Synthesis and antibacterial activity of novel 11-[3-[(arylcarbamoyl)oxy]propylamino]-11-deoxy-6-O-methyl-3-oxoerythromycin A 11-N,12-O-cyclic carbamate derivatives

Article abstract of DOI:10.1038/ja.2016.42

A series of novel 11-[3-[(arylcarbamoyl)oxy]propylamino]-11-deoxy-6-O-methyl-3-oxoerythromycin A 11-N,12-O-cyclic carbamate derivatives (6a-h) were designed, synthesized and evaluated for their antibacterial activities in vitro. Most of these compounds had significant antibacterial activity against two groups of pathogens of Methicillin-sensitive Staphylococcus aureus (MIC 50 =0.031-2 μg ml -1) except 6g and Methicillin-sensitive S. epidermidis (MIC 50 =0.031-0.5 μg ml -1). MIC 90 of 6d against Methicillin-resistant S. epidermidis was at least 16-fold better than that of erythromycin (EMA), azithromycin (AZM) and ABT-773. 6d and 6e had more potent antibacterial activity against S. pneumoniae than EMA, AZM and ABT-773. In particular, compounds 6d and 6e also showed relatively potent activity against Haemophilus influenzae and Streptococcus hemolyticus.

Full text of DOI:10.1038/ja.2016.42

The Journal of Antibiotics (2016), 1–7
2016 Japan Antibiotics Research Association All rights reserved 0021-8820/16
www.nature.com/ja
&
ORIGINAL ARTICLE
Synthesis and antibacterial activity of novel
1
1-[3-[(arylcarbamoyl)oxy]propylamino]-11-deoxy-6-
O-methyl-3-oxoerythromycin A 11-N,12-O-cyclic
carbamate derivatives
1
1
1
2
2
Zhonghui Zheng , Deping Du , Lili Cao , Jun Liu and Xiaofang Chen
A series of novel 11-[3-[(arylcarbamoyl)oxy]propylamino]-11-deoxy-6-O-methyl-3-oxoerythromycin A 11-N,12-O-cyclic carbamate
derivatives (6a–h) were designed, synthesized and evaluated for their antibacterial activities in vitro. Most of these compounds
had significant antibacterial activity against two groups of pathogens of Methicillin-sensitive Staphylococcus aureus
MIC50 = 0.031–2 μg ml− ) except 6g and Methicillin-sensitive S. epidermidis (MIC50 = 0.031–0.5 μg ml ). MIC90 of 6d
1
− 1
(
against Methicillin-resistant S. epidermidis was at least 16-fold better than that of erythromycin (EMA), azithromycin (AZM) and
ABT-773. 6d and 6e had more potent antibacterial activity against S. pneumoniae than EMA, AZM and ABT-773. In particular,
compounds 6d and 6e also showed relatively potent activity against Haemophilus influenzae and Streptococcus hemolyticus.
The Journal of Antibiotics advance online publication, 27 April 2016; doi:10.1038/ja.2016.42
INTRODUCTION
(Figure 1), have been developed and widely prescribed for upper
The rapid development of antibiotics-resistant strains such as and lower respiratory tract infections.5
,6
These compounds
Methicillin-resistant Staphylococcus aureus, Vancomycin-resistant demonstrated a broader spectrum of antibacterial activity, better
Enterococcus, Penicillin-resistant S. pneumoniae, has created a serious pharmacokinetic properties and fewer gastrointestinal side effects as
1
problem for the clinical treatment in recent years. In a research on compared with EMA. Unfortunately, the therapeutic utility of these
clinic ophthalmic bacteria, 87% of the Methicillin-resistant macrolides has resulted in the increasing emergence of resistant
Staphylococcus aureus isolates were resistant to azithromycin (AZM) pathogens. The two primary mechanisms of macrolide resistance are
and 42% of the Methicillin-resistant S. epidermidis (MRSE) strains mediated by erm-encoded methylation of 23S ribosomal RNA and
2
7,8
tested were resistant to AZM, respectively. The clinically relevant mef-encoded efflux, respectively.
coagulase-negative Staphylococcal species, S. epidermidis are among the To overcome the growing problems of macrolide resistance, the
leading causes of nosocomial infections in humans, particularly in research has focused on the discovery of novel macrolides with greater
neonates, immunocompromised patients and patients with indwelling efficacy and safety. The third-generation macrolides, ketolides such as
3
4
9,10
and implanted devices. Farrell et al. reported that resistant telithromycin and cethromycin (Figure 1),
displayed improved
S. pneumoniae possessing both erm and mef genes markedly increase activity against some of the resistant strains and may offer alternative
in only 3 years in the United States. Therefore, there is an urgent need therapy for Gram-positive infections attributable to resistant
for novel macrolide antibiotics to suppress the resistance. Macrolides pathogens. Both telithromycin and cethromycin share the same key
antibiotics, which are active against Gram-positive bacteria, especially structure features, including 3-keto group, 11,12-cyclic carbamate and
S. pneumoniae, belong to one of the most commonly used families of a proper hetero-arylalkyl side chain, which is essential for interacting
with the 23S ribosomal RNA of bacteria.1
1,12
clinically important antibiotics.
Erythromycin A (EMA), the representative of first-generation
Recently, intensive research focusing on the structural modifications
macrolides, has been widely used to treat respiratory infections for of the ketolide core skeleton in search of novel potent ketolides has
1
0,13–15
almost 60 years. However, EMA is prone to degrade under acidic yielded many ketolides derivatives, such as 6-O-alkyl ketolides,
conditions, leading to the undesirable gastrointestinal side effects and 9-oxime macrolides,1
6–18
11,12-cyclic carbamate ketolides,19–21
2
2–24
low bioavailability. With the purpose of improving the acid stability, 13-substituents ketolides and 6,11-bridged ketolides.
Herein, we
second-generation macrolides, including clarithromycin and AZM described the synthesis and in vitro biological evaluation of a set of
1
2
Shandong Xinhua Pharmaceutical Co., Ltd, Zibo City, Shandong Province, China and Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking
Union Medical College, Beijing, China
Correspondence: Dr Z Zheng or Dr X Chen, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, tiantanxli 1#, Beijing
1
00050, China.
E-mail: zhengzhonghui@sina.com or chenchemistry@hotmail.com
Received 12 October 2015; revised 24 February 2016; accepted 14 March 2016

A series of novel ketolide derivatives
Z Zheng et al
2
Figure 1 Structures of erythromycin, clarithromycin, azithromycin, telithromycin and cethromycin (ABT-773).
novel 14-membered macrolide analogs that comprised the essential
features for addressing macrolide resistance especially by erm-encoded
methylation of 23S ribosomal RNA. By introducing various substituted-
phenyl carbamate propyl chain to the 11-N of the 11-amino-11-deoxy-3-
des(hexopyranosyloxy)-6-O-methyl-3-oxoerythromycin A 11-N, 12-O
cyclic carbamate, a series of novel 11-N,12-O-cyclic carbamate ketolides
were obtained.
RESULTS AND DISCUSSION
A simple and efficient method for preparation of novel 14-membered
macrolide analogs was developed. The objective compounds were
evaluated for antibacterial activity against macolide-susceptible and
-
resistant pathogens. Most of the compounds tested showed potent Scheme 1 Synthesis of a set of isocyanate (2a–h).
activity against most resistant bacteria, indicating that the introduction
of phenyl substituents to the 11-N position can markedly enhance the result suggested that the 3-substituent was very important for the
antibacterial activity. Accounding to the structure–activity relationship activity. In addition, 6f with a chloro group substitution in the 2-
studies it is demonstrated that 11,12-cyclic carbamate would increase position showed more potent activity than 6g. These results indicated
the stability of the conformation of the ketolides, and meanwhile the importance of the presence and location of the functional groups
might be beneficial for the activitiy against macrolide-susceptible and for activity. Further research on the structure–activity relationship is
-resistant bacteria. Accordingly, we hoped that introducing a carba- necessary especially on 3-postion substitution, which maybe is useful
mate group to the 11-N-alkyl position might remarkbly increase the for designing new ketolides with broader antibacterial spectrum. On
antibacterial activity. However, almost all of the compounds did not the whole, 6d and 6e showed potent activity against MSSA-EAR,
possess better antibacterial activities than those of compounds with MRSE and Haemophilus influenzae, whereas 6g was the least active
alkyl substituents at the 11-N position.
compound.
In general, the derivative 6a without substituents on the phenyl ring
was less active than those containing substituents except 6g. Chemistry
The position and properties of substituents on the benzene ring had The synthetic method of aryl isocyanates (2) is shown in Scheme 1.
great influence on the in vitro antibacterial activity. In the Condensation of 1 with bis(trichloromethyl) carbonate gave the
4
-substitution, a comparison among 6b, 6c, 6d and 6h indicated that desired aryl isocyanates (2a–h). Scheme 2 describes the synthesis of
electrical property had little effect on the activity. MIC90 of 6d with 11-[3-[(arylcarbamoyl)oxy]propylamino]-11-deoxy-3-des(hexopyranosy-
-nitro substituent against MRSE was better than other derivatives loxy)-6-O-methyl-3-oxoerythromycin A 11-N,12-O-cyclic carbamate
4
with the 4-substitution group. 6h had the least activity against (6) starting from 2′-O-benzoyl-10,11-dehydro-3-des(hexopyranosy-
S. pneumoniae among the four compounds. In contrast, the derivatives loxy)-12-O-imidazolylcarbonyl-6-O-methyl-3-oxoerythromycin A (3).
6
e and 6g with substitution at the 3-position of the phenyl ring Treatment of 3 with 1-amino propanol in N,N-Dimethylformamide
displayed a great difference on antibacterial activity. 6e with a methyl (DMF) at room temperature afforded compound 4. Compounds (6a–h)
group was much powerful than 6g containing a chloro group. This were prepared by reacting compound 4 with corresponding aryl
The Journal of Antibiotics

A series of novel ketolide derivatives
Z Zheng et al
3
O
Scheme 2 Reagents and conditions: (a) NH2CH2CH2CH2OH, N,N-Dimethylformamide (DMF), room temperature (rt), 62 h, 85%; (b) dicyclohexylcarbodiimide
DCC), 4-dimethylaminopyridine (DMAP), RNCO is R-N ¼ C¼ O, DMAP, CH2Cl2, rt, 20 h, 75–90%; (c) CH3OH, reflux, 20 h, 90 ~ 98%.
(
Table 1 In vitro antibacterial activity (MIC (μg ml− 1)) of prepared macrolides against S. aureus and S. epidermidis
MSSA-EASa
MSSA-EARb
MRSAc
MRSEd
MSSEe
Compound/strain
MIC50
MIC90
MIC50
MIC90
MIC50
MIC90
MIC50
MIC90
MIC50
MIC90
6
6
6
6
6
6
6
6
4
a
b
c
d
e
f
1
2
2
2
0.125
0.25
0.5
256
128
256
256
2
0.062
16
16
256
32
0.5
0.062
0.031
0.25
2
0.062
0.031
0.25
0.125
0.125
0.25
0.125
0.125
0.5
0.062
0.062
0.25
256
4256
4256
256
4256
128
1
8
0.125
0.062
0.25
0.125
0.125
0.5
0.25
0.25
0.25
4256
2
1
128
32
0.031
0.25
0.031
0.25
0.125
4256
0.062
0.5
128
256
0.5
4256
2
g
h
4256
256
4256
4256
4256
4256
4256
4256
4256
256
4256
128
4256
4256
0.25
0.25
0.062
0.5
0.25
0.125
0.25
0.5
0.5
1
4256
256
2
0.25
ABT-773
EMA
o0.016
0.125
0.031
o0.016
0.25
o0.016
4256
4256
o0.016
4256
4256
o0.016
4256
o0.016
0.125
o0.016
o0.016
0.125
0.031
4256
4256
AZM
0.125
4256
Abbreviations: ABT-773, cethromycin; AZM, azithromycin; EMA, erythromycin; MRSA, methicillin resistant Staphylococcus aureus; MRSE, methicillin resistant Staphylococcus epidermidis;
MSSA-EAS, methicillin susceptible Staphylococcus aureus and erythromycin susceptible; MSSA-EAR, methicillin susceptible Staphylococcus aureus and erythromycin resistant; MSSE, methicillin
susceptible Staphylococcus epidermidis.
a
1
1
0 strains for MSSA-EAS.
0 strains for MSSA-EAR.
0 strains for MRSA.
0 strains for MRSE.
b
c
1
d
e
1
1
0 strains for MSSE.
isocyanates (2a–h) in the presence of dicyclohexylcarbodiimide (DCC)
and 4-dimethylaminopyridine (DMAP) at room temperature, followed [3-[(arylcarbamoyl)oxy]propylamino]-11-deoxy-6-O-methyl-3-oxoer-
The results in Tables 1 and 2 show the antibacterial activity of 11-
25
by deprotection of the benzoyl group with methanol.
ythromycin A 11-N,12-O-cyclic carbamate derivatives and reference
compounds (ABT-773, EMA and AZM). MIC50 (the concentration
in which growth of 50% of strains were inhibited) and MIC90
Antibacterial activity
The 11-[3-[(arylcarbamoyl)oxy]propylamino]-11-deoxy-6-O-methyl- (the concentration in which 90% of strains were inhibited) were
-oxoerythromycin A 11-N,12-O-cyclic carbamate derivatives, as well tested. All of the tested compounds except 6g proved to have
3
as cethromycin (ABT-773), EMA, azithromycin as references, were good antibacterial activity against MSSA (MIC = 0.031–2 μg ml− ),
1
5
0
−
1
tested for in vitro antibacterial activity against three groups of MSSE (MIC50 = 0.031–0.5 μg ml ), Streptococcus pneumoniae
−
1
S. aureus, two groups of S. epidermis, Enterococcus faecalis, Streptococcus (MIC50 = 0.062–16 μg ml ). The MIC90 of 6d for MRSE were 2–16
pneumoniae, Haemophilus influenzae and Streptococcus hemolyticus. times better than EMA, AZM and ABT-773. Compounds 6d and 6e
The activities are reported in Tables 1 and 2 MICs determined using had more potent antibacterial activity against Streptococcus pneumoniae
the broth microdilution method.
than the reference compounds EMA, AZM and ABT-773. Specifically,
The Journal of Antibiotics

A series of novel ketolide derivatives
Z Zheng et al
4
Table 2 In vitro antibacterial activity (MIC (μg mL 1)) of prepared
−
4-Methoxyphenyl isocyanate (2c)
macrolides against other strains
1c (12.4 g, 0.1 mol) in CHCl was added dropwise according to the method for
3
phenyl isocyanate. When the addition was finished, the reaction mixture was
stirred at room temperature for 1 h. The solvent was evaporated to give 12.75 g
(85%) of 2c as colorless liquid: bp 75–77 °C per 30 mm Hg.
Enterococcus
faecalisa
Streptococcus Haemophilus Streptococcus
pneumoniaeb influenzaec hemolyticusd
Compound/
strain
MIC50 MIC90 MIC50 MIC90 MIC50 MIC90 MIC50 MIC90
4
-Nitrophenyl isocyanate (2d)
1
d (13.8 g, 0.1 mol) in CHCl3 was added dropwise according to the method for
6
6
6
6
6
6
6
4
a
b
c
d
e
f
4256 4256
4256 4256
16
32
2
32
16
16
4
32
64
32
8
4
1
32
2
phenyl isocyanate. When the addition was finished, the reaction mixture was
0.5
stirred at room temperature for 3 h. The solvent was evaporated to give 13.27 g
4256 4256 0.25
2
2
16
2
(81%) of 2d as yellow solid: bp 85–86 °C per 30 mm Hg.
4256 4256 0.125 0.25
4256 4256 0.062 0.125
2
4
8
1
2
4256 4256
4256 4256
4256 4256
2
4
8
32
8
64
32
16
1
128
64
16
2
8
8
3-Methylphenyl isocyanate (2e)
h
2
4
1e (10.8 g, 0.1 mol) in CHCl3 was added dropwise according to the method for
phenyl isocyanate. When the addition was finished, the reaction mixture was
stirred at room temperature for 3 h. The solvent was evaporated to give 11.13 g
(70%) of 2e as colorless liquid: bp 69–70 °C per 30 mm Hg.
4
2
8
ABT-773
EMA
32
32
0.5
2
1
1
2
4256 4256
4256 4256
4
4
8
2
4
AZM
1
2
2
8
16
16
a
1
1
0 strains for E. faecalis.
2-Chlorophenyl isocyanate (2f)
b
0 strains for S. pneumoniae.
c
1f (12.85 g, 0.1 mol) in CHCl was added dropwise according to the method
3
1
0 strains for H. influenzae.
0 strains for S. hemolyticus.
d
1
for phenyl isocyanate. When the addition was finished, the reaction mixture
was stirred at room temperature for 1.5 h. The solvent was evaporated to give
1
1.87 g (77%) of 2f as colorless liquid: bp 64–66 °C per 20 mm Hg.
compounds 6d and 6e showed more potent activity against
S. hemolyticus than EMA and AZM, which was similar with ABT-773.
3
-Chlorophenyl isocyanate (2g)
1
g (12.86 g, 0.1 mol) in CHCl3 was added dropwise according to the method
EXPERIMENTAL PROCEDURE
for phenyl isocyanate. When the addition was finished, the reaction mixture
All necessary solvents were purified before use, unless noted otherwise.
Reactions were monitored by TLC using 0.20-mm pre-coated silica gel plates
Merck DC-alurolle Kieselgel 60GF254. Column chromatography was
performed with the indicated solvents using silica gel H (Qingdao Marine
was stirred at room temperature for 3.5 h. The solvent was evaporated to give
11.29 g (73%) of 2g as colorless liquid: bp 66–68 °C per 20 mm Hg.
chemical plant, Shandong, China). IR spectra were recorded on KBr pellets 4-Trifluoromethylphenyl isocyanate (2h)
1
using a Shimadzu IR-435 spectrometer. H NMR spectra were recorded on a 1h (16.1 g, 0.1 mol) in CHCl was added dropwise according to the method for
3
WYS-300 or VarianX1-400 or Inova-500 spectrometer at ambient temperature
phenyl isocyanate. When the addition was finished, the reaction mixture was
(
TMS as internal standard of chemical shifts). Mass spectra were obtained on a
stirred at room temperature for 3 h. The solvent was evaporated to give 15.01 g
ZAB-2F or Autospect-Ultima ETOF mass spactrometer for FAB-MS or ESI-MS.
Melting points are uncorrected and were determined on an X-6 or RY-1
melting point apparatus. The starting material, 2′-O-benzoyl-10,11-dehydro-3-
(
80%) of 2h as colorless liquid: bp 71–73 °C per 30 mm Hg.
2
′-O-Benzoyl-11-deoxy-3-des(hexopyranosyloxy)-11-(3-
des(hexopyranosyloxy)-12-O-imidazolylcarbonyl-6-O-methyl-3-oxoerythromy-
cin A (3), was prepared according to the published procedure.26
hydroxyprolylamino)-6-O-methyl-3-oxoerythromycin A 11-N,12-O-
cyclic carbamate (4)
2
′-O-Benzoyl-10,11-dehydro-3-des(hexopyranosyloxy)-12-O-imidazolylcarbonyl-
-O-methyl-3-oxoerythromycin (3) (10.7 g, 13.9 mmol) and 1-amino
General methods for aryl isocyanate (2a–h)
To a solution of bis(trichloromethyl) carbonate in CHCl3 was added dropwise
6
A
propanol (11 ml, 14.3 mmol) were dissolved in DMF (80 ml) and the mixture
was stirred for 62 h at room temperature. Water (150 ml) was added to the
resulting solution and the aqueous layer was extracted with ethyl acetate
aromatic amines in CHCl in an ice bath. When the addition was finished, the
3
reaction mixture was stirred at room temperature for 1–8 h and then heated at
reflux until the reaction solution clarified. After the solvent was evaporated
under atmospheric pressure, the residual liquid could be evaporated under
reduced pressure.
(3 × 100 ml). The combined organic layers were washed with water (150 ml),
brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated in
vacuum. The residue was purified by flash chromatography (acetone:hexane, 3:6)
to give 10.7 g (85%) of 4 as a white solid.
Phenyl isocyanate (2a)
To a solution of bis(trichloromethyl) carbonate (16.3 g, 0.55 mol) in CHCl3
1
H
NMR (CDCl3, 400 MHz) δ 8.05(d, J = 7.6 Hz, 2H, phenyl-H2,
phenyl-H6), 7.63(t, J = 6.9 Hz, 1H, phenyl-H4), 7.49(t, J = 7.6 Hz, 2H,
phenyl-H3, phenyl-H5), 4.92(dd, J = 2.1, 8.7 Hz, 1H, 13-H), 4.57(dd, J = 8.0,
(
60 ml) was added dropwise 1a (9.3 g, 0.1 mol) in CHCl3 (40 ml) in an ice
bath. When the addition was finished, the reaction mixture was stirred at room
temperature for 1 h and then heated at reflux until the reaction solution 10.1 Hz, 1H, 2′-H), 4.12(d, 1H, J = 10.8 Hz, 5-H), 3.83(q, J =7.8 Hz, 1H, 2-H),
clarified. After the solvent was evaporated under atmospheric pressure, the
3.72(m, 2H, CH2CH2CH2OH), 3.55(d, J = 2.5 Hz, 1H, 11-H), 3.50(m, 1H,
residual liquid was evaporated under reduced pressure to give 10.1 g (85%) of 5′-H), 3.41(m, 1H, 4-H), 3.10(q, J =7.0 Hz, 1H, 8-H), 3.05(ql, J = 6.9 Hz, 1H,
a as colorless liquid: boiling point (bp) 65–68 °C per 30 mm Hg.
10-H), 2.86(m, 2H, NCH2CH2CH2OH), 2.78(s, 3H, 6-O-CH3), 2.7(m, 1H,
′-H), 2.26(s, 6H, N(CH3)2), 1.93(m, 1H, 14-Ha), 1.73(m, 1H, 4′-Ha),
2
3
4
-Methylphenyl isocyanate (2b)
1.65(m, 2H, NCH2CH2CH2OH), 1.63(m, 1H, 14-Hb), 1.52(s, 3H, 6-CH3),
1.38(m, 1H, 7-Ha), 1.32(m, 1H, 7-Hb), 1.26(s, 3H, 12-CH3), 1.24(m, 1H,
4′-Hb), 1.17(d, J =7.0 Hz, 3H, 8-CH3), 1.13(d, J = 7.8 Hz, 3H, 2-CH3),
1b (10.8 g, 0.1 mol) in CHCl3 was added dropwise according to the method for
phenyl isocyanate. When the addition was finished, the reaction mixture was
stirred at room temperature for 2 h. The solvent was evaporated to give 14.04 g 1.12(d, J = 6.9 Hz, 3H, 10-CH3), 1.10(d, J = 7.4 Hz, 3H, 4-CH3),
+
(
90%) of 2b as colorless liquid: bp 69–70 °C per 30 mm Hg.
0.80(t, J = 7.2 Hz, 3H, 15-H). ESI-MS (m/z):775(M+H) .
The Journal of Antibiotics

A series of novel ketolide derivatives
Z Zheng et al
5
General methods for 11-[3-[(arylcarbamoyl)oxy]propylamino]-2′-
O-benzoyl-11-deoxy-3-des(hexopyranosyloxy)-6-O-methyl-3-
oxoerythromycin A 11-N,12-O-cyclic carbamates (5a-h)
6-CH3), 1.38(m, 1H, 7-Ha), 1.32(m, 1H, 7-Hb), 1.26(s, 3H, 12-CH3), 1.24
(m, 1H, 4′-Hb), 1.17(d, J = 7.0 Hz, 3H, 8-CH3), 1.13(d, J = 7.8 Hz, 3H, 2-CH3),
1.12(d, J =6.9 Hz, 3H, 10-CH3), 1.10(d, J =7.4 Hz, 3H, 4-CH3),
solution of 2′-O-benzoyl-11-deoxy-3-des(hexopyranosyloxy)-11- 0.78(t, J = 7.2 Hz, 3H, 15-H). ESI-MS(m/z): 924(M+H)+.
To
3-hydroxyprolylamino)-6-O-methyl-3-oxoerythromycin A 11-N,12-O-cyclic
carbamate (4) (0.4 g, 0.516 mmol), DCC (0.11 g, 0.516 mmol) and DMAP 2′-O-Benzoyl-11-deoxy-3-des(hexopyranosyloxy)-6-O-methyl-11-
0.063 g, 0.516 mmol) in CH2Cl2 (20 ml) was added dropwise corresponding
a
(
(
[3-[(4-nitrophenylcarbamoyl)oxy]propylamino]-3-oxoerythromycin
aryl isocyanate (2.58 mmol) in CH2Cl2 (10 ml) in an ice bath. The reaction
mixture was allowed to slowly warm to room temperature and was stirred for
A 11-N,12-O-cyclic carbamate (5d)
1
White solid, yield 78%. H NMR (CDCl3, 400 MHz) δ 8.08(d, J = 7.8 Hz, 2H,
2
0 h under nitrogen. The reaction was quenched with methanol (3 ml), filtered
and concentrated in vacuum. The residue was purified by flash chromatography
cyclohexane-ethyl acetate, 5:1 ~ 2:1) to afford products 5a-h as a white solid.
phenyl-H2, phenyl-H6), 8.05(d, J = 8.2 Hz, 2H, phenyl-H2, phenyl-H6), 7.68
(
t, J = 6.9 Hz, 1H, phenyl-H4), 7.63(d, J = 8.2 Hz, 2H, phenyl-H3, phenyl-H5),
(
7.49(t, J =6.0 Hz, 2H, phenyl-H3, phenyl-H5), 4.92(dd, J = 2.1, 8.7 Hz, 1H,
1
3-H), 4.57(dd, J = 8.0, 10.1 Hz, 1H, 2′-H), 4.12(d, J = 10.8 Hz, 1H, 5-H), 3.83
2
′-O-Benzoyl-11-deoxy-3-des(hexopyranosyloxy)-6-O-methyl-3-
oxo-11-[3-[(phenylcarbamoyl)oxy]propylamino]erythromycin A
1-N,12-O-cyclic carbamate (5a)
(
q, J = 7.8 Hz, 1H, 2-H), 3.72(m, 2H, CH CH CH OH), 3.60(s, 3H,
2 2 2
phenyl-OCH ), 3.55(d, J = 2.5 Hz, 1H, 11-H), 3.50(m, 1H, 5′-H), 3.41
3
1
(
m, 1H, 4-H), 3.10(q, J = 7.0 Hz, 1H, 8-H), 3.05(ql, J = 6.9 Hz, 1H, 10-H),
1
White solid, yield 82%. H NMR (CDCl3, 400 MHz) δ 8.08(d, J = 7.8 Hz, 2H,
phenyl-H2, phenyl-H6), 7.68(t, J = 6.9 Hz, 1H, phenyl-H4), 7.49(t, J = 6.0 Hz,
2
.86(m, 2H, NCH CH CH OH), 2.78(s, 3H, 6-O-CH ), 2.7(m, 1H, 3′-H), 2.27
2
2
2
3
(
s, 6H, N(CH ) ), 2.24(s, 3H, phenyl-CH ), 1.93(m, 1H, 14-Ha,), 1.73(m, 1H,
3 2 3
2
7
H, phenyl-H3, phenyl-H5), 7.38(d, J = 8.0 Hz, 2H, phenyl-H2, phenyl-H6),
.28(d, J = 8.0 Hz, 2H, phenyl-H3, phenyl-H5), 7.05(t, J = 7.6 Hz, 1H, phenyl-
4′-Ha), 1.65(m, 2H, NCH2CH2CH2OH), 1.63(m, 1H, 14-Hb), 1.52(s, 3H,
6-CH3), 1.38(m, 1H, 7-Ha), 1.32(m, 1H, 7-Hb), 1.26(s, 3H, 12-CH3),
1.24(m, 1H, 4′-Hb), 1.17(d, J = 7.0 Hz, 3H, 8-CH3), 1.13(d, J =7.8 Hz,
3H, 2-CH3), 1.12(d, J = 6.9 Hz, 3H, 10-CH3), 1.10(d, J =7.4 Hz, 3H, 4-CH3),
0
H4), 4.92(dd, J = 2.1, 8.7 Hz, 1H, 13-H), 4.57(dd, J =8.0, 10.1 Hz, 1H, 2′-H),
.12(d, 1H, J = 10.8 Hz, 5-H), 3.83(q, J = 7.8 Hz, 1H, 2-H), 3.72(m, 2H,
4
CH2CH2CH2OH), 3.55(d, J =2.5 Hz, 1H, 11-H), 3.50(m, 1H, 5′-H),
+
.78(t, J = 7.2 Hz, 3H, 15-H). ESI-MS(m/z): 939(M+H) .
3.41(m, 1H, 4-H), 3.10(q, J = 7.0 Hz, 1H, 8-H), 3.05(ql, J = 6.9 Hz, 1H,
1
0-H), 2.86(m, 2H, NCH2CH2CH2OH), 2.78(s, 3H, 6-O-CH3), 2.7(m, 1H,
2
′-O-Benzoyl-11-deoxy-3-des(hexopyranosyloxy)-6-O-methyl-11-
3
2
7
′-H), 2.26(s, 6H, N(CH3)2), 1.93(m, 1H, 14-Ha), 1.73(m, 1H, 4′-Ha), 1.65(m,
[3-[(3-methylphenylcarbamoyl)oxy]propylamino]-3-oxoery-
H, NCH2CH2CH2OH), 1.63(m, 1H, 14-Hb), 1.52(s, 3H, 6-CH3), 1.38(m, 1H,
-Ha), 1.32(m, 1H, 7-Hb), 1.26(s, 3H, 12-CH3), 1.24(m, 1H, 4′-Hb), 1.17 thromycin A 11-N,12-O-cyclic carbamate (5e)
1
(
d, J = 7.0 Hz, 3H, 8-CH ), 1.13(d, J = 7.8 Hz, 3H, 2-CH ), 1.12(d, J = 6.9 Hz, White solid, yield 85%. H NMR (CDCl3, 400 MHz) δ 8.08(d, J = 7.8 Hz, 2H,
3
3
3
H, 10-CH3), 1.10(d, J = 7.4 Hz, 3H, 4-CH3), 0.78(t, J = 7.2 Hz, 3H, 15-H). phenyl-H2, phenyl-H6), 7.68(t, J = 6.9 Hz, 1H, phenyl-H4), 7.50(s, 1H,
+
ESI-MS(m/z): 894(M+H) .
phenyl-H2), 7.49(t, J =6.0 Hz, 2H, phenyl-H3, phenyl-H5), 7.45(d,
J = 7.7 Hz, 1H, phenyl-H6), 7.04(d, J = 7.7 Hz, 1H, phenyl-H5), 6.82(d,
J = 7.7 Hz, 1H, phenyl-H4), 4.92(dd, J = 2.1, 8.7 Hz, 1H, 13-H), 4.57(dd,
J = 8.0, 10.1 Hz, 1H, 2′-H), 4.12(d, 1H, J = 10.8 Hz, 5-H), 3.83(q, J = 7.8 Hz,
1H, 2-H), 3.72(m, 2H, CH2CH2CH2OH), 3.55(d, J = 2.5 Hz, 1H, 11-H), 3.50
2
′-O-Benzoyl-11-deoxy-3-des(hexopyranosyloxy)-6-O-methyl-11-
3-[(4-methylphenylcarbamoyl)oxy]propylamino]-3-oxoery-
thromycin A 11-N,12-O-cyclic carbamate (5b)
[
1
White solid, yield 85%. H NMR (CDCl3, 400 MHz) δ 8.08(d, J = 7.8 Hz, 2H, (m, 1H, 5′-H), 3.41(m, 1H, 4-H), 3.10(q, J =7.0 Hz, 1H, 8-H), 3.05
phenyl-H2, phenyl-H6), 7.68(t, J = 6.9 Hz, 1H, phenyl-H4), 7.49(t, J = 6.0 Hz,
(ql, J = 6.9 Hz, 1H, 10-H), 2.86(m, 2H, NCH2CH2CH2OH), 2.78(s, 3H,
H, phenyl-H3, phenyl-H5), 7.37(d, J = 8.0 Hz, 2H, phenyl-H2, phenyl-H6), 6-O-CH ), 2.7(m, 1H, 3′-H), 2.27(s, 6H, N(CH ) ), 2.24(s, 3H, phenyl-CH ),
2
7
1
3
3 2
3
.06(d, J = 8.0 Hz, 2H, phenyl-H3, phenyl-H5), 4.92(dd, J = 2.1, 8.7 Hz, 1H, 1.93(m, 1H, 14-Ha), 1.73(m, 1H, 4′-Ha), 1.65(m, 2H, NCH CH CH OH),
2
2
2
3-H), 4.57(dd, J = 8.0, 10.1 Hz, 1H, 2′-H), 4.12(d, 1H, J = 10.8 Hz, 5-H), 3.83 1.63(m, 1H, 14-Hb), 1.52(s, 3H, 6-CH ), 1.38(m, 1H, 7-Ha), 1.32(m, 1H,
3
(q, J = 7.8 Hz, 1H, 2-H), 3.72(m, 2H, CH CH CH OH), 3.55(d, J = 2.5 Hz, 1H,
2 2 2
7-Hb), 1.26(s, 3H, 12-CH ), 1.24(m, 1H, 4′-Hb), 1.17(d, J = 7.0 Hz, 3H,
3
1
1-H), 3.50(m, 1H, 5′-H), 3.41(m, 1H, 4-H), 3.10(q, J =7.0 Hz, 1H, 8-H), 3.05
8
1
9
-CH ), 1.13(d, J = 7.8 Hz, 3H, 2-CH ), 1.12(d, J = 6.9 Hz, 3H, 10-CH ),
3
3
3
(ql, J = 6.9 Hz, 1H, 10-H), 2.86(m, 2H, NCH2CH2CH2OH), 2.78(s, 3H,
.10(d, J = 7.4 Hz, 3H, 4-CH3), 0.78(t, J = 7.2 Hz, 3H, 15-H). ESI-MS(m/z):
6
1
1
7
8
1
9
-O-CH3), 2.7(m, 1H, 3′-H), 2.27(s, 6H, N(CH3)2), 2.24(s, 3H, phenyl-CH3),
+
08(M+H) .
.93(m, 1H, 14-Ha), 1.73(m, 1H, 4′-Ha), 1.65(m, 2H, NCH2CH2CH2OH),
.63(m, 1H, 14-Hb), 1.52(s, 3H, 6-CH ), 1.38(m, 1H, 7-Hb), 1.32(m, 1H,
-Hb), 1.26(s, 3H, 12-CH3), 1.24(m, 1H, 4′-Hb), 1.17(d, J = 7.0 Hz, 3H,
-CH ), 1.13(d, J =7.8 Hz, 3H, 2-CH ), 1.12(d, J =6.9 Hz, 3H, 10-CH ),
.10(d, J = 7.4 Hz, 3H, 4-CH3), 0.78(t, J = 7.2 Hz, 3H, 15-H). ESI-MS(m/z):
08(M+H) .
3
2
1
′-O-Benzoyl-11-[3-[(2-chlorophenylcarbamoyl)oxy]propylamino]-
1-deoxy-3-des(hexopyranosyloxy)-6-O-methyl-3-oxoerythromycin
3
3
3
A 11-N,12-O-cyclic carbamate (5f)
White solid, yield 78%. 1H NMR (CDCl3, 400 MHz) δ 8.10(t, J = 6.9 Hz,
+
1H, phenyl-H6), 8.08(d, J = 7.8 Hz, 2H, phenyl-H2, phenyl-H6), 7.85(s, 1H,
phenyl-H2), 7.68(t, J = 6.9 Hz, 1H, phenyl-H4), 7.49(t, J = 6.0 Hz, 2H,
phenyl-H3, phenyl-H5), 7.15(t, J = 7.7 Hz, phenyl-H3), 7.00(t, J =8.0 Hz,
2
′-O-Benzoyl-11-deoxy-3-des(hexopyranosyloxy)-6-O-methyl-11-
[3-[(4-methoxyphenylcarbamoyl)oxy]propylamino]-3-oxoery-
1
1
3
1
3
6
1
1
H, phenyl-H5), 6.92(t, J = 8.0 Hz, 1H, phenyl-H4), 4.92(dd, J = 2.1, 8.7 Hz,
H, 13-H), 4.57(dd, J = 8.0, 10.1 Hz, 1H, 2′-H), 4.12(d, J = 10.8 Hz, 1H, 5-H),
.83(q, J = 7.8 Hz, 1H, 2-H), 3.72(m, 2H, CH2CH2CH2OH), 3.55(d, J = 2.5 Hz,
H, 11-H), 3.50(m, 1H, 5′-H), 3.41(m, 1H, 4-H), 3.10(q, J = 7.0 Hz, 1H, 8-H),
.05(ql, J = 6.9 Hz, 1H, 10-H), 2.86(m, 2H, NCH2CH2CH2OH), 2.78(s, 3H,
-O-CH3), 2.7(m, 1H, 3′-H), 2.27(s, 6H, N(CH3)2), 2.24(s, 3H, phenyl-CH3),
.93(m, 1H, 14-Ha), 1.73(m, 1H, 4′-Ha), 1.65(m, 2H, NCH2CH2CH2OH),
.63(m, 1H, 14-Hb), 1.52(s, 3H, 6-CH3), 1.38(m, 1H, 7-Ha), 1.32(m, 1H,
thromycin A 11-N,12-O-cyclic carbamate (5c)
White solid, yield 83%. H NMR (CDCl3, 400 MHz) δ 8.08(d, J = 7.8 Hz, 2H,
phenyl-H2, phenyl-H6), 7.68(t, J = 6.9 Hz, 1H, phenyl-H4), 7.49(t, J = 6.0 Hz,
1
2
6
1
H, phenyl-H3, phenyl-H5), 7.47(d, J = 8.0 Hz, 2H, phenyl-H2, phenyl-H6),
.89(d, J = 8.0 Hz, 2H, phenyl-H3, phenyl-H5), 4.92(dd, J = 2.1, 8.7 Hz, 1H,
3-H), 4.57(dd, J = 8.0, 10.1 Hz, 1H, 2′-H), 4.12(d, 1H, J = 10.8 Hz, 5-H), 3.83
(q, J = 7.8 Hz, 1H, 2-H), 3.72(m, 2H, CH CH CH OH), 3.60(s, 3H,
2 2 2
phenyl-OCH3), 3.55(d, J = 2.5 Hz, 1H, 11-H), 3.50(m, 1H, 5′-H), 3.41
(
m, 1H, 4-H), 3.10(q, J = 7.0 Hz, 1H, 8-H), 3.05(ql, J = 6.9 Hz, 1H, 10-H), 7-Hb), 1.26(s, 3H, 12-CH3), 1.24(m, 1H, 4′-Hb), 1.17(d, J = 7.0 Hz, 3H,
8-CH3), 1.13(d, J = 7.8 Hz, 3H, 2-CH3), 1.12(d, J = 6.9 Hz, 3H, 10-CH3),
s, 6H, N(CH3)2), 2.24(s, 3H, phenyl-CH3), 1.93(m,1H, 14-Ha), 1.73(m,1H, 1.10(d, J = 7.4 Hz, 3H, 4-CH3), 0.78(t, J = 7.2 Hz, 3H, 15-H). ESI-MS(m/z):
2
(
.86(m, 2H, NCH2CH2CH2OH), 2.78(s, 3H, 6-O-CH3), 2.7(m, 1H, 3′-H), 2.27
+
4
′-Ha), 1.65(m, 2H, NCH CH CH OH), 1.63(m,1H, 14-Hb), 1.52(s, 3H, 928(M+H) .
2
2
2
The Journal of Antibiotics

A series of novel ketolide derivatives
Z Zheng et al
6
2
1
′-O-Benzoyl-11-[3-[(3-chlorophenylcarbamoyl)oxy]propylamino]-
1-deoxy-3-des(hexopyranosyloxy)-6-O-methyl-3-oxoerythromycin
3H, 10-CH3), 1.10(d, J = 7.4 Hz, 3H, 4-CH3), 0.85(t, J = 7.2 Hz, 3H, 15-H).
ESI-MS(m/z): 790(M+H) .
+
A 11-N,12-O-cyclic carbamate (5g)
1
White solid, yield 75%. H NMR (CDCl3, 400 MHz) δ 8.08(d, J = 7.8 Hz, 2H, 11-Deoxy-3-des(hexopyranosyloxy)-6-O-methyl-11-[3-[(4-
phenyl-H2, phenyl-H6), 7.85(s, 1H, phenyl-H2), 7.68(t, J = 6.9 Hz, 1H, methylphenylcarbamoyl)oxy]propylamino]-3-oxoerythromycin A
phenyl-H4), 7.55(d, J = 7.7 Hz, 1H, phenyl-H6), 7.49(t, J = 6.0 Hz, 2H, 11-N,12-O-cyclic carbamate (6b)
1
phenyl-H3, phenyl-H5), 7.21(d, J = 7.7 Hz, 1H, phenyl-H5), 7.03
d, J = 7.7 Hz, 1H, phenyl-H4), 4.92(dd, J = 2.1, 8.7 Hz, 1H, 13-H),
.57(dd, J = 8.0, 10.1 Hz, 1H, 2′-H), 4.12(d, J = 10.8 Hz, 1H, 5-H), 3.83 (d, J = 8.0 Hz, 2H, phenyl-H3, phenyl-H5), 4.97(dd, J = 2.1, 8.7 Hz, 1H,
White solid, yield 96%.
H NMR(CDCl3, 400 MHz) δ 8.9(s, 1H,
(
4
(
OCONHphenyl), 7.37(d, J = 8.0 Hz, 2H, phenyl-H2, phenyl-H6), 7.06
q, J =7.8 Hz, 1H, 2-H), 3.72(m, 2H, CH2CH2CH2OH), 3.55(d, J = 2.5 Hz,
13-H), 4.27(d, J = 7.5 Hz, 1H, 1′-H), 4.23(d, J = 8.0 Hz, 1H, 5-H), 3.83
(q, J = 7.0 Hz, 1H, 2-H), 3.70(m, 2H, CH2CH2CH2OCON), 3.59
(d, J = 2.5 Hz, 1H, 11-H), 3.50(m, 1H, 5′-H), 3.10(m, 2H, 10-H, 4-H), 3.20
(dd, J = 7.5, 8.8 Hz, 1H, 2′-H), 3.10(q, J = 7.0 Hz, 1H, 8-H), 2.86(m, 2H,
NCH2CH2CH2OH), 2.61(s, 3H, 6-O-CH3), 2.48(m, 1H, 3′-H), 2.29(s, 6H,
N(CH3)2), 2.24(s, 3H, phenyl-CH3), 1.93(m, 1H, 14-Ha), 1.73(m, 1H, 4′-Ha),
1
3
6
1
1
7
3
1
9
H, 11-H), 3.50(m, 1H, 5′-H), 3.41(m, 1H, 4-H), 3.10(q, J = 7.0 Hz, 1H, 8-H),
.05(ql, J = 6.9 Hz, 1H, 10-H), 2.86(m, 2H, NCH2CH2CH2OH), 2.78(s, 3H,
-O-CH ), 2.7(m, 1H, 3′-H), 2.27(s, 6H, N(CH ) ), 2.24(s, 3H, phenyl-CH ),
3
3 2
3
.93(m, 1H, 14-Ha), 1.73(m, 1H, 4′-Ha), 1.65(m, 2H, NCH2CH2CH2OH),
.63(m, 1H, 14-Hb), 1.52(s, 3H, 6-CH ), 1.38(m, 1H, 7-Ha), 1.32(m, 1H,
3
1
(
1
.65(m, 2H, NCH CH CH O), 1.63(m, 1H, 14-Hb), 1.47(s, 3H, 12-CH ), 1.38
-Hb), 1.26(s, 3H, 12-CH3), 1.24(m, 1H, 4′-Hb), 1.17(d, J = 7.0 Hz,
H, 8-CH ), 1.13(d, J = 7.8 Hz, 3H, 2-CH ), 1.12(d, J = 6.9 Hz, 3H, 10-CH ),
2
2
2
3
m, 1H, 7-Ha), 1.34(s, 3H, 6-CH ), 1.32(m, 1H, 7-Hb), 1.24(m, 1H, 4′-Hb),
.17(d, J = 7.0 Hz, 3H, 8-CH3), 1.13(d, J = 7.8 Hz, 3H, 2-CH3), 1.12
(d, J = 6.9 Hz, 3H, 10-CH3), 1.10(d, J = 7.4 Hz, 3H, 4-CH3), 0.85
t, J = 7.2 Hz, 3H, 15-H). ESI-MS(m/z): 804(M+H) .
3
3
3
3
.10(d, J = 7.4 Hz, 3H, 4-CH3), 0.78(t, J = 7.2 Hz, 3H, 15-H). ESI-MS(m/z):
+
28(M+H) .
+
(
2
′-O-Benzoyl-11-deoxy-3-des(hexopyranosyloxy)-6-O-methyl-3-
1
1-Deoxy-3-des(hexopyranosyloxy)-6-O-methyl-11-[3-[(4-
oxo-11-[3-[(4-trifluoromethylphenylcarbamoyl)oxy]propylamino]
erythromycin A 11-N,12-O-cyclic carbamate (5h)
White solid, yield 92%. 1H NMR (CDCl3, 400 MHz) δ 8.08(d, J = 7.8 Hz,
methoxyphenylcarbamoyl)oxy]propylamino]-3-oxoerythromycin A
11-N,12-O-cyclic carbamate (6c)
White solid, yield 93%.
1
H NMR (CDCl3, 400 MHz) δ 8.78(s, 1H,
2
7
H, phenyl-H2, phenyl-H6), 7.85(d, J = 7.2 Hz, 2H, phenyl-H3, phenyl-H5),
.68(t, J =6.9 Hz, 1H, phenyl-H4), 7.49(t, J =6.0 Hz, 2H, phenyl-H3,
OCONHphenyl), 7.47(d, J = 8.0 Hz, 2H, phenyl-H2, phenyl-H6), 6.89
d, J = 8.0 Hz, 2H, phenyl-H3, phenyl-H5), 4.97(dd, J = 2.1, 8.7 Hz, 1H,
3-H), 4.27(d, J = 7.5 Hz, 1H, 1′-H), 4.23(d, J = 8.0 Hz, 1H, 5-H), 3.83
q, J = 7.8 Hz, 1H, 2-H), 3.70(m, 2H, CH CH CH OCON), 3.60(s, 3H,
(
1
(
phenyl-H5), 7.44(d, J = 7.2 Hz, 2H, phenyl-H2, phenyl-H6), 4.92(dd, J = 2.1,
8
.7 Hz, 1H, 13-H), 4.57(dd, J = 8.0, 10.1 Hz, 1H, 2′-H), 4.12(d, 1H, J = 10.8 Hz,
2
2
2
5-H), 3.83(q, J = 7.8 Hz, 1H, 2-H), 3.72(m, 2H, CH2CH2CH2OH), 3.60(s, 3H,
phenyl-OCH ), 3.59(d, J = 2.5 Hz, 1H, 11-H), 3.50(m, 1H, 5′-H), 3.10
3
phenyl-OCH3), 3.55(d, J = 2.5 Hz, 1H, 11-H), 3.50(m, 1H, 5′-H), 3.41(m, 1H,
-H), 3.10(q, J =7.0 Hz, 1H, 8-H), 3.05(ql, J = 6.9 Hz, 1H, 10-H), 2.86(m, 2H,
(
1
m, 2H, 10-H, 4-H), 3.20(dd, J = 7.5, 8.8 Hz, 1H, 2′-H), 3.10(q, J = 7.0 Hz,
4
H, 8-H), 2.86(m, 2H, NCH2CH2CH2OH), 2.61(s, 3H, 6-O-CH3), 2.48(m, 1H,
NCH2CH2CH2OH), 2.78(s, 3H, 6-O-CH3), 2.7(m, 1H, 3′-H),2.27(s, 6H,
N(CH3)2), 2.24(s, 3H, phenyl-CH3), 1.93(m, 1H, 14-Ha), 1.73(m, 1H,
3
′-H), 2.29(s, 6H, N(CH3)2), 1.93(m, 1H, 14-Ha), 1.73(m, 1H, 4′-Ha), 1.65
(m, 2H, NCH2CH2CH2O), 1.63(m, 1H, 14-Hb), 1.47(s, 3H, 12-CH3), 1.38
4
6
1
2
0
′-Ha), 1.65(m, 2H, NCH2CH2CH2OH), 1.63(m, 1H, 14-Hb), 1.52(s, 3H,
-CH3), 1.38(m, 1H, 7-Ha), 1.32(m, 1H, 7-Hb), 1.26(s, 3H, 12-CH3),
.24(m, 1H, 4′-Hb), 1.17(d, J = 7.0 Hz, 3H, 8-CH3), 1.13(d, J = 7.8 Hz, 3H,
-CH3), 1.12(d, J = 6.9 Hz, 3H, 10-CH3), 1.10(d, J = 7.4 Hz, 3H, 4-CH3),
(
1
m, 1H, 7-Ha), 1.34(s, 3H, 6-CH3), 1.32(m, 1H, 7-Hb), 1.24(m, 1H, 4′-Hb),
.17(d, J = 7.0 Hz, 3H, 8-CH3), 1.13(d, J = 7.8 Hz, 3H, 2-CH3), 1.12
(d, J = 6.9 Hz, 3H, 10-CH3), 1.10(d, J = 7.4 Hz, 3H, 4-CH3), 0.84
+
(t, J = 7.2 Hz, 3H, 15-H). ESI-MS(m/z): 820(M+H) .
+
.79(t, J = 7.2 Hz, 3H, 15-H). ESI-MS(m/z): 962(M+H) .
1
1-Deoxy-3-des(hexopyranosyloxy)-6-O-methyl-11-[3-[(4-nitro-
phenylcarbamoyl)oxy]propylamino]-3-oxoerythromycin A 11-N,
2-O-cyclic carbamate (6d)
General methods for 11-[3-[(arylcarbamoyl)oxy]propylamino]-11-
deoxy-3-des(hexopyranosyloxy)-6-O-methyl-3-oxoerythromycin A
1
1
1
(
1-N,12-O-cyclic carbamates (6a-h)
1-[3-[(Arylcarbamoyl)oxy]propylamino]-2′-O-benzoyl-11-deoxy-3-des
hexopyranosyloxy)-6-O-methyl-3-oxoerythromycin A 11-N,12-O-cyclic carba-
1
White solid, yield 86%.
OCONHphenyl), 8.05(d, J = 8.2 Hz, 2H, phenyl-H2, phenyl-H6), 7.63
d, J = 8.2 Hz, 2H, phenyl-H3, phenyl-H5), 4.97(dd, J = 2.1, 8.7 Hz, 1H,
3-H), 4.27(d, J = 7.5 Hz, 1H, 1′-H), 4.23(d, J = 8.0 Hz,1H, 5-H), 3.83
H NMR (CDCl3, 400 MHz) δ 9.08(s, 1H,
(
1
mate (5) (0.5 mmol) was dissolved in methanol (20 ml) and the solution was
refluxed for 20 h under nitrogen. The reaction mixture was filtered and
concentrated in vacuum. The residue was purified by flash chromatography
(q, J = 7.8 Hz, 1H, 2-H), 3.70(m, 2H, CH2CH2CH2OCON), 3.59
(d, J = 2.5 Hz, 1H, 11-H), 3.50(m, 1H, 5′-H), 3.10(m, 2H, 10-H, 4-H), 3.20
(dd, J = 7.5, 8.8 Hz, 1H, 2′-H), 3.10(q, J = 7.0 Hz, 1H, 8-H), 2.86(m, 2H,
(
cyclohexane-ethyl acetate, 5:2) to afford product 6 as a white solid.
NCH2CH2CH2O), 2.61(s, 3H, 6-O-CH3), 2.48(m, 1H, 3′-H), 2.29(s, 6H, N
(CH ) ), 1.93(m, 1H, 14-Ha), 1.73(m, 1H, 4′-Ha), 1.65(m, 2H,
1
[
1-Deoxy-3-des(hexopyranosyloxy)-6-O-methyl-3-oxo-11-[3-
(phenylcarbamoyl)oxy]propylamino]erythromycin A 11-N,12-O-
cyclic carbamate (6a)
3
2
NCH CH CH O), 1.63(m, 1H, 14-Hb), 1.47(s, 3H, 12-CH ), 1.38(m, 1H,
2
2
2
3
7-Ha), 1.34(s, 3H, 6-CH3), 1.32(m, 1H, 7-Hb), 1.24(m, 1H, 4′-Hb), 1.17
(d, J = 7.0 Hz, 3H, 8-CH3), 1.13(d, J =7.8 Hz, 3H, 2-CH3), 1.12(d, J = 6.9 Hz,
3H, 10-CH3), 1.10(d, J = 7.4 Hz, 3H, 4-CH3), 0.84(t, J = 7.2 Hz, 3H, 15-H).
1
White solid, yield 95%. H NMR (CDCl3, 400 MHz) δ 8.01(s, 1H, OCONH-
phenyl), 7.39(d, J = 7.8 Hz, 2H, phenyl-H2, phenyl-H6), 7.29(d, J =8.1 Hz, 2H,
phenyl-H3, phenyl-H5), 7.03(t, J =7.8 Hz, 1H, phenyl-H4), 4.97(dd, J = 2.1,
+
ESI-MS(m/z): 835(M+H) .
8
3
.7 Hz, 1H, 13-H), 4.27(d, J = 7.5 Hz, 1H, 1′-H), 4.23(d, 1H, J = 8.0 Hz, 5-H),
.83(q, J = 7.8 Hz, 1H, 2-H), 3.70(m, 2H, CH2CH2CH2OCON), 3.59 11-Deoxy-3-des(hexopyranosyloxy)-6-O-methyl-11-[3-[(3-methyl-
(
(
d, J =2.5 Hz, 1H, 11-H), 3.50(m, 1H, 5′-H), 3.10(m, 2H, 10-H, 4-H), 3.20 phenylcarbamoyl)oxy]propylamino]-3-oxoerythromycin A 11-N,
dd, J = 7.5, 8.8 Hz, 1H, 2′-H), 3.10(q, J = 7.0 Hz, 1H, 8-H), 2.86(m, 2H, 12-O-cyclic carbamate (6e)
1
NCH CH CH OH), 2.61(s, 3H, 6-O-CH ), 2.48(m, 1H, 3′-H), 2.29(s, 6H, N
(
NCH CH CH OH), 1.63(m, 1H, 14-Hb), 1.47(s, 3H, 12-CH ), 1.38(m, 1H,
White solid, yield 96%.
H NMR (CDCl3, 400 MHz) δ 9.61(s, 1H,
2
2
2
3
CH3)2), 1.93(m, 1H, 14-Ha), 1.73(m, 1H, 4′-Ha), 1.65(m, 2H,
OCONHphenyl), 7.50(s, 1H, phenyl-H2), 7.45(d, J = 7.7 Hz, 1H, phenyl-H6),
7.04(d, J = 7.7 Hz, 1H, phenyl-H5), 6.82(d, J = 7.7 Hz, 1H, phenyl-H4),
2
2
2
3
7
-Ha), 1.34(s, 3H, 6-CH3), 1.32(m, 1H, 7-Hb), 1.24(m, 1H, 4′-Hb), 1.17 4.97(dd, J = 2.1, 8.7 Hz, 1H, 13-H), 4.27(d, J =7.5 Hz, 1H, 1′-H), 4.23
(
d, J = 7.0 Hz, 3H, 8-CH ), 1.13(d, J = 7.8 Hz, 3H, 2-CH ), 1.12(d, J = 6.9 Hz, (d, 1H, J = 8.0 Hz, 5-H), 3.83(q, J = 7.8 Hz, 1H, 2-H), 3.70(m, 2H,
3
3
The Journal of Antibiotics

A series of novel ketolide derivatives
Z Zheng et al
7
CH2CH2CH2OCON), 3.59(d, J = 2.5 Hz, 1H, 11-H), 3.50(m, 1H, 5′-H), 3.10 CONFLICT OF INTEREST
(
m, 2H, 10-H, 4-H), 3.20(dd, J = 7.5, 8.8 Hz, 1H, 2′-H), 3.10(q, J = 7.0 Hz, The authors declare no conflict of interest.
1
3
1
H, 8-H), 2.86(m, 2H, NCH CH CH OH), 2.61(s, 3H, 6-O-CH ), 2.48(m, 1H,
2 2 2 3
′-H), 2.29(s, 6H, N(CH3)2), 2.24(s, 3H, phenyl-CH3), 1.93(m, 1H, 14-Ha), ACKNOWLEDGEMENTS
.73(m, 1H, 4′-Ha), 1.65(m, 2H, NCH2CH2CH2O), 1.63(m, 1H, 14-Hb), 1.47
This research was supported by Shandong Xinhua Pharmaceutical Co., Ltd.,
(s, 3H, 12-CH ), 1.38(m, 1H, 7-Ha), 1.34(s, 3H, 6-CH ), 1.32(m, 1H, 7-Hb), and National Natural Science Foundation of China (30801427).
3
3
1.24(m, 1H, 4′-Hb), 1.17(d, J = 7.0 Hz, 3H, 8-CH3), 1.13(d, J = 7.8 Hz, 3H,
2-CH3), 1.12(d, J =6.9 Hz, 3H, 10-CH3), 1.10(d, J = 7.4 Hz, 3H, 4-CH3),
0.84(t, J = 7.2 Hz, 3H, 15-H). ESI-MS(m/z): 804(M+H)
1
2
Metz, M. & Shlaes, D. M. Eight more ways to deal with antibiotic resistance. Antimicrob.
Agents Chemother. 58, 4253–4256 (2014).
McManus, B. A. et al. Susceptibility of methicillin-resistant Staphylococci clinical
isolates to netilmicin and other antibiotics commonly used in ophthalmic therapy.
Curr. Eye Res. 38, 811–816 (2013)
McManus, B. A. et al. Comparative genotypes, Staphylococcal Cassette Chromosome
mec (SCCmec) genes and antimicrobial resistance amongst Staphylococcus
epidermidis and Staphylococcus haemolyticus isolates from infections in humans and
companion animals. PLoS ONE. 10, e0138079 (2015)
1
1-[3-[(2-Chlorophenylcarbamoyl)oxy]propylamino]-11-deoxy-3-
des(hexopyranosyloxy)-6-O-methyl-3-oxoerythromycin A 11-N,
2-O-cyclic carbamate (6f)
1
1
White solid, yield 91%. H NMR (CDCl3, 400 MHz) δ 8.10(t, J = 6.9 Hz, 1H,
phenyl-H6), 7.85(s, 1H, phenyl-H2), 7.78(s, 1H, OCONHphenyl), 7.15
3
(
6
(
2
t, J = 7.7 Hz, 1H, phenyl-H3), 7.00(t, J = 8.0 Hz, 1H, phenyl-H5),
.92(t, J = 8.0 Hz, 1H, phenyl-H4), 4.97(dd, J = 2.1, 8.7 Hz, 1H, 13-H), 4.27
d, J = 7.5 Hz, 1H, 1′-H), 4.23(d, J = 8.0 Hz, 1H, 5-H), 3.83(q, J = 7.8 Hz, 1H,
-H), 3.70(m, 2H, CH CH CH OCON), 3.59(d, J = 2.5 Hz, 1H, 11-H), 3.50
4
5
Farrell, D. J. et al. Emergence and spread of Streptococcus pneumoniae with erm(B)
and mef(A) resistance. Emerg. Infect. Dis. 11, 851–858 (2005)
Morimoto, S., Takahashi, Y., Watanabe, Y.
& Omura, S. Chemical modification
2
2
2
of erythromycins. I. Synthesis and antibacterial activity of 6-O-methylerythromycins A.
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Zhanel, G. G. et al. Review of macrolides and ketolides focus on respiratory tract
infections. Drugs 61, 443–498 (2001).
Leclercq, R. & Courvalin, P. Bacterial resistance to macrolide, lincosamide, and
(
m, 1H, 5′-H), 3.10(m, 2H, 10-H, 4-H), 3.20(dd, J = 7.5, 8.8 Hz, 1H, 2′-H),
3
6
1
.10(q, J = 7.0 Hz, 1H, 8-H), 2.86(m, 2H, NCH2CH2CH2O), 2.61(s, 3H,
6
7
-O-CH ), 2.48(m, 1H, 3′-H), 2.29(s, 6H, N(CH )2), 1.93(m, 1H, 14-Ha),
.73(m, 1H, 4′-Ha), 1.65(m, 2H, NCH2CH2CH2O), 1.63(m, 1H, 14-Hb), 1.47
3
3
streptogramin antibiotics by target modification. Antimicrob. Agents Chemother. 35,
(s, 3H, 12-CH3), 1.38(m, 1H, 7-Ha), 1.34(s, 3H, 6-CH3), 1.32(m, 1H, 7-Hb),
1
267–1272 (1991).
1
2
0
.24(m, 1H, 4′-Hb), 1.17(d, J = 7.0 Hz, 3H, 8-CH ), 1.13(d, J = 7.8 Hz, 3H,
8
9
Leclercq, R. & Courvalin, P. Resistance to macrolides and related antibiotics in
S. pneumoniae. Antimicrob. Agents Chemother. 46, 2727–2734 (2002).
Denis, A. et al. Synthesis and antibacterial activity of HMR 3647 a new ketolide highly
potent against erythromycin-resistant and susceptible pathogens. Bioorg. Med. Chem.
Lett. 9, 3075–3080 (1999).
3
-CH ), 1.12(d, J =6.9 Hz, 3H, 10-CH ), 1.10(d, J = 7.4 Hz, 3H, 4-CH ),
3
3
3
+
.84(t, J = 7.2 Hz, 3H, 15-H). ESI-MS(m/z): 824(M+H) .
1
0 Or, Y. S. et al. Design, synthesis, and antimicrobial activity of 6-O-substituted
ketolides active against resistant respiratory tract pathogens. J. Med. Chem. 43,
1
1-[3-[(3-Chlorophenylcarbamoyl)oxy]propylamino]-11-deoxy-3-
des(hexopyranosyloxy)-6-O-methyl-3-oxoerythromycin A 11-N,
1045–1049 (2000).
1
2-O-cyclic carbamate (6g)
11 Champney, W. S. & Tober, C. L. Structure-activity relationship for six ketolide
White solid, yield 90%. 1H NMR (CDCl3, 400 MHz) δ 10.61(s, 1H,
antibiotics. Curr. Microbiol. 42, 203–210 (2001).
1
1
2 Zhanel, G. G. et al. The ketolides: a critical review. Drugs 62, 1771–1804 (2002).
3 Keyes, R. F. et al. Synthesis and antibacterial activity of 6-O-arylbutynyl ketolides with
improved activity against some key erythromycin-resistant pathogens. J. Med. Chem.
46, 1795–1798 (2003).
OCONHphenyl), 7.85(s, 1H, phenyl-H2), 7.55(d, J = 7.7 Hz, 1H, phenyl-H6),
7.21(d, J = 7.7 Hz, 1H, phenyl-H5), 7.03(d, J = 7.7 Hz, 1H, phenyl-H4), 4.97
(
1
dd, J = 2.1, 8.7 Hz, 1H, 13-H), 4.27(d, J = 7.5 Hz, 1H, 1′-H), 4.23(d, J = 8.0 Hz,
1
4 Yong, H. et al. Design, synthesis and structure–activity relationships of
H, 5-H), 3.83(q, J = 7.8 Hz, 1H, 2-H), 3.70(m, 2H, CH CH CH OCON),
2 2 2
6-O-arylpropargyl diazalides with potent activity against multidrug-resistant
3
.59(d, J = 2.5 Hz, 1H, 11-H), 3.50(m, 1H, 5′-H), 3.10(m, 2H, 10-H, 4-H), 3.20
Streptococcus pneumoniae. Bioorg. Med. Chem. Lett. 15, 2653–2658 (2005).
15 Sugimoto, T. et al. Synthesis and antibacterial activity of 6-O-(heteroaryl-isoxazolyl)
propynyl 2-fluoro ketolides. Bioorg. Med. Chem. Lett 22, 5739–5743 (2012).
(
dd, J = 7.5, 8.8 Hz, 1H, 2′-H), 3.10(q, J = 7.0 Hz, 1H, 8-H), 2.86(m, 2H,
NCH CH CH O), 2.61(s, 3H, 6-O-CH ), 2.48(m, 1H, 3′-H), 2.29(s, 6H, N
2
2
2
3
1
6 Nomura, T., Yasukata, T., Narukawa, Y. & Uotani, K. 9-Oxime-3-ketolides: modification
at the C-11,12-diol moiety and antibacterial activities against key respiratory pathogens.
Bioorg. Med. Chem. 13, 6054–6063 (2005).
(CH3)2), 1.93(m, 1H, 14-Ha), 1.73(m, 1H, 4′-Ha), 1.65(m, 2H,
NCH2CH2CH2O), 1.63(m, 1H, 14-Hb), 1.47(s, 3H, 12-CH3), 1.38(m, 1H,
7
-Ha), 1.34(s, 3H, 6-CH3), 1.32(m, 1H, 7-Hb), 1.24(m, 1H, 4′-Hb),
17 Beebe, X. et al. Synthesis and antibacterial activity of 6-O-arylpropargyl-9-oxime-11,
2-carbamate ketolides. Bioorg. Med. Chem. Lett. 14, 2417–2421 (2004).
8 Liang, J.-H. et al. Synthesis and antibacterial activities of 6-O-methylerythromycin A
-O-(3-aryl-2-propenyl) oxime ketolide, 2,3-enol ether, and alkylide analogues.
Eur. J. Med. Chem. 45, 3627–3635 (2010).
9 Hunziker, D. et al. Novel ketolide antibiotics with a fused five-membered lactone
ring–synthesis, physicochemical and antimicrobial properties. Bioorg. Med. Chem. 12,
1
1.17(d, J = 7.0 Hz, 3H, 8-CH3), 1.13(d, J = 7.8 Hz, 3H, 2-CH3), 1.12
1
1
(d, J = 6.9 Hz, 3H, 10-CH3), 1.10(d, J = 7.4 Hz, 3H, 4-CH3), 0.85
9
+
(t, J = 7.2 Hz, 3H, 15-H). ESI-MS(m/z): 824(M+H) .
1
1-Deoxy-3-des(hexopyranosyloxy)-6-O-methyl-3-oxo-11-[3-[(4-
trifluoromethylphenylcarbamoyl)oxy]propylamino]erythromycin A
1-N,12-O-cyclic carbamate (6h)
3
503–3519 (2004).
20 Zhu, B. et al. Synthesis and antibacterial activity of 3-keto-6-O-carbamoyl-11,12-cyclic
thiocarbamate erythromycin derivatives. Bioorg. Med. Chem. Lett. 17,
900–3904 (2007).
A
1
3
1
White solid, yield 93%. H NMR (CDCl3, 400 MHz) δ 7.85(d, J = 7.2 Hz, 2H,
phenyl-H3, phenyl-H5), 7.68(t, J = 6.9 Hz, 1H, phenyl-H4), 7.44(d, J = 7.2 Hz,
2
1 Elliott, R. L. et al. Anhydrolide Macrolides. 1. Synthesis and Antibacterial Activity of
2,3-Anhydro-6-O-methyl-11,12-carbamate Erythromycin A Analogues. J. Med. Chem.
41, 1651–1659 (1998).
2H, phenyl-H2, phenyl-H6), 4.97(dd, J = 2.1, 8.7 Hz, 1H, 13-H), 4.27
2
2
2 Wang, G. et al. 6-11 Bridged oxime erythromycin derivatives WO 2006119313,
accessed on 9 November 2006.
3 Sato, T. et al. In vitro antibacterial activity of modithromycin, a novel 6, 11-bridged
(d, J = 7.5 Hz, 1H, 1′-H), 4.23(d, J = 8.0 Hz, 1H, 5-H), 3.83(q, J = 7.8 Hz,
1
3
3
6
1
H, 2-H), 3.70(m, 2H, CH2CH2CH2OCON), 3.59(d, J = 2.5 Hz, 1H, 11-H),
.50(m, 1H, 5′-H), 3.10(m, 2H, 10-H, 4-H), 3.20(dd, J = 7.5, 8.8 Hz, 1H, 2′-H),
.10(q, J = 7.0 Hz, 1H, 8-H), 2.86(m, 2H, NCH2CH2CH2O), 2.61(s, 3H,
-O-CH3), 2.48(m, 1H, 3′-H), 2.29(s, 6H, N(CH3)2), 1.93(m, 1H, 14-Ha),
.73(m, 1H, 4′-Ha), 1.65(m, 2H, NCH CH CH O), 1.63(m, 1H, 14-Hb), 1.47
bicyclolide,
against
respiratory
pathogens,
including
macrolide-resistant
gram-positive cocci. Antimicrob. Agents Chemother. 55, 1588–1593 (2011).
4 Or, Y. S. et al. 6-11 Bicyclic ketolide derivatives WO 2005061525, accessed on 7 July
2
2005.
2
2
2
25 Downey, A. M. & Cairo, C. W. Synthesis of α-brominated phosphonates and their
(s, 3H, 12-CH3), 1.38(m, 1H, 7-Ha), 1.34(s, 3H, 6-CH3), 1.32(m, 1H, 7-Hb),
application as phosphate bioisosteres. Med. Chem. Commun. 5, 1619–1633 (2014).
2
6 Agours, C. et al. Synthesis and antibacterial activity of ketolides (6-O-Methyl-3-
oxoerythromycin derivatives): new class of antibacterials highly potent against
1
2
0
.24(m, 1H, 4′-Hb), 1.17(d, J = 7.0 Hz, 3H, 8-CH3), 1.13(d, J = 7.8 Hz, 3H,
a
-CH ), 1.12(d, J =6.9 Hz, 3H, 10-CH ), 1.10(d, J = 7.4 Hz, 3H, 4-CH ),
3
3
3
macrolides-resistant and susceptible respiratiory pathogents. J. Med. Chem. 41,
4080–4100 (1998).
+
.85(t, J = 7.2 Hz, 3H, 15-H). ESI-MS(m/z): 858(M+H) .
The Journal of Antibiotics