Novel azalides derived from 16-membered macrolides. Part II: Isolation of the linear 9-formylcarboxylic acid and its sequential macrocyclization with an amino alcohol or an azidoamine

Article abstract of DOI:10.1016/j.bmc.2008.09.054

The design and synthesis of novel 14- to 16-membered 11-azalides starting from 16-membered macrolides are reported. A linear 9-formylcarboxylic acid was isolated via a mobile dialdehyde previously reported. Sequential macrocyclization of the formylcarboxy

Full text of DOI:10.1016/j.bmc.2008.09.054

Bioorganic & Medicinal Chemistry 16 (2008) 10129–10156
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Novel azalides derived from 16-membered macrolides. Part II: Isolation
of the linear 9-formylcarboxylic acid and its sequential macrocyclization
with an amino alcohol or an azidoamine
*
Tomoaki Miura , Kenichi Kanemoto, Satomi Natsume, Kunio Atsumi, Hideki Fushimi, Takuji Yoshida,
*
Keiichi Ajito
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The design and synthesis of novel 14- to 16-membered 11-azalides starting from 16-membered macro-
lides are reported. A linear 9-formylcarboxylic acid was isolated via a mobile dialdehyde previously
reported. Sequential macrocyclization of the formylcarboxylic acid with amino alcohol followed by
deprotection afforded corresponding 14- to 16-membered azalides. On the other hand, reductive amina-
tion of the formylcarboxylic acid with an azidoamine followed by macrolactam formation with an amine
generated from the azide gave 14- to 16-membered azalactams. Among these derivatives, 15-membered
azalactams and 16-membered azalides exhibited characteristic in vitro antibacterial activities. Although
optimization of 15-membered azalactams including demycarosyl analogues did not provide remarkably
promising molecules, SAR studies of 16-membered azalides disclosed that substitution at the 15 position
was very important for identification of a clinical candidate.
Received 13 August 2008
Revised 19 September 2008
Accepted 20 September 2008
Available online 25 September 2008
Keywords:
Sixteen-membered macrolide
Midecamycin A1
Miokamycin
Azalide
Ó 2008 Elsevier Ltd. All rights reserved.
Azalactam
1. Introduction
Macrolide antibiotics1 are active against Gram-positive bacteria
(especially Streptococcus pneumoniae), Moraxella catarrhalis, Haem-
ophillus influenzae, and Mycoplasma pneumoniae, and regarded as
very important chemotherapeutics from a clinical viewpoint. Clar-
ithromycin2 (CAM) and azithromycin3 (AZM) (Fig. 1), which are
representatives of widely used macrolides and are derived from
14-membered erythromycin, exhibited enhanced antibacterial
activities and characteristic pharmacokinetics, respectively. As
one of the next generation macrolides, that is, ketolides, telithro-
mycin4 (TEL) has recently been launched as an efficient antibiotic
which is effective against clinically important pathogens including
erythromycin-resistant S. pneumoniae (ERSP). Moreover, a novel
ketolide, S-0134205 is under clinical trials.
Although TEL exhibits improved antibacterial activities against
resistant bacteria of S. pneumoniae with an erm gene, it is not al-
ways sufficient. Specifically, it is affected by efflux pump function
of resistant bacteria in S. pneumoniae, and its safety6 is seriously
concerned in clinical site especially in the US. In 2001, we started
a novel drug discovery program applying 16-membered macrolide
antibiotics which have been proved to be safe and effective against
* Corresponding authors. Tel.: +81 45 545 3131; fax: +81 45 543 9771.
E-mail addresses: tomoaki_miura@meiji.co.jp (T. Miura), keiichi_ajito@meiji.
co.jp (K. Ajito).
Figure 1. Structures of representative macrolide antibiotics.
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.09.054

10130
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
Figure 2. Research concept using formylcarboxylic acid (2).
resistant bacteria of S. pneumoniae with efflux pump, so called ‘a
mef gene’.
optimized reductive amination protocol. As the first step, an amino
alcohol and formylcarboxylic acid were kept in anhydrous dimeth-
ylformamide with molecular sieves 3A for 4 h in order to form a
reactive intermediate, and then excess sodium borohydride was
added to give compound 4. In the case without the intermediate
formation step, desired compound 4 could not be detected and
an aldehyde was partially converted to a primary alcohol.
Macrolactonization of compound 4 was performed following
Yamaguchi protocol. 2,4,6-Trichlorobenzoyl chloride (1.2 equiv)
and 2 equiv of triethylamine were reacted in tetrahydrofuran at
room temperature for 2 h. Then 6 equiv of 4-dimethylaminopyri-
dine (DMAP) in highly diluted benzene solution were slowly added
at room temperature taking 2 h. This reaction condition sup-
pressed the formation of dimer and the yield of desired 5 was
43%. Fast addition of DMAP resulted in 29% yield of 5 and 22% of
undesired dimer. In this macrolactonization, the higher reaction
temperature tends to provide better reaction yield. The reaction
condition at 80 °C, however, gave a mixture of compound 5 and
its 2-eno derivative (6) (FAB-MS m/z 1021 (M+H)+), which could
not be easily separated from compound 5. Then, we performed this
lactonization at room temperature.
At the end of a synthetic route, deprotection had to be done.
First, the 20-O-acetyl group was removed by methanolysis. Com-
pound 5 was kept in methanol solution at room temperature for
76 h, and compounds 7 and 8 were isolated in 32% and 24%, respec-
tively. When the reaction period became longer, methanolysis
excessively proceeded and the lactone moiety was affected, which
gave more undesired methylester (9) (FAB-MS m/z 1043 (M+H)+).
The lactone ring possessing a substituent at the C-14 position,
however, did not provide a corresponding methyl ester.20 We will
shortly mention reaction mechanism of these methanolysis. The
20-O-acetyl group is removed by neighboring effect of the dimeth-
ylamino group at the C-30 and the 9-O-acetyl group is also removed
by the same effects of tertiary amine at the N-11. Because the ami-
no sugar portion is always rigid, neighboring effect is constant. 15-
Membered azalactone does not provide an appropriate distance
between the 11-nitrogen atom and the 9-O-acetyl group, so this ef-
fect is not enough to remove the 9-O-acetyl group completely for
compound 5. As a matter of fact, methanolysis at the C-9 position
could not be observed in 14-membered azalides. Thus, long-term
methanolysis (5 days) of compound 1020 selectively provided the
9-O-acetyl derivative (11) in 89% yield. It is presumed that the ter-
tiary amine at the N-11 did not spatially approach to the 9-O-acetyl
group in 14-membered azalides. Deprotection of dimethyl acetals
Before we started this research program, we had partially estab-
lished a practical approach to overcome resistant bacteria by
medicinal chemistry using 16-membered macrolides. Owing to
this approach, antibacterial activities against resistant pathogens
in 16-membered macrolides were clearly enhanced7 by the intro-
duction of an appropriate aromatic ring with an adjusted length
of an alkyl spacer into the lactone ring. There is, however, limita-
tion in molecular design and synthesis of novel compounds, as long
as we utilize known pharmacophores. We had to explore a novel
pharmacophore. Therefore, we proposed synthesis of 15-mem-
bered 11-azalides and 16-membered diazalide as a novel template,
and figured out their antibacterial activities.8
Our first approach using dialdehyde (1) (Fig. 2), however, en-
abled us to structurally diversify only a small area in an original
lactone moiety as in the case of other related approaches.9–14 Then,
we practically utilized 9-formylcarboxylic acid (2) as a key inter-
mediate for sequential macrocyclization in order to provide a vari-
ety of novel templates. In this paper, we report the design and
synthesis of novel 14- to 16-membered 11-azalides and 14- to
16-membered azalactams starting from 16-membered macrolides.
Although related medicinal chemistry using erythromycin has
been reported,15,16 no derivatives that are active against resistant
S. pneumoniae possessing the erm gene or the mef gene have been
identified.
2. Results and discussion
2.1. Synthesis of 15-membered azalides
An outline of the synthesis of 15-membered azalides is shown
in Scheme 1. A key intermediate, 9-formylcarboxylic acid (2),
was prepared under organic basic condition in 35% yield as
dimethylacetal17 from mobile 20-acetylated dialdehyde (1).8 On
the other hand, compound 2 was isolated with 52% yield via two
steps starting from tetraol (3)8 without purification of dialdehyde
(1) (see Section 4).
As the second step, an amino alcohol had to be introduced onto
an aldehyde group. Because we were planning to explore a new
template, which is active against resistant S. pneumoniae, we intro-
duced an arylalkyl moiety (e.g., the 4-phenylbutyl group) into an
amino alcohol. In Scheme 1,3-(4-phenylbutylamino)propanol
(1.5 equiv) was reacted with formylcarboxylic acid (2) in 65% by

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
10131
Scheme 1. Synthesis of 15-membered 11-azalides (12 and 13). Reagents and conditions: (a) DBU (1.5 equiv), MeCN, rt, 6 h, 35% (52% via two steps based on 3, see Section 4);
(b) i—3-(4-phenylbutylamino)propanol (1.5 equiv), AcOH (10 equiv), molecular sieves 3A, DMF, rt, 4 h; ii—NaBH4 (1.0 equiv), rt, 1.5 h, 65%; (c) i—2,4,6-Cl3C6H2COCl
(1.2 equiv), TEA (2.0 equiv), THF, rt, 2 h; ii—DMAP (6 equiv) in PhH, slowly added, rt, 2 h, 43%; (d) MeOH, rt, 76 h, 32% for 7, 24% for 8, trace of 9; MeOH, rt, 5 days, 89% for 11;
(e) difluoroacetic acid (30 equiv), MeCN–H2O, rt, 25 h, 78% for 12, 73% for 13.
(7 and 8) by difluoroacetic acid17 proceeded to provide desired 15-
membered azalides (12 and 13), respectively. In the case of mioka-
mycin18 (MOM) derivatives whose 300-position is an acetoxyl group
(see Fig. 5, for miokamycin), a neutral sugar is stable under these
acidic conditions because of its 1,3-diaxial hindrance. On the other
hand, a neutral sugar moiety of midecamycin19 derivatives whose
300-position is a hydroxyl group is unstable under acidic conditions,
so the neutral sugar is partially removed during this deprotection
step (see compound 44 in Scheme 3).
diphenylphosphoryl azide quantitatively gave 14-membered
azalactam (16).
Partial methanolysis mainly gave the 20-hydroxyl derivative
(17) and the 9-O-acetyl group was not affected under this methan-
olysis condition in the case of 14-membered azalactam as previ-
ously mentioned. On the other hand, 9-O-acetyl group was
partially or dominantly removed in the same condition in the case
of 15- or 16-membered azalactams. Final acidic hydrolysis afforded
14-membered 11-azalactam (18).
2.2. Synthesis of 14-membered azalactams
2.3. SAR analysis of 14- to 16-membered azalides and
azalactams
Utilization of the formylcarboxylic acid (2) enabled us to theo-
retically generate any structures of the Western hemisphere
(framework between the aldehyde at C-10 and the carboxylic acid
at C-1) of the macrolactone ring (Fig. 2), and thus we applied azi-
doamine instead of amino alcohol in order to construct azalactam.
We used N-(2-azidoethyl)-4-phenylbutylamine to afford the
desired coupling product (14) in moderate yield as shown in
Scheme 2. Although the coupling reaction of amino alcohol with
aldehyde required the intermediate (iminium ion, tentatively) for-
mation step, application of azidoamine did not necessarily require
this step. As a matter of fact, a yield of a coupling reaction in appli-
cation of azidoamine accompanied with the intermediate forma-
tion step, was further increased to about 80% (see compound 37
in Scheme 3). Reduction of the azide by triphenylphosphine
smoothly provided aminoacid (15), and its macrocyclization with
According to the synthesis of 12 and 13 shown in Scheme 1,
azalides 19–25 were synthesized (Fig. 3). Azalactams 26–33
(Fig. 4) were also synthesized by a similar procedure to 18 as
shown in Scheme 2. Preparation procedures of amino alcohols
and azidoamines applied to the synthesis of azalides or azalactams
are disclosed in our patent.20
Antibacterial activities of 14- to 16-membered azalides are
shown in Table 1 and those of 14- to 16-azalactams are shown in
Table 2. Although both 15-membered compounds and 16-mem-
bered compounds exhibited remarkable antibacterial activities,
14-membered azalides and azalactams did not show strong po-
tency. In general, 15-membered compounds exhibited strong
activities against H. influenzae compared to MOM (Table 3), and
their strong tendency was more clearly observed in 15-membered

10132
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
characteristic side chain, 3-(quinolin-4-yl)propyl group (Fig. 5) to
11-position of 15-membered lactam, which was proved to be one
of the most effective substituents at 11-position for enhancing
antibacterial activities in our previous studies.8
As shown in Scheme 3, we synthesized midecamycin type 15-
membered azalactam (43) and its demycarosyl analogue (44)
starting from the tetraol intermediate (34)8 (see Fig. 5 for mideca-
19
mycin A1 (MDM)). Although a neutral sugar moiety is not be-
lieved to be essential for antibacterial activity in erythromycin
derivatives,4,21 we had to clarify antibacterial activities of demy-
carosyl analogues. Although the synthetic route is fundamentally
same as in the preparation of 18 shown in Scheme 2, acidic
hydrolysis of 42 gave demycarosyl derivative (44) accompanied
with 43 because of poor 1,3-diaxial steric hindrance between
the 100- and 300-position compared to that in 8. Being different
from lactone synthesis, complete methanolysis in heating condi-
tion is applicable to the deprotection of the 9-O-acetyl group in
lactam synthesis (41 to 42). Moreover, considering of efficiency
in the chemical screening of 11-substituted 15-membered azalac-
tam, we modified the synthetic scheme in application of the com-
mon synthetic intermediate (40) as shown in Scheme 3. An
efficient chemical screening using 40 will be reported elsewhere.
Because 15-membered azalactams with a substituent at 11-posi-
tion exhibited stronger antibacterial activity against H. influenzae
(vide infra, Table 3), we pursued further optimization utilizing the
15-membered azalactam template.
Figure 3. Eleven-substituted 14- to 16-membered 11-azalides.
Next, we investigated the design, synthesis, and evaluation of
novel 15-membered azalactams with an appropriate side chain
at the 14-position, in order to explore possibilities of optimization
of 15-membered azalactam as shown in Scheme 4. There are a
variety of strategies to construct meaningful and applicable ‘small
molecule focused library’ derived from structurally complicated
natural substances, like anticancer natural products or antibiotics.
As characteristic examples, one-by-one synthesis and its perfect
structure determination by conventional research, or split-and-
pool methodology for peptide synthesis are well known. On the
other hand, attractive strategies such as ‘chemical biology stud-
ies’22 and ‘click chemistry’23 were subsequently introduced as a
novel approach to construct a qualified library. We chose ( )-N-
(3-azido-5-hexenyl)-N-methylamine20,24 as an important building
azalactams compared to 15-membered azalides (20, 21, 12, and 13
vs 29–32). On the other hand, 16-membered analogues exhibited
rather strong activities against S. pneumoniae including the erm-
type resistant bacteria, and their positive phenomena were de-
tected in 16-membered azalide (azalactone) as shown in com-
pounds 23 and 24.
2.4. Chemical modification of 15-membered azalactams
In the above SAR studies, we could find several attractive tem-
plates. Fifteen-membered molecules exhibited strong activities
against H. influenzae strains, and 15-membered lactam was some-
how stronger than 15-membered lactone. We first introduced a
Figure 4. Eleven-substituted 14- to 16-membered 11-azalactams.

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
10133
Figure 5. Fifteen-membered azalactams (43 and 44) and structurally related azalide (45).
Scheme 2. Synthesis of 14-membered 11-azalactam (18). Reagents and conditions: (a) N-(2-azidoethyl)-4-phenylbutylamine (1.5 equiv), NaBH3CN (0.45 equiv), AcOH
(8.4 equiv), EtOH, rt, 21 h, 52%; (b) PPh3 (5.0 eq), 10% H2O/THF, 60 °C, 36 h, 64%; (c) (PhO)2PON3 (3.4 equiv), NaHCO3 (18 equiv), DMF, rt, 19 h, 96%; (d) MeOH, rt, 5 h, 70%; (e)
difluoroacetic acid (30 equiv), MeCN/H2O (1:1), rt, 25 h, 85%.
block including a tether part for preparation of the common
intermediates (48 and 49), and isolated each diastereoisomer
48/49. These intermediates were quite productive for expanding
diversity of the library and rapid synthesis. After separation of
these isomers, medicinal chemistry has been performed with a
single stereochemistry at the C-14, but its configuration could
not be figured out. Because we could not find an excellent lead
compound for further modification from the compounds shown
in Figure 6 or Figure 7, we did not define stereochemistry at
the C-14 in Figure 6 and the C-13 in Figure 7. But we defined ste-
reochemistry at the C-15 for more promising compounds shown
in Figure 8. Heck reactions of 48/49 with 4-bromoquinoline as
shown in Scheme 4 afforded 3-(quinolin-4-yl)allyl derivatives
(50/51), and subsequent deprotections of them gave desired 54/
55 and their demycarosyl analogues. In this series (14-substituted
15-membered azalactams), palladium acetate and tri-o-tolylphos-
phine25 were used for Heck reaction. Even though we used a sim-
ilar protocol, rearrangement of the double bond occurred
depending on its side chain structure (Fig. 6) during Heck reac-
tion. For example, the reaction with 3-bromoquinoline did not
provide rearrangement products, but the reaction with 4-bromo-
quinoline led to rearrangement and generated an isomer as by-
product (58 and 59 in Fig. 6).
2.5. SAR analysis of optimized 15-membered azalactams
Antibacterial activities of 11-substituted 15-membered azalac-
tam 43 and 44,8 and those of several reference compounds are
shown in Table 3. Antibacterial activities of azalactam (43) were
slightly weaker than those of 15-membered azalide (45) except
for the activities against H. influenzae, even though 43 possessed
an optimized side chain, the 3-(quinolin-4-yl)propyl group, in
SAR studies of 11-substituted 15-membered azalides.8 Thus, we
did not pursue further optimization of substituents at the N-11
and we started SAR studies of 14-substituted 15-membered
azalactams as novel pharmacophore. As a matter of fact, antibacte-
rial activities of 44 against M. catarrhalis or H. influenzae were
stronger than those of the demycarosyl analogue of midecamycin
A3 (data are not shown), so we decided to isolate and evaluate each
demycarosyl analogue in this series.
Antibacterial activities of 14-substituted 15-membered azalac-
tams with mycarose are shown in Table 4. As we expected, the
activities against H. influenzae of these analogues were generally
stronger than those of MDM, but their activities against the erm-
type resistant bacteria of S. pneumoniae were none or weak as a
lead compound for further modifications. Then we moved to inves-
tigation of 16-membered azalides. On the other hand, the demy-

10134
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
Scheme 3. Synthesis of midecamycin type 15-membered 11-azalactam (43) and its demycarosyl analogue (44) by a convergent approach. Reagents and conditions: (a)
Pb(OAc)4 (2.5 equiv), Na2CO3 (8.0 equiv), PhH, rt, 30 min; (b) DBU (1.5 equiv), MeCN, rt, 5 h, 70% via two steps; (c) i—N-(3-azidopropyl)-4-methoxybenzylamine (1.5 equiv),
AcOH (10 equiv), molecular sieves 3A, DMF, rt, 4 h; ii—NaBH4 (1.0 equiv), rt, 1.5 h, 79%; (d) PPh3 (5.0 equiv), 10% H2O/THF, 60 °C, 36 h, 76%; (e) (PhO)2PON3 (3.4 equiv),
NaHCO3 (18 equiv), DMF, rt, 19 h, 72%; (f) 10% Pd/C, 1, 4-dioxane, rt, 24 h, 91%; (g) i—3-(quinolin-4-yl)propionaldehyde (1.2 equiv), AcOH (5.0 equiv), EtOH, 0 °C, 30 min; ii—
NaBH3CN (3.0 equiv), 0 °C to rt, 3.5 h, 66%; (h) MeOH, 50 °C, 150 h, 83%; (i) difluoroacetic acid (30 equiv), MeCN/H2O (1:1), rt, 25 h, 45% for 43 and 24% for 44 (total yield: 69%).
Table 1
Antibacterial activities of 14- to 16-membered 11-azalides with a 4-phenylbutyl group at the N-11 position.
Test organism
Characteristics
(MIC,
lg/ml)
19
20
21
12
13
22
23
24
25
1
2
3
4
5
6
Staphylococcus aureus 209P JC-1
S. aureus #2
S. aureus #3
S. aureus #4
S. aureus #5
Susceptible
Susceptible
Susceptible
ermA (c)*
4
>128
4
>128
4
8
0.5
1
0.5
>128
0.5
0.13
0.5
0.25
>128
0.5
0.5
1
0.5
>128
0.5
1
0.25
1
0.25
>128
0.25
0.5
0.5
2
1
>128
1
2
0.25
1
0.25
>128
0.25
0.5
0.13
0.5
0.25
>128
0.13
0.5
0.25
0.5
0.25
>128
0.25
0.5
ermB (i)**
S. aureus #6
ermC (i)
1
0.5
7
8
9
Streptococcus pneumoniae DP1 TypeI
S. pneumoniae #2
S. pneumoniae #5
S. pneumoniae #6
S. pneumoniae #7
S. pneumoniae #8
S. pneumoniae #9
S. pneumoniae #10
Streptococcus pyogenes #1
S. pyogenes #2
Susceptible
Susceptible
ermB + mefA (c)
ermB (c)
ermB (i)
ermB (i)
mefA efflux
mefA efflux
Susceptible
ermB (c)
mefA efflux
Susceptible
Susceptible
Susceptible
Susceptible
Susceptible
Susceptible
1
2
0.25
0.25
>128
>128
>128
>128
0.5
0.25
0.25
>128
0.5
0.25
0.5
>128
2
16
16
0.06
0.13
128***
>128
8
0.25
0.25
>128
N.T.
8
0.13
0.13
>128
N.T.
4
0.25
0.25
>128
>128
4
0.06
0.06
>128
64
1
1
0.13
0.06
0.13
64
0.25
0.25
0.5
0.03
0.06
>128
>128
2
0.03
0.06
>128
>128
8
>128
>128
>128
>128
2
2
2
>128
4
8
>128
>128
>128
>128
>128
10
11
12
13
14
15
16
17
18
19
20
21
22
23
8
32
16
4
2
4
0.06
0.06
0.06
>128
0.13
0.13
0.25
32
0.5
0.25
0.25
>128
0.25
0.25
0.5
>128
2
0.25
0.13
0.06
>128
0.13
0.13
0.25
16
0.25
0.13
0.25
>128
1
1
2
>128
4
>128
>128
0.06
0.06
0.06
32
0.25
0.13
0.5
32
2
8
8
0.06
0.06
0.06
>128
0.25
0.13
0.5
64
4
16
8
S. pyogenes #3
Moraxella catarrhalis #1
M. catarrhalis #2
Haemophilus influenzae #1
H. influenzae #2
H. influenzae #3
H. influenzae #4
32
0.5
8
16
1
4
8
1
4
8
4
8
NT, not tested.
*
Constitutive.
Inducible.
**
***
Test organism: S. pneumoniae #11 (ermB methylase(c)).

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
10135
Table 2
Antibacterial activities of 14- to 16-membered 11-azalactams with a 4-phenylbutyl group at the N-11 position and compound 28.
Test organism
Characteristics
(MIC,
lg/ml)
26
18
27
28
29
30
31
32
33
1
2
3
4
5
6
Staphylococcus aureus 209P JC-1
S. aureus #2
S. aureus #3
S. aureus #4
S. aureus #5
Susceptible
Susceptible
Susceptible
ermA (c)*
1
4
2
>128
1
0.5
2
1
>128
1
2
1
2
1
>128
1
1
2
1
>128
0.5
1
0.25
1
0.25
>128
0.25
0.5
0.25
1
0.25
>128
0.25
0.5
0.25
1
0.5
>128
0.25
1
0.25
1
0.25
>128
0.25
0.5
0.25
1
0.5
>128
0.25
1
ermB (i)**
S. aureus #6
ermC (i)
2
2
7
8
9
Streptococcus pneumoniae DP1 TypeI
S. pneumoniae #2
S. pneumoniae #5
S. pneumoniae #6
S. pneumoniae #7
S. pneumoniae #8
S. pneumoniae #9
S. pneumoniae #10
Streptococcus pyogenes #1
S. pyogenes #2
susceptible
Susceptible
ermB + mefA (c)
ermB (c)
ermB (i)
ermB (i)
mefA efflux
mefA efflux
Susceptible
ermB (c)
mefA efflux
Susceptible
Susceptible
Susceptible
Susceptible
Susceptible
Susceptible
0.5
1
0.5
0.5
>128
>128
>128
>128
1
0.5
0.5
>128
1
0.5
1
>128
2
8
8
0.5
1
0.13
0.5
>128
>128
16
0.06
0.13
>128
>128
128
128
0.25
0.25
0.06
>128
0.25
0.13
0.13
16
0.13
0.25
>128
>128
32
0.25
0.5
>128
>128
32
0.13
0.25
>128
>128
16
0.13
0.25
>128
>128
8
>128
>128
32
32
1
>128
>128
>128
>128
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
16
32
32
16
8
0.5
0.5
0.5
>128
2
1
2
>128
8
>128
16
0.25
0.25
0.06
>128
0.25
0.13
0.25
32
0.25
0.25
0.13
>128
0.5
0.25
0.25
16
0.25
0.25
0.13
>128
0.5
0.13
0.25
8
0.13
0.13
0.06
>128
0.25
0.13
0.25
16
1
1
0.5
>128
1
1
1
>128
4
16
16
0.5
>128
1
1
1
>128
4
16
16
S. pyogenes #3
Moraxella catarrhalis #1
M. catarrhalis #2
Haemophilus influenzae #1
H. influenzae #2
H. influenzae #3
H. influenzae #4
1
4
4
1
8
8
0.5
2
4
0.5
2
4
1
4
8
*
Constitutive.
Inducible.
**
Table 3
Antibacterial activities of 15-membered azalactams (43 and 44) and structurally related azalide (45).
Test organism
Characteristics
(MIC, lg/ml)
43
44
MDM
45
MOM
1
2
3
4
5
6
7
8
Staphylococcus aureus 209P JC-1
S. aureus #2
S. aureus #3
S. aureus #4
S. aureus #5
Susceptible
Susceptible
Susceptible
ermA (c)*
0.5
1
64
32
64
>128
64
64
16
16
>128
>128
>128
>128
32
32
16
>128
128
8
0.5
0.5
0.5
>128
0.5
0.13
0.5
0.5
1
0.5
>128
0.5
1
0.25
0.5
>128
>128
64
128
0.5
0.5
0.25
>128
0.5
1
0.5
>128
0.5
0.5
0.06
0.13
>128
>128
16
0.25
>128
0.13
0.25
0.06
0.06
>128***
>128
4
ermB (i)**
S. aureus #6
ermC (i)
0.5
Streptococcus pneumoniae DP1 TypeI
S. pneumoniae #2
S. pneumoniae #5
S. pneumoniae #6
S. pneumoniae #7
S. pneumoniae #8
S. pneumoniae #9
S. pneumoniae #10
Streptococcus pyogenes #1
S. pyogenes #2
Susceptible
Susceptible
ermB + mefA (c)
ermB (c)
ermB (i)
ermB (i)
mefA efflux
mefA efflux
susceptible
ermB (c)
mefA efflux
Susceptible
Susceptible
Susceptible
Susceptible
Susceptible
Susceptible
0.13
0.25
>128
>128
>128
>128
0.5
0.25
0.25
>128
1
2
2
64
4
16
16
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
16
8
0.13
0.13
0.25
>128
1
2
1
16
1
0.13
0.13
0.06
>128
0.13
0.25
0.25
16
S. pyogenes #3
Moraxella catarrhalis #1
M. catarrhalis #2
Haemophilus influenzae #1
H. influenzae #2
H. influenzae #3
H. influenzae #4
8
64
8
64
2
64
2
32
1
8
8
4
8
128
16
*
**
Constitutive.
Inducible.
***
Test organism: S. pneumoniae #11 (ermB methylase(c)).
carosyl analogues (R = H in Fig. 6) did not exhibit remarkable activ-
ities (data are not shown).
substituted 15-membered azalactams shown in Scheme 4. Macrol-
actonization successfully proceeded with Shiina protocol27 using
the anhydride instead of the acid chloride. When we used a novel
method28 in application of tri-tert-butyl phosphine in Heck reac-
tion, isomers generated by rearrangement of the double bond were
only detected. Then, a small amount of cis-isomers were detected
accompanied with major trans-isomers in some cases. In this series
(Scheme 5), Heck reactions with other bromoquinolines, for exam-
ple, 6-bromo-, 8-bromoquinoline, or 4-bromoisoquinoline, re-
sulted in very low yield (15–25%, see Section 4). There might be
2.6. Chemical modification of 16-membered azalides
We next examined possibilities of 16-membered azalides as a
clinical candidate. First, 13-substituted analogues were synthe-
sized as shown in Scheme 5. Thirteen-substituted 16-membered
azalides were synthesized with 3-(methylaminomethyl)-5-hexen-
1-ol26 by a basically similar method as a synthetic route for 14-

10136
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
Scheme 4. Synthesis of 15-membered 11-azalactams with the quinolinylallyl group at the C-14 position. Reagents and conditions: (a) N-(3-azido-5-hexenyl)-N-methylamine
(1.5 equiv), NaBH3CN (0.45 equiv), AcOH (8.4 equiv), EtOH, rt, 21 h, 54%; (b) PMe3 (3.0 equiv), 10% H2O/MeCN, 80 °C, 6.5 h, 53%; (c) (PhO)2PON3 (3.4 equiv), NaHCO3
(18 equiv), DMF, rt, 19 h, 73% (38% + 35%); (d) palladium (II) acetate (0.21 equiv), tri-o-tolylphosphine (0.4 equiv), 4-bromoquinoline (2.3 equiv), Et3N (2.0 equiv), 47% for 50
(plus 7% for rearrangement product of double bond) and 52% for 51 (plus 11% for rearrangement product of double bond); (e) MeOH, rt, 5 h, 86% for 52 and 53; (f)
difluoroacetic acid (30 equiv), MeCN/H2O (1:1), rt, 25 h, 40% for 54 and 37% for 56 (total yield: 77%), 49% for 55 and 38% for 57 (total yield: 87%).
some relationships between these low yields and easy rearrange-
ment of a double bond in the substituent at the C-13 position.
According to the synthetic method shown in Scheme 5, com-
pounds 81–90 were prepared (Fig. 7). Because low yields and com-
plicated rearrangement of the double bond of the 13-substituent
during Heck reaction bothered us, we simultaneously performed
synthetic studies of 15-substituted 16-membered azalides as
shown in Scheme 6. Heck reaction of 92 or 93 with several kinds
of bromoheterocycles afforded desired coupling products in rather
higher yields compared to those of the reactions with 73 or 74, and
double bond rearrangement products could not be clearly detected
(Fig. 8).
In this 15-substituted 16-membered azalides series, we first
prepared both diastereoisomers at the C-15 position and did not
define their stereochemistry. Antibacterial activities of these mol-
ecules (vide infra, Table 6), however, were good enough for further
modifications, so we defined their stereochemistry at the C-15 and
established the synthetic method for efficient preparation of single
diastereoisomer of 15-substituted 16-membered azalides. As later
mentioned, b-isomers exhibited stronger activities against the
inducible erm-type resistant bacteria of S. pneumoniae. In order
to synthesize only b-isomer (Fig. 8) at the C-15, we prepared com-
pound 93 in the stereoselective manner. The coupling reaction of
36 with (R)-7-methylamino-1-hepten-4-ol20 gave (15R)-91 (seco
acid of 93) as a single diasteroisomer. Macrolactonization of this
compound afforded a 16-membered azalide whose spectral data
were consistent with those of compound 93. (R)-7-Methylamino-
1-hepten-4-ol was prepared from
D-ornithine hydrochloride via
eight steps.20
2.7. SAR analysis of optimized 16-membered azalides
Antibacterial activities of 13-substituted 16-membered azalides
and 15-substituted 16-membered azalides are shown in Tables 5
and 6, respectively. Almost all 16-membered azalides possessing
an arylalkyl substituent at the C-13 or C-15 exhibited well-bal-
anced antibacterial activities for upper and lower respiratory
pathogens (S. pneumoniae, Streptococcus pyogenes, M. catarrhalis,
and H. influenzae) and very effective against the mef-type resistant
bacteria of S. pneiumoniae. They are also somehow effective against
the inducible erm-type resistant bacteria of S. pneumoniae (except
compounds 80, 83, and 85). Because several compounds synthe-

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
10137
Figure 6. Fourteen-substituted 15-membered azalactams.
Figure 7. Thirteen-substituted 16-membered azalides.
sized by Heck reaction using 4-bromoquinoline exhibited strong
antibacterial activities, we defined their stereochemistry at the C-
15. Comparing antibacterial activities of 98 and 100 with those
of 99 and 101, these analogues possessing b-configuration at the
C-15 exhibited stronger activities against the inducible erm-type
naphthalene ring exhibited weak response to the constitutive
erm-type resistant bacteria of S. pneumoniae, although their activ-
ities against H. influenzae were decreased. For example, compounds
106 and 107 with the 3-quinolinyl moiety showed more potent
antibacterial activities compared to MDM against almost all test
organisms, and were active against the inducible erm-type and
the mef-type resistant bacteria of S. pneumoniae. According to the
above SAR studies, 15-substituted 16-membered azalides might
resistant bacteria of S. pneumoniae than the corresponding
a-dia-
stereoisomers. Thus, we prepared b-isomer only for other ana-
logues. Among these compounds, 104 and 105 possessing the

10138
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
Figure 8. Fifteen-substituted 16-membered azalides.
Table 4
Antibacterial activities of 14-substituted 15-membered azalactams.
Test organism
Characteristics
(MIC,
60
l
g/ml)
54
55
58
59
62
64
66
67
69
1
2
3
4
5
6
7
8
Staphylococcus aureus 209P JC-1
S. aureus #2
S. aureus #3
S. aureus #4
S. aureus #5
Susceptible
Susceptible
Susceptible
ermA (c)*
1
2
0.5
>128
0.5
1
0.13
0.13
0.25
>128
>128
>128
>128
>128
0.25
0.25
0.5
>128
2
4
8
2
>128
2
0.5
1
2
4
1
>128
2
1
1
0.5
>128
1
4
8
2
>128
4
0.5
1
0.25
>128
0.5
1
0.06
0.13
0.13
>128
>128
>128
32
1
2
0.5
>128
1
0.5
1
0.25
>128
0.5
1
2
0.5
>128
0.5
0.5
0.03
0.13
0.06
>128
>128
>128
8
0.5
>128
0.5
0.5
0.03
0.06
0.06
>128
>128
>128
8
ermB (i)**
S. aureus #6
ermC (i)
4
2
1
4
1
0.5
Streptococcus pneumoniae DP1 TypeI
S. pneumoniae #2
S. pneumoniae #3
S. pneumoniae #4
S. pneumoniae #5
S. pneumoniae #6
S. pneumoniae #7
S. pneumoniae #8
S. pneumoniae #9
S. pneumoniae #10
Streptococcus pyogenes #1
S. pyogenes #2
Susceptible
Susceptible
Susceptible
ermB (c)
ermB + mefA (c)
ermB (c)
0.25
0.25
0.25
>128
>128
>128
>128
>128
0.5
0.25
0.5
>128
2
8
4
64
4
16
16
0.13
0.25
0.25
>128
>128
>128
64
0.06
0.13
0.13
>128
>128
>128
32
0.13
0.25
0.25
>128
>128
>128
64
0.13
0.25
0.25
>128
>128
>128
>128
>128
0.5
0.25
0.5
>128
4
8
4
64
4
16
32
0.03
0.06
0.06
>128
>128
>128
16
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
ermB (i)
ermB (i)
8
64
32
64
32
64
8
mefA efflux
mefA efflux
susceptible
ermB (c)
mefA efflux
Susceptible
Susceptible
Susceptible
Susceptible
Susceptible
Susceptible
0.13
0.13
0.25
>128
1
1
2
32
1
0.25
0.25
0.5
>128
2
4
4
32
1
0.13
0.13
0.25
>128
2
2
2
32
2
0.25
0.25
0.5
>128
2
8
8
64
2
0.13
0.13
0.25
>128
1
2
2
32
2
0.06
0.06
0.13
>128
0.5
2
2
32
1
0.06
0.06
0.25
>128
1
8
4
32
2
S. pyogenes #3
Moraxella catarrhalis #1
M. catarrhalis #2
Haemophilus influenzae #1
H. influenzae #2
H. influenzae #3
H. influenzae #4
2
1
64
2
16
32
8
8
8
16
8
8
16
8
16
16
8
16
8
16
*
Constitutive.
Inducible.
**
be recognized as attractive lead compounds for further chemical
modifications toward a clinical candidate.
effective against the mef-type resistant bacteria of S. pneumoniae.
As the first step of our research, we developed one-pot macrocyc-
lization and synthesis of 15-membered azalides and 16-membered
diazalide.8 This approach, however, could only provide limited
structural diversity (Fig. 2). Then, we utilized 9-formylcarboxylic
acid (2) as a key intermediate for sequential macrocyclization to
provide a variety of novel templates.
We prepared 14- to 16-membered azalides and 14- to 16-mem-
bered azalactams using this key intermediate (2). Among them, 15-
membered azalactams and 16-membered azalides were chosen as
3. Conclusion
We have been studying new templates to explore novel semi-
synthetic macrolide antibiotics that are effective against both
resistant S. pneumoniae and H. influenzae. In order to discover a
new efficient template, we chose 16-membered macloride as start-
ing material, because it has been proven to be clinically safe and

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
10139
Scheme 5. Synthesis of 13-substituted 16-membered azalides. Reagents and conditions: (a) i—3-(methylaminomethyl)-5-hexen-1-ol (1.5 equiv), AcOH (10 equiv), molecular
sieves 3A, DMF, rt, 4 h; ii—NaBH4 (1.0 equiv), rt, 1.5 h, 40% for 71 and 30% for 72 (total yield: 70%); (b) 2-methy-6-nitrobenzoic anhydride (1.5 equiv), DMAP (3.0 equiv),
CH2Cl2, 0 °C, 4.5 h, 63% for 73 and 54% for 74; (c) 3-bromoquinoline (2.0 equiv), tris(dibenzylideneacetone)dipalladium (0) (0.3 equiv), tBu3P (0.6 equiv), dicyclohexylm-
ethylamine (2.0 equiv), 1,4-dioxane, 50 °C, 48 h, 5.8% for 75 accompanied with 2.8% for its cis-isomer, total yield of this Heck reaction was 8.6%, 28% for 76; (d) MeOH, 40 °C,
48 h, 33% for 77 and 21% for 78; (e) difluoroacetic acid (30 equiv), MeCN–H2O, rt, 25 h, 51% for 79 and 45% for 80.
Scheme 6. Synthesis of 15-substituted 16-membered azalides. Reagents and conditions: (a) i—7-methylamino-1-hepten-4-ol (1.5 equiv), AcOH (10 equiv), molecular sieves
3A, DMF, rt, 4 h; ii—NaBH4 (1.0 equiv), rt, 1.5 h, 66%; (b) 2-methy-6-nitrobenzoic anhydride (1.5 equiv), DMAP (3.0 equiv), CH2Cl2, 0 °C, 2.5 h and rt, 2 h, 21% for 92 and 47% for
93 (total yield: 68%); (c) 4-bromoquinoline (2.0 equiv), tris(dibenzylideneacetone)dipalladium (0) (0.3 equiv), tBu3P (0.6 equiv), dicyclohexylmethylamine (2.0 equiv), 1, 4-
dioxane, 50 °C, 48 h, 25% for 94 and 42% for 95; (d) MeOH, rt, 5 h, 61% for 96, 41% for 97; (e) difluoroacetic acid (30 equiv), MeCN–H2O, rt, 25 h, 51% for 98, 61% for 99.

10140
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
Table 5
Antibacterial activities of 13-substituted 16-membered azalides.
Test organism
Characteristics
(MIC,
84
l
g/ml)
79
80
81
82
83
85
86
87
88
89
90
1
2
3
4
5
6
7
8
Staphylococcus aureus 209P JC-1
S. aureus #2
S. aureus #3
S. aureus #4
S. aureus #5
Susceptible
Susceptible
Susceptible
ermA (c)*
0.13
0.25
0.13
>128
0.13
0.25
<0.008
0.03
0.015
128
128
128
1
0.25
0.5
0.25
>128
0.25
0.5
0.015
0.06
0.03
>128
>128
>128
128
128
0.06
0.06
0.13
>128
0.5
0.5
1
0.25
>64
0.25
1
0.06
0.25
0.13
>64
>64
>64
8
0.13
0.5
0.25
1
0.25
>128
0.25
0.5
0.03
0.06
0.03
>128
>128
>128
128
128
0.06
0.06
0.13
>128
0.25
2
0.25
1
0.25
>128
0.25
0.5
0.03
0.06
0.06
>128
>128
>128
8
2
4
2
>128
2
4
0.5
1
0.5
>128
>128
>128
>128
>128
1
1
1
>128
4
16
16
>128
32
128
128
0.25
0.5
0.25
>128
0.25
0.5
0.015
0.03
0.03
>128
>128
>128
16
0.25
0.5
0.25
>128
0.25
0.5
0.015
0.06
0.03
>128
>128
>128
16
0.13
0.25
0.13
>128
0.13
0.25
0.015
0.03
0.015
>128
>128
128
2
0.25
0.5
0.25
>128
0.25
0.5
0.015
0.015
0.015
128
128
128
8
0.25
0.5
0.13
>128
0.13
0.25
0.015
0.03
0.03
>128
>128
>128
8
0.13
>128
0.13
0.25
0.015
0.03
0.015
128
128
128
8
ermB (i)**
S. aureus #6
ermC (i)
Streptococcus pneumoniae DP1 TypeI
S. pneumoniae #2
S. pneumoniae #3
S. pneumoniae #4
S. pneumoniae #5
S. pneumoniae #6
S. pneumoniae #7
S. pneumoniae #8
S. pneumoniae #9
S. pneumoniae #10
Streptococcus pyogenes #1
S. pyogenes #2
Susceptible
Susceptible
Susceptible
ermB (c)
ermB + mefA (c)
ermB (c)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
ermB (i)
ermB (i)
1
8
8
8
16
16
2
8
8
mefA efflux
mefA efflux
Suseptible
ermB (c)
mefA efflux
Susceptible
Susceptible
Susceptible
Susceptible
Susceptible
Susceptible
0.015
0.015
0.03
>128
0.13
1
1
32
2
8
0.13
0.13
0.13
>64
0.5
2
2
>64
8
0.03
0.03
0.03
>128
0.13
1
1
16
NT
8
0.06
0.06
0.13
>128
0.5
2
2
64
NT
0.03
0.03
0.06
>128
0.25
1
1
32
NT
8
0.06
0.06
0.06
>128
0.25
1
1
16
2
8
0.015
0.015
0.03
>128
0.25
1
1
32
2
8
0.03
0.03
0.06
>128
0.25
1
2
32
2
8
0.015
0.03
0.03
>128
0.25
1
1
32
2
8
S. pyogenes #3
Moraxella catarrhalis #1
M. catarrhalis #2
Haemophilus influenzae #1
H. influenzae #2
H. influenzae #3
H. influenzae #4
2
2
64
4
16
16
2
32
4
16
16
16
16
16
4
8
16
8
8
8
8
8
NT, not tested.
*
Constitutive.
Inducible.
**
Table 6
Antibacterial activities of 15-substituted 16-membered azalides.
Test organism
Characteristics
(MIC, lg/ml)
98
99
100
101
102
103
104
105
106
107
108
1
2
3
4
5
6
7
8
Staphylococcus aureus 209P JC-1
S. aureus #2
S. aureus #3
S. aureus #4
S. aureus #5
Susceptible
Susceptible
Susceptible
ermA (c)*
0.5
1
0.25
1
0.25
>128
0.25
0.5
0.03
0.06
0.015
>128
>128
>128
8
0.25
0.5
0.25
>128
0.25
0.5
0.03
0.06
0.06
>128
>128
>128
32
0.5
1
0.5
1
0.25
0.5
1
0.25
1
2
0.5
2
0.5
64
0.5
1
0.06
0.06
0.13
32
32
32
8
0.5
1
0.13
0.25
0.13
>128
0.13
0.25
<0.008
0.015
<0.008
128
128
128
4
0.25
0.5
0.25
>128
0.25
0.5
0.13
0.13
0.06
>128
>128
>128
32
0.25
>128
0.5
0.5
0.03
0.06
0.06
>128
>128
>128
8
0.5
>128
0.5
1
0.06
0.13
0.06
64
64
64
4
0.25
>128
0.25
0.5
0.015
0.03
0.03
128
128
128
8
0.25
>128
0.25
0.25
0.015
0.03
0.015
>128
>128
>128
8
>128
0.25
0.5
0.03
0.06
0.06
128
>128
>128
2
>128
0.25
0.5
0.015
0.03
0.03
>128
>128
>128
32
ermB (i)**
S. aureus #6
ermC (i)
Streptococcus pneumoniae DP1 TypeI
S. pneumoniae #2
S. pneumoniae #3
S. pneumoniae #4
S. pneumoniae #5
S. pneumoniae #6
S. pneumoniae #7
S. pneumoniae #8
S. pneumoniae #9
S. pneumoniae #10
Streptococcus pyogenes #1
S. pyogenes #2
Susceptible
Susceptible
Susceptible
ermB (c)
ermB + mefA (c)
ermB (c)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
ermB (i)
ermB (i)
32
4
32
8
4
32
2
8
8
4
8
mefA efflux
mefA efflux
susceptible
ermB (c)
mefA efflux
Susceptible
Susceptible
Susceptible
Susceptible
Susceptible
Susceptible
0.13
0.13
0.25
>128
0.5
2
4
64
8
0.06
0.06
0.13
>128
0.5
1
1
32
2
0.06
0.06
0.13
>128
0.5
2
2
64
4
0.06
0.06
0.06
>128
0.5
2
2
32
4
16
0.06
0.06
0.13
>128
0.5
1
1
64
8
16
0.03
0.03
0.06
>128
0.5
1
1
32
2
0.06
0.06
0.25
64
1
2
2
64
16
16
16
0.13
0.13
0.25
32
1
2
2
32
8
16
16
0.06
0.03
0.06
>128
0.5
1
1
32
2
8
0.015
0.015
0.015
>128
0.13
1
1
32
2
8
0.03
0.03
0.06
>128
0.25
1
1
32
4
8
S. pyogenes #3
Moraxella catarrhalis #1
M. catarrhalis #2
Haemophilus influenzae #1
H. influenzae #2
H. influenzae #3
H. influenzae #4
16
16
8
8
8
8
8
16
16
8
8
8
8
*
Constitutive.
Inducible.
**
characteristic templates, and modified. As we expected, the activi-
ties against H. influenzae of 15-membered azalactams were gener-
ally stronger than those of MDM, but their activities against the
erm-type resistant bacteria of S. pneumoniae were none or weak as
a lead compound for further modifications. Although several opti-
mized 14-substituted 15-membered azalactams exhibited stronger
activities against H. influenzae than MDM and kept one of positive
characters of 16-membered maclorides, that is, effectiveness
against the mef-type resistant bacteria of S. pneumoniae, they are
not enough as lead compounds for further modifications.
On the other hand, several optimized 13-substituted and 15-
substituted 16-membered azalides exhibited well-balanced anti-

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
10141
bacterial activities for upper and lower respiratory pathogens and
very effective against the mef-type resistant bacteria of S. pneumo-
niae. They are also somehow effective against the inducible erm-
type resistant bacteria of S. pneumoniae. Although there were not
big differences between 13-substituted and 15-substituted ana-
logues, we chose 15-substituted 16-membered azalides with
b-configuration at the C-15 for further modifications toward a clin-
ical candidate, because they have higher yields and less rearrange-
ments of the double bond during Heck reaction. Optimization of
structure of the arylalkyl moiety and modification at the neutral
sugar moiety29 for improvement of pharmacokinetics would be
soon investigated.
was washed with saturated brine. The organic layer was separated,
and then the aqueous layer was extracted with chloroform. The
combined organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated. The resulting residue was purified by
silica gel column chromatography (chloroform/methanol (50:1 to
30:1)) to obtain 1.82 g (52% via two steps) of 2 as a colorless solid.
4.1.2. Synthesis of 4
Compound 2 (400 mg, 0.434 mmol) and 3-(4-phenylbutylami-
no)propanol (135 mg, 0.651 mmol) were dissolved in dimethyl-
formamide (1.0 ml). Molecular sieves 3A (800 mg) and acetic acid
(0.25 ml, 4.37 mmol) were added and the reaction mixture was stir-
red at room temperature for 4 h. Then, sodium borohydride
(17.1 mg, 0.452 mmol) was added, and further stirred at the same
temperaturefor1.5 h. ThereactionmixturewasfilteredthroughCel-
ite by using ethyl acetate (100 ml). The filtrate was successively
washed twice with water (30 ml) and twice with saturated brine
(30 ml). The organic layer was dried over anhydrous sodium sulfate
and filtered. The filtrate was concentrated, and the resulting residue
was purified by silica gel column chromatography (chloroform/
methanol (80:1 to 30:1)) to obtain 314 mg (65%) of 4 as a colorless
4. Experimental
4.1. Chemistry
Optical rotations were measured on a Perkin-Elmer 241 Polar-
imeter or Jasco P-1030 Polarimeter. Fast-atom bombardment
(FAB) mass spectra and high-resolution mass spectra (HRMS) were
recorded on a JEOL JMS-700 instrument. 1H NMR spectra were re-
corded on Varian Gemini-300 spectrometers for 300 MHz with
chemical shifts reported in ppm relative to internal tetramethylsil-
ane. Silica gel chromatography and preparative TLC were per-
formed on Wako C-200 or C-300 and Merck TLC 60F254 Art. 5744,
respectively. Evaporation was carried out under reduced pressure
below 35 °C, unless otherwise noted.
solid; ½a 2D3
ꢀ
ꢁ66° (c 0.65, CHCl3); FAB-MS m/z 1113 (M+H)+; 1H
NMR (CDCl3) d 0.87 (d, 8-CH3), 1.03 (br dd, 7-H), 1.07 (d, 600-H),
1.15 (t, 3-OCOCH2CH3), 1.19 (d, 60-H), 1.20 (t, 400-OCOCH2CH3), 1.30
(m, 7-H), 1.42 (s, 300-CH3), 1.66 (dd, 200-Hax), 1.85 (m, 8-H), 1.98 (s,
300-OCOCH3), 2.03 (s, 9-OCOCH3), 2.03 (s, 20-OCOCH3), 2.43 (s, 30-
N(CH3)2), 2.62 (t, 30-H), 2.88 (dd, 2-H), 3.12 (t, 40-H), 3.19 (d, 200-
Heq), 3.20 (s, CH(OCH3)2), 3.26 (s, CH(OCH3)2), 3.54 (br d, 4-H),
3.57 (s, 4-OCH3), 3.88 (br d, 5-H), 4.49 (dq, 500-H), 4.53 (dd,
CH(OCH3)2), 4.57 (d, 400-H), 4.72 (d, 10-H), 4.80 (d, 100-H), 4.95 (dd,
20-H), 5.24 (br dd, 9-H), 5.32 (br d, 3-H), 7.12–7.34 (m, C6H5).
4.1.1. Synthesis of 2
Compound 18 (3.20 g, 3.23 mmol) was dissolved in aceto-
nitrile (64 ml), and 1, 8-diazabicyclo[5.4.0]-7-undecene (0.72 ml,
4.82 mmol) was added. The solution was kept at room temperature
for 6 h. The reaction mixture was concentrated under reduced pres-
sure, and then extracted with chloroform, and the organic layer was
washed with saturated brine. The organic layer was separated and
the aqueous layer was extracted with chloroform. The combined or-
ganic layer was dried over anhydrous sodium sulfate, filtered, and
concentrated. The resulting residue was purified by silica gel column
chromatography (chloroform/methanol (50:1 to 30:1)) to obtain
1.04 g (35%) of 2 as a colorless solid; FAB-MS m/z 922 (M+H)+; 1H
NMR (CDCl3) d 1.03 (d, 8-CH3), 1.07 (d, 600-H), 1.14 (t, 3-OCOCH2CH3),
1.20 (d, 60-H), 1.20 (t, 400-OCOCH2CH3), 1.42 (s, 300-CH3), 1.51 (m, 6-
CH2), 1.68 (dd, 200-Hax), 1.86 (m, 6-CH2), 2.03 (s, 300-OCOCH3), 2.06
(s, 20-OCOCH3), 2.15 (m, 8-H), 2.20 (s, 9-OCOCH3), 2.43 (s, 30-
N(CH3)2), 2.62 (t, 30-H), 2.69 (dd, 2-H), 2.83 (dd, 2-H), 3.13 (t, 40-H),
3.18 (s, CH(OCH3)2), 3.19 (d, 200-Heq), 3.26 (s, CH(OCH3)2), 3.48 (br
d, 4-H), 3.55 (s, 4-OCH3), 3.83 (br d, 5-H), 4.44 (dd, CH(OCH3)2),
4.49 (dq, 500-H), 4.57 (d, 400-H), 4.66 (d, 10-H), 4.81 (d, 100-H), 4.87 (d,
9-H), 5.24 (br dd, 3-H), 9.56 (s, 10-H).
4.1.3. Synthesis of 5
Compound 4 (132 mg, 0.119 mmol) was dissolved with tetra-
hydrofuran (3.5 ml), and triethylamine (0.032 ml, 0.223 mmol)
and 2,4,6-trichlorobenzoyl chloride (0.022 ml, 0.141 mmol) were
added. The solution was kept at room temperature for 2 h. The
reaction mixture was poured into a solution of 4-dimethylamino-
pyridine (86.9 mg, 0.711 mmol) in anhydrous benzene (23 ml) in
a dropwise manner over 30 min under ice cooling. The mixture
was further stirred for 1 h at room temperature, and then water
was added. Macrolactone was extracted with ethyl acetate, and
the organic layer was successively washed with water, saturated
aqueous sodium bicarbonate, and saturated brine. The organic
layer was dried over anhydrous sodium sulfate, filtered, and con-
centrated. The resulting residue was purified by silica gel column
chromatography (chloroform/ethyl acetate (15:1 to 5:1)), and fur-
ther purified by preparative TLC (chloroform/ethyl acetate (2:1)) to
obtain 55.9 mg (43%) of 5 as a colorless solid; ½a D19
ꢁ85° (c 1.0,
ꢀ
CHCl3); FAB-MS m/z 1095 (M+H)+; 1H NMR (CDCl3) d 0.91 (d, 8-
CH3), 1.07 (d, 600-H), 1.15 (t, 3-OCOCH2CH3), 1.20 (t, 400-
OCOCH2CH3), 1.20 (d, 60-H), 1.42 (s, 300-CH3), 1.68 (dd, 200-Hax),
1.99 (s, 300-OCOCH3), 2.02 (s, 9-OCOCH3), 2.04 (s, 20-OCOCH3),
2.44 (s, 30-N(CH3)2), 2.62 (t, 30-H), 2.74 (dd, 2-H), 2.86 (dd, 2-H),
3.12 (s, CH(OCH3)2), 3.15 (t, 40-H), 3.19 (d, 200-Heq), 3.25 (s,
CH(OCH3)2), 3.27 (m, 50-H), 3.36 (br d, 4-H), 3.53 (s, 4-OCH3),
3.95 (br d, 5-H), 4.08 (m, 14-H), 4.41 (m, 14-H), 4.48 (m, 500-H),
4.57 (d, 400-H), 4.67 (d, 10-H), 4.77 (m, 9-H), 4.81 (d, 100-H), 4.97
(dd, 20-H), 5.17 (m, 3-H), 7.14–7.31 (m, C6H5).
Compound 38 (4.00 g, 3.79 mmol) was dissolved in benzene
(130 ml), and sodium carbonate (3.22 g, 30.4 mmol) was added.
Moreover, lead tetraacetate (4.20 g, 9.47 mmol) was added with
five portions for 20 min. The reaction mixture was stirred at room
temperature for 1 h, and then the supernatant was transferred to a
separating funnel. The residue was extracted with benzene, and
the supernatant was transferred to the same funnel. The same pro-
cedure was repeated three times. The combined organic layer was
washed with mixture of water and saturated aqueous sodium
bicarbonate. The organic layer was further washed with saturated
brine, dried over anhydrous sodium sulfate, and filtered. The fil-
trate was concentrated to obtain crude 1. This was dissolved in
acetonitrile (78 ml), and 1, 8-diazabicyclo[5.4.0]-7-undecene
(0.85 ml, 5.70 mmol) was added. After the solution was kept at
room temperature for 6 h, the reaction mixture was concentrated.
The residue was extracted with chloroform and the organic layer
4.1.4. Synthesis of 7 and 8
Compound 5 (84.0 mg, 0.0767 mmol) was dissolved in metha-
nol (3.4 ml) and the solution was kept at room temperature for
76 h. The reaction mixture was concentrated, and the resulting res-
idue was purified by preparative TLC (chloroform/methanol (30:1))

10142
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
to obtain 25.8 mg (32%) of 7 as a colorless solid and 18.6 mg (24%)
of 8 as a colorless solid. Total yield of this reaction was 56%. Com-
(4.1 mg, 0.108 mmol) were added under ice cooling, and the mix-
ture was stirred at room temperature for 21 h. The reaction mix-
ture was diluted with ethyl acetate, and washed with 8%
aqueous sodium bicarbonate. The aqueous layer was extracted
twice with ethyl acetate. The organic layers were combined and
washed with 25% brine. The organic layer was dried over anhy-
drous sodium sulfate and concentrated. The resulting residue
was purified by silica gel column chromatography (chloroform/
methanol (30:1)) to obtain 85.0 mg (52%) of 14 as a colorless solid;
pound 7: ½a 2D0
ꢀ
ꢁ60° (c 1.0, CHCl3); FAB-MS m/z 1053 (M+H)+; 1H
NMR (CDCl3)
d
0.92 (d, 8-CH3), 1.09 (d, 600-H), 1.15 (t, 3-
OCOCH2CH3), 1.20 (t, 400-OCOCH2CH3), 1.21 (d, 60-H), 1.42 (s, 300-
CH3), 1.47 (quint, C6H5(CH2)4), 1.59 (quint, C6H5(CH2)4), 1.70 (dd,
200-Hax), 2.00 (s, 300-OCOCH3), 2.02 (s, 9-OCOCH3), 2.55 (s, 30-
N(CH3)2), 2.61 (t, C6H5(CH2)4), 2.75 (dd, 2-H), 2.89 (dd, 2-H), 3.15
(s, CH(OCH3)2), 3.23 (d, 200-Heq), 3.27 (s, CH(OCH3)2), 3.42 (dd, 20-
H), 3.47 (br d, 4-H), 3.61 (s, 4-OCH3), 3.94 (br d, 5-H), 4.09 (m,
14-H), 4.39 (m, 14-H), 4.47 (d, 10-H), 4.48 (dd, CH(OCH3)2), 4.56
(m, 500-H), 4.59 (d, 400-H), 4.81 (m, 9-H), 4.86 (d, 100-H), 5.21 (m,
½
a 1D8
ꢀ
ꢁ64° (c 1.0, CHCl3); FAB-MS m/z 1124 (M+H)+; 1 H NMR
(CDCl3) d 0.87 (d, 8-CH3), 1.07 (d, 600-H), 1.16 (t, 3-OCOCH2CH3),
1.19 (t, 400-OCOCH2CH3), 1.20 (d, 60-H), 1.31 (m, 7-H), 1.41 (s, 300-
CH3), 1.49 (m, 6-CH2), 1.67 (dd, 200-Hax), 1.90 (m, 6-CH2), 2.00 (s,
300-OCOCH3), 2.03 (s, 9-OCOCH3), 2.03 (s, 20-OCOCH3), 2.43 (s, 30-
N(CH3)2), 2.62 (t, 30-H), 2.74 (dd, 2-H), 2.83 (m, 12-H), 3.13 (t, 40-
H), 3.19 (d, 200-Heq), 3.22 (s, CH(OCH3)2), 3.26 (s, CH(OCH3)2),
3.53 (s, 4-OCH3), 3.44 (br d, 4-H), 3.55 (m, 13-H), 3.88 (br d, 5-
H), 4.50 (dq, 500-H), 4.57 (d, 400-H), 4.69 (d, 10-H), 4.80 (d, 100-H),
4.96 (dd, 20-H), 7.12–7.33 (m, C6H5).
3-H), 7.14–7.29 (m, C6H5). Compound 8: ½a D20
ꢁ51° (c 1.0, CHCl3);
ꢀ
FAB-MS m/z 1011 (M+H)+; 1H NMR (CDCl3) d 0.93 (d, 8-CH3),
1.07 (d, 600-H), 1.12 (t, 3-OCOCH2CH3), 1.18 (t, 400-OCOCH2CH3),
1.19 (d, 60-H), 1.40 (s, 300-CH3), 1.68 (dd, 200-Hax), 2.00 (s, 300-
OCOCH3), 2.53 (s, 30-N(CH3)2), 2.64 (dd, 2-H), 2.81 (dd, 2-H), 3.09
(s, CH(OCH3)2), 3.20 (m, 50-H), 3.21 (d, 200-Heq), 3.24 (m, 40-H),
3.24 (s, CH(OCH3)2), 3.39 (dd, 20-H), 3.50 (br d, 4-H), 3.62 (s, 4-
OCH3), 3.90 (br d, 5-H), 4.10 (m, 14-H), 4.28 (m, 14-H), 4.48 (dd,
CH(OCH3)2), 4.48 (d, 10-H), 4.54 (m, 500-H), 4.57 (d, 400-H), 4.84 (d,
100-H), 5.23 (m, 3-H), 7.12–7.30 (m, C6H5).
4.1.8. Synthesis of 15
Compound 14 (84.1 mg, 0.0748 mmol) was dissolved in tetrahy-
drofuran (5.0 ml) and water (0.5 ml), and triphenylphosphine
(98.5 mg, 0.376 mmol) was added. The reaction mixture was stirred
at 60 °C for 36 h, and then concentrated. The resulting residue was
purified by silica gel column chromatography (chloroform/metha-
nol (40:1 to 10:1)) to obtain 52.6 mg (64%) of 15 as a colorless solid;
4.1.5. Synthesis of 12
Compound 7 (30.0 mg, 0.0285 mmol) was dissolved in an
equivolume mixed solvent of acetonitrile–water (1.2 ml), and
difluoroacetic acid (0.054 ml, 0.859 mmol) was added. The solution
was kept at room temperature for 25 h. The reaction mixture was
diluted with chloroform, and washed with saturated aqueous so-
dium bicarbonate. The organic layer was further successively
washed with saturated aqueous sodium bicarbonate, and saturated
brine, dried over anhydrous sodium sulfate, and then filtered. The
filtrate was concentrated, and the resulting residue was purified by
preparative TLC (chloroform/methanol (25:1)) to obtain 22.4 mg
½
a 2D0
ꢀ
ꢁ82° (c 1.0, CHCl3); FAB-MSm/z 1098 (M+H)+; 1H NMR(CDCl3) d
0.95 (d, 8-CH3), 1.07 (d, 600-H), 1.11 (t, 3-OCOCH2CH3), 1.18 (d, 60-H),
1.19 (t, 400-OCOCH2CH3), 1.41 (s, 300-CH3), 1.67 (dd, 200-Hax), 2.00 (s,
300-OCOCH3), 2.01 (s, 20-OCOCH3), 2.03 (s, 9-OCOCH3), 2.43 (s, 30-
N(CH3)2), 2.61 (t, 30-H), 3.13 (s, CH(OCH3)2), 3.19 (d, 200-Heq), 3.24
(s, CH(OCH3)2), 3.55 (s, 4-OCH3), 3.60 (br d, 4-H), 3.84 (br d, 5-H),
4.50 (dq, 500-H), 4.57 (d, 400-H), 4.71 (d, 10-H), 4.80 (d, 100-H), 4.96
(dd, 20-H), 5.14 (br dd, 3-H), 7.12–7.33 (m, C6H5).
(78%) of 12 as a colorless solid; ½a D19
ꢁ67° (c 0.67, CHCl3); FAB-
ꢀ
MS m/z 1007 (M+H)+; HRMS: Calcd for C52H82N2O17: 1007.5692.
Found: 1007.5684 (M+H)+; 1 H NMR CDCl3) d 0.91 (d, 8-CH3),
1.08 (d, 600-H), 1.13 (d, 60-H), 1.16 (t, 3-OCOCH2CH3), 1.18 (t, 400-
OCOCH2CH3), 1.40 (s, 300-CH3), 1.69 (dd, 200-Hax), 1.99 (s, 300-
OCOCH3), 1.99 (s, 9-OCOCH3), 2.04 (m, 6-H), 2.34 (dd, 6-CH2),
2.54 (s, 30-N(CH3)2), 2.70 (dd, 2-H), 2.87 (dd, 2-H), 2.93 (dd, 6-
CH2), 3.20 (m, 40-H), 3.20 (m, 50-H), 3.21 (d, 200-Heq), 3.32 (dd, 20-
H), 3.51 (dd, 4-H), 3.61 (s, 4-OCH3), 3.90 (br d, 5-H), 4.10 (m, 14-
H), 4.32 (m, 14-H), 4.41 (d, 10-H), 4.49 (dq, 500-H), 4.57 (d, 400-H),
4.79 (m, 9-H), 4.85 (d, 100-H), 5.36 (m, 3-H), 7.14–7.29 (m, C6H5),
9.62 (s, CHO).
4.1.9. Synthesis of 16
Compound 15 (43.2 mg, 0.0393 mmol) was dissolved in
dimethylformamide (9.0 ml) under argon atmosphere, and sodium
bicarbonate (58.6 mg, 0.698 mmol) was added. Then, diphenyl-
phosphoryl azide (0.030 ml, 0.133 mmol) was added under ice
cooling, and the mixture was stirred at room temperature for
19 h. The reaction mixture was diluted with ethyl acetate, and
washed twice with water, and once with 25% brine. The organic
layer was dried over anhydrous sodium sulfate and concentrated.
The resulting residue was purified by silica gel column chromatog-
raphy (ethyl acetate) to obtain 40.8 mg (96%) of 16 as a colorless
4.1.6. Preparation of 13
solid; ½a 2D0
ꢀ
ꢁ47° (c 0.43, CHCl3); FAB-MS m/z 1080 (M+H)+; 1H
Reaction of 8 with difluoroacetic acid gave 13 in 73% yield by a
NMR (CDCl3)
d
0.88 (d, 8-CH3), 1.07 (d, 600-H), 1.15 (t, 3-
similar procedure to 12; ½a D20
ꢀ
ꢁ65° (c 0.52, CHCl3); FAB-MS m/z 965
OCOCH2CH3), 1.19 (t, 400-OCOCH2CH3), 1.20 (d, 60-H), 1.42 (s, 300-
CH3), 1.67 (dd, 200-Hax), 1.77 (m, 8-H), 1.88 (m, 6-CH2), 2.01 (s,
300-OCOCH3), 2.02 (s, 9-OCOCH3), 2.02 (s, 20-OCOCH3), 2.43 (s, 30-
N(CH3)2), 2.93 (m, 13-H), 3.13 (s, CH(OCH3)2), 3.19 (d, 200-Heq),
3.25 (s, CH(OCH3)2), 3.69 (s, 4-OCH3), 3.93 (br d, 5-H), 4.50 (dq,
500-H), 4.57 (d, 400-H), 4.73 (d, 10-H), 4.80 (d, 100-H), 4.95 (dd, 20-
H), 5.05 (br dd, 3-H), 6.49 (br s,NH), 7.05–7.36 (m, C6H5).
(M+H)+; HRMS: Calcd for C50H80N2O16: 965.5586. Found: 965.5587
(M+H)+; 1H NMR (CDCl3) d 0.96 (d, 8-CH3), 0.98 (br dd, 7-H), 1.08
(d, 600-H), 1.12 (d, 60-H), 1.16 (t, 3-OCOCH2CH3), 1.18 (t, 400-
OCOCH2CH3), 1.40 (s, 300-CH3), 1.68 (dd, 200-Hax), 1.99 (s, 300-
OCOCH3), 2.54 (s, 30-N(CH3)2), 2.82 (dd, 2-H), 2.96 (dd, 6-CH2),
3.20 (m, 40-H), 3.20 (m, 50-H), 3.21 (d, 200-Heq), 3.33 (dd, 20-H),
3.45 (br d, 9-H), 3.53 (br d, 4-H), 3.62 (s, 4-OCH3), 3.88 (br d, 5-
H), 4.14 (m, 14-H), 4.25 (m, 14-H), 4.42 (d, 10-H), 4.50 (dq, 500-H),
4.57 (d, 400-H), 4.84 (d, 100-H), 5.37 (m, 3-H), 7.14–7.29 (m, C6H5),
9.63 (s, CHO).
4.1.10. Synthesis of 17
Compound 16 (40.0 mg, 0.0370 mmol) was dissolved in meth-
anol (1.6 ml) and the solution was kept at room temperature for
5 h. The reaction mixture was concentrated, and the resulting res-
idue was purified by preparative TLC (chloroform/methanol (30:1))
4.1.7. Synthesis of 14
Compound 2 (134 mg, 0.145 mmol) was dissolved in ethanol
(6.5 ml) under argon atmosphere, and 2-(4-phenylbutylami-
no)ethylazide (49.2 mg, 0.225 mmol) was added. Moreover, acetic
acid (0.070 ml, 1.22 mmol) (8.4 equiv) and sodium borohydride
to obtain 27.0 mg (70%) of 17 as a colorless solid; ½a D19
ꢁ38° (c 0.41,
ꢀ
CHCl3); FAB-MS m/z 1038 (M+H)+; 1H NMR (CDCl3) d 0.89 (d, 8-
CH3), 1.09 (d, 600-H), 1.15 (t, 3-OCOCH2CH3), 1.20 (t, 400-

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
10143
OCOCH2CH3), 1.21 (d, 60-H), 1.42 (s, 300-CH3), 1.69 (dd, 200-Hax),
1.80 (m, 8-H), 2.02 (s, 9-OCOCH3), 2.02 (s, 300-OCOCH3), 2.54 (s,
30-N(CH3)2), 3.16 (s, CH(OCH3)2), 3.22 (d, 200-Heq), 3.27 (s,
CH(OCH3)2), 3.41 (dd, 20-H), 3.46 (br d, 4-H), 3.67 (m, 13-H), 3.73
(s, 4-OCH3), 3.95 (br d, 5-H), 4.59 (d, 400-H), 4.80 (m, 9-H), 4.85
(d, 100-H), 5.07 (br d, 3-H), 6.42 (br s, NH), 7.05–7.37 (m, C6H5).
dd, 7-H), 1.09 (d, 600-H), 1.14 (d, 60-H), 1.16 (t, 3-OCOCH2CH3),
1.19 (t, 400-OCOCH2CH3), 1.24 (d, 15-CH3), 1.42 (s, 300-CH3), 1.70
(dd, 200-Hax), 1.98 (s, 9-OCOCH3), 2.01 (s, 300-OCOCH3), 2.17 (m,
6-H), 2.26 (br d, 6-CH2), 2.55 (s, 30-N(CH3)2), 2.78 (dd, 2-H), 2.94
(dd, 6-CH2), 3.22 (m, 40-H), 3.22 (m, 50-H), 3.22 (d, 200-Heq), 3.34
(dd, 20-H), 3.50 (dd, 4-H), 3.59 (s, 4-OCH3), 3.85 (br d, 5-H), 4.42
(d, 10-H), 4.51 (dq, 500-H), 4.59 (d, 400-H), 4.84 (m, 15-H), 4.85 (d,
100-H), 4.95 (m, 9-H), 5.52 (m, 3-H), 7.16–7.27 (m, C6H5), 9.62 (s,
CHO).
4.1.11. Preparation of 18
Reaction of 17 with difluoroacetic acid gave 18 in 85% yield by a
similar procedure to 12; ½a D18
ꢁ47° (c 0.34, CHCl3); FAB-MS m/z 992
ꢀ
(M+H)+; HRMS: Calcd for C51H81N3O16: 992.5695. Found: 992.5705
4.1.12.5. Compound 23 . ½a D24
ꢁ48° (c 0.64, CHCl3); FAB-MS m/z
ꢀ
1
(M+H)+; H NMR (CDCl3) d 0.86 (d, 8-CH3), 1.09 (d, 600-H), 1.14 (d,
993 (M+H)+; HRMS: Calcd for C52H84N2O16: 993.5900. Found:
993.5896 (M+H)+; 1H NMR (CDCl3) d 0.85 (d, 8-CH3), 1.04 (br dd,
7-H), 1.09 (d, 600-H), 1.13 (d, 60-H), 1.16 (t, 3-OCOCH2CH3), 1.19
(t, 400-OCOCH2CH3), 1.23 (d, 15-CH3), 1.31 (m, 8-H), 1.42 (s, 300-
CH3), 1.69 (dd, 200-Hax), 1.81 (br dd, 7-H), 2.01 (s, 300-OCOCH3),
2.15 (m, 6-H), 2.30 (br d, 6-CH2), 2.55 (s, 30-N(CH3)2), 2.94 (dd, 6-
CH2), 3.21 (m, 40-H), 3.21 (m, 50-H), 3.22 (d, 200-Heq), 3.36 (dd, 20-
H), 3.57 (br d, 4-H), 3.60 (s, 4-OCH3), 3.80 (br dd, 9-H), 3.87 (br
d, 5-H), 4.42 (d, 10-H), 4.52 (dq, 500-H), 4.59 (d, 400-H), 4.77 (m,
15-H), 4.85 (d, 100-H), 5.54 (br dd, 3-H), 7.14–7.32 (m, C6H5), 9.63
(s, CHO).
60-H), 1.19 (t, 3-OCOCH2CH3), 1.20 (t, 400-OCOCH2CH3), 1.42 (s,
300-CH3), 1.69 (dd, 200-Hax), 1.83 (m, 8-H), 2.01 (s, 9-OCOCH3),
2.01 (s, 300-OCOCH3), 2.55 (s, 30-N(CH3)2), 3.00 (m, 13-H), 3.07 (m,
6-CH2), 3.22 (d, 200-Heq), 3.34 (dd, 20-H), 3.49 (br d, 4-H), 3.58
(m, 13-H), 3.73 (s, 4-OCH3), 3.92 (br d, 5-H), 4.45 (d, 10-H), 4.52
(dq, 500-H), 4.59 (d, 400-H), 4.78 (m, 9-H), 4.85 (d, 100-H), 5.13 (br
d, 3-H), 6.42 (br s, NH), 7.05–7.36 (m, C6H5), 9.63 (s, CHO).
4.1.12. According to synthesis of 12 and 13 shown in Scheme 1,
azalides 19 and 22–25 were synthesized. Preparations of amino
alcohols applied for synthesis of azalides were disclosed in our
publication20
4.1.12.6. 9,20-Di-O-acetyl dimethylacetal of 24 (polar than 9,20-
di-O-acetyl dimethylacetal of 25 in TLC developed by chloro-
form/ethyl acetate (1:2)). FAB-MS m/z 1121 (M+H)+; 1H NMR
(CDCl3) d 0.91 (d, 8-CH3), 1.07 (d, 600-H), 1.16 (t, 3-OCOCH2CH3),
1.19 (t, 400-OCOCH2CH3), 1.20 (d, 60-H), 1.33 (d, 15-CH3), 1.42 (s,
300-CH3), 1.67 (dd, 200-Hax), 1.87 (br dd, 6-CH2), 2.02 (s, 300-
OCOCH3), 2.02 (s, 9-OCOCH3), 2.05 (s, 20-OCOCH3), 2.44 (s, 30-
N(CH3)2), 2.78 (dd, 2-H), 3.14 (s, CH(OCH3)2), 3.19 (d, 200-Heq),
3.24 (s, CH(OCH3)2), 3.55 (s, 4-OCH3), 3.86 (br d, 5-H), 4.45 (dd,
CH(OCH3)2), 4.49 (dq, 500-H), 4.57 (d, 400-H), 4.68 (d, 10-H), 4.81 (d,
100-H), 4.98 (dd, 20-H), 5.06 (br d, 9-H), 5.17 (m, 3-H), 5.28 (dq,
15-H), 5.49 (dd, 14-H), 5.87 (m, 13-H), 7.13–7.31 (m, C6H5).
4.1.12.1 20-O-Acetyl dimethylacetal of 19
.
½
a 2D0
ꢀ
ꢁ66° (c 0.7,
CHCl3); FAB-MS m/z 1095 (M+H)+; 1H NMR (CDCl3) d 0.75 (m, 7-
H), 0.92 (d, 8-CH3), 1.07 (d, 600-H), 1.14 (t, 3-OCOCH2CH3), 1.19 (t,
400-OCOCH2CH3), 1.21 (d, 60-H), 1.22 (d, 13-CH3), 1.42 (s, 300-CH3),
1.68 (dd, 200-Hax), 2.02 (s, 300-OCOCH3), 2.04 (s, 9-OCOCH3), 2.08
(s, 20-OCOCH3), 2.44 (s, 30-N(CH3)2), 2.81 (dd, 12-H), 2.96 (dd, 2-
H), 3.13 (m, 40-H), 3.14 (s, CH(OCH3)2), 3.20 (d, 200-Heq), 3.25 (s,
CH(OCH3)2), 3.27 (m, 50-H), 3.57 (s, 4-OCH3), 3.71 (br d, 4-H),
3.86 (br d, 5-H), 4.45 (m, CH(OCH3)2), 4.47 (dq, 500-H), 4.57 (d,
400-H), 4.71 (d, 10-H), 4.81 (d, 100-H), 4.84 (m, 9-H), 4.98 (dd, 20-H),
5.07 (m, 13-H), 5.18 (br d, 3-H), 7.05–7.36 (m, C6H5).
4.1.12.2. Compound 19. ½a D20
ꢀ
ꢁ61° (c 0.6, CHCl3); FAB-MS m/z
4.1.12.7. Compound 24 . ½a D23
ꢁ60° (c 0.35, CHCl3); FAB-MS m/z
ꢀ
1007 (M+H)+; HRMS: Calcd for C52H82N2O17: 1007.5692. Found:
1007.5684 (M+H)+; 1H NMR (CDCl3) d 0.93 (d, 8-CH3), 1.10 (d,
600-H), 1.15 (d, 60-H), 1.18 (t, 3-OCOCH2CH3), 1.19 (t, 400-
OCOCH2CH3), 1.24 (d, 13-CH3), 1.42 (s, 300-CH3), 1.55 (quint,
C6H5(CH2)4), 1.71 (dd, 200-Hax), 1.76 (m, 8-H), 2.01 (s, 300-OCOCH3),
2.04 (s, 9-OCOCH3), 2.24 (dd, 6-CH2), 2.37 (dd, 10-H), 2.56 (s, 30-
N(CH3)2), 2.61 (t, C6H5(CH2)4), 2.72 (dd, 12-H), 2.88 (dd, 10-H),
2.99 (dd, 2-H), 3.05 (dd, 6-CH2), 3.23 (m, 40-H), 3.23 (m, 50-H),
3.23 (d, 200-Heq), 3.35 (dd, 20-H), 3.64 (s, 4-OCH3), 3.87 (br s, 4-
H), 3.87 (br s, 5-H), 4.43 (d, 10-H), 4.50 (dq, 500-H), 4.59 (d, 400-H),
4.87 (d, 100-H), 4.93 (m, 9-H), 5.07 (br dq, 13-H), 5.36 (br d, 3-H),
7.05–7.36 (m, C6H5), 9.63 (s, CHO).
991 (M+H)+; HRMS: Calcd for C52H82N2O16: 991.5743. Found:
1
991.5739 (M+H)+; H NMR (CDCl3) d 0.87 (d, 8-CH3), 1.09 (d, 600-
H), 1.14 (d, 60-H), 1.16 (t, 3-OCOCH2CH3), 1.19 (t, 400-OCOCH2CH3),
1.34 (d, 15-CH3), 1.42 (s, 300-CH3), 1.48 (m, 8-H), 1.69 (dd, 200-Hax),
2.01 (s, 300-OCOCH3), 2.55 (s, 30-N(CH3)2), 2.66 (dd, 2-H), 2.79 (dd,
2-H), 2.96 (dd, 6-CH2), 3.11 (m, 12-H), 3.21 (m, 40-H), 3.21 (m, 50-
H), 3.22 (d, 200-Heq), 3.40 (m, 9-H), 3.40 (dd, 20-H), 3.55 (dd, 4-H),
3.59 (s, 4-OCH3), 3.93 (br d, 5-H), 4.44 (d, 10-H), 4.54 (dq, 500-H),
4.59 (d, 400-H), 4.85 (d, 100-H), 5.27 (dq, 15-H), 5.39 (br d, 3-H),
5.64 (dd, 14-H), 5.84 (m, 13-H), 7.14–7.31 (m, C6H5), 9.64 (s, CHO).
4.1.12.8. 9,20-Di-O-acetyl dimethylacetal of 25 (less polar than
9,20-di-O-acetyl dimethylacetal of 24 in TLC developed by
4.1.12.3. 20-O-Acetyl dimethylacetal of 22 (9,20-di-O-acetyl
chloroform/ethyl acetate (1:2)). ½a D25
ꢁ55° (c 0.31, CHCl3); FAB-
ꢀ
dimethylacetal of 23). ½a D21
ꢀ
ꢁ67° (c 0.50, CHCl3); FAB-MS m/z
MS m/z 1121 (M+H)+; 1H NMR (CDCl3) d 0.89 (d, 8-CH3), 1.07 (d,
600-H), 1.14 (t, 3-OCOCH2CH3), 1.19 (d, 60-H), 1.19 (t, 400-
OCOCH2CH3), 1.37 (d, 15-CH3), 1.41 (s, 300-CH3), 1.67 (dd, 200-
Hax), 1.82 (br dd, 6-CH2), 2.02 (s, 300-OCOCH3), 2.06 (s, 9-OCOCH3),
2.08 (s, 20-OCOCH3), 2.43 (s, 30-N(CH3)2), 2.86 (dd, 2-H), 2.98 (m,
12-H), 3.13 (s, CH(OCH3)2), 3.19 (d, 200-Heq), 3.23 (s, CH(OCH3)2),
3.32 (br d, 4-H), 3.55 (s, 4-OCH3), 3.88 (br d, 5-H), 4.43 (dd,
CH(OCH3)2), 4.51 (dq, 500-H), 4.57 (d, 400-H), 4.67 (d, 10-H), 4.80 (d,
100-H), 4.96 (dd, 20-H), 5.02 (m, 9-H), 5.15 (m, 3-H), 5.33 (dq, 15-
H), 5.58 (dd, 14-H), 5.84 (m, 13-H), 7.15–7.29 (m, C6H5).
1
1123 (M+H)+; H NMR (CDCl3) d 0.89 (d, 8-CH3), 1.07 (d, 600-H),
1.14 (t, 3-OCOCH2CH3), 1.18 (d, 60-H), 1.19 (t, 400-OCOCH2CH3),
1.23 (d, 15-CH3), 1.36 (br dd, 7-H), 1.41 (s, 300-CH3), 1.67 (dd, 200-
Hax), 1.87 (br dd, 6-CH2), 2.02 (s, 300-OCOCH3), 2.03 (s, 9-OCOCH3),
2.05 (s, 20-OCOCH3), 2.43 (s, 30-N(CH3)2), 2.80 (dd, 2-H), 3.13 (t, 40-
H), 3.15 (s, CH(OCH3)2), 3.19 (d, 200-Heq), 3.24 (s, CH(OCH3)2), 3.33
(br d, 4-H), 3.52 (s, 4-OCH3), 3.82 (br d, 5-H), 4.39 (dd, CH(OCH3)2),
4.48 (dq, 500-H), 4.57 (d, 400-H), 4.67 (d, 10-H), 4.81 (d, 100-H), 4.90
(m, 9-H), 4.90 (m, 15-H), 4.95 (dd, 20-H), 5.32 (br t, 3-H), 7.13–
7.32 (m, C6H5).
4.1.12.9. Compound 25. ½a D23
ꢁ37° (c 0.39, CHCl3); FAB-MS m/z
ꢀ
4.1.12.4. Compound 22. ½a D23
ꢀ
ꢁ43° (c 0.54, CHCl3); FAB-MS m/z
991 (M+H)+; HRMS: Calcd for C52H82N2O16: 991.5743. Found:
991.5747 (M+H)+; 1H NMR (300 MHz, CDCl3) d 0.86 (m, 7-H),
0.97 (d, 8-CH3), 1.09 (d, 600-H), 1.13 (d, 60-H), 1.18 (t, 3-
1035 (M+H)+; HRMS: Calcd for C54H86N2O17: 1035.6005. Found:
1035.6007 (M+H)+; 1H NMR (CDCl3) d 0.89 (d, 8-CH3), 1.04 (br

10144
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
OCOCH2CH3), 1.19 (t, 400-OCOCH2CH3), 1.33 (d, 15-CH3), 1.42 (s, 300-
CH3), 1.43 (m, 8-H), 1.55 (m, 7-H), 1.70 (dd, 200-Hax), 2.01 (s, 300-
OCOCH3), 2.05 (m, 6-H), 2.29 (dd, 6-CH2), 2.55 (s, 30-N(CH3)2),
2.80 (dd, 2-H), 2.87 (br dd, 12-H), 3.01 (dd, 6-CH2), 3.21 (m, 50-
H), 3.22 (d, 200-Heq), 3.23 (m, 40-H), 3.33 (dd, 20-H), 3.39 (dd, 4-
H), 3.59 (s, 4-OCH3), 3.91 (br d, 5-H), 4.40 (d, 10-H), 4.52 (dq, 500-
H), 4.59 (d, 400-H), 4.86 (d, 100-H), 5.25 (dq, 15-H), 5.39 (br dd, 3-
H), 5.49 (dd, 14-H), 5.86 (m, 13-H), 7.16–7.31 (m, C6H5), 9.62 (s,
CHO).
978.5903 (M+H)+; 1H NMR (CDCl3) d 0.84 (d, 8-CH3), 1.02 (d,
600-H), 1.07 (d, 60-H), 1.10 (t, 3-OCOCH2CH3), 1.12 (t, 400-
OCOCH2CH3), 1.21 (d, 14-CH3), 1.35 (s, 300-CH3), 1.45 (m, 8-H),
1.62 (dd, 200-Hax), 1.80 (m, 13-H), 1.93 (s, 300-OCOCH3), 2.48 (s,
30-N(CH3)2), 2.92 (dd, 6-CH2), 3.15 (d, 200-Heq), 3.28 (dd, 20-H),
3.50 (m, 14-H), 3.57 (s, 4-OCH3), 3.80 (dd, 5-H), 4.36 (d, 10-H),
4.43 (dq, 500-H), 4.51 (d, 400-H), 4.78 (d, 100-H), 5.10 (m, 3-H),
6.65 (dd, NH), 7.08–7.12 (m, C6H5), 7.18–7.23 (m, C6H5), 9.58
(s, CHO).
4.1.13. Azalactams 26–33were synthesized bya similar procedure
to 18 as shown in Scheme 2. Preparations of azidoamines applied
for synthesis of azalactams were disclosed in ourpublication20
4.1.13.6. 9,20-Di-O-acetyl dimethylacetal of 30 (less polar than
9,20-di-O-acetyl dimethylacetal of 29 in TLC developed by
chloroform/methanol (20:1)). ½a D24
ꢁ76° (c 0.67, CHCl3); FAB-MS
ꢀ
4.1.13.1. Compound 26
.
½
a 1D8
ꢀ
ꢁ58° (c 0.39, CHCl3); FAB-MS m/z
m/z 1108 (M+H)+; H NMR (CDCl3) d 0.80 (d, 8-CH3), 1.00 (d, 600-
H), 1.06 (t, 3-OCOCH2CH3), 1.07 (d, 14-CH3), 1.12 (d, 60-H), 1.12
(t, 400-OCOCH2CH3), 1.19 (br dd, 7-H), 1.34 (s, 300-CH3), 1.59 (dd,
200-Hax), 1.88 (s, 300-OCOCH3), 1.95 (s, 9-OCOCH3), 1.98 (s, 20-
OCOCH3), 2.36 (s, 30-N(CH3)2), 2.53 (t, C6H5(CH2)4), 2.54 (t, 30-H),
2.67 (dd, 2-H), 2.95 (s, CH(OCH3)2), 3.05 (t, 40-H), 3.12 (d, 200-
Heq), 3.16 (s, CH(OCH3)2), 3.21 (dq, 50-H), 3.34 (br d, 4-H), 3.65
(s, 4-OCH3), 3.91 (br d, 5-H), 3.97 (m, 14-H), 4.40 (dq, 500-H), 4.49
(d, 400-H), 4.65 (d, 10-H), 4.73 (d, 100-H), 4.75 (br d, 9-H), 4.86 (br
d, 3-H), 4.88 (dd, 20-H), 6.55 (d, NH), 7.07–7.11 (m, C6H5), 7.17–
7.22 (m, C6H5).
1
1006 (M+H)+; HRMS: Calcd for C52H83N3O16: 1006.5852. Found:
1006.5848 (M+H)+; 1H NMR (CDCl3) d 0.89 (d, 8-CH3), 1.09 (d,
600-H), 1.14 (d, 60-H), 1.19 (t, 3-OCOCH2CH3), 1.19 (t, 400-
OCOCH2CH3), 1.24 (d, 13-CH3), 1.42 (s, 300-CH3), 1.70 (dd, 200-
Hax), 1.85 (m, 8-H), 2.02 (s, 9-OCOCH3), 2.02 (s, 300-OCOCH3),
2.30 (dd, 6-CH2), 2.55 (s, 30-N(CH3)2), 3.09 (dd, 6-CH2), 3.22 (d,
200-Heq), 3.38 (dd, 20-H), 3.55 (ddq, 13-H), 3.64 (s, 4-OCH3), 3.79
(br d, 4-H), 3.88 (br d, 5-H), 4.41 (d, 10-H), 4.51 (dq, 500-H), 4.59
(d, 400-H), 4.85 (d, 100-H), 5.26 (m, 3-H), 6.35 (br s, NH), 7.16–7.20
(m, C6H5), 7.23–7.30 (m, C6H5), 9.63 (s, CHO).
4.1.13.2. Compound 27 . ½a D24
ꢀ
ꢁ45° (c 0.25, CHCl3); FAB-MS m/z
4.1.13.7. Compound 30 . ½a D26
ꢁ77° (c 0.68, CHCl3); FAB-MS m/z
ꢀ
1006 (M+H)+; HRMS: Calcd for C52H83N3O16: 1006.5852. Found:
1006.5852 (M+H)+; 1H NMR (CDCl3) d 0.59 (m, 7-H), 0.82 (d, 8-
CH3), 1.02 (d, 600-H), 1.05 (d, 60-H), 1.12 (t, 3-OCOCH2CH3), 1.14
(t, 400-OCOCH2CH3), 1.35 (s, 300-CH3), 1.62 (dd, 200-Hax), 1.74 (m,
7-H), 1.94 (s, 9-OCOCH3), 1.98 (s, 300-OCOCH3), 2.08 (d, 6-CH2),
2.48 (s, 30-N(CH3)2), 3.02 (dd, 6-CH2), 3.15 (d, 200-Heq), 3.24 (s,
NCH3), 3.28 (dd, 20-H), 3.44 (br d, 4-H), 3.78 (s, 4-OCH3), 3.86 (br
d, 5-H), 4.17 (m, 13-H), 4.41 (d, 10-H), 4.44 (dq, 500-H), 4.52 (d,
400-H), 4.61 (br dd, 9-H), 4.77 (d, 100-H), 5.10 (br dd, 3-H), 7.08–
7.11 (m, C6H5), 7.19–7.23 (m, C6H5), 9.53 (s, CHO).
978 (M+H)+; HRMS: Calcd for C51H83N3O15: 978.5902. Found:
978.5903 (M+H)+; 1H NMR (CDCl3) d 0.81 (d, 8-CH3), 0.93 (br dd,
7-H), 1.02 (d, 600-H), 1.07 (d, 14-CH3), 1.07 (d, 60-H), 1.12 (t, 3-
OCOCH2CH3), 1.12 (t, 400-OCOCH2CH3), 1.26 (br dd, 7-H), 1.34 (s,
300-CH3), 1.62 (dd, 200-Hax), 1.78 (m, 13-H), 1.84 (m, 6-H), 1.93 (s,
300-OCOCH3), 2.48 (s, 30-N(CH3)2), 2.55 (t, C6H5(CH2)4), 2.76 (dd,
2-H), 2.93 (dd, 6-CH2), 3.14 (m, 40-H), 3.14 (m, 50-H), 3.15 (d, 200-
Heq), 3.30 (dd, 20-H), 3.58 (dd, 4-H), 3.51 (s, 4-OCH3), 3.83 (br d,
5-H), 3.98 (m, 14-H), 4.37 (d, 10-H), 4.44 (dq, 500-H), 4.51 (d, 400-
H), 4.78 (d, 100-H), 4.90 (br d, 3-H), 6.13 (br d, NH), 7.08–7.12 (m,
C6H5), 7.18–7.23 (m, C6H5), 9.58 (s, CHO).
4.1.13.3. Compound 28 . ½a D23
ꢁ50° (c 0.3, CHCl3); FAB-MS m/z
ꢀ
1006 (M+H)+; HRMS: Calcd for C52H83N3O16: 1006.5852. Found:
1006.5854 (M+H)+; 1H NMR (CDCl3) d 0.72 (m, 7-H), 0.87 (d, 8-
CH3), 1.08 (d, 600-H), 1.11 (d, 60-H), 1.18 (t, 3-OCOCH2CH3), 1.19
(t, 400-OCOCH2CH3), 1.41 (s, 300-CH3), 1.67 (dd, 200-Hax), 1.78 (m,
8-H), 2.00 (s, 300-OCOCH3), 2.04 (s, 9-OCOCH3), 2.22 (s, NCH3),
2.41 (t, 30-H), 2.54 (s, 30-N(CH3)2), 2.65 (t, C6H5 (CH2)3CH2), 2.74
(dd, 2-H), 3.10 (dd, 6-CH2), 3.15 (m, 40-H), 3.20 (m, 50-H), 3.55
(dd, 20-H), 3.49 (br d, 4-H), 3.84 (s, 4-OCH3), 3.92 (br d, 5-H), 4.47
(d, 10-H), 4.51 (dq, 500-H), 4.58 (d, 400-H), 4.71 (br dd, 9-H), 4.83
(d, 100-H), 5.09 (br dd, 3-H), 7.13–7.21 (m, C6H5), 7.22–7.30 (m,
C6H5), 9.58 (s, CHO).
4.1.13.8. Compound 31. FAB-MS m/z 1006 (M+H)+; HRMS: Calcd
for C52H83N3O16: 1006.5852. Found: 1006.5848 (M+H)+; 1H NMR
(CDCl3) d 0.81 (d, 8-CH3), 1.02 (d, 600-H), 1.07 (d, 60-H), 1.10 (t, 3-
OCOCH2CH3), 1.12 (t, 400-OCOCH2CH3), 1.34 (s, 300-CH3), 1.62 (dd,
200-Hax), 1.73 (m, 13-H), 1.91 (s, 9-OCOCH3), 1.93 (s, 300-OCOCH3),
2.48 (s, 30-N(CH3)2), 2.68 (dd, 2-H), 2.88 (dd, 6-CH2), 3.15 (d, 200-
Heq), 3.25 (dd, 20-H), 3.45 (dd, 4-H), 3.58 (m, 14-H), 3.63 (s, 4-
OCH3), 3.86 (br d, 5-H), 4.39 (d, 10-H), 4.43 (dq, 500-H), 4.51 (d,
400-H), 4.69 (br d, 9-H), 4.78 (d, 100-H), 5.05 (br d, 3-H), 7.07–7.13
(m, C6H5), 7.17–7.21 (m, C6H5), 9.57 (s, CHO).
4.1.13.9. Compound 32 . ½a D24
ꢁ81° (c 0.36, CHCl3); FAB-MS m/z
ꢀ
4.1.13.4. 9,20-Di-O-acetyl dimethylacetal of 29 (polar than 9,20-
di-O-acetyl dimethylacetal of 30 in TLC developed by chloro-
964 (M+H)+; HRMS: Calcd for C50H81N3O15: 964.5746. Found:
964.5750 (M+H)+; 1H NMR (CDCl3) d 0.81 (d, 8-CH3), 0.93 (br dd,
7-H), 1.01 (d, 600-H), 1.06 (d, 60-H), 1.11 (t, 3-OCOCH2CH3), 1.12
(t, 400-OCOCH2CH3), 1.23 (m, 7-H), 1.34 (s, 300-CH3), 1.62 (dd, 200-
Hax), 1.84 (m, 6-H), 1.93 (s, 300-OCOCH3), 2.16 (m, 10-H), 2.27
(dd, 2-H), 2.48 (s, 30-N(CH3)2), 2.54 (t, C6H5(CH2)4), 2.74 (dd, 2-
H), 2.93 (dd, 6-CH2), 3.14 (d, 200-Heq), 3.28 (dd, 20-H), 3.39 (d, 9-
H), 3.54 (dd, 4-H), 3.69 (s, 4-OCH3), 3.83 (br d, 5-H), 4.38 (d, 10-
H), 4.43 (dq, 500-H), 4.51 (d, 400-H), 4.77 (d, 100-H), 4.91 (br d, 3-H),
6.65 (dd, NH), 7.07–7.12 (m, C6H5), 7.17–7.22 (m, C6H5), 9.58 (s,
CHO).
form/methanol (20:1)). ½a D26
ꢁ71° (c 0.52, CHCl3); FAB-MS m/z
ꢀ
1
1108 (M+H)+; H NMR (CDCl3) d 0.82 (d, 8-CH3), 0.99 (d, 600-H),
1.06 (t, 3-OCOCH2CH3), 1.12 (d, 60-H), 1.12 (t, 400-OCOCH2CH3),
1.19 (d, 14-CH3), 1.34 (s, 300-CH3), 1.59 (dd, 200-Hax), 1.90 (s, 300-
OCOCH3), 1.94 (s, 9-OCOCH3), 1.94 (s, 20-OCOCH3), 2.36 (s, 30-
N(CH3)2), 2.53 (t, 30-H), 3.00 (s, CH(OCH3)2), 3.05 (t, 40-H), 3.12
(d, 200-Heq), 3.17 (s, CH(OCH3)2), 3.20 (dq, 50-H), 3.27 (br d, 4-H),
3.45 (m, 14-H), 3.51 (s, 4-OCH3), 3.84 (br d, 5-H), 4.40 (dq, 500-H),
4.49 (d, 400-H), 4.61 (d, 10-H), 4.68 (br d, 9-H), 4.73 (d, 100-H), 4.88
(dd, 20-H), 5.02 (br dd, 3-H), 7.06–7.11 (m, C6H5), 7.16–7.21 (m,
C6H5), 7.30 (br s, NH).
4.1.13.10. Compound 33. ½a D24
ꢁ66° (c 0.45, CHCl3); FAB-MS m/z
ꢀ
978 (M+H)+; HRMS: Calcd for C51H83N3O15: 978.5902. Found:
4.1.13.5. Compound 29. ½a D25
ꢀ
ꢁ61° (c 0.47, CHCl3); FAB-MS m/z
978.5903 (M+H)+; H NMR (CDCl3) d 0.78 (d, 8-CH3), 1.01 (d, 600-
1
978 (M+H)+; HRMS: Calcd for C51H83N3O15: 978.5902. Found:
H), 1.07 (d, 60-H), 1.11 (t, 3-OCOCH2CH3), 1.12 (t, 400-OCOCH2CH3),

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
10145
1.27 (m, 8-H), 1.34 (s, 300-CH3), 1.61 (dd, 200-Hax), 1.94 (s, 300-
4.1.17. Preparation of 39
OCOCH3), 2.47 (s, 30-N(CH3)2), 2.55 (t, C6H5(CH2)4), 2.72 (dd, 2-H),
2.83 (dd, 6-CH2), 3.10 (m, 40-H), 3.13 (m, 50-H), 3.14 (d, 200-Heq),
3.33 (dd, 20-H), 3.64 (s, 4-OCH3), 3.71 (br d, 4-H), 3.81 (br d, 5-H),
4.33 (d, 10-H), 4.45 (dq, 500-H), 4.51 (d, 400-H), 4.77 (d, 100-H), 5.35
(br dd, 3-H), 6.35 (br d, NH), 7.08–7.12 (m, C6H5), 7.18–7.23 (m,
C6H5), 9.59 (s, CHO).
Reaction of 38 with diphenylphosphoryl azide gave 39 in 72%
yield by a similar procedure to 16; ½a D26
ꢁ90° (c 0.40, CHCl3);
ꢀ
FAB-MS m/z 1040 (M+H)+; 1H NMR (CDCl3) d 0.81 (d, 8-CH3),
1.11 (s, 300-CH3), 1.12 (t, 3-OCOCH2CH3), 1.13 (d, 600-H), 1.16 (t,
400-OCOCH2CH3), 1.25 (d, 60-H), 1.50 (m, 6-CH2), 1.83 (dd, 200-
Hax), 1.98 (s, 9-OCOCH3), 2.00 (d, 200-Heq), 2.03 (s, 20-OCOCH3),
2.40 (s, 30-N(CH3)2), 2.71 (t, 30-H), 3.03 (s, CH(OCH3)2), 3.22 (s,
CH(OCH3)2), 3.31 (m, 40-H), 3.34 (m, 50-H), 3.35 (br d, 4-H), 3.38
(d, C6H4CH2), 3.56 (d, C6H4CH2), 3.64 (s, 4-OCH3), 3.78 (s, C6H4-
OCH3), 3.98 (br d, 5-H), 4.36 (dq, 500-H), 4.50 (dd, CH(OCH3)2),
4.60 (d, 400-H), 4.73 (d, 10-H), 4.86 (br d, 9-H), 4.98 (dd, 20-H),
5.04 (br dd, 3-H), 5.06 (d, 100-H), 6.81 (d, C6H4), 6.96 (br d, NH),
7.18 (d, C6H4).
4.1.14. Synthesis of 36
Compound 348 (10.0 g, 9.88 mmol) was dissolved in benzene
(300 ml), and sodium carbonate (8.38 g, 79.1 mmol) was added.
Lead tetraacetate (11.0 g, 24.8 mmol) was added as three portions
with intervals of 5 min. The reaction mixture was stirred at room
temperature for 30 min, and then insoluble matter was removed
by filtration through a Celite by using ethyl acetate (260 ml).
After the filtrate was concentrated to about 80 ml, acetonitrile
(100 ml) was added to the mixture. The resulting solution was
concentrated to about 80 ml. The same substitution and concen-
tration procedures were further repeated twice to obtain about
80 ml of a solution containing 35. Without purification of 35, ace-
tonitrile (300 ml) and 1, 8-diazabicyclo[5.4.0]-7-undecene (2.2 ml,
14.7 mmol) were added to this solution, and the mixture was stir-
red at room temperature for 5 h. The reaction mixture was con-
centrated, and the resulting residue was purified by silica gel
column chromatography (chloroform/methanol (30:1 to 20:1))
4.1.18. Synthesis of 40
Compound 39 (300 mg, 0.288 mmol) was dissolved in 1, 4-diox-
ane (12 ml), and 10% Pd/C (75 mg) was added. The reaction vessel
was purged with hydrogen, and the reaction mixture was stirred at
room temperature for 24 h. After the catalyst was removed by fil-
tration, the filtrate was washed with ethyl acetate, and concen-
trated. The resulting residue was purified by preparative TLC
(chloroform/methanol (10:1)) to obtain 241 mg of 40 (91%) as a
colorless solid; FAB-MS m/z 920 (M+H)+; 1H NMR (CDCl3) d 0.90
(d, 8-CH3), 1.10 (s, 300-CH3), 1.12 (t, 3-OCOCH2CH3), 1.13 (d, 600-
H), 1.16 (t, 400-OCOCH2CH3), 1.25 (d, 60-H), 1.50 (m, 6-CH2), 1.83
(dd, 200-Hax), 2.01 (d, 200-Heq), 2.04 (s, 9-OCOCH3), 2.08 (s, 20-
OCOCH3), 2.40 (s, 30-N(CH3)2), 2.72 (t, 30-H), 3.12 (s, CH(OCH3)2),
3.23 (s, CH(OCH3)2), 3.29 (dd, 4-H), 3.30 (m, 40-H), 3.30 (m, 50-H),
3.57 (s, 4-OCH3), 3.92 (br d, 5-H), 4.36 (dq, 500-H), 4.49 (dd,
CH(OCH3)2), 4.60 (d, 400-H), 4.69 (d, 10-H), 4.98 (dd, 20-H), 5.00 (br
dd, 3-H), 5.05 (d, 100-H), 7.92 (br d, NH).
to obtain 6.07 g (70%) of 36 as a colorless solid; ½a D25
ꢁ53° (c
ꢀ
0.56, CHCl3); FAB-MS m/z 880 (M+H)+; 1H NMR (CDCl3) d 0.95
(d, 8-CH3), 1.04 (s, 300-CH3), 1.04 (t, 3-OCOCH2CH3), 1.05 (d, 600-
H), 1.10 (t, 400-OCOCH2CH3), 1.19 (d, 60-H), 1.43 (m, 6-CH2), 1.56
(m, 7-H), 1.77 (dd, 200-Hax), 1.94 (d, 200-Heq), 1.99 (s, 20-OCOCH3),
2.11 (s, 9-OCOCH3), 2.33 (s, 30-N(CH3)2), 2.58 (dd, 2-H), 2.65 (t, 30-
H), 2.72 (dd, 2-H), 3.09 (s, CH(OCH3)2), 3.18 (s, CH(OCH3)2), 3.26
(t, 40-H), 3.26 (t, 50-H), 3.42 (br d, 4-H), 3.46 (s, 4-OCH3), 3.76
(br d, 5-H), 4.31 (dq, 500-H), 4.37 (dd, CH(OCH3)2), 4.54 (d, 400-
H), 4.62 (d, 10-H), 4.80 (br d, 9-H), 4.91 (dd, 20-H), 4.99 (d, 100-
H), 5.17 (br dd, 3-H), 9.48 (s, 10-H).
4.1.19. Synthesis of 41
Compound 40 (241 mg, 0.262 mmol) was dissolved in ethanol
(12 ml),
and
3-(quinolin-4-yl)propionaldehyde
(58.2 mg,
0.314 mmol) and acetic acid (0.075 ml, 1.31 mmol) were added un-
der ice cooling. After the reaction mixture was stirred at the same
temperature for 30 min, sodium cyanoborohydride (49.4 mg,
0.786 mmol) was added under ice cooling. The reaction mixture
was further stirred at room temperature for 3.5 h. The reaction mix-
ture was diluted with ethyl acetate, successively washed with satu-
rated aqueous sodium bicarbonate, and saturated brine. The organic
layer was dried over anhydrous sodium sulfate and concentrated.
The resulting residue was purified by preparative TLC (chloroform/
methanol (10:1)) to obtain 187 mg of 41 (66%) as a colorless solid;
4.1.15. Preparation of 37
Reaction of 36 with 3-(4-methoxybenzylamino)propylazide
gave 37 in 79% yield by a similar procedure to 4; ½a D23
ꢁ56° (c
ꢀ
0.30, CHCl3); FAB-MS m/z 1084 (M+H)+; 1H NMR (CDCl3) d 0.84
(d, 8-CH3), 1.11 (s, 300-CH3), 1.12 (t, 3-OCOCH2CH3), 1.14 (d, 600-
H), 1.16 (t, 400-OCOCH2CH3), 1.25 (d, 60-H), 1.47 (m, 6-CH2), 1.62
(m, 7-H), 1.83 (dd, 200-Hax), 1.86 (m,(CH2)3N3), 2.01 (d, 200-Heq),
2.01 (s, 9-OCOCH3), 2.04 (s, 20-OCOCH3), 2.39 (s, 30-N(CH3)2), 2.70
(m, (CH2)3N3), 3.19 (s, CH(OCH3)2), 3.25 (s, CH(OCH3)2), 3.30 (m,
40-H), 3.33 (m, 50-H), 3.47 (br d, 4-H), 3.49 (s, 4-OCH3), 3.78 (s,
C6H4-OCH3), 3.79 (s, C6H4CH2), 3.87 (br d, 5-H), 4.37 (dq, 500-H),
4.52 (dd, CH(OCH3)2), 4.60 (d, 400-H), 4.71 (d, 10-H), 4.97 (dd, 20-
H), 5.05 (d, 100-H), 5.13 (br d, 9-H), 5.14 (br dd, 3-H), 6.86 (d,
C6H4), 7.29 (d, C6H4).
½
a 2D6
ꢀ
ꢁ81° (c 0.22, CHCl3); FAB-MS m/z 1089 (M+H)+; 1H NMR (CDCl3)
d 0.90 (d, 8-CH3), 1.11 (t, 3-OCOCH2CH3), 1.11 (s, 300-CH3), 1.13 (d, 600-
H), 1.17 (t, 400-OCOCH2CH3), 1.26 (d, 60-H), 1.54 (m, 6-CH2), 1.83 (dd,
200-Hax), 1.92 (s, 9-OCOCH3), 2.01 (d, 200-Heq), 2.04 (s, 20-OCOCH3),
2.40 (s, 30-N(CH3)2), 2.72 (t, 30-H), 3.03 (s, CH(OCH3)2), 3.23 (s,
CH(OCH3)2), 3.32 (m, 40-H), 3.35 (m, 50-H), 3.39 (br d, 4-H), 3.66 (s,
4-OCH3), 3.99 (br d, 5-H), 4.37 (dq, 500-H), 4.51 (dd, CH(OCH3)2),
4.61 (d, 400-H), 4.74 (d, 10-H), 4.85 (br d, 9-H), 4.99 (dd, 20-H), 5.02
(br dd, 3-H), 5.06 (d, 100-H), 6.97 (br d, NH), 7.24 (d, quinoline), 7.55
(ddd, quinoline), 7.69 (ddd, quinoline), 8.04 (dd, quinoline), 8.10
(dd, quinoline), 8.79 (d, quinoline).
4.1.16. Preparation of 38
Reaction of 37 with triphenylphosphine gave 38 in 76% yield by
a similar procedure to 15; ½a D25
ꢁ64° (c 0.42, CHCl3); FAB-MS m/z
ꢀ
1058 (M+H)+; 1H NMR (CDCl3) d 0.95 (d, 8-CH3), 1.08 (t, 3-
OCOCH2CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.17 (t, 400-
OCOCH2CH3), 1.26 (d, 60-H), 1.48 (m, 6-CH2), 1.72 (m, 7-H), 1.83
(dd, 200-Hax), 2.02 (d, 200-Heq), 2.06 (s, 9-OCOCH3), 2.21 (s, 20-
OCOCH3), 2.40 (s, 30-N(CH3)2), 2.71 (m, (CH2)3NH2), 3.08 (s,
CH(OCH3)2), 3.10 (br d, 4-H), 3.24 (s, CH(OCH3)2), 3.32 (m, 40-H),
3.35 (m, 50-H), 3.64 (s, 4-OCH3), 3.69 (d, C6H4CH2), 3.78 (s, C6H4-
OCH3), 3.88 (d, C6H4CH2), 4.00 (br d, 5-H), 4.38 (dq, 500-H), 4.49
(dd, CH(OCH3)2), 4.61 (d, 400-H), 4.81 (d, 10-H), 5.01 (dd, 20-H),
5.07 (d, 100-H), 5.27 (br dd, 3-H), 5.44 (br d, 9-H), 6.82 (d, C6H4),
7.03 (d, C6H4).
4.1.20. Synthesis of 42
Compound 41 (90.0 mg, 0.0826 mmol) was dissolved in metha-
nol (6.3 ml), and the reaction mixture was heated at 50 °C for
150 h. The reaction mixture was concentrated, and the resulting
residue was purified by preparative TLC (chloroform/methanol/
aqueous ammonia (10:1:0.1)) to obtain 69.0 mg of 42 (83%) as a
color less solid; ½a D21
ꢁ53° (c 0.50, CHCl3); FAB-MS m/z 1005
ꢀ

10146
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
(M+H)+; 1H NMR (CDCl3) d 0.88 (d, 8-CH3), 1.11 (s, 300-CH3), 1.12 (t,
3-OCOCH2CH3), 1.12 (d, 600-H), 1.17 (t, 400-OCOCH2CH3), 1.26 (d, 60-
H), 1.64 (m, 6-CH2), 1.83 (dd, 200-Hax), 2.00 (d, 200-Heq), 2.50 (s, 30-
N(CH3)2), 2.78 (dd, 2-H), 3.10 (s, CH(OCH3)2), 3.25 (s, CH(OCH3)2),
3.32 (m, 40-H), 3.32 (m, 50-H), 3.46 (br d, 9-H), 3.57 (dd, 20-H),
3.59 (br d, 4-H), 3.75 (s, 4-OCH3), 3.98 (br d, 5-H), 4.45 (dq, 500-
H), 4.48 (dd, CH(OCH3)2), 4.49 (d, 10-H), 4.61 (d, 400-H), 4.90 (br
dd, 3-H), 5.07 (d, 100-H), 6.48 (br d, NH), 7.23 (d, quinoline), 7.55
(ddd, quinoline), 7.70 (ddd, quinoline), 8.02 (dd, quinoline), 8.10
(dd, quinoline), 8.80 (d, quinoline).
60-CH3), 1.38 (m, 6-CH2), 1.61 (m, 8-H), 1.77 (dd, 200-Hax), 1.95
(d, 200-Heq), 2.19 and 2.23 (each s, NCH3), 2.34 (s, 30-N(CH3)2),
3.06 (s, CH(OCH3)2), 3.18 and 3.18 (each s, CH(OCH3)2), 3.27 (m,
40-H), 3.27 (m, 50-H), 3.43 and 3.59 (each br d, 4-H), 3.53 and
3.56 (each s, 4-OCH3), 3.81 (br d, 5-H), 4.31 (dq, 500-H), 4.41 (m,
CH(OCH3)2), 4.54 (d, 400-H), 4.72 and 4.75 (each d, 10-H), 4.93 (dd,
20-H), 5.00 (d, 100-H), 5.03 (m, CH2@CH), 5.58 (m, CH2@CH).
4.1.24. Preparation of 48 and 49
Reaction of 47 with diphenylphosphoryl azide gave 48 in 38%
yield and 49 in 35% yield, respectively, by a similar procedure to
16. Total yield of this reaction was 73%. Compound 48; Less polar;
Rf value = 0.60, chloroform/methanol/aqueous. NH4OH (10:1:0.1);
4.1.21. Preparation of 43 and 44
Reaction of 42 with difluoroacetic acid gave 43 in 45% yield and
44 in 24% yield by a similar procedure to 12. Total yield of this
½
a 2D1
ꢀ
ꢁ57° (c 0.52, CHCl3); FAB-MS m/z 974 (M+H)+; 1H NMR
(CDCl3) d 0.81 (d, 8-CH3), 1.05 (s, 300-CH3), 1.05 (d, 600-H), 1.06 (t,
3-OCOCH2CH3), 1.10 (t, 400-OCOCH2CH3), 1.20 (d, 60-H), 1.50 (br
dd, 6-CH2), 1.57 (m, 8-H), 1.77 (dd, 200-Hax), 1.95 (d, 200-Heq),
1.95 (s, 9-OCOCH3), 1.99 (s, 20-OCOCH3), 2.19 (s, NCH3), 2.34 (s,
30-N(CH3)2), 2.65 (t, 30-H), 2.69 (dd, 2-H), 2.99 (s, CH(OCH3)2),
3.17 (s, CH(OCH3)2), 3.26 (t, 50-H), 3.39 (br d, 4-H), 3.65 (s, 4-
OCH3), 3.94 (br d, 5-H), 3.99 (m, 14-H), 4.30 (dq, 500-H), 4.49 (dd,
CH(OCH3)2), 4.55 (d, 400-H), 4.69 (d, 10-H), 4.84 (br dd, 3-H), 4.93
(dd, 20-H), 4.99 (m, CH2@CH), 5.00 (d, 100-H), 5.66 (ddt, CH2@CH),
6.45 (br d, NH). Compound 49: polar; Rf value = 0.49, chloroform/
reaction was 69%. Compound 43: ½a D21
ꢁ78° (c 0.50, CHCl3); FAB-
ꢀ
MS m/z 959 (M+H)+; HRMS: Calcd for C50H78N4O14: 959.5593.
Found: 959.5581 (M+H)+; 1H NMR (CDCl3) d 0.89 (d, 8-CH3), 1.10
(s, 300-CH3), 1.12 (d, 600-H), 1.16 (t, 3-OCOCH2CH3), 1.16 (t, 400-
OCOCH2CH3), 1.18 (d, 60-H), 1.49 (br d, 8-H), 1.82 (dd, 200-Hax),
1.91 (m, quinoline-(CH2)3), 2.00 (d, 200-Heq), 2.50 (s, 30-N(CH3)2),
2.64 (m, quinoline-(CH2)3), 2.97 (br dd, 6-CH2), 3.08 (m, quino-
line-(CH2)3), 3.27 (m, 40-H), 3.28 (m, 50-H), 3.48 (br d, 9-H), 3.52
(dd, 20-H), 3.64 (dd, 4-H), 3.73 (s, 4-OCH3), 3.91 (br d, 5-H), 4.44
(d, 10-H), 4.45 (dq, 500-H), 4.61 (d, 400-H), 4.97 (br dd, 3-H), 5.06
(d, 100-H), 6.63 (br d, NH), 7.23 (d, quinoline), 7.55 (ddd, quinoline),
7.69 (ddd, quinoline), 8.01 (dd, quinoline), 8.10 (dd, quinoline),
methanol/aqueous NH4OH (10:1:0.1); ½a D24
ꢁ53° (c 0.40, CHCl3);
ꢀ
FAB-MS m/z 974 (M+H)+; 1H NMR (CDCl3) d 0.85 (d, 8-CH3), 1.05
(s, 300-CH3), 1.06 (d, 600-H), 1.07 (t, 3-OCOCH2CH3), 1.10 (t, 400-
OCOCH2CH3), 1.20 (d, 60-H), 1.43 (br dd, 6-CH2), 1.77 (dd, 200-
Hax), 1.95 (d, 200-Heq), 1.95 (s, 9-OCOCH3), 1.95 (s, 20-OCOCH3),
2.10 (dd, 10-H), 2.19 (s, NCH3), 2.34 (s, 30-N(CH3)2), 2.65 (t, 30-H),
3.06 (s, CH(OCH3)2), 3.06 (t, 40-H), 3.18 (s, CH(OCH3)2), 3.27 (br d,
4-H), 3.29 (dq, 50-H), 3.49 (s, 4-OCH3), 3.87 (br d, 5-H), 4.31 (dq,
500-H), 4.47 (m, CH(OCH3)2), 4.55 (d, 400-H), 4.67 (d, 10-H), 4.76
(m, 9-H), 4.94 (dd, 20-H), 5.00 (d, 100-H), 5.68 (ddt, CH2@CH).
8.80 (d, quinoline), 9.64 (s, CHO). Compound 44: ½a D22
ꢁ48° (c
ꢀ
0.35, CHCl3); FAB-MS m/z 759 (M+H)+; HRMS: Calcd for
C40H62N4O10: 747.4431. Found: 747.4433 (M+H)+; 1H NMR (CDCl3)
d 0.89 (d, 8-CH3), 1.16 (t, 3-OCOCH2CH3), 1.23 (d, 60-H), 1.50 (br d,
8-H), 1.92 (m, quinoline-(CH2)3), 2.51 (s, 30-N(CH3)2), 2.63 (m,
quinoline-(CH2)3), 3.02 (br dd, 6-CH2), 3.08 (m, quinoline-(CH2)3),
3.29 (m, 50-H), 3.47 (br d, 9-H), 3.51 (dd, 20-H), 3.63 (dd, 4-H),
3.74 (s, 4-OCH3), 3.92 (br d, 5-H), 24.46 (d, 10-H), 4.97 (br dd, 3-
H), 6.64 (br d, NH), 7.23 (d, quinoline), 7.55 (ddd, quinoline), 7.70
(ddd, quinoline), 8.01 (dd, quinoline), 8.10 (dd, quinoline), 8.79
(d, quinoline), 9.66 (s, CHO).
4.1.25. Synthesis of 50
Compound 48 (338 mg, 0.347 mmol) was dissolved in acetoni-
trile (20 ml) under argon atmosphere, and palladium (II) acetate
(16.6 mg,
0.0739 mmol),
tri-o-tolylphosphine
(44.0 mg,
4.1.22. Preparation of 46
Reaction of 36 with N-(3-azido-5-hexenyl)-N-methylamine24
gave 46 as an about 1:1 mixture of diastereoisomers at the C-14
0.145 mmol), 4-bromoquinoline (165 mg, 0.793 mmol), and trieth-
ylamine (0.098 ml, 0.730 mmol) were added. The reaction mixture
was stirred at 80 °C for 16 h. Then, the reaction mixture was di-
luted with ethyl acetate, and washed with 8% aqueous sodium
hydrogencarbonate. After the aqueous layer was extracted twice
with ethyl acetate, and the organic layers were combined, and
washed with 25% brine. The organic layer was dried over anhy-
drous sodium sulfate and concentrated. The resulting residue
was purified by silica gel column chromatography (chloroform/
methanol (50:1)), and further purified by preparative TLC (chloro-
form/methanol/aqueous ammonia (20:1:0.1)) to obtain 181 mg of
50 (47%) as a colorless solid accompanied with 28.0 mg (7%) of 9,
20-di-O-acetyl dimethyacetal of 58 as a colorless solid. Total yield
position in 54% yield by a similar procedure to 14; ½a D24
ꢁ54° (c
ꢀ
0.84, CHCl3); FAB-MS m/z 1018 (M+H)+; 1H NMR (CDCl3) d 0.81
(d, 8-CH3), 1.04 (s, 300-CH3), 1.05 (d, 600-H), 1.06 (t, 3-OCOCH2CH3),
1.10 (t, 400-OCOCH2CH3), 1.19 (d, 60-CH3), 1.26 (m, 7-H), 1.47 (m, 6-
CH2), 1.76 (dd, 200-Hax), 1.94 (d, 200-Heq), 2.33 (s, 30-N(CH3)2), 2.42
(s, NCH3), 2.74 (br t, 12-H), 3.14 (s, CH(OCH3)2), 3.19 (s,
CH(OCH3)2), 3.26 (m, 40-H), 3.26 (m, 50-H), 3.41 (br d, 4-H), 3.46
and 3.48 (each s, 4-OCH3), 3.81 (br d, 5-H), 4.30 (dq, 500-H), 4.47
(dd, CH(OCH3)2), 4.54 (d, 400-H), 4.66 (d, 10-H), 4.92 (dd, 20-H),
4.99 (d, 100-H), 5.06 (m, 3-H), 5.09 (m, CH2@CH), 5.73 (ddt,
CH2@CH).
of this Heck reaction was 54%. Compound 50; ½a D20
ꢁ49° (c 0.78,
ꢀ
CHCl3); FAB-MS m/z 1101 (M+H)+; 1H NMR (300 MHz, CDCl3) d
0.81 (d, 8-CH3), 1.03 (s, 300-CH3), 1.03 (t, 3-OCOCH2CH3), 1.04 (d,
600-H), 1.08 (t, 400-OCOCH2CH3), 1.18 (d, 60-H), 1.24 (m, 7-H), 1.48
(br dd, 6-CH2), 1.57 (m, 8-H), 1.75 (dd, 200-Hax), 1.92 (d, 200-Heq),
1.94 (s, 9-OCOCH3), 1.97 (s, 20-OCOCH3), 2.21 (s, NCH3), 2.32 (s,
30-N(CH3)2), 2.64 (t, 30-H), 2.98 (s, CH(OCH3)2), 3.15 (s, CH(OCH3)2),
3.24 (m, 40-H), 3.27 (m, 50-H), 3.34 (br d, 4-H), 3.62 (s, 4-OCH3),
3.93 (br d, 5-H), 4.14 (m, 14-H), 4.29 (dq, 500-H), 4.47 (dd,
CH(OCH3)2), 4.57 (d, 400-H), 4.67 (d, 10-H), 4.83 (m, 9-H), 4.85 (br
dd, 3-H), 4.91 (dd, 20-H), 4.98 (d, 100-H), 6.32 (dt, J = 15.4, 7.4 Hz,
quinoline-CH@CH), 6.80 (br d, NH), 7.05 (d, J = 15.4 Hz, quino-
line-CH), 7.33 (d, quinoline), 7.45 (ddd, quinoline), 7.61 (ddd, quin-
oline), 8.00 (br d, quinoline), 8.00 (br d, quinoline), 8.74 (d,
4.1.23. Synthesis of 47
Compound 46 (1.06 g, 1.04 mmol) was dissolved in acetonitrile
(50 ml) and water (5.0 ml), and a 0.52 M solution of trimethylphos-
phine in toluene (6.0 ml, 3.12 mmol) was added. The reaction mix-
ture was stirred at 80 °C for 6.5 h. The reaction mixture was
concentrated, and the resulting residue was purified by silica gel
column chromatography (chloroform/methanol (10:1 to 5:1)) to
obtain 548 mg of compound 47 (53%) as a colorless solid. It was
an about 1:1 mixture of diastereoisomers at the C-14 position;
½
a 2D0
ꢀ
ꢁ49° (c 0.86, CHCl3); FAB-MS m/z 992 (M+H)+; 1H NMR
(CDCl3) d 0.84 (d, 8-CH3), 1.02 and 1.03 (each t, 3-OCOCH2CH3),
1.05 (s, 300-CH3), 1.06 (d, 600-H), 1.10 (t, 400-OCOCH2CH3), 1.19 (d,

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
10147
quinoline). 9,20-Di-O-acetyl dimethyacetal of 58; FAB-MS m/z 1101
(M+H)+; 1H NMR (CDCl3) d 0.79 (d, 8-CH3), 1.04 (s, 300-CH3), 1.05 (d,
600-H), 1.05 (t, 3-OCOCH2CH3), 1.10 (t, 400-OCOCH2CH3), 1.19 (d, 60-
H), 1.46 (br dd, 6-CH2), 1.59 (m, 8-H), 1.70 (br dd, 6-CH2), 1.77 (dd,
200-Hax), 1.93 (s, 9-OCOCH3), 1.97 (s, 20-OCOCH3), 2.15 (s, NCH3),
2.33 (s, 30-N(CH3)2), 2.65 (t, 30-H), 2.69 (dd, 2-H), 2.99 (s,
CH(OCH3)2), 3.16 (s, CH(OCH3)2), 3.22 (m, 40-H), 3.25 (m, 50-H),
3.32 (br d, 4-H), 3.61 (s, 4-OCH3), 3.75 (br d, quinoline-CH2), 3.92
(br d, 5-H), 4.30 (dq, 500-H), 4.48 (dd, CH(OCH3)2), 4.54 (d, 400-H),
4.68 (d, 10-H), 4.80 (br d, 9-H), 4.85 (br d, 3-H), 4.92 (dd, 20-H),
5.00 (d, 100-H), 5.42 (dd, J = 15.7, 5.5 Hz, 14-CH), 5.77 (ddd,
J = 15.7, 5.8, 1.2 Hz, 14-CH@CH), 6.98 (br d, NH), 7.16 (d, quinoline),
7.48 (ddd, quinoline), 7.63 (ddd, quinoline), 7.91 (dd, quinoline),
8.04 (dd, quinoline), 8.75 (d, quinoline).
NCH3), 2.42 (s, 30-N(CH3)2), 2.71 (dd, 2-H), 3.12 (s, CH(OCH3)2),
3.20 (s, CH(OCH3)2), 3.21 (m, 40-H), 3.24 (m, 50-H), 3.37 (br d, 4-
H), 3.48 (dd, 20-H), 3.53 (s, 4-OCH3), 3.56 (br d, 9-H), 3.81 (br d,
5-H), 3.96 (m, 14-H), 4.34 (d, 10-H), 4.39 (m, 500-H), 4.55 (d, 400-
H), 5.00 (d, 100-H), 5.14 (br dd, 3-H), 6.35 (dt, CH@CH), 7.07 (d, quin-
oline-CH), 7.33 (d, quinoline), 7.48 (ddd, quinoline), 7.63 (ddd,
quinoline), 8.00 (br d, quinoline), 8.02 (br d, quinoline), 8.76 (d,
quinoline).
4.1.29. Preparation of 54 and 56
Reaction of 52 with difluoroacetic acid gave 54 in 40% yield and
56 in 37% yield by a similar procedure to 12. Total yield of this
reaction was 77%. Compound 54; ½a D20
ꢁ44° (c 0.78, CHCl3); FAB-
ꢀ
MS m/z 971 (M+H)+; HRMS: Calcd for C51H78N4O14: 971.5593.
Found: 971.5587 (M+H)+; 1H NMR (CDCl3) d 0.88 (d, 8-CH3), 1.04
(s, 300-CH3), 1.06 (d, 600-H), 1.08 (t, 3-OCOCH2CH3), 1.11 (t, 400-
OCOCH2CH3), 1.13 (d, 60-H), 1.28 (br t, 8-H), 1.54 (br dd, 7-H),
1.76 (dd, 200-Hax), 1.93 (d, 200-Heq), 2.20 (s, NCH3), 2.44 (s, 30-
N(CH3)2), 2.78 (dd, 2-H), 2.90 (dd, 6-CH2), 3.21 (m, 40-H), 3.21 (m,
50-H), 3.38 (br dd, 9-H), 3.48 (dd, 20-H), 3.68 (s, 4-OCH3), 3.76 (br
d, 4-H), 3.82 (br d, 5-H), 4.26 (m, 14-H), 4.34 (d, 10-H), 4.39 (dq,
500-H), 4.55 (d, 400-H), 4.95 (br d, 3-H), 4.99 (d, 100-H), 6.28 (br d,
NH), 6.34 (dt, CH@CH), 7.08 (d, quinoline-CH), 7.35 (d, quinoline),
7.47 (ddd, quinoline), 7.63 (ddd, quinoline), 8.00 (br d, quinoline),
8.03 (br d, quinoline), 8.76 (d, quinoline), 9.59 (s, CHO).
4.1.26. Preparation of 51
Reaction of 49 with 4-bromoquinoline gave 51 in 52% yield and
9,20-di-O-acetyl dimethyacetal of 59 in 11% yield by a similar proce-
dure to 50. Total yield of this Heck reaction was 63%. Compound 51;
½
a 2D2
ꢀ
ꢁ46° (c 0.89, CHCl3); FAB-MS m/z 1101 (M+H)+; 1H NMR (CDCl3)
d 0.84 (d, 8-CH3), 1.04 (s, 300-CH3), 1.05 (d, 600-H), 1.09 (t, 3-
OCOCH2CH3), 1.10 (t, 400-OCOCH2CH3), 1.20 (d, 60-H), 1.43 (br dd,
6-CH2), 1.63 (m, 8-H), 1.76 (dd, 200-Hax), 1.89 (d, 200-Heq), 1.95 (s,
9-OCOCH3), 1.95 (s, 20-OCOCH3), 2.20 (s, NCH3), 2.32 (s, 30-
N(CH3)2), 2.64 (t, 30-H), 3.05 (s, CH(OCH3)2), 3.17 (s, CH(OCH3)2),
3.49 (s, 4-OCH3), 3.87 (br d, 5-H), 4.30 (dq, 500-H), 4.45 (m,
CH(OCH3)2), 4.54 (d, 400-H), 4.65 (d, 10-H), 4.77 (m, 9-H), 4.93 (dd,
20-H), 4.99 (d, 100-H), 5.03 (br dd, 3-H), 6.35 (dt, J = 15.7, 7.4 Hz,
CH@CH), 7.08 (d, J = 15.7 Hz, quinoline-CH), 7.34 (d, quinoline),
7.48 (ddd, quinoline), 7.63 (ddd, quinoline), 8.01 (br d, quinoline),
8.01 (br d, quinoline), 8.70 (d, quinoline). 9,20-Di-O-acetyl dimethyl-
Compound 56: ½a 2D1
ꢀ
ꢁ8.7° (c 0.57, CHCl3); FAB-MS m/z 771
(M+H)+; HRMS: Calcd for C41H62N4O10
:
771.4544. Found:
771.4529 (M+H)+; 1H NMR (CDCl3) d0.88 (d, 8-CH3), 1.08 (t, 3-
OCOCH2CH3), 1.17 (d, 60-H), 1.30 (br t, 8-H), 1.45 (m, 13-H), 1.53
(br dd, 7-H), 1.89 (m, 6-H), 1.92 (m, 13-H), 2.22 (s, NCH3), 2.46
(s, 30-N(CH3)2), 2.78 (dd, 2-H), 2.92 (br dd, 6-CH2), 2.97 (t, 40-H),
3.22 (dq, 50-H), 3.40 (br dd, 9-H), 3.47 (dd, 20-H), 3.69 (s, 4-
OCH3), 3.76 (br d, 4-H), 3.83 (br d, 5-H), 4.26 (m, 14-H), 4.35 (d,
10-H), 4.95 (br d, 3-H), 6.34 (dt, CH@CH), 7.18 (d, quinoline-CH),
7.35 (d, quinoline), 7.48 (br dd, quinoline), 7.64 (br dd, quinoline),
8.00 (br d, quinoline), 8.03 (br d, quinoline), 8.76 (d, quinoline),
9.61 (s, CHO).
acetal of 59; ½a 2D0
ꢀ
ꢁ43° (c 0.64, CHCl3); FAB-MS m/z 1101 (M+H)+; 1H
NMR (CDCl3) d 0.75 (d, 8-CH3), 1.04 (d, 600-H), 1.04 (s, 300-CH3), 1.06 (t,
3-OCOCH2CH3), 1.10 (t, 400-OCOCH2CH3), 1.19 (d, 60-H), 1.38 (br dd,
6-CH2), 1.62 (m, 8-H), 1.76 (dd, 200-Hax), 1.93 (d, 200-Heq), 1.93 (s,
9-OCOCH3), 1.93 (s, 20-OCOCH3), 2.14 (s, NCH3), 2.29 (s, 30-
N(CH3)2), 2.62 (t, 30-H), 3.04 (s, CH(OCH3)2), 3.16 (s, CH(OCH3)2),
3.23 (m, 40-H), 3.26 (m, 50-H), 3.44 (s, 4-OCH3), 3.74 (br d, quino-
line-CH2), 3.87 (br d, 5-H), 4.29 (dq, 500-H), 4.45 (m, CH(OCH3)2),
4.53 (d, 400-H), 4.63 (d, 10-H), 4.74 (m, 9-H), 4.90 (dd, 20-H), 4.99 (d,
100-H), 5.54 (br d, 14-CH), 5.75 (br dd, 14-CH@CH), 7.22 (d, quino-
line), 7.48 (br dd, quinoline), 7.63 (br dd, quinoline), 7.91 (br d, quin-
oline), 8.03 (br d, quinoline), 8.12 (br d, NH), 8.74 (d, quinoline).
4.1.30. Preparation of 55 and 57
Reaction of 53 with difluoroacetic acid gave 55 in 49% yield
and 57 in 38% yield by a similar procedure to 12. Total yield of
this reaction was 87%. Compound 55: ½a D20
ꢁ49° (c 0.92, CHCl3);
ꢀ
FAB-MS m/z 971 (M+H)+; HRMS: Calcd for C51H78N4O14
:
971.5593. Found: 971.5587 (M+H)+; 1H NMR (CDCl3) d 0.85 (d,
8-CH3), 1.04 (s, 300-CH3), 1.05 (d, 600-H), 1.07 (t, 3-OCOCH2CH3),
1.10 (t, 400-OCOCH2CH3), 1.11 (d, 60-H), 1.40 (br d, 8-H), 1.76
(dd, 200-Hax), 1.80 (m, 13-H), 1.93 (d, 200-Heq), 2.36 (s, NCH3),
2.42 (s, 30-N(CH3)2), 2.75 (dd, 10-H), 2.93 (dd, 6-CH2), 3.21 (m,
40-H), 3.21 (m, 50-H), 3.43 (dd, 20-H), 3.52 (s, 4-OCH3), 3.62 (br
d, 9-H), 3.79 (br d, 5-H), 3.84 (m, 14-H), 4.34 (d, 10-H), 4.38 (dq,
500-H), 4.54 (d, 400-H), 4.99 (d, 100-H), 5.19 (br dd, 3-H), 6.36 (dt,
quinoline –CH@CH), 7.07 (d, quinoline-CH), 7.35 (d, quinoline),
7.48 (ddd, quinoline), 7.63 (ddd, quinoline), 8.00 (br d, quinoline),
8.02 (br d, quinoline), 8.76 (d, quinoline), 9.57 (s, CHO). Com-
4.1.27. Preparation of 52
Reaction of 50 with methanol gave 52 in 86% yield by a similar
procedure to 8; ½a D20
ꢁ28° (c 0.50, CHCl3); FAB-MS m/z 1017
ꢀ
(M+H)+; 1H NMR (CDCl3) d 0.87 (d, 8-CH3), 1.04 (t, 3-OCOCH2CH3),
1.04 (s, 300-CH3), 1.05 (d, 600-H), 1.10 (t, 400-OCOCH2CH3), 1.20 (d, 60-
H), 1.39 (m, 13-H), 1.56 (br dd, 6-CH2), 1.72 (br dd, 6-CH2), 1.76
(dd, 200-Hax), 1.93 (d, 200-Heq), 2.18 (s, NCH3), 2.44 (s, 30-N(CH3)2),
2.76 (dd, 2-H), 3.06 (s, CH(OCH3)2), 3.19 (s, CH(OCH3)2), 3.22 (m,
40-H), 3.22 (m, 50-H), 3.36 (br dd, 9-H), 3.53 (dd, 20-H), 3.70 (s, 4-
OCH3), 3.75 (br d, 4-H), 3.88 (br d, 5-H), 4.28 (m, 14-H), 4.37 (d,
10-H), 4.40 (dq, 500-H), 4.55 (d, 400-H), 4.82 (br d, 3-H), 5.00 (d, 100-
H), 6.15 (br d, NH), 6.34 (dt, CH@CH), 7.07 (d, quinoline-CH),
7.34 (d, quinoline), 7.45 (ddd, quinoline), 7.63 (ddd, quinoline),
7.99 (br d, quinoline), 8.02 (br d, quinoline), 8.76 (d, quinoline).
pound 57: ½a 2D1
ꢀ
ꢁ20° (c 0.56, CHCl3); FAB-MS m/z 771 (M+H)+;
HRMS: Calcd for C41H62N4O10
: 771.4544. Found: 771.4529
(M+H)+; 1H NMR (CDCl3) d 0.85 (d, 8-CH3), 0.95 (br dd, 7-H),
1.04 (s, 300-CH3), 1.07 (t, 3-OCOCH2CH3), 1.16 (d, 60-H), 1.38 (br
dd, 7-H), 1.42 (m, 8-H), 1.80 (m, 13-H), 2.35 (s, NCH3), 2.41 (s,
30-N(CH3)2), 2.76 (dd, 10-H), 2.95 (d, 6-CH2), 3.00 (t, 40-H), 3.21
(dq, 50-H), 3.40 (dd, 20-H), 3.52 (s, 4-OCH3), 3.63 (br d, 9-H),
3.81 (br d, 5-H), 3.85 (m, 14-H), 4.36 (d, 10-H), 5.19 (br dd, 3-
H), 6.36 (dt, CH@CH), 7.08 (d, quinoline-CH), 7.36 (d, quinoline),
7.49 (ddd, quinoline), 7.64 (ddd, quinoline), 7.69 (br s, NH), 8.00
(br d, quinoline), 8.03 (br d, quinoline), 8.76 (d, quinoline), 9.59
(s, CHO).
4.1.28. Preparation of 53
Reaction of 51 with methanol gave 53 in 86% yield by a similar
procedure to 8; ½a D17
ꢁ39° (c 0.69, CHCl3); FAB-MS m/z 1017
ꢀ
(M+H)+; 1H NMR (CDCl3) d 0.84 (d, 8-CH3), 0.96 (br dd, 7-H), 1.03
(t, 3-OCOCH2CH3), 1.04 (s, 300-CH3), 1.05 (d, 600-H), 1.11 (t, 400-
OCOCH2CH3), 1.20 (d, 60-H), 1.33 (br dd, 7-H), 1.51 (br dd, 6-
CH2), 1.54 (m, 8-H), 1.76 (dd, 200-Hax), 1.94 (d, 200-Heq), 2.29 (s,

10148
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
4.1.31. Preparation of 58 and 59
4.55 (d, 400-H), 4.91 (br d, 3-H), 5.00 (d, 100-H), 7.15 (d, quinoline),
7.48 (ddd, quinoline), 7.63 (ddd, quinoline), 7.94 (br d, quinoline),
8.03 (br d, quinoline), 8.73 (d, quinoline), 9.58 (s, CHO). Compound
Reaction of 9,20-di-O-acetyl dimethyacetal of 58 and 9,20-di-O-
acetyl dimethyacetal of 59 with methanol gave dimethyacetal of
58 in 65% yield and dimethyacetal of 59 in 55% yield, respectively,
by a similar procedure to 8. Then, these compounds with difluoro-
acetic acid gave 58 in 38% yield and 59 in 55% yield, respectively,
61: ½a 2D6
ꢀ
ꢁ21° (c 0.44, CHCl3); FAB-MS m/z 773 (M+H)+; HRMS:
Calcd for C41H64N4O10: 773.4701. Found: 773.4716 (M+H)+; 1H
NMR (CDCl3) d 0.87 (d, 8-CH3), 1.10 (t, 3-OCOCH2CH3), 1.18 (d,
60-H), 1.29 (br dd, 7-H), 1.35 (m, 13-H), 1.74 (m, quinoline-
CH2CH2), 1.86 (br t, 6-H), 2.20 (s, NCH3), 2.46 (s, 30-N(CH3)2), 2.79
(dd, 2-H), 2.94 (dd, 6-CH2), 2.98 (t, 40-H), 3.02 (ddd, quinoline-
CH2), 3.23 (dq, 50-H), 3.38 (br dd, 9-H), 3.47 (dd, 20-H), 3.70 (s, 4-
OCH3), 3.76 (br d, 4-H), 3.83 (br d, 5-H), 4.07 (m, 14-H), 4.36 (d,
10-H), 4.92 (br d, 3-H), 6.02 (br d, NH), 7.15 (d, quinoline), 7.48
(ddd, quinoline), 7.63 (ddd, quinoline), 7.94 (br d, quinoline),
8.04 (br d, quinoline), 8.73 (d, quinoline), 9.60 (s, CHO).
by a similar procedure to 12. 58; ½a D19
ꢁ34° (c 0.31, CHCl3); FAB-
ꢀ
MS m/z 971 (M+H)+; HRMS: Calcd for C51H78N4O14: 971.5593.
Found: 971.5587 (M+H)+; 1H NMR (CDCl3) d 0.87 (d, 8-CH3), 1.05
(s, 300-CH3), 1.06 (d, 600-H), 1.10 (t, 3-OCOCH2CH3), 1.11 (t, 400-
OCOCH2CH3), 1.13 (d, 60-H), 1.26 (br dd, 7-H), 1.39 (m, 13-H),
1.52 (br dd, 8-H), 1.77 (dd, 200-Hax), 1.94 (d, 200-Heq), 2.18 (s,
NCH3), 2.45 (s, 30-N(CH3)2), 2.79 (dd, 2-H), 2.90 (dd, 6-CH2), 3.21
(m, 40-H), 3.21 (m, 50-H), 3.38 (br dd, 9-H), 3.48 (dd, 20-H), 3.68
(s, 4-OCH3), 3.74 (br d, 4-H), 3.82 (br d, 5-H), 4.35 (d, 10-H), 4.40
(dq, 500-H), 4.55 (d, 400-H), 4.60 (m, 14-H), 4.93 (br d, 3-H), 5.00
(d, 100-H), 5.43 (dd, 14-CH), 5.80 (ddd, 14-CH@CH), 6.30 (br
d,NH), 7.16 (d, quinoline), 7.50 (ddd, quinoline), 7.65 (ddd, quino-
line), 7.92 (br d, quinoline), 8.05 (br d, quinoline), 8.77 (d, quino-
4.1.34. Preparation of dimethylacetal of 62
Hydrogenolysis of 53 gave dimethylacetal of 62 in 71% yield by
a similar procedure to dimethylacetal of 60; ½a D22
ꢁ36° (c 0.43,
ꢀ
CHCl3); FAB-MS m/z 1019 (M+H)+; 1H NMR (CDCl3) d 0.84 (d, 8-
CH3), 0.92 (br dd, 7-H), 1.04 (s, 300-CH3), 1.05 (t, 3-OCOCH2CH3),
1.05 (d, 600-H), 1.10 (t, 400-OCOCH2CH3), 1.20 (d, 60-H), 1.32 (br dd,
7-H), 1.76 (dd, 200-Hax), 1.83 (br dd, 6-CH2), 1.93 (d, 200-Heq),
2.27 (s, NCH3), 2.43 (s, 30-N(CH3)2), 2.54 (br t, 13-H), 3.01 (ddd,
quinoline-CH2), 3.12 (s, CH(OCH3)2), 3.19 (s, CH(OCH3)2), 3.21 (m,
40-H), 3.24 (m, 50-H), 3.28 (br d, 4-H), 3.51 (s, 4-OCH3), 3.79 (br d,
5-H), 3.84 (m, 14-H), 4.32 (d, 10-H), 4.37 (dd, CH(OCH3)2), 4.39
(dq, 500-H), 4.54 (d, 400-H), 5.00 (d, 100-H), 5.11 (br dd, 3-H), 6.73
(br s, NH), 7.13 (d, quinoline), 7.48 (br dd, quinoline), 7.62 (br dd,
quinoline), 7.94 (br d, quinoline), 8.02 (br d, quinoline), 8.71 (d,
quinoline).
line), 9.59 (s, CHO). Compound 59: ½a D18
ꢁ66° (c 0.39, CHCl3);
ꢀ
FAB-MS m/z 971 (M+H)+; HRMS: Calcd for C51H78N4O14
:
971.5593. Found: 971.5587 (M+H)+; 1H NMR (CDCl3) d 0.74 (d, 8-
CH3), 1.05 (s, 300-CH3), 1.06 (d, 600-H), 1.06 (t, 3-OCOCH2CH3), 1.10
(d, 60-H), 1.11 (t, 400-OCOCH2CH3), 1.30 (br dd, 8-H), 1.61 (m, 13-
H), 1.77 (dd, 200-Hax), 1.95 (d, 200-Heq), 2.14 (dd, 6-CH2), 2.28 (s,
NCH3), 2.50 (s, 30-N(CH3)2), 2.97 (dd, 6-CH2), 3.12 (br d, 4-H),
3.21 (m, 40-H), 3.21 (m, 50-H), 3.33 (s, 4-OCH3), 3.52 (dd, 20-H),
3.58 (br dd, 9-H), 4.34 (d, 10-H), 4.42 (dq, 500-H), 4.56 (d, 400-H),
5.01 (m, 3-H), 5.01 (d, 100-H), 5.29 (dd, 14-CH), 5.76 (ddd, 14-
CH@CH), 7.20 (d, quinoline), 7.50 (ddd, quinoline), 7.63 (ddd, quin-
oline), 7.93 (dd, quinoline), 8.02 (dd, quinoline), 8.22 (br d, NH),
8.73 (d, quinoline), 9.55 (s, CHO).
4.1.35. Preparation of 62 and 63
Reaction of 9,20-di-O-acetyl dimethyacetal of 62 with difluoro-
acetic acid gave 62 in 51% yield and 63 in 40% yield by a similar
procedure to 12. Total yield of this reaction was 91%. Compound
4.1.32. Synthesis of dimethylacetal of 60
Compound 52 (104 mg, 0.102 mmol) was dissolved in ethanol
(10 ml), and acetic acid (0.12 ml, 2.10 mmol) and 10% Pd/C catalyst
(52.3 mg) were added. The reaction vessel was purged with hydro-
gen, and the reaction mixture was stirred for 5 h. The reaction mix-
62; ½a 2D3
ꢀ
ꢁ43° (c 0.85, CHCl3); FAB-MS m/z 973 (M+H)+; HRMS:
Calcd for C51H80N4O14: 973.5749. Found: 973.5754 (M+H)+; 1H
NMR (CDCl3) d 0.87 (d, 8-CH3), 0.91 (br dd, 7-H), 1.04 (s, 300-CH3),
1.06 (d, 600-H), 1.08 (t, 3-OCOCH2CH3), 1.10 (t, 400-OCOCH2CH3),
1.11 (d, 60-H), 1.38 (m, 8-H), 1.48 (br dd, 13-H), 1.76 (dd, 200-
Hax), 1.94 (d, 200-Heq), 2.23 (dd, 6-CH2), 2.33 (s, NCH3), 2.45 (s,
30-N(CH3)2), 2.91 (dd, 6-CH2), 3.02 (br dd, quinoline-CH2), 3.20
(m, 40-H), 3.21 (m, 50-H), 3.43 (br d, 4-H), 3.49 (s, 4-OCH3), 3.56
(br d, 9-H), 3.71 (m, 14-H), 3.77 (br d, 5-H), 4.34 (d, 10-H), 4.39
(dq, 500-H), 4.55 (d, 400-H), 4.99 (d, 100-H), 5.15 (br dd, 3-H), 7.14
(d, quinoline), 7.26 (br s, NH), 7.48 (ddd, quinoline), 7.62 (ddd,
quinoline), 7.94 (br d, quinoline), 8.02 (br d, quinoline), 8.71 (d,
ture was filtered through
a Celite layer, and washed with
methanol. The filtrate was concentrated, and the resulting residue
was purified by silica gel column chromatography (chloroform/
methanol (25:1)) to obtain 49.2 mg of dimethylacetal of 60 (47%)
as a colorless solid; FAB-MS m/z 1019 (M+H)+; 1H NMR (CDCl3) d
0.85 (d, 8-CH3), 1.05 (d, 600-H), 1.05 (t, 3-OCOCH2CH3), 1.05 (s,
300-CH3), 1.10 (t, 400-OCOCH2CH3), 1.20 (d, 60-H), 1.76 (dd, 200-
Hax), 1.94 (d, 200-Heq), 2.45 (s, 30-N(CH3)2), 2.76 (dd, 2-H), 3.00
(m, quinoline-CH2), 3.04 (s, CH(OCH3)2), 3.18 (s, CH(OCH3)2), 3.25
(m, 40-H), 3.25 (m, 50-H), 3.51 (dd, 20-H), 3.70 (s, 4-OCH3), 3.89
(br d, 5-H), 4.02 (m, 14-H), 4.40 (d, 10-H), 4.38 (dq, 500-H), 4.55 (d,
400-H), 4.80 (br d, 3-H), 5.01 (d, 100-H), 7.14 (d, quinoline), 7.47 (br
dd, quinoline), 7.62 (br dd, quinoline), 7.93 (br d, quinoline), 8.03
(br d, quinoline), 8.72 (d, quinoline).
quinoline), 9.56 (s, CHO). Compound 63; ½a D23
ꢁ14° (c 0.53, CHCl3);
ꢀ
FAB-MS m/z 773 (M+H)+; HRMS: Calcd for C41H64N4O10: 773.4701.
Found: 773.4716 (M+H)+; 1H NMR (CDCl3) d 0.86 (d, 8-CH3), 0.93
(br dd, 7-H), 1.08 (t, 3-OCOCH2CH3), 1.16 (d, 60-H), 1.96 (br t, 6-
H), 2.31 (s, NCH3), 2.43 (s, 30-N(CH3)2), 2.96 (dd, 6-CH2), 2.96 (t,
40-H), 3.21 (dq, 50-H), 3.42 (br d, 4-H), 3.44 (dd, 20-H), 3.50 (s, 4-
OCH3), 3.57 (br d, 9-H), 3.72 (m, 14-H), 3.79 (br d, 5-H), 4.36 (d,
10-H), 5.16 (br dd, 3-H), 7.15 (d, quinoline), 7.25 (br s, NH), 7.49
(ddd, quinoline), 7.63 (ddd, quinoline), 7.94 (br d, quinoline),
8.03 (br d, quinoline), 8.72 (d, quinoline), 9.59 (s, CHO).
4.1.33. Preparation of 60 and 61
Reaction of 9, 20-di-O-acetyl dimethyacetal of 60 with difluoro-
acetic acid gave 60 in 38% yield and 61 in 40% yield by a similar
procedure to 12. Total yield of this reaction was 78%. Compound
60; ½a 2D0
ꢀ
ꢁ51° (c 0.53, CHCl3); FAB-MS m/z 973 (M+H)+; HRMS:
Calcd for C51H80N4O14: 973.5749. Found: 973.5754 (M+H)+; 1H
NMR (CDCl3) d 0.87 (d, 8-CH3), 1.05 (s, 300-CH3), 1.06 (d, 600-H),
1.07 (t, 3-OCOCH2CH3), 1.11 (t, 400-OCOCH2CH3), 1.13 (d, 60-H),
1.29 (br dd, 7-H), 1.36 (m, 13-H), 1.76 (dd, 200-Hax), 1.94 (d, 200-
Heq), 2.21 (s, NCH3), 2.44 (s, 30-N(CH3)2), 2.79 (dd, 2-H), 2.89 (dd,
6-CH2), 3.01 (ddd, quinoline-CH2), 3.20 (m, 40-H), 3.22 (m, 50-H),
3.39 (br d, 9-H), 3.48 (dd, 20-H), 3.70 (s, 4-OCH3), 3.76 (br d, 4-H),
3.82 (br d, 5-H), 4.06 (m, 14-H), 4.35 (d, 10-H), 4.40 (dq, 500-H),
4.1.36. Preparation of 9,20-di-O-acetyl dimethylacetal of 64
Reaction of 48 with 3-bromoquinoline gave 9,20-di-O-acetyl
dimethylacetal of 64 in 59% yield by a similar procedure to 50;
½
a 2D8
ꢀ
ꢁ55° (c 0.65, CHCl3); FAB-MS m/z 1101 (M+H)+; 1H NMR
(CDCl3) d 0.81 (d, 8-CH3), 1.04 (t, 3-OCOCH2CH3), 1.04 (s, 300-CH3),
1.05 (d, 600-H), 1.10 (t, 400-OCOCH2CH3), 1.19 (d, 60-H), 1.24 (br dd,
7-H), 1.36 (m, 13-H), 1.50 (br dd, 6-CH2), 1.58 (m, 8-H), 1.68 (br

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
10149
dd, 6-CH2), 1.76 (dd, 200-Hax), 1.94 (d, 200-Heq), 1.95 (s, 9-OCOCH3),
1.98 (s, 20-OCOCH3), 2.21 (s, NCH3), 2.33 (s, 30-N(CH3)2), 2.65 (t, 30-
H), 2.68 (dd, 2-H), 2.99 (s, CH(OCH3)2), 3.16 (s, CH(OCH3)2), 3.25
(m, 40-H), 3.28 (m, 50-H), 3.36 (br d, 4-H), 3.63 (s, 4-OCH3), 3.93
(br d, 5-H), 4.14 (m, 14-H), 4.30 (dq, 500-H), 4.48 (dd, CH(OCH3)2),
4.54 (d, 400-H), 4.68 (d, 10-H), 4.83 (m, 9-H), 4.85 (br d, 3-H), 4.92
(dd, 20-H), 4.99 (d, 100-H), 6.30 (dt, CH@CH), 6.50 (d, quinoline-
CH), 6.62 (br d, NH), 7.44 (ddd, quinoline), 7.57 (ddd, quinoline),
7.70 (br d, quinoline), 7.93 (d, quinoline), 7.87 (br d, quinoline),
8.86 (d, quinoline).
1.11 (d, 600-H), 1.13 (t, 400-OCOCH2CH3), 1.77 (dd, 200-Hax), 1.97
(d, 200-Heq), 2.10 (s, NCH3), 2.61 (s, 30-N(CH3)2), 2.72 (dd, 2-H),
2.81 (dd, 6-CH2), 3.23 (m, 40-H), 3.25 (m, 50-H), 3.59 (br d, 4-H),
3.72 (s, 4-OCH3), 3.91 (br d, 5-H), 3.93 (m, 14-H), 4.47 (dq, 500-
H), 4.51 (d, 10-H), 4.57 (d, 400-H), 5.03 (d, 100-H), 5.05 (m, 3-H),
6.42 (br dd, CH@CH), 6.53 (d, quinoline-CH), 7.49 (ddd, quino-
line), 7.62 (ddd, quinoline), 7.72 (br d, quinoline), 7.88 (br s, quin-
oline), 8.02 (br d, quinoline), 8.77 (br d, NH), 9.04 (br s,
quinoline), 9.53 (s, CHO).
4.1.40. Preparation of 67 and 68
4.1.37. Preparation of 64 and 65
Hydrogenolysis of dimethylacetal of 64 gave dimethylacetal of
67 in 64% yield by a similar procedure to dimethylacetal of 60.
Reaction of dimethylacetal of 67 with difluoroacetic acid gave 67
in 51% yield and 68 in 30% yield by a similar procedure to 12. Total
Reaction of 9,20-Di-O-acetyl dimethyacetal of 64 with methanol
gave dimethyacetal of 64 in 92% yield by a similar procedure to 8.
Then, dimethyacetal of 64 with difluoroacetic acid gave 64 in 43%
yield and 65 in 32% yield by a similar procedure to 12. Total yield of
yield of this reaction was 81%. Compound 67; ½a D22
ꢁ54° (c 1.0,
ꢀ
this reaction was 75%. Compound 64; ½a D23
ꢀ
ꢁ48° (c 0.83, CHCl3);
CHCl3); FAB-MS m/z 973 (M+H)+; HRMS: Calcd for C51H80N4O14
:
FAB-MS m/z 971 (M+H)+; HRMS: Calcd for C51H78N4O14
:
973.5749. Found: 973.5754 (M+H)+; 1H NMR (CDCl3) d 0.86 (d, 8-
CH3), 1.04 (s, 300-CH3), 1.06 (d, 600-H), 1.09 (t, 3-OCOCH2CH3), 1.10
(t, 400-OCOCH2CH3), 1.12 (d, 60-H), 1.28 (m, 8-H), 1.33 (m, 13-H),
1.69 (m, quinoline-CH2CH2), 1.69 (m, 6-H), 1.76 (dd, 200-Hax),
1.93 (d, 200-Heq), 2.19 (s, NCH3), 2.44 (s, 30-N(CH3)2), 2.73 (m, quin-
oline-CH2), 2.79 (dd, 2-H), 2.89 (dd, 6-CH2), 3.20 (m, 40-H), 3.21 (m,
50-H), 3.37 (br dd, 9-H), 3.48 (dd, 20-H), 3.69 (s, 4-OCH3), 3.76 (br d,
4-H), 3.82 (br d, 5-H), 4.04 (m, 14-H), 4.34 (d, 10-H), 4.39 (dq, 500-H),
4.55 (d, 400-H), 4.91 (br d, 3-H), 4.99 (d, 100-H), 6.00 (br d, NH), 7.45
(ddd, quinoline), 7.58 (ddd, quinoline), 7.69 (br d, quinoline), 7.83
(d, quinoline), 8.00 (br d, quinoline), 8.68 (d, quinoline), 9.58 (s,
971.5593. Found: 971.5591 (M+H)+; 1H NMR (CDCl3) d 0.83 (br
dd, 7-H), 0.87 (d, 8-CH3), 1.04 (s, 300-CH3), 1.05 (d, 600-H), 1.09 (t,
3-OCOCH2CH3), 1.11 (t, 400-OCOCH2CH3), 1.12 (d, 60-H), 1.29 (m,
8-H), 1.41 (m, 13-H), 1.52 (br dd, 7-H), 1.76 (dd, 200-Hax), 1.93 (d,
200-Heq), 2.21 (s, NCH3), 2.44 (s, 30-N(CH3)2), 2.78 (dd, 2-H), 2.90
(dd, 6-CH2), 3.20 (m, 40-H), 3.20 (m, 50-H), 3.38 (br dd, 9-H), 3.48
(dd, 20-H), 3.69 (s, 4-OCH3), 3.76 (br d, 4-H), 3.82 (br d, 5-H), 4.22
(m, 14-H), 4.34 (d, 10-H), 4.40 (dq, 500-H), 4.55 (d, 400-H), 4.94 (br
d, 3-H), 5.00 (d, 100-H), 6.21 (br d, NH), 6.31 (dt, CH@CH), 6.52 (d,
quinoline-CH2), 7.45 (ddd, quinoline), 7.59 (ddd, quinoline), 7.71
(br d, quinoline), 7.94 (br s, quinoline), 7.98 (br d, quinoline),
CHO). Compound 68: ½a D22
ꢀ
ꢁ21° (c 0.47, CHCl3); FAB-MS m/z 773
8.87 (d, quinoline), 9.59 (s, CHO). Compound 65; ½a D23
ꢀ
ꢁ14° (c
(M+H)+; HRMS: Calcd for C41H64N4O10
: 773.4701. Found:
0.50, CHCl3); FAB-MS m/z 771 (M+H)+; HRMS: Calcd for
C41H62N4O10: 771.4544. Found: 771.4529 (M+H)+; 1H NMR (CDCl3)
d 0.88 (d, 8-CH3), 1.09 (t, 3-OCOCH2CH3), 1.18 (d, 60-H), 1.30 (m, 8-
H), 1.43 (m, 13-H), 1.53 (br dd, 7-H), 1.85 (m, 6-H), 1.91 (m, 13-H),
2.22 (s, NCH3), 2.46 (s, 30-N(CH3)2), 2.78 (dd, 2-H), 2.95 (dd, 6-CH2),
2.98 (t, 40-H), 3.23 (dq, 50-H), 3.39 (br dd, 9-H), 3.47 (dd, 20-H), 3.69
(s, 4-OCH3), 3.77 (br d, 4-H), 3.83 (brd, 5-H), 4.22 (m, 14-H), 4.36
(d, 10-H), 4.95 (br d, 3-H), 6.22 (br d, NH), 6.32 (dt, CH@CH), 6.53
(d, quinoline-CH2), 7.45 (ddd, quinoline), 7.59 (ddd, quinoline),
7.72 (br d, quinoline), 7.95 (br s, quinoline), 7.99 (br d, quinoline),
8.87 (d, quinoline), 9.61 (s, CHO).
773.4716 (M+H)+; 1H NMR (CDCl3) d 0.87 (d, 8-CH3), 1.10 (t, 3-
OCOCH2CH3), 1.18 (d, 60-H), 1.29 (m, 8-H), 1.36 (m, 13-H), 1.70
(m, quinoline-CH2CH2), 1.78 (m, 13-H), 1.86 (br t, 6-H), 2.20 (s,
NCH3), 2.47 (s, 30-N(CH3)2), 2.75 (m, quinoline-CH2), 2.80 (dd, 2-
H), 2.94 (dd, 6-CH2), 2.98 (t, 40-H), 3.23 (dq, 50-H), 3.38 (br dd, 9-
H), 3.47 (dd, 20-H), 3.70 (s, 4-OCH3), 3.76 (br d, 4-H), 3.83 (br d,
5-H), 4.05 (m, 14-H), 4.36 (d, 10-H), 4.91 (br d, 3-H), 5.99 (br d,
NH), 7.45 (ddd, quinoline), 7.59 (ddd, quinoline), 7.70 (br d, quin-
oline), 7.84 (d, quinoline), 8.00 (br d, quinoline), 8.68 (d, quinoline),
9.60 (s, CHO).
4.1.41. Preparation of 69 and 70
4.1.38. Preparation of 9,20-di-O-acetyl dimethylacetal of 66
Reaction of 49 with 3-bromoquinoline gave 9, 20-di-O-acetyl
dimethylacetal of 66 in 42% yield by a similar procedure to 50;
Hydrogenolysis of dimethylacetal of 66 gave dimethylacetal of
69 in 85% yield by a similar procedure to dimethylacetal of 60.
Reaction of dimethylacetal of 69 with difluoroacetic acid gave
69 in 24% yield and 70 in 59% yield by a similar procedure to
½
a 1D8
ꢀ
ꢁ37° (c 0.70, CHCl3); FAB-MS m/z 1,101 (M+H)+; 1H NMR
12. Total yield of this reaction was 83%. Compound 69; ½a D16
ꢀ
(CDCl3) d 0.83 (d, 8-CH3), 1.04 (d, 600-H), 1.04 (s, 300-CH3), 1.05 (t,
3-OCOCH2CH3), 1.09 (t, 400-OCOCH2CH3), 1.20 (d, 60-H), 1.41 (br
dd, 6-CH2), 1.65 (m, 8-H), 1.76 (dd, 200-Hax), 1.93 (s, 9-OCOCH3),
1.95 (s, 20-OCOCH3), 2.18 (s, NCH3), 2.32 (s, 30-N(CH3)2), 2.65 (t,
30-H), 3.04 (s, CH(OCH3)2), 3.17 (s, CH(OCH3)2), 3.24 (m, 40-H),
3.27 (m, 50-H), 3.50 (s, 4-OCH3), 3.87 (br d, 5-H), 4.30 (dq, 500-H),
4.46 (m, CH(OCH3)2), 4.54 (d, 400-H), 4.66 (d, 10-H), 4.76 (m, 3-H),
4.94 (dd, 20-H), 4.99 (d, 100-H), 5.00 (m, 9-H), 6.32 (dt, CH@CH),
6.52 (d, quinoline-CH), 7.44 (ddd, quinoline), 7.58 (ddd, quinoline),
7.71 (br d, quinoline), 7.93 (br s, quinoline), 7.97 (br d, quinoline),
8.86 (d, quinoline).
ꢁ75° (c 0.39, CHCl3); FAB-MS m/z 973 (M+H)+; HRMS: Calcd for
C51H80N4O14
:
973.5749. Found: 973.5760 (M+H)+; 1H NMR
(CDCl3) d 0.18 (d, 8-CH3), 1.04 (s, 300-CH3), 1.06 (t, 3-OCOCH2CH3),
1.08 (d, 600-H), 1.12 (d, 60-H), 1.12 (t, 400-OCOCH2CH3), 1.78 (dd, 200-
Hax), 1.97 (d, 200-Heq), 2.89 (br d, 6-CH2), 2.55 (s, 30-N(CH3)2), 2.88
(m, quinoline-CH2), 2.93 (dd, 6-CH2), 3.26 (m, 40-H), 3.26 (m, 50-
H), 3.52 (m, 9-H), 3.69 (s, 4-OCH3), 3.79 (br d, 5-H), 4.02 (m, 14-
H), 4.49 (dq, 500-H), 4.50 (d, 10-H), 4.57 (d, 400-H), 4.88 (br d, 3-
H), 5.05 (d, 100-H), 7.48 (ddd, quinoline), 7.63 (ddd, quinoline),
7.74 (br d, quinoline), 7.87 (d, quinoline), 7.96 (br d, quinoline),
8.24 (br s, NH), 8.65 (d, quinoline), 9.54 (s, CHO). Compound 70;
a 1D7
ꢀ
ꢁ54° (c 0.77, CHCl3); FAB-MS m/z 773 (M+H)+; HRMS: Calcd
4.1.39. Preparation of 66
½
Reaction of 9,20-di-O-acetyl dimethyacetal of 66 with metha-
nol gave dimethyacetal of 66 in 80% yield by a similar procedure
to 8. Then, dimethyacetal of 66 with difluoroacetic acid gave 66 in
for C41H64N4O10: 773.4701. Found: 773.4716 (M+H)+; 1H NMR
(CDCl3) d 0.14 (d, 8-CH3), 0.31 (m, 7-H), 1.06 (t, 3-OCOCH2CH3),
1.16 (d, 60-H), 1.26 (m, 14-CH2), 1.42 (m, 13-H), 1.78 (m, 13-H),
1.93 (m, 10-H), 2.01 (br d, 6-CH2), 2.17 (br d, 10-H), 2.25 (s,
NCH3), 2.41 (t, 30-H), 2.56 (s, 30-N(CH3)2), 2.90 (br dd, quinoline-
CH2), 2.97 (dd, 6-CH2), 3.00 (t, 40-H), 3.12 (br d, 4-H), 3.27 (dq,
50-H), 3.49 (m, 9-H), 3.68 (s, 4-OCH3), 3.78 (dd, 20-H), 3.81 (br d,
41% yield by a similar procedure to 12; ½a D18
ꢁ119° (c 0.41,
ꢀ
CHCl3); FAB-MS m/z 971 (M+H)+; HRMS: Calcd for C51H78N4O14
:
971.5593. Found: 971.5587 (M+H)+; 1H NMR (CDCl3) d 0.43 (d,
8-CH3), 1.07 (s, 300-CH3), 1.09 (t, 3-OCOCH2CH3), 1.11 (d, 60-H),

10150
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
5-H), 4.03 (m, 14-H), 4.53 (d, 10-H), 4.84 (br dd, 3-H), 7.48 (ddd,
quinoline), 7.63 (ddd, quinoline), 7.74 (br d, quinoline), 7.87 (d,
quinoline), 7.94 (br d, quinoline), 8.22 (br d, NH), 8.64 (d, quino-
line), 9.55 (s, CHO).
4.1.45. Synthesis of 75 and its cis-isomer, 9,20-di-O-acetyl
dimethylacetal of 81
Compound 73 (485 mg, 0.493 mmol) and 3-bromoquinoline
(204 mg, 0.981 mmol) were dissolved in 1,4-dioxane (4.9 ml), and
tris(dibenzylideneacetone)dipalladium (0) (135 mg, 0.147 mmol)
and dicyclohexylmethylamine (0.21 ml, 0.989 mmol) were added.
The reaction vessel was purged with argon, and then a 0.174 M solu-
tion of tri-tert-butylphosphine in 1,4-dioxane(1.69 ml, 0.294 mmol)
was added to the reaction mixture. After the reaction mixture was
stirred at 50 °C for 48 h, the catalyst was removed by filtration. The
filtrate was concentrated under reduced pressure, and the resulting
residue was purified by silica gel column chromatography (ethyl
acetate/acetone (2:1) and chloroform/methanol (20:1)) to obtain
31.7 mg (5.8%) of 75 as a colorless solid and 15.3 mg (2.8%) of its
cis-isomer, 9,20-di-O-acetyl dimethylacetal of 81 as a colorless solid.
4.1.42. Preparation of 71 and 72
Reaction of 36 with 3-(methylaminomethyl)-5-hexen-1-ol26
gave 71 in 40% yield and 72 in 30% yield by a similar procedure
to 4. Total yield of this reaction was 70%. Compound 71: less polar;
Rf value = 0.34, chloroform/methanol (5:1); ½a D17
ꢁ56° (c 0.80,
ꢀ
CHCl3); FAB-MS m/z 1007 (M+H)+; 1H NMR (CDCl3) d 0.90 (d, 8-
CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.14 (t, 3-OCOCH2CH3), 1.16
(t, 400-OCOCH2CH3), 1.17 (d, 60-H), 1.83 (dd, 200-Hax), 2.00 (d, 200-
Heq), 2.03 (s, 9-OCOCH3), 2.05 (s, 20-OCOCH3), 2.39 (s, 30-
N(CH3)2), 2.48 (s, NCH3), 2.58 (dd, 10-H), 2.71 (t, 30-H), 3.16 (s,
CH(OCH3)2), 3.24 (s, CH(OCH3)2), 3.30 (m, 40-H), 3.33 (m, 50-H),
3.55 (s, 4-OCH3), 3.76 (m, 15-H), 3.86 (br d, 5-H), 4.37 (dq, 500-H),
4.50 (dd, CH(OCH3)2), 4.60 (d, 400-H), 4.73 (d, 10-H), 4.98 (dd, 20-
H), 5.03 (m, CH@CH2), 5.06 (dd, 100-H), 5.15 (m, 9-H), 5.16 (m, 3-
H), 5.70 (ddt, CH@CH2). Compound 72: polar; Rf value = 0.14, chlo-
Total yield of this Heck reaction was 8.6%. Compound 75; ½a D25
ꢁ64°
ꢀ
(c 0.35, CHCl3); FAB-MS m/z 1116 (M+H)+; 1H NMR (CDCl3) d 0.95 (d,
8-CH3), 1.02 (t, 3-OCOCH2CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.17
(t, 400-OCOCH2CH3), 1.26 (d, 60-H), 1.39 (m, 14-H), 1.83 (dd, 200-Hax),
2.00 (d, 200-Heq), 2.03 (s, 9-OCOCH3), 2.05 (s, 20-OCOCH3), 2.12 (m,
14-H), 2.28 (s, NCH3), 2.40 (s, 30-N(CH3)2), 3.12 (s, CH(OCH3)2), 3.22
(s, CH(OCH3)2), 3.52 (d, quinoline-CH2), 3.53 (s, 4-OCH3), 3.88 (d,
5-H), 4.16 (m, 15-H), 4.37 (dq, 500-H), 4.45 (dd, CH(OCH3)2), 4.61 (d,
400-H), 4.70 (d, 10-H), 5.00 (dd, 20-H), 5.06 (d, 100-H), 5.23 (m, 3-H),
5.29 (dd, J = 15.4, 8.2 Hz, 13-CH), 5.84 (dt, J = 15.4, 5.9 Hz, CH@CH),
7.51 (ddd, quinoline), 7.65 (ddd, quinoline), 7.77 (br d, quinoline),
7.96 (d, quinoline), 8.06 (br d, quinoline), 8.74 (d, quinoline). 750s
roform/methanol (5:1); ½a D17
ꢁ42° (c 1.5, CHCl3); FAB-MS m/z 1007
ꢀ
(M+H)+; 1H NMR (CDCl3) d 0.91 (d, 8-CH3), 1.11 (s, 300-CH3), 1.12 (d,
600-H), 1.13 (t, 3-OCOCH2CH3), 1.15 (t, 400-OCOCH2CH3), 1.25 (d, 60-
H), 1.83 (dd, 200-Hax), 1.94 (m, 13-H), 1.99 (d, 200-Heq), 2.00 (d, 200-
Heq), 2.03 (s, 9-OCOCH3), 2.06 (s, 20-OCOCH3), 2.40 (s, 30-N(CH3)2),
2.51 (s, NCH3), 2.71 (t, 30-H), 3.19 (s, CH(OCH3)2), 3.25 (s,
CH(OCH3)2), 3.30 (m, 40-H), 3.33 (m, 50-H), 3.54 (s, 4-OCH3), 3.56
(br d, 4-H), 3.77 (m, 15-H), 3.86 (br d, 5-H), 4.37 (dq, 500-H), 4.61
(d, 400-H), 4.72 (d, 10-H), 4.80 (dd, CH(OCH3)2), 4.98 (dd, 20-H),
5.03 (m, CH@CH2), 5.07 (d, 100-H), 5.19 (m, 9-H), 5.21 (m, 3-H),
5.71 (ddt, CH@CH2).
cis-isomer, 9,20-di-O-acetyl dimethylacetal of 81; ½a 2D4
ꢁ61° (c 0.77,
ꢀ
CHCl3); FAB: m/z 1116 (M+H)+; 1H NMR (CDCl3) d 0.96 (d, 8-CH3),
1.01 (t, 3-OCOCH2CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.17 (t, 400-
OCOCH2CH3), 1.26 (d, 60-H), 1.84 (dd, 200-Hax), 2.00 (d, 200-Heq),
2.04 (s, 9-OCOCH3), 2.06 (s, 20-OCOCH3), 2.31 (s, NCH3), 2.40 (s, 30-
N(CH3)2), 2.49 (dd, 2-H), 3.08 (s, CH(OCH3)2), 3.21 (s, CH(OCH3)2),
3.55 (s, 4-OCH3), 3.69 (d, J = 7.7 Hz, quinoline-CH2), 3.89 (d, 5-H),
4.07 (m, 15-H), 4.37 (dq, 500-H), 4.50 (m, CH(OCH3)2), 4.61 (d, 400-
H), 4.71 (d, 10-H), 5.06 (d, 100-H), 5.23 (m, 3-H), 5.31 (m, 13-CH),
5.70 (dt, J = 10.4, 7.7 Hz, CH@CH), 7.51 (ddd, quinoline), 7.65
(ddd,quinoline), 7.77 (br d, quinoline), 7.94 (d, quinoline), 8.05 (br
d, quinoline), 8.80 (d, quinoline).
4.1.43. Synthesis of 73
2-Methyl-6-nitrobenzoic anhydride27 (374 mg, 0.773 mmol)
and 4-dimethylaminopyridine (266 mg, 2.18 mmol) were dis-
solved in methylene chloride (200 ml). A solution of 71 (730 mg,
0.725 mmol) in methylene chloride (200 ml) was dropwised over
2.5 h under ice cooling, and then stirred for 2 h. Saturated aqueous
ammonium chloride was added to the reaction mixture, and ex-
tracted with chloroform. The organic layer was dried over anhy-
drous magnesium sulfate and concentrated. The resulting residue
was purified by silica gel column chromatography (diethyl ether/
acetone/aqueous ammonia (100:5:0.1)) to obtain 339 mg (63%) of
4.1.46. Preparation of 76
Reaction of 74 with 3-bromoquinoline gave 76 in 28% yield by a
similar procedure to 75; ½a D25
ꢁ34° (c 0.66, CHCl3); FAB-MS m/z
ꢀ
73 as a colorless solid; ½a D19
ꢁ70° (c 0.3, CHCl3); FAB-MS m/z 989
ꢀ
1116 (M+H)+; 1H NMR (CDCl3) d 0.93 (d, 8-CH3), 1.08 (t, 3-
OCOCH2CH3), 1.10 (s, 300-CH3), 1.11 (d, 600-H), 1.16 (t, 400-
OCOCH2CH3), 1.26 (d, 60-H), 1.83 (dd, 200-Hax), 1.95 (s, 9-OCOCH3),
1.97 (s, 20-OCOCH3), 2.27 (s, NCH3), 2.38 (s, 30-N(CH3)2), 2.70 (t, 30-
H), 3.11 (s, CH(OCH3)2), 3.23 (s, CH(OCH3)2), 3.31 (t, 40-H), 3.51 (s,
4-OCH3), 3.51 (d, J = 6.3 Hz, quinoline-CH2), 3.89 (d, 5-H), 4.22 (m,
15-H), 4.36 (dq, 500-H), 4.49 (dd, CH(OCH3)2), 4.60 (d, 400-H), 4.70 (d,
10-H), 4.98 (dd, 20-H), 5.05 (d, 100-H), 5.24 (t, 3-H), 5.48 (dd, J = 15.1,
6.0 Hz, 13-CH), 5.62 (dt, J = 15.1, 6.3 Hz, CH@CH), 7.51 (t, quino-
line), 7.65 (m, quinoline), 7.76 (d, quinoline), 7.90 (d, quinoline),
8.05 (d, quinoline), 8.73 (d, quinoline).
1
(M+H)+; H NMR (CDCl3) d 0.94 (d, 8-CH3), 1.11 (s, 300-CH3), 1.12
(d, 600-H), 1.13 (t, 3-OCOCH2CH3), 1.17 (t, 400-OCOCH2CH3), 1.26
(d, 60-H), 1.58 (m, 14-H), 1.84 (dd, 200-Hax), 2.00 (d, 200-Heq), 2.03
(s, 9-OCOCH3), 2.04 (s, 20-OCOCH3), 2.40 (s, NCH3), 2.40 (s, 30-
N(CH3)2), 2.61 (dd, 10-H), 2.71 (t, 30-H), 3.16 (s, CH(OCH3)2), 3.24
(s, CH(OCH3)2), 3.26 (br d, 4-H), 3.28 (t, 40-H), 3.33 (dq, 50-H),
3.53 (s, 4-OCH3), 3.90 (br d, 5-H), 4.20 (m, 15-H), 4.38 (dq, 500-H),
4.50 (dd, CH(OCH3)2), 4.61 (d, 400-H), 4.70 (d, 10-H), 5.07 (d, 100-H),
5.19 (br dd, 3-H), 5.75 (ddt, CH=CH2).
4.1.44. Preparation of 74
4.1.47. Preparation of 79, 80, and 81
Macrolactonization of 72 gave 74 in 54% yield by a similar pro-
cedure to 73; ½a 1D9
ꢀ
ꢁ68° (c 0.3, CHCl3); FAB-MS m/z 989 (M+H)+; 1H
Reaction of 75 with methanol at 40 °C for 48 h gave 77 in 33%
yield. Reaction of 77 with difluoroacetic acid gave 79 in 51% yield
by a similar procedure to 12. Compounds 80 and 81 were prepared
from 76 and 9,20-di-O-acetyl dimethylacetal of 81, respectively, by
NMR (CDCl3) d 0.94 (d, 8-CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.12
(t, 3-OCOCH2CH3), 1.17 (t, 400-OCOCH2CH3), 1.26 (d, 60-H), 1.84 (dd,
200-Hax), 1.95 (br dd, 13-H), 2.01 (d, 200-Heq), 2.03 (s, 9-OCOCH3),
2.05 (s, 20-OCOCH3), 2.25 (s, NCH3), 2.41 (s, 30-N(CH3)2), 2.53 (dd,
10-H), 2.69 (m, 2-H), 2.72 (t, 30-H), 3.13 (s, CH(OCH3)2), 3.24 (s,
CH(OCH3)2), 3.33 (m, 40-H), 3.34 (br d, 4-H), 3.35 (m, 50-H), 3.54
(s, 4-OCH3), 3.89 (br d, 5-H), 4.16 (m, 15-H), 4.38 (dq, 500-H), 4.49
(dd, CH(OCH3)2), 4.61 (d, 400-H), 4.72 (d, 10-H), 5.07 (d, 100-H), 5.23
(br dd, 3-H), 5.72 (ddd, CH@CH2).
a similar procedure to 79. Compound 79; ½a D25
ꢁ61° (c 0.24, CHCl3);
ꢀ
FAB-MS m/z 986 (M+H)+; HRMS: Calcd for C52H79N3O15: 986.5589.
Found: 986.5586 (M+H)+; 1H NMR (CDCl3) d 0.90 (d, 8-CH3), 1.00 (t,
3-OCOCH2CH3), 1.12 (s, 300-CH3), 1.13 (d, 600-H), 1.18 (t, 400-
OCOCH2CH3), 1.20 (d, 60-H), 1.44 (m, 14-H), 1.83 (dd, 200-Hax),
2.00 (d, 200-Heq), 2.11 (m, 14-H), 2.32 (s, NCH3), 2.50 (s, 30-

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
10151
N(CH3)2), 2.60 (m, 2-H), 2.85 (dd, 6-CH2), 3.25 (t, 40-H), 3.53 (d,
quinoline-CH2), 3.59 (s, 4-OCH3), 3.62 (d, 4-H), 3.82 (d, 5-H), 4.07
(m, 15-H), 4.33 (d, 10-H), 4.46 (dq, 500-H), 4.61 (d, 400-H), 5.06 (d,
100-H), 5.24 (dd, 13-CH), 5.85 (t, 3-H), 5.95 (dt, CH@CH), 7.53
(ddd, quinoline), 7.66 (ddd, quinoline), 7.78 (dd, quinoline), 7.91
(d, quinoline), 8.07 (br d, quinoline), 8.75 (d, quinoline), 9.62 (s,
yl dimethylacetal of 85 in 5.1% yield by a similar procedure to 75.
Total yield of this reaction was 45%. 9,20-Di-O-acetyl dimethylace-
tal of 83; ½a 1D7
ꢀ
ꢁ29° (c 1.3, CHCl3); FAB-MS m/z 1116 (M+H)+; 1H
NMR (CDCl3) d 0.93 (d, 8-CH3), 1.11 (s, 300-CH3), 1.11 (t, 3-
OCOCH2CH3), 1.12 (d, 600-H), 1.17 (t, 400-OCOCH2CH3), 1.26 (d, 60-
H), 1.83 (dd, 200-Hax), 1.92 (s, 9-OCOCH3), 1.99 (s, 20-OCOCH3),
2.01 (d, 200-Heq), 2.25 (s, NCH3), 2.39 (s, 30-N(CH3)2), 2.66 (m, 2-
H), 2.70 (t, 30-H), 3.11 (s, CH(OCH3)2), 3.23 (s, CH(OCH3)2), 3.32
(m, 40-H), 3.34 (m, 50-H), 3.51 (s, 4-OCH3), 3.80 (br d, quinoline-
CH2), 3.90 (br d, 5-H), 4.10 (m, 15-H), 4.17 (m, 15-H), 4.26 (br s,
300-OH), 4.37 (dq, 500-H), 4.49 (dd, CH(OCH3)2), 4.61 (d, 400-H), 4.70
(d, 10-H), 4.96 (m, 9-H), 4.99 (dd, 20-H), 5.06 (d, 100-H), 5.24 (br
dd, 3-H), 5.50 (dd, J = 15.7, 6.2 Hz, 13-CH), 5.65 (dt, J = 15.7,
6.3 Hz, CH@CH), 7.24 (d, quinoline), 7.55 (ddd, quinoline), 7.70
(ddd, quinoline), 8.02 (br d, quinoline), 8.09 (br d, quinoline),
CHO). Compound 80; ½a D26
ꢁ50° (c 0.25, CHCl3); FAB-MS m/z 986
ꢀ
(M+H)+; HRMS: Calcd for C52H79N3O15
:
986.5589. Found:
986.5586 (M+H)+; H NMR (CDCl3) d 0.94 (d, 8-CH3), 1.13 (d, 600-
H), 1.16 (s, 300-CH3), 1.18 (t, 400-OCOCH2CH3), 1.19 (d, 60-H), 1.84
(dd, 200-Hax), 2.01 (d, 200-Heq), 2.36 (s, NCH3), 2.53 (s, 30-N(CH3)2),
2.91 (dd, 6-CH2), 3.59 (s, 4-OCH3), 3.90 (d, 5-H), 4.09 (m, 15-H),
4.26 (m, 15-H), 4.44 (d, 10-H), 4.62 (d, 400-H), 5.07 (d, 100-H), 5.44
(m, 3-H), 5.47 (dd, 13-CH), 5.75 (dt, CH@CH), 7.52 (t, quinoline),
7.66 (t, quinoline), 7.78 (d, quinoline), 7.94 (s, quinoline), 8.08 (d,
1
quinoline), 8.77 (d, quinoline), 9.64 (s, CHO). Compound 81; ½a D26
ꢀ
8.81 (d, quinoline). 9,20-Di-O-acetyl dimethylacetal of 85; ½a 1D8
ꢀ
ꢁ32° (c 0.35, CHCl3); FAB-MS m/z 986 (M+H)+; HRMS: Calcd for
C52H79N3O15: 986.5589. Found: 986.5586 (M+H)+; 1H NMR (CDCl3)
d 0.83 (d, 8-CH3), 1.04 (t, 3-OCOCH2CH3), 1.11 (s, 300-CH3), 1.13 (d,
600-H), 1.18 (t, 400-OCOCH2CH3), 1.19 (d, 60-H), 1.83 (dd, 200-Hax),
2.00 (d, 200-Heq), 2.30 (s, NCH3), 2.50 (s, 30-N(CH3)2), 2.69 (dd, 2-
H), 2.88 (dd, 6-CH2), 2.94 (m, 13-H), 3.55 (dd, 20-H), 3.59 (s, 4-
OCH3), 3.83 (m, quinoline-CH2), 4.01 (m, 15-H), 4.27 (m, 15-H),
4.35 (d, 10-H), 4.46 (dq, 500-H), 4.61 (d, 400-H), 5.06 (d, 100-H), 5.31
(t, 13-CH), 5.74 (m, 3-H), 5.79 (dt, CH@CH), 7.51 (ddd, quinoline),
7.65 (ddd, quinoline), 7.75 (dd, quinoline), 7.93 (d, quinoline),
8.05 (br d, quinoline), 8.78 (d, quinoline), 9.63 (s, CHO).
ꢁ32° (c 0.3, CHCl3); FAB-MS m/z 1116 (M+H)+; 1H NMR (CDCl3) d
0.95 (d, 8-CH3), 1.11 (s, 300-CH3), 1.11 (t, 3-OCOCH2CH3), 1.12 (d,
600-H), 1.17 (t, 400-OCOCH2CH3), 1.26 (d, 60-H), 1.83 (dd, 200-Hax),
1.93 (s, 9-OCOCH3), 1.96 (d, 200-Heq), 2.00 (s, 20-OCOCH3), 2.23 (s,
NCH3), 2.38 (s, 30-N(CH3)2), 2.52 (dd, 10-H), 2.59 (dd, 2-H), 2.70
(t, 30-H), 2.82 (m, 13-H), 3.13 (s, CH(OCH3)2), 3.23 (s, CH(OCH3)2),
3.25 (br d, 4-H), 3.31 (m, 40-H), 3.33 (m, 50-H), 3.87 (m, quino-
line-CH2), 4.11 (m, 15-H), 4.24 (m, 15-H), 4.36 (dq, 500-H), 4.50
(dd, CH(OCH3)2), 4.61 (d, 400-H), 4.69 (d, 10-H), 4.98 (dd, 20-H),
5.06 (d, 100-H), 5.25 (br dd, 3-H), 5.53 (dd, J = 10.4, 1.2 Hz, 13-CH),
5.70 (dt, J = 10.4, 6.9 Hz, CH@CH), 7.27 (d, quinoline), 7.56 (ddd,
quinoline), 7.71 (ddd, quinoline), 8.04 (br d, quinoline), 8.11 (br
d, quinoline), 8.81 (d, quinoline).
4.1.48. Preparation of 9,20-di-O-acetyl dimethylacetal of 82 and
its cis-isomer, 9,20-di-O-acetyl dimethylacetal of 84
Reaction of 73 with 4-bromoquinoline gave 9,20-di-O-acetyl
dimethylacetal of 82 in 45% yield and its cis-isomer, 9,20-di-O-acet-
yl dimethylacetal of 84 in 4.4% yield by a similar procedure to 75.
Total yield of this reaction was 49%. 9,20-Di-O-acetyl dimethylace-
4.1.50. Preparation of 82 and 83
Reaction of 9,20-Di-O-acetyl dimethyacetal of 82 and 9,20-Di-O-
acetyl dimethyacetal of 83 with methanol gave dimethyacetal of
82 in 41% yield and dimethyacetal of 83 in 31% yield, respectively,
by a similar procedure to 42. Then, these compounds with difluoro-
acetic acid gave 82 in 57% yield and 83 in 27% yield, respectively, by
tal of 82; ½a 2D0
ꢀ
ꢁ64° (c 1.0, CHCl3); FAB-MS m/z 1116 (M+H)+; 1H
NMR (CDCl3) d 0.94 (d, 8-CH3), 1.02 (t, 3-OCOCH2CH3), 1.12 (d,
600-H), 1.16 (t, 400-OCOCH2CH3), 1.19 (s, 300-CH3), 1.24 (d, 60-H),
1.83 (dd, 200-Hax), 2.00 (d, 200-Heq), 2.02 (s, 9-OCOCH3), 2.03 (s,
20-OCOCH3), 2.25 (s, NCH3), 2.39 (s, 30-N(CH3)2), 3.08 (s,
CH(OCH3)2), 3.21 (s, CH(OCH3)2), 3.32 (m, 40-H), 3.32 (m, 50-H),
3.52 (s, 4-OCH3), 3.78 (d, J = 6.4 Hz, quinoline-CH2), 3.87 (br d, 5-
H), 4.12 (m, 15-H), 4.26 (br s, 300-OH), 4.36 (dq, 500-H), 4.44 (dd,
CH(OCH3)2), 4.60 (d, 400-H), 4.69 (d, 10-H), 4.99 (dd, 20-H), 5.05 (d,
100-H), 5.22 (m, 3-H), 5.25 (dd, J = 15.2, 8.7 Hz, 13-CH), 5.88 (dt,
J = 15.2, 6.4 Hz, CH@CH), 7.23 (d, quinoline), 7.53 (ddd, quinoline),
7.69 (ddd, quinoline), 8.00 (br d, quinoline), 8.09 (br d, quinoline),
a similar procedure to 12. Compound 82; ½a D20
ꢁ48° (c 0.9, CHCl3);
ꢀ
FAB-MS m/z 986 (M+H)+; HRMS: Calcd for C52H79N3O15
:
986.5589. Found: 986.5583 (M+H)+; 1H NMR (CDCl3) d 0.88 (d, 8-
CH3), 0.93 (m, 7-H), 1.01 (t, 3-OCOCH2CH3), 1.11 (s, 300-CH3), 1.12
(d, 600-H), 1.17 (t, 400-OCOCH2CH3), 1.19 (d, 60-H), 1.38 (m, 14-H),
1.82 (dd, 200-Hax), 1.99 (d, 200-Heq), 2.06 (m, 14-H), 2.28 (s, NCH3),
2.49 (s, 30-N(CH3)2), 2.84 (dd, 6-CH2), 3.25 (m, 40-H), 3.25 (m, 50-
H), 3.53 (dd, 20-H), 3.60 (br d, 4-H), 3.57 (s, 4-OCH3), 3.78 (br d, quin-
oline-CH2), 3.81 (br d, 5-H), 4.33 (d, 10-H), 4.46 (dq, 500-H), 4.60 (d,
400-H), 5.05 (d, 100-H), 5.18 (dd, 13-CH), 5.82 (br dd, 3-H), 5.97 (dt,
CH@CH), 7.24 (d, quinoline), 7.54 (ddd, quinoline), 7.69 (ddd, quin-
oline), 8.00 (dd, quinoline), 8.10 (dd, quinoline), 8.81 (d, quinoline),
8.80 (d, quinoline). 9,20-Di-O-acetyl dimethylacetal of 84; ½a 2D0
ꢀ
ꢁ65° (c 0.9, CHCl3); FAB-MS m/z 1116 (M+H)+; 1H NMR (CDCl3) d
0.93 (t, 3-OCOCH2CH3), 0.95 (d, 8-CH3), 1.10 (s, 300-CH3), 1.11 (d,
600-H), 1.16 (t, 400-OCOCH2CH3), 1.24 (d, 60-H), 1.83 (dd, 200-Hax),
2.00 (d, 200-Heq), 2.03 (s, 9-OCOCH3), 2.05 (s, 20-OCOCH3), 2.31 (s,
NCH3), 2.39 (s, 30-N(CH3)2), 3.05 (s, CH(OCH3)2), 3.20 (s,
CH(OCH3)2), 3.33 (m, 40-H), 3.33 (m, 50-H), 3.35 (br d, 4-H), 3.54
(s, 4-OCH3), 3.87 (br d, 5-H), 3.93 (d, J = 6.9 Hz, quinoline-CH2),
4.07 (dd, 15-H), 4.26 (br s, 300-OH), 4.36 (dd, 15-H), 4.37 (m, 500-
H), 4.49 (dd, CH(OCH3)2), 4.60 (d, 400-H), 4.69 (d, 10-H), 4.99 (dd,
20-H), 5.05 (d, 100-H), 5.21 (m, 3-H), 5.33 (dd, J = 10.7, 1.0 Hz, 13-
CH), 5.69 (dt, J = 10.7, 6.9 Hz, CH@CH), 7.27 (d, quinoline), 7.53
(ddd,quinoline), 7.69 (ddd, quinoline), 8.06 (br d, quinoline), 8.10
(br d, quinoline), 8.80 (d, quinoline).
9.61 (s, CHO). Compound 83; ½a D19
ꢁ46° (c 0.3, CHCl3); FAB-MS m/z
ꢀ
986 (M+H)+; HRMS: Calcd for C52H79N3O15: 986.5589. Found:
1
986.5583 (M+H)+; H NMR (CDCl3) d 1.02 (d, 8-CH3), 1.08 (d, 600-
H), 1.11 (s, 300-CH3), 1.14 (t, 3-OCOCH2CH3), 1.17 (t, 400-OCOCH2CH3),
1.24 (d, 60-H), 1.83 (dd, 200-Hax), 2.00 (d, 200-Heq), 2.51 (s, 30-
N(CH3)2), 3.28 (m, 40-H), 3.28 (m, 50-H), 3.55 (s, 4-OCH3), 4.43 (d,
10-H), 4.45 (dq, 500-H), 4.61 (d, 400-H), 5.06 (d, 100-H), 5.41 (m, 3-H),
5.51 (dd, 13-CH), 5.79 (dt, CH@CH), 7.25 (d, quinoline), 7.54 (ddd,
quinoline), 7.69 (ddd, quinoline), 8.04 (br d, quinoline), 8.04 (br d,
quinoline), 8.10 (d, quinoline), 9.63 (s, CHO).
4.1.51. Preparation of 84 and 85
Reaction of 9,20-di-O-acetyl dimethyacetal of 84 and 9,20-di-O-
acetyl dimethyacetal of 85 with methanol gave dimethyacetal of
84 in 52% yield and dimethyacetal of 85 in 33% yield, respectively,
by a similar procedure to 42. Then, these compounds with difluoro-
acetic acid gave 84 in 55% yield and 85 in 40% yield, respectively, by a
4.1.49. Preparation of 9, 20-di-O-acetyl dimethylacetal of 83 and
its cis-isomer, 9,20-di-O-acetyl dimethylacetal of 85
Reaction of 74 with 4-bromoquinoline gave 9,20-di-O-acetyl
dimethylacetal of 83 in 40% yield and its cis-isomer, 9,20-di-O-acet-

10152
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
similar procedure to 12. Compound 84; ½a D20
ꢀ
ꢁ37° (c 0.2, CHCl3);
(c 1.0, CHCl3); FAB-MS m/z 1116 (M+H)+; 1H NMR (CDCl3) d 0.95
FAB-MS m/z 986 (M+H)+; HRMS: Calcd for C52H79N3O15: 986.5589.
Found: 986.5593 (M+H)+; 1H NMR (CDCl3) d 0.92 (d, 8-CH3), 0.93
(t, 3-OCOCH2CH3), 1.13 (d, 600-H), 1.17 (t, 400-OCOCH2CH3), 1.24 (d,
60-H), 1.82 (dd, 200-Hax), 2.00 (d, 200-Heq), 2.50 (s, 30-N(CH3)2), 3.27
(m, 40-H), 3.27 (m, 50-H), 3.57 (s, 4-OCH3), 4.33 (d, 10-H), 4.46 (m,
500-H), 4.60 (d, 400-H), 5.05 (d, 100-H), 7.24 (d, quinoline), 7.54 (ddd,
quinoline), 7.69 (ddd, quinoline), 8.00 (br d, quinoline), 8.10 (br d,
(d, 8-CH3), 1.04 (t, 3-OCOCH2CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-
H), 1.17 (t, 400-OCOCH2CH3), 1.26 (d, 60-H), 1.84 (dd, 200-Hax), 2.00
(d, 200-Heq), 2.03 (s, 9-OCOCH3), 2.04 (s, 20-OCOCH3), 2.10 (m, 14-
H), 2.26 (s, NCH3), 2.32 (dq, 3-OCOCH2CH3), 2.40 (s, 30-N(CH3)2),
2.43 (dq, OCOCH2CH3), 2.72 (t, 30-H), 3.13 (s, CH(OCH3)2), 3.23 (s,
CH(OCH3)2), 3.32 (t, 40-H), 3.53 (s, 4-OCH3), 3.87 (d, 5-H), 4.01 (d,
quinoine-CH2), 4.10 (dt, 15-H), 4.19 (dt, 15-H), 4.37 (dq, 500-H),
4.46 (dd, CH(OCH3)2), 4.61 (d, 400-H), 4.70 (d, 10-H), 4.94 (dd, 9-
H), 5.00 (dd, 20-H), 5.06 (d, 100-H), 5.23 (m, 3-H), 5.31 (dd, 13-CH),
5.92 (dt, CH@CH), 7.39 (dd, quinoline), 7.46 (t, quinoline), 7.54
(d, quinoline), 7.67 (d, quinoline), 8.13 (dd, quinoline), 8.92 (dd,
quinoline), 8.81 (d, quinoline), 9.61 (s, CHO). Compound 85; ½a D19
ꢀ
ꢁ23° (c 0.3, CHCl3); FAB-MS m/z 1028 (M+H)+; HRMS: Calcd for
C52H79N3O15: 986.5589. Found: 986.5584 (M+H)+; 1H NMR (CDCl3)
d 0.98 (d, 8-CH3), 1.12 (s, 300-CH3), 1.13 (d, 600-H), 1.17 (t, 3-
OCOCH2CH3), 1.23 (t, 400-OCOCH2CH3), 1.24 (d, 60-H), 1.84 (dd, 200-
Hax), 1.96 (d, 200-Heq), 2.03 (s, 9-OCOCH3), 2.75 (m, 2-H), 3.60 (s,
4-OCH3), 3.93 (m, 15-H), 4.20 (m, 15-H), 4.41 (dq, 500-H), 4.62 (d,
400-H), 5.07 (d, 100-H), 5.43 (m, 3-H), 5.61 (dd, 13-CH), 5.99 (dt,
CH=CH), 7.18 (d, quinoline), 7.52 (ddd, quinoline), 7.69 (ddd, quino-
line), 8.10 (br d, quinoline), 8.10 (br d, quinoline), 8.82 (d, quinoline),
9.62 (s, CHO).
quinoline). 9,20-Di-O-acetyl dimethylacetal of 90; ½a 2D5
ꢁ49° (c
ꢀ
1.0, CHCl3); FAB-MS m/z 1116 (M+H)+; 1H NMR (CDCl3) d 0.92 (d,
8-CH3), 1.06 (d, 600-H), 1.13 (t, 3-OCOCH2CH3), 1.10 (s, 300-CH3),
1.18 (t, 400-OCOCH2CH3), 1.25 (d, 60-H), 1.55 (m, 6-CH2), 1.76 (m,
8-H), 1.83 (dd, 200-Hax), 2.00 (s, 9-OCOCH3), 2.01 (s, 200-OCOCH3),
2.24 (s, NCH3), 2.30 (m, 10-H), 2.39 (s, 30-N(CH3)2), 2.68 (m, 30-
H), 3.08 (s, CH(OCH3)2), 3.20 (s, CH(OCH3)2), 3.32 (m, 40-H), 3.32
(m, 50-H), 3.52 (dd, 4-OCH3), 3.72 (d, isoquinoline-CH2), 3.86 (m,
5-H), 4.36 (d, 500-H), 4.42 (dd, CH(OCH3)2), 4.60 (d, 400-H), 4.68 (d,
10-H), 4.96 (m, 9-H), 4.98 (dd, 20-H), 5.06 (d, 100-H), 5.21 (dd,
CH@CH), 5.85 (dt, CH@CH), 7.58 (t, isoquinoline), 7.69 (t, isoquin-
oline), 7.96 (d, isoquinoline), 8.00 (m, isoquinoline), 8.34 (s, iso-
quinoline), 9.11 (d, isoquinoline).
4.1.52. Preparation of 86 and 87
Compounds 86 and 87 were sequentially prepared from
dimethylacetal of 82 and dimethylacetal of 83, respectively, by a
similar procedure to 60. Reaction yield in hydrogenolysis step is
24% and 62%, respectively. The double bond in dimethylacetal of
82 was not easily reduced, and a quinoline moiety was partially re-
duced as a result. Compound 86; ½a D19
ꢁ47° (c 0.3, CHCl3); FAB-MS
ꢀ
4.1.54. Preparation of 88, 89, and 90
m/z 988 (M+H)+; HRMS: Calcd for C52H81N3O15: 988.5746. Found:
988.5737 (M+H)+; 1H NMR (CDCl3) d 0.88 (d, 8-CH3), 1.07 (t, 3-
OCOCH2CH3), 1.11 (s, 300-CH3), 1.11 (d, 600-H), 1.17 (t, 400-
OCOCH2CH3), 1.25 (d, 60-H), 1.82 (dd, 200-Hax), 2.00 (d, 200-Heq),
2.50 (s, 30-N(CH3)2), 2.65 (m, 2-H), 3.26 (m, 40-H), 3.26 (m, 50-H),
3.56 (dd, 20-H), 3.61 (s, 4-OCH3), 3.80 (br d, 5-H), 4.34 (d, 10-H),
4.46 (m, 500-H), 4.61 (d, 400-H), 5.07 (d, 100-H), 5.82 (m, 3-H), 7.23
(d, quinoline), 7.55 (ddd, quinoline), 7.70 (ddd, quinoline), 8.02
(br d, quinoline), 8.11 (br d, quinoline), 8.79 (d, quinoline), 9.60
Reaction of the corresponding 9,20-di-O-acetyl dimethylacetals
with methanol gave the corresponding dimethyacetals in 49%,
55%, and 53% yield, respectively, by a similar procedure to 42. Then,
these compounds with difluoroacetic acid gave 88 in 55% yield, 89 in
56% yield and 90 in 56% yield, respectively, by a similar procedure to
12. Compound 88: ½a D24
ꢁ51° (c 0.39, CHCl3); FAB-MS m/z 986
ꢀ
(M+H)+; HRMS: Calcd for C52H79N3O15: 986.5589. Found: 986.5586
(M+H)+; 1H NMR (CDCl3) d 0.90 (d, 8-CH3), 0.99 (t, 3-OCOCH2CH3),
1.12 (s, 300-CH3), 1.13 (d, 600-H), 1.18 (t, 400-OCOCH2CH3), 1.20 (d, 60-
H), 1.45 (m, 14-H), 1.83 (dd, 200-Hax), 2.00 (d, 200-Heq), 2.32 (s,
NCH3), 2.50 (s, 30-N(CH3)2), 2.66 (d, 2-H), 2.85 (dd, 6-CH2), 3.53 (d,
quinoline-CH2), 3.59 (s, 4-OCH3), 3.62 (d, 4-H), 3.82 (d, 5-H), 4.08
(m, 15-H), 4.33 (d, 10-H), 4.46 (dq, 500-H), 4.61 (d, 400-H), 5.06 (d, 100-
H), 5.23 (dd, 13-CH), 5.84 (t, 3-H), 5.94 (dt, CH@CH), 7.38 (dd, quin-
oline), 7.54 (dd, quinoline), 7.57 (s, quinoline), 8.02 (d, quinoline),
8.12 (d, quinoline), 8.86 (d, quinoline), 9.62 (s, CHO). Compound
(s, CHO). Compound 87; ½a D21
ꢁ48° (c 0.4, CHCl3); FAB-MS m/z
ꢀ
988 (M+H)+; HRMS: Calcd for C52H81N3O15: 988.5746. Found:
1
988.5739 (M+H)+; H NMR (CDCl3) d 1.12 (s, 300-H), 1.14 (d, 600-
H), 1.16 (d, 8-CH3), 1.17 (d, 60-H), 1.17 (t, 3-OCOCH2CH3), 1.24 (t,
400-OCOCH2CH3), 1.83 (dd, 200-Hax), 2.01 (d, 200-Heq), 2.52 (s, 30-
N(CH3)2), 2.64 (dd, 2-H), 3.27 (m, 40-H), 3.27 (m, 50-H), 3.50 (dd,
20-H), 3.52 (s, 4-OCH3), 3.82 (br d, 5-H), 4.03 (m, 15-H), 4.22 (m,
15-H), 4.43 (d, 10-H), 4.44 (dq, 500-H), 4.62 (d, 400-H), 5.06 (d, 100-
H), 5.27 (m, 3-H), 7.32 (d, quinoline), 7.57 (ddd, quinoline), 7.69
(ddd, quinoline), 8.10 (br d, quinoline), 8.10 (br d, quinoline),
8.80 (d, quinoline), 9.63 (s, CHO).
89; ½a 2D5
ꢀ
ꢁ61° (c 0.23, CHCl3); FAB-MS m/z 986 (M+H)+; HRMS: Calcd
for C52H79N3O15: 986.5589. Found: 986.5586 (M+H)+; 1H NMR
(CDCl3) d 0.89 (d, 8-CH3), 0.99 (t, 3-OCOCH2CH3), 1.12 (s, 300-CH3),
1.13 (d, 600-H), 1.18 (t, 400-OCOCH2CH3), 1.20 (d, 60-H), 1.30 (m, 8-
H), 1.46 (m, 14-H), 1.83 (dd, 200-Hax), 2.00 (d, 200-Heq), 2.07 (m, 14-
H), 2.26 (dd, 6-CH2), 2.30 (s, NCH3), 2.50 (s, 30-N(CH3)2), 2.65 (d, 2-
H), 2.85 (dd, 6-CH2), 3.25 (t, 40-H), 3.55 (dd, 20-H), 3.59 (s, 4-OCH3),
3.63 (d, 4-H), 3.81 (d, 5-H), 4.02 (d, quinoline-CH2), 4.10 (m, 15-H),
4.32 (d, 10-H), 4.47 (dq, 500-H), 4.62 (d, 400-H), 5.06 (d, 100-H), 5.27
(dd, 13-CH), 5.79 (t, 3-H), 6.00 (dt, CH@CH), 7.40 (dd, quinoline),
7.48 (t, quinoline), 7.55 (d, quinoline), 7.68 (dd, quinoline), 8.14
(dd, quinoline), 8.93 (dd, quinoline), 9.63 (s, CHO). Compound 90;
4.1.53. Preparation of 9,20-di-O-acetyl dimethylacetal of 88,
9,20-di-O-acetyl dimethylacetal of 89, and 9,20-di-O-acetyl
dimethylacetal of 90
Reaction of 73 with 6-bromoquinoline, 8-bromoquinoline and
4-bromoisoquinoline gave the corresponding 9, 20-di-O-acetyl
dimethylacetals in 25%, 15%, and 19% yield, respectively, by a sim-
ilar procedure to 75. 9,20-Di-O-acetyl dimethylacetal of 88; ½a 2D6
ꢀ
ꢁ60° (c 0.73, CHCl3); FAB-MS m/z 1116 (M+H)+; 1H NMR (CDCl3)
0.95 (d, 8-CH3), 1.02 (t, 3-OCOCH2CH3), 1.11 (s, 300-CH3), 1.12 (d,
600-H), 1.17 (t, 400-OCOCH2CH3), 1.25 (d, 60-H), 1.83 (dd, 200-Hax),
2.01 (d, 200-Heq), 2.02 (s, 9-OCOCH3), 2.05 (s, 20-OCOCH3), 2.28 (s,
NCH3), 2.40 (s, 30-N(CH3)2), 3.11 (s, CH(OCH3)2), 3.21 (s,
CH(OCH3)2), 3.52 (d, quinoline-CH2), 3.53 (s, 4-OCH3), 3.87 (d, 5-
H), 4.37 (dq, 500-H), 4.45 (dd, CH(OCH3)2), 4.61 (d, 400-H), 4.69 (d,
10-H), 4.99 (dd, 20-H), 5.06 (d, 100-H), 5.24 (m, 3-H), 5.28 (dd, 13-
CH), 5.84 (dt, CH@CH), 7.36 (dd, quinoline), 7.54 (d, quinoline),
7.56 (s, quinoline), 8.00 (d, quinoline), 8.10 (d, quinoline), 8.85
½
a 6D0
ꢀ
ꢁ44° (c 0.9, CHCl3); FAB-MS m/z 986 (M+H)+; HRMS: Calcd for
C52H79N3O15: 986.5589. Found: 986.5583 (M+H)+; 1H NMR (CDCl3)
d 0.89 (d, 8-CH3), 1.00 (t, 3-OCOCH2CH3), 1.11 (s, 300-CH3), 1.14 (d,
600-H), 1.17 (t, 400-OCOCH2CH3), 1.18 (d, 60-H), 1.29 (m, 8-H), 1.82
(dd, 200-Hax), 1.99 (d, 200-Heq), 2.24 (m, 6-CH2), 2.30 (s, NCH3), 2.50
(s, 30-N(CH3)2), 2.64 (m, 2-H), 3.25 (m, 40 -H), 3.25 (m, 50 -H), 3.54
(dd, 20-H), 3.58 (s, 4-OCH3), 3.60 (m, 4-H), 3.72 (d, isoquinoline-
CH2), 3.80 (br d, 5-H), 4.32 (d, 10-H), 4.45 (m, 500-H), 4.60 (d, 400-H),
5.06 (d, 100-H), 5.16 (m, CH@CH), 5.79 (m, 3-H), 5.96 (m, CH@CH),
7.58 (t, isoquinoline), 7.69 (t, isoquinoline), 7.98 (m, isoquinoline),
8.36 (s, isoquinoline), 9.15 (s, isoquinoline), 9.64 (s, CHO).
(d, quinoline). 9, 20-Di-O-acetyl dimethylacetal of 89; ½a 2D6
ꢁ59°
ꢀ

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
10153
4.1.55. Synthesis of 92 and 93
(d, 60-H), 1.81 (dd, 200-Hax), 1.98 (d, 200-Heq), 2.34 (s, NCH3), 2.46
(s, 30-N(CH3)2), 3.15 (s, CH(OCH3)2), 3.24 (s, CH(OCH3)2), 3.49 (br
d, 4-H), 3.51 (s, 4-OCH3), 3.56 (dd, 20-H), 3.82 (br d, 5-H), 4.43 (d,
10-H), 4.46 (dd, CH(OCH3)2), 4.49 (dq, 500-H), 4.60 (d, 400-H), 4.99
(m, 15-H), 5.05 (d, 100-H), 5.36 (br dd, 3-H), 6.36 (dt, CH@CH),
7.11 (d, CH@CH), 7.42 (d, quinoline), 7.53 (ddd, quinoline), 7.69
(ddd, quinoline), 8.04 (br d, quinoline), 8.08 (br d, quinoline),
8.83 (d, quinoline).
Reaction of 36 with 7-methylamino-1-hepten-4-ol20 gave 91 in
66% yield by a similar procedure to 4. Macrolactonization of 91
gave 92 in 21% yield and 93 in 47% yield by a similar procedure
to 73. Compound 92: ½a D17
ꢁ58° (c 3.3, CHCl3); FAB-MS m/z 989
ꢀ
1
(M+H)+; H NMR (CDCl3) d 0.94 (d, 8-CH3), 1.10 (s, 300-CH3), 1.11
(d, 600-H), 1.12 (t, 3-OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3), 1.26
(d, 60-H), 1.56 (br dd, 6-CH2), 1.65 (m, 14-H), 1.83 (dd, 200-Hax),
1.99 (d, 200-Heq), 2.03 (s, 9-OCOCH3), 2.03 (s, 20-OCOCH3), 2.20 (s,
NCH3), 2.29 (m, 15-CH2), 2.39 (s, 30-N(CH3)2), 2.50 (m, 10-H),
2.62 (br d, 2-H), 2.71 (t, 30-H), 2.73 (dd, 2-H), 3.16 (s, CH(OCH3)2),
3.24 (s, CH(OCH3)2), 3.34 (m, 40-H), 3.39 (m, 50-H), 3.40 (br d, 4-
H), 3.52 (s, 4-OCH3), 3.89 (br d, 5-H), 4.25 (s, 300-OH), 4.36 (dq,
500-H), 4.49 (dd, CH(OCH3)2), 4.60 (d, 400-H), 4.69 (d, 10-H), 5.05
(dd, 20-H), 5.05 (m, 9-H), 5.06 (m, 15-H), 5.10 (d, 100-H), 5.10 (d,
4.1.59. Preparation of 97
Reaction of 95 with methanol gave 97 in 41% yield by a similar
procedure to 17; ½a D18
ꢁ35° (c 0.71, CHCl3); FAB-MS m/z 1032
ꢀ
(M+H)+; 1H NMR (CDCl3) d 0.87 (d, 8-CH3), 1.08 (t, 3-OCOCH2CH3),
1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.17 (t, 400-OCOCH2CH3), 1.26 (d, 60-
H), 1.82 (dd, 200-Hax), 1.99 (d, 200-Heq), 2.33 (s, NCH3), 2.49 (s, 30-
N(CH3)2), 2.61 (dd, 2-H), 2.61 (m, 15-CH2), 2.79 (dd, 2-H), 3.15 (s,
CH(OCH3)2), 3.24 (s, CH(OCH3)2), 3.35 (m, 9-H), 3.58 (s, 4-OCH3),
3.89 (br d, 5-H), 4.31 (d, 10-H), 4.45 (dq, 500-H), 4.46 (dd,
CH(OCH3)2), 4.61 (d, 400-H), 5.07 (d, 100-H), 5.17 (m, 15-H), 5.47
(m, 3-H), 6.35 (dt, CH@CH), 7.12 (d, CH@CH), 7.37 (d, quinoline),
7.54 (ddd, quinoline), 7.70 (ddd, quinoline), 8.07 (br d, quinoline),
8.09 (br d, quinoline), 8.81 (d, quinoline).
CH@CH2), 5.23 (br dd, 3-H), 5.71 (m, CH@CH2). 93; ½a D15
ꢁ47° (c
ꢀ
2.0, CHCl3); FAB-MS m/z 989 (M+H)+; 1H NMR (CDCl3) d 0.91 (d,
8-CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.13 (t, 3-OCOCH2CH3),
1.17 (t, 400-OCOCH2CH3), 1.27 (d, 60-H), 1.83 (dd, 200-Hax), 2.01 (d,
200-Heq), 2.04 (s, 9-OCOCH3), 2.04 (s, 20-OCOCH3), 2.21 (s, NCH3),
2.25 (m, 15-CH2), 2.37 (m, 10-H), 2.40 (s, 30-N(CH3)2), 2.57 (dd,
2-H), 2.72 (t, 30-H), 2.86 (dd, 2-H), 3.14 (s, CH(OCH3)2), 3.25 (s,
CH(OCH3)2), 3.29 (m, 40-H), 3.31 (m, 50-H), 3.61 (s, 4-OCH3), 3.66
(br d, 4-H), 3.93 (br d, 5-H), 4.28 (s, 300-OH), 4.38 ((dq, 500-H),
4.55 (dd, CH(OCH3)2), 4.61 (d, 400-H), 4.73 (d, 10-H), 4.90 (m, 9-H),
4.97 (dd, 200-H), 4.99 (br dd, 3-H), 4.99 (m, 15-H), 5.01 (d, 100-H),
5.02 (d, CH@CH2), 5.71 (m, CH@CH2).
4.1.60. Preparation of 98
Reaction of 96 with difluoroacetic acid gave 98 in 51% yield by a
similar procedure to 12; ½a D17
ꢁ49° (c 0.53, CHCl3); FAB-MS m/z 986
ꢀ
(M+H)+; HRMS: Calcd for C52H79N3O15: 986.5589. Found: 986.5586
(M+H)+; 1H NMR (CDCl3) d 1.04 (d, 8-CH3), 1.10 (s, 300-CH3), 1.12 (d,
600-H), 1.15 (t, 3-OCOCH2CH3), 1.16 (d, 60-H), 1.17 (t, 400-
OCOCH2CH3), 1.81 (dd, 200-Hax), 1.99 (d, 200-Heq), 2.35 (s, NCH3),
2.47 (s, 30-N(CH3)2), 2.91 (dd, 6-CH2), 3.24 (m, 40-H), 3.24 (m, 50-
H), 3.47 (dd, 20-H), 3.48 (s, 4-OCH3), 3.56 (br d, 4-H), 3.84 (br d,
5-H), 4.29 (br s, 300-OH), 4.35 (d, 10-H), 4.44 (dq, 500-H), 4.61 (d,
400-H), 5.01 (m, 15-H), 5.05 (d, 100-H), 5.48 (br dd, 3-H), 6.42 (dt,
CH@CH), 7.14 (d, CH@CH), 7.48 (d, quinoline), 7.55 (ddd, quino-
line), 7.70 (ddd, quinoline), 8.05 (br d, quinoline), 8.09 (br d, quin-
oline), 8.85 (d, quinoline), 9.63 (s, CHO).
4.1.56. Synthesis of 94
Heck reaction of 92 gave 94 in 25% yield by a similar procedure
to 75; ½a 1D8
ꢀ
ꢁ59° (c 1.1, CHCl3); FAB-MS m/z 1116 (M+H)+; 1H NMR
(CDCl3) d 0.94 (d, 8-CH3), 1.10 (s, 300-CH3), 1.11 (d, 600-H), 1.12 (t, 3-
OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3), 1.26 (d, 60-H), 1.82 (dd, 200-
Hax), 1.99 (d, 200-Heq), 2.00 (s, 9-OCOCH3), 2.03 (s, 20-OCOCH3),
2.23 (s, NCH3), 2.39 (s, 30-N(CH3)2), 2.70 (t, 30-H), 3.16 (s,
CH(OCH3)2), 3.24 (s, CH(OCH3)2), 3.31 (m, 40-H), 3.33 (m, 50-H),
3.39 (br d, 4-H), 3.52 (s, 4-OCH3), 3.88 (br d, 5-H), 4.24 (s, 300-
OH), 4.36 (dq, 500-H), 4.49 (dd, CH(OCH3)2), 4.60 (d, 400-H), 4.69
(d, 10-H), 4.99 (dd, 20-H), 5.05 (d, 100-H), 5.14 (m, 15-H), 5.25 (br
dd, 3-H), 6.36 (dt, J = 15.7, 7.1 Hz, CH@CH), 7.12 (d, J = 15.7 Hz,
CH@CH), 7.38 (d, quinoline), 7.54 (ddd, quinoline), 7.69 (ddd, quin-
oline), 8.05 (br d, quinoline), 8.08 (br d, quinoline), 8.83 (d,
quinoline).
4.1.61. Preparation of 99
Reaction of 97 with difluoroacetic acid gave 99 in 61% yield by a
similar procedure to 12; ½a D18
ꢁ38° (c 0.41, CHCl3); FAB-MS m/z 986
ꢀ
(M+H)+; HRMS: Calcd for C52H79N3O15: 986.5589. Found: 986.5583
(M+H)+; 1H NMR (CDCl3) d 0.91 (d, 8-CH3), 1.11 (s, 300-CH3), 1.12 (d,
600-H), 1.14 (t, 3-OCOCH2CH3), 1.17 (t, 400-OCOCH2CH3), 1.20 (d, 60-
H), 1.82 (dd, 200-Hax), 1.99 (d, 200-Heq), 2.33 (s, NCH3), 2.50 (s, 30-
N(CH3)2), 2.63 (dd, 2-H), 3.24 (m, 40-H), 3.27 (m, 50-H), 3.36 (m,
9-H), 3.54 (dd, 20-H), 3.58 (s, 4-OCH3), 3.85 (br d, 4-H), 3.99 (br d,
5-H), 4.36 (d, 10-H), 4.47 (dq, 500-H), 4.61 (d, 400-H), 5.06 (d, 100-H),
5.17 (m, 15-H), 5.54 (m, 3-H), 6.35 (dt, CH@CH), 7.13 (d, CH@CH),
7.38 (d, quinoline), 7.55 (ddd, quinoline), 7.71 (ddd, quinoline),
8.06 (br d, quinoline), 8.09 (br d, quinoline), 8.82 (d, quinoline),
9.64 (s, CHO).
4.1.57. Synthesis of 95
Reaction of 93 with 4-bromoquinoline gave 95 in 42% yield by a
similar procedure to 75; ½a D20
ꢁ21° (c 1.1, CHCl3); FAB-MS m/z 1116
ꢀ
(M+H)+; 1H NMR (CDCl3) d 0.91 (d, 8-CH3), 1.11 (s, 300-CH3), 1.11 (t,
3-OCOCH2CH3), 1.12 (d, 600-H), 1.16 (t, 400-OCOCH2CH3), 1.26 (d, 60-
H), 1.83 (dd, 200-Hax), 1.99 (d, 200-Heq), 2.03 (s, 9-OCOCH3), 2.04 (s,
20-OCOCH3), 2.23 (s, NCH3), 2.40 (s, 30-N(CH3)2), 2.45 (m, 10-H),
2.59 (dd, 2-H), 2.61 (m, 15-CH2), 2.71 (t, 30-H), 2.84 (dd, 2-H),
3.14 (s, CH(OCH3)2), 3.24 (s, CH(OCH3)2), 3.32 (m, 40-H), 3.37 (m,
50-H), 3.55 (s, 4-OCH3), 3.61 (br d, 4-H), 3.93 (br d, 5-H), 4.26 (br
s, 300-OH), 4.37 (dq, 500-H), 4.55 (dd, CH(OCH3)2), 4.60 (d, 400-H),
4.71 (d, 10-H), 4.91 (m, 9-H), 5.00 (dd, 20-H), 5.06 (d, 100-H), 5.06
(br dd, 3-H), 5.18 (m, 15-H), 6.36 (dt, J = 15.9, 7.1 Hz, CH@CH),
7.14 (d, J = 15.9 Hz, CH@CH), 7.39 (d, quinoline), 7.54 (ddd, quino-
line), 7.70 (ddd, quinoline), 8.07 (br d, quinoline), 8.09 (br d, quin-
oline), 8.82 (d, quinoline).
4.1.62. Preparation of 100
Hydrogenolysis of 96 in 1, 4-dioxane-H2O (2:1) gave dimethyl-
acetal of 100 in 95% yield by a similar procedure to 40. Reaction of
dimethylacetal of 100 with difluoroacetic acid gave 100 in 41%
yield by a similar procedure to 12; ½a D15
ꢁ45° (c 0.40, CHCl3);
ꢀ
FAB-MS m/z 988 (M+H)+; HRMS: Calcd for C52H81N3O15
:
988.5746. Found: 988.5757 (M+H)+; 1H NMR (CDCl3) d 1.00 (d, 8-
CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.15 (t, 3-OCOCH2CH3), 1.17
(t, 400-OCOCH2CH3), 1.18 (d, 60-H), 1.83 (dd, 200-Hax), 2.00 (d, 200-
Heq), 2.34 (s, NCH3), 2.50 (s, 30-N(CH3)2), 2.91 (dd, 6-CH2), 3.07
(br t, quinoline-CH2), 3.26 (m, 40-H), 3.26 (m, 50-H), 3.51 (dd,
20-H), 3.52 (s, 4-OCH3), 3.86 (br d, 5-H), 4.38 (d, 10-H), 4.46 (dq,
500-H), 4.61 (d, 400-H), 4.90 (m, 15-H), 5.06 (d, 100-H), 5.42 (br dd,
4.1.58. Preparation of 96
Reaction of 94 with methanol gave 96 in 61% yield by a similar
procedure to 17; ½a D16
ꢁ53° (c 2.2, CHCl3); FAB-MS m/z 1032
ꢀ
1
(M+H)+; H NMR (CDCl3) d 0.99 (d, 8-CH3), 1.10 (s, 300-CH3), 1.10
(t, 3-OCOCH2CH3), 1.11 (d, 600-H), 1.16 (t, 400-OCOCH2CH3), 1.24

10154
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
3-H), 7.21 (d, quinoline), 7.56 (ddd, quinoline), 7.70 (ddd, quino-
line), 7.99 (br d, quinoline), 8.11 (br d, quinoline), 8.80 (d, quino-
line), 9.63 (s, CHO).
H), 4.46 (dq, 500-H), 4.61 (d, 400-H), 5.06 (d, 100-H), 5.09 (m, 15-H),
5.52 (m, 3-H), 7.25–7.34 (m, C6H5), 9.64 (s, CHO).
4.1.67. Preparation of 9, 20-di-O-acetyl dimethylacetal of 103
Reaction of 93 with 3-bromopyridine gave the corresponding
9,20-di-O-acetyl dimethylacetal in 81% yield by a similar proce-
4.1.63. Preparation of 101
Hydrogenolysis of 97 in 1, 4-dioxane/H2O (2:1) gave dimethyl-
acetal of 101 in 61% yield by a similar procedure to 40. Reaction of
dimethylacetal of 101 with difluoroacetic acid gave 101 in 60%
dure to 95;
½
a 2D7
ꢀ
ꢁ43° (c 1.00, CHCl3); FAB-MS m/z 1066
(M+H)+; H NMR (CDCl3) d 0.89 (d, 8-CH3), 1.09 (s, 300-CH3),
1.10 (d, 600-H), 1.11 (t, 3-OCOCH2CH3), 1.15 (t, 400-OCOCH2CH3),
1.25 (d, 60-H), 1.82 (dd, 200-Hax), 1.99 (d, 200-Heq), 2.02 (s, 9-
OCOCH3), 2.02 (s, 20-OCOCH3), 2.20 (s, NCH3), 2.39 (s, 30-
N(CH3)2), 2.47 (m, 15-CH2), 2.56 (dd, 2-H), 2.71 (t, 30-H), 2.83
(dd, 2-H), 3.13 (s, CH(OCH3)2), 3.23 (s, CH(OCH3)2), 3.32 (m, 40-
H), 3.32 (m, 50-H), 3.56 (s, 4-OCH3), 3.59 (d, 4-H), 3.92 (d, 5-H),
4.25 (br s, 300-OH), 4.36 (dq, 500-H), 4.53 (dd, CH(OCH3)2), 4.59
(d, 400-H), 4.70 (d, 10-H), 4.88 (m, 9-H), 4.99 (dd, 20-H), 5.05 (d,
100-H), 6.17 (dt, 15-CH2CH@CH), 6.40 (d, 15-CH2CH@CH), 7.19
(dd, pyridine), 7.63 (dt, pyridine), 8.41 (dd, pyridine), 8.52 (d,
pyridine).
1
yield by a similar procedure to 12; ½a D15
ꢁ34° (c 0.44, CHCl3);
ꢀ
FAB-MS m/z 988 (M+H)+; HRMS: Calcd for C52H81N3O15
:
988.5746. Found: 988.5757 (M+H)+; 1H NMR (CDCl3) d 0.93 (d, 8-
CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.13 (t, 3-OCOCH2CH3), 1.17
(t, 400-OCOCH2CH3), 1.25 (d, 60-H), 1.82 (dd, 200-Hax), 2.00 (d, 200-
Heq), 2.33 (s, NCH3), 2.50 (s, 30-N(CH3)2), 2.58 (dd, 2-H), 3.07 (t,
quinoline-CH2), 3.26 (m, 40-H), 3.29 (m, 50-H), 3.56 (dd, 20-H),
3.65 (s, 4-OCH3), 3.86 (br d, 4-H), 3.99 (br d, 5-H), 4.38 (d, 10-H),
4.46 (dq, 500-H), 4.61 (d, 400-H), 5.06 (d, 100-H), 5.09 (m, 15-H),
5.45 (m, 3-H), 7.21 (d, quinoline), 7.55 (ddd, quinoline), 7.70
(ddd, quinoline), 8.01 (br d, quinoline), 8.11 (dd, quinoline), 8.79
(d, quinoline), 9.64 (s, CHO).
4.1.68. Preparation of 103
Reaction of 9,20-di-O-acetyl dimethylacetal of 103 with meth-
anol gave dimethylacetal of 103 in 53% yield by a similar proce-
dure to 17. Reaction of dimethylacetal of 103 with difluoroacetic
4.1.64. Stereoselective preparation of seco acid of 93
Reaction of 36 with (R)-7-methylamino-1-hepten-4-ol30 gave
seco acid of 93 in 75% yield by a similar procedure to 4; ½a D22
ꢀ
ꢁ57° (c 1.12, CHCl3); FAB-MS: m/z 1007 (M+H)+; 1H NMR (CDCl3)
d 0.88 (d, 8-CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.14 (t, 3-
OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3), 1.26 (d, 60-H), 1.83 (dd,
200-Hax), 2.00 (d, 200-Heq), 2.04 (s, 9-OCOCH3), 2.04 (s, 20-OCOCH3),
2.23 (m, 15-CH2), 2.40 (s, 30-N(CH3)2), 2.48 (s, NCH3), 2.72 (dd, 30-
H), 2.74 (dd, 2-H), 2.87 (dd, 2-H), 3.21 (s, CH(OCH3)2), 3.25 (s,
CH(OCH3)2), 3.31 (dd, 40-H), 3.32 (m, 50-H), 3.46 (d, 4-H), 3.55 (s,
4-OCH3), 3.65 (m, 15-H), 3.88 (d, 5-H), 4.25 (br s, 300-OH), 4.37
(dq, 500-H), 4.54 (dd, CH(OCH3)2), 4.61 (d, 400-H), 4.73 (d, 10-H),
4.98 (dd, 20-H), 5.04 (d, 100-H), 5.07 (m, 15-CH2CH@CH), 5.14 (br
t, 3-H), 5.14 (m, 9-H), 5.81 (m, 15-CH2CH@CH).
acid gave 103 in 54% yield by a similar procedure to 12; ½a D26
ꢀ
ꢁ52° (c 0.90, CHCl3); FAB-MS m/z 936 (M+H)+; HRMS: Calcd for
C48H77N3O15
:
936.5433. Found: 936.5431 (M+H)+; 1H NMR
(CDCl3) d 0.90 (d, 8-CH3), 1.10 (s, 300-CH3), 1.12 (d, 600-H), 1.14
(t, 3-OCOCH2CH3), 1.17 (t, 400-OCOCH2CH3), 1.18 (d, 60-H), 1.82
(dd, 200-Hax), 1.99 (d, 200-Heq), 2.30 (d, 10-H), 2.30 (s, NCH3),
2.43 (q, 3-OCOCH2CH3), 2.44 (q, 400-OCOCH2CH3), 2.49 (s, 30-
N(CH3)2), 2.60 (dd, 2-H), 2.86 (dd, 2-H), 3.27 (m, 40-H), 3.27 (m,
50-H), 3.32 (m, 9-H), 3.55 (dd, 20-H), 3.62 (s, 4-OCH3), 3.85 (d,
4-H), 3.99 (d, 5-H), 4.36 (d, 10-H), 4.47 (dq, 500-H), 4.61 (d, 400-
H), 5.06 (d, 100-H), 5.08 (m, 15-H), 5.53 (m, 3-H), 6.17 (dt, 15-
CH2CH@CH), 6.40 (d, 15-CH2CH@CH), 7.20 (dd, pyridine), 7.62
(dt, pyridine), 8.43 (dd, pyridine), 8.52 (d, pyridine), 9.64 (s,
CHO).
4.1.64. Preparation of 9,20-di-O-acetyl dimethylacetal of 102
Reaction of seco acid of 93 with 2-methyl-6-nitrobenzoic anhy-
dride gave 93 in 53% yield by a similar procedure to 92 and 93
starting from 91.Reaction of 93 with bromobenzene gave the cor-
responding 9,20-di-O-acetyl dimethylacetal in 81% yield by a simi-
lar procedure to 95; FAB-MS m/z 1065 (M+H)+; 1H NMR (CDCl3) d
0.90 (d, 8-CH3), 1.10 (s, 300-CH3), 1.11 (t, 3-OCOCH2CH3), 1.12 (d,
600-H), 1.16 (t, 400-OCOCH2CH3), 1.25 (d, 60-H), 1.72 (m, 8-H), 1.83
(dd, 200-Hax), 2.00 (d, 200-Heq), 2.04 (s, 9-OCOCH3), 2.04 (s, 20-
OCOCH3), 2.20 (s, NCH3), 2.40 (s, 30-N(CH3)2), 2.42 (m, 10-H),
2.44 (dd, 15-CH2), 2.57 (m, 2-H), 2.71 (t, 30-H), 2.84 (dd, 20-H),
3.13 (s, CH(OCH3)2), 3.23 (s, CH(OCH3)2), 3.34 (m, 40-H), 3.34 (m,
50-H), 3.58 (s, 4-OCH3), 3.65 (br d, 4-H), 3.92 (br d, 5-H), 4.37 (dq,
500-H), 4.55 (dd, CH(OCH3)2), 4.60 (d, 400-H), 4.72 (d, 10-H), 4.88
(m, 9-H), 5.00 (dd, 20-H), 5.06 (d, 100-H), 6.09 (dt, CH@CH), 6.42
(d, CH@CH), 7.25–7.35 (m, C6H5).
4.1.69. Preparation of 9,20-di-O-acetyl dimethylacetal of 104
Reaction of 93 with 1-bromonaphthalene gave the correspond-
ing 9,20-di-O-acetyl dimethylacetal in 58% yield by a similar proce-
dure to 95; ½a 2D2
ꢀ
ꢁ43° (c 1.0, CHCl3); FAB-MS m/z 1115 (M+H)+; 1H
NMR (CDCl3) d 0.91 (d, 8-CH3), 1.11 (s, 300-CH3), 1.11 (t, 3-
OCOCH2CH3), 1.12 (d, 600-H), 1.17 (t, 400-OCOCH2CH3), 1.26 (d, 60-
H), 1.83 (dd, 200-Hax), 2.00 (d, 200-Heq), 2.03 (s, 9-OCOCH3), 2.05
(s, 20-OCOCH3), 2.23 (s, NCH3), 2.40 (s, 30-N(CH3)2), 2.55 (m, 15-
CH2), 2.60 (dd, 2-H), 2.71 (t, 30-H), 2.85 (dd, 2-H), 3.14 (s,
CH(OCH3)2), 3.24 (s, CH(OCH3)2), 3.32 (m, 40-H), 3.32 (m, 50-H),
3.56 (s, 4-OCH3), 3.68 (d, 4-H), 3.93 (d, 5-H), 4.28 (br s, 300-OH),
4.38 (dq, 500-H), 4.56 (dd, CH(OCH3)2), 4.61 (d, 400-H), 4.72 (d, 10-
H), 4.91 (m, 9-H), 5.00 (dd, 20-H), 5.06 (d, 100-H), 5.17 (m, 15-H),
6.11 (dt, 15-CH2CH@CH), 7.15 (d, 15-CH2CH@CH), 7.40 (t, naphtha-
lene), 7.48 (m, naphthalene), 7.74 (d, naphthalene), 7.83 (m, naph-
thalene), 7.86 (m, naphthalene).
4.1.66. Preparation of 102
Reaction of 9, 20-di-O-acetyl dimethylacetal of 102 with metha-
nol gave dimethylacetal of 102 in 59% yield by a similar procedure
to 17. Reaction of dimethylacetal of 102 with difluoroacetic acid
4.1.70. Preparation of 104
gave 102 in 53% yield by a similar procedure to 12; ½a D16
ꢀ
ꢁ55° (c
Reaction of 9,20-di-O-acetyl dimethylacetal of 104 with metha-
nol gave dimethylacetal of 104 in 86% yield by a similar procedure
to 17. Reaction of dimethylacetal of 104 with difluoroacetic acid
1.0, CHCl3); FAB-MS m/z 935 (M+H)+; HRMS: Calcd for
C49H78N2O15: 935.548. Found: 935.5466 (M+H)+; 1H NMR (CDCl3)
d 0.90 (d, 8-CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.14 (t, 3-
OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3), 1.19 (d, 60-H), 1.30 (m, 8-
H), 1.82 (dd, 200-Hax), 2.00 (d, 200-Heq), 2.30 (s, NCH3), 2.45 (m,
30-H), 2.49 (s, 30-N(CH3)2), 2.61 (dd, 2-H), 2.82 (dd, 2-H), 2.88 (dd,
6-CH2), 3.28 (m, 40-H), 3.28 (m, 50-H), 3.36 (m, 9-H), 3.55 (dd, 20-
H), 3.60 (s, 4-OCH3), 3.84 (br d, 4-H), 4.00 (br d, 5-H), 4.36 (d, 10-
gave 104 in 54% yield by a similar procedure to 12; ½a D22
ꢁ44° (c
ꢀ
1.0, CHCl3); FAB-MS m/z 985 (M+H)+; HRMS: Calcd for
C53H80N2O15: 985.5637. Found: 985.5634 (M+H)+; 1H NMR (CDCl3)
d 0.90 (d, 8-CH3), 1.10 (s, 300-CH3), 1.12 (d, 600-H), 1.13 (t, 3-
OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3), 1.18 (d, 60-H), 1.82 (dd,
200-Hax), 1.99 (d, 200-Heq), 2.31 (d, 10-H), 2.31 (s, NCH3), 2.41 (q,

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
10155
3-OCOCH2CH3), 2.43 (q, 400-OCOCH2CH3), 2.49 (s, 30-N(CH3)2), 2.58
(dd, 2-H), 2.82 (dd, 2-H), 3.27 (m, 40-H), 3.27 (m, 50-H), 3.34 (m, 9-
H), 3.54 (dd, 20-H), 3.57 (s, 4-OCH3), 3.84 (d, 4-H), 4.02 (d, 5-H),
4.36 (d, 10-H), 4.47 (dq, 500-H), 4.60 (d, 400-H), 5.05 (d, 100-H), 5.16
(m, 15-H), 5.53 (m, 3-H), 6.10 (dt, 15-CH2CH@CH), 7.14 (d, 15-
CH2CH@CH), 7.39 (dt, naphthalene), 7.47 (dt, naphthalene), 7.73
(dd, naphthalene), 7.82 (d, naphthalene), 8.04 (d, naphthalene),
9.63 (s, CHO).
C52H79N3O15:
986.5589. Found: 986.5601 (M+H)+; 1H NMR
(CDCl3) d 0.91 (d, 8-CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.14
(t, 3-OCOCH2CH3), 1.17 (t, 400-OCOCH2CH3), 1.18 (d, 60-H), 1.32
(m, 8-H), 1.82 (dd, 200-Hax), 2.00 (d, 200-Heq), 2.33 (s, NCH3),
2.49 (s, 30-N(CH3)2), 2.62 (dd, 2-H), 2.84 (dd, 2-H), 2.87 (dd, 6-
CH2), 3.25 (m, 40-H), 3.25 (m, 50-H), 3.38 (m, 9-H), 3.55 (dd, 20-
H), 3.62 (s, 4-OCH3), 3.85 (br d, 4-H), 3.99 (br d, 5-H), 4.37 (d,
10-H), 4.46 (dq, 500-H), 4.61 (d, 400-H), 5.06 (d, 100-H), 5.13 (m,
15-H), 5.53 (m, 3-H), 6.34 (dt, CH@CH), 6.58 (d, CH@CH), 7.52
(ddd, quinoline), 7.65 (ddd, quinoline), 7.76 (dd, quinoline), 7.98
(d, quinoline), 8.05 (br d, quinoline), 8.92 (d, quinoline), 9.64 (s,
CHO).
4.1.71. Preparation of 9,20-di-O-acetyl dimethylacetal of 105
Reaction of 93 with 2-bromonaphthalene gave the correspond-
ing 9,20-di-O-acetyl dimethylacetal in 45% yield by a similar proce-
dure to 95; ½a 2D7
ꢀ
ꢁ48° (c 1.0, CHCl3); FAB-MS m/z 1115 (M+H)+; 1H
NMR (CDCl3) d 0.90 (d, 8-CH3), 1.10 (s, 300-CH3), 1.11 (d, 600-H), 1.11
(t, 3-OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3), 1.26 (d, 60-H), 1.82 (dd,
200-Hax), 2.00 (d, 200-Heq), 2.03 (s, 9-OCOCH3), 2.04 (s, 20-OCOCH3),
2.22 (s, NCH3), 2.39 (s, 30-N(CH3)2), 2.51 (m, 15-CH2), 2.59 (dd, 2-
H), 2.71 (t, 30-H), 2.84 (dd, 2-H), 3.14 (s, CH(OCH3)2), 3.24 (s,
CH(OCH3)2), 3.32 (m, 40-H), 3.32 (m, 50-H), 3.56 (s, 4-OCH3), 3.64
(d, 4-H), 3.92 (d, 5-H), 4.26 (br s, 300-OH), 4.37 (dq, 500-H), 4.54
(dd, CH(OCH3)2), 4.60 (d, 400-H), 4.71 (d, 10-H), 4.90 (m, 9-H), 5.00
(dd, 20-H), 5.05 (d, 100-H), 5.05 (br t, 3-H), 5.12 (m, 15-H), 6.22
(dt, 15-CH2CH@CH), 6.58 (d, 15-CH2CH@CH), 7.41 (m, naphtha-
lene), 7.53 (dd, naphthalene), 7.65 (s, naphthalene), 7.75 (m,
naphthalene).
4.1.75. Preparation of 107
Hydrogenolysis of dimethylacetal of 106 in 1, 4-dioxane/H2O
(2:1) gave dimethylacetal of 107 in 63% yield by a similar proce-
dure to 40. Reaction of dimethylacetal of 107 with difluoroacetic
acid gave 107 in 36% yield by a similar procedure to 12. ½a D24
ꢀ
ꢁ57° (c 0.43, CHCl3); FAB-MS m/z 988 (M+H)+; HRMS: Calcd for
C52H81N3O15: 988.5746. Found: 988.5751 (M+H)+; 1H NMR (CDCl3)
d 0.91 (d, 8-CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.13 (t, 3-
OCOCH2CH3), 1.17 (t, 400-OCOCH2CH3), 1.21 (d, 60-H), 1.81 (dd,
200-Hax), 2.00 (d, 200-Heq), 2.29 (s, NCH3), 2.29 (d, 10-H), 2.43 (q,
3-OCOCH2CH3), 2.44 (q, 400-OCOCH2CH3), 2.50 (s, 30-N(CH3)2),
2.60 (dd, 2-H), 2.84 (dd, 2-H), 3.27 (m, 40-H), 3.27 (m, 50-H), 3.36
(m, 9-H), 3.56 (dd, 20-H), 3.66 (s, 4-OCH3), 3.85 (d, 4-H), 4.00 (d,
5-H), 4.37 (d, 10-H), 4.46 (dq, 500-H), 4.62 (d, 400-H), 5.04 (m, 15-
H), 5.06 (d, 100-H), 5.47 (m, 3-H), 7.52 (ddd, quinoline), 7.65 (ddd,
quinoline), 7.75 (dd, quinoline), 7.89 (d, quinoline), 8.06 (br d,
quinoline), 8.74 (d, quinoline), 9.64 (s, CHO).
4.1.72. Preparation of 105
Reaction of 9,20-di-O-acetyl dimethylacetal of 105 with metha-
nol gave dimethylacetal of 105 in 54% yield by a similar procedure
to 17. Reaction of dimethylacetal of 105 with difluoroacetic acid
gave 105 in 61% yield by a similar procedure to 12; ½a D26
ꢁ41° (c
ꢀ
1.07, CHCl3); FAB-MS m/z 985 (M+H)+; HRMS: Calcd for
C53H80N2O15: 985.5637. Found: 985.5630 (M+H)+; 1H NMR (CDCl3)
d 0.91 (d, 8-CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.14 (t, 3-
OCOCH2CH3), 1.17 (t, 400-OCOCH2CH3), 1.18 (d, 60-H), 1.82 (dd,
200-Hax), 2.00 (d, 200-Heq), 2.30 (d, 10-H), 2.31 (s, NCH3), 2.43 (q,
3-OCOCH2CH3), 2.44 (q, 400-OCOCH2CH3), 2.49 (s, 30-N(CH3)2),
2.62 (dd, 2-H), 2.84 (dd, 2-H), 3.27 (m, 40-H), 3.27 (m, 50-H), 3.35
(m, 9-H), 3.55 (dd, 20-H), 3.60 (s, 4-OCH3), 3.85 (d, 4-H), 4.01 (d,
5-H), 4.36 (d, 10-H), 4.47 (dq, 500-H), 4.61 (d, 400-H), 5.06 (d, 100-H),
5.13 (m, 15-H), 5.53 (m, 3-H), 6.21 (dt, 15-CH2CH@CH), 6.58 (d,
15-CH2CH@CH), 7.43 (m, naphthalene), 7.53 (dd, naphthalene),
7.65 (s, naphthalene), 7.76 (dt, naphthalene), 9.64 (s, CHO).
4.1.76. Preparation of 9, 20-di-O-acetyl dimethylacetal of 108
Reaction of 93 with 6-bromoquinoline gave the corresponding
9,20-di-O-acetyl dimethylacetal in 43% yield by a similar procedure
to 95; ½a 2D7
ꢀ
ꢁ45° (c 1.0, CHCl3); FAB-MS m/z 1116 (M+H)+; 1H NMR
(CDCl3) d 0.90 (d, 8-CH3), 1.10 (s, 300-CH3), 1.10 (t, 3-OCOCH2CH3),
1.11 (d, 600-H), 1.15 (t, 400-OCOCH2CH3), 1.25 (d, 60-H), 1.82 (dd,
200-Hax), 2.00 (d, 200-Heq), 2.02 (s, 9-OCOCH3), 2.03 (s, 20-OCOCH3),
2.21 (s, NCH3), 2.39 (s, 30-N(CH3)2), 2.52 (m, 15-CH2), 2.58 (dd, 2-
H), 2.70 (t, 30-H), 2.83 (dd, 2-H), 3.13 (s, CH(OCH3)2), 3.23 (s,
CH(OCH3)2), 3.32 (dd, 40-H), 3.32 (m, 50-H), 3.55 (s, 4-OCH3), 3.61
(d, 4-H), 3.92 (d, 5-H), 4.26 (br s, 300-OH), 4.36 (dq, 500-H), 4.53
(dd, CH(OCH3)2), 4.59 (d, 400-H), 4.70 (d, 10-H), 4.89 (m, 9-H), 4.99
(dd, 20-H), 5.05 (d, 100-H), 5.05 (br t, 3-H), 5.12 (m, 15-H), 6.27
(dt, 15-CH2CH@CH), 6.58 (d, 15-CH2CH@CH), 7.35 (dd, quinoline),
7.63 (d, quinoline), 7.77 (dd, quinoline), 7.99 (d, quinoline), 8.08
(dd, quinoline), 8.82 (dd, quinoline).
4.1.73. Preparation of 9,20-di-O-acetyl dimethylacetal of 106
Reaction of 93 with 3-bromoquinoline gave the corresponding
9,20-di-O-acetyl dimethylacetal in 25% yield by a similar procedure
to 95; ½a 2D1
ꢀ
ꢁ42° (c 1.5, CHCl3); FAB-MS m/z 1116 (M+H)+; 1H NMR
(CDCl3) d 0.90 (d, 8-CH3), 1.10 (s, 300-CH3), 1.11 (d, 600-H), 1.11 (t, 3-
OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3), 1.25 (d, 60-H), 1.82 (dd, 200-
Hax), 2.00 (d, 200-Heq), 2.02 (s, 9-OCOCH3), 2.04 (s, 20-OCOCH3),
2.22 (s, NCH3), 2.39 (s, 30-N(CH3)2), 2.54 (m, 15-CH2), 2.71 (t, 30-
H), 2.84 (dd, 2-H), 3.13 (s, CH(OCH3)2), 3.23 (s, CH(OCH3)2), 3.31
(m, 40-H), 3.34 (m, 50-H), 3.56 (s, 4-OCH3), 3.93 (br d, 5-H), 4.27
(br s, 300-OH), 4.36 (dq, 500-H), 4.54 (dd, CH(OCH3)2), 4.60 (d, 400-
H), 4.71 (d, 10-H), 4.89 (m, 9-H), 4.99 (dd, 20-H), 5.05 (d, 100-H),
5.13 (m, 15-H), 6.34 (dt, CH@CH), 6.59 (d, CH@CH), 7.50 (br t, quin-
oline), 7.64 (ddd, quinoline), 7.76 (br d, quinoline), 7.99 (d, quino-
line), 8.03 (d, quinoline), 8.92 (d,quinoline).
4.1.77. Preparation of 108
Reaction of 9,20-di-O-acetyl dimethylacetal of 108 with metha-
nol gave dimethylacetal of 108 in 66% yield by a similar procedure
to 17. Reaction of dimethylacetal of 108 with difluoroacetic acid
gave 108 in 65% yield by a similar procedure to 12; ½a D24
ꢁ34° (c
ꢀ
1.0, CHCl3); FAB-MS m/z 986 (M+H)+; HRMS: Calcd for
C52H79N3O15: 986.5589. Found: 986.5583 (M+H)+; 1H NMR (CDCl3)
d 0.90 (d, 8-CH3), 1.10 (s, 300-CH3), 1.12 (d, 600-H), 1.14 (t, 3-
OCOCH2CH3), 1.17 (t, 400-OCOCH2CH3), 1.20 (d, 60-H), 1.82 (dd,
200-Hax), 1.99 (d, 200-Heq), 2.30 (d, 10-H), 2.30 (s, NCH3), 2.42 (q,
3-OCOCH2CH3), 2.44 (q, 400-OCOCH2CH3), 2.49 (s, 30-N(CH3)2),
2.61 (dd, 2-H), 2.86 (dd, 2-H), 3.26 (t, 40-H), 3.27 (m, 50-H), 3.38
(m, 9-H), 3.54 (dd, 20-H), 3.60 (s, 4-OCH3), 3.86 (d, 4-H), 4.00 (d,
5-H), 4.35 (d, 10-H), 4.46 (dq, 500-H), 4.60 (d, 400-H), 5.05 (d, 100-H),
5.13 (m, 15-H), 5.54 (m, 3-H), 6.26 (dt, 15-CH2CH@CH), 6.58 (d,
15-CH2CH@CH), 7.37 (dd, quinoline), 7.62 (d, quinoline), 7.76
(dd, quinoline), 8.01 (d, quinoline), 8.09 (dd, quinoline), 8.83 (dd,
quinoline), 9.64 (s, CHO).
4.1.74. Preparation of 106
Reaction of 9,20-di-O-acetyl dimethylacetal of 106 with meth-
anol gave dimethylacetal of 106 in 61% yield by a similar proce-
dure to 17. Reaction of dimethylacetal of 106 with difluoroacetic
acid gave 106 in 45% yield by a similar procedure to 12; ½a D20
ꢀ
ꢁ51° (c 0.36, CHCl3); FAB-MS m/z 986 (M+H)+; HRMS: Calcd for

10156
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 10129–10156
6. Mathews, A. W. Fraud, errors taint key study of Sanofi drug (from The Wall
4.2. Biology
Street Journal). Dow Jones Newswires, May 1, 2006, Ó 2006 Dow Jones &
Company, Inc.
4.2.1. In vitro antibacterial activity
7. (a) Furuuchi, T.; Kurihara, K.; Ajito, K.; Yoshida, T.; Fushimi, H. JP 2004217562,
2004.; (b) Kurihara, K.; Miura, T.; Okura, N.; Yoshida, T.; Furuuchi, T.; Ajito, K.
WO 02/064607 A1, 2002.; (c) Kurihara, K.; Miura, T.; Okura, N.; Yoshida, T.;
Furuuchi, T.; Fujihira, Y.; Yoshida, T.; Fushimi, H.; Ajito, K. WO 06/073172 A1,
2006; (d) Furuuchi, T.; Miura, T.; Kurihara, K.; Yoshida, T.; Ajito, K. Bioorg. Med.
Chem. 2008, 16, 4401; (e) Miura, T.; Kurihara, K.; Furuuchi, T.; Yoshida, T.; Ajito,
K. Bioorg. Med. Chem. 2008, 16, 3985.
8. (a) Miura, T.; Natsume, S.; Kanemoto, K.; Atsumi, K.; Fushimi, H.; Sasai, H.; Arai,
T.; Yoshida, T.; Ajito, K. J. Antibiot. 2007, 60, 407; (b) Miura, T.; Kurihara, K.;
Yoshida, T.; Ajito, K. US 2005/0209446 A1, 2005.
9. Kobrehel, G.; Djokic, S. US Patent 4,517,359, 1985.
10. Jones, A. B. J. Org. Chem. 1992, 57, 4361.
11. Shankaran, K.; Wilkening, R. R. EP 0 549 040 A1, 1993.
12. Lazarevski, G.; Kobrehel, G.; Kelneric, Z. WO 99/51616, 1994.
13. Lopotar, N.; Djokic, S. EP 0 410 433 B1, 1996.
Minimum inhibitory concentration (MIC) was determined by
the agar dilution method. Test strains were subjected to seed cul-
ture using Sensitivity test broth (STB, Nissui Pharmaceutical) for
Staphylococcus aureus, or cultured on blood agar plate for S. pneu-
moniae, S. pyogenes, M. catarrhalis, and H. influenzae. A 5 ll portion
of cell suspension of the test strains having about 106 CFU/ml was
inoculated into Sensitivity disk agar (SDA, Nissui Pharmaceutical)
supplemented with 5% horse blood and incubated at 37 °C for
20 h. Then, MIC was defined as the lowest drug concentration that
prevented visible growth.
14. Mutak, S. J. Antibiot. 2007, 60, 85.
15. Waddell, S. T.; Blizzard, T. A. WO 94/15617, 1994.
Acknowledgments
16. Waddell, S. T.; Blizzard, T. A. Tetrahedron Lett. 1993, 34, 5385.
17. (a) Freiberg, L. A.; Egan, R. S.; Washburn, W. H. J. Org. Chem. 1974, 39, 2474; (b)
Furuuchi, T.; Kurihara, K.; Yoshida, T.; Ajito, K. J. Antibiot. 2003, 56, 399.
18. Omoto, S.; Iwamatsu, K.; Inouye, S.; Niida, T. J. Antibiot. 1976, 29, 536.
19. Tsuruoka, T.; Shomura, T.; Ezaki, N.; Watanabe, H.; Akita, E.; Inouye, S.; Niida, T.
J. Antibiot. 1971, 24, 452.
The authors thank Drs. Y. Otsuka, T. Okonogi, S. Hoshiko, for
encouragement and valuable discussion. We are grateful to Drs.
S. Inouye, S. Shibahara and S. Gomi for supervision through our
in-house drug discovery program in macrolide field. We also
thank Mrs. K. Kobayashi for direction in intellectual properties,
Drs. M. Oyama, Y. Takeuchi, K. Kurihara, T. Furuuchi, Mr. N.
Okura, Mr. T. Watanabe, Mrs. T. Miyara, and Miss S. Miki for con-
tribution toward analytical and synthetic chemistry, Mr. Y. Takay-
ama for in vitro evaluation, Mrs. Y. Saito for manuscript, and Mrs.
M. Takagi for English.
20. Miura, T.; Kanemoto, K.; Natsume, S.; Okura, N.; Fujihira, Y.; Watanabe, T.;
Atsumi, K.; Ajito, K. WO05/019238 A1, 2005.
21. Agouridas, C.; Benedetti, Y.; Chantot, J. F.; Denis, A.; Martret, O. L. EP 0 676 409
B1, 1995.
22. Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Angew. Chem. Int. Ed. 1998, 37,
2014.
23. (a) Kolb, H. C.; Sharpless, K. B. Drug Discov. Today 2003, 8, 1128; (b) Hirose, T.;
¯
Sunazuka, T.; Noguchi, Y.; Yamaguchi, Y.; Hanaki, H.; Sharpless, K. B.; Omura, S.
Heterocycles 2006, 69, 55; (c) Sugawara, A.; Sunazuka, T.; Hirose, T.; Nagai, K.;
¯
Yamaguchi, Y.; Hanaki, H.; Sharpless, K. B.; Omura, S. Bioorg. Med. Chem. Lett.
References and notes
2007, 17, 6340.
24. 1H NMR (300 MHz, CDCl3) d 1.64 (m, 5-H), 2.27 (dd, 3-H), 2.38 (s, NCH3), 2.63
(m, 6-H), 3.42 (m, 4-H), 5.09 (m, 1-H), 5.75 (ddt, 2-H).
25. Ziegler, C. B.; Heck, R. F. J. Org. Chem. 1978, 43, 2941.
26. FAB-MS m/z 144 (M+H)+ as C8H17NO; 1H NMR (300 MHz, CDCl3) d 1.45 (m, 2-
H), 1.57 (m, 3-H), 1.76 (m, 2-H), 2.02 (m, 4-H), 2.33 (dd, 3-CH2), 2.39 (s, NCH3),
2.65 (dd, 3-CH2), 3.46 (ddd, HOCH2), 3.65 (ddd, HOCH2), 5.00 (m, 1-H), 5.73 (m,
2-H).
1. (a) Omura, S. Macrolide Antibiotics. Chemistry, Biology, and Practice; Academic
Press Inc., 1984; (b) Omura, S. Macrolide Antibiotics. Chemistry, Biology, and
Practice, 2nd ed.; Academic Press Inc., 2002.
2. Morimoto, S.; Takahashi, Y.; Watanabe, Y.; Omura, S. J. Antibiot. 1984, 37, 187.
3. Slobodan, D.; Gabrijela, K.; Nevenka, L.; Boris, K.; Ante, N.; Draginja, M. J. Chem.
Res. Synop. 1988, 152.
27. Shiina, I.; Kubota, M.; Ibuka, R. Tetrahedron Lett. 2002, 43, 7535.
28. Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989.
29. (a) Ajito, K.; Kurihara, K.; Shibahara, S.; Hara, O.; Shimizu, A.; Araake, M.;
Omoto, S. J. Antibiot. 1997, 50, 92; (b) Kurihara, K.; Kikuchi, N.; Ajito, K. J.
Antibiot. 1997, 50, 32.
4. Denis, A.; Agouridas, C.; Auger, J. M.; Benedetti, Y.; Bonnefoy, A.; Bretin, F.;
Chantot, J. F.; Dussarat, A.; Fromentin, C.; D’Ambrieres, S. G.; Lachaud, S.;
Laurin, P.; Martret, O. L.; Loyau, V.; Tessot, N.; Pejac, J. M.; Perron, S. Bioorg. Med.
Chem. Lett. 1999, 9, 3075.
5. Or, Y. S.; Wang, G.; Phan, L. T.; Niu, D.; Vo, N. H.; Qiu, Y. -L.; Wang, Y.; Busuyek,
M.; Hou, Y.; Peng, Y.; Kim, H.; Liu, T.; Farmer, J. J.; Xu G. WO 03/097659 A1,
2003.
30. ½ ꢀ
a 2D4 9.8° (c 1.2, CHCl3); ES-MS m/z 144 (M+H)+ as C8H17NO, preparation of (R)-
7-methylamino-1-hepten-4-ol: see our original patent.20
.