Synthesis of novel 6,11-o-bridged bicyclic ketolides via a palladium-catalyzed bis-allylation

Article abstract of DOI:10.1021/ol048336r

(Chemical equation presented) A bridging chemistry process was developed to form an ether bridge between 6-O and 11-O of erythromycin A via a tandem or stepwise palladium-catalyzed bis-π-allylation. By applying this bridging process, new 6,11-O-bridged bicyclic ketolides (BBKs) were synthesized. These BBKs showed good antibacterial activities against the macrolide-susceptible strains as well as mef-resistant strains and served as a good core for further modifications to study the structure-activity relationship (SAR) and to overcome bacterial resistance.

Full text of DOI:10.1021/ol048336r

ORGANIC
LETTERS
2
004
Vol. 6, No. 24
455-4458
Synthesis of Novel 6,11-O-Bridged
Bicyclic Ketolides via a
4
Palladium-Catalyzed Bis-allylation
Guoqiang Wang,* Deqiang Niu, Yao-Ling Qiu, Ly Tam Phan, Zhigang Chen,
Alexander Polemeropoulos, and Yat Sun Or
Enanta Pharmaceuticals, Inc., 500 Arsenal Street, Watertown, Massachusetts 02472
wang@enanta.com
Received August 20, 2004
ABSTRACT
A bridging chemistry process was developed to form an ether bridge between 6-O and 11-O of erythromycin A via a tandem or stepwise
palladium-catalyzed bis- -allylation. By applying this bridging process, new 6,11-O-bridged bicyclic ketolides (BBKs) were synthesized. These
BBKs showed good antibacterial activities against the macrolide-susceptible strains as well as mef-resistant strains and served as a good
core for further modifications to study the structure activity relationship (SAR) and to overcome bacterial resistance.
π
−
Macrolide antibiotics have been used effectively and safely
for the treatment of respiratory tract infections for more than
1
5
0 years. However, bacterial resistance to macrolide anti-
biotics has become increasingly prevalent over the past
2
decade. There have been significant synthetic efforts to
3
discover new core structures to address this challenge. In
1
995, a novel series of macrolides was introduced. These
compounds, known as ketolides, possess a 3-keto and an
1,12-carbamate functionalities and show excellent activities
1
4
against major macrolide-resistant organisms. In addition, the
two most prominent ketolides, cethromycin (ABT-773) and
telithromycin (Figure 1), also have aromatic groups tethered
5
6
(
1) For recent reviews, see: (a) Zhanel, G. G.; Dueck, M.; Hoban, D.
J.; Vercaigne, L. M.; Embil, J. M.; Gin, A. S.; Karlowsky, J. A. Drugs
001, 61, 443-498. (b) Ma, Z.; Nemoto, P. Curr. Med. Chem.-Anti-Infect.
Agents 2002, 1, 15-34.
2) Doern, G. V.; Heilmann, K. P.; Huynh, H. K.; Rhomberg, P. R.;
Coffman, S. L.; Brueggemann, A. B. Antimicrob. Agents Chemother. 2001,
5, 1721-1729.
3) (a) Chu, D. T. W. Recent Developments in 14- and 15-Membered
Figure 1. Structures of cethromycin and telithromycin.
2
(
to the macrolide cores. The 3-keto group is believed to be
important for the improved activities against inducible and
efflux resistant organisms due to the absence of the cladinose
4
(
7
Macrolides. Expert Opin. InVest. Drugs 1995, 4, 65-94. (b) Chu, D. T. W.
Recent Developments in Macrolides and Ketolides. Curr. Opin. Microbiol.
999, 2, 467-474. (c) Bryskier, A. New Research in Macrolides and
Ketolides since 1997. Expert Opin. InVest. Drugs 1999, 8, 1171-1194.
sugar. The 11,12-carbamate group is essential for overall
antibacterial activities by increasing the rigidity of the
1
8
ketolide conformation. And the additional interaction of the
1
0.1021/ol048336r CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/26/2004

tethered aryl group with the bacterial ribosome is responsible
for the enhanced activities against the constitutively mac-
rolide-resistant organisms harboring the erm genes.
DMAP. The treatment of the resulting 9,2′,4′′-triacetate 2
with reagent 3a in the presence of Pd (dba) (2 mol %) and
2
3
dppb (4 mol %) in refluxing THF smotthly facilitated a
tandem dialkylation at the 6,11-hydroxyl groups to provide
We focused on the synthesis of 6,11-O-bridged bicyclic
9
12
ketolides, reasoning that this bridge will improve the stability
the 6,11-O-bridged macrolide 4a in 85% yield. Further
of the parent compound by preventing intramolecular hemi-
study on the scope of this bridging process showed that a
trisubstituted olefin can also be used as the dielectrophile.
For example, by reacting compound 2 with 3b, 4b (E/Z
∼1/1) was produced in 72% yield with complete regiose-
lectivity where the oxygen nucleophiles attack at the least
substituted position of the Pd-π-allyl complex.
10
ketal formation and increase the rigidity of the ketolide
conformation, as well as provide an ideal point for aryl group
attachment.
Using allylic bis(tert-butyl carbonate) 3a as a dielectro-
1
1
phile, we developed a novel bridging process for EryA-
derived macrolide via a palladium-catalyzed tandem inter-
and intramolecular 6-O,11-O-dialkylation (Scheme 1). Thus,
The cladinose sugar and 9-oxime acetate were selectively
hydrolyzed by treating 4a with 2 M HCl in ethanol at 65 °C
for 2 h to give oxime intermediate 5. Reduction of the
13
9
-oxime with TiCl
3
gave 9-imine 6. Surprisingly, the imine
group of 6 is very stable and cannot be hydrolyzed to the
corresponding 9-ketone compound under various conditions.
We believe that the stability of the imine group is due to the
constrained conformation and the lack of intramolecular
assistance for the hydrolysis. Thus, acetylation of 6, followed
by Dess-Martin oxidation of 3-OH in dichloromethane and
deprotection of 2′-acetate in methanol, gave the bridged
ketolide 7 in 85% yield over three steps. Treatment of
compound 5 with MOMCl and NaH in DMF provided a
MOM-protected oxime intermediate, which upon Dess-
Martin oxidation of the 3-OH group and the subsequent
Scheme 1. Synthesis of 6,11-O-Bridged Bicyclic Macrolides
2
′-acetyl deprotection gave the ketolide 8 (Scheme 2).
Scheme 2. Synthesis of 6,11-O-Bridged Ketolide
commercially available EryA oxime 1 was converted to its
,2′,4′′-triacetate by reacting it with acetic anhydride in THF
in the presence of triethylamine and a catalytic amount of
9
(4) (a) Agouridas, C.; Benedetti, Y.; Le Martret, O.; Chantot, J.-F. 35th
Interscience Conference on Antimicrobial Agents and Chemtherapy, San
Francisco, CA, 1995; Abstract No. F157. (b) Agouridas, C.; Denis, A.;
Augar, J.-M.; Benedetti, Y.; Bonnefoy, A.; Bretin, F.; Chantot, J.-F.;
Dussarat, A.; Fromentin, C.; D’Ambrieres, S. G.; Lachaud, S.; Laurin, P.;
Le Martret, O.; Loyau, V.; Tessot, N. J. Med. Chem. 1998, 41, 4080-
4
100.
5) (a) Ma, Z.; Clark, R. F.; Wang, S.; Nilius, A. M.; Flamm, R. K.; Or,
(
Y. S. 39th Interscience Conference on Antimicrobial Agents and Chem-
therapy, San Francisco, CA, 1999; Abstract No. F2113. (b) 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. (c) 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.; Flamm,
R.; Mitten, M.; Meulbroek, J.; Ewing, P.; Alder, J.; Or, Y. S. J. Med. Chem.
2
001, 44, 4137-4156. (c) Keyes, R. F.; Carter, J. J.; Englund, E. E.; Daly,
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6) Denis, A.; Agouridas, C.; Auger, J.-M.; Benedetti, Y.; Bonnefoy,
1
(
A.; Bretin, F.; Chantot, J.-F.; Dussarat, A.; Fromentin, C.; D’Ambrieres, S.
D.; Lachaud, S.; Laurin, P.; Le Martret, O. Loyau, V.; Tessot, N.; Pejac,
J.-M.; Perron, S. Bioorg. Med. Chem. Lett. 1999, 9, 3075-3080.
(
7) (a) Allen, N. E. Antimicrob. Agents Chemother. 1977, 11, 669-674.
(
b) Pestka, S.; Vince, R.; LeMahieu, R.; Weiss, F.; Fern, L.; Unowsky, J.
Antimicrob. Agents Chemother. 1976, 9, 128-130.
4456
Org. Lett., Vol. 6, No. 24, 2004

erythromycin 4. Treatment of triacetate 2 with reagent 9 in
the presence of Pd (dba) (2 mol %) and dppb (4 mol %) in
2
3
refluxing THF selectively gave 6-O-allylated compound 10
in 90% yield. Deprotection of 2′- and 9-oxime acetates in
refluxing methanol followed by deoximation, which also
removed the TBS group, provided 9-keto compound 11. The
6
,11-O-bridge was introduced in three steps from 11. First,
the 2′-hydroxyl group was selectively protected with acetic
anhydride in dichloromethane in the absence of base. Then
the allylic alcohol was transformed into corresponding tert-
butyl carbonate. Finally, another palladium-catalyzed intra-
molecular allylation successfully bridged the 6-O and 11-O
positions to provide 6,11-O-bridged 9-ketoerythromycin 12
in 85% yield from 11. Selective hydrolysis of the cladinose
sugar provided 13. Dess-Martin oxidation of the C-3
hydroxyl group followed by deprotection of 2′-acetate gave
the desired 6,11-O-bridged 9-ketoketolide 14 in 91% yield.
The 6,11-O-bridged ketolides 7, 8, and 14 and the
reference compound, erythromycin A, were tested against a
panel of representative respiratory pathogens. Various mac-
rolide- and multidrug-resistant isolates were included in the
panel in order to identify potent analogues that could
overcome macrolide resistance. Staphylococcus aureus 29213,
Streptococcus pyogenes 19615, and Streptococcus pneumo-
niae 49619 are erythromycin-susceptible strains. S. aureus
Figure 2. X-ray single-crystal structure of 6,11-O-bridged ketolide
7
.
The structure of ketolide 7 was confirmed by the X-ray
crystallography (Figure 2).
To prepare 6,11-O-bridged 9-keto ketolide, a stepwise
bisallylation process was developed. As shown in Scheme
3, monoallylated compound 10 was synthesized in an
analogous fashion to the preparation of 6,11-O-bridged
2
7660 is an inducibly MLS
ermA gene. S. aureus 33591 is an MRSA. S. pyogenes 2912
is constitutive MLS -resistant strain encoded by an ermA
B
-resistant strain encoded by an
Scheme 3. Synthesis of 9-Keto 6,11-O-Bridged Ketolide
B
gene, and S. pneumoniae 700906 is resistant strains encoded
by an erm gene. S. pyogenes 1323 and S. pneumoniae 7701
are efflux-resistant strains encoded by mefA genes. Haemo-
philus influenzae 33929 is an ampicillin-resistant strain with
a â-lactamase positive determinant. The in vitro antibacterial
activities are reported as minimum inhibitory concentrations
(MICs), which were determined by the broth microdilution
method as recommended by the NCCLS (National Com-
1
4
mittee for Clinical Laboratory Standards). The in vitro
antibacterial activities of ketolides 7, 8, and 14 and reference
compound are shown in Table 1.
(8) (a) Baker, W. R.; Clark, J. D.; Stephens, R. L.; Kim, K. H. J. Org.
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3
9
1
3, 78-81.
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(
87-990.
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971, 27, 362.
(
11) (a) Huang, Y.; Lu, X. Tetrahedron Lett. 1988, 29, 5663. (b) Buono,
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(
A. R.; Leanna, M. R.; Patel, S. R.; Plata, D. L.; Premchandran, R. H.;
Rasmussen, M. J. Org. Chem. 2003, 68, 8847-8852.
(
13) (a) Timms, G. H.; Wildsmith, E. Tetrahedron Lett. 1971, 12, 195.
(
3
b) Gasparski, C. M.; Ghosh, A.; Miller, M. J. J. Org. Chem. 1992, 57,
546.
14) The MIC assays were performed in accordance with the National
(
Committee of Clinical Laboratory Standards (NCCLS) guidelines: (a)
Methods for Dilution Antimicrobial Susceptibility Tests for Bacterial that
Grow Aerobically, 5th ed.; NCCLS Document M7-A5; NCCLS, January
2000; Vol. 20, No. 2. (b) Performance Standards for Antimicrobial
Susceptibility Testing: EleVenth Informational Supplement; NCCLS Docu-
ment M100-S11; NCCLS, January 2001; Vol. 21, No. 1. (c) Amsterdam,
D. Susceptibility Testing of Antimicrobials in Liquid Media. In Antibiotics
in Laboratory Medicine, 4th ed.; Lorain, V., Ed.; Williams & Wilkins:
Baltimore, MD, 1996; pp 52-111.
Org. Lett., Vol. 6, No. 24, 2004
4457

In conclusion, we developed a bridging chemistry process
for erythromycin-derived macrolide via a palladium-cata-
lyzed tandem or stepwise inter- and intramolecular 6-O,11-
O-dialkylation. By applying this process, we synthesized
novel 6,11-O-bridged ketolide cores, which showed good
antibacterial activities. Further modifications of these new
cores to develop novel ketolides with improved activities
against a broad panel of macrolide-resistant bacterial strains
are in progress.
Table 1. Antibacterial Activity of 6,11-O-Bridged Ketolides
MIC (µg/mL)
organism
7
8
14
EryA
S. aureus 229213
S. aureus 27660
Ery S
Ery R-i
1.0
2.0
1.0
2.0
1.0
2.0
0.25
>64
S. aureus 33591
S. pneumoniae 49619
S. pneumoniae 7701
Ery MRSA >64 >64 >64 >64
Ery S 0.25 0.13 0.13 <0.06
Ery R-mef 0.5 0.5 0.5
4
S. pneumoniae 700906 Ery R-erm >64 >64 >64 >64
S. pyogenes 19615
S. pyogenes 1323
S. pyogenes 2912
H. influenzae 33929
Ery S
Ery R-mef 0.5
Ery R-erm >64 >64 >64 >64
Amp R >64 >64 >64
0.25 0.5
0.5
0.5
0.8
0.03
16
Acknowledgment. We thank Dr. Emil Lobkovsky of
Cornell University for help with the X-ray structure of
compound 7.
4
Supporting Information Available: Detailed experi-
mental procedures for the synthesis of and characterization
data for compounds 4, 7, 8, and 14. This material is available
free of charge via the Internet at http://pubs.acs.org.
All ketolides 7, 8, and 14 showed good antibacterial
activities against the susceptible strains as well as mef-
resistant strains. These results strongly suggested that the
6,11-O-bridged ketolides are good cores for further modi-
fications.
OL048336R
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Org. Lett., Vol. 6, No. 24, 2004