Ionic-liquid-supported total synthesis of sansalvamide A peptide

Article abstract of DOI:10.1080/00397910701749633

A facile and efficient total synthesis of bioactive sansalvamide A peptide has been accomplished, including the-ionic-liquid supported method and final PyBOP-promoted ring closure. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701749633

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Ionic‐Liquid‐Supported Total Synthesis of
Sansalvamide A Peptide
Ling Chen a , Mingfang Zheng a , Yu Zhou a b , Hong Liu a & Hualiang Jiang a c
a Center for Drug Discovery and Design, State Key Laboratory of Drug
Research, Shanghai Institute of Materia Medica, Shanghai Institutes for
Biological Sciences, and Chinese Academy of Sciences, Shanghai, China
b School of Pharmaceutical Engineering, Shenyang Pharmaceutical
University, Shenyang, Liaoning, China
c School of Pharmacy, East China University of Science and Technology,
Shanghai, China
Published online: 18 Jan 2008.
To cite this article: Ling Chen , Mingfang Zheng , Yu Zhou , Hong Liu & Hualiang Jiang (2008)
Ionic‐Liquid‐Supported Total Synthesis of Sansalvamide A Peptide, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:2, 239-248, DOI:
10.1080/00397910701749633
To link to this article: http://dx.doi.org/10.1080/00397910701749633
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Synthetic Communicationsw, 38: 239–248, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701749633
Ionic-Liquid-Supported Total Synthesis
of Sansalvamide A Peptide
Ling Chen,1 Mingfang Zheng,1 Yu Zhou,1,2 Hong Liu,1
and Hualiang Jiang1,3
1Center for Drug Discovery and Design, State Key Laboratory of Drug
Research, Shanghai Institute of Materia Medica, Shanghai Institutes for
Biological Sciences, and Chinese Academy of Sciences, Shanghai, China
2School of Pharmaceutical Engineering, Shenyang Pharmaceutical
University, Shenyang, Liaoning, China
3School of Pharmacy, East China University of Science and Technology,
Shanghai, China
Abstract: A facile and efficient total synthesis of bioactive sansalvamide A peptide has
been accomplished, including the-ionic-liquid supported method and final PyBOP-
promoted ring closure.
Keywords: ionic liquid, sansalvamide A peptide, total synthesis
INTRODUCTION
Sansalvamide A (San A, 1) is a cyclic depsipeptide, isolated from organic
extracts of the mycelium of a fungus of the genus Fusarium collected from
the surface of the seagrass Halodule wrightii.[1] It showed a mean IC50
value of 27.4 mg/mL against the National Cancer Institute’s 60-cell-line
panel and an in vitro IC50 value of 9.8 mg/mL toward HCT-116 colon
carcinona.[1,2] This natural product was found to inhibit virus-encoded type-
1 topoisomerase, which is likely to be required for molluscum contagiosum
Received in Japan June 20, 2006
Address correspondence to Hong Liu, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park,
Shanghai 201203, China. E-mail: hliu@mail.shcnc.ac.cn
239

240
L. Chen et al.
virus (MCV) replication.[3] Silverman’s group reported the solid-phase-
supported synthesis of the corresponding cyclic peptide of San A (2), as
well as its N-methyl derivatives.[2,4] Styers et al. reported several San A
derivatives that demonstrated promising anticancer properties,[5] and
compound 3 demonstrates IC50 values of 0.80 mM for HCT-116 and
0.65 mM for HCT-15, which are much more potent than San A peptide 2
and 5-fluorouracil against two microsatellite-unstable (MSI) colon-cancer
cell lines (HCT-116 and HCT-15).[5d]
Silverman’s group synthesized San A peptide and derivatives using a
solid phase,[4] whereas Styers et al. employed the strategy of solution-phase
synthesis.[5b] The two approaches have different characteristics. Cyclic
peptides such as San A peptide derivatives show good inhibitory activities
against several different tumor cell lines.[2,5] Therefore, we want to develop
a new and potentially rapid synthesis approach that combines the advantages
of the two current methods, such as high loading capacity, low excess reagent,
facile purification, routine spectroscopic analysis, and relatively low cost.
Recently, more attention has been paid to functionalized ionic liquids
(ILs) at room temperature as environmentally benign reaction media
because of their intriguing properties, including good solvability, high
thermal and chemical stability, negligible vapor pressure, and ionic conduc-
tivity. Numerous chemical reactions, such as Diels–Alder reactions,[6] hydro-
genation reactions,[7] Heck reactions,[8] Meerwein reactions,[9] and some
enzymatic reactions,[10] have been mediated by ionic liquids. In recent
years, ionic-liquid-supported methods have been developed as efficient and
useful approaches for the synthesis of oligosaccharides[11] and pentapep-
tides[12] and also have been applied to synthesize useful chemical intermedi-
ates.[13,14] Herein, we describe an efficient ionic-liquid-supported synthesis of
the cyclic San A peptide.
RESULTS AND DISCUSSION
The functional ionic liquid, using as a support for the synthesis of San A
peptide, was synthesized as shown in Scheme 1. Treatment of N-methylimida-
zole with chlorohydrin under microwave irradiation obtained the ionic liquid

Sansalvamide A Peptide
241
Scheme 1. Reagents and conditions: (a) chlorohydrin (1 equiv), N2, microwave
1208C, 5 min; (b) NaBF4 (2 equiv), CH3CN, 808C, 24 h.
3,[13] which was then converted to 3-hydroxyethyl-(1-methylimidazolium)-
tetrafluoroborate 4 by anion exchange.
In the loading procedure, ionic liquid support 4 was treated with Boc-Leu-
OH, N,N0-dicyclohexylcarbodiimide (DCC), and 4-dimethylaminopyridine
(DMAP) in dry CH3CN at room temperature under nitrogen. After the
mixture was filtrated and concentrated, the crude residue was washed with
ether, dissolved in CH2Cl2, washed with 2 M HCl, dried, and concentrated
to afford ionic-liquid-supported Leu-Boc 5.[12] Compound 5 deprotected the
Boc group with trifluoroacetic acid (TFA) in dry CH2Cl2 at room temperature
under nitrogen. After concentration of the reaction mixture, the residue was
washed with ether and then gave ionic-liquid-supported Leu-NH2 6.
Compound 6 was reacted with Boc-Val-OH in the presence of diisopropy-
lethylamine (DIPEA) and a highly effective activating reagent, benzotria-
zole-1-yl-oxy trispyrrolidinophosphonium hexafluorophosphate (PyBOP), in
dry CH3CN at 358C under nitrogen. Then resulting reaction mixture was
concentrated and washed in the same procedure as compound 5 to afford
ionic-liquid-supported Leu-Val-Boc 7. After deprotection of the Boc group
of 7 and washing, the ionic-liquid-supported peptides were extended
through the same set of conditions for coupling reaction, washing, depro-
tection, and washing as before, using Boc-Leu-OH, Boc-Leu-OH, and
Boc-Phe-OH successively in the peptide elongation as shown in Scheme 2.
Then the linear pentapeptide 11 was released from the ionic liquid support
using 1 M aqueous sodium hydroxide and cyclized using PyBOP to afford
cyclic peptide 2.
In experimentation, it was found that the linear ionic-liquid-supported
peptides are soluble in polar organic solvents such as acetonitrile, methanol,
acetone, and dichloromethane but are not soluble in ether. Additionally, the
undesired by-products and excessive raw material can be washed out by
ether and water after each of the coupling and deprotection reactions, and
the obtained ionic-liquid-supported peptides were pure enough to react to
the next Boc-protected amino acid without further chromatographic purifi-
cation. All the intermediates of ionic-liquid-supported peptides could be
1
confirmed with H NMR and mass spectra (MS). An important advantage
of the strategy outlined here is that the cation of ionic-liquid-supported
peptides 5–11 could be detected easily as the most intense peak in the MS
obtained by electrospray ionization (ESI) as shown in Table 1.
A survey of different reaction conditions was carried out in the ring-
closure step, and the results are summarized in Table 2. Direct cyclization

242
L. Chen et al.
Scheme 2. Reagents and conditions: (a) DCC (2 equiv), DMAP (0.4 equiv), dry
CH3CN, N2, rt, 18 h; (b) 40% TFA in CH2Cl2, N2, rt, 40 min; (c) Boc-Val-OH (1.5
equiv), PyBOP (1.2 equiv), DIPEA (3 equiv), dry CH3CN, N2, 358C, 12 h; (d) Boc-
Leu-OH (1.5 equiv), PyBOP (1.2 equiv), DIPEA (3 equiv), dry CH3CN, N2, 358C,
12 h; (e) Boc-Leu-OH (1.5 equiv), PyBOP (1.2 equiv), DIPEA (3 equiv), dry
CH3CN, N2, 358C, 12 h; (f) Boc-Phe-OH (1.5 equiv), PyBOP (1.2 equiv), DIPEA (3
equiv), dry CH3CN, N2, 358C, 12 h; (g) NaOH (1 equiv), THF/H2O (1:1, v/v), rt,
6 h; (h) PyBOP (5 equiv), DIPEA (15 equiv), NMP, N2, rt, 24 h.
of 11 was first attempted using HBTU in DMF at room temperature, in the
presence of DIPEA. No product was detected after 3 days. Other reaction con-
ditions were altered, such as changing the solvent or raising the temperature to
358C, and still no product was found. The peptide 2 was achieved from ionic-
liquid-supported peptide 11 in one step, by using NaOH to cleave ionic liquid
support, and then cyclization by adding PyBOP directly to the reaction
mixture. However, the yield turned out to be low, with only 5% of crude
Table 1. Ionic-liquid-supported synthesis of cyclic peptide sansalvamide A
Entry
Products
ESI found (100%)
Yields (%)
1
2
3
4
5
6
7
8
5
6
Mþ ¼ 340.1
2Mþ þ BF24 ¼ 566.9
Mþ ¼ 439.2
70
98
7
92
8
Mþ ¼ 339.2
96
9
Mþ ¼ 452.3
87a
89a
87a
60
10
11
12
Mþ ¼ 565.4
Mþ ¼ 712.5
M þ 1 ¼ 604.2
aYields of two steps.

Sansalvamide A Peptide
243
Table 2. Methods investigated for cyclization of the linear peptide
Entry
Precursors
Reagents
Conditionsc
Yields (%)
1
2
3
11
11
11
HBTU (5 equiv)/DIPEA DMF/rt/3 days
HBTU (5 equiv)/DIPEA THF/358C/24 h
no product
no product
no product
PyBOP (5 equiv)/
DIPEA
CH3CN/358C/24 h
4
5
6
7
11a
12b
12
PyBOP (5 equiv)/NaOH NMP, CH3CN/358C/
24 h
5
23
51
10
HATU (5 equiv)/
DIPEA
DMF/rt/24 h
PyBOP (5 equiv)/
DIPEA
NMP/rt/24 h
12
PyBOP (5 equiv)/
DIPEA
DMF, CH2Cl2/rt/24 h
aFirst NaOH was used to cleave away ionic liquid, and then PyBOP was added
directly.
bRaw material 12 was the crude product without purification.
cAll reactions were performed under nitrogen.
product. The linear pentapeptide 12 was prepared by cleaving the ionic liquid
support with 1 M aqueous sodium hydroxide in THF/H2O,[12] and methods
other than direct cyclization were investigated to increase the yield of the
cyclization step. Three cyclization conditions were used to prepare peptide
2 from 12 as listed in Table 2. The condition of using PyBOP in the
presence of DIPEA in NMP provided the highest yield (51%) among all the
methods. The desired cyclic peptide 2 was purified using reverse phase high
performance liquid chromatography (HPLC) and confirmed via liquid chrom-
atography tandem mass spectrometry (LC/MS).
Compared with the reported solid-phase synthesis of San A peptide,[4] the
loading step of ionic-liquid-supported synthesis is more facile with only one
step, relatively lower costs, and higher loading capacity. Additionally, the
intermediates could be detected by routine spectroscopic analysis.
Compared with the reported solution-phase synthesis of San
A
peptide,[5a,5b] more facile purification is achieved by ionic liquid strategy,
and the final PyBOP-promoted ring-closure is a time-saving protocol, which
reduced the reaction time from 4 days[5a] to 24 h with the same yields.
In summary, we have demonstrated the application of ionic liquid for the
synthesis of bioactive cyclic peptide San A. It is noteworthy that the strategy
achieved high loading capacity and had simple purification of intermediates
using only sequential ether and aqueous washing. This approach is a proof
of principle for the synthesis of cyclic peptides in an efficient and potentially
fast way. Further studies of other cyclic peptides and improvements of the
strategy are in progress.

244
L. Chen et al.
EXPERIMENTAL
The reagents (chemicals) were purchased from Shanghai Chemical Reagent
Company, Lancaster, and Acros and were used without further purification.
Yields were not optimized. Nuclear magnetic resonance (NMR) spectra
were recorded on a Brucker AMX-300 NMR (TMS as internal standard).
Chemical shifts were reported in parts per million (ppm, d) downfield from
tetramethylsilane. Proton coupling patterns were described as singlet (s),
doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). Low- and
high-resolution mass spectra (LRMS and HRMS) were obtained by electro-
spray ionization (ESI) produced by a LCQ-DECA spectrometer.
Preparation of 1-(2-Hydroxyethyl)-3-methylimidazolium Chloride 3
A mixture of 1-methylimidazole (2.06 g, 0.025 mol) and chlorohydrin (2.01 g,
0.025 mol) was placed in a 20-mL microwave vial, and the vial was sealed
after filling with nitrogen. The mixture was then irradiated for 5 min at
1208C. After the reaction was cooled to ambient temperature, the formed
viscous solid was washed successively with ether (10 mL ꢀ 3), and then
dried at 508C under vacuum for 4 h. The hydroxyl-functionalized ionic
1
liquid 3 was obtained as white crystals (3.98 g, 98%). H NMR (300 MHz,
D2O): d 3.99 (s, 3H), 4.01 (t, J ¼ 3.6 Hz, 2H), 4.40 (t, J ¼ 3.9 Hz, 2H),
7.54 (s, 1H), 7.60 (s, 1H), 8.84 (s, 1H).
Preparation of 1-(2-Hydroxyethyl)-3-methylimidazolium
Tetrafluoroborate 4
A mixture of 1-(2-hydroxyethyl)-3-methylimidazolium chloride (3.98 g,
0.024 mol), NaBF4 (5.28 g, 0.048 mol), and dry acetonitrile (40 mL) was
heated to reflux with stirring for 25 h under nitrogen. Upon cooling, the
white precipitate was filtered off and washed with acetonitrile (10 mL ꢀ 2).
Concentration of the combined filtrates gave product 4 as a light yellow oil
1
(4.88 g, 95%). H NMR (300 MHz, acetone-d6) d 3.70 (t, J ¼ 5.1 Hz, 2H),
3.85 (s, 3H), 4.19 (t, J ¼ 5.1 Hz, 2H), 7.68 (s, 1H), 7.69 (s, 1H), 9.02
(s, 1H); MS (ESI): m/z [M]þ (100%): 127.1, [M]2 (100%): 87.1.
Preparation of the Ionic-Liquid-Support Boc-Leucine 5
.
A mixture of ionic liquid 4 (3.10 g, 14 mmol), Boc-Leu-OH H2O (7.21 g,
28 mmol), dicyclohexylcarbodiimide (5.97 g, 28 mmol), and dimethylamino-
pyridine (0.71 g, 5.6 mmol) was added in dry acetonitrile (40 mL) and dry
dichloromethane (10 mL). The mixture was stirred vigorously for 18 h at

Sansalvamide A Peptide
245
room temperature under nitrogen. After filtration through a plug of celitew, the
Celite plug was washed with acetonitrile, and the combined organic phase was
concentrated in vacuum. The residue was washed with ether (30 mL ꢀ 3),
then dissolved in CH2Cl2 and washed with 2M HCl (10 mL ꢀ 3). The
organic phase was dried over Na2SO4 and concentrated to give ionic-liquid-
supported Boc-Leu 5 4.32 g (70%) as a pale yellow oil. 1H NMR
(300 MHz, acetone-d6) d 0.86–0.92 (m, 6H), 1.40 (s, 9H), 1.51–1.58
(m, 3H), 4.07 (s, 3H), 4.15–4.20 (m, 1H), 4.40–4.58 (m, 2H), 4.60–4.66
(m, 2H), 6.41 (br, 1H), 7.73 (s, 1H), 7.83 (s, 1H), 9.12 (s, 1H); MS (ESI):
m/z [M]þ (100%): 340.1.
General Procedure for the Deprotection and Coupling Reactions
of Ionic Supported Peptides 6–11
A solution of ionic-liquid-supported Boc-peptide (6 mmol) was treated with
40% TFA in dry CH2Cl2 (25 mL) for 1 h at room temperature under
nitrogen. After concentration of the reaction mixture, the residue was
washed with ether (20 mL ꢀ 3) and dried at 358C under vacuum line to give
the deprotected ionic-liquid-supported peptide as TFA salt. Then DIPEA
(18 mmol), was added dropwise into the mixture of ionic-liquid-supported
peptide TFA salt, the next Boc-protected amino acid (9 mmol), and PyBOP
(7.2 mmol) in dry CH3CN (40 mL). The resulting reaction mixture was
stirred at 358C under nitrogen for 12 h. After evaporation in vacuum, the
residue was washed with ether (30 mL ꢀ 3), then dissolved in CH2Cl2 and
washed with water (10 mL ꢀ 3). The organic phase was dried over Na2SO4
and concentrated to afford the ionic-liquid-supported Boc-peptide.
Characteristic Data for 6–11
Ionic-liquid-supported Leu-NH2 6: 1H NMR (300 MHz, acetone-d6) d
0.91–0.93 (m, 6H), 1.81–1.83 (m, 3H), 4.01 (s, 3H), 4.21–4.27 (m, 1H),
4.58–4.76 (m, 4H), 7.67 (s, 1H), 7.82 (s, 1H), 9.15 (s, 1H); MS (ESI): m/z
[2Mþ þ BF24 ] (100%): 566.9.
1
Ionic-liquid-supported Leu-Val-Boc 7: H NMR (300 MHz, acetone-d6) d
0.85–0.93 (m, 12H), 1.40–1.43 (m, 12H), 1.55–1.71 (m, 3H), 4.07 (s, 3H),
4.38–4.49 (m, 2H), 4.61–4.69 (m, 3H), 7.70 (s, 1H), 7.81 (s, 1H), 9.11
(s, 1H); MS (ESI): m/z [M]þ (100%): 439.2.
1
Ionic-liquid-supported Leu-Val-NH2 8: H NMR (300 MHz, acetone-d6) d
0.87–0.92 (m, 6H), 1.05–1.11 (m, 6H), 1.41–1.45 (m, 3H), 1.52–1.72
(m, 3H), 4.07 (s, 3H), 4.43–4.51 (m, 2H), 4.68–4.75 (m, 3H), 7.72 (s, 1H),
7.83 (s, 1H), 9.16 (s, 1H); MS (ESI): m/z [M]þ (100%): 339.2.

246
L. Chen et al.
Ionic-liquid-supported Leu-Val-Leu-Boc: 1H NMR (300 MHz, acetone-d6)
d 0.85–0.93 (m, 16H), 1.41–1.45 (m, 15H), 1.55–1.65 (m, 4H), 4.10 (s, 3H),
4.43–4.51 (m, 2H), 4.37–4.41 (m, 1H), 4.51–4.58 (m, 1H), 4.69–4.71
(m, 2H), 7.70 (s, 1H), 7.82 (s, 1H), 9.13 (s, 1H); MS (ESI): m/z [M]þ
(100%): 552.3.
1
Ionic-liquid-supported Leu-Val-Leu-NH2 9: H NMR (300 MHz, acetone-
d6) d 0.83–0.98 (m, 16H), 1.36–1.38 (m, 6H), 1.54–1.68 (m, 3H), 1.79–
1.83 (m, 1H), 4.03 (s, 3H), 4.26–4.50 (m, 4H), 4.60–4.63 (s, br, 2H), 7.65
(s, 1H), 7.76 (s, 1H), 9.02 (s, 1H); MS (ESI): m/z [M]þ (100%): 452.3.
Ionic-liquid-supported Leu-Val-Leu-Leu-Boc: 1H NMR (300 MHz,
acetone-d6) d 0.85–0.95 (m, 24H), 1.19–1.43 (m, 16H), 1.56–1.76
(m, 8H), 3.12–3.18 (m, 3H), 4.06 (s, 3H), 4.20–4.25 (m, 1H), 4.43–4.60
(m, 1H), 4.61–4.78 (m, 1H), 7.68 (s, 1H), 7.80 (s, 1H), 9.08 (s, 1H); MS
(ESI): m/z [M]þ (100%): 665.4.
Ionic-liquid-supported Leu-Val-Leu-Leu-NH2 10: 1H NMR (300 MHz,
acetone-d6) d 0.84–0.96 (m, 24H), 1.39–1.45 (m, 7H), 1.61–1.67 (m, 6H),
1.79–1.84 (m, 2H), 3.20 (s, br, 3H), 4.08 (s, 3H), 4.22–4.29 (m, 2H),
4.35–4.42 (m, 1H), 4.52–4.70 (m, 2H), 7.70 (s, 1H), 7.80 (s, 1H), 9.10
(s, 1H); MS (ESI): m/z [M]þ (100%): 565.4.
Ionic-liquid-supported Leu-Val-Leu-Leu-Phe-Boc: 1H NMR (300 MHz,
acetone-d6) d 0.84–1.01 (m, 24H), 1.33–1.40 (m, 17H), 1.55–1.71
(m, 5H), 1.96 (s, 1H), 3.50 (s, br, 5H), 4.08 (s, 3H), 4.14–4.19 (m, 1H),
4.30–4.39 (m, 3H), 4.50–4.56 (m, 2H), 7.18–7.32 (m, 5H), 7.59 (s, 1H),
7.78 (s, 1H), 9.06 (s, 1H); MS (ESI): m/z [M]þ (100%): 812.7.
Ionic-liquid-supported Leu-Val-Leu-Leu-Phe-NH2 11: 1H NMR (300 MHz,
acetone-d6) d 0.83–0.95 (m, 23H), 1.38–1.43 (m, 8H), 1.62–1.71 (m, 5H),
1.79–1.81 (m, 1H), 3.13–3.35 (m, 5H), 4.06 (s, 3H), 4.52–4.55 (m, 5H),
7.27–7.37 (m, 5H), 7.67 (s, 1H), 7.77 (s, 1H), 9.11 (s, 1H); MS (ESI): m/z
[M]þ (100%): 712.5.
Procedure for the Cleavage of Ionic-Liquid Supported Reaction
The ionic-liquid-supported pentapeptide 11 (200 mg, 0.25 mmol) was dissolved
in THF/H2O (1:1, v/v, 4.0 ml), followed by the addition of 1M NaOH aqueous
solution (0.25 mL), and stirred at room temperature for 6 h. After evaporation in
vacuum, the residue was acidified to pH 5–6. The precipitate was collected by
filtration, washed with distilled water, and dried on the vacuum line to give linear
1
pentapeptide 12 (91 mg, 60%). H NMR (300 MHz, CD3OD): d 0.86–0.97
(m, 24H), 1.28–1.39 (m, 2H), 1.53–1.70 (m, 8H), 2.00–2.05 (m, 1H),

Sansalvamide A Peptide
247
2.93–3.01 (m, 1H), 4.07–4.14 (m, 1H), 4.35–4.52 (m, 4H), 7.26–7.38 (m, 5H);
MS (ESI): m/z [M þ 1]þ (100%): 604.3.
Procedure for Cyclization
DIPEA (353 mL, 2.14 mmol) was added dropwise to a solution of pentapep-
tide 12 (86 mg, 0.14 mmol) and PyBOP (375 mg, 0.71 mmol) in NMP
(5 mL). The reaction mixture was stirred for 24 h at room temperature
under nitrogen. The mixture was diluted with 100 mL of CH2Cl2 and 20 mL
of H2O. The organic phase was then washed with saturated aqueous NaCl,
dried over anhydrous Na2SO4, filtrated, and concentrated under reduced
pressure to yield the crude product (58 mg, 51%). The desired cyclic
peptide 2 was then purified using reverse-phase HPLC and confirmed via
1
LC/MS. H NMR (300 MHz, CD3OD): d 0.85–0.99 (m, 24H), 1.38–1.41
(m, 1H), 1.42–1.49 (m, 3H), 1.57–1.82 (m, 6H), 2.33–2.36 (m, 1H), 3.16–
3.21 (m, 2H), 3.63–3.66 (d, J ¼ 9.3 Hz, 1H), 4.06 (m, 1H), 4.19–4.34
(m, 3H), 7.21–7.24 (m, 5H); 13C NMR (75 MHz, CD3OD): d 19.9, 20.4,
22.3, 22.4, 22.8, 23.4, 23.7, 23.8, 26.51, 26.57, 26.8, 31.0, 37.6, 41.1, 41.6,
41.7, 55.4, 55.8, 56.0, 58.7, 64.4, 128.3, 130.0, 130.7, 139.0, 173.8, 174.4,
174.8, 174.9, 175.1; HRMS (ESI) m/z [M þ Na]þ calcd. for C32H51N5O5Na
608.3788; found 608.3823.
ACKNOWLEDGMENTS
We gratefully acknowledge generous support from the National Natural
Science Foundation of China (Grants 20372069, 29725203, and 20472094),
the Key Technologies R&D Program from CAS (Grants 2005BA711A01),
and the 863 Hi-Tech Program of China (Grants 2006AA020402 and
2006AA020602).
REFERENCES
1. Belofsky, G. N.; Jensen, P. R.; Fenical, W. Sansalvamide: A new cytotoxic cyclic
depsipeptide produced by a marine fungus of the genus Fusarium. Tetrahedron
Lett. 1999, 40, 2913–2916.
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