinum bistra-
tum, was first achieved from two kinds of dehydrotripeptides.
ene).9 Subsequently, according to the method reported previous-
ly,10 simultaneous bromination and methoxylation of 5 with
NBS (N-bromosuccinimide) in MeOH gave the corresponding
ꢀ-methoxylated ꢁ-bromoalanyltripeptide 6. Oxazolination of 6
with Cs2CO3 in dioxane gave the corresponding 4-methoxyoxa-
zoline derivative 7, the methoxy group of which was eliminated
with camphorsulfonic acid (CSA) to give the expected oxazole
derivative 8. After hydrolysis of the methyl ester of 8 with
1 M LiOH, the obtained hydrolysate 9 was amidated with
ClCOOEt in the presence of Et3N and then with 28% aq. NH3
to give the corresponding carboxamide 10. Finally, thiocarbony-
lation of 10 with Lawesson’s reagent gave the required thiocar-
boxamide 2, as shown in Scheme 1.
Bistratamide G (1),1,2 one of many bistratamide-type poly-
heterocyclic cyclopeptides, isolated recently from the southern
Philippines ascidian Lissoclinum bistratum, shows activity in
the human colon tumor HCT-116 cell line assay. The natural 1
features an interesting macrocyclic structure constituted of three
kinds of heterocyclic (thiazole and oxazole) amino acid residues,
as shown in Figure 1.
So far, various useful synthetic methods for the above-men-
tioned heterocyclic amino acids, and other similar amino acids
have been already reported by a number of workers.3 According-
ly, the total synthesis of bistratamide-type dendroamide A and
similar natural products has been also achieved by the stepwise
elongation of the above amino acids and then by macrocycliza-
tion by four groups of investigators.4–7 However, though such
syntheses have been already reported, for the interesting bioac-
tivities of the polyheterocyclic cyclopeptides, here, a new and
general synthetic method for the bistratamides from ꢀ2-and
ꢀ3-dehydrotripeptides8 has been developed and achieved. In
particular, these elongation reactions were carried out without
any special condensing agent except for the last macrocycliza-
tion
O
O
H
ii)
i)
H
N
N
OMe
OMe
OMe
CbzHN
CbzHN
N
CbzHN
CbzHN
N
H
H
93%
95%
O
O
O
O
O
O
O
OH
4
5
O
O
iii)
H
N
iv)
OMe
N
N
N
H
N
H
95%
60%
OMe
O
OMe
O
Br
6
7
O
vi)
N
OR
NH2
CbzHN
N
H
CbzHN
N
H
92%
O
O
X
O
8 : R = Me
9 : R = H 98%
10 : X = O
X = S 92 %
v)
vii)
2
O
S
O
H
N
Scheme 1. Reagents and conditions: i) MsCl, Et3N, DBU, ii)
NBS, MeOH, rt, 1 h, iii) Cs2CO3, dioxane, 60 ꢁC, 6 h, iv)
CSA, toluene, 70 ꢁC, v) 1M LiOH, vi) ClCOOEt, Et3N, then
28% aq. NH3, vii) Lawesson’s Reagent.
CbzHN
O
NH2
N
N
H
O
O
2
N
N
+
O
Br
O
NH
HN
O
H
N
On the other hand, to synthesize 3, firstly, similarly to the
case of 5, N,O-isopropylidene (Ip)-N-t-butoxycarbonyl (Boc)-
L-Ser-L-Val-(Z)-ꢀAbu-OMe (12) (ꢀAbu = 2-amino-2-butenoic
acid) was prepared by the dehydration of the Thr residue of N,O-
Ip-N-Boc-L-Ser-L-Val-L-Thr-OMe (11).9 In the case of the bro-
mination of the ꢀAbu residue, it has been already reported that
the direct oxazolation of the ꢀAbu residue-containing peptide
with NBS and then with Cs2CO3 proceeds smoothly.9,10 There-
fore, the bromination of 12 with NBS in CHCl3, instead of
MeOH, was performed to give ꢀ3-dehydrotripeptide 138 con-
taining ꢁ-Br-ꢀAbu residue, which was then oxazolated with
Cs2CO3 to give the desired 5-methyloxazole derivative 14. Sec-
ondly, selective ꢁ-elimination of the Ip group with trifluoroace-
tic acid (TFA) and CHCl3 (4:96 v/v), followed by dehydration
of the formed N-Boc-seryldipeptide 15 was carried out, similarly
to the cases of 5 and 12. That is, dehydration of the Ser residue of
15 and bromination of the obtained ꢀ2-dehydrodipeptide 168
with NBS in MeOH were carried out consecutively to give the
N
OMe
O
N
S
O
O
3
Figure 1. Retrosynthesis of bistratamide G (1).
The syntheses of two kinds of building blocks, (S)-2-[1-(N-
Cbzamino)-2-methylpropyl]oxazole-L-valine thioamide (2) and
methyl (S)-2-{1-[N-(3-bromo-2-oxopropanoyl)amino]-2-meth-
ylpropyl}-5-methyloxazole-4-carboxylate (3) as the left- and
right-half components of the linear triheterocyclic peptide 18
as the precursor of 1, respectively, were accomplished as fol-
lows. First of all, to synthesize 2, the starting ꢀ2-dehydrotripep-
tide8 (Cbz-L-Val-ꢀAla-L-Val-OMe (5), Cbz = benzyloxycar-
bonyl, ꢀAla = ꢀ-dehydroalanine residue) was prepared by the
usual dehydration of the Ser residue of Cbz-L-Val-L-Ser-L-Val-
OMe (4) with methanesulfonyl chloride (MsCl) in the presence
of Et3N and then with DBU (1,8-diazabicyclo[5.4.0]undec-7-
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.6 (2004)
665
corresponding ꢀ-methoxylated ꢁ-bromoalanyldipeptide deriva-
tive 17. Thirdly, deprotection of the Boc group of 17 with
TFA and then hydrolysis proceeded smoothly to give 3, as
shown in Scheme 2. However, because of its lability, without pu-
rification the formed 3 was used in the next thiazolation with 2.
for the various bistratamide-type metabolites has been efficiently
developed.
This work was supported in part by Grant-in-Aid for
Scientific Research No. 14550829 from the Ministry of
Education, Culture, Sports, Science and Technology and by
‘‘High-Tech Research Project’’ from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
O
X
O
OH
OMe
O
iii)
O
i)
H
H
N
N
OMe
N
Boc
N
N
Boc
N
87%
98%
H
H
O
O
O
O
O
References and Notes
12 : X = H
11
14
ii)
13 : X = Br70%
1
2
3
D. J. Faulkner, J. Nat. Prod. Rep., 19, 1 (2002).
L. J. Perez and D. J. Faulkner, J. Nat. Prod., 66, 247 (2003).
For examples: a) D. A. Evans, J. R. Gege, and J. L.
Leightow, J. Am. Chem. Soc., 114, 9434 (1992). b) S. K.
Chattopadhyay, J. Kempson, A. McNeil, G. Pattenden, M.
Reader, D. E. Rippon, and D. Waite, J. Chem. Soc., Perkin
Trans. 1, 2000, 2415. c) P. Wipf and C. P. Miller,
Tetrahedron Lett., 33, 907 (1992). d) Y. Hamada, M.
Shibata, T. Sugiura, S. Kata, and T. Shioiri, J. Org. Chem.,
52, 1252 (1987).
O
HO
O
O
iv)
i)
H
N
H
N
OMe
OMe
N
Boc
N
BocHN
N
97%
98%
O
O
O
O
15
17
Br
OMe
O
O
vi)
v)
H
N
H
N
OMe
OMe
BocHN
N
BocHN
N
97%
80%
O
O
O
16
3
Br
O
O
4
5
6
C. D. Smith and Z. Xia, J. Org. Chem., 66, 3459 (2001).
A. Bertram and G. Pattenden, Heterocycles, 58, 521 (2002).
a) S. L. You and J. W. Kelly, J. Org. Chem., 68, 9506 (2003).
b) S. L. You and J. W. Kelly, Chem.—Eur. J., 10, 71 (2004).
S. V. Downing, E. Aguilar, and A. I. Meyers, J. Org. Chem.,
64, 826 (1999).
In this paper, the symbols ꢀ1, ꢀ2, and ꢀ3 indicate the
position number of the ꢀ-dehydroamino acid residue from
the N-terminus in sequence.
H
N
OMe
N
O
O
7
8
Scheme 2. Reagents and conditions: i) MsCl, Et3N, CHCl3,
0 ꢁC, 1 h, then DBU, rt, 30 min, ii) NBS, CHCl3, rt, 1 h, Et3N,
rt, 30 min, iii) Cs2CO3, dioxane, 60 ꢁC, 6 h, iv) TFA:CHCl3
(4:96 v/v), rt, 5 h, v) NBS, MeOH, rt, 30 min, vi) TFA, rt,
30 min, then H2O, rt, 10 min.
9
a) T. Kayano, Y. Yonezawa, and C. Shin, Chem. Lett., 33, 72
(2004). b) H. Saito, T. Yamada, K. Okumura, Y. Yonezawa,
and C. Shin, Chem. Lett., 2002, 1098.
Finally, thiazolation between the thiocarboxamide group of
2 and the bromoacyl group of 3 by successive treatments with
KHCO3 in dimethoxyethane (DME), with trifluoroacetic anhy-
dride (TFAA) and pyridine, and then with 28% aq. NH3 gave
a linear triheterocyclic peptide 18.11 Hydrolysis of the ester with
1 M LiOH and deprotection of the Cbz group of the hydrolysate
19 with 10% Pd-C/H2, followed finally by macrocyclization of
the obtained N,O-deprotected triheterocyclic peptide 20 with
BOP and (i-Pr)2NEt in DMF under high-dilution conditions
(1 mmol/L) at room temperature for 12 h gave the expected
112 in 51% yield from 20, as shown in Scheme 3.
10 N. Endoh, K. Tsuboi, R. Kim, Y. Yonezawa, and C. Shin,
Heterocycles, 60, 1567 (2003).
26
11 18: Colorless solid. mp 71.0–71.5 ꢁC. ½ꢀꢂD þ4:2ꢁ (c 0.93,
CHCl3). 1H NMR (CDCl3, 600 MHz) ꢂ ¼ 0:91 (d, 3H,
J ¼ 6:6 Hz), 0.93 (d, 3H, J ¼ 6:6 Hz), 0.95 (d, 3H, J ¼
7:2 Hz), 0.97 (d, 3H, J ¼ 7:2 Hz), 0.99 (d, 3H, J ¼ 7:2 Hz),
1.12 (d, 3H, J ¼ 7:2 Hz), 2.23–2.25, 2.35–2.37 and 2.56–
2.62 (each m, 1H ꢄ 3), 2.61 (s, 3H), 3.91 (s, 3H), 4.84–
4.88 (m, 1H), 5.08–5.14 (m, 2H), 5.17–5.20, 5.32–5.38,
and 5.49–5.52 (each m, 1H ꢄ 3), 7.33–7.36 (m, 5H), 7.45
and 7.85 (each br d, 1H ꢄ 2, J ¼ 9:6 Hz), 8.03 (s, 1H),
8.17 (s, 1H). Found: C, 58.83; H, 6.23; N, 12.48%. Calcd
for C34H42N6O8S: C, 58.77; H, 6.09; N, 12.19%.
O
i)
S
O
iii)
H
N
H
N
XHN
2 + 3
1
OY
N
N
N
83%
51%
26
12 1: Colorless solid. mp 85.0–85.5 ꢁC. ½ꢀꢂD ꢃ82:3ꢁ (c 1.00,
O
O
O
MeOH). IR (KBr) 3396, 2964, 1685, 1676, 1597, 1533,
1508 cmꢃ1
18 : X=Cbz, Y=Me
19 : X=Cbz, Y=H
20 : X=Y=H
iia)
quant
.
1H NMR (DMSO-d6, 600 MHz) ꢂ ¼ 0:79 (d,
quant iib)
3H, J ¼ 6:6 Hz), 0.80 (d, 3H, J ¼ 6:6 Hz), 0.83 (d, 3H,
J ¼ 7:2 Hz), 0.84 (d, 3H, J ¼ 7:2 Hz), 0.86 (d, 3H, J ¼
7:2 Hz), 0.87 (d, 3H, J ¼ 7:2 Hz), 2.04–2.09 (m, 1H), 2.11–
2.14 (m, 1H), 2.17–2.21 (m, 1H), 2.46 (s, 3H), 4.91 (dd, 1H,
J ¼ 7:2, 4.2 Hz), 4.97 (dd, 1H, J ¼ 9:0, 6.0 Hz), 5.28 (dd,
1H, J ¼ 9:0, 6.0 Hz), 8.20 (br d, 1H, J ¼ 7:2 Hz), 8.22 (br
d, 1H, J ¼ 9:0 Hz), 8.23 (s, 1H), 8.36 (br d, 1H, J ¼
9:0 Hz), 8.68 (s, 1H). 13C NMR (DMSO-d6, 150 MHz) ꢂ ¼
11:1, 18.0, 18.1, 18.1, 18.2, 18.3, 18.6, 32.6, 32.9, 34.6,
52.1, 52.7, 54.8, 125.2, 128.0, 134.5, 143.0, 147.9, 152.9,
158.4, 159.3, 160.3, 160.6, 163.2, 168.3. MALDI-TOFMS
Found: m=z 528.10 (M þ Hþ). Calcd for C25H32N6O5S:
528.63 (M þ Hþ).
Scheme 3. Reagents and conditions: i) KHCO3, DME, 0 ꢁC, 30
min, 50 ꢁC, overnight, b) TFAA, pyridine, 0 ꢁC, 1 h, c) 28% aq.
NH3, 0 ꢁC, ii) a) 1 M LiOH, H2O-dioxane (1:1 v/v), rt, 30 min,
b) 10% Pd-C, H2, rt, 3 h, iii) BOP, (i-Pr)2NEt, DMF, 12 h.
The structures of all new products thus obtained were con-
firmed by the 1H and 13C NMR spectral data and the satisfactory
results of the elemental analyses. In particular, the chemical and
26
physical constants of the synthetic 1 (½ꢀꢂD ꢃ82:3ꢁ (c 1.00,
MeOH)) were fully identical with those of the natural 1 (½ꢀꢂD
ꢃ73:8ꢁ (c 1.0, MeOH)).
In conclusion, a convenient and general synthetic method
Published on the web (Advance View) June 5, 2004; DOI 10.1246/cl.2004.664