Total synthesis and reassignment of stereochemistry of obyanamide

Article abstract of DOI:10.1016/j.tet.2006.08.002

The total synthesis of a marine cytotoxic cyclic depsipeptide obyanamide is reported. The synthesis has led to a reassignment of the C-3 configuration in β-amino acid residue. And this revision is also supported by biological test.

Full text of DOI:10.1016/j.tet.2006.08.002

Tetrahedron 62 (2006) 9966–9972
Total synthesis and reassignment of stereochemistry
of obyanamide
*
Wei Zhang, Zhen-Hua Ma, Duo Mei, Chun-Xia Li, Xiu-Li Zhang and Ying-Xia Li
Key Laboratory of Marine Drugs, The Ministration of Education of China, School of Pharmacy, Ocean University of China,
Qingdao 266003, China
Received 7 June 2006; revised 1 August 2006; accepted 2 August 2006
Available online 22 August 2006
Abstract—The total synthesis of a marine cytotoxic cyclic depsipeptide obyanamide is reported. The synthesis has led to a reassignment of
the C-3 configuration in b-amino acid residue. And this revision is also supported by biological test.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Ala(Thz)
O
O
Marine cyanobacteria are well known to be a rich source of
bioactive peptides and depsipeptides,1 many of which are
commonly synthetic focus in the quest for new leads in phar-
maceutical field. Structurally these molecules can be cyclic,
contain modified amino acid units and polyketide portions,
or be any combination thereof.
MePhe
10
R3
13
S
S
S
N
N
H
S
H
O
N
N
O
N
N
N
MeVal
S
23
HN
S
O
HN
O
N
R4
R2
R1
R
3
S
1
O
O
L-LaOc
O
29
Apa
R5
O
O
Obyanamide (1)
Obyanamide (1, Fig. 1) is a cyclic depsipeptide that was iso-
lated from the marine cyanobacterium Lyngbya confer-
voides by Moore and co-workers.2 Some other structural
analogues (Fig. 1) have also been isolated, namely guine-
amides A and B3 and ulongamides A–E.4 The structures of
obyanamide and its congeners were determined by a combi-
nation of NMR spectroscopy, MS, and chemical degradation.
Structurally these compounds consist of similar five sub-
units: b-amino acid residues, Ala (Thz) units, two N-methyl-
ated a-amino acids (including aromatic amino acids,
commonly Phe or Tyr), and a-hydroxy acids. Through
in vitro studies on cytotoxicity against several tumor cells,
all these compounds above were found to have low to moder-
ate activities. Structure–activity relationship (SAR) studies
on these compounds might help to find out more efficient
agents. So we decided to explore an efficient synthesis of
obyanamide and its analogues. Previous studies5 suggested
that the structure of the natural obyanamide should be
revised. And now, we would like to amend its stereochemis-
try at C-3 position.
R2
R3
R1
R5
R4
Guineamide A
Guineamide B
Ulongamide A
Ulongamide B
Ulongamide C
Ulongamide D
Ulongamide E
Et
Bn
Bn
Me
i-Pr
Me
Me
Me
i-Pr
Me*
Me#
Me**
Me**
Me**
Me*
Me*
i-Pr
i-Pr
Me#
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
i-Pr
Bn
p-OH Bn
p-OH Bn
p-OH Bn
p-OH Bn
i-Pr
Bn
i-Pr
i-Pr
S
Figure 1. Obyanamide and some structure related natural products. *S con-
figuration; #unknown; **R configuration.
2. Results and discussion
Our retrosynthetic analysis of 1 is displayed as Scheme 1.
The route required, therefore, the preparation of two pro-
tected fragments before macrocyclization.
Keywords: Total synthesis; Cyclic depsipeptide; Obyanamide; Stereochem-
istry revision.
The starting material (S)-2-aminobutyric acid 5 (Scheme 2)
was first converted to diazoketone via protection of amino
* Corresponding author. Tel.: +86 53282032150; fax: +86 53282033054;
e-mail: liyx417@ouc.edu.cn
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.002

W. Zhang et al. / Tetrahedron 62 (2006) 9966–9972
9967
peptide. And this reaction gave moderate to high yield.
However, incorporation of (S)-lactic acid with the amine
H-MeVal-MePhe-OtBu from 8 in the presence of EDC–
HOAt or 2-bromo-1-ethyl pyridinium tetrafluoroborate
(BEP)10 gave complex products. This might result from
the nucleophilic competition between the amine and the
a-hydroxyl group of the acid. Thus, the hydroxy acid was
first treated with BnBr and sodium metal in liquid ammo-
nia,11 to give the corresponding (S)-2-benzyloxy lactic
acid 9, which was then used in the following coupling step
instead of lactic acid, giving satisfied result. Removal of
the benzyl group gave fragment 3 in 98% yield.
Macrocyclization
7
O
10
13
S
S
O
S
N
8
H
3
O
N
N
S
t
10
1
BocHN
O Bu
8
23
N
O
N
N
N
HN
O
S
10
+
S
29
O
O
HN
O
1
3
O
13
S
18
1
OH
O
O
O
Esterification
3
1
2
Scheme 1. Retrosynthetic analysis of 1.
With two fragments in hand, we could now progress to the
cyclic depsipeptide (Scheme 4). However, coupling of the
alcohol 3 with the free acid from dipeptide 2 using EDC
and 4-(dimethylamino) pyridine (DMAP) as coupling
reagents in CH2Cl2 gave low yield, probably due to steric
limitations. Thus, Yamaguchi’s procedure12 was adopted
and worked well to produce the linear pentapeptide 11 in
94% yield. Treatment of 11 with TFA in CH2Cl2 and finally
cyclization gave compound 1 in 59% yield over two steps.
O
NHBoc
NHR
NHBoc
b
c
HO
a
d
O
N2
7
O
O
f
5: R = H
6: R = Boc
2
CO2Et
N
ref. 7
e
Boc-Ala-OH
BocHN
S
4
Scheme 2. Reagents and conditions: (a) (Boc)2O, 91%; (b) ClCO2Et, Et3N,
then CH2N2; (c) AgOAc, MeOH, 61% for two steps; (d) TFA; (e) LiOH,
THF–MeOH–H2O; (f) EDC, HOAt, DIPEA, 98% for three steps.
30
BocHN
N
O
group with tert-butyloxycarbonyl (Boc), activation of car-
bonyl group with ethyl chloroformate, and treatment with
diazomethane. Then this intermediate was directly subjected
to Wolff’s rearrangement in absolute methanol. Thus, the
desired b-amino acid moiety 7 was obtained in three steps
in a satisfied yield.6 Removal of the Boc protection of 7
with trifluoroacetic acid (TFA) and coupling with the free
acid from 47 gave dipeptide 2 in 98% yield.
S
O
t
S
O Bu
N
H
27
HN
3
O
N
N
N
1
O
O
22
a, b
c, d
2
N
O
10
HN
O
O
13
O
O
N
O
19
16
O
11
1
Scheme 4. Reagents and conditions: (a) LiOH, THF–MeOH–H2O; (b)
2,4,6-trichlorobenzoyl chloride, DIPEA, THF, then 3 in DMAP–toluene,
94%; (c) TFA; (d) HATU, DIPEA, THF, 59% for two steps.
In order to construct fragment 3 (Scheme 3), two N-methyl-
ated amino acid units, Cbz-MePhe-OH and Cbz-MeVal-OH,
were prepared with McDermott’s method.8 After protection
of the carboxylic acid of Cbz-MePhe-OH with tert-butyl
(tBu) group,9 the two units were coupled. 1-(3-Dimethyl-
aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
and the efficient additive 1-hydroxy-7-azabenzotriazole
(HOAt) were used as coupling reagents to form the hindered
To our surprise, the analytical data of 1 were inconsistent
with those published for natural product, with some differ-
1
ences in both the H and 13C NMR spectra. What is more,
the value and sign of optical rotation of the synthetic sample
were also quite different from that of the natural product
{[a]D28 ꢀ96.3 (c 0.06, MeOH) while lit.2 [a]2D7 +20 (c 0.04,
MeOH)}. We were confident that the structure of the syn-
thetic obyanamide is correct; we therefore turned our
thoughts to the source of stereochemical assignment. All
the compounds in Figure 1 are isolated from the species
Lyngbya, and all of the amino groups in b-amino acid resi-
dues are R configuration except for compound 1. Sowe doubt
the correctness of stereochemistry at this position. To this
end, we synthesized Boc-(R)-Apa-OMe following the same
synthesis as for 7, but starting with (R)-2-aminobutyric
acid. This was readily achieved, and Boc-(R)-Apa-OMe
was incorporated into the synthesis as previously performed
to afford 1a with no adverse consequences (Scheme 5). To
our glad, it was indeed found that the data for the newly syn-
thesized compound 1a was an excellent match for the litera-
ture data on obyanamide (Fig. 2). Notably, the consequence
of chemical shifts of five protons connecting to the chiral
7
O
O
3
t
a
b, c
O Bu
1
OH
N
O
10
NCbz
12
NCbz
16
HO
O
13
8
NCbz
b
O
d
t
O Bu
10: R = Bn
3: R = H
O
N
O
e
O
OBn
OR
HO
N
9
carbon atoms of 1a (dH-3<dH-10<dH-23<dH-29<dH-13
was consistent with the natural product, while that of com-
pound 1 (dH-3<dH-23<dH-13<dH-10<dH-29) was not.
)
Scheme 3. Reagents and conditions: (a) tBuOH, EDC, DMAP, 85%; (b) H2,
Pd–C, EtOAc, 2 h; (c) EDC, HOAt, DIPEA, CH2Cl2, 78% for two steps; (d)
EDC, HOAt, DIPEA, 87% for two steps; (e) H2, Pd–C, EtOAc, 3 h, 98%.

9968
W. Zhang et al. / Tetrahedron 62 (2006) 9966–9972
Figure 2. Differences in 13C NMR shifts between natural obyanamide, compound 1 (left), and compound 1a (right).
4.1.1. Synthesis of compound 1.
4.1.1.1. (S)-2-tert-Butoxycarbonylaminobutyric acid
O
(6). To a solution of (S)-2-aminobutyric acid 5 (1.55 g,
15.0 mmol) in 15 mL of 1 M NaOH and 10 mL MeOH
was added (Boc)2O (4.14 mL, 18.0 mmol) at 0 ꢁC. The reac-
tion mixture was warmed to room temperature and stirred for
12 h. After most of the methanol was evaporated, the solu-
tion was acidified to pH 2 with 1 M HCl and extracted
with EtOAc (3ꢂ50 mL). The organic extracts were com-
bined and washed with brine (2ꢂ10 mL). Evaporation of
the solvent gave the title compound (2.77 g, 91%) as an
oil: Rf ¼0.43 (n-hexane–EtOAc–HOAc¼10:10:1); [a]D29
ꢀ15.2 (c 1.0, MeOH); 1H NMR (DMSO-d6) d 0.91
S
N
H
NH2
O
N
N
N
HO
HN
O
O
O
R
O
(R)-2-aminobutyric acid
O
1a
Scheme 5. Synthesis of compound 1a.
Both of the two synthetic cyclic depsipeptides were sub-
jected to biological test on several cancer cell lines. At a
concentration of 10 mM, compound 1 showed no inhibition
of KB, LoVo, HL-60, P388, A-549, or BEL-7402. While
1a exhibited moderate cytotoxicity against KB, HL-60,
and LoVo cells with IC50 values of 6.7, 6.8, and 19.0 mM,
respectively.13
t
(t, J¼7.3 Hz, 3H, H-4), 1.42 (s, 9H, Bu), 1.56–1.64 (m,
1H, H-3a), 1.68–1.75 (m, 1H, H-3b), 3.81–3.84 (m, 1H,
H-2), 7.09 (d, J¼8.0 Hz, 1H, NH), 12.46 (s, 1H, CO2H);
HRESIMS calcd for C9H17NO4Na [M+Na]+ 226.1055,
found 226.1046.
4.1.1.2. (S)-Methyl 3-(tert-butoxycarbonylamino)-
pentanoate (7). Compound 6 (732 mg, 3.6 mmol) was
dissolved in dry THF (20 mL) and cooled to ꢀ20 ꢁC under
argon. After addition of Et3N (510 mL, 3.6 mmol) and
ClCO2Et (345 mL, 3.6 mmol), the mixture was stirred
for 20 min at that temperature. Avery carefully dried, cooled
etheral solution of CH2N2 (obtained from 1.55 g, 15.0 mmol
of N-methyl-N-nitrosourea) was added. Stirring was contin-
ued for 4 h as the mixture was allowed to warm to room tem-
perature. Excess CH2N2 was destroyed by the addition of
a few drops of HOAc. The mixture was then diluted with
Et2O and washed with saturated NaHCO3 and brine. The
organic phase was dried over Na2SO4 and concentrated
in vacuo. The residue was purified by silica gel column chro-
matography (EtOAc–petroleum ether¼1:5 to 1:3) to give the
diazoketone, which was dried under high vacuum for 4 h and
then dissolved in dry methanol (20 mL). After addition of
Et3N (1.5 mL, 10.7 mmol) and AgOAc (66 mg, 0.4 mmol)
at ꢀ20 ꢁC, the resulting mixture was allowed to warm to
room temperature and stirred for 3 h. The mixture was
then filtered through a pad of Celite and the resulting filtrate
was evaporated in vacuo. The residue was dissolved in
EtOAc and washed with saturated NaHCO3 solution and
brine, dried (Na2SO4), and evaporated to leave an oil. The
oil was purified by silica gel chromatography using EtOAc–
petroleum ether (1:9 to 1:6) as eluent to give the ester
7 (511 mg, 61% over two steps) as a white solid: Rf ¼
0.39 (EtOAc–petroleum ether¼1:3); [a]2D0 ꢀ16.8 (c 1.0,
3. Conclusion
The marine cytotoxic cyclic depsipeptide obyanamide has
been synthesized. As a result, the configuration at C-3 posi-
tion has been amended as R.
4. Experimental
4.1. General information
Solvents were purified by standard methods. TLC was car-
ried out on Merck 60 F254 silica gel plates and visualized
by UV irradiation or by staining with iodine absorbed on
silica gel, ninhydrin solution, or with aqueous acidic ammo-
nium molybdate solution as appropriate. Flash column chro-
matography was performed on silica gel (200–300 mesh,
Qingdao, China). Optical rotations were obtained using a
JASCO P-1020 digital polarimeter. NMR spectra were
recorded on JEOL JNM-ECP 600 MHz spectrometers.
Chemical shifts are reported in parts per million (ppm), rel-
ative to the signals due to the solvent. Data are described
as the followings: chemical shift, multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, br¼broad, m¼multiplet),
coupling constants (Hz), integration, and assignment. Mass
spectra were obtained on a Q-Tof Ultima Global mass
spectrometer.
1
MeOH); H NMR (CDCl3) d 0.93 (t, J¼7.7 Hz, 3H, H-5),

W. Zhang et al. / Tetrahedron 62 (2006) 9966–9972
9969
t
1.44 (s, 9H, tBu), 1.52–1.56 (m, 2H, H-4), 2.48–2.55 (m, 2H,
H-2), 3.68 (s, 3H, CO2CH3), 3.83–3.84 (m, 1H, H-3), 4.90(br,
1H, NH); 13C NMR (CDCl3) d 10.6 (C-5), 27.6 (C-4), 28.3
((CH3)3COC]O), 38.8 (C-2), 49.0 (C-3), 51.6 (CO2CH3),
79.2 ((CH3)3COC]O), 155.4 ((CH3)3COC]O), 172.2
(C-1); HRESIMS calcd for C11H21NO4Na [M+Na]+
254.1368, found 254.1364.
one rotamer of two) d 1.42 (s, 9H, Bu), 2.80 (s, 3H, N-
CH3), 2.95 (dd, J¼14.5, 11.2 Hz, 1H, H-3a), 3.24 (dd,
J¼14.7, 5.0 Hz, 1H, H-3b), 4.74 (dd, J¼10.6, 5.0 Hz, 1H,
H-2), 4.95–5.11 (m, overlapped, 2H, C6H5CH2OC]O),
7.11–7.33 (m, 10H, Ar H); HRESIMS calcd for
C22H27NO4Na [M+Na]+ 392.1838, found 392.1835.
4.1.1.5. Cbz-MeVal-MePhe-OtBu (8). Palladium on
charcoal (75 mg, 10 wt %) was added to a solution of Cbz-
MePhe-OtBu (739 mg, 2.0 mmol) in EtOAc (10 mL). The
reaction mixture was purged with hydrogen three times
and stirred for 2 h at room temperature. The suspension
was filtered through a pad of Celite, washed with EtOAc
(3ꢂ5 mL), and concentrated in vacuo. The amine was dried
under high vacuum for 4 h and used directly in the next step.
4.1.1.3. Boc-Ala(Thz)-(S)-Apa-OMe (2). LiOH mono-
hydrate (126 mg, 3.0 mmol) was added to a solution of ester
47 (451 mg, 1.5 mmol) in THF–MeOH–H2O (4 mL/2 mL/
1 mL) at 0 ꢁC. The reaction mixture was warmed to room
temperature and stirred for 2 h. After most of the solvent
was evaporated, the solution was acidified to pH 2 with
1 M HCl and extracted with EtOAc (3ꢂ20 mL). The organic
extracts were combined and washed with brine (2ꢂ5 mL).
Evaporation of the solvent gave the corresponding acid,
which was used directly in the next step.
DIPEA (542 mL, 3.0 mmol) and EDC (460 mg, 2.4 mmol)
were added successively to a suspension of Cbz-MeVal-
OH (531 mg, 2.0 mmol), amine, and HOAt (327 mg,
2.4 mmol) in CH2Cl2 (10 mL) at 0 ꢁC. The reaction mixture
was allowed to stir at that temperature for 2 h and at room
temperature for another 18 h. After diluted with EtOAc
(50 mL), the whole mixture was washed with 10% citric
acid (3ꢂ5 mL), 5% NaHCO3 (3ꢂ5 mL), and brine (3ꢂ
5 mL), dried (Na2SO4), and concentrated in vacuo. The
residue was purified by column chromatography (EtOAc–
petroleum ether¼1:6 to 1:4) to give dipeptide 8 as a colorless
oil (750 mg, 78%): Rf ¼0.35 (EtOAc–petroleum ether¼1:3);
TFA (3 mL) was added to a solution of 7 (347 mg, 1.5 mmol)
in 3 mL CH2Cl2 at 0 ꢁC. The reaction mixture was warmed
to room temperature and stirred for 2 h. The solvent was
evaporated and the residual oil was dissolved twice in
CH2Cl2 (3 mL) with evaporation each time to give TFA
salt, which was used directly in the next step.
EDC (288 mg, 1.5 mmol) was added to a suspension of the
carboxylic acid, the TFA salt, and HOAt (204 mg,
1.5 mmol) in CH2Cl2 (5 mL) at 0 ꢁC followed by DIPEA
(524 mL, 3.0 mmol). The reaction mixture was warmed to
room temperature and stirred overnight. After diluted with
EtOAc (80 mL), the whole mixture was washed with 10%
citric acid (3ꢂ10 mL), 5% NaHCO3 (3ꢂ10 mL), and brine
(3ꢂ10 mL), dried (Na2SO4), and concentrated in vacuo.
The residue was purified by column chromatography
(EtOAc–petroleum ether¼1:4 to 1:2) to give dipeptide 2
(566 mg, 98%) as a colorless oil: Rf ¼0.30 (EtOAc–petrol-
eum¼1:1); [a]2D9 ꢀ21.3 (c 0.41, MeOH); 1H NMR (CDCl3)
1
[a]2D9 ꢀ102.3 (c 1.0, MeOH); H NMR (CDCl3, one main
rotamer of four) d 0.79 (d, J¼7.0 Hz, 3H, H-14), 0.89 (d,
t
J¼6.6 Hz, 3H, H-15), 1.45 (s, 9H, Bu), 2.09–2.12 (m, 1H,
H-13), 2.86 (s, 3H, N-CH3), 2.91 (s, 3H, N-CH3), 3.30 (dd,
J¼10.3, 4.7 Hz, 1H, H-3a), 3.34 (dd, J¼10.9, 5.1 Hz, 1H,
H-3b), 4.58 (d, J¼10.7 Hz, 1H, H-12), 5.00–5.41 (d and
dd like, overlapped, 3H, H-2 and C6H5CH2OC]O), 7.03–
7.51 (m, 10H, Ar H); 13C NMR (CDCl3, one main rotamer
of four) d 17.6 (C-14), 19.4 (C-15), 26.3 (C-13), 27.9
(C(CH3)3), 28.6 (N-CH3), 29.5 (N-CH3), 34.3 (C-3), 58.3
(C-2), 60.0 (C-12), 67.1 (C6H5CH2OC]O), 81.7
(C(CH3)3), 126.4, 126.9, 128.4, 128.9, 129.1 and 129.3
(Ar CH), 136.8 and 137.1 (Ar C), 156.6, 169.8 and 170.3
(C]O ꢂ3); HRESIMS calcd for C28H38N2O5Na [M+Na]+
505.2678, found 505.2695.
t
d 0.98 (t, J¼7.3 Hz, 3H, H-5), 1.47 (s, 9H, Bu), 1.61 (d,
J¼6.5 Hz, 3H, H-11), 1.67–1.72 (m, 2H, H-4), 2.64 (dd,
J¼15.6, 5.4 Hz, 1H, H-2a), 2.66 (dd, J¼15.6, 5.4 Hz, 1H,
H-2b), 3.70 (s, 3H, CO2CH3), 4.32–4.38 (m, 1H, H-3),
5.06–5.08 (m, 1H, H-10), 5.13 (br, 1H, NH), 7.63 (d,
J¼9.2 Hz, 1H, NH), 8.00 (s, 1H, H-8); 13C NMR (CDCl3)
d 10.7 (C-5), 21.6 (C-11), 27.3 (C-4), 28.3 ((CH3)3COC]O),
38.5 (C-2), 47.6 (C-3), 48.7 (C-10), 51.7 (CO2CH3), 80.2
((CH3)3COC]O), 123.0 (C-8), 150.0 (C-7), 155.0, 160.6,
171.9 and 174.0 (4 quat. C); HRESIMS calcd for
C17H27N3O5SNa [M+Na]+ 408.1569, found 408.1581.
4.1.1.6. BnO-Lac-OH (9). Freshly cut sodium metal
(575 mg, 25.0 mmol) was added to anhydrous ammonia
(60 mL) at ꢀ70 ꢁC, and 10 min later (S)-lactic acid
(900 mg, 10.0 mmol) was added with vigorous stirring
under argon. To the mixture was added BnBr (2.4 mL,
20.0 mmol) after another 10 min. The turbid solution was
stirred for 1 h at ꢀ50 ꢁC. The ammonia was then removed
by slow evaporation. The residue was dissolved in distilled
water (50 mL) and the solution was extracted with Et2O (3ꢂ
10 mL). The aqueous phase was chilled and acidified to pH 2
with 2 M HCl, and extracted with EtOAc (5ꢂ20 mL). The
combined organic layers were washed with brine (2ꢂ
10 mL), dried (Na2SO4), and concentrated in vacuo. The
residue was purified by column chromatography (CHCl3–
MeOH¼60:1 to 30:1) followed by recrystallization from
n-hexane to give the acid (609 mg, 34%) as a colorless solid:
Rf ¼0.40 (CHCl3–MeOH¼10:1); [a]2D6 ꢀ74.2 (c 4.6, C6H6)
{lit.14 [a]D25 ꢀ53 (c 4.6, C6H6)}; 1H NMR (DMSO-d6)
d 1.32 (d, J¼6.9 Hz, 3H, H-3), 4.00 (q, J¼6.9 Hz, 1H,
4.1.1.4. Cbz-MePhe-OtBu. To a solution of Cbz-MePhe-
OH8 (1.57 g, 5.0 mmol) and tBuOH (7.41 g, 100.0 mmol) in
CH2Cl2 (25 mL) were added EDC (1.44 g, 7.5 mmol) and
DMAP (307 mg, 2.5 mmol) at 0 ꢁC. The reaction mixture
was warmed to room temperature and stirred overnight.
The solvent was evaporated and the residue was dissolved
in EtOAc (200 mL) and washed with 10% citric acid (3ꢂ
20 mL), 5% NaHCO3 (3ꢂ20 mL), and brine (3ꢂ20 mL).
The organic layer was dried over Na2SO4 and concentrated.
The residue was purified by column chromatography
(EtOAc–petroleum¼1:12 to 1:8) to give the title compound
(1.57 g, 85%) as a colorless oil: Rf ¼0.40 (EtOAc–petroleum
1
ether¼1:4); [a]2D0 ꢀ73.0 (c 0.2, MeOH); H NMR (CDCl3,

9970
W. Zhang et al. / Tetrahedron 62 (2006) 9966–9972
H-2), 4.41 (d, J¼11.9 Hz, 1H, C6H5CHaHb), 4.59 (d,
J¼11.9 Hz, 1H, C6H5CHaHb), 7.29–7.35 (m, 5H, Ar H),
12.72 (s, 1H, CO2H); 13C NMR (DMSO-d6) d 18.5 (C-3),
70.8 (C6H5CH2), 73.4 (C-2), 127.5, 127.6, 128.2 (Ar CH),
138.1 (Ar C), 174.2 (CO2H); HRESIMS calcd for
C10H12O3Na [M+Na]+ 203.0684, found 203.0692.
(m, 5H, Ar H); 13C NMR (CDCl3) d 17.8 (C-14), 19.6
(C-15), 20.9 (C-19), 27.9 (C(CH3)3), 29.0 (C-13), 29.5 (N-
CH3), 31.4 (N-CH3), 34.2 (C-3), 57.8 (C-2), 59.0 (C-12),
64.3 (C-18), 82.0 (C(CH3)3), 126.6 (C-7), 128.8 and 129.4
(C-5, C-6, C-8, and C-9), 137.1 (C-4), 169.5, 169.6 and
175.3 (C]O ꢂ3); HRESIMS calcd for C23H36N2O5Na
[M+Na]+ 443.2522, found 443.2520.
4.1.1.7. BnO-Lac-MeVal-MePhe-OtBu (10). To a solu-
tion of Cbz-MeVal-MePhe-OtBu 8 (965 mg, 2.0 mmol)
in EtOAc (10 mL) was added palladium on charcoal
(100 mg, 10 wt %). The reaction mixture was purged with
hydrogen three times and stirred for 2 h at room temperature.
The suspension was filtered through a pad of Celite, washed
with EtOAc (3ꢂ5 mL), and concentrated in vacuo. The
amine was dried under high vacuum for 4 h and used directly
in the next step.
4.1.1.9. Pentapeptide (11). LiOH monohydrate (21 mg,
0.50 mmol) was added to a solution of ester 2 (88 mg,
0.23 mmol) in THF–MeOH–H2O (1 mL/0.5 mL/0.3 mL) at
0 ꢁC. The reaction mixture was warmed to room temperature
and stirred for 2 h. After most of the solvent was evaporated,
the solution was acidified to pH 2 with 1 M HCl and
extracted with EtOAc (3ꢂ5 mL). The organic extracts were
combined and washed with brine (2ꢂ2 mL). Evaporation
of the solvent gave the corresponding acid, which was dried
under high vacuum for 4 h and then dissolved in 2 mL dry
THF followed by addition of DIPEA (156 mL, 0.89 mmol)
and 2,4,6-trichlorobenzoyl chloride (105 mL, 0.67 mmol).
The reaction mixture was allowed to stir at room temperature
for 3 h before it was concentrated to dryness under argon.
The residue was dissolved in dry toluene (3 mL), and alcohol
3 (84 mg, 0.20 mmol) and DMAP (110 mg) were added. The
mixture was stirred for 3 h at room temperature, diluted with
EtOAc (20 mL), and washed with 10% citric acid (3ꢂ2 mL),
5% NaHCO3 (3ꢂ2 mL), and brine (3ꢂ2 mL). The organic
layer was dried (Na2SO4) and concentrated in vacuo. The
residue was purified by column chromatography (EtOAc–
petroleum¼1:5 to 1:2) to give the pentapeptide 11 as a
white foam (146 mg, 94%): Rf ¼0.31 (EtOAc–petroleum
DIPEA (542 mL, 3.0 mmol) and EDC (460 mg, 2.4 mmol)
were added successively to a suspension of BnO-Lac-OH
9
(531 mg, 2.0 mmol), amine, and HOAt (327 mg,
2.4 mmol) in CH2Cl2 (10 mL) at 0 ꢁC. The reaction mixture
was allowed to stir at that temperature for 2 h and at room
temperature for another 12 h. After diluted with EtOAc
(50 mL), the whole mixture was washed with 10% citric
acid (3ꢂ5 mL), 5% NaHCO3 (3ꢂ5 mL), and brine
(3ꢂ5 mL), dried (Na2SO4), and concentrated in vacuo.
The residue was purified by column chromatography
(EtOAc–petroleum ether¼1:5 to 1:2) to give 10 as a colorless
oil (950 mg, 93%): Rf ¼0.52 (EtOAc–petroleum ether¼1:1);
1
[a]2D0 ꢀ124.6 (c 1.0, MeOH); H NMR (CDCl3, one main
rotamer of four) d 0.81 (d, J¼6.4 Hz, 3H, H-14), 0.94 (d,
J¼6.4 Hz, 3H, H-15), 1.21 (d, J¼6.4 Hz, 3H, H-19), 1.46
1
ether¼2:1); [a]2D0 ꢀ87.4 (c 0.1, MeOH); H NMR (CDCl3,
t
(s, 9H, Bu), 2.18–2.28 (m, 1H, H-13), 2.39 (s, 3H, N-
one main rotamer) d 0.49 (d, J¼6.4 Hz, 3H, H-14), 0.72
(d, J¼6.9 Hz, 3H, H-15), 0.94–0.98 (t like, overlapped,
3H, H-24), 1.41 (d, J¼6.8 Hz, 3H, H-19), 1.45 (s, 9H,
tBu), 1.46 (s, 9H, Boc), 1.59 (d, J¼6.9 Hz, 3H, H-30),
1.62–1.70 (m, 2H, H-23), 2.14–2.26 (m, 1H, H-13), 2.64–
2.70 (dd and dd like, overlapped, 2H, H-21a and H-21b),
2.82 (s, 3H, N-CH3), 2.94 (s, 3H, N-CH3), 2.95–2.99 (dd
like, overlapped, 1H, H-3a), 3.35 (dd, J¼15.1, 5.0 Hz, 1H,
H-3b), 4.38–4.39 (m, 1H, H-22), 4.95 (d, J¼10.6 Hz, 1H,
H-12), 5.07 (q, J¼6.9 Hz, 1H, H-18), 5.27–5.30 (m, overlap-
ped, 2H, H-2 and H-29), 7.15–7.25 (m, 5H, Ar H), 7.58 (d,
J¼9.1 Hz, 1H, 22-NH), 8.00 (s, 1H, H-27); 13C NMR
(CDCl3, one main rotamer) d 10.6 (C-24), 16.4 (C-19),
17.7 (C-15), 19.0 (C-14), 21.5 (C-30), 27.2 (C-13), 27.3
(C-23), 28.0 ((CH3)3C), 28.3 ((CH3)3COC]O), 29.7 (N-
CH3), 32.2 (N-CH3), 34.3 (C-3), 38.4 (C-21), 47.5 (C-22),
48.7 (C-29), 58.2 (C-12), 58.8 (C-2), 67.3 (C-18), 81.7
((CH3)3C), 81.9 ((CH3)3COC]O), 123.0 (C-27), 126.6
(C-7), 128.4 and 128.6 (C-5, C-6, C-8, and C-9), 137.1
(C-4), 149.8 (C-26), 154.9, 160.6, 169.6, 170.0, 170.8 and
170.9 (quat. C); HRESIMS calcd for C39H59N5O9SNa
[M+Na]+ 796.3931, found 796.3948.
CH3), 2.85 (s, 3H, N-CH3), 2.93–2.95 (dd like, overlapped,
1H, H-3a), 3.36 (dd, J¼14.6, 4.1 Hz, 1H, H-3b), 4.15 (q, J¼
6.4 Hz, 1H, H-18), 4.25 (d, J¼11.4 Hz, 1H, C6H5CHaHbO),
4.54 (d, J¼11.9 Hz, 1H, C6H5CHaHbO), 5.09 (d, J¼10.5 Hz,
1H, H-12), 5.47 (dd, J¼11.4, 4.1 Hz, 1H, H-2), 7.16–7.32
(m, 10H, Ar H); 13C NMR (CDCl3, one main rotamer of
four) d 17.5 (C-19), 18.0 (C-14), 19.6 (C-15), 26.6 (C-13),
28.0 (C(CH3)3), 29.1 (N-CH3), 31.8 (N-CH3), 34.3 (C-3),
58.0 (C-2), 58.3 (C-12), 70.7 (C6H5CH2O), 72.1 (C-18),
81.9 (C(CH3)3), 126.5, 126.9, 127.9, 128.4, 128.8 and
129.5 (Ar CH), 137.2 and 137.6 (Ar C), 169.7, 170.1 and
171.8 (C]O ꢂ3); HRESIMS calcd for C30H42N2O5Na
[M+Na]+ 533.2991, found 533.2974.
4.1.1.8. HO-Lac-MeVal-MePhe-OtBu (3). Palladium on
charcoal (75 mg, 10 wt %) was added to a solution of BnO-
Lac-MeVal-MePhe-OtBu 10 (709 mg, 1.4 mmol) in EtOAc
(10 mL). The reaction mixture was purged with hydrogen
three times and stirred for 3 h at room temperature. The sus-
pension was filtered through a pad of Celite, washed with
EtOAc (3ꢂ5 mL), and concentrated in vacuo to give the
alcohol 3 (572 mg, 98%) as a wax solid: Rf ¼0.39 (EtOAc–
petroleum ether¼1:1); [a]2D0 ꢀ103.8 (c 1.0, MeOH); 1H
NMR (CDCl3) d 0.75 (d, J¼6.8 Hz, 3H, H-14), 0.94 (d,
J¼6.8 Hz, 3H, H-15), 1.05 (d, J¼6.4 Hz, 3H, H-19), 1.47
4.1.1.10. Obyanamide (1). To a solution of pentapeptide
11 (65.0 mg, 0.084 mmol) in CH2Cl2 (0.5 mL) was added
TFA (1 mL) at 0 ꢁC. The reaction mixture was warmed to
room temperature and stirred for 4 h. Residual TFA was
removed by successive addition and evaporation of
CH2Cl2 (3ꢂ2 mL). The residue was dissolved in dry THF
(170 mL), and then HATU (160 mg, 0.42 mmol) and DIPEA
(117 mL, 0.67 mmol) were added successively. The resultant
t
(s, 9H, Bu), 2.27–2.31 (m, 1H, H-13), 2.33 (s, 3H, N-
CH3), 2.79 (s, 3H, N-CH3), 2.93 (dd, J¼15.1, 12.4 Hz, 1H,
H-3a), 3.39 (dd, J¼15.1, 4.6 Hz, 1H, H-3b), 3.63 (br, 1H,
Lac OH), 4.27–4.31 (m, 1H, H-18), 4.99 (d, J¼10.5 Hz,
1H, H-12), 5.52 (dd, J¼12.4, 4.6 Hz, 1H, H-2), 7.16–7.33

W. Zhang et al. / Tetrahedron 62 (2006) 9966–9972
9971
mixture was stirred for 3 days at room temperature and con-
centrated in vacuo. The residue was dissolved in EtOAc
(20 mL) and washed with 10% citric acid (3ꢂ2 mL), 5%
NaHCO3 (3ꢂ2 mL), and brine (3ꢂ2 mL). The organic layer
was dried (Na2SO4) and concentrated in vacuo. The residue
was purified by silica gel column (CHCl3–MeOH¼80:1 to
40:1) followed by Pharmadex LH-20 (CHCl3–MeOH¼1:1)
to give compound 1 (29.3 mg, 59%) as a colorless solid:
Rf ¼0.46 (CHCl3–MeOH¼20:1); [a]2D8 ꢀ96.3 (c 0.06,
5.5 Hz, 1H, H-2b), 3.70 (s, 3H, CO2CH3), 4.32–4.38 (m,
1H, H-3), 5.08 (br, 1H, H-10), 5.14 (br, 1H, NH), 7.64 (d,
J¼8.8 Hz, 1H, NH), 8.00 (s, 1H, H-8); 13C NMR (CDCl3)
d
10.7 (C-5), 21.6 (C-11), 27.3 (C-4), 28.3
((CH3)3COC]O), 38.4 (C-2), 47.5 (C-3), 48.7 (C-10),
51.7 (CO2CH3), 80.3 ((CH3)3COC]O), 123.0 (C-8),
149.9 (C-7), 155.0, 160.6, 171.9 and 174.0 (4 quat. C);
HRESIMS calcd for C17H27N3O5SNa [M+Na]+ 408.1569,
found 408.1586.
1
MeOH); H NMR (CDCl3) d 0.59 (d, J¼6.4 Hz, 3H, H-
25), 0.87 (d, J¼6.4 Hz, 3H, H-26), 1.01 (t, J¼7.4 Hz, 3H,
H-5), 1.45 (d, J¼6.4 Hz, 3H, H-11), 1.49 (d, J¼6.2 Hz,
3H, H-30), 1.69–1.76 (m, 1H, H-4a), 1.94–2.01 (m, 1H, H-
4b), 2.26–2.32 (m, 1H, H-24), 2.73 (dd, J¼16.5, 4.1 Hz,
1H, H-2a), 2.79–2.84 (m, overlapped, 2H, H-2b and H-
14a), 3.07 (s, 3H, H-21), 3.20 (s, 3H, H-27), 3.44 (dd,
J¼13.5, 8.7 Hz, 1H, H-14b), 4.09–4.14 (m, 1H, H-3), 5.02
(d, J¼10.5 Hz, 1H, H-23), 5.15 (dd, J¼8.7, 5.9 Hz, 1H,
H-13), 5.30–5.34 (m, 1H, H-10), 5.41 (q, J¼6.4 Hz, 1H,
H-29), 7.16 (t like, J¼7.3, 6.8 Hz, 1H, H-18), 7.18–7.24 (d
and dd like, overlapped, 4H, H-16, H-17, H-19, and H-20),
7.95 (s, 1H, H-8), 7.99 (d, J¼7.3 Hz, 1H, 10-NH), 8.81 (d,
J¼9.1 Hz, 1H, 3-NH); 13C NMR (CDCl3) d 11.4 (C-5),
16.3 (C-30), 18.8 (C-26), 18.9 (C-25), 23.4 (C-11), 27.6
(C-4), 27.7 (C-24), 29.0 (C-21), 30.1 (C-27), 36.5 (C-14),
37.8 (C-2), 46.6 (C-10), 47.9 (C-3), 57.3 (C-23), 61.0 (C-
13), 67.4 (C-29), 122.2 (C-8), 127.0 (C-18), 128.8 (C-16
and C-20), 129.4 (C-17 and C-19), 136.4 (C-15), 150.5
(C-7), 160.4 (C-6), 167.3 (C-12), 168.9 (C-9), 170.0 (C-1),
170.4 (C-22), 171.9 (C-28); HRESIMS calcd for
C30H42N5O6S [M+H]+ 600.2856, found 600.2848.
4.1.2.4. Linear pentapeptide Boc-Ala(Thz)-(R)-Apa-
Lac-MeVal-MePhe-OtBu. Obtained from Boc-Ala(Thz)-
(R)-Apa-OMe and compound 3 according to the preparation
of 11. A white foam: Rf ¼0.11 (EtOAc–petroleum
ether¼3:2); [a]D27 ꢀ96.6 (c 0.15, MeOH); 1H NMR
(CDCl3, one main rotamer) d 0.77 (d, J¼6.5 Hz, 3H, H-
14), 0.91 (d, J¼6.2 Hz, 3H, H-15), 0.95 (t, J¼7.4 Hz, 3H,
t
H-24), 1.15 (d, J¼6.6 Hz, 3H, H-19), 1.46 (s, 9H, Bu),
1.47 (s, 9H, Boc), 1.49 (d like, overlapped, 3H, H-30),
1.56–1.65 (m, 2H, H-23), 2.23–2.28 (m, 1H, H-13), 2.44
(s, 3H, N-CH3), 2.64–2.76 (dd and dd like, overlapped,
2H, H-21a and H-21b), 2.79 (s, 3H, N-CH3), 2.90–2.95
(m, 1H, H-3a), 3.38 (dd, J¼15.0, 4.4 Hz, 1H, H-3b), 4.33–
4.38 (m, 1H, H-22), 4.95 (d, J¼10.6 Hz, 1H, H-12), 5.05–
5.11 (m, overlapped, 2H, H-29 and H-18), 5.53 (dd,
J¼12.0, 4.0 Hz, 1H, H-2), 7.17–7.28 (m, 5H, Ar H), 7.82
(d, J¼8.8 Hz, 1H, 22-NH), 8.00 (s, 1H, H-27); 13C NMR
(CDCl3, one main rotamer) d 10.7 (C-24), 16.1 (C-19),
17.8 (C-15), 19.7 (C-14), 21.5 (C-30), 26.8 (C-13), 27.2
(C-23), 28.0 ((CH3)3C), 28.3 ((CH3)3COC]O), 29.2 (N-
CH3), 31.4 (N-CH3), 34.3 (C-3), 38.3 (C-21), 47.6 (C-22),
48.7 (C-29), 57.6 (C-12), 58.3 (C-2), 67.0 (C-18), 80.3
((CH3)3COC]O), 81.9 ((CH3)3COC]O), 122.9 (C-27),
126.6 (C-7), 128.4 and 128.8 (C-5, C-6, C-8, and C-9),
137.2 (C-4), 150.1 (C-26), 154.9, 160.6, 169.6, 170.0,
170.8 (quat. C); HRESIMS calcd for C39H59N5O9SNa
[M+Na]+ 796.3931, found 796.3962.
4.1.2. Synthesis of compound 1a.
4.1.2.1. (R)-2-tert-Butoxycarbonylaminobutyric acid.
Obtained from the (R)-2-aminobutyric acid according to
the preparation of 6. A colorless oil: Rf ¼0.43 (n-hexane–
1
EtOAc–HOAc¼10:10:1); [a]2D9 +17.3 (c 1.02, MeOH); H
NMR (DMSO-d6) d 0.87 (t, J¼7.3 Hz, 3H, H-4), 1.38 (s,
t
9H, Bu), 1.52–1.59 (m, 1H, H-3a), 1.64–1.71 (m, 1H, H-
4.1.2.5. Cyclic depsipeptide (1a). The same preparation
as of compound 1. A colorless solid: Rf ¼0.45 (CHCl3–
MeOH¼20:1); [a]D27 +22.2 (c 0.07, MeOH); 1H NMR
(CDCl3) d 0.50 (d, J¼6.4 Hz, 3H, H-25), 0.86 (d,
J¼6.9 Hz, 3H, H-26), 1.07 (t, J¼7.3 Hz, 3H, H-5), 1.24 (d,
J¼6.8 Hz, 3H, H-30), 1.43 (d, J¼6.9 Hz, 3H, H-11), 1.61–
1.69 (m, 2H, H-4), 2.28–2.34 (m, 1H, H-24), 2.41 (dd,
J¼11.9, 2.8 Hz, 1H, H-2a), 2.79 (dd, J¼11.9, 5.0 Hz, 1H,
H-2b), 2.90 (dd, J¼13.7, 6.4 Hz, 1H, H-14a), 3.13 (s, 3H,
H-27), 3.14 (s, 3H, H-21), 3.28 (dd, J¼13.7, 8.2 Hz, 1H,
H-14b), 4.40–4.46 (m, 1H, H-3), 5.04–5.07 (m, overlapped,
1H, H-10), 5.07 (d, J¼10.1 Hz, 1H, H-23), 5.20 (q,
J¼6.8 Hz, 1H, H-29), 5.45 (t like, J¼8.2, 6.9 Hz, 1H, H-
13), 7.08 (t, J¼7.3 Hz, 1H, H-18), 7.17 (d, J¼7.8 Hz, 1H,
H-16 and H-20), 7.19–7.22 (dd like, 2H, H-17 and H-19),
7.94 (d, J¼6.0 Hz, 1H, 10-NH), 8.02 (s, 1H, H-8), 9.14 (d,
J¼10.1 Hz, 1H, 3-NH); 13C NMR (CDCl3) d 11.2 (C-5),
15.8 (C-30), 18.5 (C-25 and C-26), 24.1 (C-11), 25.9
(C-4), 27.4 (C-24), 29.0 (C-21), 29.8 (C-27), 37.0 (C-14),
38.8 (C-2), 47.3 (C-3), 48.0 (C-10), 57.8 (C-23), 60.7
(C-13), 67.5 (C-29), 123.1 (C-8), 127.0 (C-18), 128.7
(C-16 and C-20), 129.1 (C-17 and C-19), 136.3 (C-15),
148.6 (C-7), 160.4 (C-6), 168.0 (C-12), 169.5 (C-9), 169.9
(C-22), 170.3 (C-1), 172.9 (C-28); HRESIMS calcd for
C30H42N5O6S [M+H]+ 600.2856, found 600.2875.
3b), 3.76–3.80 (m, 1H, H-2), 7.05 (d, J¼8.0 Hz, 1H, NH),
12.42 (s, 1H, CO2H); HRESIMS calcd for C9H17NO4Na
[M+Na]+ 226.1055, found 226.1049.
4.1.2.2. (R)-Methyl 3-(tert-butoxycarbonylamino)-
pentanoate. Obtained from the (R)-2-tert-butoxycarbonyl-
aminobutyric acid according to the preparation of 7. A
colorless solid: Rf ¼0.38 (EtOAc–petroleum ether¼1:3);
1
[a]2D9 +17.4 (c 1.1, MeOH); H NMR (CDCl3) d 0.93 (t,
t
J¼7.3 Hz, 3H, H-5), 1.44 (s, 9H, Bu), 1.52–1.56 (m, 2H,
H-4), 2.48–2.55 (m, 2H, H-2), 3.68 (s, 3H, CO2CH3), 3.81–
3.86 (m, 1H, H-3), 4.91 (br, 1H, NH); 13C NMR (CDCl3)
d 10.6 (C-5), 27.5 (C-4), 28.3 ((CH3)3COC]O), 38.7
(C-2), 49.0 (C-3), 51.6 (CO2CH3), 79.2 ((CH3)3COC]O),
155.4 ((CH3)3COC]O), 172.2 (C-1); HRESIMS calcd for
C11H21NO4Na [M+Na]+ 254.1368, found 254.1357.
4.1.2.3. Boc-Ala(Thz)-(R)-Apa-OMe. Obtained from the
Boc-(R)-Apa-OMe and Boc-Ala(Thz)-OEt 4 according to
the preparation of 2. A colorless oil: Rf ¼0.30 (EtOAc–petro-
1
leum ether¼1:1); [a]D29 ꢀ24.5 (c 0.28, MeOH); H NMR
t
(CDCl3) d 0.98 (t, J¼7.3 Hz, 3H, H-5), 1.47 (s, 9H, Bu),
1.62 (d, J¼6.6 Hz, 3H, H-11), 1.67–1.73 (m, 2H, H-4),
2.64 (dd, J¼16.1, 5.9 Hz, 1H, H-2a), 2.67 (dd, J¼15.8,

9972
W. Zhang et al. / Tetrahedron 62 (2006) 9966–9972
6. (a) Plucinska, K.; Liberek, B. Tetrahedron 1987, 43, 3509–
Acknowledgements
3517; (b) Guichard, G.; Abele, S.; Seebach, D. Helv. Chim.
Acta 1998, 81, 187–206; (c) Wiberg, K. B.; Hutton, T. W.
J. Am. Chem. Soc. 1956, 78, 1640–1645.
This work was financially supported by the National Natural
Science Foundation of China (No. 30572245). The authors
thank Professor Jian Ding (Shanghai Institute of Materia
Medica, Chinese Academy of Sciences) for kindly perform-
ing the cytotoxic bioassays.
7. Kigoshi, H.; Yamada, S. Tetrahedron 1999, 55, 12301–
12308.
8. McDermott, J. R.; Benoiton, N. L. Can. J. Chem. 1973, 51,
1915–1918.
9. Dhaon, M. K.; Olsen, R. K.; Ramasamy, K. J. Org. Chem. 1982,
47, 1962–1965.
References and notes
10. Li, P.; Xu, J.-C. Tetrahedron 2000, 56, 8119–8131.
11. Hruby, V. J.; Ehler, K. W. J. Org. Chem. 1970, 35, 1690.
12. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
13. The natural product exhibited cytotoxicity against KB and
LoVo cells with IC50 values of 1 and 5 mM, respectively.
14. Bischofberger, N.; Waldmann, H.; Saito, T.; Simon, S. E.;
Lees, W.; Bednarski, M. D.; Whitesides, G. M. J. Org.
Chem. 1988, 53, 3457–3465; this compound was reported
as an oil whereas in our hands it was a white crystalline
solid.
1. Burjar, A. M.; Banaigs, B.; Abou-Mansour, E.; Burgess, J. G.;
Wright, P. C. Tetrahedron 2001, 57, 9347–9377.
2. Williams, P. G.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J. J. Nat.
Prod. 2002, 65, 29–31.
3. Tan, T.; Sitachitta, N.; Gerwick, W. H. J. Nat. Prod. 2003, 66,
764–771.
4. Luesch, H.; Williams, P. G.; Yoshida, W. Y.; Moore, R. E.; Paul,
V. J. J. Nat. Prod. 2002, 65, 996–1000.
5. Zhang, W.; Song, N.; Li, Z.-Z.; Li, Y.-X. Chin. Chem. Lett.
2006, 17, 285–288.