Design and synthesis of novel leucomycin analogues modified at the C-3 position. Part II: 3-O-(3-Aryl-2-propenyl)leucomycin analogues

Article abstract of DOI:10.1016/j.bmc.2008.02.064

The design and synthesis of 16-membered macrolides modified at the C-3 position are described. Starting from fully protected intermediate (5), appropriate modifications including Heck reaction were performed to furnish 3-O-(3-aryl-2-propenyl)leucomycin A<

Full text of DOI:10.1016/j.bmc.2008.02.064

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 4401–4418
Design and synthesis of novel leucomycin analogues
modified at the C-3 position. Part II: 3-O-(3-Aryl-
2-propenyl)leucomycin analogues
Takeshi Furuuchi,* Tomoaki Miura,* Ken-ichi Kurihara, Takuji Yoshida,
Takashi Watanabe and Keiichi Ajito
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan
Received 15 January 2008; revised 18 February 2008; accepted 19 February 2008
Available online 23 February 2008
Abstract—The design and synthesis of 16-membered macrolides modified at the C-3 position are described. Starting from fully pro-
tected intermediate (5), appropriate modifications including Heck reaction were performed to furnish 3-O-(3-aryl-2-propenyl)leuco-
mycin A7 analogues (9a–9m). These leucomycin A7 derivatives showed improved in vitro antibacterial activities against clinically
important pathogens including erythromycin-resistant Streptococcus pneumoniae (ERSP). SAR analysis of derivatives modified at
the C-3 and C-300 positions suggested that single modification at C-3 or C-300 was effective for in vitro antibacterial activity.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
(MOM)11,12 and rokitamycin (RKM)13,14 (Fig. 2) are
not affected by efflux pumps. These two semisynthetic
16-membered macrolide antibiotics have been already
proven to be safe in clinical use. Thus, drug discovery in
the field of 16-membered macrolides is important for
anti-infective chemotherapy in the future.
Macrolide antibiotics have been used in the treatment of
bacterial infections for many years. They inhibit protein
biosynthesis by binding to ribosomal RNA (rRNA) of
the bacterial ribosome to exhibit antibiotic activities.
Clarithromycin1–5 (Fig. 1) and azithromycin6–8 (Fig. 1)
are synthesized from 14-membered erythromycin. They
are the representatives of widely used macrolides andhave
clinical importance. Ketolides have been developed as one
of the next generation macrolides, and telithromycin9
(Fig. 1) has been recently launched as a promising antibi-
otic. It is effective against important critical pathogens
including MLS resistant Streptococcus pneumoniae and
penicillin-resistant S. pneumoniae (PRSP). Enanta has
found a new ketolide, S-01342010 (Fig. 1) which is now un-
der clinical trials. Although telithromycin exhibits strong
potency against resistant bacteria of S. pneumoniae, it is
still influenced by efflux pumps of resistant S. pneumoniae.
Its clinical usage in pediatrics is not allowed because it has
not been proven to be safe. On the other hand, some of the
16-membered macrolides, such as miokamycin
In the previous paper,15 we synthesized 3-O-methyl ana-
logues of three key 16-membered macrolides in our re-
search (Fig. 3), and successfully improved both
antibacterial activity and biological stability. We also
found that a quinoline side chain in 3-O-[(2-quino-
lyl)carbonyl]leucomycin A7 (Fig. 3) was effective to
overcome resistants of S. pneumoniae. Being encouraged
by these results and SAR studies in ketolides,9,16,17 we
decided to introduce a hetero aromatic ring which would
coordinate with a new binding site of rRNA with an
appropriate spacer. The spacer should be attached via
ether bond, as we have already confirmed its stability
under metabolic condition.
2. Results and discussion
Keywords: Macrolide antibiotics; 16-Membered macrolides; 3-O-(3-
Aryl-2-propenyl)leucomycin A7 analogues; MLS resistant; Heck reac-
tion; Antibacterial activity.
2.1. Synthesis and evaluation of 3-O-[3-(3-quinolyl)-2-
propenyl]rokitamycin
*
Corresponding authors. Tel.: +81 45 561 2521; fax: +81 45 541
0667; e-mail addresses: takeshi_furuuchi@meiji.co.jp; tomoaki_
miura@meiji.co.jp
Since RKM is the most potent 16-membered macrolide
in clinical use, we first synthesized 3-O-[3-(3-quinolyl)-
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.02.064

4402
T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
Figure 1. Structures of representative semisynthetic macrolides.
microorganisms. Although methylation of the C-3 hy-
droxyl group of RKM resulted in enhancement of anti-
biotic activity,15 the bulky quinoline moiety caused an
inappropriate effect.
By the way, X-ray crystallographic analysis of RKM 18-
methylhemiacetal implied that the propionyl group at
the C-300 position extended toward macrolide aglycon
(Fig. 4).19 This information led us to a hypothesis that
a large substituent at the C-3 position caused steric
repulsion between C-3 and C-300 side chains. As a result,
the quinolylpropenyl side chain at the C-3 hydroxyl
group in the RKM analogue prevented the C-300 propi-
onyl group from coordinating with rRNA binding site
to decrease its antibiotic activity.
Figure 2. Leucomycin A7 and semisynthetic 16-membered macrolides,
MOM and RKM.
This hypothesis prompted us to modify the C-3 position
of leucomycin A7 (LM-A7, Fig. 2) which has a free hy-
droxyl group at the C-300 position in order to evaluate
substantial potency of a variety of arylalkyl side chains
at the C-3 position.
2-propenyl]rokitamycin (4) from the previously re-
ported intermediate (1)15 as shown in Scheme 1.
Fully protected RKM (1) was allylated using KOH
and allyl iodide to give 3-O-allyl derivative (2) in
70% based on the recovery of the starting material.
Heck reaction of 2 with 3-bromoquinoline was per-
formed under Jeffery’s condition18 to introduce the
quinoline side chain onto the allyl group at the C-3
position. After removal of the acetyl group on the
C-20 hydroxyl group, the TBS group and the di-
methyl acetal were simultaneously deprotected15 to
furnish 4.
2.2. Synthesis and evaluation of 3-O-(3-aryl-2-prope-
nyl)leucomycin A7 analogues
Synthesis of 3-O-(3-aryl-2-propenyl)leucomycin A7
analogues (9a–9m) is shown in Scheme 2. All steps
were conducted almost in the same way as in
RKM derivatives shown in Scheme 1. Allyl ether
(6) was obtained by using KOH and allyl iodide in
63% based on the recovery of the starting material
(5). Palladium catalyzed allylation20 turned out to
be an alternative method for this allylation and we
obtained 6 in 44% yield (71% based on the recovery
In vitro antibacterial activities of 3-O-[3-(3-quinolyl)-2-
propenyl]rokitamycin (4) is shown in Table 1. Com-
pound 4 was much less active than RKM against target
of 5). While we were introducing
a variety of

T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
4403
Figure 3. Previously reported leucomycin analogues modified at the C-3 position.
Scheme 1. Synthesis of 3-O-[3-(3-quinolyl)-2-propenyl]rokitamycin (4). Reagents and conditions: (a) KOH, allyl iodide, DMSO, rt, 4 h, 35%, 70%
based on the recovery of 1; (b) Pd(OAc)2, 3-bromoquinoline, K2CO3, n-Bu4NCl, DMF, 50 °C, 4 d, 41%; (c) i—MeOH/H2O (9:1), 50 °C, 22 h, 89%;
ii—CHF2COOH, MeCN/H2O (1:1), rt, 2 d, 62%.
aromatic side chains to 6 by Heck reaction, we found
that an allylic double bond was isomerized. After
examining many reaction conditions, this isomeriza-
tion was effectively prevented by using palladacycle21
or PdCl2. With fully modified intermediates (7a–7m)
at hand, tandem removal of the acetyl group, the
TBS group and the dimethyl acetal was conducted
to furnish 9a–9m.
to overcome even RKM (see compounds 9a–9e, 9h,
and 9m). Some side chains at the C-3 position
seemed to compensate for the propionyl group at
C-300 in RKM. Similar effects were observed when
we focused on resistant strains. Although LM-A7 is
inactive against the inducible resistant strains, C-3
aromatic rings played a role to enhance antibacterial
activities of LM-A7 as the C-300 propionyl moiety did
in RKM (see compounds 9a–9c and 9m). As far as
we know, compound 9m was the first 16-membered
leucomycin analogue that was active against constitu-
tively resistant S. pneumoniae (9a was also somewhat
active). Some potent ketolides also possess effective
side chains containing imidazole9,10 (Fig. 1) or quino-
line16,17 ring. Basic nitrogen atoms of these hetero
aromatic rings seemed to enhance the rRNA binding
abilities of 9m and 9a, and increased their
antimicrobial activities. These results suggested that
Table 2 shows in vitro antibacterial activities of 9a–
9m. Most of the derivatives exhibited stronger antibi-
otic activities than LM-A7 as we expected. Generally
speaking, in vitro activity of LM-A7 is half as strong
as RKM because LM-A7 lacks propionyl side chain
at the C-300 position (Fig. 2). However, introducing
an appropriate arylalkyl group at the C-3 position
resulted in enhancing in vitro activity against suscepti-
ble strains in Staphylococcus aureus and S. pneumoniae

4404
T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
Table 1. Antibacterial activities of 3-O-[3-(3-quinolyl)-2-propenyl]rokitamycin (4)
Test organisms
Characteristics
4
RKM
CAM
Staphylococcus aureus 209P JC-1
Staphylococcus aureus #2
Staphylococcus aureus #3
Staphylococcus aureus #4
Staphylococcus aureus #5
Staphylococcus aureus #6
Standard
1
0.13
0.25
0.13
>128
0.13
0.25
0.13
0.13
0.13
>128
>128
4
Susceptible
2
Susceptible
1
ermA methylase(c*)
ermB methylase(i**)
ermC methylase(i**)
>128
1
2
Streptococcus pneumoniae DP1 Type I
Streptococcus pneumoniae #2
Streptococcus pneumoniae #3
Streptococcus pneumoniae #4
Streptococcus pneumoniae #5
Streptococcus pneumoniae #6
Streptococcus pneumoniae #7
Streptococcus pneumoniae #8
Standard
0.25
0.25
>128
>128
8
0.06
0.13
>128
>128
4
0.015
0.03
>128
>128
>128
>128
0.5
Susceptible
ermB methylase(c*)
ermB methylase(c*)
ermB methylase(i**)
ermB methylase(i**)
mefA efflux
8
4
0.25
0.25
0.13
0.06
mefA efflux
0.5
Streptococcus pyogenes #1
Streptococcus pyogenes #2
Streptococcus pyogenes #3
Standard
0.25
32
0.06
>128
0.06
0.015
>128
4
ermB methylase(c*)
mefA efflux
0.25
Moraxella catarrhalis #1
Moraxella catarrhalis #2
Haemophilus influenzae #1
Haemophilus influenzae #2
Haemophilus influenzae #3
Standard
Standard
Standard
Standard
Susceptible
2
0.13
0.13
2
0.13
0.13
2
4
>128
>128
>128
4
8
8
8
c*, constitutive resistant; i**, inducible resistant.
Acidic hydrolysis of the TBS group at the C-9 posi-
tion was subsequently conducted to give 12.
As shown in Table 3, the in vitro antibacterial profile of
12 was similar to that of RKM. Compound 12 exhibited
strong activities against susceptible G (+) strains and
was also effective against inducible resistant S.
pneumoniae.
With the results observed above, we concluded that
single modification at either C-3 or C-300 position
was promising, but modifying both of them caused
reduction of antibacterial activities. Although we tried
to determine the conformations of 4, 9a–9m and 12,
we did not succeed in crystallization or NMR analyses
of these compounds. Then we carried out conforma-
tional analyses on newly introduced side chains at
the C-3 and/or C-300 positions of 4, 9a, and 12.23
Our calculation results implied that two sugar moieties
of the minimized structure of 4 were dislocated up-
ward from their original position (refer to the sugar
moieties of RKM in Fig. 4), which presumably de-
creased its antibiotic activity. Furthermore, the C-3
quinoline ring and the C-300 propionyl side chain of
4 seemed to be placed close indicating that there
was a van der Waals interaction between these side
chains. The minimized structures of 9a and 12 were
almost identical with that of RKM without any shift
of the sugar moieties. More interestingly, the quino-
line ring at the C-3 position of 9a and the benzene
ring at the C-300 position of 12 seemed to be able to
overlap three-dimensionally. Although the conforma-
tional analyses were performed only on the side chains
at the C-3 and/or C-300 positions, SARs of our leuco-
mycin derivatives were efficiently explained by our
molecular modeling studies.
Figure 4. X-ray single crystallographic analysis of RKM (18-
methylhemiacetal).
16-membered macrolides could also overcome resis-
tant microorganisms, which encouraged us to explore
new chemical modifications of 16-membered macro-
lide antibiotics.
2.3. Synthesis and biological evaluation of 300-O-(3-
phenylpropionyl)leucomycin A7
To investigate the relationship between the C-3 and
C-300 position, we synthesized 300-O-(3-phenylpropio-
nyl)leucomycin A7 (12) which had a bulky side chain
at the C-300 position and free hydroxyl group at the
C-3 position (Scheme 3). Preparation of the starting
material (10) was already reported by Kurihara
et al.22 Free hydroxyl group of 10 was acylated by
3-phenylpropionyl chloride to furnish 11 in applica-
tion of the reported procedure for RKM synthesis.3
After deprotection of the C-20 acetyl group, the TBS
acetal was successfully removed by diluted TBAF in
THF without migration of C-10–C-12 double bonds.

T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
4405
Scheme 2. Synthesis of 3-O-(3-aryl-2-propenyl)leucomycin A7 analogues (9a–9m). Reagents and conditions: (a) KOH, allyl iodide, DMSO, rt, 2 h,
27%, 63% based on the recovery of 5; (b) Pd2(dba)3, 1,4-bis(diphenylphosphino)butane, allyl ethyl carbonate, THF, 90 °C, sealed tube, 25 h, 44%,
71% based on the recovery of 5; (c) palladium catalysts, aryl halides (see Section 4), 22–66%; (d) MeOH/H2O (10:1), 50 °C, 36 h–3 d; (e)
a
CHF2COOH, MeCN/H2O (1:1), rt, 37 h–5 d, 53–78% overall two steps. Aromatic rings: (a) 3-quinolyl; (b) 4-isoquinolyl; (c) phenyl; (d) 3-pyridyl;
(e) 5-pyrimidinyl; (f) 1-naphthyl; (g) 2-naphthyl; (h) 4-nitrophenyl; (i) 4-methoxyphenyl; (j) 4-fluorophenyl; (k) 4-trifluoromethylphenyl; (l) 4-
biphenylyl; (m) 4-(1-imidazolyl)phenyl.
3. Conclusion
and HRMS or Agilent HP5989A for TSP-MS or
HITACHI M-80B for EI-MS. H NMR spectra were
1
On the basis of the SAR analysis of our reported in-
house compounds and ketolides, we synthesized and
evaluated a variety of 3-O-(3-aryl-2-propenyl)leucomy-
cin A7 analogues (9a–9m). As a result, we successfully
improved antibacterial activity against clinically impor-
tant microorganisms including resistant strains. We con-
firmed that the single modification at the C-3 position is
promising for in vitro activity. Introduction of side
chains only at the C-300 position was also effective as
we discussed in 2.3. However, it was unsuccessful to
modify both C-3 and C-300 positions simultaneously. To-
gether with the X-ray information of RKM and our re-
sults of conformational analyses on 4, 9a, and 12, these
experimental data suggested that side chains at the C-3
and C-300 positions in leucomycin analogues would occu-
py three-dimensionally overlapped spaces.
measured with a Varian Gemini-300 for 300 MHz in
CDCl3 using CHCl3 as internal standard. Silica gel
chromatography and preparative TLC were per-
formed on Wako C-300 and Merck TLC 60F254
,
respectively. In general, the organic layer was dried
with anhydrous Na2SO4, evaporation and concentra-
tion were carried out under reduced pressure below
35 °C, unless otherwise noted.
4.2. Antibacterial activity in vitro
Minimum inhibitory concentration (MIC) was deter-
mined by the agar dilution method. Test strains were
subjected to seed culture using sensitivity test broth
(STB, Nissui Pharmaceutical) for S. aureus, or cultured
on blood agar plate for S. pneumoniae, Streptococcus
pyogenes, Moraxella catarrhalis, and Haemophilus influ-
enzae. A 5 ll portion of cell suspension of the test strains
having about 106 CFU/ml was inoculated into sensitiv-
ity disk agar (SDA, Nissui Pharmaceutical) supple-
mented with 5% horse blood, 5 lg/ml hemin and
15 lg/ml nicotinamide adenine dinucleotide and incu-
bated at 37 °C for 20 h. Then, MIC was measured.
To explore novel possibilities of macrolide antibiotics,
other modifications of 16-membered macrolides (i.e.
western hemisphere) are now undergoing. Using our
information about the C-3 and C-300 positions, we will
continuously explore novel modification focusing on
clinically promising 16-membered macrolides for the
next generation.
4.2.1. 20-O-Acetyl-3-O-allyl-9-O-(tert-butyldimethylsilyl)-
rokitamycin 18-dimethylacetal (2). To a stirred solution
of 1 (101 mg, 97.6 lmol) in 0.5 ml of DMSO, allyl iodide
(0.100 ml, 1.09 mmol) and KOH (77.9 mg, 1.18 mmol)
were added and the reaction mixture was stirred for
4 h at room temperature. Water was added to the reac-
tion mixture and the aqueous layer was extracted with
Et2O. The extract was washed with 10% aqueous
Na2S2O3 solution, water, saturated aqueous NaHCO3
4. Experimental
4.1. General methods
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

Table 2. Antibacterial activities of 3-O-(3-aryl-2-propenyl)leucomycin A7 analogues (9a–9m)
Test organisms
Characteristics
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
LM-A7
RKM
CAM
Staphylococcus aureus 209P JC-1
Staphylococcus aureus #2
Staphylococcus aureus #3
Staphylococcus aureus #4
Staphylococcus aureus #5
Staphylococcus aureus #6
Standard
0.06
0.13
0.06
>128
0.06
0.13
0.06
0.13
0.06
>128
0.06
0.13
0.13
0.25
0.13
>128
0.13
0.13
0.13
0.25
0.13
>128
0.13
0.25
0.13
0.25
0.13
>128
0.13
0.25
0.13
0.25
0.25
>128
0.25
0.25
0.25
0.25
0.25
>128
0.25
0.5
0.06
0.13
0.13
>128
0.06
0.13
0.13
0.25
0.13
>128
0.13
0.25
0.13
0.25
0.13
>128
0.13
0.25
0.5
1
1
0.13
0.25
0.13
>128
0.13
0.25
0.25
0.5
0.13
0.25
0.13
>128
0.13
0.25
0.13
0.13
0.13
>128
>128
4
Susceptible
2
Susceptible
0.5
>128
0.5
1
1
0.25
>128
0.25
0.5
ermA methylase(c*)
ermB methylase(i**)
ermC methylase(i**)
>128
1
2
Streptococcus pneumoniae DP1 Type I
Streptococcus pneumoniae #2
Streptococcus pneumoniae #3
Streptococcus pneumoniae #4
Streptococcus pneumoniae #5
Streptococcus pneumoniae #6
Streptococcus pneumoniae #7
Streptococcus pneumoniae #8
Standard
0.03
0.03
64
0.015
0.015
>128
>128
128
0.03
0.06
128
64
0.03
0.03
0.03
0.03
>128
>128
>128
8
0.06
0.06
>128
>128
>128
8
0.06
0.06
>128
>128
>128
128
0.06
0.06
>128
>128
>128
16
0.06
0.25
0.5
0.25
0.25
>128
>128
>128
>128
0.25
2
0.03
0.03
16
0.13
0.06
0.13
>128
>128
4
0.015
0.03
>128
>128
>128
>128
0.5
Susceptible
0.03
0.06
0.13
0.25
ermB methylase(c*)
ermB methylase(c*)
ermB methylase(i**)
ermB methylase(i**)
mefA efflux
>128
>128
>128
>128
0.03
>128
>128
>128
>128
0.06
>128
>128
>128
>128
0.13
>128
>128
>128
>128
0.5
>128
>128
>128
>128
0.13
64
32
32
64
0.5
2
16
32
64
4
0.03
0.015
<0.008
0.015
0.03
0.015
0.03
0.03
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.03
0.13
0.06
mefA efflux
0.015
0.03
0.25
1
0.13
0.5
Streptococcus pyogenes #1
Streptococcus pyogenes #2
Streptococcus pyogenes #3
Standard
0.03
64
0.015
>128
0.06
0.03
>128
0.06
0.03
>128
0.03
0.06
>128
0.13
0.06
>128
0.25
0.06
>128
0.25
0.03
>128
0.13
0.06
>128
0.13
0.06
>128
0.13
0.25
>128
0.5
0.25
>128
0.5
0.06
>128
0.13
0.13
>128
0.25
0.06
>128
0.06
0.015
>128
4
ermB methylase(c*)
mefA efflux
0.06
Moraxella catarrhalis #1
Moraxella catarrhalis #2
Haemophilus influenzae #1
Haemophilus influenzae #2
Haemophilus influenzae #3
Standard
Standard
Standard
Standard
Susceptible
0.5
0.5
2
0.5
0.5
1
0.5
1
0.5
1
0.5
1
1
1
0.5
1
1
1
4
8
1
1
2
8
8
1
1
2
8
8
0.13
0.13
2
0.13
0.13
2
1
2
1
1
4
8
2
1
1
4
8
2
4
4
32
>128
>128
>128
8
4
8
8
8
16
16
32
16
8
16
8
8
>128
>128
4
8
4
4
8
4
8
8
16
8
8
c*, constitutive resistant; i**, inducible resistant.

T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
4407
Scheme 3. Synthesis of 300-O-(3-phenylpropionyl)leucomycin A7 (12). Reagents and conditions: (a) 3-phenylpropionyl chloride, tribenzylamine, 1,2-
dichloroethane, 75 °C, 2 d, 56%; (b) i—MeOH/H2O (10:1), 45 °C, overnight, 78%; ii—0.1 M TBAF, THF, rt, 15 min; iii—CHF2COOH, MeCN/H2O
(1:1), rt, overnight, 82% overall three steps.
Table 3. Antibacterial activities of 300-O-(3-phenylpropionyl)leucomycin A7 (12)
Test organisms
Characteristics
12
RKM
CAM
Staphylococcus aureus 209P JC-1
Staphylococcus aureus #2
Staphylococcus aureus #3
Staphylococcus aureus #4
Staphylococcus aureus #5
Staphylococcus aureus #6
Standard
0.10
0.39
0.20
>100
0.20
0.20
0.10
0.39
0.20
>100
0.39
0.20
0.10
0.10
0.10
>100
>100
3.13
Susceptible
Susceptible
ermA methylase(c*)
ermB methylase(i**)
ermC methylase(i**)
Streptococcus pneumoniae DP1 Type I
Streptococcus pneumoniae #2
Streptococcus pneumoniae #3
Streptococcus pneumoniae #4
Streptococcus pneumoniae #5
Streptococcus pneumoniae #6
Streptococcus pneumoniae #7
Streptococcus pneumoniae #8
Standard
0.05
0.10
>100
>100
1.56
3.13
0.10
0.10
0.05
0.10
100
0.025
0.025
>100
>100
>100
>100
0.78
Susceptible
ermB methylase(c*)
ermB methylase(c*)
ermB methylase(i**)
ermB methylase(i**)
mefA efflux
>100
0.78
1.56
0.10
0.10
mefA efflux
0.78
Streptococcus pyogenes #1
Streptococcus pyogenes #2
Streptococcus pyogenes #3
Standard
0.025
>100
0.025
0.05
100
0.013
>100
1.56
ermB methylase(c*)
mefA efflux
0.05
Moraxella catarrhalis #1
Moraxella catarrhalis #2
Haemophilus influenzae #1
Haemophilus influenzae #2
Haemophilus influenzae #3
Standard
Standard
Standard
Standard
Susceptible
0.05
0.20
1.56
6.25
6.25
0.10
0.20
1.56
3.13
6.25
0.10
0.10
1.56
3.13
3.13
c*, constitutive resistant; i**, inducible resistant.
solution, and brine. After the organic layer was dried
and concentrated, the residue was purified by silica gel
chromatography [14 g, hexane/EtOAc (20:1–10:1–5:1–
1:1)] to give 2 (37.0 mg, 35%, 70% based on the recovery
of 1).
(sex, 7.4 Hz, 2H, 400-OCOCH2CH2CH3), 2.00 (s, 3H,
20-OCOCH3), 2.11 (dt, 14.3, 10.4 Hz, 1H, 14-H),
2.15–2.36 (m, 2H, 300-OCOCH2CH3), 2.36 (t, 7.4 Hz,
2H, 400-OCOCH2CH2CH3), 2.36–2.47 (m, 1H, 2-H),
2.39 (s, 6H, 30-N(CH3)2), 2.40–2.44 (m, 1H, 14-H),
2.59 (t, 10.0 Hz, 1H, 30-H), 2.66 (dd, 16.7, 6.0 Hz,
1H, 2-H), 2.78 (dd, 3.8, 1.0 Hz, 1H, 4-H), 3.07 (t,
9.5 Hz, 1H, 40-H), 3.16 (d, 14.5 Hz, 1H, 200-Heq),
3.15–3.22 (m, 1H, 50-H), 3.27 (s, 3H, 18-OCH3), 3.30
(s, 3H, 18-OCH3), 3.38 (s, 3H, 4-OCH3), 3.48 (br,
1H, 3-H), 3.92 (br dd, 12.0, 5.9 Hz, 1H, 3-O–
CH2CH@CH2), 3.98 (br dd, 12.0, 5.9 Hz, 1H, 3-O–
CH2CH@CH2), 4.15 (dd, 7.4, 3.8 Hz, 1H, 9-H), 4.18
(br d, 5.8 Hz, 1H, 5-H), 4.45 (dq, 9.9, 6.0 Hz, 1H,
500-H), 4.49 (dd, 8.4, 3.0 Hz, 1H, 18-H), 4.54 (d,
22
½aꢀ
ꢁ103° (c 0.58, CHCl3); FAB-MS m/z 1070
D
(M+H)+; 1H NMR d ꢁ0.04 (s, 3H, SiCH3), 0.01 (s,
3H, SiCH3), 0.85 (s, 9H, SiC(CH3)3), 0.95 (d,
6.6 Hz, 3H, 19-H), 0.96 (t, 7.3 Hz, 3H, 400-
OCOCH2CH2CH3), 1.04 (d, 6.0 Hz, 3H, 600-H), 1.11
(t, 7.6 Hz, 3H, 300-OCOCH2CH3), 1.17 (d, 5.8 Hz,
3H, 60-H), 1.19–1.32 (m, 1H, 7-H), 1.27 (d, 6.3 Hz,
3H, 16-H), 1.39 (s, 3H, 300-CH3), 1.50–1.82 (m, 3H,
8-, 17-H), 1.65 (dd, 14.5, 3.9 Hz, 1H, 200-Hax), 1.67

4408
T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
9.9 Hz, 1H, 400-H), 4.62 (d, 7.7 Hz, 1H, 10-H), 4.77 (d,
3.9 Hz, 1H, 100-H), 4.94 (dd, 10.3, 7.7 Hz, 1H, 20-H),
5.08–5.15 (m, 1H, 15-H), 5.16 (dd, 10.3, 1.3 Hz, 1H,
3-O–CH2CH@CH2), 5.25 (dd, 17.2, 1.5 Hz, 1H, 3-O–
CH2CH@CH2), 5.52 (ddd, 14.5, 10.4, 3.8 Hz, 1H,
13-H), 5.59 (dd, 13.4, 7.4 Hz, 1H, 10-H), 5.89 (ddt,
17.0, 10.4, 5.9 Hz, 1H, 3-O–CH2CH@CH2), 5.97–6.10
(m 2H, 11-, 12-H).
(100:1–50:1)] to give 9-O-(tert-butyldimethylsilyl)-3-O-
[3-(3-quinolyl)-2-propenyl]rokitamycin 18-dimethylace-
tal (103 mg, 89%).
To a stirred solution of this compound (95.7 mg,
82.8 lmol) in 28 ml of MeCN/H2O (1:1), difluoroacetic
acid (27.0 ll, 429 lmol) was added and the reaction mix-
ture was stirred for 2 days at room temperature. Satu-
rated NaHCO3 solution was added to the reaction
mixture and the aqueous layer was extracted with
CHCl3. The extract was washed with brine, dried, and
concentrated. The residue was purified by preparative
TLC [CHCl3/MeOH/NH4OH (100:10:1)] to afford 4
(51.0 mg, 62%).
4.2.2. 20-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-
(3-quinolyl)-2-propenyl]rokitamycin
18-dimethylacetal
(3). To a stirred solution of 2 (71.4 mg, 66.7 lmol),
potassium carbonate (27.8 mg, 201 lmol), tetra-n-butyl-
ammonium chloride (77.9 mg, 281 lmol) and palla-
dium(II) acetate (2.6 mg, 11.6 lmol) in 0.7 ml of
DMF, 3-bromoquinoline (36.0 ll, 265 lmol) was added.
After the reaction mixture was stirred for 4 days at
50 °C, EtOAc was added to the reaction mixture and fil-
trated. The organic layer was washed with water, satu-
rated NaHCO3 solution, and brine. After the organic
layer was dried and concentrated, the residue was puri-
fied by silica gel chromatography [7 g, hexane/EtOAc
(3:1)] to give 3 (32.5 mg, 41%).
24
½aꢀ ꢁ32° (c 0.59, CHCl3); FAB-MS m/z 995 (M+H)+;
D
1H NMR d 0.95 (t, 7.5 Hz, 3H, 400-OCOCH2CH2CH3),
1.00 (d, 6.6 Hz, 3H, 19-H), 1.02 (d, 6.9 Hz, 3H, 60-H),
1.03 (t, 7.4 Hz, 3H, 300-OCOCH2CH3), 1.05 (d, 6.0 Hz,
3H, 600-H), 1.10 (m, 1H, 7-H), 1.29 (d, 6.0 Hz, 3H, 16-
H), 1.37 (s, 3H, 300-CH3), 1.39 (m, 1H, 7-H), 1.62 (dd,
15.2, 4.3 Hz, 1H, 200-Hax), 1.66 (sex, 7.5 Hz, 2H, 400-
OCOCH2CH2CH3), 1.83 (m, 1H, 8-H), 2.08–2.20 (m,
2H, 6-, 14-H), 2.12–2.25 (m, 2H, 300-OCOCH2CH3),
2.28–2.46 (m, 4H, 2-, 14-, 17-, 30-H), 2.34 (t, 7.1 Hz,
2H, 400-OCOCH2CH2CH3), 2.50 (s, 6H, 30-N(CH3)2),
2.81 (dd, 15.6, 7.8 Hz, 1H, 2-H), 2.96 (dd, 18.0,
9.9 Hz, 1H, 17-H), 3.01 (dd, 7.8, 2.1 Hz, 1H, 4-H),
3.06–3.16 (m, 1H, 50-H), 3.13 (t, 8.1 Hz, 1H, 40-H),
3.13 (d, 15.2 Hz, 1H, 200-Heq), 3.36 (dd, 10.1 Hz, 1H,
20-H), 3.51 (s, 3H, 4-OCH3), 3.73 (br, 1H, 3-H),
3.91 (br, 1H, 5-H), 4.09 (br dd, 8.4, 3.9 Hz, 1H, 9-
H), 4.34 (dd, 12.0, 5.7 Hz, 1H, 3-O–CH2CH@CH–
Ar), 4.42 (d, 7.8 Hz, 1H, 10-H), 4.44 (dd, 12.0,
5.7 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.46 (m, 1H, 500-
H), 4.53 (d, 9.9 Hz, 1H, 400-H), 4.76 (d, 4.0 Hz, 1H,
100-H), 5.11 (m, 1H, 15-H), 5.60 (ddd, 14.5, 10.5,
3.9 Hz, 1H, 13-H), 5.67 (dd, 14.8, 8.4 Hz, 1H, 10-H),
6.05 (br dd, 14.7, 10.7 Hz, 1H, 12-H), 6.24 (dd, 15.1,
10.4 Hz, 1H, 11-H), 6.63 (dt, 15.9, 6.0 Hz, 1H, 3-O–
CH2CH@CH–Ar), 6.78 (d, 15.9 Hz, 1H, 3-O–
CH2CH@CH–Ar), 7.49 (ddd, 7.8, 6.9, 1.2 Hz, 1H,
quinoline), 7.63 (ddd, 8.4, 6.9, 1.3 Hz, 1H, quinoline),
7.81 (dd, 7.5, 1.0 Hz, 1H, quinoline), 8.04 (d, 8.4 Hz,
1H, quinoline), 8.10 (d, 1.8 Hz, 1H, quinoline), 9.02
(d, 2.4 Hz, 1H, quinoline), 9.75 (br s, 1 H, 18-H);
HRMS: Calcd for C54H78N2O15: 995.5480. Found:
995.5478.
22
½aꢀ ꢁ68° (c 0.87, CHCl3); FAB-MS m/z 1197 (M+H)+;
D
1H NMR d ꢁ0.04 (s, 3H, SiCH3), 0.00 (s, 3H, SiCH3),
0.85 (s, 9H, SiC(CH3)3), 0.95 (d, 6.6 Hz, 3H, 19-H),
0.96 (t, 7.4 Hz, 3H, 400-OCOCH2CH2CH3), 1.04 (d,
6.0 Hz, 3H, 600-H), 1.11 (t, 7.5 Hz, 3H, 300-
OCOCH2CH3), 1.12 (d, 6.6 Hz, 3H, 60-H), 1.20–1.32
(m, 1H, 7-H), 1.28 (d, 6.3 Hz, 3H, 16-H), 1.39 (s, 3H,
300-CH3), 1.54–1.84 (m, 3H, 8-, 17-H), 1.61 (dd, 15.3,
4.2 Hz, 1H, 200-Hax), 1.67 (sex, 7.4 Hz, 2H, 400-
OCOCH2CH2CH3), 2.02 (s, 3H, 20-OCOCH3), 2.12
(dt, 13.7, 10.8 Hz, 1H, 14-H), 2.16–2.34 (m, 2H, 300-
OCOCH2CH3),
2.35
(t,
7.4 Hz,
2H,
400-
OCOCH2CH2CH3), 2.35–2.47 (m, 2H, 2-, 14-H), 2.40
(s, 6H, 30-N(CH3)2), 2.59 (t, 9.9 Hz, 1H, 30-H), 2.75
(dd, 15.9, 7.2 Hz, 1H, 2-H), 2.91 (dd, 7.6, 2.3 Hz, 1H,
4-H), 3.09 (t, 9.5 Hz, 1H, 40-H), 3.12 (d, 15.3 Hz, 1H,
200-Heq), 3.16–3.28 (m, 1H, 50-H), 3.20 (s, 3H, 18-
OCH3), 3.25 (s, 3H, 18-OCH3), 3.44 (s, 3H, 4-OCH3),
3.64 (br, 1H, 3-H), 4.02 (br, 1H, 5-H), 4.15 (dd, 8.1,
3.9 Hz, 1H, 9-H), 4.30 (br dd, 12.1, 5.9 Hz, 1H, 3-O–
CH2CH@CH–Ar), 4.37 (br dd, 12.1, 5.9 Hz, 1H, 3-O–
CH2CH@CH–Ar), 4.45 (dq, 9.9, 6.0 Hz, 1H, 500-H),
4.53 (d, 9.9 Hz, 1H, 400-H), 4.55 (m, 1H, 18-H), 4.68
(d, 7.5 Hz, 1H, 10-H), 4.74 (d, 4.2 Hz, 1H, 100-H), 4.96
(dd, 10.2, 7.8 Hz, 1H, 20-H), 5.12 (m, 1H, 15-H), 5.52
(m, 1H, 13-H), 5.62 (dd, 13.9, 8.2 Hz, 1H, 10-H),
5.96–6.11 (m, 2H, 11-, 12-H), 6.54 (dt, 16.2, 5.9 Hz,
1H, 3-O–CH2CH@CH–Ar), 6.75 (d, 16.2 Hz, 1H, 3-O–
CH2CH@CH–Ar), 7.52 (ddd, 7.9, 6.9, 1.2 Hz, 1H, quin-
oline), 7.65 (ddd, 8.4, 7.0, 1.3 Hz, 1H, quinoline), 7.83
(dd, 7.8, 0.9 Hz, 1H, quinoline), 8.04 (br d, 8.4 Hz,
1H, quinoline), 8.06 (s, 1H, quinoline), 8.98 (d, 2.4 Hz,
1H, quinoline).
4.2.4. 20-O-Acetyl-3-O-allyl-9-O-(tert-butyldimethylsi-
lyl)leucomycin A7 18-dimethylacetal (6). Method a. To
a stirred solution of 5 (0.545 g, 0.567 mmol) in 5 ml of
DMSO, allyl iodide (0.520 ml, 5.69 mmol) and KOH
(0.519 g, 7.87 mmol) were added and the reaction mix-
ture was stirred for 2 h at room temperature. Water
was added to the reaction mixture and the aqueous layer
was extracted with Et2O. The extract was washed with
10% aqueous Na2S2O3 solution, water, saturated aque-
ous NaHCO3 solution, and brine. After the organic
layer was dried and concentrated, the residue was puri-
fied by silica gel chromatography [40 g, hexane/EtOAc
(2:1)] to give 6 (154 mg, 27%, 63% based on the recovery
of 5).
4.2.3. 3-O-[3-(3-Quinolyl)-2-propenyl]rokitamycin (4). A
solution of 3 (120 mg, 100 lmol) in 6 ml of MeOH/
H2O (9:1) was stirred for 22 h at 50 °C. The reaction
mixture was concentrated and the residue was purified
by silica gel chromatography [12 g, CHCl3/MeOH

T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
4409
Methodb. A solution of 5 (0.706 g, 0.735 mmol), tris(diben-
zylideneacetone)dipalladium (16.3 mg, 17.8 lmol), 1,4-
bis(diphenylphosphino)butane (31.3 mg, 73.4 lmol) and
allyl ethyl carbonate (0.970 ml, 7.38 mmol) in 7 ml of
THF was stirred at 90 °C for 25 h in sealed tube. The
reaction mixture was concentrated and the residue
was purified by silica gel chromatography [25 g, hexane/
EtOAc (2:1)] to give 6 (326 mg, 44%, 71% based on the
recovery of 5).
OCOCH3), 2.13 (dt, 13.9, 10.8 Hz, 1H, 14-H), 2.35–
2.47 (m, 2H, 400-OCOCH2CH3), 2.35–2.49 (m, 2H, 2-,
14-H), 2.37 (s, 6H, 30-N(CH3)2), 2.71 (t, 10.0 Hz, 1H,
30-H), 2.75 (dd, 15.9, 6.9 Hz, 1H, 2-H), 2.90 (dd, 7.8,
1.8 Hz, 1H, 4-H), 3.20–3.33 (m, 2H, 40-, 50-H), 3.24 (s,
3H, 18-OCH3), 3.29 (s, 3H, 18-OCH3), 3.43 (s, 3H, 4-
OCH3), 3.60 (br, 1H, 3-H), 4.04 (br, 1H, 5-H), 4.16
(dd, 8.0, 4.0 Hz, 1H, 9-H), 4.24 (br dd, 12.2, 5.8 Hz,
1H, 3-O–CH2CH@CH–Ar), 4.34 (dq, 10.2, 6.3 Hz, 1H,
500-H), 4.39 (br dd, 12.3, 5.7 Hz, 1H, 3-O–
CH2CH@CH–Ar), 4.55 (d, 10.2 Hz, 1H, 400-H), 4.57
(m, 1H, 18-H), 4.72 (d, 7.8 Hz, 1H, 10-H), 4.95 (d,
3.5 Hz, 1H, 100-H), 5.00 (dd, 10.3, 7.7 Hz, 1H, 20-H),
5.15 (m, 1H, 15-H), 5.54 (m, 1H, 13-H), 5.62 (dd, 14.6,
8.0 Hz, 1H, 10-H), 5.97–6.12 (m, 2H, 11-, 12-H), 6.55
(dt, 15.9, 5.9 Hz, 1H, 3-O–CH2CH@CH–Ar), 6.76 (d,
16.2 Hz, 1H, 3-O–CH2CH@CH–Ar), 7.51 (ddd, 8.0,
7.1, 0.9 Hz, 1H, quinoline), 7.65 (ddd, 8.2, 6.9, 1.2 Hz,
1H, quinoline), 7.77 (dd, 8.1, 1.2 Hz, 1H, quinoline),
8.03 (d, 1.5 Hz, 1H, quinoline), 8.04 (d, 8.1 Hz, 1H,
quinoline), 8.97 (d, 1.8 Hz, 1H, quinoline).
21
D
½aꢀ
ꢁ103° (c 0.42, CHCl3); FAB-MS m/z 1000
(M+H)+; 1H NMR d ꢁ0.03 (s, 3H, SiCH3), 0.02 (s,
3H, SiCH3), 0.85 (s, 9H, SiC(CH3)3), 0.96 (d, 6.9 Hz,
3H, 19-H), 1.10 (s, 3H, 300-CH3), 1.10–1.15 (m, 1H, 7-
H), 1.11 (d, 6.2 Hz, 3H, 600-H), 1.16 (t, 7.7 Hz, 3H, 400-
OCOCH2CH3), 1.20–1.33 (m, 1H, 7-H), 1.25 (d,
5.7 Hz, 3H, 60-H), 1.27 (d, 6.3 Hz, 3H, 16-H), 1.53–
1.63 (m, 1H, 17-H), 1.65–1.80 (m, 3H, 6-, 8-, 17-H),
1.82 (dd, 14.5, 3.9 Hz, 1H, 200-Hax), 1.99 (br d,
14.5 Hz, 1H, 200-Heq), 2.01 (s, 3H, 20-OCOCH3), 2.12
(dt, 13.8, 10.8 Hz, 1H, 14-H), 2.36–2.47 (m, 2H, 400-
OCOCH2CH3), 2.37–2.48 (m, 2H, 2-, 14-H), 2.38 (s,
6H, 30-N(CH3)2), 2.67 (dd, 16.2, 6.3 Hz, 1H, 2-H),
2.71 (t, 10.6 Hz, 1H, 30-H), 2.81 (dd, 7.6, 2.0 Hz, 1H,
4-H), 3.23–3.33 (m, 2H, 40-, 50-H), 3.27 (s, 3H, 18-
OCH3), 3.31 (s, 3H, 18-OCH3), 3.38 (s, 3H, 4-OCH3),
3.50 (br, 1H, 3-H), 3.97 (br dd, 12.3, 6.0 Hz, 1H, 3-O–
CH2CH@CH2), 3.97 (br, 1H, 5-H), 4.16 (br dd, 12.3,
6.0 Hz, 1H, 3-O–CH2CH@CH2), 4.16 (dd, 7.5, 4.1 Hz,
1H, 9-H), 4.37 (dq, 10.2, 6.2 Hz, 1H, 500-H), 4.49 (dd,
8.6, 2.9 Hz, 1H, 18-H), 4.60 (d, 10.2 Hz, 1H, 400-H),
4.67 (d, 7.8 Hz, 1H, 10-H), 4.99 (dd, 10.4, 7.7 Hz, 1H,
20-H), 5.05 (d, 3.6 Hz, 1H, 100-H), 5.13 (dq, 10.2,
1.8 Hz, 1H, 3-O–CH2CH@CH2), 5.13 (m, 15-H), 5.25
(dq, 17.1, 1.8 Hz, 1H, 3-O–CH2CH@CH2), 5.51 (m,
13-H), 5.60 (dd, 13.8, 7.5 Hz, 1H, 10-H), 5.90 (ddt,
17.1, 10.2, 6.0 Hz, 1H, 3-O–CH2CH@CH2), 5.98–6.10
(m, 2H, 11-, 12-H).
4.2.6. 20-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-
(4-isoquinolyl)-2-propenyl]leucomycin A7 18-dimethylace-
tal (7b). To a stirred solution of 6 (439 mg, 439 lmol),
sodium acetate (133 mg, 1.62 mmol), trans-di(l-aceta-
to)bis[O-(di-O-tolylphosphino)benzyl]dipalladium(II)
(44.0 mg, 46.9 lmol), and tetra-n-butylammonium bro-
mide (2.83 g, 8.78 mmol) in 5.0 ml of DMF, 4-bromo-
isoquinoline (276 mg, 1.33 mmol) was added and the
reaction mixture was stirred for 3 days at 100 °C. EtOAc
was added to the reaction mixture and the organic layer
was washed with 10% aqueous KHSO4 solution, satu-
rated NaHCO3 solution, and brine. After the organic
layer was dried and concentrated, the residue was puri-
fied by silica gel chromatography [60 g, hexane/EtOAc
(2:1)] to give 7b (231 mg, 47%).
21
½aꢀ ꢁ72° (c 0.68, CHCl3); FAB-MS m/z 1127 (M+H)+;
D
4.2.5. 20-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-
(3-quinolyl)-2-propenyl]leucomycin A7 18-dimethylacetal
(7a). To a stirred solution of 6 (268 mg, 268 lmol), so-
dium acetate (83.7 mg, 1.01 mmol), trans-di(l-aceta-
to)bis[O-(di-O-tolylphosphino)benzyl]dipalladium(II)
(48.1 mg, 51.3 lmol) and tetra-n-butylammonium bro-
mide (1.55 g, 4.81 mmol) in 6.0 ml of N,N-dimethylacet-
amide, 3-bromoquinoline (110 ll, 810 lmol) was added
and the reaction mixture was stirred for 17 h at
100 °C. EtOAc was added to the reaction mixture and
the organic layer was washed with 10% aqueous KHSO4
solution, saturated NaHCO3 solution, and brine. After
the organic layer was dried and concentrated, the resi-
due was purified by silica gel chromatography [35 g, hex-
ane/EtOAc (2:1–1:1)] to give 7a (142 mg, 47%).
1H NMR d ꢁ0.03 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3),
0.86 (s, 9H, SiC(CH3)3), 0.97 (d, 6.6 Hz, 3H, 19-H),
1.08 (d, 6.1 Hz, 3H, 600-H), 1.09 (s, 3H, 300-CH3), 1.10
(d, 6.0 Hz, 3H, 60-H), 1.16 (t, 7.5 Hz, 3H, 400-
OCOCH2CH3), 1.20–1.33 (m, 1H, 7-H), 1.30 (d,
6.3 Hz, 3H, 16-H), 1.55–1.68 (m, 1H, 17-H), 1.68–1.88
(m, 3H, 6-, 8-, 17-H), 1.74 (dd, 14.2, 3.7 Hz, 1H, 200-
Hax), 1.84 (br d, 14.0 Hz, 1H, 200-Heq), 2.02 (s, 3H, 20-
OCOCH3), 2.14 (dt, 14.1 Hz, 1H, 14-H), 2.34–2.50 (m,
2H, 400-OCOCH2CH3), 2.34–2.52 (m, 2H, 2-, 14-H),
2.37 (s, 6H, 30-N(CH3)2), 2.68 (t, 9.8 Hz, 1H, 30-H),
2.78 (dd, 16.0, 6.8 Hz, 1H, 2-H), 2.90 (dd, 7.8, 1.8 Hz,
1H, 4-H), 3.17–3.28 (m, 2H, 40-, 50-H), 3.21 (s, 3H, 18-
OCH3), 3.24 (s, 3H, 18-OCH3), 3.44 (s, 3H, 4-OCH3),
3.65 (br, 1H, 3-H), 4.05 (br, 1H, 5-H), 4.16 (dd, 7.9,
3.8 Hz, 1H, 9-H), 4.30 (br dd, 12.3, 6.0 Hz, 1H, 3-O–
CH2CH@CH–Ar), 4.34 (dq, 9.9, 6.1 Hz, 1H, 500-H),
4.45 (br dd, 12.3, 6.0 Hz, 1H, 3-O–CH2CH@CH–Ar),
4.55 (dd, 8.1, 3.3 Hz, 1H, 18-H), 4.57 (d, 9.9 Hz, 1H,
400-H), 4.72 (d, 7.8 Hz, 1H, 10-H), 4.91 (d, 3.3 Hz, 1H,
100-H), 4.99 (dd, 10.3, 7.8 Hz, 1H, 20-H), 5.17 (m, 1H,
15-H), 5.55 (m, 1H, 13-H), 5.63 (dd, 13.8, 8.1 Hz, 1H,
10-H), 5.96–6.12 (m, 2H, 11-, 12-H), 6.41 (dt, 15.8,
5.9 Hz, 1H, 3-O–CH2CH@CH–Ar), 7.22 (d, 15.8 Hz,
22
½aꢀ ꢁ62° (c 0.53, CHCl3); FAB-MS m/z 1127 (M+H)+;
D
1H NMR d ꢁ0.03 (s, 3H, SiCH3), 0.01 (s, 3H, SiCH3),
0.85 (s, 9H, SiC(CH3)3), 0.97 (d, 6.6 Hz, 3H, 19-H),
1.04 (s, 3H, 300-CH3), 1.08 (d, 6.3 Hz, 3H, 600-H), 1.15
(d, 6.0 Hz, 3H, 60-H), 1.15 (t, 7.5 Hz, 3H, 400-
OCOCH2CH3), 1.29 (d, 6.3 Hz, 3H, 16-H), 1.55–1.84
(m, 4H, 6-, 8-, 17-H), 1.68 (dd, 14.1, 3.9 Hz, 1H, 200-
Hax), 1.76 (br d, 14.1 Hz, 1H, 200-Heq), 2.02 (s, 3H, 20-

4410
T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
1H, 3-O–CH2CH@CH–Ar), 7.61 (br t, 7.5 Hz, 1H, iso-
quinoline), 7.72 (ddd, 8.1, 7.1, 1.2 Hz, 1H, isoquinoline),
7.96 (br d, 8.1 Hz, 1H, isoquinoline), 8.10 (br d, 8.1 Hz,
1H, isoquinoline), 8.60 (s, 1H, isoquinoline), 9.14 (s, 1H,
isoquinoline).
12.6, 5.8 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.35 (dq, 1H,
10.2, 6.3 Hz, 500-H), 4.55 (m, 1H, 18-H), 4.58 (d,
10.2 Hz, 1H, 400-H), 4.69 (d, 7.5 Hz, 1H, 10-H), 4.96 (d,
3.0 Hz, 1H, 100-H), 4.99 (dd, 10.3, 7.7 Hz, 1H, 20-H),
5.13 (m, 1H, 15-H), 5.52 (m, 1H, 13-H), 5.62 (dd, 14.1,
8.0 Hz, 1H, 10-H), 5.97–6.10 (m, 2H, 11-, 12-H), 6.38
(dt, 16.1, 5.8 Hz, 1H, 3-O–CH2CH@CH–Ar), 6.57 (d,
15.9 Hz, 1H, 3-O–CH2CH@CH–Ar), 7.23 (dd, 7.8,
4.8 Hz, 1H, pyridine), 7.68 (dt, 7.8, 1.8 Hz, 1H, pyri-
dine), 8.44 (dd, 4.5, 1.5 Hz, pyridine), 8.56 (d, 1.8 Hz,
1H, pyridine).
4.2.7. 20-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-(3-
phenyl-2-propenyl)leucomycin A7 18-dimethylacetal (7c).
Reaction of 6 (198 mg, 198 lmol) with iodobenzene
(67.0 ll, 601 lmol) gave 7c (161 mg, 76%) by a similar
procedure to 7b.
22
D
½aꢀ ꢁ75° (c 0.62, CHCl3); FAB-MS m/z 1076 (M+H)+;
4.2.9. 20-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-
(5-pyrimidinyl)-2-propenyl]leucomycin A7 18-dimethyl-
acetal (7e). Reaction of 6 (306 mg, 306 lmol) with 5-bro-
mopyrimidine (148 mg, 933 lmol) gave 7e (177 mg,
54%) by a similar procedure to 7b.
1H NMR d ꢁ0.03 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3),
0.86 (s, 9H, SiC(CH3)3), 0.96 (d, 6.6 Hz, 3H, 19-H),
1.09 (s, 3H, 300-CH3), 1.09 (d, 6.3 Hz, 3H, 600-H), 1.12
(d, 6.0 Hz, 3H, 60-H), 1.16 (t, 7.6 Hz, 3H, 400-
OCOCH2CH3), 1.18–1.32 (m, 1H, 7-H), 1.28 (d,
6.6 Hz, 3H, 16-H), 1.55–1.64 (m, 1H, 17-H), 1.65–1.86
(m, 3H, 6-, 8-, 17-H), 1.73 (dd, 14.2, 3.4 Hz, 1H, 200-
Hax), 1.82 (br d, 14.0 Hz, 1H, 200-Heq), 2.01 (s, 3H, 20-
OCOCH3), 2.13 (dt, 13.8, 10.3 Hz, 1H, 14-H), 2.36–
2.47 (m, 2H, 400-OCOCH2CH3), 2.36–2.52 (m, 2H, 2-,
14-H), 2.37 (s, 6H, 30-N(CH3)2), 2.70 (t, 10.0 Hz, 1H,
30-H), 2.72 (dd, 16.5, 6.6 Hz, 1H, 2-H), 2.83 (dd, 7.5,
1.8 Hz, 1H, 4-H), 3.18–3.32 (m, 2H, 40-, 50-H), 3.25 (s,
3H, 18-OCH3), 3.29 (s, 3H, 18-OCH3), 3.41 (s, 3H, 4-
OCH3), 3.55 (br, 1H, 3-H), 4.00 (br, 1H, 5-H), 4.13
(br dd, 12.0, 6.0 Hz, 1H, 3-O–CH2CH@CH–Ph), 4.15
(dd, 7.5, 3.7 Hz, 1H, 9-H), 4.34 (br dd, 12.0, 6.0 Hz,
1H, 3-O–CH2CH@CH–Ph), 4.35 (dq, 10.0, 6.3 Hz, 1H,
500-H), 4.54 (m, 1H, 18-H), 4.57 (d, 9.9 Hz, 1H, 400-H),
4.69 (d, 7.8 Hz, 1H, 10-H), 4.91 (d, 3.0 Hz, 1H, 100-H),
4.99 (dd, 10.5, 7.8 Hz, 1H, 20-H), 5.16 (m, 1H, 15-H),
5.53 (m, 1H, 13-H), 5.60 (dd, 13.8, 7.5 Hz, 1H, 10-H),
5.96–6.10 (m, 2H, 11-, 12-H), 6.30 (dt, 15.9, 5.9 Hz,
1H, 3-O–CH2CH@CH–Ph), 6.57 (d, 15.9 Hz, 1H, 3-O–
CH2CH@CH–Ph), 7.15–7.38 (m, 5H, Ph).
21
½aꢀ ꢁ66° (c 0.63, CHCl3); FAB-MS m/z 1078 (M+H)+;
D
1H NMR d ꢁ0.03 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3),
0.86 (s, 9H, SiC(CH3)3), 0.97 (d, 6.6 Hz, 3H, 19-H),
1.06 (m, 1H, 7-H), 1.10 (s, 3H, 300-CH3), 1.10 (d,
6.0 Hz, 3H, 600-H), 1.16 (t, 7.5 Hz, 3H, 400-
OCOCH2CH3), 1.18 (d, 6.0 Hz, 3H, 60-H), 1.26–1.34
(m, 1H, 7-H), 1.29 (d, 6.3 Hz, 3H, 16-H), 1.62 (m, 1H,
17-H), 1.70–1.86 (m, 3H, 6-, 8-, 17-H), 1.80 (dd, 14.1,
3.6 Hz, 1H, 200-Hax), 1.96 (br d, 14.1 Hz, 1H, 200-Heq),
2.02 (s, 3H, 20-OCOCH3), 2.13 (dt, 14.2, 10.8 Hz, 1H,
14-H), 2.36–2.50 (m, 2H, 2-, 14-H), 2.36–2.50 (m, 2H,
400-OCOCH2CH3), 2.38 (s, 6H, 30-N(CH3)2), 2.71 (t,
10.0 Hz, 1H, 30-H), 2.73 (dd, 16.2, 7.2 Hz, 1H, 2-H),
2.92 (dd, 7.8, 2.4 Hz, 1H, 4-H), 3.20–3.33 (m, 2H, 40-,
50-H), 3.24 (s, 3H, 18-OCH3), 3.26 (s, 3H, 18-OCH3),
3.43 (s, 3H, 4-OCH3), 3.61 (br, 1H, 3-H), 3.99 (br, 1H,
5-H), 4.15 (dd, 8.4, 3.9 Hz, 1H, 9-H), 4.25 (br dd,
12.7, 4.4 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.36 (br dd,
12.7, 4.4 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.36 (dq,
10.5, 6.0 Hz, 1H, 500-H), 4.56 (m, 1H, 18-H), 4.59 (d,
10.5 Hz, 1H, 400-H), 4.71 (d, 7.5 Hz, 1H, 10-H), 5.00
(dd, 10.3, 7.5 Hz, 1H, 20-H), 5.00 (d, 3.0 Hz, 1H, 100-
H), 5.11 (m, 1H, 15-H), 5.51 (m, 1H, 13-H), 5.63 (dd,
13.8, 8.4 Hz, 1H, 10-H), 5.97–6.10 (m, 2H, 11-, 12-H),
6.48 (dt, 16.2, 4.5 Hz, 1H, 3-O–CH2CH@CH–Ar), 6.54
(d, 16.2 Hz, 1H, 3-O–CH2CH@CH–Ar), 8.71 (s, 1H,
pyrimidine), 9.05 (s, 1H, pyrimidine).
4.2.8. 20-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-
(3-pyridyl)-2-propenyl]leucomycin A7 18-dimethylacetal
(7d). Reaction of 6 (215 mg, 215 lmol) with 3-bromo-
pyridine (63.0 ll, 654 lmol) gave 7d (56.1 mg, 24%) by
a similar procedure to 7b.
22
½aꢀ ꢁ69° (c 0.52, CHCl3); FAB-MS m/z 1077 (M+H)+;
D
1H NMR d ꢁ0.03 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3),
0.85 (s, 9H, SiC(CH3)3), 0.96 (d, 6.6 Hz, 3H, 19-H),
1.00–1.12 (m, 1H, 7-H), 1.08 (d, 6.3 Hz, 3H, 600-H),
1.09 (s, 3H, 300-CH3), 1.14 (d, 6.0 Hz, 3H, 60-H), 1.16
(t, 7.6 Hz, 3H, 400-OCOCH2CH3), 1.20–1.32 (m, 1H, 7-
H), 1.28 (d, 6.3 Hz, 3H, 16-H), 1.61 (m, 1H, 17-H),
1.68–1.82 (m, 3H, 6-, 8-, 17-H), 1.77 (dd, 14.1, 3.4 Hz,
1H, 200-Hax), 1.88 (br d, 14.1 Hz, 1H, 200-Heq), 2.01 (s,
3H, 20-OCOCH3), 2.13 (dt, 13.9, 10.8 Hz, 1H, 14-H),
2.36–2.47 (m, 2H, 400-OCOCH2CH3), 2.36–2.49 (m,
2H, 2-, 14-H), 2.37 (s, 6H, 30-N(CH3)2), 2.70 (t,
10.0 Hz, 1H, 30-H), 2.72 (dd, 16.0, 6.9 Hz, 1H, 2-H),
2.88 (dd, 7.6, 1.5 Hz, 1H, 4-H), 3.19–3.31 (m, 2H, 40-,
50-H), 3.24 (s, 3H, 18-OCH3), 3.28 (s, 3H, 18-OCH3),
3.42 (s, 3H, 4-OCH3), 3.57 (br, 1H, 3-H), 4.00 (br, 1H,
5-H), 4.15 (dd, 8.0, 4.0 Hz, 1H, 9-H), 4.18 (br dd,
12.6, 5.8 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.34 (br dd,
4.2.10. 20-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-
(1-naphthyl)-2-propenyl]leucomycin A7 18-dimethylacetal
(7f). To a stirred solution of 6 (214 mg, 214 lmol), PdCl2
(9.4 mg, 53 lmol), 1,3-bis(diphenylphosphino)propane
(40.6 mg, 98.4 lmol), and NaHCO3 (75.9 mg, 903 lmol)
in 4.0 ml of DMF, 1-bromonaphthalene (90.0 ll,
643 lmol) was added and the reaction mixture was stir-
red for 3 days at 100 °C. EtOAc was added to the reac-
tion mixture and the organic layer was washed with
water and brine. After the organic layer was dried and
concentrated, the residue was purified by silica gel chro-
matography [20 g, hexane/EtOAc (4:1–3:1)] to give 7f
(157 mg, 65%).
21
½aꢀ ꢁ73° (c 0.63, CHCl3); FAB-MS m/z 1126 (M+H)+;
D
1H NMR d ꢁ0.03 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3),
0.86 (s, 9H, SiC(CH3)3), 0.97 (d, 6.6 Hz, 3H, 19-H),

T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
4411
1.08 (d, 6.0 Hz, 3H, 600-H), 1.09 (s, 3H, 300-CH3), 1.11 (d,
6.0 Hz, 3H, 60-H), 1.16 (t, 7.5 Hz, 3H, 400-
OCOCH2CH3), 1.29 (d, 6.3 Hz, 3H, 16-H), 1.54–1.64
(m, 1H, 17-H), 1.66–1.85 (m, 3H, 6-, 8-, 17-H), 1.70
(dd, 14.1, 3.8 Hz, 1H, 200-Hax), 1.77 (br d, 14.1 Hz,
1H, 200-Heq), 2.02 (s, 3H, 20-OCOCH3), 2.14 (dt, 13.8,
10.8 Hz, 1H, 14-H), 2.34–2.48 (m, 2H, 400-
OCOCH2CH3), 2.34–2.54 (m, 2H, 2-, 14-H), 2.37 (s,
6H, 30-N(CH3)2), 2.69 (t, 10.0 Hz, 1H, 30-H), 2.77 (dd,
15.9, 6.3 Hz, 1H, 2-H), 2.87 (dd, 7.6, 1.9 Hz, 1H, 4-H),
3.19–3.33 (m, 2H, 40-, 50-H), 3.21 (s, 3H, 18-OCH3),
3.26 (s, 3H, 18-OCH3), 3.43 (s, 3H, 4-OCH3), 3.63 (br,
1H, 3-H), 4.05 (br, 1H, 5-H), 4.15 (dd, 7.8, 4.2 Hz,
1H, 9-H), 4.27 (br dd, 12.4, 5.9 Hz, 1H, 3-O–
CH2CH@CH–Ar), 4.33 (dq, 10.2, 6.0 Hz, 1H, 500-H),
4.45 (br dd, 12.4, 5.9 Hz, 1H, 3-O–CH2CH@CH–Ar),
4.54 (m, 1H, 18-H), 4.56 (d, 10.2 Hz, 1H, 400-H), 4.72
(d, 7.5 Hz, 1H, 10-H), 4.85 (d, 3.4 Hz, 1H, 100-H), 4.99
(dd, 10.2, 7.8 Hz, 1H, 20-H), 5.20 (m, 1H, 15-H), 5.56
(m, 1H, 13-H), 5.62 (dd, 14.2, 7.8 Hz, 1H, 10-H),
5.99–6.11 (m, 2H, 11-, 12-H), 6.34 (dt, 15.6, 6.2 Hz,
1H, 3-O–CH2CH@CH–Ar), 7.34–7.54 (m, 3H, naphtha-
lene), 7.36 (d, 15.6 Hz, 1H, 3-O–CH2CH@CH–Ar), 7.59
(br d, 6.6 Hz, 1H, naphthalene), 7.75 (br d, 8.1 Hz, 1H,
naphthalene), 7.83 (m, 1H, naphthalene), 8.12 (br d,
9.0 Hz, 1H, naphthalene).
4.2.12. 20-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-
(4-nitrophenyl)-2-propenyl]leucomycin A7 18-dimethyl-
acetal (7h). Reaction of 6 (203 mg, 203 lmol) with 4-
iodonitrobenzene (167 mg, 670 lmol) gave 7h (153 mg,
67%) by a similar procedure to 7b.
22
½aꢀ ꢁ63° (c 0.65, CHCl3); FAB-MS m/z 1121 (M+H)+;
D
1H NMR d ꢁ0.03 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3),
0.86 (s, 9H, SiC(CH3)3), 0.97 (d, 6.6 Hz, 3H, 19-H),
1.04–1.16 (m, 1H, 7-H), 1.09 (s, 3H, 300-CH3), 1.10 (d,
6.0 Hz, 3H, 600-H), 1.12 (d, 6.0 Hz, 3H, 60-H), 1.16 (t,
7.5 Hz, 3H, 400-OCOCH2CH3), 1.20–1.32 (m, 1H, 7-H),
1.29 (d, 6.3 Hz, 3H, 16-H), 1.57–1.66 (m, 1H, 17-H),
1.68–1.86 (m, 3H, 6-, 8-, 17-H), 1.78 (dd, 14.4, 3.9 Hz,
1H, 200-Hax), 1.86 (br d, 14.0 Hz, 1H, 200-Heq), 2.02 (s,
3H, 20-OCOCH3), 2.13 (dt, 14.1, 10.9 Hz, 1H, 14-H),
2.36–2.47 (m, 2H, 400-OCOCH2CH3), 2.36–2.50 (m,
2H, 2-, 14-H), 2.38 (s, 6H, 30-N(CH3)2), 2.70 (t,
10.0 Hz, 1H, 30-H), 2.73 (dd, 15.9, 6.9 Hz, 1H, 2-H),
2.90 (dd, 7.8, 2.1 Hz, 1H, 4-H), 3.18–3.33 (m, 2H, 40-,
50-H), 3.24 (s, 3H, 18-OCH3), 3.28 (s, 3H, 18-OCH3),
3.43 (s, 3H, 4-OCH3), 3.58 (br, 1H, 3-H), 4.00 (br, 1H,
5-H), 4.15 (dd, 8.4, 3.9 Hz, 1H, 9-H), 4.23 (br dd,
12.3, 5.4 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.36 (dq,
10.2, 6.0 Hz, 1H, 500-H), 4.37 (br dd, 12.3, 5.4 Hz, 1H,
3-O–CH2CH@CH–Ar), 4.55 (m, 1H, 18-H), 4.58 (d,
10.2 Hz, 1H, 400-H), 4.70 (d, 7.8 Hz, 1H, 10-H), 4.96 (d,
3.6 Hz, 1H, 100-H), 5.00 (dd, 10.5, 7.8 Hz, 1H, 20-H),
5.12 (m, 1H, 15-H), 5.51 (m, 1H, 13-H), 5.63 (dd, 13.7,
8.0 Hz, 1H, 10-H), 5.98–6.10 (m, 1H, 11-, 12-H), 6.50
(dt, 15.9, 5.4 Hz, 1H, 3-O–CH2CH@CH–Ar), 6.65 (d,
15.9 Hz, 1H, 3-O–CH2CH@CH–Ar), 7.48 (d, 8.7 Hz,
2H, C6H4–NO2), 8.16 (d, 8.7 Hz, 2H, C6H4–NO2).
4.2.11. 20-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-
(2-naphthyl)-2-propenyl]leucomycin A7 18-dimethylacetal
(7g). Reaction of 6 (167 mg, 167 lmol) with 2-bromo-
naphthalene (109 mg, 525 lmol) gave 7g (164 mg,
87%) by a similar procedure to 7f.
21
½aꢀ ꢁ67° (c 0.27, CHCl3); FAB-MS m/z 1126 (M+H)+;
D
1H NMR d ꢁ0.03 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3),
0.86 (s, 9H, SiC(CH3)3), 0.97 (d, 6.6 Hz, 3H, 19-H),
1.02 (s, 3H, 300-CH3), 1.07 (d, 6.3 Hz, 3H, 600-H), 1.10
(d, 6.0 Hz, 3H, 60-H), 1.15 (t, 7.6 Hz, 3H, 400-
OCOCH2CH3), 1.29 (d, 6.3 Hz, 3H, 16-H), 1.54–1.64
(m, 1H, 17-H), 1.67–1.86 (m, 3H, 6-, 8-, 17-H), 1.74
(dd, 14.1, 3.6 Hz, 1H, 200-Hax), 1.82 (br d, 14.1 Hz,
1H, 200-Heq), 2.02 (s, 3H, 20-OCOCH3), 2.13 (dt, 14.1,
10.8 Hz, 1H, 14-H), 2.34–2.46 (m, 2H, 400-
OCOCH2CH3), 2.34–2.53 (m, 2H, 2-, 14-H), 2.37 (s,
6H, 30-N(CH3)2), 2.71 (t, 10.0 Hz, 1H, 30-H), 2.75 (dd,
15.9, 6.6 Hz, 1H, 2-H), 2.86 (dd, 7.5, 1.5 Hz, 1H, 4-H),
3.14–3.33 (m, 2H, 40-, 50-H), 3.26 (s, 3H, 18-OCH3),
3.31 (s, 3H, 18-OCH3), 3.42 (s, 3H, 4-OCH3), 3.58 (br,
1H, 3-H), 4.02 (br, 1H, 5-H), 4.16 (dd, 7.7, 4.0 Hz,
1H, 9-H), 4.19 (br dd, 11.4, 5.4 Hz, 1H, 3-O–
CH2CH@CH–Ar), 4.32 (dq, 10.2, 6.2 Hz, 1H, 500-H),
4.40 (br dd, 11.4, 5.4 Hz, 1H, 3-O–CH2CH@CH–Ar),
4.52 (d, 10.5 Hz, 1H, 400-H), 4.57 (m, 1H, 18-H), 4.71
(d, 7.8 Hz, 1H, 10-H), 4.82 (br s, 1H, 100-H), 4.99 (dd,
10.5, 8.1 Hz, 1H, 20-H), 5.18 (m, 1H, 15-H), 5.54 (m,
1H, 13-H), 5.61 (dd, 14.4, 7.9 Hz, 1H, 10-H), 5.96–
6.12 (m, 2H, 11-, 12-H), 6.44 (dt, 15.9, 6.0 Hz, 1H, 3-
O–CH2CH@CH–Ar), 6.74 (d, 16.2 Hz, 1H, 3-O–
CH2CH@CH–Ar), 7.37–7.47 (m, 2H, naphthalene),
7.58 (dd, 8.4, 1.5 Hz, 1H, naphthalene), 7.69 (br s, 1H,
naphthalene), 7.76 (br d, 7.5 Hz, 1H, naphthalene),
7.76 (br d, 7.5 Hz, 1H, naphthalene), 7.76 (br d,
7.4 Hz, 1H, naphthalene).
4.2.13. 20-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-
(4-methoxyphenyl)-2-propenyl]leucomycin A7 18-dimeth-
ylacetal (7i). Reaction of 6 (254 mg, 254 lmol) with 4-
iodoanisole (190 mg, 814 lmol) gave 7i (203 mg, 72%)
by a similar procedure to 7b.
24
½aꢀ ꢁ79° (c 0.61, CHCl3); FAB-MS m/z 1106 (M+H)+;
D
1H NMR d ꢁ0.03 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3),
0.86 (s, 9H, SiC(CH3)3), 0.96 (d, 6.9 Hz, 3H, 19-H),
1.09 (s, 3H, 300-CH3), 1.09 (d, 6.3 Hz, 3H, 600-H), 1.11
(d, 6.0 Hz, 3H, 60-H), 1.16 (t, 7.5 Hz, 3H, 400-
OCOCH2CH3), 1.16–1.31 (m, 1H, 7-H), 1.28 (d,
6.3 Hz, 3H, 16-H), 1.56–1.64 (m, 1H, 17-H), 1.66–1.82
(m, 3H, 6-, 8-, 17-H), 1.74 (dd, 14.2, 3.7 Hz, 1H, 200-
Hax), 1.82 (br d, 13.8 Hz, 1H, 200-Heq), 2.01 (s, 3H, 20-
OCOCH3), 2.13 (dt, 14.4, 10.7 Hz, 1H, 14-H), 2.36–
2.46 (m, 2H, 400-OCOCH2CH3), 2.36–2.52 (m, 2H, 2-,
14-H), 2.37 (s, 6H, 30-N(CH3)2), 2.70 (t, 10.0 Hz, 1H,
30-H), 2.72 (dd, 16.2, 5.7 Hz, 1H, 2-H), 2.82 (dd, 7.2,
1.9 Hz, 1H, 4-H), 3.16-3.33 (m, 2H, 40-, 50-H), 3.25 (s,
3H, 18-OCH3), 3.30 (s, 3H, 18-OCH3), 3.40 (s, 3H, 4-
OCH3), 3.54 (br, 1H, 3-H), 3.78 (s, 3H, C6H4–OCH3),
3.99 (br, 1H, 5-H), 4.09 (br dd, 12.6, 6.8 Hz, 1H, 3-O–
CH2CH@CH–Ar), 4.15 (dd, 7.5, 3.9 Hz, 1H, 9-H),
4.30 (br dd, 12.6, 6.0 Hz, 1H, 3-O–CH2CH@CH–Ar),
4.34 (dq, 10.2, 6.3 Hz, 1H, 500-H), 4.54 (m, 1H, 18-H),
4.57 (d, 10.2 Hz, 1H, 400-H), 4.68 (d, 7.5 Hz, 1H, 10-H),
4.92 (d, 1H, 3.0 Hz, 100-H), 4.98 (dd, 10.5, 7.5 Hz, 1H,
20-H), 5.16 (m, 1H, 15-H), 5.52 (m, 1H, 13-H), 5.60

4412
T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
(dd, 13.8, 7.5 Hz, 1H, 10-H), 5.97–6.10 (m, 2H, 11-, 12-
H), 6.16 (dt, 16.0, 6.3 Hz, 1H, 3-O–CH2CH@CH–Ar),
6.51 (d, 15.7 Hz, 1H, 3-O–CH2CH@CH–Ar), 6.82 (d,
8.7 Hz, 2H, C6H4–OCH3), 7.28 (d, 8.7 Hz, 2H, C6H4–
OCH3).
1H, 3-O–CH2CH@CH–Ar), 4.35 (dq, 10.2, 6.0 Hz, 1H,
500-H), 4.36 (br dd, 12.3, 6.3 Hz, 1H, 3-O–
CH2CH@CH–Ar), 4.54 (m, 1H, 18-H), 4.58 (d,
10.2 Hz, 1H, 400-H), 4.70 (d, 7.5 Hz, 1H, 10-H), 4.93 (d,
3.3 Hz, 1H, 100-H), 4.99 (dd, 10.5, 7.5 Hz, 1H, 20-H),
5.15 (m, 1H, 15-H), 5.52 (m, 1H, 13-H), 5.62 (dd, 13.9,
7.8 Hz, 1H, 10-H), 5.98–6.11 (m, 2H, 11-, 12-H), 6.41
(dt, 15.9, 5.7 Hz, 1H, 3-O–CH2CH@CH–Ar), 6.61 (d,
15.9 Hz, 1H, 3-O–CH2CH@CH–Ar), 7.44 (d, 8.1 Hz,
2H, C6H4–CF3), 7.55 (d, 8.1 Hz, 2H, C6H4–CF3).
4.2.14. 20-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-
(4-fluorophenyl)-2-propenyl]leucomycin A7 18-dimethyl-
acetal (7j). Reaction of 6 (206 mg, 206 lmol) with 4-fluo-
roiodobenzene (72.0 ll, 623 lmol) gave 7j (168 mg, 74%)
by a similar procedure to 7b.
4.2.16. 20-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-
(4-biphenylyl)-2-propenyl]leucomycin A7 18-dimethylace-
tal (7l). Reaction of 6 (220 mg, 220 lmol) with 4-bromo-
biphenyl (156 mg, 670 lmol) gave 7l (193 mg, 76%) by a
similar procedure to 7b.
23
D
½aꢀ ꢁ79° (c 0.34, CHCl3); FAB-MS m/z 1094 (M+H)+;
1H NMR d ꢁ0.03 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3),
0.86 (s, 9H, SiC(CH3)3), 0.96 (d, 6.6 Hz, 3H, 19-H),
1.09 (d, 6.0 Hz, 3H, 600-H), 1.10 (s, 3H, 300-CH3), 1.11
(d, 6.0 Hz, 3H, 60-H), 1.16 (t, 7.6 Hz, 3H, 400-
OCOCH2CH3), 1.20–1.32 (m, 1H, 7-H), 1.28 (d,
6.3 Hz, 3H, 16-H), 1.61 (m, 1H, 17-H), 1.66–1.85 (m,
3H, 6-, 8-, 17-H), 1.75 (dd, 14.2, 3.4 Hz, 1H, 200-Hax),
1.82 (br d, 13.8 Hz, 1H, 200-Heq), 2.01 (s, 3H, 20-
OCOCH3), 2.13 (dt, 14.4, 10.8 Hz, 1H, 14-H), 2.36–
2.47 (m, 2H, 400-OCOCH2CH3), 2.36–2.51 (m, 2H, 2-,
14-H), 2.37 (s, 6H, 30-N(CH3)2), 2.69 (t, 10.5 Hz, 1H,
30-H), 2.71 (dd, 15.9, 6.0 Hz, 1H, 2-H), 2.84 (dd, 7.8,
1.8 Hz, 1H, 4-H), 3.16-3.33 (m, 2H, 40-, 50-H), 3.25 (s,
3H, 18-OCH3), 3.29 (s, 3H, 18-OCH3), 3.41 (s, 3H, 4-
OCH3), 3.54 (br, 1H, 3-H), 3.99 (br, 1H, 5-H), 4.11
(br dd, 12.4, 6.6 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.15
(dd, 7.7, 4.3 Hz, 1H, 9-H), 4.32 (br dd, 12.4, 6.0 Hz,
1H, 3-O–CH2CH@CH–Ar), 4.35 (dq, 10.2, 6.3 Hz, 1H,
500-H), 4.54 (m, 1H, 18-H), 4.57 (d, 10.2 Hz, 1H, 400-H),
4.68 (d, 8.1 Hz, 1H, 10-H), 4.92 (d, 3.0 Hz, 1H, 100-H),
4.99 (dd, 10.2, 7.8 Hz, 1H, 20-H), 5.16 (m, 1H, 15-H),
5.52 (m, 1H, 13-H), 5.61 (dd, 13.8, 7.8 Hz, 1H, 10-H),
5.96–6.10 (m, 2H, 11-, 12-H), 6.22 (dt, 15.9, 5.9 Hz,
1H, 3-O–CH2CH@CH–Ar), 6.53 (d, 15.9 Hz, 1H, 3-O–
CH2CH@CH–Ar), 6.99 (t, 8.7 Hz, 2H, C6H4–F), 7.31
(dd, 8.7, 5.4 Hz, 2H, C6H4–F).
22
½aꢀ ꢁ68° (c 0.59, CHCl3); FAB-MS m/z 1152 (M+H)+;
D
1H NMR d ꢁ0.03 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3),
0.86 (s, 9H, SiC(CH3)3), 0.97 (d, 6.6 Hz, 3H, 19-H),
0.98 (s, 3H, 300-CH3), 1.08 (d, 6.3 Hz, 3H, 600-H), 1.12
(d, 6.0 Hz, 3H, 60-H), 1.15 (t, 7.5 Hz, 3H, 400-
OCOCH2CH3), 1.18–1.32 (m, 1H, 7-H), 1.29 (d,
6.3 Hz, 3H, 16-H), 1.54–1.65 (m, 1H, 17-H), 1.65–1.82
(m, 3H, 6-, 8-, 17-H), 1.66 (dd, 14.1, 3.7 Hz, 1H, 200-
Hax), 1.77 (br d, 14.0 Hz, 1H, 200-Heq), 2.02 (s, 3H, 20-
OCOCH3), 2.14 (dt, 13.8, 10.7 Hz, 1H, 14-H), 2.36–
2.48 (m, 1H, 2-H), 2.36–2.48 (m, 2H, 400-OCOCH2CH3),
2.37 (s, 6H, 30-N(CH3)2), 2.48 (br d, 13.8 Hz, 1H, 14-H),
2.72 (t, 10.0 Hz, 1H, 30-H), 2.73 (dd, 16.0, 6.6 Hz, 1H, 2-
H), 2.85 (dd, 7.7, 2.0 Hz, 1H, 4-H), 3.20–3.33 (m, 2H, 40-
, 50-H), 3.27 (s, 3H, 18-OCH3), 3.31 (s, 3H, 18-OCH3),
3.42 (s, 3H, 4-OCH3), 3.56 (br, 1H, 3-H), 4.02 (br, 1H,
5-H), 4.15 (br dd, 11.4, 6.8 Hz, 1H, 3-O–
CH2CH@CH–Ar), 4.16 (dd, 7.2, 4.2 Hz, 1H, 9-H),
4.33 (dq, 10.7, 6.3 Hz, 1H, 500-H), 4.36 (br dd, 11.4,
6.3 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.53 (d, 10.7 Hz,
1H, 400-H), 4.56 (dd, 9.0, 2.1 Hz, 1H, 18-H), 4.70 (d,
7.8 Hz, 1H, 10-H), 4.90 (d, 3.3 Hz, 1H, 100-H), 4.99 (dd,
10.3, 7.7 Hz, 1H, 20-H), 5.18 (m, 1H, 15-H), 5.54 (m,
1H, 13-H), 5.61 (dd, 14.0, 7.2 Hz, 1H, 10-H), 5.98–
6.12 (m, 2H, 11-, 12-H), 6.36 (dt, 15.9, 6.2 Hz, 1H, 3-
O–CH2CH@CH–Ar), 6.61 (d, 15.9 Hz, 1H, 3-O–
CH2CH@CH–Ar), 7.26–7.34 (m, 1H, C6H4-Ph), 7.37–
7.46 (m, 2H, C6H4–Ph), 7.42 (br d, 8.5 Hz, 2H, C6H4–
Ph), 7.54 (br d, 8.7 Hz, 2H, C6H4–Ph), 7.52–7.62 (m,
2H, C6H4–Ph).
4.2.15. 20-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-[3-
(4-trifluoromethylphenyl)-2-propenyl]leucomycin A7 18-
dimethylacetal (7k). Reaction of 6 (204 mg, 204 lmol)
with 4-iodobenzotrifluoride (90.0 ll, 612 lmol) gave 7k
(150 mg, 64%) by a similar procedure to 7b.
23
½aꢀ ꢁ72° (c 0.34, CHCl3); FAB-MS m/z 1144 (M+H)+;
D
1H NMR d ꢁ0.03 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3),
0.86 (s, 9H, SiC(CH3)3), 0.97 (d, 6.6 Hz, 3H, 19-H),
1.09 (s, 3H, 300-CH3), 1.10 (d, 6.0 Hz, 3H, 60-H), 1.10
(d, 6.0 Hz, 3H, 600-H), 1.16 (t, 7.5 Hz, 3H, 400-
OCOCH2CH3), 1.20–1.31 (m, 1H, 7-H), 1.28 (d,
6.3 Hz, 3H, 16-H), 1.62 (m, 1H, 17-H), 1.67–1.86 (m,
3H, 6-, 8-, 17-H), 1.76 (dd, 14.4, 3.6 Hz, 1H, 200-Hax),
1.83 (br d, 14.0 Hz, 1H, 200-Heq), 2.02 (s, 3H, 20-
OCOCH3), 2.13 (dt, 14.0, 10.8 Hz, 1H, 14-H), 2.36–
2.48 (m, 2H, 400-OCOCH2CH3), 2.36–2.50 (m, 2H, 2-,
14-H), 2.38 (s, 6H, 30-N(CH3)2), 2.71 (t, 10.0 Hz, 1H,
30-H), 2.72 (dd, 16.0, 6.8 Hz, 1H, 2-H), 2.87 (dd, 7.8,
1.8 Hz, 1H, 4-H), 3.16–3.33 (m, 2H, 40-, 50-H), 3.24 (s,
3H, 18-OCH3), 3.28 (s, 3H, 18-OCH3), 3.42 (s, 3H, 4-
OCH3), 3.56 (br, 1H, 3-H), 4.00 (br, 1H, 5-H), 4.15
(dd, 7.7, 3.7 Hz, 1H, 9-H), 4.18 (br dd, 12.3, 6.6 Hz,
4.2.17. 20-O-Acetyl-9-O-(tert-butyldimethylsilyl)-3-O-{3-
[4-(1-imidazolyl)phenyl]-2-propenyl}leucomycin A7 18-
dimethylacetal (7m). Reaction of 6 (244 mg, 244 lmol)
with 4-(1-imidazolyl)bromobenzene (146 mg, 655 lmol)
gave 7m (187 mg, 67%) by a similar procedure to 7f.
21
½aꢀ ꢁ52° (c 0.40, CHCl3); FAB-MS m/z 1142 (M+H)+;
D
1H NMR d ꢁ0.03 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3),
0.86 (s, 9H, SiC(CH3)3), 0.97 (d, 6.6 Hz, 3H, 19-H),
1.03 (s, 3H, 300-CH3), 1.09 (d, 6.0 Hz, 3H, 600-H), 1.11
(d, 6.0 Hz, 3H, 60-H), 1.15 (t, 7.6 Hz, 3H, 400-
OCOCH2CH3), 1.20–1.32 (m, 1H, 7-H), 1.29 (d,
6.3 Hz, 3H, 16-H), 1.61 (m, 1H, 17-H), 1.67–1.87 (m,
3H, 6-, 8-, 17-H), 1.75 (dd, 13.8, 3.6 Hz, 1H, 200-Hax),
1.83 (br d, 13.8 Hz, 1H, 200-Heq), 2.02 (s, 3H, 20-

T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
4413
OCOCH3), 2.13 (dt, 14.1, 10.8 Hz, 1H, 14-H), 2.34–2.48
(m, 2H, 400-OCOCH2CH3), 2.36–2.50 (m, 2H, 2-, 14-H),
2.38 (s, 6H, 30-N(CH3)2), 2.70 (t, 10.0 Hz, 1H, 30-H),
2.73 (dd, 15.9, 7.0 Hz, 1H, 2-H), 2.88 (dd, 7.8, 1.8 Hz,
1H, 4-H), 3.15–3.35 (m, 2H, 40-, 50-H), 3.26 (s, 3H, 18-
OCH3), 3.29 (s, 3H, 18-OCH3), 3.42 (s, 3H, 4-OCH3),
3.57 (br, 1H, 3-H), 4.00 (br, 1H, 5-H), 4.16 (dd, 7.7,
4.0 Hz, 1H, 9-H), 4.18 (m, 1H, 3-O–CH2CH@CH–Ar),
4.34 (m, 1H, 3-O–CH2CH@CH–Ar), 4.35 (dq, 10.2,
6.0 Hz, 1H, 500-H), 4.56 (m, 1H, 18-H), 4.57 (d,
10.2 Hz, 1H, 400-H), 4.71 (d, 7.5 Hz, 1H, 10-H), 4.96 (d,
3.3 Hz, 1H, 100-H), 5.00 (dd, 10.2, 7.5 Hz, 1H, 20-H),
5.13 (m, 1H, 15-H), 5.52 (m, 1H, 13-H), 5.62 (dd, 14.1,
7.8 Hz, 1H, 10-H), 5.98–6.11 (m, 2H, 11-, 12-H), 6.34
(dt, 15.9, 6.0 Hz, 1H, 3-O–CH2CH@CH–Ar), 6.59 (d,
15.9 Hz, 1H, 3-O–CH2CH@CH–Ar), 7.19 (br s, 1H,
imidazole), 7.22–7.34 (br, 1H, imidazole), 7.31 (d,
8.7 Hz, 2H, C6H4–imidazole), 7.44 (d, 8.4 Hz, 2H,
C6H4–imidazole), 7.72–7.84 (br, 1H, imidazole).
7.0, 1.3 Hz, 1H, quinoline), 7.78 (dd, 7.2, 1.0 Hz, 1H,
quinoline), 8.04 (d, 8.4 Hz, 1H, quinoline), 8.07 (d,
1.9 Hz, 1H, quinoline), 9.00 (d, 2.1 Hz, 1H, quinoline),
9.77 (br s, 1H, 18-H); HRMS: Calcd for C50H72N2O14:
925.5062. Found: 925.5072.
4.2.19. 3-O-[3-(4-Isoquinolyl)-2-propenyl]leucomycin A7
(9b). By a similar procedure to 9a, 7b (215 mg,
191 lmol) was deacetylated to give 8b (193 mg, 93%).
Subsequently, 8b (187 mg, 177 lmol) was deprotected
to furnish 147 mg of 9b. A portion of 9b (34.2 mg) was
purified by preparative TLC to afford 9b (29.7 mg, 80%).
20
½aꢀ ꢁ44° (c 0.57, CHCl3); FAB-MS m/z 925 (M+H)+;
D
1H NMR d 0.01 (d, 6.3 Hz, 3H, 19-H), 1.08 (d, 6.3 Hz,
3H, 60-H), 1.08 (s, 3H, 300-CH3), 1.10 (d, 6.0 Hz, 3H,
600-H), 1.15 (t, 7.5 Hz, 3H, 400-OCOCH2CH3), 1.28 (d,
6.3 Hz, 3H, 16-H), 1.32 (m, 1H, 7-H), 1.74 (dd, 14.4,
3.9 Hz, 1H, 200-Hax), 1.76–1.85 (m, 1H, 8-H), 1.84 (br
d, 14.4 Hz, 1H, 200-Heq), 2.05–2.15 (m, 1H, 6-H), 2.15
(dt, 14.1, 10.8 Hz, 1H, 14-H), 2.30–2.51 (m, 4H, 2-, 14-
, 17-, 30-H), 2.36–2.49 (m, 2H, 400-OCOCH2CH3), 2.43
(s, 6H, 30-N(CH3)2), 2.81 (dd, 16.3, 6.5 Hz, 1H, 2-H),
2.95 (dd, 16.8, 9.6 Hz, 1H, 17-H), 2.99 (m, 1H, 4-H),
3.09 (m, 1H, 50-H), 3.17 (t, 9.4 Hz, 1H, 40-H), 3.51 (s,
3H, 4-OCH3), 3.51 (m, 1H, 20-H), 3.80 (br, 1H, 3-H),
3.86 (br, 1H, 5-H), 4.13 (dd, 8.1, 3.9 Hz, 1H, 9-H),
4.34–4.49 (m, 2H, 3-O–CH2CH@CH–Ar), 4.39 (d,
7.5 Hz, 1H, 10-H), 4.43 (m, 1H, 500-H), 4.56 (d, 1H,
9.9 Hz, 400-H), 4.91 (d, 1H, 3.6 Hz, 100-H), 5.19 (m, 1H,
15-H), 5.63 (m, 1H, 13-H), 5.67 (dd, 15.0, 8.1 Hz, 1H,
10-H), 6.06 (br dd, 14.6, 10.6 Hz, 1H, 12-H), 6.24 (dd,
15.0, 10.5 Hz, 1H, 11-H), 6.44 (dt, 15.7, 5.8 Hz, 1H, 3-
O–CH2CH@CH–Ar), 7.25 (d, 15.9 Hz, 1H, 3-O–
CH2CH@CH–Ar), 7.59 (br t, 7.4 Hz, 1H, isoquinoline),
7.70 (br t, 7.5 Hz, 1H, isoquinoline), 7.94 (br d, 8.1 Hz,
1H, isoquinoline), 8.11 (br d, 8.4 Hz, 1H, isoquinoline),
8.62 (s, 1H, isoquinoline), 9.12 (s, 1H, isoquinoline),
9.76 (br s, 1H, 18-H); HRMS: Calcd for C50H72N2O14:
925.5062. Found: 925.5052.
4.2.18. 3-O-[3-(3-Quinolyl)-2-propenyl]leucomycin A7
(9a). A solution of 7a (196 mg, 174 lmol) in 7.7 ml of
MeOH/H2O (10:1) was stirred for 46 h at 50 °C. The
reaction mixture was concentrated and the residue was
purified by silica gel chromatography [10 g, CHCl3/
MeOH (50:1)] to give 8a (183 mg, 97%).
To a stirred solution of 8a (177 mg, 163 lmol) in 54 ml
of MeCN/H2O (1:1), difluoroacetic acid (62.0 ll,
985 lmol) was added and the reaction mixture was stir-
red for 5 days at room temperature. Saturated NaHCO3
solution was added and the aqueous layer was extracted
with CHCl3. The extract was washed with brine, dried,
and concentrated. The residue was purified by silica
gel chromatography [30 g, CHCl3/MeOH/NH4OH
(200:10:1)] to give 137 mg of 9a. A portion of 9a
(24.0 mg) was again purified by preparative TLC
[CHCl3/MeOH/NH4OH (100:10:1)] to afford 9a
(18.9 mg, 80%).
24
½aꢀ ꢁ39° (c 0.82, CHCl3); FAB-MS m/z 925 (M+H)+;
D
1H NMR d 0.02 (d, 6.6 Hz, 3H, 19-H), 1.05 (s, 3H, 300-
CH3), 1.06 (d, 6.3 Hz, 3H, 60-H), 1.08 (d, 6.0 Hz, 3H,
600-H), 1.15 (t, 7.6 Hz, 3H, 400-OCOCH2CH3), 1.29 (d,
6.3 Hz, 3H, 16-H), 1.33 (m, 1H, 7-H), 1.70 (dd, 14.4,
3.6 Hz, 1H, 200-Hax), 1.74–1.86 (m, 1H, 8-H), 1.78 (br
d, 14.1 Hz, 1H, 200-Heq), 2.01–2.16 (m, 1H, 6-H), 2.16
(dt, 14.1 Hz, 1H, 14-H), 2.36–2.48 (m, 2H, 400-
OCOCH2CH3), 2.36–2.52 (m, 4H, 2-, 14-, 17-, 30-H),
2.47 (s, 30-N(CH3)2), 2.79 (dd, 16.2, 6.6 Hz, 1H, 2-H),
2.95 (m, 1H, 17-H), 2.98 (dd, 7.2, 2.4 Hz, 1H, 4-H),
3.11–3.22 (m, 1H, 50-H), 3.20 (t, 9.3 Hz, 1H, 40-H),
3.50 (s, 3H, 4-OCH3), 3.53 (dd, 10.5, 7.8 Hz, 1H, 20-
H), 3.76 (br, 1H, 3-H), 3.88 (br, 1H, 5-H), 4.13 (dd,
7.9, 4.0 Hz, 1H, 9-H), 4.32–4.47 (m, 2H, 3-O–
CH2CH@CH–Ar), 4.40 (m, 1H, 500-H), 4.41 (d, 7.8 Hz,
1H, 10-H), 4.55 (d, 10.2 Hz, 1H, 400-H), 4.91 (d, 3.2 Hz,
1H, 100-H), 5.19 (m, 1H, 15-H), 5.63 (m, 1H, 13-H),
5.67 (dd, 14.9, 7.9 Hz, 1H, 10-H), 6.07 (br dd, 15.1,
10.5 Hz, 1H, 12-H), 6.24 (dd, 14.9, 10.5 Hz, 1H, 11-
H), 6.59 (dt, 15.9, 5.9 Hz, 1H, 3-O–CH2CH@CH–Ar),
6.78 (d, 15.9 Hz, 1H, 3-O–CH2CH@CH–Ar), 7.51
(ddd, 8.0, 6.8, 1.2 Hz, 1H, quinoline), 7.64 (ddd, 8.4,
4.2.20. 3-O-(3-Phenyl-2-propenyl)leucomycin A7 (9c). By
a similar procedure to 9a, 7c (160 mg, 149 lmol) was
deacetylated to give 8c (137 mg, 89%). Subsequently,
8c (83.0 mg, 80.2 lmol) was deprotected to furnish 9c
(46.2 mg, 66%).
22
½aꢀ ꢁ63° (c 0.58, CHCl3); FAB-MS m/z 874 (M+H)+;
D
1H NMR d 0.01 (d, 6.6 Hz, 3H, 19-H), 1.04 (d, 6.3 Hz,
3H, 60-H), 1.09 (s, 3H, 300-CH3), 1.09 (d, 6.0 Hz, 3H,
600-H), 1.16 (t, 7.5 Hz, 3H, 400-OCOCH2CH3), 1.26–
1.36 (m, 1H, 7-H), 1.28 (d, 6.3 Hz, 3H, 16-H), 1.75
(dd, 14.2, 3.6 Hz, 1H, 200-Hax), 1.72–1.84 (m, 1H, 8-
H), 1.86 (br d, 14.2 Hz, 1H, 200-Heq), 1.94–2.06 (m,
1H, 6-H), 2.16 (dt, 14.4, 10.8 Hz, 1H, 14-H), 2.32–2.60
(m, 2H, 400-OCOCH2CH3), 2.32–2.62 (m, 4H, 2-, 14-,
17-, 30-H), 2.46 (s, 6H, 30-N(CH3)2), 2.75 (dd, 16.2,
5.7 Hz, 1H, 2-H), 2.91 (dd, 16.9, 9.6 Hz, 1H, 17-H),
2.92 (dd, 7.2, 2.4 Hz, 1H, 4-H), 3.09 (m, 1H, 50-H),
3.17 (t, 9.3 Hz, 1H, 40-H), 3.48 (s, 3H, 4-OCH3), 3.52
(m, 1H, 20-H), 3.72 (br, 1H, 3-H), 3.81 (br, 1H, 5-H),
4.12 (dd, 8.1, 3.7 Hz, 1H, 9-H), 4.21 (br dd, 11.5,
6.7 Hz, 3-O–CH2CH@CH–Ph), 4.35 (br dd, 11.5,

4414
T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
6.0 Hz, 1H, 3-O–CH2CH@CH–Ph), 4.38 (d, 7.5 Hz, 1H,
10-H), 4.42 (dq, 10.2, 6.0 Hz, 1H, 500-H), 4.57 (d, 10.2 Hz,
1H, 400-H), 4.93 (d, 3.3 Hz, 1H, 100-H), 5.21 (m, 1H, 15-
H), 5.63 (m, 1H, 13-H), 5.64 (dd, 15.0, 8.1 Hz, 1H, 10-
H), 6.06 (br dd, 15.3, 10.3 Hz, 1H, 12-H), 6.22 (dd,
15.0, 10.3 Hz, 1H, 11-H), 6.32 (dt, 15.9, 6.3 Hz, 1H, 3-
O–CH2CH@CH–Ph), 6.59 (d, 15.9 Hz, 1H, 3-O–
CH2CH@CH–Ph), 6.98–7.24 (m, 5H, Ph), 9.76 (br s,
1H, 18-H); HRMS: Calcd for C47H71NO14: 874.4953.
Found: 874.4943.
1H, 2-H), 2.96 (m, 1H, 17-H), 2.98 (dd, 7.2, 2.4 Hz,
1H, 4-H), 3.14–3.23 (m, 1H, 50-H), 3.23 (t, 9.0 Hz,
1H, 40-H), 3.48 (s, 3H, 4-OCH3), 3.52 (dd, 10.2,
7.5 Hz, 1H, 20-H), 3.72 (br, 1H, 3-H), 3.86 (br, 1H,
5-H), 4.10 (dd, 8.4, 3.9 Hz, 1H, 9-H), 4.29–4.43 (m,
2H, 3-O–CH2CH@CH–Ar), 4.37 (d, 7.5 Hz, 1H, 10-
H), 4.42 (dq, 10.2, 6.0 Hz, 1H, 500-H), 4.58 (d,
10.2 Hz, 1H, 400-H), 5.00 (d, 3.6 Hz, 1H, 100-H), 5.14
(m, 1H, 15-H), 5.60 (m, 1H, 13-H), 5.66 (dd, 15.0,
8.5 Hz, 1H, 10-H), 6.05 (br dd, 15.0, 10.8 Hz, 1H,
12-H), 6.22 (dd, 14.7, 10.5 Hz, 1H, 11-H), 6.53 (dt,
16.0, 4.5 Hz, 1H, 3-O–CH2CH@CH–Ar), 6.57 (d,
16.0 Hz, 1H, 3-O–CH2CH@CH–Ar), 8.74 (s, 1H,
pyrimidine), 9.03 (s, 1H, pyrimidine), 9.74 (br s, 1H,
18-H); HRMS: Calcd for C45H69N3O14: 876.4858.
Found: 876.4856.
4.2.21. 3-O-[3-(3-Pyridyl)-2-propenyl]leucomycin A7 (9d).
By a similar procedure to 9a, 7d (72.9 mg, 67.7 lmol)
was deacetylated to give 8d (65.0 mg, 93%). Subse-
quently, 8d (65.0 mg, 62.8 lmol) was deprotected to fur-
nish 9d (39.9 mg, 73%).
23
½aꢀ ꢁ56° (c 0.53, CHCl3); FAB-MS m/z 875 (M+H)+;
4.2.23. 3-O-[3-(1-Naphthyl)-2-propenyl]leucomycin A7
(9f). By a similar procedure to 9a, 7f (122 mg, 109 lmol)
was deacetylated to give 8f (104 mg, 88%). Subse-
quently, 8f (74.6 mg, 68.8 lmol) was deprotected to fur-
nish 9f (40.0 mg, 63%).
D
1H NMR d 0.01 (d, 6.6 Hz, 3H, 19-H), 1.09 (d, 6.0 Hz,
3H, 60-H), 1.09 (s, 3H, 300-CH3), 1.09 (d, 6.0 Hz, 3H,
600-H), 1.15 (t, 7.6 Hz, 3H, 400-OCOCH2CH3), 1.28 (d,
6.0 Hz, 3H, 16-H), 1.32 (m, 1H, 7-H), 1.75–1.86 (m,
1H, 8-H), 1.78 (dd, 14.1, 3.7 Hz, 1H, 200-Hax), 1.89 (br
d, 14.1 Hz, 1H, 200-Heq), 1.99–2.09 (m, 1H, 6-H), 2.15
(dt, 14.1, 10.8 Hz, 1H, 14-H), 2.34–2.48 (m, 2H, 400-
OCOCH2CH3), 2.34–2.51 (m, 4H, 2-, 14-, 17-, 30-H),
2.46 (s, 6H, 30-N(CH3)2), 2.76 (dd, 16.0, 6.4 Hz, 1H, 2-
H), 2.94 (dd, 17.4, 10.2 Hz, 1H, 17-H), 2.95 (dd, 7.2,
2.4 Hz, 1H, 4-H), 3.12 (dq, 9.6, 6.0 Hz, 1H, 50-H), 3.20
(t, 9.6 Hz, 1H, 40-H), 3.48 (s, 3H, 4-OCH3), 3.52 (dd,
9.9, 7.5 Hz, 1H, 20-H), 3.72 (br, 1H, 3-H), 3.84 (br,
1H, 5-H), 4.11 (dd, 8.4, 3.9 Hz, 1H, 9-H), 4.30 (br dd,
12.6, 6.5 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.34 (m, 1H,
3-O–CH2CH@CH–Ar), 4.37 (d, 7.5 Hz, 1H, 10-H),
4.43 (dq, 10.5, 6.0 Hz, 1H, 500-H), 4.58 (d, 10.5 Hz, 1H,
400-H), 4.96 (d, 3.3 Hz, 1H, 100-H), 5.17 (m, 1H, 15-H),
5.62 (m, 1H, 13-H), 5.66 (dd, 14.7, 8.4 Hz, 1H, 10-H),
6.05 (br dd, 15.0, 10.5 Hz, 1H, 12-H), 6.22 (dd, 14.7,
10.4 Hz, 1H, 11-H), 6.42 (dt, 16.0, 5.9 Hz, 1H, 3-O–
CH2CH@CH–Ar), 6.60 (d, 16.2 Hz, 1H, 3-O–
CH2CH@CH–Ar), 7.23 (dd, 7.5, 4.6 Hz, 1H, pyridine),
7.72 (dt, 7.8, 1.9 Hz, 1H, pyridine), 8.42 (dd, 4.8,
1.5 Hz, 1H, pyridine), 8.56 (d, 2.1 Hz, 1H, pyridine),
9.75 (br s, 1H, 18-H); HRMS: Calcd for C46H70N2O14:
875.4905. Found: 875.4905.
23
½aꢀ ꢁ46° (c 0.51, CHCl3); FAB-MS m/z 924 (M+H)+;
D
1H NMR d 0.89 (d, 6.0 Hz, 3H, 60-H), 1.01 (d, 6.6 Hz,
3H, 19-H), 1.08 (d, 6.0 Hz, 3H, 600-H), 1.10 (s, 3H, 300-
CH3), 1.16 (t, 7.5 Hz, 3H, 400-OCOCH2CH3), 1.28 (d,
6.3 Hz, 3H, 16-H), 1.30 (m, 1H, 7-H), 1.71–1.85 (m,
1H, 8-H), 1.71 (dd, 14.4, 3.6 Hz, 1H, 200-Hax), 1.79 (br
d, 14.0 Hz, 1H, 200-Heq), 2.00-2.13 (m, 1H, 6-H), 2.16
(dt, 14.1, 10.6 Hz, 1H, 14-H), 2.33–2.48 (m, 2H, 400-
OCOCH2CH3), 2.33–2.55 (m, 3H, 2-, 14-, 17-H), 2.34
(t, 10.2 Hz, 1H, 30-H), 2.44 (s, 6H, 30-N(CH3)2), 2.80
(dd, 16.3, 5.9 Hz, 1H, 2-H), 2.90–3.02 (m, 1H, 50-H),
2.92 (m, 1H, 17-H), 2.96 (dd, 7.2, 2.7 Hz, 1H, 4-H),
3.12 (t, 9.5 Hz, 1H, 40-H), 3.50 (dd, 10.2, 7.8 Hz, 1H,
20-H), 3.51 (s, 3H, 4-OCH3), 3.81 (br, 1H, 3-H), 3.84
(br, 1H, 5-H), 4.12 (dd, 8.0, 3.9 Hz, 1H, 9-H), 4.34 (br
dd, 12.1, 6.0 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.38 (d,
7.8 Hz, 1H, 10-H), 4.42 (dq, 10.2, 6.0 Hz, 1H, 500-H),
4.47 (br dd, 12.1, 5.7 Hz, 1H, 3-O–CH2CH@CH–Ar),
4.55 (d, 10.2 Hz, 1H, 400-H), 4.84 (d, 3.3 Hz, 1H, 100-
H), 5.22 (m, 1H, 15-H), 5.64 (m, 1H, 13-H), 5.66 (dd,
15.0, 8.4 Hz, 1H, 10-H), 6.06 (br dd, 15.3, 10.4 Hz,
1H, 12-H), 6.23 (dd, 14.9, 10.5 Hz, 1H, 11-H), 6.37
(dt, 15.5, 6.1 Hz, 1H, 3-O–CH2CH@CH–Ar), 7.39 (d,
15.2 Hz, 1H, 3-O–CH2CH@CH–Ar), 7.35–7.53 (m,
3H, naphthalene), 7.63 (br d, 6.9 Hz, 1H, naphthalene),
7.75 (br d, 8.1 Hz, 1H, naphthalene), 7.81 (m, 1H, naph-
thalene), 8.15 (br d, 9.0 Hz, 1H, naphthalene), 9.76 (br s,
1H, 18-H); HRMS: Calcd for C51H73NO14: 924.5109.
Found: 924.5109.
4.2.22. 3-O-[3-(5-Pyrimidinyl)-2-propenyl]leucomycin A7
(9e). By a similar procedure to 9a, 7e (166 mg, 154 lmol)
was deacetylated to give 8e (131 mg, 82%). Subse-
quently, 8e (125 mg, 121 lmol) was deprotected to fur-
nish 93.3 mg of 9e. A portion of 9e (30.9 mg) was
purified by preparative TLC to afford 9e (29.2 mg, 84%).
20
½aꢀ ꢁ47° (c 0.54, CHCl3); FAB-MS m/z 876 (M+H)+;
4.2.24. 3-O-[3-(2-Naphthyl)-2-propenyl]leucomycin A7
(9g). By a similar procedure to 9a, 7g (130 mg,
115 lmol) was deacetylated to give 8g (114 mg, 91%).
Subsequently, 8g (82.8 mg, 76.4 lmol) was deprotected
to furnish 9g (41.7 mg, 59%).
D
1H NMR d 0.01 (d, 6.6 Hz, 3H, 19-H), 1.08 (s, 3H, 300-
CH3), 1.09 (d, 6.0 Hz, 3H, 600-H), 1.13 (d, 6.0 Hz, 3H,
60-H), 1.15 (t, 7.5 Hz, 3H, 400-OCOCH2CH3), 1.28 (d,
6.3 Hz, 3H, 16-H), 1.34 (m, 1H, 7-H), 1.79 (dd, 14.4,
3.9 Hz, 1H, 200-Hax), 1.77–1.87 (m, 1H, 8-H), 1.94
(br d, 14.2 Hz, 1H, 200-Heq), 2.03–2.13 (m, 1H, 6-H),
2.14 (dt, 13.9, 12.0 Hz, 1H, 14-H), 2.36–2.46 (m, 2H,
400-OCOCH2CH3), 2.36–2.50 (m, 4H, 2-, 14-, 17-, 30-
H), 2.47 (s, 6H, 30-N(CH3)2), 2.77 (dd, 15.9, 6.9 Hz,
23
½aꢀ ꢁ39° (c 0.49, CHCl3); FAB-MS m/z 924 (M+H)+;
D
1H NMR d 0.98 (d, 6.0 Hz, 3H, 60-H), 1.02 (d, 6.9 Hz,
3H, 19-H), 1.05 (s, 3H, 300-CH3), 1.07 (d, 6.0 Hz, 3H,
600-H), 1.16 (t, 7.6 Hz, 3H, 400-OCOCH2CH3), 1.26–

T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
4415
23
D
1.36 (m, 1H, 7-H), 1.29 (d, 6.0 Hz, 3H, 16-H), 1.63 (br s,
2H, 200-H), 1.74–1.85 (m, 1H, 8-H), 1.96–2.10 (m, 1H, 6-
H), 2.16 (dt, 13.8, 10.5 Hz, 1H, 14-H), 2.36–2.48 (m, 2H,
400-OCOCH2CH3), 2.36–2.56 (m, 4H, 2-, 14-, 17-, 30-H),
2.46 (s, 6H, 30-N(CH3)2), 2.77 (dd, 16.2, 5.7 Hz, 1H, 2-
H), 2.93 (m, 1H, 17-H), 2.94 (dd, 7.0, 2.7 Hz, 1H, 4-
H), 3.05 (dq, 9.5, 6.0 Hz, 1H, 50-H), 3.14 (t, 9.5 Hz,
1H, 40-H), 3.50 (s, 3H, 4-OCH3), 3.52 (dd, 10.5,
7.6 Hz, 1H, 20-H), 3.75 (br, 1H, 3-H), 3.84 (br, 1H, 5-
H), 4.12 (dd, 8.1, 3.9 Hz, 1H, 9-H), 4.27 (br dd, 12.0,
6.6 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.32–4.48 (m, 2H,
3-O–CH2CH@CH–Ar, 500-H), 4.40 (d, 7.8 Hz, 1H, 10-
H), 4.53 (d, 10.2 Hz, 1H, 400-H), 4.82 (br s, 1H, 100-H),
5.22 (m, 1H, 15-H), 5.64 (m, 1H, 13-H), 5.65 (dd, 14.9,
8.0 Hz, 1H, 10-H), 6.06 (br dd, 15.1, 10.4 Hz, 1H, 12-
H), 6.23 (dd, 14.9, 10.6 Hz, 1H, 11-H), 6.46 (dt, 7.8,
6.3 Hz, 1H, 3-O–CH2CH@CH–Ar), 6.76 (d, 8.0 Hz,
1H, 3-O–CH2CH@CH–Ar), 7.34–7.47 (m, 2H, naphtha-
lene), 7.61 (dd, 8.4, 1.5 Hz, 1H, naphthalene), 7.71 (br s,
1H, naphthalene), 7.77 (br d, 9.0 Hz, 1H, naphthalene),
7.77 (br d, 9.0 Hz, 1H, naphthalene), 7.77 (br d, 9.0 Hz,
1H, naphthalene), 9.78 (br s, 1H, 18-H); HRMS: Calcd
for C51H73NO14: 924.5109. Found: 924.5119.
½aꢀ ꢁ56° (c 0.60, CHCl3); FAB-MS m/z 904 (M+H)+;
1H NMR d 0.01 (d, 6.6 Hz, 3H, 19-H), 1.06 (d, 5.7 Hz,
3H, 60-H), 1.09 (s, 3H, 300-CH3), 1.09 (d, 6.1 Hz, 3H,
600-H), 1.16 (t, 7.6 Hz, 3H, 400-OCOCH2CH3), 1.25–
1.35 (m, 1H, 7-H), 1.28 (d, 6.3 Hz, 3H, 16-H), 1.73–
1.85 (m, 1H, 8-H), 1.75 (dd, 14.2, 3.7 Hz, 1H, 200-Hax),
1.86 (br d, 14.1 Hz, 1H, 200-Heq), 1.96–2.05 (m, 1H, 6-
H), 2.15 (dt, 14.4, 10.8 Hz, 1H, 14-H), 2.32–2.53 (m,
4H, 2-, 14-, 17-, 30-H), 2.35–2.48 (m, 2H, 400-
OCOCH2CH3), 2.46 (s, 6H, 30-N(CH3)2), 2.73 (dd,
16.2, 5.4 Hz, 1H, 2-H), 2.90 (dd, 6.6, 2.4 Hz, 1H, 4-H),
2.90 (dd, 16.0, 10.0 Hz, 1H, 17-H), 3.10 (dq, 9.3,
5.7 Hz, 1H, 50-H), 3.17 (t, 9.3 Hz, 1H, 40-H), 3.48 (s,
3H, 4-OCH3), 3.52 (dd, 9.9, 7.5 Hz, 1H, 20-H), 3.71
(br, 1H, 3-H), 3.74–3.83 (m, 1H, 5-H), 3.78 (s, 3H,
C6H4-OCH3), 4.12 (m, 1H, 9-H), 4.16 (br dd, 11.1,
7.2 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.31 (br dd, 11.1,
6.1 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.39 (d, 7.8 Hz,
1H, 10-H), 4.42 (dq, 9.9, 6.1 Hz, 1H, 500-H), 4.57 (d,
9.9 Hz, 1H, 400-H), 4.94 (d, 3.4 Hz, 1H, 100-H), 5.20 (m,
1H, 15-H), 5.63 (m, 1H, 13-H), 5.64 (dd, 14.7, 8.4 Hz,
1H, 10-H), 6.04 (br dd, 14.9, 10.1 Hz, 1H, 12-H), 6.17
(dt, 15.9, 6.4 Hz, 1H, 3-O–CH2CH@CH–Ar), 6.21 (dd,
14.7, 10.5 Hz, 1H, 11-H), 6.53 (d, 15.6 Hz, 1H, 3-O–
CH2CH@CH–Ar), 6.83 (d, 8.7 Hz, 2H, C6H4–OCH3),
7.30 (d, 8.7 Hz, 2H, C6H4–OCH3), 9.76 (br s, 1H, 18-
H); HRMS: Calcd for C48H73NO15: 904.5058. Found:
904.5052.
4.2.25. 3-O-[3-(4-Nitrophenyl)-2-propenyl]leucomycin A7
(9h). By a similar procedure to 9a, 7h (102 mg,
91.0 lmol) was deacetylated to give crude 8h, which
was deprotected to furnish 9h (48.5 mg, 58% in two
steps).
4.2.27. 3-O-[3-(4-Fluorophenyl)-2-propenyl]leucomycin
A7 (9j). By a similar procedure to 9a, 7j (113 mg,
103 lmol) was deacetylated to give crude 8j, which
was deprotected to furnish 9j (48.6 mg, 53% in two
steps).
23
½aꢀ ꢁ40° (c 0.48, CHCl3); FAB-MS m/z 919 (M+H)+;
D
1H NMR d 0.01 (d, 6.6 Hz, 3H, 19-H), 1.07 (d, 6.0 Hz,
3H, 60-H), 1.08 (s, 3H, 300-CH3), 1.09 (d, 6.3 Hz, 3H,
600-H), 1.15 (t, 7.5 Hz, 3H, 400-OCOCH2CH3), 1.28 (d,
6.3 Hz, 3H, 16-H), 1.30 (m, 1H, 7-H), 1.76–1.86 (m,
1H, 8-H), 1.77 (dd, 14.2, 3.7 Hz, 1H, 200-Hax), 1.86 (br
d, 14.2 Hz, 1H, 200-Heq), 2.00–2.14 (m, 1H, 6-H), 2.15
(dt, 14.0, 10.8 Hz, 1H, 14-H), 2.33–2.48 (m, 2H, 400-
OCOCH2CH3), 2.33–2.50 (m, 4H, 2-, 14-, 17-, 30-H),
2.46 (s, 6H, 30-N(CH3)2), 2.76 (dd, 16.2, 6.6 Hz, 1H, 2-
H), 2.93 (m, 1H, 17-H), 2.96 (dd, 7.5, 2.1 Hz, 1H, 4-
H), 3.11 (dq, 9.0, 6.0 Hz, 1H, 50-H), 3.19 (t, 9.3 Hz,
1H, 40-H), 3.48 (s, 3H, 4-OCH3), 3.52 (dd, 10.0,
7.2 Hz, 1H, 20-H), 3.71 (br, 1H, 3-H), 3.83 (br, 1H, 5-
H), 4.10 (dd, 8.3, 4.0 Hz, 1H, 9-H), 4.28–4.43 (m, 2H,
3-O–CH2CH@CH–Ar), 4.36 (d, 7.2 Hz, 1H, 10-H),
4.42 (dq, 10.2, 6.3 Hz, 1H, 500-H), 4.57 (d, 10.2 Hz, 1H,
400-H), 4.95 (d, 3.3 Hz, 1H, 100-H), 5.16 (m, 1H, 15-H),
5.61 (m, 1H, 13-H), 5.65 (dd, 15.0, 8.4 Hz, 1H, 10-H),
6.04 (br dd, 15.2, 10.5 Hz, 1H, 12-H), 6.21 (dd, 15.0,
10.6 Hz, 1H, 11-H), 6.53 (dt, 15.9, 5.7 Hz, 1H, 3-O–
CH2CH@CH–Ar), 6.68 (d, 16.1 Hz, 1H, 3-O–
CH2CH@CH–Ar), 7.50 (d, 9.0 Hz, 2H, C6H4–NO2),
8.15 (d, 9.3 Hz, 2H, C6H4–NO2), 9.74 (br s, 1H, 18-
H); HRMS: Calcd for C47H70N2O16: 919.4804. Found:
919.4819.
21
½aꢀ ꢁ58° (c 0.68, CHCl3); FAB-MS m/z 892 (M+H)+;
D
1H NMR d 0.00 (d, 6.9 Hz, 3H, 19-H), 1.03 (d, 6.0 Hz,
3H, 60-H), 1.08 (d, 6.0 Hz, 3H, 600-H), 1.09 (s, 3H, 300-
CH3), 1.15 (t, 7.5 Hz, 3H, 400-OCOCH2CH3), 1.24–1.35
(m, 1H, 7-H), 1.27 (d, 6.3 Hz, 3H, 16-H), 1.72–1.85
(m, 1H, 8-H), 1.76 (dd, 13.8, 3.7 Hz, 1H, 200-Hax), 1.84
(br d, 13.8 Hz, 1H, 200-Heq), 1.95–2.06 (m, 1H, 6-H),
2.14 (dt, 14.1, 10.9 Hz, 1H, 14-H), 2.34–2.48 (m, 2H,
400-OCOCH2CH3), 2.34–2.52 (m, 4H, 2-, 14-, 17-, 30-
H), 2.45 (s, 6H, 30-N(CH3)2), 2.73 (dd, 16.2, 5.7 Hz,
1H, 2-H), 2.90 (dd, 6.6, 2.7 Hz, 1H, 4-H), 2.90 (m, 1H,
17-H), 3.06 (dq, 9.3, 6.0 Hz, 1H, 50-H), 3.16 (t, 9.3 Hz,
1H, 40-H), 3.47 (s, 3H, 4-OCH3), 3.51 (dd, 10.5,
8.1 Hz, 1H, 20-H), 3.70 (br, 1H, 3-H), 3.79 (br, 1H, 5-
H), 4.11 (dd, 8.0, 3.9 Hz, 1H, 9-H), 4.18 (br dd, 11.1,
6.6 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.32 (br dd, 11.1,
5.7 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.37 (d, 7.8 Hz,
1H, 10-H), 4.42 (dq, 10.2, 6.0 Hz, 1H, 500-H), 4.57 (d,
10.2 Hz, 1H, 400-H), 4.93 (d, 3.3 Hz, 1H, 100-H), 5.19
(m, 1H, 15-H), 5.62 (m, 1H, 13-H), 5.64 (dd, 15.0,
7.8 Hz, 1H, 10-H), 6.04 (br dd, 15.0, 10.8 Hz, 1H, 12-
H), 6.21 (dd, 15.0, 10.6 Hz, 1H, 11-H), 6.23 (dt, 15.9,
6.1 Hz, 1H, 3-O–CH2CH@CH–Ar), 6.55 (d, 15.9 Hz,
1H, 3-O–CH2CH@CH–Ar), 6.98 (t, 8.7 Hz, 2H, C6H4-
F), 7.33 (dd, 8.7, 5.4 Hz, 2H, C6H4-F), 9.75 (br s, 1H,
18-H); HRMS: Calcd for C47H70FNO14: 892.4859.
Found: 892.4860.
4.2.26. 3-O-[3-(4-Methoxyphenyl)-2-propenyl]leucomycin
A7 (9i). By a similar procedure to 9a, 7i (112 mg,
101 lmol) was deacetylated to give crude 8i, which
was deprotected to furnish 9i (55.4 mg, 60% in two
steps).

4416
T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
4.2.28. 3-O-[3-(4-Trifluoromethylphenyl)-2-propenyl]leu-
comycin A7 (9k). By a similar procedure to 9a, 7k
(108 mg, 94.4 lmol) was deacetylated to give crude 8k,
which was deprotected to furnish 9k (58.3 mg, 66% in
two steps).
7.39 (br d, 7.8 Hz, 2H, C6H4–Ph), 7.45 (br d, 8.8 Hz,
2H, C6H4–Ph), 7.53–7.61 (m, 2H, C6H4–Ph), 7.55 (br
d, 9.0 Hz, 2H, C6H4–Ph), 9.78 (br s, 1H, 18-H); HRMS:
Calcd for C53H75NO14: 950.5266. Found: 950.5264.
4.2.30. 3-O-{3-[4-(1-Imidazolyl)phenyl]-2-propenyl}leuco-
mycin A7 (9m). By a similar procedure to 9a, 7m
(167 mg, 146 lmol) was deacetylated to give crude 8m,
which was deprotected to furnish 100 mg of 9m. A por-
tion of 9m (49.6 mg) was purified by preparative TLC to
afford 9m (39.9 mg, 56% in two steps).
21
D
½aꢀ ꢁ49° (c 0.55, CHCl3); FAB-MS m/z 942 (M+H)+;
1H NMR d 0.00 (d, 6.6 Hz, 3H, 19-H), 1.03 (d, 6.0 Hz,
3H, 60-H), 1.07 (s, Hz, 3H, 300-CH3), 1.08 (d, 6.0 Hz,
3H, 600-H), 1.15 (t, 7.6 Hz, 3H, 400-OCOCH2CH3),
1.25–1.36 (m, 1H, 7-H), 1.27 (d, 6.3 Hz, 3H, 16-H),
1.74–1.85 (m, 1H, 8-H), 1.75 (dd, 14.4, 3.9 Hz, 1H, 200-
Hax), 1.85 (br d, 14.4 Hz, 1H, 200-Heq), 1.97–2.09 (m,
1H, 6-H), 2.14 (dt, 14.1, 10.8 Hz, 1H, 14-H), 2.34–2.46
(m, 2H, 400-OCOCH2CH3), 2.34–2.51 (m, 4H, 2-, 14-,
17-, 30-H), 2.46 (s, 6H, 30-N(CH3)2), 2.74 (dd, 16.2,
6.0 Hz, 1H, 2-H), 2.91 (m, 1H, 17-H), 2.93 (dd, 6.9,
2.7 Hz, 1H, 4-H), 3.08 (dq, 9.6, 6.0 Hz, 1H, 50-H), 3.18
(t, 9.6 Hz, 1H, 40-H), 3.47 (s, 3H, 4-OCH3), 3.52 (dd,
10.3, 8.1 Hz, 1H, 20-H), 3.71 (br, 1H, 3-H), 3.80 (br,
1H, 5-H), 4.11 (dd, 8.1, 3.6 Hz, 1H, 9-H), 4.26 (br dd,
12.6, 6.3 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.36 (br dd,
12.6, 6.9 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.36 (d,
7.8 Hz, 1H, 10-H), 4.42 (dq, 10.2, 6.0 Hz, 1H, 500-H),
4.56 (d, 10.2 Hz, 1H, 400-H), 4.93 (d, 3.5 Hz, 1H, 100-
H), 5.17 (m, 1H, 15-H), 5.60 (m, 1H, 13-H), 5.64 (dd,
14.9, 8.1 Hz, 1H, 10-H), 6.04 (br dd, 15.0, 10.3 Hz,
1H, 12-H), 6.20 (dd, 15.1, 10.3 Hz, 1H, 11-H), 6.42
(dt, 15.9, 6.0 Hz, 1H, 3-O–CH2CH@CH–Ar), 6.62 (d,
15.9 Hz, 1H, 3-O–CH2CH@CH–Ar), 7.45 (d, 8.4 Hz,
2H, C6H4–CF3), 7.53 (d, 8.4 Hz, 2H, C6H4–CF3), 9.74
(br s, 1H, 18-H); HRMS: Calcd for C48H70F3NO14:
942.4827. Found: 942.4810.
23
½aꢀ ꢁ40° (c 0.50, CHCl3); FAB-MS m/z 940 (M+H)+;
D
1H NMR d 0.02 (d, 6.6 Hz, 3H, 19-H), 1.03 (s, 3H, 300-
CH3), 1.08 (d, 6.0 Hz, 3H, 600-H), 1.10 (d, 6.0 Hz, 3H,
60-H), 1.15 (t, 7.5 Hz, 3H, 400-OCOCH2CH3), 1.16–1.39
(m, 2H, 7-H), 1.28 (d, 6.3 Hz, 3H, 16-H), 1.72–1.84
(m, 1H, 8-H), 1.74 (dd, 14.2, 3.4 Hz, 1H, 200-Hax), 1.82
(br d, 14.2 Hz, 1H, 200-Heq), 1.96–2.10 (m, 1H, 6-H),
2.15 (dt, 14.4, 10.8 Hz, 1H, 14-H), 2.36–2.52 (m, 4H,
2-, 14-, 17-, 30-H), 2.37–2.48 (m, 2H, 400-OCOCH2CH3),
2.46 (s, 6H, 30-N(CH3)2), 2.76 (dd, 16.2, 6.3 Hz, 1H, 2-
H), 2.93 (dd, 18.0, 10.2 Hz, 1H, 17-H), 2.95 (dd, 6.5,
2.3 Hz, 1H, 4-H), 3.12 (dq, 9.6, 6.0 Hz, 1H, 50-H), 3.19
(t, 9.6 Hz, 1H, 40-H), 3.49 (s, 3H, 4-OCH3), 3.53 (dd,
9.6, 7.5 Hz, 1H, 20-H), 3.72 (br, Hz, 1H, 3-H), 3.83
(br, 1H, 5-H), 4.12 (dd, 8.1, 4.0 Hz, 1H, 9-H), 4.27 (br
dd, 12.3, 6.3 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.35 (br
dd, 12.3, 6.3 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.38 (d,
7.5 Hz, 1H, 10-H), 4.42 (dq, 9.6, 6.0 Hz, 1H, 500-H),
4.56 (d, 9.6 Hz, 1H, 400-H), 4.95 (d, 3.1 Hz, 1H, 100-H),
5.18 (m, 1H, 15-H), 5.62 (m, 1H, 13-H), 5.66 (dd, 15.0,
8.4 Hz, 1H, 10-H), 6.06 (br dd, 14.9, 10.1 Hz, 1H, 12-
H), 6.22 (dd, 15.0, 10.4 Hz, 1H, 11-H), 6.36 (dt, 15.9,
6.1 Hz, 1H, 3-O–CH2CH@CHAr), 6.62 (d, 15.9 Hz,
1H, 3-O–CH2CH@CH–Ar), 7.16 (br s, 1H, imidazole),
7.27 (br s, 1H, imidazole), 7.32 (d, 8.4 Hz, 2H, C6H4–
imidazole), 7.47 (d, 8.4 Hz, 2H, C6H4–imidazole), 7.85
(br s, 1H, imidazole), 9.76 (br s, 1H, 18-H); HRMS:
Calcd for C50H73N3O14: 940.5171. Found: 940.5185.
4.2.29. 3-O-[3-(4-Biphenylyl)-2-propenyl]leucomycin A7
(9l). By a similar procedure to 9a, 7l (162 mg, 141 lmol)
was deacetylated to give crude 8l, which was deprotected
to furnish 9l (74.6 mg, 59% in two steps).
20
½aꢀ ꢁ40° (c 0.52, CHCl3); FAB-MS m/z 950 (M+H)+;
D
1H NMR d 0.98 (s, 3H, 300-CH3), 1.02 (d, 6.9, Hz, 3H,
19-H), 1.06 (d, 6.0 Hz, 3H, 60-H), 1.08 (d, 6.0 Hz, 3H,
600-H), 1.15 (t, 7.6 Hz, 3H, 400-OCOCH2CH3), 1.24–
1.36 (m, 1H, 7-H), 1.29 (d, 6.3 Hz, 3H, 16-H), 1.60–
1.80 (m, 1H, 8-H), 1.66 (dd, 14.4, 3.9 Hz, 1H, 200-Hax),
1.77 (br d, 14.4 Hz, 1H, 200-Heq), 1.97–2.10 (m, 1H, 6-
H), 2.16 (dt, 14.1, 10.8 Hz, 1H, 14-H), 2.33–2.48 (m,
2H, 400-OCOCH2CH3), 2.33–2.55 (m, 4H, 2-, 14-, 17-,
30-H), 2.47 (s, 6H, 30-N(CH3)2), 2.76 (dd, 16.5, 5.4 Hz,
1H, 2-H), 2.94 (dd, 7.0, 2.0 Hz, 1H, 4-H), 2.94 (m, 1H,
17-H), 3.11 (dq, 9.3, 6.0 Hz, 1H, 50-H), 3.18 (t, 9.3 Hz,
1H, 40-H), 3.50 (s, 3H, 4-OCH3), 3.54 (dd, 10.0,
7.6 Hz, 1H, 20-H), 3.74 (br, 1H, 3-H), 3.83 (br, 1H, 5-
H), 4.14 (dd, 8.1, 3.2 Hz, 1H, 9-H), 4.24 (br dd, 12.3,
6.6 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.38 (br dd, 12.3,
5.8 Hz, 1H, 3-O–CH2CH@CH–Ar), 4.40 (d, 7.5 Hz,
1H, 10-H), 4.42 (dq, 10.2, 6.0 Hz, 1H, 500-H), 4.54 (d,
10.2 Hz, 1H, 400-H), 4.91 (d, 3.3 Hz, 1H, 100-H), 5.22
(m, 1H, 15-H), 5.65 (m, 1H, 13-H), 5.66 (dd, 14.7,
8.4 Hz, 1H, 10-H), 6.06 (br dd, 15.3, 10.5 Hz, 1H, 12-
H), 6.23 (dd, 15.0, 10.5 Hz, 1H, 11-H), 6.37 (dt, 15.9,
6.3 Hz, 1H, 3-O–CH2CH@CH–Ar), 6.63 (d, 15.9 Hz,
1H, 3-O–CH2CH@CH–Ar), 7.31 (m, 1H, C6H4-Ph),
4.2.31. 20-O-Acetyl-9,18-di-O-(tert-butyldimethylsilyl)-
300-O-(3-phenylpropionyl)leucomycin A7 3,18-acetal (11).
To a stirred solution of 10 (0.300 g, 0.292 mmol) and
tribenzylamine (0.516 g, 1.80 mmol) in 1 ml of 1,2-
dichloroethane, 3-phenylpropionyl chloride (0.125 ml,
0.841 mmol) was added and the reaction mixture was
stirred for 2 days at 75 °C. Saturated aqueous NaHCO3
solution was added to the reaction mixture and the
aqueous layer was extracted with CHCl3. The extract
was washed with 5% aqueous KHSO4 solution, satu-
rated aqueous NaHCO3 solution, and brine. After the
organic layer was dried and concentrated, the residue
was purified by silica gel chromatography [30 g, hex-
ane/EtOAc (5:1–4:1)] to give 11 (191 mg, 56%).
25
½aꢀ ꢁ32° (c 0.51, CHCl3); FAB-MS m/z 1160 (M+H)+;
D
1H NMR d 0.00 (s, 3H, SiCH3), 0.04 (s, 3H, SiCH3),
0.05 (s, 3H, SiCH3), 0.09 (s, 3H, SiCH3), 0.42 (br t,
12.7 Hz, 1H, 7-H), 0.88 (s, 9H, SiC(CH3)3), 0.92 (d,
7.6 Hz, 3H, 19-H), 0.94 (s, 9H, SiC(CH3)3), 1.09 (d,
6.0 Hz, 3H, 600-H), 1.19 (t, 7.6 Hz, 3H, 400-
OCOCH2CH3), 1.21 (d, 6.4 Hz, 3H, 60-H), 1.31 (d,

T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
4417
6.0 Hz, 3H, 16-H), 1.40 (s, 3H, 300-CH3), 1.45 (br d,
14.4 Hz, 1H, 17-H), 1.52 (m, 1H, 8-H), 1.59–1.69 (m,
1H, 17-H), 1.71 (dd, 14.8, 4.0 Hz, 1H, 200-Hax), 2.11 (s,
3H, 20-OCOCH3), 2.21 (dd, 13.2, 1.6 Hz, 1H, 2-H),
2.21 (m, 1H, 6-H), 2.28–2.46 (m, 3H, 7-, 14-H), 2.34–
2.44 (m, 2H, 400-OCOCH2CH3), 2.43 (s, 6H, 30-
N(CH3)2), 2.52–2.70 (m, 2H, 300-OCOCH2CH2Ph),
2.68 (t, 10.2 Hz, 1H, 30-H), 2.66–2.72 (m, 1H, 2-H),
2.92 (br s, 1H, 4-H), 2.93–2.99 (m, 2H, 300-
OCOCH2CH2Ph), 3.06–3.17 (m, 2H, 40-, 50-H), 3.23
(d, 14.8 Hz, 1H, 200-Heq), 3.28 (br d, 10.0 Hz, 1H, 5-
H), 3.34 (s, 3H, 4-OCH3), 4.13 (br d, 12.5 Hz, 1H, 3-
H), 4.19 (m, 1H, 9-H), 4.20 (d, 7.6 Hz, 1H, 10-H), 4.52
(m, 1H, 500-H), 4.53 (br d, 12.4 Hz, 1H, 18-H), 4.58 (d,
9.6 Hz, 1H, 400-H), 4.65 (m, 1H, 15-H), 4.83 (d, 4.0 Hz,
1H, 100-H), 5.07 (dd, 10.2, 7.8 Hz, 1H, 20-H), 5.47
(ddd, 15.2, 9.6, 5.8 Hz, 1H, 13-H), 5.93 (dd, 16.1,
8.6 Hz, 1H, 11-H), 5.96 (dd, 16.1, 5.6 Hz, 1H, 10-H),
6.31 (br dd, 15.0, 8.6 Hz, 1H, 12-H), 7.19–7.32 (m, 5H,
300-OCOCH2CH2Ph).
2.86 (br dd, 16.8, 9.6 Hz, 1H, 17-H), 2.92 (br t, 7.8 Hz,
2H, 300-OCOCH2CH2Ph), 3.08 (br d, 4.2 Hz, 1H, 4-H),
3.11 (dq, 9.4, 6.0 Hz, 1H, 50-H), 3.21 (t, 9.4 Hz, 1H,
40-H), 3.23 (d, 14.7 Hz, 1H, 200-Heq), 3.31 (dd, 10.0,
7.6 Hz, 1H, 20-H), 3.52 (s, 3H, 4-OCH3), 3.79 (br d,
10.8 Hz, 1H, 3-H), 4.07–4.13 (m, 1H, 5-H), 4.11 (br
dd, 9.6, 4.0 Hz, 1H, 9-H), 4.47 (dq, 9.6, 6.2 Hz, 1H,
500-H), 4.49 (d, 7.6 Hz, 1H, 10-H), 4.58 (d, 9.6 Hz, 1H,
400-H), 4.86 (d, 4.4 Hz, 1H, 100-H), 5.29 (m, 1H, 15-H),
5.62 (ddd, 15.2, 11.2, 4.4 Hz, 1H, 13-H), 5.68 (dd,
15.0, 9.6 Hz, 1H, 10-H), 6.03 (br dd, 15.2, 10.4 Hz,
1H, 12-H), 6.27 (dd, 15.0, 10.6 Hz, 1H, 11-H), 7.18–
7.31 (m, 5H, 300-OCOCH2CH2Ph), 9.80 (s, 1H, 18-H);
HRMS: Calcd for C47H71NO15: 890.4902, Found:
890.4910.
Acknowledgments
We wish to thank Dr. H. Fushimi and Mrs. M. Tabata
for biological studies, and Drs. S. Hoshiko, H. Watabe,
Y. Otsuka, T. Okonogi, K. Atsumi and S. Gomi for
valuable scientific discussion. We are also grateful to
Dr. N. Aman and Mr. A. Shimizu for providing LM-
A7, and Mrs. Takagi for the manuscript.
4.2.32. 300-O-(3-Phenylpropionyl)leucomycin A7 (12). A
solution of 11 (215 mg, 0.185 mmol) in 12 ml of
MeOH/H2O (10:1) was stirred overnight at 45 °C. The
reaction mixture was concentrated and the residue was
purified by silica gel chromatography [20 g, hexane/
EtOAc (5:1)] to give 9,18-di-O-(tert-butyldimethylsilyl)-
300-O-(3-phenylpropionyl)leucomycin A7 3,18-acetal
(162 mg, 78%).
References and notes
1. Morimoto, S.; Takahashi, Y.; Watanabe, Y.; Omura, S.
J. Antibiot. 1984, 37, 187–189.
To a stirred solution of this compound (89.5 mg,
80.0 lmol) in 1.5 ml of THF, 0.1 M solution of TBAF
(1.60 ml, 160 lmol) was added and the reaction mixture
was stirred for 15 min at room temperature. Five
percentage aqueous KHSO4 solution was added to the
reaction mixture and the aqueous layer was extracted
with CHCl3. After the extract was washed with brine,
the organic layer was dried and concentrated to give
crude 9-O-(tert-butyldimethylsilyl)-300-O-(3-phenylpro-
pionyl)leucomycin A7.
2. Watanabe, Y.; Adachi, T.; Asaka, T.; Kashimura, M.;
Morimoto, S. Heterocycles 1990, 31, 2121–2124.
3. Morimoto, S.; Nagate, T.; Sugita, K.; Ono, T.; Numata,
K.; Miyachi, J.; Misawa, Y.; Yamada, K.; Omura, S.
J. Antibiot. 1990, 43, 295–305.
4. Kohno, Y.; Yoshida, H.; Suwa, T.; Suga, T. Antimicrob.
Agents Chemother. 1989, 33, 751–756.
5. Adachi, T.; Morimoto, S.; Kondoh, H.; Nagate, T.;
Watanabe, Y.; Sota, K. J. Antibiot. 1988, 41, 966–975.
´
6. Djokic, S.; Kobrehel, G.; Lazarevski, G.; Lopotar, N.;
Tamburasev, Z. J. Chem. Soc. Perkin Trans. I 1986, 1881–
ˇ
To a stirred solution of this crude product in 26 ml of
MeCN/H2O (1:1), difluoroacetic acid (25.0 ll, 397 lmol)
was added and the reaction mixture was stirred over-
night at room temperature. Saturated NaHCO3 solution
was added and the aqueous layer was extracted with
CHCl3. The extract was washed with brine, dried, and
concentrated. The residue was purified by preparative
TLC [CHCl3/MeOH/NH4OH (100:10:1)] to afford 12
(58.1 mg, 82%).
1890.
7. Bright, G. M.; Nagel, A. A.; Bordner, J.; Desai, K. A.;
Dibrino, J. N.; Nowakowska, J.; Vincent, 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,
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1988, 41, 1029–1047.
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Mason, R. Antimicrob. Agents Chemother. 1987, 31, 1939–
1947.
25
½aꢀ ꢁ58° (c 0.50, CHCl3); FAB-MS m/z 890 (M+H)+;
D
1H NMR d 0.92 (m, 1H, 7-H), 0.99 (d, 6.4 Hz, 3H, 19-
H), 1.08 (d, 6.2 Hz, 3H, 600-H), 1.15 (d, 6.0 Hz, 3H, 60-
H), 1.17 (t, 7.6 Hz, 3H, 400-OCOCH2CH3), 1.31 (d,
6.4 Hz, 3H, 16-H), 1.38 (s, 3H, 300-CH3), 1.55 (br dt,
2.4, 13.3, Hz, 1H, 7-H), 1.71 (dd, 14.7, 4.4 Hz, 1H, 200-
Hax), 1.91 (m, 1H, 8-H), 2.12 (dt, 13.2, 11.2 Hz, 1H,
14-H), 2.23 (br d, 14.8 Hz, 1H, 2-H), 2.25–2.42 (m,
2H, 6-, 17-H), 2.33 (t, 9.8 Hz, 1H, 30-H), 2.39 (q,
7.6 Hz, 2H, 400-OCOCH2CH3), 2.48–2.56 (m, 1H, 14-
H), 2.52 (s, 6H, 30-N(CH3)2), 2.54–2.68 (m, 2H, 300-
OCOCH2CH2Ph), 2.70 (dd, 14.8, 10.8 Hz, 1H, 2-H),
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, 44, 3075–3080.
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Y. L.; Wang, Y.; Busuyek, M.; Hou, Y.; Peng, Y.; Kim,
H.; Liu, T.; Farmer, J.J.; Xu, G. WO 03/097659, 2003.
11. Omoto, S.; Iwamatsu, K.; Inouye, S.; Niida, T. J. Antibiot.
1976, 29, 536–548.
12. Kawaharajo, K.; Sekizawa, Y.; Inoue, M. J. Antibiot.
1981, 34, 436–442.

4418
T. Furuuchi et al. / Bioorg. Med. Chem. 16 (2008) 4401–4418
13. Sakakibara, H.; Okekawa, O.; Fujiwara, T.; Otani, M.;
Omura, S. J. Antibiot. 1981, 34, 1001–1010.
14. Sakakibara, H.; Okekawa, O.; Fujiwara, T.; Aizawa, M.;
Omura, S. J. Antibiot. 1981, 34, 1011–1018.
19. Unpublished communication from Dr. Takenuki.
20. Sinou, D.; Lakhmiri, R.; Lhoste, P. Tetrahedron Lett.
1989, 30, 4669–4672.
21. Herrmann, W. A.; Brossmer, C.; Reisinger, C. P.; Rier-
¨
meier, T. H.; Ofele, K.; Beller, M. Chem. Eur. J. 1997, 3,
1357–1364.
15. Furuuchi, T.; Kurihara, K.; Yoshida, T.; Ajito, K.
J. Antibiot. 2003, 56, 399–414.
16. Or, Y. S.; Clark, R. F.; Wang, S.; Chu, D. T. W.; Nilius,
A. M.; Flamm, R. K.; Mitten, M.; Ewing, P.; Alder, J.;
Ma, Z. J. Med. Chem. 2000, 43, 1045–1049.
22. Kurihara, K.; Ajito, K.; Shibahara, S.; Hara, O.;
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17. 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. W.; Plattner, J. J.; Zhang, X.;
Zhong, P.; Cao, Z.; Nilius, A. M.; Shortridge, V. D.;
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18. Jeffery, T. Synthesis 1987, 70–71.
23. Molecular modeling software, Quanta/CHARMm (Accel-
rys Software Inc.) was used for our studies. Initial
structures and conformations of 4, 9a, and 12 were
constructed by referring the X-ray single crystallographic
data of RKM.19 Systematic search was carried out on the
torsional angles of the side chains at the C-3 and/or C-300
positions for conformational analyses.