Synthesis and antibacterial activity of 3-O-carbamoyl derivatives of 6,11-di-O-methylerythromycin A: A novel class of acylides

Article abstract of DOI:10.1016/j.ejmech.2010.05.009

A novel series of acylides, 3-O-carbamoyl derivatives of 6,11-di-O-methylerythromycin A, were synthesized and evaluated for their antibacterial activity. These compounds have significant antibacterial activity against Gram-positive pathogens, including erythromycin-resistant but methicillin-susceptible Staphylococcus aureus, erythromycin-resistant and methicillin-resistant S. aureus, erythromycin-resistant Streptococcus pneumoniae, and Gram-negative pathogens, such as Haemophilus influenzae. Among the derivatives tested, compounds 4p, 4r, 4w, 4x and 4z were found to have potent activity against most susceptible and resistant bacteria. Compound 4p exhibited excellent antibacterial activity in comparison to the others. Novel 3-O-carbamate derivatives of 6,11-di-O-methylerythromycin A were synthesized by substituting l-cladinose with various carbamate groups. This new class of antibiotics exhibited potent activity against some key erythromycin-resistant pathogens.

Full text of DOI:10.1016/j.ejmech.2010.05.009

European Journal of Medicinal Chemistry 45 (2010) 3636e3644
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 3-O-carbamoyl derivatives of
6,11-di-O-methylerythromycin A: A novel class of acylides
Zhongyuan Wu a, Yong Lu a, Ming Luo a, Xianran He a, Yuling Xiao a, Jin Yang a, Yuanhu Pan b, Guofu Qiu a,
,
Hao Guo a, Hao Hu a, Dingshan Zhou a, Xianming Hu a
*
a State Key Laboratory of Virology, College of Pharmacy, Laojiashan, Wuhan University, Wuhan 430072, China
b Huazhong Agricultural University, Wuhan 430070, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of acylides, 3-O-carbamoyl derivatives of 6,11-di-O-methylerythromycin A, were synthe-
sized and evaluated for their antibacterial activity. These compounds have significant antibacterial
activity against Gram-positive pathogens, including erythromycin-resistant but methicillin-susceptible
Staphylococcus aureus, erythromycin-resistant and methicillin-resistant S. aureus, erythromycin-resistant
Streptococcus pneumoniae, and Gram-negative pathogens, such as Haemophilus influenzae. Among the
derivatives tested, compounds 4p, 4r, 4w, 4x and 4z were found to have potent activity against most
susceptible and resistant bacteria. Compound 4p exhibited excellent antibacterial activity in comparison
to the others.
Received 10 March 2010
Received in revised form
3 May 2010
Accepted 5 May 2010
Available online 12 May 2010
Keywords:
Synthesis
Antibacterial activity
3-O-Carbamoyl derivatives
Acylide
Ó 2010 Elsevier Masson SAS. All rights reserved.
1. Introduction
resolution X-ray co-crystal structures has shown that the 3-posi-
tion group of macrolides is located near G2505 and C2610, and the
The rapid development of antibiotic resistance among the major
respiratory pathogens has created a serious problem for the effec-
tive management of respiratory tract infections [1e6]. There is
a great medical need for new antibiotics to address the problem of
antibiotic resistance. Under these circumstances, a substantial
amount work has been carried out on novel macrolides. These
investigations have led to the discovery of the 3-acylides. Acylides,
the C-3 acylated analogs of erythromycin A, were first reported in
1997 by Asaka et al. [7,8].
The C-3 cladinose group was long considered to be crucial for
the antibacterial activity of erythromycin A. However, recent
structural studies have revealed that the C3 substituent of macro-
lides and ketolides contributes little to the binding interaction with
the bacterial ribosome, and appears to occupy a region of consid-
erable steric bulk tolerance. In addition, researchers have shown
that macrolides in which the cladinose sugar is replaced by a C3-O-
acyl group are active against many bacterial respiratory pathogens,
including erythromycin-resistant strains [9e11]. The study of high-
cladinose group of erythromycin or clarithromycin is located at and
fits with the cavity formed by G2505, C2610 and C2611 in domain V
of the erythromycin binding site [12e14]. The C-3 cladinose sugar
attached to the 14-membered ring macrolides is believed to be
responsible for the inducibility of macrolide resistance. This moiety
also appears to be responsible for efflux resistance. Removal of the
cladinose can also improve activity against efflux [15]. Both FMA
199 and FMA 481 (Fig. 1) appear to have well-balanced in vitro
activity against Streptococcus pneumoniae [16]. TEA 0777 (Fig. 2)
shows significant potent activity against erythromycin-susceptible
Gram-positive pathogens and macrolides-lincosamides-streptog-
ramin B (MLSB) resistant Staphylococcus aureus and efflux-resistant
S. pneumoniae [17]. FMA 0122 (Fig. 2) is active against Haemophilus
influenzae. However, TEA 0929 (Fig. 2), which shows potent anti-
bacterial activity against almost all of the main causative pathogens
of community-acquired pneumonia tested, exhibits excellent in
vivo efficacy [11]. These results indicate that acylides have potential
as next-generation macrolide antibiotics.
The new macrolide derivatives such as FMA 199, FMA 481
(Fig. 1), TEA 0929, CP-544372 (Fig. 2), telithromycin (Fig. 3) [18]
and cethromycin (Fig. 3) [19] are carbamate macrolide deriva-
tives modified by introduction of various carbamate groups. The
compound CP-544372 also demonstrates good in vitro and in vivo
* Corresponding author. College of Pharmacy, Wuhan University, Wuhan 430072,
China. Tel.: þ86 27 68759887; fax: þ86 27 68759850.
E-mail address: xmhu@whu.edu.cn (X. Hu).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.05.009

Z. Wu et al. / European Journal of Medicinal Chemistry 45 (2010) 3636e3644
3637
N
R2
N
N
R1
O
FMA 199: R1=Me, R2=
OMe
N
HO
N
O
N
O
N
O
O
N
NMe2
N
O
N
HO
O
N
FMA 481: R1=H, R2=
O
O
HO
OMe
O
O
H
N
O
O
O
N
O
Fig. 1. Structures of FMA 199 and FMA 481.
O
O
O
O
O
O
activity against macrolide-susceptible and -resistant organisms
[13e17]. Compounds CAM-4j and CAM-4k (Fig. 4) appeared
potent activity against erythromycin-susceptible S. aureus,
Streptococcus pyogenes and S. pneumoniae. Compounds CAM-4d,
CAM-4h and CAM-4i (Fig. 4) showed potent activity against
erythromycin-resistant S. pneumoniae encoded by the mef gene
and compounds CAM-4h and CAM-4i displayed greatly improved
activity against erythromycin-resistant S. pneumoniae encoded by
the erm gene. Compound AZM-7c (Fig. 4) exhibited improved
activity against erythromycin-resistant S. pneumoniae encoded by
the erm and mef genes [20]. Also, 6,11-di-O-methylerythromycin
A (Fig. 5) exhibits excellent in vitro and in vivo antibacterial
activity against Gram-positive bacteria and Mycoplasma pneu-
moniae [21]. The structural modification of existing antibiotics,
therefore, remains one of the most effective approaches for
overcoming bacterial resistance.
On the basis of the above details, we obtained some new
derivatives of 6,11-di-O-methylerythromycin A by substituting
-cladinose with various carbamate groups. Herein, we describe the
synthesis and biological properties of a novel class of acylides, 3-O-
carbamoyl derivatives of 6,11-di-O-methylerythromycin A, which
showed significant antibacterial activity against Gram-positive
pathogens and H. influenzae.
O
O
O
Cethromycin(ABT-773)
Telithromycin
Fig. 3. Structures of Telithromycin and Cethromycin.
methylerythromycin A was treated with diluted acid to accom-
plish cleavage of cladinose producing compound 1. Desosamine
sugar remains intact under these conditions. In order to perform
chemical transformations on the hydroxyl group at position 3, 20-
hydroxyl group, which is the most reactive one, must be suitably
protected. Hydroxyl groups at position 12 is much less reactive.
Consequently, reaction of macrolides 1 with acetic anhydride in
acetone at room temperature selectively gave 20-acetate 2 as
a
sole product, which can be later easily deprotected by
methanolysis.
By using the method of Baker et al. [18,22,23], 2 was treated
with excess 1,1-carbonyldiimidazole (CDI) and sodium hydride in
DMF at 0 ꢀC for 1 h, 20-O-acetyl-3-O-acylimidazolyl-5-O-des-
osaminyl-6, 11-di-O-methylerythronolide A (3) was obtained in
a yield of 76%. The structure of 3 was confirmed by 13C NMR
spectrum in which two carbon peaks of carbonate and carbamate
L
could be found at
d 169.7 and d 148.6. Compounds 4a-z were
prepared by reacting compound 3 with corresponding amines and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), followed by depro-
tection of the acetate group with methanol (Scheme 1). The
structures of 4a-z were determined by 13C NMR, 1H NMR, MS and IR
spectra.
2. Chemistry
3-O-Carbamoyl derivatives of 6,11-di-O-methylerythromycin
A
were synthesized as follows (Scheme 1). 6,11-di-O-
O
N
N
HO
O
HO
O
OMe
HO
HO
O
O
O
O
O
O
O
O
O
N
O
NO2
O
TEA 0777
HO
OMe
O
FMA 0122
N
O
N
HO
OH
O
O
H
N
HO
HO
O
O
O
O
O
O
O
O
O
O
N
O
O
N
H
O
N
O
O
TEA 0929
CP-544372
Fig. 2. Structures of TEA 0777, FMA 0122, TEA 0929 and CP-544372.

3638
Z. Wu et al. / European Journal of Medicinal Chemistry 45 (2010) 3636e3644
N
N
N
O
HO
HO
OMe
HO
OMe
O
O
N
O
OMe
O
O
O
HO
HO
O
MeO
HO
O
O
H
N
H
N
O
O
R
O
R
O
O
O
O
O
O
O
CAM-4
AZM-7
O
OH
OMe
AZM-7c
R=2-chlorophenethyl
CAM-4d
CAM-4h
CAM-4i
CAM-4j
CAM-4k
R=2-chlorophenethyl
R=propyl
Fig. 5. Structure of 6,11-di-O-methylerythromycin A.
R=propenyl
R=butyl
R=pentyl
To evaluate the potential of each analog to overcome macrolide
resistance, various macrolide-resistant strains were included: S.
aureus ATCC25923: erythromycin-susceptible strain; S. aureus
A265: erythromycin-resistant but methicillin-susceptible strain; S.
aureus A333: erythromycin-resistant and methicillin-resistant
strain; S. pneumoniae ATCC49619: erythromycin-susceptible strain.
S. pneumoniae 3469: erythromycin-resistant strain; H. influenzae
ATCC49247: ampicillin-susceptible strain; and H. influenzae 3300:
ampicillin-resistant strain.
Fig. 4. Structures of CAM-4 and AZM-7.
3. Antibacterial activity
All of the 3-O-carbamoyl derivatives synthesized, as well as
erythromycin, clarithromycin and azithromycin as reference
compounds, were tested for in vitro antibacterial activity against
three strains of S. aureus and two strains of each S. pneumoniae and
H. influenzae. The activities are reported in Table 1 as minimum
inhibitory concentrations (MICs) determined by the broth micro-
dilution method, as recommended by the National Committee for
Clinical Laboratory Standards.
4. Results and discussion
The results tabulated in Table 1 show the antibacterial activity of
3-O-carbamates with reference compounds (erythromycin,
N
HO
O
N
HO
O
OMe
MeO
HO
OMe
O
O
MeO
HO
O
O
b
a
O
O
O
OH
O
O
OH
OMe
O
1
N
N
O
AcO
O
AcO
OMe
O
O
OMe
MeO
HO
,
d
e
O
N
MeO
HO
O
c
O
N
O
OH
O
O
O
O
2
3
R= 4a: propyl
4c: pentyl
4b: butyl
4d: cyclohexyl
N
HO
OMe
O
4e: 3-methoxypropyl
O
4f: 3-ethoxypropyl
4h: 3-butoxypropyl
4j: furfuryl
4g: 3-isopropoxidepropyl
MeO
HO
4i: 3-hydroxypropyl
O
R
4k: thiazole-2-yl
4l: benzyl
4m: 4-methoxybenzyl
4o: 4-chlorobenzyl
4n: 4-fluorobenzyl
4p: 4-bromobenzyl
4r: 4-methylbenzyl
4t: 4-methoxyphenylethyl
H
N
O
O
O
4q: 4-hydroxybenzyl
4s: phenylethyl
4u: 3,4-dimethoxyphenylethyl
4w: 4-fluorophenylethyl
4y: 2-chlorophenylethyl
O
4v: 4-hydroxyphenylethyl
4x: 2-fluorophenylethyl
4z: 2-bromophenylethyl
4
Scheme 1. Reagents and conditions: (a) H2O, HCl, pH ¼ 1; (b) acetic anhydride, acetone, K2CO3, NaHCO3, 24 h; (c) CDI, NaH, DMF, 0 ꢀC, 1 h; (d) RNH2, CH3CN, H2O, 65 ꢀC, 12 h or
RNH2, DMF, DBU, rt, 24 h; (e) CH3OH, 55 ꢀC, 20 h.

Z. Wu et al. / European Journal of Medicinal Chemistry 45 (2010) 3636e3644
3639
Table 1
In vitro antibacterial activities of prepared macrolides.
Compound
MIC (mg/mL)
S. aureus
S. pneumoniae
H. influenzae
ATCC25923
A265
A333
ATCC49619
3469
0.125
ATCC49247
3300
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
2
1
2
8
8
8
4
4
1
1
4
2
4
8
4
16
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
32
0.125
0.125
0.125
0.125
0.125
0.125
0.5
2
1
0.5
0.125
0.125
0.5
0.125
0.125
0.125
1
>64
4
4
4
32
8
16
32
32
2
32
8
1
4
2
2
1
4
4
16
32
8
8
16
8
8
4
8
16
64
4
4
4
16
8
32
64
32
2
32
4
0.5
4
4
2
1
4
4
16
32
8
0.125
0.25
0.125
0.125
0.125
8
>64
4
2
32
2
0.125
4
4
0.125
1
0.25
8
4
2
4
2
16
1
32
8
16
8
0.125
0.5
0.125
0.5
0.125
32
0.25
64
0.125
0.25
0.25
0.125
0.125
0.125
8
0.125
0.125
0.125
0.125
0.125
0.25
0.125
8
8
8
2
2
16
1
4
8
4
2
>64
64
0.125
4
4s
4t
>64
>64
>64
>64
32
64
>64
64
0.125
0.125
0.25
0.125
0.125
0.125
0.125
0.5
4u
4v
4w
4x
4y
8
8
4
4
16
16
4
4
8
4z
AZM
CAM
EMA
0.5
0.25
0.125
>64
>64
>64
4
2
1
0.25
0.25
16
AZM: azithromycin; CAM: clarithromycin; EMA: erythromycin; S. aureus ATCC25923: erythromycin-susceptible strain; S. aureus A265: erythromycin-resistant but methi-
cillin-susceptible strain; S. aureus A333: erythromycin-resistant and methicillin-resistant strain; S. pneumoniae ATCC49619: erythromycin-susceptible strain. S. pneumoniae
3469: erythromycin-resistant strain; H. influenzae ATCC49247: ampicillin-susceptible strain; and H. influenzae 3300: ampicillin-resistant strain.
clarithromycin and azithromycin). The C-3 cladinose sugar attached
to the 14-membered ring macrolides is believed to be responsible
for the inducibility of macrolide resistance. Removal of the L-cla-
dinosyl moiety of clarithromycin resulted in a complete loss of
antibacterial activity. Simple introduction of an acetyl group at the
3-O-position did not completely restore the antibacterial activity,
although it did seem to be slightly effective against the erythro-
mycin-susceptible strain. Accordingly, we obtained some new
side chain inplace of L-cladinose at the 3-O-position. This new class of
antibiotics exhibited potent activity against some key erythromycin-
resistant and -susceptible pathogens. The results suggested that the
3-O-carbamoyl side chain in their structures could interact with the
binding sites in the cavity formed by G2505, C2610 and C2611 in
domain V, resulting in a higher affinity to bacterial ribosomes.
5. Conclusion
derivatives of 6,11-di-O-methylerythromycin A by substituting L-
cladinose with various carbamate groups, such as alkylcarbamoyl,
hydroxy-alkylcarbamoy, alkoxy-alkylcarbamoyl, heterocyclic-car-
A simple and efficient method for preparation of 3-O-carbamoyl
analogs of 5-O-desosaminyl-6, 11-di-O-methylerythronolide A was
developed. These carbamates were evaluated for antibacterial
activity against macrolide-susceptible and macrolide-resistant
pathogens. Among the target derivatives, compounds 4p, 4q, 4w, 4x
and 4z were found to have potent activity against most susceptible
and resistant bacteria. In particular, compound 4p exhibited
excellent antibacterial activity in comparison to the others. The
results suggested that introduction of the 3-O-carbamoyl side
chains at the 3-O-position shows improved the activity against
erythromycin-resistant against the erythromycin-resistant but
methicillin-susceptible S. aureus, and introduction of the 3-O-car-
bamoyl side chain at the 3-O-position may increase the activity
against erythromycin-resistant and methicillin-resistant S. aureus
and ampicillin-resistant and -suscepible H. influenzae.
The improved antibacterial activity against resistant bacteria
achieved by these derivatives is possibly due to the C-3 cladinose
sugar attached to the 14-membered ring macrolides which is
believed to be responsible for the inducibility of macrolide resis-
tance. It is worthy of notice that 3-O-carbamate derivatives of 14-
membered macrolides are probably the effective management of
macrolide resistance, and this study possibly presents a major
bamoyl,
phenethylcarbamoyl.
Among the tested compounds, some new derivatives of 6,11-di-
O-methylerythromycin by substituting -cladinose with
substituted
benzylcarbamoyl,
and
substituted
A
L
substituted benzylcarbamoyl (4le4r) were found to have more
potent activity (MIC 0.125e0.25 mg/mL) against the erythromycin-
resistant but methicillin-susceptible S. aureus A265, which were
comparable to the other new 3-O-carbamates and reference
compounds. In addition, compounds 4p, 4r, 4w, 4x and 4z improved
the activity (MIC 32e64 mg/mL) against erythromycin-resistant and
methicillin-resistant S. aureus A333, MIC values for AZM, CAM and
ERM are >64 mg/mL. Most of the new compounds displayed
excellent activity against erythromycin-resistant and -suscepible S.
pneumoniae such as S. pneumoniae 3469 and S. pneumoniae
ATCC49619. Moreover, most of the new 3-O-carbamates have potent
activity against ampicillin-resistant and -suscepible H. influenzae
such as H. influenzae ATCC49247 and H. influenzae 3300, among
them, 4me4s were more active than others.
The 3-O-carbamoyl derivatives of 6,11-di-O-methylerythromycin
A are 14-membered macrolide derivatives with the 3-O-carbamoyl

3640
Z. Wu et al. / European Journal of Medicinal Chemistry 45 (2010) 3636e3644
opportunity for the development of new macrolide antibiotics to
combat the growing problem of antibiotic resistance.
Anal. calcd. (%) for C33H59NO11: C 61.37, H 9.21, N 2.17; Found: C
61.34, H 9.20, N 2.18.
6. Experimental
6.3. 20-O-acetyl-3-O-acylimidazolyl -3-O-descladinosyl-6,11-di-O-
methylerythromycin A (3)
Reagents were purchased from commercial sources. Solvents
and reagents were dried and purified according to the literature
methods. Melting points were uncorrected and measured on an XT-
4 apparatus. IR spectra were recorded from KBr pellets at a range of
400e4000 cmꢁ1 on a PerkineElmer (Spectrum One) spectrometer.
1H NMR and 13C NMR spectra were obtained on a Varian Mercury
VX400 apparatus in CDCl3 with TMS as internal standard. The
elemental analysis (C, H, N) data were obtained from a Vario EL III
(German) elemental analyzer. All the ampicillin-resistant and
erythromycin-resistant strains chosen in this test are constitutively
resistant strains supplied by the Ministry of Health National Anti-
microbial Resistance Investigation Net (MOHNARIN, China).
To a solution of 2 (1.29 g, 2 mmol) in DMF (20 mL) was added NaH
(0.096 g, 4 mmol, 2.0 equiv)and CDI (0.705 g, 4 mmol, 2.0 equiv). The
resulting solution was stirred at 0 ꢀC for 1 h. The reaction was
quenched with saturated NaHCO3 (20 ml) and the aqueous layer was
extracted with CH2Cl2 (3 ꢂ 10 mL). The combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated in
vacuum. Theresiduewas purified bychromatographytoafford 1.12 g
(76%) of 3 as a white solid, mp 88e91 ꢀC.
IR (KBr): 3448, 2977, 2928, 1765, 1711, 1463, 1400, 1377, 1343,
1314, 1290, 1240, 1172, 1108, 1006 cmꢁ1 1H NMR (400 MHz,
;
CDCl3):
d
8.24 (s, 1H), 7.52 (s, 1H), 7.18 (s, 1H), 5.16 (d, J ¼ 11.2 Hz,
1H), 5.07 (d, J ¼ 9.2 Hz, 1H), 4.63 (m, 1H), 3.88 (d, J ¼ 7.4 Hz, 1H),
3.80 (d, J ¼ 3.2 Hz, 1H), 3.60 (s, 3H), 3.43 (s, 1H), 3.14 (s, 3H), 3.12
(m, 1H), 3.10-3.03 (m, 2H), 2.56 (m, 1H), 2.41-2.32 (m, 2H), 2.23
(m, 1H), 2.18 (s, 6H), 2.10 (s, 3H), 2.04-1.94 (m, 1H), 1.73 (m, 1H),
1.53 (m, 1H), 1.50 (m, 3H), 1.46-1.36 (m, 2H), 1.28 (s, 3H), 1.26-1.07
(m, 16H), 0.86-0.83 (m, 3H); 13C NMR (400 MHz, CDCl3): 216.6,
173.0, 169.7, 148.6, 131.3, 117.0, 100.1, 82.6, 78.6, 78.4, 78.0, 75.9,
75.8, 71.1, 69.1, 63.0, 61.0, 50.0, 45.9, 42.4, 40.5, 37.6, 36.9, 35.9,
30.1, 21.6, 21.4, 20.9, 19.5, 19.2, 17.6, 14.8, 13.0, 11.1, 10.4, 8.8; MS
(ESI) m/z calcd. for C37H61N3O13 739.89; found (M þ Naþ) 762.1;
Anal. calcd. (%) for C37H61N3O12: C 60.06, H 8.31, N 5.68; Found: C
60.04, H 8.27, N 5.71.
6.1. 3-O-descladinosyl-6,11-di-O-methylerythromycin A (1)
6,11-Di-O-methylerythromycin A (3.05 g, 4.0 mmol) was suspended
in water (20 mL) and the pH was adjusted to 1 using 6 N HCl. The
reaction mixture was stirred for 24 h at room temperature, CH2Cl2
(10 mL)wasadded, and pHadjusted to8. Thelayerswereseparated and
aqueous layer extracted with CH2Cl2 (2 ꢂ 10 mL). Combined organic
extracts were rinsed with saturated aqueous NaHCO3 solution, brine,
and water, and dried over anhydrous Na2SO4. The solvent was evapo-
rated to afford 1 (1.89 g, 78%) as a white solid, mp 110e113 ꢀC.
IR (KBr): 3458, 2975, 2931, 2875, 1724, 1458, 1376, 1346, 1169,
1108, 1075 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 4.99 (m, 1H), 4.42 (d,
J ¼ 4.4 Hz, 1H), 3.77 (d, J ¼ 1.2 Hz, 1H), 3.67 (m, 1H), 3.57 (s, 3H),
3.55-3.52 (m, 2H), 3.49 (m, 1H), 3.25 (m, 1H), 3.14 (s, 1H), 3.02 (s,
3H), 2.97 (m, 1H), 2.71 (m, 1H), 2.61 (m, 1H), 2.47 (m, 1H), 2.25 (s,
6H), 2.13 (m, 1H), 1.97-1.91 (m, 3H), 1.68-1.65 (m, 3H), 1.52-1.48 (m,
2H), 1.39 (s, 3H), 1.28-1.10 (m, 17H), 0.87-0.82 (m, 3H); 13C NMR
(400 MHz, CDCl3): 216.8, 175.3, 106.4, 86.9, 78.8, 78.5, 78.4, 77.7,
76.0, 70.6, 70.1, 65.6, 61.1, 49.4, 45.8, 44.6, 40.2, 37.9, 37.5, 36.2, 28.0,
21.8, 21.3, 19.2, 18.9, 17.4, 15.1, 12.9, 10.4, 8.35; MS (ESI) m/z calcd. for
C31H57NO10 603.40; found (M þ Hþ) 604.2; Anal. calcd. (%) for
C31H57NO10: C 61.67, H 9.52, N 2.32; Found: C 61.64, H 9.50, N 2.34.
6.4. General methods for the preparation of 3-O-
arylalkylcarbamoyl-3-O-descladinosyl-6,11-di-O-
methylerythromycin A derivatives (4a-z)
Method I: To a solution of 3 (1.11 g, 1.50 mmol) in CH3CN (20 mL)
and water (2 mL) was added the corresponding alkylamine
(7.5 mmol, 1.5 equiv). The resulting solution was stirred for 12 h at
65 ꢀC. The reaction was quenched with 0.5 M NaH2PO4 (15 mL) and
the aqueous layer was extracted with ethyl acetate (3 ꢂ 15 mL). The
combined organic layers were washed with brine, and dried over
anhydrous Na2SO4, filtered. The filtrate was concentrated in
vacuum to afford a crude product. A solution of the above crude
product in methanol (15 mL) was heated to 55 ꢀC and stirred for
12 h at the same temperature. After concentrating the reaction
solution in vacuo, the residue was purified by chromatography to
afford the desired products 4(a-i).
6.2. 20-O-acetyl-3-O-descladinosyl-6,11-di-O-methylerythromycin
A (2)
Compound 1 (1.81 g, 3.0 mmol) in acetone (15 mL) at room
temperature was added acetic anhydride (5.6 mL,
6 mmol,
2.0 equiv) and K2CO3 (0.83 g, 6 mmol, 2.0 equiv). The resulting
solution was allowed to stir for 24 h at the same temperature. The
reaction was quenched with 5% aqueous NaHCO3 (15 mL) and the
aqueous layer was extracted with CH2Cl2 (3 ꢂ 20 mL). The
combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuum. The residue was crystallized
to afford 1.80 g (93%) of 2 as a white solid, mp 129e131 ꢀC.
IR (KBr): 3474, 2970, 2936, 2359, 1749, 1732, 1716, 1456, 1374,
Method II: To a solution of 3 (1.11 g, 1.50 mmol) in DMF (15 mL)
at 0 ꢀC was added DBU (0.33 mL, 2.25 mmol, 1.5 equiv) and corre-
sponding amine (2.25 mmol, 1.5 equiv). The resulting solution was
raised to room temperature and stirred for 24 h at the same
temperature. The reaction was quenched with water (30 mL) and
the aqueous layer was extracted with ethyl acetate (3 ꢂ 15 mL). The
combined organic layers were washed with brine, and dried over
anhydrous Na2SO4, filtered. The filtrate was concentrated in
vacuum to afford a crude product. A solution of the above crude
product in methanol (15 mL) was heated to 55 ꢀC and stirred for
20 h at the same temperature. After concentrating the reaction
solution in vacuum, the residue was purified by chromatography to
afford products 4 (jez).
1239, 1167, 1110, 1064 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 5.00 (m,
1H), 4.77(m, 1H), 4.60 (d, J ¼ 7.6 Hz, 1H), 3.80 (d, J ¼ 2.6 Hz, 1H),
3.57 (s, 3H), 3.41-3.51 (m, 2H), 3.12 (s, 1H), 3.03 (m, 1H), 2.99 (s,
1H), 3.02 (s, 3H), 2.75-2.69 (m, 2H), 2.57 (m, 1H), 2.61 (m, 1H), 2.26
(s, 6H), 2.13 (m, 1H), 2.08 (s, 3H), 2.03 (m, 1H), 1.93 (m, 1H), 1.81
(m, 1H), 1.72 (m, 3H), 1.51 (m, 1H), 1.38 (m, 1H), 1.29 (s, 3H), 1.28-
1.09 (m, 13H), 0.97 (d, J ¼ 0.97 Hz, 3H), 0.85-0.82 (m, 3H); 13C NMR
(400 MHz, CDCl3): 217.1, 174.9, 170.0, 99.7, 79.8, 78.7, 78.1, 77.6,
77.4, 76.0, 71.4, 68.7, 63.2, 61.1, 49.6, 46.0, 44.1, 40.6, 37.6, 37.2,
36.0, 30.9, 21.8, 21.5, 21.1, 19.6, 19.3, 17.5, 15.2, 13.0, 10.4, 8.2; MS
(ESI) m/z calcd. for C33H59NO11 645.41; found (M þ Hþ) 646.1;
6.4.1. 3-O-((Propyl)carbamoyl)-3-O-descladinosyl-6,11-di-O-
methylerythromycin A (4a)
White solid, yield 82%, mp 142e146 ꢀC; IR (KBr): 3377, 2971,
2940, 2881, 2360, 1725, 1652, 1541, 1460, 1377, 1344, 1258, 1174,
1109,1075 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 5.05 (m,1H), 5.02 (m,

Z. Wu et al. / European Journal of Medicinal Chemistry 45 (2010) 3636e3644
3641
1H), 4.86 (d, J ¼ 11.0 Hz, 1H), 4.08 (d, J ¼ 7.4 Hz, 1H), 3.87 (m, 1H),
6.4.5. 3-O-((3-methoxypropyl)carbamoyl)-3-O-descladinosyl-6,11-
di-O-methylerythromycin A (4e)
White solid, yield 74%, mp 240e243 ꢀC; IR (KBr): 3419, 2957,
2928, 2857, 1728, 1459, 1380, 1256, 1173, 1111, 1075 cmꢁ1 1H NMR
(400 MHz, CDCl3):
5.51 (m, 1H), 5.03 (m, 1H), 4.86 (d, J ¼ 11.1 Hz,
3.58 (s, 3H), 3.48 (m, 1H), 3.36 (m, 1H), 3.27 (m, 2H), 3.20 (m, 1H),
3.17 (s, 3H), 3.04 (m, 2H), 2.86 (m, 1H), 2.74 (m, 1H), 2.57 (m, 1H),
2.40 (m, 1H), 2.28 (s, 6H), 2.22 (m, 1H), 1.98-1.83 (m, 4H), 1.65-1.48
(m, 6H),1.30 (s, 3H),1.25-1.07 (m,16H), 0.96-0.92 (m, 3H), 0.84-0.81
(m, 3H); 13C NMR (400 MHz, CDCl3): 217.0, 174.1, 156.6, 103.0, 79.6,
78.5, 78.0, 77.9, 77.7, 76.0, 70.6, 69.5, 65.9, 61.1, 49.9, 45.9, 43.0, 42.9,
40.3, 37.6, 37.4, 35.7, 28.6, 23.2, 21.7, 21.2, 19.7, 19.4, 17.3, 14.7, 13.0,
12.3, 10.5, 9.2; MS (ESI) m/z calcd. for C35H64N2O11 688.45; found
(M þ Hþ) 689.1; Anal. calcd. (%) for C35H64N2O11: C 61.02, H 9.36, N
4.07; Found: C 60.99, H 9.35, N 4.06.
;
d
1H), 4.13 (d, J ¼ 7.2 Hz,1H), 3.87 (d, J ¼ 3.1 Hz,1H), 3.59 (s, 3H), 3.48-
3.40 (m, 5H), 3.45 (s, 3H), 3.30-3.18 (m,3H), 3.10 (s, 3H), 3.04 (m,
1H), 2.88 (m, 1H), 2.67 (m, 1H), 2.60 (m, 1H), 2.39 (s, 6H), 2.31-2.17
(m, 1H), 1.97-1.86 (m, 1H), 1.83-1.78 (m, 2H), 1.76-1.65 (m, 4H), 1.51-
1.40 (m, 3H), 1.30 (s, 3H), 1.25-1.08 (m, 16H), 0.96(m, 1H), 0.85-0.81
(m, 3H); 13C NMR (400 MHz, CDCl3): 217.0, 174.2, 156.6, 102.5, 79.4,
78.5, 78.0, 77.7, 76.0, 71.0, 70.5, 69.1, 65.8, 65.6, 61.6, 58.8, 49.9, 45.9,
43.0, 40.2, 39.2, 37.6, 35.7, 34.4, 30.5, 29.7, 21.1, 19.7, 19.1, 17.3, 14.7,
13.7, 13.0, 10.5, 9.2; MS (ESI) m/z calcd. for C36H66N2O12 718.46;
found (M þ Hþ) 719.0; Anal. calcd. (%) for C36H66N2O12: C 60.14, H
9.25, N 3.90; Found: C 60.11, H 9.23, N 3.87.
6.4.2. 3-O-((Butyl)carbamoyl)-3-O-descladinosyl-6,11-di-O-
methylerythromycin A (4b)
White solid, yield 77%, mp 135e138 ꢀC; IR (KBr): 3445, 2974,
2954, 2875, 1733, 1532, 1457, 1380, 1345, 1251, 1172, 1109, 1064,
1027 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 5.19 (m, 1H), 5.05 (m, 1H),
4.86 (d, J ¼ 11.0 Hz, 1H), 4.09 (d, J ¼ 7.3 Hz, 1H), 3.87 (d, J ¼ 2.9 Hz,
1H), 3.59 (s, 3H), 3.51 (m, 1H), 3.38 (m, 1H), 3.29 (m, 1H), 3.26-3.14
(m, 2H), 3.10 (s, 3H), 3.06 (m, 1H), 3.03 (m, 1H), 2.87 (m, 1H), 2.59
(m, 1H), 2.45 (m, 1H), 2.29 (s, 6H), 2.22 (m, 1H), 1.98-1.84 (m, 3H),
1.62 (m, 1H), 1.53-1.50 (m, 5H), 1.40-1.34 (m, 3H), 1.31 (s, 3H), 1.23-
1.08 (m, 16H), 0.95-0.92 (m, 4H), 0.85-0.82 (m, 3H); 13C NMR
(400 MHz, CDCl3): 217.0, 174.1, 156.5, 102.9, 79.5, 79.4, 78.5, 78.0,
77.7, 76.0, 70.5, 69.4, 65.9, 61.0, 49.9, 46.0, 43.0, 40.9, 40.3, 37.6, 37.3,
35.7, 32.0, 28.6, 21.7, 21.1, 20.0, 19.9, 19.6, 17.3, 14.6, 13.7, 13.0, 10.4,
9.1; MS (ESI) m/z calcd. for C36H66N2O11 702.47; found (M þ Hþ)
703.2; Anal. calcd. (%) for C36H66N2O11: C 61.51, H 9.46, N 3.99;
Found: C 61.49, H 9.45, N 4.02.
6.4.6. 3-O-((3-ethoxypropyl)carbamoyl)-3-O-descladinosyl-6,11-
di-O-methylerythromycin A (4f)
White solid, yield 76%, mp 99e103 ꢀC; IR (KBr): 3450, 2974,
2938, 2875, 1729, 1527, 1460, 1378, 1345, 1253, 1174, 1111,
1072 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 5.45 (m, 1H), 5.01 (m, 1H),
4.82 (d, J ¼ 11.0 Hz, 1H), 4.06 (d, J ¼ 7.2 Hz, 1H), 3.86 (m, 1H), 3.55 (s,
3H), 3.49-3.42 (m, 5H), 3.40-3.32 (m, 2H), 3.19-3.13 (m, 3H), 3.07 (s,
3H), 2.99 (m, 1H), 2.85 (m, 1H), 2.54 (m, 1H), 2.42 (m, 1H), 2.25 (s,
6H), 2.22 (m, 1H), 1.93-1.84 (m, 2H), 1.80-1.66 (m, 2H), 1.62 (m, 1H),
1.49-1.34 (m, 4H), 1.27 (s, 3H), 1.22-1.04 (m, 20H), 0.93 (m, 1H),
0.81-0.77 (m, 3H); 13C NMR (400 MHz, CDCl3): 217.0, 174.1, 156.5,
102.7, 79.0, 78.5, 78.0, 77.5, 76.0, 70.5, 69.3, 68.8, 66.3, 65.8, 61.0,
52.7, 49.9, 45.9, 42.9, 42.0, 40.2, 37.6, 37.3, 35.7, 29.6, 28.6, 21.6, 21.1,
19.6, 19.3, 17.3, 15.1, 14.6, 12.9, 10.3, 9.1; MS (ESI) m/z calcd. for
C37H68N2O12 732.48; found (M þ Hþ) 733.2; Anal. calcd. (%) for
C37H68N2O12: C 60.63, H 9.35, N 3.82; Found: C 60.61, H 9.32, N 3.84.
6.4.3. 3-O-((Pentyl)carbamoyl)-3-O-descladinosyl-6,11-di-O-
methylerythromycin A (4c)
White solid, yield 76%, mp 131e133 ꢀC; IR (KBr): 3340, 2962,
2932, 2872, 1727, 1528, 1460, 1377, 1344, 1246, 1175, 1109,
1072 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
4.98 (m, 1H), 4.94 (m, 1H),
6.4.7. 3-O-((3-isopropoxidepropyl)carbamoyl)-3-O-descladinosyl-
6,11-di-O-methylerythromycin A (4g)
4.79 (d, J ¼ 11.0 Hz, 1H), 4.01 (d, J ¼ 7.3 Hz, 1H), 3.81 (d, J ¼ 3.0 Hz,
1H), 3.52 (s, 3H), 3.41 (d, J ¼ 3.6 Hz, 1H), 3.32-3.18 (m, 2H), 3.13 (m,
1H), 3.03 (s, 3H), 2.98 (m, 3H), 2.81 (m, 1H), 2.52 (m, 1H), 2.38 (m,
1H), 2.22 (s, 6H), 2.16 (m, 1H), 2.10 (m, 1H), 1.92-1.77 (m, 3H), 1.59
(m, 1H), 1.47-1.36 (m, 5H), 1.26-1.25 (m, 3H), 1.24 (s, 3H), 1.19-1.00
(m, 18H), 0.85-0.81 (m, 3H), 0.78-0.74 (m, 3H); 13C NMR (400 MHz,
CDCl3): 217.0, 174.0, 156.6, 102.7, 79.3, 78.4, 77.9, 77.5, 75.9, 70.5,
69.2, 65.8, 60.9, 50.2, 49.8, 45.8, 42.9, 41.1, 40.2, 37.5, 37.3, 35.6, 29.6,
29.5, 28.9, 28.6, 22.2, 21.6, 21.1, 19.6, 19.2, 17.3, 14.6, 13.9, 12.9, 10.3,
9.1; MS (ESI) m/z calcd. for C37H68N2O11 716.48; found (M þ Hþ)
717.2; Anal. calcd. (%) for C37H68N2O11: C 61.98, H 9.56, N 3.91;
Found: C 61.96, H 9.55, N 3.89.
White solid, yield 73%, mp 98e102 ꢀC; IR (KBr): 3451, 2974,
2936, 2879, 1729, 1639, 1529, 1460, 1376, 1343, 1255, 1174, 1109,
1074 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 5.49 (m, 1H), 5.02 (m, 1H),
4.85 (d, J ¼ 11.0 Hz, 1H), 4.11 (d, J ¼ 7.2 Hz, 1H), 3.89 (d, J ¼ 3.1 Hz,
1H), 3.62 (m, 1H), 3.59 (s, 3H), 3.55 (m, 1H), 3.53-3.50 (m, 2H), 3.48
(m, 1H), 3.43-3.36 (m, 2H), 3.24-3.18 (m, 2H), 3.10 (s, 3H), 3.03 (m,
1H), 2.90 (m, 1H), 2.59 (m, 1H), 2.47 (m, 1H), 2.30 (s, 6H), 2.22 (m,
1H), 1.83-2.05 (m, 4H), 1.80-1.71 (m, 2H), 1.63 (m, 1H), 1.52-1.45 (m,
3H), 1.30 (s, 3H), 1.25-1.08 (m, 23H), 0.85-0.81 (m, 3H); 13C NMR
(400 MHz, CDCl3): 217.0, 174.1, 156.5, 102.7, 79.1, 78.5, 78.0, 77.6,
76.0, 71.7, 70.5, 69.4, 66.5, 65.8, 61.1, 52.9, 49.9, 45.9, 42.9, 40.3, 39.7,
37.6, 37.4, 35.7, 29.8, 28.7, 22.1, 21.7, 21.2, 19.7, 19.4, 17.3, 14.7, 13.0,
10.4, 9.1; MS (ESI) m/z calcd. for C38H70N2O12 746.49; found
(M þ Hþ) 747.1; Anal. calcd. (%) for C38H70N2O12: C 61.10, H 9.45, N
3.75; Found: C 61.07, H 9.42, N 3.72.
6.4.4. 3-O-((Cyclohexyl)carbamoyl)-3-O-descladinosyl-6,11-di-O-
methylerythromycin A (4d)
White solid, yield 70%, mp 113e117 ꢀC; IR (KBr): 3453, 2974,
2935, 2857, 2784, 1727, 1533, 1458, 1376, 1345, 1273, 1240, 1174,
1108, 1056 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
5.02 (m, 1H), 4.91
6.4.8. 3-O-((3-butoxypropyl)carbamoyl)-3-O-descladinosyl-6,11-
di-O-methylerythromycin A (4h)
(d, J ¼ 8.2 Hz, 1H), 4.85 (d, J ¼ 10.9 Hz, 1H), 4.09 (d, J ¼ 3.3 Hz, 1H),
3.85 (d, J ¼ 3.1 Hz, 1H), 3.59 (s, 3H), 3.48 (m, 1H), 3.40 (m, 1H), 3.20
(m, 1H), 3.10 (s, 3H), 3.02 (m, 1H), 2.87 (m, 1H), 2.58 (m, 1H), 2.48
(m, 1H), 2.30 (s, 6H), 2.27 (m, 1H), 2.17-1.81 (m, 5H), 1.72-1.62 (m,
5H), 1.54-1.51 (m, 3H), 1.36 (m, 1H), 1.31 (s, 3H), 1.25-1.07 (m, 23H),
0.85-0.81 (m, 3H); 13C NMR (400 MHz, CDCl3): 216.9, 174.1, 155.8,
103.1, 80.0, 78.5, 78.0, 77.7, 77.6, 76.0, 70.5, 69.3, 65.9, 61.1, 50.4,
50.2, 49.9, 45.9, 43.1, 40.2, 37.6, 37.4, 35.7, 33.4, 30.9, 25.5, 25.0,
24.6, 21.7, 21.2, 19.7, 19.3, 17.3, 14.7, 13.0, 10.4, 9.2; MS (ESI) m/z
calcd. for C38H68N2O11 728.48; found (M þ Hþ) 729.2; Anal. calcd.
(%) for C38H68N2O11: C 62.61, H 9.40, N 3.84; Found: C 62.58, H
9.37, N 3.81.
White solid, yield 72%, mp 107e110 ꢀC; IR (KBr): 3335, 2970,
2938, 2875, 2788, 1732, 1458, 1377, 1342, 1252, 1173, 1109, 1076,
1051 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 5.43 (s, 1H), 4.97 (m, 1H),
4.78 (d, J ¼ 11.0 Hz, 1H), 4.03 (d, J ¼ 7.3 Hz, 1H), 3.82 (d, J ¼ 3.0 Hz,
1H), 3.52 (s, 3H), 3.47-3.41 (m, 4H), 3.37-3.34 (m, 3H), 3.31-3.29 (m,
2H), 3.14 (m, 3H), 3.03 (s, 3H), 2.97 (m, 1H), 2.81 (m, 1H), 2.52 (m,
1H), 2.41 (m, 1H), 2.22 (s, 6H), 2.15 (m, 1H), 1.86 (m, 1H), 1.79-1.57
(m, 2H), 1.53-1.39 (m, 3H), 1.37-1.27 (m, 2H), 1.23 (s, 3H), 1.18-1.00
(m, 21H), 0.88-0.85 (m, 3H), 0.78-0.74 (m, 3H); 13C NMR (400 MHz,
CDCl3): 216.9, 174.1, 156.5, 102.7, 79.0, 78.5, 77.9, 77.6, 76.0, 70.9,
70.5, 69.6, 69.5, 69.4, 65.8, 61.0, 49.9, 45.9, 42.9, 40.2, 39.8, 37.6,

3642
Z. Wu et al. / European Journal of Medicinal Chemistry 45 (2010) 3636e3644
37.3, 35.7, 31.7, 29.6, 28.6, 21.7, 21.2, 19.7, 19.4, 19.3, 17.3, 14.7, 13.9,
13.0, 10.4, 9.0; MS (ESI) m/z calcd. for C39H72N2O12 760.51; found
(M þ Hþ) 761.2; Anal. calcd. (%) for C39H72N2O12: C 61.55, H 9.54, N
3.68; Found: C 61.52, H 9.52, N 3.70.
J ¼ 2.9 Hz, 1H), 3.58 (s, 3H), 3.48 (m, 1H), 3.45 (m, 1H), 3.14 (m,
1H), 3.09 (s, 3H), 3.05 (m, 1H), 3.01 (m, 1H), 2.88 (m, 1H), 2.57 (m,
1H), 2.25 (m, 1H), 2.23 (s, 6H), 2.21 (m, 1H), 2.19-1.93 (m, 2H), 1.86-
1.83 (m, 2H), 1.52-1.44 (m, 3H), 1.29 (s, 3H), 1.28-1.06 (m, 17H),
0.85-0.81 (m, 3H); 13C NMR (400 MHz, CDCl3): 217.0, 174.1, 156.6,
138.4, 128.8, 127.8, 127.7, 103.0, 80.0, 78.5, 78.4, 78.0, 77.7, 76.0,
70.5, 69.2, 65.6, 61.1, 49.9, 45.9, 45.2, 43.1, 40.2, 37.6, 37.4, 35.7,
28.5, 21.7, 21.2, 19.7, 19.3, 17.3, 14.9, 13.0, 10.4, 9.2; MS (ESI) m/z
calcd. for C39H64N2O11 736.45; found (M þ Hþ) 737.1; Anal. calcd.
(%) for C39H64N2O11: C 63.56, H 8.75, N 3.80; Found: C 63.54, H
8.73, N 3.82.
6.4.9. 3-O-((3-hydroxypropyl)carbamoyl)-3-O-descladinosyl-6,11-
di-O-methylerythromycin A (4i)
White solid, yield 67%, mp 181e186 ꢀC; IR (KBr): 3367, 2974,
2944, 2883, 1719, 1654, 1459, 1377, 1346, 1252, 1175, 1108,
1060 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 5.50 (s, 1H), 5.04 (m, 1H),
4.88 (d, J ¼ 11.0 Hz, 1H), 4.10 (d, J ¼ 7.6 Hz, 1H), 3.85 (d, J ¼ 3.0 Hz,
1H), 3.75-3.70 (m, 2H), 3.60 (s, 3H), 3.51-3.48 (m, 2H), 3.37 (m, 1H),
3.26-3.20 (m, 2H), 3.11 (s, 3H), 3.05 (m, 1H), 2.90 (m, 1H), 2.59 (m,
1H), 2.50 (m, 1H), 2.31 (s, 6H), 2.29-2.20 (m, 3H), 1.98-1.90 (m, 2H),
1.86 (m, 1H), 1.78 (m, 1H), 1.73-1.66 (m, 2H), 1.55-1.48 (m, 3H), 1.32
(s, 3H), 1.28-1.14 (m, 15H), 1.11-1.09 (m, 3H), 0.86-0.82 (m, 3H); 13C
NMR (400 MHz, CDCl3): 217.1, 174.1, 157.3, 103.1, 80.0, 78.5, 78.0,
77.7, 76.0, 70.7, 69.4, 65.7, 61.1, 59.8, 49.9, 45.9, 43.0, 40.3, 38.2, 37.6,
37.4, 35.7, 32.4, 29.4, 28.6, 21.7, 21.2, 19.7, 19.3, 17.3, 14.7, 13.0, 10.5,
9.2; MS (ESI) m/z calcd for C35H64N2O12 704.45; found (M þ Hþ)
705.1; Anal. calcd (%) for C35H64N2O12: C 59.64, H 9.15, N 3.97;
Found: C 59.62, H 9.12, N 3.96.
6.4.13. 3-O-((4-methoxybenzyl)carbamoyl)-3-O-descladinosyl-
6,11-di-O-methylerythromycin A (4m)
White solid, yield 74%, mp 230e234 ꢀC; IR (KBr): 3450, 2962,
2934, 1728, 1637, 1536, 1457, 1342, 1244, 1173, 1112, 1077 cmꢁ1; 1H
NMR (400 MHz, CDCl3):
d
7.25-7.21 (d, J ¼ 8.5 Hz, 2H), 6.86-6.84 (d,
J ¼ 8.6 Hz, 2H), 5.47 (m, 1H), 5.04 (m, 1H), 4.88 (d, J ¼ 11.0 Hz, 1H),
4.34-4.29 (m, 2H), 3.98 (d, J ¼ 7.3 Hz, 1H), 3.82 (m, 1H), 3.79 (m, 1H),
3.59 (s, 3H), 3.57 (s, 1H), 3.48 (s, 1H), 3.15 (m, 1H), 3.13 (s, 3H), 3.01
(m, 2H), 2.87 (m, 1H), 2.60-2.56 (m, 1H), 2.26-2.22 (m, 2H), 2.24 (s,
6H), 2.20 (m, 1H), 1.95-1.85 (m, 2H), 1.54-1.39 (m, 3H), 1.30 (s, 3H),
1.26-1.07 (m, 21H), 0.88-0.83 (m, 3H); 13C NMR (400 MHz, CDCl3):
217.0, 174.1, 159.1, 156.5, 130.5, 129.2, 114.1, 103.1, 80.2, 78.5, 78.4,
78.0, 77.7, 76.0, 70.5, 69.2, 65.7, 61.1, 55.3, 49.9, 45.9, 44.7, 43.1, 40.2,
37.6, 37.4, 35.7, 28.4, 21.7, 21.2, 19.7,19.3,17.3,14.9,13.0,10.5, 9.2; MS
(ESI) m/z calcd. for C40H66N2O12 766.46; found (M þ Hþ) 767.2;
Anal. calcd. (%) for C40H66N2O12: C 62.64, H 8.67, N 3.65; Found: C
62.61, H 8.65, N 3.62.
6.4.10. 3-O-(Furfurylcarbamoyl)-3-O-descladinosyl-6,11-di-O-
methylerythromycin A (4j)
White solid, yield 61%, mp 190e193 ꢀC; IR (KBr): 3446, 2962,
2927, 2357, 1732, 1653, 1457, 1378, 1344, 1260, 1170, 1109,
1078 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
8.21 (d, J ¼ 3.0 Hz, 1H),
7.63 (m,1H), 7.47 (d, J ¼ 3.1 Hz,1H), 4.94 (m,1H), 4.79 (d, J ¼ 10.6 Hz,
1H), 4.37-4.32 (m, 2H), 4.30 (d, J ¼ 7.3 Hz, 1H), 3.86 (d, J ¼ 3.2 Hz,
1H), 3.70 (m, 1H), 3.51 (s, 3H), 3.41 (m, 1H), 3.26-3.09 (m, 3H), 3.01
(s, 3H), 2.81 (m, 1H), 2.64 (m, 1H), 2.47 (m, 1H), 2.21 (s, 6H), 2.05 (m,
1H), 1.96-1.74 (m, 4H), 1.58-1.66 (m, 2H), 1.44-1.38 (m, 3H), 1.30 (s,
3H), 1.25-0.99 (m, 17H), 0.77-0.74 (m, 3H); 13C NMR (400 MHz,
CDCl3): 217.1, 174.1, 156.7, 137.4, 133.2, 130.9, 106.4, 103.1, 87.0, 78.5,
78.0, 77.7, 76.0, 70.7, 70.1, 65.7, 61.1, 58.7, 49.9, 45.9, 43.2, 40.3, 37.6,
36.3, 35.7, 34.4, 29.7, 21.3, 21.1,19.7,19.3,17.3,14.8,12.9,10.4, 9.3; MS
(ESI) m/z calcd. for C37H62N2O12 726.43; found (M þ Hþ) 727.1; Anal.
calcd. (%) for C37H62N2O12: C 61.14, H 8.60, N 3.85; Found: C 61.11, H
8.58, N 3.84.
6.4.14. 3-O-((4-fluorobenzyl)carbamoyl)-3-O-descladinosyl-6,11-
di-O-methylerythromycin A (4n)
White solid, yield 70%, mp 94e98 ꢀC; IR (KBr): 3453, 2975,
2939, 2878, 1729, 1606, 1511, 1458, 1343, 1254, 1172, 1109,
1077 cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 7.30-7.23 (m, 2H), 7.02-
6.98 (m, 2H), 5.63 (s, 1H), 5.02 (d, J ¼ 10.6 Hz, 1H), 4.86 (d,
J ¼ 3.0 Hz, 1H), 4.43-4.24 (m, 2H), 3.97 (d, J ¼ 3.1 Hz, 1H), 3.82 (m,
1H), 3.57 (s, 3H), 3.55 (m, 1H), 3.45 (m, 1H), 3.11-3.15 (m, 2H), 3.08
(s, 3H), 3.02-3.00 (m, 2H), 2.87 (m, 1H), 2.56 (m, 1H), 2.23 (s, 6H),
2.21-2.17 (m, 3H), 1.92-1.80 (m, 2H), 1.49-1.37 (m, 3H), 1.29 (s, 3H),
1.24-1.05 (m, 18H), 0.83-0.80 (m, 3H); 13C NMR (400 MHz, CDCl3):
217.1, 174.0, 165.8, 156.7, 134.6, 129.5, 115.5, 102.8, 79.7, 78.5, 78.3,
78.0, 77.6, 75.9, 70.4, 69.1, 65.6, 61.0, 49.8, 45.8, 44.3, 43.0, 40.2,
37.6, 37.3, 35.6, 29.7, 21.6, 21.1, 19.6, 19.2, 17.2, 14.7, 13.0, 10.4, 9.1;
MS (ESI) m/z calcd. for C39H63FN2O11 754.44; found (M þ Hþ)
755.1; Anal. calcd. (%) for C39H63FN2O11: C 62.05, H 8.41, F 2.52, N
3.71; Found: C 62.01, H 8.39, F 2.51, N 3.68.
6.4.11. 3-O-((Thiazole-2-yl)carbamoyl)-3-O-descladinosyl-6,11-di-
O-methylerythromycin A (4k)
White solid, yield 59%, mp 148e151 ꢀC; IR (KBr): 3446, 2975,
2936, 2788, 2359, 1733, 1564, 1458, 1376, 1333, 1235, 1173, 1108,
1073 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
7.49 (d, J ¼ 3.6 Hz, 1H),
7.00 (d, J ¼ 3.6 Hz, 1H), 5.08 (m, 1H), 5.05 (m, 1H), 4.10 (d, J ¼ 6.9 Hz,
1H), 3.95 (d, J ¼ 2.8 Hz, 1H), 3.63 (s, 3H), 3.52 (m, 1H), 3.16 (s, 3H),
3.11-2.99 (m, 4H), 2.61 (m,1H), 2.34 (m,1H), 2.19 (s,1H), 2.14 (s, 6H),
2.01-1.86 (m, 3H), 1.58-1.51 (m, 2H), 1.42 (m, 1H), 1.35 (s, 3H), 1.33-
1.27 (m, 5H), 1.22-1.07 (m, 13H), 1.07-1.05 (m, 3H), 0.87-0.84 (m,
3H); 13C NMR (400 MHz, CDCl3): 216.7, 173.6, 161.3, 154.0, 137.2,
112.7, 103.4, 81.1, 80.4, 78.6, 78.1, 76.0, 70.3, 69.5, 65.7, 61.1, 50.0,
45.9, 42.9, 40.3, 37.7, 37.4, 36.0, 29.7, 28.3, 21.7, 21.0, 19.8, 19.3, 17.4,
14.9, 13.0, 10.5, 9.3; MS (ESI) m/z calcd. for C35H59N3O11S 729.39;
found (M þ Hþ) 730.1; Anal. calcd. (%) for C35H59N3O11S: C 57.59, H
8.15, N 5.76, S 4.39; Found: C 57.56, H 8.12, N 5.74, S 4.38.
6.4.15. 3-O-((4-chlorobenzyl)carbamoyl)-3-O-descladinosyl-6,11-
di-O-methylerythromycin A (4o)
White solid, yield 77%, mp 86e91 ꢀC; IR (KBr): 3453, 2974, 2939,
2877, 2784, 1732, 1531, 1458, 1344, 1250, 1171, 1109, 1076 cmꢁ1; 1H
NMR (400 MHz, CDCl3):
d
7.73 (d, J ¼ 8.4 Hz, 2H), 7.55 (d, J ¼ 8.5 Hz,
2H), 5.80 (s, 1H), 5.04 (m, 1H), 4.88 (d, J ¼ 10.7 Hz, 1H), 4.36 (m, 1H),
4.24 (m, 1H), 3.98 (d, J ¼ 7.2 Hz, 1H), 3.79 (d, J ¼ 2.5 Hz, 1H), 3.61 (s,
3H), 3.58 (m, 1H), 3.50 (m, 1H), 3.19-3.16 (m, 2H), 3.11(s, 3H), 3.04
(m, 1H), 2.91 (m, 1H), 2.61 (m, 1H), 2.34 (s, 6H), 2.31-2.19 (m, 2H),
1.99-1.87 (m, 2H), 1.76-1.70 (m, 3H), 1.45-1.31 (m, 3H), 1.27 (s, 3H),
1.19-0.93 (m, 17H), 0.87-0.83 (m, 3H); 13C NMR (400 MHz, CDCl3):
216.7, 173.9, 168.0, 156.5, 138.8, 130.9, 128.8, 102.9, 80.6, 78.6, 78.5,
78.0, 77.8, 76.0, 70.5, 68.2, 65.6, 61.1, 49.9, 45.9, 44.4, 43.2, 40.1, 38.7,
37.6, 35.7, 29.7, 23.7, 22.7,19.7,19.2,17.3,13.7,13.0,10.5, 9.3; MS (ESI)
m/z calcd. for C39H63ClN2O11 770.41; found (M þ Hþ) 771.0; Anal.
calcd. (%) for C39H63ClN2O11: C 60.72, H 8.23, Cl 4.60, N 3.63; Found:
C 60.68, H 8.21, Cl 4.58, N 3.61.
6.4.12. 3-O-((Benzyl)carbamoyl)-3-O-descladinosyl-6,11-di-O-
methylerythromycin A (4l)
White solid, yield 76%, mp 156e160 ꢀC; IR (KBr): 3515, 3347,
2973, 2938, 2877, 2788, 1736, 1456, 1380, 1343, 1256, 1170, 1142,
1108, 1078 cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 7.36-7.25 (m, 5H),
5.63 (m, 1H), 5.04 (m, 1H), 4.89 (d, J ¼ 11.0 Hz, 1H), 4.46 (m, 1H),
4.41 (m, 1H), 4.34 (m, 1H), 4.01 (d, J ¼ 3.2 Hz, 1H), 3.84 (d,

Z. Wu et al. / European Journal of Medicinal Chemistry 45 (2010) 3636e3644
3643
6.4.16. 3-O-((4-bromobenzyl)carbamoyl)-3-O-descladinosyl-6,11-
di-O-methylerythromycin A (4p)
(s, 3H), 1.22-1.09 (m, 18H), 0.87-0.85 (m, 3H); 13C NMR (400 MHz,
CDCl3): 216.9, 174.1, 156.5, 138.4, 128.7, 126.7, 102.7, 81.2, 79.1, 78.5,
78.0, 77.7, 76.0, 70.6, 69.5, 65.9, 61.1, 50.0, 45.9, 42.9, 42.3, 40.3, 37.7,
37.4, 36.1, 35.4, 28.6, 21.7, 21.2, 19.7, 19.4, 17.3, 14.7, 13.0, 10.4, 9.1; MS
(ESI) m/z calcd. for C40H66N2O11 750.47; found (M þ Hþ) 751.2; Anal.
calcd. (%) for C40H66N2O11: C 63.98, H 8.86, N 3.73; Found: C 63.96,
H 8.83, N 3.70.
White solid, yield 75%, mp 85e88 ꢀC; IR (KBr): 3444, 3285,
2970, 2933, 2358, 1727, 1652, 1536, 1458, 1379, 1172, 1108,
1071 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
7.45 (d, J ¼ 8.3 Hz, 2H),
7.22 (d, J ¼ 8.3 Hz, 2H), 5.73 (m, 1H), 5.02 (m, 1H), 4.87 (d,
J ¼ 11.0 Hz, 1H), 4.34-4.31 (m, 2H), 3.94 (d, J ¼ 6.0 Hz, 1H), 3.80 (d,
J ¼ 2.7 Hz, 1H), 3.59 (s, 3H), 3.53 (m, 1H), 3.41 (m, 1H), 3.11-3.15 (m,
2H), 3.09 (s, 3H), 3.02 (m, 1H), 2.93-2.86 (m, 2H), 2.58 (m, 1H), 2.23
(s, 6H), 2.22-2.14 (m, 2H), 1.97-1.82 (m, 4H), 1.54-1.39 (m, 3H), 1.32
(m, 1H), 1.29 (s, 3H), 1.21-1.11 (m, 13H), 1.08-1.06 (m, 3H), 0.85-0.81
(m, 3H); 13C NMR (400 MHz, CDCl3): 217.1, 174.0, 161.2, 156.6, 136.8,
131.8, 129.7, 103.1, 80.2, 78.5, 78.0, 77.7, 76.0, 70.5, 69.2, 65.6, 61.1,
49.9, 45.9, 44.5, 42.9, 41.4, 40.2, 37.6, 37.4, 35.7, 29.7, 21.7, 21.2, 19.7,
19.3, 17.3, 14.9, 13.0, 10.5, 9.3; MS (ESI) m/z calcd. for C39H63BrN2O11
6.4.20. 3-O-((4-methoxyphenylethyl)carbamoyl)-3-O-
descladinosyl-6,11-di-O-methylerythromycin A (4t)
White solid, yield 66%, mp 48e51 ꢀC; IR (KBr): 3442, 2965,
2927, 1727, 1642, 1558, 1457, 1255, 1172, 1074 cmꢁ1 1H NMR
;
(400 MHz, CDCl3):
d
7.03 (d, J ¼ 8.4 Hz, 2H), 6.78 (d, J ¼ 8.3 Hz,
2H), 4.96 (m, 1H), 4.79 (d, J ¼ 11.2 Hz, 1H), 4.24 (m, 1H), 4.15 (m,
1H), 3.98 (d, J ¼ 7.2 Hz, 1H), 3.80 (d, J ¼ 2.9 Hz, 1H), 3.72 (s, 3H),
3.57 (m, 1H), 3.51 (s, 3H), 3.41 (m, 1H), 3.31-3.20 (m, 2H), 3.12 (m,
1H), 3.04 (s, 3H), 2.95 (m, 1H), 2.78 (m, 1H), 2.73-2.69 (m, 2H),
2.50 (m, 1H), 2.31 (m, 1H), 2.21 (s, 6H), 2.19 (s, 1H), 1.92-1.75 (m,
3H), 1.65-1.52 (m, 3H), 1.44-1.25 (m, 2H), 1.23 (s, 3H), 1.18-1.00 (m,
17H), 0.78-0.74 (m, 3H); 13C NMR (400 MHz, CDCl3): 216.0, 173.1,
157.3, 155.6, 131.2, 128.6, 113.1, 101.6, 77.9, 77.8, 77.5, 77.0, 75.0,
69.5, 68.3, 67.1, 60.0, 57.5, 54.2, 48.9, 44.9, 41.9, 41.5, 39.2, 37.6,
36.7, 34.7, 34.2, 28.6, 20.7, 20.2, 18.7, 18.1, 16.3, 13.7, 12.0, 9.4, 8.1;
MS (ESI) m/z calcd. for C41H68N2O12 780.48; found (M þ Hþ) 781.1;
Anal. calcd. (%) for C41H68N2O12: C 63.05, H 8.78, N 3.59; Found: C
63.02, H 8.75, N 3.62.
814.36; found (M þ Hþ) 815.0; Anal. calcd. (%) for C39H63BrN2O11
:
C 57.42, H 7.78, Br 9.79, N 3.43; Found: C 57.38, H 7.75, Br 9.77, N
3.41.
6.4.17. 3-O-((4-hydroxybenzyl)carbamoyl)-3-O-descladinosyl-6,11-
di-O-methylerythromycin A (4q)
White solid, yield 68%, mp 147e151 ꢀC; IR (KBr): 3408, 2976,
2936, 2875, 1729, 1621, 1518, 1458, 1376, 1346, 1252, 1173,
1072 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
7.14 (d, J ¼ 8.1 Hz, 2H), 6.81
(d, J ¼ 8.2 Hz, 2H), 5.47 (m, 1H), 5.31 (s, 1H), 5.03 (m, 1H), 4.87 (d,
J ¼ 10.8 Hz, 1H), 4.34-4.21 (m, 2H), 3.97 (d, J ¼ 7.2 Hz, 1H), 3.84 (d,
J ¼ 2.5 Hz, 1H), 3.59 (s, 3H), 3.49 (m, 1H), 3.29 (m, 1H), 3.19-3.15 (m,
2H), 3.09 (s, 3H), 3.05-3.02 (m, 2H), 2.87 (m, 1H), 2.58 (m, 1H), 2.27
(s, 6H), 2.24 (m, 1H), 1.99-1.92 (m, 3H), 1.88-1.81 (m, 2H), 1.67 (m,
1H), 1.50 (m, 3H), 1.29 (s, 3H), 1.26-1.07 (m, 16H), 0.85-0.81 (m, 3H);
13C NMR (400 MHz, CDCl3): 217.4, 174.1, 157.3, 156.3, 138.8, 128.8,
115.7, 102.3, 80.2, 78.5, 78.3, 78.0, 77.7, 76.0, 70.7, 69.2, 65.4, 61.2,
49.9, 45.9, 44.8, 43.1, 40.3, 37.7, 37.4, 35.7, 29.7, 21.7, 21.1, 19.7, 19.3,
17.3, 14.7, 13.0,10.5, 9.3; MS (ESI) m/z calcd. for C39H64N2O12 752.46;
found (M þ Hþ) 753.1; Anal. calcd. (%) for C39H64N2O12: C 62.21, H
8.57, N 3.72; Found: C 62.18, H 8.55, N 3.73.
6.4.21. 3-O-((3,4-dimethoxy-phenylethyl)carbamoyl)-3-O-
descladinosyl-6,11-di-O-methylerythromycin A (4u)
White solid, yield 79%, mp 49e54 ꢀC; IR (KBr): 3444, 2962,
2926, 2855, 1726, 1643, 1561, 1460, 1211, 1170, 1109 cmꢁ1; 1H NMR
(400 MHz, CDCl3):
d
6.75 (d, J ¼ 7.9 Hz, 1H), 6.68 (m, 1H), 6.64 (d,
J ¼ 7.9 Hz, 1H), 5.06 (m, 1H), 5.01-4.95 (m, 2H), 4.79 (d, J ¼ 11.2 Hz,
1H), 3.99 (d, J ¼ 7.3 Hz, 1H), 3.81 (m, 1H), 3.80 (s, 3H), 3.79 (s, 3H),
3.59 (m, 1H), 3.52 (s, 3H), 3.40 (m, 1H), 3.30-3.18 (m, 3H), 3.12 (m,
1H), 3.06 (s, 3H), 2.95 (m, 1H), 2.73-2.68 (m, 3H), 2.49 (m, 1H),
2.33 (m, 1H), 2.22 (s, 6H), 2.18 (m, 1H), 1.96-1.75 (m, 4H), 1.53 (m,
1H), 1.48-1.45(m, 2H), 1.28 (s, 3H), 1.25-1.00 (m, 17H), 0.78-0.74
(m, 3H); 13C NMR (400 MHz, CDCl3): 216.0, 173.1, 155.5, 148.0,
146.7, 130.0, 119.6, 110.9, 110.8, 101.7, 78.2, 77.5, 77.0, 76.8, 76.6,
75.0, 69.5, 68.3, 64.8, 60.1, 57.7, 54.9, 48.9, 44.9, 41.9, 41.4, 39.2,
36.6, 36.3, 34.8, 34.1, 28.6, 20.7, 20.2, 18.7, 18.3, 16.3, 13.7, 12.0, 9.4,
8.1; MS (ESI) m/z calcd. for C42H70N2O13 810.49; found (M þ Hþ)
811.1; Anal. calcd. (%) for C42H70N2O13: C 62.20, H 8.70, N 3.45;
Found: C 62.18, H 8.67, N 3.42.
6.4.18. 3-O-((4-methylbenzyl)carbamoyl)-3-O-descladinosyl-6,11-
di-O-methylerythromycin A (4r)
White solid, yield 69%, mp 65e68 ꢀC; IR (KBr): 3444, 2966, 2934,
2875, 1728, 1668, 1548, 1458, 1379, 1345, 1252, 1172, 1110,
1074 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 7.23-7.15 (m, 4H), 5.36 (m,
1H), 5.05 (m,1H), 4.91 (d, J ¼ 11.0 Hz,1H), 4.49-4.29 (m, 3H), 4.00 (d,
J ¼ 7.4 Hz, 1H), 3.86 (d, J ¼ 3.0 Hz, 1H), 3.61 (s, 3H), 3.51 (s, 1H), 3.16
(m, 1H), 3.12 (s, 3H), 3.05 (m, 1H), 2.90 (m, 1H), 2.60 (m, 1H), 2.36
(m, 1H), 2.35 (s, 3H), 2.31-2.28 (m, 2H), 2.25 (s, 6H), 2.19 (m, 1H),
2.05-1.84 (m, 4H), 1.80-1.63 (m, 3H), 1.53-1.44 (m, 1H), 1.32 (s, 3H),
1.27-1.09 (m, 16H), 0.87-0.84 (m, 3H); 13C NMR (400 MHz, CDCl3):
216.8, 174.1, 156.5, 137.4, 137.3, 129.4, 127.8, 103.1, 80.0, 78.6, 78.5,
78.1, 77.7, 76.0, 70.5, 69.2, 66.0, 61.1, 49.9, 46.0, 44.6, 42.0, 40.2, 37.7,
37.5, 35.8, 28.5, 21.8, 21.2, 21.1,19.8,19.4,17.3,14.9,13.0,10.5, 9.2; MS
(ESI) m/z calcd. for C40H66N2O11 750.47; found (M þ Hþ) 751.2; Anal.
calcd. (%) for C40H66N2O11: C 63.98, H 8.86, N 3.73; Found: C 63.96,
H 8.85, N 3.70.
6.4.22. 3-O-((4-hydroxyphenethyl)carbamoyl)-3-O-descladinosyl-
6,11-di-O-methyl erythromycin A (4v)
White solid, yield 68%, mp 76e80 ꢀC; IR (KBr): 3443, 2967,
2870, 2345, 1728, 1651, 1554, 1416, 1259, 1173, 1108 cmꢁ1 1H
;
NMR (400 MHz, CDCl3):
d
7.05 (d, J ¼ 8.3 Hz, 2H), 6.83 (d,
J ¼ 8.4 Hz, 2H), 5.73 (s, 1H), 5.06 (m, 1H), 5.00 (m, 1H), 4.86 (d,
J ¼ 11.2 Hz, 1H), 4.01 (d, J ¼ 7.2 Hz, 1H), 3.87 (d, J ¼ 3.3 Hz, 1H),
3.65 (m, 1H), 3.60 (s, 3H), 3.57-3.52 (m, 2H), 3.42-3.48 (m, 2H),
3.32 (m, 1H), 3.25-3.20 (m, 2H), 3.11 (s, 3H), 3.05-3.03 (m, 2H),
2.86 (m, 1H), 2.82-2.73 (m, 2H), 2.60 (m, 1H), 2.40 (m, 1H), 2.36
(s, 6H), 2.25 (m, 1H), 2.20 (m, 1H), 1.95 (m, 1H), 1.86 (m, 1H), 1.65
(m, 1H), 1.52-1.46 (m, 2H), 1.30 (s, 3H), 1.28 (s, 3H), 1.21-1.09 (m,
13H), 0.88-0.85(m, 3H); 13C NMR (400 MHz, CDCl3): 217.4, 174.2,
161.8, 155.3, 133.8, 129.7, 115.8, 102.2, 78.7, 78.5, 78.0, 77.8, 77.7,
76.1, 70.8, 69.3, 65.3, 60.9, 50.2, 45.9, 42.9, 42.6, 40.4, 39.7, 37.7,
37.4, 34.5, 29.2, 21.7, 21.1, 19.7, 19.4, 17.4, 14.7, 13.0, 10.5, 9.2; MS
(ESI) m/z calcd. for C40H66N2O11 766.46; found (M þ Hþ) 767.2;
Anal. calcd. (%) for C40H66N2O11: C 62.64, H 8.67, N 3.65; Found: C
62.61, H 8.64, N 3.62.
6.4.19. 3-O-((Phenylethyl)carbamoyl)-3-O-descladinosyl-6,11-di-
O-methylerythromycin A (4s)
White solid, yield 78%, mp 179e184 ꢀC; IR (KBr): 3371, 2976,
2941, 2878, 1735, 1532, 1457, 1378, 1343, 1247, 1171, 1142, 1108,
1075 cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 7.36-7.32 (m, 2H), 7.28-
7.20 (m, 3H), 5.05 (m,1H), 4.96 (m,1H), 4.88 (d, J ¼ 11.2 Hz,1H), 4.05
(d, J ¼ 7.3 Hz, 1H), 3.90 (d, J ¼ 3.3 Hz, 1H), 3.68 (m, 1H), 3.61 (s, 3H),
3.51 (m, 1H), 3.32-3.26 (m, 3H), 3.18 (m, 1H), 3.13 (s, 3H), 3.05 (m,
1H), 2.89-2.83 (m, 3H), 2.59 (m, 1H), 2.36 (m, 1H), 2.28 (s, 6H), 2.19
(m, 1H), 1.96-1.84 (m, 2H), 1.81-1.67 (m, 3H), 1.62-1.49 (m, 2H), 1.32

3644
Z. Wu et al. / European Journal of Medicinal Chemistry 45 (2010) 3636e3644
6.4.23. 3-O-((4-fluorophenylethyl)carbamoyl)-3-O-descladinosyl-
6,11-di-O-methylerythromycin A (4w)
5.05 (m, 1H), 4.96 (m, 1H), 4.79 (d, J ¼ 11.0 Hz, 1H), 3.98 (d,
J ¼ 7.2 Hz, 1H), 3.81 (d, J ¼ 2.6 Hz, 1H), 3.56 (m, 1H), 3.51 (s, 3H),
3.47-3.33 (m, 2H), 3.31-3.21 (m, 2H), 3.08 (m,1H), 3.03 (s, 3H), 2.98-
2.89 (m, 3H), 2.80 (m, 1H), 2.50 (m, 1H), 2.34 (m, 1H), 2.20 (s, 6H),
2.18 (m, 1H), 1.88-1.75 (m, 2H), 1.54 (m, 1H), 1.47-1.39 (m, 2H), 1.23
(s, 3H), 1.18-1.00 (m, 20H), 0.78-0.74 (m, 3H); 13C NMR (400 MHz,
CDCl3): 217.0, 174.1, 156.5, 137.8, 133.0, 131.0, 128.4, 127.6, 124.5,
102.8, 79.2, 78.5, 78.0, 77.6, 76.0, 70.5, 69.5, 65.9, 61.1, 50.0, 45.9,
42.9, 40.7, 40.3, 37.6, 37.4, 36.7, 36.3, 35.7, 28.6, 21.7, 21.2, 19.7, 19.4,
17.3, 14.8, 13.0, 10.5, 9.1; MS (ESI) m/z calcd. for C40H65BrN2O11
828.38; found (M þ Hþ) 829.0; Anal. calcd. (%) for C40H65BrN2O11: C
57.89, H 7.89, Br 9.63, N 3.38; Found: C 57.87, H 7.86, Br 9.60, N 3.40.
White solid, yield 70%, mp 116e119 ꢀC; IR (KBr): 3444, 2970,
2930, 1714, 1639, 1540, 1459, 1249, 1170, 1108, 1074 cmꢁ1; 1H NMR
(400 MHz, CDCl3):
d 7.10-7.07 (m, 2H), 6.95-6.93 (m, 2H), 5.04 (m,
1H), 4.96 (m, 1H), 4.78 (d, J ¼ 11.0 Hz, 1H), 3.98 (d, J ¼ 7.2 Hz, 1H),
3.80 (d, J ¼ 2.9 Hz, 1H), 3.58 (m, 1H), 3.52 (s, 3H), 3.40 (m, 1H), 3.27-
3.16 (m, 3H), 3.14-3.08 (m, 2H), 3.03 (s, 3H), 2.95 (m, 1H), 2.80-2.70
(m, 3H), 2.50 (m, 1H), 2.33 (m, 1H), 2.21 (s, 6H), 2.17 (m, 1H), 1.94-
1.75 (m, 3H), 1.54-1.51 (m, 2H), 1.44-1.39 (m, 3H), 1.23 (s, 3H), 1.18-
1.00 (m, 16H), 0.78-0.75 (m, 3H); 13C NMR (400 MHz, CDCl3): 217.0,
174.1, 160.4, 156.5, 134.2, 130.1, 115.4, 102.7, 79.0, 78.5, 78.0, 77.8,
77.6, 76.0, 70.5, 69.3, 65.8, 61.0, 49.9, 45.9, 42.9, 42.3, 40.2, 37.6, 37.3,
35.7, 35.3, 29.6, 21.7, 21.2, 19.7,19.3,17.3,14.7,13.0,10.4, 9.1; MS (ESI)
m/z calcd. for C40H65FN2O11 768.46; found (M þ Hþ) 769.1; Anal.
calcd. (%) for C40H65FN2O11: C 62.48, H 8.52, F 2.47, N 3.64; Found: C
62.45, H 8.49, F 2.45, N 3.67.
Acknowledgments
This research was supported by the Important National Science
& Technology Specific Projects (No. 2009ZX09301-14).
6.4.24. 3-O-((2-fluorophenylethyl)carbamoyl)-3-O-descladinosyl-
6,11-di-O-methylerythromycin A (4x)
References
White solid, yield 72%, mp 110e114 ꢀC; IR (KBr): 3452, 2976,
2940, 1729, 1535, 1499, 1458, 1378, 1345, 1242, 1173, 1109,
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1072 cmꢁ1 1H NMR (400 MHz, CDCl3):
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(d, J ¼ 7.2 Hz, 1H), 3.89 (d, J ¼ 3.2 Hz, 1H), 3.65 (m, 1H), 3.60 (s, 3H),
3.57 (m, 1H), 3.50 (m, 1H), 3.33-3.28 (m, 2H), 3.19 (m, 1H), 3.12 (s,
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(s, 6H), 2.25 (m, 1H), 1.98-1.84 (m, 4H), 1.60-1.50 (m, 3H), 1.31 (s,
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6.4.25. 3-O-((2-chlorophenylethyl)carbamoyl)-3-O-descladinosyl-
6,11-di-O-methylerythromycin A (4y)
White solid, yield 74%, mp 110e114 ꢀC; IR (KBr): 3445, 2975,
2939, 1729, 1524, 1461, 1376, 1342, 1248, 1172, 1109, 1070 cmꢁ1; 1H
NMR (400 MHz, CDCl3):
d 7.37 (m, 1H), 7.24-7.21 (m, 3H), 5.19 (m,
1H), 5.03 (m, 1H), 4.86 (d, J ¼ 11.0 Hz, 1H), 4.05 (d, J ¼ 7.3 Hz, 1H),
3.87 (d, J ¼ 3.0 Hz, 1H), 3.61 (s, 3H), 3.58 (m, 1H), 3.51-3.47 (m, 3H),
3.38-3.29 (m, 2H), 3.17 (m, 1H), 3.10 (s, 3H), 3.04-2.95 (m, 3H), 2.86
(m, 1H), 2.57 (m, 1H), 2.39 (m, 1H), 2.27 (s, 6H), 2.24 (m, 1H), 1.95-
1.85 (m, 3H), 1.62-1.58 (m, 2H), 1.51-1.48 (m, 3H), 1.30 (s, 3H), 1.28-
1.07 (m, 16H), 0.85-0.81 (m, 3H); 13C NMR (400 MHz, CDCl3): 217.0,
174.1, 156.5, 136.1, 134.0, 131.0, 129.7, 128.3, 127.1, 102.8, 79.3, 78.5,
78.0, 77.7, 76.0, 70.6, 69.5, 65.8, 61.1, 49.9, 45.9, 42.9, 40.6, 40.3, 37.8,
37.6, 37.4, 35.7, 33.8, 28.6, 21.7, 21.2, 19.7, 19.4, 17.3, 14.8, 13.0, 10.5,
9.2; MS (ESI) m/z calcd. for C40H65ClN2O11 784.43; found (M þ Hþ)
785.1; Anal. calcd. (%) for C40H65ClN2O11: C 61.17, H 8.34, Cl 4.51, N
3.57; Found: C 61.15, H 8.31, Cl 4.48, N 3.59.
6.4.26. 3-O-((2-bromophenylethyl)carbamoyl)-3-O-descladinosyl-
6,11-di-O-methylerythromycin A (4z)
White solid, yield 73%, mp 96e99 ꢀC; IR (KBr): 3354, 2974, 2939,
1729, 1524, 1461, 1376, 1342, 1248, 1172, 1109, 1070 cmꢁ1 1H NMR
;
(400 MHz, CDCl3):
d 7.47 (m, 1H), 7.21-7.16 (m, 2H), 7.03 (m, 1H),