Chemistry of ecteinascidins. Part 3: Preparation of 2′-N-acyl derivatives of ecteinascidin 770 and evaluation of cytotoxicity

Article abstract of DOI:10.1016/j.bmc.2011.06.047

A three-step transformation of ecteinascidin 770 (1b) into 2′-N-indole-3-carbonyl derivative 3 via 18,6′-O-bisallyl-protected derivative 4a, which was shown to have higher cytotoxicity than 1b, is presented. In addition, a number of 2′-N amide derivatives

Full text of DOI:10.1016/j.bmc.2011.06.047

Bioorganic & Medicinal Chemistry 19 (2011) 4421–4436
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Chemistry of ecteinascidins. Part 3: Preparation of 20-N-acyl derivatives
of ecteinascidin 770 and evaluation of cytotoxicity
Panithi Saktrakulkla a,c, Satoru Toriumi b, Mitsuhiro Tsujimoto b, Chamnan Patarapanich a,
b,
Khanit Suwanborirux c, , Naoki Saito
⇑
⇑
a Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand
b Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
c Center for Bioactive Natural Products from Marine Organisms and Endophytic Fungi (BNPME), Department of Pharmacognosy and Pharmaceutical Botany,
Faculty of Pharmaceutical Sciences, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand
a r t i c l e i n f o
a b s t r a c t
A three-step transformation of ecteinascidin 770 (1b) into 20-N-indole-3-carbonyl derivative 3 via 18,60-
O-bisallyl-protected derivative 4a, which was shown to have higher cytotoxicity than 1b, is presented. In
addition, a number of 20-N amide derivatives of 1b have been prepared from 4a and their in vitro cyto-
toxicity were determined by measuring IC50 values against human cell lines HCT116, QG56, and DU145.
Benzoyl amide derivatives 7a–c showed similar in vitro cytotoxicity to 1b, whereas the nitrogen-contain-
ing heterocyclic derivatives 7d–h and cinnamoyl derivatives 9a–b showed higher cytotoxicity than 1b. In
contrast, the 18,60-O-bisallyl protected derivatives 4a–c, 6a–h, and 8a–b showed dramatic decreases in
cytotoxicity relative to 1b.
Article history:
Received 19 May 2011
Revised 14 June 2011
Accepted 15 June 2011
Available online 21 June 2011
Keywords:
Ecteinascidin
Marine natural product
Cytotoxicity
Ó 2011 Elsevier Ltd. All rights reserved.
Structure–activity relationship study
1. Introduction
30 steps,18,19 this semisynthetic process for the preparation of 1a
will eventually be used for gram scale production. Many struc-
Members of the tetrahydroisoquinoline family of natural
products have attracted considerable interest for more than
30 years due to their novel structures and meager availability
in nature, and for their potent antitumor activity (Fig. 1).1 Of
particular significance is ecteinascidin 743 (1a), which has been
demonstrated to possess extremely potent in vitro cytotoxicity
(0.1–1 ng/mL) in a variety of tumor cell lines.2,3 YondelisÒ (tra-
bectedin, Et 743),4 a marine anticancer agent, was the approved
in 2007 for use in humans with soft tissue sarcoma in the Euro-
pean Union.
A common problem associated with the isolation of marine
natural products is their low concentrations in the organisms
that produce them. The complexity of their structures has at-
tracted the attention of synthetic organic chemists worldwide.
To date, three total syntheses have been accomplished by the
groups of Corey,5,6 Fukuyama,7 and Zhu.8 Formal total syntheses
has been reported by Danishefsky9 and Williams.10 A semisyn-
thetic process starting from cyanosafracin B, an antibiotic pro-
duced by the fermentation of Pseudomonas fluorescens,11–17 has
been developed by Pharma Mar in the synthesis of 1a. Less than
ture–activity relationship (SAR) studies including those of the re-
lated natural products saframycins and renieramycins, have been
reported,20–27 but few examples of SAR studies on ecteinascidins
have been reported.28
As part of our search for new metabolites via the isolation
and characterization of biologically active compounds from Thai
marine animals, we were able to isolate ecteinascidin 770 (1b)
on a large scale from the Thai tunicate Ecteinascidia thurstoni
by pretreatment with potassium cyanide in buffer solution. Dur-
ing the course of this work we elucidated the structure of ecte-
inascidin 770 (1b).29 We have reported the preparation 60-O-acyl
derivatives of ecteinascidin 770 (2) and determined their cyto-
toxicity in several human tumor cell lines (Fig. 2).30 We found
that the nitrogen-containing heterocyclic ester derivatives
showed similar in vitro cytotoxicity to 1b. We also discovered
that the coupling of 1b with indole-3-carboxylic acid in the pres-
ence of N,N0-dicyclohexylcarbodiimide (DCC) provided 200-N-
amide 3, which exhibited high cytotoxicity relative to 1b. The
high cytotoxicity of 3 prompted us to explore a general method
for the preparation of derivatives of 1b and to evaluate their
cytotoxicity. In this paper, we report a three-step transformation
of 1b into 20-N-amides 7 and 9 via 18,60-O-bisallyl protected
derivative 4a. We also report the in vitro cytotoxicity of the
resulting 20-N-amides.
⇑
Corresponding authors. Tel./fax: +662 218 8357 (K.S.); +81 42 495 8794 (N.S.).
E-mail addresses: skhanit@chula.ac.th (K. Suwanborirux), naoki@my-phar-
m.ac.jp (N. Saito).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.06.047

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P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
2. Chemistry
R
O
6'
O
We first examined the preparation of 3 from 1b in order to de-
velop a general route to 20-N-amides via a three-step protocol: (1)
18,60-O-bisallyl protection leading to 4a, (2) 20-N-amide formation,
and (3) deprotection of the ally group. A mixture of 1b and
25 equiv of K2CO3 in acetone was treated with allyl bromide
(20 equiv) at 25 °C for 10 h to generate the desired product 4a
(81%) along with 60-O-allyl Et 770 4b (2.7%) and triallyl Et 770 4c
(5.5%) (Scheme 1). The structure of 4c was easily confirmed by
NMR and MS data. The 1H and 13C NMR spectral data of 4a and
4c were very similar, the only major difference being the presence
of additional signals attributable to the 20-N-allyl group in 4c [1H
NMR: d 5.58 (1H, N–CH2CH@CH2), 5.13 and 5.04 (each 1H, N–
CH2CH@CH2), 3.09 (2H, N–CH2CH@CH2); 13C NMR: d 138.0 (N–
CH2CH@CH2), 115.3 (N-CH2CH@CH2), 54.2 (N–CH2CH@CH2)]. The
assignment of the signals for the allyl substituents of 4b was made
by conducting further NMR experiments. All proton and carbon
signals of 4b were assigned by using H-H, H-C COSY and a series
of 1H detected two-dimensional heteronuclear multiple bond cor-
relation (HMBC) experiments (see Experimental). The NOE spectra
of compound 4b showed a sharp phenolic OH signal at d 5.73 with
an NOE enhancement of the 17-OCH3 methyl proton signal at 3.79.
The data indicated that the OH group might be located at C18 in 4b.
This is consistent with the long-range correlations between 18-OH
and C17 (d 143.0), C18 (d 147.8), and C19 (d 118.1). Thus, the struc-
ture of 4b was confirmed to be 60-O-allyl Et 770.
The transformation of 1b into the desired 4a took place
smoothly in 81% yield. It was desirable to recover 1b from the fully
allylated compound 4c. Accordingly, reaction31,32 of 4c with tribu-
tyltin hydride, (Ph3P)2PdCl2 and AcOH in THF at 25 °C for 6 h gave
1b (33%) along with 20-N-allyl Et 770 4d (28%). The 1H NMR spec-
trum of 4d showed two characteristic phenolic proton signals at d
5.69 and 5.42.
Coupling of 4a with indole-3-carboxylic acid in the presence of
DCC at 25 °C for 6 h provided amide 5 in 90% yield. Deprotection of
5 at 25 °C for 1.5 h under the same conditions described above gave
3 in 42.9% yield,33 which was identical in all respects with the
authentic sample.30
2' NH
OCH3
CH3O
CH3
HO
CH3
O
S
AcO
H
H
H
O
N
CH3
N
H
Y
O
O
H
CN
2
X
Y
Y
R =
Z
Z
Z
X = H, NO2, Br, OCH3, Y, Z = CH, N
Figure 2. 60-O-Acyl derivatives of ecteinascidin 770.
compound 4a with a variety of carboxylic acids, such as pyri-
dine-2-carboxylic acid, indole-5-carboxylic acid, 4-imidazolecarb-
oxylic acid, and 4-pyrazolecarboxylic acid in the presence of DCC
in CH2Cl2 failed and lead only to the recovery of the starting mate-
rial. However, treatment of 4a with the corresponding acid chlo-
ride and a catalytic amount of 4-dimethylaminopyridine (DMAP)
in pyridine at 60 °C for several hours gave 20-N-benzoyl derivatives
6a–c and 6i in 80–92% yields (Fig. 3). In contrast, the condensation
of 4a with 2-bromobenzoyl chloride under the same conditions
proceeded relatively slowly and the yield of a desired product 6j
was low (29%). Deprotection of 6a–c using the same conditions de-
scribed above afforded within 1 h the desired amides 7a–c in mod-
erate yields (48–51%). Attempted deprotection of 6i or 6j under the
same conditions was unsuccessful and gave only polar polymeric
materials.
Five nitrogen-containing heterocyclic aromatic amide deriva-
tives 7d–h were prepared by acylation (73–91% yield), followed
by deallylation (65–98%). The 1H NMR signals of 6f, 6g, 7f, and
7g revealed mixtures of rotational isomers are present. Finally, cin-
namoyl amide derivatives 9a and 9b were prepared from 4a via 8a
and 8b, respectively. In this case, 18-O-allyl derivatives 10a and
10b were also obtained in 18.3% and 22.6% yields, respectively.
Subsequently, we examined the transformation of 4a into the
corresponding aromatic ester derivatives. In contrast to the trans-
formation of 1b into 20-N-indole-3-carboxylic acid 5 employing
DCC, treatment of 1b with 4-nitrobenzoic acid and DCC in CH2Cl2
under the same conditions gave only 60-O-400-nitrobenzoyl Et 770
2 (R = COC6H4NO2-400) in 81.6% yield. No 20-N-acyl derivative was
produced. It is surprising that the attempted condensation of
OCH3
5'
4'
1'
O
H
CH3
O
HO
3'
O
O
OCH3
4
1
H
NH
12' HO 18
CH3
CH3O
11
8'
O 11'
CH3
N
CH3
3
14
2
S
H
N
Y
AcO
21
H
13
H
CH3O
15
H
O
CH3
H
4
11
N
CH3
X
3
22
22
14
N
21
13
H
1
O
O
H
X
saframycins
S: X = OH, Y = NHCOCOCH3
A: X = CN, Y = NHCOCOCH3
ecteinascidins
743: X = OH (1a)
770: X = CN (1b)
renieramycins
E: X = OH, Y = OCOC(CH3)=CHCH3-Z
M: X = CN, Y = OCOC(CH3)=CHCH3-Z
Figure 1. Structures of representative isoquinoline natural products.

P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
4423
H
N
CO2H
HO
OCH3
N
N
H
CH3O
O
N
HO
H
CH3
O
DCC, CH2Cl2
S
AcO
H
H
1b
O
CH3
CH3
65%
N
H
O
O
H
CN
3
Br
K2CO3, acetone
81%
42.9%
(Ph3P)2PdCl2
n-Bu3SnH, AcOH
H
N
O
O
CH3O
CO2H
OCH3
N
OCH3
NH
RO
CH3O
O
N
H
O
RO
CH3
CH3
O
S
AcO
H
H
S
AcO
H
H
DCC, CH2Cl2
H
H
O
CH3
O
CH3
N
CH3
N
CH3
N
90%
N
H
O
H
O
O
H
CN
O
H
CN
5: R = Allyl
4a: R = Allyl
6'
R3O
2'
NR2
OCH3
CH3O
18
R1O
CH3
O
AcO
S
H
H
H
O
CH3
N
CH3
N
H
O
O
H
CN
4b: R1 = R2 = H, R3 = Allyl
4c: R1 = R2 = R3 = Allyl
4d: R1 = R3 = H, R2 = Allyl
Scheme 1. Preparation of compound 3.
nM order. Among the four allylated Et 770 derivatives 4a–d, 20-
N-monoallylated Et 770 4d had similar cytotoxicity to 1b, whereas
60-O-monoallylated 770 4b showed five-hold lower cytotoxicity
than 1b. The 18-O-Protected Et 770 derivatives, such as 4a and
4c, showed decreased cytotoxicity as well. The aromatic carboxylic
acid amide derivatives 6a–j, including 5 and the two cinnamoyl
amides 8a–b, all of which had a 60-O-allyl protecting group present,
exhibited dramatically decreased cytotoxicity.
3. Biological evaluation
The analogues synthesized above, including ecteinascidin 770
(1b), were tested in vitro for cytotoxicity using three representa-
tive human solid tumor cell lines (HCT116 colon carcinoma,
QG56 lung carcinoma, and DU145 prostate carcinoma) using the
standard MTT method (Table 1). It can be seen from the data in Ta-
ble 1 that the IC50 values of ecteinascidin 770 analogues were of

4424
P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
6'
R'O
HO
R
R
O
2' N
R'O
N
OCH3
OCH3
CH3O
CH3O
CH3
O
CH3
HO
H
CH3
O
O
AcO
S
S
H
AcO
H
H
H
H
O
O
CH3
N
CH3
N
CH3
N
N
H
H
O
O
O
O
H
CN
H
CN
6a-j: R' = CH2CH=CH2
7a-h
NO2
N
R =
NO2
R =
R =
N
R =
R =
6a, 7a
6b, 7b
6c, 7c
6d, 7d
6e, 7e
Br
N
Br
R =
R =
N
R =
R =
R =
N
6i
6j
6f, 7f
6g, 7g
6h, 7h
X
R'O
OCH3
N
CH3O
O
N
RO
H
CH3
O
AcO
8a: R = R' = CH2CH=CH2, X = H
S
H
8b: R = R' = CH2CH=CH2, X = NO2
9a: R = R' = X = H
H
O
CH3
CH3
9b: R = R' = H, X = NO2
N
10a: R = CH2CH=CH2, R' = X = H
H
O
10b: R = CH2CH=CH2, R' = H, X = NO2
O
H
CN
Figure 3. 20-N-Acyl derivatives of ecteinascidin 770.
Of particular interest was compound 5 which showed highly
specific cytotoxicity in the HCT116 cell line in contrast to most of
the 20-N-acyl derivatives of Et 770 that showed considerable cyto-
toxicity to all these three cell lines. On the other hand, nitrogen-
containing heterocyclic amides (3, 7d–h) exhibited higher cytotox-
icity than 1b. It is noteworthy that compound 7h having a 600-quin-
olinecarbonyl group, which was the most potent of the 30
compounds prepared, showed approximately 10- to 20-fold higher
cytotoxicity than 1b. It exhibited very potent inhibitory activity
against HCT116 and DU145 cell lines with IC50 values of 0.045
nM and 0.043 nM, respectively.
lung carcinoma, and DU145 prostate carcinoma cell lines. The pro-
tection of both 18- and 60-phenolic hydroxyl groups resulted in
diminished cytotoxicity, whereas the introduction of acyl groups
at the 20-N position enhanced cytotoxicity. We found that 20-N-
(600-quinolinecarbonyl) Et 770 analogue 7h was the most potent
among all the analogues prepared exhibiting approximately 10-
to 20-fold increase in cytotoxicity relative to 1b.
Our findings indicate that the potent antitumor activity of our
analogue 7h is promising. Efforts to explore the therapeutic poten-
tial of other ecteinascidin analogues are under way and will be re-
ported in due course.
From these results, we conclude that the 20-N-acyl derivative of
Et 770 having 18,60-bishydroxy groups showed high cytotoxicity.
These data show that the 20-N-acyl group of the ecteinascidin
770 derivative warrant further biological activity.
5. Experimental section
Optical rotations were measured with a Horiba-SEPA polarime-
ter. IR spectra were obtained with a Shimadzu Prestige 21/IRA
Affinity-1 FT-IR spectrometer. 1H and 13C NMR spectra were re-
corded on a JEOL-JNM-ECA500 FT NMR spectrometer at 500 MHz
for 1H and 125 MHz for 13C, on a JEOL-JNM-AL400 NMR spectrom-
eter at 400 MHz for 1H and 100 MHz for 13C, and on a JEOL-JNM-
AL300 NMR spectrometer at 300 MHz for 1H and 75 MHz for 13C
4. Conclusion
Eleven 20-N-amide analogues of 1b were prepared from 18,60-O-
bisallyl-protected derivative 4a in two steps and evaluated in vitro
for their cytotoxicity in human HCT116 colon carcinoma, QG56

P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
4425
Table 1
Cytotoxicities of ecteinascidin 770 and related analogues to three carcinoma cell lines (IC50 nM)
Entry
Compound
Comments
Cytotoxicity
QG56a
HCT116a
DU145a
1
1b
1bb
4a
4b
4c
4d
5
Ecteinascidin 770
0.60
0.40
54
2.4
1.8
0.81
0.66
2
3
4
5
6
7
18,60-O-Bisallyl Et 770
60-O-Allyl Et 770
triallyl Et 770
20-N-Allyl Et 770
18,60-O-Bisallyl-20-N-indole-3-carbonyl Et 770
20-N-Indole-3-carbonyl Et 770
1.6 ꢀ 102
12
1.0 ꢀ 102
7.1
2.4
6.2 ꢀ 102
>1.0 ꢀ 103
1.8
>1.0 ꢀ 103
1.2
0.50
0.45
0.16
>1.0 ꢀ 103
>1.0 ꢀ 103
3
0.46
0.45
3b
0.07
0.53
0.37
8
9
6a
7a
6b
7b
6c
7c
6d
7d
6e
7e
6fc
7fc
6gc
7gc
6h
7h
8a
9a
8b
9b
10b
6i
18,60-O-Bisallyl-20-N-Bz Et 770
1.9 ꢀ 102
0.37
6.9 ꢀ 102
1.0
5.4 ꢀ 102
1.1
20-N-Bz Et 770
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
18,60-O-Bisallyl-20-N-(4-nitroBz) Et 770
20-N-(4-NitroBz) Et 770
2.6 ꢀ 102
0.38
7.9 ꢀ 102
1.1
5.9 ꢀ 102
1.0
18,60-O-Bisallyl-20-N-(3-nitroBz) Et 770
20-N-(3-NitroBz) Et 770
1.8 ꢀ 102
0.14
5.2 ꢀ 102
0.43
2.7 ꢀ 102
0.73
18,60-O-Bisallyl-20-N-(isonicotinyl) Et 770
20-N-(Isonicotinyl) Et 770
2.8 ꢀ 102
0.045
7.9 ꢀ 102
0.20
5.9 ꢀ 102
0.30
18,60-O-Bisallyl-20-N-(nicotinyl) Et 770
20-N-(Nicotinyl) Et 770
3.9 ꢀ 102
0.13
>1.0 ꢀ 103
0.40
6.8 ꢀ 102
0.72
18,60-O-Bisallyl-20-N-(4-quinolinecarbonyl) Et 770
20-N-(4-Quinolinecarbonyl) Et 770
18,60-O-Bisallyl-20-N-(5-quinolinecarbonyl) Et 770
20-N-(5-Quinolinecarbonyl) Et 770
18,60-O-Bisallyl-20-N-(6-quinolinecarbonyl) Et 770
20-N-(6-Quinolinecarbonyl) Et 770
18,60-O-Bisallyl-20-N-(cinnamoyl) Et 770
20-N-(Cinnamoyl) Et 770
3.1 ꢀ 102
0.067
4.2 ꢀ 102
0.23
4.2 ꢀ 102
0.16
3.2 ꢀ 102
0.086
6.4 ꢀ 102
0.36
5.5 ꢀ 102
0.92
1.5 ꢀ 102
0.045
2.6 ꢀ 102
0.16
1.8 ꢀ 102
0.043
6.3 ꢀ 102
0.053
>1.0 ꢀ 103
0.33
>1.0 ꢀ 103
0.24
18,60-O-Bisallyl-20-N-(4-nitrocinnamoyl) Et 770
20-N-(4-Nitrocinnamoyl) Et 770
18-O-Allyl-20-N-(4-nitrocinnamoyl) Et 770
18,60-O-Bisallyl-20-N-(4-bromoBz) Et 770
18,60-O-Bisallyl-20-N-(2-bromoBz) Et 770
5.2 ꢀ 102
8.5 ꢀ 103
7.5 ꢀ 103
0.60
2.40
0.81
2.7
9.8
5.0
4.8 ꢀ 102
>1.0 ꢀ 103
7.3 ꢀ 102
6j
>1.0 ꢀ 103
>1.0 ꢀ 103
>1.0 ꢀ 103
a
b
c
HCT116: human colon carcinoma; QG56: human lung carcinoma. DU145: human prostate carcinoma.
For previous cytotoxicity data, see Ref. 30.
A mixture of rotational isomers.
(ppm, J in Hz with TMS as internal standard). All protons and car-
bon signals were assigned by extensive NMR measurements
including correlation spectroscopy (COSY), 1H-detected heteronu-
clear multiple bond coherence) HMBC, and 1H-detected heteronu-
clear multiple-quantum coherence (HMQC) techniques. Mass
spectra were recorded on a JEOL JMS 700 instrument with a direct
inlet system operating at 70 eV.
(80 mL) and extracted with chloroform (80 mL ꢀ 3). The combined
extracts were washed with brine, dried, and concentrated in vacuo
to give a residue. Chromatography on a silica gel flash column
using elution of a gradient of hexane–ethyl acetate 10:1 to 1:1 as
eluent gave 4a (275.6 mg, 81.1%) along with 60-O-allyl Et 770
(4b: 9.0 mg, 2.7%) and triallyl Et 770 (4c: 19.5 mg, 5.5%).
5.1.1.1. Compound 4a.
Colorless amorphous powder, ½a D16
ꢂ
5.1. Extraction and isolation of Et 770
ꢁ55.3 (c 0.47, CHCl3); IR (KBr) 3447, 2930, 2250w, 1769, 1742,
1518, 1485, 1458, 1445, 1431, 1369, 1323, 1261, 1221, 1194,
1167, 1144, 1125, 1107, 1089, 1069, 1055, 1028, 1101, 959, 914,
Stocked frozen animals of E. thurstoni (22.5 kg, wet weight),
which were collected in April 2009, were homogenized and phos-
phate buffer was added until pH reached 7, followed by the addi-
tion of 10% potassium cyanide solution. Stirring was continued
for 5 h. The mixture was macerated with methanol (20 L ꢀ 5) and
filtered, and the combined filtrates were concentrated in vacuo
to an aqueous emulsion, that was partitioned with ethyl acetate
to give a dark-brown oily residue. The residue was re-dissolved
in methanol (100 mL) and the methanol solution was partitioned
with hexane (100 mL ꢀ 3), dried, and concentrated in vacuo to af-
ford a residue (26.62 g). After performing conventional purification
procedure, 276.4 mg (1.23 ꢀ 10ꢁ3% of wet weight) of Et 770 (1b)
was obtained as colorless fine needles.
806 cmꢁ1 1H NMR (CDCl3, 500 MHz) d 6.79 (1H, s, 15-H), 6.48
;
(1H, br s, 80-H), 6.41 (1H, s, 50-H), 6.10 (1H, ddd, J = 17.1, 10.4,
5.2 Hz, 18-OCH2CH@CH2), 6.05 (1H, d, J = 1.2 Hz, OCHO), 5.99
(1H, ddd, J = 17.1, 10.7, 5.2 Hz, 60-OCH2CH@CH2), 5.98 (1H, d,
J = 1.2 Hz, OCHO), 5.45 (1H, dd, J = 17.1, 1.5 Hz, 18-OCH2CH@CH2),
5.31 (1H, dd, J = 17.1, 1.3 Hz, 60-OCH2CH@CH2), 5.25 (1H, dd, 1H,
dd, J = 10.4, 1.5 Hz, 18-OCH2CH@CH2), 5.22 (1H, dd, J = 10.7,
1.3 Hz, 60-OCH2CH@CH2), 5.02 (1H, d, J = 11.3 Hz, 22-H), 4.80 (1H,
dd, J = 12.6, 5.2 Hz, 18-OCHCH), 4.54 (1H, br s, 4-H), 4.49 (2H, d,
J = 5.2 Hz, 60-OCH2CH), 4.35 (1H, dd, J = 12.6, 5.2 Hz, 18-OCHCH),
4.33 (1H, br s, 1-H), 4.25 (1H, d, J = 4.0 Hz, 11-H), 4.19 (1H, d,
J = 1.4 Hz, 21-H), 4.13 (1H, d, J = 11.3 Hz, 22-H), 3.83 (3H, s, 17-
OCH3), 3.61 (3H, s, 70-OCH3), 3.52 (1H, br d, J = 4.0 Hz, 3-H), 3.43
(1H, dd, J = 8.2, 1.4 Hz, 13-H), 3.12 (1H, m, 30-H), 2.95 (2H, d,
J = 8.2 Hz, 14-H2), 2.81 (1H, br t, 30-H), 2.63 (1H, m, 40-H), 2.49
(1H, br t, J = 15.9 Hz, 40-H), 2.33 (1H, br s, 120-H), 2.29 (3H, s, 16-
CH3), 2.24 (3H, s, OCOCH3), 2.20 (3H, s, NCH3), 2.14 (1H, br d,
120-H), 2.04 (3H, s, 6-CH3); 13C NMR (CDCl3, 125 MHz) d 172.5
(10-CO), 168.1 (5-OCO), 150.6 (C-18), 148.9 (C-17), 147.0 (C-60
5.1.1. 18, 60-O-Bisallyl Et 770 4a
Allyl bromide (0.69 mL, 8.0 mmol) was added to a mixture of Et
770 (1b: 308.0 mg, 0.4 mmol) and anhydrous K2CO3 (1.38 g,
10 mmol) in acetone (100 mL) for 5 min at 0 °C, and the resulting
mixture was stirred for 10 h at 25 °C. After the reaction mixture
was concentrated in vacuo, the residue was diluted with water

4426
P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
and C-70), 145.4 (C-7), 141.3 (C-5), 140.2 (C-8), 134.6 (18-
OCH2CH@CH2), 133.2 (60-OCH2CH@CH2), 131.3 (C-16), 130.3 (C-
20), 128.3 (C-100), 126.5 (C-90), 124.7 (C-19), 124.5 (C-15), 121.2
(C-10), 118.1 (21-CN), 117.8 (60-OCH2CH@CH2), 116.7 (18-
OCH2CH@CH2), 114.0 (C-9), 113.3 (C-6), 113.2 (C-50), 110.9 (C-80),
101.9 (OCH2O), 72.9 (18-OCH2CH), 69.6 (60-OCH2CH), 64.6 (C-10),
61.2 (C-1), 59.8 (C-3 and C-22), 59.4 (17-OCH3), 59.3 (C-21), 55.2
(70-OCH3), 55.1 (C-11), 54.7 (C-13), 42.0 (C-120), 41.9 (C-4), 41.7
(NCH3), 39.6 (C-30), 28.9 (C-40), 24.2 (C-14), 20.3 (COCH3), 15.8
(16-CH3), 9.7 (6-CH3); FABMS m/z 851 (MH+); HRFABMS m/z
3.09 (2H, m, NCH2CH), 2.96 (1H, dd, J = 17.1, 9.2 Hz, 14-H
a), 2.96
(1H, m. 30-H, signals overlapped with 14-H
a), 2.81 (1H, d,
J = 17.1 Hz, 14-Hb), 2.76 (1H, m, 30-H), 2.59 (1H, ddd, J = 15.9,
10.5, 5.6 Hz, 40-H), 2.44 (1H, m, 40-H), 2.32 (1H, br dd, J = 16.1,
5.1 Hz, 120-H), 2.26 (3H, s, OCOCH3), 2.23 (3H, s, 16-CH3), 2.12
(3H, s, NCH3), 2.05 (1H, m, 120-H), 2.03 (3H, s, 6-CH3); 13C NMR
(CDCl3, 125 MHz) d 169.2 (10-CO), 168.0 (5-OCO), 150.0 (C-18),
148.7 (C-17), 146.8 (C-60), 146.4 (C-70), 145.5 (C-7), 141.5 (C-5),
140.4 (C-8), 138.0 (NCH2CH@CH2), 134.5 (18-OCH2CH@CH2),
133.0 (60-OCH2CH@CH2), 131.1 (C-16), 130.0 (C-20), 129.3 (C-
100), 128.0 (C-90), 124.9 (C-15), 124.8 (C-19), 121.3 (C-10), 118.1
(21-CN), 117.7 (60-OCH2CH@CH2), 116.7 (18-OCH2CH@CH2),
115.3 (NCH2CH@CH2), 114.2 (C-9), 112.6 (C-50), 112.4 (C-6 and C-
80), 101.9 (OCH2O), 72.9 (18-OCH2CH), 71.0 (C-10), 69.5 (60-
OCH2CH), 61.1 (C-3), 60.6 (C-1 and C-22), 59.8 (C-21), 59.3 (17-
OCH3), 55.7 (70-OCH3), 55.4 (C-11), 54.8 (C-13), 54.2 (NCH2CH),
43.8 (C-30), 43.0 (C-4), 41.9 (NCH3), 39.7(C-120), 28.0 (C-40), 25.0
(C-14), 20.3 (COCH3), 16.4 (16-CH3), 9.8 (6-CH3); FABMS m/z 891
(MH+); HRFABMS m/z 891.3636 (MH+, calcd for C49H55N4O10S,
891.3639).
851.3328 (MH+, calcd for C46H51N4O10S, 851.3326). CD
11.7
M, methanol, 23 °C) 8.0 (210), ꢁ89.3 (220), 0 (239), 23.4
(254), 0 (276), ꢁ10.8 (292), 0 (310).
De nm (c
l
5.1.1.2. Compound 4b.
Colorless amorphous powder, ½a D16
ꢂ
ꢁ25.1 (c 0.26, CHCl3); IR (KBr) 3443, 2926, 2852, 2250w, 1763,
1744, 1517, 1458, 1431, 1369, 1261, 1223, 1194, 1167, 1125,
1107, 1055, 1028, 804 cmꢁ1 1H NMR (CDCl3, 500 MHz) d 6.60
;
(1H, s, 15-H), 6.48 (1H, br s, 80-H), 6.44 (1H, br, NH), 6.41 (1H, s,
50-H), 6.05 (1H, d, J = 1.2 Hz, OCHO), 5.99 (1H, ddd, J = 17.4, 10.7,
5.2 Hz, 60-OCH2CH@CH2), 5.98 (1H, d, J = 1.2 Hz, OCHO), 5.73 (1H,
OH), 5.32 (1H, dd, J = 17.4, 1.2 Hz, 60-OCH2CH@CH2), 5.22 (1H, dd,
J = 10.7, 1.2 Hz, 60-OCH2CH@CH2), 5.02 (1H, d, J = 11.3 Hz, 22-H),
4.56 (1H, br s, 4-H), 4.49 (2H, d, J = 5.4 Hz, 60-OCH2CH), 4.33 (1H,
br s, 1-H), 4.28 (1H, d, J = 4.2 Hz, 11-H), 4.18 (1H, d, J = 2.7 Hz,
21-H), 4.12 (1H, d, J = 11.3 Hz, 22-H), 3.79 (3H, s, 17-OCH3), 3.61
(3H, s, 70-OCH3), 3.51 (1H, br d, J = 4.2 Hz, 3-H), 3.42 (1H, dd,
J = 6.1, 2.7 Hz, 13-H), 3.12 (1H, m, 30-H), 2.79 (1H, br t, 30-H), 2.78
(2H, d, J = 6.1 Hz, 14-H2), 2.61 (1H, m, 40-H), 2.47 (1H, br t,
J = 15.6 Hz, 40-H), 2.35 (1H, br s, 120-H), 2.33 (3H, s, 16-CH3), 2.27
(3H, s, OCOCH3), 2.22 (3H, s, NCH3), 2.22 (1H, m, 120-H, the signals
overlapped with the methyl signals), 2.04 (3H, s, 6-CH3); 13C NMR
(CDCl3, 125 MHz) d 172.6 (10-CO), 168.1 (5-OCO), 147.8 (C-18),
147.0 (C-60 and C-70), 145.4 (C-7), 143.0 (C-17), 141.3 (C-5), 140.1
(C-8), 133.2 (60-OCH2CH@CH2), 130.8 (C-20), 129.3 (C-16), 128.4
(C-100), 126.6 (C-90), 121.2 (C-10), 120.7 (C-15), 118.1 (21-CN and
C-19), 117.8 (60-OCH2CH@CH2), 114.0 (C-9), 113.2 (C-50), 113.2
(C-6), 110.0 (C-80), 101.9 (OCH2O), 69.6 (60-OCH2CH), 64.6 (C-10),
61.1 (C-1), 60.4 (17-OCH3), 60.0 (C-22), 59.6 (C-3 and C-21), 55.3
(70-OCH3), 54.7 (C-11), 54.5 (C-13), 42.1 (C-120), 41.9 (C-4), 41.6
(NCH3), 39.7 (C-30), 29.0 (C-40), 24.2 (C-14), 20.4 (COCH3), 15.8
(16-CH3), 9.7 (6-CH3); FABMS m/z 811 (MH+); HRFABMS m/z
5.1.2. Deallylation of 4c: 20-N-allyl Et 770 4d
Tributyltin hydride (0.16 mL, 0.61 mmol) was added dropwise
over 10 min to a vigorously stirred solution of 4c (32.9 mg,
37.0
lmol), (Ph3P)2PdCl2 (15.6 mg, 22.2
lmol), and AcOH
(79.4
l
L, 1.39 mmol) in THF (10 mL) at 25 °C, and the mixture
was stirred for 6 h at 25 °C. The mixture was diluted with water
(10 mL), made alkaline with 5% aqueous NaHCO3, and extracted
with chloroform (30 mL ꢀ 3). The combined extracts were washed
with 5% aqueous NaHCO3, dried, and concentrated in vacuo to give
a residue. Chromatography on a silica gel column with hexane–
ethyl acetate (5:1) to gave 1b (9.5 mg, 33.4%) as a colorless solid,
whose spectral data were in complete agreement with those of
the authentic sample. Further elution with hexane–ethyl acetate
(2:1) afforded 20-N-Allyl Et 770 (4d: 8.3 mg, 27.8%). ½a 2D2
ꢁ80.1 (c
ꢂ
0.25, CHCl3); IR (KBr) 3447br, 2930, 2250w, 1749, 1508, 1458,
1375, 1234, 1196, 1161, 1107, 1086, 1005, 914 cmꢁ1 1H NMR
;
(CDCl3, 500 MHz) d 6.47 (1H, s, 15-H), 6.45 (1H, s, 50-H), 6.22
(1H, s, 80-H), 6.08 (1H, d, J = 1.2 Hz, OCHO), 5.97 (1H, d, J = 1.2 Hz,
OCHO), 5.69 (1H, s, 18-OH), 5.57 (1H, ddt, J = 17.0, 10.2, 6.3 Hz,
NCH2CH@CH2), 5.42 (1H, br s, 60-OH), 5.11 (1H, dd, J = 17.0,
1.7 Hz, NCH2CH@CH2), 5.02 (1H, dd, J = 10.2, 1.7 Hz, NCH2CH@CH2),
4.96 (1H, d, J = 11.4 Hz, 22-H), 4.62 (1H, br s, 4-H), 4.37 (1H, d,
J = 2.3 Hz, 1-H), 4.26 (1H, dd, J = 5.1, 1.2 Hz, 11-H), 4.11 (1H, d,
J = 2.9 Hz, 21-H), 3.91 (1H, dd, J = 11.4, 2.9 Hz, 22-H), 3.76 (3H, s,
17-OCH3), 3.56 (3H, s, 70-OCH3), 3.53 (1H, d, J = 5.1 Hz, 3-H), 3.42
(1H, br d, J = 9.0 Hz, 13-H), 3.08 (2H, br d, NCH2CH), 2.95 (1H, dd,
811.3019 (MH+, calcd for C43H47N4O10S, 811.3013). CD
12.3
M, methanol, 23 °C) 42.0 (210), ꢁ157.5 (221), 0 (240), 39.9
(253), 0 (269), ꢁ33.4 (287), 0 (317).
De nm (c
l
5.1.1.3. Compound 4c.
Colorless amorphous powder, ½a D16
ꢂ
ꢁ71.1 (c 0.97, CHCl3); IR (KBr) 3435, 2928, 2250w, 1767, 1738,
J = 17.0, 9.1 Hz, 14-Ha
), 2.94 (1H, m. 30-H), 2.80 (1H, d,
1518, 1464, 1445, 1429, 1416, 1375, 1333, 1261, 1234, 1196,
J = 17.0 Hz, 14-Hb), 2.74 (1H, dt, J = 12.5, 4.5 Hz, 30-H), 2.56 (1H,
ddd, J = 15.8, 10.2, 5.1 Hz, 40-H), 2.56 (1H, br, 120-H), 2.49 (1H, m,
120-H), 2.34 (1H, dt, J = 15.8, 3.9 Hz, 40-H), 2.30 (3H, s, OCOCH3),
2.25 (3H, s, 16-CH3), 2.11 (3H, s, NCH3), 2.03 (3H, s, 6-CH3); 13C
NMR (CDCl3, 125 MHz) d 169.6 (10-CO), 168.4 (5-OCO), 147.3 (C-
18), 145.5 (C-7), 144.5 (C-60), 144.1 (C-70), 142.9 (C-17), 141.8 (C-
5), 140.6 (C-8), 138.1 (NCH2CH@CH2), 130.7 (C-20), 130.2 (C-100),
129.4 (C-16), 127.4 (C-90), 121.6 (C-10), 121.2 (C-15), 118.4 (C-
19), 118.3 (21-CN), 115.4 (NCH2CH@CH2), 114.5 (C-9), 113.9 (C-
50), 112.5 (C-6), 110.9 (C-80), 102.0 (OCH2O), 71.1 (C-10), 61.1 (C-
3), 60.7 (C-22), 60.4 (C-1), 60.1 (17-OCH3), 60.0 (C-21), 55.4 (70-
OCH3), 54.9 (C-11), 54.7 (C-13), 54.2 (NCH2CH), 43.7 (C-30), 43.0
(C-4), 41.8 (NCH3), 39.7(C-120), 27.8 (C-40), 24.9 (C-14), 20.3
(COCH3), 16.1 (16-CH3), 9.7 (6-CH3); FABMS m/z 811 (MH+);
HRFABMS m/z 811.3011 (MH+, calcd for C43H47N4O10S, 811.3013),
1163, 1109, 1088, 1070, 1028, 1003, 914, 804 cmꢁ1 1H NMR
;
(CDCl3, 500 MHz) d 6.67 (1H, s, 15-H), 6.37 (1H, s, 50-H), 6.24
(1H, s, 80-H), 6.09 (1H, ddd, J = 17.3, 10.3, 5.1 Hz, 18-OCH2CH@CH2),
6.08 (1H, d, J = 1.2 Hz, OCHO), 5.99 (1H, ddd, J = 17.3, 10.5, 5.4 Hz,
60-OCH2CH@CH2), 5.97 (1H, d, J = 1.2 Hz, OCHO), 5.58 (1H, ddd,
J = 17.1, 10.3, 5.6 Hz, NCH2CH@CH2), 5.45 (1H, dd, J = 17.3, 1.5 Hz,
18-OCH2CH@CH2), 5.32 (1H, dd, J = 17.3, 1.3 Hz, 60-OCH2CH@CH2),
5.25 (1H, dd, 1H, dd, J = 10.3, 1.5 Hz, 18-OCH2CH@CH2), 5.22 (1H,
dd, J = 10.5, 1.3 Hz, 60-OCH2CH@CH2), 5.13 (1H, dd, J = 17.1,
1.7 Hz, NCH2CH@CH2), 5.04 (1H, dd, J = 10.3, 1.7 Hz, NCH2CH@CH2),
4.95 (1H, d, J = 11.2 Hz, 22-H), 4.81 (1H, dd, J = 12.7, 5.1 Hz, 18-
OCHCH), 4.60 (1H, br s, 4-H), 4.49 (2H, d, J = 5.4 Hz, 60-OCH2CH),
4.37 (1H, d, J = 1.2 Hz, 1-H), 4.33 (1H, dd, J = 12.7, 5.6 Hz, 18-
OCHCH), 4.22 (1H, dd, J = 5.4, 1.5 Hz, 11-H), 4.12 (1H, d,
J = 2.8 Hz, 21-H), 3.91 (1H, dd, J = 11.2, 2.6 Hz, 22-H), 3.80 (3H, s,
17-OCH3), 3.55 (3H, s, 70-OCH3), 3.53 (1H, br, 3-H, the signals over-
lapped with the methyl signals), 3.43 (1H, br d, J = 9.2 Hz, 13-H),
CD
D
e
nm (c 12.3
l
M, methanol, 32 °C) ꢁ29.4 (210), ꢁ66.7 (218),
0 (244), 9.6 (253), 0 (270), ꢁ13.8 (286), 0 (320).

P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
4427
5.1.3. 18, 60-O-Bisallyl-20-N-300-indolecarbonyl Et 770 5
Indole-3-carboxylic acid (14.5 mg, 90 mol) was added to a stir-
J = 7.0, 1.1 Hz, 500-H), 7.34 (1H, td, J = 7.0, 1.1 Hz, 600-H), 6.48 (1H,
br s, 80-H), 6.40 (1H, s, 50-H), 6.09 (1H, d, J = 1.3 Hz, OCHO), 6.00
(1H, d, J = 1.2 Hz, OCHO), 5.65 (1H, br s, 18-OH), 5.47 (2H, br s,
15H and 60-OH), 4.67 (1H, br d, J = 11.4 Hz, 22-H), 4.66 (1H, br s,
4-H), 4.54 (1H, dd, J = 11.4, 2.2 Hz, 22-H), 4.36 (1H, br s, 1-H),
4.21 (1H, dd, J = 5.3, 1.4 Hz, 11-H), 4.19 (1H, d, J = 2.7 Hz, 21-H),
4.06 (1H, dd, J = 14.3, 3.1 Hz, 30-H), 3.95 (1H, d, J = 14.8 Hz, 120-
H), 3.71 (3H, s, 17-OCH3), 3.59 (3H, s, 70-OCH3), 3.55 (1H, br d,
J = 4.8 Hz, 3-H), 3.53 (1H, m, 30-H), 3.47 (1H, m, 120-H), 3.42 (1H,
m, 13-H), 2.85 (2H, d, J = 5.1 Hz, 14-H2), 2.49 (2H, m, 30-H and 40-
H), 2.34 (3H, s, OCOCH3), 2.29 (1H, m, 40-H), 2.09 (3H, s, NCH3),
2.06 (3H, s, 6-CH3), 1.13 (3H, s, 16-CH3); FABMS m/z 914 (MH+);
HRFABMS m/z 914.3064 (MH+, calcd for C47H48N5O11S, 914.3071).
l
red solution of 4a (15.3 mg, 18.0 mmol) and DCC (92.8 mg,
0.45 mmol) in CH2Cl2 (2.0 mL) and the reaction mixture was stirred
at 25 °C for 6 h. After the reaction mixture was concentrated in va-
cuo, the residue was subjected to chromatography with CH2Cl2–
ethyl acetate (9:1) as the eluent to afford 5 (16.0 mg, 90.0%) as a
colorless amorphous powder. ½a D16
ꢁ0.14 (c 0.61, CHCl3); IR (KBr)
ꢂ
3393, 2932, 2250w, 1749, 1636, 1518, 1458, 1429, 1375, 1339,
1260, 1244, 1194, 1169, 1109, 1086, 997, 895, 750 cmꢁ1 1H
;
NMR (CDCl3, 500 MHz) d 8.69 (1H, br s, NH), 8.13 (1H, d,
J = 7.9 Hz, 400-H), 7.58 (1H, d, J = 2.5 Hz, 200-H), 7.46 (1H, d,
J = 8.3 Hz, 700-H), 7.41 (1H, ddd, J = 7.9, 7.0, 1.1 Hz, 500-H), 7.34
(1H, ddd, J = 8.3, 7.0, 1.1 Hz, 600-H), 6.47 (1H, br s, 80-H), 6.33 (1H,
s, 50-H), 6.08 (1H, d, J = 1.2 Hz, OCHO), 6.03 (1H, ddd, J = 17.1,
10.7, 5.4 Hz, 18-OCH2CH = CH2), 5.99 (1H, d, J = 1.2 Hz, OCHO),
5.97 (1H, ddd, J = 17.1, 10.7, 5.5 Hz, 60-OCH2CH@CH2), 5.69 (1H,
br s, 15-H), 5.40 (1H, dd, J = 17.3, 1.5 Hz, 18-OCH2CH@CH2), 5.30
(1H, ddd, J = 17.3, 3.1, 1.7 Hz, 60-OCH2CH@CH2), 5.20 (2H, m, 18-
OCH2CH@CH2 and 60-OCH2CH@CH2), 4.74 (1H, br d, J = 11.4 Hz,
22-H), 4.72 (1H, dt, J = 12.8, 5.4 Hz, 18-OCHCH), 4.62 (1H, br s, 4-
H), 4.47 (2H, dt, J = 5.4, 1.5 Hz, 60-OCH2CH), 4.44 (1H, dd, J = 11.4,
2.0 Hz, 22-H), 4.37 (1H, br s, 1-H), 4.22 (1H, dt, J = 11.3, 5.4 Hz,
18-OCHCH), 4.21 (1H, d, J = 1.4 Hz, 21-H), 4.18 (1H, dd, J = 5.5,
1.3 Hz, 11-H), 4.06 (1H, dd, J = 14.3, 3.1 Hz, 30-H), 3.93 (1H, d,
J = 14.7 Hz, 120-H), 3.69 (3H, s, 17-OCH3), 3.66 (3H, s, 70-OCH3),
3.55 (1H, br d, J = 5.5 Hz, 3-H), 3.53 (1H, m, 30-H), 3.43 (1H, br d,
J = 7.9, 1.4 Hz, 13-H), 2.95 (1H, d, J = 17.4 Hz, 14-Hb), 2.84 (1H,
CD
D
e
nm (c 10.9
l
M, methanol, 32 °C) ꢁ154.1 (210), ꢁ30.2
(222), ꢁ30.5 (226), 0 (235), 46.4 (252), 0 (276), ꢁ10.5 (288), 0
(305).
18-O-Allyl-20-N-indole-3-carbonyl Et 770: IR (KBr) 3387,
2932, 2250w, 1749, 1620, 1518, 1458, 1431, 1391, 1375, 1337,
1319, 1304, 1261, 1234, 1196, 1170, 1109, 1086, 1028, 960,
930, 912, 895, 868, 806 cmꢁ1
;
1H NMR (CDCl3, 300 MHz) d
8.44 (1H, br s, NH), 8.11 (1H, d, J = 7.7 Hz, 400-H), 7.59 (1H, d,
J = 2.6 Hz, 200-H), 7.48 (1H, d, J = 7.7 Hz, 700-H), 7.35 (1H, td,
J = 7.0, 1.5 Hz, 500-H), 7.34 (1H, td, J = 7.0, 1.5 Hz, 600-H), 6.45
(1H, br s, 80-H), 6.40 (1H, s, 50-H), 6.09 (1H, s, OCHO), 6.04
(1H, ddd, J = 17.6, 10.3, 5.4 Hz, 18-OCH2CH@CH2), 6.00 (1H, s,
OCHO), 5.63 (1H, br s, 15-H), 5.44 (1H, s, 60-OH), 5.40 (1H, dd,
J = 17.6, 1.5 Hz, 18-OCH2CH@CH2), 5.19 (1H, dd, J = 10.3, 1.5 Hz,
18-OCH2CH@CH2), 4.72 (1H, dd, J = 12.6, 5.4 Hz, 18-OCHCH),
4.69 (1H, br d, J = 11.2 Hz, 22-H), 4.64 (1H, br s, 4-H), 4.51
(1H, dd, J = 11.2, 1.9 Hz, 22-H), 4.36 (1H, br s, 1-H), 4.21 (1H,
d, J = 2.2 Hz, 21-H), 4.20 (1H, dd, J = 12.6, 5.4 Hz, 18-OCHCH),
4.17 (1H, d, J = 5.3 Hz, 11-H), 4.03 (1H, dd, J = 14.5, 3.7 Hz, 30-
H), 3.93 (1H, d, J = 14.8 Hz, 120-H), 3.70 (6H, s, 17-OCH3 and
70-OCH3), 3.55 (1H, br d, J = 4.9 Hz, 3-H), 3.53 (1H, m, 30-H),
3.48 (1H, m, 120-H), 3.42 (1H, m, 13-H), 2.86 (2H, d, J = 8.4 Hz,
14-H2), 2.43 (2H, m, 30-H and 40-H), 2.31 (3H, s, OCOCH3), 2.30
(1H, m, 40-H), 2.09 (3H, s, NCH3), 2.06 (3H, s, 6-CH3), 1.10 (3H,
s, 16-CH3); FABMS m/z 954 (MH+); HRFABMS m/z 954.3383
(MH+, calcd for C52H52N5O11S, 954.3384).
dd, J = 17.4, 9.1 Hz, 14-Ha), 2.50 (1H, ddd, J = 16.5, 10.9, 6.2 Hz,
40-H), 2.50 (1H, m, 120-H, the signals overlapped with 40-H), 2.30
(3H, s, OCOCH3), 2.27 (1H, br d, J = 16.5 Hz, 40-H), 2.08 (3H, s,
NCH3), 2.06 (3H, s, 6-CH3), 1.09 (3H, s, 16-CH3); 13C NMR (CDCl3,
125 MHz) d 170.5 (10-CO), 168.4 (5-OCO), 168.1 (NCO), 150.8 (C-
18), 148.5 (C-17), 147.3 (C-70), 147.1 (C-60), 145.5 (C-7), 141.2 (C-
8), 141.1 (C-5), 135.8 (C-800), 134.9 (18-OCH2CH@CH2), 133.3 (60-
OCH2CH@CH2), 131.6 (C-16), 129.5 (C-20 and C-200), 128.4 (C-90),
127.0 (C-100), 125.2 (C-15), 125.1 (C-900), 123.9 (C-19), 122.9 (C-
600), 122.8 (C-10), 122.6 (C-400), 121.4 (C-500), 118.4 (21-CN), 117.9
(60-OCH2CH@CH2), 116.7 (18-OCH2CH@CH2), 114.3 (C-300), 113.5
(C-9), 112.8 (C-6 and C-50), 111.5 (C-700), 111.3 (C-80), 102.1
(OCH2O), 73.0 (18-OCH2CH), 70.5 (C-10), 69.7 (60-OCH2CH), 61.1
(C-3), 60.9 (C-1), 60.4 (C-22), 59.5 (C-21 and 17-OCH3), 55.4 (C-
11), 55.3 (70-OCH3), 55.0 (C-13), 46.7 (C-30), 42.1 (C-4), 41.8
(NCH3), 38.5 (C-120), 29.4 (C-40), 24.8 (C-14), 20.4 (COCH3), 14.3
(16-CH3), 9.9 (6-CH3); FABMS m/z 851 (MH+); HRFABMS m/z
5.2. Condensation of Et 770 1b and 4-nitrobenzoic acid with DCC
4-Nitrobenzoic acid (14.5 mg, 90 lmol) was added to a stirred
solution of 1b (7.6 mg, 0.1 mmol) and DCC (103.1 mg, 0.5 mmol)
in CH2Cl2 (2.0 mL) and the reaction mixture was stirred at 25 °C
for 17 h. The reaction mixture was quenched with 2.5% NaHCO3
solution, and extracted with CH2Cl2 (10 mL ꢀ 3). The combined ex-
tracts were washed with brine, dried, and concentrated in vacuo to
give a residue. Chromatography on a silica gel column afforded 60-
O-400-nitrobenzoyl Et 770 2 (R = COC6H4NO2-400: 7.4 mg, 81.6%) as
colorless amorphous powder, which was identical in all respects
to the authentic sample.
994.3696 (MH+, calcd for C55H56N5O11S, 994.3697). CD
10.0
(228), 0 (235), 53.9 (252), 0 (276), ꢁ5.0 (292), 0 (300).
De nm (c
l
M, methanol, 32 °C) ꢁ173.1 (210), ꢁ29.3 (222), ꢁ20.2
5.1.4. Deallylation of compound 5
Tributyltin hydride (0.07 mL, 0.61
over 10 min to vigorously stirred solution of
15.3 mol), (Ph3P)2PdCl2 (6.4 mg, 9.2 mol), and AcOH (32.8 l
l
mol) was added dropwise
(15.2 mg,
L,
a
5
l
l
0.57 mmol) in THF (10 mL) at 25 °C, and the mixture was stirred
for 1.5 h at 25 °C. The mixture was diluted with water (10 mL),
made alkaline with 5% aqueous NaHCO3, and extracted with chlo-
roform (30 mL ꢀ 3). The combined extracts were washed with 5%
aqueous NaHCO3, dried, and concentrated in vacuo to give a resi-
due. Chromatography on a silica gel column with hexane–ethyl
acetate (3:2) afforded 3 (6.0 mg, 42.9%) as a colorless solid, whose
spectral data were in complete agreement with those of the
5.3. General procedure for the preparation of N-acyl derivatives
of 4a
Compound 4a (15.3 mg, 0.018 mmol) and DMAP (1.1 mg) were
dissolved in pyridine (1.5 mL), and 15 equimolar quantity of vari-
ous acid chlorides was added to this mixture at 0 °C. The reaction
mixture was heated at 60 °C for 2 h. After the solvent was removed
in vacuo, the residue was diluted with water (10 mL), and ex-
tracted with chloroform (15 mL ꢀ 3). The combined extracts were
washed with brine (15 mL), dried, and concentrated in vacuo to
give a residue. This residue was purified by silica gel column chro-
matography using an appropriate eluent to give the corresponding
purified product.
authentic sample. ½a D22
ꢂ
+5.3 (c 0.20, CHCl3); IR (KBr) 3420, 2928,
2855, 2250w, 1749, 1616, 1522, 1508, 1458, 1435, 1375, 1261,
1234, 1196, 1171, 1109, 1085, 1028 cmꢁ1
;
1H NMR (CDCl3,
300 MHz) d 8.52 (1H, br s, NH), 8.06 (1H, d, J = 7.0 Hz, 400-H), 7.56
(1H, d, J = 2.7 Hz, 200-H), 7.51 (1H, d, J = 7.0 Hz, 700-H), 7.39 (1H, td,

4428
P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
5.3.1. 18, 60-O-Bisallyl-20-N-benzoyl Et 770 6a (yield 79.8%)
ꢁ55.4 (c 0.82, CHCl3); IR (KBr) 3447, 2928, 2855, 2250w,
1763, 1657, 1518, 1447, 1375, 1260, 1196, 1142, 1109, 1086,
1070, 1028, 993, 802 cmꢁ1 1H NMR (CDCl3, 400 MHz) d 7.47 (5H,
(C-50), 112.6 (C-6), 111.0 (C-80), 102.0 (OCH2O), 72.9 (18-OCH2CH),
69.9 (C-10), 69.6 (60-OCH2CH), 61.0 (C-3), 60.8 (C-22), 60.6 (C-1),
59.6 (C-21), 59.4 (17-OCH3), 55.5 (C-11), 55.2 (70-OCH3), 54.9 (C-
13), 45.9 (C-30), 42.2 (C-4), 41.9 (NCH3), 39.2 (C-120), 29.3 (C-40),
24.2 (C-14), 20.4 (COCH3), 15.9 (16-CH3), 9.9 (6-CH3); FABMS m/z
1000 (MH+); HRFABMS m/z 1000.3434 (MH+, calcd for
½ ꢂ
a 2D1
;
m, ArH), 6.61 (1H, br s, 15-H), 6.60 (1H, br s, 80-H), 6.34 (1H, s,
50-H), 6.10 (1H, d, J = 1.2 Hz, OCHO), 6.09 (1H, ddd, J = 17.1, 10.5,
5.4 Hz, 18-OCH2CH@CH2), 6.02 (1H, d, J = 1.2 Hz, OCHO), 5.98
(1H, ddd, J = 17.1, 10.5, 5.4 Hz, 60-OCH2CH@CH2), 5.44 (1H, dd,
J = 17.2, 1.6 Hz, 18-OCH2CH@CH2), 5.32 (1H, dd, J = 17.2, 1.2 Hz,
60-OCH2CH@CH2), 5.23 (1H, dd, J = 10.5, 1.5 Hz, 18-OCH2CH@CH2),
5.22 (1H, dd, J = 10.5, 1.5 Hz, 60-OCH2CH@CH2), 4.79 (1H, dt,
J = 12.4, 5.4 Hz, 18-OCHCH), 4.61 (1H, br s, 4-H), 4.61 (1H, br s,
22-H), 4.48 (2H, dt, J = 5.2, 1.5 Hz, 60-OCH2CH), 4.39 (1H, br s, 22-
H), 4.31 (1H, s, 1-H), 4.30 (1H, dd, J = 12.4, 5.2 Hz, 18-OCHCH),
4.23 (1H, d, J = 4.0 Hz, 11-H), 4.10 (1H, br s, 21-H), 3.73 (3H, s,
17-OCH3), 3.66 (3H, s, 70-OCH3), 3.61 (1H, br d, J = 5.5 Hz, 3-H),
3.54 (1H, m, 30-H), 3.50 (1H, m, 120-H), 3.50 (1H, m, 30-H), 3.44
C53H54N5O13S, 1000.3439), CD De nm (c 10.0 lM, methanol,
23 °C) ꢁ54.0 (210), ꢁ102.4 (216), 0 (246), 7.5 (255), 0 (283),
ꢁ4.6 (292), 0 (300).
5.3.3. 18, 60-O-Bisallyl-20-N-300-nitrobenzoyl Et 770 6c (yield
91.8%)
½
a 1D6
ꢂ
ꢁ56.0 (c 0.32, CHCl3); IR (KBr) 3456, 2926, 2250w, 1761,
1748, 1663, 1610, 1533, 1521, 1447, 1435,1412, 1350, 1258,
1196, 1109, 1086, 1069, 1028, 999, 808 cmꢁ1 1H NMR (CDCl3,
;
400 MHz) d 8.37 (1H, dt, J = 7.6, 1.2 Hz, 400-H), 8.34 (1H, t,
J = 1.2 Hz, 200-H), 7.83 (1H, dt, J = 7.6, 1.2 Hz, C-500), 7.67 (1H, t,
J = 7.6 Hz, 500-H), 6.60 (1H, br s, 15-H), 6.42 (1H, br s, 80-H), 6.39
(1H, s, 50-H), 6.09 (1H, d, J = 1.2 Hz, OCHO), 6.07 (1H, ddd,
J = 17.2, 10.5, 5.4 Hz, 18-OCH2CH@CH2), 6.00 (1H, d, J = 1.2 Hz,
OCHO), 5.99 (1H, ddd, J = 17.2, 10.5, 5.4 Hz, 60-OCH2CH@CH2),
5.42 (1H, dd, J = 17.2, 1.2 Hz, 18-OCH2CH@CH2), 5.32 (1H, dd,
J = 17.2, 1.2 Hz, 60-OCH2CH@CH2), 5.22 (2H, dt, J = 10.5, 1.2 Hz 18-
OCH2CH@CH2 and 60-OCH2CH@CH2), 4.77 (1H, dd, J = 13.2, 5.4 Hz,
18-OCHCH), 4.71 (1H, br s, 4-H), 4.67 (1H, br, 22-H), 4.51 (2H, dt,
J = 5.4, 1.2 Hz, 60-OCH2CH), 4.38 (1H, s, 1-H), 4.35 (1H, br, 22-H),
4.27 (1H, dt, J = 13.2, 5.4 Hz, 18-OCHCH), 4.22 (1H, dd, J = 5.2,
1.2 Hz, 11-H), 4.20 (1H, br s, 21-H), 3.69 (3H, s, 17-OCH3), 3.66
(1H, m, 120-H, signals overlapped with 70-OCH3), 3.65 (3H, s, 70-
OCH3), 3.56 (1H, d, J = 5.2 Hz, 3-H), 3.53 (1H, m, 30-H), 3.49 (1H,
m, 30-H), 3.48 (1H, br d, J = 10.8 Hz, 13-H), 3.01 (1H, dd, J = 17.2,
(1H, br d, J = 8.4 Hz, 13-H), 2.98 (1H, dd, J = 17.6, 9.6 Hz, 14-Ha),
2.83 (1H, d, J = 17.6 Hz, 14-Hb), 2.38 (2H, m, 40-H), 2.32 (1H, m,
120-H), 2.29 (3H, s, OCOCH3), 2.15 (3H, s, NCH3), 2.04 (3H, s, 6-
CH3), 1.85 (3H, s, 16-CH3); 13C NMR (CDCl3, 100 MHz) d 172.7
(10-CO), 169.2 (NCO), 168.0 (5-OCO), 150.3 (C-18), 148.4 (C-17),
147.1 (C-70), 146.8 (C-60), 145.3 (C-7), 141.4 (C-8), 140.9 (C-5),
136.6 (C-100), 134.5 (18-OCH2CH@CH2), 133.0 (60-OCH2CH@CH2),
131.1 (C-16), 130.1 (C-400), 129.9 (C-20), 128.3 (C-100), 128.2 (C-
300), 128.1 (C-200), 125.6 (C-90), 124.5 (C-15), 124.1 (C-19), 122.1
(C-10), 118.1 (21-CN), 117.7 (60-OCH2CH@CH2), 116.6 (18-
OCH2CH@CH2), 113.0 (C-9), 112.8 (C-50), 112.4 (C-6), 111.2 (C-80),
102.0 (OCH2O), 73.0 (18-OCH2CH), 69.6 (C-10), 69.6 (60-OCH2CH),
61.0 (C-3), 60.4 (C-22), 60.3 (C-1), 59.7 (C-21), 59.4 (17-OCH3),
55.5 (C-11), 55.2 (70-OCH3), 54.9 (C-13), 45.4 (C-30), 41.9 (C-4),
41.9 (NCH3), 39.9 (C-120), 29.8 (C-40), 25.1 (C-14), 20.4 (COCH3),
15.7 (16-CH3), 9.8 (6-CH3); FABMS m/z 955 (MH+); HRFABMS m/z
8.8 Hz, 14-Ha), 2.93 (1H, d, J = 17.2 Hz, 14-Hb), 2.50 (1H, ddd,
J = 16.6, 10.3, 6.4 Hz, 40-H), 2.50 (1H, m, 120-H, signals overlapped
with 40-H), 2.33 (1H, m, 40-H), 2.31 (3H, s, OCOCH3), 2.12 (3H, s,
NCH3), 2.05 (3H, s, 6-CH3), 1.51 (3H, s, 16-CH3); 13C NMR (CDCl3,
100 MHz) d 169.1 (NCO), 169.1 (10-CO), 168.0 (5-OCO), 150.1 (C-
18), 148.7 (C-17), 147.9 (C-300), 147.3 (C-70), 147.1 (C-60), 145.3
(C-7), 141.2 (C-5), 140.9 (C-8), 139.0 (C-100), 134.5 (18-
OCH2CH@CH2), 133.9 (C-600), 132.9 (60-OCH2CH@CH2), 130.8 (C-
16), 130.0 (C-20), 129.5 (C-500), 127.5 (C-90), 125.7 (C-100), 124.6
(C-400), 124.4 (C-19), 124.1 (C-15), 123.1 (C-200), 122.2 (C-10),
118.1 (21-CN), 117.8 (60-OCH2CH@CH2), 116.6 (18-OCH2CH@CH2),
113.3 (C-9), 112.8 (C-6), 112.5 (C-50), 111.0 (C-80), 102.0 (OCH2O),
72.9 (18-OCH2CH), 70.6 (C-10), 69.6 (60-OCH2CH), 60.9 (C-3), 60.8
(C-1), 60.6 (C-22), 59.4 (C-21), 59.4 (17-OCH3), 55.4 (C-11), 55.3
(70-OCH3), 54.9 (C-13), 46.6 (C-30), 42.3 (C-4), 41.9 (NCH3), 38.7
(C-120), 29.2 (C-40), 24.8 (C-14), 20.4 (COCH3), 15.5 (16-CH3), 9.9
(6-CH3); FABMS m/z 1000 (MH+); HRFABMS m/z 1000.3441 (MH+,
955.3593 (MH+, calcd for C53H55N4O11S, 955.3588), CD
10.0
M, methanol, 23 °C) ꢁ60.9 (210), ꢁ79.8 (216), 0 (241), 10.8
(254), 0 (279), ꢁ6.1 (294), 0 (310).
De nm (c
l
5.3.2. 18, 60-O-Bisallyl-20-N-400-nitrobenzoyl Et 770 6b (yield
89.0%)
½
a 1D6
ꢂ
ꢁ38.6 (c 0.64, CHCl3); IR (KBr) 3468, 2926, 2853, 2250w,
1748, 1663, 1522, 1460, 1348, 1319, 1302, 1260, 1234, 1196,
1144, 1107, 1086, 1070, 1028, 999, 914, 866, 856, 802 cmꢁ1 1H
;
NMR (CDCl3, 400 MHz) d 8.37 (2H, d, J = 8.4 Hz, 300-H), 7.46 (2H,
d, J = 8.4 Hz, 200-H), 6.55 (1H, br s, 15-H), 6.45 (1H, br s, 80-H),
6.35 (1H, s, 50-H), 6.09 (1H, br s, OCHO), 6.07 (1H, ddd, J = 16.8,
10.4, 5.4 Hz, 18-OCH2CH@CH2), 6.01 (1H, br s, OCHO), 5.98 (1H,
ddd, J = 17.1, 10.5, 5.4 Hz, 60-OCH2CH@CH2), 5.43 (1H, dd, J = 17.2,
1.6 Hz, 18-OCH2CH@CH2), 5.33 (1H, dd, J = 17.2, 1.4 Hz, 60-
OCH2CH@CH2), 5.23 (2H, d, J = 10.4 Hz, 18-OCH2CH@CH2 and 60-
OCH2CH@CH2), 4.78 (1H, dd, J = 12.8, 5.2 Hz, 18-OCHCH), 4.65
(1H, br s, 4-H), 4.63 (1H, br, 22-H), 4.49 (2H, d, J = 5.2 Hz, 60-
OCH2CH), 4.38 (1H, br, 22-H), 4.36 (1H, s, 1-H), 4.29 (1H, dd,
J = 12.8, 5.2 Hz, 18-OCHCH), 4.22 (1H, d, J = 4.4 Hz, 11-H), 4.14
(1H, br s, 21-H), 3.70 (3H, s, 17-OCH3), 3.64 (3H, s, 70-OCH3), 3.58
(1H, dd, J = 9.6, 4.4 Hz, 3-H), 3.58 (1H, m, 120-H), 3.46 (3H, m, 30-
calcd for C53H54N5O13S, 1000.3439), CD De nm (c 10.0 lM, metha-
nol, 23 °C) ꢁ45.2 (210), ꢁ75.5 (216), 0 (241), 14.6 (254), 0 (284),
ꢁ5.8 (294), 0 (309).
5.3.4. 18, 60-O-Bisallyl-20-N-400-pyridinecarbonyl Et 770 6d (yield
90.9%)
½
a 1D6
ꢂ
ꢁ50.0 (c 0.66, CHCl3); IR (KBr) 3447, 2930, 2855, 2250w,
1761, 1749, 1662, 1519, 1458, 1446, 1410, 1375, 1321, 1288,
1259, 1234, 1196, 1146, 1109, 1086, 1069, 1028, 999 cmꢁ1 1H
H2 and 13-H), 3.00 (1H, dd, J = 17.6, 9.6 Hz, 14-Ha), 2.87 (1H, d,
J = 17.6 Hz, 14-Hb), 2.47 (1H, m, 40-H), 2.36 (1H, m, 40-H), 2.30
(3H, s, OCOCH3), 2.13 (3H, s, NCH3), 2.05 (1H, m, 120-H, signals
overlapped with 6-CH3), 2.05 (3H, s, 6-CH3), 1.73 (3H, s, 16-CH3);
13C NMR (CDCl3, 100 MHz) d 169.6 (NCO), 168.8 (10-CO), 168.0
(5-OCO), 150.3 (C-18), 148.6 (C-17), 148.4 (C-400), 147.3 (C-70),
147.1 (C-60), 145.4 (C-7), 143.1 (C-100), 141.2 (C-8), 141.0 (C-5),
134.4 (18-OCH2CH@CH2), 132.9 (60-OCH2CH@CH2), 130.8 (C-16),
130.0 (C-20), 128.8 (C-200), 127.5 (C-90), 125.5 (C-100), 124.6 (C-
19), 123.7 (C-15), 123.6 (C-300), 122.1 (C-10), 118.0 (21-CN), 117.8
(60-OCH2CH@CH2), 116.7 (18-OCH2CH@CH2), 113.2 (C-9), 112.7
;
NMR (CDCl3, 400 MHz) d 8.77 (2H, d, J = 5.2 Hz, 200-H), 7.34 (2H,
d, J = 5.2 Hz, 300-H), 6.57 (1H, br s, 15-H), 6.43 (1H, br s, 80-H),
6.35 (1H, s, 50-H), 6.09 (1H, d, J = 1.2 Hz, OCHO), 6.08 (1H, ddd,
J = 16.8, 10.4, 5.4 Hz, 18-OCH2CH@CH2), 6.00 (1H, d, J = 1.2 Hz,
OCHO), 5.99 (1H, ddd, J = 17.1, 10.5, 5.4 Hz, 60-OCH2CH@CH2),
5.44 (1H, dd, J = 17.2, 1.6 Hz, 18-OCH2CH@CH2), 5.32 (1H, dd,
J = 17.2, 1.4 Hz, 60-OCH2CH@CH2), 5.23 (2H, d, J = 10.4, 18-
OCH2CH@CH2 and 60-OCH2CH@CH2), 4.78 (1H, dd, J = 12.4, 5.2 Hz,
18-OCHCH), 4.65 (1H, br s, 4-H), 4.63 (1H, br, 22-H), 4.49 (2H,

P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
4429
dd, J = 5.6, 1.2 Hz, 60-OCH2CH), 4.38 (1H, br, 22-H), 4.36 (1H, s, 1-H),
4.30 (1H, dd, J = 12.4, 5.6 Hz, 18-OCHCH), 4.23 (1H, d, J = 5.6 Hz, 11-
H), 4.14 (1H, d, J = 2.4 Hz, 21-H), 3.71 (3H, s, 17-OCH3), 3.64 (3H, s,
70-OCH3), 3.58 (1H, br s, 3-H), 3.56 (1H, br d, 120-H), 3.47 (3H, m, 30-
5.3.6. 18, 60-O-Bisallyl-20-N-400-quinolinecarbonyl Et 770 6f (yield
73.0%)
½
a 2D5
ꢂ
ꢁ76.1 (c 0.41, CHCl3); IR (KBr) 3443, 2933, 2870, 2808,
2250w, 1761, 1660, 1518, 1508, 1464, 1447, 1429, 1412, 1318,
1321, 1256, 1234, 1194, 1109, 1086, 1069, 1028, 997, 775 cmꢁ1
;
H2 and 13-H), 2.99 (1H, dd, J = 17.2, 9.2 Hz, 14-H
a), 2.94 (1H, d,
J = 17.2 Hz, 14-Hb), 2.51 (1H, dd, J = 16.8, 5.2 Hz, 40-H), 2.48 (1H,
dd, J = 16.8, 8.0 Hz, 40-H), 2.30 (3H, s, OCOCH3), 2.13 (3H, s,
NCH3), 2.05 (1H, m, 120-H, signals overlapped with 6-CH3), 2.05
(3H, s, 6-CH3), 1.77 (3H, s, 16-CH3); 13C NMR (CDCl3, 100 MHz) d
169.2 (NCO), 168.7 (10-CO), 167.5 (5-OCO), 150.2 (C-18), 149.9
(C-200), 148.6 (C-17), 147.3 (C-70), 147.0 (C-60), 145.3 (C-7), 144.8
(C-400), 141.2 (C-5), 140.9 (C-8), 134.5 (18-OCH2CH@CH2), 132.8
(60-OCH2CH@CH2), 131.0 (C-16), 129.9 (C-20), 127.5 (C-90), 125.6
(C-100), 124.5 (C-19), 124.4 (C-15), 122.1 (C-10), 121.9 (C-300),
118.0 (21-CN), 117.8 (60-OCH2CH@CH2), 116.6 (18-OCH2CH@CH2),
113.2 (C-9), 112.7 (C-6), 112.5 (C-50), 111.0 (C-80), 102.0 (OCH2O),
72.9 (18-OCH2CH), 69.9 (C-10), 69.6 (60-OCH2CH), 61.0 (C-3), 60.7
(C-22), 60.6 (C-1), 59.6 (C-21), 59.4 (17-OCH3), 55.5 (C-11), 55.2
(70-OCH3), 54.8 (C-13), 45.7 (C-30), 42.2 (C-4), 41.9 (NCH3), 39.2
(C-120), 29.3 (C-40), 25.0 (C-14), 20.4 (COCH3), 15.9 (16-CH3), 9.9
(6-CH3); FABMS m/z 956 (MH+); HRFABMS m/z 956.3534 (MH+,
1H NMR (CDCl3, 500 MHz, this compound was a mixture of rota-
tional isomers, ratio 7:3, and only the signals of major isomer are
presented) d 8.98 (7/10H, d, J = 4.3 Hz, 200-H), 8.38 (7/10H, d,
J = 7.7 Hz, 500-H), 8.21 (7/10H, d, J = 7.7 Hz, 800-H), 7.86 (7/10H, t,
J = 7.7 Hz, 700-H), 7.79 (7/10H, t, J = 7.7 Hz, 600-H), 7.26 (7/10H, d,
J = 4.3 Hz, 300-H), 6.38 (7/10H, br s, 80-H), 6.34 (7/10H, s, 50-H),
6.24 (7/10H, br s, 15-H), 6.09 (7/10H, d, J = 1.1 Hz, OCHO), 6.08
(7/10H, ddd, J = 17.2, 10.5, 5.3 Hz, 18-OCH2CH@CH2), 6.00 (7/10H,
d, J = 1.1 Hz, OCHO), 5.99 (7/10H, ddd, J = 17.2, 10.5, 5.4 Hz, 60-
OCH2CH@CH2), 5.44 (7/10H, d, J = 17.0 Hz, 18-OCH2CH@CH2),
5.32 (7/10H, dd, J = 17.2, 1.2 Hz, 60-OCH2CH@CH2), 5.23 (7/5H, d,
J = 10.5, 1.2 Hz, 18-OCH2CH@CH2 and 60-OCH2CH@CH2), 4.78 (1H,
dd, J = 12.8, 5.3 Hz, 18-OCHCH), 4.78 (7/10H, br, 22-H), 4.71 (7/
10H, br s, 4-H), 4.49 (7/5H, d, J = 5.4 Hz, 60-OCH2CH), 4.44 (7/10H,
s, 1-H), 4.42 (7/10H, br, 22-H), 4.29 (7/10H, dd, J = 12.8, 5.3 Hz,
18-OCHCH), 4.24 (7/10H, d, J = 5.1 Hz, 11-H), 4.20 (7/10H, d,
J = 2.6 Hz, 21-H), 3.76 (21/10H, s, 17-OCH3), 3.63 (21/10H, s, 70-
OCH3), 3.59 (7/10H, br d, J = 4.5 Hz, 3-H), 3.54 (7/10H, br, 120-H),
3.49 (7/10H, br, 13-H), 3.29 (7/5H, m, 30-H2), 3.03 (7/10H, dd,
calcd for C52H54N5O11S, 956.3541), CD
De nm (c 10.0 lM, metha-
nol, 23 °C) ꢁ49.6 (210), ꢁ93.5 (217), 0 (245), 12.1 (254), 0 (275),
ꢁ7.6 (293), 0 (308).
J = 17.6, 8.3 Hz, 14-Ha), 2.97 (7/10H, d, J = 17.6 Hz, 14-Hb), 2.68
(7/10H, br, 120-H), 2.41 (7/10H, dd, J = 15.8, 5.7 Hz, 40-H), 2.31
(21/10H, s, OCOCH3), 2.28 (7/10H, dd, J = 15.8, 8.5 Hz, 40-H), 2.13
(21/10H, s, NCH3), 2.06 (21/10H, s, 6-CH3), 1.34 (21/10H, s, 16-
5.3.5. 18, 60-O-Bisallyl-20-N-300-pyridinecarbonyl Et 770 6e (yield
90.9%)
a 1D6
ꢂ
ꢁ50.0 (c 0.61, CHCl3); IR (KBr) 3451, 2930, 2250w, 1761,
1748, 1659, 1520, 1447, 1430, 1412, 1393, 1375, 1260, 1234,
1196, 1146, 1109, 1086, 1067, 1028, 999 cmꢁ1 1H NMR (CDCl3,
13
CH3); C NMR (CDCl3, 125 MHz) d 168.9 (10-CO), 168.4 (5-OCO),
½
166.5 (NCO), 150.3 (C-200), 150.2 (C-18), 149.5 (C-900), 148.7 (C-
17), 147.6 (C-70), 147.4 (C-60), 144.8 (C-400), 145.5 (C-7), 141.5 (C-
5), 140.0 (C-8), 134.7 (18-OCH2CH@CH2), 133.0 (60-OCH2CH@CH2),
130.9 (C-16), 130.5 (C-20), 130.0 (C-600), 129.5 (C-800), 127.8 (C-700),
127.5 (C-90), 126.6 (C-500), 125.4 (C-100), 124.8 (C-19), 124.4 (C-15),
123.9 (C-1000), 122.8 (C-10), 119.1 (C-300), 118.2 (21-CN), 118.0 (60-
OCH2CH@CH2), 116.7 (18-OCH2CH@CH2), 113.6 (C-9), 112.7 (C-6),
112.5 (C-50), 111.3 (C-80), 102.1 (OCH2O), 72.8 (18-OCH2CH), 71.0
(C-10), 69.6 (60-OCH2CH), 61.6 (C-22), 61.4 (C-3), 60.5 (C-1), 59.8
(C-21), 59.3 (17-OCH3), 55.4 (C-11), 55.4 (70-OCH3), 54.9 (C-13),
45.3 (C-30), 42.4 (C-4), 41.8 (NCH3), 39.7 (C-120), 29.6 (C-40), 24.9
(C-14), 20.3 (COCH3), 15.0 (16-CH3), 9.8 (6-CH3); FABMS m/z
1006 (MH+); HRFABMS m/z 1006.3701 (MH+, calcd for C56H56N5
;
400 MHz) d 8.76 (1H, d, J = 4.4 Hz, 600-H), 8.73 (1H, s, 200-H), 7.79
(1H, d, J = 7.7 Hz, 400-H), 7.42 (1H, dd, J = 7.7, 4.4 Hz, 500-H), 6.61
(1H, br s, 15-H), 6.51 (1H, br s, 80-H), 6.35 (1H, s, 50-H), 6.09 (1H,
s, OCHO), 6.07 (1H, ddd, J = 17.1, 10.5, 5.4 Hz, 18-OCH2CH@CH2),
6.01 (1H, s, OCHO), 5.98 (1H, ddd, J = 17.3, 10.5, 5.4 Hz, 60-
OCH2CH@CH2), 5.43 (1H, dd, J = 17.3, 1.4 Hz, 18-OCH2CH@CH2),
5.32 (1H, dd, J = 17.2, 1.3 Hz, 60-OCH2CH@CH2), 5.22 (2H, dd,
J = 10.5, 1.4 Hz, 18-OCH2CH@CH2 and 60-OCH2CH@CH2), 4.77 (1H,
dd, J = 12.8, 5.1 Hz, 18-OCHCH), 4.64 (1H, br s, 4-H), 4.56 (1H, br
d, J = 11.4 Hz, 22-H), 4.49 (2H, d, J = 5.4 Hz, 60-OCH2CH), 4.48 (1H,
br d, J = 11.4 Hz, 22-H), 4.34 (1H, s, 1-H), 4.29 (1H, dd, J = 12.8,
5.6 Hz, 18-OCHCH), 4.23 (1H, d, J = 5.1 Hz, 11-H), 4.15 (1H, br s,
21-H), 3.71 (3H, s, 17-OCH3), 3.66 (3H, s, 70-OCH3), 3.60 (1H, d,
J = 10.3 Hz, 120-H), 3.58 (1H, s, 3-H), 3.52 (1H, m, 30-H), 3.47 (1H,
m, 30-H), 3.45 (1H, br d, J = 8.3 Hz, 13-H), 2.99 (1H, dd, J = 17.5,
O11S, 1006.3697), CD
D
e
nm (c 10.0
l
M, methanol, 21 °C) ꢁ18.8
(210), ꢁ63.6 (217), ꢁ18.2 (235), 0 (248), 10.3 (256), 0 (277), ꢁ5.6
(293), 0 (299), 1.2 (304), 0 (320).
5.3.7. 18, 60-O-Bisallyl-20-N-500-quinolinecarbonyl Et 770 6g
9.2 Hz, 14-Ha), 2.87 (1H, d, J = 17.5 Hz, 14-Hb), 2.48 (1H, dd,
J = 16.4, 7.1 Hz, 40-H), 2.42 (1H, m, 120-H), 2.38 (1H, dd, J = 16.4,
4.9 Hz, 40-H), 2.30 (3H, s, OCOCH3), 2.15 (3H, s, NCH3), 2.05 (3H,
s, 6-CH3), 1.70 (3H, s, 16-CH3); 13C NMR (CDCl3, 100 MHz) d
169.7 (NCO), 169.1 (10-CO), 168.0 (5-OCO), 150.6 (C-600), 150.2
(C-18), 149.1 (C-200), 148.5 (C-17), 147.3 (C-70), 147.0 (C-60), 145.3
(C-7), 141.1 (C-5), 141.1 (C-8), 135.8 (C-400), 134.5 (18-
OCH2CH@CH2), 132.9 (60-OCH2CH@CH2), 132.8 (C-300), 131.2 (C-
16), 129.9 (C-20), 127.7 (C-90), 125.5 (C-100), 124.5 (C-15), 124.2
(C-19), 123.0 (C-500), 122.1 (C-10), 118.0 (21-CN), 117.8
(60-OCH2CH@CH2), 116.7 (18-OCH2CH@CH2), 113.1 (C-9), 112.7
(C-6), 112.6 (C-50), 111.0 (C-80), 102.0 (OCH2O), 72.9 (18-OCH2CH),
69.6 (60-OCH2CH), 69.5 (C-10), 60.9 (C-3), 60.5 (C-22), 60.5 (C-1),
59.5 (C-21), 59.4 (17-OCH3), 55.4 (C-11), 55.2 (70-OCH3), 54.9
(C-13), 46.1 (C-30), 42.1 (C-4), 41.9 (NCH3), 39.2 (C-120), 29.2
(C-40), 25.0 (C-14), 20.4 (COCH3), 15.5 (16-CH3), 9.9 (6-CH3); FAB-
MS m/z 956 (MH+); HRFABMS m/z 956.3543 (MH+, calcd for
(yield 75.2%)
½
a 2D5
ꢂ
ꢁ76.1 (c 0.46, CHCl3); IR (KBr) 3447, 2934, 2808, 2250w,
1761, 1748, 1655, 1518, 1501, 1487, 1458, 1447, 1429, 1414,
1375, 1319, 1260, 1194, 1109, 1086, 1070, 1028 cmꢁ1 1H NMR
;
(CDCl3, 500 MHz, this compound was a mixture of rotational iso-
mers, ratio 7:3, and only the signals of major isomer are presented)
d 9.04 (7/10H, d, J = 2.5 Hz, 200-H), 8.76 (7/10H, br d, J = 6.2 Hz, 400-
H), 8.21 (7/10H, d, J = 8.2 Hz, 800-H), 7.77 (7/10H, dd, J = 8.2,
7.1 Hz, 700-H), 7.60 (7/10H, d, J = 2.5 Hz, 300-H), 7.51 (7/10H, d,
J = 7.1 Hz, 600-H), 6.43 (7/10H, s, 80-H), 6.33 (7/10H, s, 50-H), 6.18
(7/10H, br s, 15-H), 6.10 (7/10H, d, J = 1.1 Hz, OCHO), 6.06 (7/
10H, ddd, J = 17.0, 10.4, 5.8 Hz, 18-OCH2CH@CH2), 6.02 (7/10H, d,
J = 1.1 Hz, OCHO), 5.98 (7/10H, ddd, J = 17.3, 10.5, 5.4 Hz, 60-
OCH2CH@CH2), 5.44 (7/10H, d, J = 17.0 Hz, 18-OCH2CH@CH2),
5.32 (7/10H, dd, J = 17.3, 1.2 Hz, 60-OCH2CH@CH2), 5.23 (7/5H, d,
J = 10.4, 1.2 Hz, 18-OCH2CH@CH2 and 60-OCH2CH@CH2), 4.77 (1H,
dd, J = 12.8, 5.3 Hz, 18-OCHCH), 4.68 (7/10H, br s, 4-H), 4.64 (7/
10H, br, 22-H), 4.48 (7/5H, d, J = 5.4 Hz, 60-OCH2CH), 4.46 (7/10H,
br, 22-H), 4.41 (7/10H, s, 1-H), 4.29 (7/10H, dd, J = 12.8, 5.3 Hz,
C52H54N5O11S, 956.3541), CD De nm (c 10.0 lM, methanol, 23 °C)
ꢁ81.6 (210), ꢁ128.5 (217), 0 (242), 20.7 (253), 0 (282), ꢁ9.4
(292), 0 (309).

4430
P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
18-OCHCH), 4.24 (7/10H, d, J = 4.3 Hz, 11-H), 4.17 (7/10H, br s, 21-
H), 3.76 (21/10H, s, 17-OCH3), 3.66 (21/10H, s, 70-OCH3), 3.60 (7/
10H, br, 3-H), 3.54 (7/10H, br, 120-H), 3.47 (7/10H, br, 13-H), 3.27
(7/5H, br t, 30-H2), 2.97 (7/5H, br d, J = 7.6 Hz, 14-H2), 2.56 (7/
10H, br, 120-H), 2.39 (7/10H, dd, J = 15.8, 5.7 Hz, 40-H), 2.31 (21/
10H, s, OCOCH3), 2.28 (7/10H, m, 40-H), 2.13 (21/10H, s, NCH3),
2.06 (21/10H, s, 6-CH3), 1.41 (21/10H, s, 16-CH3); 13C NMR (CDCl3,
125 MHz) d 169.5 (10-CO), 168.9 (NCO), 168.3 (5-OCO), 150.7 (C-
200), 150.4 (C-18), 148.6 (C-17), 147.7 (C-500), 147.5 (C-70), 147.3
(C-60), 145.5 (C-7), 141.4 (C-5), 141.2 (C-8), 135.5 (C-900), 135.1
(C-400), 134.7 (18-OCH2CH@CH2), 133.0 (60-OCH2CH@CH2), 131.2
(C-800), 130.8 (C-16), 129.4 (C-20), 128.9 (C-700), 127.9 (C-90),
126.5 (C-600), 126.1 (C-100), 125.2 (C-15), 125.0 (C-1000), 124.3 (C-
19), 122.6 (C-10), 122.1 (C-300), 118.2 (21-CN), 117.9 (60-
OCH2CH@CH2), 116.7 (18-OCH2CH@CH2), 113.6 (C-9), 112.7 (C-
6), 112.5 (C-50), 111.3 (C-80), 102.1 (OCH2O), 72.9 (18-OCH2CH),
70.0 (C-10), 69.6 (60-OCH2CH), 61.5 (C-22), 61.4 (C-3), 60.4 (C-1),
60.0 (C-21), 59.3 (17-OCH3), 55.4 (C-11), 55.3 (70-OCH3), 54.9 (C-
13), 45.2 (C-30), 42.1 (C-4), 41.8 (NCH3), 40.0 (C-120), 29.6 (C-40),
25.0 (C-14), 20.3 (COCH3), 15.0 (16-CH3), 9.8 (6-CH3); FABMS m/z
1006 (MH+); HRFABMS m/z 1006.3702 (MH+, calcd for
nol, 21 °C) ꢁ33.3 (210), ꢁ53.5 (216), 0 (245), 6.6 (256), 0 (281),
ꢁ3.6 (293), 0 (299), 0.9 (311), 0 (327).
5.3.9. 18, 60-O-Bisallyl-20-N-400-bromobenzoyl Et 770 6i (yield
84.5%)
½
a 1D6
ꢂ
ꢁ38.2 (c 0.45, CHCl3); IR (KBr) 3470, 2961, 2928, 2854,
2250w, 1763, 1746, 1659, 1520, 1462, 1445, 1432, 1412, 1396,
1375, 1260, 1234, 1194, 1175, 1142, 1107, 1086, 1069, 1028,
1013, 802 cmꢁ1
; d 7.60 (2H, d,
1H NMR (CDCl3, 400 MHz)
J = 8.4 Hz, 300-H), 7.35 (2H, d, J = 8.4 Hz, 200-H), 6.55 (1H, br s, 15-
H), 6.53 (1H, br s, 80-H), 6.34 (1H, s, 50-H), 6.09 (1H, d, J = 1.2 Hz,
OCHO), 6.07 (1H, ddd, J = 16.9, 10.7, 5.1 Hz, 18-OCH2CH@CH2),
6.01 (1H, d, J = 1.2 Hz, OCHO), 5.98 (1H, ddd, J = 17.3, 10.5, 5.4 Hz,
60-OCH2CH@CH2), 5.43 (1H, dd, J = 16.9, 1.6 Hz, 18-OCH2CH@CH2),
5.32 (1H, dd, J = 17.3, 1.6 Hz, 60-OCH2CH@CH2), 5.22 (2H, dd,
J = 10.8, 1.4 Hz 18-OCH2CH@CH2 and 60-OCH2CH@CH2), 4.78 (1H,
dd, J = 12.8, 5.2 Hz, 18-OCHCH), 4.62 (1H, br s, 22-H), 4.51 (1H, br
s, 4-H), 4.51 (1H, br s, 22-H), 4.48 (2H, d, J = 5.6 Hz, 60-OCH2CH),
4.32 (1H, s, 1-H), 4.29 (1H, dd, J = 12.8, 5.2 Hz, 18-OCHCH), 4.22
(1H, d, J = 5.2 Hz, 11-H), 4.11 (1H, d, J = 2.0 Hz, 21-H), 3.71 (3H, s,
17-OCH3), 3.65 (3H, s, 70-OCH3), 3.60 (1H, dd, J = 9.0, 4.4 Hz, 3-H),
3.57 (1H, d, J = 15.4 Hz, 120-H), 3.50 (2H, t, J = 5.6 Hz, 30-H2), 3.45
(1H, dd, J = 9.6, 2.0 Hz, 13-H), 2.98 (1H, dd, J = 17.2, 9.6 Hz, 14-
C56H56N5O11S, 1006.3697), CD De nm (c 10.0 lM, methanol,
21 °C) ꢁ45.8 (210), ꢁ82.9 (217), 0 (238), 12.9 (252), 0 (275),
ꢁ5.7 (293), 0 (306), 1.2 (304), 0 (320).
Ha
), 2.82 (1H, d, J = 17.2 Hz, 14-Hb), 2.39 (1H, m, 40-H), 2.36 (1H,
d, J = 15.4 Hz, 120-H), 2.32 (1H, m, 40-H), 2.29 (3H, s, OCOCH3),
2.13 (3H, s, NCH3), 2.04 (3H, s, 6-CH3), 1.82 (3H, s, 16-CH3); 13C
NMR (CDCl3, 100 MHz) d 171.4 (NCO), 169.2 (10-CO), 168.9 (5-
OCO), 150.3 (C-18), 148.5 (C-17), 147.2 (C-70), 146.9 (C-60), 145.4
(C-7), 141.2 (C-8), 141.0 (C-5), 135.6 (C-100), 134.5 (18-
OCH2CH@CH2), 132.9 (60-OCH2CH@CH2), 131.5 (C-300), 131.1 (C-
16), 129.9 (C-20), 129.9 (C-200), 127.9 (C-90), 125.6 (C-100), 125.6
(C-15), 124.5 (C-400), 124.4 (C-19), 122.1 (C-10), 118.0 (60-
OCH2CH@CH2), 117.8 (21-CN), 116.7 (18-OCH2CH@CH2), 113.0
(C-9), 112.7 (C-50), 112.5 (C-6), 111.1 (C-80), 102.0 (OCH2O), 73.0
(18-OCH2CH), 69.6 (60-OCH2CH), 68.9 (C-10), 61.0 (C-3), 60.5 (C-
22), 60.4 (C-1), 59.6 (C-21), 59.4 (17-OCH3), 55.5 (C-11), 55.2 (70-
OCH3), 54.9 (C-13), 45.7 (C-30), 42.0 (C-4), 41.9 (NCH3), 39.5 (C-
120), 29.2 (C-40), 25.1 (C-14), 20.4 (COCH3), 15.8 (16-CH3), 9.9 (6-
CH3); FABMS m/z 1033 (MH+); HRFABMS m/z 1033.2697 (MH+,
5.3.8. 18, 60-O-Bisallyl-20-N-600-quinolinecarbonyl Et 770 6h
(yield 88.4%)
½
a 2D5
ꢂ
ꢁ58.1 (c 0.47, CHCl3); IR (KBr) 3447, 2934, 2250w, 1761,
1749, 1655, 1518, 1508, 1487, 1458, 1447, 1429, 1375, 1319,
1260, 1234, 1194, 1132, 1107, 1086, 1049, 1028, 999, 914,
;
787 cmꢁ1 1H NMR (CDCl3, 500 MHz) d 9.03 (1H, dd, J = 4.7,
1.7 Hz, 200-H), 8.29 (1H, dd, J = 8.2, 1.7 Hz, 400-H), 8.27 (1H, dd,
J = 8.5, 1.4 Hz, 800-H), 8.01 (1H, d, J = 1.4 Hz, 500-H), 7.82 (1H, dd,
J = 8.5, 1.4 Hz, 700-H), 7.53 (1H, dd, J = 8.2, 4.5 Hz, 300-H), 6.54 (2H,
br s, 80-H and 15-H), 6.35 (1H, s, 50-H), 6.10 (1H, d, J = 1.3 Hz,
OCHO), 6.06 (1H, ddd, J = 17.0, 10.5, 5.4 Hz, 18-OCH2CH@CH2),
6.02 (1H, d, J = 1.3 Hz, OCHO), 5.98 (1H, ddd, J = 17.3, 10.5, 5.4 Hz,
60-OCH2CH@CH2), 5.43 (1H, dd, J = 17.0, 1.4 Hz, 18-OCH2CH@CH2),
5.32 (1H, dd, J = 17.3, 1.4 Hz, 60-OCH2CH@CH2), 5.22 (2H, d, J = 10.4,
1.4 Hz, 18-OCH2CH@CH2 and 60-OCH2CH@CH2), 4.76 (1H, dt,
J = 12.7, 5.1 Hz, 18-OCHCH), 4.65 (1H, br s, 4-H), 4.58 (1H, br, 22-
H), 4.52 (1H, br, 22-H), 4.49 (2H, dt, J = 5.4, 1.4 Hz, 60-OCH2CH),
4.36 (1H, s, 1-H), 4.28 (1H, ddd, J = 12.7, 5.4, 1.4 Hz, 18-OCHCH),
4.23 (1H, dd, J = 5.3, 1.3 Hz, 11-H), 4.16 (1H, br s, 21-H), 3.74 (3H,
s, 17-OCH3), 3.70 (3H, s, 70-OCH3), 3.65 (1H, d, J = 15.8 Hz, 120-H),
3.64 (1H, br d, J = 15.8 Hz, 30-H), 3.60 (1H, d, J = 5.1 Hz, 3-H), 3.52
(1H, m, 30-H), 3.47 (1H, d, J = 8.8 Hz, 13-H), 3.02 (1H, dd, J = 17.3,
calcd for C53H54N4O11SBr, 1033.2693), CD De nm (c 60.0 lM, meth-
anol, 23 °C) ꢁ99.1 (210), ꢁ149.8 (216), 0 (243), 19.9 (254), 0 (282),
ꢁ7.7 (292), 0 (325).
5.3.10. 18, 60-O-Bisallyl-20-N-200-bromobenzoyl Et 770 6j (yield
29.0%)
½
a 2D2
ꢂ
ꢁ57.5 (c 0.34, CHCl3); IR (KBr) 3446, 2932, 2250w, 1761,
1668, 1518, 1458, 1430, 1396, 1261, 1194, 1148, 1109, 1086,
1028, 999, 920 cmꢁ1 1H NMR (CDCl3, 500 MHz) d 7.57 (1H, d,
9.3 Hz, 14-Ha), 2.91 (1H, d, J = 17.3 Hz, 14-Hb), 2.46 (1H, ddd,
;
J = 16.2, 8.5, 6.0 Hz, 40-H), 2.46 (1H, m, 120-H, signals overlapped
with 40-H), 2.36 (1H, dt, J = 16.2, 4.3 Hz, 40-H), 2.31 (3H, s, OCOCH3),
2.13 (3H, s, NCH3), 2.05 (3H, s, 6-CH3), 1.49 (3H, s, 16-CH3); 13C
NMR (CDCl3, 125 MHz) d 171.6 (NCO), 169.5 (10-CO), 168.3 (5-
OCO), 151.3 (C-200), 150.4 (C-18), 148.6 (C-17), 148.5 (C-900), 147.4
(C-70), 147.1 (C-60), 145.5 (C-7), 141.3 (C-8), 141.3 (C-5), 137.0
(C-400), 135.5 (C-600), 134.7 (18-OCH2CH@CH2), 133.1 (60-
OCH2CH@CH2), 131.2 (C-16), 130.0 (C-20), 129.2 (C-800), 129.2 (C-
700), 128.4 (C-500), 128.1 (C-90), 127.9 (C-1000), 125.9 (C-100), 124.5
(C-19), 124.4 (C-15), 122.3 (C-10), 121.8 (C-300), 118.2 (21-CN),
117.9 (60-OCH2CH@CH2), 116.8 (18-OCH2CH@CH2), 113.2 (C-9),
112.8 (C-6), 112.8 (C-50), 111.3 (C-80), 102.1 (OCH2O), 72.9 (18-
OCH2CH), 69.6 (C-10), 69.6 (60-OCH2CH), 60.9 (C-3), 60.5 (C-22),
60.5 (C-1), 59.5 (C-21), 59.4 (17-OCH3), 55.4 (C-11), 55.2 (70-
OCH3), 54.8 (C-13), 45.8 (C-30), 42.0 (C-4), 41.8 (NCH3), 39.3 (C-
120), 29.1 (C-40), 24.9 (C-14), 20.2 (COCH3), 15.3 (16-CH3), 9.7 (6-
CH3); FABMS m/z 1006 (MH+); HRFABMS m/z 1006.3693 (MH+,
J = 7.4 Hz, 300-H), 7.44 (1H, t, J = 7.4 Hz, 400-H), 7.33 (1H, d,
J = 7.4 Hz, 600-H), 7.27 (1H, t, J = 7.4 Hz, 200-H), 6.58 (1H, br s, 15-
H), 6.37 (1H, s, 80-H), 6.37 (1H, s, 50-H), 6.08 (1H, d, J = 0.8 Hz,
OCHO), 6.07 (1H, ddd, J = 17.0, 10.5, 5.4 Hz, 18-OCH2CH@CH2),
5.99 (1H, d, J = 0.8 Hz, OCHO), 5.99 (1H, ddd, J = 17.3, 10.5, 5.1 Hz,
60-OCH2CH@CH2), 5.43 (1H, br d, J = 17.0 Hz, 18-OCH2CH@CH2),
5.32 (1H, dd, J = 17.3, 1.3 Hz, 60-OCH2CH@CH2), 5.22 (2H, dd,
J = 10.7, 1.3 Hz, 18-OCH2CH@CH2 and 60-OCH2CH@CH2), 4.80 (1H,
dd, J = 12.7, 5.1 Hz, 18-OCHCH), 4.76 (1H, d, J = 11.4 Hz, 22-H),
4.64 (1H, br s, 4-H), 4.49 (2H, dd, J = 5.5, 1.4 Hz, 60-OCH2CH), 4.40
(1H, s, 1-H), 4.32 (1H, dd, J = 12.7, 5.2 Hz, 18-OCHCH), 4.30 (1H,
d, J = 5.2 Hz, 11-H), 4.23 (1H, d, J = 11.4 Hz, 22-H), 4.22 (1H, s, 21-
H), 3.77 (1H, d, J = 15.3 Hz, 120-H), 3.76 (3H, s, 17-OCH3), 3.63
(3H, s, 70-OCH3), 3.55 (1H, dd, J = 9.6, 2.0 Hz, 13-H), 3.60 (1H, dd,
J = 9.0, 4.4 Hz, 3-H), 3.47 (1H, ddd, J = 14.2, 5.4, 3.1 Hz, 30-H), 3.28
(1H, ddd, J = 14.2, 10.9, 4.2 Hz, 30-H), 2.99 (2H, br s, 14-H2),
2.78(1H, ddd, J = 16.0, 10.9, 5.6 Hz, 40-H), 2.57 (1H, d, J = 15.3 Hz,
120-H), 2.34 (1H, m, 40-H), 2.30 (3H, s, OCOCH3), 2.18 (3H, s,
calcd for C56H56N5O11S, 1006.3697), CD De nm (c 10.0 lM, metha-

P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
4431
NCH3), 2.05 (3H, s, 6-CH3), 1.77 (3H, s, 16-CH3); 13C NMR (CDCl3,
125 MHz) d 169.2 (10-CO), 168.3 (NCO), 168.2 (5-OCO), 150.4 (C-
18), 148.9 (C-17), 147.3 (C-70), 147.2 (C-60), 145.5 (C-7), 141.5 (C-
5), 141.0 (C-8), 139.3 (C-100), 134.6 (18-OCH2CH@CH2), 133.2 (C-
300), 133.1 (60-OCH2CH@CH2), 131.9 (C-16), 129.9 (C-400), 129.3 (C-
20), 128.9 (C-600), 127.9 (C-90), 127.4 (C-500), 126.8 (C-100), 124.6
(C-15), 123.8 (C-19), 122.5 (C-10), 119.9 (C-200), 117.9 (60-
OCH2CH@CH2), 117.9 (21-CN), 117.0 (18-OCH2CH@CH2), 113.3
(C-9), 113.1 (C-6), 112.6 (C-50), 111.4 (C-80), 102.0 (OCH2O), 72.9
(18-OCH2CH), 70.9 (C-10), 69.6 (60-OCH2CH), 61.0 (C-3), 60.7 (C-
22), 60.7 (C-1), 59.7 (17-OCH3), 59.4 (C-21), 55.6 (C-11), 55.3 (70-
OCH3), 54.9 (C-13), 46.0 (C-30), 42.2 (C-4), 41.8 (NCH3), 38.8 (C-
120), 29.8 (C-40), 25.3 (C-14), 20.3 (COCH3), 15.8 (16-CH3), 9.8 (6-
CH3); FABMS m/z 1033 (MH+); HRFABMS m/z 1033.2693 (MH+,
residue. Chromatography on a silica gel column with hexane–ethyl
acetate (2:1) gave 7b (7.3 mg, 49.7%) as a colorless amorphous
powder. ½a 2D8
ꢁ25.0 (c 0.43, CHCl3); IR (KBr) 3524, 3447, 2936,
ꢂ
2250w, 1749, 1653, 1522, 1508, 1456, 1348, 1260, 1234, 1198,
;
1107, 1086 cmꢁ1 1H NMR (CDCl3, 500 MHz) d 8.32 (2H, d,
J = 8.7 Hz, 300-H), 7.58 (2H, d, J = 8.4 Hz, 200-H), 6.45 (1H, br s, 80-
H), 6.43 (1H, s, 50-H), 6.36 (1H, br s, 15-H), 6.10 (1H, d, J = 1.3 Hz,
OCHO), 6.00 (1H, d, J = 1.3 Hz, OCHO), 5.74 (1H, br s, 18-OH),
5.50 (1H, s, 60-OH), 4.70 (1H, br s, 4-H), 4.59 (1H, br d, J = 9.9 Hz,
22-H), 4.47 (1H, br d, J = 9.9 Hz, 22-H), 4.38 (1H, s, 1-H), 4.33
(1H, br s, 11-H), 4.19 (1H, br s, 21-H), 3.69 (3H, s, 17-OCH3), 3.64
(3H, s, 70-OCH3), 3.63 (2H, br, 3-H and 13-H, signals overlapped
with 70-OCH3), 3.59 (1H, d, J = 15.3 Hz, 120-H), 3.41 (3H, m, 30-
H2), 3.03 (1H, dd, J = 16.9, 9.6 Hz, 14-Ha), 2.89 (1H, d, J = 16.9 Hz,
calcd for C53H54N4O11SBr, 1033.2693), CD
D
e
nm (c 60.0
lM, meth-
14-Hb), 2.46 (1H, dd, J = 16.2, 8.2 Hz, 40-H), 2.37 (1H, dt, J = 16.2,
4.8 Hz, 40-H), 2.36 (1H, br d, J = 15.3 Hz, 120-H), 2.33 (3H, s,
OCOCH3), 2.18 (3H, s, NCH3), 2.05 (3H, s, 6-CH3), 1.75 (3H, s, 16-
anol, 23 °C) ꢁ22.2 (210), ꢁ54.0 (216), 0 (242), 8.3 (252), 0 (278),
ꢁ75.2 (293), 0 (315).
13
CH3); C NMR (CDCl3, 125 MHz) d 169.8 (NCO), 169.3 (10-CO),
5.3.11. N-Benzoyl derivative of Et 770 7a
Tributyltin hydride (0.064 mL, 0.237 mmol) was added drop-
wise over 10 min to a vigorously stirred solution of 6a (13.7 mg,
168.4 (5-OCO), 148.6 (C-400), 147.7 (C-18), 145.6 (C-7), 145.0 (C-
70), 144.9 (C-60), 143.2 (C-17), 143.2 (C-100), 141.3 (C-8), 141.3 (C-
5), 130.3 (C-20), 129.4 (C-16), 128.9 (C-200), 126.9 (C-90), 126.4 (C-
100), 123.8 (C-300), 122.0 (C-10), 120.7 (C-15), 117.9 (C-19), 117.9
(21-CN), 113.8 (C-50), 113.1 (C-9), 112.8 (C-6), 111.3 (C-80), 102.1
(OCH2O), 69.6 (C-10), 61.0 (C-22), 60.8 (C-3), 60.3 (C-1), 60.1 (17-
OCH3), 59.6 (C-21), 55.3 (70-OCH3), 55.1 (C-11), 54.7 (C-13), 45.8
(C-30), 41.9 (C-4), 41.7 (NCH3), 39.2 (C-120), 28.9 (C-40), 25.2 (C-
14), 20.4 (COCH3), 15.7 (16-CH3), 9.8 (6-CH3); FABMS m/z 920
(MH+); HRFABMS m/z 920.2812 (MH+, calcd for C47H45N5O13S,
14.4 lmol), (Ph3P)2PdCl2 (6.0 mg, 8.6 lmol), and AcOH (0.03 mL,
0.54 mmol) in THF (4 mL) at 25 °C, and the mixture was stirred
for 1 h at 25 °C. The mixture was diluted with water (10 mL), made
alkaline with 5% aqueous NaHCO3, and extracted with chloroform
(30 mL ꢀ 3). The combined extracts were washed with 5% aqueous
NaHCO3, dried, and concentrated in vacuo to give a residue. Chro-
matography on a silica gel column with benzene–ethyl acetate
(6:1) gave 7a (6.4 mg, 51.0%) as a colorless amorphous powder.
920.2813), CD
D
e
nm (c 11.4
l
M, methanol, 23 °C) ꢁ18.7 (210),
½
a 2D8
ꢂ
+2.0 (c 0.33, CHCl3); IR (KBr) 3447, 2926, 2853, 2361, 2344,
1749, 1653, 1508, 1456, 1447, 1431, 1375, 1258, 1234, 1196,
1109, 1085 cmꢁ1 1H NMR (CDCl3, 500 MHz) d 7.43 (5H, m, ArH),
ꢁ32.4 (217), 0 (247), 1.5 (252), 0 (263), ꢁ3.6 (288), 0 (325).
;
5.3.13. N-300-Nitrobenzoyl derivative of Et 770 7c
6.59 (1H, br s, 80-H), 6.41 (1H, br s, 15-H), 6.41 (1H, s, 50-H), 6.10
(1H, s, OCHO), 6.01 (1H, s, OCHO), 5.78 (1H, s, 18-OH), 5.49 (1H,
s, 60-OH), 4.68 (2H, br s, 4-H and 22-H), 4.42 (2H, br s, 22-H and
11-H), 4.36 (1H, s, 1-H), 4.28 (1H, br s, 21-H), 3.76 (3H, s, 17-
OCH3), 3.76 (1H, br, 3-H, signals overlapped with 17-OCH3), 3.70
(3H, s, 70-OCH3), 3.65 (1H, br, 13-H, signals overlapped with 70-
OCH3), 3.58 (1H, d, J = 15.3 Hz, 120-H), 3.51 (1H, m, 30-H), 3.42
Tributyltin hydride (58
over 10 min to a vigorously stirred solution of 6c (13.0 mg,
13.0 mol), (Ph3P)2PdCl2 (5.5 mg, 7.8 mol), and AcOH (30 L,
lL, 0.215 mmol) was added dropwise
l
l
l
0.49 mmol) in THF (3.5 mL) at 25 °C, and the mixture was stirred
for 1 h at 25 °C. The mixture was diluted with water (10 mL), made
alkaline with 5% aqueous NaHCO3, and extracted with chloroform
(30 mL ꢀ 3). The combined extracts were washed with 5% aqueous
NaHCO3, dried, and concentrated in vacuo to give a residue. Chro-
matography on a silica gel column with benzene–ethyl acetate
(5:1) gave 7c (5.8 mg, 48.7%) as a colorless amorphous powder.
(1H, m, 30-H), 3.00 (1H, dd, J = 17.3, 9.5 Hz, 14-H
a), 2.83 (1H, d,
J = 17.3 Hz, 14-Hb), 2.40 (2H, m, 40-H), 2.36 (1H, m, 120-H), 2.32
(3H, s, OCOCH3), 2.27 (3H, s, NCH3), 2.03 (3H, s, 6-CH3), 1.81 (3H,
s, 16-CH3); C NMR (CDCl3, 100 MHz) d 172.9 (NCO), 169.8 (10-
½
a 2D8
ꢂ
ꢁ13.9 (c 0.42, CHCl3); IR (KBr) 3524, 3447, 2934, 2250w,
1749, 1653, 1533, 1508, 1458, 1437, 1396, 1375, 1350, 1254,
1234, 1198, 1150, 1109, 1086, 1062, 1028 cmꢁ1 1H NMR (CDCl3,
13
CO), 168.3 (5-OCO), 147.6 (C-18), 145.6 (C-7), 144.8 (C-70), 144.7
(C-60), 143.7 (C-17), 141.6 (C-8), 141.1 (C-5), 136.9 (C-100), 130.2
(C-400), 128.8 (C-16), 128.5 (C-20), 128.3 (C-300), 128.2 (C-200),
127.5 (C-90), 126.6 (C-100), 122.8 (C-10), 120.9 (C-15), 117.6 (C-
19), 117.6 (21-CN), 113.9 (C-50), 112.8 (C-9), 112.7 (C-6), 111.0
(C-80), 102.3 (OCH2O), 68.6 (C-10), 60.6 (C-1), 60.6 (C-22), 60.2
(17-OCH3), 59.4 (C-21), 59.4 (C-3), 59.3 (70-OCH3), 55.2 (C-11),
54.8 (C-13), 45.6 (C-30), 41.5 (C-4), 41.5 (NCH3), 39.7 (C-120), 28.8
(C-40), 25.6 (C-14), 20.4 (COCH3), 15.2 (16-CH3), 9.8 (6-CH3); FAB-
MS m/z 875 (MH+); HRFABMS m/z 875.2964 (MH+, calcd for
;
500 MHz) d 8.37 (1H, ddd, J = 8.3, 2.3, 1.2 Hz, 400-H), 8.31 (1H, dd,
J = 2.3, 1.2 Hz, 200-H), 7.77 (1H, dt, J = 7.8, 1.2 Hz, C-500), 7.67 (1H,
dd, J = 8.3, 7.6 Hz, 500-H), 6.44 (1H, br s, 80-H), 6.43 (1H, s, 50-H),
6.22 (1H, br s, 15-H), 6.10 (1H, d, J = 1.3 Hz, OCHO), 6.00 (1H, d,
J = 1.3 Hz, OCHO), 5.74 (1H, s, 18-OH), 5.51 (1H, s, 60-OH), 4.72
(1H, br s, 4-H), 4.67 (1H, br d, J = 10.9 Hz, 22-H), 4.47 (1H, br d,
J = 10.9 Hz, 22-H), 4.41 (1H, s, 1-H), 4.35 (1H, br s, 11-H), 4.27
(1H, br s, 21-H), 3.70 (3H, s, 17-OCH3), 3.70 (1H, d, J = 15.3 Hz,
120-H), 3.56 (1H, d, J = 5.2 Hz, 3-H), 3.61 (3H, s, 70-OCH3), 3.61
(1H, br, 13-H, signals overlapped with 70-OCH3), 3.52 (1H, ddd,
J = 14.4, 6.0, 4.0 Hz, 30-H), 3.40 (1H, ddd, J = 14.4, 10.2, 4.0 Hz, 30-
C47H47N4O11S, 875.2962), CD De nm (c 11.4 lM, methanol, 23 °C)
ꢁ60.9 (210), ꢁ71.9 (217), 0 (242), 11.0 (254), 0 (271), ꢁ8.6 (287),
0 (311).
H), 3.06 (1H, dd, J = 17.3, 7.4 Hz, 14-Ha), 2.97 (1H, d, J = 17.3 Hz,
5.3.12. N-400-Nitrobenzoyl derivative of Et 770 7b
Tributyltin hydride (0.07 mL, 0.264 mmol) was added dropwise
over 10 min to a vigorously stirred solution of 6b (16.0 mg,
14-Hb), 2.57 (1H, br d, J = 15.3 Hz, 120-H), 2.48 (1H, ddd, J = 16.2,
10.2, 6.40 Hz, 40-H), 2.35 (1H, dt, J = 16.2, 4.0, 40-H), 2.34 (3H, s,
OCOCH3), 2.20 (3H, s, NCH3), 2.05 (3H, s, 6-CH3), 1.53 (3H, s, 16-
13
16.0
l
mol), (Ph3P)2PdCl2 (6.7 mg, 9.6
lmol), and AcOH (34
lL,
CH3); C NMR (CDCl3, 100 MHz) d 169.6 (10-CO), 169.4 (NCO),
0.38 mmol) in THF (4 mL) at 25 °C, and the mixture was stirred
for 30 min at 25 °C. The mixture was diluted with water (10 mL),
made alkaline with 5% aqueous NaHCO3, and extracted with chlo-
roform (30 mL ꢀ 3). The combined extracts were washed with 5%
aqueous NaHCO3, dried, and concentrated in vacuo to give a
168.3 (5-OCO), 148.1 (C-300), 147.6 (C-18), 145.6 (C-17), 145.0 (C-
70), 144.9 (C-60), 143.1 (C-7), 141.3 (C-5), 141.3 (C-8), 139.0
(C-100), 134.0 (C-600), 130.1 (C-20), 129.8 (C-16), 129.7 (C-500),
126.9 (C-90), 126.5 (C-100), 124.8 (C-400), 123.2 (C-200), 122.2 (C-
10), 120.5 (C-15), 117.8 (21-CN), 117.8 (C-19), 113.7 (C-50), 113.1

4432
P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
(C-9), 112.9 (C-6), 110.3 (C-80), 102.8 (OCH2O), 70.4 (C-10), 60.8 (C-
22), 60.8 (C-3), 60.5 (C-1), 60.1 (17-OCH3), 59.3 (C-21), 55.4 (70-
OCH3), 55.0 (C-11), 54.8 (C-13), 46.6 (C-30), 41.9 (C-4), 41.6
(NCH3), 38.7 (C-120), 28.8 (C-40), 25.1 (C-14), 20.4 (COCH3), 15.2
(16-CH3), 9.9 (6-CH3); FABMS m/z 920 (MH+); HRFABMS m/z
1684, 1653, 1636, 1558, 1541, 1522, 1508, 1456, 1418, 1375,
1304, 1260, 1234, 1148, 1109, 1086 cmꢁ1 1H NMR (CDCl3,
;
500 MHz) d 8.76 (1H, dd, J = 5.1, 1.7 Hz, 600-H), 8.70 (1H, d,
J = 1.4 Hz, 200-H), 7.79 (1H, d, J = 7.6 Hz, 400-H), 7.43 (1H, dd,
J = 7.6, 5.1 Hz, 500-H), 6.52 (1H, br s, 80-H), 6.43 (1H, s, 15-H), 6.43
(1H, s, 50-H), 6.10 (1H, d, J = 1.3 Hz, OCHO), 6.00 (1H, d, J = 1.3 Hz,
OCHO), 5.74 (1H, br s, 18-OH), 5.56 (1H, br s, 60-OH), 4.68 (1H, br
s, 4-H), 4.54 (2H, br s, 22-H2), 4.49 (2H, d, J = 5.4 Hz, 60-OCH2CH),
4.34 (1H, s, 1-H), 4.28 (1H, d, J = 4.3 Hz, 11-H), 4.14 (1H, br s, 21-
H), 3.70 (3H, s, 17-OCH3), 3.64 (3H, s, 70-OCH3), 3.60 (2H, br, 120-
H and 3-H), 3.47 (2H, br, 30-H2), 3.46 (1H, br d, J = 8.2 Hz, 13-H),
920.2812 (MH+, calcd for C47H45N5O13S, 920.2813), CD
10.8
De nm (c
l
M, methanol, 27 °C) ꢁ18.1 (210), ꢁ31.5 (218), 0 (242), 6.2
(253), 0 (274), ꢁ3.8 (291), 0 (314).
5.3.14. N-400-Pyridinecarbonyl derivative of Et 770 7d
Tributyltin hydride (71
over 10 min to a vigorously stirred solution of 6d (15.3 mg,
16.0 mol), (Ph3P)2PdCl2 (6.7 mg, 9.6 mol), and AcOH (34 L,
lL, 0.264 mmol) was added dropwise
3.00 (1H, dd, J = 17.6, 9.6 Hz, 14-Ha), 2.85 (1H, d, J = 17.6 Hz, 14-
l
l
l
Hb), 2.47 (1H, dd, J = 16.7, 7.3 Hz, 40-H), 2.42 (1H, m, 120-H), 2.38
(1H, dd, J = 16.7, 5.9 Hz, 40-H), 2.33 (3H, s, OCOCH3), 2.15 (3H, s,
NCH3), 2.04 (3H, s, 6-CH3), 1.74 (3H, s, 16-CH3); 13C NMR (CDCl3,
125 MHz) d 169.7 (NCO), 169.4 (10-CO), 168.3 (5-OCO), 150.5 (C-
600), 148.9 (C-200), 147.5 (C-18), 145.5 (C-7), 145.9 (C-60), 144.8 (C-
70), 143.0 (C-17), 141.4 (C-8), 141.2 (C-5), 136.3 (C-400), 133.1 (C-
300), 130.4 (C-20), 129.5 (C-16), 127.1 (C-90), 126.4 (C-100), 123.6
(C-500), 122.1 (C-10), 120.9 (C-15), 118.1 (21-CN), 117.6 (C-19),
113.9 (C-50), 113.1 (C-9), 112.7 (C-6), 111.3 (C-80), 102.1 (OCH2O),
69.5 (C-10), 60.7 (C-22), 60.9 (C-3), 60.3 (C-1), 60.1 (17-OCH3),
59.7 (C-21), 55.3 (70-OCH3), 54.9 (C-11), 54.7 (C-13), 46.1 (C-30),
41.9 (C-4), 41.7 (NCH3), 39.2 (C-120), 28.8 (C-40), 24.9 (C-14), 20.4
(COCH3), 15.3 (16-CH3), 9.8 (6-CH3); FABMS m/z 876 (MH+);
HRFABMS m/z 876.2922 (MH+, calcd for C46H45N5O11S, 876.2914),
0.60 mmol) in THF (4.0 mL) at 25 °C, and the mixture was stirred
for 1 h at 25 °C. The mixture was diluted with ethyl acetate
(10 mL) and extracted with 2 N aqueous HCl solution
(20 mL ꢀ 3). The combined extracts were made alkaline with satu-
rated Na2CO3, and extracted with chloroform (30 mL ꢀ 3). The
combined extracts were washed with brine, dried, and concen-
trated in vacuo to give a residue (14.4 mg). Chromatography on a
silica gel column with CH2Cl2–MeOH (50:1) gave 7d (12.1 mg,
86.4%) as a colorless amorphous powder. ½a D28
ꢁ43.3 (c 0.45,
ꢂ
CHCl3); IR (KBr) 3435, 2931, 2250w, 1751, 1655, 1595, 1516,
1458, 1418, 1375, 1304, 1260, 1234, 1198, 1148, 1109, 1086,
1065, 1028, 960 cmꢁ1 1H NMR (CDCl3, 500 MHz) d 8.76 (2H, d,
;
J = 5.5 Hz, 200-H), 7.33 (2H, d, J = 5.5 Hz, 300-H), 6.44 (1H, br s, 80-
H), 6.43 (1H, s, 50-H), 6.38 (1H, s, 15-H), 6.10 (1H, d, J = 1.2 Hz,
OCHO), 6.00 (1H, d, J = 1.2 Hz, OCHO), 5.75 (1H, s, 18-OH), 5.57
(1H, s, 60-OH), 4.69 (1H, br s, 4-H), 4.60 (1H, br d, J = 10.0 Hz, 22-
H), 4.43 (1H, br d, J = 10.0 Hz, 22-H), 4.36 (1H, s, 1-H), 4.27 (1H,
dd, J = 4.9, 1.2 Hz, 11-H), 4.19 (1H, d, J = 2.1 Hz, 21-H), 3.68 (3H,
s, 17-OCH3), 3.63 (3H, s, 70-OCH3), 3.58 (1H, br s, 3-H), 3.58 (1H,
br d, J = 16.8 Hz, 120-H), 3.46 (1H, br d, J = 10.3 Hz, 13-H), 3.43
(2H, dd, J = 9.5, 5.2 Hz, 30-H2), 2.99 (1H, dd, J = 17.3, 9.5 Hz, 14-
CD
D
e
nm (c 11.4
l
M, methanol, 23 °C) ꢁ44.1 (210), ꢁ70.8 (216),
0 (242), 11.4 (253), 0 (270), ꢁ18.7 (291), 0 (332).
5.3.16. N-400-Quinolinecarbonyl derivative of Et 770 7f
Tributyltin hydride (52
over 10 min to a vigorously stirred solution of 6f (11.7 mg,
11.6 mol), (Ph3P)2PdCl2 (4.9 mg, 7.0 mol), and AcOH (25 L,
lL, 0.191 mmol) was added dropwise
l
l
l
0.44 mmol) in THF (4.0 mL) at 25 °C, and the mixture was stirred
for 5 h at 25 °C. The mixture was diluted with ethyl acetate
(10 mL), and extracted with 2 N aqueous HCl solution
(20 mL ꢀ 3). The combined extracts were made alkaline with satu-
rated Na2CO3, and extracted with chloroform (30 mL ꢀ 3). The
combined extracts were washed with brine, dried, and concen-
trated in vacuo to give a residue (9.5 mg). Chromatography on a sil-
ica gel column with CH2Cl2–MeOH (60:1) gave 7f (7.0 mg, 65.0%)
Ha), 2.85 (1H, d, J = 17.3 Hz, 14-Hb), 2.47 (1H, dd, J = 16.5, 7.6 Hz,
40-H), 2.37 (1H, dd, J = 16.5, 10.0 Hz, 40-H), 2.37 (1H, br d,
J = 16.8 Hz, 120-H), 2.33 (3H, s, OCOCH3), 2.13 (3H, s, NCH3), 2.05
(3H, s, 6-CH3), 1.80 (3H, s, 16-CH3); 13C NMR (CDCl3, 125 MHz) d
169.4 (NCO), 169.1 (10-CO), 168.3 (5-OCO), 150.0 (C-200), 147.6 (C-
18), 145.5 (C-7), 145.2 (C-400), 145.0 (C-60), 144.9 (C-70), 143.1 (C-
17), 141.3 (C-5), 141.2 (C-8), 130.5 (C-20), 129.2 (C-16), 126.9 (C-
90), 126.6 (C-100), 122.2 (C-10), 122.1 (C-300), 120.8 (C-15), 118.1
(21-CN), 118.0 (C-19), 113.8 (C-50), 113.3 (C-9), 112.7 (C-6), 111.3
(C-80), 102.1 (OCH2O), 69.8 (C-10), 60.9 (C-3), 60.9 (C-22), 60.4 (C-
1), 60.1 (17-OCH3), 59.8 (C-21), 55.3 (70-OCH3), 55.0 (C-11), 54.8
(C-13), 45.6 (C-30), 42.0 (C-4), 41.7 (NCH3), 39.2 (C-120), 29.0 (C-
40), 25.0 (C-14), 20.4 (COCH3), 15.6 (16-CH3), 9.8 (6-CH3); FABMS
m/z 876 (MH+); HRFABMS m/z 876.2909 (MH+, calcd for
as a colorless amorphous powder. ½a D25
ꢁ65.7 (c 0.17, CHCl3); IR
ꢂ
(KBr) 3447, 2930, 2853, 2810, 2250w, 1749, 1655, 1508, 1431,
1420, 1375, 1261, 1194, 1107, 1086, 1063, 1028, 802 cmꢁ1 1H
;
NMR (CDCl3, 500 MHz, this compound was a mixture of rotational
isomers, ratio 7:3, and only the signals of major isomer are pre-
sented)
d
8.98 (7/10H, d, J = 4.2 Hz, 200-H), 8.36 (7/10H, d,
J = 7.7 Hz, 500-H), 8.25 (7/10H, d, J = 7.7 Hz, 800-H), 7.88 (7/10H, t,
J = 7.7 Hz, 700-H), 7.80 (7/10H, t, J = 7.7 Hz, 600-H), 7.26 (7/10H, d,
J = 4.3 Hz, 300-H), 6.43 (7/10H, s, 50-H), 6.35 (7/10H, br s, 80-H),
6.11 (7/10H, d, J = 0.8 Hz, OCHO), 6.03 (7/10H, br s, 15-H), 6.00
(7/10H, d, J = 0.8 Hz, OCHO), 5.75 (7/10H, s, 18-OH), 5.59 (7/10H,
br s, 60-OH), 4.77 (7/10H, d, J = 10.2 Hz, 22-H), 4.76 (7/10H, br s,
4-H), 4.44 (7/10H, s, 1-H), 4.34 (7/10H, d, J = 10.2 Hz, 22-H), 4.27
(7/10H, d, J = 4.5 Hz, 11-H), 4.19 (7/10H, br s, 21-H), 3.67 (21/
10H, s, 70-OCH3), 3.65 (21/10H, s, 170-OCH3), 3.58 (7/10H, br d,
J = 4.2 Hz, 3-H), 3.55 (7/10H, br d, J = 12.5 Hz, 120-H), 3.47 (7/10H,
br, 13-H), 3.25 (7/5H, m, 30-H2), 2.98 (7/5H, d, J = 8.3 Hz, 14-H2),
2.68 (7/10H, br d, J = 12.5 Hz, 120-H), 2.40 (7/10H, dd, J = 15.8,
5.7 Hz, 40-H), 2.35 (21/10H, s, OCOCH3), 2.30 (7/10H, dd, J = 15.8,
8.5 Hz, 40-H), 2.14 (21/10H, s, NCH3), 2.06 (21/10H, s, 6-CH3),
C46H45N5O11S, 876.2914), CD De nm (c 11.4 lM, methanol, 23 °C)
ꢁ68.3 (210), ꢁ123.9 (216), 0 (245), 17.3 (255), 0 (270), ꢁ16.5
(287), 0 (305).
5.3.15. N-300-Pyridinecarbonyl derivatives of Et 770 7e
Tributyltin hydride (73
over 10 min to a vigorously stirred solution of 6e (15.8 mg,
16.5 mol), (Ph3P)2PdCl2 (6.9 mg, 9.9 mol), and AcOH (35 L,
lL, 0.273 mmol) was added dropwise
l
l
l
0.62 mmol) in THF (4.0 mL) at 25 °C, and the mixture was stirred
for 1 h at 25 °C. The mixture was diluted with ethyl acetate
(10 mL), and extracted with 2 N aqueous HCl solution
(20 mL ꢀ 3). The combined extracts were made alkaline with satu-
rated Na2CO3, and extracted with chloroform (30 mL ꢀ 3). The
combined extracts were washed with brine, dried, and concen-
trated in vacuo to give a residue (16.4 mg). Chromatography on a
silica gel column with CH2Cl2–MeOH (60:1) gave 7e (12.7 mg,
13
1.35 (21/10H, s, 16-CH3); C NMR (CDCl3, 125 MHz) d 169.0 (10-
CO), 168.5 (5-OCO), 166.8 (NCO), 149.8 (C-200), 147.6 (C-900), 147.4
(C-18), 145.5 (C-7), 145.1 (C-70), 145.5 (C-400), 145.0 (C-60), 143.0
(C-17), 141.5 (C-5), 141.1 (C-8), 130.3 (C-600), 129.9 (C-20), 129.4
(C-800), 129.0 (C-16), 128.1 (C-700), 127.1 (C-90), 126.8 (C-100),
87.6%) as a colorless amorphous powder. ½a D28
ꢁ49.6 (c 0.45,
ꢂ
CHCl3); IR (KBr) 3447, 2934, 2250w, 1749, 1734, 1717, 1699,

P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
4433
126.6 (C-500), 123.8 (C-1000), 122.8 (C-10), 121.6 (C-15), 119.1 (C-300),
118.2 (21-CN), 117.7 (C-19), 113.8 (C-50), 113.6 (C-9), 112.6 (C-6),
110.4 (C-80), 102.0 (OCH2O), 70.8 (C-10), 61.6 (C-22), 61.3 (C-3),
60.4 (C-1), 60.1 (17-OCH3), 59.8 (C-21), 55.4 (70-OCH3), 55.0 (C-
11), 54.8 (C-13), 45.3 (C-30), 42.2 (C-4), 41.7 (NCH3), 39.8 (C-120),
29.6 (C-40), 25.0 (C-14), 20.4 (COCH3), 15.0 (16-CH3), 9.9 (6-CH3);
FABMS m/z 926 (MH+); HRFABMS m/z 926.3062 (MH+, calcd for
(20 mL ꢀ 3). The combined extracts were made alkaline with satu-
rated Na2CO3, and extracted with chloroform (30 mL ꢀ 3). The
combined extracts were washed with brine, dried, and concen-
trated in vacuo to give a residue (14.4 mg). Chromatography on a
silica gel column with hexane–ethyl acetate (3:7) gave 7h
(12.5 mg, 85.0%) as a colorless amorphous powder. ½a D25
ꢁ43.9 (c
ꢂ
0.44, CHCl3); IR (KBr) 3447, 2932, 2855, 2808, 2250w, 1749,
1734, 1653, 1624, 1593, 1516, 1508, 1458, 1449, 1429, 1420,
C50H48N5O11S, 926.3071), CD De nm (c 10.8 lM, methanol, 21 °C)
ꢁ9.8 (210), ꢁ36.1 (218), ꢁ18.0 (231), ꢁ14.2 (237), 0 (247), 4.8
1395, 1375, 1261, 1238, 1194, 1107, 1086, 1063, 1028 cmꢁ1 1H
;
(255), 0 (271), ꢁ5.0 (288), 0 (300), 1.2 (304), 0 (320).
NMR (500 MHz) d 9.02 (1H, dd, J = 4.3, 1.4 Hz, 200-H), 8.26 (1H,
dd, J = 8.5, 1.7 Hz, 400-H), 8.22 (1H, d, J = 8.5, 800-H), 7.97 (1H, d,
J = 1.4 Hz, 500-H), 7.65 (1H, dd, J = 8.5, 1.4 Hz, 700-H), 7.51 (1H, dd,
J = 8.5, 4.3 Hz, 300-H), 6.57 (1H, br s, 80-H), 6.42 (1H, s, 50-H), 6.36
(1H, s, 15-H), 6.11 (1H, d, J = 1.3 Hz, OCHO), 6.02 (1H, d,
J = 1.3 Hz, OCHO), 5.74 (1H, br s, 18-OH), 5.59 (1H, s, 60-OH), 4.68
(1H, br s, 4-H), 4.58 (1H, br, 22-H), 4.53 (1H, br, 22-H), 4.35 (1H,
s, 1-H), 4.26 (1H, dd, J = 4.8, 1.4 Hz, 11-H), 4.14 (1H, br s, 21-H),
3.71 (3H, s, 17-OCH3), 3.64 (1H, d, J = 15.3 Hz, 120-H), 3.61 (3H, s,
70-OCH3), 3.61 (1H, br, 3-H, signals overlapped with 70-OCH3),
3.56 (1H, m, 30-H), 3.49 (1H, m, 30-H), 3.46 (1H, d, J = 8.5 Hz, 13-
5.3.17. N-500-Quinolinecarbonyl derivative of Et 770 7g
Tributyltin hydride (60
over 10 min to a vigorously stirred solution of 6g (13.6 mg,
13.5 mol), (Ph3P)2PdCl2 (5.7 mg, 8.1 mol), and AcOH (29 L,
lL, 0.223 mmol) was added dropwise
l
l
l
0.51 mmol) in THF (4.0 mL) at 25 °C, and the mixture was stirred
for 1 h at 25 °C. The mixture was diluted with ethyl acetate
(10 mL) and extracted with 2 N aqueous HCl solution
(20 mL ꢀ 3). The combined extracts were made alkaline with satu-
rated Na2CO3, and extracted with chloroform (30 mL ꢀ 3). The
combined extracts were washed with brine, dried, and concen-
trated in vacuo to give a residue (16.4 mg). Chromatography on a
silica gel column with CH2Cl2–MeOH (60:1) gave 7g (12.2 mg,
H), 3.01 (1H, dd, J = 17.2, 9.4 Hz, 14-Ha), 2.88 (1H, d, J = 17.2 Hz,
14-Hb), 2.45 (1H, dd, J = 16.2, 8.5 Hz, 40-H), 2.39 (2H, m, 120-H
and 40-H), 2.31 (3H, s, OCOCH3), 2.13 (3H, s, NCH3), 2.05 (3H, s,
6-CH3), 1.51 (3H, s, 16-CH3); 13C NMR (CDCl3, 125 MHz) d 171.8
(NCO), 169.7 (10-CO), 168.4 (5-OCO), 151.6 (C-200), 148.8 (C-900),
147.5 (C-18), 144.9 (C-70), 144.8 (C-60), 145.5 (C-7), 143.0 (C-17),
141.5 (C-8), 141.2 (C-5), 136.7 (C-400), 135.2 (C-600), 130.4 (C-20),
129.5 (C-800), 129.3 (C-16), 129.0 (C-700), 128.4 (C-500), 127.8 (C-
1000), 127.3 (C-90), 126.7 (C-100), 122.2 (C-10), 121.8 (C-300), 120.8
(C-15), 118.2 (21-CN), 117.8 (C-19), 113.9 (C-50), 113.2 (C-9),
112.6 (C-6), 110.4 (C-80), 102.1 (OCH2O), 69.2 (C-10), 61.0 (C-3),
60.7 (C-22), 60.3 (C-1), 60.1 (17-OCH3), 59.8 (C-21), 55.3 (70-
OCH3), 55.0 (C-13), 54.8 (C-11), 45.8 (C-30), 41.9 (C-4), 41.7
(NCH3), 39.5 (C-120), 29.7 (C-40), 25.0 (C-14), 20.4 (COCH3), 15.3
(16-CH3), 9.8 (6-CH3); FABMS m/z 926 (MH+); HRFABMS m/z
97.7%) as a colorless amorphous powder. ½a D26
ꢁ61.2 (c 0.39,
ꢂ
CHCl3); IR (KBr) 3443, 2936, 2250w, 1749, 1653, 1593, 1503,
1458, 1449, 1431, 1420, 1375, 1261, 1237, 1236, 1196, 1142,
;
1109, 1086, 1063, 1028, 1005, 810 cmꢁ1 1H NMR (CDCl3,
500 MHz, this compound was a mixture of rotational isomers, ratio
3:2, and only the signals of major isomer are presented) d 9.03 (3/
5H, d, J = 2.9 Hz, 200-H), 8.76 (3/5H, br d, J = 6.2 Hz, 400-H), 8.21 (3/
5H, d, J = 8.5 Hz, 800-H), 7.75 (3/5H, dd, J = 8.5, 7.1 Hz, 700-H), 7.60
(3/5H, d, J = 2.5 Hz, 300-H), 7.49 (3/5H, d, J = 7.1 Hz, 600-H), 6.47 (3/
5H, s, 80-H), 6.41 (3/5H, s, 50-H), 6.10 (3/5H, s, OCHO), 6.02 (3/5H,
s, OCHO), 5.97 (73/5H, s, 15-H), 5.77 (3/5H, s, 18-OH), 5.63 (3/5H,
s, 60-OH), 4.72 (3/5H, br s, 4-H), 4.59 (3/5H, br, 22-H), 4.55 (3/5H,
br, 22-H), 4.40 (3/5H, s, 1-H), 4.26 (3/5H, d, J = 4.3 Hz, 11-H), 4.16
(3/5H, br s, 21-H), 3.70 (9/5H, s, 17-OCH3), 3.65 (9/5H, s, 70-
OCH3), 3.60 (3/5H, br, 3-H), 3.57 (3/5H, br d, J = 15.3 Hz, 120-H),
3.47 (3/5H, br, 13-H), 3.24 (6/5H, br t, 30-H2), 2.96 (3/5H, dd,
926.3074 (MH+, calcd for C50H48N5O11S, 926.3071), CD
10.8
(254), 0 (273), ꢁ7.1 (288), 0 (302), 1.2 (310), 0 (337).
De nm (c
l
M, methanol, 21 °C) ꢁ39.9 (210), ꢁ68.8 (218), 0 (247), 7.7
J = 17.3, 7.9 Hz, 14-Ha), 2.90 (3/5H, d, J = 17.3 Hz, 14-Hb), 2.58 (3/
5.3.19. 18,60-O-Bisallyl-20-N-cinnamoyl Et 770 8a
5H, br d, J = 15.3 Hz, 120-H), 2.38 (3/5H, dd, J = 15.8, 5.7 Hz, 40-H),
2.35 (9/5H, s, OCOCH3), 2.27 (3/5H, m, 40-H), 2.14 (9/5H, s,
NCH3), 2.06 (9/5H, s, 6-CH3), 1.43 (9/5H, s, 16-CH3); 13C NMR
(CDCl3, 125 MHz) d 169.6 (10-CO), 169.0 (NCO), 168.4 (5-OCO),
150.7 (C-200), 147.6 (C-18), 147.5 (C-500), 145.5 (C-7), 145.0 (C-60),
144.9 (C-70), 143.0 (C-17), 141.4 (C-5), 141.3 (C-8), 135.4 (C-900),
135.1 (C-400), 131.3 (C-800), 129.8 (C-20), 128.9 (C-16), 128.9 (C-
700), 127.9 (C-90), 126.9 (C-100), 126.6 (C-600), 125.0 (C-1000), 122.6
(C-10), 122.1 (C-300), 121.5 (C-15), 118.2 (21-CN), 117.7 (C-19),
113.9 (C-50),113.2 (C-9), 112.5 (C-6), 110.4 (C-80), 102.1 (OCH2O),
70.0 (C-10), 61.7 (C-22), 61.5 (C-3), 60.3 (C-1), 60.3 (C-21), 60.1
(17-OCH3), 55.4 (70-OCH3), 55.0 (C-11), 54.8 (C-13), 45.3 (C-30),
42.0 (C-4), 41.7 (NCH3), 40.1 (C-120), 29.4 (C-40), 25.1 (C-14), 20.4
(COCH3), 14.9 (16-CH3), 9.8 (6-CH3); FABMS m/z 926 (MH+);
HRFABMS m/z 926.3069 (MH+, calcd for C50H48N5O11S, 926.3071),
Compound 4a (15.3 mg, 0.018 mmol) and DMAP (1.1 mg) were
dissolved in pyridine (1.5 mL), and a THF solution of cinnamoyl
chloride (1 M, 0.27 mL, 0.27 mmol) was added to this mixture at
0 °C. The reaction mixture was heated at 60 °C for 1 h. After the sol-
vent was removed in vacuo, the residue was diluted with 5% aque-
ous NaHCO3 solution (20 mL) and extracted with chloroform
(15 mL ꢀ 3). The combined extracts were washed with brine
(15 mL), dried, and concentrated in vacuo to give a residue
(49.4 mg). Chromatography on a silica gel column with hexane–
ethyl acetate (4:1) gave 8a (15.6 mg, 88.4%) as a colorless amor-
phous powder. ½a D22
ꢁ35.4 (c 0.51, CHCl3); IR (KBr) 3447, 3082,
ꢂ
2934, 2835, 2806, 2250w, 1759, 1659, 1616, 1518, 1487, 1449,
1414, 1375, 1321, 1260, 1238, 1194, 1109, 1086, 1069, 1028,
999, 974, 935, 914, 895, 862 cmꢁ1 1H NMR (CDCl3, 500 MHz) d
;
7.54 (2H, d, J = 7.1 Hz, 200-H), 7.40 (4H, m, 300-H, 400-H, NCOCH@-
CHAr), 6.77 (1H, d, J = 15.6 Hz, NCOCH@CHAr), 6.61 (1H, s, 15-H),
6.37 (1H, s, 50-H), 6.34 (1H, br s, 80-H), 6.08 (1H, ddd, J = 17.3,
10.5, 5.7 Hz, 18-OCH2CH@CH2), 6.06 (1H, d, J = 0.8 Hz, OCHO),
5.98 (1H, d, J = 0.8 Hz, OCHO), 5.97 (1H, ddd, J = 17.3, 11.1, 5.4 Hz,
60-OCH2CH@CH2), 5.44 (1H, dd, J = 17.0, 1.5 Hz, 18-OCH2CH@CH2),
5.31 (1H, dd, J = 17.2, 1.4 Hz, 60-OCH2CH@CH2), 5.23 (1H, dd,
J = 10.3, 1.5 Hz, 18-OCH2CH@CH2), 5.22 (1H, dd, J = 10.5, 1.4 Hz,
60-OCH2CH@CH2), 4.79 (1H, ddt, J = 12.8, 5.3, 1.0 Hz, 18-OCHCH),
4.61 (1H, br, 22-H), 4.60 (1H, br s, 4-H), 4.48 (2H, dt, J = 5.4,
1.0 Hz, 60-OCH2CH), 4.32 (1H, s, 1-H), 4.31 (1H, dd, J = 12.8,
5.3 Hz, 18-OCHCH), 4.30 (1H, br, 22-H), 4.22 (1H, d, J = 4.0 Hz,
CD
D
e
nm (c 10.8
l
M, methanol, 21 °C) ꢁ9.8 (210), ꢁ36.1 (218),
ꢁ18.0 (231), ꢁ14.2 (237), 0 (247), 4.8 (255), 0 (271), ꢁ5.0 (288),
0 (300), 1.2 (304), 0 (320).
5.3.18. N-600-Quinolinecarbonyl derivative of Et 770 7h
Tributyltin hydride (71
over 10 min to a vigorously stirred solution of 6h (16.0 mg,
15.9 mol), (Ph3P)2PdCl2 (6.7 mg, 9.6 mol), and AcOH (34 L,
lL, 0.262 mmol) was added dropwise
l
l
l
0.60 mmol) in THF (4.0 mL) at 25 °C, and the mixture was stirred
for 1 h at 25 °C. The mixture was diluted with ethyl acetate
(10 mL) and extracted with 2 N aqueous HCl solution

4434
P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
11-H), 4.11 (1H, d, J = 2.9 Hz, 21-H), 3.84 (3H, s, 17-OCH3), 3.72
(2H, m, 30-H2), 3.61 (3H, s, 70-OCH3), 3.57 (1H, br d, J = 5.1 Hz, 3-
H), 3.48 (1H, d, J = 15.0 Hz, 120-H), 3.41 (1H, br, 13-H), 2.92 (2H,
d, J = 5.7 Hz, 14-H2), 2.57 (2H, t, J = 6.0 Hz, 40-H2), 2.30 (3H, s,
OCOCH3), 2.30 (1H, br, 120-H, signals overlapped with OCOCH3),
2.15 (3H, s, NCH3), 2.04 (3H, s, 6-CH3), 1.99 (3H, s, 16-CH3); 13C
NMR (CDCl3, 125 MHz) d 169.1 (10-CO), 168.3 (5-OCO), 167.5
(NCO), 150.3 (C-18), 148.5 (C-17), 147.4 (C-70), 147.0 (C-60), 145.3
(C-7), 141.4 (NCOCH@CHAr), 141.3 (C-5), 140.8 (C-8), 135.4 (C-
100), 134.7 (18-OCH2CH@CH2), 133.1 (60-OCH2CH@CH2), 131.0 (C-
16), 130.2 (C-20), 129.5 (C-400), 128.8 (C-300), 128.7 (C-90), 127.6
(C-200), 126.3 (C-100), 124.3 (C-19), 124.5 (C-15), 122.4 (C-10),
120.9 (NCOCH@CHAr), 118.3 (21-CN), 117.9 (60-OCH2CH@CH2),
116.6 (18-OCH2CH@CH2), 113.6 (C-9), 112.8 (C-50), 112.7 (C-6),
110.7 (C-80), 102.0 (OCH2O), 72.9 (18-OCH2CH), 69.6 (60-OCH2CH),
69.5 (C-10), 60.9 (C-22), 60.8 (C-3), 60.2 (C-1), 59.7 (C-21), 59.4
(17-OCH3), 55.3 (C-11), 55.1 (70-OCH3), 54.8 (C-13), 43.7 (C-30),
41.9 (C-4), 41.8 (NCH3), 39.1 (C-120), 29.1 (C-40), 24.7 (C-14), 20.5
(COCH3), 16.1 (16-CH3), 9.7 (6-CH3); FABMS m/z 981 (MH+);
HRFABMS m/z 981.3748 (MH+, calcd for C55H57N4O11S, 981.3744),
70.1 (C-10), 69.7 (60-OCH2CH), 61.0 (C-22), 60.8 (C-3), 60.4 (C-1),
59.7 (C-21), 59.4 (17-OCH3), 55.3 (C-11), 55.1 (70-OCH3), 54.7 (C-
13), 44.0 (C-30), 42.0 (C-4), 41.8 (NCH3), 38.9 (C-120), 29.2 (C-40),
24.6 (C-14), 20.53 (COCH3), 16.3 (16-CH3), 9.7 (6-CH3); FABMS m/
z
1026 (MH+); HRFABMS m/z 1026.3595 (MH+, calcd for
C55H56N5O13S, 1026.3595), CD De nm (c 10.2 lM, methanol,
21 °C) ꢁ60.4 (210), ꢁ99.4 (215), 0 (241), 9.7 (252), 0 (268),
ꢁ10.4 (286), 0 (299), 5.5 (318), 0 (376).
5.3.21. 20-N-Cinnamoyl Et 770 9a
Tributyltin hydride (64
over 10 min to a vigorously stirred solution of 8a (14.2 mg,
14.5 mol), (Ph3P)2PdCl2 (6.1 mg, 8.7 mol), and AcOH (31 L,
lL, 0.24 mmol) was added dropwise
l
l
l
0.54 mmol) in THF (4.0 mL) at 25 °C, and the mixture was stirred
for 2 h at 25 °C. The mixture was diluted with water (10 mL), made
alkaline with 5% aqueous NaHCO3, and extracted with chloroform
(30 mL ꢀ 3). The combined extracts were washed with 5% aqueous
NaHCO3, dried, and concentrated in vacuo to give a residue
(88.0 mg). The residue was subjected to chromatography on a silica
gel with hexane–ethyl acetate (1:1) to afford 9a (6.0 mg, 46.0%)
and 10a (2.5 mg, 18.3%).
CD
D
e
nm (c 10.2
l
M, methanol, 21 °C) ꢁ31.5 (210), ꢁ56.9 (215),
ꢁ2.1 (243), 0 (247), 4.4 (254), 0 (272), ꢁ1.7 (286), 0 (295), 3.2
(303), 0 (333).
5.3.21.1. Compound 9a.
A colorless amorphous powder, ½a D22
ꢂ
ꢁ13.8 (c 0.1, CHCl3); IR (KBr) 3447, 2934, 2250w, 1757, 1653, 1616,
5.3.20. 18,60-O-Bisallyl-20-N-400-nitrocinnamoyl Et 770 8b
1593, 1514, 1449, 1431, 1420, 1402, 1395, 1373, 1304, 1263, 1196,
Compound 4a (15.3 mg, 0.018 mmol) and DMAP (1.1 mg) were
dissolved in pyridine (1.5 mL), and a THF solution of 4-nitrocinna-
moyl chloride (0.2 M, 1.35 mL, 0.27 mmol) was added to this mix-
ture at 0 °C. The reaction mixture was heated at 60 °C for 1 h. After
the solvent was removed in vacuo, the residue was diluted with 5%
aqueous NaHCO3 solution (20 mL) and extracted with chloroform
(15 mL ꢀ 3). The combined extracts were washed with brine
(15 mL), dried, and concentrated in vacuo to give a residue
(45.0 mg). Chromatography on a silica gel column with hexane–
ethyl acetate (4:1) gave 8b (17.7 mg, 95.9%) as a colorless amor-
1107, 1086, 1065, 1028, 1005, 974, 962, 862 cmꢁ1 1H NMR
;
(500 MHz) d 7.52 (2H, dd, J = 8.2, 1.2 Hz, 200-H), 7.46–7.40 (4H, m,
300-H, 400-H, NCOCH@CHAr), 6.75 (1H, d, J = 15.5 Hz, NCOCH@CHAr),
6.44 (1H, s, 50-H), 6.42 (1H, s, 15-H), 6.36 (1H, br s, 80-H), 6.07 (1H,
d, J = 1.3, OCHO), 5.98 (1H, d, J = 1.3 Hz, OCHO), 5.71 (1H, s, 18-OH),
5.45 (1H, s, OH), 4.61 (1H, br s, 4-H), 4.59 (1H, br d, J = 11.1 Hz, 22-
H), 4.34 (1H, br d, J = 11.1 Hz, 22-H), 4.32 (1H, s, 1-H), 4.25 (1H, dd,
J = 4.7, 1.4 Hz, 11-H), 4.10 (1H, d, J = 2.6 Hz, 21-H), 3.77 (3H, s, 17-
OCH3), 3.68 (2H, br t, 30-H2), 3.65 (3H, s, 70-OCH3), 3.56 (1H, br d,
J = 4.8 Hz, 3-H), 3.51 (1H, d, J = 15.5 Hz, 120-H), 3.40 (1H, br, 13-
phous powder. ½a D22
ꢂ
ꢁ13.8 (c 0.10, CHCl3); IR (KBr) 3447, 3078,
H), 2.93 (1H, dd, J = 17.5, 8.5 Hz, 14-Ha), 2.88 (1H, d, J = 17.5 Hz,
2934, 2808, 2250w, 1759, 1661, 1597, 1520, 1487, 1456, 1447,
1418, 1395, 1373, 1344, 1321, 1260, 1244, 1194, 1109, 1086,
14-Hb), 2.56 (2H, t, J = 6.0 Hz, 40-H2), 2.33 (3H, s, OCOCH3), 2.32
(1H, br d, J = 15.5 Hz, 120-H), 2.15 (3H, s, NCH3), 2.04 (3H, s, 6-
CH3), 2.01 (3H, s, 16-CH3); 13C NMR (CDCl3, 125 MHz) d 169.2
(10-CO), 168.4 (5-OCO), 167.5 (NCO), 147.5 (C-18), 144.8 (C-70),
144.8 (C-60), 147.7 (C-17), 141.4 (NCOCH@CHAr), 141.3 (C-5),
140.9 (C-7), 140.9 (C-8), 135.3 (C-100), 130.6 (C-20), 129.5 (C-400),
129.2 (C-16), 128.9 (C-300), 128.0 (C-90), 127.6 (C-200), 127.2 (C-
100), 122.3 (C-10), 120.9 (NCOCH@CHAr), 120.7 (C-15), 118.3 (21-
CN), 117.9 (C-19), 113.8 (C-50), 113.6 (C-9), 112.6 (C-6), 1109.9
(C-80), 102.0 (OCH2O), 69.5 (C-10), 61.1 (C-22), 60.9 (C-3), 60.2 (C-
21), 60.2 (17-OCH3), 60.0 (C-1), 55.3 (70-OCH3), 54.9 (C-11), 54.8
(C-13), 43.8 (C-30), 41.9 (C-4), 41.7 (NCH3), 39.3 (C-120), 28.9 (C-
40), 24.7 (C-14), 20.4 (COCH3), 16.1 (16-CH3), 9.8 (6-CH3); FABMS
m/z 901 (MH+); HRFABMS m/z 901.3124 (MH+, calcd for
1069, 1028, 999, 975, 935, 841 cmꢁ1 1H NMR (CDCl3, 500 MHz)
;
d 8.28 (2H, d, J = 8.8 Hz, 300-H), 7.67 (2H, d, J = 8.8 Hz, 200-H), 7.39
(1H, d, J = 15.5 Hz, NCOCH@CHAr), 6.92 (1H, d, J = 15.5 Hz, NCOCH
@CHAr), 6.58 (1H, s, 15-H), 6.38 (1H, s, 50-H), 6.30 (1H, br s, 80-
H), 6.08 (1H, ddd, J = 17.3, 10.5, 5.1 Hz, 18-OCH2CH@CH2), 6.06
(1H, d, J = 1.1 Hz, OCHO), 5.99 (1H, ddd, J = 17.3, 10.5, 5.4 Hz, 60-
OCH2CH@CH2), 5.98 (1H, d, J = 1.1 Hz, OCHO), 5.45 (1H, dd,
J = 17.3, 1.4 Hz, 18-OCH2CH@CH2), 5.32 (1H, dd, J = 17.2, 1.4 Hz,
60-OCH2CH@CH2), 5.24 (1H, dd, J = 10.5, 1.5 Hz, 18-OCH2CH@CH2),
5.22 (1H, dd, J = 10.5, 1.4 Hz, 60-OCH2CH@CH2), 4.79 (1H, ddt,
J = 12.8, 5.3, 1.0 Hz, 18-OCHCH), 4.68 (1H, br d, J = 11.4 Hz, 22-H),
4.62 (1H, br s, 4-H), 4.49 (2H, dt, J = 5.4, 1.0 Hz, 60-OCH2CH), 4.34
(1H, s, 1-H), 4.32 (1H, dd, J = 12.8, 5.3 Hz, 18-OCHCH), 4.23 (1H,
br, 22-H), 4.22 (1H, d, J = 5.1 Hz, 11-H), 4.12 (1H, d, J = 2.9 Hz, 21-
H), 3.84 (3H, s, 17-OCH3), 3.74 (2H, m, 30-H2), 3.61 (3H, s, 70-
OCH3), 3.56 (1H, br d, J = 5.1 Hz, 3-H), 3.50 (1H, d, J = 15.5 Hz,
120-H), 3.42 (1H, br, 13-H), 2.92 (2H, d, J = 5.6 Hz, 14-H2), 2.59
(2H, t, J = 6.0 Hz, 40-H2), 2.41 (1H, br, 120-H), 2.30 (3H, s, OCOCH3),
2.15 (3H, s, NCH3), 2.04 (3H, s, 6-CH3), 1.95 (3H, s, 16-CH3); 13C
NMR (CDCl3, 125 MHz) d 168.8 (10-CO), 168.2 (5-OCO), 166.2
(NCO), 150.3 (C-18), 148.6 (C-17), 148.4 (C-400), 147.6 (C-70),
147.2 (C-60), 145.4 (C-7), 141.6 (C-100), 141.4 (C-5), 140.7 (C-8),
138.3 (NCOCH@CHAr), 134.7 (18-OCH2CH@CH2), 133.1 (60-
OCH2CH@CH2), 130.7 (C-16), 130.3 (C-20), 128.3 (C-100), 128.0
(C-200), 126.1 (C-90), 125.6 (NCOCH@CHAr), 124.6 (C-19), 124.3 (C-
15), 124.2 (C-300), 122.3 (C-10), 118.2 (21-CN), 117.9 (60-
OCH2CH@CH2), 116.7 (18-OCH2CH@CH2), 113.9 (C-9), 112.7 (C-
50), 112.7 (C-6), 110.7 (C-80), 102.0 (OCH2O), 72.9 (18-OCH2CH),
C49H49N4O11S, 901.3119), CD De nm (c 10.8 lM, methanol, 21 °C)
ꢁ37.6 (210), ꢁ60.7 (218), 0 (244), 5.8 (254), 0 (267), ꢁ9.1 (287),
0 (297), 3.2 (303), 0 (339).
5.3.21.2. Compound 10a.
A colorless amorphous powder, IR
(KBr) 3424, 2928, 2853, 2808, 2250w, 1759, 1655, 1616, 1514,
1449, 1418, 1375, 1321, 1263, 1236, 1194, 1107, 1085, 1068,
1028, 993, 974, 912, 895, 866 cmꢁ1 1H NMR (300 MHz) d 7.53
;
(2H, dd, J = 7.8, 1.2 Hz, 200-H), 7.43–7.35 (4H, m, 300-H, 400-H,
NCOCH@CHAr), 6.75 (1H, d, J = 15.6 Hz, NCOCH@CHAr), 6.61 (1H,
s, 50-H), 6.44 (1H, s, 15-H), 6.40 (1H, br s, 80-H), 6.09 (1H, ddd,
J = 17.3, 10.5, 5.1 Hz, 18-OCH2CH@CH2), 6.07 (1H, d, J = 1.3, OCHO),
5.98 (1H, d, J = 1.3 Hz, OCHO), 5.45 (1H, dd, J = 17.4, 1.7 Hz, 18-
OCH2CH@CH2), 5.43 (1H, s, 60-OH), 5.23 (1H, dd, J = 10.4, 1.7 Hz,
18-OCH2CH@CH2), 4.79 (1H, dd, J = 12.6, 5.0 Hz, 18-OCH2CH@CH2),
4.58 (1H, br s, 4-H), 4.58 (1H, br d, J = 11.1 Hz, 22-H), 4.34 (1H, br d,

P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
4435
J = 11.1 Hz, 22-H), 4.34 (1H, dd, J = 12.6, 1.7 Hz, 18-OCH2CH@CH2),
4.32 (1H, s, 1-H), 4.22 (1H, dd, J = 5.0, 1.6 Hz, 11-H), 4.11 (1H, d,
J = 2.7 Hz, 21-H), 3.84 (3H, s, 17-OCH3), 3.67 (2H, br t, 30-H2),
3.65 (3H, s, 70-OCH3), 3.56 (1H, br d, J = 4.6 Hz, 3-H), 3.49 (1H, d,
J = 14.7 Hz, 120-H), 3.41 (1H, br, 13-H), 2.91 (2H, br d, J = 7.9 Hz,
14-H2), 2.58 (2H, t, J = 5.7 Hz, 40-H2), 2.41 (1H, br d, J = 15.5 Hz,
120-H), 2.33 (3H, s, OCOCH3), 2.15 (3H, s, NCH3), 2.04 (3H, s, 6-
CH3), 1.98 (3H, s, 16-CH3); FABMS m/z 941 (MH+); HRFABMS m/z
941.3428 (MH+, calcd for C52H53N4O11S, 941.3432).
21 °C) ꢁ35.7 (210), ꢁ52.7 (215), 0 (242), 5.1 (253), 0 (268), ꢁ5.8
(292), 0 (308), 2.8 (312), 0 (380).
6. Cell growth inhibition assay (IC50
)
A single-cell suspension (2 ꢀ 103 cells/well) was added to seri-
ally diluted test compounds in a microplate. The cells were then
cultured for 4 d. Cells were enumerated with a cell counting kit
(DOJINDO, Osaka, Japan). IC50 was expressed as the concentration
at which cell growth was inhibited by 50% compared with the un-
treated control.
5.3.22. 20-N-400-Nitrocinnamoyl Et 770 9b
Tributyltin hydride (77
over 10 min to a vigorously stirred solution of 8b (17.7 mg,
17.3 mol), (Ph3P)2PdCl2 (7.3 mg, 8.7 mol), and AcOH (37 L,
lL, 0.29 mmol) was added dropwise
Acknowledgments
l
l
l
0.65 mmol) in THF (4.0 mL) at 25 °C, and the mixture was stirred
for 1 h at 25 °C. The mixture was diluted with water (10 mL), made
alkaline with 5% aqueous NaHCO3, and extracted with chloroform
(30 mL ꢀ 3). The combined extracts were washed with 5% aqueous
NaHCO3, dried, and concentrated in vacuo to give a residue
(98.2 mg). The residue was subjected to chromatography on a silica
gel with hexane–ethyl acetate (1:1) to afford 9b (3.3 mg, 20.2%)
and 10b (3.7 mg, 22.6%).
This work is supported by a Grant-in Aid (No. 23590019) for
Scientific Research from the Ministry of Education, Culture, Sports,
Science. This work is also partially supported by the Japan Society
for the Promotion of Science (JSPS) Asia-Africa Science Platform
Program (2010–2012) and a grant from the High-Tech Research
Center Project, the Ministry of Education, Culture, Sports, Science
and Technology (MEXT), Japan (S0801043). We are grateful to JSPS
and the National Research Cooperation of Thailand (NRCT) for sup-
porting the collaboration between Thai and Japanese researchers in
this work. We are grateful to Dr. Nobuo Shimma and Dr. Takuo
Tsukuda (Chugai Pharmaceutical Company Kamakura Research
Center) for conducting the cytotoxicity assay.
5.3.22.1. Compound 9b.
A pale yellow amorphous powder,
IR (KBr) 3447, 2934, 2855, 2808, 2250w, 1757, 1751, 1655,
1618, 1597, 1520, 1458, 1420, 1373, 1344, 1263, 1236, 1196,
1086, 1065, 1028, 862 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 8.28
;
(2H, d, J = 8.8 Hz, 300-H), 7.65 (2H, d, J = 8.8 Hz, 200-H), 7.36 (1H,
d, J = 15.5 Hz, NCOCH@CHAr), 6.89 (1H, d, J = 15.5 Hz, NCOCH
@CHAr), 6.46 (1H, s, 15-H), 6.40 (1H, s, 50-H), 6.32 (1H, br s,
80-H), 6.07 (1H, d, J = 1.1 Hz, OCHO), 5.98 (1H, d, J = 1.1 Hz,
OCHO), 5.70 (1H, s, 18-OH), 5.47 (1H, s, 60-OH), 4.66 (1H, br d,
J = 10.8 Hz, 22-H), 4.65 (1H, br s, 4-H), 4.34 (1H, s, 1-H), 4.23
(1H, br, 22-H), 4.25 (1H, dd, J = 4.9, 1.2 Hz, 11-H), 4.11 (1H, d,
J = 2.7 Hz, 21-H), 3.77 (3H, s, 17-OCH3), 3.70 (2H, m, 30-H2),
3.65 (3H, s, 70-OCH3), 3.55 (1H, d, J = 6.2 Hz, 3-H), 3.50 (1H, d,
J = 14.5 Hz, 120-H), 3.42 (1H, br, 13-H), 2.91 (2H, d, J = 6.2 Hz,
14-H2), 2.58 (2H, t, J = 5.7 Hz, 40-H2), 2.41 (1H, br, 120-H), 2.33
(3H, s, OCOCH3), 2.15 (3H, s, NCH3), 2.04 (3H, s, 6-CH3), 1.98
(3H, s, 16-CH3); FABMS m/z 946 (MH+); HRFABMS m/z
References and notes
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6.0 (251), 0 (264), ꢁ10.3 (287), 0 (308), 2.6 (314), 0 (385).
De nm
l
5.3.22.2. Compound 10b. A pale yellow amorphous powder,
IR (KBr) 3447, 2934, 2853, 1808, 2250w, 1751, 1655, 1618, 1597,
1520, 1447, 1418, 1373, 1344, 1321, 1265, 1236, 1196, 1109,
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1086, 1069, 1028, 999 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 8.28
;
(2H, d, J = 8.8 Hz, 300-H), 7.67 (2H, d, J = 8.8 Hz, 200-H), 7.38 (1H, d,
J = 15.7 Hz, NCOCH@CHAr), 6.90 (1H, d, J = 15.7 Hz, NCOCH@CHAr),
6.58 (1H, s, 15-H), 6.45 (1H, s, 50-H), 6.31 (1H, br s, 80-H), 6.09 (1H,
ddd, J = 17.3, 10.5, 5.1 Hz, 18-OCH2CH@CH2), 6.07 (1H, d, J = 1.1 Hz,
OCHO), 5.98 (1H, d, J = 1.1 Hz, OCHO), 5.45 (1H, ddd, J = 17.3, 10.5,
5.1 Hz, 18-OCH2CH@CH2), 5.45 (1H, s, 60-OH), 5.24 (1H, ddd,
J = 17.3, 10.5, 1.5 Hz, 18-OCH2CH@CH2), 4.79 (1H, ddt, J = 12.8,
5.1, 1.5 Hz, 18-OCH2CH@CH2), 4.63 (1H, br d, J = 11.5 Hz, 22-H),
4.62 (1H, br s, 4-H), 4.36 (1H, dd, J = 12.8, 5.1 Hz, 18-
OCH2CH@CH2), 4.33 (1H, s, 1-H), 4.26 (1H, br, 22-H), 4.23 (1H,
dd, J = 4.9, 1.3 Hz, 11-H), 4.12 (1H, d, J = 2.7 Hz, 21-H), 3.84 (3H,
s, 17-OCH3), 3.71 (2H, t, J = 5.7 Hz, 30-H2), 3.65 (3H, s, 70-OCH3),
3.55 (1H, d, J = 4.9 Hz, 3-H), 3.51 (1H, d, J = 14.5 Hz, 120-H), 3.42
(1H, br, 13-H), 2.91 (2H, d, J = 5.3 Hz, 14-H2), 2.58 (2H, t,
J = 5.8 Hz, 40-H2), 2.38 (1H, br d, J = 15.6 Hz, 120-H), 2.30 (3H, s,
OCOCH3), 2.15 (3H, s, NCH3), 2.05 (3H, s, 6-CH3), 1.95 (3H, s, 16-
CH3); FABMS m/z 986 (MH+); HRFABMS m/z 986.3284 (MH+, calcd
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De nm (c 10.1 lM, methanol,

4436
P. Saktrakulkla et al. / Bioorg. Med. Chem. 19 (2011) 4421–4436
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33. 18-O-Allyl-20-N-indole-3-carbonyl Et 770 was isolated in 24.0% yield. Because
of its limited amount of this compound permits to present IR, 1H NMR and MS
measurements could be conducted (see, Experimental). It was proposed that
the steric influence of the 18-O-allyl group might have hindered the
deprotection reaction. When the reaction time (90 h) was prolonged both 5
and 18-O-allyl-20-N-indole-3-carbonyl Et 770 were consumed in the reaction:
however, the yield of 3 only 36.5%.