Novel 16-membered macrolides modified at C-12 and C-13 positions of midecamycin A1 and miokamycin. Part 1: Synthesis and evaluation of 12,13-carbamate and 12-arylalkylamino-13-hydroxy analogues

Article abstract of DOI:10.1016/j.bmc.2008.01.027

Design and synthesis of 16-membered macrolides modified at the C-12 and 13 positions are described. The compounds we report here have an arylalkylamino group attached to the C-12 position of the macrolactone. Both types of derivatives, 12,13-cyclic carbamates and non-carbamate analogues, were synthesized via 12-amino-13-hydroxy intermediates derived from 12,13-epoxide that was prepared by selective epoxidation at the C-12 and C-13 positions. 4′-Hydroxyl analogues were also prepared by acidic hydrolysis of a neutral sugar. These compounds were evaluated for in vitro antibacterial activity against respiratory tract pathogens. Some of these analogues exhibited an improved activity compared with the corresponding parent compound.

Full text of DOI:10.1016/j.bmc.2008.01.027

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 3985–4002
Novel 16-membered macrolides modified at C-12 and C-13
positions of midecamycin A1 and miokamycin.
Part 1: Synthesis and evaluation of 12,13-carbamate
and 12-arylalkylamino-13-hydroxy analogues
Tomoaki Miura,* Ken-ichi Kurihara, Takeshi Furuuchi, Takuji Yoshida and Keiichi Ajito*
Pharmaceutical Research Center, Meiji Seika Kaisha Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan
Received 6 November 2007; revised 15 January 2008; accepted 16 January 2008
Available online 19 January 2008
Abstract—Design and synthesis of 16-membered macrolides modified at the C-12 and 13 positions are described. The compounds we
report here have an arylalkylamino group attached to the C-12 position of the macrolactone. Both types of derivatives, 12,13-cyclic
carbamates and non-carbamate analogues, were synthesized via 12-amino-13-hydroxy intermediates derived from 12,13-epoxide
that was prepared by selective epoxidation at the C-12 and C-13 positions. 40-Hydroxyl analogues were also prepared by acidic
hydrolysis of a neutral sugar. These compounds were evaluated for in vitro antibacterial activity against respiratory tract pathogens.
Some of these analogues exhibited an improved activity compared with the corresponding parent compound.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Macrolide antibiotics generally have low toxicity and
are orally available. Therefore they play an important
role in therapeutic treatments of bacterial infectious dis-
eases. In particular, clinically representative macrolides
such as clarithromycin (CAM)1–6 and azithromycin
(AZM)7,8 derived from 14-membered erythromycin ex-
hibit strong antibacterial activities against respiratory
tract pathogens and have characteristic pharmacokinet-
ics. An extensive use of these macrolides has, however,
allowed an increase in emergence of erythromycin-resis-
tant gram-positive bacteria, especially Streptococcus
pneumoniae. Macrolide-resistant S. pneumoniae are
roughly classified into ribosome methylation by an erm
gene and efflux of macrolides by a mef gene. Recently,
several researches have been made to overcome macro-
lide resistance, which resulted in the discovery of keto-
lides such as telithromycin (TEL)9 and cethromycin
(ABT-773)10,11 (Fig. 1). These ketolides synthesized
from 14-membered erythromycin showed strong po-
tency against the erm- and mef-resistant S. pneumoniae.
Figure 1. Structures of ketolides.
Keywords: 16-Membered macrolide; Midecamycin A1; Miokamycin;
Streptococcus pneumoniae; Antibacterial activity.
On the other hand, 16-membered macrolides that
possess enough effects against resistant pathogens are
rarely known. Some derivatives of leucomycin-type
*
Corresponding authors. Tel.: +81 45 545 3131; fax: +81 45 543 9771
(T.M.); e-mail addresses: tomoaki_miura@meiji.co.jp; keiichi_
ajito@meiji.co.jp
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.01.027

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T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
16-membered macrolides such as miokamycin (MOM)12
and rokitamycin (RKM)13,14 (Fig. 2) are not affected by
efflux pumps. If we can discover the 16-membered mac-
rolides possessing an activity against the erm-resistant S.
pneumoniae, it would be very beneficial for chemother-
apy against infectious diseases.
A3 with m-chloroperbenzoic acid (m-CPBA) to afford
the epoxy-N-oxide, and then reduced the N-oxide moi-
ety with Na2S2O4 to give the epoxide.21 On the basis
of this knowledge, we decided to synthesize an epoxide
(3) by regio- and stereoselective reaction of 2 with m-
CPBA. We planned to perform a ring-opening reaction
of the epoxide (3) at an allylic position, which would af-
ford an azide (4). It would then be converted into an
amine intermediate (5).
There is an aryl group in the ketolide molecule in gen-
eral. The ketolide class compounds, such as TEL and
HMR 300415 (Fig. 1), possess an arylalkyl-type side
chain attached to the 11,12-cyclic carbamate in the wes-
tern hemisphere of the macrolactone. It was reported
that the arylalkyl group protected A752 residue in do-
main II of ribosomal RNA against chemical modifica-
tion.16 These observations suggested that the aryl side
chain might interact with the second binding site in
rRNA. Further, X-ray crystallographic analysis on
ketolide–ribosome complex indicated that the aryl
group of TEL or ABT-773 bound to domain II through
stacking or hydrogen bonding.17,18 Thus, the aryl side
chain is significantly important for antibacterial activi-
ties against erythromycin-resistant pathogens. We re-
cently exemplified novel azalides synthesized from
leucomycin-type 16-membered macrolide.19,20 To our
knowledge, this is information on the introduction of
an arylalkyl side chain in the western hemisphere as
far as leucomycin analogues are concerned.
In order to analyze fundamental structure–activity rela-
tionships (SAR), we chose midecamycin A1 (MDM) as a
starting material. Then, we decided to use 9-O-acetyl
derivative (2) for accomplishment of regioselective epox-
idation at the C-12,13 positions.
The synthetic methods of 12,13-cyclic carbamates are
shown in Scheme 1. Protection at the C-18 position of
9-O-acetylmidecamycin A1 (1)22 afforded dimethyl ace-
tal (2). Epoxidation of 2 with m-CPBA followed by
reduction of a 30-N-oxide using Na2S2O4 gave the epox-
ide (3) regio- and stereoselectively. The structure of the
epoxide (3) was determined by X-ray crystallographic
analysis. Ring-opening reaction of the epoxide with so-
dium azide proceeded at the allylic position to generate
the azide (4a), which was converted to 4b by acetic anhy-
dride without a base. Then, treatment of 4a or 4b with
triphenylphosphine gave the corresponding 12-amino
analogues (5a or 5b). Conversion of 5b to the cyclic car-
bamate (6a) was achieved with 1,10-carbonyldiimidazole
(CDI) at room temperature. Although the benzyl ana-
logue (6b) was also obtained by reductive alkylation of
5b with benzaldehyde followed by cyclization with
CDI, higher reaction temperature and longer reaction
time were required in this cyclization step. The phen-
ylalkyl analogues (9a–c) were therefore prepared by
treatment of the secondary amines (8a–c) derived from
5a with triphosgene and triethylamine. Deprotection of
6a, b and 9a–c afforded the final products (7a, b and
10a–c).
In this paper, we would like to disclose preparation and
potency of 12,13-carbamate and 12-arylalkylamino-13-
hydroxy analogues of midecamycin A1.
2. Results and discussion
2.1. Preparation of 12,13-cyclic carbamates and their
antibacterial activities
For introduction of an aryl moiety onto a macrolactone,
we focused on the conjugated diene at the C-10 to 13
positions in leucomycin-type 16-membered macrolide.
Muroi et al. described stereoselective and non-regiose-
lective epoxidation at the C-10 to 13 positions in leuco-
mycin A3 (josamycin). They first peroxidized leucomycin
In compound 10b, NOEs were observed between the
proton at C-11 and the methylene proton at C-14, and
also between the methine proton at C-12 and the
methine proton at C-13. This result suggested that 10b
adopted 12R and 13S configuration (A in Fig. 3). On
the other hand, in case of 12S and 13S configuration,
NOE was not observed between the protons at the C-
11 and C-14 positions or between the protons at the
C-12 and C-13 positions (B in Fig. 3). We thus finally
concluded that substitution by azide anion of the epox-
ide (3) proceeded through trans ring-opening reaction.
As shown in Table 1, antibacterial activities of these
compounds against gram-positive bacteria were gener-
ally comparable with that of compound 1 or MDM.
All compounds maintained antibacterial activities
against efflux-resistant S. pneumoniae and characteristics
of 16-membered macrolides as we had expected. An in-
crease in the spacer length, however, led to a decrease in
the activities against Haemophilus influenzae. On the
other hand, 7b, 10a, and 10c having phenylalkyl groups
showed weak antibacterial activities against inducible-
Figure 2. Natural antibiotic, midecamycin A1 and representative
semisynthetic 16-membered macrolides, miokamycin and rokitamycin.

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
3987
Scheme 1. Synthesis of 12,13-cyclic carbamates of MDM. Reagents and conditions: (a) AcCl, pyridine, CH2Cl2, 0 °C, 45 min, quant; (b) pyridinium
p-toluenesulfonate, CH(OMe)3, MeOH, 50 °C, 33 h, 80%; (c) 1—m-CPBA, CHCl3, rt, 14 h; 2—aq Na2S2O4, EtOH, 0 °C, 30 min, 62% overall two
steps; (d) NaN3, NH4Cl, EtOH/H2O (8:1), 80 °C, 21 h, 73%; (e) Ac2O, MeCN, 50 °C, 8 h, 90%; (f) Ph3P, MeCN, rt, 23 h then H2O, rt, 6 h, 67–68%;
(g) CDI, THF, rt, 3 h, 88%; (h) 1—PhCHO, NaBH(OAc)3, AcOH, Cl(CH2)2Cl, rt, 2 h, 80%; 2—CDI, THF, reflux, 26 h, 81%; (i) Ph(CH2)nꢀ1CHO,
NaBH3CN, AcOH, MeOH, rt, 1–1.5 h, 33–59%; (j) triphosgene, Et3N, CH2Cl2, 0 °C, 45 min–1.5 h, 42–90%; (k) MeOH/H2O (9:1), 50 °C, 24–27 h,
97%; (l) CHF2COOH, MeCN/H2O (1:1), rt–35 °C, 26.5–41 h, 61–69%.
resistant S. pneumoniae. Although improved antibacte-
rial activities were expected by converting the phenyl
group to a certain heterocycle shown in ketolides
(Fig. 1), for example, the quinolinyl group, we supposed
that the construction of cyclic carbamate at the western
hemisphere in 16-membered macrolide was not always
an appropriate approach for seeking strong antimicro-
bial activities. We therefore decided to investigate fun-
damental SAR of compounds without the ring
structure in the western hemisphere.
2.2. Preparation of 12-arylalkylamino-13-hydroxy ana-
logues and their antibacterial activities
Scheme 2 describes the synthesis of 12-arylalkylamino-
13-hydroxy analogues starting from the amine, 5a.
Reductive methylation of 5a and 8a–c with formalde-
hyde gave the corresponding 12-dialkylamino analogues
(11a and 11c–e). Moreover, other analogues (11b and
11f–h) with a phenyl group attached to a different meth-
ylene linker or 11i–m with a variety of aryl groups at-

3988
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
40-oxygen atom and the 300-O-acetyl group. This phe-
nomenon is often observed and acidic hydrolysis at the
neutral sugar is believed to be spatially disturbed by
the acetyl group.
The 12-dimethylamino analogue (12a) without a phenyl
group was a little less active than 1 as shown in Table 2.
The 12-phenylalkylamino analogues (12f–h) that have
the spacer length of C5–C7 exhibited weak antibacterial
activities against not only inducible-resistant S. pneumo-
niae but also constitutive ones. The activities of the 12-
phenylpropylamino analogue (12d), however, seemed
to exhibit the best-balanced antibacterial spectrum ex-
cept against constitutive-resistant S. pneumoniae. We
prepared some compounds with a variety of substitu-
ents, for example, methoxy, dimethylamino, fluoro, ni-
tro etc., on the benzene ring of 12d, but antibacterial
activities of these compounds were not enhanced com-
pared with those of 12d (data not shown). Thus, the phe-
nyl group of 12d was converted into various aryl groups.
The antibacterial activities against inducible-resistant S.
pneumoniae were decreased, when a nitrogen atom was
introduced into the benzene ring in 12d (see 12i in Table
3). On the other hand, introduction of a nitrogen atom
into the naphthalene ring of 12j was effective, namely,
12l generally exhibited enhanced antibacterial activities
and had the strongest activities among 300-OH ana-
logues. Antibacterial activities of 12l against resistant
S. pneumoniae were stronger than those of CAM. Com-
pound 12l was also effective against constitutive-resis-
tant S. pneumoniae. We expected that the activity of
the compound 12m having the side chain of TEL would
be enhanced, but its activity was not remarkable.
Figure 3. Possible configuration at the C-12 and C-13 positions in
cyclic carbamates.
tached to a propyl group were prepared from 5a by
sequential reductive alkylations. Deprotection of 11a–
m with difluoroacetic acid furnished the desired prod-
ucts (12a–m) in 24–64% yield accompanied with the
monosaccharide analogues (13d and 13i–m) in which
the neutral sugar was removed.
By the way, MOM, 300-O-acetyl analogue of 1, was much
more active than 1 against inducible-resistant S. pneu-
moniae. Then, we decided to prepare the 300-O-acetyl
analogue of 12d, compound 18, as a model study focus-
ing on antibacterial activities against erm-resistant S.
pneumoniae. As shown in Scheme 3, compound 18 was
synthesized by a similar method to 12d starting from
MOM. In this case, hydrolysis of the neutral sugar in
the final deprotection step was not observed at all, un-
like in the case of deprotection of 11. The chemical sta-
bility of compound 18 under acidic conditions could be
explained by 1, 3-diaxial relationship between the
Table 1. Antibacterial activities of 12,13-cyclic carbamates
Test organisma
Characteristics
(MIC, lg/ml)
7a
7b
10a
10b
10c
1
MDM
S. aureus
Standard
Susceptible
Susceptible
ermA (c)b
ermB (i)c
0.39
0.78
0.39
>100
0.39
0.78
0.2
0.39
0.78
0.39
>100
0.39
0.78
0.2
0.78
0.78
0.39
>100
6.25
1.56
0.2
0.78
0.78
0.78
>100
1.56
0.78
0.2
0.78
0.78
0.39
>100
0.39
0.78
0.2
0.39
0.78
0.39
>100
0.39
0.78
0.2
0.39
0.78
0.78
>100
0.78
0.78
0.39
0.78
>100
>100
>100
0.2
S. aureus
S. aureus
S. aureus
S. aureus
S. aureus
ermC (i)c
Susceptible
Susceptible
ermB (c)b
ermB (i)c
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pyogenes
S. pyogenes
S. pyogenes
M. catarrhalis
M. catarrhalis
H. influenzae
H. influenzae
H. influenzae
0.39
>100
>100
>100
0.2
0.39
>100
100
0.39
>100
50
0.39
>100
>100
>100
0.39
0.2
N.T.d
>100
0.2
0.2
0.39
>100
100
>100
100
100
ermB (i)c
100
0.2
>100
0.2
>100
0.2
mefE efflux
mefE efflux
Standard
ermB (c)b
mefE efflux
Standard
Standard
Standard
Standard
Susceptible
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
N.T.d
>100
0.2
N.T.d
>100
0.2
N.T.d
>100
0.1
N.T.d
>100
0.39
3.13
3.13
6.25
>100
>100
N.T.d
>100
0.39
0.78
1.56
3.13
12.5
25
>100
0.78
1.56
1.56
3.13
12.5
12.5
0.39
0.78
0.78
6.25
6.25
1.56
1.56
3.13
12.5
25
0.78
1.56
3.13
25
1.56
3.13
6.25
50
25
100
a S. aureus, Staphylococcus aureus; S. pneumoniae, Streptococcus pneumoniae; S. pyogenes, Streptococcus pyogenes; M. catarrhalis, Moraxella
catarrhalis; H. influenzae, Haemophilus influenzae.
b Constitutive resistant.
c Inducible resistant.
d Not tested.

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
3989
Scheme 2. Synthesis of 12-arylalkylamino analogues of MDM. Reagents and conditions: (a) HCHO, AcOH, NaBH3CN, MeCN or MeOH, 0 °C–rt,
0.5–3 h, 60–97%; (b) the corresponding aldehyde, AcOH, NaBH(OAc)3 or NaBH3CN, AcOH, Cl(CH2)2Cl or MeOH, rt, 1–4 h, 36–81%; (c)
CHF2COOH, MeCN/H2O (1:1), rt, 4–75 h, 24–64% for 12, 16–44% for 13. aR: (a) Me; (b) benzyl; (c) 2-phenylethyl; (d) 3-phenylpropyl; (e) 4-
phenylbutyl; (f) 5-phenylpentyl; (g) 6-phenylhexyl; (h) 7-phenylheptyl; (i) 3-(pyridin-4-yl)propyl; (j) 3-(naphthalen-1-yl)propyl; (k) 3-(quinolin-3-
yl)propyl; (l) 3-(quinolin-4-yl)propyl; (m) 3-[4-(pyridin-3-yl)-imidazol-1-yl]propyl.
As a result, introduction of an acetyl group at the C-300
position was shown to be important for enhancement of
antibacterial activities against inducible-resistant
S. pneumoniae in comparison between 12d and 18 in Ta-
ble 3. In general, a neutral sugar enhances its antibacte-
rial activities, and the above-mentioned result was

3990
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
Scheme 3. Synthesis of 12-(3-phenylpropyl)amino analogue of MOM. Reagents and conditions: (a) pyridinium p-toluenesulfonate, CH(OMe)3,
MeOH, 45 °C, 3 days, 79%; (b) 1—m-CPBA, CHCl3, rt, 14 h; 2—aq Na2S2O4, EtOH, 0 °C, 30 min, 53% overall two steps; (c) 1—NaN3, NH4Cl,
EtOH/H2O (8:1), 80 °C, 32 h; 2—Ph3P, MeCN, rt, 21 h then H2O, rt, 6 h, 69% overall two steps; (d) 1—Ph(CH2)2CHO, NaBH3CN, AcOH, MeOH,
rt, 2 h; 2—HCHO, NaBH3CN, AcOH, MeOH, 0 °C, 1 h, 40% overall two steps; (e) CHF2COOH, MeCN/H2O (1:1), rt, 24 h, 87%.
Table 2. Antibacterial activities of 12-phenylalkylamino analogues with a variety of spacer length
Test organisma
Characteristics
(MIC, lg/ml)
12a
12b
12c
12d
12e
12f
12g
12h
1
MDM
S. aureus
Standard
Susceptible
Susceptible
ermA (c)b
ermB (i)c
0.78
1.56
0.78
>100
1.56
0.78
0.2
0.39
0.78
0.39
>100
0.2
0.39
0.78
0.39
>100
0.78
0.39
0.1
0.2
0.39
0.78
0.39
>100
1.56
0.78
0.05
0.1
0.39
0.78
0.39
>100
0.78
0.39
0.1
0.39
0.78
0.39
100
0.2
1.56
3.13
0.78
100
0.78
1.56
0.39
0.78
25
0.39
0.78
0.39
>100
0.39
0.78
0.2
0.39
0.78
0.78
>100
0.78
0.78
0.39
0.78
>100
>100
>100
0.2
S. aureus
0.39
0.2
S. aureus
S. aureus
>100
0.2
0.2
S. aureus
S. aureus
ermC (i)c
Susceptible
Susceptible
ermB (c)b
ermB (i)c
0.39
0.1
0.39
0.1
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pyogenes
S. pyogenes
S. pyogenes
M. catarrhalis
M. catarrhalis
H. influenzae
H. influenzae
H. influenzae
0.05
0.1
0.39
>100
>100
>100
0.2
0.2
0.2
0.2
0.2
50
0.39
>100
100
>100
100
100
0.2
>100
50
25
>100
12.5
12.5
0.1
>100
25
100
12.5
12.5
0.2
6.25
12.5
0.2
12.5
25
ermB (i)c
12.5
0.2
>100
0.2
mefE efflux
mefE efflux
standard
0.2
0.78
0.39
0.39
25
0.2
0.2
0.1
0.1
0.1
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
N.T.d
>100
0.2
N.T.d
100
0.1
N.T.d
100
N.T.d
25
N.T.d
>100
0.39
0.78
1.56
3.13
12.5
25
ermB (c)b
mefE efflux
Standard
Standard
Standard
Standard
Susceptible
>100
0.39
1.56
1.56
1.56
12.5
25
>100
0.39
0.39
1.56
3.13
12.5
25
25
0.2
>100
0.78
1.56
1.56
3.13
12.5
12.5
0.2
0.2
0.78
3.13
3.13
12.5
25
0.39
0.78
1.56
12.5
25
0.39
0.78
1.56
6.25
25
0.78
1.56
3.13
12.5
25
0.39
0.78
3.13
12.5
25
0.78
1.56
6.25
12.5
25
25
a S. aureus, Staphylococcus aureus; S. pneumoniae, Streptococcus pneumoniae; S. pyogenes, Streptococcus pyogenes; M. catarrhalis, Moraxella
catarrhalis; H. influenzae, Haemophilus influenzae.
b Constitutive resistant.
c Inducible resistant.
d Not tested.
corresponding to the report saying modification of the
neutral sugar was useful for an improvement in activities
against resistant bacteria.13 In order to clarify the role of
a neutral sugar in this series, we also evaluated antibac-
terial activities of monosaccharide analogues (13d and
13i–m) as shown in Table 4. Beyond our expectation,
13j and 13l had comparatively excellent potency, and
we found that activities of all monosaccharide analogues
against gram-negative bacteria were stronger than those
of the corresponding disaccharide analogues. To our
regret, however, their activities against erm-resistant S.
pneumoniae decreased, and it was revealed that the exis-
tence of the neutral sugar was necessary for an improve-
ment in activities against resistant bacteria in this series.
3. Conclusion
On the basis of the structure of ketolides, the 12,13-cyc-
lic carbamates were designed and synthesized starting

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
Table 3. Antibacterial activities of 12-arylpropylamino analogues
3991
Test organisma
Characteristics
(MIC, lg/ml)
12i
12j
12k
12l
12m
18
1
MDM
MOM
CAM
S. aureus
Standard
Susceptible
Susceptible
ermA (c)b
ermB (i)c
0.2
0.39
0.78
0.39
>100
3.13
0.78
0.1
0.39
0.78
0.39
>100
0.2
0.1
0.39
0.78
0.2
0.39
0.78
0.39
>100
0.2
0.39
0.78
0.39
>100
0.39
0.78
0.2
0.39
0.78
0.78
>100
0.78
0.78
0.39
0.78
>100
>100
>100
0.2
0.2
0.1
0.1
S. aureus
0.39
0.2
0.39
0.1
0.78
0.78
>100
1.56
0.78
0.1
S. aureus
0.1
S. aureus
S. aureus
>100
0.2
>100
0.1
0.2
>100
0.39
0.39
0.06
0.1
>100
>100
1.56
0.025
0.025
>100
>100
>100
0.78
0.78
N.T.d
>100
3.13
0.1
S. aureus
ermC (i)c
Susceptible
Susceptible
ermB (c)b
ermB (i)c
0.39
0.05
0.1
0.39
0.05
0.1
0.39
0.05
0.1
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pyogenes
S. pyogenes
S. pyogenes
M. catarrhalis
M. catarrhalis
H. influenzae
H. influenzae
H. influenzae
0.013
0.025
50
0.1
50
0.39
>100
100
0.2
>100
>100
>100
0.1
>100
12.5
50
>100
>100
100
>100
1.56
1.56
0.2
>100
6.25
6.25
0.39
0.2
6.25
25
3.13
0.78
0.025
0.05
0.05
>100
0.1
ermB (i)c
>100
0.2
mefE efflux
mefE efflux
Standard
ermB (c)b
mefE efflux
Standard
Standard
Standard
Standard
Susceptible
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.2
0.2
N.T.d
>100
0.1
0.1
50
0.1
>100
0.2
0.1
>100
0.2
0.05
50
N.T.d
>100
0.39
0.78
1.56
3.13
12.5
25
0.1
>100
0.2
>100
0.78
1.56
1.56
3.13
12.5
12.5
0.2
0.1
0.78
0.78
1.56
6.25
12.5
0.78
1.56
6.25
25
0.78
1.56
3.13
12.5
25
0.39
0.78
1.56
12.5
12.5
1.56
1.56
1.56
12.5
25
0.39
0.78
3.13
12.5
25
0.78
1.56
3.13
12.5
25
0.1
1.56
6.25
6.25
25
a S. aureus, Staphylococcus aureus; S. pneumoniae, Streptococcus pneumoniae; S. pyogenes, Streptococcus pyogenes; M. catarrhalis, Moraxella
catarrhalis; H. influenzae, Haemophilus influenzae.
b Constitutive resistant.
c Inducible resistant.
d Not tested.
Table 4. Antibacterial activities of monosaccharide analogues with a variety of aryl groups
Test organisma
Characteristics
(MIC, lg/ml)
13d
13i
13j
13k
13l
13m
1
MDM
S. aureus
Standard
Susceptible
Susceptible
ermA (c)b
ermB (i)c
0.39
0.78
0.78
>100
1.56
1.56
0.2
0.78
1.56
1.56
>100
1.56
1.56
0.39
0.39
>100
>100
>100
1.56
1.56
N.T.d
>100
6.25
0.1
0.39
0.78
0.78
>100
0.78
0.78
0.025
0.05
>100
100
1.56
1.56
1.56
>100
1.56
1.56
0.2
0.2
3.13
3.13
3.13
>100
6.25
6.25
0.2
0.39
0.78
0.39
>100
0.39
0.78
0.2
0.39
0.78
0.78
>100
0.78
0.78
0.39
0.78
>100
>100
>100
0.2
S. aureus
0.39
0.39
>50
0.39
0.39
0.025
0.025
>50
12.5
12.5
0.1
S. aureus
S. aureus
S. aureus
S. aureus
ermC (i)c
Susceptible
Susceptible
ermB (c)b
ermB (i)c
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pneumoniae
S. pyogenes
S. pyogenes
S. pyogenes
M. catarrhalis
M. catarrhalis
H. influenzae
H. influenzae
H. influenzae
0.2
0.2
0.2
0.39
>100
100
>100
>100
>100
0.39
0.39
0.39
>100
0.78
0.025
0.025
0.39
0.78
3.13
>100
>100
>100
0.39
0.78
0.78
>100
3.13
0.2
>100
>100
>100
1.56
0.78
1.56
>100
25
ermB (i)c
100
0.1
>100
0.2
mefE efflux
mefE efflux
Standard
ermB (c)b
mefE efflux
Standard
Standard
Standard
Standard
Susceptible
0.1
0.1
0.1
0.1
0.2
0.2
0.2
N.T.d
>100
0.39
0.78
1.56
3.13
12.5
25
>100
0.39
0.025
0.05
0.78
1.56
3.13
>50
1.56
0.05
0.05
0.39
0.78
1.56
>100
0.78
1.56
1.56
3.13
12.5
12.5
0.39
0.39
0.78
6.25
12.5
0.1
0.2
0.39
1.56
3.13
1.56
3.13
6.25
a S. aureus, Staphylococcus aureus; S. pneumoniae, Streptococcus pneumoniae; S. pyogenes, Streptococcus pyogenes; M. catarrhalis, Moraxella
catarrhalis; H. influenzae, Haemophilus influenzae.
b Constitutive resistant.
c Inducible resistant.
d Not tested.
from 16-membered macrolide. Epoxidation of a sequen-
tially protected intermediate (2) followed by reduction
afforded the epoxide (3) regioselectively and stereoselec-
tively. The cyclic carbamates (7b, 10a–c) possessing a
phenylalkyl group were prepared from 3 via trans
ring-opening reaction, but they did not show significant
improvement in antibacterial activities compared to the
parent compound (MDM) or compound 1. Next, we

3992
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
investigated the potential of non-cyclic 12-arylalkylami-
no-13-hydroxy 16-membered macrolides. After determi-
nation of the spacer length, we optimized an aryl group
at the C-12 position. As a result, the 4-quinolinyl ana-
logue (12l) exhibited the most potent antibacterial activ-
ities in 300-OH series, and was especially effective against
both inducible- and efflux-resistant S. pneumoniae. Fur-
thermore, we synthesized the 300-O-acetyl analogue of
12d, compound 18, from MOM in order to examine
the effect of an acyl group at the C-300 position on anti-
bacterial activities against erm-resistant strains. Finally,
18 was 8-fold more active than 12d against inducible-
resistant S. pneumoniae.
4.1.2. 9-O-Acetyl-12,13-dihydro-12,13-epoxymidecamy-
cin 18-dimethylacetal (3). To a solution of 2 (4.51 g,
5.0 mmol) in CHCl3 (70 ml), 3-chloroperbenzoic acid
(3.08 g, 12.5 mmol) was added and the reaction mixture
was stirred for 14 h at room temperature. After EtOH
(140 ml) was added, 5% aqueous Na2S2O4 (50 ml) was
added dropwise under ice cooling, and the mixture
was stirred for 15 min. The reaction mixture was evapo-
rated, and saturated aqueous NaHCO3 was added. The
aqueous layer was extracted with CHCl3 and the extract
was washed with saturated aqueous NaHCO3 and brine.
The organic layer was dried and concentrated. The res-
idue was purified by silica gel chromatography [CHCl3/
MeOH (70:1)] to give 3 (2.84 g, 62%) as a colorless solid.
This work suggests the possibility of 16-membered mac-
rolides for overcoming resistant S. pneumoniae. SAR
indicated here would be useful for the exploration of a
new class of 16-membered macrolides in the future.
Recrystallization from CHCl3/hexane afforded an ana-
20
lytically pure sample as colorless plate crystals; ½aꢁ
D
1
ꢀ41° (c 1.0, CHCl3); FAB-MS m/z 918 (M+H)+; H
NMR d 0.89 (br t, 7-H), 1.01 (d, 19-H), 1.09 (t, 3-
OCOCH2CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.17
(t, 400-OCOCH2CH3), 1.26 (d, 16-H), 1.27 (d, 60-H),
1.43 (ddd, 14-H), 1.55 (br t, 7-H), 1.83 (dd, 200-Hax),
2.00 (d, 200-Heq), 2.00 (s, 9-OCOCH3), 2.22 (br d, 14-
H), 2.35 (dd, 2-H), 2.50 (s, 30-N(CH3)2), 2.72 (dd, 2-
H), 3.14 (dd, 12-H), 3.17 (s, 18-OCH3), 3.27 (s, 18-
OCH3), 3.54 (s, 4-OCH3), 3.57 (dd, 20-H), 3.97 (br d,
5-H), 4.48 (dq, 500-H), 4.53 (d, 10-H), 4.58 (dd, 18-H),
4.62 (d, 400-H), 4.91 (ddq, 15-H), 5.07 (d, 100-H), 5.11
(br dd, 3-H), 5.32 (dd, 9-H), 5.75 (dd, 11-H), 6.01 (dd,
10-H).
4. Experimental
4.1. Chemistry
Optical rotations were measured on a Perkin-Elmer
241 polarimeter or JASCO DIP-370. Mass spectra were
obtained on a JEOL JMS-700 for FAB-MS or Agilent
HP5989A for TSP-MS. 1H NMR spectra were mea-
sured with a Varian Gemini-300 for 300 MHz in
CDCl3 using CHCl3 as internal standard. Silica gel
chromatography and preparative TLC were performed
on Wako C-300 and Merck TLC 60F254, respectively.
In general, organic layer was dried with anhydrous
Na2SO4, evaporation and concentration were carried
out under reduced pressure below 35 °C, unless other-
wise noted.
4.1.3. 9-O-Acetyl-12-azide-12,13-dihydro-13-hydroxymi-
decamycin 18-dimethylacetal (4a). To a solution of 3
(1.00 g, 1.09 mmol) and ammonium chloride (292 mg,
5.46 mmol) in EtOH/H2O (8:1) (30 ml) was added so-
dium azide (709 mg, 10.9 mmol), and the reaction mix-
ture was stirred for 21 h at 85 °C. Water was added
and the mixture was evaporated. The aqueous layer
was extracted with CHCl3 and the extract was washed
with saturated aqueous NaHCO3 and brine. After the
organic layer was dried and concentrated, the residue
was purified by silica gel chromatography [CHCl3/
4.1.1. 9-O-Acetylmidecamycin 18-dimethylacetal (2). To
a solution of crude 9-O-acetyl midecamycin (1)22
(2.0 g, 2.34 mmol) in MeOH (30 ml), trimethyl ortho-
formate (26 ml) and pyridinium p-toluenesulfonate
(1.17 g, 2.34 mmol) were added and the reaction mix-
ture was stirred for 33 h at 50 °C. Saturated aqueous
NaHCO3 was added and the mixture was evaporated.
The aqueous layer was extracted with CHCl3 and the
extract was washed with saturated aqueous NaHCO3
and brine. After the organic layer was dried and con-
centrated, the residue was purified by silica gel chroma-
MeOH/NH4OH (90:1:0.1–80:1:0.1)] to give 4a (763 mg,
20
73%) as a colorless solid; ½aꢁ ꢀ54° (c 1.0, CHCl3);
D
1
FAB-MS m/z 961 (M+H)+; H NMR d 0.95 (d, 19-H),
1.04 (br t, 7-H), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.12
(t, 3-OCOCH2CH3), 1.17 (t, 400-OCOCH2CH3), 1.27
(d, 60-H), 1.31 (d, 16-H), 1.50 (br t, 7-H), 1.63 (br dd,
14-H), 1.83 (dd, 200-Hax), 2.01 (d, 200-Heq), 2.05 (s, 9-
OCOCH3), 2.50 (s, 30-N(CH3)2), 2.60 (dd, 2-H), 2.84
(dd, 2-H), 3.16 (s, 18-OCH3), 3.27 (s, 18-OCH3), 3.48
(dd, 4-H), 3.53 (s, 4-OCH3), 3.57 (dd, 20-H), 3.95 (br
dd, 13-H), 3.99 (br d, 5-H), 4.25 (br s, 12-H), 4.47 (dq,
500-H), 4.51 (d, 10-H), 4.58 (t, 18-H), 4.61 (d, 400-H),
5.07 (d, 100-H), 5.11 (ddq, 15-H), 5.12 (br dd, 3-H),
5.32 (br s, 9-H), 5.77 (br d, 10-H), 5.81 (br d, 11-H).
tography [CHCl3/MeOH/NH4OH (120:1:0.1)] to give 2
24
(1.68 g, 80%) as a colorless solid; ½aꢁ ꢀ32° (c 1.0,
D
1
CHCl3); FAB-MS m/z 902 (M + H)+; H NMR d
0.92 (br t, 7-H), 0.97 (d, 19-H), 1.11 (s, 300-CH3), 1.12
(d, 600-H), 1.14 (t, 3-OCOCH2CH3), 1.17 (t, 400-
OCOCH2CH3), 1.24 (d, 16-H), 1.27 (d, 60-H), 1.49
(br t, 7-H), 1.82 (dd, 200-Hax), 2.00 (d, 200-Heq), 2.00
(s, 9-OCOCH3), 2.13 (ddd, 14-H), 2.25 (dd, 2-H),
2.49 (s, 30-N(CH3)2), 2.69 (dd, 2-H), 3.22 (br d, 4-H),
3.24 (s, 18-OCH3), 3.28 (s, 18-OCH3), 3.52 (s, 4-
OCH3), 3.56 (dd, 20-H), 3.89 (br d, 5-H), 4.47 (dq,
500-H), 4.48 (d, 10-H), 4.52 (dd, 18-H), 4.61 (d, 400-H),
4.96 (ddq, 15-H), 5.05 (br dd, 3-H), 5.07 (d, 100-H),
5.29 (dd, 9-H), 5.56 (dd, 10-H), 5.82 (ddd, 13-H),
6.05 (dd, 12-H), 6.64 (dd, 11-H).
4.1.4. 9,20-Di-O-acetyl-12-azide-12,13-dihydro-13-hydrox-
ymidecamycin 18-dimethylacetal (4b). To a solution of 4a
(30 mg, 31.2 lmol) in CH3CN (0.9 ml) was added acetic
anhydride (6 ll, 63.5 lmol). After the reaction mixture
was stirred for 27 h at 50 °C, acetic anhydride (6 ll,
63.5 lmol) was added and the reaction mixture was stir-
red for another 5 h at 50 °C. Saturated aqueous NaH-

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
3993
CO3 and water were added and the aqueous layer was
extracted twice with EtOAc. The organic layer was
washed with saturated aqueous NaHCO3 and brine,
dried, and concentrated to give a residue which was
purified by preparative TLC [CHCl3/MeOH/NH4OH
4.1.7. 9,20-Di-O-acetyl-12-amino-12,13-dihydro-13-hydrox-
ymidecamycin 18-dimethylacetal 12-N,13-O-cyclic carba-
mate (6a). To a solution of 5b (32 mg, 32.7 lmol) in THF
(1.6 ml) was added CDI (10.6 mg, 65.4 lmol), and the
reaction mixture was stirred for 3 h at room temperature.
Saturated aqueous NaHCO3 was added and the aqueous
layer was extracted with EtOAc. The organic layer was
washed with brine, dried, and concentrated to give a res-
idue which was purified by preparative TLC [CHCl3/
(30:1:0.1)] to afford 4b (28.0 mg, 90%) as a colorless so-
24
lid; ½aꢁ ꢀ74° (c 1.0, CHCl3); FAB-MS m/z 1003
D
1
(M+H)+; H NMR d 0.93 (d, 19-H), 1.10 (s, 300-CH3),
1.11 (d, 600-H), 1.11 (t, 3-OCOCH2CH3), 1.16 (t, 400-
OCOCH2CH3), 1.27 (d, 60-H), 1.29 (d, 16-H), 1.48 (br
dd, 7-H), 1.63 (br dd, 14-H), 1.70 (br dd, 17-H), 1.83
(dd, 200-Hax), 1.86 (br dd, 14-H), 1.99 (s, 20-OCOCH3),
2.00 (d, 200-Heq), 2.04 (s, 9-OCOCH3), 2.39 (s, 30-
N(CH3)2), 2.60 (dd, 2-H), 2.70 (t, 30-H), 2.79 (dd, 2-
H), 3.11 (s, 18-OCH3), 3.24 (s, 18-OCH3), 3.32 (m, 40-
H), 3.32 (m, 50-H), 3.35 (dd, 4-H), 3.48 (s, 4-OCH3),
3.93 (br d, 5-H), 3.93 (br dd, 13-H), 4.25 (br s, 12-H),
4.37 (dq, 500-H), 4.60 (d, 400-H), 4.63 (dd, 18-H), 4.75
(d, 10-H), 4.99 (dd, 20-H), 5.06 (d, 100-H), 5.10 (br dd,
3-H), 5.11 (ddq, 15-H), 5.30 (br s, 9-H), 5.76 (br d, 11-
H), 5.79 (br d, 10-H).
MeOH/NH4OH (30:1:0.1)] to afford 6a (29.0 mg, 88%)
22
as a colorless solid; ½aꢁ ꢀ16° (c 1.0, CHCl3); FAB-MS
D
1
m/z 1003 (M+H)+; H NMR d 0.88 (br t, 7-H), 0.97 (d,
19-H), 1.10 (s, 300-CH3), 1.11 (d, 600-H), 1.13 (t, 3-
OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3), 1.27 (d, 60-
H), 1.30 (d, 16-H), 1.45 (br t, 7-H), 1.70 (br s, 17-H),
1.83 (dd, 200-Hax), 1.95 (s, 20-OCOCH3), 2.00 (d, 200-
Heq), 2.05 (s, 9-OCOCH3), 2.39 (s, 30-N(CH3)2), 2.70 (t,
30-H), 2.75 (m, 2-H), 3.15 (br d, 4-H), 3.16 (s, 18-
OCH3), 3.25 (s, 18-OCH3), 3.33 (m, 40-H), 3.33 (m, 50-
H), 3.49 (s, 4-OCH3), 3.91 (br d, 5-H), 4.36 (dq, 500-H),
4.60 (d, 400-H), 4.61 (t, 18-H), 4.72 (d, 10-H), 5.00 (dd,
20-H), 5.07 (d, 100-H), 5.11 (ddq, 15-H), 5.38 (br s, 9-H),
5.72 (br dd, 11-H), 6.14 (dd, 10-H).
4.1.5. 9-O-Acetyl-12-amino-12,13-dihydro-13-hydroxymi-
decamycin 18-dimethylacetal (5a). To a solution of 4a
(154 mg, 156 lmol) in CH3CN (4.6 ml) was added tri-
phenylphosphine (63 mg, 240 lmol). After the reaction
mixture was stirred for 23 h at room temperature, water
(0.5 ml) was added and the reaction mixture was stirred
for another 6 h at room temperature. Evaporation gave
a residue which was purified by silica gel chromatogra-
4.1.8. 9,20-Di-O-acetyl-12-benzylamino-12,13-dihydro-
13-hydroxymidecamycin 18-dimethylacetal 12-N,13-O-
cyclic carbamate (6b). To a solution of 5b (94 mg,
96.2 lmol) in 1,2-dichloroethane (1.9 ml), benzalde-
hyde (12 ll, 118 lmol), acetic acid (6 ll, 105 lmol),
and sodium triacetoxyborohydride (31 mg, 144 lmol)
were added and the reaction mixture was stirred for
2 h at room temperature. Saturated aqueous NaHCO3
and water were added to the resulting mixture and the
aqueous layer was extracted twice with CHCl3. The or-
ganic layer was washed with saturated aqueous NaH-
CO3 and brine, dried, and concentrated. The
resulting residue was purified by silica gel chromatog-
raphy [CHCl3/MeOH/NH4OH (60:1:0.1)] and prepara-
tive TLC [CHCl3/MeOH/NH4OH (25:1:0.1)] to afford
phy [CHCl3/MeOH/NH4OH (30:1:0.1)] to give 5a
24
(101 mg, 68%) as a colorless solid; ½aꢁ ꢀ32° (c 1.0,
D
1
CHCl3); FAB-MS m/z 935 (M+H)+; H NMR d 0.94
(d, 19-H), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.12 (t, 3-
OCOCH2CH3), 1.17 (t, 400-OCOCH2CH3), 1.27 (d, 60-
H), 1.29 (d, 16-H), 1.47 (br t, 7-H), 1.59 (br dd, 14-H),
1.75 (br dd, 14-H), 1.83 (dd, 200-Hax), 2.00 (d, 200-Heq),
2.03 (s, 9-OCOCH3), 2.50 (s, 30-N(CH3)2), 2.63 (dd, 2-
H), 2.87 (dd, 2-H), 3.16 (s, 18-OCH3), 3.27 (s, 18-
OCH3), 3.52 (s, 4-OCH3), 3.57 (dd, 20-H), 3.72 (br s,
12-H), 3.81 (br dd, 13-H), 3.99 (br d, 5-H), 4.46 (dq,
500-H), 4.51 (d, 10-H), 4.58 (t, 18-H), 4.61 (d, 400-H),
5.07 (d, 100-H), 5.13 (ddq, 15-H), 5.16 (br dd, 3-H),
5.28 (dd, 9-H), 5.67 (dd, 10-H), 5.82 (dd, 11-H).
the 12-N-benzyl derivative of 5b (82 mg, 80%) as a col-
22
orless solid; ½aꢁ ꢀ59° (c 1.0, CHCl3); FAB-MS m/z
D
1
1067 (M+H)+; H NMR d 0.93 (d, 19-H), 1.10 (s, 300-
CH3), 1.11 (d, 600-H), 1.13 (t, 3-OCOCH2CH3), 1.16
(t, 400-OCOCH2CH3), 1.25 (d, 60-H), 1.27 (d, 16-H),
1.43 (br t, 7-H), 1.61 (br dd, 14-H), 1.83 (dd, 200-
Hax), 1.97 (s, 20-OCOCH3), 2.00 (d, 200-Heq), 2.03 (s,
9-OCOCH3), 2.39 (s, 30-N(CH3)2), 2.54 (dd, 2-H),
2.70 (t, 30-H), 2.76 (dd, 2-H), 3.14 (s, 18-OCH3), 3.24
(s, 18-OCH3), 3.32 (m, 40-H), 3.32 (m, 50-H), 3.35 (br
d, 4-H), 3.46 (s, 4-OCH3), 3.71 (d, 12-NCH2C6H5),
3.81 (br dd, 13-H), 3.85 (d, 12-NCH2C6H5), 3.92 (br
d, 5-H), 4.37 (dq, 500-H), 4.60 (d, 400-H), 4.64 (t, 18-
H), 4.74 (d, 10-H), 4.99 (dd, 20-H), 5.06 (ddq, 15-H),
5.06 (d, 100-H), 5.13 (br dd, 3-H), 5.32 (br dd, 9-H),
5.74 (br dd, 11-H), 5.83 (br dd, 10-H), 7.28 (m, C6H5).
4.1.6. 9,20-Di-O-acetyl-12-amino-12,13-dihydro-13-hydrox-
ymidecamycin 18-dimethylacetal (5b). Reaction of 4b
with triphenylphosphine gave 5b as a colorless solid in
25
68% yield by a similar procedure to 5a; ½aꢁ ꢀ50° (c
D
1
1.0, CHCl3); FAB-MS m/z 977 (M+H)+; H NMR d
0.93 (d, 19-H), 0.96 (br t, 7-H), 1.11 (s, 300-CH3), 1.12
(d, 600-H), 1.12 (t, 3-OCOCH2CH3), 1.17 (t, 400-
OCOCH2CH3), 1.28 (d, 16-H), 1.28 (d, 60-H), 1.49 (br
t, 7-H), 1.55 (br dd, 14-H), 1.73 (br dd, 14-H), 1.84
(dd, 200-Hax), 1.99 (s, 20-OCOCH3), 2.00 (d, 200-Heq),
2.02 (s, 9-OCOCH3), 2.40 (s, 30-N(CH3)2), 2.64 (dd, 2-
H), 2.71 (t, 30-H), 2.83 (dd, 2-H), 3.12 (s, 18-OCH3),
3.24 (s, 18-OCH3), 3.32 (t, 40-H), 3.35 (dq, 50-H), 3.41
(br d, 4-H), 3.48 (s, 4-OCH3), 3.69 (br s, 12-H), 3.78
(br d, 13-H), 3.95 (br d, 5-H), 4.37 (dq, 500-H), 4.61 (d,
400-H), 4.65 (dd, 18-H), 4.76 (d, 10-H), 5.00 (dd, 20-H),
5.07 (d, 100-H), 5.14 (ddq, 15-H), 5.15 (br dd, 3-H),
5.28 (br dd, 9-H), 5.65 (br dd, 11-H), 5.80 (br dd, 10-H).
Reaction of the 12-N-benzyl derivative of 5b with CDI
under reflux condition gave 6b as a colorless solid in
22
81% yield by a similar procedure to 6a; ½aꢁ ꢀ45° (c
D
1
1.0, CHCl3); FAB-MS m/z 1093 (M+H)+; H NMR d
0.97 (d, 19-H), 1.10 (s, 300-CH3), 1.11 (d, 600-H), 1.15 (t,
3-OCOCH2CH3), 1.15 (t, 400-OCOCH2CH3), 1.27 (d,
16-H), 1.27 (d, 60-H), 1.83 (dd, 200-Hax), 1.94 (s, 20-

3994
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
OCOCH3), 1.99 (d, 200-Heq), 2.06 (s, 9-OCOCH3), 2.38
(s, 30-N(CH3)2), 2.57 (dd, 2-H), 2.66 (dd, 2-H), 3.10
(br d, 4-H), 3.19 (s, 18-OCH3), 3.26 (s, 18-OCH3), 3.32
(m, 40-H), 3.32 (m, 50-H), 3.46 (s, 4-OCH3), 3.84 (d,
12-NCH2C6H5), 3.89 (br d, 5-H), 4.11 (br t, 12-H),
4.36 (dq, 500-H), 4.38 (br dd, 13-H), 4.60 (d, 400-H),
4.67 (d, 12-NCH2C6H5), 4.98 (dd, 20-H), 5.03 (br dd,
3-H), 5.05 (d, 100-H), 5.34 (br s, 9-H), 5.59 (br dd, 11-
H), 6.22 (br dd, 10-H), 7.31 (m, C6H5).
50-H), 3.50 (s, 4-OCH3), 3.55 (dd, 20-H), 3.87 (d, 12-
NCH2C6H5), 3.94 (br d, 5-H), 4.14 (br t, 12-H), 4.40
(br dd, 13-H), 4.40 (dq, 500-H), 4.51 (d, 10-H), 4.57 (t,
18-H), 4.61 (d, 400-H), 4.69 (d, 12-NCH2C6H5), 5.00
(br dd, 3-H), 5.00 (ddq, 15-H), 5.07 (d, 100-H), 5.35
(br s, 9-H), 5.59 (br s, 11-H), 6.17 (br dd, 10-H),
7.31 (m, C6H5).
Reaction of the deacetylated derivative of 6a with diflu-
oroacetic acid gave 7b as a colorless solid in 67% yield
23
4.1.9. 9-O-Acetyl-12-amino-12,13-dihydro-13-hydroxymi-
decamycin 12-N,13-O-cyclic carbamate (7a). A solution
of 6a (90 mg, 89.7 lmol) in MeOH and water (9:1)
(3.6 ml) was stirred for 24 h at 50°C. The reaction mix-
by a similar procedure to 7a; ½aꢁD ꢀ42° (c 1.0, CHCl3);
FAB-MS m/z 1005 (M+H)+; 1H NMR d 0.96 (d, 19-H),
1.10 (s, 300-CH3), 1.12 (d, 600-H), 1.16 (t, 3-
OCOCH2CH3), 1.17 (d, 60-H), 1.21 (t, 400-
OCOCH2CH3), 1.30 (d, 16-H), 1.46 (dt, 7-H), 1.83
(dd, 200-Hax), 2.00 (d, 200-Heq), 2.07 (s, 9-OCOCH3),
2.29 (br dd, 14-H), 2.50 (s, 30-N(CH3)2), 2.57 (dd, 2-
H), 2.75 (dd, 2-H), 2.92 (dd, 17-H), 3.20 (br d, 4-H),
3.27 (m, 40-H), 3.27 (m, 50-H), 3.48 (dd, 20-H), 3.49 (s,
4-OCH3), 3.88 (d, 12-NCH2C6H5), 3.94 (dd, 5-H), 4.18
(dd, 12-H), 4.41 (d, 10-H), 4.41 (dq, 500-H), 4.61 (d, 400-
H), 4.70 (d, 12-NCH2C6H5), 5.00 (ddq, 15-H), 5.05 (d,
100-H), 5.14 (br dd, 3-H), 5.17 (dd, 9-H), 5.66 (dd, 11-
H), 6.22 (dd, 10-H), 7.32 (m, C6H5), 9.67 (s, 18-H).
ture was concentrated to give the deacetylated derivative
22
of 6a (84 mg, 97%) as a colorless solid; ½aꢁ ꢀ3.2° (c 1.0,
D
CHCl3); FAB-MS m/z 961 (M+H)+; 1H NMR d 0.97 (d,
19-H), 1.10 (s, 300-CH3), 1.12 (d, 600-H), 1.13 (t, 3-
OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3), 1.23 (d, 60-
H), 1.32 (d, 16-H), 1.46 (br t, 7-H), 1.83 (dd, 200-Hax),
2.00 (d, 200-Heq), 2.06 (s, 9-OCOCH3), 2.49 (s, 30-
N(CH3)2), 2.72 (dd, 2-H), 2.79 (dd, 2-H), 3.20 (s, 18-
OCH3), 3.27 (s, 18-OCH3), 3.53 (s, 4-OCH3), 3.54 (dd,
20-H), 3.96 (br d, 5-H), 4.36 (br t, 12-H), 4.47 (dq, 500-
H), 4.61 (d, 400-H), 5.07 (br dd, 3-H), 5.11 (d, 100-H),
5.37 (br t, 9-H), 5.72 (br dd, 11-H), 6.10 (dd, 10-H).
4.1.11. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-(2-phenyl-
ethyl)aminomidecamycin 18-dimethylacetal (8a). To a
solution of 5a (170 mg, 182 lmol) in MeOH (5.1 ml)
were added phenylacetaldehyde (31 ll, 236 lmol) and
acetic acid (42 ll, 727 lmol), and the reaction mixture
was stirred for 40 min at room temperature. Sodium
cyanoborohydride (34 mg, 545 lmol) was added to the
resulting solution, and the mixture was stirred for
1.5 h at room temperature. Saturated aqueous NaHCO3
was added to the resulting mixture and the aqueous
layer was extracted twice with EtOAc. The organic layer
was washed with saturated aqueous NaHCO3 and brine,
dried, and concentrated. The resulting residue was puri-
fied by silica gel chromatography [CHCl3/MeOH/
To a solution of deacetylated derivative of 6a (83 mg,
86.4 lmol) in acetonitrile and water (1:1) (5 ml) was
added difluoroacetic acid (35 ll, 509 lmol). After stir-
ring at room temperature for 24 h, the reaction mixture
was further stirred for 2.5 h at 35 °C. The resulting mix-
ture was diluted with chloroform, and the extract was
washed with saturated aqueous NaHCO3 and brine,
dried, and concentrated. The resulting residue was puri-
fied by preparative TLC [CHCl3/MeOH/NH4OH
(20:1:0.1)] to give 7a (50 mg, 63%) as a colorless solid;
23
½aꢁ ꢀ15° (c 1.0, CHCl3); FAB-MS m/z 915 (M+H)+;
D
1H NMR d 0.96 (d, 19-H), 1.10 (s, 300-CH3), 1.12 (d,
600-H), 1.16 (t, 3-OCOCH2CH3), 1.16 (t, 400-
OCOCH2CH3), 1.17 (d, 60-H), 1.33 (d, 16-H), 1.46 (dt,
7-H), 1.84 (dd, 200-Hax), 2.00 (d, 200-Heq), 2.06 (s, 9-
OCOCH3), 2.50 (s, 30-N(CH3)2), 2.77 (dd, 2-H), 2.84
(dd, 2-H), 2.92 (dd, 17-H), 3.24 (br d, 4-H), 3.27 (m,
40-H), 3.27 (m, 50-H), 3.47 (dd, 20-H), 3.52 (s, 4-
OCH3), 3.95 (br d, 5-H), 4.41 (d, 10-H), 4.41 (dq, 500-
H), 4.61 (d, 400-H), 4.62 (br dd, 13-H), 5.05 (d, 100-H),
5.20 (br dd, 3-H), 5.80 (dd, 11-H), 6.13 (dd, 10-H),
9.65 (s, 18-H).
NH4OH (60:1:0.1)] to afford 8a (62 mg, 33%) as a color-
22
less solid; ½aꢁ ꢀ42° (c 0.75, CHCl3); FAB-MS m/z 1039
D
1
(M+H)+; H NMR d 0.89 (d, 19-H), 1.11 (s, 300-CH3),
1.12 (d, 600-H), 1.12 (t, 3-OCOCH2CH3), 1.17 (t, 400-
OCOCH2CH3), 1.27 (d, 16-H), 1.27 (d, 60-H), 1.45 (br
t, 7-H), 1.52 (br dd, 14-H), 1.83 (dd, 200-Hax), 2.01 (d,
200-Heq), 2.04 (s, 9-OCOCH3), 2.50 (s, 30-N(CH3)2),
2.63 (dd, 2-H), 3.18 (s, 18-OCH3), 3.28 (s, 18-OCH3),
3.31 (dq, 50-H), 3.40 (br dd, 12-H), 3.48 (br d, 4-H),
3.51 (s, 4-OCH3), 3.57 (dd, 20-H), 3.73 (br dd, 13-H),
3.98 (br d, 5-H), 4.47 (dq, 500-H), 4.50 (d, 10-H), 4.58
(t, 18-H), 4.62 (d, 400-H), 5.06 (ddq, 15-H), 5.07 (d, 100-
H), 5.16 (br dd, 3-H), 5.29 (br dd, 9-H), 5.61 (br dd,
11-H), 5.69 (br dd, 10-H), 7.20 (m, C6H5), 7.27 (m,
C6H5).
4.1.10. 9-O-Acetyl-12-benzylamino-12,13-dihydro-13-
hydroxymidecamycin 12-N,13-O-cyclic carbamate
(7b). Reaction of 6b with aqueous MeOH gave deacet-
ylated derivative of 6b as a colorless solid in 97% yield
by a similar procedure to the deacetylated derivative
22
D
1
of 6a; ½aꢁ ꢀ32° (c 1.0, CHCl3); FAB-MS m/z 1051
4.1.12. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-(3-phenyl-
propyl)aminomidecamycin 18-dimethylacetal (8b). Reac-
tion of 5a with phenylpropionaldehyde gave 8b as a
(M+H)+; H NMR d 0.98 (d, 19-H), 1.11 (s, 300-
CH3), 1.11 (d, 600-H), 1.16 (t, 3-OCOCH2CH3), 1.16
(t, 400-OCOCH2CH3), 1.27 (d, 60-H), 1.29 (d, 16-H),
1.46 (br t, 7-H), 1.83 (dd, 200-Hax), 2.00 (d, 200-Heq),
2.07 (s, 9-OCOCH3), 2.28 (br dd, 14-H), 2.54 (s, 30-
N(CH3)2), 2.57 (dd, 2-H), 2.72 (dd, 2-H), 3.23 (s, 18-
OCH3), 3.28 (s, 18-OCH3), 3.31 (m, 40-H), 3.31 (m,
colorless solid in 55% yield by a similar procedure to
23
8a; ½aꢁ ꢀ39° (c 1.0, CHCl3); FAB-MS m/z 1053
D
1
(M+H)+; H NMR d 0.94 (d, 19-H), 1.11 (s, 300-CH3),
1.12 (d, 600-H), 1.12 (t, 3-OCOCH2CH3), 1.16 (t, 400-
OCOCH2CH3), 1.27 (d, 60-H), 1.28 (d, 16-H), 1.45 (dt,

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
3995
21
D
7-H), 1.57 (br dd, 14-H), 1.80 (m, 12-N(CH2)3C6H5),
1.83 (dd, 200-Hax), 1.92 (dt, 14-H), 2.00 (d, 200-Heq),
2.02 (s, 9-OCOCH3), 2.50 (s, 30-N(CH3)2), 2.63 (dd, 2-
H), 2.65 (t, 12-N(CH2)3C6H5), 2.84 (dd, 2-H), 3.18 (s,
18-OCH3), 3.27 (s, 18-OCH3), 3.31 (dq, 50-H), 3.36 (br
d, 12-H), 3.48 (br d, 4-H), 3.51 (s, 4-OCH3), 3.57 (dd,
20-H), 3.78 (br dd, 13-H), 3.98 (br d, 5-H), 4.47 (dq,
500-H), 4.50 (d, 10-H), 4.58 (t, 18-H), 4.61 (d, 400-H),
5.06 (ddq, 15-H), 5.07 (d, 100-H), 5.16 (br dd, 3-H),
5.30 (br s, 9-H), 5.69 (br dd, 11-H), 5.74 (br d, 10-H),
7.16 (m, C6H5), 7.26 (m, C6H5).
½aꢁ ꢀ17° (c 0.60, CHCl3); FAB-MS m/z 1079 (M+H)+;
1H NMR d 0.99 (d, 19-H), 1.16 (s, 300-CH3), 1.17 (d, 600-
H), 1.17 (t, 3-OCOCH2CH3), 1.22 (t, 400-OCOCH2CH3),
1.33 (d, 60-H), 1.34 (d, 16-H), 1.54 (br t, 7-H), 1.88 (dd,
200-Hax), 2.02 (d, 200-Heq), 2.05 (s, 9-OCOCH3), 2.27
(ddd, 14-H), 2.55 (s, 30-N(CH3)2), 2.95 (dd, 2-H), 3.29
(s, 18-OCH3), 3.34 (s, 18-OCH3), 3.55 (dd, 20-H), 3.58
(s, 4-OCH3), 4.04 (br d, 5-H), 4.10 (br dd, 13-H), 4.22
(br t, 12-H), 4.52 (dq, 500-H), 4.56 (d, 10-H), 4.65 (t, 18-
H), 4.66 (d, 400-H), 5.06 (ddq, 15-H), 5.12 (d, 100-H), 5.14
(br dd, 3-H), 5.39 (br s, 9-H), 5.54 (dd, 11-H), 6.22 (dd,
10-H), 7.24 (m, C6H5).
4.1.13.9-O-Acetyl-12,13-dihydro-13-hydroxy-12-(4-phenyl-
butyl)aminomidecamycin 18-dimethylacetal (8c). Reac-
tion of 5a with 4-phenylbutanal gave 8c as a colorless
4.1.16. 9-O-Acetyl-12,13-dihydro-12-(4-phenylbutyl)ami-
nomidecamycin 18-dimethylacetal 12-N,13-O-cyclic car-
bamate (9c). Reaction of 8c with triphosgene gave 9c as
23
solid in 59% yield by a similar procedure to 8a; ½aꢁD
1
ꢀ36° (c 1.0, CHCl3); FAB-MS m/z 1067 (M+H)+; H
a colorless solid in 90% yield by a similar procedure to
21
NMR d 0.94 (d, 19-H), 1.11 (s, 300-CH3), 1.12 (d, 600-
H), 1.12 (t, 3-OCOCH2CH3), 1.17 (t, 400-OCOCH2CH3),
1.27 (d, 60-H), 1.28 (d, 16-H), 1.51 (m, 12-
N(CH2)4C6H5), 1.63 (m, 12-N(CH2)4C6H5), 1.83 (dd,
200-Hax), 1.93 (ddd, 14-H), 2.00 (d, 200-Heq), 2.03 (s, 9-
OCOCH3), 2.50 (s, 30-N(CH3)2), 2.61 (t, 12-
N(CH2)3C6H5), 2.84 (dd, 2-H), 3.18 (s, 18-OCH3), 3.27
(s, 18-OCH3), 3.31 (m, 50-H), 3.36 (br d, 12-H), 3.48
(br d, 4-H), 3.51 (s, 4-OCH3), 3.57 (dd, 20-H), 3.79 (br
s, 13-H), 3.98 (br d, 5-H), 4.47 (dq, 500-H), 4.50 (d, 10-
H), 4.58 (t, 18-H), 4.61 (d, 400-H), 5.07 (ddq, 15-H),
5.07 (d, 100-H), 5.16 (br dd, 3-H), 5.31 (br s, 9-H), 5.70
(dd, 11-H), 5.76 (dd, 10-H), 7.16 (m, C6H5), 7.25 (m,
C6H5).
9a; ½aꢁ ꢀ18° (c 1.0, CHCl3); FAB-MS m/z 1093
D
1
(M+H)+; H NMR d 0.97 (d, 19-H), 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), 1.31 (d, 16-H), 1.49 (br
dd, 7-H), 1.63 (m, 12-N(CH2)4C6H5), 1.84 (dd, 200-
Hax), 2.00 (d, 200-Heq), 2.04 (s, 9-OCOCH3), 2.50 (s,
30-N(CH3)2), 2.64 (m, 12-N(CH2)4C6H5), 2.69 (m, 2-
H), 3.22 (s, 18-OCH3), 3.28 (s, 18-OCH3), 3.46 (dd, 20-
H), 3.53 (s, 4-OCH3), 3.88 (br d, 5-H), 4.27 (br dd, 12-
H), 4.44 (d, 10-H), 4.44 (dq, 500-H), 4.61 (d, 400-H), 5.07
(br dd, 3-H), 5.07 (ddq, 15-H), 5.07 (d, 100-H), 5.36 (br
s, 9-H), 5.55 (br dd, 11-H), 6.16 (br dd, 10-H), 7.16
(m, C6H5), 7.25 (m, C6H5).
4.1.17. 9-O-Acetyl-12,13-dihydro-12-(2-phenylethyl)ami-
nomidecamycin 12-N,13-O-cyclic carbamate (10a). Reac-
tion of 9a with difluoroacetic acid gave 10a as a colorless
4.1.14. 9-O-Acetyl-12,13-dihydro-12-(2-phenylethyl)ami-
nomidecamycin 18-dimethylacetal 12-N,13-O-cyclic car-
bamate (9a). To a solution of 8a (62 mg, 59.7 lmol) and
triethylamine (42 ll, 300 lmol) in CH2Cl2 (1.5 ml), a
solution of triphosgene (10.6 mg, 35.8 lmol) in CH2Cl2
(1.5 ml) was added under ice cooling and the reaction
mixture was stirred for 45 minutes at the same tempera-
ture. Chloroform and saturated aqueous NaHCO3 were
added to the reaction mixture. The extract was washed
with saturated aqueous NaHCO3 and brine, dried, and
concentrated to give a residue which was purified by sil-
23
solid in 62% yield by a similar procedure to 7a; ½aꢁ ꢀ27°
D
(c 0.80, CHCl3); FAB-MS m/z 1019 (M+H)+; 1H NMR d
0.94 (d, 19-H), 1.11 (s, 300-CH3), 1.17 (t, 400-
OCOCH2CH3), 1.30 (d, 16-H), 1.47 (br t, 7-H), 1.84
(dd, 200-Hax), 2.01 (d, 200-Heq), 2.03 (s, 9-OCOCH3),
2.25 (br dd, 14-H), 2.50 (s, 30-N(CH3)2), 3.21 (br d, 4-
H), 3.28 (m, 40-H), 3.28 (m, 50-H), 3.48 (dd, 20-H), 3.52
(s, 4-OCH3), 3.75 (m, 12-N(CH2)2C6H5), 3.97 (br d, 5-
H), 4.15 (dd, 12-H), 4.30 (dd, 13-H), 4.41 (dq, 500-H),
4.43 (d, 10-H), 4.61 (d, 400-H), 5.03 (ddq, 15-H), 5.05 (d,
100-H), 5.18 (br dd, 3-H), 5.18 (br s, 9-H), 5.62 (dd, 11-
H), 5.64 (dd, 10-H), 7.20 (m, C6H5), 9.72 (s, 18-H).
ica gel chromatography [CHCl3/MeOH (60:1)] to give 9a
21
(57 mg, 90%) as a colorless/solid; ½aꢁ ꢀ18° (c 1.0,
D
1
CHCl3); FAB-MS m/z 1065 (M+H)+; H NMR d 0.96
(d, 19-H), 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), 1.29 (d, 16-H), 1.49 (br dd, 7-H), 1.84 (dd, 200-
Hax), 2.01 (d, 200-Heq), 2.04 (s, 9-OCOCH3), 2.22 (br
t, 14-H), 2.50 (s, 30-N(CH3)2), 2.67 (dd, 2-H), 3.04 (m,
12-N(CH2)2C6H5), 3.24 (s, 18-OCH3), 3.29 (s, 18-
OCH3), 3.34 (m, 40-H), 3.34 (m, 50-H), 3.52 (s, 4-
OCH3), 3.58 (dd, 20-H), 3.75 (m, 12-N(CH2)2C6H5),
4.28 (d, 10-H), 4.30 (br dd, 13-H), 4.47 (dq, 500-H), 4.59
(t, 18-H), 4.61 (d, 400-H), 5.03 (ddq, 15-H), 5.07 (d, 100-
H), 5.11 (br dd, 3-H), 5.38 (br s, 9-H), 5.55 (br dd, 11-
H), 6.19 (br dd, 10-H), 7.20 (m, C6H5).
4.1.18. 9-O-Acetyl-12,13-dihydro-12-(3-phenylpropyl)ami-
nomidecamycin 12-N,13-O-cyclic carbamate (10b). Reac-
tion of 9b with difluoroacetic acid gave 10b as a
colorless solid in 69% yield by a similar procedure to 7a;
23
½aꢁ ꢀ27° (c 0.80, CHCl3); FAB-MS m/z 1033 (M+H)+;
D
1H NMR d 0.97 (d, 19-H), 1.16 (s, 300-CH3), 1.17 (d, 600-
H), 1.24 (t, 400-OCOCH2CH3), 1.31 (d, 60-H), 1.35 (d,
16-H), 1.53 (br t, 7-H), 1.89 (dd, 200-Hax), 2.04 (s, 9-
OCOCH3), 2.06 (d, 200-Heq), 2.26 (ddd, 14-H), 2.54 (s,
30-N(CH3)2), 3.00 (dd, 17-H), 3.26 (br d, 4-H), 3.32 (m,
40-H), 3.32 (m, 50-H), 3.53 (dd, 20-H), 3.57 (s, 4-OCH3),
4.01 (br d, 5-H), 4.11 (dd, 13-H), 4.28 (dd, 12-H), 4.45
(dq, 500-H), 4.48 (d, 10-H), 4.66 (d, 400-H), 5.07 (ddq, 15-
H), 5.11 (d, 100-H), 5.19 (dd, 9-H), 5.23 (br dd, 3-H),
5.60 (dd, 11-H), 6.23 (dd, 10-H), 7.18 (m, C6H5), 9.65 (s,
18-H).
4.1.15. 9-O-Acetyl-12,13-dihydro-12-(3-phenylpropyl)ami-
nomidecamycin 18-dimethylacetal 12-N,13-O-cyclic carba-
mate (9b). Reaction of 8b with triphosgene gave 9b as a
colorless solid in 42% yield by a similar procedure to 9a;

3996
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
4.1.19. 9-O-Acetyl-12,13-dihydro-12-(4-phenylbutyl)ami-
nomidecamycin 12-N,13-O-cyclic carbamate (10c). Reac-
tion of 9c with difluoroacetic acid gave 10c as a colorless
NCH2C6H5), 3.99 (br d, 5-H), 4.07 (br dd, 13-H), 4.47
(dq, 500-H), 4.51 (d, 10-H), 4.61 (d, 400-H), 5.04 (ddq,
15-H), 5.06 (d, 100-H), 5.22 (br dd, 3-H), 5.42 (br s, 9-
H), 5.79 (br d, 11-H), 5.85 (br d, 10-H), 7.29 (m, C6H5).
22
solid in 61% yield by a similar procedure to 7a; ½aꢁ
D
1
ꢀ26° (c 1.0, CHCl3); FAB-MS m/z 1047 (M+H)+; H
NMR d 0.95 (d, 19-H), 1.00 (br t, 7-H), 1.11 (s, 300-
CH3), 1.12 (d, 600-H), 1.16 (t, 3-OCOCH2CH3), 1.18 (d,
60-H), 1.18 (t, 400-OCOCH2CH3), 1.32 (d, 16-H), 1.48
(dt, 7-H), 1.84 (dd, 200-Hax), 2.01 (d, 200-Heq), 2.04 (s,
9-OCOCH3), 2.29 (ddd, 14-H), 2.50 (s, 30-N(CH3)2),
2.79 (dd, 2-H), 2.94 (dd, 17-H), 3.22 (br d, 4-H), 3.28
(m, 40-H), 3.28 (m, 50-H), 3.48 (dd, 20-H), 3.53 (s, 4-
OCH3), 3.97 (br d, 5-H), 4.33 (dd, 12-H), 4.43 (br dd,
13-H), 4.43 (d, 10-H), 4.44 (dq, 500-H), 4.61 (d, 400-H),
5.06 (ddq, 15-H), 5.06 (d, 100-H), 5.17 (br dd, 3-H),
5.17 (br s, 9-H), 5.61 (dd, 11-H), 6.19 (dd, 10-H), 7.16
(m, C6H5), 7.24 (t, C6H5), 9.67 (s, 18-H).
4.1.22. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(2-phenylethyl)amino] midecamycin 18-dimethylacetal
(11c). Reaction of 8a with 37% aqueous formaldehyde
solution gave 11c as a colorless solid in 63% yield by a
21
similar procedure to 11a; ½aꢁ ꢀ41° (c 0.85, CHCl3);
D
1
FAB-MS m/z 1053 (M+H)+; H NMR d 0.91 (d, 19-
H), 1.08 (t, 3-OCOCH2CH3), 1.11 (s, 300-CH3), 1.12 (d,
600-H), 1.16 (t, 400-OCOCH2CH3), 1.26 (d, 16-H), 1.26
(d, 60-H), 1.49 (br t, 7-H), 1.53 (br dd, 14-H), 1.82 (dd,
200-Hax), 2.00 (d, 200-Heq), 2.04 (s, 9-OCOCH3), 2.39
(s, 12-NCH3), 2.49 (s, 30-N(CH3)2), 2.67 (dd, 2-H),
3.18 (s, 18-OCH3), 3.27 (s, 18-OCH3), 3.30 (m, 40-H),
3.30 (m, 50-H), 3.43 (br d, 4-H), 3.51 (s, 4-OCH3), 3.55
(dd, 20-H), 3.97 (br d, 5-H), 3.97 (br dd, 13-H), 4.47
(dq, 500-H), 4.51 (d, 10-H), 4.59 (t,18-H), 4.61 (d, 400-H),
5.00 (ddq, 15-H), 5.06 (d, 100-H), 5.20 (br dd, 3-H),
5.41 (br s, 9-H), 5.72 (br d, 11-H), 5.84 (br d, 10-H),
7.17 (m, C6H5), 7.26 (m, C6H5).
4.1.20. 9-O-Acetyl-12,13-dihydro-12-(N,N-dimethylamino)-
13-hydroxymidecamycin 18-dimethylacetal (11a). To a
solution of 5a (71 mg, 75.9 lmol) in MeCN (1.4 ml)
were added 37% aqueous formaldehyde solution
(62 ll, 759 lmol), acetic acid (40 ll, 759 lmol) and so-
dium cyanoborohydride (14 mg, 228 lmol). After stir-
ring for 1 h at room temperature, saturated aqueous
NaHCO3 was added to the resulting mixture. The aque-
ous layer was extracted twice with EtOAc and the or-
ganic layer was washed with saturated aqueous
NaHCO3 and brine, dried, and concentrated. The result-
ing residue was purified by preparative TLC [CHCl3/
4.1.23. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(3-phenylpropyl)amino]midecamycin 18-dimethylacetal
(11d). Reaction of 8b with 37% aqueous formaldehyde
solution gave 11d as a colorless solid in 63% yield by a
23
similar procedure to 11a; ½aꢁ ꢀ45° (c 0.90, CHCl3);
D
1
FAB-MS m/z 1067 (M+H)+; H NMR d 0.91 (d, 19-
H), 1.11 (s, 300-CH3), 1.11 (t, 3-OCOCH2CH3), 1.12 (d,
600-H), 1.17 (t, 400-OCOCH2CH3), 1.27 (d, 16-H), 1.27
(d, 60-H), 1.49 (br t, 7-H), 1.58 (br dd, 14-H), 1.80 (m,
12-N(CH2)3C6H5), 1.83 (dd, 200-Hax), 2.00 (d, 200-Heq),
2.05 (s, 9-OCOCH3), 2.30 (s, 12-NCH3), 2.50 (s, 30-
N(CH3)2), 2.58 (t, 12-N(CH2)3C6H5), 2.66 (dd, 2-H),
2.77 (dd, 2-H), 3.18 (s, 18-OCH3), 3.27 (s, 18-OCH3),
3.31 (m, 40-H), 3.31 (m, 50-H), 3.45 (br d, 4-H), 3.52
(s, 4-OCH3), 3.56 (dd, 20-H), 3.98 (br d, 5-H), 3.98 (br
dd, 13-H), 4.47 (dq, 500-H), 4.52 (d, 10-H), 4.59 (t, 18-
H), 4.61 (d, 400-H), 5.04 (ddq, 15-H), 5.07 (d, 100-H),
5.20 (br dd, 3-H), 5.38 (br s, 9-H), 5.72 (br d, 11-H),
5.80 (br d, 10-H), 7.16 (m, C6H5), 7.25 (m, C6H5).
MeOH/NH4OH (15:1:0.1)] to afford 11a (44 mg, 60%)
23
as a colorless solid; ½aꢁ ꢀ48° (c 1.0, CHCl3); FAB-
D
1
MS m/z 963 (M+H)+; H NMR d 0.95 (d, 19-H), 1.11
(s, 300-CH3), 1.12 (d, 600-H), 1.13 (t, 3-OCOCH2CH3),
1.17 (t, 400-OCOCH2CH3), 1.28 (d, 60-H), 1.30 (d, 16-
H), 1.48 (br t, 7-H), 1.74 (ddd, 14-H), 1.83 (dd, 200-
Hax), 2.01 (d, 200-Heq), 2.07 (s, 9-OCOCH3), 2.30 (s,
12-N(CH3)2), 2.50 (s, 30-N(CH3)2), 2.70 (dd, 2-H), 2.79
(dd, 2-H), 3.20 (s, 18-OCH3), 3.28 (s, 18-OCH3), 3.31
(m, 40-H), 3.31 (m, 50-H), 3.44 (br d, 4-H), 3.53 (s, 4-
OCH3), 3.57 (dd, 20-H), 4.00 (br d, 5-H), 4.00 (br dd,
13-H), 4.47 (dq, 500-H), 4.52 (d, 10-H), 4.58 (t, 18-H),
4.62 (d, 400-H), 5.04 (ddq, 15-H), 5.07 (d, 100-H), 5.21
(br dd, 3-H), 5.39 (br dd, 9-H), 5.71 (br dd, 11-H),
5.90 (br dd, 10-H).
4.1.24. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(4-phenylbutyl)amino]midecamycin 18-dimethylacetal
(11e). Reaction of 8c with 37% aqueous formaldehyde
4.1.21. 9-O-Acetyl-12-(N-benzyl-N-methylamino)-12,13-
dihydro-13-hydroxymidecamycin 18-dimethylacetal (11b).
Reaction of 5a with benzaldehyde gave the 12-N-benzyl
derivative of 5a as a colorless solid in 81% yield by a
similar procedure to the 12-N-benzyl derivative of 5b
(see 6b). Then, reaction of this compound with 37%
solution gave 11e as a colorless solid in 69% yield by a
23
similar procedure to 11a; ½aꢁ ꢀ51° (c 1.0, CHCl3);
D
1
FAB-MS m/z 1081 (M+H)+; H NMR d 0.92 (d, 19-
H), 1.10 (s, 300-CH3), 1.11 (d, 600-H), 1.11 (t, 3-
OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3), 1.27 (d, 60-
H), 1.29 (d, 16-H), 1.56 (m, 12-N(CH2)4C6H5), 1.66
(br dd, 14-H), 1.83 (dd, 200-Hax), 2.00 (d, 200-Heq), 2.04
(s, 9-OCOCH3), 2.25 (s, 12-NCH3), 2.49 (s, 30-
N(CH3)2), 2.60 (t, 12-N(CH2)4C6H5), 2.66 (dd, 2-H),
2.77 (dd, 2-H), 3.18 (s, 18-OCH3), 3.27 (s, 18-OCH3),
3.31 (m, 40-H), 3.31 (m, 50-H), 3.45 (br d, 4-H), 3.52
(s, 4-OCH3), 3.55 (dd, 20-H), 3.98 (br d, 5-H), 3.98 (br
dd, 13-H), 4.47 (dq, 500-H), 4.53 (d, 10-H), 4.59 (t, 18-
H), 4.61 (d, 400-H), 5.06 (ddq, 15-H), 5.06 (d, 100-H),
5.21 (br dd, 3-H), 5.39 (br s, 9-H), 5.72 (br d, 11-H),
5.82 (br d, 10-H), 7.15 (m, C6H5), 7.25 (m, C6H5).
aqueous formaldehyde solution gave 11b as a colorless
20
D
1
solid in 62% yield by a similar procedure to 11a; ½aꢁ
ꢀ53° (c 1.0, CHCl3); FAB-MS m/z 1039 (M+H)+; H
NMR d 0.93 (d, 19-H), 1.10 (s, 300-CH3), 1.11 (d, 600-
H), 1.13 (t, 3-OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3),
1.27 (d, 60-H), 1.29 (d, 16-H), 1.49 (br t, 7-H), 1.70 (br
dd, 14-H), 1.82 (dd, 200-Hax), 2.00 (d, 200-Heq), 2.05 (s,
9-OCOCH3), 2.22 (s, 12-NCH3), 2.49 (s, 30-N(CH3)2),
2.65 (dd, 2-H), 2.75 (dd, 2-H), 3.18 (s, 18-OCH3), 3.27
(s, 18-OCH3), 3.45 (br d, 4-H), 3.52 (s, 4-OCH3), 3.56
(dd, 20-H), 3.58 (d, 12-NCH2C6H5), 3.69 (d, 12-

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
3997
4.1.25. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(5-phenylpentyl)amino]midecamycin 18-dimethylacetal
(11f). Reaction of 5a with 5-phenylpentanal gave the 12-
N-(5-phenylpentyl) derivative of 5a as a colorless solid
in 51% yield by a similar procedure to 8a. Then, reaction
of this compound with 37% aqueous formaldehyde solu-
(s, 4-OCH3), 3.56 (dd, 20-H), 3.98 (br d, 5-H), 3.98 (br
dd, 13-H), 4.47 (dq, 500-H), 4.52 (d, 10-H), 4.58 (t, 18-
H), 4.59 (d, 400-H), 5.07 (ddq, 15-H), 5.07 (d, 100-H),
5.21 (br dd, 3-H), 5.39 (br s, 9-H), 5.72 (br d, 11-H),
5.81 (br d, 10-H), 7.16 (m, C6H5), 7.25 (m, C6H5).
tion gave 11f as a colorless solid in 70% yield by a sim-
4.1.28. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(3-(pyridin-4-yl)propyl)amino]midecamycin 18-dimeth-
ylacetal (11i). Reaction of 5a with 3-(pyridin-4-yl)propi-
onaldehyde gave the 12-N-(3-(pyridin-4-yl)propyl)
derivative of 5a as a colorless solid in 36% yield by a
similar procedure to 8a. Then, reaction of this com-
pound with 37% aqueous formaldehyde solution gave
23
ilar procedure to 11a; ½aꢁ ꢀ47° (c 1.0, CHCl3); FAB-
D
MS m/z 1095 (M+H)+; 1H NMR d 0.92 (d, 19-H),
1.10 (t, 3-OCOCH2CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-
H), 1.17 (t, 400-OCOCH2CH3), 1.27 (d, 60-H), 1.29 (d,
16-H), 1.51 (m, 12-N(CH2)5C6H5), 1.62 (m, 12-
N(CH2)5C6H5), 1.83 (dd, 200-Hax), 2.00 (d, 200-Heq),
2.04 (s, 9-OCOCH3), 2.27 (s, 12-NCH3), 2.50 (s, 30-
N(CH3)2), 2.59 (t, 12-N(CH2)4C6H5), 2.68 (dd, 2-H),
2.78 (dd, 2-H), 3.18 (s, 18-OCH3), 3.27 (s, 18-OCH3),
3.31 (m, 40-H), 3.31 (m, 50-H), 3.45 (br d, 4-H), 3.52
(s, 4-OCH3), 3.55 (dd, 20-H), 3.99 (br d, 5-H), 3.99 (br
dd, 13-H), 4.47 (dq, 500-H), 4.51 (d, 10-H), 4.58 (t, 18-
H), 4.61 (d, 400-H), 5.06 (ddq, 15-H), 5.07 (d, 100-H),
5.20 (br dd, 3-H), 5.39 (br s, 9-H), 5.72 (br d, 11-H),
5.83 (br d, 10-H), 7.15 (m, C6H5), 7.25 (m, C6H5).
11i as a colorless solid in 97% yield by a similar proce-
19
dure to 11a; ½aꢁ ꢀ47° (c 0.50, CHCl3); FAB-MS m/z
D
1
1068 (M+H)+; H NMR d 0.91 (d, 19-H), 1.09 (t, 3-
OCOCH2CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.17
(t, 400-OCOCH2CH3), 1.25 (d, 60-H), 1.27 (d, 16-H),
1.47 (br t, 7-H), 1.59 (br dd, 14-H), 1.78 (m, 12-
N(CH2)3-pyridine), 1.83 (dd, 200-Hax), 2.00 (d, 200-
Heq), 2.05 (s, 9-OCOCH3), 2.29 (s, 12-NCH3), 2.50 (s,
30-N(CH3)2), 2.61 (dd, 2-H), 2.69 (t, 12-N(CH2)3-pyri-
dine), 3.17 (s, 18-OCH3), 3.27 (s, 18-OCH3), 3.29 (br
d, 12-H), 3.31 (m, 40-H), 3.31 (m, 50-H), 3.45 (br d, 4-
H), 3.53 (s, 4-OCH3), 3.57 (dd, 20-H), 3.93 (br d, 5-H),
3.98 (br dd, 13-H), 4.46 (dq, 500-H), 4.53 (d, 10-H), 4.59
(t, 18-H), 4.61 (d, 400-H), 5.06 (ddq, 15-H), 5.07 (d, 100-
H), 5.19 (br dd, 3-H), 5.38 (br s, 9-H), 5.68 (dd, 11-
H), 5.81 (dd, 10-H), 7.11 (dd, pyridine), 8.46 (dd,
pyridine).
4.1.26. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(6-phenylhexyl)amino]midecamycin 18-dimethylacetal
(11g). Reaction of 5a with 6-phenylhexanal gave the
12-N-(6-phenylhexyl) derivative of 5a as a colorless solid
in 41% yield by a similar procedure to 8a. Then, reaction
of this compound with 37% aqueous formaldehyde solu-
tion gave 11g as a colorless solid in 79% yield by a sim-
22
ilar procedure to 11a; ½aꢁ ꢀ51° (c 1.0, CHCl3); FAB-
D
MS m/z 1109 (M+H)+; 1H NMR d 0.92 (d, 19-H),
1.11 (s, 300-CH3), 1.11 (t, 3-OCOCH2CH3), 1.12 (d, 600-
H), 1.17 (t, 400-OCOCH2CH3), 1.27 (d, 60-H), 1.29 (d,
16-H), 1.46 (m, 12-N(CH2)6C6H5), 1.60 (m, 12-
N(CH2)6C6H5), 1.83 (dd, 200-Hax), 2.00 (d, 200-Heq),
2.05 (s, 9-OCOCH3), 2.25 (s, 12-NCH3), 2.50 (s, 30-
N(CH3)2), 2.58 (t, 12-N(CH2)6C6H5), 2.69 (dd, 2-H),
2.78 (dd, 2-H), 3.18 (s, 18-OCH3), 3.27 (s, 18-OCH3),
3.31 (m, 40-H), 3.31 (m, 50-H), 3.46 (br d, 4-H), 3.52
(s, 4-OCH3), 3.55 (dd, 20-H), 3.97 (br d, 5-H), 3.97 (br
dd, 13-H), 4.47 (dq, 500-H), 4.51 (d, 10-H), 4.59 (t, 18-
H), 4.61 (d, 400-H), 5.07 (ddq, 15-H), 5.07 (d, 100-H),
5.21 (br dd, 3-H), 5.39 (br s, 9-H), 5.72 (dd, 11-H),
5.80 (dd, 10-H), 7.15 (m, C6H5), 7.25 (t, C6H5).
4.1.29. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(3-(naphthalen-1-yl)propyl) amino]midecamycin 18-
dimethylacetal (11j). Reaction of 5a with 3-(naphtha-
len-1-yl)propionaldehyde gave the 12-N-(3-(naphtha-
len-1-yl)propyl) derivative of 5a as a colorless solid in
55% yield by a similar procedure to 8a. Then, reaction
of this compound with 37% aqueous formaldehyde solu-
tion gave 11j as a colorless solid in 94% yield by a similar
20
procedure to 11a; ½aꢁ ꢀ46° (c 0.50, CHCl3); FAB-MS
D
1
m/z 1117 (M+H)+; H NMR d 0.91 (d, 19-H), 1.09 (t,
3-OCOCH2CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.17
(t, 400-OCOCH2CH3), 1.23 (d, 16-H), 1.28 (d, 60-H),
1.48 (br t, 7-H), 1.55 (br dd, 14-H), 1.80 (m, 12-
N(CH2)3-naphthalene), 1.83 (dd, 200-Hax), 1.91 (br dt,
14-H), 2.01 (d, 200-Heq), 2.05 (s, 9-OCOCH3), 2.29 (s,
12-NCH3), 2.50 (s, 30-N(CH3)2), 2.61 (br t, 12-
N(CH2)3-naphthalene), 2.71 (m, 2-H), 3.06 (m, 12-
N(CH2)3-naphthalene), 3.18 (s, 18-OCH3), 3.28 (s, 18-
OCH3), 3.31 (t, 40-H), 3.32 (dq, 50-H), 3.45 (br d, 4-
H), 3.52 (s, 4-OCH3), 3.57 (dd, 20-H), 3.97 (br d, 5-H),
3.98 (br dd, 13-H), 4.46 (dq, 500-H), 4.52 (d, 10-H), 4.60
(t, 18-H), 4.62 (d, 400-H), 5.04 (ddq, 15-H), 5.07 (d, 100-
H), 5.21 (br dd, 3-H), 5.40 (br s, 9-H), 5.76 (br s, 10-
H), 5.76 (br s, 11-H), 7.30 (d, naphthalene), 7.37 (t,
naphthalene), 7.47 (m, naphthalene), 7.69 (d, naphtha-
lene), 7.83 (dd, naphthalene), 8.01 (d, naphthalene).
4.1.27. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(7-phenylheptyl)amino]midecamycin 18-dimethylacetal
(11h). Reaction of 5a with 7-phenylheptanal gave the 12-
N-(7-phenylheptyl) derivative of 5a as a colorless solid
in 42% yield by a similar procedure to 8a. Then, reaction
of this compound with 37% aqueous formaldehyde
solution gave 11h as a colorless solid in 71% yield by a
22
similar procedure to 11a; ½aꢁ ꢀ46° (c 1.0, CHCl3);
D
1
FAB-MS m/z 1123 (M+H)+; H NMR d 0.92 (d, 19-
H), 1.11 (t, 3-OCOCH2CH3), 1.11 (s, 300-CH3), 1.12 (d,
600-H), 1.17 (t, 400-OCOCH2CH3), 1.27 (d, 60-H), 1.30
(d, 16-H), 1.46 (m, 12-N(CH2)7C6H5), 1.59 (m, 12-
N(CH2)7C6H5), 1.83 (dd, 200-Hax), 2.01 (d, 200-Heq),
2.06 (s, 9-OCOCH3), 2.26 (s, 12-NCH3), 2.50 (s, 30-
N(CH3)2), 2.58 (t, 12-N(CH2)7C6H5), 2.69 (dd, 2-H),
2.78 (dd, 2-H), 3.18 (s, 18-OCH3), 3.27 (s, 18-OCH3),
3.31 (m, 40-H), 3.31 (m, 50-H), 3.46 (br d, 4-H), 3.52
4.1.30.
9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-
methyl-N-(3-(quinolin-3-yl)propyl)amino]midecamycin
18-dimethylacetal (11k). Reaction of 5a with 3-(quino-
lin-3-yl)propionaldehyde gave the 12-N-(3-(quinolin-3-
yl)propyl) derivative of 5a as a colorless solid in 63%

3998
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
yield by a similar procedure to 8a. Then, reaction of this
compound with 37% aqueous formaldehyde solution
gave 11k as a colorless solid in 89% yield by a similar
(s, 30-N(CH3)2), 2.70 (dd, 2-H), 2.83 (dd, 2-H), 3.12 (s,
18-OCH3), 3.23 (s, 18-OCH3), 3.28 (br s, 12-H), 3.29
(t, 40-H), 3.31 (dq, 50-H), 3.61 (s, 4-OCH3), 3.61 (dd,
20-H), 3.74 (br d, 4-H), 3.96 (br d, 5-H), 4.02 (m, pyrid-
inylimidazole), 4.07 (br dd, 13-H), 4.47 (dq, 500-H), 4.59
(d, 10-H), 4.61 (d, 400-H), 4.62 (t, 18-H), 5.02 (ddq, 15-H),
5.07 (d, 100-H), 5.23 (br dd, 3-H), 5.37 (br t, 9-H), 5.68
(dd, 11-H), 5.78 (dd, 10-H), 7.25 (d, imidazole), 7.27
(dd, pyridine), 7.61 (d, imidazole), 7.96 (dt, pyridine),
8.41 (dd, pyridine), 9.04 (d, pyridine).
22
procedure to 11a; ½aꢁ ꢀ46° (c 1.0, CHCl3); FAB-MS
D
1
m/z 1118 (M+H)+; H NMR d 0.90 (d, 19-H), 1.05 (t,
3-OCOCH2CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.17
(t, 400-OCOCH2CH3), 1.25 (d, 16-H), 1.27 (d, 60-H),
1.51 (br t, 7-H), 1.62 (br dd, 14-H), 1.83 (dd, 200-Hax),
1.92 (m, 12-N(CH2)3-quinoline), 2.00 (d, 200-Heq), 2.03
(s, 9-OCOCH3), 2.30 (s, 12-NCH3), 2.50 (s, 30-
N(CH3)2), 2.59 (m, 12-N(CH2)3-quinoline), 2.70 (dd,
2-H), 2.78 (m, 12-N(CH2)3-quinoline), 3.18 (s, 18-
OCH3), 3.27 (s, 18-OCH3), 3.31 (m, 40-H), 3.31 (m, 50-
H), 3.44 (br d, 4-H), 3.52 (s, 4-OCH3), 3.56 (dd, 20-
H), 3.98 (br d, 5-H), 3.98 (br dd, 13-H), 4.45 (dq, 500-
H), 4.52 (d, 10-H), 4.58 (t, 18-H), 4.61 (d, 400-H), 5.04
(ddq, 15-H), 5.06 (d, 100-H), 5.20 (br dd, 3-H), 5.39 (br
s, 9-H), 5.72 (dd, 11-H), 5.83 (dd, 10-H), 7.50 (br dd,
quinoline), 7.64 (br dd, quinoline), 7.75 (br dd, quino-
line), 7.92 (br d, quinoline), 8.05 (d, quinoline), 8.77
(d, quinoline).
4.1.33. 9-O-Acetyl-12,13-dihydro-12-(N,N-dimethylamino)-
13-hydroxymidecamycin (12a). Reaction of 11a with
difluoroacetic acid gave 12a as a colorless solid in 27%
23
yield by a similar procedure to 7a; ½aꢁ ꢀ67° (c 0.53,
D
1
CHCl3); FAB-MS m/z 917 (M+H)+; H NMR d 0.93
(d, 19-H), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.17 (t, 3-
OCOCH2CH3), 1.17 (t, 400-OCOCH2CH3), 1.18 (d, 60-
H), 1.31 (d, 16-H), 1.47 (dt, 7-H), 1.74 (ddd, 14-H),
1.83 (dd, 200-Hax), 2.01 (d, 200-Heq), 2.06 (s, 9-
OCOCH3), 2.29 (s, 12-N(CH3)2), 2.50 (s, 30-N(CH3)2),
2.71 (dd, 2-H), 2.80 (dd, 2-H), 2.92 (dd, 17-H), 3.28
(m, 40-H), 3.28 (m, 50-H), 3.40 (br d, 4-H), 3.49 (dd,
20-H), 3.53 (s, 4-OCH3), 3.97 (br d, 5-H), 4.02 (ddd,
13-H), 4.42 (d, 10-H), 4.44 (dq, 500-H), 4.61 (d, 400-H),
5.03 (ddq, 15-H), 5.06 (d, 100-H), 5.22 (br t, 9-H), 5.30
(br dd, 3-H), 5.75 (br dd, 11-H), 5.91 (br dd, 10-H),
9.67 (s, 18-H).
4.1.31. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(3-(quinolin-4-yl)propyl)amino]midecamycin 18-dime-
thylacetal (11l). Reaction of 5a with 3-(quinolin-4-
yl)propionaldehyde gave the 12-N-(3-(quinolin-4-yl)
propyl) derivative of 5a as a colorless solid in 45% yield
by a similar procedure to 8a. Then, reaction of this com-
pound with 37% aqueous formaldehyde solution gave
11l as a colorless solid in 84% yield by a similar proce-
4.1.34. 9-O-Acetyl-12-(N-benzyl-N-methylamino)-12,13-
dihydro-13-hydroxymidecamycin (12b). Reaction of 11b
with difluoroacetic acid gave 12b as a colorless solid in
22
dure to 11a; ½aꢁ ꢀ43° (c 1.0, CHCl3); FAB-MS m/z
D
1
1118 (M+H)+; H NMR d 0.92 (d, 19-H), 1.06 (t, 3-
OCOCH2CH3), 1.11 (s, 300-CH3), 1.17 (t, 400-
OCOCH2CH3), 1.28 (d, 16-H), 1.28 (d, 60-H), 1.51 (br
t, 7-H), 1.51 (br dd, 14-H), 1.83 (dd, 200-Hax), 2.02 (d,
200-Heq), 2.05 (s, 9-OCOCH3), 2.35 (s, 12-NCH3), 2.51
(s, 30-N(CH3)2), 2.65 (m, 12-N(CH2)3-quinoline), 2.74
(dd, 2-H), 3.17 (s, 18-OCH3), 3.27 (s, 18-OCH3), 3.32
(m, 40-H), 3.32 (m, 50-H), 3.43 (br d, 4-H), 3.53 (s, 4-
OCH3), 3.59 (dd, 20-H), 3.98 (br d, 5-H), 3.98 (br dd,
13-H), 4.48 (dq, 500-H), 4.54 (d, 10-H), 4.58 (t, 18-H),
4.61 (d, 400-H), 5.00 (ddq, 15-H), 5.07 (d, 100-H), 5.16
(br dd, 3-H), 5.38 (br s, 9-H), 5.72 (br d, 11-H), 5.81
(br d, 10-H), 7.24 (d, quinoline), 7.56 (ddd, quinoline),
7.69 (ddd, quinoline), 8.03 (br d, quinoline), 8.09 (br
d, quinoline), 8.78 (d, quinoline).
23
59% yield by a similar procedure to 7a; ½aꢁ ꢀ68° (c
D
1
1.0, CHCl3); FAB-MS m/z 993 (M+H)+; H NMR d
0.93 (d, 19-H), 1.01 (dt, 7-H), 1.11 (s, 300-CH3), 1.12
(d, 600-H), 1.16 (t, 3-OCOCH2CH3), 1.17 (t, 400-
OCOCH2CH3), 1.18 (d, 60-H), 1.31 (d, 16-H), 1.50 (dt,
7-H), 1.65 (br dd, 14-H), 1.84 (dd, 200-Hax), 2.01 (d,
200-Heq), 2.05 (s, 9-OCOCH3), 2.51 (s, 30-N(CH3)2),
2.60 (dd, 2-H), 2.70 (dd, 17-H), 3.28 (m, 40-H), 3.28
(m, 50-H), 3.52 (s, 4-OCH3), 3.96 (br d, 5-H), 3.96 (br
dd, 13-H), 4.24 (br dd, 12-H), 4.43 (d, 10-H), 4.43 (dq,
500-H), 4.61 (d, 400-H), 5.06 (d, 100-H), 5.11 (ddq, 15-H),
5.13 (br dd, 9-H), 5.21 (br dd, 3-H), 5.81 (br dd, 11-
H), 5.86 (br dd, 10-H), 9.65 (s, 18-H).
4.1.35. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-
4.1.32.
9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-
methyl-N-(2-phenylethyl)amino]midecamycin (12c).
Reaction of 11c with difluoroacetic acid gave 12c as a
colorless solid in 48% yield by a similar procedure to
methyl-N-(3-(4-(pyridin-3-yl)-imidazol-1-yl)propyl)amino]-
midecamycin 18-dimethylacetal (11m). Reaction of 5a
with 3-(4-(pyridin-3-yl)-imidazol-1-yl)propionaldehyde
gave the 12-N-(3-(4-(pyridin-3-yl)-imidazol-1-yl)propyl)
derivative of 5a as a colorless solid in 47% yield by a
similar procedure to 8a. Then, reaction of this com-
pound with 37% aqueous formaldehyde solution gave
23
7a; ½aꢁ ꢀ53° (c 0.89, CHCl3); FAB-MS m/z 1007
D
1
(M+H)+; H NMR d 0.89 (d, 19-H), 1.11 (s, 300-CH3),
1.12 (d, 600-H), 1.13 (t, 3-OCOCH2CH3), 1.17 (t, 400-
OCOCH2CH3), 1.18 (d, 60-H), 1.28 (d, 16-H), 1.48 (dt,
7-H), 1.55 (br dd, 14-H), 1.83 (dd, 200-Hax), 2.01 (d,
200-Heq), 2.05 (s, 9-OCOCH3), 2.41 (s, 12-NCH3), 2.50
(s, 30-N(CH3)2), 2.67 (dd, 2-H), 2.92 (dd, 17-H), 3.27
(m, 40-H), 3.27 (m, 50-H), 3.37 (br d, 4-H), 3.48 (dd,
20-H), 3.51 (s, 4-OCH3), 3.96 (br d, 5-H), 4.01 (br s,
13-H), 4.42 (d, 10-H), 4.43 (dq, 500-H), 4.61 (d, 400-H),
4.99 (ddq, 15-H), 5.05 (d, 100-H), 5.22 (br s, 9-H), 5.28
(br dd, 3-H), 5.79 (dd, 11-H), 5.87 (br d, 10-H), 7.18
(m, C6H5), 7.27 (m, C6H5), 9.65 (s, 18-H).
11m as a colorless solid in 89% yield by a similar proce-
22
D
1
dure to 11a; ½aꢁ ꢀ75° (c 0.50, CHCl3); FAB-MS m/z
1134 (M+H)+; H NMR d 0.66 (d, 19-H), 1.07 (t, 3-
OCOCH2CH3), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.16
(t, 400-OCOCH2CH3), 1.24 (d, 16-H), 1.26 (d, 60-H),
1.48 (br t, 7-H), 1.58 (br dd, 14-H), 1.73 (m, pyridinylim-
idazole), 1.82 (dd, 200-Hax), 1.96 (br dt, 14-H), 2.01 (d,
200-Heq), 2.02 (s, 9-OCOCH3), 2.36 (s, 12-NCH3), 2.54

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
3999
4.1.36. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-
methyl-N-(3-phenylpropyl)amino]midecamycin (12d) and
9-O-acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-N-
(3-phenylpropyl)amino]demycarosylplatenomycin (13d).
Reaction of 11d with difluoroacetic acid gave 12d as a
colorless solid in 26% yield and 13d as a colorless solid
(m, 40-H), 3.27 (m, 50-H), 3.40 (br d, 4-H), 3.49 (dd,
20-H), 3.52 (s, 4-OCH3), 3.97 (br d, 5-H), 4.03 (br dd,
13-H), 4.42 (d, 10-H), 4.43 (dq, 500-H), 4.61 (d, 400-H),
5.02 (ddq, 15-H), 5.05 (d, 100-H), 5.22 (br s, 9-H), 5.29
(br dd, 3-H), 5.76 (br d, 11-H), 5.83 (br d, 10-H), 7.15
(m, C6H5), 7.25 (m, C6H5), 9.66 (s, 18-H).
in 16%, respectively, by a similar procedure to 7a. Total
22
D
1
recovery was 42% in this reaction; 12d; ½aꢁ ꢀ62° (c
4.1.39. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-(N-methyl-
N-(6-phenylhexyl)amino)midecamycin (12g). Reaction of
11g with difluoroacetic acid gave 12g as a colorless solid
0.50, CHCl3); FAB-MS m/z 1021 (M+H)+; H NMR d
0.88 (d, 19-H), 1.10 (s, 300-CH3), 1.12 (d, 600-H), 1.15 (t,
3-OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3), 1.18 (d,
60-H), 1.28 (d, 16-H), 1.48 (dt, 7-H), 1.58 (br dd, 14-
H), 1.78 (m, 12-N(CH2)3C6H5), 1.83 (dd, 200-Hax), 2.00
(d, 200-Heq), 2.04 (s, 9-OCOCH3), 2.29 (s, 12-NCH3),
2.50 (s, 30-N(CH3)2), 2.59 (t, 12-N(CH2)3C6H5), 2.92
(dd, 17-H), 3.24 (br s, 12-H), 3.27 (m, 40-H), 3.27 (m,
50-H), 3.39 (br d, 4-H), 3.49 (dd, 20-H), 3.52 (s, 4-
OCH3), 3.96 (dd, 5-H), 4.02 (br dd, 13-H), 4.42 (d, 10-
H), 4.43 (dq, 500-H), 4.61 (d, 400-H), 5.03 (ddq, 15-H),
5.05 (d, 100-H), 5.20 (br d, 9-H), 5.28 (br dd, 3-H), 5.77
22
in 59% yield by a similar procedure to 7a; ½aꢁ ꢀ64° (c
D
1
0.66, CHCl3); FAB-MS m/z 1063 (M+H)+; H NMR d
0.90 (d, 19-H), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.15 (t,
3-OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3), 1.30 (d, 16-
H), 1.30 (d, 60-H), 1.45 (m, 12-N(CH2)6C6H5), 1.60 (m,
12-N(CH2)6C6H5), 1.83 (dd, 200-Hax), 2.00 (d, 200-Heq),
2.06 (s, 9-OCOCH3), 2.25 (s, 12-NCH3), 2.50 (s, 30-
N(CH3)2), 2.58 (t, 12-N(CH2)6C6H5), 2.91 (dd, 17-H),
3.19 (br s, 12-H), 3.27 (m, 40-H), 3.27 (m, 50-H), 3.41 (br
d, 4-H), 3.49 (dd, 20-H), 3.52 (s, 4-OCH3), 3.97 (br d, 5-
H), 4.02 (br dd, 13-H), 4.42 (d, 10-H), 4.42 (dq, 500-H),
4.61 (d, 400-H), 5.05 (ddq, 15-H), 5.05 (d, 100-H), 5.22 (br
s, 9-H), 5.29 (br dd, 3-H), 5.77 (dd, 11-H), 5.82 (dd, 10-
H), 7.15 (m, C6H5), 7.25 (m, C6H5), 9.65 (s, 18-H).
(br d, 11-H), 5.81 (br d, 10-H), 7.16 (m, C6H5), 7.25
23
(m, C6H5), 9.65 (s, 18-H). 13d; ½aꢁD ꢀ38° (c 0.75,
CHCl3); FAB-MS m/z 821 (M+H)+; H NMR d 0.89
1
(d, 19-H), 1.09 (br t, 7-H), 1.17 (t, 3-OCOCH2CH3),
1.23 (d, 60-H), 1.29 (d, 16-H), 1.51 (dt, 7-H), 1.59 (br
dd, 14-H), 1.83 (m, 12-N(CH2)3C6H5), 2.06 (s, 9-
OCOCH3), 2.30 (s, 12-NCH3), 2.34 (t, 30-H), 2.50 (s,
30-N(CH3)2), 2.61 (t, 12-N(CH2)3C6H5), 2.99 (dd, 17-
H), 3.07 (t, 40-H), 3.24 (br s, 12-H), 3.28 (dq, 50-H),
3.42 (br d, 4-H), 3.48 (dd, 20-H), 3.55 (s, 4-OCH3),
4.00 (br d, 5-H), 4.03 (br dd, 13-H), 4.45 (d, 10-H),
5.05 (ddq, 15-H), 5.22 (br d, 9-H), 5.31 (br dd, 3-H),
5.78 (br d, 11-H), 5.82 (br d, 10-H), 7.17 (m, C6H5),
7.27 (m, C6H5), 9.65 (s, 18-H).
4.1.40. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(7-phenylheptyl)amino]midecamycin (12h). Reaction of
11h with difluoroacetic acid gave 12h as a colorless solid
22
in 53% yield by a similar procedure to 7a; ½aꢁ ꢀ62° (c
D
1
0.55, CHCl3); FAB-MS m/z 1077 (M+H)+; H NMR d
0.90 (d, 19-H), 1.11 (s, 300-CH3), 1.12 (d, 600-H), 1.15 (t,
3-OCOCH2CH3), 1.17 (t, 400-OCOCH2CH3), 1.30 (d,
16-H), 1.30 (d, 60-H), 1.45 (m, 12-N(CH2)7C6H5), 1.59
(m, 12-N(CH2)7C6H5), 1.65 (br dd, 14-H), 1.83 (dd,
200-Hax), 2.01 (d, 200-Heq), 2.06 (s, 9-OCOCH3), 2.26
(s, 12-NCH3), 2.50 (s, 30-N(CH3)2), 2.58 (t, 12-
N(CH2)7C6H5), 2.92 (dd, 17-H), 3.19 (br s, 12-H), 3.27
(m, 40-H), 3.27 (m, 50-H), 3.41 (br d, 4-H), 3.49 (dd,
20-H), 3.52 (s, 4-OCH3), 3.97 (br d, 5-H), 4.03 (br dd,
13-H), 4.42 (d, 10-H), 4.42 (dq, 500-H), 4.61 (d, 400-H),
5.06 (ddq, 15-H), 5.06 (d, 100-H), 5.22 (br s, 9-H), 5.30
(br dd, 3-H), 5.77 (br d, 11-H), 5.83 (br d, 10-H), 7.15
(m, C6H5), 7.25 (m, C6H5), 9.66 (s, 18-H).
4.1.37. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-(N-methyl-
N-(4-phenylbutyl)amino)midecamycin (12e). Reaction of
11e with difluoroacetic acid gave 12e as a colorless solid
21
in 53% yield by a similar procedure to 7a; ½aꢁ ꢀ59° (c
D
1
0.90, CHCl3); FAB-MS m/z 1035 (M+H)+; H NMR d
0.90 (d, 19-H), 1.10 (s, 300-CH3), 1.12 (d, 600-H), 1.15 (t,
3-OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3), 1.17 (d, 60-
H), 1.30 (d, 16-H), 1.57 (m, 12-N(CH2)4C6H5), 1.83 (dd,
200-Hax), 2.01 (d, 200-Heq), 2.04 (s, 9-OCOCH3), 2.25 (s,
12-NCH3), 2.50 (s, 30-N(CH3)2), 2.92 (dd, 17-H), 3.20
(br s, 12-H), 3.27 (m, 40-H), 3.27 (m, 50-H), 3.40 (br d, 4-
H), 3.49 (dd, 20-H), 3.52 (s, 4-OCH3), 3.97 (br d, 5-H),
4.04 (br dd, 13-H), 4.42 (d, 10-H), 4.42 (dq, 500-H), 4.61
(d, 400-H), 5.04 (ddq, 15-H), 5.05 (d, 100-H), 5.21 (br s, 9-
H), 5.28 (br dd, 3-H), 5.78 (dd, 11-H), 5.84 (br d, 10-H),
7.16 (m, C6H5), 7.25 (m, C6H5), 9.66 (s, 18-H).
4.1.41. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(3-(pyridin-4-yl)propyl)amino]midecamycin (12i) and
9-O-acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-N-
(3-(pyridin-4-yl)propyl)amino]demycarosylplatenomycin
(13i). Reaction of 11i with difluoroacetic acid gave 12i as
a colorless solid in 24% yield and 13i as a colorless solid
in 41%, respectively, by a similar procedure to 7a. Total
20
recovery was 65% in this reaction. 12i; ½aꢁ ꢀ67° (c 0.49,
D
1
4.1.38. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-(N-methyl-
N-(5-phenylpentyl)amino)midecamycin (12f). Reaction of
11f with difluoroacetic acid gave 12f as a colorless solid
CHCl3); FAB-MS m/z 1022 (M+H)+; H NMR d 0.89
(d, 19-H), 1.03 (br t, 7-H), 1.11 (s, 300-CH3), 1.13 (d,
600-H), 1.14 (t, 3-OCOCH2CH3), 1.17 (t, 400-
OCOCH2CH3), 1.26 (d, 60-H), 1.29 (d, 16-H), 1.49 (br
t, 7-H), 1.62 (br dd, 14-H), 1.84 (dd, 200-Hax), 1.85 (m,
12-N(CH2)3-pyridine), 2.01 (d, 200-Heq), 2.05 (s, 9-
OCOCH3), 2.09 (br dt, 14-H), 2.33 (s, 12-NCH3), 2.51
(s, 30-N(CH3)2), 2.61 (dd, 2-H), 2.75 (t, 12-N(CH2)3-pyr-
idine), 2.93 (dd, 17-H), 3.24 (m, 40-H), 3.27 (m, 50-H),
3.28 (br d, 12-H), 3.38 (br d, 4-H), 3.51 (dd, 20-H),
3.53 (s, 4-OCH3), 3.96 (br d, 5-H), 4.05 (br dd, 13-H),
21
in 59% yield by a similar procedure to 7a; ½aꢁ ꢀ60° (c
D
1
0.85, CHCl3); FAB-MS m/z 1049 (M+H)+; H NMR d
0.90 (d, 19-H), 1.10 (s, 300-CH3), 1.12 (d, 600-H), 1.14 (t,
3-OCOCH2CH3), 1.16 (t, 400-OCOCH2CH3), 1.30 (d,
16-H), 1.30 (d, 60-H), 1.49 (m, 12-N(CH2)5C6H5), 1.62
(m, 12-N(CH2)5C6H5), 1.83 (dd, 200-Hax), 2.00 (d, 200-
Heq), 2.04 (s, 9-OCOCH3), 2.25 (s, 12-NCH3), 2.50 (s,
30-N(CH3)2), 2.91 (dd, 17-H), 3.19 (br d, 12-H), 3.27

4000
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
4.43 (d, 10-H), 4.44 (dq, 500-H), 4.62 (d, 400-H), 5.02 (ddq,
15-H), 5.06 (d, 100-H), 5.19 (br t, 9-H), 5.27 (br t, 3-H),
5.76 (dd, 11-H), 5.86 (dd, 10-H), 7.11 (d, pyridine),
solid in 40%, respectively, by a similar procedure to
21
7a. Total recovery was 68% in this reaction. 12k; ½aꢁ
D
1
ꢀ63° (c 0.55, CHCl3); FAB-MS m/z 1072 (M+H)+; H
NMR d 0.88 (d, 19-H), 1.08 (br t, 7-H), 1.13 (t, 3-
OCOCH2CH3), 1.13 (s, 300-CH3), 1.14 (d, 600-H), 1.19
(t, 400-OCOCH2CH3), 1.20 (d, 60-H), 1.28 (d, 16-H),
1.48 (dt, 7-H), 1.64 (br dd, 14-H), 1.85 (dd, 200-Hax),
1.98 (m, 12-N(CH2)3-quinoline), 2.02 (d, 200-Heq), 2.03
(s, 9-OCOCH3), 2.32 (s, 12-NCH3), 2.53 (s, 30-
N(CH3)2), 2.60 (m, 12-N(CH2)3-quinoline), 2.82 (m,
12-N(CH2)3-quinoline), 2.94 (dd, 17-H), 3.24 (m, 12-
H), 3.29 (m, 40-H), 3.29 (m, 50-H), 3.31 (br d, 4-H),
3.52 (dd, 20-H), 3.54 (s, 4-OCH3), 3.98 (br d, 5-H),
4.07 (br dd, 13-H), 4.45 (d, 10-H), 4.46 (dq, 500-H), 4.63
(d, 400-H), 5.04 (ddq, 15-H), 5.08 (d, 100-H), 5.20 (br s,
9-H), 5.30 (br t, 3-H), 5.79 (dd, 11-H), 5.85 (dd, 10-
H), 7.52 (br dd, quinoline), 7.66 (br dd, quinoline),
19
8.47 (d, pyridine), 9.65 (s, 18-H). 13i; ½aꢁ ꢀ43° (c
D
1
0.50, CHCl3); FAB-MS m/z 822 (M+H)+; H NMR d
0.88 (d, 19-H), 1.08 (br t, 7-H), 1.14 (t, 3-OCOCH2CH3),
1.22 (d, 60-H), 1.29 (d, 16-H), 1.50 (br t, 7-H), 1.60 (br
dd, 14-H), 1.83 (m, 12-N(CH2)3-pyridine), 2.05 (s, 9-
OCOCH3), 2.10 (br dt, 14-H), 2.29 (s, 12-NCH3), 2.33
(t, 30-H), 2.50 (s, 30-N(CH3)2), 2.75 (dt, 12-N(CH2)3-pyr-
idine), 2.98 (dd, 17-H), 3.06 (t, 40-H), 3.20 (br t, 12-H),
3.27 (dq, 50-H), 3.40 (br d, 4-H), 3.47 (dd, 20-H), 3.54
(s, 4-OCH3), 3.97 (br d, 5-H), 4.01 (br dd, 13-H), 4.45
(d, 10-H), 5.04 (ddq, 15-H), 5.21 (br t, 9-H), 5.28 (br t,
3-H), 5.74 (dd, 11-H), 5.83 (dd, 10-H), 7.11 (dd, pyri-
dine), 8.46 (dd, pyridine), 9.67 (s, 18-H).
4.1.42. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(3-(naphthalen-1-yl)propyl)amino]midecamycin (12j)
and 9-O-acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(3-(naphthalen-1-yl)propyl)amino]demycarosylplateno-
mycin (13j). Reaction of 11j with difluoroacetic acid
gave 12j as a colorless solid in 46% yield and 13j as a col-
7.77 (br d, quinoline), 7.95 (br d, quinoline), 8.06 (d,
22
quinoline), 8.78 (d, quinoline), 9.67 (s, 18-H). 13k; ½aꢁ
D
1
ꢀ34° (c 0.51, CHCl3); FAB-MS m/z 872 (M+H)+; H
NMR d 0.88 (d, 19-H), 1.08 (br t, 7-H), 1.14 (t, 3-
OCOCH2CH3), 1.23 (d, 60-H), 1.28 (d, 16-H), 1.51 (dt,
7-H), 1.64 (br dd, 14-H), 1.95 (m, 12-N(CH2)3-quino-
line), 2.03 (s, 9-OCOCH3), 2.31 (s, 12-NCH3), 2.35 (t,
30-H), 2.51 (s, 30-N(CH3)2), 2.60 (m, 12-N(CH2)3-quino-
line), 3.00 (dd, 17-H), 3.08 (t, 40-H), 3.24 (m, 12-H), 3.28
(dq, 50-H), 3.43 (dd, 4-H), 3.49 (dd, 20-H), 3.55 (s, 4-
OCH3), 4.00 (br d, 5-H), 4.06 (br dd, 13-H), 4.46 (d,
10-H), 5.05 (ddq, 15-H), 5.21 (br s, 9-H), 5.31 (br t, 3-
H), 5.79 (dd, 11-H), 5.85 (dd, 10-H), 7.52 (br dd, quin-
oline), 7.66 (br dd, quinoline), 7.70 (br d, quinoline),
7.96 (br d, quinoline), 8.07 (d, quinoline), 8.79 (d, quin-
oline), 9.69 (s, 18-H).
orless solid in 25%, respectively, by a similar procedure
19
D
1
to 7a. Total recovery was 71% in this reaction. 12j; ½aꢁ
ꢀ61° (c 0.50, CHCl3); FAB-MS m/z 1071 (M+H)+; H
NMR d 0.89 (d, 19-H), 1.11 (t, 3-OCOCH2CH3), 1.11
(s, 300-CH3), 1.15 (d, 600-H), 1.17 (t, 400-OCOCH2CH3),
1.23 (d, 16-H), 1.24 (d, 60-H), 1.49 (br t, 7-H), 1.58 (br
dd, 14-H), 1.84 (dd, 200-Hax), 1.93 (br dt, 14-H), 2.01
(d, 200-Heq), 2.04 (s, 9-OCOCH3), 2.06 (m, 12-
N(CH2)3-naphthalene), 2.32 (s, 12-NCH3), 2.51 (s, 30-
N(CH3)2), 2.64 (t, 12-N(CH2)3-naphthalene), 2.75 (m,
2-H), 2.92 (dd, 17-H), 3.07 (dq, 50-H), 3.26 (br d, 12-
H), 3.28 (t, 40-H), 3.39 (br d, 4-H), 3.50 (dd, 20-H),
3.52 (s, 4-OCH3), 3.97 (br d, 5-H), 4.05 (br dd, 13-H),
4.43 (d, 10-H), 4.45 (dq, 500-H), 4.62 (d, 400-H), 5.01
(ddq, 15-H), 5.06 (d, 100-H), 5.18 (br d, 9-H), 5.28 (br
dd, 3-H), 5.80 (br s, 11-H), 5.81 (br s, 10-H), 7.30 (d,
naphthalene), 7.37 (t, naphthalene), 7.47 (m, naphtha-
4.1.44. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(3-(quinolin-4-yl)propyl)amino] midecamycin (12l) and
9-O-acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-N-
(3-(quinolin-4-yl)propyl)amino]demycarosylplatenomycin
(13l). Reaction of 11l with difluoroacetic acid gave 12l as
a colorless solid in 39% yield and 13l as a colorless solid
lene), 7.69 (d, naphthalene), 7.83 (dd, naphthalene),
in 33%, respectively, by a similar procedure to 7a. Total
20
24
8.02 (d, naphthalene), 9.66 (s, 18-H). 13j; ½aꢁ ꢀ433°
recovery was 72% in this reaction. 12l; ½aꢁ ꢀ58° (c 0.70,
D
1
D
1
(c 0.74, CHCl3); FAB-MS m/z 871 (M+H)+; H NMR
d 0.88 (d, 19-H), 1.14 (t, 3-OCOCH2CH3), 1.22 (d, 16-
H), 1.24 (d, 60-H), 1.46 (br t, 7-H), 1.54 (br dd, 14-H),
1.95 (m, 12-N(CH2)3-naphthalene), 2.04 (s, 9-
OCOCH3), 2.10 (br dt, 14-H), 2.32 (s, 12-NCH3), 2.51
(s, 30-N(CH3)2), 2.73 (dt, 12-N(CH2)3-naphthalene),
2.76 (m, 2-H), 2.98 (dd, 17-H), 3.06 (t, 40-H), 3.25 (br
d, 12-H), 3.28 (dq, 50-H), 3.40 (br d, 4-H), 3.47 (dd,
20-H), 3.53 (s, 4-OCH3), 3.98 (br d, 5-H), 4.04 (br dd,
13-H), 4.44 (d, 10-H), 5.01 (ddq, 15-H), 5.18 (br d, 9-
H), 5.29 (br dd, 3-H), 5.79 (br s, 11-H), 5.80 (br s, 10-
H), 7.30 (d, naphthalene), 7.37 (t, naphthalene), 7.47
(m, naphthalene), 7.69 (d, naphthalene), 7.83 (dd, naph-
thalene), 8.02 (d, naphthalene), 9.68 (s, 18-H).
CHCl3); FAB-MS m/z 1072 (M+H)+; H NMR d 0.88
(d, 19-H), 1.11 (t, 3-OCOCH2CH3), 1.11 (s, 300-CH3),
1.12 (d, 600-H), 1.16 (t, 400-OCOCH2CH3), 1.17 (d, 60-
H), 1.20 (d, 16-H), 1.47 (br t, 7-H), 1.54 (br dd, 14-H),
1.83 (dd, 200-Hax), 2.01 (d, 200-Heq), 2.03 (s, 9-
OCOCH3), 2.32 (s, 12-NCH3), 2.51 (s, 30-N(CH3)2),
2.93 (dd, 17-H), 3.27 (m, 40-H), 3.27 (m, 50-H), 3.37
(br t, 4-H), 3.51 (dd, 20-H), 3.52 (s, 4-OCH3), 3.95 (br
d, 5-H), 4.01 (br dd, 13-H), 4.43 (d, 10-H), 4.44 (dq,
500-H), 4.61 (d, 400-H), 5.00 (ddq, 15-H), 5.05 (d, 100-H),
5.16 (br s, 9-H), 5.25 (br t, 3-H), 5.75 (br d, 11-H),
5.81 (br d, 10-H), 7.22 (d, quinoline), 7.54 (ddd, quino-
line), 7.68 (ddd, quinoline), 8.03 (br d, quinoline), 8.08
(br d, quinoline), 8.77 (d, quinoline), 9.65 (s, 18-H).
24
13l; ½aꢁ ꢀ34° (c 0.50, CHCl3); FAB-MS m/z 872
D
1
4.1.43. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(3-(quinolin-3-yl)propyl)amino]midecamycin (12k) and
9-O-acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-N-
(3-(quinolin-3-yl)propyl)amino]demycarosylplatenomycin
(13k). Reaction of 11k with difluoroacetic acid gave 12k
as a colorless solid in 28% yield and 13k as a colorless
(M+H)+; H NMR d 0.88 (d, 19-H), 1.05 (br t, 7-H),
1.12 (t, 3-OCOCH2CH3), 1.21 (d, 60-H), 1.22 (d, 16-
H), 1.50 (dt, 7-H), 1.55 (br dd, 14-H), 2.02 (m, 12-
N(CH2)3-quinoline), 2.04 (s, 9-OCOCH3), 2.32 (s, 12-
NCH3), 2.34 (t, 30-H), 2.50 (s, 30-N(CH3)2), 2.99 (dd,
17-H), 3.06 (t, 40-H), 3.27 (dq, 50-H), 3.39 (br d, 4-H),

T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
4001
3.48 (dd, 20-H), 3.54 (s, 4-OCH3), 3.97 (br d, 5-H), 4.02
(br dd, 13-H), 4.45 (d, 10-H), 5.00 (ddq, 15-H), 5.17 (br s,
9-H), 5.26 (br t, 3-H), 5.76 (dd, 11-H), 5.82 (br d, 10-H),
7.23 (d, quinoline), 7.54 (dd, quinoline), 7.68 (dd, quin-
oline), 8.04 (d, quinoline), 8.09 (d, quinoline), 8.78 (d,
quinoline), 9.67 (s, 18-H).
d, 4-H), 3.57 (s, 4-OCH3), 3.94 (br d, 5-H), 4.51 (dq,
500-H), 4.60 (d, 10-H), 4.60 (d, 400-H), 4.62 (t, 18-H),
4.88 (d, 100-H), 4.91 (ddq, 15-H), 5.10 (br d, 3-H), 5.35
(dd, 9-H), 5.76 (dd, 11-H), 6.02 (dd, 10-H).
4.1.47. 9,300-Di-O-acetyl-12-amino-12,13-dihydro-13-hydrox-
ymidecamycin 18-dimethylacetal (16). Reaction of 15 in
MeOH with sodium azide gave 9,300-di-O-acetyl-12-
azide-12,13-dihydro-13-hydroxymidecamycin 18-dimeth-
ylacetal by a similar procedure to 4a. Then, reaction
of this compound with triphenylphosphine gave 16 as
4.1.45. 9-O-Acetyl-12,13-dihydro-13-hydroxy-12-[N-methyl-
N-(3-(4-pyridin-3-yl-imidazol-1-yl)propyl)amino]mideca-
mycin (12m) and 9-O-acetyl-12,13-dihydro-13-hydroxy-
12-[N-methyl-N-(3-(4-pyridin-3-yl-imidazol-1-yl)propyl)-
amino]demycarosylplatenomycin (13m). Reaction of 11m
with difluoroacetic acid gave 12m as a colorless solid in
38% yield and 13m as a colorless solid in 44%, respec-
a colorless solid in 69% yield (overall two steps) by a
23
similar procedure to 5a; ½aꢁ ꢀ41° (c 1.5, CHCl3);
D
1
FAB-MS m/z 977 (M+H)+; H NMR d 0.95 (d, 19-H),
1.09 (d, 600-H), 1.13 (t, 3-OCOCH2CH3), 1.19 (t, 400-
OCOCH2CH3), 1.22 (d, 60-H), 1.31 (d, 16-H), 1.42 (s,
300-CH3), 1.54 (br t, 7-H), 1.59 (br dd, 14-H), 1.70 (dd,
200-Hax), 2.01 (s, 300-OCOCH3), 2.04 (s, 9-OCOCH3),
2.36 (t, 30-H), 2.56 (s, 30-N(CH3)2), 2.64 (dd, 2-H),
2.90 (dd, 2-H), 3.16 (s, 18-OCH3), 3.23 (d, 200-Heq),
3.27 (s, 18-OCH3), 3.38 (dd, 20-H), 3.53 (br d, 4-H),
3.55 (s, 4-OCH3), 3.75 (br s, 12-H), 3.86 (br dd, 13-H),
3.95 (br d, 5-H), 4.52 (dq, 500-H), 4.56 (d, 10-H), 4.59
(d, 400-H), 4.61 (t, 18-H), 4.86 (d, 100-H), 5.12 (ddq, 15-
H), 5.18 (br dd, 3-H), 5.30 (dd, 9-H), 5.70 (br d, 10-
H), 5.82 (dd, 11-H).
tively, by a similar procedure to 7a. Total recovery
22
was 82% in this reaction. 12m; ½aꢁ ꢀ123° (c 0.50,
D
1
CHCl3); FAB-MS m/z 1088 (M+H)+; H NMR d 0.41
(d, 19-H), 1.12 (s, 300-CH3), 1.13 (t, 3-OCOCH2CH3),
1.14 (d, 600-H), 1.17 (t, 400-OCOCH2CH3), 1.25 (d, 60-
H), 1.32 (d, 16-H), 1.64 (br dd, 14-H), 1.82 (dd, 200-
Hax), 1.99 (s, 9-OCOCH3), 2.01 (d, 200-Heq), 2.13 (br
dt, 14-H), 2.41 (s, 12-NCH3), 2.60 (s, 30-N(CH3)2),
2.78 (dd, 2-H), 2.85 (m, 12-N(CH2)3-imidazole), 2.89
(dd, 17-H), 3.12 (br t, 12-H), 3.25 (br d, 4-H), 3.26 (t,
40-H), 3.27 (dq, 50-H), 3.60 (dd, 20-H), 3.75 (s, 4-
OCH3), 3.95 (br d, 5-H), 4.06 (m, 12-N(CH2)3-imidaz-
ole), 4.20 (br dd, 13-H), 4.47 (dq, 500-H), 4.54 (d, 10-
H), 4.62 (d, 400-H), 5.05 (ddq, 15-H), 5.07 (d, 100-H),
5.12 (br s, 9-H), 5.32 (br dd, 3-H), 5.69 (dd, 11-H),
5.79 (dd, 10-H), 7.25 (d, imidazole), 7.28 (dd, pyridine),
4.1.48. 9,300-Di-O-acetyl-12,13-dihydro-13-hydroxy-12-
[N-methyl-N-(3-phenylpropyl)amino]midecamycin 18-
dimethylacetal (17). Reaction of 16 with phenylpropion-
aldehyde gave the crude 12-N-(3-phenylpropyl) deriva-
tive of 16 as a colorless solid by a similar procedure to
8a. Then, reaction of this compound with 37% aqueous
formaldehyde solution gave 17 as a colorless solid in
7.67 (d, imidazole), 7.90 (dt, pyridine), 8.39 (dd, pyri-
23
D
1
dine), 9.19 (d, pyridine), 9.60 (s, 18-H). 13m; ½aꢁ
ꢀ109° (c 0.50, CHCl3); FAB-MS m/z 888 (M+H)+; H
NMR d 0.42 (d, 19-H), 1.13 (t, 3-OCOCH2CH3), 1.19
(d, 60-H), 1.32 (d, 16-H), 1.63 (br dd, 14-H), 2.00 (s, 9-
OCOCH3), 2.10 (br dt, 14-H), 2.38 (s, 12-NCH3), 2.60
(s, 30-N(CH3)2), 2.78 (dd, 2-H), 2.87 (m, 12-N(CH2)3-
imidazole), 2.91 (dd, 17-H), 3.09 (br t, 12-H), 3.27 (br
d, 4-H), 3.28 (t, 40-H), 3.31 (dq, 50-H), 3.57 (dd, 20-H),
3.74 (s, 4-OCH3), 3.96 (br d, 5-H), 4.04 (m, 12-
N(CH2)3-imidazole), 4.17 (br dd, 13-H), 4.55 (d, 10-H),
5.06 (ddq, 15-H), 5.13 (br s, 9-H), 5.33 (br dd, 3-H),
5.67 (dd, 11-H), 5.78 (dd, 10-H), 7.25 (d, imidazole),
7.28 (dd, pyridine), 7.66 (d, imidazole), 7.91 (dt, pyri-
dine), 8.38 (dd, pyridine), 9.18 (d, pyridine), 9.62 (s,
18-H).
37% yield (overall two steps) by a similar procedure to
22
11a; ½aꢁ ꢀ59° (c 1.0, CHCl3); TSP-MS m/z 1109
D
1
(M+H)+; H NMR d 0.92 (d, 19-H), 1.10 (d, 600-H),
1.12 (t, 3-OCOCH2CH3), 1.20 (t, 400-OCOCH2CH3),
1.23 (d, 60-H), 1.29 (d, 16-H), 1.43 (s, 300-CH3), 1.55
(br t, 7-H), 1.62 (br dd, 14-H), 2.02 (s, 300-OCOCH3),
2.07 (s, 9-OCOCH3), 2.36 (s, 12-NCH3), 2.56 (s, 30-
N(CH3)2), 2.61 (t, 12-N(CH2)3C6H5), 2.64 (dd, 2-H),
2.80 (dd, 2-H), 3.19 (s, 18-OCH3), 3.24 (d, 200-Heq),
3.28 (s, 18-OCH3), 3.38 (dd, 20-H), 3.47 (br d, 4-H),
3.56 (s, 4-OCH3), 3.96 (br d, 5-H), 4.05 (br dd, 13-H),
4.52 (dq, 500-H), 4.57 (d, 10-H), 4.59 (d, 400-H), 4.63 (t,
18-H), 4.87 (d, 100-H), 5.05 (ddq, 15-H), 5.21 (br dd, 3-
H), 5.41 (br s, 9-H), 5.74 (dd, 11-H), 5.87 (br d, 10-H),
7.18 (m, C6H5), 7.27 (m, C6H5).
4.1.46. 9,300-Di-O-acetyl-12,13-dihydro-12,13-epoxymi-
decamycin 18-dimethylacetal (15). Reaction of 9,300-di-
O-acetylmidecamycin in MeOH with pyridinium p-tolu-
enesulfonate gave 14 as a colorless solid in 79% yield by
a similar procedure to 2. Then, reaction of 14 with 3-
4.1.49. 9,300-Di-O-acetyl-12,13-dihydro-13-hydroxy-12-
[N-methyl-N-(3-phenylpropyl)amino]midecamycin (18).
Reaction of 17 with difluoroacetic acid gave 18 as a col-
chroloperbenzoic acid gave 15 as a colorless solid in
23
42% yield by a similar procedure to 3; ½aꢁ ꢀ45° (c
orless solid in 87% yield by a similar procedure to 7a;
D
1
23
1.0, CHCl3); FAB-MS m/z 960 (M+H)+; H NMR d
0.89 (dt, 7-H), 1.01 (d, 19-H), 1.09 (d, 600-H), 1.10 (t,
3-OCOCH2CH3), 1.19 (t, 400-OCOCH2CH3), 1.22 (d,
60-H), 1.27 (d, 16-H), 1.42 (s, 300-CH3), 1.47 (br dd, 14-
H), 1.63 (dt, 7-H), 1.70 (dd, 200-Hax), 2.00 (s, 300-
OCOCH3), 2.01 (s, 9-OCOCH3), 2.23 (br d, 14-H),
2.38 (q, 3-OCOCH2CH3), 2.43 (q, 400-OCOCH2CH3),
2.57 (s, 30-N(CH3)2), 2.74 (dd, 2-H), 3.16 (s, 18-
OCH3), 3.22 (d, 200-Heq), 3.26 (s, 18-OCH3), 3.30 (br
½aꢁ ꢀ73° (c 1.0, CHCl3); TSP-MS m/z 1063 (M+H)+;
D
1H NMR d 0.89 (d, 19-H), 1.10 (d, 600-H), 1.14 (d, 60-
H), 1.17 (t, 3-OCOCH2CH3), 1.20 (t, 400-OCOCH2CH3),
1.29 (d, 16-H), 1.43 (s, 300-CH3), 1.56 (dt, 7-H), 1.59 (br
dd, 14-H), 1.72 (dd, 200-Hax), 1.85 (m, 12-
N(CH2)3C6H5), 2.01 (s, 300-OCOCH3), 2.07 (s, 9-
OCOCH3), 2.33 (s, 12-NCH3), 2.57 (s, 30-N(CH3)2),
2.80 (dd, 2-H), 2.97 (dd, 17-H), 3.43 (br d, 4-H), 3.57
(s, 4-OCH3), 3.96 (br d, 5-H), 4.06 (br dd, 13-H), 4.47

4002
T. Miura et al. / Bioorg. Med. Chem. 16 (2008) 3985–4002
(d, 10-H), 4.48 (dq, 500-H), 4.60 (d, 400-H), 4.88 (d, 100-H),
5.04 (ddq, 15-H), 5.22 (br d, 9-H), 5.30 (br dd, 3-H), 5.79
(br d, 11-H), 5.83 (br d, 10-H), 7.18 (m, C6H5), 7.27 (m,
C6H5), 9.67 (s, 18-H).
7. Bright, G. M.; Nagel, A. A.; Bordner, J.; Desai, K. A.;
Dibrino, J. N.; Nowakowska, J.; Vincemt, L.; Watrous, R.
M.; Sciavolino, F. C.; English, A. R.; Retsema, J. A.;
Anderson, M. R.; Brennan, L. A.; Borovoy, R. J.;
Cimochowski, C. R.; Faiella, J. A.; Girard, A. E.; Girard,
D.; Herbert, C.; Manousos, M.; Mason, R. J. Antibiot.
1988, 41, 1029.
4.2. Biology
8. Slobodan, D.; Gabrijela, K.; Nevenka, L.; Boris, K.; Ante,
N.; Draginja, M. J. Chem. Res. Synop. 1988, 152.
9. 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.
10. Or, Y. S.; Clark, R. F.; Wang, S.; Chu, D. T.; Nilius, A.
M.; Flamm, R. K.; Mitten, M.; Ewing, P.; Alder, J.; Ma,
Z. J. Med. Chem. 2000, 43, 1045.
11. Ma, Z.; Clark, R. F.; Brazzale, A.; Wang, S.; Rupp,
M. J.; Li, L.; Griesgraber, G.; Zhang, S.; Yong, H.;
Phan, L. T.; Nemoto, P. A.; Chu, D. T.; Plattner, J. J.;
Zhang, X.; Zhong, P.; Cao, Z.; Nilius, A. M.;
Shortridge, V. D.; Flamm, R. K.; Mitten, M.; Meulb-
roek, J.; Ewing, P.; Alder, J.; Or, Y. S. J. Med. Chem.
2001, 44, 4137.
4.2.1. Antibacterial activity in vitro. Minimum inhibitory
concentration (MIC) was determined by the agar dilu-
tion method. Test strains were subjected to seed culture
using Sensitivity test broth (STB, Nissui Pharmaceuti-
cal) for Staphylococcus aureus, or cultured on blood
agar plate for S. pneumoniae, Streptococcus pyogenes,
Moraxella 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 measured.
Acknowledgments
12. Omoto, S.; Iwamatsu, K.; Inouye, S.; Niida, T. J. Antibiot.
1976, 29, 536.
13. Sakakibara, H.; Okekawa, O.; Fujiwara, T.; Otani, M.;
We thank Drs. S. Hoshiko, H. Watabe, and Mr. Y.
Takayama for biological studies, and Drs. T. Okonogi
and K. Atsumi for valuable scientific discussion. We
are also grateful to Drs. M. Oyama, Y. Takeuchi, Mr.
N. Okura, Mr. T. Watanabe, Mrs. T. Miyara, and Miss
S. Miki for contribution toward analytical and synthetic
chemistry, and Mrs. Takagi for manuscript.
ꢀ
Omura, S. J. Antibiot. 1981, 34, 1001.
14. Sakakibara, H.; Okekawa, O.; Fujiwara, T.; Aizawa, M.;
ꢀ
Omura, S. J. Antibiot. 1981, 34, 1011.
15. Agouridas, C.; Denis, A.; Auger, J. M.; Benedetti, Y.;
Bonnefoy, A.; Bretin, F.; Chantot, J. F.; Dussarat, A.;
Fromentin, C.; D’Ambrieres, S. G.; Lachaud, S.; Laurin,
P.; Le Martret, O. L.; Loyau, V.; Tessot, N. J. Med. Chem.
1998, 41, 4080.
16. Hansen, L. H.; Mauvais, P.; Douthwaite, S. Mol. Micro-
biol. 1999, 31, 623.
17. Schlunzen, F.; Harms, J. M.; Franceschi, F.; Hansen, H.
¨
A. S.; Bartels, H.; Zarivach, R.; Yonath, A. Structure
2003, 11, 329.
18. Berisio, R.; Harms, J.; Schlunzen, F.; Zarivach, R.;
¨
Hansen, H. A. S.; Fucini, P.; Yonath, A. J. Bacteriology
2003, 185, 4276.
19. Miura, T.; Kurihara, K.; Yoshida, T.; Ajito, K. WO 03/
072589 A1, 1995.
20. Miura, T.; Kanemoto, K.; Natsume, S.; Okura, N.;
Fujihira, Y.; Watanabe, T.; Atsumi, K.; Ajito, K.
WO05/019238 A1, 2005.
21. Muroi, M.; Kishi, T. Chem. Pharm. Bull. 1978, 26, 2718.
22. Omoto, S.; Inouye, S.; Niida, T. Japan Kokai 13380,
1973.
References and notes
ꢀ
1. Morimoto, S.; Takahashi, Y.; Watanabe, Y.; Omura, S.
J. Antibiot. 1984, 37, 187.
2. Watanabe, Y.; Adachi, T.; Asaka, T.; Kashimura, M.;
Morimoto, S. Heterocycles 1990, 31, 2121.
3. Morimoto, S.; Misawa, Y.; Adachi, T.; Nagate, T.;
ꢀ
Watanabe, W.; Omura, S. J. Antibiot. 1990, 43, 286.
4. Morimoto, S.; Nagate, T.; Sugita, K.; Ono, T.; Numata,
ꢀ
K.; Miyachi, J.; Misawa, Y.; Yamada, K.; Omura, S.
J. Antibiot. 1990, 43, 295.
5. Kohno, Y.; Yoshida, H.; Suwa, T.; Suga, T. Antimicrob.
Agents Chemother. 1989, 33, 751.
6. Adachi, T.; Morimoto, S.; Kondoh, H.; Nagate, T.;
Watanabe, Y.; Sota, K. J. Antibiot. 1988, 41, 966.