Design and synthesis via click chemistry of 8,9-anhydroerythromycin A 6,9-hemiketal analogues with anti-MRSA and -VRE activity

Article abstract of DOI:10.1016/j.bmcl.2007.08.068

An erythromycin analogue, 11,12-di-O-iso-butyryl-8,9-anhydroerythromycin A 6,9-hemiketal (1b), was found to be a potential anti-MRSA and anti-VRE agent. The use of copper catalyzed azide-acetylene cycloaddition, and click chemistry, readily provided 10 ty

Full text of DOI:10.1016/j.bmcl.2007.08.068

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 17 (2007) 6340–6344
Design and synthesis via click chemistry
of 8,9-anhydroerythromycin A 6,9-hemiketal analogues
with anti-MRSA and -VRE activity
Akihiro Sugawara,a Toshiaki Sunazuka,a Tomoyasu Hirose,a Kenichiro Nagai,a
a
a
b
a,
*
ꢀ
Yukie Yamaguchi, Hideaki Hanaki, K. Barry Sharpless and Satoshi Omura
aThe Kitasato Institute, and Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences,
Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
bThe Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
BCC-315, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Received 23 June 2007; revised 27 August 2007; accepted 29 August 2007
Available online 1 September 2007
Abstract—An erythromycin analogue, 11,12-di-O-iso-butyryl-8,9-anhydroerythromycin A 6,9-hemiketal (1b), was found to be a
potential anti-MRSA and anti-VRE agent. The use of copper catalyzed azide–acetylene cycloaddition, and click chemistry, readily
provided 10 types of triazole analogues of 1b in good to nearly quantitative yield. Among the library, 5b exhibited activity against
MRSA and VRE bacterial strains, representing more than twice the potency of 1b.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Although macrolides, including erythromycin
A
(MIC) against four types of MRSA strains and two
types of VRE strains.
(EMA), have been widely prescribed for more than 50
years,1 the emergence of widespread bacterial resistance
is a serious and expanding problem.2 There is a great
medical need for new macrolide antibiotics to specifi-
cally cope with the problems of antibiotic resistant,
against not only erythromycin-resistant Streptococcus
pneumoniae (ERSP) but also methicillin-resistant Staph-
ylococcus aureus (MRSA) and vancomycin-resistant
Enterococcus (VRE) strains of bacteria. More recently,
third generation macrolides, such as telithromycin,3
have been developed as effective means to overcome
resistant strains. Despite tremendous efforts, however,
only a few macrolide candidates with activity against
MRSA have been identified to date.4 Consequently,
we have re-examined various derivatives of EMA, which
have been previously synthesized at The Kitasato Insti-
tute, evaluating them against 12 types of Gram-positive
bacteria, including macrolide-resistant strains, and one
Gram-negative organism.5 We found that 11,12-di-O-
butyryl-8,9-anhydroerythromycin A 6,9-hemiketal (1a)6
showed moderate minimum inhibitory concentration
We envisioned that 11,12-di-O-acyl groups are essential
for anti-MRSA and -VRE activity. We thus began our
investigations by looking into several 11,12-di-O-acyl-
8,9-anhydroerythromycin A 6,9-hemiketal derivatives
to elucidate the structure–activity relationships against
anti-MRSA and -VRE strains. After screening various
diacyl compounds, 11,12-di-O-iso-butyryl-8,9-anhydro-
erythromycin A 6,9-hemiketal (1b)7 was found to be a
potential agent against MRSA and VRE strains (Fig. 1).
To obtain more potent derivatives, we decided to syn-
thesize new 8,9-anhydroerythromycin A 6,9-hemiketal
O
9
N
N
9
HO
3'
HO
HO
O
RO
RO
O
HO
HO
O
O
O
O
6
6
11
12
O
O
O
O
O
O
OH
OH
O
O
O
Erythromycin A (EMA)
1a : R = butyryl
1b : R = isobutyryl
Keywords: Erythromycin A; Macrolides; Click chemistry; Anti-MRSA
and -VRE agent.
*
Figure 1. Structures of erythromycin A, 1a, and 1b.
Corresponding author. E-mail: omura-s@kitasato.or.jp
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.08.068

A. Sugawara et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6340–6344
6341
Table 1. Minimum inhibitory concentrations (MICs) value of EMA
and 1b, and 2–4
derivatives by using a copper catalyzed azide–alkyne
cyclization reaction,8 which is one of the most reliable
methodologies for ideal ‘click chemistry’. The methodol-
ogy of click chemistry has found applications in drug
discovery, bioconjugations, and materials science.9 Since
EMA and its derivatives have many reactive functional
groups, containing four kinds of hydroxy groups at
the 11, 12, 20, 400 positions and 30-dimethyl amino group
on desosamine, click chemistry application would easily
introduce a specific triazole group without the need for
any protection and deprotection procedures to synthe-
size a triazole derivative. Thus we replaced the cladinose
moiety on the C3 hydroxy with a –CH2–C„CH group,
to enable a fast SAR in this sector using click chemistry.
This was done because the cladinose of EMA is not
essential for its anti-bacterial activity10 but also because
this moiety induces macrolide-drug resistance. We here-
in report a quick and simple route for the preparation of
3-O-alkyl derivatives from one common alkyne precur-
sor 4, with 10 kinds of azide blocks, together with their
anti-bacterial activities.
Strain/compound
MICs (lg/mL)
EMA 1b
2
3
4
S. aureus FDA209Pa
S. aureus Smitha
60.5 16
60.5 16
>256 16
16
16
16
16
16
NTj
16
16
32
16
32
32
64 32
>128 32
MRSA N315 IR94b
64
64
16
16
16
16
32
16
32
16
16
16
MRSA N315 IR94 HR-1b >256 16
MRSA 70b
>256 32
>128 32
>256 32
>256 16
64
64
MRSA 92-1191b
S. aureus ISP447c
S. aureus ISP217d
128
64
S. aureus 8325 (pEP2104)e 64
32
128
64
S. aureus 8325 (pMS97)f
E. faecalis NCTC12201g
E. faecium NCTC12203h
E. coli NIHJ JC-2i
>256 16
>256 64
>256 32
64
64
>256 >128 >128 >128 >128
NT, not tested.
a Staphylococcus aureus FDA209P and Smith: susceptible strains.
b S. aureus MRSA N315 IR94, MRSA N315 IR94 HR-1, MRSA 70,
and MRSA 92-1191: MRSA strains isolated from clinical patients.
c S. aureus ISP447: inducibly resistant strain.
d S. aureus ISP217: constitutively resistant strain.
e S. aureus 8325 (pEP2104): encoded by erm gene.
We designed 3-de-O-cladinosyl-11,12-di-O-iso-butyryl-
3-O-propargyl-8,9-anhydroerythromycin A 6,9-hemike-
tal (4) as a precursor of a 1,2,3-triazole reaction in the
presence of copper (I), and synthesis of 4 is outlined in
Scheme 1. Treatment of EMA with acetic acid provided
the 8,9-anhydroerythromycin A 6,9-hemiketal in 73%
yield by using the known procedure,11 followed by selec-
tive protection at 20, 400-hydroxy groups with acetic
anhydride12 and acetic formic anhydride,13 respectively,
in 86% yield for 2 steps. O-Diacylation at the 11,12-hy-
droxy groups afforded the required diacylated product
(2) in quantitative yield. Removal of cladinose with
10-camphorsulfonic acid in MeOH at room temperature
f S. aureus 8325 (pMS97): encoded by erm and mef gene.
g Enterococcus faecalis NCTC12201: encoded by van A gene.
h E. faecium NCTC12203: encoded by van A gene.
i E. coli NIHJ JC-2: susceptible Gram-negative strain.
gave decladinosyl (3) in 97% yield. Finally, to synthesize
the triazole reaction precursor (4), O-alkylation at the 3-
hydroxy group with propargyl bromide in the presence
of sodium hydride without N-alkylated product, fol-
lowed by methanolysis, furnished 4 in 72% yield for 2
steps.
O
9
O
2'
N
N
9
AcO
HO
a, b, c, d
O
O
O
O
HO
HO
O
O
O
O
6
HO
6
11
12
O
O
O
O
O
O
O
O
OH
O
H
O
O
4"
O
EMA
2
e
O
O
2'
N
N
AcO
HO
O
O
f, g
O
O
O
O
O
O
O
3
O
3
OH
O
O
O
O
O
O
O
3
4
Scheme 1. Synthesis of 4 as a precursor of click reaction. Reagents and conditions: (a) acetic acid, rt, 0.5 h, 73%; (b) acetic anhydride, acetone, rt, 1 h;
(c) aceticformic anhydride, pyridine, 4-dimethylaminopyridine, THF, 0 ꢁC, 1 h, 86% (for 2 steps); (d) iso-butyric anhydride, 4-dimethylaminopyridine
(excess), pyridine, rt, 48 h, quant; (e) 10-camphorsulfonic acid, MeOH, rt, 6 h, 97%; (f) propargyl bromide, NaH, THF, rt, 3.5 h, 72%; (g) MeOH,
50 ꢁC, 12 h, quant.

6342
A. Sugawara et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6340–6344
Table 2. Copper-catalyzed 1,2,3-triazole formation
R-N3
Cu(0)turning
CuSO4
O
O
N
N
HO
HO
N
t
-BuOH/H2O
O
O
O
O
O
O
O
O
N
(1/1), rt
O
O
O
O
O
O
O
O
R
O
O
N
4
5a-j
Compound
R
Time
Yieldsa
92%
5a
1 d
5b
5c
5d
5e
5f
1.5 d
1 d
97%
S
N
quant.
quant.
quant.
quant.
17 h
2.5 d
2.5 d
N
5g
5h
1.5 d
1.5 d
85%
96%
HO
HOOC
N
H
N
5i
12 h
1 d
92%
90%
O
5j
BnOOC
a Isolated yield.
We subsequently evaluated the anti-bacterial activity of
1b and 2–4 against twelve Gram-positive strains (S. aur-
eus FDA209P; S. aureus MRSA N315 IR94, MRSA
N315 IR94 HR-1, MRSA 70, and MRSA 92-1191; S.
aureus ISP447; S. aureus ISP217; S. aureus 8325
(pEP2104); S. aureus 8325 (pMS97); E. faecalis
NCTC12201; E. faecium NCTC12203) and one Gram-
negative (E. coli NIHJ JC-2) strain using standard seri-
al-dilution techniques5 (Table 1). The 20, 400-protected
product (2) showed similar activity compared with 1b.
In contrast, the alcohol (3) exhibited 2- to 4-fold less
activity against MRSA and VRE strains than the lead
derivative (1b). Interestingly, the propargyl compound
(4) possessed better anti-bacterial activity than 3, sug-
gesting that the propargyl group and/or its derivatives
could be substituted instead of cladinose without
decreasing either anti-MRSA or anti-VRE activity.
tions in good-to-quantitative yield without 1,5-disubsti-
tuted triazole products14 (Table 2). This result also
suggested that click chemistry methodology allowed
apparently useful selective reactions for EMA, including
many reactive functional groups, without difficulties.
As a consequence, 10 kinds of triazole compounds were
efficiently prepared for in vitro anti-bacterial testing (vide
ante), using standard serial-dilution techniques5 (Table
3). Although EMA demonstrates no activity against clin-
ically isolated MRSA strains and VRE strains (MICs
>256 lg/mL, Table 3), di-iso-butyryl 4 is slightly effective
against MRSA and VRE strains (MICs 16 lg/mL, Table
2). Notably, the adamantyl-triazole derivative (5b)
showed 2-fold greater activity against MRSA and VRE
strains (MICs 8 lg/mL, Table 3) than the lead derivative
(1b) and 4. In contrast, hydrophilic triazole derivatives
(5g and 5h) show no activity (Table 3).
The acetylene compound, 4, was readily converted to
the 1,4-disubstituted triazole products 5a–j with 10 azide
compounds in the presence of copper catalyzed condi-
In conclusion, we found that the propargyl (4) and some
triazole groups (5a–5f, 5i–j) can be substituted instead of

A. Sugawara et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6340–6344
Table 3. Minimum inhibitory concentrations (MICs) value of EMA and analogues
6343
Strain/compound
MICs (lg/mL)
EMA
1b
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
S. aureus FDA209Pa
S. aureus Smitha
60.5
60.5
>256
>256
>256
>128
>256
>256
64
16
16
16
16
32
32
32
16
32
16
64
32
>128
16
32
8
8
16
32
8
16
32
8
32
64
32
64
16
16
16
32
32
16
64
16
32
16
>128
64
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
>128
32
32
32
16
8
>128
64
64
128
16
MRSA N315 IR94b
MRSA N315 IR94 HR-1b
MRSA 70b
16
16
16
16
8
8
8
16
16
16
32
16
32
8
16
16
16
16
16
16
16
8
8
16
16
16
16
16
16
16
16
>128
16
32
64
32
32
MRSA 92–1191b
8
128
>128
128
128
64
32
64
S. aureus ISP447c
16
8
64
16
32
16
S. aureus ISP217d
16
64
S. aureus 8325 (pEP2104)e
S. aureus 8325 (pMS97)f
E. faecalis NCTC12201g
E. faecium NCTC12203h
E. coli NIHJ JC-2i
16
8
128
16
32
16
>256
>256
>256
>256
16
32
16
16
>128
8
32
16
>128
32
16
128
64
>128
32
>128
8
>128
32
>128
>128
>128
a Staphylococcus aureus FDA209P and Smith: susceptible strains.
b S. aureus MRSA N315 IR94, MRSA N315 IR94 HR-1, MRSA 70, and MRSA 92-1191: MRSA strains isolated from clinical patients.
c S. aureus ISP447: inducibly resistant strain.
d S. aureus ISP217: constitutively resistant strain.
e S. aureus 8325 (pEP2104): encoded by erm gene.
f S. aureus 8325 (pMS97): encoded by erm and mef gene.
g Enterococcus faecalis NCTC12201: encoded by van A gene.
h E. faecium NCTC12203: encoded by van A gene.
i E. coli NIHJ JC-2: susceptible Gram-negative strain.
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.
cladinose, to produce anti-MRSA and anti-VRE activ-
ity. Moreover, the use of copper catalyzed azide–acety-
lene cycloaddition efficiently provided various triazole
libraries with azide compounds, avoiding complicated
production mechanisms. Additionally, one of 10 kinds
of triazole compounds, the adamantyl-triazole product
5b, was produced as a potential lead of new antibiotic
for use against MRSA and VRE strains, using click
methodology. We believe this click methodology could
be widely applied in the preparation of complicated nat-
ural-product analogues. Further in vitro and in vivo
studies on these erythromycin analogues are in progress.
4. (a) Misawa, Y.; Asaka, T.; Kashimura, M.; Morimoto, S.;
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ꢀ
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Acknowledgments
7. Mp 219–222 ꢁC, 1H NMR (600 MHz, CDCl3), d (ppm):
5.30 (d, J = 9.4 Hz, 1H), 4.89 (d, J = 4.7 Hz, 1H), 4.77 (m,
1H), 4.42 (d, J = 7.2 Hz, 1H), 4.39 (bs, 1H), 4.03 (dq,
J = 15.4, 12.7, 6.3 Hz 1H), 3.96 (d, J = 8.0 Hz, 1H), 3.59
(m, 1H), 3.52 (m, 1H), 3.23 (s, 3H), 3.21 (dd, J = 9.9,
7.4 Hz, 1H), 3.05 (appear, t, J = 9.6 Hz, 1H), 2.70 (d,
J = 16.0 Hz, 1H), 2.68 (m, 1H), 2.56–2.44 (complex
mixture, 3H), 2.37 (d, J = 15.4 Hz, 1H), 2.30 (s, 6H),
2.14 (d, J = 10.5 Hz, 1H), 2.05 (appear, t, J = 6.1 Hz, 1H),
1.91 (d, J = 15.4 Hz, 1H), 1.78 (m, 1H), 1.69 (bd,
J = 11.8 Hz, 1H), 1.62 (d, J = 5.0 Hz, 1H), 1.60 (s, 3H),
1.49 (s, 3H), 1.46 (m, 1H), 1.33 (s, 3H), 1.28 (d, J = 6.3 Hz,
3H), 1.23–1.22 (complex mixture, 4H), 1.17 (d, J = 7.2 Hz,
3H), 1.15–1.13 (complex mixture, 15H), 1.10 (d,
J = 7.4 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H), 0.89 (t,
J = 7.4 Hz, 3H), 13C NMR (150 MHz, CDCl3), d (ppm):
175.4, 175.2, 174.6, 151.0, 103.2, 102.3, 95.8, 86.6, 85.5,
80.4, 78.2, 76.8, 76.2, 73.1, 70.9, 70.5, 68.8, 65.8, 65.3, 49.4,
44.0, 42.9, 42.6, 40.3 (C · 2), 35.0, 34.7, 34.3, 32.0, 29.0,
25.8, 23.1, 21.7, 21.2, 19.2 (C · 2), 19.0, 18.8, 18.1, 15.8,
14.3, 13.5, 12.0, 11.4, 8.9, HR-MS (FAB) (matrix; m-
NBA, PEG600+NaI), m/z: 856.5432 [M+H]+, calcd for
C45H78NO14: 856.5422 [M+H].
This work was supported by a grant from the 21st Cen-
tury COE Program, Ministry of Education, Culture,
Sports, Science and Technology. We also thank Ms.
A. Nakagawa, Ms. C. Sakabe, and Ms. N. Sato for
the various instrumental analysis.
References and notes
ꢀ
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6344
A. Sugawara et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6340–6344
Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem.
0.013 mmol) were suspended in a 1:1 mixture of water and
t-BuOH (1.3 mL). To this mixture were added copper
turning and copper sulfate solution (0.0013 mmol). The
mixture was stirred at room temperature for 1.5 days.
After completion of the reaction, the copper turning was
removed and the mixture was extracted with CHCl3
(10 mL ·1), then the organic layer washed with satd NaCl
aq solution (5 mL ·1), dried over Na2SO4, and concen-
trated. Flash chromatography (CHCl3:MeOH:30% aq
NH4OH = 50:1:0.1) afforded 5b in 97% yield as a white
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1
amorphous. H NMR (600 MHz, CDCl3) d (ppm): 8.21
(s, 1H), 5.43 (d, J = 8.8 Hz, 1H), 5.22 (d, J = 12.1 Hz, 1H),
4.73 (d, J = 12.7 Hz, 1H), 4.69 (m, 1H), 4.18 (d,
J = 6.3 Hz, 1H), 3.99 (s, 1H), 3.90 (bs, 1H), 3.43–3.41
(complex mixture, m, 2H), 3.17 (dd, J = 9.9, 7.2 Hz, 1H),
2.88–2.84 (complex mixture, m, 2H), 2.56–246 (complex
mixture, m, 5H), 2.25–2.24 (complex mixture, m, 9H), 2.17
(bs, 3H), 2.06 (d, J = 15.7 Hz, 1H), 1.85 (m, 1H), 1.76–1.70
(complex mixture, m, 6H), 1.65–1.59 (complex mixture, m,
4H), 1.52 (s, 3H), 1.43 (m, 1H), 1.34–1.33 (d, J = 6.9 Hz,
1H), 1.18–1.16 (complex mixture, m, 15H), 1.14 (d,
J = 7.2 Hz, 1H), 1.08 (d, J = 6.1 Hz, 1H), 1.10 (d,
J = 7.2 Hz, 1H), 0.94–0.91 (complex mixture, m, 6H),
13C NMR (150 MHz, CDCl3) d (ppm): 175.4, 174.9, 171.7,
150.1, 145.9, 120.5, 105.3, 102.5, 89.7, 85.5, 83.6, 80.3,
76.8, 71.0, 70.5, 69.6, 65.8, 58.9, 43.0, 42.8 (C · 3), 42.0,
40.3 (C · 2), 36.0 (C · 3), 35.8, 34.9, 34.2, 31.8, 29.5
(C · 3), 28.3, 28.2, 23.9, 21.1, 19.3 (C · 2), 49.2, 19.0, 18.6,
16.9, 15.0, 14.3, 12.3, 11.8, HR-MS (FAB) (matrix;
m-NBA, PEG600+NaI) m/z: 913.5941 [M+H]+, calcd for
C50H81N4O11: 913.5902 [M+H].
ꢀ
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14. Typical experimental procedure; 3-O-[(1-adamantyl)-
1,2,3-triazol-4-yl]methyl-3-de-O-cladinosyl-11,12-di-O-iso-
butyryl 8,9-anhydroerythromycin A 6,9-hemiketal (5b); 4
(9.8 mg, 0.013 mmol) and 1-azidoadamantane (2.4 mg,