Total synthesis of emericellamide A: A secondary metabolite of marine cyclic depsipeptide with antimicrobial properties

Article abstract of DOI:10.1055/s-0029-1217158

Emericellamide A is a secondary metabolite of marine cyclic depsipeptide from the co-culture of the marine-derived fungus Emericella sp. and actinomycete Salinispora arenicola. A general method for the total synthesis of emericellamide A is depicted in th

Full text of DOI:10.1055/s-0029-1217158

LETTER
1307
Total Synthesis of Emericellamide A: A Secondary Metabolite of Marine
Cyclic Depsipeptide with Antimicrobial Properties
Total
Syn
i
o
n
f
Emericella
g
mide
A
-Yi Ma,a Long-Fei Xu,a Wen-Feng Huang,a Bang-Guo Wei,*a Guo-Qiang Lin*a,b
a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China
Fax +86(21)54237757; E-mail: bgwei1974@fudan.edu.cn.
b
Institute of Biomedical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032, P. R. of China
Received 11 December 2008
O
macrolactamization
Abstract: Emericellamide A is a secondary metabolite of marine
cyclic depsipeptide from the co-culture of the marine-derived fun-
gus Emericella sp. and actinomycete Salinispora arenicola. A gen-
eral method for the total synthesis of emericellamide A is depicted
in this report.
H
20
19
22
N
18
21
HN
23
1
macrolactonization
emericellamide A
O
O
14
13
O
O
H
5
N
O
NH
4
7
2
N
Key words: cyclic depsipeptide, macrolactamization, antifungal
agents, emericellamide, total synthesis
H
8
O
peptide formation
N-Boc-Ala-OH
+
HO
O
C6H13
O
Emericellamides A and B are secondary metabolites of
marine cyclic depsipeptide with interesting bioactivity.
They were isolated by Fenical and co-workers1 from the
co-culture of the marine-derived fungus Emericella sp.
and actinomycete Salinispora arenicola. Emericellamide
A display an antimicrobial activity against methicillin-
resistant Staphylococcus aureus (MIC 3.8 mM), as well as
cytotoxicity against the HCT-116 human colon carcinoma
cell line (IC50 23 mM). With the help of chemical and spec-
troscopic methods, the planar structures of these com-
pounds were established, and the absolute configurations
of emericellamides A and B were determined afterwards
based on Marfey’s method2 and the modified Mosher
method.3 The first total synthesis of emericellamide A
was published by Ghosh and co-workers this year.4 We re-
port herein the total synthesis of emericellamide A using
a novel method.
20
22
BnO
O
21
23
Bu
OH
10
BocHN
12
+
HO
Bu
N-Gly-OBn
dipeptide (C4–C17)
O
OH
HDMD
Scheme 1 Strategic bond disconnections of emericellamide A
Bn
PivCl, NMM, THF
Bn
NaHMDS, MeI
O
HOOC
N
–78 °C to r.t., 82%
THF
O
NLi
O
O
1
2
O
–78 °C to r.t., 87%
Bn
O
BnBr
LiBH4
NaH, DMF
Retrosynthetically, the strategic bond disconnections of
the emericellamides are outlined in Scheme 1. For emeri-
cellamide A, which contains a highly methylated
(2R,3R,4S)-3-hydroxy-2,4-dimethylheptanoic acid (HD-
MD) unit, the most critical steps in its assembly is the con-
nection of the sterically hindered unit (HDMD) with the
other peptide or amino acid moiety. The Yamaguchi pro-
tocol was found to be an inefficient for such connection.4
For this reason, direct esterification with small Ala-OH
was our first choice. On the other hand, achieving a gen-
eral method for preparation of HDMD and convenient re-
moval of the protecting groups for all these units are
required.
O
HO
N
THF, H2O
0 °C, quant.
–78 °C to r.t.
88%
O
4
3
O3, CH2Cl2, –78 °C, 2 h
O
BnO
OBn
Me2S, –78 °C to r.t., 3 h
76%
6
5
Scheme 2
ride and added to the lithium salt of oxazolidinone to give
amide 2 (yield 87%), which was methylated with MeI at –
78 °C to afford product 3 with high diastereoselectivity
(96:4) in 82% yield. Removal of the auxiliary5 (LiBH4,
H2O) and protection (NaH, BnBr) of primary alcohol 4
gave benzyl ether 5 in 88% overall yield. Oxidation6 of the
double bond (O3, –78 °C) afforded aldehyde 6 in 76%
yield (Scheme 2).
In order to find a general method to prepare HDMD moi-
ety, we selected vinylacetic acid 1 as a starting material.
Thus, vinylacetic acid 1 was activated with pivaloyl chlo-
SYNLETT 2009, No. 8, pp 1307–1310
Advanced online publication: 07.05.2009
DOI: 10.1055/s-0029-1217158; Art ID: W18908ST
x
x.
x
x.
2
0
0
9
The aldehyde 6 prepared above, was converted to alde-
hyde 7 according to a known procedure7 using the well-
© Georg Thieme Verlag Stuttgart · New York

1308
J.-Y. Ma et al.
LETTER
established Evans’ asymmetric aldol methodology8 to
built the three contiguous stereogenic centers. The alde-
hyde 7 was directly subjected to Wittig reaction with pen-
tyltriphenylphosphonium bromide to generate the mixture
of olefin 8 (ratio of Z/E = 93:7), which was easily separat-
ed by chromatography on silica gel.9 Hydrogenation
Bu
N-Boc-Ala-OH
EDCI, DMAP
MeOH–HCl
OBn
HO
8
0 °C to r.t.
CH2Cl2, 57%
0 °C to r.t.
quant.
OH
10
Bu
H2, Pd/C
MeOH
r.t.
BnO
C6H13
10
[Pd(OH)2/C, MeOH] and oxidation with RuCl3–NaIO4
gave protected acid 9 in 75% overall yield (Scheme 3).
O
O
O
O
O
RuCl3, NaIO4
MeCN, CCl4
0 °C to r.t.
2
BocHN
12
BocHN
ref. 7
76%
(C5H11 + Ph3P)Br
H
OBn
11
6
H
N
n-BuLi, THF
0 °C, 93%
BnOOC
O
OTBS
OBn
C6H13
N-Gly-OBn
HOBt, EDCI
7
TFA
CH2Cl2
O
O
O
H2, Pd(OH)2/C
MeOH
DMF
–15 °C to r.t.
80%
r.t., quant.
OH
Bu
BocHN
C6H13
TBSO
RuCl3, NaIO4
MeCN, CCl4
OTBS
O
13
Z/E = 93:7
0 °C to r.t., 75%
H
9
8
N-Cbz-Val-Leu-Ala-OH
HOBt, EDCI
BnOOC
N
C6H13
Scheme 3
O
O
DMF
–15 °C to r.t., 71%
O
The next step was the macrocyclization reaction. Due to
the steric hindrance in emericellamide A, several methods
such as the Yamaguchi protocol11 did not work efficiently
for this macrocylization.4,11 Therefore, we turned to inner
condensation reaction between Gly-Val-Leu-Ala-OH and
N-Ala (Scheme 4). Condensation of acid 9 with N-Gly-
Val-Leu-Ala-OMe gave tripeptide 16 (EDC, HOBt) in
65% yield. Removal of silyl protecting group with TBAF
produced secondary alcohol 17, which was esterified with
N-Boc-Ala-OH. Unfortunately, the yield of esterification
(DCC or EDC) was very low (12%) and product 18 was
epimerized in a 1:1 ratio at C-2, possibly because of the
steric hindrance of the secondary alcohol caused by the
presence of vicinal methyl groups.12
H2N
TFA
14
O
H
N
C6H13
BnO
H2, Pd/C
MeOH
O
O
NHCbz
O
O
FDPP, DIPEA
MeCN
0 °C to r.t.
51%
HN
N
O
NH
H
O
emericellamide A
15
Scheme 5
Facing the fact that the esterification of deprotected 17
with Boc-Ala-OH did not work well, we use less hin-
drance secondary alcohol in 10 instead to complete the
crucial esterification step (Scheme 5). Gratefully, connec-
tion of 10 with N-Boc-Ala-OH in the presence of EDC
and DMAP in CH2Cl2 at 0 °C gave ester 11 in 57% yield
and product 11 was epimerized in 12:1 ratio at C-2,12
while the starting material could be recovered. The minor
epimer of 11 was easily separated by chromatography on
silica gel.13 Hydrogenation (Pd/C, quant.) of the ester 11
was followed by oxidation (RuCl3–NaIO4)10 to afford the
crude acid 12. Without further purification, acid 12 was
condensated with N-Gly-OBn in the presence of EDC/
HOBt to produce 13 in 80% yield (three steps).14 Depro-
tection of the Boc group (TFA, CH2Cl2) of 13 gave salt 14,
which was coupled with Cbz-Val-Leu-Ala-OH under the
same conditions as mentioned above to give peptide 15 in
71% yield (two steps).15 Removal of the Bn and Cbz pro-
tecting group (Pd/C, MeOH) gave free acid and amine in
one pot, which was subjected to macrolactamization by
treatment with pentafluorophenyl diphenylphosphinate
(FDPP)16 and DIPEA under highly diluted solution (10–3M)
of the substrate in MeCN at room temperature to give
O
H
N
N-Gly-Val-Leu-Ala-OMe
HOBt, EDCI
HN
C6H13
9
O
OTBS
OMe
DMF
–15 °C to r.t., 65%
O
H
N
O
NH
O
16
TBAF, THF
r.t.
87%
17
N-Boc-Ala-OH
EDCI, DMAP
CH2Cl2
0 °C to r.t
12%
O
H
N
HN
C6H13
O
O
O
O
H
N
O
NH
OMe
NHBoc
O
18
emericellamide A in 51% yield (two steps);4,17 [a]D
25
–42.89 (c 0.26, MeOH) {lit.1 [a]D25 –43 (c 0.23, MeOH);
Scheme 4
Synlett 2009, No. 8, 1307–1310 © Thieme Stuttgart · New York

LETTER
Total Synthesis of Emericellamide A
1309
ESI-MS: 427.3 [M + Na+]. HRMS (ESI): m/z calcd for
[C25H44O2Si + Na+]: 427.3010; found: 427.3020.
(10) Carlsen, P. H.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936.
lit.4 [a]D25 –42.99 (c 0.2, MeOH)}. The spectroscopic and
physical data of the synthetic emericellamide A were
identical with those described in the literature.1,4
In conclusion, we have achieved a general and convenient
route for total synthesis of emericellamide A with 5.6%
overall yield. Especially, the present method for prepara-
tion of aldehyde 7 from vinylacetic acid 1 is rather effi-
cient, this would assist assembling emericellamides A, B,
and their analogues in a diversified way that thereby could
be beneficial for their structure–activity relationship stud-
ies, as well as exploring their possible antimicrobial
mechanism.
(11) Inanaga, J.; Hirata, K.; Seaki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(12) Yu, S. Y.; Pan, X. H.; Ma, D. W. Chem. Eur. J. 2006, 12,
6572.
(13) Preparation of Ester 11
To a solution of alcohol 10 (1.50 g, 5.17 mmol), EDCI (4.93
g, 25.83 mmol) in dry CH2Cl2 (20 mL) was added N-Boc-
Ala-OH (2.93 g, 15.50 mmol) at 0 °C under argon atmo-
sphere and stirred for 0.5 h, then DMAP (315 mg, 2.58
mmol) was added in one portion. After being stirred for 3 h,
the mixture was warmed to r.t. and stirred for 6 h at this
temperature. The resulting mixture was diluted with CH2Cl2
(30 mL), the organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (2 × 30 mL). The combined
organic layers were washed with HCl (5%), sat. aq NaHCO3
and brine, then dried and concentrated. The residue was
purified by chromatography on SiO2 (Et2O–PE = 1:50 to
1:30) to give ester 11 (1.35 g, yield 57%; 87% based on the
recovered starting material) as a light yellow oil.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors are grateful to the National Natural Science Foundation
of China (20702007, 20832005), and Fudan University for financial
support.
Analytical and Spectral Data of Ester 11
[a]D25 +8.25 (c 3.50, CHCl3). IR (film): nmax = 3373, 2966,
2930, 1716, 1497, 1454, 1366, 1167 cm–1. 1H NMR (600
MHz, CDCl3): d = 7.36–7.26 (m, 5 H), 5.37–5.31 (m, 1 H),
5.14–5.08 (m, 2 H), 4.90–4.84 (m, 1 H), 4.46 (s, 2 H), 4.29
(dd, J = 6.74, 7.54 Hz, 1 H), 3.51 (dd, J = 4.56, 9.26 Hz, 1
H), 3.24 (dd, J = 7.28, 9.26 Hz, 1 H), 2.85–2.81 (m, 1 H),
2.24–2.08 (m, 1 H), 2.04–1.87 (m, 2 H), 1.44 (s, 9 H), 1.39
(d, J = 6.90 Hz, 3 H), 1.36–1.25 (m, 4 H), 0.99 (d, J = 6.72
Hz, 3 H), 0.91–0.85 (m, 6 H) ppm. 13C NMR (150 MHz,
CDCl3): d = 171.6, 155.1, 138.6, 131.0, 130.6, 128.3 (2 C),
127.6 (2 C), 127.5, 80.4, 79.7, 73.1, 71.5, 49.5, 35.5, 35.7,
33.3, 31.7, 28.3 (3 C), 27.3, 22.4, 16.3, 15.0, 14.0 ppm. ESI-
MS: 484.3 [M + Na+]. HRMS (MALDI): m/z calcd for
[C27H43NO5 + Na+]: 484.3039; found: 484.3035.
References and Notes
(1) Oh, D.-C.; Kauffman, C. A.; Jensen, P. R.; Fenical, W.
J. Nat. Prod. 2007, 70, 515.
(2) Marfey, P. Carlsberg Res. Commun. 1984, 49, 591.
(3) Séco, J. M.; Quiňoa, E.; Riguera, R. Tetrahedron:
Asymmetry 2001, 12, 2915.
(4) Ghosh, S.; Pradham, T. K. Tetrahedron Lett. 2008, 49, 3697.
(5) Smith, A. B. III; Lee, D. J. Am. Chem. Soc. 2007, 129,
10957.
(6) Ornum, S. G.; Champeau, R. M.; Pariza, R. Chem. Rev.
2006, 106, 2990.
(7) Zampella, A.; Sorgente, M.; D’Auria, M. V. Tetrahedron:
Asymmetry 2002, 13, 681.
(8) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127.
(14) Preparation of Peptide 13
To a suspension of Pd/C (10%, 50 mg) in MeOH (10 mL)
was added a solution of 11 (495 mg, 1.074 mmol) in MeOH
(2 mL) at r.t. under H2 atmosphere (1.013 bar). After being
stirred for 4 h at the same conditions, the catalyst was filtered
carefully, and the filtrate was concentrated in vacuo to give
the crude alcohol (400 mg, quant.) as a colorless oil.
[a]D25 –27.0 (c 1.31, CHCl3). IR (film): nmax = 3460, 3368,
2965, 2929, 1715, 1518, 1456, 1169 cm –1. 1H NMR (600
MHz, CDCl3): d = 5.04 (d, J = 6.9 Hz, 1 H), 4.90 (d,
J = 10.02 Hz, 1 H), 4.32–4.46 (m, 1 H), 3.60–3.56 (m, 1 H),
3.48–3.44 (m, 1 H), 2.47 (br s, 1 H), 1.88–1.83 (m, 1 H),
1.78–1.73 (m, 1 H), 1.45 (s, 9 H), 1.41 (d, J = 5.10 Hz, 3 H),
1.32–1.21 (m, 9 H), 1.01 (d, J = 6.96 Hz, 3 H), 0.92 (d,
J = 6.84 Hz, 3 H), 0.88 (t, J = 7.00 Hz, 3 H) ppm. 13C NMR
(150 MHz, CDCl3): d = 174.8, 155.4, 80.1, 78.4, 64.1, 49.7,
36.9, 34.2, 33.7, 31.8, 29.4, 28.3 (3 C), 27.1, 22.6, 14.0 (2 C),
13.0 (2 C) ppm. ESI-MS: 396.3 [M + Na+]. HRMS
(MALDI): m/z calcd for [C20H39NO5 + Na+]: 396.2726;
found: 396.2730.
To a stirred solution of the above alcohol (400 mg, 1.07
mmol) in CCl4 (5 mL) were added MeCN (5 mL) and H2O
(7.5 mL), then NaIO4 (916 mg, 4.28 mmol) and RuCl3 (10.8
mg, 0.04 mmol) were added sequentially at r.t. After being
stirred for 4 h, the reaction was diluted with Et2O (20 mL)
and stirred for 20 min to precipitate black RuO2. Then the
mixture was dried and filtered through Celite, the solid
residue was washed with Et2O, and the combined organic
phases were concentrated in vacuo to give the carboxylic
(9) Preparation of Compound 8
To a suspension of pentyltriphenylphosphonium bromide
(11.2 g, 27.18 mmol) in dry THF (70 mL) was dropped n-
BuLi (15.9 mL, 1.6 M in hexane, 25.5 mmol) at r.t. under
argon atmosphere. After the red mixture was stirred for 30
min, a solution of aldehyde 7 (1.80 g, 5.14 mmol) in dry THF
(10 mL) was dropped and stirred for 2 h. The mixture was
diluted with EtOAc and washed with sat. aq NaHCO3 and
brine. Dried, filtered, and concentrated, the residue was
purified by chromatography on SiO2 (EtOAc–PE = 1:150) to
give major-8 (1.79 g, 86.5%) and minor-8 (135 mg, 6.5%)
both as a colorless oil.
Analytical and Spectral Data of Polypeptide major-8
[a]D25 +9.5 (c 1.2, CHCl3). IR (film): nmax = 3000, 2928,
2856, 1464, 1406, 1252, 1097 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.36–7.27 (m, 5 H), 5.29–5.17 (m, 2 H), 4.47 (s,
2 H), 3.57 (dd, J = 5.09, 9.39 Hz, 1 H), 3.43 (dd, J = 3.88,
6.26 Hz, 1 H), 3.27 (dd, J = 7.82, 9.40 Hz, 1 H), 2.70–2.59
(m, 1 H), 2.08–1.92 (m, 3 H), 1.35–1.25 (m, 4 H), 0.99 (d,
J = 7.04 Hz, 3 H), 0.92 (d, J = 7.05 Hz, 3 H), 0.90–0.87 (m,
12 H), 0.04 (s, 3 H), 0.03 (s, 3 H) pp.; 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): d = 138.8, 133.8, 128.8, 128.2 (2 C),
127.5 (2 C), 127.3, 78.5, 72.9, 72.7, 38.4, 35.3, 31.9, 27.2,
26.2 (3 C), 22.5, 18.4, 17.4, 14.9, 14.0, –3.7, –3.9 ppm.
Synlett 2009, No. 8, 1307–1310 © Thieme Stuttgart · New York

1310
J.-Y. Ma et al.
LETTER
acid 12 without further purification. The crude acid 12 (415
mg, 1.07 mmol) and HOBt (159 mg, 1.18 mmol) were added
in dry DMF (8 mL) and stirred for 15 min at r.t., then the
reaction mixture was cooled to –15 °C, and EDCI (225 mg,
1.18 mmol) was added in one portion. After being stirred for
1.5 h at –15 °C, N-Gly-OBn (194 mg, 1.18 mmol) was added
and stirred overnight at r.t. The mixture was quenched with
H2O (20 mL) and extracted with Et2O (3 × 30 mL). The
combined organic layers were washed with H2O, sat. aq
NaHCO3 and brine. Dried and concentrated, the residue was
purified by chromatography on SiO2 (EtOAc–PE = 1:5) to
give 13 (458 mg, 80%) as a colorless oil.
(ddd, J = 6.84, 13.58, 16.60 Hz, 1 H), 1.96–1.91 (m, 1 H),
1.71–1.65 (m, 1 H), 1.62–1.56 (m, 1 H), 1.43–1.38 (m, 2 H),
1.27–1.14 (m, 15 H), 1.04–0.99 (m, 1 H), 0.95 (d, J = 6.96
Hz, 3 H), 0.86–0.77 (m, 18 H) ppm. 13C NMR (150 MHz,
DMSO-d6): d = 174.0, 172.0, 171.9, 171.6, 171.5, 170.3,
156.6, 137.6, 136.4, 128.9 (2 C), 128.8 (2 C), 128.5 (2 C),
128.4 (2 C), 128.2, 128.1, 79.6, 77.5, 66.3, 65.8, 60.7, 51.2,
48.2, 48.0, 42.1, 41.1, 33.8, 33.6, 31.7, 30.7, 29.3, 27.0, 24.5,
23.5, 22.5, 21.9, 19.7, 18.7, 18.6, 17.8, 14.6, 14.4, 13.6 ppm.
ESI-MS: 874.5 [M + Na+]. HRMS (MALDI): m/z calcd for
[C46H69N5O10 + Na+]: 874.4942; found: 874.4931.
(16) Chen, S.; Xu, J. Tetrahedron Lett. 1991, 32, 6711.
(17) To a suspension of Pd/C (10%, 15 mg) in MeOH was added
a solution of 15 (105 mg, 0.123 mmol) in MeOH (3 mL) at
r.t. under H2 atmosphere (1.013 bar). After being stirred for
3 h at the same conditions, the catalyst was filtered carefully,
and the filtrate was concentrated in vacuo to give the crude
product (73 mg, 95%) without further purification. The
crude product was suspended in anhyd MeCN (120 mL,
1.0·10–3 M) and cooled to 0 °C, pentafluorophenyl-
Analytical and Spectral Data of Peptide 13
[a]D25 –9.56 (c 0.68, CHCl3). IR (film): nmax = 3323, 2929,
2929, 1744, 1716, 1525, 1456, 1174 cm–1. 1H NMR (600
MHz, CDCl3): d = 7.40–7.33 (m, 5 H), 6.40 (m, 1 H), 5.21
(d, J = 12.24 Hz, 1 H), 5.17 (d, J = 12.24 Hz, 1 H), 5.09–5.06
(m, 1 H), 4.34–4.27 (m, 1 H), 4.09 (dd, J = 2.40, 4.74 Hz, 2
H), 2.71–2.67 (m, 1 H), 1.81–1.77 (m, 1 H), 1.42 (s, 9 H),
1.39 (d, J = 7.20 Hz, 3 H), 1.36–1.21 (m, 9 H), 1.16 (d,
J = 7.08 Hz, 3 H), 1.15–1.10 (m, 1 H), 0.90–0.86 (m, 6 H)
ppm. 13C NMR (150 MHz, CDCl3): d = 173.7, 172.7, 170.1,
155.3, 135.2, 128.6 (2 C), 128.5 (2 C), 128.3, 79.8, 78.6,
67.2, 49.4, 43.6, 41.4, 34.3, 33.5, 31.8, 29.4, 28.3 (3 C), 26.8,
22.6, 14.7, 14.1 (2 C), 13.6 (2 C) ppm. ESI-MS: 557.3 [M +
Na+]. HRMS (MALDI): m/z calcd for [C29H46N2O7 + Na+]:
557.3203; found: 557.3193.
diphenylphosphinate (FDPP) reagent (90 mg, 0.234 mmol)
was added in one portion and stirred for 20 min at the same
temperature. Then DIPEA (82 mL, 0.468 mmol) was slowly
dropped over a period of 30 min. After beeing stirred for 26
h at r.t., the mixture was concentrated in vacuo. The residue
was purified by RP C18 HPLC with 70% aq MeCN (Sepax-
tech Amethyst C18 semipreparative column, 10 mm × 150
mm, 2 mL/min, refractive index detection) to give
(15) Preparation of Peptide 15
To a solution of 13 (200 mg, 0.374 mmol) in CH2Cl2 (3 mL)
was added TFA (3 mL) and stirred for 2 h at r.t. The solvent
was removed in vacuo, and the residue was dissolved in
DCE (3 mL) and removed. This process repeated for three
times to give crude amide 14. HOBt (50.5 mg, 0.374 mmol)
was added to a solution of N-Cbz-Val-Leu-Ala-OH (148 mg,
0.339 mmol) in dry DMF (5 mL) at –15 °C. After 30 min of
stirring, EDCI (71.2 mg, 0.374 mmol) was added and stirred
at –15 °C for 1.5 h, then NMM (82 mL, 0.745 mmol) and a
solution of salt 14 in DMF was added. After being stirred for
overnight at r.t., the reaction was quenched with H2O (15
mL) and extracted with EtOAc (3 × 30 mL). The combined
organic extracts were washed with H2O, sat. aq NaHCO3 and
brine. Dried and concentrated, the residue was purified by
chromatography on SiO2 (MeOH–CH2Cl2 = 1:60) to give 15
(225 mg, 71%) as a white solid.
emericellamide A (37 mg, 51%).
Analytical and Spectral Data of Emericellamide A
[a]D25 –42.89 (c 0.26, MeOH) {lit.1 [a]D25 –43 (c 0.23,
MeOH); lit.4 [a]D25 –42.99 (c 0.2, MeOH)}. IR (KBr): nmax
=
3323, 2931, 1755, 1668, 1650, 1538 cm–1. 1H NMR (600
MHz, DMSO-d6): d = 8.07 (d, J = 6.24 Hz, 1 H), 8.01 (br s,
1 H), 7.94 (d, J = 7.74 Hz, 1 H), 7.51 (br s, 1 H), 7.39 (d,
J = 6.18 Hz, 1 H), 4.92 (dd, J = 2.40, 10.02 Hz, 1 H), 4.31
(dd, J = 5.73, 17.52 Hz, 1 H), 4.09–4.00 (m, 3 H), 3.97 (dd,
J = 8.22, 8.28 Hz, 1 H), 3.61 (dd, J = 2.40, 17.52 Hz, 1 H),
2.85 (dq, J = 6.96, 9.81 Hz, 1 H), 1.91–1.84 (m, 1 H), 1.69–
1.63 (m, 1 H), 1.59–1.52 (m, 2 H), 1.31–1.16 (m, 8 H), 1.23
(d, J = 7.38 Hz, 3 H), 1.21 (d, J = 6.96 Hz, 3 H), 1.15–1.08
(m, 1 H), 1.05–0.98 (m, 1 H), 0.89 (d, J = 6.78 Hz, 3 H), 0.88
(d, J = 6.84 Hz, 3 H), 0.87 (d, J = 7.08 Hz, 3 H), 0.86 (d,
J = 7.03 Hz, 3 H), 0.83 (t, J = 6.94 Hz, 3 H), 0.82 (d, J = 7.08
Hz, 3 H), 0.80 (d, J = 6.48 Hz, 3 H) ppm. 13C NMR (150
MHz, DMSO-d6): d = 173.3, 171.9, 171.7, 171.6, 171.3,
169.2, 77.1, 60.5, 52.3, 48.7. 47.8, 42.9, 41.5, 33.9, 33.7,
31.6, 30.6, 29.3, 27.0, 25.0, 23.6, 22.5, 21.2, 19.5, 19.2, 18.7,
16.8, 14.8, 14.4, 13.4 ppm. ESI-MS: 610.4 [M + H+]. HRMS
(MALDI): m/z calcd for [C31H55N5O7 + Na+]: 632.3999;
found: 632.4004.
Analytical and Spectral Data of Polypeptide 15
[a]D25 –34.2 (c 0.32, CHCl3). IR (film): nmax = 3279, 2959,
2928, 1741, 1699, 1634, 1538, 1210 cm –1. 1H NMR (600
MHz, DMSO-d6): d = 8.24 (m, 1 H), 8.03 (m, 1 H), 7.92–
7.87 (m, 2 H), 7.38–7.28 (m, 11 H), 5.11 (d, J = 12.72 Hz, 1
H), 5.09 (d, J = 12.72 Hz, 1 H), 5.03 (d, J = 14.49 Hz, 1 H),
5.01 (d, J = 14.49 Hz, 1 H), 4.94 (dd, J = 2.28, 9.48 Hz, 1 H),
4.33–4.23 (m, 3 H), 3.89–3.82 (m, 2 H), 3.77 (m, 1 H), 2.66
Synlett 2009, No. 8, 1307–1310 © Thieme Stuttgart · New York

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