Total synthesis of argyrins A and e

Article abstract of DOI:10.1016/j.tetlet.2011.03.021

The total synthesis of argyrins A and E were accomplished using a convergent strategy by condensation of one tripeptide and two dipeptide fragments. The synthesis strategy, which was developed for the protection of peptide fragments and identification of the optimum macrocylization site, can be applied to further synthetic studies involving other members of the argyrin family.

Full text of DOI:10.1016/j.tetlet.2011.03.021

Tetrahedron Letters 52 (2011) 2488–2491
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of argyrins A and E
a
b
c
a,
⇑
Wenbin Wu , Zheng Li , Guangbiao Zhou , Sheng Jiang
a
Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, CAS, Guangzhou, Guangdong 510530, PR China
Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA
Laboratory of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology,
b
c
Chinese Academy of Sciences, Beijing 100101, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of argyrins A and E were accomplished using a convergent strategy by condensation of
one tripeptide and two dipeptide fragments. The synthesis strategy, which was developed for the protec-
tion of peptide fragments and identification of the optimum macrocylization site, can be applied to fur-
ther synthetic studies involving other members of the argyrin family.
Received 9 January 2011
Revised 22 February 2011
Accepted 3 March 2011
Available online 11 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
The proteasome, a multicatalytic proteinase complex, is respon-
sible for the degradation of a large proportion of intracellular pro-
teins. Therefore, the proteasome is an interesting target for
cyclization rates, facilitating side-reactions such as oligomerization
and/or epimerization of the C-terminal residue. Analyzing the
8
1
sequences of the molecules, we chose the achiral glycine as the
C-terminal end to avoid racemization during backbone macrocyc-
lization. In addition, such disconnection makes the turn-inducing
thiazole residues to be located in the middle of the linear peptide
precursor, which will result in the N- and C-termini approaching
each other to make the head–tail macrocyclization more robust.
The various components of argyrins A (1) and E (2) were syn-
thesized by different routes. Our synthesis of intermediate 5 used
therapeutic agents that inhibit cell proliferation in diseases such
2
as cancer. Numerous proteasome inhibitors that have promising
3
potential in clinical trials have been recently developed. Bortezo-
mib was approved by the U.S. food and drug administration (FDA)
for treatment of multiple myeloma and mantle-cell lymphoma.
However, the designing of proteasome inhibitors with high speci-
ficity and wide clinical applicability remains to be accomplished
because some inhibitors display cytotoxicity, whereas others inhi-
bit other proteases such as calpains and cathepsins.3e
a straightforward route from N-Boc-D-alanine 7 (Boc = tert-butyl-
oxycarbonyl) following the procedure (Scheme 1) provided in liter-
9
In 2002, argyrin A and its congeners were originally isolated
from Archangium gephyra during the screening of myxobacteria
ature. The ethyl ester group of 8 was saponified with LiOH and
then coupled with the methyl ester of tryptophan to provide the
dipeptide 5.
4
for new antibiotics (Fig. 1). Recently, Malek’s group found that arg-
yrin A shows biological activity at remarkably low concentrations
without significant cytotoxic effects. In addition, all antitumoral
activities of argyrin A were found to depend on the prevention of
The synthesis of the key intermediate 13 started from the pre-
viously characterized compound 10, which was obtained from
commercially available 3-methoxybenzeneamine, 9 (Scheme 2).
Boc-protected 3-methoxybenzeneamine 10, was lithiated with
2.1 equiv of tert-butyllithium in diethyl ether, followed by iodin-
ation with molecular iodine to give tert-butyl (2-iodo-3-methoxy-
phenyl) carbamate, 11, in 90% yield; subsequent deprotection of
the Boc group yielded the desired compound 12. The key interme-
diate 15 was easily derived through a palladium-catalyzed hetero-
annulation reaction between the amine 12 and the aldehyde 14,
kip1
kip1
p27
destruction, because loss of p27
expression confers resis-
tance to this compound. Malek et al. hence concluded that argyrin A
is a more specific proteasome inhibitor than bortezomib.5 These
excellent properties of argyrins have attracted significant attention,
and the total syntheses of argyrin B and F have been accomplished
by two research groups.6 To further understand the structure–
activity relationship of argyrin A, we here report a convergent
macrocycle-assembly strategy to synthesize argyrins A and E in
parallel from three fragments: two dipeptides and a tripeptide
1
0
,7
the latter being synthesized from the dimethyl ester of N-Boc-L-
1
1,12
glutamic acid in two steps.
Bismuth–bromide-based catalytic
1
3
(Fig. 1).
selective deprotection of the Boc group of 13, followed by hydro-
lysis of the methyl ester group and coupling with glycine methyl
ester, yielded the dipeptide 3. Analogously, the dipeptide 4 was
easily prepared in 82% yield by coupling Boc-protected tryptophan
In the retrosynthetic analyses of argyrins A and E, the macrocyc-
lization site is so important that it can ultimately determine the
success of the synthesis. Poor disconnections can lead to slow
1
6 with glycine methyl ester.
⇑
Corresponding author. Tel.: +86 20 32015318; fax: +86 20 32290606.
E-mail address: jiang_sheng@gibh.ac.cn (S. Jiang).
Then, we turned our attention to the synthesis of the tripeptide
6,
which was prepared from Boc-protected
D-alanine, 17
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.021

W. Wu et al. / Tetrahedron Letters 52 (2011) 2488–2491
2489
fragments coupling
S
H
O
N
N
O
N
HN
HN
Argyrin A, 1: R = OCH3
Argyrin E, 2: R = H
O
N
O
O
H
N
H
HN
N
H
fragments coupling
R
O
O
macrocyclization
HN
R
O
O
S
OCH3
N
N
HN
H3CO
H
BocHN
NH
NHBoc
O
HN
O
3
4
: R = OCH3
: R = H
5
O
O
BocHN
N
N
OCH3
H
O
6
Figure 1. Structure and retrosynthetic analysis of argyrin A and E.
(
Scheme 3). Sequential coupling with
L
-serine methyl ester yielded
O
S
ref.6
a) LiOH, THF/ H2O
the dipeptide 18, which was further subjected to mesylation, fol-
lowed by elimination, to provide the dehydroalanine moiety 19.
The next peptide coupling was carried out after hydrolysis of the
ester group with the sarcosine ethyl ester (Sar-OEt), using bro-
mo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP)
as the coupling reagent, to provide fragment 6.
BocHN
BocHN
OEt
NH2
N
b) H-Trp-OMe, EDC
DIPEA, DCM, 95%
O
8
7
S
N
Coupling of the above three fragments and completion of the to-
tal syntheses of argyrins A and E were accomplished as shown in
Scheme 4. Removal of the protective group Boc from the dipeptide
5 and coupling with the free acid from tripeptide 6 gave the
product 20 in 92% yield. Subsequently, the methyl ester of 20
was cleaved by LiOH in quantitative yield. The free acid was
H
NH
OCH3
BocHN
N
O
O
5
Scheme 1. Synthesis of the linear dipeptide 5.
OCH3
OCH3
OCH3
I
TFA/CH2Cl2
100%
(
Boc) O, Et N
2 3
t-BuLi, I2
diethyl ether
NH2 CH CN/H O, 96%
NHBoc
O
3
2
NHBoc
90%
9
10
11
OCH3
O
OMe
I
OMe
Pd(OAc) , 14
BiBr3, (10 mol%)
MeCN, rt, 93%
OCH3
NHBoc
2
OCH3
NH2
DABCO, DMF
5
N(Boc)2
1
2
N
N
H
0%
H
1
3
15
O
O
O
O
1
) LiOH, THF/H O;
2
OCH3
N
H
OCH3
H
2
) EDC, DIPEA,
H-Gly-OMe, DCM
2%
NHBoc
O
N(Boc)2
OCH3
HN
1
4
3
8
O
OH
NHBoc
EDC, DIPEA,
O
H-Gly-OMe, DCM
N
N
H
82%
H
HN
NHBoc
O
1
6
4
Scheme 2. Synthesis of the linear dipeptides 3 and 4.

2
490
W. Wu et al. / Tetrahedron Letters 52 (2011) 2488–2491
O
H
OH EDCI, HOBt, CH Cl
N
MsCl, DMAP
2
2
BocHN
BocHN
OCH3
BocHN
O
7
H-Ser-OMe, 90%
Et N, DCM, 92%
O
OH
3
1
1
8
O
H
O
H
N
a) LiOH, THF/H O
N
OEt
N
2
O
BocHN
b) H-Sar-OEt, DIPEA
PyBroP, DCM, 43%
O
O
O
6
19
Scheme 3. Synthesis of the linear tripeptide 6.
O
LiOH,
THF/H O
2
HN
HNBoc
6
EDC, DIPEA,
DCM , HOBt,
rt, 92%
O
NH
N
O
TFA,
OCH3
3 or 4
CH Cl2
2
NH
N
S
5
N
O
H
O
LiOH, THF
MeOH, H2O
TFA, DCM
20
EDC, HOBt
DIPEA, DCM
6%
6
O
1
. LiOH, THF,
HN
HNBoc
MeOH, H O, rt
2
2
. TFA, DCM, rt
O
NH
Argyrin A, 1: R = OCH3
Argyrin E, 2: R = H
N
O
3
. HATU, DIPEA,
O
H
O
HOAt, DMF,
6%, rt
N
N
5
NH
N
S
N
H
O
O
H
O
NH
R
2
1: R = OCH3
2: R = H
2
Scheme 4. Synthesis of argyrins A and E.
immediately coupled with the Boc-deprotected fragment from 3 or
, respectively, using 1-ethyl-3-(3-dimethylaminopropyl) carbodi-
Acknowledgments
4
imide (EDC) and HOBt, to yield the linear heptapeptides 21 and 22,
respectively, in 66% yield. Before macrocyclization, the two pro-
tecting groups were removed by hydrolysis (for the methyl ester
group) and with trifluoroacetic acid (TFA) in dichloromethane
We thank the National Natural Science Foundation (Grant No.
20802078, 20972160, 81071930), the National Basic Research Pro-
gram of China (Grant No. 2009CB940900, 2010CB529201), the Key
Project of Knowledge Innovation Program of the Chinese Academy
of Sciences (KSCX2-YW-R-215, KSCX2-YW-R-235), the National
Major Scientific and Technological Program for Drug Discovery
(2009ZX09103-101) for their financial support.
(
for the N-terminal Boc group). After examining several macrocyc-
lization conditions, we successfully obtained argyrins A and E in
6% yield, respectively, using HATU as the condensation reagent
5
in DMF solution (0.7 mM). This step was repeated three times,
and in all cases, comparable chemical yields were obtained. The
spectroscopic ( H NMR and C NMR) and the optical rotation data
1
13
Supplementary data
for the synthetic argyrins A and E fully matched the data published
for the corresponding natural products.14
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.021.
In summary, the total synthesis of argyrins A and E were accom-
plished through a convergent macrocycle-assembly strategy from
a tripeptide fragment and two dipeptide intermediates (11% over-
all yield from 3-methoxybenzeneamine, with the longest linear se-
quence comprising 14 steps). The methods developed to ensure the
protection of both the peptide fragments and the optimum macro-
cylization site are the useful outcomes of this study, which may
potentially be applicable to the synthesis of other analogs of this
family. Efforts toward applying these methods to other natural
products are currently underway in our laboratory and will be re-
ported in due course.
References and notes
1. Goldberg, A. L. Biochem. Soc. Trans. 2007, 35, 12–17.
2.
(a) Adams, J. Cancer Cell. 2004, 5, 417–421; (b) Adams, J. Nat. Rev. Cancer 2004,
, 349–360.
4
3.
Recent reviews for proteasome inhibitors: (a) Voorhees, P. M.; Orlowski, R. Z.
Annu. Rev. Pharmacol. Toxicol. 2006, 46, 189–213; (b) Borissenko, L.; Groll, M.
Chem. Rev. 2007, 107, 687–717; (c) Orlowski, R. Z.; Kuhn, D. J. Clin. Cancer Res.
2008, 14, 1649–1657; (d) Kisselev, A. F. Chem. Biol. 2008, 15, 419–421; (e)
Marques, A. J.; Palanimurugan, R.; Matias, A. C.; Ramos, P. C.; Dohmen, R. J.
Chem. Rev. 2009, 109, 1509–1536.

W. Wu et al. / Tetrahedron Letters 52 (2011) 2488–2491
2491
4
5
.
.
Sasse, F.; Steinmetz, H.; Schupp, T.; Petersen, F.; Memmert, K.; Hofmann, H.;
Heusser, C.; Brinkmann, V.; von Matt, P.; Höfle, G.; Reichenbach, H. J. Antibiot.
8.52 (d, J = 2.0 Hz, 1 H), 8.05 (s, 1 H), 7.33–7.31 (m, 2 H), 7.05 (d, J = 8.0 Hz, 1 H),
6.97 (d, J = 2.4 Hz, 1 H), 6.91–6.86 (m, 3 H), 6.82 (d, J = 2.4 Hz, 1 H), 6.34 (t,
J = 7.2 Hz, 1 H), 5.51–5.44 (m, 1 H), 5.40 (d, J = 7.6 Hz, 1 H), 5.08–5.04 (m, 1 H),
5.01 (d, J = 1.6 Hz, 1 H), 4.95 (d, J = 16.8 Hz, 1H), 4.71 (d, J = 1.2 Hz, 1 H), 4.54–
4.50 (m, 1 H), 4.33 (s, 3 H), 4.26–4.21 (m, 2 H), 3.54–3.46 (m, 3 H), 3.40 (d,
J = 16.8 Hz, 1 H), 3.32 (dd, J = 14.8, 4.0 Hz, 1 H), 3.07 (s, 3 H), 2.84 (dd, J = 15.2,
3.2 Hz, 1 H), 1.73 (d, J = 7.2 Hz, 3 H), 1.42 (d, J = 7.2 Hz, 3 H), 1.05 (dd, J = 17.4,
2
002, 55, 543–551.
Nickeleit, I.; Zender, S.; Sasse, F.; Geffers, R.; Brandes, G.; SÖrensen, I.;
Steinmetz, H.; Kubicka, S.; Carlomagno, T.; Menche, D.; Gutgemann, I.; Buer,
J.; Gossler, A.; Manns, M. P.; Kalesse, M.; Frank, R.; Malek, N. P. Cancer Cell 2008,
14, 23–35.
6
.
.
(a) Ley, S. V.; Priour, A.; Heusser, C. Org. Lett. 2002, 4, 711–714; (b) Ley, S. V.;
Priour, A. Eur. J. Org. Chem. 2002, 3995–4004.
BÜlow, L.; Nickeleit, I.; Girbig, A.-K.; Brodmann, T.; Rentsch, A.; Eggert, U.;
Sasse, F.; Steinmetz, H.; Frank, R.; Carlomagno, T.; Malek, N. P.; Kalesse, M.
ChemMedChem 2010, 5, 832–836.
Jiang, S.; Li, Z.; Ding, K.; Roller, P. P. Curr. Org. Chem. 2008, 12, 1502–1542.
(a) Kigoshi, H.; Yamada, S. Tetrahedron 1999, 55, 12301–12308; (b) Aguilar, E.;
Meyers, A. I. Tetrahedron Lett. 1994, 35, 2473–2477.
5.0 Hz, 1 H). 13C NMR (100 MHz, CDCl
3
) 172.9, 171.0, 170.9, 170.1, 169.8, 168.3,
166.8, 159.8, 152.3, 150.4, 138.4, 136.8, 134.7, 126.5, 125.5, 123.7, 123.6, 122.9,
121.2, 119.2, 117.4, 116.0, 111.3, 108.2, 106.6, 105.7, 101.2. 99.7, 57.7, 56.1,
52.1, 51.0, 48.4, 45.3, 40.5, 37.4, 26.9, 26.6, 20.3, 13.9. MS (ESI, m/z) found 847.3
7
+
25
); Lit. 7: ½
25
D
([M+Na] ). ½
aꢀ
= +140.9 (c 0.1, CHCl
3
aꢀ
3
= +145.2 (c 0.91, CHCl ).
D
1
8
9
.
.
Argyrin E (2): H NMR (400 MHz, CDCl
3
) 10.59 (br, 1H), 9.40 (s, 1H), 8.86–8.83
(m, 2H), 8.65 (d, J = 7.6 Hz, 1H), 7.97 (s, 1H), 7.51–7.48 (m, 2H), 7.28–7.24 (m,
3H), 7.15–7.12 (m, 1H), 7.09–7.07 (m, 1H), 6.97–6.96 (m, 1H), 6.93–6.90 (m,
1H), 6.86–6.84 (m, 1H), 6.45–6.39 (m, 2H), 5.51–5.43 (m, 1H), 5.20–5.17 (m,
1H), 5.05–5.02 (m, 1H), 4.94 (d, J = 17.2 Hz, 1H), 4.86 (br, 1H), 4.73 (s, 1H),
4.30–4.23 (m, 2H), 3.56–3.33 (m, 4H), 3.26–3.14 (m, 2H), 3.11 (s, 3H), 1.71 (d,
J = 7.2 Hz, 3H), 1.37 (d, J = 7.2 Hz, 3H), 1.27–1.11 (m, 1H). 13C NMR (100 MHz,
1
1
0. Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997, 62, 6507–6511.
1. Padrón, J. M.; Kokotos, G.; Martín, T.; Markidis, T.; Gibbons, W. A.; Martín, V. S.
Tetrahedron: Asymmetry 1998, 9, 3381–3394.
1
1
1
2. (a) Jia, Y.; Zhu, J. Synlett. 2005, 2469–2472; (b) Jia, Y.; Zhu, J. J. Org. Chem. 2006,
71, 7826–7834.
3
CDCl ) 172.8, 171.2, 170.8, 170.5, 169.9, 168.3, 167.0, 160.2, 150.0, 136.8,
3. Zheng, J.; Yin, B.; Huang, W.; Li, X.; Yao, H.; Liu, Z.; Zhang, J.; Jiang, S.
136.6, 134.9, 127.4, 126.5, 125.3, 123.4, 123.0, 121.6, 120.4, 119.7, 118.1, 115.9,
111.8, 111.6, 109.1, 106.0, 100.0, 56.2, 52.2, 51.1, 48.3, 45.4, 41.2, 37.5, 27.0,
Tetrahedron Lett. 2009, 50, 5094–5097.
4. Spectroscopic data of argyrin A (1): 1H NMR (400 MHz, CDCl
) 10.68 (s, 1 H), 9.47
s, 1 H), 8.82 (d, J = 8.4 Hz, 1 H), 8.60 (d, J = 1.6 Hz, 1 H), 8.57 (d, J = 7.2 Hz, 1 H),
26.5, 20.5, 14.0. MS (ESI, m/z) found 817.2 ([M+Na] ). ½
+
aꢀ
25
D
= + 123.2 (c 0.2,
3
acetone); Lit. 4: ½
aꢀ
25
D
= +127 (c 0.73, acetone).
(