A new type of ketolides bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether synthesis and structure-activity relationships

Article abstract of DOI:10.1016/j.bmc.2005.07.041

A new type of ketolides, bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether and a cyclic carbonate at the C-11,12 position was prepared and the antibacterial activities of the compounds were evaluated. Some of the derivatives showed potent ant

Full text of DOI:10.1016/j.bmc.2005.07.041

Bioorganic & Medicinal Chemistry 13 (2005) 6615–6628
A new type of ketolides bearing an N-aryl-alkyl acetamide
moiety at the C-9 iminoether synthesis
and structure–activity relationships
Takashi Nomura,* Tsutomu Iwaki, Tatsuro Yasukata, Koichi Nishi,
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 21 June 2005; revised 12 July 2005; accepted 13 July 2005
Available online 2 September 2005
Abstract—A new type of ketolides, bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether and a cyclic carbonate at the
C-11,12 position was prepared and the antibacterial activities of the compounds were evaluated. Some of the derivatives showed
potent antibacterial activity against both Haemophilus influenzae and Streptococcus pneumoniae, which are clinically important
respiratory tract pathogens. Among the derivatives prepared, compound 5s with a quinolin-4-yl moiety was found to have potent
and well-balanced activity against S. pneumoniae and H. influenzae including erythromycin-resistant strains.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Both them are 3-keto derivatives of CAM with an aryl-
alkyl moiety at the C-11,12 cyclic carbamate group.
Another derivative of ketolides, ABT-7737 (cethromy-
cin, Abbott Laboratories), has an aryl-alkyl moiety at
its C-6 position.
The macrolide antibiotic erythromycin A (EM) has been
widely used for the treatment of gram-positive bacterial
infections. However due to its acid instability and low bio-
availability, new semi-synthetic analogues of EM have
been pursued. Clarithromycin (CAM)1 is one of the
semi-synthetic analogues of EM, which has good acid sta-
bility in the stomach and bioavailability. Azithromycin
(AZM)2 is another analogue that has an improved T1/2
and enhanced activity against gram-negative pathogens.
Though these compounds have improved properties, they
are still inactive against erythromycin-resistant strains,
which have increased significantly in recent years.3
Though all the above three C-9 keto compounds are
effective for erythromycin-resistant strains and have po-
tent activity against H. influenzae and S. pneumoniae,
no ketolide derivatives exhibiting potent activity have
thus far been reported with an aryl-alkyl moiety at the
C-9 position.8 The location of the aryl group on the
ketolide skeleton is considered to be a very important
factor for the activity against such pathogens.
Recently, 3-keto derivatives of EM, called ketolides,4
have been developed (Fig. 1). They are active against
erythromycin-resistant strains, while maintaining their
activity against erythromycin-susceptible ones. RU-
0045 (Hoechst-Marion Roussel) is a pioneer compound,
which was evaluated clinically, and Telithromycin6
(Aventis Pharma) is the first ketolide, which was
launched on the market in 2001 in the EU.
In this paper, we describe the synthesis and the struc-
ture–activity relationships of ketolides with an aryl-alkyl
moiety on the C-9 iminoether group and a cyclic carbon-
ate at the C-11,12 position.
2. Synthesis
9-Iminoether derivatives were prepared using allyl ether
19 as a starting material. Since compounds with a C-
11,12 carbonate showed potent antibacterial activities
in the series of C-9 oxime derivatives,9 we prepared 9-
iminoether derivatives with a C-11,12 carbonate moiety.
We used carboxylic acid 3, readily accessible from 1 by
Keywords: Ketolide; N-aryl-alkyl acetamide; 9-Iminoether; Erythro-
mycin resistant; Macrolide; C-11,12 carbonate.
*
Corresponding author. Tel.: +81 6 6458 5861; fax: +81 6 6458
0987; e-mail: takashi.nomura@shionogi.co.jp
0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.07.041

6616
T. Nomura et al. / Bioorg. Med. Chem. 13 (2005) 6615–6628
N
N
N
N
NMe2
O
NMe2
O
HO
O
NMe2
O
O
NMe2
O
N
HO
O
9
HO
O
O
HO
O
6
O
NH
HO
HO
9
9
9
H
N
O
O
6
RO
6
N
N
O
O
O
6
3
O
MeO
MeO
O
O
O
O
3
3
O
3
O
O
O
O
O
O
O
OH
OMe
O
O
O
R = H EM
R = Me CAM
Telithromycin
RU-004
ABT-773
Figure 1. Structure of macrolide antibiotics.
carbonate formation, followed by oxidation of allyl
ether, as a key intermediate for the introduction of a
variety of substituents at the C-9 iminoether by amide
linkage. Amidation of 3 with various primary amines
using oxalyl chloride and a catalytic amount of dimeth-
ylformamide gave 4, which was subjected to deprotec-
tion and subsequent N-methylation (20% Pd(OH)2/H2,
HCHO aq), afforded amide derivatives 5, as shown in
Scheme 1. We prepared the derivatives 5a–5f with vari-
ous lengths of methylene linker (Table 1) and 5g–5s with
a variety of aryl groups (Tables 3 and 4).
Another amide derivative having an N-methyl carbamoyl
derivative 8 was prepared, as shown in Scheme 2.
Amide 6 prepared from 3 and N-methylpropargylamine
coupled with iodobenzene (Sonogashira coupling) gave
7, which was subjected to deprotection, and subsequent
N-methylation afforded N-methyl carbamoyl derivative
8. Derivatives other than amides were prepared, as
shown in Schemes 3 and 4. Compound 11 with a meth-
ylene spacers instead of amide 5d, was prepared by cou-
pling 1 with triflate 9 (Suzuki coupling) to give 10 (a
mixture of E/Z isomers), which was converted to 11 by
Cbz NMe
Cbz O
R
O
N
Cbz NMe
Cbz O
O
N
9
9
6
R =
R =
2
HO
HO
a
6
O
O
O
O
O
O
MeO
O
R
b
MeO
HO
3
3
3
O
O
O
O
1
O
O
O
c
H
N
H
N
NMe2
Cbz NMe
R
O
O
N
HO
O
Cbz O
O
N
O
9
9
6
6
d
O
O
O
O
O
O
O
O
O
MeO
MeO
3
3
O
O
O
O
O
O
5
4
Scheme 1. Reagents and conditions: (a) (CCl3O)2CO, pyridine, THF; (b) (1) O3, SMe2, (2) NaClO2, NaH2PO4Æ2H2O, Me2C@CHMe; (c) (ClCO)2,
cat. DMF, RNH2; (d) (1) H2, 20% Pd(OH)2/C, (2) H2, 20% Pd(OH)2/C, HCHO aq acetate buffer (pH 4.4).
Table 1. In vitro antibacterial activities of compounds 5a–5f
H
Ph
N
NMe2
O
O
N
(CH2)n
HO
O
O
9
6
O
O
O
MeO
3
O
O
O
5
Strain
MIC (lg/mL)
5d (n = 3)
5a (n = 0)
5b (n = 1)
5c (n = 2)
5e (n = 4)
5f (n = 5)
CAM
0.2
>100
0.025
>100
3.13
S.aureus Smith
0.2
0.78
0.2
0.39
0.39
0.78
0.05
100
0.2
0.2
0.39
0.39
0.025
25
0.78
0.78
0.1
S. aureus SR17347(EM-R)
S. pneumoniae Type I
S. pneumoniae SR16651(EM-R)
H. influenzae SR88562
0.025
>100
50
0.025
>100
25
0.025
0.78
6.25
6.25
25
50
50

T. Nomura et al. / Bioorg. Med. Chem. 13 (2005) 6615–6628
6617
R
Me
Me
Ph
N
N
NMe2
O
Cbz NMe
Cbz O
O
N
O
N
HO
O
O
O
9
9
c
a
6
6
O
O
O
O
O
O
O
3
O
MeO
MeO
3
3
O
O
O
O
O
O
6: R = H
7: R = Ph
8
b
Scheme 2. Reagents and conditions: (a) (ClCO)2, cat. DMF, N-methylpropargylamine; (b) PhI, NEt3, CuI, cat. Cl2Pd(PPh3)2, CH3CN; (c) (1) H2,
20% Pd(OH)2/C, (2) H2, 20% Pd(OH)2/C, HCHO aq acetate buffer (pH 4.4).
Cbz NMe
Cbz O
Ph
Cbz NMe
Cbz O
Ph
O
N
NMe2
O
O
N
O
N
HO
O
9
9
9
a, b
6
6
HO
HO
c, d
O
6
O
HO
HO
O
O
O
O
MeO
MeO
O
MeO
3
3
3
O
O
Ph
OTf
O
O
O
O
O
1
9
O
10
O
11
Scheme 3. Reagents and conditions: (a) 9-BBN, THF; (b) cat. Cl2Pd(PPh3)2, 1 N NaOH, 9; (c) (CCl3O)2CO, pyridine, THF; (d) H2, 20% Pd(OH)2/C;
(e) H2, 20% Pd(OH)2/C, HCHO aq acetate buffer (pH 4.4).
Ph
O
Ph
O
Cbz NMe
Cbz O
NMe2
O
O
N
O
N
HO
O
O
O
9
b, c
9
a
6
6
O
O
3
O
O
O
O
O
O
MeO
MeO
3
3
O
O
O
O
O
O
12
13
Scheme 4. Reagents and conditions: (a) (1) (ClCO)2, cat. DMF, toluene; (2) 3-phenyl-1-propanol, pyridine, cat. DMAP, toluene; (b) H2, 20%
Pd(OH)2/C; (c) H2, 20% Pd(OH)2/C, HCHO aq acetate buffer (pH 4.4).
carbonate formation, and subsequent deprotection and
N-methylation. An ester derivative 13 was prepared
via esterification of 3 with 3-phenyl propanol.
3-Arylpropylamines used for the synthesis of 5 were pre-
pared, as shown in Scheme 5. Other amines, not listed in
Scheme 5, were commercially available or prepared
from the corresponding 3-arylpropanols.
Method A
Boc
a
Boc
N
Ar-X
b
N
+
H
3. Results and discussion
Ar
H
14
c
All the ketolides prepared were evaluated in vitro by
the standard agar dilution method with various strains.
Their antibacterial activities against erythromycin-sus-
ceptible and -resistant S. aureus and S. pneumoniae,
including one strain of H. influenzae, are shown in
Table 1. All ketolides showed potent antibacterial
activities against both erythromycin-susceptible and
-resistant S. aureus and erythromycin-susceptible S.
pneumoniae. Their activities against erythromycin-sus-
ceptible strains were almost comparable to CAM.
Although all ketolides shown in Table 1 displayed po-
tent activities against erythromycin-resistant S. aureus,
they showed weak activities against erythromycin-resis-
tant S. pneumoniae and H. influenzae, except for com-
pound 5d. As for the activity of H. influenzae, 5d
showed superior activity to other ketolides, but its
activity was slightly inferior to that of CAM. It was
considered that the spacer length between the amide
and the phenyl ring was an important factor in the
activity against erythromycin-resistant S. pneumoniae
Boc
Ar
NH2
Ar
N
H
16
15
Method B
Ar-X
d
Boc
Boc
Ar
N
+
N
H
H
15
16
c
Ar
NH2
16a, 3-o-Tolyl-propylamine
16b, 3-mTolyl-propylamine
16c, 3-p-Tolyl-propylamine
16d, 3-(4-Fluoro-phenyl)-propylamine
16e, 3-(4-Nitro-phenyl)-propylamine
16f, 3-Biphenyl-4-yl-propylamine
16g, 3-Naphthalen-2-yl-propylamine
16h, 3-Naphthalen-1-yl-propylamine
16i, 3-Quinolin-3-yl-propylamine
16j, 3-Quinolin-4-yl-propylamine
Scheme 5. Reagents and conditions: (a) NEt3, CuI, cat. Cl2Pd(PPh3)2;
(b) H2, 20% Pd(OH)2/C; (c) CF3CO2H; (d) 9-BBN, cat. Cl2Pd(PPh3)2,
1 N NaOH.

6618
T. Nomura et al. / Bioorg. Med. Chem. 13 (2005) 6615–6628
Table 2. In vitro antibacterial activities of 5d and its analogues 8, 11, and 13
R
R
NMe2
O
Me
N
O
N
Ph
Ph
Ph
HO
O
8
(CH2)3
(CH2)3
(CH2)3
9
O
6
O
O
O
MeO
11
13
3
O
O
O
O
O
Strain
MIC (lg/mL)
5d
8
11
13
0.78
CAM
0.2
>100
0.025
>100
3.13
S. aureus Smith
0.2
0.2
0.39
3.13
3.13
S. aureus SR17347(EM-R)
S. pneumoniae Type I
S. pneumoniae SR16651(EM-R)
H. influenzae SR88562
0.39
0.05
6.25
0.78
0.2
0.025
0.78
6.25
0.78
6.25
6.25
12.5
>100
25
and H. influenzae, and the spacer of three methylenes
was found to be the most favorable.
niae was much lower than that of 5d. Other analogues
with a para-substituted phenyl group (5j–5l) also
showed weak activity. The results given in Table 3 clear-
ly showed that substituents on a phenyl ring were not
effective for antibacterial activities, and we next focused
our investigation on aryl rings other than phenyl. There-
fore, derivatives 5m–5s bearing various aryl ring groups
were prepared and the antibacterial activities of the rep-
resentative compounds are given in Table 4. Com-
pounds 5m, 5n, and 5o bearing a pyridine ring showed
increased activity against H. influenzae compared to
5d, but their activity against erythromycin-resistant S.
pneumoniae was much more inferior to that of 5d,
though it maintained the activity against other strains.
Compounds 5p and 5q bearing a naphthalene ring
exhibited interesting activities against erythromycin-re-
sistant S. pneumoniae and H. influenzae, respectively.
As for the activity against erythromycin-resistant S.
pneumoniae, compound 5p with a b-naphthyl substituent
showed activity twice as potent as 5d, whereas 5q with
an a-naphthyl one showed a much lower activity. On
the other hand, against H. influenzae, compound 5q
was twice as active as 5d, while 5p showed activity com-
parable to that of 5d. These findings that the b-naphthyl
moiety contributes to the activity against erythromycin-
resistant S. pneumoniae and the a-naphthyl one to the
activity against H. influenzae led us to the design of com-
We next examined the effect of the amide group and its N–
H bond. Table 2 presents the antibacterial activity of 5d
and its analogues 8, 11, and 13 with the same spacer length
as 5d. Clearly, the analogues 8, 11, and 13 are less active
than 5d against the strains tested, especially against eryth-
romycin-resistant strains. Compound 13 bearing an ester
group showed a much lower antibacterial activity and
compound 11 almost lost its activity. N-Methylcarba-
moyl analogue 8 was less active than 5d against erythro-
mycin-resistant S. pneumoniae, while retaining an
almost comparable activity to 5d against other strains.
These results strongly suggest that amide is the best link-
age for the C-9 iminoether moiety and the NH group of
the amide also plays an important role in the activity
against erythromycin-resistant S. pneumoniae.
Next, the effects of the substituent on the phenyl ring
were examined. Table 3 presents the activities of 5d
derivatives with a substituent on the phenyl ring. The
introduction of a methyl substituent (5g–5i) resulted in
a remarkable decrease of their activity against erythro-
mycin-resistant S. pneumoniae. Among them, 5i with a
para-substituent showed a rather strong activity, but
the activity against erythromycin-resistant S. pneumo-
Table 3. In vitro antibacterial activities of compound 5d and its analogues 5g–51
Ar
Me
H
Ar
N
NMe2
O
O
N
(CH2)3
Me
HO
O
O
Me
5g
9
6
5i
5h
O
O
O
MeO
3
Ph
F
Me2N
O
O
O
5
5l
5k
5j
Strain
MIC (lg/mL)
5d
5g
5h
5i
5j
5k
0.39
5l
CAM
0.2
>100
0.025
>100
3.13
S. aureus Smith
0.2
0.2
0.2
0.2
0.39
0.39
0.39
0.39
0.2
0.39
1.56
1.56
0.2
S. aureus SR17347(EM-R)
S. pneumoniae Type I
S. pneumoniae SR16651(EM-R)
H. influenzae SR88562
0.39
0.05
0.025
0.78
6.25
0.025
25
6.25
0.025
12.5
6.25
0.025
6.25
6.25
0.025
6.25
6.25
50
12.5
6.25
>100

T. Nomura et al. / Bioorg. Med. Chem. 13 (2005) 6615–6628
Table 4. In vitro antibacterial activities of compound 5d and its analogues 5m–5s
6619
Ar
H
N
N
Ar
N
N
NMe2
O
O
N
(CH2)3
HO
O
O
9
6
5p
5m
5n
5o
O
O
O
MeO
3
N
N
O
O
O
5
5q
5r
5s
Strain
MIC (lg/mL)
5d
5m
5n
5o
5p
5q
5r
5s
CAM
0.2
>100
0.025
>100
3.13
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
0.39
0.025
0.39
0.39
0.05
0.39
6.25
0.39
0.39
0.2
0.2
0.2
0.2
0.025
0.025
100
3.13
0.025
50
1.56
0.025
12.5
3.13
0.0125
0.1
3.13
0.0125
0.78
0.78
S. pneumoniae SR16651(EM-R)
H. influenzae SR88562
0.78
6.25
100
3.13
Table 5. In vivo efficacy in the mouse lung infection models
Compound
S. pneumoniae
ED50 (mg/kg)
Rat
MIC (lg/mL)
Mouse serum free (%)
Lung AUC (0–6 h) (lg h/g)a
5d
5s
CAM
0.025
0.0125
0.025
21.8
35.9
11.6
2.9
5.9
26
19
52.8
221
a Dose 20 mg/kg (PO).
pounds 5r and 5s with a quinolynyl moiety. As shown in
Table 4, as expected, both compounds had potent activ-
ities including erythromycin-resistant S. pneumoniae and
H. influenzae. Between the two, compound 5s with a
quinolin-4-yl moiety was considered to be the better
one in terms of its balanced activity against erythromy-
cin-resistant S. pneumoniae and H. influenzae, while 5r
with the quinolin-3-yl moiety showed remarkable activ-
ity against erythromycin-resistant S. pneumoniae.
ysis of RU-00410 and ABT-7737 indicated that their aryl
groups were located on their hydrophilic face with al-
most the same spatial positioning. We conducted the
conformational analysis of 5s with RU-004 and ABT-
773 by locating the aryl groups in a similar spatial area
with the computer software MOE.11 Although many
conformations arose from superposing compound 5s
on the other, we finally obtained a conformation of
the three compounds with their aryl groups located in
almost the same spatial area. As shown in Figure 2, all
aryl groups of 5s (green), RU-004 (red), and ABT-773
(blue) can occupy almost the same spatial area on the
hydrophilic face. The conformation depicted in this
The in vivo efficacy (ED50) of 5s and 5d, as well as that
of CAM, in the mouse lung infection model was evalu-
ated, as presented in Table 5. It was disappointing to
find that these ketolides bearing an N-aryl-propyl actet-
amide group were less efficacious in vivo than CAM in
the lung infection model although they had in vitro
activity as potent as CAM. The weak in vivo efficacy
was presumably attributed to their low free fraction in
mouse serum and their poor pharmacokinetic proper-
ties. The lung AUCs of 5d and 5s in mice would be much
lower than that of CAM as in the case with the AUC in
rats shown in Table 5.
4. Molecular modeling
We conducted an extensive study on ketolides bearing
an N-aryl-alkyl acetamide group at the C-9 iminoether,
and found the analogue 5s to be a ketolide with potent
and balanced antibacterial activities. A macrolide has
two faces on its molecular surface, a hydrophobic face
and a hydrophilic one, which can be easily differentiated
on its molecular model. The hydrophilic face has most
of the oxygen-containing groups. Conformational anal-
Figure 2. Conformation model of 5s (green), RU-004 (red), and
ABT-773 (blue).

6620
T. Nomura et al. / Bioorg. Med. Chem. 13 (2005) 6615–6628
model12 is similar to that of ABT-773 in a complex with
ribosome,13 leading to the suggestion that this type of
ketolide bearing an N-aryl-propyl acetamide group at
the C-9 iminoether could be promising as a compound
against pathogens resistant to erythromycin.
À78 °C with stirring for 30 min at À78 °C. The reaction
mixture was poured into H2O and extracted with CHCl3
(50 mL). The aqueous layer was extracted with CHCl3
(50 mL) and the combined organic layer was washed
with brine, dried over MgSO4, filtered, and concentrated
in vacuo. The residue was diluted with tert-BuOH
(30 mL) and H2O (10 mL), and to this solution were
added 2-methy-2-butene (2.7 mL, 25.4 mmol), NaH2-
PO4Æ2H2O (850 mg, 5.45 mmol), and 80% NaClO2
(2.2 g, 11.2 mmol) at room temperature. After stirring
for 3.5 h at room temperature, to the reaction mixture
was added 1 N HCl (50 mL) under cooling with an
ice-water bath. The mixture was poured into H2O and
extracted with CHCl3 (50 mL). The aqueous layer was
extracted with CHCl3 (50 mL) and the combined organ-
ic layer was washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo. The residue was
purified by column chromatography on silicagel (n-hex-
ane/AcOEt = 1/1–1/4 and CHCl3/MeOH = 4/1) to give
4.95 g of compound 3 as a colorless foam (two conform-
ers 97%).
5. Conclusion
A series of ketolides bearing an N-aryl-propyl acetamide
group at the C-9 iminoether was found to have potent
activities against key respiratory pathogens, including
erythromycin-resistant ones. Extensive study on the
modification of the C-9 iminoether moiety revealed that
the amide and its NH group were essential for potent
activity, and led to the discovery of novel compounds,
such as, 5s, with potent activity against the key respira-
tory pathogens. Although this type of ketolides showed
excellent activities in vitro, they exhibited poor in vivo
efficacy in experimental animal infection models, pre-
sumably due to their poor pharmacokinetic profiles.
These results directed us to the pursuit of other deriva-
tives with an improved pharmacokinetic profile along
with potent activities, which will be reported elsewhere
in the future.
MS (FAB) 963+(M+Na+); HRMS (FAB) calcd for
C48H64N2O17Na (M+Na+) 963.4103, found 963.4106;
Anal. calcd for C48H64N2O17(H2O)2: C, 59.01; H, 7.01;
N, 2.87, found: C, 58.95; H, 6.76; N, 2.93; IR (KBr)
3430, 3065, 3032, 2975, 2938, 2881, 1809, 1752, 1703,
1618, 1497, 1455, 1406, 1382, 1329, 1290, 1253, 1167,
1113, 1082, 1067 (cmÀ1); 1H NMR (CDCl3) d 2.66
(3H, s), 2.80, 2.84 (3H, two s); 13C NMR (CDCl3) d
10.3, 13.0, 13.8, 13.9, 14.1, 15.3, 15.5, 18.5, 19.7, 20.6,
21.0, 22.3, 26.5, 28.9, 29.6, 33.0, 35.7, 36.2, 37.8, 46.9,
47.0, 49.5, 50.9, 54.8, 60.4, 67.2, 67.3, 68.7, 69.4, 69.6,
70.9, 74.6, 76.2, 76.4, 78.1, 82.7, 84.8, 100.6, 125.2,
127.5, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.4,
129.0, 135.4, 135.5, 136.6, 154.3, 154.4, 156.1, 156.5,
167.1, 167.2, 169.0, 203.8, 204.1 (two rotational isomers
6. Experimental
Infrared (IR) spectra were taken on a JASCO FT/IR-
1
700 spectrometer. H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were recorded on a Varian Gemini-
300. Chemical shifts are reported in ppm using tetra-
methylsilane (TMS) as an internal standard. HR-MS
(FAB)/MS (FAB) 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
silica gel 60 F254 and visualized with UV light or 10%
H2SO4 containing 5% ammonium molybdate and
0.2% ceric sulfate. Flash chromatography was per-
formed with Merck silica gel 60 (230–400 mesh).
1
were observed by H NMR and 13C NMR spectra).
6.3. Preparation of compound 5d
6.3.1. Amidation. To
a solution of 3 (300 mg,
0.318 mmol) in toluene (6 mL) were added DMF
(2 lL, 0.03 mmol) and oxalyl chloride (59 lL, 0.636
mmol) at room temperature, and the reaction mixture
was stirred for 90 min at room temperature. To this
solution, phenylpropylamine (181 lL, 1.27 mmol) was
added, and the reaction mixture was stirred for 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 combined organic layer was washed with
brine, dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatog-
raphy on silicagel (n-hexane/AcOEt = 4/1–1/1) to give
298 mg of compound 4 bearing N-phenypropylaceta-
mide group as a colorless foam (89%).
6.1. Measurement of in vitro antibacterial activity
MICs were determined by a serial twofold dilution
method in Sensivity Disk Agar-N (Nissui Pharmaceuti-
cal, Tokyo, Japan). The overnight cultures of antibacte-
rial 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.
6.2. Preparation of compound 3
A solution of compound 29 (5.0 g, 5.42 mmol) in
CH2Cl2 (50 mL)–MeOH (10 mL) was cooled to
À78 °C, and O3 gas was bubbled through the solution
with stirring until the solution turned blue. Next, N2
gas was bubbled through the solution with stirring until
the blue color discharged. After that, Me2S (2 mL,
27.2 mmol) was added to the reaction mixture at
MS (FAB) 1080+(M+Na+); HRMS (FAB) calcd for
C57H75N3O16Na
(M+Na+)
1080.5045,
found
1080.5056; IR (KBr) 3434, 33371, 3063, 3029, 2974,
2938, 2879, 1811, 1752, 1702, 1604, 1586, 1532, 1497,
1455, 1381, 1330, 1289, 1253, 1167, 1113, 1067, 1003

T. Nomura et al. / Bioorg. Med. Chem. 13 (2005) 6615–6628
6621
(cmÀ1); 1H NMR (CDCl3) d 2.65 (3H, s), 2.80, 2.84 (3H,
two s); 13C NMR (CDCl3) d 10.2, 12.9, 13.8, 15.3, 15.5,
18.8, 19.8, 20.5, 22.3, 26.2, 29.0, 30.8, 33.1, 35.7, 36.1,
37.6, 38.7, 46.9, 47.0, 49.6, 50.9, 54.8, 67.1, 67.2, 68.7,
69.3, 69.5, 72.9, 74.6, 76.1, 78.2, 82.2, 84.4, 100.6,
125.7, 127.5, 127.6, 127.8, 127.9, 128.2, 128.3, 128.4,
135.4, 135.5, 136.6, 141.4, 153.7, 154.3, 154.4, 156.0,
156.4, 167.2, 169.0, 170.1, 203.6, 203.8 (two rotational
isomers were observed by 1H NMR and 13C NMR
spectra).
0.91 (3H, t, J = 7.5 Hz), 1.06 (3H, d, J = 6.6 Hz), 1.25
(3H, d, J = 7.2 Hz), 1.27 (3H, d, J = 8.4 Hz), 1.31 (3H,
d, J = 6.6 Hz), 1.36 (3H, d, J = 6.6 Hz), 1.41 (3H, s),
1.58 (3H, s), 1.54–1.94 (5H, m), 2.29 (6H, s), 2.40–2.65
(3H, m), 2.63 (3H, s), 3.02 (1H, quintet, J = 7.8 Hz),
3.20 (1H, dd, J = 7.5 and 9.9 Hz), 3.40–3.80 (3H, m),
3.84 (1H, q, J = 6.9 Hz), 4.21 (1H, d, J = 8.1 Hz), 4.30
(1H, d, J = 7.2 Hz), 4.59 (2H, s), 4.87 (1H, s), 5.03
(1H, dd, J = 2.1 and 10.2 Hz), 7.06–7.59 (5H, m), 8.53
(1H, br s); 13C NMR (CDCl3) d 10.3, 13.0, 14.3, 15.5,
15.6, 18.8, 19.9, 21.1, 22.3, 26.5, 28.3, 33.2, 38.1, 40.1,
47.6, 49.7, 51.0, 65.8, 69.4, 70.2, 73.5, 76.1, 78.4, 78.6,
82.3, 84.6, 103.7, 120.1, 124.3, 128.9, 137.3, 153.9,
168.4, 168.6, 169.1, 203.8.
6.3.2. Deprotection and N-methylation. This colorless
foam 4 (298 mg) with N-phenypropylacetamide was
diluted with EtOH (24 mL) and 0.2 M acetate buffer
(6 mL, pH 4.4). To this solution was added 20%
Pd(OH)2/C (89 mg, 0.168 mmol) with stirring at room
temperature under a H2 atmosphere for 1 h. After con-
firming the disappearance of 4 by TLC, 37% aqueous
HCHO (2.1 mL) was added to the reaction mixture
and stirred at room temperature under H2 atmosphere
for an additional 2 h. The mixture was filtered and con-
centrated. After being diluted with water, the mixture
was basified with 5% aqueous NaHCO3 and then
extracted with AcOEt. The resultant residue was puri-
fied by column chromatography on silicagel (CHCl3/
MeOH = 80/1–40/1) to give 182 mg of compound 5d as
a colorless foam (87%).
6.4.2. Compound 5b. MS (FAB) 776+(M+H+); HRMS
(FAB) calcd for C40H62N3O12 (M+H+) 776.4333, found
776.4338; IR (KBr) 3435, 2974, 2938, 2879, 1810, 1751,
1715, 1675, 1530, 1455, 1379, 1323, 1283, 1258, 1231,
1166, 1110, 1078, 1048 (cmÀ1); 1H NMR (CDCl3) d
0.92 (3H, t, J = 8.4 Hz), 0.93 (3H, d, J = 7.2 Hz), 1.16
(3H, d, J = 6.9 Hz), 1.25 (3H, d, J = 6.3 Hz), 1.26 (3H,
d, J = 7.5 Hz), 1.33 (3H, s), 1.36 (3H, d, J = 6.6 Hz),
1.53 (3H, s), 1.40–1.98 (6H, m), 2.27 (6H, s), 2.40–2.53
(2H, m), 2.52 (3H, s), 2.91 (1H, br s), 2.99 (1H, quintet,
J = 7.8 Hz), 3.17 (1H, dd, J = 7.2 and 9.9 Hz), 3.49–3.70
(2H, m), 3.81 (1H, q, J = 6.6 Hz), 4.18 (1H, d,
J = 7.8 Hz), 4.29 (1H, d, J = 7.5 Hz), 4.42 (1H, dd,
J = 5.1 and 14.7 Hz), 4.53 (1H, dd, J = 5.1 and
14.7 Hz), 4.52 (2H, s), 4.72 (1H, s), 4.93 (1H, dd,
J = 2.7 and 9.9 Hz), 7.04 (1H, t, J = 5.1 Hz), 7.20–7.38
(5H, m); 13C NMR (CDCl3) d 10.4, 13.0, 14.2, 15.3,
15.5, 18.7, 19.8, 21.1, 22.4, 26.3, 28.2, 33.1, 38.0, 40.1,
43.2, 47.5, 49.6, 51.0, 65.8, 69.4, 70.2, 72.9, 76.3, 78.2,
78.5, 82.4, 84.4, 103.6, 127.4, 128.1, 128.6, 137.9,
153.8, 167.7, 168.9, 170.1, 204.0.
MS (FAB) 804+(M+H+); HRMS (FAB) calcd for
C42H66N3O12 (M+H+) 804.4647, found 804.4650; IR
(KBr) 3433, 3061, 2973, 2936, 2878, 2785, 1809, 1751,
1716, 1671, 1536, 1495, 1455, 1380, 1321, 1284, 1259,
1
1232, 1166, 1110, 1078, 1048 (cmÀ1); H NMR (CDCl3)
d 0.89 (3H, t, J = 7.2 Hz), 1.01 (3H, d, J = 6.9 Hz), 1.24
(3H, d, J = 6.3 Hz), 1.26 (3H, d, J = 6.9 Hz), 1.27 (3H,
d, J = 7.5 Hz), 1.37 (3H, d, J = 6.9 Hz), 1.38 (3H, s),
1.56 (3H, s), 1.20–1.94 (8H, m), 2.31 (6H, s), 2.55 (2H,
m), 2.66 (2H, t, J = 8.1 Hz), 2.69 (3H, s), 3.02 (1H, quin-
tet, J = 7.5 Hz), 3.16–3.28 (2H, m), 3.32–3.46 (1H, m),
3.48–3.74 (2H, m), 3.83 (1H, q, J = 6.9 Hz), 4.22 (1H,
d, J = 7.5 Hz), 4.31 (1H, d, J = 7.2 Hz), 4.45 (2H, s),
4.82 (1H, s), 5.00 (1H, dd, J = 2.4 and 9.9 Hz), 6.90
(1H, brt, J = 5.4 Hz), 7.12–7.30 (5H, m); 13C NMR
(CDCl3) d 10.3, 12.9, 14.3, 15.4, 15.6, 18.8, 19.9, 21.1,
22.3, 26.3, 28.5, 30.9, 33.1, 38.0, 38.8, 40.1, 47.6, 49.8,
51.0, 65.9, 69.3, 70.2, 73.0, 76.1, 78.4, 78.6, 82.3, 84.5,
103.6, 125.7, 128.3, 128.4, 141.5, 153.8, 167.5, 169.2,
170.3, 203.9.
6.4.3. Compound 5c. MS (FAB) 790+(M+H+); HRMS
(FAB) calcd for C41H64N3O12 (M+H+) 790.4490, found
790.4492; IR (KBr) 3432, 3062, 2973, 2937, 2879, 2784,
1810, 1751, 1716, 1675, 1604, 1531, 1496, 1455, 1380,
1363, 1322, 1305, 1284, 1257, 1234, 1166, 1141, 1110,
1078, 1047, 1004 (cmÀ1); 1H NMR (CDCl3) d 0.90
(3H, t, J = 6.9 Hz), 0.95 (3H, d, J = 7.2 Hz), 1.21 (3H,
d, J = 6.9 Hz), 1.26 (3H, d, J = 6.0 Hz), 1.28 (3H, d,
J = 7.5 Hz), 1.35 (3H, s), 1.37 (3H, d, J = 7.2 Hz), 1.56
(3H, s), 1.44–1.99 (5H, m), 2.29 (6H, s), 2.40–2.60
(2H, m), 2.65 (3H, s), 2.87 (2H, m), 3.02 (1H, quintet,
J = 7.2 Hz), 3.20 (1H, t, J = 8.1 Hz), 3.32 (1H, br s),
3.40–3.70 (5H, m), 3.83 (1H, q, J = 6.9 Hz), 4.21 (1H,
d, J = 8.4 Hz), 4.31 (1H, d, J = 6.9 Hz), 4.46 (2H, s),
4.82 (1H, s), 5.03 (1H, dd, J = 2.4 and 10.2 Hz), 6.89
(1H, t, J = 5.4 Hz), 7.18–7.36 (5H, m); 13C NMR
(CDCl3) d 10.3, 12.9, 14.2, 15.3, 15.6, 18.8, 19.8, 21.1,
22.3, 26.3, 28.3, 33.1, 35.6, 38.0, 40.1, 40.2, 47.6, 49.6,
51.0, 65.8, 69.4, 70.2, 72.9, 76.1, 78.3, 78.6, 82.3, 84.6,
103.7, 126.2, 128.4, 128.7, 138.9, 153.9, 167.4, 169.2,
170.1, 203.9.
6.4. Preparation of compounds 5a, 5b, 5c, 5e, and 5f
Compounds 5a, 5b, 5c, 5e, and 5f were prepared in
the same procedure as that described for the synthesis
of 5d with aniline, benzylamine, phenethylamine,
4-phenyl-butylamine, and 5-phenyl-pentylamine,15
respectively.
6.4.1. Compound 5a. MS (FAB) 762+(M+H+); HRMS
(FAB) calcd for C39H60N3O12 (M+H+) 762.4177, found
762.4174; IR (KBr) 3413, 3361, 2972, 2936, 2879, 2786,
1810, 1751, 1714, 1685, 1636, 1600, 1536, 1499, 1456,
1444, 1379, 1361, 1320, 1284, 1256, 1235, 1167, 1141,
1109, 1078, 1047, 1006 (cmÀ1); 1H NMR (CDCl3) d
6.4.4. Compound 5e. MS (FAB) 818+(M+H+); HRMS
(FAB) calcd for C43H68N3O12 (M+H+) 818.4803, found
818.4801; IR (KBr) 3435, 2973, 2937, 2879, 2786, 1809,
1752, 1716, 1654, 1456, 1379, 1324, 1283, 1260, 1229,

6622
T. Nomura et al. / Bioorg. Med. Chem. 13 (2005) 6615–6628
1166, 1110, 1079, 1049 (cmÀ1); 1H NMR (CDCl3) d 0.90
(3H, t, J = 7.8 Hz), 1.01 (3H, d, J = 7.2 Hz), 1.25 (6H, d,
J = 5.7 Hz), 1.28 (3H, d, J = 7.8 Hz), 1.38 (3H, d,
J = 6.6 Hz), 1.39 (3H, s), 1.56 (3H, s), 1.42–1.96 (8H,
m), 2.27 (6H, s), 2.40–2.60 (2H, m), 2.63 (2H, t,
J = 7.8 Hz), 2.68 (3H, s), 2.90–3.42 (6H, m), 3.50–3.74
(2H, m), 3.84 (1H, q, J = 6.9 Hz), 4.22 (1H, d, J = 8.1
Hz), 4.30 (1H, d, J = 7.2 Hz), 4.45 (2H, s), 4.82 (1H,
s), 5.04 (1H, dd, J = 2.4 and 10.5 Hz), 6.86 (1H, brt,
J = 5.7 Hz), 7.14–7.29 (5H, m); 13C NMR (CDCl3) d
10.1, 12.7, 14.1, 15.1, 15.5, 18.6, 19.7, 21.0, 22.1, 26.1,
28.0, 28.5, 28.9, 32.9, 35.2, 37.8, 38.7, 40.0, 47.4, 49.6,
50.8, 65.6, 69.3, 70.0, 72.7, 75.9, 78.2, 78.5, 82.1, 84.4,
103.5, 125.4, 128.0, 128.2, 142.1, 153.6, 167.3, 169.0,
170.0, 203.7.
brt, J = 5.7 Hz), 7.02–7.18 (4H, m); 13C NMR (CDCl3)
d 10.2, 12.9, 14.2, 15.3, 15.6, 18.8, 19.2, 19.9, 21.1,
22.2, 26.3, 28.1, 29.7, 30.4, 33.1, 38.0, 39.0, 40.2, 47.6,
49.7, 51.0, 65.8, 69.5, 70.2, 73.0, 76.0, 78.3, 78.6, 82.3,
84.5, 103.7, 125.8, 128.6, 130.0, 135.8, 139.6, 153.8,
167.4, 169.1, 170.2, 203.9.
6.5.2. Compound 5h. MS (FAB) 818+(M+H+); HRMS
(FAB) calcd for C43H68N3O12 (M+H+) 818.4803, found
818.4802; IR (CHCl3) 3426, 3350, 2998, 2970, 2934,
2870, 2782, 1805, 1751, 1715, 1663, 1607, 1536, 1454,
1381, 1361, 1345, 1322, 1305, 1282, 1255, 1229, 1219,
1
1165, 1139, 1107, 1075, 1046, 1004 (cmÀ1); H NMR
(CDCl3) d 0.89 (3H, t, J = 7.2 Hz), 1.01 (3H, d,
J = 6.9 Hz), 1.24 (3H, d, J = 6.0 Hz), 1.26 (3H, d,
J = 6.6 Hz), 1.28 (3H, d, J = 6.9 Hz), 1.37 (3H, d,
J = 6.9 Hz), 1.39 (3H, s), 1.56 (3H, s), 1.15–1.93 (8H,
m), 2.28 (6H, s), 2.31 (3H, s), 2.48 (1H, m), 2.56 (1H,
q, J = 6.9 Hz), 2.62 (2H, t, J = 7.8 Hz), 2.68 (3H, s),
3.02 (1H, quintet, J = 7.8 Hz), 3.19 (1H, dd, J = 7.2
and 10.5 Hz), 3.22 (1H, m), 3.37 (1H, m), 3.48–3.73
(2H, m), 3.83 (1H, q, J = 6.9 Hz), 4.21 (1H, d,
J = 8.1 Hz), 4.30 (1H, d, J = 7.2 Hz), 4.45 (2H, s), 4.82
(1H, s), 5.00 (1H, dd, J = 2.4 and 9.9 Hz), 6.88 (1H,
brt, J = 5.7 Hz), 6.95–7.02 (3H, m), 7.15 (1H, t,
J = 7.5 Hz); 13C NMR (CDCl3) d 10.2, 12.9, 14.2,
15.3, 15.6, 18.8, 19.9, 21.1, 21.3, 22.3, 26.3, 28.1, 30.9,
33.1, 33.2, 38.0, 38.8, 40.2, 47.6, 49.7, 51.0, 65.8, 69.5,
70.2, 73.0, 76.0, 78.4, 78.7, 82.3, 84.5, 103.7, 125.3,
126.5, 128.1, 129.1, 137.7, 141.4, 153.8, 167.4, 169.1,
170.2, 203.9.
6.4.5. Compound 5f. MS (FAB) 832+(M+H+); HRMS
(FAB) calcd for C44H70N3O12 (M+H+) 832.4959, found
832.4968; IR (KBr) 3435, 2972, 2936, 2877, 2857, 2785,
1811, 1751, 1717, 1671, 1534, 1496, 1455, 1380, 1362,
1323, 1304, 1283, 1258, 1234, 1219, 1167, 1142, 1109,
1078, 1048, 1004 (cmÀ1); 1H NMR (CDCl3) d 0.85
(3H, t, J = 7.2 Hz), 1.00 (3H, d, J = 7.2 Hz), 1.24 (3H,
d, J = 6.3 Hz), 1.26 (3H, d, J = 6.9 Hz), 1.28 (3H, d,
J = 7.2 Hz), 1.37 (3H, d, J = 7.2 Hz), 1.39 (3H, s), 1.56
(3H, s), 1.22–1.96 (12H, m), 2.26 (6H, s), 2.40–2.65
(5H, m), 2.69 (3H, s), 3.02 (1H, quintet, J = 7.8 Hz),
3.10–3.40 (3H, m), 3.48–3.75 (2H, m), 3.84 (1H, q,
J = 6.9 Hz), 4.22 (1H, d, J = 8.1 Hz), 4.30 (1H, d,
J = 7.2 Hz), 4.45 (2H, s), 4.82 (1H, s), 5.02 (1H, dd,
J = 2.7 and 10.2 Hz), 6.87 (1H, brt, J = 5.7 Hz), 7.12–
7.28 (5H, m); 13C NMR (CDCl3) d 10.2, 12.9, 14.3,
15.3, 15.6, 18.9, 19.9, 21.1, 22.3, 26.3, 26.6, 28.1, 29.3,
31.1, 33.1, 35.7, 38.0, 39.1, 40.2, 47.6, 49.8, 51.0, 65.8,
69.5, 70.3, 73.0, 76.1, 78.4, 78.7, 82.3, 84.5, 103.8, 125.5,
128.1, 128.4, 142.6, 153.8, 167.4, 169.2, 170.2, 203.9.
6.5.3. Compound 5i. MS (FAB) 818+(M+H+); HRMS
(FAB) calcd for C43H68N3O12 (M+H+) 818.4803, found
818.4799; IR (CHCl3) 3426, 3354, 2970, 2934, 2870,
2780, 1805, 1751, 1715, 1663, 1537, 1515, 1454, 1380,
1361, 1345, 1323, 1305, 1282, 1256, 1230, 1220, 1165,
1139, 1107, 1075, 1046, 1004 (cmÀ1); 1H NMR (CDCl3)
d 0.88 (3H, t, J = 7.2 Hz), 1.01 (3H, d, J = 6.6 Hz), 1.24
(3H, d, J = 5.4 Hz), 1.26 (3H, d, J = 6.0 Hz), 1.28 (3H,
d, J = 6.9 Hz), 1.37 (3H, d, J = 6.3 Hz), 1.38 (3H, s),
1.55 (3H, s), 1.16–2.05 (8H, m), 2.27 (6H, s), 2.29 (3H,
s), 2.46 (1H, m), 2.56 (1H, q, J = 6.9 Hz), 2.61 (2H, t,
J = 7.8 Hz), 2.68 (3H, s), 3.02 (1H, quintet,
J = 7.5 Hz), 3.18 (1H, dd, J = 7.5 and 9.9 Hz), 3.23
(1H, m), 3.36 (1H, m), 3.45–3.72 (2H, m), 3.83 (1H, q,
J = 7.2 Hz), 4.21 (1H, d, J = 7.8 Hz), 4.30 (1H, d,
J = 7.2 Hz), 4.45 (2H, s), 4.81 (1H, s), 5.00 (1H, dd,
J = 2.7 and 10.2 Hz), 6.86 (1H, brt, J = 6.0 Hz), 7.06–
7.15 (4H, m); 13C NMR (CDCl3) d 10.2, 12.9, 14.2,
15.3, 15.6, 18.8, 19.9, 20.9, 21.1, 22.2, 26.3, 28.1, 30.9,
32.7, 33.1, 38.0, 38.7, 40.2, 47.6, 49.7, 51.0, 65.8, 69.5,
70.2, 72.9, 76.0, 78.4, 78.7, 82.3, 84.5, 103.7, 128.2,
128.9, 135.0, 138.4, 153.8, 167.5, 169.1, 170.2, 203.9.
6.5. Preparation of compounds 5g–5l
Compounds 5g–5l were prepared in the same procedure
as that described for the synthesis of 5d with 3-o-tolyl-
propylamine (16a), 3-m-tolyl-propylamine (16b),
3-p-tolyl-propylamine (16c), 3-(4-fluoro-phenyl)-propyl-
amine (16d), 3-(4-nitro-phenyl)-propylamine (16e), and
3-biphenyl-4-yl-propylamine (16f), respectively.
6.5.1. Compound 5g. MS (FAB) 818+(M+H+); HRMS
(FAB) calcd for C43H68N3O12 (M+H+) 818.4803, found
818.4803; IR (CHCl3) 3426, 3350, 2970, 2934, 2870,
2830, 2780, 1805, 1751, 1715, 1663, 1536, 1490, 1455,
1381, 1361, 1345, 1322, 1305, 1282, 1256, 1230, 1220,
1
1165, 1139, 1107, 1074, 1046, 1004 (cmÀ1); H NMR
(CDCl3) d 0.89 (3H, t, J = 7.2 Hz), 1.01 (3H, d,
J = 6.6 Hz), 1.24 (3H, d, J = 5.4 Hz), 1.26 (3H, d,
J = 6.0 Hz), 1.28 (3H, d, J = 6.9 Hz), 1.37 (3H, d,
J = 6.9 Hz), 1.39 (3H, s), 1.56 (3H, s), 1.25–1.94 (8H,
m), 2.28 (6H, s), 2.29 (3H, s), 2.47 (1H, m), 2.56 (1H,
q, J = 6.9 Hz), 2.63 (2H, t, J = 8.1 Hz), 2.69 (3H, s),
3.02 (1H, quintet, J = 7.5 Hz), 3.19 (1H, dd, J = 7.5
and 10.2 Hz), 3.27 (1H, m), 3.41 (1H, m), 3.45–3.75
(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), 4.47 (2H, s), 4.82
(1H, s), 5.00 (1H, dd, J = 2.4 and 9.9 Hz), 6.92 (1H,
6.5.4. Compound 5j. MS (FAB) 822+(M+H+); HRMS
(FAB) calcd for C42H65F1N3O12 (M+H+) 822.4552,
found 822.4551; IR (KBr) 3435, 2973, 2938, 2878,
2785, 1811, 1751, 1717, 1673, 1601, 1533, 1509, 1456,
1380, 1362, 1323, 1304, 1283, 1257, 1220, 1166, 1142,
1109, 1078, 1048, 1004 (cmÀ1); 1H NMR (CDCl3) d
0.89 (3H, t, J = 7.2 Hz), 1.02 (3H, d, J = 6.9 Hz), 1.24
(3H, d, J = 5.7 Hz), 1.26 (3H, d, J = 6.6 Hz), 1.28 (3H,

T. Nomura et al. / Bioorg. Med. Chem. 13 (2005) 6615–6628
6623
d, J = 6.9 Hz), 1.37 (3H, d, J = 6.9 Hz), 1.39 (3H, s),
1.56 (3H, s), 1.54–1.93 (8H, m), 2.27 (6H, s), 2.40–2.60
(2H, m), 2.63 (2H, t, J = 8.1 Hz), 2.68 (3H, s), 3.02
(1H, quintet, J = 7.5 Hz), 3.16–3.75 (5H, m), 3.84 (1H,
q, J = 7.2 Hz), 4.22 (1H, d, J = 8.1 Hz), 4.30 (1H, d,
J = 7.2 Hz), 4.44 (2H, s), 4.82 (1H, s), 4.98 (1H, dd,
J = 2.4 and 9.9 Hz), 6.90–6.98 (2H, m), 6.99 (1H, t,
J = 5.1 Hz), 7.13–7.19 (2H, m); 13C NMR (CDCl3) d
10.2, 12.9, 14.3, 15.3, 15.5, 18.9, 19.9, 21.1, 22.3, 26.3,
28.2, 31.0, 32.4, 33.2, 38.0, 38.7, 40.2, 47.6, 49.8, 51.1,
65.9, 69.6, 70.3, 73.0, 76.1, 78.5, 78.6, 82.3, 84.6, 103.8,
114.7, 115.2, 129.6, 129.8, 137.2, 137.3, 153.7, 158.8,
163.6, 167.6, 169.2, 170.3, 203.8.
3-pyridin-2-yl-propylamine,16 3-naphthalen-2-yl-propyl-
amine (16g), 3-naphthalen-1-yl-propylamine (16h),
3-quinolin-3-yl-propylamine (16i), and 3-quinolin-4yl-
propylamine (16j), respectively.
6.6.1. Compound 5m. MS (FAB) 805+(M+H+); HRMS
(FAB) calcd for C41H65N4O12 (M+H+) 805.4599, found
805.4604; IR (KBr) 3432, 2971, 2934, 2877, 2784, 1809,
1751, 1716, 1674, 1603, 1534, 1456, 1416, 1378, 1322,
1305, 1284, 1259, 1222, 1166, 1110, 1078, 1048 (cmÀ1);
1H NMR (CDCl3) d 0.89 (3H, t, J = 6.6 Hz), 1.01 (3H,
d, J = 6.9 Hz), 1.25 (3H, d, J = 6.6 Hz), 1.27 (3H, d,
J = 9.0 Hz), 1.28 (3H, d, J = 9.3 Hz), 1.38 (3H, d,
J = 5.4 Hz), 1.39 (3H, s), 1.57 (3H, s), 1.54–1.94 (8H,
m), 2.30 (6H, s), 2.44–2.70 (4H, m), 2.69 (3H, s), 2.95–
3.05 (1H, m), 3.14–3.23 (2H, m), 3.40–3.98 (5H, m),
4.23 (1H, d, J = 7.5 Hz), 4.30 (1H, d, J = 7.2 Hz), 4.43
(2H, s), 4.83 (1H, s), 4.98 (1H, brd J = 10.8 Hz), 7.18
(3H, br s), 8.48 (2H, br s); 13C NMR (CDCl3) d 10.2,
12.8, 14.3, 15.3, 15.6, 18.8, 19.9, 21.1, 22.2, 26.3, 28.3,
29.6, 32.4, 33.1, 37.9, 38.7, 40.1, 47.6, 49.8, 51.0, 65.8,
69.4, 70.2, 72.9, 75.9, 78.4, 78.6, 82.3, 84.6, 103.7,
123.9, 149.5, 153.8, 167.6, 169.3, 170.5, 203.8.
6.5.5. Compound 5k. MS (SI) 847+(M+H+); HRMS (SI)
calcd for C44H71N4O12 (M+H+) 847.4986, found
846.4993; IR (KBr) 3451, 2974, 2938, 2880, 2786,
1810, 1751, 1689, 1632, 1591, 1457, 1380, 1324, 1284,
1
1257, 1231, 1166, 1110, 1078, 1048 (cmÀ1); H NMR
(CDCl3) d 0.89 (3H, t, J = 7.2 Hz), 1.01 (3H, d,
J = 6.9 Hz), 1.24 (3H, d, J = 6.9 Hz), 1.25 (3H,
d, J = 6.3 Hz), 1.28 (3H, d, J = 6.9 Hz), 1.37 (3H, d,
J = 6.9 Hz), 1.38 (3H, s), 1.55 (3H, s), 1.54–1.94 (8H,
m), 2.28 (6H, s), 2.30–2.50 (2H, m), 2.56 (2H, m), 2.69
(3H, s), 2.89 (6H, s), 3.02 (1H, quintet, J = 7.8 Hz),
3.15–3.74 (5H, m), 3.83 (1H, q, J = 6.9 Hz), 4.21 (1H,
d, J = 8.1 Hz), 4.30 (1H, d, J = 7.2 Hz), 4.46 (2H, s),
4.82 (1H, s), 5.02 (1H, dd, J = 2.4 and 9.9 Hz), 6.60–
6.71 (2H, m), 6.76 (1H, m), 7.03–7.09 (2H, m); 13C
NMR (CDCl3) d 10.2, 12.9, 14.2, 15.3, 15.5, 18.7, 19.7,
21.0, 22.2, 26.2, 28.1, 29.5, 31.0, 31.9, 33.1, 37.9, 38.7,
40.0, 40.8, 47.5, 49.6, 50.9, 65.7, 69.3, 70.1, 72.9, 76.0,
78.3, 78.6, 82.2, 84.4, 103.6, 113.0, 128.8, 129.6, 148.9,
153.7, 167.3, 169.0, 170.0, 203.8.
6.6.2. Compound 5n. MS (SI) 805+(M+H+); HRMS (SI)
calcd for C41H65N4O12 (M+H+) 805.4595, found
805.4606; IR (KBr) 3433, 2972, 2937, 2878, 2784,
1810, 1751, 1716, 1673, 1575, 1534, 1456, 1423, 1380,
1363, 1322, 1305, 1284, 1258, 1234, 1220, 1167, 1142,
1109, 1079, 1048, 1005 (cmÀ1); 1H NMR (CDCl3) d
0.89 (3H, t, J = 7.2 Hz), 1.01 (3H, d, J = 6.9 Hz), 1.24
(3H, d, J = 6.3 Hz), 1.26 (3H, d, J = 6.0 Hz), 1.28 (3H,
d, J = 6.6 Hz), 1.38 (3H, d, J = 6.9 Hz), 1.39 (3H, s),
1.56 (3H, s), 1.54–1.94 (8H, m), 2.29 (6H, s), 2.44–2.67
(4H, m), 2.69 (3H, s), 3.01 (1H, quintet, J = 7.5 Hz),
3.15–3.75 (5H, m), 3.85 (1H, q, J = 6.9 Hz), 3.93 (1H,
br s), 4.22 (1H, d, J = 7.8 Hz), 4.30 (1H, d,
J = 7.2 Hz), 4.45 (2H, s), 4.83 (1H, s), 4.99 (1H, dd,
J = 2.7 and 10.5 Hz), 7.11 (1H, brt, J = 5.7 Hz), 7.21
(1H, m), 7.57 (1H, brd, J = 8.1 Hz), 8.44 (2H, m); 13C
NMR (CDCl3) d 10.2, 12.9, 14.3, 15.3, 15.6, 18.8, 19.9,
21.1, 22.2, 26.3, 28.3, 30.2, 30.6, 33.1, 37.9, 38.6, 40.1,
47.6, 49.8, 51.0, 65.8, 69.4, 70.2, 72.9, 75.9, 78.4, 78.6,
82.3, 84.6, 103.7, 123.3, 135.9, 136.9, 147.2, 149.7,
153.8, 167.6, 169.3, 170.4, 203.8.
6.5.6. Compound 5l. MS (FAB) 880+(M+H+); HRMS
(FAB) calcd for C48H70N3O12 (M+H+) 880.4960, found
880.4963; IR (CHCl3) 3436, 3354, 3024, 3006, 2976,
2936, 2874, 1805, 1751, 1715, 1665, 1536, 1485, 1454,
1410, 1381, 1362, 1346, 1319, 1305, 1282, 1256, 1229,
1220, 1166, 1139, 1107, 1078, 1045, 1004 (cmÀ1); 1H
NMR (CDCl3) d 0.86 (3H, t, J = 7.5 Hz), 1.01 (3H, d,
J = 6.9 Hz), 1.23 (3H, d, J = 6.0 Hz), 1.25 (3H,
d, J = 6.6 Hz), 1.28 (3H, d, J = 6.9 Hz), 1.38 (3H, d,
J = 7.2 Hz), 1.39 (3H, s), 1.56 (3H, s), 1.54–1.94 (8H,
m), 2.26 (6H, s), 2.26–2.48 (1H, m), 2.56 (1H, q,
J = 6.9 Hz), 2.70 (3H, s), 2.70 (2H, t, J = 7.5 Hz), 3.02
(1H, quintet, J = 7.5 Hz), 3.14–3.74 (6H, m), 3.84
(1H, q, J = 7.2 Hz), 4.22 (1H, d, J = 8.1 Hz), 4.30 (1H,
d, J = 7.2 Hz), 4.46 (2H, s), 4.83 (1H, s), 5.00 (1H, dd,
J = 2.4 and 9.9 Hz), 6.96 (1H, t, J = 5.4 Hz), 7.26–7.59
(9H, m); 13C NMR (CDCl3) d 10.2, 12.9, 14.2, 15.3,
15.6, 18.8, 19.9, 21.1, 22.2, 26.3, 28.1, 30.8, 32.7, 33.1,
38.0, 38.8, 40.2, 47.6, 49.8, 51.0, 65.8, 69.5, 70.2, 73.0,
76.0, 78.4, 78.6, 82.3, 84.5, 103.7, 126.8, 126.9, 127.0,
128.6, 128.7, 138.6, 140.7, 141.1, 153.8, 167.5, 169.2,
170.3, 203.8.
6.6.3. Compound 5o. MS (FAB) 805+(M+H+); HRMS
(FAB) calcd for C41H65N4O12 (M+H+) 805.4599, found
805.4594; IR (KBr) 3434, 2972, 2937, 2878, 2784, 1810,
1751, 1716, 1674, 1591, 1568, 1533, 1456, 1380, 1363,
1322, 1305, 1284, 1257, 1233, 1219, 1167, 1109, 1078,
1
1048, 1004 (cmÀ1); H NMR (CDCl3) d 0.89 (3H, t,
J = 7.5 Hz), 1.03 (3H, d, J = 6.9 Hz), 1.25 (3H, d,
J = 6.9 Hz), 1.27 (3H, d, J = 7.2 Hz), 1.27 (3H, d,
J = 5.8 Hz), 1.37 (3H, d, J = 6.9 Hz), 1.37 (3H, s), 1.56
(3H, s), 1.54–1.96 (6H, m), 1.99 (2H, t, J = 7.8 Hz),
2.47 (6H, br s), 2.55 (2H, m), 2.69 (3H, s), 2.84 (2H, t,
J = 7.2 Hz), 3.03 (1H, quintet, J = 7.8 Hz), 3.21–3.74
(5H, m), 3.83 (1H, q, J = 6.9 Hz), 4.21 (1H, d,
J = 7.5 Hz), 4.34 (1H, d, J = 7.2 Hz), 4.46 (2H, s), 4.82
(1H, s), 5.03 (1H, dd, J = 2.4 and 9.9 Hz), 6.90 (1H,
m), 7.06–7.11 (1H, m), 7.19 (1H, d, J = 7.8 Hz), 7.58
(1H, dt, J = 2.1 and 7.8 Hz), 8.49 (1H, m); 13C NMR
6.6. Preparation of compounds 5m–5s
Compounds 5m–5s were prepared by the same proce-
dure as that described for the synthesis of 5d with 3-pyri-
din-4-yl-propylamine,16 3-pyridin-3-yl-propylamine,16

6624
T. Nomura et al. / Bioorg. Med. Chem. 13 (2005) 6615–6628
(CDCl3) d 10.3, 13.0, 14.3, 15.3, 15.6, 18.9, 19.9, 21.1,
22.3, 26.4, 28.3, 29.2, 33.2, 35.3, 38.1, 38.5, 40.2, 47.6,
49.8, 51.1, 65.9, 69.5, 70.3, 73.0, 76.1, 78.4, 78.7, 82.4,
84.6, 103.7, 121.0, 122.8, 136.3, 149.1, 153.8, 161.2,
167.4, 169.2, 170.2, 203.9.
d, J = 7.2 Hz), 1.36 (3H, d, J = 6.6 Hz), 1.39 (3H, s),
1.55 (3H, s), 1.24–2.06 (8H, m), 2.27 (6H, s), 2.58 (1H,
m), 2.56 (1H, q, J = 6.6 Hz), 2.70 (3H, s), 2.86 (2H, t,
J = 8.1 Hz), 3.01 (1H, quintet, J = 7.8 Hz), 3.18 (1H,
dd, J = 7.2 and 10.2 Hz), 3.22–3.74 (4H, m), 3.83 (1H,
q, J = 7.2 Hz), 4.22 (1H, d, J = 8.1 Hz), 4.29 (1H, d,
J = 7.5 Hz), 4.46 (2H, s), 4.83 (1H, s), 4.98 (1H, dd,
J = 2.4 and 7.8 Hz), 7.16 (1H, br s,), 7.50 (1H, m),
7.64 (1H, m), 7.80 (1H, dd, J = 0.9 and 8.1 Hz), 8.02
(1H, d, J = 1.2 Hz), 8.05 (1H, d, J = 8.4 Hz), 8.79 (1H,
d, J = 2.1 Hz); 13C NMR (CDCl3) d 10.1, 12.9, 14.3,
15.3, 15.6, 18.8, 19.9, 21.1, 22.2, 26.3, 28.2, 30.4, 30.5,
33.1, 38.0, 38.8, 40.2, 47.6, 49.8, 51.0, 65.9, 69.5, 70.2,
73.0, 75.9, 78.4, 78.6, 82.3, 84.6, 103.7, 125.2, 126.4,
127.5, 128.2, 128.4, 129.0, 134.2, 146.8, 152.0, 153.8,
167.6, 169.3, 170.5, 203.8.
6.6.4. Compound 5p. MS (FAB) 854+(M+H+); HRMS
(FAB) calcd for C46H68N3O12 (M+H+) 854.4803, found
854.4810; IR (CHCl3) 3428, 3350, 2970, 2934, 2870,
2780, 1805, 1751, 1714, 1661, 1537, 1507, 1454, 1381,
1361, 1345, 1322, 1304, 1282, 1256, 1232, 1222, 1165,
1
1138, 1107, 1078, 1047, 1004 (cmÀ1); H NMR (CDCl3)
d 0.81 (3H, t, J = 7.5 Hz), 1.01 (3H, d, J = 6.9 Hz), 1.22
(3H, d, J = 6.0 Hz), 1.26 (3H, d, J = 6.9 Hz), 1.27 (3H,
d, J = 7.5 Hz), 1.37 (3H, d, J = 7.2 Hz), 1.38 (3H, s),
1.55 (3H, s), 1.16–1.92 (6H, m), 1.99 (2H, quintet,
J = 7.8 Hz), 2.27 (6H, s), 2.29 (3H, s), 2.46 (1H, m),
2.56 (1H, q, J = 6.9 Hz), 2.70 (3H, s), 2.83 (2H, t,
J = 7.8 Hz), 3.01 (1H, quintet, J = 7.8 Hz), 3.18 (1H,
dd, J = 7.8 and 9.9 Hz), 3.28 (1H, m), 3.43 (1H, m),
3.45–3.74 (2H, m), 3.83 (1H, q, J = 6.9 Hz), 4.22 (1H,
d, J = 7.5 Hz), 4.29 (1H, d, J = 7.8 Hz), 4.46 (2H, s),
4.82 (1H, s), 4.98 (1H, dd, J = 2.4 and 9.9 Hz), 6.95
(1H, brt, J = 5.7 Hz), 7.31–7.45 (3H, m), 7.65 (1H, br
s), 7.73–7.79 (3H, m); 13C NMR (CDCl3) d 10.1, 12.9,
14.2, 15.3, 15.6, 18.8, 19.9, 21.1, 22.2, 26.3, 28.1, 30.7,
33.1, 33.3, 38.0, 38.9, 40.2, 47.6, 49.8, 51.0, 65.8, 69.5,
70.2, 73.0, 76.0, 78.4, 78.7, 82.3, 84.5, 103.7, 124.9,
125.7, 126.3, 127.2, 127.4, 127.8, 131.9, 133.6, 139.0,
153.8, 162.8, 167.5, 169.2, 170.2, 203.8.
6.6.7. Compound 5s. MS (SI) 855+(M+H+); HRMS (SI)
calcd for C45H67N4O12 (M+H+) 855.4751, found
855.4749; IR (KBr) 3434, 2971, 2935, 2877, 2854,
2784, 1811, 1751, 1717, 1673, 1591, 1533, 1509, 1456,
1380, 1362, 1322, 1305, 1284, 1257, 1234, 1219, 1167,
1141, 1109, 1078, 1048, 1004 (cmÀ1); 1H NMR (CDCl3)
d 0.87 (3H, t, J = 7.2 Hz), 1.00 (3H, d, J = 6.9 Hz), 1.23
(3H, d, J = 6.0 Hz), 1.24 (3H, d, J = 7.5 Hz), 1.28 (3H,
d, J = 7.2 Hz), 1.37 (3H, d, J = 7.2 Hz), 1.39 (3H, s),
1.56 (3H, s), 1.54–2.12 (8H, m), 2.27 (6H, s), 2.46 (1H,
m), 2.56 (1H, q, J = 7.2 Hz), 2.69 (3H, s), 3.01 (1H,
quintet, J = 7.5 Hz), 3.13 (2H, dd, J = 4.2 and 8.4 Hz),
3.18 (1H, dd, J = 7.5 and 9.9 Hz), 3.33 (1H, m), 3.54
(3H, m), 3.68 (1H, m), 3.83 (1H, q, J = 6.9 Hz), 4.22
(1H, d, J = 8.1 Hz), 4.29 (1H, d, J = 7.5 Hz), 4.44 and
4.49 (2H, Abq, J = 14.1 Hz), 4.85 (1H, s), 4.99 (1H,
dd, J = 2.7 and 10.5 Hz), 7.23 (1H, brt, J = 6.3 Hz),
7.31 (1H, d, J = 4.5 Hz), 7.57 (1H, m), 7.69 (1H, m),
8.05 (1H, dd, J = 0.9 and 8.4 Hz), 8.09 (1H, d,
J = 8.1 Hz), 8.81 (1H, d, J = 4.5 Hz); 13C NMR (CDCl3)
d 10.2, 12.9, 14.3, 15.3, 15.6, 18.8, 19.9, 21.1, 22.2, 26.3,
28.2, 29.3, 29.7, 33.1, 38.0, 39.0, 40.2, 47.6, 49.8, 51.0,
65.8, 69.5, 70.3, 73.0, 75.9, 78.4, 78.6, 82.3, 84.6, 103.7,
120.6, 123.5, 126.3, 127.5, 128.9, 130.0, 147.5, 148.2,
150.2, 153.8, 167.6, 169.3, 170.5, 203.8.
6.6.5. Compound 5q. MS (FAB) 854+(M+H+); HRMS
(FAB) calcd for C46H68N3O12 (M+H+) 854.4803, found
854.4799; IR (KBr) 3435, 2972, 2937, 2877, 1811, 1751,
1716, 1675, 1532, 1456, 1380, 1362, 1323, 1304, 1283,
1258, 1233, 1219, 1167, 1142, 1109, 1078, 1048, 1004
1
(cmÀ1); H NMR (CDCl3) d 0.88 (3H, t, J = 7.2 Hz),
1.00 (3H, d, J = 7.2 Hz), 1.22 (3H, d, J = 6.0 Hz), 1.25
(3H, d, J = 7.5 Hz), 1.27 (3H, d, J = 7.8 Hz), 1.37 (3H,
d, J = 7.2 Hz), 1.38 (3H, s), 1.55 (3H, s), 1.24–2.08
(8H, m), 2.27 (6H, s), 2.46 (1H, m), 2.56 (1H, q,
J = 6.6 Hz), 2.69 (3H, s), 2.68–2.86 (1H, br s), 3.01
(1H, quintet, J = 8.1 Hz), 3.12 (2H, t, J = 7.5 Hz), 3.19
(1H, m), 3.28–3.73 (4H, m), 3.83 (1H, q, J = 6.9 Hz),
4.21 (1H, d, J = 8.4 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 9.9 Hz),
6.93 (1H, brt, J = 5.4 Hz), 7.33–7.54 (4H, m), 7.69
(1H, dd, J = 0.6 and 7.8 Hz), 7.83 (1H, dd, J = 1.5 and
8.1 Hz), 8.03 (1H, d, J = 8.4 Hz); 13C NMR (CDCl3) d
10.3, 12.9, 14.3, 15.4, 15.6, 18.9, 19.9, 21.1, 22.3, 26.4,
28.2, 30.2, 33.2, 38.0, 39.1, 40.2, 47.6, 49.8, 51.1, 65.9,
69.5, 70.3, 73.0, 76.1, 78.4, 78.7, 82.3, 84.6, 103.7,
123.7, 125.4, 125.5, 125.8, 125.9, 126.6, 128.7, 131.8,
133.8, 137.5, 153.8, 167.5, 169.2, 170.3, 203.9.
6.7. Preparation of compound 8
6.7.1. Amidation. Compound 6 was prepared from 3
with N-methylpropargylamine in 82% yield as a color-
less foam by the same procedure as that described for
the synthesis of 5d.
MS (FAB) 992+(M+H+); HRMS (FAB) calcd for
C52H70N3O16 (M+H+), 992.4756 found 992.4747; IR
(KBr) 3428, 3290, 3064, 3032, 2975, 2938, 2880, 1809,
1752, 1702, 1587, 1496, 1455, 1405, 1382, 1350, 1330,
1289, 1255, 1167, 1114, 1068 (cmÀ1); 1H NMR (CDCl3)
d 2.66 (3H, s), 2.81, 2.85 (3H, two s), 3.00, 3.12 (3H, two
s); 13C NMR (CDCl3) d 10.3, 13.0, 13.8, 15.4, 15.5, 15.6,
15.7, 18.7, 19.7, 20.6, 22.4, 26.2, 26.3, 28.8, 28.9, 33.1,
33.4, 33.7, 35.7, 36.2, 37.8, 39.2, 47.0, 47.1, 49.5, 49.6,
51.0, 54.7, 54.8, 67.1, 67.2, 68.7, 69.3, 69.5, 71.1, 72.0,
72.8, 74.7, 76.3, 78.2, 78.3, 78.4, 82.6, 84.6, 100.7,
127.5, 127.7, 127.8, 127.9, 128.2, 128.3, 128.4, 135.5,
135.6, 136.7, 154.3, 154.4, 154.5, 156.1, 156.5, 158.8,
6.6.6. Compound 5r. MS (FAB) 855+(M+H+); HRMS
(FAB) calcd for C45H67N4O12 (M+H+) 855.4755, found
855.4747; IR (KBr) 3433, 2972, 2937, 2878, 2784, 1810,
1751, 1717, 1673, 1637, 1569, 1534, 1496, 1456, 1380,
1363, 1323, 1305, 1283, 1258, 1234, 1219, 1167, 1141,
1109, 1079, 1048, 1004 (cmÀ1); 1H NMR (CDCl3) d
0.81 (3H, t, J = 7.2 Hz), 1.01 (3H, d, J = 6.9 Hz), 1.23
(3H, d, J = 6.0 Hz), 1.27 (3H, d, J = 6.6 Hz), 1.28 (3H,

T. Nomura et al. / Bioorg. Med. Chem. 13 (2005) 6615–6628
6625
1
165.8, 165.9, 168.6, 168.8, 169.0, 203.7, 203.9 (two rota-
tional isomers were observed by 1H NMR and 13C
NMR spectra).
rotational isomers were observed by H NMR and 13C
NMR spectra).
6.8. Preparation of compound 11
6.7.2. Coupling reaction. To a solution of 6 (256 mg,
0.262 mmol) in CH3CN (5 mL) were successively added
NEt3 (36 lL, 0.26 mmol), CuI (5 mg, 0.026 mmol),
p-iodobenzene (59 lL, 0.524 mmol), and Cl2Pd(PPh3)2
(9.2 mg, 0.01 mmol). The reaction mixture was stirred
at room temperature for 1 h. The mixture was filtered
and diluted with water, and then the mixture was
extracted with AcOEt. The resultant residue was puri-
fied by column chromatography on silicagel (n-hexane/
AcOEt = 8/1–1/1) to give 192 mg of compound 7 as a
colorless foam (87%).
Compound 19 (2.96 g, 3.3 mmol) was dissolved in THF
(30 mL) under N2 atmosphere. To this solution was add-
ed 0.5 M 9-BBN (19.8 mL, THF solution) and stirred at
room temperature for 1 h. After cooling the mixture
with an ice-water bath, trifluoro methanesulfonic acid
3-phenyl-propenyl ester 914 (0.8 g, 3 mmol) in THF
(2 mL), Cl2Pd(PPh3)2 (118 mg, 0.168 mmol), and 1 N
NaOH (9.9 mL) were added to the mixture successively.
After being stirred at room temperature for an addition-
al 1 h, the reaction mixture was poured into saturated
aqueous NH4Cl and extracted with AcOEt (150 mL).
The aqueous layer was extracted with AcOEt (70 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 silicagel (n-hexane/AcOEt = 4/1–1/1) to give 2.26 g
of compound 10 as a colorless foam (mixture of E/Z
isomers. 77%).
MS (FAB) 1068+(M+H+); HRMS (FAB) calcd for
C58H74N3O16 (M+H+), 1068.5069, found 1068.5073;
IR (KBr) 3429, 3064, 3032, 2974, 2938, 2880, 1810,
1752, 1702, 1658, 1489, 1455, 1404, 1382, 1350, 1330,
1
1288, 1254, 1167, 1114, 1068 (cmÀ1); H NMR (CDCl3)
d 2.67 (3H, s), 2.81, 2.85 (3H, two s), 3.07, 3.17 (3H, two
s); 13C NMR (CDCl3) d 10.3, 13.0, 13.8, 15.4, 15.5, 15.6,
18.8, 19.7, 20.6, 22.4, 26.3, 26.4, 28.8, 28.9, 33.0, 33.1,
33.5, 33.7, 35.7, 36.2, 37.8, 39.9, 47.1, 47.2, 49.5, 49.6,
51.0, 54.8, 67.1, 67.2, 68.7, 69.3, 69.5, 71.2, 74.8, 76.3,
76.4, 78.3, 78.4, 82.6, 83.7, 83.9, 84.4, 84.6, 100.7,
122.4, 122.7, 127.6, 127.7, 127.9, 128.2, 128.3, 128.4,
131.7, 131.8, 135.5, 135.6, 136.7, 154.3, 154.4, 154.5,
156.1, 158.8, 165.7, 165.9, 168.5, 168.8, 169.0, 203.7,
203.9 (two rotational isomers were observed by 1H
NMR and 13C NMR spectra).
MS (FAB) 1015+(M+H+); HRMS (FAB) calcd for
C57H79N2O14 (M+H+) 1015.5531, found 1015.5547; IR
(KBr) 3507, 3383, 3065, 3031, 3013, 2976, 2938, 2876,
1744, 1695, 1495, 1454, 1407, 1381, 1351, 1333, 1293,
1263, 1223, 1212, 1205, 1168, 1115, 1069 (cmÀ1); 1H
NMR (CDCl3) d 2.70 (3H, s), 2.81, 2.85 (3H, two s).
Compound 10 (880 mg, 0.87 mmol) was dissolved in
THF (13 mL) under N2 atmosphere. To this solution
were added pyridine (0.7 mL, 8.65 mmol) and (CCl3O)2-
CO (570 mg, 1.92 mmol) with stirring overnight at room
temperature. The reaction mixture was carefully
quenched with saturated aqueous NaHCO3 under cool-
ing with 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 (30 mL), and
the combined organic layer was washed with saturated
aqueous NH4Cl and brine, dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified
by column chromatography on silicagel (n-hexane/
AcOEt = 4/1–1/2) to give 680 mg of compound bearing
C-11,12 carbonate group as a colorless foam (89%).
Subsequently, deprotection and N-methylation were
performed by the same procedure as that described for
the synthesis of 5d, and compound 11 (344 mg, colorless
foam) was obtained in 76% yield.
6.7.3. Hydrogenation, deprotection, and N-methylation.
Subsequently, 7 (192 mg, 0.182 mmol) was diluted with
EtOH (16 mL) and 0.2 M acetate buffer (4 mL, pH
4.4). To this solution was added 20% Pd(OH)2/C
(58 mg, 0.109 mmol) and stirred at room temperature
under H2 atmosphere for 2 h. After confirming the dis-
appearance of 7 by TLC, 37% aqueous HCHO (2
mL) was added to the reaction mixture and stirred at
room temperature under H2 atmosphere for an addi-
tional 1 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 silicagel (CHCl3/MeOH = 80/1–40/
1) to give 118 mg of compound 8 as a colorless foam
(79%).
MS (FAB) 818+(M+H+); HRMS (FAB) calcd for
C43H68N3O12 (M+H+) 818.4803, found 818.4805; IR
(KBr) 3447, 3060, 2972, 2937, 2878, 2785, 1809, 1752,
1717, 1653, 1560, 1541, 1495, 1455, 1380, 1361, 1323,
1304, 1283, 1258, 1233, 1219, 1167, 1142, 1109, 1079,
MS (FAB) 789+(M+H+); HRMS (FAB) calcd for
C43H69N2O11 (M+H+) 789.4901, found 789.4908; IR
(KBr) 3458, 3061, 2973, 2936, 2876, 2785, 1810, 1751,
1716, 1627, 1603, 1496, 1455, 1381, 1361, 1324, 1305,
1284, 1257, 1219, 1167, 1142, 1110, 1076, 1048, 1005
1
1048, 1005 (cmÀ1); H NMR (CDCl3) d 2.27 (6H, s),
1
2.68, 2.70 (3H, two s), 2.92, 3.00 (3H, two s); 13C
NMR (CDCl3) d 10.3, 13.1, 14.3, 15.4, 15.5, 15.8, 18.8,
18.9, 21.2, 22.4, 26.5, 28.2, 28.6, 29.6, 29.8, 32.7, 33.1,
33.2, 34.6, 38.3, 40.2, 47.5, 47.8, 48.7, 49.7, 51.0, 65.9,
69.5, 70.3, 70.9, 71.4, 76.3, 78.5, 79.4, 82.7, 84.7, 84.8,
103.8, 125.8, 126.1, 128.3, 128.4, 128.5, 140.9, 141.7,
154.4, 165.7, 165.8, 168.7, 168.8, 169.1, 204.0 (two
(cmÀ1); H NMR (CDCl3) d 0.89 (3H, t, J = 7.2 Hz),
0.963 (3H, d, J = 6.9 Hz), 1.19–1.32 (12H, m), 1.37
(6H, d, J = 6.9 Hz), 140 (3H, s), 1.54 (3H, s), 1.50–1.95
(7H, m), 2.26 (6H, s), 2.38–2.55 (2H, m), 2.60 (2H, t,
J = 7.5 Hz), 2.68 (3H, s), 3.04 (1H, m), 3.18 (1H,
dd, J = 7.2 and 10.2 Hz), 3.42–3.70 (3H, m), 3.82
(1H, q, J = 6.6 Hz), 3.93–4.07 (2H, m), 4.18 (1H, d,

6626
T. Nomura et al. / Bioorg. Med. Chem. 13 (2005) 6615–6628
J = 8.4 Hz), 4.29 (1H, d, J = 7.5 Hz), 4.77 (1H, s), 5.04
(1H, dd, J = 2.4 and 9.9 Hz), 7.15–7.29 (5H, m).
(1H, d, J = 7.2 Hz), 4.54 and 4.67 (2H, Abq,
J = 16.5 Hz), 4.77 (1H, s), 5.02 (1H, dd, J = 2.7 and
9.6 Hz), 7.12–7.30 (5H, m); 13C NMR (CDCl3) d 10.4,
13.2, 14.3, 15.3, 15.8, 18.8, 19.7, 21.1, 22.5, 26.7, 28.2,
29.7, 30.1, 32.1, 38.3, 40.2, 47.8, 49.7, 51.1, 64.0, 65.9,
69.5, 70.3, 70.5, 76.4, 78.5, 79.5, 82.5, 84.8, 103.8,
126.0, 128.4, 128.5, 141.1, 154.3, 166.0, 169.1, 170.1,
204.1.
13C NMR (CDCl3) d 10.4, 13.2, 14.3, 15.5, 15.9, 18.9,
19.7, 21.2, 22.5, 26.0, 26.1, 28.2, 29.1, 31.5, 33.0, 35.9,
38.3, 40.2, 47.9, 49.6, 51.1, 65.9, 69.5, 70.4, 73.6, 76.4,
78.4, 79.5, 83.0, 84.7, 103.9, 125.6, 128.2, 128.4, 142.8,
154.5, 163.5, 169.1, 204.0.
6.9. Preparation of compound 13
6.10. Preparation of compound 16i (Method A)
To a solution of 3 (100 mg, 0.106 mmol) in toluene
(6 mL) were added DMF (1 lL, 0.01 mmol) and oxalyl
chloride (12 lL, 0.13 mmol) at room temperature, and
the reaction mixture was stirred for 30 min at room
temperature. To this solution, 3-phenyl-1-propanol
(29 lL, 0.21 mmol), pyridine (17 lL, 0.21 mmol), and
N,N-dimethylamino pyridine (1 mg) were added and
the reaction mixture was stirred overnight. The reac-
tion mixture was quenched with saturated aqueous
NH4Cl and extracted with AcOEt (20 mL). The aque-
ous 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
silicagel (n-hexane/AcOEt = 4/1–1/1) to give 88 mg of
compound 8 bearing an ester group as a colorless foam
(78%).
To a solution of N-Boc-propargylamine (4.66 g,
30 mmol) in CH3CN (50 mL) were successively added
NEt3(6.96 mL, 30 mmol), CuI (76 mg, 0.4 mmol), 3-bro-
mo-quinoline (1.34 mL, 10 mmol), and Cl2Pd(PPh3)2
(140 mg, 0.2 mmol). The reaction mixture was stirred
at room temperature for 1 h and for 5 h at 60 °C. The
mixture was cooled to room temperature and filtered,
then diluted with 5% aqueous NaHCO3, and finally
extracted with AcOEt. The resultant residue was puri-
fied by column chromatography on silicagel (n-hexane/
AcOEt = 4/1–1/1) to give 2.8 g of compound 14i (99%).
1H-NMR (CDCl3) d 1.49 (9H, s), 4.23 (2H, d,
J = 5.4 Hz), 4.83 (1H, br s), 7.57 (1H, m), 7.73 (1H,
m), 7.78 (1H, d, J = 8.4 Hz), 8.08 (1H, d, J = 8.7 Hz),
8.21 (1H, d, J = 1.8 Hz), 8.89 (1H, d, J = 1.8 Hz).
Compound 14i (2.8 g, 9.9 mmol) was dissolved in EtOH
(60 mL). To this solution was added 20% Pd(OH)2/C
(754 mg, 1.4 mmol) with stirring at room temperature
under H2 atmosphere for 2 h. The mixture was filtered
and concentrated, and 2.7 g of compound 15i was ob-
tained (95%).
MS (FAB) 1059+(M+H+); HRMS (FAB) calcd for
C57H75N2O17 (M+H+) 1059.5066, found 1059.5050; IR
(KBr) : 3433, 3063, 3029, 2973, 2938, 2879, 1811,
1752, 1703, 1633, 1605, 1497, 1455, 1382, 1351, 1329,
1289, 1254, 1213, 1167, 1112, 1084, 1067, 1047 (cmÀ1);
1H NMR (CDCl3) d 2.69 (3H, s), 2.81, 2.85 (3H, two
s); 13C NMR (CDCl3) d 10.4, 13.1, 13.8, 15.3, 15.6,
15.7, 18.7, 19.6, 20.6, 22.4, 26.5, 28.8, 30.0, 32.0, 33.1,
35.7, 36.1, 37.8, 47.0, 47.1, 49.5, 50.9, 54.7, 63.8, 67.0,
67.1, 68.6, 69.2, 69.4, 70.3, 74.6, 76.3, 78.1, 78.3, 82.4,
84.4, 100.5, 125.7, 127.3, 127.5, 127.6, 127.7, 128.0,
128.1, 128.2, 135.2, 135.3, 136.4, 140.8, 154.0, 154.1,
154.2, 155.8, 156.2, 165.5, 168.6, 169.7, 203.3, 203.5
(two rotational isomers were observed by 1H NMR
and 13C NMR spectra).
1H NMR (CDCl3) d 1.45 (9H, s), 1.94 (2H, m), 2.88 (2H,
t, J = 7.2 Hz), 3.23 (2H, m), 4.62 (1H, br s), 7.59 (1H,
m), 7.73 (1H, m), 7.82 (1H, d, J = 8.4 Hz), 8.08 (1H,
m), 8.21 (1H, dd, J = 1.2 and 9.6 Hz), 8.81 (1H, d,
J = 2.1 Hz).
Compound 15i (2.8 g, 9.4 mmol) was dissolved in
CH2Cl2 (30 mL) and stirred on an ice-water bath. To
this solution was added CF3CO2H (6 mL), and the reac-
tion mixture was stirred at room temperature for 1 h
and concentrated in vacuo. The resultant residue was
quenched with diluted aqueous NaOH and extracted
with AcOEt. The aqueous layer was extracted with
AcOEt, and the combined organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. Finally,
2.7 g of compound 16i was obtained (95%).
Compound 13 (12 mg) was prepared in 32% yield from
12 (51 mg) as a colorless foam by the same procedure as
that described for the synthesis of 5d.
MS (SI) 805+(M+H+); HRMS (SI) calcd for
C42H65N2O13 (M+H+) 805.4483, found 805.4486; IR
(KBr) 3447, 2924, 2877, 2851, 2785, 1810, 1752, 1653,
1636, 1628, 1604, 1569, 1560, 1542, 1508, 1497, 1456,
1381, 1362, 1323, 1304, 1284, 1258, 1167, 1142, 1108,
1084, 1047, 1004 (cmÀ1); 1H NMR (CDCl3) d 0.89
(3H, t, J = 7.2 Hz), 1.03 (3H, d, J = 6.9 Hz), 1.23 (3H,
d, J = 6.0 Hz), 1.25 (3H, d, J = 6.9 Hz), 1.27 (3H, d,
J = 7.8 Hz), 1.37 (3H, d, J = 6.9 Hz), 1.42 (3H, s), 1.54
(3H, s), 1.54–2.02 (8H, m), 2.27 (6H, s), 2.40–2.60
(3H, m), 2.69 (2H, t, J = 7.8 Hz), 2.72 (3H, s), 3.05
(1H, quintet, J = 7.8 Hz), 3.19 (1H, dd, J = 7.2 and
9.9 Hz), 3.48–3.74 (2H, m), 3.83 (1H, q, J = 6.9 Hz),
4.16 (2H, t, J = 6.6 Hz), 4.20 (1H, d, J = 7.5 Hz), 4.30
1H NMR (CDCl3) d 2.02 (2H, m), 2.81 (2H, t,
J = 10.8 Hz), 2.93 (2H, m), 5.04 (2H, br s), 7.48 (1H,
m), 7.62 (1H, m), 7.69 (1H, d, J = 8.4 Hz), 7.88 (1H,
d, J = 2.4 Hz), 8.00 (1H, d, J = 8.1 Hz), 8.73 (1H, d,
J = 1.5 Hz).
6.11. Preparation of compound 16e (Method B)
N-Boc-allylamine (500 mg, 3.2 mmol) was dissolved in
THF (5 mL) under N2 atmosphere. To this solution
was added 0.5 M 9-BBN (9.5 mL, THF solution), with

T. Nomura et al. / Bioorg. Med. Chem. 13 (2005) 6615–6628
6627
stirring at room temperature for 2 h. Next, 1-iodo-4-ni-
6.13. Preparation of compounds 16f, 16g, and 16j
tro-benzene (633 mg, 2.5 mmol), Cl2Pd(PPh3)2 (111 mg,
0.16 mmol), and 1 N NaOH (4.7 mL) were successively
added to the mixture. After stirring at room temperature
for an additional 1.5 h, the reaction mixture was poured
into saturated aqueous NH4Cl and extracted with
AcOEt (150 mL). The aqueous layer was extracted with
AcOEt (70 mL), and the combined organic layer was
washed with brine, dried over MgSO4, filtered, and con-
centrated in vacuo. The residue was purified on silicagel
column (n-hexane/AcOEt = 10/1–2/1) to give 651 mg of
compound 15e (91%).
Compounds 16f, 16g, and 16j were prepared in the same
procedure (Method A) as that described for the synthe-
sis of 16i with 4-bromo-biphenyl, 2-bromo-naphthalene,
and 4-iodo-quinoline,17 respectively.
1
6.13.1. 16f. H NMR (CDCl3) d 1.71 (2H, br s), 1.82
(2H, m), 2.70 (2H, t, J = 7.8 Hz), 2.77 (2H, t, J = 6.9
Hz), 7.24–7.60 (9H, m).
1
6.13.2. 16g. H NMR (CDCl3) d 1.38 (2H, br s), 1.86
(2H, m), 2.77 (2H, t, J = 7.2 Hz), 2.82 (2H, t, J = 7.5
Hz), 7.34 (1H, dd, J = 1.8 and 8.4 Hz), 7.38–7.48 (2H,
m), 7.62 (1H, d, J = 0.6 Hz), 7.76–7.81 (3H, m).
1H NMR (CDCl3) d 1.45 (9H, s), 1.85 (2H, m), 2.75 (2H,
t, J = 8.1 Hz), 3.17 (2H, m), 4.58 (1H, br s), 7.34 (2H, d,
J = 8.4 Hz), 8.15 (2H, d, J = 8.4 Hz).
6.13.3. 16j. 1H NMR (CDCl3) d 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).
Compound 15e (600 mg, 2.1 mmol) was dissolved in
CH2Cl2 (6 mL) and stirred on an ice-water bath. To this
solution was added CF3CO2H (6 mL), and the reaction
mixture was stirred at room temperature for 1 h and
concentrated in vacuo. The resultant residue was
quenched with diluted aqueous NaOH and extracted
with AcOEt. The aqueous layer was extracted with
AcOEt, and the combined organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The residue
was purified on silicagel column to give 331 mg of com-
pound 16e (86%).
References and notes
1. Morimoto, S.; Takahashi, Y.; Watanabe, Y.; Omura, S.
J. Antibiot. 1984, 37, 187–189.
2. Djokic, S.; Kobrehel, G.; Lazarevski, G. J. Antibiot. 1987,
40, 1006–1015.
3. Doern, G. V.; Brown, S. D. J. Infect 2004, 48, 56–65.
4. Agouridas, C.; Denis, A.; Auger, J.; Benedetti, Y.;
Bonnefoy, A.; Bretin, F.; Chantot, J.; Dussarat, A.;
Fromentin, C.; DꢀAmbrieres, S.; Lachaud, S.; Laurin, P.;
Martret, O.; Loyau, V.; Tessot, N. J. Med. Chem. 1998,
41, 4080–4100.
1H NMR (CDCl3) d 1.83 (2H, m), 2.04 (2H, br s), 2.78
(2H, t, J = 6.3 Hz), 2.78 (2H, t, J = 7.8 Hz), 7.35 (2H, d,
J = 8.4 Hz), 8.14 (2H, d, J = 8.4 Hz).
6.12. Preparation of compounds 16a–16d, and 16h
5. Agouridas, C.; Benedetti, Y.; Denis, A.; Le Martret, O.;
Chantot, J. F., Ketolides: A new distinct class of macro-
lide antibacterials. Synthesis and structural characteriza-
tion of RU004. 35th Interscience Conference on
Antimicrobial Agents and Chemiotherapy, San Francisco,
CA, 1995; Abstr. No. F157.
6. Denis, A.; Agouridas, C.; Auger, J.; Benedetti, Y.;
Bonnefoy, A.; Bretin, F.; Chantot, J.; Dussarat, A.;
Fromentin, C.; DꢀAmbrieres, S.; Lachaud, S.; Laurin, P.;
Martret, O.; Loyau, V.; Tessot, N.; Pejac, J.; Perron, S.
Bioorg. Med. Chem. Lett. 1999, 9, 3075–3080.
Compounds 16a–16d, and 16h were prepared in the
same procedure (Method B) as that described for the
synthesis of 16e with 1-iodo-2-methyl-benzene, 1-iodo-
3-methyl-benzene, 1-iodo-4-methyl-benzene, 1-fluoro-4-
iodo-benzene, and 1-iodo-naphthalene, respectively.
6.12.1. 6a(CF3CO2H salt). 1H NMR (CDCl3) d 1.91
(2H, m), 2.24 (3H, s), 2.62 (2H, t, J = 7.8 Hz), 2.94
(2H, m), 7.05–7.12 (4H, m), 7.67 (3H, br s).
7. (a) Sun, Y.; Clark, R.; Wang, S.; Chu, D.; Nilius Ma, Z.
J. Med. Chem. 2000, 43, 1045–1049; (b) Ma, Z.; Clark,
R., et al. J. Med. Chem. 2001, 44, 4137–4156.
8. (a) Su, W.; Smyth, K.; Rainville, J. et al. The in vitro and
in vivo activity of CP-642, 959 and its related diastereo-
mers. 41st ICAAC. Chicago, USA, 2001; Abstract F-1169;
(b) Nishimoto, A.; Narita, K.; Ohmoto, S.; Takahashi, Y.;
Yashizumi, S.; Yoshida, T.; Kado, N.; Okezaki, E.; Kato,
H. Chem. Pharm. Bull. 2001, 49, 1120–1127.
1
6.12.2. 16b(CF3CO2H salt). H NMR (CDCl3) d 1.82
(2H, m), 2.32 (3H, s), 2.62 (2H, t, J = 7.8 Hz), 2.74
(2H, t, J = 7.2 Hz), 6.98–7.22 (7H, m).
1
6.12.3. 16c(CF3CO2H salt). H NMR (CDCl3) d 1.94
(2H, m), 2.60 (2H, t, J = 7.5 Hz), 2.92 (2H, m), 7.01
(2H, d, J = 7.8 Hz), 7.08 (2H, d, J = 7.8 Hz), 7.52 (3H,
br s).
9. Nomura, T.; Yasukata, T.; Narukawa, Y.; Uotani, K.
Bioorg. Med. Chem. 2005, in press.
6.12.4. 16d. 1H NMR (CDCl3) d 1.87 (2H, m), 2.61 (2H,
t, J = 7.8 Hz), 2.84 (2H, t, J = 7.5 Hz), 4.10–4.90 (2H, br
s), 6.92–7.11 (4H, m).
10. Bertho, G.; Gharbi-Benarous, J.; Delaforge, M.; Lang, C.;
Parent, A.; Girault, J.-P. J. Med. Chem. 1998, 41, 3373–3386.
11. MOE: The Molecular Operating Environment from
Chemical Computing Group Inc. 1010 Sherbrooke Street
W, Suite 910, Montreal, Quebec, Canada H3A 2R7.
12. This model was one of the models arisen from a flexible
alignment module of MOE with ABT-773, RU-004 and 5s.
13. Schlunzen, F.; Harms, J. M.; Franceschi, F.; Hansen, H.;
Bartels, H.; Zarivach, R.; Yonath, A. Structure 2003, 11,
329–338.
6.12.5. 16h. 1H NMR (CDCl3) d 1.94 (2H, m), 2.83 (2H,
t, J = 7.2 Hz), 3.06 (2H, t, J = 7.8 Hz), 3.75 (2H, br s),
7.27 (1H, d, J = 6.9 Hz), 7.35 (1H, t, J = 8.1 Hz), 7.42–
7.51 (2H, m), 7.69 (1H, d, J = 8.1 Hz), 7.81–7.84 (1H,
m), 7.95–7.99 (1H, m).

6628
T. Nomura et al. / Bioorg. Med. Chem. 13 (2005) 6615–6628
14. (a) Lipshutz, P.; Bruce, H.; Elworthy, P.; Todd, R. J. Org.
Chem. 1990, 55, 1695–1696; (b) Fleming, I.; Miwaniki, J.
M. J. Chem. Soc., Perkin Trans. 1 1998, 7, 1237–1247.
15. 5-phenyl-pentylamine was prepared from (5-bromo-pen-
tyl)benzene. Zwierzak, A.; Pilichowska, S. Synthesis 1982,
922; 1H NMR (CDCl3) d 1.33–1.53 (4H, m), 1.63 (2H, m),
2.62 (2H, t, J = 7.8 Hz), 2.68 (2H, t, J = 7.2 Hz), 7.15–7.30
(5H, m).
16. 3-Pyridin-4-yl-propylamine, 3-Pyridin-2-yl-propylamine
were prepared from 3-(4-pyridyl)-1-propanol, 3-(3-pyr-
idyl)-1-propanol, and 3-(2-pyridyl)-1-propanol, respective-
ly Gibson, J. S.; Pilichowska, S. Angew. Chem. Int. Ed. 1968,
7, 919–9303-Pyridin-4-yl-propylamine; 1H NMR (CDCl3) d
1.29 (2H, br s), 1.78 (2H, m), 2.67 (2H, t, J = 7.8 Hz),
2.75 (2H, t, J = 7.2 Hz), 7.12 (2H, d, J = 5.7 Hz), 8.49
(2H, d, J = 5.7 Hz).; 3-Pyridin-3-yl-propylamine; 1H NMR
(CDCl3) d 1.35 (2H, br s), 1.78 (2H, m), 2.67 (2H, t,
J = 8.2 Hz), 2.75 (2H, t, J = 6.8 Hz), 7.18–7.24 (1H, m),
7.47–7.54 (1H, m), 8.42–8.46 (2H, m).; 3-Pyridin-2-yl-
propylamine; 1H NMR (CDCl3) d 2.02 (2H, m), 2.94 (2H,
t, J = 10.8 Hz), 2.95 (2H, t, J = 9.9 Hz), 5.02 (2H, br s),
7.10–7.21 (2H, m), 7.58–7.64 (1H, m), 8.43–8.52 (1H, m).
17. Tsumambac, G. E.; Villalobos, C. N. Synlett 2003, 12,
1801–1804.