Synthesis and antibacterial activity of novel modified 5-O-mycaminose 14-membered ketolides

Article abstract of DOI:10.1016/j.ejmech.2013.08.023

A practicable method of introducing a side chain to the C-4′ position of 5-O-desosamine in the 14-membered ketolides was developed. And using this method, a series of novel modified 5-O-mycaminose ketolides were synthesized. These ketolides containing 5-O

Full text of DOI:10.1016/j.ejmech.2013.08.023

European Journal of Medicinal Chemistry 69 (2013) 174e181
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antibacterial activity of novel modified 5-O-
mycaminose 14-membered ketolides
Yanpeng Xu, Xiaozhuo Chen, Di Zhu, Yi Liu, Zhehui Zhao, Longlong Jin, Chao Liu,
*
Pingsheng Lei
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of Active Substances Discovery and Drugability
Evaluation, Department of Medicinal Chemistry, Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences,
Beijing 100050, PR China
a r t i c l e i n f o
a b s t r a c t
A practicable method of introducing a side chain to the C-40 position of 5-O-desosamine in the 14-
membered ketolides was developed. And using this method, a series of novel modified 5-O-mycami-
nose ketolides were synthesized. These ketolides containing 5-O-40-carbamate mycaminose were eval-
uated for their in vitro antibacterial activities against some respiratory pathogens. 15b and 18e showed
comparable activity to telithromycin and clarithromycin.
Article history:
Received 27 May 2013
Received in revised form
8 July 2013
Accepted 12 August 2013
Available online 23 August 2013
Ó 2013 Elsevier Masson SAS. All rights reserved.
Keywords:
14-Membered ketolide
Desosamine
Mycaminose
Synthesis
Antibacterial activity
1. Introduction
derivatives with 20- or 30-modified desosamine [6]. They concluded
from the results that the erm-type resistance (A2058-dimethylated
Macrolide antibiotics have been widely utilized to treat bacterial
infections for nearly 60 years. They are especially effective for the
treatment of the upper and lower respiratory tract infections [1].
However, bacterial resistance to macrolide antibiotics has become
increasingly prevalent over the past decades, due to the extensive
usage [2e4]. Recently, great efforts have been made to find struc-
tures which possess activity toward resistant pathogens.
The 5-O-desosamine residue is considered to be indispensable
for the antibacterial activity. The 20-hydroxyl group, together with
the 30-N,N-dimethylamino group, bind with the 23S RNA, residues
A2058 and A2059 [5]. These interactions contribute significantly to
the inhibition of the peptide bond formation.
strains) did not result from steric clash or the loss of hydrogen
bond. Furthermore, they hypothesized that it might involve non-
bonding interactions between N-6 methyl group(s) of A2058 and
water molecules coordinated to the Mg2þ cation bound to phos-
phate groups of G2056 and G2057 residues of 23S RNA. C. Liang
et al. replaced the 5-O-desosamine with its mimetics, and they
synthesized several 5-O-(60-O-benzoyl)-desosamine ketolides [7].
Ketolides containing the hydrophobic 60-O-benzoyl group dis-
played excellent activities against some erythromycin-resistant
strains. In our previous work [8], X. Chen et al. synthesized three
14-membered ketolides containing 40-modified desosamine, the 40-
hydroxyl (namely mycaminose), 40-O-benzyl, and 40-O-allyl de-
rivatives. Among them, the 40-hydroxyl ketolide showed potent
activity against certain sensitive pathogens while the other two
proved to be noneffective.
Due to the importance of the 5-O-desosamine, researchers have
made considerable efforts to modify the sugar with the purpose of
investigating the interaction between the desosamine and rRNA.
Recently N. LeTourneau et al. prepared several macrolide
As the major origination of the binding energy with the ribo-
some, slight modifications to the 5-O-desosamine might result in
change of antibacterial activity [9,10]. Therefore such researches
contribute to understand the action mechanism of desosamine
from different perspectives.
* Corresponding author. Institute of Materia Medica, Peking Union Medical Col-
lege & Chinese Academy of Medical Sciences, Room 408, East Building, No. 2
Nanwei Road, Xicheng District, Beijing 100050, PR China. Tel.: þ86 10 63162006;
fax: þ86 10 63017757.
16-Membered macrolides have a mycaminose-mycarose disac-
charide at the C-5 position, which is oriented similarly to the 5-O-
E-mail address: lei@imm.ac.cn (P. Lei).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.08.023

Y. Xu et al. / European Journal of Medicinal Chemistry 69 (2013) 174e181
175
desosamine of 14-membered macrolides. Furthermore the mycar-
ose reaches to the peptidyl transferase center (PTC), making addi-
tional interactions at G2505 and U2506, and directly inhibits
peptide bond formation. However, 14-membered macrolides with a
shorter 5-O-desosamine could not inhibit peptide bond formation,
but can block elongation of nascent peptides [11,12]. In the research
of 16-membered macrolides, Ly T. Phan et al. removed the mycarose
sugar of tylosin and synthesized 40-substituted macrolides [13].
Some of them, such as the 40-O-phenethylcarbamate analog,
exhibited improved activities against certain resistant pathogens.
The introduced arylalkyl side chain (a, b seen in Fig. 1) was thought
to be important for the improvement of the activities. The authors
80 ꢀC (90% yield). Following that, the cladinose sugar was hydrolyzed
by treating compound1 with 2 N HCl inwaterat room temperature to
give compound2 in a yield of 76%. Selective acetylation of 20- and 9-E-
oxime hydroxyl, and formation of 11,12-carbonate provided com-
pound 4 (90% yield) [15]. Afterward, Swern oxidation of 3-OH and
deprotection of 9,20-acetate in methanol gave compound 6 (64% yield
for 2 steps). Then 9-E-oxime hydroxyl was benzoylated selectively
at ꢁ20ꢀC with equivalent mole of benzoyl chloride and triethylamine
to give compound 7 (78% yield). Ultimately oxidation of 20-hydroxyl
to 20-ketone gave the unstable intermediate 8, which was stirred in
methanol at 50 ꢀC to remove the desosamine (67% yield for 2 steps)
1
[16]. The structure of acceptor 9 was confirmed by its H NMR, 13
C
inferred it might have
pep
stacking and hydrophobic interactions
NMR and HRMS spectra (Scheme 1).
with ribosome RNA bases.
With the acceptor 9 in hand, we proceeded to synthesize the
donor 13. It was synthesized from compound 10, the synthetic
method of which was reported in our previous work [8]. Treatment of
10 with acetic anhydride, acetic acid and sulfuric acid (1:1:0.5) yiel-
ded the 1,4-diacetyl compound 11, as a mixture of anomers [17]. Then
the 1-acetyl was removed selectively by hydrazine acetate in DMF to
form compound 12 (55% yield for 2 steps). And donor 13 can be ob-
tained smoothly by the reaction of 12 with trichloroacetonitrile,
catalyzed by 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (Scheme 2).
Then the donor 13 and acceptor 9 were coupled using TMSOTf as
a promoter to produce compound 14 (62% yield) (Scheme 3). The
neighboring group participation effect of 2-O-benzoyl in the donor
Based on that, we intended to modify the C-40 position of 14-
membered ketolides. We presumed if suitable substituent, such
as an aryl or alkyl group, could be introduced to the C-40 position of
5-O-desosamine they probably have different effects on the inter-
action between the desosamine and the ribosome binding site.
In this report, we constructed a practicable method of intro-
ducing a side chain to the C-40 position of 5-O-desosamine in the
14-membered ketolides by using commercially available starting
materials. And adopting this method, we synthesized a novel series
of 14-membered ketolides bearing 5-O-40-carbamate mycaminose.
In fact, modifications to the C-40 position of 14-membered ketolides
have rarely been reported for the synthetic difficulty. We hoped
such structural modification helped to better understand the
mechanism of the macrolide-ribosome interaction and to find new
effective antibiotics against resistant pathogens.
13 determined the product was of
b
-configuration (H-10: J ¼ 7.8 Hz;
C-10: 100.9 ppm). It is noteworthy that usually only catalytic
amount of promoter is needed in the glycosidation of tri-
chloroacetimidate donor [18]. However, in our glycosidation reac-
tion, the promoter TMSOTf was used in slight excess (1.1 equiv) to
glycosyl acceptor 9. That is because the dimethylamino group in the
donor acts as an acid-capturer, lowering the reactivity of the Lewis
acid TMSOTf. Despite trichloroacetimidate donor 13 was unstable
in the presence of excess TMSOTf, we obtained the desired product
efficiently by keeping the reaction system anhydrous carefully.
Following that, the 9-E-oxime benzoate and the 40-acetate were
selectively removed by treating compound 14 with 2 N HCl in
ethanol at 65 ꢀC for 6 h to afford 15a [19]. Deprotection of the 20-OH
from 15a gave compound 15b. Finally, 40- and 9-E-oxime carbamate
derivatives 16aee were produced from 15a by reacting with a se-
ries of isocyanates. The structures were confirmed by their 1H NMR,
13C NMR and HRMS spectra. And unmasking of the 20-hydroxyl via
methanolysis gave the target compounds. This deprotection pro-
cess lasted from 12 h to 48 h, and the reactions were monitored by
TLC from time to time. When the reaction starting material dis-
appeared, compounds 16a, 16b, 16c and 16d turned into com-
pounds 17a, 17b, 17c and 18d respectively. Methanolysis of 16e gave
two products, which were isolated and confirmed to be compounds
17e and 18e. We judged that 9-E-oxime carbamate in 18d, 18e was
also cleaved according to their 1H NMR and HRMS spectra. In
2. Chemistry
To synthesize the 5-O-40-carbamate mycaminose target com-
pounds, compound 14 is an important intermediate. It could be
synthesized by glycosylation of the acceptor 9 with the tri-
chloroacetimidate donor 13 (Scheme 3) [14].
To get the 5-hydroxyl macrolide skeleton as acceptor 9, we
transformed the 9-ketone to 9-E-oxime. It proved that the 9-E-
oxime played a vital role, compared with our previous method [8],
in which the 9-ketone was retained all alone. The 5-hydroxyl-9-
ketone compound was unstable since the 5-hydroxyl would
attack the 9-ketone to form hemiacetal under acid conditions, even
on the silica gel column. Therefore it was difficult to get the pure
product efficiently and in high yield. As far as the subsequent
glycosylation, degradation occurred similarly in the presence of
Lewis acid. Converting 9-ketone to 9-E-oxime overcame these
drawbacks and the reactions became tractable with highly
improved yield.
Acceptor 9 was synthesized by using clarithromycin as a starting
material. The C-9 ketone was converted to the oxime group in the
presence of hydroxylamine hydrochloride and sodium acetate at
1
compound 18d the H NMR signals for 40-H shifted downfield to
Fig. 1. Structures of telithromycin and tylosin.

176
Y. Xu et al. / European Journal of Medicinal Chemistry 69 (2013) 174e181
Scheme 1. Reagents and conditions: a) NaOAc, NH2OH$HCl, 80 ꢀC, 90%; b) 2 N HCl/H2O, 76%; c) Ac2O, Et3N, 85%; d) ClCOOCCl3, pyridine, 90%; e) (COCl)2, DMSO, Et3N, 73%; f) MeOH,
50 ꢀC, 88%; g) BzCl, Et3N, ꢁ20 ꢀC, 78%; h) (COCl)2, DMSO, Et3N; i) MeOH, 50 ꢀC, 67% for 2 steps.
1
4.85 ppm, similarly in compound 18e the H NMR signals for 40-H
shifted downfield to 5.12 ppm. It proved that the 40-carbamate side
chain still remained while the 9-E-oxime carbamate was removed.
The reaction results implied that 9-E-oxime alkylcarbamate was
more stable than the arylcarbamate in the methanolysis process.
concentration (MIC), which was determined by the broth micro-
dilution method as recommended by the CLSI [20].
ATCC 29213, 15 and 09-06 are methicillin-sensitive Staphylo-
coccus aureus (MSSA). ATCC 33591 and 09-13 are methicillin-
resistant S. aureus (MRSA). ATCC 12228 and 09-9 are methicillin-
sensitive Staphylococcus epidermidis (MSSE). 09-3 is a methicillin-
resistant S. epidermidis (MRSE).
3. Pharmacology
The antibacterial activities of the target compounds were
assessed against some respiratory pathogens, including macrolide
drug sensitive and resistant strains. Telithromycin and clari-
thromycin were chosen as the reference compounds. The in vitro
antibacterial activity was reported as minimum inhibitory
4. Results and discussion
MIC values for the target compounds are presented in Table 1.
Compounds 15b and 18e displayed approximately equivalent
antibacterial activity to the references, although they all showed no
Scheme 2. Reagents and conditions: a) Ac2O/AcOH/H2SO4 (1:1:0.5), rt; b) H2NNH2$AcOH, DMF, 55% for 2 steps; c) CCl3CN, DBU, 78%.

Y. Xu et al. / European Journal of Medicinal Chemistry 69 (2013) 174e181
177
Scheme 3. Reagents and conditions: a) TMSOTf, 4A MS, rt, 62%; b) 2 N HCl, C2H5OH, 65 ꢀC, 82%; c) RNCO, Et3N, dichloromethane, 88e93%; d) MeOH, 50 ꢀC, 76e90%.
ꢀ
activity to the resistant pathogens. As the most effective sample,
compound 18e was especially potent against S. aureus 15 and S.
epidermidis 09-9. 18e contains 40-O-phenethylcarbamate and the
result was similar to Ly T. Phan’s report about 40-modified 16-
membered macrolides [13].
center (PTC) in the exit tunnel and interfere more directly with
peptide bond formation, as the mycaminose-mycarose disaccha-
ride at the C-5 position in 16-membered macrolides.
5. Conclusion
15b bears 40-OH, and the result was consistent with the reported
similar ketolide [7]. Compared with 18e, introduction of 9-E-oxime
phenethylcarbamate in 17e resulted in the loss of activity. It verified
the view that bulky groups at the 9-E-oxime might weaken the
interaction of 11-O and 12-O with the corresponding ribosomal
binding site, thus reduced the activities [21]. Compound 18d,
analogous to 18e, contains 40-O-(4-trifluoromethylphenyl) carba-
mate, whereas it displayed no activity. The result suggests there are
certain requirements for the length of the C-40 side chain. It seems
inappropriate to introduce alkyl groups to the C-40 position since
17a, 17b, 17c were inactive. No interactions between the alkyl
groups and the ribosomal binding site should explain this.
In summary, we presumed that the C-40 elongated arylalkyl side
chain with proper length might reach into the peptidyl transferase
In conclusion, we constructed a method of introducing a side
chain to the C-40 position of 5-O-desosamine in the 14-membered
ketolides, and several novel 14-membered ketolides bearing 5-O-
40-carbamate mycaminose were synthesized. Compound 15b
showed weak activity and 18e retained potential antibacterial ac-
tivity, especially against S. aureus15 and S. epidermidis 09-9. We
presumed that the C-40 elongated side chain might reach into the
peptidyl transferase center (PTC) in the exit tunnel and inhibit
peptide bond formation. From the antibacterial profile we reasoned
the structureeactivity relationships which were helpful for better
understanding of the mechanism of the macrolide-ribosome
interaction. Further modification on the C-40 position of 14-
membered macrolides is ongoing.

178
Y. Xu et al. / European Journal of Medicinal Chemistry 69 (2013) 174e181
Table 1
In vitro antibacterial activities of the target compounds.
Compound
MIC (mg/mL)
S. aureus
ATCC 29213
MSSA
S. epidermidis
ATCC 12228
MSSE
ATCC 33591
15
09-6
09-13
09-3
09-9
MSSE
4
MRSA
MSSA
MSSA
MRSA
MRSE
CLAa
TELb
15b
17a
17b
17c
17e
18d
18e
0.06
0.5
2
>32
>64
32
>32
>32
1
>64
>32
>64
>32
>64
>32
>32
>32
>32
0.5
2
0.06
0.5
2
>64
>32
>64
>32
>64
>32
>32
>32
>32
0.06
0.06
2
>32
>64
32
>32
32
0.5
>64
32
0.06
>64
>32
>64
>32
>32
>32
1
>64
>32
>64
>32
>32
>32
>32
2
>32
>64
>32
>32
>32
2
>32
>64
>32
>32
>32
1
a
CLA: clarithromycin.
TEL: telithromycin.
b
6. Experimental
1H NMR (300 MHz, CDCl3)
d
5.01 (d, J ¼ 8.1 Hz, 1H, H-13), 4.76 (s,
1H, H-11), 4.27 (d, J ¼ 6.9 Hz, 1H, H-10), 4.17 (d, J ¼ 8.7 Hz, 1H), 3.79
All solvents and reagents were obtained from commercial
sources and used without further purification unless otherwise
noted. All NMR spectra were recorded on Mercury-300, 400, 500 or
600 MHz spectrometers in CDCl3. The chemical shifts were re-
ported in parts per million (ppm) with tetramethylsilane (TMS) as
an internal standard. HRMS experiments were performed using an
Agilent 1100 series LC/MSD TOF. Analytical thin layer chromatog-
raphy (TLC) was carried out on TLC plates silica gel HSGF254
percolated by Branch of Qingdao Haiyang Chemical Plant. Chro-
matography was performed with silica gel H (HG/T2354-92).
All the strains chosen in the antibacterial activity test were
supplied by Institute of Medicinal Biotechnology, Academy of
Medical Sciences & Peking Union Medical College.
(m, 2H), 3.52 (m, 2H), 3.19 (m, 1H), 2.98 (m, 1H), 2.64 (s, 3H, 6-
OCH3), 2.28 (s, 6H, N(CH3)2); 13C NMR (75 MHz, CDCl3)
d 203.7,
169.0, 164.8, 153.9, 103.6, 84.4, 82.9, 79.4, 78.3, 76.1, 72.3, 70.3, 69.2,
65.8, 61.6, 50.9, 49.7, 47.7, 40.2, 38.2, 28.4, 25.2, 22.2, 21.0, 19.6, 18.6,
15.7, 15.3, 14.1, 13.0, 10.2; HRMS (ESI) [M þ H]þ m/z 629.3640, calcd
for C31H53N2O11 629.3571.
6.3. (E)-3-O-Descladinosyl-3-oxo-6-O-methyl-erythromycin A 9-O-
(benzoyl)oxime 11,12-cyclic-carbonate (7)
To a cooled to ꢁ20 ꢀC solution of compound 6 (28.2 g,
44.9 mmol) in CH2Cl2 (300 mL) was added triethylamine (6.3 mL,
44.9 mmol), and then benzoyl chloride (5.8 mL, 49.4 mmol) drop-
wise. The solution was stirred for 5 h, and then washed with
NaHCO3, saturated brine, dried over Na2SO4. Purified by column
chromatography on silica gel (20:1 CH2Cl2/MeOH) to afford com-
pound 7 (25.6 g, 35.0 mmol, 78%).
6.1. (E)-20-O-Acetyl-3-O-descladinosyl-3-oxo-6-O-methyl-
erythromycin A 9-O-(acetyl)oxime 11,12-cyclic-carbonate (5)
A solution of oxalyl chloride (23.4 mL, 245.3 mmol) in 300 mL
CH2Cl2 under argon was cooled to ꢁ70 ꢀC. Dimethylsulfoxide
(25.8 mL, 364.5 mmol) in CH2Cl2 (100 mL) was added dropwise.
After stirring for 20 min, compound 4 (50.0 g, 70.1 mmol) dissolved
in 80 mL CH2Cl2 was injected in. The reaction solution was warmed
up to ꢁ60 ꢀC and kept stirring for 4.5 h. Then triethylamine (85 mL,
616.9 mmol) was added in and stirred for additional 2 h at rt. The
solution was washed with NaHCO3, brine, dried over Na2SO4. The
concentrate was purified by column chromatography (30:1 CH2Cl2/
MeOH) to give compound 5 (36.4 g, 51.1 mmol, 73%).
1H NMR (300 MHz, CDCl3)
d
8.02 (d, J ¼ 7.5 Hz, 2H), 7.55 (t,
J ¼ 7.2 Hz,1H), 7.44 (t, J ¼ 7.5 Hz, 2H), 5.06 (dd, J ¼ 9.6, 2.4 Hz,1H, H-
13), 4.85 (s, 1H, H-11), 4.77 (br s, 1H), 4.31 (d, J ¼ 7.2 Hz, 1H, H-10),
4.22 (d, J ¼ 7.5 Hz, 1H), 3.82 (m, 1H), 3.53 (m, 2H), 3.22 (m, 1H), 3.04
(m, 1H), 2.72 (s, 3H, 6-OCH3), 2.34 (s, 6H, N(CH3)2); 13C NMR
(75 MHz, CDCl3)
d 203.9, 175.3, 169.0, 163.5, 153.6, 133.0, 129.4,
128.4, 127.7, 103.3, 78.5, 78.1, 76.4, 70.0, 69.1, 65.9, 51.0, 49.9, 47.3,
39.9, 38.4, 28.5, 22.4, 21.0,19.7,18.5,15.4,15.2,14.2,13.2,10.2; HRMS
(ESI) [M þ H]þ m/z 733.3835, calcd for C38H57N2O12 733.3833.
1H NMR (300 MHz, CDCl3)
d
5.06 (d, J ¼ 8.1 Hz, 1H, H-13), 4.78 (s,
1H, H-11), 4.73 (m, 1H, H-20), 4.38 (d, J ¼ 7.5 Hz, 1H, H-10), 4.19 (d,
J ¼ 7.5 Hz,1H, H-5), 3.81 (q, J ¼ 6.6 Hz, 1H, H-2), 3.56 (m, 2H, H-8, H-
50), 2.66 (s, 3H, 6-OCH3), 2.27 (s, 9H, 9-NOAc, 30-NMe2), 2.06 (s, 3H,
20-OAc), 1.57 (s, 3H), 0.88 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz,
6.4. (E)-5-Hydroxyl-3-oxo-6-O-methyl-erythronolide A 9-O-
(benzoyl)oxime 11,12-cyclic-carbonate (9)
Compound 7 (25.6 g, 35.0 mmol) was oxidized firstly following
the procedure for compound 5. The obtained crude product 8 was
refluxed in methanol at 50 ꢀC for 8 h. The residue was purified by
column chromatography on silica gel (20:30:1 petroleum ether/
CHCl3/MeOH) to yield compound 9 (13.5 g, 23.4 mmol, 67% for 2
steps).
CDCl3) d 203.8, 172.2, 169.6, 169.0, 153.8, 101.3, 82.0, 78.3, 77.6, 76.5,
71.5, 69.1, 63.4, 53.3, 51.0, 49.7, 46.9, 40.6, 38.0, 30.4, 27.8, 22.4, 21.3,
20.9, 20.2, 19.7, 18.6, 15.3, 15.1, 14.1, 13.2, 10.3; HRMS (ESI) [M þ H]þ
m/z 713.3892, calcd for C35H57N2O13 713.3860.
6.2. (E)-3-O-Descladinosyl-3-oxo-6-O-methyl-erythromycin A 9-
oxime 11,12-cyclic-carbonate (6)
1H NMR (300 MHz, CDCl3)
d
8.01 (d, J ¼ 6.9 Hz, 2H), 7.56 (t,
J ¼ 7.5 Hz,1H), 7.44 (t, J ¼ 7.5 Hz, 2H), 5.01 (dd, J ¼ 9.6, 2.7 Hz, 1H, H-
13), 4.81 (s, 1H, H-11), 4.11 (d, J ¼ 8.7 Hz, 1H), 3.78 (m, 1H), 2.72 (s,
Compound 5 (36.4 g, 51.1 mmol) dissolved in 300 mL methanol
was stirred at 50 ꢀC overnight. The solvent was evaporated off and
the residue was purified by column chromatography on silica gel
(40:1 CH2Cl2/MeOH) to yield compound 6 (28.2 g, 44.9 mmol, 88%).
3H, 6-OCH3); 13C NMR (75 MHz, CDCl3)
d 203.9, 175.1, 168.7, 163.6,
153.6, 133.1, 129.3, 129.0, 128.5, 78.6, 76.3, 74.0, 51.4, 49.9, 47.1, 37.4,
28.7, 22.4, 19.9, 18.9, 16.3, 15.3, 14.3, 13.3, 10.3; HRMS (ESI) [M þ H]þ
m/z 576.2756, calcd for C30H42NO10 576.2730.

Y. Xu et al. / European Journal of Medicinal Chemistry 69 (2013) 174e181
179
6.5. 1,4-O-Acetyl-2-O-Benzoyl-3,6-dideoxy-3-dimethylamino-
glucopyranose (11)
D-
2H), 2.91 (m, 2H), 2.72 (s, 3H, 6-OCH3), 2.32 (s, 6H, N(CH3)2), 2.06 (s,
3H, 40-OAc); 13C NMR (100 MHz, CDCl3)
204.2, 169.8, 168.9, 168.7,
d
164.5, 163.5, 153.6, 133.0, 129.6, 129.4, 128.5, 128.3, 100.9, 81.9, 78.0,
76.4, 72.7, 71.4, 71.1, 70.8, 67.3, 63.9, 51.5, 51.0, 50.1, 49.9, 46.5, 43.3,
43.0, 41.4, 38.0, 28.4, 22.5, 21.1, 19.7, 18.8, 17.4, 15.5, 14.8, 14.1, 13.3,
10.2; HRMS (ESI) [M þ H]þ m/z 895.4169, calcd for C47H63N2O15
895.4150.
Compound 10 (3.0 g, 7.5 mmol) was treated with a mixture of
acetic anhydride, acetic acid and sulfuric acid (1:1:0.5; 15 ml) and
stirred at room temperature for 2 days. The reaction mixture was
neutralized with saturated NaHCO3 and extracted with CH2Cl2. The
organic phase was washed with saturated brine, dried over Na2SO4.
The filtrate was concentrated in vacuum to give the crude product
11 for the next step.
6.9. (E)-5-(2-O-benzoyl-mycaminosyl)-3-O-descladinosyl-6-O-
methyl-3-oxo-erythronolide A 9-oxime 11,12-cyclic carbonate (15a)
6.6. 4-O-Acetyl-2-O-benzoyl-3,6-dideoxy-3-dimethylamino-
glucopyranose (12)
D
-
Compound 14 (514 mg, 0.57 mmol) was treated with 2 N HCl in
ethanol at 65 ꢀC for 6 h. Then the solution was cooled and
neutralized to pH 8 by NaHCO3 and extracted with CH2Cl2. The
combined organic phase was washed with NaHCO3 and brine. The
residue was purified by column chromatography (8:1 petroleum
ether/acetone) to afford compound 15a (350 mg, 0.47 mmol, 82%).
To a solution of the crude product 11 in dimethyl formamide
(20 mL) was added hydrazine acetate (2.5 g, 27.8 mmol). The so-
lution was stirred for 4 h at room temperature. Then the reaction
mixture was diluted with ethyl acetate and washed with water,
saturated brine, dried over Na2SO4. The crude mixture was purified
by column chromatography on silica gel (8:1 petroleum ether/ethyl
acetate) to yield compound 12 (1.4 g, 4.1 mmol, 55% for 2 steps).
1H NMR (400 MHz, CDCl3)
d
7.96 (d, J ¼ 7.6 Hz, 2H), 7.51 (d,
J ¼ 7.6 Hz, 1H), 7.41 (t, J ¼ 7.2 Hz, 2H), 5.23 (t, J ¼ 8.4, 9.6 Hz, 1H, H-
20), 4.93 (d, J ¼ 10.0 Hz, 1H, H-13), 4.70 (s, 1H, H-11), 4.52 (d,
J ¼ 7.2 Hz, 1H, H-10), 4.00 (d, J ¼ 7.6 Hz, 1H, H-5), 3.71 (br s, 1H), 3.59
(dd, J ¼ 6.4, 12.4 Hz, 1H), 3.36 (m, 1H), 3.05 (m, 1H), 2.81 (m, 1H),
2.69 (m, 1H), 2.64 (s, 3H, 6-OCH3), 2.37 (s, 6H, N(CH3)2); 13C NMR
(
a
-Configuration) 1H NMR (400 MHz, CDCl3)
d
8.08 (d, J ¼ 7.6 Hz,
2H, Bz), 7.58 (m, 1H, Bz), 7.46 (m, 2H, Bz), 5.45 (d, J ¼ 3.6 Hz, 1H, H-
1), 5.19 (dd, J ¼ 10.8, 3.6 Hz, 1H, H-2), 4.77 (t, J ¼ 10.0 Hz, 1H, H-4),
4.14 (m, 1H, H-5), 3.33 (t, J ¼ 10.4 Hz, 1H, H-3), 2.39 (s, 6H, NMe2),
2.09 (s, 3H, 4-OAc), 1.19 (d, J ¼ 6.4 Hz, 3H, 5-Me); HRMS (ESI)
[M þ H]þ m/z 338.1595, calcd for C17H24NO6 338.1525.
(100 MHz, CDCl3)
d 203.8, 168.9, 165.2, 164.5, 153.9, 133.3, 130.8,
129.8, 128.8, 101.3, 84.4, 82.9, 78.2, 76.3, 73.0, 70.7, 70.4, 69.6, 68.1,
65.5, 50.9, 49.7, 47.0, 41.3, 37.8, 32.7, 30.5, 25.1, 22.3, 19.7, 19.1, 18.5,
18.0, 15.2, 14.0, 13.7, 13.0, 10.2; HRMS (ESI) [M þ H]þ m/z 749.3848,
calcd for C38H57N2O13 749.3782.
6.7. 4-O-Acetyl-2-O-benzoyl-3,6-dideoxy-3-dimethylamino-D-
glucopyranosyl trichloroacetimidate (13)
6.10. General methods for compounds 16aee
To an ice-cold solution 12 (1.39 g, 4.1 mmol) in anhydrous
CH2Cl2 (30 mL) under argon were added trichloroacetonitrile
(2.5 ml, 24.6 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU)
(0.2 ml, 1.4 mmol). The mixture then restored up to room tem-
perature and was stirred for 10 h. The reaction mixture was purified
by column chromatography on silica gel (deactivated by 15% Et3N/
petroleum ether) (10:1 petroleum ether/ethyl acetate) to yield
compound 13 (1.5 g, 3.2 mmol, 78%).
To a solution of the reactant in anhydrous CH2Cl2 under argon
were added triethylamine (2.3 equiv) and the corresponding iso-
cyanate (2.3 equiv). The solution was stirred at room temperature
for 3 h, then quenched with water. Afterward, the mixture solution
was diluted with CH2Cl2 and washed with H2O, saturated brine,
dried over Na2SO4. The residue was purified by column chroma-
tography on silica gel (8:1 petroleum ether/acetone) to afford the
desired products (88e93%).
(a d 8.48 (s, 1H, C]
-Configuration) 1H NMR (300 MHz, CDCl3)
NH), 8.01 (d, J ¼ 7.5 Hz, 2H, Bz), 7.57 (t, J ¼ 7.5 Hz, 1H, Bz), 7.42 (t,
J ¼ 8.1 Hz, 2H, Bz), 6.52 (d, J ¼ 3.6 Hz, 1H, H-1), 5.42 (dd, J ¼ 3.6,
11.1 Hz, 1H, H-2), 4.87 (t, J ¼ 9.9 Hz, 1H, H-4), 4.10 (m, 1H, H-5), 3.38
(t, J ¼ 10.5 Hz, 1H, H-3), 2.39 (s, 6H, NMe2), 2.10 (s, 3H, 4-OAc), 1.24
(d, J ¼ 9.0 Hz, 3H, 5-Me) HRMS (ESI) [M þ H]þ m/z 481.0706, calcd
for C19H24Cl3N2O6 481.0622.
6.10.1. (E)-5-(2-O-Benzoyl-4-O-(2-chloroethyl)carbamoyl-mycami-
nosyl)-3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A 9-O-
((2-chloroethyl)carbamoyl)oxime 11,12-cyclic carbonate (16a)
1H NMR (300 MHz, CDCl3)
d
7.94 (d, J ¼ 6.9 Hz, 2H), 7.66 (m, 1H),
7.51 (m, 2H), 5.07 (t, J ¼ 9.6 Hz, 1H, H-20), 4.98 (d, J ¼ 10.5 Hz, 1H, H-
13), 4.67 (s, 1H, H-11), 4.60 (d, J ¼ 9.6 Hz, 1H, H-40), 4.52 (d,
J ¼ 7.5 Hz, 1H, H-10), 4.12 (d, J ¼ 6.9 Hz, 1H), 3.69 (m, 1H), 3.67 (m,
1H), 3.48 (m, 3H), 2.27 (m, 2H), 2.60 (s, 3H, 6-OCH3), 2.28 (s, 6H,
6.8. (E)-5-(4-O-Acetyl-2-O-benzoyl-mycaminosyl)-3-O-descladin-
osyl-6-O-methyl-3-oxo-erythronolide A 9-O-(benzoyl)oxime 11,12-
cyclic carbonate (14)
N(CH3)2); HRMS (ESI) [M
44H65Cl2N4O15 959.3745.
þ
H]þ m/z 959.3690, calcd for
C
A solution of compound 13 (1.3 g, 2.8 mmol) in 20 mL anhydrous
CH2Cl2 under argon was cooled to ꢁ20 ꢀC. Trimethylsilyl tri-
6.10.2. (E)-5-(2-O-Benzoyl-4-O-pentylcarbamoyl-mycaminosyl)-3-
O-descladinosyl-6-O-methyl-3-oxo-erythronolide A 9-O-(pentylca-
rbamoyl)oxime 11,12-cyclic carbonate (16b)
fluoromethanesulfonate (282 mL, 1.53 mmol) was added dropwise.
After stirring for 20 min, compound 9 (800 mg, 1.4 mmol) dissolved
1H NMR (400 MHz, CDCl3)
d
8.00 (d, J ¼ 7.2 Hz, 2H), 7.71 (m, 1H),
in 3 mL CH2Cl2 was injected in. The mixture solution was warmed
7.52 (m, 2H), 5.15 (t, J ¼ 8.0, 9.6 Hz,1H, H-20), 5.02 (d, J ¼ 10.4 Hz,1H,
H-13), 4.73 (s,1H, H-11), 4.67 (m,1H, H-40), 4.57 (d, J ¼ 7.6 Hz,1H, H-
10), 4.18 (d, J ¼ ¼ 7.2 Hz,1H), 3.78 (m,1H), 3.71 (m,1H), 3.22 (m, 3H),
2.86 (m, 2H), 2.63 (s, 3H, 6-OCH3), 2.52 (m, 1H), 2.34 (s, 6H,
up to 20 ꢀC and kept stirring for 20 h. Then triethylamine (214
mL,
1.53 mmol) was added in and stirred for 30 min to quench the
reaction. Followed by filtration and purification by column chro-
matography (8:1 petroleum ether/acetone) to give compound 14
(514 mg, 0.57 mmol, recycled compound 9 266 mg, 62%).
N(CH3)2); 13C NMR (150 MHz, CDCl3)
d 202.9, 168.9, 168.1, 166.7,
163.6, 154.5, 154.1, 152.7, 131.2, 129.9, 128.8, 127.8, 127.5, 99.9, 83.3,
81.5, 77.2, 75.4, 70.5, 64.5, 49.8, 48.6, 45.6, 40.2, 40.0, 36.9, 32.4,
29.5, 28.6, 28.5, 28.2, 27.7, 26.5, 21.2, 19.0, 18.1, 17.2, 16.2, 14.5, 13.9,
13.1, 12.9, 12.7, 12.0, 9.2; HRMS (ESI) [M þ H]þ m/z 975.5470, calcd
for C50H79N4O15 975.5464.
1H NMR (300 MHz, CDCl3)
d 8.02 (m, 4H), 7.57 (m, 2H), 7.46 (m,
4H), 5.16 (t, J ¼ 7.8 Hz, 1H, H-20), 5.05 (d, J ¼ 7.5 Hz, 1H, H-13), 4.86
(s, 1H, H-11), 4.80 (t, J ¼ 9.9, 9.9 Hz, 1H, H-40), 4.61 (d, J ¼ 7.8 Hz, 1H,
H-10), 4.21 (d, J ¼ 7.2 Hz, 1H, H-5), 3.71 (d, J ¼ 6.9 Hz, 1H), 3.54 (m,

180
Y. Xu et al. / European Journal of Medicinal Chemistry 69 (2013) 174e181
6.10.3. (E)-5-(2-O-Benzoyl-4-O-cyclohexylcarbamoyl-mycami-
nosyl)-3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A 9-O-
(cyclohexylcarbamoyl)oxime 11,12-cyclic carbonate (16c)
HRMS (ESI) [M þ H]þ m/z 855.3428, calcd for C37H61Cl2N4O14
855.3483.
1H NMR (500 MHz, CDCl3)
d
7.99 (d, J ¼ 8.5 Hz, 2H), 7.56 (m, 1H),
6.11.2. (E)-5-(4-O-Pentylcarbamoyl-mycaminosyl)-3-O-desclad-
inosyl-6-O-methyl-3-oxo-erythronolide A 9-O-(pentylcarbamoyl)
oxime 11,12-cyclic carbonate (17b)
7.42 (m, 2H), 5.12 (t, J ¼ 9.0 Hz, 1H, H-20), 5.04 (d, J ¼ 10.5 Hz, 1H, H-
13), 4.74 (s, 1H, H-11), 4.69 (t, J ¼ 10.0 Hz, 1H, H-40), 4.58 (d, 1H, H-
10), 4.17 (d, J ¼ 7.0 Hz, 1H), 3.76 (m, 1H), 3.72 (m, 1H), 3.68 (m, 1H),
3.48 (m, 2H), 2.85 (m, 2H), 2.63 (s, 3H, 6-OCH3), 2.39 (s, 6H,
1H NMR (400 MHz, CDCl3)
d
5.06 (d, J ¼ 10.2 Hz, 1H, H-13), 4.76
(s, 1H, H-11), 4.75 (m, 1H, H-40), 4.71 (br s, 1H), 4.36 (d, J ¼ 7.2 Hz,
1H), 4.19 (d, J ¼ 7.8 Hz, 1H), 3.85 (m, 1H), 3.39 (m, 1H), 3.23 (m, 3H),
2.99 (m, 1H), 2.63 (s, 3H, 6-OCH3), 2.51 (s, 6H, N(CH3)2); 13C NMR
N(CH3)2); 13C NMR (125 MHz, CDCl3)
d 201.9, 169.7, 169.2, 167.7,
164.7, 154.8, 153.7, 132.9, 132.3, 130.3, 129.7, 128.3, 101.3, 84.3, 82.5,
78.3, 76.7, 76.3, 71.6, 71.0, 67.7, 65.5, 50.8, 49.6, 46.8, 41.3, 38.0, 33.5,
32.8, 32.6, 30.5, 29.7, 27.5, 25.4, 24.8, 24.3, 22.1, 20.0, 19.1, 18.2, 17.3,
15.6, 14.9, 14.2, 13.7, 12.9, 10.1; HRMS (ESI) [M þ H]þ m/z 999.5598,
calcd for C52H79N4O15 999.5464.
(150 MHz, CDCl3)
d 203.8, 170.0, 169.2, 155.6, 154.7, 153.8, 102.8,
84.4, 82.5, 79.4, 78.2, 76.3, 71.6, 71.3, 69.2, 50.9, 49.7, 47.4, 41.1, 41.0,
38.4, 33.4, 29.6, 29.2, 28.8, 27.6, 22.6, 22.2, 20.0, 18.3, 17.0, 15.6, 15.3,
14.2, 13.9, 13.0, 10.2; HRMS (ESI) [M þ H]þ m/z 871.5149, calcd for
C43H75N4O14 871.5202.
6.10.4. (E)-5-(2-O-Benzoyl-4-O-(4-trifluoromethylphenyl)
carbamoyl-mycaminosyl)-3-O-descladinosyl-6-O-methyl-3-oxo-
erythronolide A 9-O-((4-trifluoromethylphenyl)carbamoyl)oxime
11,12-cyclic carbonate (16d)
6.11.3. (E)-5-(4-O-Cyclohexylcarbamoyl-mycaminosyl)-3-O-des-
cladinosyl-6-O-methyl-3-oxo-erythronolide A 9-O-(cyclohexylcarb-
amoyl)oxime 11,12-cyclic carbonate (17c)
1H NMR (400 MHz, CDCl3)
d
8.02 (d, J ¼ 7.2 Hz, 2H), 7.70 (d,
1H NMR (500 MHz, CDCl3)
d
5.08 (d, J ¼ 10.8 Hz, 1H, H-13), 4.77
J ¼ 8.4 Hz, 2H), 7.56 (m, 6H), 7.45 (t, J ¼ 7.6 Hz, 2H), 7.26 (s, 1H), 5.25
(t, J ¼ ¼ 8.4, 9.2 Hz, 1H, H-20), 5.06 (d, J ¼ 10.0 Hz, 1H, H-13), 4.82 (s,
1H, H-11), 4.76 (t, J ¼ 9.6, 9.6 Hz, 1H, H-40), 4.63 (d, J ¼ 7.6 Hz, 1H, H-
10), 4.21 (d, J ¼ 6.4 Hz, 1H), 3.78 (br s, 1H), 3.72 (m, 1H), 3.58 (m, 1H),
3.04 (m, 1H), 2.95 (m,1H), 2.87 (m,1H), 2.65 (s, 3H, 6-OCH3), 2.37 (s,
(s, 1H, H-11), 4.75 (t, J ¼ 8.4 Hz, 1H, H-40), 4.39 (d, J ¼ 7.2 Hz, 1H, H-
10), 4.18 (d, J ¼ 7.8 Hz, 1H), 3.84 (m, 1H), 3.77 (m, 1H), 3.61 (m, 1H),
3.43 (m, 3H), 2.99 (m, 2H), 2.65 (s, 3H, 6-OCH3), 2.63 (s, 6H,
N(CH3)2); 13C NMR (150 MHz, CDCl3)
d 203.9, 169.7, 169.3, 154.8,
153.7, 102.5, 84.4, 82.5, 79.3, 78.2, 76.7, 76.3, 71.2, 70.6, 69.1, 50.9,
50.3, 49.7, 49.5, 47.3, 38.3, 33.5, 33.2, 32.8, 32.6, 29.6, 27.6, 25.3, 24.7,
24.3, 22.1, 20.0, 18.2, 16.9, 15.6, 15.3, 14.2, 13.0, 10.2; HRMS (ESI)
[M þ H]þ m/z 895.5200, calcd for C45H75N4O14 895.5202.
6H, N(CH3)2); 13C NMR (125 MHz, CDCl3)
d 204.1, 171.0, 169.2, 167.7,
164.6, 153.6, 151.9, 140.8, 140.3, 133.1, 132.3, 130.8, 130.0, 129.7,
128.8,128.4,126.3,118.7,118.2,101.1, 84.6, 82.4, 78.2, 77.7, 76.4, 72.9,
71.2, 70.8, 67.6, 65.5, 51.1, 50.8, 49.7, 46.6, 41.4, 38.0, 30.5, 27.9, 22.1,
19.9, 19.1, 18.2, 17.5, 15.7, 14.7, 14.2, 13.7, 12.9, 10.2; HRMS (ESI)
[M þ H]þ m/z 1123.4310, calcd for C54H65F6N4O15 1123.4272.
6.11.4. (E)-5-(4-O-(4-Trifluoromethylphenyl)carbamoyl-mycami-
nosyl)-3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A 9-
oxime 11,12-cyclic carbonate (18d)
6.10.5. (E)-5-(2-O-Benzoyl-4-O-phenethylcarbamoyl-mycamin-
osyl)-3-O-descladinosyl-6-O-methyl-3-oxo-erythronolide A 9-O-
(phenethylcarbamoyl)oxime 11,12-cyclic carbonate (16e)
1H NMR (500 MHz, CDCl3)
d
7.78 (d, J ¼ 8.5 Hz, 2H), 7.53 (m, 2H),
5.05 (d, J ¼ 8.0 Hz, 1H, H-13), 4.85 (m, 1H, H-40), 4.80 (s, 1H, H-11),
4.42 (d, J ¼ 7.5 Hz, 1H, H-10), 4.30 (t, J ¼ 6.5 Hz, 1H), 4.19 (d, 1H), 3.84
(m,1H), 3.50 (m,1H), 3.39 (m,1H), 3.06 (m,1H), 2.70 (s, 3H, 6-OCH3),
1H NMR (500 MHz, CDCl3)
d
8.00 (d, J ¼ 7.0 Hz, 2H), 7.56 (m, 1H),
7.43 (m, 2H), 7.27 (m, 4H), 7.17 (m, 6H), 5.19 (m, 1H, H-20), 4.99 (d,
J ¼ 10.5 Hz, 1H, H-13), 4.77 (m, 1H, H-40), 4.73 (s, 1H, H-11), 4.65 (d,
J ¼ 7.6 Hz, 1H, H-10), 4.16 (d, J ¼ 7.0 Hz, 1H), 3.78 (m, 2H), 3.69 (m,
1H), 3.52 (m, 4H), 2.87 (m, 5H), 2.53(s, 3H, 6-OCH3), 2.37 (s, 6H,
2.52 (s, 6H, N(CH3)2); 13C NMR (125 MHz, CDCl3)
d 204.2,169.3,165.7,
154.3, 151.8, 150.0, 140.7, 131.1, 129.0, 127.1, 126.6, 118.5, 103.1, 84.9,
83.2, 80.1, 78.4, 71.7, 69.8, 66.1, 58.7, 51.3, 50.1, 47.8, 41.6, 38.5, 32.1,
29.6, 25.5, 22.9, 22.6, 20.0, 18.9, 17.4, 16.9, 15.9, 14.4, 13.4, 10.5; HRMS
(ESI) [M þ H]þ m/z 832.3734, calcd for C39H57F3N3O13 832.3765.
N(CH3)2); 13C NMR (125 MHz, CDCl3)
d 203.9, 178.2, 176.5, 170.1,
169.0, 164.6, 155.5, 155.0, 153.7, 138.6, 138.4, 130.0, 129.7, 128.7,
128.5, 128.4, 126.4, 126.3, 99.9, 84.3, 83.7, 82.5, 78.1, 77.3, 76.7, 76.5,
71.5, 71.3, 50.8, 49.7, 46.6, 42.2, 38.0, 35.6, 33.4, 29.6, 27.6, 22.6, 22.3,
20.0, 18.2, 17.2, 15.4, 14.8, 14.1, 13.0, 10.3; HRMS (ESI) [M þ H]þ m/z
1043.5309, calcd for C56H75N4O15 1043.5151.
6.11.5. (E)-5-(4-O-Phenethylcarbamoyl-mycaminosyl)-3-O-descl-
adinosyl-6-O-methyl-3-oxo-erythronolide A 9-O-(phenethylcar-
bamoyl)oxime 11,12-cyclic carbonate (17e)
1H NMR (500 MHz, CDCl3)
d 7.22 (m, 4H), 7.17 (m, 3H), 7.10 (m,
3H), 4.96 (d, J ¼ 10.5 Hz, 1H, H-13), 4.70 (t, J ¼ 10.0 Hz, 1H, H-40),
4.61 (s, 1H, H-11), 4.35 (d, J ¼ 7.0 Hz, 1H, H-10), 4.06 (d, J ¼ 7.0 Hz,
1H), 3.77 (m, 1H), 3.67 (m, 1H), 3.50 (m, 2H), 3.42 (m, 2H), 3.34 (m,
1H), 2.80 (s, 3H, 6-OCH3), 2.72 (m, 2H), 2.47 (s, 6H, N(CH3)2); 13C
6.11. General methods for compounds 15b, 17aec,e, 18d,e
The corresponding reactant was dissolved in methanol
and refluxed at 50 ꢀC for 12e48 h. After column chromatography
(5:1 petroleum ether/acetone), the desired product was obtained
(76e90%).
NMR (125 MHz, CDCl3) d 204.4, 170.4, 169.4, 155.8, 154.3, 154.0,
138.6, 138.0, 129.0, 128.9, 128.8, 128.4, 127.1, 126.6, 102.0, 84.7, 82.5,
79.6, 78.3, 73.7, 70.5, 70.1, 69.1, 51.1, 49.9, 47.4, 45.9, 42.5, 42.2, 38.5,
36.0, 35.9, 33.7, 32.1, 29.9, 29.6, 27.9, 22.9, 22.5, 20.3, 18.5, 17.0, 15.7,
15.4, 14.4, 13.4, 10.6; HRMS (ESI) [M þ H]þ m/z 939.5013, calcd for
6.11.1. (E)-5-(4-O-(2-Chloroethyl)carbamoyl-mycaminosyl)-3-O-
descladinosyl-6-O-methyl-3-oxo-erythronolide A 9-O-((2-chlor-
oethyl)carbamoyl)oxime 11,12-cyclic carbonate (17a)
C49H71N4O14 939.4889.
6.11.6. (E)-5-(4-O-Phenethylcarbamoyl-mycaminosyl)-3-O-descla-
dinosyl-6-O-methyl-3-oxo-erythronolide A 9-oxime 11,12-cyclic
carbonate (18e)
1H NMR (500 MHz, CDCl3)
d
5.07 (d, J ¼ 7.8 Hz, 1H, H-13), 4.84 (t,
J ¼ 9.6 Hz, 1H, H-40), 4.78 (s, 1H, H-11), 4.46 (d, J ¼ 7.8 Hz, 1H, H-10),
4.19 (d, J ¼ 7.2 Hz, 1H), 3.85 (m, 1H), 3.78 (m, 2H), 3.51 (m, 3H), 2.88
(s, 3H, 6-OCH3), 2.65 (s, 6H, N(CH3)2); 13C NMR (150 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
d
7.30 (t, J ¼ 7.4 Hz, 1H), 7.25 (m, 2H),
7.22 (m, 2H), 5.12 (m, 1H, H-40), 5.05 (d, J ¼ 10.0 Hz, 1H, H-13), 4.70
(s, 1H, H-11), 4.38 (d, J ¼ 6.8 Hz, 1H, H-10), 4.21 (d, J ¼ 6.8 Hz, 1H),
3.82 (m, 1H), 3.75 (m, 1H), 3.58 (m, 3H), 3.38 (m, 2H), 3.31 (m, 1H),
3.07 (m, 1H), 2.89 (s, 3H, 6-OCH3), 2.59 (s, 6H, N(CH3)2); 13C NMR
d
204.2, 170.8, 169.2, 167.7, 155.6, 154.2, 153.7, 101.8, 84.5, 82.4, 79.2,
78.1, 73.4, 70.4, 68.1, 65.5, 53.4, 49.7, 47.1, 43.6, 42.9, 42.7, 38.7, 37.3,
33.6, 31.9, 29.8, 27.0, 23.1, 22.6, 20.1, 18.5, 16.8, 15.6, 14.1, 13.7, 10.2;

Y. Xu et al. / European Journal of Medicinal Chemistry 69 (2013) 174e181
181
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(150 MHz, CDCl3)
d 203.9, 170.3, 169.1, 155.6, 153.6, 138.3, 128.7,
128.6, 126.4, 102.1, 84.4, 82.5, 78.3, 78.1, 76.6, 72.7, 70.2, 51.0, 49.7,
46.8, 42.2, 42.1, 38.3, 35.6, 32.1, 29.2, 27.6, 26.3, 23.4, 22.6, 22.3, 19.8,
18.3, 17.4, 15.5, 15.0, 14.3, 14.1, 13.1, 10.3; HRMS (ESI) [M þ H]þ m/z
792.4185, calcd for C40H62N3O13 792.4204.
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6.11.7. (E)-5-Mycaminosyl-3-O-descladinosyl-6-O-methyl-3-oxo-
erythronolide A 9-oxime 11,12-cyclic carbonate (15b)
1H NMR (500 MHz, CDCl3)
d
5.05 (d, J ¼ 10.5 Hz, 1H, H-13), 4.82
(s,1H, H-11), 4.41 (br s,1H), 4.30 (t, J ¼ 7.0 Hz,1H), 4.20 (d, J ¼ 7.5 Hz,
1H), 3.81 (m, 1H), 3.42 (m, 2H), 2.99 (m, 2H), 2.69 (s, 3H, 6-OCH3),
2.04 (s, 6H, N(CH3)2); 13C NMR (125 MHz, CDCl3)
d 204.1, 171.4,
167.9, 165.3, 102.0, 79.6, 78.3, 73.9, 72.8, 69.7, 65.8, 60.6, 51.3, 47.3,
38.4, 33.9, 32.1, 30.8, 29.9, 26.9, 25.5, 22.6, 21.2, 19.9, 18.8, 17.6, 15.6,
14.6, 13.9, 13.3, 10.5; HRMS (ESI) [M þ H]þ m/z 645.3495, calcd for
C
31H53N2O12 645.3520.
Acknowledgments
This work was supported by the National S&T Major Special
Project on Major New Drug Innovation (Item Number:
2008ZX09401-004 and 2009ZX09301-003) and National Natural
Science Foundation of China (81072524). And we are grateful to
Professor Xuefu You for the antibacterial activity test.
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