A new type of ketolide bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether: Synthesis and structure-activity relationships (2)

Article abstract of DOI:10.1016/j.bmc.2006.01.036

A new type of ketolide bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether and its analogues were prepared, and their antibacterial activities and pharmacokinetic properties were evaluated. We found that the introduction of an (R)-alkyl group between the amide and iminoether groups could improve the pharmacokinetic properties while maintaining the activity against erythromycin-resistant Streptococcus pneumoniae. Among the ketolides prepared with the (R)-alkyl group, compound 5p with an N-(3-quinoxalin-6-yl-propyl)-propionamide moiety was found to have in vivo efficacy comparable to CAM with potent in vitro antibacterial activities against the key respiratory pathogens including Haemophilus influenzae and erythromycin-resistant S. pneumoniae.

Full text of DOI:10.1016/j.bmc.2006.01.036

Bioorganic & Medicinal Chemistry 14 (2006) 3697–3711
A new type of ketolide bearing an N-aryl-alkyl acetamide moiety
at the C-9 iminoether: Synthesis and structure–activity
relationships (2)
Takashi Nomura,* Tsutomu Iwaki, Yukitoshi Narukawa, Koichi Uotani,
Toshihiko Hori and Hideaki Miwa
Discovery Research Laboratories, Shionogi & Co., Ltd, 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan
Received 24 November 2005; revised 11 January 2006; accepted 12 January 2006
Available online 7 February 2006
Abstract—A new type of ketolide bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether and its analogues were prepared,
and their antibacterial activities and pharmacokinetic properties were evaluated. We found that the introduction of an (R)-alkyl
group between the amide and iminoether groups could improve the pharmacokinetic properties while maintaining the activity
against erythromycin-resistant Streptococcus pneumoniae. Among the ketolides prepared with the (R)-alkyl group, compound 5p
with an N-(3-quinoxalin-6-yl-propyl)-propionamide moiety was found to have in vivo efficacy comparable to CAM with potent
in vitro antibacterial activities against the key respiratory pathogens including Haemophilus influenzae and erythromycin-resistant
S. pneumoniae.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
NMe2
HO
O
R = H
Erythromycin (EM)
9
6
The macrolide antibiotics have been used for respiratory
HO
HO
O
O
RO
3
tract infections, especially for those caused by Gram-po-
sitive pathogens. Among them, clarithromycin1 (CAM)
has favorable pharmacokinetic properties and has been
used against the key respiratory tract pathogens.
R = Me
Clarithromycin (CAM)
O
O
O
O
OH
OMe
N
N
However, second-generation derivatives of erythromy-
cin A (EM) typified by CAM do not have activity
against erythromycin (EM)-resistant strains, which have
increased significantly in recent years. Third-generation
derivatives of EM, the ketolides such as telithromycin2
and cethromycin,3 have potent activity against key respi-
ratory pathogens including Haemophilus influenzae and
EM-resistant Streptococcus pneumoniae (Fig. 1).
N
NMe2
NMe2
N
HO
HO
O
O
9
9
O
H
N
O
6
N
O
O
O
O
6
O
O
O
MeO
3
3
O
O
O
O
O
O
Telithromycin
Cethromycin
Figure 1. Structure of macrolide antibiotics.
These two ketolides have structural similarity in terms of
the aryl-alkyl group and the C-11,12 carbamate moiety.
We have already reported a new type of 9-iminoether
ketolide4 with C-11,12-carbonate and an N-aryl-alkyl
acetamide group at the C-9 iminoether moiety such as
14 and 24 (Fig. 2), which showed potent antibacterial
activities in vitro. However, it was disappointing that
they exhibited only poor in vivo efficacy compared to
CAM in the lung infection model. That is likely to be
due to their pharmacokinetic profile, especially their
Keywords: Ketolide; Antibacterial activity; C-9 iminoether; N-Aryl-
alkyl acetamide; Pharmacokinetic property; Erythromycin-resistant;
Macrolide; Antibiotic.
*
Corresponding author. Tel.: +81 6 6458 5861; fax: +81 6 6458
0987; e-mail: takashi.nomura@shionogi.co.jp
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.01.036

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T. Nomura et al. / Bioorg. Med. Chem. 14 (2006) 3697–3711
H
since compounds with heteroaryls cannot be prepared
by catalytic hydrogenation.
Ar
N
NMe2
O
O
N
HO
O
O
9
6
O
O
O
MeO
Compound 3A was prepared by the procedure described
in our previous paper.4 Compounds 3B–F were prepared
from 9-oxime-C-11,12-diol 66 as shown in Scheme 2.
Treatment of 6 with allyl a-bromocarboxylate 7 and
NaH gave compound 8, which was transformed into 9
bearing C-11,12 carbonate using triphosgene and pyri-
dine in THF. The conversion from allyl ester 9 to car-
3
O
O
O
N
Ar =
boxylic acid 3 was accomplished using catalytic
Pd(PPh3)4 and PPh3 and pyrrolidine.
Figure 2. Structure of 9-iminoether ketolide.
3-Aryl-propylamines used for the synthesis of 5 were
prepared as shown in Schemes 3–5. Other amines not
listed in the above schemes were commercially available
or prepared by known methods. Allyl a-bromocarboxy-
lates 7 used for the synthesis of carboxylic acid 3 were
prepared from the corresponding a-bromocarboxylic
acids, which are commercially available.
low total amount of distribution in lung tissue and low
free rate in plasma.
We report herein the modification of 9-iminoether keto-
lide and optimization of the aryl group to improve the
pharmacokinetic profile while maintaining their potent
antibacterial activities.
3. Results and discussion
2. Synthesis
All the ketolides were evaluated in vitro by standard
agar dilution method with various strains. Their anti-
bacterial activity against both EM-susceptible and
-resistant Staphylococcus aureus and S. pneumoniae
along with one strain of Haemophilus influenzae are
shown in Tables 1–5.
9-Iminoether derivatives bearing an N-aryl-alkylamide
group were prepared by using carboxylic acid 3. Amida-
tion of 3 with various primary amines by using oxalyl
chloride and a catalytic amount of dimethylformamide
gave 4, which was subjected to deprotection and subse-
quent N-methylation, to afford amide derivatives 5a–u
as shown in Scheme 1. In the step for deprotection
and subsequent N-methylation, we used method A ((1)
20% Pd(OH)2; (2) 20% Pd(OH)2, H2, HCHO aq) for
compound 5a–i, and method B5 ((1) TMS-I, AlCl3/
anisole; (2) HCO2H, HCHO aq) for compound 5j–u,
In our previous paper,4 we presented the ketolides
shown in Figure 2 and demonstrated that their propyl
linker between their amide and aryl groups was essential
for the potent antibacterial activities.
These ketolides had potent antibacterial activities
against key respiratory pathogens, including EM-resis-
tant strains. On the other hand, they had poor pharma-
cokinetic properties (low total amount of antibiotics
distributed in lung tissue and low free rate in plasma),
which seemed to lead to weak in vivo efficacy.
R2
O
R2
O
R1
R1
H
N
HO
O
Cbz NMe
Cbz O
Cbz NMe
Cbz O
O
N
O
N
R
a
O
O
O
O
O
O
O
O
O
MeO
MeO
For the improvement of these properties with maintain-
ing potent antibacterial activity, we utilized 14 as a mod-
el compound. First, we examined the effect of the hetero
atoms in the linker between the aryl and amide groups,
and also the effect of the substituent group between the
amide and iminoether.
O
O
O
O
O
O
4
3
3A: R1 = H, R2 = H
3B: R1 = Me, R2 = H
3C: R1 = H, R2 = Me
3D: R1 = Me, R2 = Me
3E: R1 = Et, R2 = H
3F: R1 = i-Pr, R2 = H
b
Table 1 presents the antibacterial activities of 5a–d bear-
ing a hetero atom in their linker and 5e–g bearing a sub-
stituent between the amide and iminoether groups. All
analogues bearing the hetero atom linker lost the activ-
ity against EM-resistant S. pneumoniae though com-
pounds 5b and d showed activity twice as potent as 1
against H. influenzae. On the other hand, among the
derivatives with substituent group between the amide
and iminoether groups, compound 5e bearing the (R)-
methyl group showed activity as potent as 1 against
EM-resistant S. pneumoniae. These results prompted
us to prepare compound 5h and i bearing (R)-ethyl
and (R)-isopropyl groups.
R2
R1
H
N
NMe2
O
O
N
R
HO
O
O
O
O
O
MeO
O
O
O
5a-5u
Scheme 1. Reagents and conditions. Method A: (a) (ClCO)2, cat.
DMF, RNH2; (b) 1—H2, 20% Pd(OH)2/C; 2—H2, 20% Pd(OH)2/C,
HCHO aq, acetate buffer (pH 4.4). Method B: (a) (ClCO)2, cat. DMF,
RNH2; (b) 1—TMSI, AlCl3/anisole; 2—HCOOH, HCHO aq.

T. Nomura et al. / Bioorg. Med. Chem. 14 (2006) 3697–3711
3699
R2
R1
O
Cbz NMe
Cbz O
Cbz NMe
Cbz O
OH
N
O
N
O
a
HO
HO
O
HO
HO
O
O
O
MeO
MeO
R1 R2
O
O
O
Br
O
O
O
7
O
O
8
6
R2
R1
R2
R1
O
O
Cbz NMe
Cbz O
HO
O
O
N
Cbz NMe
O
N
O
Cbz O
O
c
b
O
O
O
O
O
O
O
O
MeO
MeO
O
O
O
O
O
9
O
3
3E: R1 = Et, R2 = H
3F: R1 = i-Pr, R2 = H
3B: R1 = Me, R2 = H
3C: R1 = H, R2 = Me
3D: R1 = Me, R2 = Me
Scheme 2. Reagents and conditions: (a) NaH/DMF, 6; (b) (CCl3O)2CO, pyridine/THF; (c) Pd(PPh3)4, PPh3, pyrrolidine/CH3CN.
Boc
a
ing potent antibacterial activity against EM-resistant
S. pneumoniae. However, compound 5i showed some-
what decreased activity against H. influenzae and
EM-resistant S. aureus.
Boc
N
N
Ar-X
+
H
Ar
H
(X = Cl, Br, I)
10
b
c
Boc
Ar
NH2
Ar
N
H
Since compounds 5e and h had potent activities compa-
rable to that of 1, their lung AUCs were also evaluated
(Table 3). It is noteworthy that these values increase
with increasing molecular weight of the substituent,
and their lung AUCs are superior to that of CAM.
12
11
12a Ar =
12c Ar =
N
12b Ar =
12d Ar =
N
N
Further improvement of the pharmacokinetic profiles
was achieved by investigating aryl groups other than
the phenyl ring. The derivatives of 5e,h, and 1 prepared
are shown in Figure 3 (5j–u). The antibacterial activi-
ties, lung AUCs, and serum free rate of the derivatives
listed in Figure 3 are summarized in Table 4. All com-
pounds showed activities nearly equal to that of teli-
N
N
N
Scheme 3. Reagents and conditions: (a) NEt3, CuI, cat. Cl2Pd(PPh3)2;
(b) H2, 5% Pd/C; (c) TMS-I.
Table 2 summarizes the activities of analogues bearing
an (R)-alkyl group between the amide and imionoether
groups. All compounds in Table 2 with the (R)-alkyl
group showed potent antibacterial activities against
Gram-positive EM-susceptible strains, while maintain-
thromycin against the strains listed in Table 4
including the EM-resistant ones. From the viewpoint
of lung AUC improvement, the (R)-methyl group was
found to be better than the (R)-ethyl group for all aryl
groups in Table 4.
NH2
NHCbz
Boc
Boc
a
H2N
b
Boc
N
+
N
N
CbzHN
CbzHN
OTf
NHCbz
H
H
H
15
14
13
Boc
N
H
c
NH2
d
N
N
N
N
11e
12e
Scheme 4. Reagents and conditions: (a) NEt3, CuI, cat. Cl2Pd(PPh3)2; (b) H2, 10% Pd(OH)2/C, CH3CO2H; (c) (CHO)2, EtOH, reflux; (d) TMS-I.

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T. Nomura et al. / Bioorg. Med. Chem. 14 (2006) 3697–3711
O
O
N
N
N
NH
a
N
N
+
Br
N
O
N
O
17
N
N
16
b
N
NH2
12f
Scheme 5. Reagents and conditions: (a) NaH/DMF; (b) NH2NH2/EtOH, reflux.
Table 1. In vitro antibacterial activities of compounds 5a–g and 1
R2 R1
H
Ph
N
5a 5b 5c
5d 5e 5f
5g
Me
Me Me
1
NMe2
O
y
x
O
N
HO
O
O
R1
R2
x
H
H
H
H
H
H
H
H
Me
H
H
H
H
O
O
O
MeO
O
CH2 NMe CH2 CH2 CH2 CH2 CH2
O
y
CH2
O
CH2 NMe CH2 CH2 CH2 CH2
O
O
Strain
MIC [lg/mL]
5a
5b
0.2
5c
5d
5e
5f
5g
0.78
1
CAM
S. aureus Smith
S. aureus SR17347 (EM-R)
S. pneumoniae Type I
0.2
0.39
0.39
0.2
0.2
0.39
0.39
0.1
0.2
0.2
0.2
0.2
0.025
0.39
0.05
0.39
0.05
0.39
0.05
0.78
6.25
0.78
0.05
>100
0.025
>100
3.13
0.025
0.025
0.78
6.25
S. pneumoniae SR16651 (EM-R)
H. influenzae SR88562
100
12.5
25
3.13
100
12.5
12.5
3.13
100
6.25
12.5
12.5
Table 2. In vitro antibacterial activities of compounds 5e,h,i, and 1
Significant improvement of lung AUCs was observed
for compound 5m bearing the 7-quinolyl group and
5p with the 6-quinoxalyl group, while in the case of
compounds 2 and 5j bearing the 4-quinolyl group,
the improvement was not notable. Compound 5u bear-
ing the imidazole-pyridine group, which is the same
moiety of telithromycin, also showed potent antibacte-
rial activities but its pharmacokinetic profile was inferi-
or to those of the other derivatives. Among the
derivatives listed in Table 4, compound 5p bearing
the 6-quinoxalyl group was found to be the best ana-
logue in terms of its potent antibacterial activities,
superior lung AUCs, and serum free rate. The in vivo
efficacy of 5p, examined using the model of mouse
infected by EM-susceptible S. pneumoniae, was found
to show equal activity to that of CAM (Table 5).
R1
H
N
Ph
NMe2
O
O
N
(CH2)3
HO
O
O
5e
Me Et
5h
5i
i-Pr
1
O
O
O
MeO
R1
H
O
O
O
Strain
MIC [lg/mL]
5e
0.2
5h
0.39
5i
0.39
0.78
1
CAM
S. aureus Smith
S. aureus SR17347
0.2
0.2
0.2
>100
0.39 0.39
(EM-R)
S. pneumoniae Type I
0.05 0.05
S. pneumoniae SR16651 0.78 0.78
0.025 0.025 0.025
>100
0.78
0.78
(EM-R)
H. influenzae SR88562
6.25 6.25 12.5
6.25
3.13
4. Conclusion
A new type of ketolide bearing an N-arylpropylaceta-
mide group at the C-9-iminoether moiety and its deriva-
tives were prepared, and their antibacterial activities,
lung AUCs, and serum free rates were evaluated. For
improvement of lung AUCs while maintaining potent
activities against EM-resistant strains, extensive struc-
tural modification was performed, which finally led to
the discovery of derivatives with an (R)-alkyl substituent
between the amide and iminoether groups at the C-9
position. Among them, compound 5p bearing the
Table 3. The lung AUCs* of 5e,h, and 1 in rats
5e
5h
347
1360
1
CAM
Lung AUC (0–6 h) [lg h/g]
Lung AUC (0–24 h) [lg h/g]
181
641
26
—
221
359
*Dose 20 mg/kg (po).

T. Nomura et al. / Bioorg. Med. Chem. 14 (2006) 3697–3711
3701
Table 4. In vitro antibacterial activities, lung AUCs in rats (dose 20 mg/kg (po)), and mouse serum free rates of compounds 5j–u, telithromycin, and
CAM
Strain
MIC [lg/mL]
2
5j
5k
51
5m
5n
Telithromycin
S. aureus Smith
S. aureus SR17347(EM-R)
S. pneumoniae Type I
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.39
0.0125
0.2
0.2
0.025
0.2
3.13
0.025
0.2
3.13
0.025
0.1
1.56
0.025
0.05
3.13
0.0125
0.1
3.13
S. pneumoniae SR16651 (EM-R)
H. influenzae SR88562
0.78
0.78
1.56
Lung AUC (0–6 h) [lg h/g]
Lung AUC (0–24 h) [lg h/g]
19.1
59.4
48.3
144
—
—
72.7
—
267
671
131
532
12.0
30.8
Mouse serum free (%)
5.9
2.6
6.8
3.6
4.0
—
9.4
5o
5p
5q
5r
5s
5t
5u
CAM
S. aureus Smith
S. aureus SR17347 (EM-R)
S. pneumoniae Type I
0.1
0.1
0.2
0.2
0.2
0.2
0.2
0.39
0.39
0.025
0.1
0.2
0.2
0.39
0.39
0.0125
0.1
0.2
0.39
0.025
0.1
>100
0.025
>100
3.13
0.0125
0.1
3.13
0.025
0.1
3.13
0.025
0.39
6.25
0.025
0.05
3.13
S. pneumoniae SR16651 (EM-R)
H. influenzae SR88562
6.25
3.13
3.13
Lung AUC (0–6 h) [lg h/g]
Lung AUC (0–24 h) [lg h/g]
20.0
49.3
154
389
111
315
76.4
154
9.71
21
92
248
7.3
20.2
221
359
Mouse serum free (%)
11.0
8.2
4.5
4.3
6.8
6.5
—
52.8
Table 5. In vivo efficacy in the mouse lung infection models
5. Experimental
Compound
S. pneumoniae
Infrared (IR) spectra were determined on a JASCO FT/
MIC [lg/mL]
ED50 [mg/kg]
1
IR-700 spectrometer. H NMR and 13C NMR spectra
5p
CAM
0.025
0.025
10.8
10.8
were recorded on a Varian Gemini-300 (300 MHz) and
Gemini-300 (75 MHz) spectrometers, respectively.
Chemical shifts are reported in parts per million from
TMS (in CDCl3) as the internal standard. HR-FAB/
MS were recorded on a JEOL LMS-SX/SX 102A and
HR-MS (SI)/MS (SI) were recorded on a Hitachi
M-90. Analytical thin layer chromatography (TLC)
was carried out on Merck precoated TLC plates with
silica gel 60 F254 and visualized with UV light or 10%
H2SO4 containing 5% ammonium molybdate and 0.2%
N-(3-quinoxalin-6-yl-propyl)-propionamide group was
identified as the best compound with balanced potent
activities and superior pharmacokinetic profiles. This
compound showed excellent activities against the key
respiratory pathogens including EM-resistant strains
in vitro, and also exhibited potent in vivo efficacy equal
to that of CAM in experimental animal infection models.
R1
H
N
Ar
NMe2
HO
O
N
(CH2)3
O
9
6
O
O
O
O
O
MeO
3
O
O
O
2
5j
5k
5l
5m
5n
N
N
N
Ar
N
N
N
R1
H
Me
Et
H
Me
Et
5o
5p
5q
5r
5s
5t
5u
N
N
N
N
N
N
N
N
N
N
Ar
N
N
N
N
N
R1
H
Me
Et
Me
H
Me
Me
Figure 3. Structures of compounds 5j–u and 2.

3702
T. Nomura et al. / Bioorg. Med. Chem. 14 (2006) 3697–3711
ceric sulfate. Flash chromatography was performed with
Merck silica gel 60 (230–400 mesh).
with saturated aqueous NH4Cl and brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel
(n-hexane:AcOEt, 3:1–2:1) to give 530 mg of 9d as a
colorless foam (99%).
5.1. Measurement of in vitro antibacterial activity
MICs were determined by a serial twofold dilution
method in Sensitivity Disk Agar-N (Nissui Pharmaceu-
tical, Tokyo, Japan). Overnight cultures of antibacterial
strains in Mueller–Hinton broth (Becton Dickinson)
were diluted to about 106 CFU/mL. Bacterial suspen-
sions of 1 lL were spotted onto agar plates containing
various concentrations of an antibiotic and incubated
for 20 h at 37 ꢁC before the MICs were scored.
5.2.2. Compound 9d. MS (FAB): 1031+ (M+Na+). HR-
MS (FAB) calcd for C53H72N2O17Na: 1031.4729.
Found: 1031.4758.
IR (KBr): 3423, 3065, 2978, 2939, 2880, 1812, 1752,
1704, 1647, 1587, 1497, 1455, 1381, 1362, 1329, 1288,
1253, 1166, 1114, 1085, 1067, 1048, 1003, 988, 930,
826, 782, 769, 755, 697, 623, 596, 518, 457 (cmÀ1).
5.2. Preparation of compound 3D
1H NMR (CDCl3) d (ppm): 2.67 (3H, s), 2.81 and 2.85
(3H, two s).
To a solution of 66 (500 mg, 0.583 mmol) in DMF
(10 mL) was added NaH 58 mg (60% in mineral oil
1.46 mmol) under cooling on an ice-water bath, and
the mixture was stirred for 30 min. To this solution, 2-
bromo-2-methyl-propionic acid allyl ester 7d (302 mg,
1.46 mmol) in DMF (1 mL) was added and the reaction
mixture was stirred another 30 min under cooling on an
ice-water bath. The reaction mixture was quenched with
saturated aqueous NH4Cl and extracted with AcOEt
(40 mL). The aqueous layer was extracted with AcOEt
(40 mL) and the combined organic layer was washed
with brine, dried over MgSO4, filtered and concentrated
in vacuo. The residue was purified by column chroma-
tography on silica gel (n-hexane:AcOEt, 8:1–2:1) to give
521 mg of 8d as a colorless foam (91%).
13C NMR (CDCl3) d (ppm): 10.4, 13.0, 13.8, 15.2, 15.7,
15.9, 18.8, 19.5, 20.6, 22.4, 23.7, 24.4, 26.0, 28.8, 33.1,
35.6, 36.1, 37.6, 47.1, 47.2, 49.4, 51.0, 54.6, 65.2, 67.0,
67.1, 68.6, 69.1, 69.4, 74.5, 76.2, 76.3, 78.1, 81.0, 82.4,
84.2, 100.5, 117.6, 127.3, 127.4, 127.6, 127.7, 128.0,
128.1, 132.0, 135.2, 135.3, 136.4, 153.9, 154.1, 154.2,
155.7, 156.1, 163.3, 168.6, 173.3, 203.3, 203.5.
Compound 9d (520 mg, 0.515 mmol) was dissolved with
CH3CN (7 mL) and AcOEt (7 mL) under N2 atmo-
sphere. After cooling this solution on an ice-water bath,
Pd(PPh3)4 (60 mg, 0.05 mmol), PPh3 (27 mg, 0.1 mmol),
pyrrolidine (65 lL, 0.77 mmol), and H2O (700 lL) were
added successively to the mixture. After stirring at room
temperature for an additional hour, the reaction mixture
was poured into saturated aqueous NH4Cl and extract-
ed with AcOEt (30 mL). The aqueous layer was extract-
ed with AcOEt (20 mL) and the combined organic layer
was washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by col-
umn chromatography on silica gel (n-hexane:AcOEt,
1:1–1:4) to give 480 mg of compound 3D as a colorless
foam (96%).
5.2.1. Compound 8d. MS (FAB): 983+(M+H+). HR-MS
(FAB) calcd for C52H75N2O16: 983.5117. Found:
983.5118.
IR (KBr): 3438, 3066, 3033, 2980, 2938, 2877, 1747, 1706,
1648, 1634, 1497, 1455, 1406, 1381, 1351, 1333, 1285,
1254, 1172, 1115, 1085, 1068, 1033, 983, 961, 935, 893,
824, 783, 754, 698, 617, 595, 576, 525, 471 (cmÀ1).
1H NMR (CDCl3) d (ppm): 2.72 (3H, s), 2.81 and 2.85
(3H, two s).
5.2.3. Compound 3D. MS (FAB): 969+ (M+H+). HR-MS
(FAB) calcd for C50H69N2O17: 969.4596. Found:
969.4612.
13C NMR (CDCl3) d (ppm): 10.6, 13.8, 13.9, 14.8, 16.2,
18.4, 19.3, 20.6, 21.5, 23.8, 24.3, 26.2, 28.9, 33.1, 35.7,
36.2, 37.2, 45.6, 45.7, 49.7, 50.7, 54.8, 65.4, 67.0, 67.1,
68.4, 68.5, 69.3, 69.5, 69.8, 73.5, 74.5, 76.3, 77.4, 77.9,
78.0, 80.8, 100.0, 118.2, 127.3, 127.5, 127.6, 127.7,
127.9, 128.1, 128.2, 128.3, 131.7, 135.0, 135.1, 136.4,
154.1, 154.2, 155.8, 156.2, 169.0, 169.5, 173.2, 205.1,
205.5.
IR (KBr): 3422, 3065, 3033, 2979, 2939, 2880, 1814,
1752, 1705, 1587, 1497, 1455, 1382, 1360, 1330, 1291,
1254, 1168, 1114, 1084, 1067, 1048, 1003, 988, 970,
932, 919, 826, 782, 755, 697, 628, 594, 542, 519, 457
(cmÀ1).
1H NMR (CDCl3) d (ppm): 2.65 (3H, s), 2.80 and 2.84
(3H, two s).
To a solution of 8d (520 mg, 0.528 mmol) in THF
(15 mL) were added (CCl3CO)2O (313 mg, 1.06 mmol)
and pyridine (427 lL, 5.28 mmol) under cooling on an
ice-water bath, and the mixture was stirred overnight
at room temperature. The reaction mixture was
quenched carefully with saturated aqueous NaHCO3
under cooling on an ice-water bath and stirred for
0.5 h at room temperature. After separating the organic
layer, the aqueous layer was extracted with AcOEt
(20 mL) and the combined organic layer was washed
13C NMR (CDCl3) d (ppm): 10.3, 12.9, 13.8, 15.2, 15.3,
18.5, 19.5, 20.6, 22.3, 23.8, 24.6, 26.3, 28.9, 33.3, 35.7,
36.1, 37.6, 46.7, 46.8, 49.6, 50.9, 54.7, 67.0, 67.1, 68.6,
69.2, 69.4, 74.5, 76.2, 78.0, 81.3, 82.0, 84.2, 100.3,
127.3, 127.4, 127.6, 127.7, 127.8, 128.0, 128.1, 128.2,
128.3, 130.0, 131.7, 131.9, 134.7, 134.8, 135.1, 135.3,
136.3, 153.3, 154.1, 154.2, 155.8, 156.2, 167.6, 168.7,
175.0, 203.4, 203.7.

T. Nomura et al. / Bioorg. Med. Chem. 14 (2006) 3697–3711
3703
5.3. Preparation of compounds 3A–C,E, and F
13C NMR (CDCl3) d (ppm): 9.6, 10.3, 13.0, 13.8, 15.1,
15.2, 15.4, 18.6, 19.5, 20.6, 22.4, 23.5, 26.4, 28.9, 33.3,
35.7, 36.2, 37.7, 46.6, 46.7, 49.6, 50.9, 54.7, 67.1, 67.2,
68.7, 69.2, 69.4, 74.6, 76.2, 78.0, 81.4, 82.1, 84.3, 100.3,
127.4, 127.5, 127.6, 127.7, 128.0, 128.1, 128.2, 135.2,
135.3, 136.4, 153.4, 154.1, 154.3, 155.9, 156.2, 167.9,
168.7, 172.3, 203.5, 203.7.
Preparation of 3A was reported in our previous paper.
Compounds 3B, 3C, 3E, and 3F were prepared in the
same procedure described for the synthesis of 3D with
(S)-2-bromo-propionic acid allyl ester 7b, (R)-2-bro-
mo-propionic acid allyl ester 7c, (S)-2-bromo-butyric
acid allyl ester 7e, and (S)-2-bromo-3-methyl-butyric
acid allyl ester 7f, respectively.
5.3.4. Compound 3F. MS (FAB): 983+ (M+H+). HR-MS
(FAB) calcd for C51H71N2O17: 983.4753. Found:
983.4745.
5.3.1. Compound 3B. MS (FAB): 955+ (M+H+). HR-MS
(FAB) calcd for C49H67N2O17: 955.4440. Found:
955.4450.
IR (KBr): 3429, 3065, 3033, 2973, 2938, 2879, 1812,
1752, 1705, 1497, 1456, 1383, 1330, 1291, 1254, 1167,
1114, 1067, 990, 933, 913, 782, 769, 754, 739, 698 (cmÀ1).
IR (KBr): 3423, 3065, 3033, 2978, 2939, 2881, 1813,
1752, 1704, 1497, 1455, 1382, 1330, 1291, 1254, 1167,
1114, 1084, 1066, 1048, 991, 951, 897, 826, 782, 770,
754, 739, 698, 624, 519, 457 (cmÀ1).
1H NMR (CDCl3) d (ppm): 2.68 (3H, s), 2.81 and 2.85
(3H, two s).
1H NMR (CDCl3) d (ppm): 2.66 (3H, s), 2.81 and 2.84
(3H, two s).
13C NMR (CDCl3) d (ppm): 10.3, 13.0, 13.8, 14.8, 15.0,
15.5, 17.2, 18.6, 19.1, 19.5, 20.6, 22.4, 26.5, 29.4, 33.3,
35.7, 37.6, 46.5, 49.6, 50.9, 54.7, 67.1, 68.7, 69.2, 69.4,
74.6, 76.2, 78.0, 82.0, 84.2, 85.0, 100.2, 127.4, 127.5,
127.7, 128.0, 128.2, 135.3, 136.4, 153.3, 154.1, 154.3,
155.8, 156.2, 168.3, 168.7, 171.3, 203.5.
13C NMR (CDCl3) d (ppm): 10.3, 12.9, 13.8, 15.1, 15.2,
15.4, 15.7, 18.5, 19.6, 20.6, 22.3, 26.4, 28.9, 33.2, 35.7,
36.2, 37.7, 46.6, 46.7, 49.6, 50.9, 54.7, 67.1, 67.2, 68.6,
69.2, 69.4, 74.6, 76.2, 76.6, 78.0, 82.1, 84.3, 100.3,
127.4, 127.5, 127.6, 127.7, 128.0, 128.1, 128.2, 135.2,
135.3, 136.4, 153.4, 154.1, 154.3, 155.9, 156.2, 167.9,
168.7, 172.8, 203.4, 203.7.
5.4. Preparation of compound 5e
5.4.1. Amidation. To
a solution of 3B (100 mg,
0.10 mmol) in toluene (6 mL) were added DMF
(2 lL, 0.03 mmol) and oxalyl chloride (11 lL,
0.12 mmol) at room temperature, and the reaction
mixture was stirred for 30 min at room temperature.
5.3.2. Compound 3C. MS (FAB): 955+ (M+H+). HR-MS
(FAB) calcd for C49H67N2O17: 955.4440. Found:
955.4442.
To
this
solution,
phenylpropylamine
(30 lL,
IR (KBr): 3429, 3065, 3033, 2977, 2939, 2881, 1812,
1752, 1704, 1587, 1497, 1455, 1382, 1331, 1289,
1254, 1166, 1113, 1083, 1068, 1048, 1003, 953, 899,
826, 782, 769, 755, 739, 698, 624, 595, 575, 518, 458
(cmÀ1).
0.21 mmol) was added, and the reaction mixture was
stirred another 15 min. The reaction mixture was
quenched with saturated aqueous NH4Cl and extracted
with AcOEt (20 mL). The aqueous layer was extracted
with AcOEt (20 mL), and the combined organic layer
was washed with brine, dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (n-hex-
ane:AcOEt, 4:1–1:1) to give 105 mg of compound 4
bearing (R)-N-(3-phenyl-propyl)-propionamide group
as a colorless foam (94%).
1H NMR (CDCl3) d (ppm): 2.65 (3H, s), 2.81 and 2.84
(3H, two s).
13C NMR (CDCl3) d (ppm): 10.3, 13.0, 13.8, 15.3, 16.9,
18.5, 19.5, 20.6, 22.3, 26.5, 28.8, 33.1, 35.7, 36.2, 37.7,
46.9, 49.4, 50.9, 54.7, 67.1, 67.2, 68.6, 69.2, 69.4, 74.6,
76.2, 78.1, 78.4, 82.4, 84.4, 84.7, 100.4, 127.4, 127.5,
127.6, 127.7, 128.0, 128.1, 128.2, 135.0, 135.1, 135.3,
135.8, 136.4, 153.8, 154.1, 154.2, 155.8, 156.2, 166.8,
168.7, 176.1, 203.4, 203.6.
MS (FAB) 1072+ (M+H+); HRMS (FAB) calcd for
C58H78N3O16 (M+H+): 1072.5382. Found: 1072.5384.
IR (KBr): 3565, 2971, 2879, 2833, 1804, 1749, 1700,
1524, 1497, 1455, 1377, 1329, 1287, 1249, 1164, 1111,
1046 (cmÀ1).
5.3.3. Compound 3E. MS (FAB): 969+ (M+H+). HR-MS
(FAB) calcd for C50H69N2O17: 969.4596. Found:
969.4603.
1H NMR (CDCl3) d 2.62 (3H, s), 2.80, 2.84 (3H, two s).
IR (KBr): 3422, 3065, 3033, 2975, 2938, 2880, 1813,
1752, 1704, 1497, 1456, 1383, 1330, 1291, 1254,
1167, 1114, 1083, 1066, 989, 953, 934, 909, 826,
782, 769, 754, 739, 698, 625, 595, 576, 518, 457
(cmÀ1).
13C NMR (CDCl3) d 10.2, 12.9, 13.9, 15.3, 15.5,
15.6, 15.9, 18.8, 19.8, 20.6, 22.3, 26.1, 28.9, 30.8,
33.2, 35.7, 36.2, 37.5, 39.0, 46.9, 47.0, 49.6, 51.0,
54.7, 67.1, 67.2, 68.7, 69.2, 69.4, 74.6, 76.0, 77.5,
78.2, 78.4, 82.2, 84.3, 100.4, 125.5, 127.4, 127.5,
127.7, 127.8, 128.0, 128.1, 128.2, 135.3, 135.4, 136.4,
141.5, 153.3, 154.1, 154.3, 155.8, 156.2, 165.7, 168.8,
171.7, 203.3, 203.5.
1H NMR (CDCl3) d (ppm): 2.67 (3H, s), 2.80 and 2.84
(3H, two s).

3704
T. Nomura et al. / Bioorg. Med. Chem. 14 (2006) 3697–3711
5.4.2. Deprotection and N-methylation (method A). This
colorless foam 4 (100 mg, 0.093 mmol) with (R)-N-(3-
phenyl-propyl)-propionamide was diluted with EtOH
(10 mL) and 0.2 M acetate buffer (3 mL, pH 4.4). To this
solution was added 20% Pd(OH)2/C (30 mg, 0.056 mmol)
with stirring at room temperature under H2 atmosphere
for 1 h. After confirming the disappearance of 4 by
TLC, 37% aqueous HCHO (1 mL) was added to the reac-
tion mixture and stirring was continued at room temper-
ature under H2 atmosphere for an additional 2 h. The
mixture was filtered and concentrated. After being diluted
with water, the mixture was basified with 5% aqueous
NaHCO3 and then extracted with AcOEt. The resultant
residue was purified by column chromatography on silica
gel (CHCl3/MeOH, 80/1–40/1) to give 61 mg of com-
pound 5e as a colorless foam (80%).
bearing (R)-N-(3-quinoxalin-6-yl-propyl)-propionamide
group as a colorless foam (94%).
MS (FAB): 1124+ (M+H+). HR-MS (FAB) calcd for
C60H78N5O16: 1124.5444. Found: 11124.5453.
IR (KBr): 3359, 2931, 2853, 1087, 1749, 1699, 1532,
1498, 1455, 1380, 1329, 1289, 1251, 1166, 1112, 1066,
1047 (cmÀ1).
1H NMR (CDCl3) d (ppm): 2.63 (3H, s), 2.80 and 2.84
(3H, two s).
13C NMR (CDCl3) d (ppm): 10.2, 12.9, 13.9, 15.3, 15.7,
18.8, 19.8, 20.6, 22.2, 26.1, 29.6, 30.5, 33.0, 33.3, 35.7,
36.1, 37.5, 38.9, 47.0, 47.1, 49.6, 50.9, 54.6, 67.1, 67.2,
68.6, 69.2, 69.4, 74.6, 75.8, 77.4, 78.1, 78.2, 82.2, 84.3,
100.4, 127.3, 127.5, 127.6, 127.7, 128.0, 128.2, 128.9,
131.4, 135.2, 135.3, 136.4, 141.5, 142.9, 143.8, 144.3,
144.5, 153.4, 154.1, 154.2, 155.8, 156.2, 165.6, 168.8,
171.8, 203.3, 203.4.
5.4.3. Compound 5e. MS (FAB): 818+ (M+H+). HR-MS
(FAB) calcd for C43H68N3O12: 818.4803. Found:
818.4809.
IR (KBr): 3438, 3061, 2974, 2938, 2878, 2785, 1812,
1752, 1717, 1673, 1529, 1497, 1455, 1379, 1322, 1283,
1257, 1233, 1167, 1142, 1109, 1082, 1047, 1005, 992,
952, 932, 899, 835, 801, 773, 750, 700, 630, 573, 555,
533, 455 (cmÀ1).
5.5.2. Deprotection and N-methylation (method B). This
colorless foam 4 (120 mg, 0.11 mmol) with (N-3-quinox-
alin-6-yl-propyl)-propionamide was dissolved with
CH2Cl2 (1.2 mL), and iodotrimethylsilane (TMS-I,
61 lL, 0.44 mmol) was added to the solution at room
temperature under N2 atmosphere. After being stirred
for 1 h at room temperature, the reaction mixture was
cooled to 0 ꢁC. To this were added AlCl3 (57 mg,
0.44 mmol) and anisole (2 mL) dissolved in CH2Cl2
(2.4 mL) with stirring for 40 min at 0 ꢁC. The reaction
mixture was diluted with H2O (1 mL) and n-hexane
(8 mL) at 0 ꢁC, and the precipitate was collected, washed
three times with n-hexane, and dissolved with MeOH–
CHCl3 (2–10 mL). This solution was poured into satu-
rated aqueous NaHCO3 and extracted twice with
CHCl3–MeOH (10:1), and the combined organic layer
was washed with diluted aqueous Na2S2O3, brine, dried
over MgSO4, filtered, and concentrated in vacuo. The
resultant residue was dissolved with MeOH (3 mL), then
98% HCO2H (8 lL) and 35% aqueous HCHO (55 lL)
were added with stirring at 75 ꢁC for 3 h. After cooling
to room temperature, the reaction mixture was poured
into saturated aqueous NaHCO3 and extracted with
AcOEt (2· 20 mL). The combined extract was washed
with brine, dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by column chroma-
tography on silica gel (CHCl3/MeOH = 40/1–5/1) to give
77 mg of compound 5p as a colorless foam (80%).
1H NMR (CDCl3) d (ppm): 0.89 (3H, t, J = 7.2 Hz), 1.00
(3H, d, J = 6.9 Hz), 1.23 (3H, d, J = 6.0 Hz), 1.26 (3H,
d, J = 6.6 Hz), 1.27 (3H, d, J = 7.5 Hz), 1.38 (3H, d,
J = 6.9 Hz), 1.38 (3H, s), 1.43 (3H, d, J = 6.9 Hz), 1.56
(3H, s), 1.20–1.94 (7H, m), 2.27 (6H, s), 2.40–2.51
(1H, m), 2.55 (1H, q, J = 7.2 Hz), 2.65 (3H, s), 2.65
(2H, t, J = 7.8 Hz), 3.02 (1H, quintet, J = 7.8 Hz),
3.04–3.16 (2H, m), 3.17 (1H, dd, J = 7.5 and 10.2 Hz),
3.41 (1H, sextet, J = 6.6 Hz), 3.48–3.75 (2H, m), 3.82
(1H, q, J = 6.6 Hz), 4.21 (1H, d, J = 8.4 Hz), 4.30 (1H,
d, J = 7.2 Hz), 4.49 (1H, q, J = 6.9 Hz), 4.82 (1H, s),
4.98 (1H, dd, J = 3.0 and 10.2 Hz), 7.01 (1H, t,
J = 5.7 Hz), 7.10–7.30 (5H, m).
13C NMR (CDCl3) d (ppm): 10.2, 12.9, 14.3, 15.3, 15.7,
15.9, 18.9, 19.9, 21.2, 22.2, 26.2, 28.2, 30.8, 33.0, 33.2,
37.9, 39.0, 40.2, 47.7, 49.7, 51.1, 65.8, 69.5, 70.3, 76.0,
78.4, 78.5, 78.6, 82.4, 84.5, 103.7, 125.6, 128.2, 128.3,
141.7, 153.8, 166.1, 169.1, 172.0, 203.9.
5.5. Preparation of compound 5p
5.5.1. Amidation. To a solution of 3B (153 mg,
0.16 mmol) in toluene (6 mL) was added DMF (2 lL,
0.03 mmol) and oxalyl chloride (17 lL, 0.19 mmol) at
room temperature, and the reaction mixture was stirred
for 90 min at room temperature. To this solution was
added 12c (120 mg, 0.64 mmol) dissolved in THF
(0.3 mL), and the reaction mixture was stirred another
15 min. The reaction mixture was quenched with satu-
rated aqueous NH4Cl and extracted with AcOEt
(20 mL). The aqueous layer was extracted with AcOEt
(20 mL), and the combined organic layer was washed
with brine, dried over MgSO4, filtered and concentrated
in vacuo. The residue was purified by column chroma-
tography on silica gel to give 170 mg of compound 4
5.5.3. Compound 5p. MS (FAB): 870+ (M+H+). HR-MS
(FAB) calcd for C45H68N5O12: 870.4864. Found:
870.4873.
IR (KBr): 3435, 2974, 2937, 2878, 2784, 1811, 1751,
1716, 1673, 1530, 1499, 1455, 1367, 1322, 1284, 1257,
1234, 1218, 1167, 1141, 1109, 1082, 1047, 1005, 992,
954, 931, 897, 866, 832, 773, 755, 693, 666, 631, 573,
458, 408 (cmÀ1).
1H NMR (CDCl3) d (ppm): 0.85 (3H, t, J = 7.2 Hz), 1.00
(3H, d, J = 6.9 Hz), 1.21 (3H, d, J = 6.0 Hz), 1.25 (3H,

T. Nomura et al. / Bioorg. Med. Chem. 14 (2006) 3697–3711
3705
d, J = 7.5 Hz), 1.27 (3H, d, J = 7.2 Hz), 1.36 (3H, d,
J = 6.9 Hz), 1.39 (3H, s), 1.44 (3H, d, J = 6.9 Hz), 1.56
(3H, s), 1.20–1.94 (6H, m), 2.03 (2H, m), 2.26 (6H, s),
2.45 (1H, m), 2.55 (1H, q, J = 7.2 Hz), 2.67 (3H, s),
2.92 (2H, dd, J = 6.9 and 8.7 Hz), 3.01 (1H, quintet,
J = 7.5 Hz), 3.10–3.22 (2H, m), 3.46–3.58 (2H, m),
3.64–3.75 (1H, m), 3.82 (1H, q, J = 6.9 Hz), 4.21 (1H,
d, J = 8.4 Hz), 4.29 (1H, d, J = 7.2 Hz), 4.49 (1H, q,
J = 6.9 Hz), 4.84 (1H, s), 4.99 (1H, dd, J = 2.7 and
10.5 Hz), 7.20 (1H, br t, J = 5.7 Hz), 7.70 (1H, dd,
J = 1.8 and 8.7 Hz), 7.91 (1H, d, J = 1.8 Hz), 8.01 (1H,
d, J = 8.7 Hz), 8.77 (1H, d, J = 8.7 Hz), 8.78 (1H, d,
J = 8.7 Hz).
IR (KBr): 3431, 2973, 2938, 2879, 2785, 1811, 1752,
1700, 1654, 1637, 1497, 1455, 1380, 1323, 1305, 1283,
1257, 1233, 1167, 1142, 1109, 1080, 1048, 1004, 992,
953, 932, 892, 834, 773, 751, 700, 631, 558, 529, 458
(cmÀ1).
1H NMR (CDCl3) d (ppm): 0.91 (3H, t, J = 7.5 Hz), 1.00
(3H, d, J = 6.9 Hz), 1.25 (3H, d, J = 6.0 Hz), 1.26 (3H,
d, J = 6.3 Hz), 1.28 (3H, d, J = 7.8 Hz), 1.36 (3H, s),
1.38 (3H, d, J = 7.2 Hz), 1.56 (3H, s), 1.20–1.92 (5H,
m), 2.32 (6H, s), 2.30–2.37 (1H, m), 2.55 (1H, q,
J = 6.3 Hz), 2.69 (3H, s), 3.01 (1H, m), 3.02 (3H, t,
J = 7.2 Hz), 3.22 (1H, m), 3.50–3.74 (3H, m), 3.84 (1H,
q, J = 6.9 Hz), 4.17–4.27 (3H, m), 4.32 (1H, d,
J = 7.2 Hz), 4.44 and 4.52 (2H, ABq, J = 15.0 Hz),
4.89 (1H, s), 5.00 (1H, dd, J = 2.7 and 10.2 Hz), 7.16–
7.32 (5H, m), 9.51 (1H, br s).
13C NMR (CDCl3) d (ppm): 10.2, 12.9, 14.3, 15.3, 15.6,
15.8, 18.9, 19.9, 21.1, 22.3, 26.2, 28.3, 30.5, 33.1, 33.4,
37.9, 39.0, 40.2, 47.6, 49.8, 51.1, 65.9, 69.5, 70.3, 76.0,
78.4, 78.5, 82.4, 84.6, 103.7, 127.8, 129.1, 131.6, 141.8,
143.2, 144.1, 144.6, 144.8, 153.8, 166.4, 169.3, 172.2,
203.9.
13C NMR (CDCl3) d (ppm): 10.2, 12.9, 14.3, 15.4, 15.5,
18.7, 19.9, 21.1, 22.2, 26.3, 28.2, 33.1, 34.4, 38.0, 40.2,
47.5, 49.8, 51.0, 65.8, 69.5, 70.2, 72.3, 76.0, 78.3, 78.4,
82.3, 84.6, 103.6, 126.1, 128.3, 128.9, 137.9, 153.6,
167.5, 167.9, 169.1, 204.0.
5.6. Preparation of compounds 5a–d
Compounds 5a–d were prepared from 3A by the proce-
dure described for the synthesis of 5e with O-phenethyl-
hydroxylamine,7 2-phenoxyethylamine,8 N-methyl-N-
phenethyl-hydrazine,9 and N-methyl-N-phenyl-ethylene-
diamine,10 respectively.
5.6.3. Compound 5c. MS (FAB): 819+ (M+H+). HRMS
(FAB) calcd for C42H67N4O12: 819.4755. Found:
819.4755.
IR (KBr): 3429, 2974, 2938, 2880, 2786, 1808, 1752,
1716, 1674, 1600, 1570, 1528, 1508, 1456, 1376, 1361,
1323, 1304, 1283, 1257, 1235, 1212, 1166, 1142, 1108,
1079, 1049, 1004, 992, 953, 932, 893, 860, 835, 801,
773, 749, 693, 634, 581, 551, 517, 456 (cmÀ1).
5.6.1. Compound 5a. MS (FAB): 806+ (M+H+). HRMS
(FAB) calcd for C41H64N3O13: 806.4439. Found:
806.4441.
IR (KBr): 3438, 2973, 2937, 2878, 2785, 1811, 1751,
1717, 1679, 1637, 1599, 1588, 1528, 1497, 1457, 1380,
1363, 1324, 1303, 1285, 1244, 1169, 1141, 1109, 1078,
1048, 1004, 993, 953, 931, 891, 773, 755, 693, 555, 512
(cmÀ1).
1H NMR (CDCl3) d (ppm): 0.90 (3H, t, J = 7.5 Hz), 0.95
(3H, d, J = 7.2 Hz), 1.23 (3H, d, J = 6.6 Hz), 1.25 (3H,
d, J = 5.9 Hz), 1.28 (3H, d, J = 8.1 Hz), 1.36 (3H, s),
1.37 (3 H, d, J = 6.0 Hz), 1.56 (3H, s), 1.20–1.98 (5H,
m), 2.27 (6H, s), 2.40–2.52 (1H, m), 2.55 (1H, q,
J = 6.6 Hz), 2.67 (3H, s), 2.95 (3H, s), 2.90–3.06 (2H,
m), 3.19 (1H, m), 3.26–3.70 (7H, m), 3.84 (1H, q,
J = 6.9 Hz), 4.21 (1H, d, J = 8.1 Hz), 4.30 (1H, d,
J = 6.6 Hz), 4.42 (2H, s), 4.84 (1H, s), 5.04 (1H, dd,
J = 3.0 and 10.5 Hz), 6.64–6.72 (1H, m), 6.76–6.83
(2H, m), 7.08–7.25 (3H, m).
1H NMR (CDCl3) d (ppm): 0.88 (3H, t, J = 7.2 Hz), 1.00
(3H, d, J = 7.2 Hz), 1.18 (3H, d, J = 6.6 Hz), 1.24 (3H,
d, J = 6.3 Hz), 1.27 (3H, d, J = 7.8 Hz), 1.37 (3H, d,
J = 6.9 Hz), 1.38 (3H, s), 1.53 (3H, s), 1.20–1.92 (6H,
m), 2.27 (6H, s), 2.38–2.52 (1H, m), 2.53 (1H, q,
J = 6.6 Hz), 2.70 (3H, s), 3.02 (1H, quintet,
J = 8.1 Hz), 3.18 (1H, dd, J = 7.5 and 10.2 Hz), 3.50–
3.75 (4H, m), 3.83 (1H, q, J = 6.9 Hz), 4.07 (2H, t,
J = 5.4 Hz), 4.21 (1H, d, J = 7.8 Hz), 4.30 (1H, d,
J = 7.2 Hz), 4.46 and 4.54 (2H, ABq, J = 15.3 Hz),
4.81 (1H, s), 5.01 (1H, dd, J = 3.0 and 10.2 Hz), 6.86–
6.96 (3H, m), 7.03 (1H, br t, J = 6.0 Hz), 7.22–7.29
(2H, m).
13C NMR (CDCl3) d (ppm): 10.3, 12.9, 14.3, 15.3, 15.5,
18.8, 19.9, 21.2, 22.3, 26.3, 28.3, 33.2, 36.2, 38.0, 38.1,
40.2, 47.6, 49.7, 51.0, 51.6, 65.9, 69.5, 70.3, 72.9, 76.1,
78.4, 78.6, 82.4, 84.7, 103.7, 112.4, 116.4, 129.1, 149.3,
153.8, 167.4, 169.2, 170.6, 203.9.
5.6.4. Compound 5d. MS (FAB): 819+ (M+H+). HR-MS
(FAB) calcd for C42H67N4O12: 819.4755. Found:
819.4762.
13C NMR (CDCl3) d (ppm): 10.2, 13.0, 14.2, 15.2, 15.5,
18.8, 19.8, 21.1, 22.2, 26.4, 28.1, 33.2, 38.0, 38.4, 40.1,
47.5, 49.6, 51.0, 65.7, 66.3, 69.4, 70.1, 72.7, 76.0, 78.2,
78.5, 82.1, 84.4, 103.4, 114.2, 120.6, 129.2, 153.6,
158.2, 167.3, 168.8, 170.1, 203.6.
IR (KBr): 3432, 3062, 2972, 2937, 2878, 2786, 1811,
1751, 1686, 1654, 1647, 1637, 1629, 1559, 1541, 1523,
1508, 1497, 1456, 1380, 1362, 1323, 1304, 1283, 1257,
1233, 1219, 1167, 1142, 1109, 1079, 1048, 1004, 993,
953, 932, 892, 859, 834, 800, 773, 751, 700, 669, 629,
555, 515, 454 (cmÀ1).
5.6.2. Compound 5b. MS (FAB): 806+ (M+H+). HR-MS
(FAB) calcd for C41H64N3O13 806.4439. Found:
806.4438.

3706
T. Nomura et al. / Bioorg. Med. Chem. 14 (2006) 3697–3711
1H NMR (CDCl3) d (ppm): 0.90 (3H, t, J = 7.5 Hz),
1.01 (3H, d, J = 6.9 Hz), 1.25 (3H, d, J = 6.6 Hz),
1.27 (3H, d, J = 7.8 Hz), 1.28 (3H, d, J = 7.8 Hz),
1.37 (3H, d, J = 6.9 Hz), 1.40 (3H, s), 1.56 (3H, s),
1.20–1.98 (6H, m), 2.27 (6H, s), 2.40–2.63 (2H, m),
2.66 (3H, s), 2.72 (3H, s), 2.68–2.74 (2H, m), 2.80–
3.25 (5H, m), 3.45–3.75 (2H, m), 3.84 (1H, q,
J = 6.6 Hz), 4.23 (1H, d, J = 8.1 Hz), 4.30 (1H, d,
J = 7.2 Hz), 4.33 and 4.44 (2H, ABq, J = 15.3 Hz),
4.82 (1H, s), 5.04 (1H, dd, J = 2.7 and 10.2 Hz),
7.17–7.32 (5H, m), 7.54 (1H, br s).
1H NMR (CDCl3) d (ppm): 0.90 (3H, t, J = 7.2 Hz), 0.99
(3H, d, J = 6.9 Hz), 1.24 (3H, d, J = 5.4 Hz), 1.26 (3H,
d, J = 6.6 Hz), 1.28 (3H, d, J = 7.8 Hz), 1.38 (3H, d,
J = 6.9 Hz), 1.40 (3H, s), 1.45 (3H, s), 1.49 (3H, s),
1.56 (3H, s), 1.20–1.94 (7H, m), 2.27 (6H, s), 2.40–2.51
(1H, m), 2.57 (1H, q, J = 6.9 Hz), 2.64 (2H, t,
J = 8.4 Hz), 2.68 (3H, s), 3.03 (1H, quintet,
J = 7.5 Hz), 3.12–3.32 (3H, m), 3.35 (1H, septet, J =
7.2 Hz), 3.48–3.77 (2H, m), 3.83 (1H, q, J = 6.6 Hz),
4.22 (1H, d, J = 7.8 Hz), 4.31 (1H, d, J = 7.2 Hz), 4.84
(1H, s), 5.01 (1H, dd, J = 2.4 and 9.9 Hz), 7.10–7.30
(6H, m).
13C NMR (CDCl3) d (ppm): 10.2, 13.0, 14.3, 15.4, 15.6,
18.9, 19.9, 21.1, 22.3, 26.4, 28.2, 29.7, 33.1, 34.0, 38.1,
40.2, 46.4, 47.6, 50.0, 51.0, 60.9, 65.9, 69.5, 70.3, 72.6,
76.1, 78.4, 78.9, 82.4, 84.5, 103.8, 125.9, 128.3, 128.7,
139.8, 153.9, 168.3, 168.6, 169.2, 203.9.
13C NMR (CDCl3) d (ppm): 10.3, 12.9, 14.3, 15.3, 15.6,
18.8, 19.7, 21.2, 22.3, 24.3, 25.2, 26.2, 28.2, 31.0, 33.2,
37.9, 38.9, 40.2, 47.6, 49.8, 51.1, 65.9, 69.5, 70.3, 76.1,
78.4, 78.5, 82.5, 82.7, 84.5, 103.7, 125.6, 128.2, 128.4,
141.8, 153.8, 166.0, 169.2, 174.8, 204.0.
5.7. Preparation of compounds 5f–i
5.7.3. Compound 5h. MS (FAB): 832+ (M+H+). HR-MS
(FAB) calcd for C44H70N3O12: 832.4960. Found:
832.4955.
Compounds 5f–i were prepared by the procedure de-
scribed for the synthesis of 5e with 3-phenylpropylamine
from 3C–F, respectively.
IR (KBr): 3437, 3085, 3061, 2972, 2937, 2878, 2785,
1811, 1751, 1717, 1673, 1527, 1497, 1455, 1380, 1362,
1324, 1304, 1283, 1257, 1233, 1167, 1141, 1109, 1081,
1048, 1005, 990, 954, 932, 912, 863, 835, 801, 771, 750,
700, 669, 631, 575, 555, 533, 455, 430 (cmÀ1).
5.7.1. Compound 5f. MS (FAB): 818+ (M+H+). HR-MS
(FAB) calcd for C43H68N3O12: 818.4803. Found:
818.4803.
IR (KBr): 3438, 3061, 2974, 2937, 2878, 2785, 1811,
1751, 1717, 1671, 1525, 1497, 1455, 1379, 1321, 1283,
1257, 1233, 1167, 1142, 1109, 1082, 1048, 1005, 992,
953, 932, 899, 835, 802, 773, 749, 700, 621, 573, 510,
420 (cmÀ1).
1H NMR (CDCl3) d (ppm): 0.89 (3H, t, J = 7.2 Hz), 0.95
(3H, t, J = 7.5 Hz), 1.00 (3H, d, J = 7.2 Hz), 1.23 (3H, d,
J = 6.0 Hz), 1.26 (3H, d, J = 6.6 Hz), 1.28 (3H, d,
J = 7.2 Hz), 1.38 (3H, d, J = 6.9 Hz), 1.39 (3H, s), 1.55
(3H, s), 1.20–2.05 (10H, m), 2.26 (6H, s), 2.44 (1H, m),
2.56 (1H, q, J = 6.9 Hz), 2.65 (2H, t, J = 7.8 Hz), 2.68
(3H, s), 3.03 (1H, quintet, J = 7.5 Hz), 3.11–3.22 (2H,
m), 3.39 (1H, sextet, J = 6.9 Hz), 3.48–3.76 (2H, m),
3.83 (1H, q, J = 6.9 Hz), 4.22 (1H, d, J = 8.1 Hz), 4.30
(1H, d, J = 6.9 Hz), 4.3 (1H, t, J = 5.1 Hz), 4.82 (1H,
s), 4.98 (1H, dd, J = 3.0 and 10.2 Hz), 6.83 (1H, t,
J = 5.7 Hz), 7.11–7.29 (5H, m).
1H NMR (CDCl3) d (ppm): 0.89 (3H, t, J = 7.2 Hz), 1.01
(3H, d, J = 7.2 Hz), 1.23 (3H, d, J = 6.6 Hz), 1.24 (3H,
d, J = 6.0 Hz), 1.28 (3H, d, J = 7.5 Hz), 1.37 (3H, d,
J = 6.9 Hz), 1.40 (3H, s), 1.46 (3H, d, J = 7.2 Hz), 1.55
(3H, s), 1.20–1.94 (7H, m), 2.27 (6H, s), 2.40–2.51
(1H, m), 2.55 (1H, q, J = 6.6 Hz), 2.65 (2H, t,
J = 7.8 Hz), 2.68 (3H, s), 3.03 (1H, quintet,
J = 7.8 Hz), 3.18 (1H, dd, J = 7.5 and 9.9 Hz), 3.25–
3.40 (3H, m), 3.50–3.74 (2H, m), 3.84 (1H, q,
J = 6.6 Hz), 4.22 (1H, d, J = 7.8 Hz), 4.30 (1H, d,
J = 7.2 Hz), 4.58 (1H, q, J = 6.9 Hz), 4.80 (1H, s), 5.02
(1H, dd, J = 2.7 and 10.2 Hz), 6.74 (1H, t, J = 5.7 Hz),
7.18–7.32 (5H, m).
13C NMR (CDCl3) d (ppm): 9.6, 10.2, 12.9, 14.3, 15.3,
15.6, 19.0, 19.9, 21.2, 22.3, 23.6, 26.4, 28.2, 30.9, 33.2,
37.9, 38.9, 40.2, 47.6, 49.8, 51.1, 65.9, 69.5, 70.3, 76.1,
78.5, 82.3, 83.5, 84.5, 103.7, 125.6, 128.2, 128.4, 141.7,
153.8, 166.6, 169.2, 171.6, 204.0.
13C NMR (CDCl3) d (ppm): 10.3, 13.0, 14.2, 15.5, 15.7,
17.5, 18.8, 19.7, 21.2, 22.3, 26.3, 28.2, 31.1, 33.1, 38.1,
38.7, 40.2, 47.7, 49.7, 51.0, 65.8, 69.5, 70.3, 76.2, 78.3,
78.8, 79.2, 82.5, 84.5, 103.7, 125.8, 128.2, 128.3, 128.4,
141.5, 153.9, 166.5, 169.1, 172.8, 203.9.
5.7.4. Compound 5i. MS (FAB): 846+ (M+H+). HR-MS
(FAB) calcd for C45H72N3O12: 846.5116. Found:
846.5109.
IR (KBr): 3436, 3061, 2965, 2930, 2874, 2854, 2785,
1810, 1750, 1717, 1671, 1527, 1496, 1455, 1381, 1323,
1304, 1284, 1257, 1233, 1219, 1167, 1141, 1109, 1079,
1047, 1007, 992, 954, 931, 913, 862, 835, 800, 777, 750,
699, 668, 577, 529, 456, 419 (cmÀ1).
5.7.2. Compound 5g. MS (FAB): 832+ (M+H+). HR-MS
(FAB) calcd for C44H70N3O12: 832.4960. Found:
832.4946.
IR (KBr): 3443, 3062, 2975, 2938, 2878, 2785, 1812,
1751, 1717, 1669, 1525, 1498, 1455, 1378, 1362, 1323,
1305, 1284, 1258, 1218, 1166, 1109, 1083, 1047, 1005,
992, 954, 930, 835, 801, 771, 750, 699, 580, 558, 457
(cmÀ1).
1H NMR (CDCl3) d (ppm): 0.89 (3H, t, J = 7.2 Hz), 0.94
(3H, t, J = 6.9 Hz), 1.01 (6H, d, J = 7.2 Hz), 1.24 (3H, d,
J = 7.5 Hz), 1.25 (3H, d, J = 6.0 Hz), 1.28 (3H, d,
J = 7.5 Hz), 1.38 (3H, d, J = 6.6 Hz), 1.41 (3H, s), 1.56
(3H, s), 1.20–1.94 (9H, m), 2.30 (6H, s), 2.40–2.60

T. Nomura et al. / Bioorg. Med. Chem. 14 (2006) 3697–3711
3707
(3H, m), 2.64 (2H, t, J = 8.4 Hz), 2.71 (3H, s), 2.87 (1H,
br s), 3.04 (1H, quintet, J = 7.2 Hz), 3.16–3.41 (3H, m),
3.50–3.80 (2H, m), 3.83 (1H, q, J = 6.9 Hz), 4.19 (1H, d,
J = 3.9 Hz), 4.24 (1H, d, J = 7.8 Hz), 4.32 (1H, d,
J = 7.2 Hz), 4.82 (1H, s), 4.99 (1H, dd, J = 3.0 and
10.5 Hz), 6.64 (1H, t, J = 5.7 Hz), 7.12–7.30 (5H, m).
1H NMR (CDCl3) d (ppm): 0.86 (3H, t, J = 7.5 Hz), 1.01
(3H, d, J = 6.9 Hz), 1.23 (3H, d, J = 6.3 Hz), 1.27 (3H, d,
J = 6.9 Hz), 1.28 (3H, d, J = 7.5 Hz), 1.37 (3H, d,
J = 6.6 Hz), 1.39 (3H, s), 1.56 (3H, s), 124–1.92 (7H, m),
2.04 (2H, quintet, J = 7.8 Hz), 2.27 (6H, s), 2.46 (1H,
m), 2.57 (1H, q, J = 7.2 Hz), 2.70 (3H, s), 2.92 (2H, t,
J = 7.5 Hz), 3.02 (1H, quintet, J = 7.5 Hz), 3.18 (1H, dd,
J = 7.2 and 10.2 Hz), 3.29 (1H, m), 3.42–3.60 (2H, m),
3.61–3.76 (1H, m), 3.83 (1H, q, J = 6.9 Hz), 4.22 (1H, d,
J = 8.1 Hz), 4.30 (1H, d, J = 7.2 Hz), 4.46 (2H, s), 4.84
(1H, s), 5.01 (1H, dd, J = 3.0 and 10.5 Hz), 7.12 (1H, t,
J = 5.4 Hz), 7.69 (1H, dd, J = 1.5 and 8.7 Hz), 7.91 (1H,
d, J = 1.5 Hz), 8.02 (1H, d, J = 8.7 Hz), 8.78 (1H, d,
J = 8.4 Hz), 8.79 (1H, d, J = 8.4 Hz).
13C NMR (CDCl3) d (ppm): 10.3, 13.0, 14.3, 15.2,
15.4, 17.0, 19.0, 19.5, 19.9, 21.2, 22.4, 26.5, 28.4,
29.5, 29.7, 31.2, 33.2, 37.9, 38.9, 40.2, 47.5, 49.8,
51.2, 66.0, 69.5, 70.3, 76.3, 78.3, 78.6, 82.2, 84.6,
87.2, 103.6, 125.7, 128.3, 128.4, 141.7, 153.9, 166.9,
169.2, 171.6, 204.1.
5.8. Preparation of compounds 5l,o, and s
13C NMR (CDCl3) d (ppm): 10.2, 12.9, 14.3, 15.3, 15.6,
18.9, 19.9, 21.1, 22.2, 26.3, 28.2, 30.5, 33.2, 33.3, 38.0,
38.8, 40.2, 47.6, 49.8, 51.1, 65.9, 69.6, 70.3, 73.0, 76.0,
78.5, 78.6, 82.3, 84.6, 103.8, 127.8, 129.2, 131.6, 141.8,
143.2, 144.1, 144.4, 144.8, 153.8, 167.7, 169.3, 170.5, 203.9.
Compounds 5l,o, and s were prepared from 3A by the
procedure described for the synthesis of 5p with 12b,c,
and d, respectively.
5.8.1. Compound 5l. MS (FAB): 855+ (M+H+). HR-MS
(FAB) calcd for C45H67N4O12: 855.4755. Found:
855.4766.
5.8.3. Compound 5s. MS (FAB): 856+ (M+H+). HR-MS
(FAB) calcd for C44H66N5 O12 856.4708. Found:
856.4714.
IR (KBr): 3434, 2973, 2937, 2878, 2784, 1810, 1751,
1716, 1672, 1625, 1596, 1534, 1503, 1455, 1380, 1363,
1320, 1284, 1257, 1233, 1219, 1167, 1142, 1109, 1079,
1047, 1004, 992, 953, 931, 892, 835, 801, 772, 754, 695,
664, 615, 555, 530, 479, 456 (cmÀ1).
IR (KBr): 3433, 3063, 2972, 2937, 2878, 2784, 1810,
1751, 1716, 1673, 1533, 1491, 1455, 1380, 1363, 1322,
1304, 1284, 1258, 1233, 1219, 1167, 1141, 1109, 1078,
1048, 1005, 992, 953, 931, 893, 859, 835, 801, 762, 695,
666, 628, 611, 557, 532, 456, 409 (cmÀ1).
1H NMR (CDCl3) d (ppm): 0.86 (3H, t, J = 7.5 Hz),
1.01 (3H, d, J = 6.6 Hz), 1.23 (3H, d, J = 5.0 Hz),
1.25 (3H, d, J = 7.2 Hz), 1.28 (3H, d, J = 7.2 Hz),
1.36 (3H, d, J = 7.2 Hz), 1.39 (3H, s), 1.55 (3H, s),
1.54–1.92 (7H, m), 2.01 (2H, quintet, J = 7.8 Hz),
2.27 (6H, s), 2.46 (1H, m), 2.59 (1H, q, J = 6.9 Hz),
2.69 (3H, s), 2.89 (2H, t, J = 8.4 Hz), 3.02 (1H, quin-
tet, J = 7.8 Hz), 3.18 (1H, dd, J = 7.8 and 10.2 Hz),
3.30 (1H, m), 3.44 (1H, m), 3.50–3.74 (2H, m), 3.83
(1H, q, J = 6.9 Hz), 4.22 (1H, d, J = 7.8 Hz), 4.29
(1H, d, J = 7.5 Hz), 4.47 (2H, s), 4.83 (1H, s), 5.01
(1H, dd, J = 2.7 and 10.2 Hz), 6.96 (1H, t,
J = 5.4 Hz), 7.33 (1H, dd, J = 3.9 and 8.1 Hz), 7.45
(1H, dd, J = 1.5 and 8.4 Hz), 7.74 (1H, d,
J = 8.7 Hz), 7.89 (1H, s), 8.10 (1H, dd, J = 1.2 and
8.1 Hz), 8.86 (1H, m).
1H NMR (CDCl3) d (ppm): 0.85 (3H, t, J = 7.2 Hz), 1.01
(3H, d, J = 6.6 Hz), 1.23 (3H, d, J = 6.0 Hz), 1.26 (3H,
d, J = 6.6 Hz), 1.28 (3H, d, J = 7.5 Hz), 1.35 (3H, d,
J = 6.6 Hz), 1.39 (3H, s), 1.55 (3H, s), 1.24–1.92 (7H,
m), 2.15 (2H, quintet, J = 7.2 Hz), 2.26 (6H, s), 2.44
(1H, m), 2.56 (1H, q, J = 6.9 Hz), 2.71 (3H, s), 2.96–
3.08 (1H, m), 3.01 (1H, quintet, J = 7.8 Hz), , 3.08
(2H, t, J = 7.8 Hz), 3.17 (1H, dd, J = 7.5 and 10.5 Hz),
3.36 (1H, m), 3.46–3.59 (2H, m), 3.62–3.75 (1H, m),
3.82 (1 H, q, J = 6.9 Hz), 4.22 (1H, d, J = 7.8 Hz), 4.29
(1H, d, J = 7.5 Hz), 4.47 (2H, s), 4.83 (1H, s), 5.01
(1H, dd, J = 2.7 and 10.2 Hz), 7.12 (1H, t, J = 6.0 Hz),
7.65–7.76 (2H, m), 8.02–8.07 (2H, m), 8.78 (1H, s).
13C NMR (CDCl3) d (ppm): 10.2, 12.9, 14.3, 15.4, 15.5,
18.9, 19.9, 21.1, 22.3, 26.3, 28.2, 28.6, 33.2, 33.5, 38.0,
38.7, 40.2, 47.6, 49.8, 51.0, 65.9, 69.5, 70.3, 73.0, 76.0,
78.4, 78.7, 82.3, 84.6, 103.8, 128.8, 129.0, 129.1, 129.7,
141.3, 142.1, 145.8, 153.8, 156.6, 167.6, 169.2, 170.4, 203.8.
13C NMR (CDCl3) d (ppm): 10.2, 12.9, 14.3, 15.3, 15.5,
18.9, 19.9, 21.1, 22.3, 26.3, 28.2, 30.7, 33.2, 33.4, 33.4,
38.0, 38.8, 40.2, 47.6, 49.8, 51.0, 65.8, 69.5, 70.3, 73.0,
76.1, 78.4, 78.7, 82.3, 84.6, 103.7, 120.3, 126.7, 127.6,
127.8, 128.0, 135.6, 143.4, 148.5, 150.2, 153.8, 167.6,
169.2, 170.3, 203.9.
5.9. Preparation of compounds 5j,m,r,t, and u
Compounds 5j,m,r,t, and u were prepared from 3B by
the procedure described for the synthesis of 5p with
12a,b,e,d, and f, respectively.
5.8.2. Compound 5o. MS (FAB): 856+ (M+H+). HR-MS
(FAB) calcd for C44H66N5O12: 856.4708. Found:
856.4716.
5.9.1. Compound 5j. MS (FAB): 869+ (M+H+). HR-MS
(FAB) calcd for C46H69N4O12: 869.4912. Found:
869.4914.
IR (KBr): 3434, 2972, 2937, 2878, 2784, 1810, 1751,
1716, 1673, 1619, 1533, 1498, 1455, 1365, 1323, 1304,
1284, 1257, 1233, 1218, 1167, 1141, 1109, 1078, 1048,
1004, 992, 955, 931, 893, 831, 773, 755, 664, 628, 556,
513, 457, 407 (cmÀ1).
IR (KBr): 3435, 2974, 2938, 2878, 2784, 1810, 1751,
1717, 1673, 1591, 1569, 1528, 1509, 1456, 1379, 1322,

3708
T. Nomura et al. / Bioorg. Med. Chem. 14 (2006) 3697–3711
1284, 1257, 1235, 1167, 1142, 1109, 1082, 1047, 1005,
992, 952, 931, 902, 835, 813, 801, 757, 694, 665, 631,
573, 532, 454, 431 (cmÀ1).
993, 952, 931, 900, 865, 835, 801, 771, 682, 632, 573,
533, 453, 431 (cmÀ1).
1H NMR (CDCl3) d (ppm): 0.87 (3H, t, J = 7.2 Hz), 0.99
(3H, d, J = 6.6 Hz), 1.20 (3H, d, J = 6.0 Hz), 1.26 (3H, d,
J = 6.3 Hz), 1.27 (3H, d, J = 7.5 Hz), 1.36 (3H, d,
J = 7.2 Hz), 1.39 (3H, s), 1.45 (3H, d, J = 6.9 Hz), 1.55
(3H, s), 1.20–1.94 (6H, m), 2.03 (2H, quintet,
J = 7.5 Hz), 2.26 (6H, s), 2.44 (1H, m), 2.54 (1H, q,
J = 7.2 Hz), 2.66 (3H, s), 3.01 (1H, quintet, J = 7.5 Hz),
3.13–3.25 (2H, m), 3.30 (2H, t, J = 7.5 Hz), 3.43–3.58
(3H, m), 3.63–3.74 (1H, m), 3.81 (1H, q, J = 6.3 Hz),
4.20 (1H, d, J = 8.1 Hz), 4.28 (1H, d, J = 7.2 Hz), 4.52
(1H, q, J = 6.9 Hz), 4.82 (1H, s), 4.94 (1H, dd, J = 2.7
and 10.2 Hz), 7.07 (1H, br t, J = 5.7 Hz), 7.67 (1H, dd,
J = 2.7 and 7.2 Hz), 7.70 (1H, dd, J = 6.9 and 7.2 Hz),
7.94 (1H, dd, J = 2.7 and 6.9 Hz), 8.83 (1H, d,
J = 5.7 Hz), 8.84 (1H, d, J = 5.7 Hz).
1H NMR (CDCl3) d (ppm): 0.87 (3H, t, J = 7.2 Hz), 1.00
(3H, d, J = 6.9 Hz), 1.22 (3H, d, J = 6.0 Hz), 1.27 (6H,
d, J = 6.9 Hz), 1.37 (3H, d, J = 6.9 Hz), 1.39 (3H, s),
1.45 (2H, d, J = 6.9 Hz), 1.56 (3H, s), 1.20–1.95 (6H,
m), 2.06 (2H, quintet, J = 7.2 Hz), 2.27 (6H, s), 2.47
(2H, m), 2.55 (1H, q, J = 6.9 Hz), 2.66 (3H, s), 3.01
(1H, quintet, J = 7.8 Hz), 3.12 (2H, dd, J = 6.6 and
8.4 Hz), 3.10–3.27 (3H, m), 3.48–3.76 (4H, m), 3.83
(1H, q, J = 6.6 Hz), 4.21 (1H, d, J = 8.1 Hz), 4.29 (1H,
d, J = 7.5 Hz), 4.50 (1H, q, J = 6.9 Hz), 4.85 (1H, s),
4.97 (1H, dd, J = 2.7 and 10.2 Hz), 7.26–7.34 (2H, m),
7.56 (1H, m), 7.68 (1H, m), 8.08 (2H, m), 8.80 (1H, br s).
13C NMR (CDCl3) d (ppm): 10.2, 12.8, 14.3, 15.2, 15.7,
15.8, 18.8, 19.9, 21.1, 22.2, 26.2, 28.3, 29.2, 33.0, 37.9,
39.1, 40.2, 47.7, 49.7, 51.0, 65.8, 69.5, 70.3, 75.9, 78.3,
78.5, 82.4, 84.7, 103.7, 120.6, 123.6, 126.3, 127.6,
128.9, 130.0, 147.8, 148.2, 150.2, 153.8, 166.3, 169.3,
172.3, 203.8.
13C NMR (CDCl3) d (ppm): 10.2, 12.9, 14.2, 15.3, 15.7,
16.1, 18.9, 19.9, 21.1, 22.2, 26.3, 28.0, 28.2, 30.3, 33.0,
37.9, 39.0, 40.2, 47.7, 49.7, 51.0, 65.8, 69.5, 70.3, 75.9,
78.4, 78.5, 78.6, 82.4, 84.5, 103.8, 127.4, 129.3, 129.8,
141.2, 141.7, 143.1, 143.7, 144.5, 153.8, 166.3, 169.1,
172.0, 203.9.
5.9.2. Compound 5m. MS (FAB): 869+ (M+H+). HR-MS
(FAB) calcd for C46H69N4O12: 869.4912. Found:
869.4921.
5.9.4. Compound 5t. MS (FAB): 870+ (M+H+). HR-MS
(FAB) calcd for C45H68N5O12: 870.4864. Found:
870.4874.
IR (KBr): 3436, 2974, 2937, 2878, 2784, 1810, 1751,
1716, 1672, 1625, 1596, 1529, 1503, 1455, 1379, 1320,
1284, 1257, 1234, 1167, 1142, 1109, 1082, 1047, 1005,
992, 952, 931, 897, 835, 801, 772, 754, 694, 663, 615,
573, 555, 530, 479, 456 (cmÀ1).
IR (KBr): 3435, 3062, 2974, 2937, 2878, 2784, 1811,
1751, 1716, 1672, 1530, 1492, 1455, 1410, 1364, 1322,
1284, 1257, 1234, 1167, 1141, 1109, 1082, 1047, 1005,
992, 952, 931, 899, 835, 801, 762, 694, 665, 631, 610,
573, 556, 532, 457, 409 (cmÀ1).
1H NMR (CDCl3) d (ppm): 0.85 (3H, t, J = 7.2 Hz), 1.00
(3H, d, J = 7.2 Hz), 1.21 (3H, d, J = 6.3 Hz), 1.27 (6H, d,
J = 6.9 Hz), 1.37 (3H, d, J = 7.2 Hz), 1.39 (3H, s), 1.44
(2H, d, J = 6.9 Hz), 1.56 (3H, s), 1.20–1.92 (7H, m), 2.03
(2H, quintet, J = 7.8 Hz), 2.26 (6H, s), 2.44 (1H, m),
2.55 (1H, q, J = 6.6 Hz), 2.67 (3H, s), 2.88 (2H, t,
J = 8.1 Hz), 3.02 (1H, quintet, J = 7.8 Hz), 3.12–3.22
(2H, m), 3.43–3.76 (3H, m), 3.82 (1H, q, J = 7.2 Hz),
4.21 (1H, d, J = 7.8 Hz), 4.29 (1H, d, J = 7.5 Hz), 4.51
(1H, q, J = 6.6 Hz), 4.84 (1H, s), 4.99 (1H, dd, J = 2.7
and 10.2 Hz), 7.07 (1H, t, J = 6.0 Hz), 7.32 (1H, dd,
J = 4.2 and 8.4 Hz), 7.46 (1H, dd, J = 1.5 and 8.4 Hz),
7.73 (1H, d, J = 8.4), 7.90 (1H, s), 8.10 (1H, dd, J = 1.2
and 8.1 Hz), 8.86 (1H, dd, J =1.5 and 4.2 Hz).
1H NMR (CDCl3) d (ppm): 0.84 (3H, t, J = 7.2 Hz), 1.00
(3H, d, J = 6.9 Hz), 1.22 (3H, d, J = 6.3 Hz), 1.27 (6H,
d, J = 6.6 Hz), 1.35 (3H, d, J = 6.9 Hz), 1.39 (3H, s),
1.44 (3H, d, J = 6.9 Hz), 1.55 (3H, s), 1.20–1.92 (6H,
m), 2.15 (2H, quintet, J = 8.1 Hz), 2.25 (6H, s), 2.47
(1H, m), 2.55 (1H, q, J =7.2 Hz), 2.67 (3H, s), 3.01
(1H, quintet, J = 7.8 Hz), 3.08 (2H, dd, J = 6.6 and
9.0 Hz), 3.18 (1H, dd, J = 7.5 and 10.2 Hz), 3.15–3.28
(1H, m), 3.49–3.76 (4H, m), 3.82 (1H, q, J = 6.6 Hz),
4.22 (1H, d, J = 8.1 Hz), 4.29 (1H, d, J = 7.2 Hz), 4.51
(1H, q, J = 6.6 Hz), 4.83 (1H, s), 4.99 (1H, dd, J = 2.7
and 10.5 Hz), 7.22 (1H, br t, J = 5.7 Hz), 7.65–7.76
(2H, m), 8.03–8.07 (2H, m), 8.78 (1H, s).
13C NMR (CDCl3) d (ppm): 10.2, 12.9, 14.3, 15.3, 15.6,
16.0, 18.9, 19.9, 21.1, 22.3, 26.3, 28.2, 30.6, 33.1, 33.5,
37.9, 39.0, 40.2, 47.6, 49.8, 51.1, 65.8, 69.5, 70.3, 76.0,
78.5, 78.6, 82.5, 84.6, 103.7, 120.3, 126.7, 127.6, 127.9,
128.0, 135.7, 143.6, 148.5, 150.2, 153.9, 166.3, 169.2,
172.1, 203.9.
13C NMR (CDCl3) d (ppm): 10.1, 12.8, 14.3, 15.3, 15.6,
15.8, 18.8, 19.9, 21.1, 22.2, 26.2, 28.3, 28.6, 33.0, 33.7,
37.9, 38.9, 40.2, 47.6, 49.8, 51.0, 65.8, 69.4, 70.3, 75.9,
78.4, 78.5, 78.6, 82.4, 84.6, 103.7, 128.7, 129.0, 129.1,
129.7, 141.2, 142.2, 145.9, 153.8, 156.8, 166.3, 169.2,
172.2, 203.8.
5.9.3. Compound 5r. MS (FAB): 870+ (M+H+). HR-MS
(FAB) calcd for C45H68N5O12: 870.4864. Found:
870.4867.
5.9.5. Compound 5u. MS (FAB): 885+ (M+H+). HR-MS
(FAB) calcd for C45H69N6O12: 885.4973. Found:
885.4971.
IR (KBr): 3436, 2973, 2937, 2878, 2784, 1811, 1751,
1716, 1674, 1577, 1528, 1490, 1456, 1379, 1361, 1322,
1283, 1257, 1233, 1167, 1142, 1109, 1082, 1047, 1005,
IR (KBr): 3430, 2975, 2937, 2879, 2784, 1806, 1749,
1716, 1673, 1600, 1575, 1533, 1500, 1457, 1407, 1375,

T. Nomura et al. / Bioorg. Med. Chem. 14 (2006) 3697–3711
3709
1322, 1284, 1234, 1166, 1141, 1110, 1081, 1047, 1006,
993, 950, 835, 811, 775, 755, 711, 694, 628, 572, 555,
530, 460, 435 (cmÀ1).
IR (KBr): 3437, 2971, 2937, 2877, 2784, 1810, 1751,
1716, 1673, 1625, 1596, 1526, 1504, 1455, 1380, 1363,
1321, 1284, 1257, 1232, 1167, 1142, 1109, 1081, 1047,
1005, 990, 953, 932, 912, 835, 801, 772, 693, 660, 633,
615, 574, 555, 531, 478, 457 (cmÀ1).
1H NMR (CDCl3) d (ppm): 0.86 (3H, t, J = 7.2 Hz), 0.99
(3H, d, J = 6.9 Hz), 1.23 (3H, d, J = 6.0 Hz), 1.26 (3H,
d, J = 7.2 Hz), 1.27 (3H, d, J = 7.2 Hz), 1.37 (3H, d,
J = 6.9 Hz), 1.39 (3H, s), 1.43 (3H, d, J = 6.6 Hz), 1.56
(3H, s), 1.20–1.94 (7H, m), 2.13 (2H, m), 2.27 (6H, s),
2.46 (1H, m), 2.55 (1H, q, J = 6.9 Hz), 2.65 (3H, s),
2.95–3.25 (3H, m), 3.50–3.75 (4H, m), 3.83 (1H, q,
J = 6.9 Hz), 4.22 (1H, d, J = 8.1 Hz), 4.29 (1H, d,
J = 7.2 Hz), 4.44 (1H, q, J = 6.9 Hz), 4.83 (1H, s), 4.95
(1H, dd, J = 2.7 and 10.2 Hz), 7.28 (1H, br t,
J = 6.3 Hz), 7.40 (1H, m), 7.47 (1H, s), 7.61 (1H, s),
8.08 (1H, m), 8.44 (1H, m), 9.00 (1H, s).
1H NMR(CDCl3) d (ppm): 0.85 (3H, t, J = 7.5 Hz),
0.96 (3H, t, J = 7.5 Hz), 1.01 (3H, d, J = 6.9 Hz), 1.21
(3H, d, J = 6.3 Hz), 1.27 (3H, d, J = 6.3 Hz), 1.27
(3H, d, J = 7.5 Hz), 1.36 (3H, d, J = 6.9 Hz), 1.40
(3H, s), 1.56 (3H, s), 1.20–2.06 (11H, m), 2.27 (6H,
s), 2.45 (1H, m), 2.56 (1H, q, J = 6.9 Hz), 2.69 (3H,
s), 2.88 (2H, t, J = 7.2 Hz), 3.03 (1H, quintet,
J = 7.8 Hz), 3.13–3.28 (2H, m), 3.40–3.58 (3H, m),
3.72 (1H, m), 3.82 (1H, q, J = 6.9 Hz), 4.22 (1H, d,
J = 7.8 Hz), 4.30 (1H, d, J = 6.9 Hz), 4.33 (1H, dd,
J = 4.8 and 7.8 Hz), 4.84 (1H, s), 5.00 (1H, dd,
J = 3.0 and 10.5 Hz), 6.89 (1H, t, J = 5.7 Hz), 7.32
(1H, dd, J = 4.2 and 8.4 Hz), 7.45 (1H, dd, J = 1.5
and 8.4 Hz), 7.73 (1H, d, J = 8.4), 7.89 (1H, s), 8.10
(1H, dd, J = 1.2 and 8.1 Hz), 8.86 (1H, dd, J = 1.5
and 4.2 Hz).
13C NMR (CDCl3) d (ppm): 10.1, 12.7, 14.3, 15.2, 15.4,
15.7, 18.8, 19.9, 21.1, 22.1, 26.2, 28.3, 30.8, 32.9, 36.6,
37.8, 40.2, 45.2, 47.7, 49.7, 51.0, 65.8, 69.5, 70.3, 75.8,
78.1, 78.4, 78.6, 82.4, 84.8, 103.7, 123.4, 130.4, 132.0,
138.0, 139.0, 146.5, 147.5, 153.9, 166.5, 169.5, 172.6, 203.7.
5.10. Preparation of compound 5k,n and q
13C NMR (CDCl3) d (ppm): 9.7, 10.2, 12.9, 14.3, 15.3,
15.6, 19.0, 19.9, 21.1, 22.3, 23.7, 26.4, 28.3, 30.8, 33.2,
33.5, 37.9, 38.9, 40.2, 47.6, 49.8, 51.1, 65.9, 69.5, 70.3,
76.1, 78.5, 78.6, 82.3, 83.5, 84.6, 103.8, 120.3, 126.7,
127.6, 127.9, 128.1, 135.7, 143.6, 148.6, 150.2, 153.9,
166.7, 169.3, 171.7, 204.0.
Compounds 5k,n and q were prepared from 3E by the
procedure described for the synthesis of 5p with 12a,b
and c, respectively.
5.10.1. Compound 5k. MS (SI): 883+ (M+H+). HR-MS
(SI): calcd for C47H71N4O12: 883.5065. Found: 883.5069.
5.10.3. Compound 5q. MS (SI): 884+ (M+H+). HR-MS
(SI): calcd for C46H70N5O12: 884.5017. Found:
884.5020.
IR (KBr): 3435, 2971, 2937, 2877, 2784, 1810, 1751,
1716, 1673, 1592, 1569, 1526, 1509, 1456, 1380, 1362,
1323, 1305, 1284, 1257, 1233, 1167, 1141, 1109, 1082,
1047, 1005, 990, 954, 932, 912, 835, 813, 800, 764, 694,
631, 574, 515, 454, 431 (cmÀ1).
IR (KBr): 3435, 2971, 2937, 2878, 2784, 1810, 1751,
1717, 1671, 1637, 1527, 1499, 1456, 1379, 1324, 1304,
1284, 1257, 1233, 1218, 1167, 1140, 1109, 1080, 1048,
1005, 990, 956, 931, 912, 866, 831, 772, 755, 693, 557,
459, 407 (cmÀ1).
1H NMR (CDCl3) d (ppm): 0.87 (3H, t, J = 7.5 Hz), 0.98
(3H, t, J = 7.2 Hz), 1.00 (3H, d, J = 7.2 Hz), 1.22 (3H, d,
J = 6.3 Hz), 1.27 (3H, d, J = 6.6 Hz), 1.28 (3H, d,
J = 7.8 Hz), 1.37 (3H, d, J = 6.9 Hz), 1.40 (3H, s), 1.56
(3 H, s), 1.20–2.10 (10 H, m), 2.27 (6H, s), 2.46 (1H,
m), 2.56 (1H, q, J = 6.9 Hz), 2.69 (3H, s), 3.02 (1H,
quintet, J = 7.5 Hz), 3.12 (2H, dd, J = 6.0 and 8.7 Hz),
3.14–3.32 (2H, m), 3.52 (2H, m), 3.74 (1H, m), 3.83
(1H, q, J = 6.9 Hz), 4.22 (1H, d, J = 8.1 Hz), 4.30 (1H,
d, J = 6.3 Hz), 4.32 (1H, t, J = 6.6 Hz), 4.85 (1H, s),
4.97 (1H, dd, J = 2.4 and 10.2 Hz), 7.09 (1H, t,
J = 5.7 Hz), 7.32 (1H, d, J = 4.5 Hz), 7.56 (1H, m),
7.68 (1H, m), 8.05 (1H, d, J = 8.7 Hz), 8.09 (1H, d,
J = 8.4 Hz), 8.81 (1H, br s).
1H NMR (CDCl3) d (ppm): 0.86 (3H, t, J = 7.2 Hz),
0.97 (3H, t, J = 7.5 Hz), 1.01 (3H, d, J = 7.2 Hz),
1.22 (3H, d, J = 6.0 Hz), 1.27 (3H, d, J = 6.6 Hz),
1.28 (3H, d, J = 7.2 Hz), 1.36 (3H, d, J = 6.9 Hz),
1.40 (3H, s), 1.56 (3H, s), 1.20–2.06 (11H, m), 2.26
(6H, s), 2.45 (1H, m), 2.56 (1H, q, J = 6.9 Hz), 2.69
(3H, s), 2.91 (2H, t, J = 7.5 Hz), 3.02 (1H, quintet,
J = 7.5 Hz), 3.17 (1H, dd, J = 7.2 and 9.9 Hz), 3.15–
3.26 (1H, m), 3.43–3.58 (3H, m), 3.72 (1H, m), 3.83
(1H, q, J = 6.9 Hz), 4.22 (1H, d, J = 7.8 Hz), 4.30
(1H, d, J = 7.5 Hz), 4.30 (1H, dd, J = 4.5 and
7.5 Hz), 4.84 (1H, s), 5.00 (1H, dd, J = 2.7 and
10.2 Hz), 7.02 (1H, t, J = 6.0 Hz), 7.69 (1H, dd,
J = 1.8 and 8.7 Hz), 7.91 (1H, d, J = 1.8 Hz), 8.01
(1H, d, J = 8.7 Hz), 8.78 (1H, d, J = 8.7 Hz), 8.79
(1H, d, J = 8.7 Hz).
13C NMR (CDCl3) d (ppm): 9.8, 10.3, 12.8, 14.3, 15.2,
15.6, 18.9, 19.9, 21.1, 22.2, 23.5, 26.3, 28.2, 29.3, 29.4,
33.1, 37.8, 39.0, 40.2, 47.6, 49.8, 51.1, 65.9, 69.5, 70.3,
76.0, 78.5, 78.6, 82.3, 83.4, 84.6, 103.7, 120.6, 123.6,
126.3, 127.6, 128.9, 130.1, 147.8, 148.2, 150.3, 153.9,
166.8, 169.3, 171.9, 203.9.
13C NMR (CDCl3) d (ppm): 9.8, 10.2, 12.9, 14.3, 15.3,
15.6, 15.7, 18.9, 19.9, 21.2, 22.2, 23.6, 26.4, 28.2, 30.6,
33.1, 33.4, 37.8, 38.8, 40.2, 47.6, 49.8, 51.1, 65.9, 69.5,
70.3, 76.0, 78.5, 82.3, 83.4, 84.6, 84.7, 103.8, 127.8,
129.1, 131.7, 141.8, 143.2, 144.1, 144.5, 144.8, 153.8,
153.9, 166.8, 169.3, 171.9, 204.0.
5.10.2. Compound 5n. MS (SI): 883+ (M+H+). HR-MS
(SI): calcd for C47H73N4O12: 883.5065. Found:
883.5068.

3710
T. Nomura et al. / Bioorg. Med. Chem. 14 (2006) 3697–3711
5.11. Preparation of compound 12d
7.90 (1H, s), 8.12 (1H, m), 8.88 (1H, dd, J = 1.8 and
4.2 Hz).
To
a solution of N-Boc-propargylamine (4.96 g,
1
32 mmol) in CH3CN (50 mL) were successively added
NEt3 (4.44 mL, 32 mmol), CuI (122 mg, 0.64 mmol),
2-chloro-quinoxaline
Cl2Pd(PPh3)2 (224 mg, 0.32 mmol). The reaction mix-
ture was stirred at room temperature for 2 h. The mix-
ture was filtered and poured into 5% aqueous
NaHCO3, and extracted with AcOEt. The resultant
residue was purified by column chromatography on sil-
ica gel (n-hexane:AcOEt, 4:1–1:1) to give 4.51 g of
compound 10d (99%).
5.12.3. Compound 12c. H NMR (CDCl3) d (ppm): 1.92
(2H, m), 2.55 (2H, br s), 2.79 (2H, t, J = 7.2 Hz), 2.92
(2H, t, J = 7.5 Hz), 7.67 (1H, dd, J = 2.8 and 8.4 Hz),
7.90 (1H, d, J = 1.2 Hz), 8.05 (1H, d, J = 8.4 Hz), 8.81
(1H, d, J = 6.3 Hz), 8.82 (1H, d, J = 6.3 Hz).
(2.64 g,
16 mmol),
and
5.13. Preparation of compound 12e
To
a solution of N-Boc-propargylamine (3.72 g,
23.7 mmol) in CH3CN (51 mL) were successively added
NEt3 (3.34 mL, 23.7 mmol), CuI (61 mg, 0.32 mmol),
compound 1312 (4.53 g, 7.9 mmol), and Cl2Pd(PPh3)2
(112 mg, 0.16 mmol). The reaction mixture was stirred
at room temperature for 1 h and then for 4 h at 70 ꢁC.
The mixture was cooled to room temperature and fil-
tered then diluted with 5% aqueous NaHCO3, and final-
ly extracted with AcOEt. The resultant residue was
purified by column chromatography on silica gel (n-hex-
ane:AcOEt, 4:1–1:1) to give 1.08 g of compound 14
(26%).
1H NMR (CDCl3) d (ppm): 1.48 (9H, s), 4.29 (2H, d,
J = 5.7 Hz), 4.89 (1H, br s), 7.75–7.82 (2H, m), 8.04–
8.11 (2H, m), 8.87 (1H, s).
Compound 10d (4.51 g, 16 mmol) was dissolved in
EtOH (80 mL) and AcOEt (80 mL). To this solution
was added 5% Pd/C (640 mg) with stirring at room tem-
perature under H2 atmosphere for 1 h. The mixture was
filtered and concentrated, and the resultant residue was
purified by column chromatography on silica gel (n-hex-
ane:AcOEt, 2:1–1:8) to give 2.20 g of compound 11d
(48%).
1H NMR (CDCl3) d (ppm): 1.45 (9H, s), 4.09 (2H, d,
J = 5.1 Hz), 4.74 (1H, br s), 5.18 (2 H, s), 5.22 (2H, s),
6.84 (1H, br s), 7.18–7.40 (12H, m), 7.78 (1H, br s),
7.85 (1H, br s).
1H NMR (CDCl3) d (ppm): 1.44 (9H, s), 2.08 (2H, m),
3.08 (2H, t, J = 7.5 Hz), 3.28 (2H, m), 4.85 (1H, br s),
7.71–7.76 (2H, m), 8.02–8.10 (2H, m), 8.75 (1H, s).
Compound 14 (1.05 g, 1.98 mmol) was dissolved in
EtOH (10.5 mL) and AcOEt (10.5 mL). To this solu-
tion were added CH3CO2H (2.6 mL) and 10% Pd/C
(210 mg) with stirring at room temperature under H2
atmosphere for 2 h. The mixture was filtered and con-
centrated. The resultant residue was diluted with aque-
ous NaHCO3 and extracted with AcOEt. The aqueous
layer was extracted with AcOEt, and the combined
organic layer was dried over MgSO4, filtered, and con-
centrated in vacuo to give 530 mg of compound 15
(91%).
Compound 11d (2.14 g, 7.45 mmol) was dissolved with
CH2Cl2 (37 mL) and stirred at À30 ꢁC. To this solution
was added TMSI (1.48 mL, 10.4 mmol), and the reac-
tion mixture was stirred on an ice-water bath for 1 h.
The reaction mixture was poured into diluted aqueous
Na2S2O3 and extracted with CHCl3/MeOH (5/1). The
aqueous layer was extracted with CHCl3/MeOH (5/1),
and the combined organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. Finally, 970 mg of
compound 12d was obtained (69%).
1H NMR (CDCl3) d (ppm): 1.45 (9H, s), 1.80 (2H, m),
2.55 (2H, t, J = 8.1 Hz), 3.17 (2H, dt, J = 6.3 and
6.6 Hz), 3.30 (4H, br s), 4.63 (1H, br s), 6.59–6.68
(3H, m).
1H NMR (CDCl3) d (ppm): 2.02 (2H, m), 2.84 (2H, t,
J = 6.9 Hz), 3.09 (2H, t, J = 7.8 Hz), 7.71–7.78 (2H,
m), 8.02–8.10 (2H, m), 8.76 (1H, s).
5.12. Preparation of compounds 12a–c
Compound 15 (400 mg, 1.5 mmol) was dissolved in
EtOH (6 mL). To this solution was added (CHO)2-
2NaHSO3-H2O (glyoxal sodium bisulfite) (0.47 g,
1.77 mmol) in hot water with stirring and the reaction
mixture was refluxed for 0.5 h and cooled to room tem-
perature. The mixture was poured into 5% aqueous
NaHCO3 and extracted with AcOEt. The resultant res-
idue was purified by column chromatography on silica
gel (n-hexane:AcOEt, 4:1–1:8) to give 187 mg of com-
pound 11e (43%).
Compounds 12a–c were prepared by the procedure de-
scribed for the synthesis of 12d from 4-iodo-quinoline,4
7-bromo-quinoline,11
respectively.
and
6-bromo-quinoxaline,
1
5.12.1. Compound 12a. H NMR (CDCl3) d (ppm): 1.82
(2H, m), 2.84 (2H, t, J = 7.2 Hz), 3.13 (2H, t,
J = 7.5 Hz), 7.24 (1H, d, J = 4.5 Hz), 7.55 (1H, m),
7.70 (1H, m), 8.06 (1H, d, J = 7.2 Hz), 8.12 (1H, d,
J = 7.5 Hz), 8.81 (1H, d, J = 4.2 Hz).
1H NMR (CDCl3) d (ppm): 1.45 (9H, s), 1.96 (2H, m),
3.17 (2H, dt, J = 6.3 and 6.9 Hz), 3.30 (2H, t,
J = 7.5 Hz), 5.00 (1H, br s), 7.63 (1H, dd, J = 1.5 and
7.2 Hz), 7.70 (1H, dd, J = 7.2 and 8.4 Hz), 7.98 (1H,
dd, J = 1.5 and 8.4 Hz), 8.84 (1H, d, J = 3.0 Hz), 8.85
(1H, d, J = 3.0 Hz).
1
5.12.2. Compound 12b. H NMR (CDCl3) d (ppm): 1.89
(2H, m), 2.79 (2H, t, J = 7.2 Hz), 2.89 (2H, t,
J = 8.1 Hz), 7.34 (1H, dd, J = 4.2 and 8.1 Hz), 7.41
(1H, dd, J = 1.8 and 8.7 Hz), 7.74 (1H, d, J = 8.7 Hz),

T. Nomura et al. / Bioorg. Med. Chem. 14 (2006) 3697–3711
3711
1
Compound 12e was prepared from 11e by the procedure
described for the synthesis of 12d from 11d.
5.14.2. Compound 12f. H NMR (CDCl3) d (ppm): 1.96
(2H, m), 2.77 (2H, t, J = 6.9 Hz), 4.11 (2H, t,
J = 7.2 Hz), 7.29 (2H, m), 7.56 (1H, s), 8.09 (1H, dt,
J = 1.5 and 8.1 Hz), 8.47 (1H, dd, J = 1.2 and 4.8 Hz),
8.96 (1H, d, J = 2.1 Hz).
1
5.13.1. Compound 12e. H NMR (CDCl3) d (ppm): 1.92
(2H, m), 2.77 (2H, t, J = 6.6 Hz), 3.32 (2H, t,
J = 7.5 Hz), 7.63 (1H, dd, J = 1.5 and 7.8 Hz), 7.71
(1H, dd, J = 7.8 and 8.1 Hz), 7.97 (1H, dd, J = 1.5 and
8.1 Hz), 8.84 (2H, br s).
References and notes
1. Morimoto, S.; Takahashi, Y.; Watanabe, Y.; Omura, S.
J. Antibiot. 1984, 37, 187–189.
5.14. Preparation of compound 12f
2. Denis, A.; Agouridas, C.; Auger, J.; Benedetti, Y.;
Bonnefoy, A.; Bretin, F.; Chantot, J.; Dussarat, A.;
Fromentin, C.; D’Ambrieres, S.; Lachaud, S.; Laurin, P.;
Martret, O.; Loyau, V.; Tessot, N.; Pejac, J.; Perron, S.
Bioorg. Med. Chem. Lett. 1999, 9, 3075–3080.
3. (a) Sun, Y.; Clark, R.; Wang, S.; Chu, D.; Nilius, A.;
Flamm, R.; Mitten, M.; Ewing, P.; Alder, J.; Ma, Z.
J. Med. Chem. 2000, 43, 1045–1049; (b) Ma, Z.; Clark, R.,
et al. J. Med. Chem. 2001, 44, 4137–4156.
4. Nomura, T.; Iwaki, T.; Yasukata, T.; Nishi, K.; Naruk-
awa, Y.; Uotani, K.; Hori, T.; Miwa, H. Bioorg. Med.
Chem. 2005, 13, 6615–6628.
5. Iwaki, T.; Nomura, T.; Narukawa, Y. J. Antibiot. 2005,
58, 679–685.
To a solution of NaH 208 mg (60% in mineral oil
5.2 mmol) in DMF (1 mL) was added dropwise com-
pound 1613 (620 mg, 4.0 mmol) in DMF (3 mL) at room
temperature, and the mixture was stirred for 30 min. To
this solution, 3-bromo-propylphthalimide 1.31 g
(4.8 mmol) in DMF (3 mL) was added dropwise and the
reaction mixture was stirred for 4.5 h at 70 ꢁC. The reac-
tion mixture was cooled to room temperature, poured
into H2O, and extracted with AcOEt. The aqueous layer
was extracted with AcOEt, and the combined organic
layer was washed with brine, dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (CHCl3:MeOH,
80:1–5:1) to give 840 mg of compound 17 (63%).
6. Nomura, T.; Yasukata, T.; Narukawa, Y.; Uotani, K.
Bioorg. Med. Chem. 2005, 13, 6054–6063.
7. (a) Alanine, A.; Bourson, A.; Buttelmann, B.; Gill, R.;
Heitz, M.; Mutel, V.; Pinard, E.; Trube, G.; Wyler, R.
Bioorg. Med. Chem. Lett. 2003, 13, 3155–3159; (b) Kim,
D.; Gam, J.; Kim, Y.; Lim, J.; Kim, H.; Kim, K. H.
J. Med. Chem. 1997, 40, 2363–2373.
8. Lin, W.; Zhang, X.; He, Z.; Jin, Y.; Gong, L.; Mi, A.
Synth. Commun. 2002, 32, 3279–3284.
9. Kauffmann, T.; Loetzsch, K.; Wolf, D. Chem. Ber. 1966,
99, 3148–3154.
1
5.14.1. Compound 17. H NMR (CDCl3) d (ppm): 2.27
(2H, m), 3.80 (2H, t, J = 6.6 Hz), 4.07 (2H, t,
J = 6.9 Hz), 7.28 (1H, m), 7.36 (1H, d, J = 1.2 Hz),
7.62 (1H, d, J = 1.2 Hz), 7.69–7.84 (4H, m), 8.03 (1H,
dt, J = 1.8 and 8.1 Hz), 8.46 (1H, dd, J = 1.5 and
4.8 Hz), 8.92 (1H, d, J = 1.8 Hz).
Compound 17 (810 mg, 2.4 mmol) was dissolved in
EtOH (15 mL). To this solution was added H2NNH2–
H2O (0.24 mL, 4.8 mmol) with stirring at room temper-
ature, and the solution was refluxed for 8 h. The
reaction mixture was cooled to room temperature, and
filtered and concentrated. The resultant residue was
diluted with 2 N NaOH (20 mL) and extracted with
CHCl3. The aqueous layer was extracted with CHCl3,
and the combined organic layer was washed with brine,
dried over MgSO4, filtered and concentrated in vacuo to
give 485 mg of compound 12f (82%).
10. (a) Murahashi, S.; Komiya, N.; Terai, H.; Nakae, T. J.
Am. Chem. Soc. 2003, 125, 15312–15313; (b) Katritzky,
A.; Xu, Y.; He, H. J. Chem. Soc., Perkin Trans. 1 2002,
592–598.
11. Butler, J.; Gordon, M. J. Heterocycl. Chem. 1975, 12,
1015–1020.
12. Frantz, D.; Weaver, D.; Carey, J.; Kress, M.; Dolling, U.
Org. Lett. 2002, 4, 4717–4718.
13. (a) Denton, T. T.; Zhang, X.; Cashman, J. R. J. Med.
Chem. 2005, 48, 224–239; (b) Kirchhoff, E.; Anderson, D.;
Zhang, S.; Cassidy, C.; Flavin, M. Org. Proc. Res. Dev.
2001, 5, 50–53.