Total synthesis and stereochemical reassignment of maedamide

Article abstract of DOI:10.1016/j.tetlet.2015.06.090

Abstract The first total synthesis of maedamide, an acyclic peptide isolated from a marine cyanobacterial assemblage of Lyngbya sp., was achieved. This synthesis led to reassignment of the allo-d-Ile of maedamide to be l-Ile, which was supported by ¹

Full text of DOI:10.1016/j.tetlet.2015.06.090

Tetrahedron Letters 56 (2015) 4947–4949
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Tetrahedron Letters
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Total synthesis and stereochemical reassignment of maedamide
⇑
Ayano Takayanagi, Arihiro Iwasaki, Kiyotake Suenaga
Department of Chemistry, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of maedamide, an acyclic peptide isolated from a marine cyanobacterial assem-
Received 29 May 2015
Revised 25 June 2015
Accepted 29 June 2015
Available online 2 July 2015
blage of Lyngbya sp., was achieved. This synthesis led to reassignment of the allo-
L
D-Ile of maedamide to be
-Ile, which was supported by 1H and 13C NMR data.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Maedamide
Total synthesis
Marine natural products
Marine cyanobacteria
Lyngbya
In 2014, we isolated maedamide, an acyclic depsipeptide, from
a marine cyanobacterial assemblage of Lyngbya sp.1 Structurally,
maedamide possesses some unusual amino acid residues, such as
4-amino-3-hydroxy-5-phenylpentanoic acid. Maedamide (2)
inhibited the growth of HeLa and HL60 cells, with IC50 values of
O
HO
O
O
O
H
O
N
OMe
N
NH
O
O
H
N
H
N
N
H
4.2 and 2.2
lM, respectively. In addition, maedamide showed inhi-
OH
O
O
bitory activity against chymotrypsin, with an IC50 value of 45
lM.
In this Letter, we describe the first total synthesis and structural
reassignment of maedamide.
Maedamide
(2, -Ile)
L
O
HO
O
Our retrosynthetic analysis of maedamide is shown in
Scheme 1. Maedamide is formed by carboxylic acid 3 and hexapep-
tide 4. Carboxylic acid 3 could be prepared by the condensation of
O
O
H
O
N
OMe
N
NH
O
O
H
N
H
N
N
H
L-valic acid and allo-D-isoleucic acid. Meanwhile, hexapeptide 4
OH
O
O
could be synthesized by stepwise condensation of the correspond-
ing amino acid moieties, starting with the C-terminal residue, O-
Me-
First, we synthesized carboxylic acid 3 as shown in Scheme 2.
Protection of a hydroxyl group of -valic acid followed by conden-
sation with O-Me-allo- -isoleucic acid afforded ester 5.
L-Pro.
Originally Proposed Maedamide
1
( , allo-D-Ile)
L
D
Demethylation of methyl ester 5 using LiI gave 6, and removal of
the TBS group under acidic conditions provided carboxylic acid 3.
The synthesis of hexapeptide 4a commenced with the conden-
sation of the known dipeptide 72 with N-Boc-glycine using stan-
dard procedures. The obtained tripeptide
condensed with N-Boc-allo- -isoleucine to give tetrapeptide 9a.
Removal of the Boc group of 9a with TFA and incorporation with
known
-amino acid 113 afforded pentapeptide 10a. Compound
8
was further
D
⇑
Corresponding author. Tel./fax: +81 45 566 1819.
E-mail address: suenaga@chem.keio.ac.jp (K. Suenaga).
c
http://dx.doi.org/10.1016/j.tetlet.2015.06.090
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

4948
A. Takayanagi et al. / Tetrahedron Letters 56 (2015) 4947–4949
O
Fmoc
O
N
OMe
N
O
NH
O
O
H
N
H
HO
O
N
O
1
N
H
(allo-
D-Ile)
H
2 ( -Ile)
L
OH
OH
O
O
3
4a
4b
(allo-
D
-Ile)
-Ile)
(
L
Scheme 1. Retrosynthetic analysis of maedamide.
O
Fmoc
O
N
OMe
O
O
N
NH
O
O
a, b, c
HO
TBSO
O
H
N
H
OH
O
N
H
N
H
OMe
OH
O
O
5
L-Valic acid
4a (allo-
D
-Ile)
d
4b
( -Ile)
L
a, b
O
O
e
TBSO
O
HO
O
O
O
H
H
O
OH
OH
HO
O
O
O
6
3
H
O
N
OMe
N
NH
O
O
H
N
H
Scheme 2. Synthesis of carboxylic acid 3. Reagents and conditions: (a) TBSCl,
imidazole, DMF, 40 °C, 22 h, quant; (b) oxalyl chloride, DMF, CH2Cl2, 0 °C to rt, 2.5 h;
N
N
H
OH
O
O
(c) O-Me-allo-
D-isoleucic acid, pyridine, CH2Cl2, rt, 4 days, 40% in two steps; (d) LiI,
pyridine, reflux, 6 h, quant.; (e) 4 M HCl, 1,4-dioxane, rt, 4 days, quant.
1
(allo-
D
-Ile)
2
( -Ile)
L
O
N
OMe
O
N
OMe
O
O
a, b
N
Boc
N
Boc
Scheme 4. Synthesis of maedamide 1 and 2. Reagents and conditions: (a) Et2NH,
CH3CN, rt, 1 h; (b) 3, HATU, HOAt, iPr2NEt, DMF, 0 °C to rt, 1 h, (1) 34% in two steps,
(2) 40% in two steps.
N
H
O
Ph
Ph
7
8
c, d
10a was converted to 4a by condensation with N-Fmoc-L-Pro
(Scheme 3).
O
OMe
O
O
H
N
H
Finally, the condensation of carboxylic acid 3 and hexapeptide
4a was carried out (Scheme 4). Removal of an Fmoc group of 4a
with DEA in MeCN followed by coupling with carboxylic acid 3
gave the target compound 14 as a colorless oil (10 steps, 5.4% yield
from 7).
However, the NMR data of 1 were inconsistent with those
reported for the natural product. A detailed comparison of the
NMR data clarified that the 1H NMR and 13C NMR signals assigned
N
Boc
N
N
H
O
Ph
9a
9b
(allo-D-Ile)
Fmoc
NH
(L-Ile)
OH
Ph OH
O
e, f
11
to allo-
for the natural product. In addition, the structurally related
cyanobacterial peptide tasiamide5 possessed
-isoleucine at the
corresponding position. Based on these data, we inferred that mae-
damide consisted of -isoleucine rather than allo- -isoleucine. To
verify this hypothesis, we synthesized the epimer of 1 possessing
-isoleucine instead of allo- -isoleucine (2).
N-Boc- -isoleucine was condensed with tripeptide 8, a common
intermediate, to give tetrapeptide 9b. Compound 9b was converted
to 4b in a similar manner as for 1. The condensation of 4b with car-
boxylic acid 3 afforded the epimer 26 (10 steps, 6.6% yield from 7).
In a comparison of the spectroscopic data of 2 with those of the
natural product, 2 corresponded to the natural product.
D-isoleucine of 1 were most different from the data reported
O
N
OMe
Fmoc
NH
O
O
H
N
H
L
N
N
H
Ph OH
O
O
Ph
L
D
10a (allo-D-Ile)
10b
(L-Ile)
L
D
L
g, h
O
Fmoc
O
N
OMe
N
NH
O
O
H
N
H
N
N
H
Ph OH
O
O
In conclusion, we have achieved the first total synthesis of mae-
damide and revised its structure. The revised structure (2) differs
from the original (1) with respect to the absolute configuration
of an Ile residue: the correct stereochemistry of the Ile residue is
Ph
4a (allo-
4b
(L-Ile)
D-Ile)
L
rather than allo-D.
Scheme 3. Synthesis of hexapeptide 4. Reagents and conditions: (a) TFA, CH2Cl2,
0 °C, 2.5 h; (b) N-Boc-glycine, HATU, iPr2NEt, DMF, 0 °C to rt, 14 h, 80% in two steps;
(c) TFA, CH2Cl2, 0 °C; (d) N-Boc-allo-D-isoleucine (9a), N-Boc-L-isoleucine (9b),
Acknowledgments
HATU, iPr2NEt, DMF, 0 °C to rt, (9a) 76% in two steps, (9b) 63% in two steps; (e) TFA,
i
CH2Cl2, 0 °C, 2 h; (f) 11, HATU, Pr2NEt, DMF, 0 °C to rt, 2 h, (10a) 54% in two steps,
This work was supported in part by a Grants-in-Aid from the
Ministry of Education, Culture, Sports, Science and Technology of
(10b) 73% in two steps; (g) Et2NH, CH3CN, rt, 3 h; (h) N-Fmoc-
L-proline, HATU,
iPr2NEt, DMF, 0 °C to rt, 3 h, (4a) 48% in two steps, (4b) 45% in two steps.

A. Takayanagi et al. / Tetrahedron Letters 56 (2015) 4947–4949
4949
(d, J = 14.2, 8.2, 1H), 3.03 (s, 3H), 3.00–2.92 (m, 2H), 2.83 (dd, J = 14.2, 7.3, 1H),
2.44–2.30 (m, 2H), 2.23–2.11 (m, 2H), 2.06–1.82 (m, 6H), 1.77 (m, 1H), 1.63 (m,
1H), 1.51–1.40 (m, 2H), 1.36–1.22 (m, 3H), 1.07 (d, J = 7.0, 3H), 1.05 (d, J = 6.7,
3H), 1.01–0.91 (m, 12H); 13C NMR (100 MHz, CD3OD) d 177.4, 174.6, 174.3,
174.0, 173.1, 171.4, 170.4, 170.1, 140.0, 138.6, 130.5, 130.4, 129.44, 129.37,
127.6, 127.5, 77.7, 76.3, 71.5, 62.4, 60.6, 58.2, 57.8, 56.3, 52.7, 42.0, 41.5, 37.8,
37.7, 37.2, 35.7, 33.4, 30.6, 30.3, 29.9, 27.3, 26.4, 26.0, 24.7, 19.3, 17.3, 15.0, 14.9,
12.1, 12.0; HR (ESI) m/z 963.5447, calcd for C51H75N6O12 [M+H]+ 963.5443.
5. Williams, P. G.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J. J. Nat. Prod. 2002, 65,
1336–1339.
Japan (24310160) and Keio Gijuku Fukuzawa Memorial Fund for
the Advancement of Education and Research.
Supplementary data
Supplementary data (1H and 13C NMR spectra for all com-
pounds. Detailed experimental procedures) associated with this
article can be found, in the online version, at http://dx.doi.org/10.
1016/j.tetlet.2015.06.090.
6. Compound 2: [a]
29 +17 (c 0.1, CH3OH); 1H NMR (400 MHz, CD3OD) d 7.29–7.16 (m,
D
10H), 5.55 (dd, J = 8.3, 7.8, 1H), 5.01 (d, J = 6.2, 1H), 4.36 (m, 1H), 4.35 (m, 1H), 4.28
(d, J = 6.5, 1H), 4.20 (m, 1H), 4.17 (d, J = 4.4, 1H), 4.13 (m, 1H), 4.09 (d, J = 17.5, 1H),
3.94 (d, J = 17.5, 1H), 3.86 (m, 1H), 3.71 (s, 3H), 3.53 (m, 1H), 3.38 (m, 1H), 3.37 (m,
1H), 3.20 (dd, J = 14.2, 8.3, 1H), 3.03 (s, 3H), 2.98 (m, 1H), 2.92 (m, 1H), 2.82 (dd,
J = 14.2, 7.8, 1H), 2.38 (m, 1H), 2.37 (m, 1H), 2.18 (m, 1H), 2.16 (m, 1H), 1.97–1.80
(m, 6H), 1.76 (m, 1H), 1.64 (m, 1H), 1.54 (m, 1H), 1.46 (m, 1H), 1.36–1,31 (m, 2H),
1.21 (m, 1H), 1.07 (d, J = 7.0, 3H), 1.05 (d, J = 6.7, 3H), 0.97–0.95 (m, 9H), 0.91 (t,
J = 7.5, 3H);13C NMR (100 MHz, CD3OD) d 177.2, 174.1, 174.00, 173.95, 173.3,
171.3, 170.3, 170.2, 140.1, 138.6, 130.5, 130.4, 129.40, 129.36, 127.6, 127.5, 77.6,
76.3, 71.1, 62.4, 60.6, 59.7, 57.8, 56.0, 52.7, 41.9, 41.2, 37.8, 37.9, 37.2, 35.7, 33.2,
30.6, 30.4, 29.9, 26.4, 26.0, 25.7, 24.8, 19.3, 17.1, 16.1, 14.9, 12.0, 11.9; HR (ESI) m/z
985.5224, calcd for C51H74N6O12Na [M+Na]+ 985.5262.
References and notes
1. Iwasaki, A.; Ohno, O.; Sumimoto, S.; Suda, S.; Suenaga, K. Tetrahedron Lett. 2014,
55, 4126–4128.
2. Ma, Z.; Song, N.; Li, C.; Zhang, W.; Wang, P.; Li, Y. J. Pept. Sci. 2008, 14, 1139–
1147.
3. Meloni, M. M.; Taddei, M. Org. Lett. 2001, 3, 337–340.
27
4. Compound 1: [
a
]
D
À4.5 (c 4.0, CH3OH); 1H NMR (400 MHz, CD3OD) d 7.31–7.15
(m, 10H), 5.58 (dd, J = 8.2, 8.2, 1H), 5.01 (d, J = 6.3, 1H), 4.46 (d, J = 5.1, 1H), 4.39–
4.34 (m, 2H), 4.24 (m, 1H), 4.18 (d, J = 4.4, 1H), 4.16 (d, J = 17.4, 1H), 4.13 (m, 1H),
3.90 (d, J = 17.4, 1H), 3.86 (m, 1H), 3.71 (s, 3H), 3.58–3.39 (m, 3H), 3.21