Novel 9a-carbamoyl- and 9a-thiocarbamoyl-3-decladinosyl-6-hydroxy and 6-methoxy derivatives of 15-membered macrolides

Article abstract of DOI:10.1016/j.bmc.2007.04.021

An efficient method for the synthesis of diverse 9a-carbamoyl- and 9a-thiocarbamoyl-3-decladinosyl-6-hydroxy and 3-decladinosyl-6-methoxy derivatives of 15-membered azalides has been developed. These derivatives bear various alkyl and aryl groups attached to macrolide scaffold through urea or thiourea moieties at 9a position. Chemical transformations of hydroxy group at position C-3 afforded range of ketolides, anhydrolides, hemiketals, cyclic ethers, and acylides. It has been shown that 6-hydroxy and 6-methoxy derivatives undergo different chemical transformations under otherwise identical reaction conditions. Antimicrobial properties of prepared compounds were evaluated.

Full text of DOI:10.1016/j.bmc.2007.04.021

Bioorganic & Medicinal Chemistry 15 (2007) 4498–4510
Novel 9a-carbamoyl- and 9a-thiocarbamoyl-3-decladinosyl-
6-hydroxy and 6-methoxy derivatives of 15-membered macrolides
*
´
´
Zorica Marusˇic Isˇtuk, Stjepan Mutak, Nedjeljko Kujundzˇic and Goran Kragol
GlaxoSmithKline Research Centre Zagreb, Prilaz B. Filipovic´a 29, Zagreb, Croatia
Received 20 November 2006; revised 5 April 2007; accepted 13 April 2007
Available online 19 April 2007
Abstract—An efficient method for the synthesis of diverse 9a-carbamoyl- and 9a-thiocarbamoyl-3-decladinosyl-6-hydroxy and 3-dec-
ladinosyl-6-methoxy derivatives of 15-membered azalides has been developed. These derivatives bear various alkyl and aryl groups
attached to macrolide scaffold through urea or thiourea moieties at 9a position. Chemical transformations of hydroxy group at posi-
tion C-3 afforded range of ketolides, anhydrolides, hemiketals, cyclic ethers, and acylides. It has been shown that 6-hydroxy and
6-methoxy derivatives undergo different chemical transformations under otherwise identical reaction conditions. Antimicrobial
properties of prepared compounds were evaluated.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
ity of 14-membered macrolides can be separated
through appropriate chemical derivatization.6
Macrolide antibiotics have been used for treatment of
bacterial infections for more than 50 years.1 However,
it seems that broad potential of macrolides has not been
fully explored yet. Most recently antibacterial macro-
lides have attracted considerable attention for two main
reasons: (a) as with other antibiotics, active use of mac-
rolides resulted in development of macrolide resistance
that fuels a search for novel types of macrolides having
better antibacterial activity, pharmacokinetic proper-
ties, and safety profiles (b) macrolide derivatives, espe-
cially 14- and 15-membered classes, have also become
interesting for treating important chronic diseases, that
is, asthma, chronic sinusitis, diffuse panbronchiolitis,
cystic fibrosis, etc.2,3 Some antibacterial macrolides
proved active in treatment of malaria4 and cancer.5
For these alternative applications antibacterial activity
of macrolides is a considerable disadvantage. The fact
that such complex molecules could be used for multiple
medical indications renders every novel macrolide class
potentially useful either as antibiotics or as agents
against other biological targets. There is also an evi-
dence that immunomodulatory and antibacterial activ-
Azalides (1) are group of semisynthetic 15-membered
macrolides having nitrogen incorporated into macrolac-
tone ring. They are derived from erythromycin (2),
14-membered macrolactone fermentation product of
Streptomyces erythreus (Fig. 1). Azithromycin7 (1, R =
CH3) is superior to erythromycin in regard of having
better antibacterial activity as well as excellent pharma-
cokinetic properties and safety profile. Although it is
one of the most widely prescribed antibiotics, azithro-
mycin also shows therapeutic use in some inflammatory
diseases and is already part of the standard therapy for
treating diffuse panbronchiolitis.2
R
O
9
N
9a
HO
HO
OH
HO
HO
OH
OH
2'
OH
6
N
N
O
O
O
1
O
3
2
O
O
O
O
O
O
O
O
4''
O
O
OH
OH
Keywords: Macrolide; Azalide; 3-Decladinosyl; Antibacterial activity.
*
1
2
R = H, alkyl etc.
Corresponding author. Tel.: +385 1 6051236; fax: +385 1 6051199;
e-mail: goran.x.kragol@gsk.com
Figure 1. Chemical structures of azalides (1) and erythromycin A (2).
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.04.021

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4499
Due to their excellent properties and multiple medical
use azalides are exquisite molecules for further chemical
derivatization in order to prepare macrolides that can be
screened against numerous biological targets of interest.
group of azalides cannot be methylated,10 6-OMe deriv-
ative 6 was produced starting from clarithromycin 9(E)-
oxime 4 by the same reaction sequence. Azalides 5 and 6
were treated with diluted acid to accomplish cleavage of
cladinose producing compounds 7 and 8 (Scheme 1).
Desosamine sugar remains intact under these
conditions.
It is expected that introduction of unsaturated unit, that
is, carbamoyl group, on nitrogen at position 9a of 1
(Fig. 1) will significantly change electronic properties
and also steric environment in the ‘upper part’ of the
macrolide. It will also serve as an excellent linker for
the attachment of various groups affording preparation
of a library of compounds. On the other hand, cleavage
of cladinose unit can be achieved selectively and thus
properties of the ‘lower part’ of 9a-carbamoyl 15-mem-
bered azalides substantially modified via further chemi-
cal modifications. While simple removal of cladinose
sugar from macrolides significantly decreases antibacte-
rial activity, some novel decladinosyl derivatives of
14-membered macrolides proved active against resistant
bacterial strains.8 We have undertaken synthetic study
reported hereafter to investigate an efficient method
for the preparation of various 3-decladinosyl derivatives
of 9a-functionalized azalides. Antimicrobial properties
of prepared compounds were also evaluated.
It has recently been shown that carbamoyl and thiocar-
bamoyl groups can be easily introduced at position 9a of
1 forming urea or thiourea moieties, respectively.9
Thanks to the great number of commercially available
isocyanates or isothiocyanates it is possible to attach
various groups (alkyl, aryl, heteroaryl, etc.) through
these linkages. As expected, high reactivity of secondary
amino group in 7 and 8 toward isocyanates and isothio-
cyanates assured highly site-selective introduction of
carbamoyl and thiocarbamoyl groups. A small library
of 9a-carbamoyl and 9a-thiocarbamoyl 3-decladinosyl
azalides was prepared according to Scheme 2.
IR spectra of prepared compounds 9–20 show new sig-
nals at 1618–1644 cmꢀ1 and 1529–1596 cmꢀ1 revealing
the presence of carbamoyl and thiocarbamoyl groups,
1
respectively. H NMR data show new signal at 4.37–
4.64 ppm that is attributed to carbamoyl NH (9a-
NCXN0-H), while 13C NMR show new singlets at
155.1–159.6 ppm for 9a-NCO or at 179.7–189.2 for 9a-
NCS. Coupling constant H-2 to H-3 (3J2,3) of 10.4 Hz
in 7 and 10.2 Hz in 8 (Table 1) defines the C-3 to C-5
‘folded out’ conformation of the macrocyclic ring.11
Since the coupling constant 3J2,3 of prepared derivatives
9–20 shows value of ꢁ10 Hz, their conformation is also
identified as ‘folded out’ indicating that the ‘lower part’
2. Results and discussion
Synthetic study started with preparation of carbamoyl
and thiocarbamoyl 3-decladinosyl derivatives of 6-hy-
droxy (6-OH) and 6-methoxy (6-OMe) azalides 7 and
8, respectively. Well-known Beckmann rearrangement
of erythromycin 9(E)-oxime 3 and hydrogenation of
intermediary iminoether lead to azalide 5.7 As 6-OH
OH
N
H
H
10
N
9
7
N
9
8
7
10
11
OH
O
OR
O
9a
N
11
OH
O
a, b
OR
O
8
HO
OH
O
N
OR
O
c
N
HO
OH
6
HO
OH
OH
6
O
O
O
O
3
O
O
O
O
O
O
OH
OH
OMe
OH
OMe
7 R = H
8 R = Me
3 R = H
4 R = Me
5 R = H
6 R = Me
Scheme 1. Reagents and condition: (a) TsCl, pyridine if R = Me or TsCl, NaHCO3, acetone if R = H; (b) H2-Pt/C, MeOH, 40 bar, 12 h; (c) water/
HCl, pH 1.
9
X = O, R1 = H, R = isopropyl
H
N
10 X = O, R1 = H, R = ethyl
11 X = O, R1 = H, R = t-butyl
R
H
X
N
9a
12 X = O, R1 = H, R = benzyl
N
OH
O
OR1
O
N
9a
HO
13 X = O, R1 = H, R = 3-trifluormethylphenyl
14 X = O, R1 = H, R = 2-trifluormethylphenyl
15 X = S, R1 = H, R = 3-trifluormethylphenyl
16 X = S, R1 = H, R = benzyl
17 X = O, R1 = H, R = 2,4-dichlorphenyl
18 X = S, R1 = H, R = allyl
a
OH
OR1
O
OH
N
6
5
HO
OH
6
5
2'
1'
O
4
3
5'
O
2
O
4
O
OH
3
2
O
OH
19 X = O, R1 = Me, R = isopropyl
20 X = O, R1 = Me, R = 2,4-dichlorphenyl
7 R1=H
8 R1=Me
Scheme 2. Reagents and conditions: (a) isocyanate or isothiocyanate, toluene, rt, 1 h.

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Z. M. Istuk et al. / Bioorg. Med. Chem. 15 (2007) 4498–4510
4500
Table 1. Key NMR data for 9a-carbamoyl and 9a-thiocarbamoyl 3-decladinosyl azalides
Compound
1H
13C (ppm)
C-10
3J2,3 (Hz)
C-6
C-3
C-20
C-50
7
10.4
73.0
78.8
106.2
70.2
69.5
9–18
8
9.6–10.5
10.2
10.2
73.6–75.9
78.8
79.5
73.0–75.9
78.5
78.9
105.2–106.1
106.6
106.6
69.2–69.5
70.3
70.3
70.1–70.6
69.9
70.0
19
20
N.D.
79.1
79.7
106.9
70.5
69.9
of new macrolides is similar to parent compounds. Com-
parison of NMR data (Table 1) of 6-OH derivatives 9–
18 to those of parent molecule 7 indicates substantial
changes for signal C-3 (shifted upfield from 78.8 in 7
to ꢁ74.5 ppm in 9–18) and some changes for C-6
(shifted downfield from 73.0 in 7 to ꢁ74.8 ppm in 9–
18). However, in the case of 6-OMe derivatives 19 and
20 no changes occurred for C-6 and C-3 in comparison
to parent compound 8. This shift of C-6 and C-3 in 9–18
can be attributed to free 6-OH group that may influence
the orientation of desosamine sugar via hydrogen bond-
ing as suggested by subtle changes in the shifts for C-10,
C-20, and C-50 in comparison to fixed positions of these
signals in 6-OMe analogs.
They afforded formation of ketolides, anhydrolides,
hemiketals, cyclic ethers, and acylides (Fig. 2). It
was interesting to notice how 6-OH and 6-OMe deriv-
atives undergo different transformations under other-
wise identical reaction conditions, the later affording
to our knowledge first 2,3-anhydrolides of 15-mem-
bered macrolides.
It was found that presence of urea and thiourea moiety
does not influence the order of reactivity of the hydroxyl
groups.12 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 positions 6, 11, and 12 are much less
reactive. Consequently, reaction of macrolides 9, 17, 19,
and 20 with acetic anhydride in the presence of a base
smoothly afforded 20-O-acetyl derivatives 21, 22, 23, and
24, respectively, that can be later easily deprotected by
methanolysis.
In order to investigate modifications of the ‘lower
part’ of macrolide via chemical transformations of hy-
droxyl group at C-3, two pairs of 9a-carbamoyl 6-OH
(9, 17) and 6-OMe azalides (19, 20) were selected.
H
N
R
X
N
OH
O
OH
O
N
HO
OH
H
O
N
R
X
O
O
N
R2
O
OMe
OH
O
N
HO
3-acylides
OH
acylation
O
O
H
O
N
R
O
H
N
X
R
X
oxidation
N
3-ketolides
N
OH
N
HO
OR1 OH
OH
O
N
HO
oxidation
R1 = Me
OH
R1 = H
O
O
H
O
N
R
O
O
O
X
O
OH
O
OH
N
dehydratation
3,6-hemiketals
OH
O
OMe
O
N
HO
OH
H
dehydratation
O
R = alkyl, aryl
X = O, S
N
R
X
O
N
OH
O
N
HO
2,3-anhydrolides
OH
O
O
O
O
3,6-cyclic ethers
Figure 2. Modifications of the ‘lower part’ of 9a-carbamoyl and 9a-thiocarbamoyl azalides.

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Z. M. Istuk et al. / Bioorg. Med. Chem. 15 (2007) 4498–4510
4501
Whereas Pfitzner–Moffat oxidation13 of 3-OH group of
3-decladinosyl-6-OH azalides 21 and 22 produces inter-
nal 3,6-hemiketal structures 25 and 26, the same reaction
conditions applied to 6-OMe derivatives 23 and 24 afford
3-keto derivatives 27 and 28 (Scheme 3). Formation of
3,6-hemiketals indicated that urea moiety at position 9a
does not influence the proximity of 6-OH to C-3 required
for the formation of 3,6-cyclic structures.14
Mass spectra of compounds 25 and 26 exhibited ions
consistent with both hemiketal and keto structures.
However, NMR data unambiguously revealed 3,6-hem-
iketal unit since the signal for C-3 is shifted from 75 to
103 ppm, while signal for C-3 in 27 and 28 is shifted
from 79 ppm to 207 ppm indicating formation of ketone
at C-3.
Introduction of mesyl group at position C-3 of 6-OH
and 6-OMe derivatives 21–24 and subsequent base-pro-
moted elimination afforded different products. Whereas
6-OH derivatives 21 and 22 produce 3,6-cyclic ethers 31
and 32, 6-OMe derivatives 23 and 24 afford 2,3-anhydro
derivatives 35 and 36, respectively (Scheme 4). It is
worth noting that in erythromycin series cyclic ethers
were easily obtained15 while anhydrolides were obtained
only when the ‘upper part’ of the molecule was con-
strained via double bond between C-10 and C-11 or
via C-11 to C-12 carbamate formation.16
H
N
H
N
R
R
O
O
O
N
N
OH
O
OH
O
O
N
N
HO
HO
a, b
OH
OH
O
O
O
O
O
O
OH
O
OH
21 R = isopropyl
22 R = 2,4-dichlorphenyl
25 R = isopropyl
26 R = 2,4-dichlorphenyl
Although mass spectra of compounds 31 and 32 showed
molecular ions consistent with both cyclic ether and
anhydro structures, missing double bond signal in
NMR spectra and weak downfield shifting of C-3 (from
75 to 83 ppm) reveal 3,6-cyclic ether structure. Struc-
tures of anhydrolides 35 and 36 were also proved by
NMR spectra. Shifting of signals for carbons C-2 from
45 to 146 ppm and C-3 from 79 to 127 ppm, respec-
tively, as well as disappearance of signal for 2-H proton
and strong downfield shift of 3-H were observed for
both anhydrolide compounds.
H
H
N
R
N
R
O
O
O
N
N
OH
O
O
N
N
OMe
OMe
O
HO
HO
a, b
OH
OH
O
O
O
O
O
OH
O
O
23 R = isopropyl
24 R = 2,4-dichlorphenyl
27 R = isopropyl
28 R = 2,4-dichlorphenyl
Among already known 3-acylides of 14-membered mac-
rolides, 3-O-(4-nitrophenyl)acetyl derivative of clari-
thromycin (TEA-0777) showed the best antibacterial
Scheme 3. Reagents and conditions: (a) EDC, DMSO, pyridinium
trifluoroacetate; (b) MeOH, rt, 24 h.
H
H
N
R
H
O
N
R
O
N
R
O
O
O
N
N
N
OH
O
O
N
b, c
OH
O
O
OH
O
HO
a
N
N
HO
OH
HO
OH
OH
O
O
O
O
O
O
O
O
OH
O
OSO2Me
O
21 R = isopropyl
22 R = 2,4-dichlorphenyl
31 R = isopropyl
32 R = 2,4-dichlorphenyl
29 R = isopropyl
30 R = 2,4-dichlorphenyl
H
H
N
R
H
O
N
R
N
R
O
O
O
O
N
N
N
O
OMe
N
OMe
b, c
O
HO
a
OH
OMe
O
N
N
OH
HO
HO
OH
OH
O
O
O
O
O
O
O
O
O
OH
O
OSO2Me
O
23 R = isopropyl
24 R = 2,4-dichlorphenyl
33 R = isopropyl
34 R = 2,4-dichlorphenyl
35 R = isopropyl
36 R = 2,4-dichlorphenyl
Scheme 4. Reagents and conditions: (a) methylsulfonyl anhydride, pyridine, rt, 3 h; (b) NaH, DMF/THF, 0 ꢁC, 5 h then rt, 20 h; (c) MeOH, rt, 24 h.

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Z. M. Istuk et al. / Bioorg. Med. Chem. 15 (2007) 4498–4510
4502
activity.17 Accordingly, we prepared 9a-carbamoyl acy-
lides having (4-nitrophenyl)acetyl functionality attached
to 3-O position (Scheme 5, compounds 37 and 38) to test
if antibacterial activity could be enhanced upon attach-
ment of favorite side-arm. Compounds 21 and 22 were
acylated using mixed anhydride obtained in situ from
4-nitrophenylacetic acid and pivaloyl chloride (Scheme
5). Subsequent methanolysis of 20-O-acetyl group affor-
ded 3-acylides 37 and 38. Their structures were con-
firmed by NMR spectra as the signal for key proton
H-3 is strongly shifted downfield from 3.9 to 5.4 ppm,
while new carbonyl signal is found at 170 ppm along
with other signals characteristic for 4-nitrophenyl
moiety.
activity against efflux resistant S. Pneumoniae is better
in comparison to erythromycin. Acylides 37 and 38 also
show weak activity toward erythromycin-resistant
S. aureus. Importantly, all compounds show no effect
on eukaryotic organism S. cerevisiae.
3. Conclusion
Simple and efficient method for preparation of 9a-car-
bamoyl and 9a-thiocarbamoyl 3-decladinosyl 15-mem-
bered azalides 9–20 is developed. These derivatives
bear various alkyl and aryl groups attached to azalide
scaffold through urea or thiourea linkage at 9a-position.
The conformation of these derivatives in solution is C-3
to C-5 ‘folded out’. They are also starting compounds
for the successful chemical transformation of hydroxyl
group at position C-3 affording ketolides, hemiketals,
cyclic ethers, acylides, and first 2,3-anhydrolides of 15-
membered macrolides. 3-Acyl, 3-keto, and 2,3-anhydro
carbamoyl derivatives of 15-membered azalides show
moderate activity against resistant pathogens. As the
structure-activity relationship of 3-decladinosyl deriva-
tives of 15-membered azalides is far less established in
contrast to 14-membered analogs, our results provide
new insight into the antibacterial activity of azalides that
will certainly help us and others in envisioning new anti-
bacterial agents.
For all new compounds antibacterial activity was deter-
mined on a panel of various bacterial strains and com-
pared to erythromycin (2). MIC values for S. aureus,
S. pneumoniae, S. pyogenes, and H. influenzae strains
are shown in Table 2. 3-Decladinosyl-6-hydroxy and
6-methoxy azalides 7 and 8 proved antibacterially inac-
tive against these strains. Attachment of 9a-carbamoyl
and 9a-thiocarbamoyl moieties bearing different alkyl
and aryl groups (compounds 9–20) did not increase anti-
bacterial activity. Exception is weak activity of 19
against S. pneumoniae. Similar situation can be seen
with 3,6-hemiketals 25, 26 and 3,6-cyclic ethers 31, 32.
However, anhydrolides 35 and 36 as well as ketolides
27 and 28 show good antibacterial activity against efflux
resistant S. pneumoniae. The best antibacterial activity
was shown by 9a-carbamoyl acylides 37 and 38 that pos-
sess 3-O-(4-nitrophenyl)acetyl group. Although they
show rather weak activity against H. influenzae, their
4. Experimental
All solvents and reagents were used as supplied, unless
noted otherwise. IR spectra were recorded on Nicolet
Magna-IR 760 FT-IR spectrometer (KBr). Mass spec-
tra were recorded on Varian MAT 311 instrument
(FAB), and Platform LCZ or LCQ Deca instruments
(ESI). HRMS (ESI) were recorded on Micromass
Qtof2. NMR spectra were recorded as CDCl3 solution
at Varian Unity Inova 600, Bruker Advance DRX
500, and Bruker Advance 300 spectrometers with tri-
methylsilane as an internal standard. For characteriza-
tion of complex organic structures one-dimensional
(1D) (1H, 13C, and APT) and two-dimensional (2D)
(COSY, HETCOR, HMBC) NMR techniques were
used. Reactions were monitored by thin layer chroma-
tography on silica gel plates (Merck Silica gel 60
F254). Melting points are uncorrected and were deter-
mined on a Fisher-Johns melting point apparatus.
H
H
N
R
O
N
R
O
O
N
N
OH
O
OH
O
OH
O
O
N
N
HO
HO
OH
OH
a, b
O
O
O
O
O
O
O
OH
NO2
21 R = isopropyl
22 R = 2,4-dichlorphenyl
37 R = isopropyl
38 R = 2,4-dichlorphenyl
Scheme 5. Reagents and conditions: (a) 4-nitrophenylacetic acid,
pivaloyl chloride, TEA, pyridine, DCM, rt, 20 h; (b) MeOH, rt, 24 h.
Table 2. In vitro antibacterial activities of prepared macrolides
Strain
MIC (lg/ml)
2
6
9–18
19
20
25
26
27
28
31
32
35
36
37
38
S. aureus-M
>64
>64
0.125
8
>64
>64
0.5
16
1
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
0.5
4
32
32
2
S. aureus-cMLS
S. pneumoniae
S. pneumoniae-M
S. pyogenes
32
>64
8
8
8
8
>64
>64
>64
>64
64
16
8
16
>64
16
16
32
4
0.125
8
2
4
S. pyogenes-M
H. influenzae
16
8
>64
>64
>64
>64
32
16
32
32
4

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Z. M. Istuk et al. / Bioorg. Med. Chem. 15 (2007) 4498–4510
4503
MICs were determined on a TECAN Genesis 150
instrument using micro-dilution method and Mueller–
Hinton media for bacterial growth.
The solvent was evaporated to afford 8 (0.64 g, 46%)
as a white solid, mp 93–97 ꢁC.
IR (KBr) 3423, 2973, 2936, 2874, 1728, 1686, 1655,
1638, 1560, 1541, 1508, 1459, 1380, 1270, 1166, 1112,
4.1. 3-Decladinosyl-9-deoxo-9-dihydro-9a-aza-9a-homo-
erythromycin A (7)
1075, 1044, 1003, 984, 973, 896, 836, 731 cmꢀ1 1H
;
NMR (300 MHz, CDCl3) d 4.99 (13-H), 4.49 (10-H),
3.70 (3-H), 3.44 (11-H), 3.81 (5-H), 3.53 (50-H), 3.22
(6-OCH3), 3.25 (20-H), 2.98 (9a-H), 2.66 (2-H), 2.61
(10-H), 2.49 (30-H), 2.25 (30-N(CH3)2,), 2.18 (4-H),
1.93 (14a-H), 1.88 (8-H), 1.88 (9b-H), 1.66 (40a-H),
1.51 (7a-H), 1.50 (14b-H), 1.33 (7b-H), 1.33 (18-
CH3), 1.31 (16-CH3), 1.25 (50-CH3), 1.25 (40b-H),
1.11 (21-CH3), 1.07 (20-CH3), 1.06 (17-CH3), 0.96
(19-CH3), 0.87 (15-CH3); 13C NMR (75 MHz, CDCl3)
d 176.3 (1-C), 106.6 (10-C), 89.0 (5-C), 78.8 (6-C), 78.5
(3-C), 77.4 (13-C), 74.2 (11-C), 73.9 (12-C), 70.3 (20-C),
69.9 (50-C), 65.6 (30-C), 58.4 (9-C), 58.2 (10-C), 49.9 (6-
OCH3), 44.5 (2-C), 40.1 (30N-(CH3)2), 40.1 (7-C), 35.5
(4-C), 27.8 (40-C), 27.7 (8-C), 21.3 (19-CH3), 21.1 (50-
CH3), 20.7 (14-C), 20.5 (15-CH3), 18.7 (18-CH3), 16.0
(21-CH3), 16.0 (16-CH3), 13.4 (20-CH3), 7.8 (17-
CH3); MS (ES) 591.7 (M+H+).
Compound 57 (2.00 g, 2.71 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) was added, and pH ad-
justed to 8. The layers were separated and aqueous layer
extracted with CH2Cl2 (2 · 10 ml). Combined organic
extracts were rinsed with saturated aqueous NaHCO3
solution, brine, and water, and dried over Na2CO3.
The solvent was evaporated to afford 7 (1.23 g, 79%)
as a white solid, mp 110–115 ꢁC.
IR (KBr) 3444, 2972, 2937, 2877, 1716, 1638, 1458, 1380,
1348, 1266, 1169, 1112, 1074, 1049, 957, 899, 862, 835,
1
706, 652 cmꢀ1; H NMR (300 MHz, CDCl3) d 4.80 (13-
H), 4.47 (10-H), 3.80 (3-H), 3.48 (11-H), 3.61 (5-H), 3.54
(50-H), 3.27 (20-H), 3.09 (9a-H), 2.64 (2-H), 2.58 (10-H),
2.51 (30-H), 2.24 (30-N(CH3)2,), 2.23 (4-H), 1.91 (14a-H),
1.78 (8-H), 1.81 (9b-H), 1.66 (40a-H), 1.54 (7a-H), 1.52
(14b-H), 1.42 (7b-H), 1.29 (6-CH3), 1.32 (2-CH3), 1.24 (50-
CH3), 1.27 (40b-H), 1.15 (12-CH3), 1.08 (10-CH3), 1.05 (4-
CH3), 0.94 (8-CH3), 0.88 (15-CH3); 13C NMR (75 MHz,
CDCl3) d 177.1 (1-C), 106.2 (10-C), 94.4 (5-C), 78.8 (3-C),
77.1 (13-C), 73.6 (11-C), 73.2 (12-C), 73.0 (6-C), 70.2 (20-
C), 69.5 (50-C), 65.2 (30-C), 57.4 (10-C), 56.5 (9-C), 44.0 (2-
C), 40.6 (7-C), 39.9 (30N-(CH3)2), 35.5 (4-C), 28.8 (8-C),
27.7 (40-C), 25.7 (6-CH3), 20.2 (8-CH3), 20.7 (50-CH3),
20.6 (14-C), 15.8 (2-CH3), 15.6 (12-CH3), 13.4 (10-CH3),
10.3 (15-CH3), 7.5 (4-CH3); MS (ES) 577.7 (M+H+).
4.3. 9a-Carbamoyl and 9a-thiocarbamoyl 3-decladinosyl-
6-hydroxy derivatives (9–18)
4.3.1. General procedure. To the solution of compound 7
in toluene (c = 0.05 g/ml) corresponding isocyanate or
isothiocyanate was added. Reaction mixture was stirred
at room temperature. After removal of solvent under re-
duced pressure crude residue was obtained. Crystalliza-
tion from a mixture of acetone–petrol ether or ethyl
ether–petrol ether afforded products 9–18 (Table 3).
4.4. 3-Decladinosyl-9-deoxo-9-dihydro-9a-(N0-isopropyl-
carbamoyl)-9a-aza-9a-homoerythromycin A (9)
4.2. 3-Decladinosyl-6-O-methyl-9-deoxo-9-dihydro-9a-
aza-9a-homoerythromycin A (8)
White solid, mp 140–145 ꢁC. IR (KBr) 3498, 3466,
2974, 2938, 2877, 1726, 1618, 1596, 1528, 1458,
1373, 1279, 1172, 1111, 1082, 1036, 978, 956, 932,
Compound 618 (1.77 g, 2.36 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) was added, and pH ad-
justed to 8. The layers were separated and aqueous layer
extracted with CH2Cl2 (2 · 10 ml). Combined organic
extracts were rinsed with saturated aqueous NaHCO3
solution, brine, and water, and dried over Na2CO3.
901, 833, 776, 689, 633 cmꢀ1 1H NMR (300 MHz,
;
CDCl3)
d
5.03 (13-H), 4.40 (10-H), 4.37 (9a-
NCON0H), 3.92 (100-H), 3.89 (3-H), 3.50 (11-H), 3.69
(50-H), 3.63 (5-H), 3.32 (20-H), 2.60 (2-H), 2.54 (30-
H), 2.28 (30-N(CH3)2), 1.88 (14-Ha), 1.72 (40-Ha),
1.58 (14-Hb), 1.56 (4-H), 1.34 (40-Hb), 1.29 (2-CH3),
Table 3. 9a-Carbamoyl and 9a-thiocarbamoyl 3-decladinosyl derivatives
Compound
X@C@N–R
Solvent
Time
Product
Yield
X
R
7 (1 g/1.73 mmol)
7 (1 g /1.73 mmol)
7 (1 g/1.73 mmol)
7 (1 g/1.73 mmol)
7 (1 g/1.73 mmol)
7 (1 g/1.73 mmol)
7 (1 g/1.73 mmol)
7 (1 g/1.73 mmol)
7 (3 g/5.19 mmol)
7 (1 g/1.73 mmol)
O
O
O
O
O
O
S
Isopropyl (0.17 g/1.9 mmol)
Ethyl (0.17 g/2.46 mmol)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1 h
1 h
9
10
11
12
13
14
15
16
17
18
0.97 g (84%)
0.98 g (87%)
0.95 g (81%)
0.82 g (66%)
0.98 g (74%)
0.84 g (63%)
0.98 g (68%)
1.06 g (84%)
2.46 g (62%)
0.72 g (61%)
tert-Butyl (0.2 g/2.0 mmol)
Benzyl (0.25 g/1.9 mmol)
1 h
1 h
3-Trifluoromethylphenyl (0.33 g/2.0 mmol)
2-Trifluoromethylphenyl (0.35 g/2.0 mmol)
3-Trifluoromethylphenyl (0.35 g/2.0 mmol)
Benzyl (0.38 g/1.9 mmol)
30 min
30 min
15 min
1 h
S
O
S
2,4-Dichlorphenyl (1.07 g/5.7 mmol)
Allyl (0.19 g/1.9 mmol)
1 h
5 h

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Z. M. Istuk et al. / Bioorg. Med. Chem. 15 (2007) 4498–4510
4504
1.27 (50-CH3), 1.26 (10-CH3), 1.13 (100-(CH3)2), 1.10
(12-CH3), 1.06 (8-CH3), 0.93 (4-CH3), 0.89 (15-
CH3); 13C NMR (75 MHz, CDCl3) d 177.3 (1-C),
158.8 (9a-NCONH), 105.8 (10-C), 95.9 (5-C), 77.7
(13-C), 77.1 (12-C), 74.5 (11-C), 74.9 (3-C), 74.2 (6-
C), 73.0 (9-C), 70.3 (50-C), 69.2 (20-C), 64.9 (30-C),
44.6 (2-C), 42.4 (100-C), 41.7 (7-C), 39.9 (30-
N(CH3)2), 38.5 (4-C), 27.6 (40-C), 25.8 (6-CH3), 23.1
(100-(CH3)2), 21.2 (14-C), 20.6 (50-CH3), 19.4 (8-
CH3), 16.6 (12-CH3), 15.9 (2-CH3), 12.2 (10-CH3),
10.0 (15-CH3), 7.7 (4-CH3); MS (FAB) 662 (M+H+);
HRMS (ES) calcd for C33H63N3O10 (M+H+)
662.4592, found 662.4562.
4.7. 3-Decladinosyl-9-deoxo-9-dihydro-9a-(N0-benzylcar-
bamoyl)-9a-aza-9a-homoerythromycin A (12)
White solid, mp 147–152 ꢁC. IR (KBr) 3404, 2975, 2936,
1731, 1625, 1529, 1454, 1384, 1349, 1319, 1274, 1172,
1111, 1091, 1049, 978, 957, 931, 900, 865, 837, 740, 700,
635 cmꢀ1; 1H NMR (300 MHz, CDCl3) d 7.35 (400-H, 600-
H), 7.30 (300-H, 700-H), 7.24 (500-H), 5.03 (13-H), 4.55 (100-
Ha), 4.48 (9a-NCON0H), 4.30 (10-H), 4.30 (100-Hb), 3.89
(3-H), 3.68 (50-H), 3.51 (11-H), 3.62 (5-H), 3.41 (9-Ha),
3.30 (20-H), 2.62 (2-H), 2.30 (30-H), 2.27 (30-N(CH3)2),
1.89 (14-Ha), 1.69 (40-Ha), 1.58 (14-Hb), 1.56 (4-H), 1.28
(40-Hb), 1.30 (2-CH3), 1.27 (50-CH3), 1.32 (10-CH3), 1.28
(6-CH3), 1.10 (12-CH3), 1.04(8-CH3), 0.93 (4-CH3), 0.89
(15-CH3); 13C NMR (75 MHz, CDCl3) [d/ppm] 176.9 (1-
C), 159.6 (9a-NCONH), 139.4 (200-C), 128.6 (400-C, 600-C),
127.3 (300-C, 700-C), 126.9 (500-C), 105.7 (10-C), 96.4 (5-C),
77.7 (13-C), 77.1 (12-C), 75.0 (11-C), 75.0 (3-C), 74.2 (6-
C), 74.4 (9-C), 70.2 (50-C), 69.2 (20-C), 64.8 (30-C), 44.7
(2-C), 44.6 (100-C), 44.6 (7-C), 40.0 (30N-(CH3)2), 38.4 (4-
C), 27.5 (40-C), 25.3 (6-CH3), 21.3 (14-C), 20.7 (50-CH3),
19.7 (8-CH3), 16.7 (12-CH3), 15.9 (2-CH3), 12.2 (10-
CH3), 10.4 (15-CH3), 7.6 (4-CH3); MS (ES) 710.6
(M+H+); HRMS (ES) calcd for C37H63N3O10 (M+H+)
710.4592, found 710.4578.
4.5. 3-Decladinosyl-9-deoxo-9-dihydro-9a-(N0-ethyl-
carbamoyl)-9a-aza-9a-homoerythromycin A (10)
White solid, mp 130–136 ꢁC. IR (KBr) 3433, 2975,
2936, 2878, 1730, 1618, 1532, 1458, 1382, 1350, 1267,
1172, 1111, 1077, 1036, 980, 956, 933, 900, 834,
764 cmꢀ1 1H NMR (300 MHz, CDCl3) d 5.03 (13-
;
H), 4.39 (10-H), 4.56 (9a-NCON0H), 3.86 (3-H), 3.57
(11-H), 3.68 (50-H), 3.62 (5-H), 3.43 (9-Ha), 3.31 (20-
H), 3.23 (N0CH2), 2.59 (2-H), 2.53 (30-H), 2.47 (9-
Hb), 2.27 (30-N(CH3)2), 1.90 (14-Ha), 1.71 (40-Ha),
1.55 (14-Hb), 1.55 (4-H), 1.33 (40-Hb), 1.28 (2-CH3),
1.28 (15-CH3), 1.28 (10-CH3), 1.27 (50-CH3), 1.11
(N0CH2CH3), 1.08 (12-CH3), 1.05 (8-CH3), 0.92 (4-
CH3), 0.87 (15-CH3); 13C NMR (75 MHz, CDCl3) d
177.0 (1-C), 159.5 (9a-NCONH), 105.7 (10-C), 96.2
(5-C), 77.7 (13-C), 77.1 (12-C), 74.5 (11-C), 75.1 (3-
C), 74.1 (6-C), 72.8 (9-C), 70.3 (50-C), 69.2 (20-C),
64.9 (30-C), 44.7 (2-C), 41.1 (7-C), 39.9 [30N-(CH3)2],
38.3 (4-C), 36.5 (N0CH2), 28.9 (8-C), 27.6 (40-C), 25.6
(6-CH3), 21.3 (14-C), 20.6 (50-CH3), 19.3 (8-CH3),
16.6 (12-CH3), 15.8 (2-CH3), 15.0 (N0CH2CH3), 12.1
(10-CH3), 10.3 (15-CH3), 7.6 (4-CH3); MS (FAB) 648
(M+H+); HRMS (ES) calcd for C32H61N3O10
(M+H+) 648.4435, found 648.4430.
4.8. 3-Decladinosyl-9-deoxo-9-dihydro-9a-[N0-(3-trifluo-
romethylphenyl)carbamoyl]-9a-aza-9a-homoerythromycin
A (13)
White solid, mp 133–139 ꢁC. IR (KBr) 3451, 2975, 2935,
1727, 1704, 1659, 1548, 1494, 1449, 1384, 1336, 1258,
1167, 1125, 1072, 1049, 979, 957, 933, 901, 864, 835,
1
794, 758, 699, 659 cmꢀ1; H NMR (300 MHz, CDCl3)
d 7.70 (200-H), 7.58 (600-H), 7.35 (500-H), 7.23 (400-H),
4.82 (13-H), 4.62 (9a-NCON0H), 4.35 (10-H), 3.87 (3-
H), 3.62 (50-H), 3.62 (5-H), 3.51 (11-H), 3.41 (9-Ha),
3.30 (20-H), 2.66 (2-H), 2.50 (30-H), 2.26 (30-N(CH3)2),
1.88 (14-Ha), 1.71 (40-Ha), 1.58 (14-Hb), 1.56 (4-H),
1.28 (6-CH3), 1.28 (2-CH3), 1.31 (40-Hb), 1.27 (50-
CH3), 1.24 (10-CH3), 1.10 (12-CH3), 1.04 (8-CH3),
0.92 (4-CH3), 0.88 (15-CH3); 13C NMR (75 MHz,
CDCl3) d 176.8 (1-C), 156.6 (9a-NCONH), 140.0 (100-
C), 131.3 (300-C), 129.2 (500-C), 122.3 (600-C), 118.9 (400-
C), 115.8 (200-C), 106.1 (10-C), 96.5 (5-C), 78.8 (13-C),
77.1 (12-C), 75.7 (3-C), 74.8 (9-C), 74.7 (6-C), 74.6
(11-C), 70.6 (50-C), 69.4 (20-C), 65.2 (30-C), 45.2 (2-C),
40.2 (30N-(CH3)2), 38.8 (4-C), 27.9 (40-C), 21.5 (14-C),
20.9 (50-CH3), 20.0 (8-CH3), 16.8 (12-CH3), 16.1 (2-
CH3), 13.8 (10-CH3), 10.9 (15-CH3), 7.7 (4-CH3); MS
(ES) 764.6 (M+H+); HRMS (ES) calcd for
C37H60F3N3O10 (M+H+) 764.4309, found 764.4281.
4.6. 3-Decladinosyl-9-deoxo-9-dihydro-9a-(N0-t-butyl-
carbamoyl)-9a-aza-9a-homoerythromycin A (11)
White solid, mp 168–172 ꢁC. IR (KBr) 3497, 2976, 2946,
1725, 1626, 1532, 1456, 1364, 1346, 1317, 1281, 1175,
1112, 1082, 1055, 1034, 977, 956, 931, 901, 865, 776, 685,
1
634 cmꢀ1; H NMR (300 MHz, CDCl3) d 5.03 (13-H),
4.52 (9a-NCON0H), 4.41 (10-H), 3.89 (3-H), 3.68 (50-H),
3.47 (11-H), 3.62 (5-H), 3.41 (9-Ha), 3.32 (20-H), 2.59 (2-
H), 2.54 (30-H), 2.28 (30-N(CH3)2), 1.88 (14-Ha), 1.72 (40-
Ha), 1.57 (14-Hb), 1.56 (4-H), 1.32 (40-Hb), 1. 31
(N0C(CH3)3), 1.30 (2-CH3), 1.28 (50-CH3), 1.24 (10-CH3),
1.11 (12-CH3), 1.05 (8-CH3), 0.92 (4-CH3), 0.88 (15-
CH3); 13C NMR (75 MHz, CDCl3) d 177.7 (1-C), 158.7
(9a-NCONH), 105.9 (10-C), 95.7 (5-C), 77.9 (13-C), 77.1
(12-C), 74.6 (11-C), 74.8 (3-C), 74.3 (6-C), 73.3 (9-C),
70.3 (50-C), 69.2 (20-C), 65.0 (30-C), 50.8 (N0C(CH3)3),
44.6 (2-C), 41.1 (7-C), 40.0 (30N-(CH3)2), 38.6 (4-C), 29.1
(N0C(CH3)3), 28.9 (8-C), 27.7 (40-C), 26.2 (6-CH3), 21.2
(14-C), 20.6 (50-CH3), 19.4 (8-CH3), 16.5 (12-CH3), 16.0
(2-CH3), 12.2 (10-CH3), 10.6 (15-CH3), 7.8 (4-CH3); MS
(FAB) 676 (M+H+); HRMS (ES) calcd for C34H65N3O10
(M+H+) 676.4748, found 676.4711.
4.9. 3-Decladinosyl-9-deoxo-9-dihydro-9a-[N0-(2-trifluo-
romethylphenyl)carbamoyl]-9a-aza-9a-homoerythromycin
A (14)
White solid, mp 125–130 ꢁC. IR (KBr) 3458, 2975, 2940,
2879, 2786, 1727, 1658, 1591, 1536, 1457, 1384, 1322,
1282, 1244, 1171, 1112, 1035, 979, 956, 934, 901, 864,
834, 762, 702 cmꢀ1 1H NMR (300 MHz, CDCl3) d
;
8.01 (600-H), 7.55 (300-H), 7.26 (400-H), 7.16 (500-H), 4.98
(13-H), 4.62 (9a-NCON0H), 4.38 (10-H), 3.90 (3-H),

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4505
3.65 (50-H), 3.64 (5-H), 3.61 (11-H), 3.31 (20-H), 2.64 (2-
H), 2.52 (30-H), 2.27 (30-N(CH3)2), 1.91 (14-Ha), 1.72 (40-
Ha), 1.57 (14-Hb), 1.56 (4-H), 1.35 (10-CH3), 1.32
(2-CH3), 1.28 (6-CH3), 1.31 (40-Hb), 1.24 (50-CH3),
1.15 (12-CH3), 1.10 (8-CH3), 0.96 (4-CH3), 0.91 (15-
CH3); 13C NMR (75 MHz, CDCl3) d 177.3 (1-C), 157.0
(9a-NCONH), 136.4 (100-C), 132.5 (300-C), 125.7 (500-C),
125.1 (400-C), 123.4 (600-C), 105.9 (10-C), 82.9 (5-C), 77.9
(13-C), 74.4 (12-C), 75.2 (3-C), 74.4 (6-C), 73.8 (11-C),
70.4 (50-C), 69.2 (20-C), 64.9 (30-C), 44.7 (2-C), 39.9
(30N-(CH3)2), 38.6 (4-C), 27.6 (40-C), 21.3 (14-C), 20.7
(50-CH3), 19.1 (8-CH3), 16.6 (12-CH3), 15.9 (2-CH3),
12.5 (10-CH3), 10.5 (15-CH3), 7.7 (4-CH3); MS (FAB)
764.3 (M+H+); HRMS (ES) calcd for C37H60F3N3O10
(M+H+) 764.4309, found 764.4298.
(12-CH3), 16.5 (2-CH3), 12.3 (10-CH3), 11.3 (15-CH3),
8.3 (4-CH3); MS (ES) 726.5 (M+H+); HRMS (ES) calcd
for C37H63N3O9S (M+H+) 726.4363, found 726.4343.
4.12. 3-Decladinosyl-9-deoxo-9-dihydro-9a-[N0-(2,4-dichlor-
phenyl)carbamoyl]-9a-aza-9a-homoerythromycin A (17)
White solid, mp 138–149 ꢁC. IR (KBr) 3428, 2973,
2934, 2878, 1718, 1659, 1580, 1517, 1459, 1382, 1345,
1297, 1229, 1176, 1110, 1086, 1048, 978, 955, 932,
901, 866, 825, 759, 731, 696, 631 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 8.17 (600-H), 7.33 (300-H), 7.17
(500-H), 4,71 (13-H), 4.57 (9a-NCON0H), 4.40 (10-H),
4.10 (5-H), 3.89 (3-H), 3.89 (50-H), 3.32 (20-H), 2.62
(2-H), 2.60 (30-H), 2.30 (30-N(CH3)2), 1.93 (14-Ha),
1.76 (40-Ha), 1.57 (14-Hb), 1.56 (4-H), 1.53 (12-CH3),
1.36 (10-CH3), 1.31 (2-CH3), 1.29 (40-Hb), 1.29 (8-
CH3), 1.27 (50-CH3), 0.94 (4-CH3), 0.90 (15-CH3);
13C NMR (75 MHz, CDCl3) d 177.2 (1-C), 156.4 (9a-
NCONH), 134.7 (100-C), 128.4 (300-C), 127.6 (200-C),
125.3 (500-C), 123.2 (400-C), 105.9 (10-C), 78.2 (13-C),
75.9 (3-C), 70.5 (50-C), 69.5 (20-C), 65.2 (30-C), 44.9
(2-C), 40.2 (30N-(CH3)2), 38.8 (4-C), 28.1 (40-C), 28.0
(8-C), 21.5 (14-C), 20.9 (50-CH3), 19.4 (6-CH3), 16.8
(12-CH3), 16.2 (2-CH3), 12.9 (10-CH3), 10.9 (15-
CH3), 8.0 (4-CH3); MS (ES) 764.5 (M+H+); HRMS
(ES) calcd for C36H59Cl2N3O10 (M+H+) 764.3656,
found 764.3627.
4.10. 3-Decladinosyl-9-deoxo-9-dihydro-9a-[N0-(3-trifluo-
romethylphenyl)thiocarbamoyl]-9a-aza-9a-homoerythromy-
cin A (15)
White solid, mp 118–124 ꢁC. IR (KBr) 3449, 2975, 2937,
1708, 1600, 1547, 1494, 1452, 1384, 1328, 1255, 1164,
1116, 1073, 1019, 980, 956, 885, 862, 793, 735,
696 cmꢀ1; 1H NMR (300 MHz, CDCl3) d 7.68 (200-bH),
7.42 (600-H), 7.26 (500-H), 7.18 (400-H), 4.82 (13-H), 4.61
(9a-NCON0H), 4.40 (10-H), 3.90 (3-H), 3.66 (50-H),
3.57 (5-H), 3.49 (11-H), 3.31 (20-H), 2.69 (2-H), 2.52
(30-H), 2.27 (30-N(CH3)2), 1.95 (14-Ha), 1.69 (40-Ha),
1.62 (14-Hb), 1.53 (4-H), 1.34 (2-CH3), 1.28 (6-CH3),
1.34 (40-Hb), 1.28 (50-CH3), 1.25 (10-CH3), 1.21 (12-
CH3), 1.08 (8-CH3), 0.98 (4-CH3), 0.94 (15-CH3); 13C
NMR (75 MHz, CDCl3) d 183.2 (9a-NCONH), 177.6
(1-C), 140.4 (100-C), 130.5 (300-C), 130.2 (500-C), 128.1
(600-C), 125.2 (400-C), 123.6 (200-C), 105.2 (10-C), 94.9 (5-
C), 79.3 (3-C), 77.7 (13-C), 77.2 (12-C), 73.5 (9-C), 73.6
(6-C), 73.4 (11-C), 70.6 (50-C), 69.5 (20-C), 65.2 (30-C),
44.5 (2-C), 41.1 (7-C), 40.2 (30N-(CH3)2), 38.8 (4-C),
28.1 (8-C), 27.9 (40-C), 25.9 (6-CH3), 21.0 (14-C), 21.0
(50-CH3), 18.9 (8-CH3), 16.6 (12-CH3), 16.1 (2-CH3),
12.8 (10-CH3), 10.8 (15-CH3), 7.6 (4-CH3); MS (FAB)
780 (M+H+); HRMS (ES) calcd for C37H60F3N3O9S
(M+H+) 780.4081, found 780.4036.
4.13. 3-Decladinosyl-9-deoxo-9-dihydro-9a-(N0-allylthiocar-
bamoyl)-9a-aza-9a-homoerythromycin A (18)
White solid, mp 116–121 ꢁC. IR (KBr) 3451, 2974, 2938,
2878, 1704, 1644, 1520, 1456, 1384, 1321, 1286, 1178,
1110, 1074, 1048, 1019, 978, 955, 934, 862, 833, 762,
1
632 cmꢀ1; H NMR (300 MHz, CDCl3) d 5.94 (200-H),
5.29 (300-Ha), 5.20 (300-Hb), 4.57 (13-H), 4.41 (10-H),
4.37 (9a-NCSN0H), 4.34 (100-Ha), 4.21 (100-Hb), 3.90
(3-H), 3.69 (50-H), 3.78 (5-H), 3.32 (20-H), 2.64 (2-H),
2.54 (30-H), 2.28 (30-N(CH3)2), 1.92 (14-Ha), 1.70 (40-
Ha), 1.60 (14-Hb), 1.52 (4-H), 1.34 (40-Hb), 1.35 (2-
CH3), 1.28 (50-CH3), 1.28 (6-CH3), 1.26 (10-CH3), 1.24
(12-CH3), 1.12 (8-CH3), 0.95 (4-CH3), 0.94 (15-CH3);
13C NMR (75 MHz, CDCl3) d 189.3 (1-C), 179.7 (9a-
NCSNH), 133.6 (200-C), 117.8 (300-C), 106.0 (10-C), 95.0
(5-C), 78.6 (13-C), 75.1 (12-C), 75.1 (6-C), 74.8 (3-C),
73.8 (11-C), 70.4 (50-C), 69.3 (20-C), 65.4 (30-C), 48.8
(100-C), 44.2 (2-C), 39.9 (30N-(CH3)2), 38.9 (4-C), 27.6
(40-C), 20.7 (14-C), 20.6 (50-CH3), 18.7 (8-CH3), 16.4
(12-CH3), 16.2 (2-CH3), 12.1 (10-CH3), 10.9 (15-CH3),
7.9 (4-CH3); MS (ES) 676.4 (M+H+); HRMS (ES) calcd
for C33H61N3O9S (M+H+) 676.4207, found 676.4181.
4.11. 3-Decladinosyl-9-deoxo-9-dihydro-9a-(N0-benzylthio-
carbamoyl)-9a-aza-9a-homoerythromycin A (16)
White solid, mp 125–132 ꢁC. IR (KBr) 3448, 2974, 2938,
1703, 1528, 1456, 1384, 1323, 1283, 1178, 1109, 1073,
1
1020, 978, 955, 934, 862, 825, 759, 699 cmꢀ1; H NMR
(300 MHz, CDCl3) d 7.34 (400-H, 600-H), 7.30 (300-H, 700-
H), 7.27 (500-H), 4.64 (9a-NCSN0H), 4.57 (13-H), 4.39
(10-H), 3.89 (3-H), 3.67 (50-H), 3.67 (5-H), 3.51 (11-H),
3.31 (20-H), 2.64 (2-H), 2.55 (30-H), 2.28 (30-N(CH3)2),
1.93 (14-Ha), 1.73 (40-Ha), 1.62 (14-Hb), 1.56 (4-H),
1.34 (2-CH3), 1.27 (40-Hb), 1.27 (50-CH3), 1.27 (10-
CH3), 1.25 (12-CH3), 0.94 (8-CH3), 0.87 (4-CH3), 0.86
(15-CH3); 13C NMR (75 MHz, CDCl3) d 189.2 (9a-
NCSNH), 179.5 (1-C), 137.5 (200-C), 128.6 (400-C, 600-
C), 128.2 (300-C, 700-C), 127.6 (500-C), 105.9 (10-C), 93.9
(5-C), 78.7 (13-C), 75.1 (12-C), 75.2 (6-C), 74.6 (3-C),
73.9 (11-C), 70.1 (50-C), 69.5 (20-C), 65.2 (30-C), 50.8
(100-C), 44.1 (2-C), 40.2 (30N-(CH3)2), 44.4 (4-C), 27.9
(40-C), 21.1 (14-C), 20.9 (50-CH3), 19.0 (8-Me), 16.7
4.14. 9a-Carbamoyl 3-decladinosyl-6-methoxy derivatives
(19, 20)
4.14.1. General procedure. To the solution of 8 in aceto-
nitrile (c = 0.01 g/ml) corresponding isocyanate was
added. Reaction mixture was stirred for 2 h at room
temperature. The solvent was evaporated and the crude
product purified by chromatography on a silica gel col-
umn using CH2Cl2:MeOH:NH4OH (90:5:0.5) as an elu-
ent (Table 4).

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4506
Table 4. 9a-Carbamoyl 3-decladinosyl 6-methoxy derivatives
Compound
X@C@N–R
Solvent
Time
Product
Yield
X
R
8 (0.2 g/0.33 mmol)
8 (0.2 g/0.33 mmol)
O
O
Isopropyl (0.07 ml/0.67 mmol)
2,4-Dichlorphenyl (0.064 g/0.33 mmol)
Acetonitrile
Acetonitrile
2 h
30 min
19
20
0.13 g (56%)
0.17 g (63%)
4.15. 3-Decladinosyl-6-O-methyl-9-deoxo-9-dihydro-9a-(N0-
isopropylcarbamoyl)-9a-aza-9a-homoerythromycin A (19)
CO3 (4.5 eq) and acetic anhydride (1.1 eq) were added
and the mixture stirred for 24 h at room temperature.
Into the reaction mixture saturated aqueous NaHCO3
solution was added, the layers were separated, and the
aqueous layer extracted two more times with CH2Cl2.
Combined organic extracts were rinsed with saturated
aqueous NaHCO3 solution and water, and evaporated
yielding 21–24 that are used without further
purifications.
White solid, mp 154–159 ꢁC. IR (KBr) 3424, 2975, 2937,
2877, 1732, 1687, 1627, 1562, 1525, 1460, 1379, 1270,
1166, 1112, 1080, 1053, 984, 958, 938, 896, 828, 766 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 5.16 (13-H), 4.44 (10-H),
3.91 (100-H), 3.65 (3-H), 3.73 (5-H), 3.53 (50-H), 3.23 (20-
H), 3.14 (6-OCH3), 2.61 (2-H), 2.48 (30-H), 2.25 (30-
N(CH3)2,), 1.82 (4-H), 1.91 (14a-H), 2.03 (8-H), 1.66 (40a-
H), 1.49 (14b-H), 1.35 (18-CH3), 1.28 (16-CH3), 1.25 (20-
CH3), 1.25 (50-CH3), 1.25 (40b-H), 1.15 (100-(CH3)2), 1.14
(21-CH3), 1.05 (17-CH3), 0.96 (19-CH3), 0.88 (15-CH3);
13C NMR (75 MHz, CDCl3) d 175.8 (1-C), 155.1 (9a-
NCONH), 106.6 (10-C), 90.2 (5-C), 79.5 (6-C), 78.9 (3-C),
74.2 (11-C), 74.7 (12-C), 70.5 (20-C), 70.0 (50-C), 65.7 (30-
C), 49.8 (6-OCH3), 44.8 (2-C), 42.7 (100-C), 40.3 (30N-
(CH3)2), 36.4 (4-C), 28.1 (40-C), 27.5 (8-C), 23.6 (18-CH3),
23.3 (100-(CH3)2), 22.3 (14-C), 21.3 (50-CH3), 20.6 (19-
CH3), 16.9 (21-CH3), 15.5 (16-CH3), 12.6 (20-CH3), 11.2
(15-CH3), 7.7 (17-CH3); MS (ES) 676.8 (M+H+); HRMS
(ES) calcd for C34H65N3O10 (M+H+) 676.4748, found
676.4711.
4.18. 20-O-Acetyl-3-decladinosyl-9-deoxo-9-dihydro-9a-(N0-
isopropylcarbamoyl)-9a-aza-9a-homoerythromycin A (21)
According to general procedure 1 g of 9 (1.51 mmol)
afforded 21 (1.10 g, quant).
IR (KBr) 3423, 2974, 2938, 2878, 1735, 1624, 1560,
1522, 1459, 1376, 1252, 1169, 1109, 1058, 987, 956,
901, 834, 771, 670 cmꢀ1; MS (ES) 704.2 (M+H+).
4.19. 20-O-Acetyl-3-decladinosyl-9-deoxo-9-dihydro-9a-
[N0-(2,4-dichlorphenyl)carbamoyl]-9a-aza-9a-homoery-
thromycin A (22)
4.16. 3-Decladinosyl-6-O-methyl-9-deoxo-9-dihydro-9a-[N0-
(2,4-dichlorphenyl)carbamoyl]-9a-aza-9a-homoerythromycin
A (20)
According to general procedure 6.6 g of 17 (8.62 mmol)
afforded 22 (6.3 g, 90%).
IR (KBr) 3545, 3448, 3393, 2972, 2940, 2882, 2831,
2787, 1727, 1638, 1586, 1522, 1490, 1460, 1382, 1335,
1309, 1298, 1247, 1201, 1166, 1100, 1057, 1036, 1006,
985, 947, 893, 864, 817, 756, 702, 669, 620 cmꢀ1; MS
(ES) 806.16 (M+H+).
White solid, mp 123–127 ꢁC. IR (KBr) 3448, 2975, 2939,
2879, 2787, 1729, 1707, 1670, 1582, 1517, 1459, 1382,
1328, 1298, 1274, 1165, 1112,ꢀ11076, 1051, 983, 956, 937,
897, 861, 822, 750, 699 cm
;
1H NMR (300 MHz,
CDCl3) d 8.13 (600-H), 7.34 (300-H), 7.18 (500-H), 5.11 (13-
H), 4.39 (10-H), 3.81 (5-H), 3.72 (3-H), 3.52 (50-H), 3.35
(6-OCH3), 3.18 (20-H), 2.61 (2-H), 2.61 (10-H), 2.50
(30-H), 2.27 (30-N(CH3)2), 2.04 (8-H), 1.93 (14a-H), 1.89
(4-H), 1.68 (40a-H), 1.52 (14b-H), 1.35 (6-CH3), 1.33
(40b-H), 1.28 (2-CH3), 1.25 (10-CH3), 1.23 (50-CH3),
1.18 (12-CH3), 1.04 (4-CH3), 1.02 (8-CH3), 0.89 (15-
CH3); 13C NMR (75 MHz, CDCl3) d 176.3 (1-C), 155.0
(9a-NCONH), 134.9 (100-C), 128.4 (300-C), 127.7 (500-C),
127.1 (200-C), 122.7 (400-C), 122.1 (600-C), 106.9 (10-C),
90.3 (5-C), 79.7 (3-C), 79.1 (6-C), 76.1 (13-C), 73.6 (11-
C), 73.6 (12-C), 70.5 (20-C), 69.9 (50-C), 65.7 (30-C), 49.9
(6-O-CH3), 44.7 (2-C), 40.3 (30N-(CH3)2), 36.7 (4-C),
35.5 (7-C), 28.3 (40-H), 28.2 (8-C), 22.4 (14-C), 21.3 (50-
CH3), 20.6 (18-CH3), 16.9 (21-CH3), 15.4 (16-CH3), 20.5
(20-CH3), 11.4 (15-CH3), 7.6 (17-CH3); MS (ES) 778.6
(M+H+); HRMS (ES) calcd for C37H61Cl2N3O10
(M+H+) 778.3812, found 778.3778.
4.20. 20-O-Acetyl-3-decladinosyl-6-O-methyl-9-deoxo-9-
dihydro-9a-(N0-isopropylcarbamoyl)-9a-aza-9a-homo-
erythromycin A (23)
According to general procedure 1.08 g of 19 (1.60 mmol)
afforded 23 (0.68 g, 60%).
IR (KBr) 3431, 2974, 2937, 2876, 1734, 1629, 1524,
1459, 1376, 1243, 1167, 1083, 1058, 985, 957, 938, 904,
806, 671 cmꢀ1; MS (ES) 718.22 (M+H+).
4.21. 20-O-Acetyl-3-decladinosyl-6-O-methyl-9-deoxo-9-
dihydro-9a-[N0-(2,4-dichlorphenyl)carbamoyl]-9a-aza-9a-
homoerythromycin A (24)
According to general procedure 0.12 g of 20 (0.15 mmol)
afforded 24 (0.115 g, 93%).
4.17. Acetylation of 20-OH (derivatives 21–24)
IR (KBr) 3449, 2973, 2939, 1748, 1730, 1668, 1582,
1517, 1459, 1377, 1298, 1261, 1239, 1165, 1098, 1050,
985, 906, 866, 809, 764, 664, 622, 584, 544, 505, 483,
463, 444, 386 cmꢀ1; MS (ES) 820.19 (M+H+).
4.17.1. General procedure. To a solution of 20-OH deriv-
atives 7, 9, 17, and 19 in CH2Cl2 (c = 0.05 g/ml), NaH-

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4507
4.22. 3,6-Hemiketals (25, 26) and 3-ketolides (derivatives
27, 28)
H), 4.91 (13-H), 4.36 (9a-NC0N0H), 4.21 (10-H), 3.80
(5-H), 3.63 (11-H), 3.51 (50-H), 3.23 (20-H), 2.59
(10-H), 2.56 (2-H), 2.49 (30-H), 2.27 (30-N(CH3)2), 2.20
(8-H), 2.09 (4-H), 1.83 (14-Ha), 1.68 (40-Ha), 1.62 (14-
Hb), 1.55 (7-Ha), 1.47 (7-Hb), 1.42 (6-CH3), 1.30
(2-CH3), 1.26 (40-Hb), 1.26 (50-CH3), 1.24 (4-CH3),
1.21 (12-CH3), 1.19 (10-CH3), 1.07 (8-CH3), 0.88 (15-
CH3);13C NMR (75 MHz, CDCl3) d 177.4 (1-C), 154.8
(9a-NCONH), 134.8 (100-C), 128.3 (300-C), 127.3 (500-C),
127.1 (200-C), 122.7 (400-C), 121.9 (600-C), 106.2 (10-C),
103.3 (3-C), 94.2 (5-C), 83.6 (6-C), 83.3 (11-C), 79.0
(13-C), 75.6 (12-C), 69.7 (20-C), 69.6 (50-C), 65.5 (30-
C), 49.2 (2-C), 48.4 (4-C), 46.3 (10-C), 41.4 (7-C), 40.3
(30N-(CH3)2), 28.6 (40-C), 28.4 (8-C), 21.6 (14-C), 23.3
(50-CH3), 26.4 (6-CH3), 21.5 (8-CH3),17.7 (12- CH3),
16.8 (12-CH3), 14.2 (10-CH3), 13.8 (2-CH3), 12.9 (4-
CH3), 10.9 (15-CH3); MS (ES) 762.12 (M+H+); HRMS
(ES) calcd for C36H57Cl2N3O10 (M+H+) 762.3499,
found 762.3511.
4.22.1. General procedure. To a solution of 21–24 in
CH2Cl2 (c = 0.05 g/ml), DMSO (12 eq) and EDC · HCl
(6 eq) were added. The reaction mixture was cooled to
15 ꢁC and a solution of pyridinium trifluoroacetate (6
eq) in CH2Cl2 (c = 0.2 g/ml) was added dropwise during
30 min. The reaction mixture was stirred at room tem-
perature for 2 h. Into the reaction mixture brine was
added and the pH was adjusted to 9.5. The layers were
separated and the aqueous layer extracted two more
times with CH2Cl2. Combined organic extracts were
rinsed with brine, saturated aqueous NaHCO3 solution,
and water, dried over K2CO3, and evaporated yielding
crude product which was dissolved in MeOH
(c = 0.02 g/ml) and stirred for 24 h at room temperature.
The solvent was evaporated and the residue purified by
low pressure chromatography on a silica gel column
using the system CH2Cl2:MeOH:NH4OH (90:3:0.3) as
eluent to afford 25–28.
4.25. 3-Keto-3-decladinosyl-6-O-methyl-9-deoxo-9-dihy-
dro-9a-(N0-isopropylcarbamoyl)-9a-aza-9a-homoery-
thromycin A (27)
4.23. 3-Decladinosyl-9-deoxo-9-dihydro-9a-(N0-isopropylcar-
bamoyl)-9a-aza-9a-homoerythromycin A 3,6-hemiketal (25)
According to general procedure 0.18 g of 23 (0.25 mmol)
afforded 27 (0.074 g, 41%) as a white solid, mp 114–
119 ꢁC.
According to general procedure 1.5 g of 21 (2.13 mmol)
afforded 25 (0.313 g, 21%) as a white solid, mp 114–
118 ꢁC.
IR (KBr) 3428, 2936, 1741, 1629, 1520, 1458, 1378,
1
IR (KBr) 3373, 2968, 2936, 2877, 1728, 1716, 1615,
1526, 1520, 1456, 1384, 1261, 1181, 1099, 1031, 961,
1260, 1172, 1111, 1077, 1050, 985, 810 cmꢀ1; H NMR
(300 MHz, CDCl3) d 5.11 (13-H), 4.42 (10-H), 4.34 (5-
H), 3.91 (100-H), 3.82 (2-H), 3.63 (50-H), 3.21 (20-H),
3.12 (4-H), 2.99 (6-OCH3), 2.57 (30-H), 2.33 (30-
N(CH3)2,), 2.04 (8-H), 1.94 (14a-H), 1.75 (40a-H), 1.54
(14 b-H), 1.38 (18-CH3), 1.33 (16-CH3), 1.26 (20-CH3),
1.27 (50-CH3), 1.27 (40b-H), 1.16 (100-(CH3)2), 1.14 (21-
CH3), 1.27 (17-CH3), 0.98 (19-CH3), 0.90 (15-CH3);
13C NMR (75 MHz, CDCl3) d 207.0 (3-C), 170.6 (1-
C), 158.0 (9a-NCONH), 102.8 (10-C), 75.8 (5-C), 79.4
(6-C), 74.4 (12-C), 74.2 (11-C), 70.3 (20-C), 69.2 (50-C),
65.8 (30-C), 50.7 (2-C), 50.1 (6-OCH3), 45.7 (4-C), 42.8
(100-C), 40.4 (30N-(CH3)2), 29.1 (40-C), 27.4 (8-C), 23.8
(18-CH3), 23.2 (100-(CH3)2), 22.4 (14-C), 21.2 (50-CH3),
20.8 (19-CH3), 16.8 (21-CH3), 14.0 (16-CH3), 13.2 (20-
CH3), 12.5 (17-CH3), 11.3 (15-CH3); MS (ES) 674.27
(M+H+); HRMS (ES) calcd for C34H63N3O10 (M+H+)
674.4592, found 674.4573.
864, 799, 737 cmꢀ1 1H NMR (300 MHz, CDCl3) d
;
4.91 (13-H), 4.21 (10-H), 4.20 (9a-NCON0H), 3.96 (100-
H), 3.63 (11-H), 3.53 (50-H), 3.78 (5-H), 3.26 (20-H),
2.64 (2-H), 2.59 (10-H), 2.54 (30-H), 2.32 (30-N(CH3)2),
2.08 (4-H), 2.06 (8-H), 1.82 (14-Ha), 1.73 (40-Ha), 1.62
(14-Hb), 1.48 (7-Ha), 1.39 (6-CH3), 1.36 (7-Hb), 1.28
(10-CH3), 1.27 (40-Hb), 1.24 (50-CH3), 1.24 (4-CH3),
1.15 (12-CH3), 1.13 (100-(CH3)2), 0.97 (8-CH3), 0.96 (2-
CH3), 0.87 (15-CH3); 13C NMR (75 MHz, CDCl3) d
176.4 (1-C), 157.4 (9a-NCONH), 103.7 (10-C), 103.1
(3-C), 94.2 (5-C), 83.8 (6-C), 83.3 (11-C), 79.0 (13-C),
75.4 (12-C), 69.7 (50-C), 69.6 (20-C), 65.4 (30-C), 49.2
(2-C), 48.3 (4-C), 46.5 (10-C), 42.6 (100-C), 41.4 (7-C),
40.4 (30-N(CH3)2), 29.0 (40-C), 28.8 (8-C), 26.3 (6-
CH3), 23.6 (100-(CH3)2), 21.6 (14-C), 21.2 (50-CH3),
21.2 (8-CH3), 17.7 (12-CH3), 14.3 (10-CH3), 13.9 (2-
CH3), 12.9 (4-CH3), 10.8 (15-CH3); MS (ES) 660.6
(M+H+); HRMS (ES) calcd for C33H61N3O10 (M+H+)
660.4435, found 660.4395.
4.26. 3-Keto-3-decladinosyl-6-O-methyl-9-deoxo-9-dihy-
dro-9a-[N0-(2,4-dichlorphenyl)carbamoyl]-9a-aza-9a-
homoerythromycin A (28)
4.24. 3-Decladinosyl-9-deoxo-9-dihydro-9a-[N0-(2,4-
dichlorphenyl)carbamoyl]-9a-aza-9a-homoerythromy-
cin A 3,6-hemiketal (26)
According to general procedure 0.73 g of 24 (0.89 mmol)
afforded 28 (0.25 g, 34%) as a white solid, mp 109–
119 ꢁC.
According to general procedure 2.0 g of 22 (2.48 mmol)
afforded 26 (0.516 g, 26%) as a white solid, mp 112–
120 ꢁC.
IR (KBr) 3448, 2976, 2938, 2877, 2786, 1741, 1719,
1665, 1580, 1515, 1459, 1381, 1298, 1230, 1197, 1167,
1147, 1110, 1076, 1051, 986, 957, 937, 895, 859, 821,
IR (KBr) 3448, 2974, 2938, 2877, 2782, 1720, 1667,
1580, 1512, 1460, 1384, 1324, 1299, 1231, 1195, 1115,
761, 753, 622 cmꢀ1 1H NMR (300 MHz, CDCl3) d
;
8.10 (600-H), 7.34 (300-H), 7.18 (500-H), 5.08 (13-H), 4.40
(10-H), 4.31 (5-H), 3.81 (2-H), 3.62 (50-H), 3.44
(6-OCH3), 3.17 (4-H), 3.16 (20-H), 2.75 (10-H), 2.49
1099, 1072, 1049, 962, 862, 823 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 8.14 (600-H), 7.32 (300-H), 7.19 (500-

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4508
(30-H), 2.28 (30-N(CH3)2), 2.19 (8-H), 1.94 (14a-H), 1.68
(40a-H), 1.56 (14b-H), 1.32 (6-CH3), 1.30 (2-CH3), 1.27
(7a-H), 1.24 (10-CH3), 1.23 (40b-H), 1.23 (50-CH3),
1.19 (12-CH3), 1.06 (4-CH3), 1.03 (7b-H), 1.02 (8-
CH3), 0.91 (15-CH3); 13C NMR (75 MHz, CDCl3) d
207.1 (3-C), 171.1 (1-C), 155.6 (9a-NCONH), 135.1
(100-C), 128.8 (300-C), 128.2 (500-C), 127.8 (200-C), 123.1
(400-C), 122.5 (600-C), 103.1 (10-C), 79.9 (6-C), 79.5 (13-
C), 76.2 (5-C), 73.9 (12-C), 73.4 (11-C), 70.8 (20-C),
69.7 (50-C), 65.9 (30-C), 51.1 (2-C), 50.9 (4-C), 50.6 (6-
O-CH3), 40.8 (30N-(CH3)2), 39.0 (7-C), 29.3 (40-H),
28.6 (8-C), 22.7 (14-C), 21.6 (50-CH3), 21.3 (19-CH3),
17.2 (21-CH3), 13.6 (16-CH3), 12.8 (20-CH3), 11.6 (15-
CH3), 7.6 (17-CH3); MS (ES) 776.6 (M+H+); HRMS
(ES) calcd for C37H59Cl2N3O10 (M+H+) 776.3656,
found 776.3638.
4.31. 20-O-Acetyl-3-O-mesyl-6-O-methyl-3-decladinosyl-
9-deoxo-9-dihydro-9a-[N0-(2,4-dichlorphenyl)carbamoyl]-
9a-aza-9a-homoerythromycin A (34)
According to general procedure 1.50 g of 24 (1.86 mmol)
afforded 34 (1.57 g, 94%).
IR (KBr) 3434, 3060, 2974, 2935, 1736, 1701, 1686,
1655, 1637, 1560, 1528, 1509, 1486, 1376, 1330, 1240,
1208, 1193, 1059, 785, 773, 753, 681, 609 cmꢀ1; MS
(ES) 898.09 (M+H+).
4.32. 3,6-Cyclic ethers (31, 32) and 2,3-anhydrolides
(35, 36)
4.32.1. General procedure. To a solution of 29, 30, 33,
and 34 in DMF/THF (3.5:1, c = 0.02 g/ml), NaH (5
eq, 60% suspension in mineral oil) was added and the
reaction mixture was stirred at 0 ꢁC for 5 h, and addi-
tional 20 h at the room temperature. Into the reaction
mixture saturated aqueous NaHCO3 solution and ethyl
acetate were added, and the layers were separated. The
aqueous layer was extracted two more times with ethyl
acetate. Combined organic extracts were rinsed with sat-
urated aqueous NaHCO3 solution and brine, dried over
MgSO4, and evaporated yielding crude product which
was dissolved in MeOH (c = 0.02 g/ml) and stirred for
24 h at room temperature. The solvent was evaporated
and the crude product purified by chromatography on
a silica gel column using CH2Cl2:MeOH:NH4OH
(90:3:0.3) as an eluent to afford 31, 32, 35, and 36,
respectively.
4.27. Mesylation of 3-OH (derivatives 29, 30, 33, 34)
4.27.1. General procedure. To a solution of 21–24 in pyr-
idine (c = 0.02 g/ml), methylsulfonyl anhydride (3.5 eq)
was added and the reaction mixture was stirred at room
temperature for 3 h. The solvent was evaporated and
residue dissolved in CH2Cl2. This solution was then
rinsed with saturated aqueous NaHCO3 solution and
brine, dried over MgSO4, and evaporated yielding 29,
30, 33, and 34, respectively, that were used without fur-
ther purification.
4.28. 20-O-Acetyl-3-O-mesyl-3-decladinosyl-9-deoxo-9-dihy-
dro-9a-(N0-isopropylcarbamoyl)-9a-aza-9a-homoerythromy-
cin A (29)
According to general procedure 1.0 g of 21 (1.42 mmol)
afforded 29 (0.87 g, 77%).
4.33. 3-Decladinosyl-9-deoxo-9-dihydro-9a-(N0-isopropylc-
arbamoyl)-9a-aza-9a-homoerythromycin A 3,6-cyclic ether
(31)
IR (KBr) 3422, 3065, 2972, 2876, 1735, 1637, 1618,
1535, 1487, 1459, 1377, 1330, 1240, 1206, 1193, 1059,
1004, 785, 773, 755, 682, 609 cmꢀ1; MS (ES) 783.2
(M+H+).
According to general procedure 0.80 g of 29 (1.00 mmol)
afforded 31 (0.17 g, 26%) as a white solid, mp 108–
113 ꢁC.
4.29. 20-O-Acetyl-3-O-mesyl-3-decladinosyl-9-deoxo-9-
dihydro-9a-[N0-(2,4-dichlorphenyl)carbamoyl]-9a-aza-9a-
homoerythromycin A (30)
IR (KBr) 3428, 2972, 2938, 2876, 1735, 1619, 1528,
1459, 1383, 1330, 1270, 1179, 1144, 1073, 1051, 1030,
961, 893, 835, 799, 759, 635 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 4.90 (13-H), 4.24 (10-H), 4.20
(9a-NCON0H), 3.95 (100-H), 3.83 (11-H), 3.64 (3-H),
3.55 (50-H), 3.57 (5-H), 3.33 (20-H), 3.25 (9-Ha), 2.92
(9-Hb), 2.76 (30-H), 2.57 (2-H), 2.48 (30-N(CH3)2),
2.06 (8-H), 2.04 (4-H), 1.92 (40-Ha), 1.83 (14-Ha),
1.64 (14-Hb), 1.64 (7-Ha), 1.33 (40-Hb), 1.29 (7-Hb),
1.28 (10-CH3), 1.26 (50-CH3), 1.24 (4-CH3), 1.23 (6-
CH3), 1.19 (2-CH3), 1.14 (12-CH3), 1.13 (100-(CH3)2),
0.96 (8-CH3), 0.88 (15-CH3); 13C NMR (75 MHz,
CDCl3) d 176.6 (1-C), 157.8 (9a-NCONH), 103.9 (10-
C), 93.4 (5-C), 84.0 (6-C), 83.6 (3-C), 78.7 (13-C),
75.5 (12-C), 69.5 (20-C), 69.4 (50-C), 65.4 (30-C), 46.5
(2-C), 45.7 (4-C), 42.6 (100-C), 40.5 (30-N(CH3)2), 40.3
(7-C), 30.1 (40-C), 28.9 (8-C), 23.6 (100-(CH3)2), 23.1
(6-CH3), 21.7 (14-C), 21.3 (8-CH3), 21.1 (50-CH3),
18.0 (12-CH3), 18.0 (4-CH3), 14.3 (2-CH3), 12.8 (10-
CH3), 11.0 (15-CH3); MS (ES) 644.2 (M+H+); HRMS
(ES) calcd for C33H61N3O9 (M+H+) 644.4486, found
644.4472.
According to general procedure 1.5 g of 22 (1.86 mmol)
afforded 30 (1.62 g, 97%).
IR (KBr) 3448, 3058, 2935, 1735, 1655, 1637, 1603,
1560, 1528, 1486, 1376, 1332,1240, 1208, 1193, 1097,
1059, 1001, 916, 822, 785, 773, 753, 681, 609 cmꢀ1; MS
(ES) 884.05 (M+H+).
4.30. 20-O-Acetyl-3-O-mesyl-6-O-methyl-3-decladinosyl-
9-deoxo-9-dihydro-9a-(N0-isopropylcarbamoyl)-9a-aza-
9a-homoerythromycin A (33)
According to general procedure 0.35 g of 23 (0.49 mmol)
afforded 33 (0.36 g, 92%).
IR (KBr) 3427, 2975, 2932, 2877, 2854, 1739, 1628,
1524, 1462, 1375, 1342, 1243, 1175, 1112, 1060, 958,
917, 830, 768, 707, 669 cmꢀ1; MS (ES) 796.28 (M+H+).

ˇ
Z. M. Istuk et al. / Bioorg. Med. Chem. 15 (2007) 4498–4510
4509
4.34. 3-Decladinosyl-9-deoxo-9-dihydro-9a-[N0-(2,4-dichlor-
phenyl)carbamoyl]-9a-aza-9a-homoerythromycin A 3,6-cyclic
ether (32)
IR (KBr) 3452, 2981, 2941, 1748, 1731, 1662, 1582,
1516, 1459, 137, 1298, 1261, 1243, 1165, 1098, 1052,
1
985, 906, 867, 810, 764, 666, 625, 587 cmꢀ1; H NMR
(300 MHz, CDCl3) d 8.12 (600-H), 7.34 (300-H), 7.18 (500-
H), 5.16 (13-H), 4.92 (3-H), 4.39 (10-H), 3.20 (5-H),
3.52 (50-H), 3.30 (6-OCH3), 3.18 (20-H), 2.61 (10-H),
2.50 (30-H), 2.27 (30-N(CH3)2), 2.04 (8-H), 1.93 (14a-
H), 1.68 (40a-H), 1.55 (4-H), 1.52 (14b-H), 1.35 (6-
CH3), 1.29 (2-CH3), 1.26 (40b-H), 1.25 (10-CH3), 1.25
(50-CH3), 1.13 (12-CH3), 1.04 (4-CH3), 0.97 (8-CH3),
0.89 (15-CH3); 13C NMR (75 MHz, CDCl3) d 176.3 (1-
C), 156.0 (9a-NCONH), 146.8 (2-C), 127.7 (3-C), 134.8
(100-C), 128.3 (300-C), 127.5 (500-C), 127.0 (200-C), 122.8
(400-C), 122.1 (600-C), 106.9 (10-C), 86.3 (5-C), 79.1 (6-
C), 76.1 (13-C), 73.4 (11-C), 73.5 (12-C), 70.7 (20-C),
69.9 (50-C), 65.7 (30-C), 50.0 (6-O-CH3), 40.3 (30N-
(CH3)2), 40.7 (4-C), 35.4 (7-C), 28.3 (40-H), 28.2 (8-C),
22.4 (14-C), 21.3 (50-CH3), 20.6 (8-CH3), 16.9 (21-
CH3), 14.2 (2-CH3), 12.8 (20-CH3), 11.4 (15-CH3), 7.6
(4-CH3); MS (ES) 760.70 (M+H+); HRMS (ES) calcd
for C37H59Cl2N3O9 (M+H+) 760.3707, found 760.3677.
According to general procedure 1.50 g of 30 (1.69 mmol)
afforded 32 (0.27 g, 21%) as a white solid, mp 88–95 ꢁC.
IR (KBr) 3448, 2971, 2936, 2875, 2782, 1736, 1670, 1579,
1510, 1460, 1383, 1327, 1299, 1260, 1177, 1142, 1115,
1099, 1072, 1047, 961, 890, 861, 829, 763, 670,
1
630 cmꢀ1; H NMR (300 MHz, CDCl3) d 8.17 (600-H),
7.32 (300-H), 7.18 (500-H), 4.91 (13-H), 4.23 (9a-NC0N0H),
4.20 (10-H), 3.88 (11-H), 3.56 (5-H), 3.51 (50-H), 3.18 (20-
H), 2.59 (2-H), 2.52 (30-H), 2.29 (30-N(CH3)2), 2.18 (8-H),
2.06 (4-H), 1.84 (14-Ha), 1.71 (14-Hb), 1.69 (40-Ha), 1.63
(7-Ha), 1.44 (40-Hb), 1.28 (10-CH3), 1.27 (7-Hb), 1.25 (6-
CH3), 1.23 (4-CH3), 1.21 (50-CH3), 1.20 (2-CH3), 1.13
(12-CH3), 1.06 (8-CH3), 0.89 (15-CH3); 13C NMR
(75 MHz, CDCl3) d 176.1 (1-C), 154.2 (9a-NCONH),
134.4 (100-C), 127.6 (300-C), 127.1 (500-C), 126.4 (200-C),
122.1 (400-C), 121.2 (600-C), 104.3 (10-C), 93.4 (5-C), 83.3
(11-C), 83.2 (6-C), 82.8 (3-C), 79.1 (13-C), 74.9 (12-C),
69.1 (50-C), 69.0 (20-C), 64.9 (30-C), 45.7 (2-C), 45.2 (4-
C), 40.1 (7-C), 39.7 (30N-(CH3)2), 30.0 (40-C), 29.2 (8-
C), 21.2 (14-C), 21.0 (50-CH3), 22.7 (6-CH3), 20.9 (8-
CH3), 12.6 (4-CH3), 17.0 (12-CH3), 12.8 (10-CH3), 13.7
(2-CH3), 10.4 (15-CH3); MS (ES) 746.02 (M+H+);
HRMS (ES) calcd for C36H57Cl2N3O9 (M+H+)
746.3550, found 746.3538.
4.37. 3-Decladinosyl-3-O-(4-nitrophenyl)acyl-9-deoxo-9-
dihydro-9a-(N0-isopropylcarbamoyl)-9a-aza-9a-homoery-
thromycin A (37)
To a solution of 4-nitrophenylacetic acid (0.85 g,
1.81 mmol) in dry CH2Cl2 (25 ml), TEA (0.65 ml,
4.68 mmol) was added and the reaction mixture was
cooled to 5 ꢁC. Pivaloyl chloride (0.57 ml, 4.68 mmol)
was then added and the reaction mixture stirred for
30 min. To the reaction mixture pyridine (1.27 ml,
15.70 mmol) and the solution of 21 (1.00 g, 1.42 mmol)
in dry CH2Cl2 (5 ml) were added and the reaction mix-
ture stirred at room temperature for 20 h. Saturated
aqueous NaHCO3 solution (30 ml) was added and the
layers were separated. The aqueous layer was extracted
two more times with CH2Cl2. Combined organic ex-
tracts were rinsed with brine, dried over K2CO3, and
evaporated yielding 1.43 g of oily product which was
dissolved in MeOH (50 ml) and stirred for 24 h at room
temperature. The solvent was evaporated and the crude
product purified by chromatography on a silica gel col-
umn using CH2Cl2:MeOH:NH4OH (90:3:0.3) as an elu-
ent to afford 37 (0.45 g, 38%) as a white solid, mp 112–
120 ꢁC.
4.35. 2,3-Anhydro-3-decladinosyl-6-O-methyl-9-deoxo-9-
dihydro-9a-(N0-isopropylcarbamoyl)-9a-aza-9a-homoery-
thromycin A (35)
According to general procedure 0.5 g of 33 (0.62 mmol)
afforded 35 (0.1 g, 20%) as a white solid, mp 100–105 ꢁC.
IR (KBr) 3439, 2974, 2937, 1735, 1628, 1520, 1459, 1381,
1336, 1270, 1175, 1111, 1075, 1051, 958, 919, 832, 766,
1
535 cmꢀ1; H NMR (300 MHz, CDCl3) d 5.16 (13-H),
4.93 (3-H), 4.56 (10-H), 3.90 (100-H), 3.23 (5-H), 3.53 (50-
H), 3.27 (20-H), 3.12 (6-OCH3), 2.70 (30-H), 2.36 (30-
N(CH3)2,), 1.52 (4-H), 1.91 (14a-H), 2.05 (8-H), 1.70
(40a-H), 1.49 (14b-H), 1.36 (18-CH3), 1.30 (16-CH3),
1.25 (20-CH3), 1.25 (50-CH3), 1.25 (40b-H), 1.15 (100-
(CH3)2), 1.12 (21-CH3), 1.06 (17-CH3), 0.96 (19-CH3),
0.88 (15-CH3); 13C NMR (75 MHz, CDCl3) d 173.2 (1-
C), 158.1 (9a-NCONH), 146.4 (2-C), 127.4 (3-C), 106.7
(10-C), 86.1 (5-C), 79.5 (6-C), 74.2 (11-C), 75.0 (12-C),
70.7 (20-C), 68.3 (50-C), 65.9 (30-C), 50.7 (6-OCH3), 42.8
(100-C), 39.0 (30N-(CH3)2), 40.4 (4-C), 29.1 (40-C), 28.4
(8-C), 23.4 (18-CH3), 22.3 (14-C), 22.1 (100-(CH3)2), 20.9
(50-CH3), 20.5 (19-CH3), 16.8 (21-CH3), 14.2 (16-CH3),
12.5 (20-CH3), 11.4 (15-CH3), 8.8 (17-CH3); MS (ES)
658.22 (M+H+); HRMS (ES) calcd for C34H63N3O9
(M+H+) 658.4642, found 658.4654.
IR (KBr) 3449, 2975, 2939, 2877, 2791, 1741, 1626,
1604, 1523, 1459, 1382, 1347, 1255, 1167, 1111, 1075,
1051, 1032, 984, 959, 856, 767, 728, 687 cmꢀ1 1H
;
NMR (300 MHz, CDCl3) d 8.21 (4000-H, 6000-H), 7,54
(3000-H, 7000-H), 5.43 (3-H), 5.06 (13-H), 4.42 (9a-
NCON0H), 4.23 (10-H), 3.92 (1000-H), 3.60 (5-H), 3.49
(50-H), 3.26 (20-H), 2.68 (2-H), 2.45 (30-H), 2.29 (30-
N(CH3)2), 2.20 (8-H), 1.95 (14-Ha), 1.90 (4-H), 1.66
(40-Ha), 1.50 (14-Hb), 1.32 (6-CH3), 1.26 (40-Hb), 1.29
(10-CH3), 1.22 (50-CH3), 1.17 (12-CH3), 1.05 (4-CH3),
0.95 (2-CH3), 1.15 (100-(CH3)2), 1.08 (8-CH3), 0.87 (15-
CH3); 13C NMR (75 MHz, CDCl3) d 174.7 (1-C),
169.9 (100-CO), 158.7 (9a-NCONH), 147.1 (5000-C),
141.5 (2000-C), 130.5 (3000-C, 7000-C), 123.6 (2000-C, 6000-C),
103.4 (10-C), 88.3 (5-C), 78.1 (13-C), 74.5 (3-C), 74.2
(6-C), 70.4 (20-C), 69.8 (50-C), 65.4 (30-C), 44.6 (2-C),
4.36. 2,3-Anhydro-3-decladinosyl-6-O-methyl-9-deoxo-9-
dihydro-9a-[N0-(2,4-dichlorphenyl)carbamoyl]-9a-aza-9a-
homoerythromycin A (36)
According to general procedure 1.00 g of 34 (1.11 mmol)
afforded 36 (0.024 g, 2.8%) as a white solid, mp 94–99 ꢁC.

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Z. M. Istuk et al. / Bioorg. Med. Chem. 15 (2007) 4498–4510
4510
41.3 (1000-C), 38.4 (4-C), 48.7 (100-C), 41.3 (7-C), 40.2 (30-
N(CH3)2), 28.7 (40-C), 27.8 (8-C), 27.4 (6-CH3), 23.2 (100-
(CH3)2), 21.7 (14-C), 20.7 (8-CH3), 20.8 (50-CH3), 16.9
(12-CH3), 15.2 (2-CH3), 12.5 (10-CH3), 11.0 (15-CH3),
8.9 (4-CH3); MS (ES) 825 (M+H+); HRMS (ES) calcd
for C41H68N4O13 (M+H+) 825.4861, found 825.4847.
Activity against S. cerevisiae was used as a test for tox-
icity toward eukaryote cells. MIC values were deter-
mined using microdilution test in Mueller–Hinton
media. Test compound was dissolved in DMF (5 mg/
ml). Concentration of substances in media was from 64
to 0.125 lg/ml. After 24 h incubation at 37 ꢁC optical
density was determined by measuring absorbance at
600 nm. MIC value is determined as a concentration at
which inhibition of bacterial growth is 90%.
4.38. 3-Decladinosyl-3-O-(4-nitrophenyl)acyl-9-deoxo-9-
dihydro-9a-[N0-(2,4-dichlorphenyl)carbamoyl]-9a-aza-9a-
homoerythromycin A (38)
To a solution of 4-nitrophenylacetic acid (0.74 g,
4.09 mmol) in dry CH2Cl2 (25 ml), TEA (0.57 ml,
4.09 mmol) was added and the reaction mixture was
cooled to 5 ꢁC. Pivaloyl chloride (0.50 ml, 4.09 mmol)
was then added and the reaction mixture stirred for
30 min. To the reaction mixture pyridine (1.1 ml,
13.60 mmol) and the solution of 22 (1.00 g, 1.23 mmol)
in dry CH2Cl2 (5 ml) were added, and the reaction mix-
ture stirred at room temperature for 20 h. Saturated
aqueous NaHCO3 solution (30 ml) was added and the
layers were separated. The aqueous layer was extracted
two more times with CH2Cl2. Combined organic ex-
tracts were rinsed with brine, dried over K2CO3, and
evaporated yielding 1.14 g of oily product which was
dissolved in MeOH (50 ml) and stirred for 24 h at room
temperature. The solvent was evaporated and the crude
product purified by chromatography on a silica gel col-
umn using CH2Cl2:MeOH:NH4OH (90:3:0.3) as an elu-
ent to afford 38 (0.52 g, 45%) as a white solid, mp 118–
125 ꢁC.
Acknowledgements
We thank G. Kobrehel and G. Lazarevski for valuable
discussions and contributions.
References and notes
1. (a) Schoenfeld, W. In Macrolide Antibiotics; Kirst, H. A.,
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ˇ
9. Kujundzˇic, N.; Kobrehel, G.; Banic, Z.; Kelneric, Z.;
IR (KBr) 3448, 2975, 2938, 2879, 2789, 1741, 1665,
1607, 1578, 1522, 1459, 1382, 1347, 1298, 1256, 1229,
1165, 1110, 1074, 1050, 983, 958, 857, 821, 731, 685,
ˇ
´
1
669 cmꢀ1; H NMR (300 MHz, CDCl3) d 8.18 (4000-H,
6000-H), 8.13 (600-H), 7.51 (3000-H, 7000-H), 7,32 (300-H),
7.18 (500-H), 5.36 (3-H), 5.03 (13-H), 4.42 (9a-NCON0H),
4.23 (10-H), 3.80 (1000-H), 3.69 (5-H), 3.49 (50-H), 3.25 (20-
H), 2.68 (2-H), 2.45 (30-H), 2.32 (30-N(CH3)2), 2.29 (8-
H), 1.92 (14-Ha), 1.92 (4-H), 1.66 (40-Ha), 1.58 (7-Ha),
1.51 (14-Hb), 1.38 (10-CH3), 1.32 (6-CH3), 1.26 (7-
Hb), 1.18 (40-Hb), 1.24 (12-CH3), 1.16 (50-CH3), 1.07
(8-CH3), 0.95 (2-CH3), 0.94 (4-CH3), 0.85 (15-CH3);
13C NMR (75 MHz, CDCl3) d 174.9 (1-C), 169.9 (100-
CO), 154.9 (9a-NCONH), 147.2 (5000-C), 141,3 (2000-C),
134.8 (100-C), 130.6 (3000-C, 7000-C), 128.5 (300-C), 127.4
(200-C, 500-C), 123.7 (2000-C, 6000-C), 122.6 (400-C), 122.2
(600-C), 103.9 (10-C), 88.3 (5-C), 77.6 (13-C), 74.3 (3-C),
74.2 (6-C), 70.5 (20-C), 69.8 (50-C), 65.5 (30-C), 47.3 (4-
C), 44.6 (2-C), 41.2 (1000-C), 41.2 (7-C), 40.5 (30-
N(CH3)2), 29.1 (40-C), 27.5 (8-C), 27.4 (6-CH3), 22.0
(14-C), 21.1 (50-CH3), 21.0 (8-CH3), 12.3 (12-CH3),
13.1 (10-CH3), 11.2 (15-CH3), 3.2 (4-CH3); MS (ES)
927.2 (M+H+); HRMS (ES) calcd for C44H64Cl2N4O13
(M+H+) 927.3925, found 927.3921.
´
´
´
´
´
Kojic-Prodic, B. Eur. J. Med. Chem. 1995, 30, 455.
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4.39. Antibacterial activity
MIC was determined for all new compounds on a panel
of macrolide susceptible Gram-positive (S. aureus, S.
pneumoniae, S. pyogenes) and Gram-negative (E. coli,
E. fecalis, H. influenzae, M. catarrhalis) bacterial strains.