Synthesis and antibacterial activity of a novel class of 15-membered macrolide antibiotics, "11a-Azalides"

Article abstract of DOI:10.1021/ml100252s

An efficient method for the reconstruction of the 9-dihydroerythromycin A macrolactone skeleton has been established. The key steps are oxidative cleavage at the 11,12-position and reconstruction after insertion of an appropriate functionalized amino alcohol. Novel 15-membered macrolides, we named as "11a-azalides", were synthesized based on the above methodology and evaluated for their antibacterial activity. Among them, (13R)-benzyloxymethyl- 11a-azalide showed the most potent Streptococcus pneumoniae activity, with improved activity against a representative erythromycin-resistant strain compared to clarithromycin (CAM).

Full text of DOI:10.1021/ml100252s

LETTER
pubs.acs.org/acsmedchemlett
Synthesis and Antibacterial Activity of a Novel Class of 15-Membered
Macrolide Antibiotics, “11a-Azalides”
Tomohiro Sugimoto* and Tetsuya Tanikawa
Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan
S Supporting Information
b
ABSTRACT: An efficient method for the reconstruction of the 9-dihydroerythromycin
A macrolactone skeleton has been established. The key steps are oxidative cleavage at the
11,12-position and reconstruction after insertion of an appropriate functionalized amino
alcohol. Novel 15-membered macrolides, we named as “11a-azalides”, were synthesized
based on the above methodology and evaluated for their antibacterial activity. Among
them, (13R)-benzyloxymethyl-11a-azalide showed the most potent Streptococcus pneu-
moniae activity, with improved activity against a representative erythromycin-resistant strain compared to clarithromycin (CAM).
KEYWORDS: Antibiotic, macrolide, 11a-azalide, resistant-pathogen, novel scaffold
acrolide antibiotics1-4 (see Figure 1 for some structures)
are a safe and effective class of drugs for the treatment of
M
respiratory tract infections. Erythromycin A (EM-A, 1), a 14-
membered macrolide antibiotic, has been widely prescribed for
more than five decades. Since EM-A decomposed to antibacter-
ialy inactive spiroketal products5 under the acidic conditions in
the stomach, its bioavailability was not high and interindividually
varied.6 To improved the pharmacokinetic profile of EM-A
caused by the acid instability, enteric-coating of the tablets and
chemical modifications of EM-A have been performed.1-4 Second-
generation macrolides, such as clarithromycin7 (CAM, 2) and
azithromycin8 (AZM, 3), were investigated in the 1980s and
eventually launched in the 1990s as a result of chemical mod-
ification efforts.
Figure 1. Structures of macrolide antibiotics.
possessing a variety of substituents on the C12 and/or C13
position.
The increasing prevalence of macrolide-resistant pathogens
among clinical isolates in recent times is of concern to public
health.9-12 To overcome resistance problems, numerous chemi-
cal modifications of EM-A have been attempted.13-15 In a
chemobiosynthesis report seeking novel scaffolds by transforma-
tion of the macrolactone skeleton, the C13 position of EM-A
promises to play a key role in the improvement of antibacterial
activity against resistant pathogens.16,17 However, chemical
modification at the C13 position has been underexplored
because of its lack of chemical reactivity. During the mid
1990s, Waddell18,19 and Nishida20 independently reported
C9-C13 modified EM-A derivatives, synthesized from the
original C1-8 or 9 fragment of EM-A and a newly prepared
C9 or 10-13 fragment. Although this “cut and paste” methodol-
ogy seemed to be a universal procedure to provide structural
diversity into the C13 region, the reported compounds were
limited to simple and primitive derivatives. Alternatively, rela-
ted ring reconstruction methodology using 16-membered
macrolide as the starting material has been reported.21 In this
paper, we report an efficient method for the reconstruction
of the macrolactone skeleton that enables us to synthesize a
novel class of 15-membered macrolide antibiotics, “11a-azalides”,
Our synthetic strategy is shown in Scheme 1. The 11,12-diol
moiety of the EM-A macrolactone skeleton was cleaved oxida-
tively. After insertion of an appropriate functionalized amino
alcohol and successive saponification of the remaining original
C12-13 residue, the resulting acyclic skeleton was intramole-
cularly cyclized by a macrolactonization reaction. The advantage
of this strategy over previous methods was that it enabled us to
provide structural diversity to both the C12 and C13 positions
using an easily prepared, functionalized amino alcohol.
Our initial approach was to establish a methodology using
reconstruction of the simplest macrolactone skeleton. EM-A (9-
keto analogue) was converted to an acyclic keto-aldehyde
intermediate by treatment with lead tetraacetate. However, the
reductive amination of the aldehyde with 2-aminoethanol failed,
presumably because of the formation of an unstable β-keto-
aldehyde intermediate. To avoid side reactions, (9S)-9-dihydro-
erythromycin (4) was selected as the starting material
Received: November 5, 2010
Accepted: December 20, 2010
Published: December 30, 2010
r
2010 American Chemical Society
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ACS Medicinal Chemistry Letters
LETTER
Scheme 1. Synthetic Strategy for 11a-Azalide
Scheme 2. Synthesis of 11a-Azalide
(Scheme 2). The 9-dihydro derivative 4 was readily prepared by
reduction of tthe 9-keto group of 1.22,23 The 9,20,400-hydroxyl
groups of 4 were selectively protected by triethylsilyl (TES)
groups to give 11,12-diol 5, which was then treated with lead
tetraacetate to give acyclic aldehyde intermediate 6.24 Reductive
amination25 of aldehyde 6 with 2-aminoethanol and subsequent
methylation of the resulting secondary amine at the 11a-position
with formaldehyde gave the desired seco-ester 7. The above three
sequential reactions were performed in a one-pot manner in 77%
yield from diol 5.
Saponification of seco-ester 7 with LiOH produced seco-acid
8 in 65% yield, and macrolactone skeleton reconstruction was
achieved using modified Yamaguchi’s macrolactonization
method.26-28 Seco-acid 8 was converted to a mixed anhydride
by the treatment with triethylamine and 2,4,6-trichlorobenzoyl
chloride in THF at 50 mM. When the mixed anhydride solution
was added dropwise to a tenth-volume of refluxing solution of
4-dimethylaminopyridine (DMAP) (25 equiv), the macrolacto-
nization reaction proceeded smoothly to give the 15-membered
macrolide 9 in 79% yield. Deprotection of the TES groups of 9
was conducted by HF-pyridine treatment to give the desired 11a-
azalide 10 in 90% yield.
Based on the established methodology, we synthesized 12-/
13-benzyloxymethyl-11a-azalides 14a-d (Table 1). Amino
alcohols 11a,b29 were prepared through reduction of optically
active O-benzyl serine with LiAlH4, and 11c,d were prepared by
ring-opening reactions of optically pure benzylglycidol with
aqueous ammonia. Seco-acids 12a-d were prepared from 5
and amino alcohols 11a-d in a manner similar to the preparation
of 8. Macrolactonization reaction of seco-acids 12a,b, which
possess a primary hydroxyl group, proceeded smoothly to give
the desired 12-substituted-11a-azalides 13a,b. On the other hand,
reaction of seco-acids 12c,d, which possess a secondary hydroxyl
group, gave the desired 15-membered products 13c,d in relatively
low yield along with an undesired 7-membered byproduct.30 In
the macrolactonization reaction of erythronolides,31,32 the 6-hy-
droxyl group of seco-acids was generally inert. However, the
same 7-membered byproduct has been observed in the case of
glycosylated seco-acid.33 HF-pyridine treatment of 13a-d gave
the desired 12-/13-substituted 11a-azalides 14a-d.
The antibacterial activities of the synthesized 11a-azalides
against Streptococcus pneumoniae were evaluated as shown in
Table 2.34 Compound 14d showed the most potent antibacterial
activity against erythromycin-susceptible S. pneumoniae com-
pared to CAM, and it showed a 4-fold improved antibacterial
activity against the erythromycin-resistant strain compared to
CAM. The position and configuration of the substituents on
the 11a-azalides turned out to have a significant impact on the
antibacterial activity.
In conclusion, we established an efficient method for the
reconstruction of the 9-dihydroerythromycin A macrolactone
skeleton. Based on this methodology, we synthesized a novel
class of 15-membered macrolides “11a-azalides” possessing a
substituent on their C12 or C13 position. Among them, (13R)-
benzyloxymethyl-11a-azalide 14d showed the most potent S.
pneumoniae activity, with improved activity against the represen-
tative erythromycin-resistant strain compared to CAM. This
methodology provides 11a-azalides as a novel scaffold, which
allows us to engage in further exploration to improve the
antibacterial activity against resistant pathogens.
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ACS Medicinal Chemistry Letters
LETTER
Table 1. Synthesis of 12-/13-Substituted 11a-Azalides
Author Contributions
T.S. led research design (chemistry) and execution (performed
synthesis) and contributed to writing of the manuscript, and is
the corresponding author; T.T. participated in research design
(chemistry) and execution (performed synthesis) and contrib-
uted to writing of the manuscript.
’ ACKNOWLEDGMENT
The authors thank Ms. Keiko Suzuki and Ms. Yukiko Yamasaki
for providing antibacterial activity data.
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MIC (μg/mL)
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S. pneumoniae ATCC49619a
S. pneumoniae 205b
4
2
1
0.12
0.03
>128
>128
128
64
32
a Erythromycin-susceptible strain. b Erythromycin-resistant strain.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
characterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
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Corresponding Author
*Telephone: þ81 48 669 3064. Fax: þ81 48 652 7254. E-mail:
tomohiro.sugimoto@po.rd.taisho.co.jp.
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LETTER
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