Novel Erythromycin Derivatives with aryl Groups Tethered to the C-6 Position Are Potent Protein Synthesis Inhibitors and Active against Multidrug-Resistant Respiratory Pathogens

Article abstract of DOI:10.1021/jm0102349

A novel series of erythromycin derivatives has been discovered with potent activity against key respiratory pathogens, including those resistant to erythromycin. These compounds are characterized by having an aryl group tethered to the C-6 position of the

Full text of DOI:10.1021/jm0102349

J . Med. Chem. 2001, 44, 4137-4156
4137
Novel Er yth r om ycin Der iva tives w ith Ar yl Gr ou p s Teth er ed to th e C-6 P osition
Ar e P oten t P r otein Syn th esis In h ibitor s a n d Active a ga in st Mu ltid r u g-Resista n t
Resp ir a tor y P a th ogen s
Zhenkun Ma,* Richard F. Clark, Antony Brazzale, Sanyi Wang, Michael J . Rupp, Leping Li,
George Griesgraber, Suoming Zhang, Hong Yong, Ly Tam Phan, Peter A. Nemoto, Daniel T. W. Chu,
J acob J . Plattner, Xiaolin Zhang, Ping Zhong, Zhensheng Cao, Angela M. Nilius, Virginia D. Shortridge,
Robert Flamm, Michael Mitten, J on Meulbroek, Patty Ewing, J eff Alder, and Yat Sun Or
Infectious Disease Research, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064-3537
Received May 25, 2001
A novel series of erythromycin derivatives has been discovered with potent activity against
key respiratory pathogens, including those resistant to erythromycin. These compounds are
characterized by having an aryl group tethered to the C-6 position of the erythronolide skeleton.
Extensive structural modification of the C-6 moiety led to the discovery of several promising
compounds with potent activity against both mef- and erm-mediated resistant Streptoccoccus
pneumoniae. Preliminary mechanistic studies indicated that the new macrolides are potent
protein synthesis inhibitors, which interact with methylated ribosomes isolated from resistant
organisms. In experimental animal models, these compounds exhibited excellent in vivo efficacy
and balanced pharmacokinetic profiles.
In tr od u ction
The growing prevalence of antibiotic resistance in
bacterial species commonly involved in respiratory tract
infections has become a serious clinical problem.1 Strep-
toccoccus pneumoniae is one of the most common and
also the most problematic respiratory pathogen. Ac-
cording to a surveillance study conducted between 1997
and 1998 in the United States, 29.5% of S. pneumoniae
isolates were intermediately or highly resistant to
penicillin, which represented a sharp increase from the
1980s, when less than 4% of these species were consid-
ered penicillin-resistant.2 Meanwhile, resistance to other
commonly prescribed antibiotics, such as macrolides,
cephalosporins, and tetracycline, has also been rising.
Studies indicated that the penicillin-resistant species
tends to be resistant to other antibiotics, which has led
to a serious multidrug resistance problem.2,3 If the
current trend continues, many of the commonly used
antibiotics will soon lose their effectiveness.
Addressing bacterial resistance problems requires a
more judicious use of the available antibiotics as well
as the development of new agents that are effective
against resistant organisms. In a previous communica-
tion, we disclosed the discovery of a novel series of C-6-
modified erythromycin derivatives highly active against
the resistant respiratory pathogens.4 Since then the
work has been continued and the series has been
extensively characterized. In this report, we wish to give
a full account of the design rationale, chemical synthe-
sis, mechanism of action, and structure-activity rela-
tionships of this novel macrolide series.
against all key respiratory pathogens. They possess
excellent safety and tolerability profiles and are widely
prescribed to children as well as adults for the treatment
Design Ra tion a le
Macrolide antibiotics, such as erythromycin (1),
clarithromycin, and azithromycin, provide good coverage
of upper and lower respiratory tract infections.5 The new
agents need to preserve all of the desirable features of
the earlier generation of macrolides, and in addition
they must be active against bacteria with the major
resistant mechanisms.
* Corresponding author: Abbott Laboratories, D47N, AP52N, 200
Abbott Park Rd., Abbott Park, IL 60064-3537. Tel 847-937-7015; fax
847-938-3403; e-mail zhenkun.ma@abbott.com.
10.1021/jm0102349 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/18/2001

4138 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Ma et al.
Two distinguished mechanisms have accounted for
the majority of macrolide resistance.6,7 The first mech-
anism involves methylation of the target ribosome by a
ribosomal methylase (Erm) encoded by erm genes.
Dimethylation of a specific adenine group (2058 adenine
based on Escherichia coli sequence) of the 23S ribosomal
RNA prevents the binding of macrolides and confers a
high level of resistance to macrolides, lincosamides, and
type B streptogramin (MLSB). The expression of Erm
may be inducible or constitutive. The second mechanism
of macrolide resistance is efflux encoded by mef genes,
which removes macrolides from intracellular space and
prevents macrolides from reaching the target. Our task,
therefore, was to identify a macrolide structure that
could bind to methylated ribosomes and avoid the efflux
protein recognition.
Since the late 1980s, a significant amount of work has
been done in order to develop a new generation of
macrolides to overcome bacterial resistance.5,8 The
structure-activity relationships developed during this
period have therefore provided a foundation for the
design of a more advanced generation of macrolide
agents. In 1989, two series of erythromycin derivatives,
aryl-substituted 11,12-carbamate macrolides exempli-
fied by 2 and C-4′′-modified 11,12-carbonate macrolides
exemplified by 3, were reported.9 Both series showed
activity against MLSB-resistant Streptococcus pyogenes.
Structure-activity relationship analysis indicated that
the aryl groups attached to the 11,12-carbamate nitro-
gen were essential for the activity against resistance.
Following these leads, a series of aryl-substituted 11,-
12-carbamate ketolides exemplified by RU-004 (4) was
prepared by removing the cladinose from the C-3
position and converting the remaining hydroxy group
to a carbonyl functionality. These compounds were
reported to be active against efflux and MLSB-resistant
organisms. The aryl groups attached to the 11,12-
carbamate nitrogen were shown to be critical pharma-
cophores for activity against MLSB resistance.10 At
about the same time, a series of tricyclic ketolides
exemplified by TE-802 (5) was reported.11 The tricyclic
ketolides, which lacked an aryl group, exhibited good
activity against efflux resistance but failed to show any
activity against MLSB-resistant organisms. With this
information in hand, we postulated that the aryl group
tethered to the macrolide skeleton is crucial for activity
against MLSB resistance and the C-3 keto group is
important for the improved activity against efflux
resistance. Since 1995, several new macrolide series,
including anhydrolides 6,12 acylides 7,13 and erythro-
mycylamine C-4′′-carbamates, exemplified by CP-544372
(8),14 have been reported and provided further support
to this hypothesis. In addition, results from these newer
series further suggested that structural modifications
other than introducing a keto group at the C-3 position
could also improve activity against efflux resistance.
with the assumption that an aryl group attached to this
position would provide a favorable conformation for
ribosomal binding. The conformations of 14-membered
ring macrolides have been the subject of many studies.15
The crystal structure of erythromycin was first reported
in 1965, which indicated that the erythronolide adopts
the Perun conformation derived from an alternative
diamond lattice.16 Recent studies suggested that the
ketolide skeleton possesses a similar conformation to
the erythronolide as indicated by X-ray crystal struc-
tures and solution conformations generated from NMR
data.10,17 Both the erythronolide and ketolide skeletons
are rigid and the solution conformations are similar to
their crystal structures.15,17,18 Conformational analysis
revealed a very important bifacial feature common to
most 14-membered ring macrolides, which is the lipo-
philicity difference between the two sides of the lactone
ring. As indicated by the crystal structure of 6-O-
methylerythromycin (clarithromycin) (Figure 1), all of
the oxygen-containing groups attached to the lactone
ring point to the front side and the majority of methyl
groups attached to the lactone ring point to the back
side of the molecule, creating a hydrophilic face and a
lipophilic face. We believed that this bifacial nature of
macrolide molecules is very important for many of their
biological functions, including interaction with ribosome,
membrane permeability, and tissue distribution. The
crystal structure of RU-004 (4) revealed that the aryl
On the basis of the above considerations, we designed
a novel structural series that consists of the essential
features for addressing macrolide resistance due to both
efflux and methylation of the ribosome. The designed
structure contains an aryl group tethered to the C-6
position for overcoming the MLSB resistance and a
carbonyl group at the C-3 position for surmounting the
efflux resistance. The C-6 linking point was selected
F igu r e 1. Crystal structure of 6-O-methylerythromycin.

Erythromycin Derivatives with C-6 Aryl Groups
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4139
moiety attached to the carbamate nitrogen is localized
on the hydrophilic face of the molecule, suggesting that
a potential secondary interaction may exist on the
hydrophilic side. According to the X-ray crystal struc-
ture of clarithromycin (Figure 1), the C-6 hydroxyl group
is localized in the middle of the hydrophilic face. It was
apparent to us that an aryl group tethered to this
position would adopt a conformation that delivers the
aryl group to a spatial position similar to that of the
aryl group in RU-004. In addition, the C-6 linkage was
likely to provide a more rigid structure with less
conformational flexibility, which could translate into a
better binding affinity and improved antibacterial activ-
ity (Figure 1).
realized that the extensive loss of allyl bromide due to
rapid reaction with KOH was likely responsible for the
retarded 6-O-allylation. To overcome this problem, we
replaced KOH with potassium tert-butoxide (KOBut), a
sterically hindered base, in order to slow the undesired
side reaction. Indeed, this modification brought the
reaction to more than 90% completion and provided the
6-O-allyl intermediate 10 in good yield. Sequential
deprotection of TMS and ketal groups followed by
deoximation19 provided 6-O-allylerythromycin (11) in
33% overall yield from 9.
The C-3 keto group was introduced in three steps from
11 (Scheme 2). Selective hydrolysis of the cladinose
sugar provided the C-3 hydroxyl compound. The C-2′
hydroxyl group was sequentially protected as the ben-
zoate ester. Finally, Corey-Kim oxidation20 of the C-3
Syn th esis
In tr od u ction of C-6 Su bstitu en ts. The synthesis
of 6-O-allylerythromycin (11) has been described in a
previous communication.4c Detailed synthetic proce-
dures for these transformations are provided in the
Experimental Section. As shown in Scheme 1, erythro-
Sch em e 2. Synthesis of 6-O-Substituted Ketolide
Derivativesa
Sch em e 1. Synthesis of 6-O-Substituted Erythromycin
Derivativesa
a
(a) Allyl bromide, KOBut, DMSO-THF. (b) (i) HOAc, H2O-
CH3CN; (ii) NaHSO3/HCO2H, EtOH-H2O. Yield 33% in three
steps from 9. (c) Ar-X (X ) Br or I), Pd(OAc)2, P(o-tolyl)3, Et3N,
CH3CN. Yield 60-80%.
a
(a) (i) HCl, EtOH; (ii) Bz2O, Et3N, CH2Cl2; (iii) NCS, Me2S,
Et3N, CH2Cl2. Yield 77% in three steps. (b) Ar-X (X ) Br or I),
Pd(OAc) , P(o-tolyl) , Et3N, CH3CN. Yield 60-80%. (c) H2, Pd-
2
3
mycin A was first protected as its 9-ketaloxime-2′,4′′-
bis(trimethylsilyl) derivative 9, which has been used for
the selective methylation of the C-6 hydroxyl group in
the synthesis of clarithromycin.19 Allylation of 9 with
allyl bromide in the presence of potassium hydroxide
(KOH) provided the 6-O-allyl product selectively but
with relatively low conversion of starting material.
Optimization of the reaction conditions brought the
reaction to only 50-60% conversion. Several other bases
such as potassium methoxide (KOMe), sodium hydride
(NaH), and lithium diisopropylamide (LDA) were ex-
plored without further improvement over KOH. We
C, MeOH. Yield 99%. (d) (i) O3, CH2Cl2, and then Me2S; (ii) PPh3,
THF. Yield 52% in two steps. (e) R-NH2, HOAc, NaBH3CN, MeOH.
Yield 50-70%.
hydroxyl group with N-chlorosuccinimide (NCS) and
dimethyl sulfide (Me2S) provided ketolide 13 in 77%
overall yield from 11. Deprotection of 13 under mild
conditions provided the 6-O-allyl ketolide 14.
The next task was to introduce an anchor group to
the C-6 side chain on the basis of the rationale discussed
previously. We decided to explore a direct carbon-
carbon bond formation strategy that could lead to a

4140 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Ma et al.
series of ketolides with an anchor group attached to the
C-6 position through a three-carbon spacer. Heck cou-
pling of 13 with aryl halides was thus employed.21
Under commonly employed Heck coupling conditions
[Ar-X/Pa(OAc)2/n-Bu4N+Cl-/NaHCO3/DMF at 80 °C for
12 h], none of the desired product 15 (Ar ) Ph) was
obtained. The major product isolated from this reaction
was 20 (30-40%), a coupling product resulted from
desosamine elimination and 9,12-enol ether formation.
A change of solvent from DMF to N-methyl-2-pyrroli-
done (NMP) prevented the 9,12-enol ether formation but
gave desosamine elimination product 21 in 66% yield.
propenyl) ketolides 16. Under optimized Heck condi-
tions, a series of 6-O-substituted ketolides with a variety
of aryl groups tethered to the C-6 position was prepared
(Chart 1). 6-O-Phenylpropyl ketolide 17, a derivative
with a saturated linker between the aryl group and the
lactone ring, was prepared by catalytic hydrogenation
of 16. For comparison purposes, 6-O-(3-aryl-2-propenyl)-
erythromycin derivatives 12 (Ar ) Ph, 3-quinolyl) were
also prepared from 11 by utilizing the optimized cou-
pling conditions (Scheme 1).
From 6-O-allyl ketolide 14, another series of ketolide
analogues 19 was prepared through the aldehyde in-
termediate 18. Ozonolysis of ketolide 13 gave a mixture
of products and no appreciable amount of the desired
aldehyde was obtained. However, ozonolysis of 14, the
C-2′-deprotected ketolide, provided the 6-O-formyl-
methyl ketolide as the N-oxide. The desired aldehyde
18 was obtained in 52% yield from 14 after the N-oxide
was reduced with PPh3 in THF. Reductive amination
of 18 provided a series of amino derivatives 19 with a
variety of R groups attached to the C-6 position through
a nitrogen-containing linker (Chart 2).
When toluene was used as solvent and triethylamine
as base [PhI/Pa(OAc)2/PPh3/Et3N/toluene], about 20%
of desired coupling product 15 was isolated. The major
material recovered was the starting material 13. How-
ever, the reaction went to completion when acetonitrile
(CH3CN) was used as solvent and provided 15 (Ar )
Ph) in 68% isolated yield. More reproducible results
were obtained when tri(o-tolyl)phosphine [P(o-tolyl)3]
was employed replacing triphenylphosphine (PPh3) as
ligand. Tri(o-tolyl)phosphine is known to form a stable
palladium(0) complex and therefore prevent the decom-
position of catalyst.22 Deprotection of the coupling
products under mild conditions provided 6-O-(3-aryl-2-
Ch a r t 2. Structures of R Groups
Syn th esis of 11,12-Ca r ba m a te Der iva tives. Baker
et al.9 reported that introduction of a cyclic carbonate
or cyclic carbamate group to the 11,12-position of
clarithromycin enhanced the antibacterial activity. In
an analogous fashion, we converted 6-O-allylerythro-
mycin (11) to the corresponding cyclic carbamate 23
(Scheme 3). After proper protection, 11 was converted
to the 12-O-acylimidazolide 22 in the presence of sodium
bis(trimethylsilyl)amide (NaHMDS) and 1,1′-carbonyl-
diimidazole (CDI). Treatment of 22 with aqueous am-
monia in acetonitrile (CH3CN) provided carbamate 23
and its C-10 epimer in a 10:1 ratio. The deprotected 6-O-
allylerythromycin-11,12-carbamate 24 was prepared in
four steps from 11 by following a sequence similar to a
published process.9 For comparison purposes, the 6-O-
(3-aryl-2-propenyl)erythromycin-11,12-carbamate 25 was
prepared from 23 by Heck coupling followed by hydroly-
sis.
Ch a r t 1. Structures of Aryl (Ar) Groups
The 11,12-carbamate ketolide 26 was prepared from
23 in two steps, which involved hydrolysis of the
cladinose and Corey-Kim oxidation of the C-3 hydroxyl
group. Deprotection of the acetate protecting group with
MeOH at room temperature provided 6-O-allyl ketolide-
11,12-carbamate 27 in excellent yield.
Alternatively, the 2′-O-benzoyl-6-O-allyl ketolide-11,-
12-carbamate 29 was prepared from 13 in two steps
through 12-O-acylimidazolide 28, which was obtained
by treatment of 13 with lithium hydride (LiH) and CDI
(Scheme 4). Reaction of 28 with aqueous ammonia
provided the 11,12-cyclic carbamate 29 and its C-10

Erythromycin Derivatives with C-6 Aryl Groups
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4141
Sch em e 3. Synthesis of
Sch em e 4. Synthesis of
6-O-Substituted-11,12-Carbamate Derivativesa
6-O-Substituted-11,12-Carbamate Ketolidesa
a
(a) (i) Ac2O, Et3N, DMAP, CH2Cl2; (ii) CDI, NaHMDS, THF-
DMF. (b) NH4OH (28%), CH3CN-THF. Yield 78% in three steps
from 11. (c) (i) Ethylene carbonate, Et3N; (ii) (TMS)2NH, CH3CN-
CH2Cl2-THF; (iii) CDI, NaH, THF; (iv) NH3, CH3CN. Yield 65%
in four steps from 11. (d) (i) Ar-X (X ) Br or I), Pd(OAc)2, P(o-
tolyl)3, Et3N, CH3CN, yield 60-80%; (ii) NaOH, MeOH, yield 61%.
(e) (i) HCl, EtOH-H2O; (ii) NCS, Me2S, and then Et3N, CH2Cl2.
Yield 84%.
epimer 30 in 51% and 32% yields, respectively. Epimer
30 was converted to the natural configuration by reac-
tion with acetic acid in ethanol. When 12-O-acylimid-
azolide 28 was treated with hydrazine, the 11,12-
carbazate 31 was obtained. In an analogous fashion, the
N-methoxy derivative 32 was obtained by reacting 28
with O-methylhydroxylamine. Alternately, when 28 was
treated with a variety of primary amines, a series of
N-substituted analogues 33 and 34 were obtained.
Finally, reaction of 28 with ethylenediamine resulted
in the formation of a tricyclic ketolide 39, after epimer-
ization under HOAc/MeOH conditions.
The carbamate ketolide intermediates 31-34 were
further derivatized by using the optimized Heck condi-
tions and provided coupling products 35-38 (Scheme
4). Similarly, tricyclic intermediate 39 was converted
to the 6-O-(3-aryl-2-propenyl) tricyclic ketolide 40.
Preliminary SAR studies suggested that ketolides
with an unsubstituted 11,12-carbamate group provided
the best antibacterial spectrum and activity. Therefore,
we focused our further efforts on modifications of the
a
(a) LiH, CDI, THF. Yield 68%. (b) NH4OH, CH3CN-H2O. Yield
for 29, 51%; for 30, 32%. (c) R-NH2 (R ) -NH2, -OMe, -Me,
-CH2CH2NMe2), CH3CN-H2O. Yield 50-80%. (d) Ar-X (X ) Br
or I), Pd(OAc)2, P(o-tolyl)3, Et3N, CH3CN 20-40%. (e) (i) H2NCH2-
CH2NH2, CH3CN; (ii) HOAc, MeOH. Yield 40%. (f) 3-Bromoquino-
line, Pd(OAc)2, P(o-tolyl)3, Et3N, CH3CN. Yield 62%.
C-6 allyl group of structure 27. The protected 6-O-allyl
ketolide-11,12-carbamates 26 and 29 were thus em-
ployed as key intermediates for such modifications
(Scheme 5). When 26 or 29 reacted with various aryl
halides under the optimized Heck conditions, a series
of 6-O-(3-aryl-2-propenyl) ketolide-11,12-carbamates 41
was obtained (Chart 1). To study the effects of the aryl
group orientation, nine positional isomers of quinoline
and isoquinoline were prepared by coupling the corre-
sponding aryl bromide, chloride, or triflate to the allylic
double bond. Various substituted 3-quinolyl derivatives
were also synthesized to study the substituent effects.
6-O-Arylpropyl ketolides 42, the saturated analogues of

4142 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Ma et al.
Sch em e 5. Synthesis of
strain with a high level of MLSB resistance. DNA
plasmid containing a pneumococcal ami promoter and
a luciferase reporter gene was constructed at Abbott
Laboratories. The reaction mixture contained 1 µg of
plasmid, 0.15 unit of S-30 extract, 0.2 mM complete
amino acid mix, and 5 µL of premix solution in a final
volume of 15 µL. The reaction was then mixed with 75
µL of luciferin reagent containing ATP and immediately
read on a Wallac Trilux Luminescence counter.
In Vitr o An tiba cter ia l Activity. The 6-O-substi-
tuted macrolides and ketolides used in this study and
the reference agent, erythromycin, were tested against
a panel of representative respiratory pathogens selected
from the Abbott clinical culture collection. Various
macrolide- and multidrug-resistant isolates were in-
cluded in the tests in order to identify potential ana-
logues that could overcome resistance. The phenotype
and the genotype of these resistant strains were char-
acterized by methods described previously (Table 1).24
The in vitro antibacterial activity is reported as the
minimum inhibitory concentrations (MICs), which were
determined by the agar dilution method as recom-
mended by the National Committee for Clinical Labora-
tory Standards.
6-O-Substituted-11,12-Carbamate Ketolidesa
In Vivo Effica cy. The in vivo efficacy of selected
compounds was assessed by mouse protection tests
(MPT) and rat lung infection models (RLI). In the mouse
protection tests, the mice were inoculated intravenously
with a 100-fold LD50 of representative organisms. Tested
compounds were administered by oral gavage at 1 h and
5 h postinoculation. Mortality rates of the mice were
monitored for a period of 7 days postinoculation with a
100% mortality rate for untreated controls. The efficacy
of each compound, based on the survival rates over a
dose range, was reported as the drug dose resulting in
a survival of 50% of treated mice over the duration of
the trial (ED50).
a
(a) (i) Ar-X (X ) Br or I), Pd(OAc)2, P(o-tolyl)3, Et3N, CH3CN;
(ii) MeOH. Yield 9-97% in two steps. (b) H2, 10% Pd-C, MeOH.
Yield 95%. (c) CH2N2, Pd(OAc)2, CH2Cl2. Yield 64% (diastereomers
in 60:40 ratio). (d) (i) MeOH; (ii) O3, CH2Cl2, and then Me2S; (iii)
PPh3, THF. (e) R-NH2, HOAc, NaBH3CN, MeOH.
In the rat lung infection models, the rats were
intratracheally inoculated with 0.5 mL of bacteria
suspension in 5% gastric hog mucin containing log
106-108 colony-forming units (cfu). Test compounds
were administered by peroral gavage once daily, days
1-3, starting 18 h postinoculation. Lung bacterial
burden was assessed from serial dilution plating of lung
tissue homogenates on day 4. The ED50 to yield a 2-log
reduction in bacteria count compared to vehicle-treated
infected controls was calculated from the group means
by linear regression.
41, were obtained by catalytic hydrogenation. Cyclopro-
panation of 41 provided the cyclopropyl analogue 43 as
a mixture of diastereomers. As illustrated in Scheme
5, a series of amine-containing derivatives 45 were also
prepared through the aldehyde intermediate 44 by
following the procedure used to prepare compounds 19.
Micr obiology
In Vitr o Tr a n scr ip tion -Tr a n sla tion Assa y. The
bacterial ribosome S-30 extracts used in the cell-free
translation assays were prepared according to the
reported procedures.23 The wild-type ribosome was
isolated from an erythromycin-susceptible strain S.
pneumoniae 5635. The methylated ribosome was iso-
lated from S. pneumoniae 1813, an erm-containing
Resu lts a n d Discu ssion
Mech a n ism of Act ion of t h e 6-O-Su b st it u t ed
Ketolid es. Macrolides exert their antimicrobial activity
Ta ble 1. Selected Organisms and Their Resistant Determinants
strain
phenotype
genotype
Staphylococcus aureus
Staphylococcus aureus
Staphylococcus aureus
Streptococcus pyogenes
Streptococcus pyogenes
Streptococcus pyogenes
Streptococcus pneumoniae
Streptococcus pneumoniae
Streptococcus pneumoniae
Haemophilus influenzae
ATCC 6538P
A 5177
A 5278
EES 61
930
PIU 2548
ATCC 6303
5737
erythromycin-susceptible
MLS-resistant (inducible)
MLS-resistant (constitutive)
erythromycin-susceptible
MLS-resistant
none
ermA
ermA
none
ermB
mefA
none
ermB
mefE
BL+
efflux
erythromycin-susceptible
MLS-resistant
efflux
5649
DILL
ampicillin-resistant

Erythromycin Derivatives with C-6 Aryl Groups
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4143
Ta ble 2. Cell-Free Inhibiting Activity of Selected Compounds
on Transcription-Translation by Ribosomes Isolated from both
Susceptible and Resistant (erm) Strains
rolides erythromycin, clarithromycin, and azithromycin
showed no activity up to 128 µg/mL. In the cell-free
translation assay performed with methylated ribosomes
isolated from MLSB-resistant strains, the reference
macrolides showed no inhibitory effect, while ketolides
41g-41y exhibited substantially improved inhibitory
activity (Table 2). These data suggested that the ke-
tolides could interact with methylated ribosomes and
exert activity against MLSB-resistant organisms. The
data also suggested that the aryl group attached to the
C-6 position is the key structural feature for the
interaction with methylated ribosomes. Without the aryl
group attached, macrolide 11 and ketolide 27 showed
no inhibitory activity against methylated ribosomes. As
we have postulated previously, and which will be further
supported by our structure-activity relationship analy-
sis in the following sections, the aryl group tethered to
the C-6 position is likely responsible for a secondary
interaction between the ketolide and the ribosome.
Ery-S straina
MLSB-R strainb
MIC
T/T IC50
MIC
T/T IC50
compound
(µg/mL)
(µM)
(µg/mL)
(µM)
erythromycin
clarithromycin
azithromycin
11
0.06
0.03
0.25
0.06
1
0.004
0.004
0.015
0.015
0.12
0.09
0.17
0.15
0.35
0.07
0.04
0.10
0.08
>128
>128
>128
>128
>128
0.5
>500
>500
>500
>500
>500
150
27
41g
41s
41v
41y
0.25
0.25
0.25
28
25
40
a
Wild-type ribosomes for cell-free transcription/translation
assay (T/T) were isolated from erythromycin-susceptible strain S.
pneumoniae 5635. The whole-cell antibacterial activity is exempli-
fied by minimum inhibitory concentrations (MICs) against S.
pneumoniae ATCC 6303, an erythromycin-susceptible strain.
b Methylated ribosomes for cell-free transcription/translation assay
(T/T) were isolated from S. pneumoniae 1813, an MLSB-resistant
strain with a high level of methylation at 2058A position. The
whole-cell antibacterial activity is exemplified by minimum inhibi-
tory concentrations (MICs) against S. pneumoniae 5737, an MLSB-
resistant strain.
Recent studies have suggested that such a secondary
interaction may be present in domain II of the 23S
rRNA.25 Chemical footprinting of bound macrolide
revealed that the aryl-containing ketolides such as 4
protected the chemical modifications of two distinct
regions on 23S rRNA, one in domain V and the other in
domain II. Mutations in these regions also conferred
resistance to such aryl-containing ketolides. The crystal
structure of the ribosome indicated that the location of
this secondary interaction in domain II is close to the
primary macrolide binding site in domain V.26
by interacting with the large subunit of bacterial
ribosome and inhibiting protein synthesis.5 The binding
region of macrolides on the bacterial ribosome has been
well studied by various means, including chemical
footprinting of bound macrolide and mutational resis-
tance.25 Recently the atomic structure of the bacterial
ribosome isolated from Haloarcula marismortui has
been disclosed and the crystal structure of the ribosome
with bound macrolide may soon become available.26 The
macrolide binding site is located in domain V of the 23S
ribosomal RNA, which overlaps with the binding site
of lincosamides and type B streptogramin antibiotics.
One of the most prevalent macrolide-resistant mecha-
nisms involves N-6 dimethylation of a single adenine
base (A2058 based on E. coli sequence) in domain V,
which reduces drug binding affinity and confers resis-
tance to macrolides, lincosamides, and type B strepto-
gramin (MLSB resistance).6 Many of the 6-O-substituted
ketolides not only showed improved activity against
erythromycin-susceptible strains but also exhibited
potent activity against MLSB-resistant organisms (Table
3 ). Mechanistic studies of ABT-773 (41s) have indicated
that this compound binds to the same binding site as
previous macrolides but with improved binding affin-
ity.23 Moreover, ABT-773 binds to the methylated ribo-
somes isolated from MLSB-resistant S. pneumoniae,
which has not been observed for the older generation
macrolides.
The improved binding ability of these new ketolides
was further supported by the luciferase transcription/
translation (T/T) assay. The inhibitory effects of a
selected group of ketolides on protein synthesis with
both wild-type and methylated ribosomes are sum-
marized in Table 2. Ketolides 41g-41y showed slightly
improved inhibitory activity (1-3-fold) against wide-
type ribosomes as compared to erythromycin. The
inhibitory IC50 data correlated very well with the MIC
data against erythromycin-susceptible strains. However,
ketolides 41g-41y exhibited significantly improved
activity against MLSB-resistant strains with MICs
between 0.25 and 0.5 µg/mL, while the reference mac-
The solution conformations of ABT-773 (41s) and RU-
004 (4) indicated that the quinolyl group attached to
the C-6 position of ABT-773 and the quinolyl group
attached to the carbamate of RU-004 occupied the same
spatial position, suggesting that the aryl groups in ABT-
773 and RU-004 might interact with the same region
of the ribosome.4 The spatial relationships between the
C-6 aryl group and the ketolide skeleton can be better
illustrated by the crystal structure of ketolide 41r
(Figure 2). We believe that the secondary interaction of
the C-6 aryl group of our ketolides with domain II of
ribosome is responsible for the improved binding affinity
to the methylated ribosome and improved activity
against MLSB-resistant organisms. The concept of bi-
nary interaction has been used widely for enhancing
ligand-receptor interaction and improving binding
specificity.27 As illustrated by Figure 3, the binary
interactions between the macrolide moiety and domain
V (∆G1), and between the C-6 aryl group and domain II
(∆G2) provide enhanced macrolide-ribosome interac-
tion, especially with methylated ribosomes, where the
binding between the macrolide moiety and domain V
(∆G1) has been compromised.
Str u ctu r e-Activity Rela tion sh ip s. The antibacte-
rial activity of the test compounds was assessed by
minimum inhibitory concentration (MIC) against a
selected group of organisms. The phenotypes and geno-
types of these pathogens are shown in Table 1, which
include erythromycin-susceptible, MLSB-resistant (erm),
and efflux (mef) resistant organisms.24 Among the
various ketolide derivatives, the 6-O-(3-aryl-2-propenyl)-
11,12-carbamate ketolides, depicted by structure 41,
exhibited the most potent and balanced activity against
both susceptible and resistant bacteria (Table 3). In

4144 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Ma et al.
F igu r e 2. Stereoview of the crystal structure of 6-O-[3-(6′-quinolyl)-2-propenyl]-11,12-carbamate ketolide (41r ).
by some earlier reports, the cladinose group is respon-
sible for the inducibility of macrolide resistance.28 Allen
and co-workers have demonstrated that some naturally
occurring macrolides without the C-3 cladinose sugar,
such as pikromycin and narbomycin, are noninducers.
Lacking the C-3 cladinose group, the 16-membered ring
macrolides are also active against inducible strains. The
inducibility of erythromycin and its derivatives can be
eliminated by removal of the C-3 cladinose as shown
by Allen28a and Pestka28b and more recently by Roussel
scientists.10
Our results clearly indicated that the C-3 cladinose
is responsible for the induction of resistance, and
removal of this group prevents such resistance (Table
3). For example, Staphylococcus aureus A5177 is an
inducibly MLSB-resistant strain against which eryth-
romycin had a MIC of 6.2 µg/mL. Macrolide 12a also
had an MIC of 6.2 µg/mL against this strain, which
represented a 15-fold reduction in activity as compared
to its activity against the susceptible S. aureus ATCC
6538P. However, the corresponding ketolide 16a , with-
out the cladinose sugar attached, was equally active
against the susceptible and inducible strains, each
having a MIC of 1.56 µg/mL. The same trend was
observed when macrolide 12s and the corresponding
ketolide 16s were compared. Compound 25s is an
erythromycin derivative with the C-3 cladinose at-
tached. This compound had an MIC of 3.1 µg/mL against
the inducible strain S. aureus A5177. The corresponding
ketolide 41s had an MIC of 0.05 µg/mL against S.
aureus A5177, which represented a 62-fold improvement
in activity against this inducibly resistant organism.
These results clearly demonstrated that the C-3 modi-
fication was the key factor for overcoming inducible
resistance.
Significant improvements in activity against efflux
resistance were also observed by introducing the C-3
carbonyl group. For instance, macrolide 12a was 67-
fold less active against efflux strain S. pneumoniae 5649
as compared to its activity against the susceptible S.
pneumoniae strain ATCC 6303. However, the corre-
sponding ketolide 16a was significantly more active
against efflux resistance. The difference between activi-
ties against susceptible and efflux strains was only
2-fold. Similarly, macrolide 12s was about 67-fold less
active against efflux stains than against susceptible
F igu r e 3. Schematic presentation of the free energy gains of
a secondary interaction and structure segments responsible
for the primary and secondary interactions. The enhanced
binding affinity is represented by the total binding free energy
(∆Gtotal), which consists of contributions from primary interac-
tion (∆G1), secondary interaction (∆G2), and entropy gain by
linking the two segments together (∆Glink).
F igu r e 4. Structure of 41, which possesses three modifica-
tions to erythromycin.
contrast, erythromycin showed either weak or no activ-
ity against the resistant organisms. Structure 41 carries
three key structural modifications to erythromycin: (1)
introduction of a 3-aryl-2-propenyl moiety at the C-6
position, (2) conversion of the C-3 cladinose to a carbonyl
group, and (3) introduction of a cyclic carbamate at the
11,12-position (Figure 4). Our structure-activity rela-
tionship analysis indicated that each of the three
modifications made significant contributions to the
improved antibacterial profiles.
Effects of C-3 Mod ifica tion . Removal of the cladi-
nose sugar from erythromycin and conversion of the C-3
hydroxy group to a carbonyl functionality resulted in
significant changes in biological activity. The most
significant effects were observed on the activity against
inducible and efflux resistant organisms. As described

Erythromycin Derivatives with C-6 Aryl Groups
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4145
Ta ble 3. In Vitro Activity of Various 6-O-Substituted Macrolides/Ketolides against Selected Respiratory Pathogensa
S. aureus
S. pneumoniae
S. pyogenes
ATCC
6538P
Ery-S
ATCC
6303
Ery-S
PIU
2548
efflux
H. flub
DILL
Amp-R
A 5177
MLSB-i
A 5278
MLSB-c
5737
MLSB
5649
efflux
EES 61
Ery-S
930
MLSB
compd
Ery
11
12a
12s
14
16a
16b
16c
16s
17a
19i
19ii
19iii
19vi
19vii
24
0.2
0.78
0.39
0.2
12.5
1.56
1.56
1.56
0.2
6.2
25
3.1
6.2
6.2
3.1
0.2
0.2
0.78
6.2
6.2
0.1
0.1
6.2
12.5
6.2
3.1
50
1.56
1.56
1.56
0.2
6.2
25
1.56
6.2
3.1
3.1
0.78
3.1
1.56
6.2
6.2
0.1
0.1
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
50
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
0.06
>128
32
0.06
>128
>128
32
16
64
16
4
32
2
2
2
0.1
4
12.5
4
8
1.56
4
8
1
1
2
4
0.5
0.5
0.25
2
4
2
0.25
0.5
0.25
0.25
2
0.25
0.125
2
0.25
0.25
0.5
1
8
32
4
0.06
0.06
4
1
1
1
0.03
1
32
128
>128
64
128
32
4
4
8
2
2
2
0.25
1
0.03
0.06
64
8
>128
>128
128
128
64
16
>64
0.25
0.25
0.5
0.2
0.5
6.2
0.5
2
0.39
0.25
0.03
0.03
0.25
0.5
64
64
32
100
64
16
32
>100
>64
>128
>100
>128
>128
8
>64
>128
>128
64
0.25
2
>64
>128
>128
>128
>128
8
>64
>128
>128
64
4
4
2
0.5
2
16
64
32
32
2
0.25
0.25
0.03
0.03
0.5
25s
27
33
1
2
0.25
0.5
2
0.25
0.5
0.25
2
64
>128
64
2
0.5
1
34
0.5
35s
36s
37s
38s
39
40s
41a
41d
41f
41g
41h
41i
0.015
0.06
0.03
0.125
0.25
0.06
0.03
0.03
0.004
0.004
0.03
0.015
0.004
0.03
0.03
0.008
0.03
0.015
0.125
0.03
0.004
0.004
0.03
0.008
0.015
0.015
0.03
0.015
0.015
0.015
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.015
0.03
0.015
0.03
0.25
0.06
0.03
0.03
0.008
0.008
0.03
0.015
0.004
0.03
0.03
0.008
0.03
0.015
0.125
0.03
0.004
0.004
0.03
0.015
0.03
0.03
0.03
0.03
0.015
0.004
0.03
0.03
0.03
0.03
0.125
0.03
0.03
64
1
4
64
4
32
8
4
8
32
4
4
8
2
2
4
4
2
4
8
4
8
16
8
4
1
2
2
2
2
2
4
0.1
0.1
0.2
1.56
0.05
0.1
0.39
1.56
0.05
0.1
>128
128
64
>128
0.5
0.5
8
0.5
1
>128
16
64
0.25
0.5
0.25
0.25
4
0.25
0.25
1
0.25
0.25
0.5
1
0.1
0.1
>128
0.05
0.05
0.1
0.1
0.1
0.2
0.1
0.1
0.2
0.05
0.05
0.1
0.1
0.1
0.2
0.1
0.1
0.1
4
1
4
16
8
64
8
64
41j
41k
41l
>128
2
8
>128
41m
41n
41o
41p
41q
41r
41s
41t
41u
41v
41w
41x
41y
41z
42s
43s
45ii
45iii
45iv
45v
45viii
45ix
32
>32
>128
64
>32
16
16
0.1
0.1
0.39
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.2
0.1
0.2
0.1
0.05
0.2
0.39
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.2
0.1
0.2
0.1
0.05
0.39
0.1
0.2
0.2
1
1
1
4
1
0.5
0.25
0.125
2
0.5
1
0.5
0.25
0.5
2
0.25
0.5
2
>128
1
1
0.5
4
2
4
2
1
4
0.25
0.25
2
0.5
0.5
0.5
0.5
0.25
2
0.25
0.25
2
2
2
0.25
0.5
0.25
0.25
1
0.5
0.25
1
2
4
2
8
32
>128
>128
16
4
4
>128
>128
64
2
4
4
4
2
4
0.2
0.2
0.39
0.1
0.2
2
0.5
2
2
2
16
4
2
>128
2
2
2
0.1
0.39
16
>100
a
b
Minimum inhibitory concentration (MIC) values are given in micrograms per milliliter. H. influenzae.
strains, but the corresponding ketolide 16s was highly
active against the efflux strain with a MIC of 0.25 µg/
mL. Other examples include macrolide 24 and the
corresponding ketolide 27, wherein the differences
between activities against susceptible and efflux strains
were 67-fold and 1/2-fold, respectively. One can draw
the same conclusions when the activities against S.
pyogenes PIU 2548 (efflux strain) and EES 61 (suscep-
tible strain) are compared. It is worth noting that the
improvement of activity against susceptible organisms
by introducing the C-6 aryl group or 11,12-carbamate
did not result in further potency increases against
efflux. This indicated that the activity of our ketolides
against efflux strains might be controlled by the drug
transport process rather than ribosomal interaction.
The effects of the C-3 group on activity against
erythromycin-susceptible strains are less profound and
explicit. For example, ketolides 14 and 27 were less
active against erythromycin-susceptible strains (S. au-
reus ATCC 6538P, S. pneumoniae ATCC 6303, and S.
pyogenes EES 61) than the corresponding macrolides 11
and 24. However, ketolide 16s and macrolide 12s

4146 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Ma et al.
Ta ble 4. In Vivo Efficacy of Selected Compounds in Mouse
showed equivalent activities against the susceptible
strains, while ketolide 41s exhibited better activities
than the corresponding macrolide 25s against the
susceptible strains.
Protection Tests
S. aureus 10649a
S. pneumoniae 6303a
MIC
ED50
MIC
ED50
compound
(µg/mL)
(mg/kg)
(µg/mL)
(mg/kg)
Effects of C-11,12 Mod ifica tion . As reported by
Baker et al.,9 introduction of a cyclic carbamate group
to the 11,12-position of macrolides had favorable effects
on antibacterial activity. Activity enhancements were
also observed when this modification was applied to our
ketolide series. Carbamate 24 exhibited 4-16-fold im-
provements in activity as compared to the corresponding
diol 11 against both erythromycin-susceptible and MLSB-
resistant organisms. The same trend was observed for
carbamate 25s as compared to the parent diol 12s,
although to a lesser extent. Similarly, carbamate keto-
lides 27, 41a , and 41s showed substantially improved
antibacterial activities as compared to the corresponding
diols 14, 16a , and 16s. Carbamate ketolides 45ii, 45iii,
and 45iv were significantly more active than the cor-
responding diols 19ii, 19iii, and 19iv. Once again the
potency enhancement was independent of the resistant
phenotypes as both erythromycin-susceptible and MLSB-
resistant strains were favorably affected by this modi-
fication.
clarithromycin
azithromycin
telithromycin
0.2
0.78
0.1
0.2
0.05
0.1
0.05
0.05
0.05
0.05
0.2
16.7
24.8
12.5
27.2
60.4
30.2
0.03
0.12
0.004
0.03
0.06
27.9
18.8
34.1
>40.0
23.5
16s
40s
41a
41g
41s
41u
41v
41x
41y
42s
0.03
>40.0
>50
0.004
0.004
0.008
0.015
0.03
9.4
12.5
12.5
9.2
<6.25
27.1
7.8
>50.0
17.3
40.3
33.1
0.1
0.1
0.015
0.015
33.0
a
Both S. aureus 10649and S. pneumoniae 6303 are erythromycin-
susceptible strains.
substituted analogue 25s showed similar activities
against various susceptible strains. However, compound
25s exhibited significantly improved activity against S.
pneumoniae 5737 and S. pyogenes 930, two erm-
containing strains.
The tether structure linking the lactone ring and the
aryl group appeared to be very important as well. The
saturated propylene derivatives 17a and 42s appeared
to be less active than the corresponding propenylene
compounds 16a and 41s, possibly an entropy effect due
to the loss of rigidity. Compound 43s with a cyclopropyl-
containing tether was also less active than the prope-
nylene analogue 41s. More dramatic effects were ob-
served when the propenylene tether was replaced with
other linkers of varying length and rigidity as exempli-
fied in structures 45ii-45ix. Among all the tether
groups studied, the propenylene tether provided the best
antibacterial activity.
In Vivo Effica cy. Many of the ketolide derivatives
exhibited excellent in vivo efficacy as compared to the
reference compounds clarithromycin, azithromycin, and
telithromycin (Table 4). Compound 41s, the 6-O-(3-
quinolyl-2-propenyl)-11,12-carbamate ketolide exhibited
significantly better efficacy than the corresponding
11,12-diol 16s and tricyclic ketolide 40s against infec-
tions caused by both S. aureus and S. pneumoniae. The
efficacy dropped when the propenylene tether was
reduced to propylene as illustrated by compound 42s.
The aryl structure also had significant effects on the in
vivo efficacy (Table 4, 41a -41y). Among various aryl
groups studied, the 3-quinolyl analogue 41s (ABT-773)
provided excellent efficacy against both S. aureus and
S. pneumoniae infections. Further evaluations of 41s
confirmed the superiority of this compound against a
series of infections caused by both susceptible and
resistant pathogens in various infection models.29
Substitution on the carbamate nitrogen had signifi-
cant effects on the antibacterial activity. N-Substituted
carbamates 35s, 36s, 37s, 38s, and 40s were less active
than the unsubstituted carbamate 41s, suggesting that
steric bulk at this position might have a negative impact
on the antibacterial activity. The same trend was
observed when comparing the N-substituted carbamates
33, 34, and 39 to the unsubstituted carbamate 27.
Effects of C-6 Mod ifica tion . We found that the
structure of the C-6 group has significant effects on the
antibacterial activity, especially against erm-mediated
MLSB resistance. Introduction of an aryl group to this
position of ketolide 27 through a Heck coupling reaction
provided a series of potent analogues 41a -41z with
significantly improved activity against both susceptible
and MLSB-resistant S. pneumoniae and S. pyogenes. The
improvement for erythromycin-susceptible strains ranged
from 4- to 125-fold and reached as high as >500-fold
for MLSB-resistant strains. Compound 41s, the 6-O-(3-
quinolyl-2-propenyl) derivative, was among the most
potent compounds prepared. This compound exhibited
potent and balanced activity against both susceptible
and resistant organisms. As discussed previously, we
believed that the activity enhancement achieved by
introducing the C-6 aryl group was the result of a
secondary interaction between the aryl group and the
ribosome. However, introduction of the C-6 aryl group
failed to improve the activity against S. aureus A5278,
a constitutively MLSB-resistant strain, to a detectable
level. The C-6 aryl group also had no significant effect
on activities against the efflux strains, which, as we
discussed earlier, are likely controlled by the drug
transportation processes.
Con clu sion
The significant effects of the C-6 aryl group on
antibacterial activity could be demonstrated by compar-
ing 6-O-allyl ketolides 14, 33, 34, and 39 to the corre-
sponding aryl analogues 16, 37, 38, and 40. The effects
of the C-6 structure on erm-mediated resistant strains
were best illustrated by comparing compounds 24 and
25s. The 6-O-allyl compound 24 and its quinolyl-
A novel series of erythromycin derivatives with potent
activity against the key respiratory pathogens, including
those resistant to the earlier generation of macrolides,
has been identified. These compounds are characterized
by having an aryl group tethered to the C-6 position of
the ketolide skeleton. Extensive structural modification
of the C-6 moiety led to the discovery of several

Erythromycin Derivatives with C-6 Aryl Groups
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4147
for C49H77N2O13 901.5426; 1H NMR (CDCl3) δ 9.13 (1H, d, J )
1.8 Hz), 8.28 (1H, d, J ) 1.8 Hz), 8.05 (1H, d, J ) 8.4 Hz),
7.80 (1H, d, J ) 8.4 Hz), 7.63 (1H, m), 7.50 (1H, m), 6.60 (2H,
m), 5.19 (1H, dd, J ) 10.8, 2.4 Hz), 4.92 (1H, d, J ) 4.5 Hz),
4.52 (1H, d, J ) 7.2 Hz), 4.25 (1H, m), 4.06 (2H, m), 3.82 (2H,
m), 3.75 (1H, s), 3.59 (1H, s), 3.50 (2H, m), 3.35 (3H, s), 3.21
(1H, m), 2.90-3.10 (5H, m), 2.63 (1H, m), 2.45 (2H, m), 2.31
(6H, s), 2.19 (1H, d, J ) 9.4 Hz), 2.10 (1H, m), 1.92 (2H, m),
1.45-1.75 (4H, m), 1.51 (1H, m), 1.35 (3H, s), 1.10-1.35 (24H,
m), 0.94 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 220.2 (C-9),
175.4 (C-1), 150.3, 147.5, 132.8, 130.3, 129.8, 129.2, 128.8,
128.6, 128.2, 127.9, 126.5, 102.4 (C-1′), 96.4 (C-1′′, 80.1, 79.3,
79.1, 77.8, 74.4, 72.8, 71.0, 68.7, 68.6, 66.0, 65.7, 65.2, 49.5,
45.5, 44.6, 40.3 (NMe2), 38.5, 38.4, 37.4, 35.0, 28.7, 21.5, 21.4,
21.3, 21.0, 18.8, 18.4, 16.1, 15.9, 12.1, 10.7, 9.3.
promising compounds with potent activity against both
mef- and erm-mediated resistant Streptococcus pneu-
moniae. Preliminary mechanistic studies indicated that
the new ketolides are potent protein synthesis inhibitors
which interact with methylated ribosomes and exert
activity against MLSB-resistant bacteria. In experimen-
tal animal models, these analogues exhibited excellent
in vivo efficacy and balanced pharmacokinetic profiles.
As a result of extensive structural modification and
optimization, ABT-773 (41s) was identified as a candi-
date for further clinical evaluation.
Exp er im en ta l Section
6-O-Allyl-2′-O-ben zoyl Ketolid e 13. To a suspension of
11 (7.73 g, 10.0 mmol) in ethanol (25 mL) and water (75 mL)
was added aqueous 1 M HCl (18 mL) over 10 min. The reaction
mixture was stirred at room temperature for 10 h and
neutralized with aqueous 2 M NaOH (9 mL, 18 mmol). The
precipitate was collected by filtration and washed with ice-
cold water (10 mL) to give the corresponding 3-OH compound
(3.11 g). A portion of the above product (2.49 g, 4.05 mmol)
was dissolved in CH2Cl2 (20 mL) and treated with Bz2O (1.46
g, 6.48 mmol) and Et3N (0.903 mL, 6.48 mmol) at room
temperature for 24 h. The reaction mixture was taken up in
EtOAc and washed with 5% Na2CO3 and brine. The organic
phase was dried (Na2SO4) and concentrated to give 2.46 g of
the 2′-O-Bz derivative after column chromatography (silica gel,
3:7 acetone/hexane). MS m/z (FAB) 720 (M + H)+.
N-Chlorosuccinimide (NCS) (0.667 g, 5.07 mmol) was dis-
solved in CH2Cl2 (20 mL) and cooled to -10 °C under nitrogen.
Me2S (0.433 mL, 5.92 mmol) was added dropwise over 5 min
and stirred at this temperature for an additional 10 min. A
solution of the above 2′-O-Bz compound (2.43 g, 3.38 mmol) in
CH2Cl2 (20 mL) was introduced over 20 min. After the mixture
was stirred for 30 min at -10 to -5 °C, Et3N (0.470 mL, 3.38
mmol) was added over 5 min, and the mixture was stirred for
an additional 45 min before warming up to room temperature.
The reaction mixture was taken up in EtOAc and washed with
5% Na2CO3 and brine. The organic phase was dried (Na2SO4)
and concentrated to give 2.27 g (77% from 11) of 13 as white
solid after column chromatography (silica gel, 3:7 acetone/
hexane): MS m/z (FAB) 718 (M + H)+; 1H NMR (CDCl3) δ 8.01
(1H, d, J ) 7.2 Hz), 8.00 (1H, d, J ) 8.4 Hz), 7.55 (1H, m),
7.43 (2H, m), 5.65(1H, m), 5.10 (3H, m), 4.59 (1H, d, J ) 6.9
Hz), 4.41 (1H, d, J ) 3.0 Hz), 3.81 (1H, br s), 3.77 (1H, q, J )
6.6 Hz), 3.65 (2H, m), 3.46 (1H, s), 3.41 (1H, s), 3.15 (2H, m),
2.98 (1H, m), 2.86 (1H, m), 2.60 (1H, m), 2.26 (6H, s), 1.95
(1H, m), 1.81 (1H, m), 1.65 (1H, m), 1.40-1.50 (3H, m), 1.36
(3H, s), 1.30 (3H, d, J ) 6.6 Hz), 1.28 (3H, d, J ) 6.6 Hz), 1.14
(3H, s), 1.11 (3H, d, J ) 6.9 Hz), 1.09 (3H, d, J ) 6.9 Hz), 1.00
(3H, d, J ) 7.5 Hz), 0.82 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3)
δ 219.3 (C-9), 206.3 (C-3), 69.6 (C-1), 165.2, 135.1, 132.7, 130.5,
129.7, 128.2, 117.5, 100.5 (C-1′), 78.4, 78.0, 75.1, 74.2, 71.9,
69.1, 68.9, 64.4, 63.6, 50.6, 45.3, 44.7, 40.7 (NMe2), 38.1, 37.6,
31.6, 21.7, 21.1, 20.2, 18.0, 16.5, 14.5, 12.6, 12.3, 10.6.
Intermediate 9, 2′,4′′-bis-O-trimethylsilylerythromycin A
9-O-(1-isopropoxycyclohexyl)oxime, was provided by the Abbott
Process Research Department. The synthesis of 9 has been
described in U.S. Patent 4,990,602. Tetrahydrofuran was
distilled from sodium/benzophenone. All solvents and reagents
were obtained from commercial sources and used without
further purification. Flash column chromatography was per-
formed on Merck silica gel 60 (230-400 mesh). Melting points
were recorded on a Fisher-J ohns apparatus and are uncor-
rected. All elemental analyses were performed by Robertson
Microlite Laboratories and the data for carbon, hydrogen, and
nitrogen reported are within 0.4% of theoretical values.
6-O-Allyler yth r om ycin A (11). To an ice-cold solution of
9 (1.032 g, 1.00 mmol) in 5 mL of DMSO and 5 mL of THF
was added freshly distilled allyl bromide (0.173 mL, 2.00
mmol), and the mixture was stirred for 5 min. A solution of
KOBut (2.0 mL of 2 M solution in THF, 2.00 mmol) in 5 mL of
DMSO and 5 mL THF was added slowly over 4 h. The reaction
mixture was taken up in ethyl acetate and the organic layer
was washed with water and brine. The organic phase was
dried over Na2SO4 and concentrated to give crude intermediate
10 (1.062 g). To a solution of 10 in 8 mL of acetonitrile and 4
mL of water was added 4 mL of acetic acid. After 12 h at room
temperature, the solvent was evaporated in a vacuum to give
off-white foam. The crude mixture was dissolved in 8 mL of
ethanol and 8 mL of water. NaHSO3 (312 mg, 3.00 mmol) and
formic acid (0.10 mL, 2.50 mmol) were added, and the mixture
was stirred at 80 °C for 8 h. The reaction mixture was allowed
to cool to room temperature, neutralized with 1 N NaOH to
pH 9-10, and extracted with ethyl acetate. The organic phase
was washed with brine, dried over Na2SO4, filtered, and
concentrated. The crude material was purified by column
chromatography, eluted with 1% MeOH in methylene chloride
containing 1% ammonium hydroxide, to give 11 (257 mg, 0.33
1
mmol, 33% from 9): MS m/z (FAB) 774 (M + H)+; H NMR
(CDCl3) δ 5.90 (1H, m), 5.13 (2H, m), 4.92 (1H, d, J ) 4.5 Hz),
4.49 (1H, d, J ) 6.9 Hz), 4.02 (2H, m), 3.86 (1H, m), 3.78 (1H,
d, J ) 6.9 Hz), 3.73 (1H, m), 3.69 (1H, s), 3.60 (1H, s), 3.51
(2H, m), 3.34 (3H, s), 3.19 (1H, m), 2.90-3.10 (5H, m), 2.62
(1H, m), 2.40 (2H, m), 2.27 (6H, s), 2.15 (1H, d, J ) 9.3 Hz),
2.04 (1H, m), 1.92 (2H, m), 1.55-1.70 (4H, m), 1.50 (1H, m),
1.44 (3H, s), 1.31 (3H, d, J ) 6.2 Hz), 1.27 (3H, s), 1.10-1.25
(18H, m), 0.94 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 219.3
(C-9), 174.8 (C-1), 135.5, 116.3, 101.9 (C-1′), 95.9 (C-1′′), 79.7,
78.8, 78.5, 74.1, 72.4, 70.6, 68.1, 65.5, 65.1, 49.0, 45.0, 44.1,
39.7 (NMe2), 37.9, 37.1, 34.6, 28.4, 21.0, 20.6, 20.8, 18.3, 18.1,
15.7, 15.6, 11.9, 10.1, 8.9. Anal. (C40H71NO13) C, H, N.
6-O-Allyl Ketolid e 14. A solution of 13 (719 mg, 1.0 mmol)
in methanol (20 mL) was heated to reflux for 6 h. The reaction
mixture was concentrated and the residue was purified by
chromatography on silica gel (95:5:0.5 dichloromethane/
methanol/ammonia) to give ketolide 14 (577 mg, 91%) as a
white solid: MS m/z (FAB) 614 (M + H)+; 1H NMR (CDCl3) δ
5.68 (1H, m), 5.19 (1H, m), 5.10 (2H, m), 4.45 (1H, d, J ) 3.3
Hz), 4.38 (1H, d, J ) 7.2 Hz), 3.91 (1H, q, J ) 6.6 Hz), 3.90
(1H, br s), 3.65 (2H, m), 3.48 (1H, br s), 3.44 (1H, m), 3.25
(1H, m), 3.18 (2H, m), 3.05 (1H, m), 2.63 (1H, m), 2.48 (1H,
m), 2.27 (6H, s), 1.99 (1H, m), 1.84 (1H, m), 1.65 (2H, m), 1.55
(1H, m), 1.42 (3H, d, J ) 7.8 Hz), 1.37 (3H, s), 1.26 (3H, s),
1.25 (3H, d, J ) 6.6 Hz), 1.13 (3H, d, J ) 6.6 Hz), 1.12 (3H, d,
J ) 6.9 Hz), 0.85 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 219.2
(C-9), 206.0 (C-3), 169.8 (C-1), 135.3, 117.5, 102.8 (C-1′), 78.4,
78.0, 75.9, 74.4, 70.3, 69.5, 69.0, 65.9, 64.6, 50.6, 45.4, 45.1,
6-O-[3-(3′-Qu in olyl)-2-p r op en yl]er yth r om ycin A (12s).
A mixture of 11 (3.09 g, 4.00 mmol), 3-bromoquinoline (1.08
mL, 8.00 mmol), Pd(OAc)2 (180 mg, 0.80 mmol), P(o-tolyl)3 (365
mg, 1.20 mmol), and Et3N (1.40 mL, 10.0 mmol) in acetonitrile
(70 mL) was flushed with nitrogen and sealed in a pressure
tube. The mixture was heated to 60 °C for 1 h and then to 100
°C for 48 h. The reaction mixture was taken up in EtOAc and
washed with 5% Na2CO3 (aq) and brine. The organic phase
was concentrated and purified by column chromatography,
eluted with 10% MeOH in methylene chloride containing 0.5%
ammonium hydroxide, to give 12s (2.73 g, 3.00 mmol, 76%):
MS m/z (ESI) 901 (M + H)+; HRMS (FAB) m/z 901.5413, calcd

4148 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Ma et al.
40.2 (NMe2), 38.6, 37.8, 31.6, 28.4, 21.8, 21.3, 20.3, 18.1, 16.5,
14.7, 12.8, 12.3, 10.6. Anal. (C32H55NO10‚0.5H2O) C, H, N.
(NMe2), 38.6, 37.6, 28.4, 21.8, 21.2, 20.3, 18.0, 16.5, 14.6, 13.0,
12.2, 10.8. Anal. (C38H58NO10Cl) C, H, N.
6-O-(3-P h en yl-2-p r op en yl) Ketolid e 16a . To a solution
of 13 (717 mg, 1.00 mmol), palladium(II) acetate (22 mg, 0.100
mmol), and triphenylphosphine (52 mg, 0.200 mmol) in aceto-
nitrile (5 mL) were added iodobenzene (220 µL, 2.00 mmol)
and triethylamine (280 µL, 2.00 mmol). The mixture was
cooled to -78 °C and degassed. The reaction mixture was then
warmed to 60 °C for 0.5 h and stirred at 80 °C for 12 h. The
reaction mixture was taken up in ethyl acetate and washed
twice with aqueous 5% sodium bicarbonate, once with aqueous
2% tris(hydroxymethyl)aminomethane, and once with brine,
dried over sodium sulfate, filtered, and concentrated in a
vacuum. The crude mixture was purified by flash column
chromatography on silica gel (95:5:0.5 dichloromethane/
methanol/ammonia) to give 15a (721 mg, 90%) as an off-white
solid: MS m/z (FAB)+ 794 (M + H)+. Anal. (C45H63NO11‚H2O)
C, H, N.
The above compound (340 mg, 0.429 mmol) was dissolved
in MeOH (10 mL) and heated to reflux for 6 h. The reaction
mixture was concentrated in a vacuum and the residue was
purified by chromatography on silica gel (95:5:0.5 dichloro-
methane/methanol/ammonia) to give ketolide 16a (203 mg,
70%) as a white solid: MS m/z (FAB) 690 (M + H)+; 1H NMR
(CDCl3) δ 7.46, (2H, m), 7.20-7.32 (3H, m), 6.42 (1H, d, J )
15.6), 6.05 (1H, m), 5.19 (1H, m), 4.50 (1H, d, J ) 3.3 Hz),
4.38 (1H, d, J ) 7.2 Hz), 3.95 (1H, q, J ) 6.6 Hz), 3.93 (1H,
m), 3.80 (1H, m), 3.62 (2H, m), 3.39 (1H, br s), 3.30 (1H, m),
3.18 (2H, m), 3.05 (1H, m), 2.63 (1H, m), 2.48 (1H, m), 2.26
(6H, s), 1.99 (1H, m), 1.84 (1H, m), 1.65 (2H, m), 1.55 (1H, m),
1.43 (3H, d, J ) 7.8 Hz), 1.41 (3H, s), 1.35 (3H, d, J ) 6.9 Hz),
1.26 (3H, s), 1.25 (3H, d, J ) 6.6 Hz), 1.13 (3H, d, J ) 6.6 Hz),
1.10 (3H, d, J ) 6.9 Hz), 0.88 (3H, t, J ) 7.5 Hz); 13C NMR
(CDCl3) δ 219.4 (C-9), 206.0 (C-3), 169.8 (C-1), 137.0, 132.6,
128.3, 127.3, 126.7, 126.6, 102.7, 78.4, 78.2, 75.9, 74.3, 70.3,
69.5, 69.1, 65.9, 64.2, 50.6, 45.4, 45.3, 40.2 (NMe2), 38.7, 37.7,
28.3, 21.9, 21.2, 20.3, 18.1, 16.5, 14.6, 13.0, 12.3, 10.8.
6-O-[3-(3′-Qu in olyl)-2-p r op en yl] Ket olid e 16s. Com-
pound 16s was prepared according to the procedures described
for the preparation of 16a , by replacing iodobenzene with
3-bromoquinloline. Compound 16s (217 mg, 30%) was obtained
1
as an off-white solid: MS m/z (FAB) 741 (M + H)+; H NMR
(CDCl3) δ 9.07 (1H, d, J ) 2.4 Hz), 8.19 (1H, d, J ) 2.4 Hz),
8.06 (1H, d, J ) 8.4 Hz), 7.82 (1H, d, J ) 8.4 Hz), 7.63 (1H,
m), 7.51 (1H, m), 6.59 (1H, d, J ) 15.6 Hz), 6.31 (1H, m), 5.22
(1H, m), 4.53 (1H, d, J ) 3.3 Hz), 4.38 (1H, d, J ) 7.2 Hz),
3.98 (1H, q, J ) 6.6 Hz), 3.85-3.95 (2H, m), 3.72 (1H, m), 3.60
(1H, m), 3.52 (1H, br s), 3.30 (1H, m), 3.20 (2H, m), 3.08 (1H,
m), 2.65 (1H, m), 2.49 (1H, m), 2.27 (6H, s), 2.00 (1H, m), 1.90
(1H, m), 1.65 (2H, m), 1.50 (1H, m), 1.46 (3H, d, J ) 7.8 Hz),
1.44 (3H, s), 1.36 (3H, d, J ) 6.9 Hz), 1.26 (3H, s), 1.25 (3H, d,
J ) 6.6 Hz), 1.15 (3H, d, J ) 6.6 Hz), 1.08 (3H, d, J ) 6.9 Hz),
0.89 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 219.7 (C-9), 205.9
(C-3), 169.8 (C-1), 152.1, 150.0, 147.5, 140.2, 132.6, 130.0,
129.2, 129.1, 128.8, 128.1, 127.9, 126.5, 102.8 (C-1′), 78.5, 78.2,
75.9, 74.2, 70.2, 69.4, 69.2, 65.9, 64.1, 50.6, 45.4, 45.3, 40.2
(NMe2), 38.7, 37.6, 28.4, 21.8, 21.2, 20.3, 18.0, 16.5, 14.6, 13.0,
12.2, 10.8. Anal. (C41H61N2O10‚0.5H2O) C, H, N.
6-O-(3-P h en ylp r op yl) Ketolid e 17a . A solution of 16a
(170 mg, 0.247 mmol) in methanol (10 mL) was flushed with
nitrogen. Palladium (10%) on carbon (50 mg) was added, and
the mixture was flushed with hydrogen and stirred for 18 h
under positive hydrogen pressure. The reaction mixture was
filtered through Celite and the filtrate was concentrated to
give colorless glass. The glass was taken up in ether, hexane
was added, and the solvents were removed to give the title
compound (167 mg, 98%) as a white solid. MS m/z (FAB) 692
1
(M + H)+; H NMR (CDCl3) δ 7.10-7.30 (5H, m), 7.20-7.32
(3H, m), 5.23 (1H, m), 4.45 (1H, d, J ) 3.3 Hz), 4.37 (1H, d, J
) 7.2 Hz), 3.85-3.95 (3H, m), 3.62 (2H, m), 3.35 (1H, br s),
3.05-3.30 (4H, m), 2.75 (1H, m), 2.65 (1H, m), 2.40-2.60 (3H,
m), 2.27 (6H, s), 1.99 (1H, m), 1.90 (1H, m), 1.50-1.70 (4H,
m), 1.43 (3H, d, J ) 7.8 Hz), 1.35 (3H, d, J ) 6.9 Hz), 1.30
(3H, s), 1.26 (3H, s), 1.25 (3H, d, J ) 6.6 Hz), 1.15 (3H, d, J )
6-O-[3-(4′-Met h oxyp h en yl)-2-p r op en yl] Ket olid e 16b .
Compound 16b was prepared according to the procedures
described for the preparation of 16a , by replacing iodobenzene
with iodoanisole. Compound 16b (575 mg, 80%) was obtained
6.6 Hz), 1.12 (3H, d, J ) 6.9 Hz), 0.85 (3H, t, J ) 7.5 Hz); 13
C
NMR (CDCl3) δ 220.2 (C-9), 206.5 (C-3), 170.0 (C-1), 142.3,
128.4, 128.1, 125.4, 102.6, 78.2, 78.0, 75.6, 74.2, 70.3, 69.5, 69.4,
65.9, 62.1, 50.6, 45.4, 44.6, 40.2, 38.8, 37.5, 32.1, 30.3, 28.4,
21.9, 21.3, 20.2, 18.4, 16.5, 14.9, 12.4, 10.6.
1
as an off-white solid: MS m/z (FAB) 720 (M + H)+; H NMR
(CDCl3) δ 7.40, (2H, d, J ) 8.4 Hz), 6.83 (2H, d, J ) 8.4 Hz),
6.37 (1H, d, J ) 15.6), 5.90 (1H, m), 5.19 (1H, m), 4.50 (1H, d,
J ) 3.3 Hz), 4.38 (1H, d, J ) 7.2 Hz), 3.96 (1H, q, J ) 6.6 Hz),
3.93 (1H, m), 3.80 (3H, s), 3.78 (1H, m), 3.62 (2H, m), 3.45
(1H, m), 3.32 (1H, br s), 3.30 (1H, m), 3.18 (2H, m), 3.05 (1H,
m), 2.63 (1H, m), 2.49 (1H, m), 2.26 (6H, s), 1.98 (1H, m), 1.84
(1H, m), 1.65 (2H, m), 1.55 (1H, m), 1.43 (3H, d, J ) 7.8 Hz),
1.41 (3H, s), 1.35 (3H, d, J ) 6.9 Hz), 1.27 (3H, s), 1.25 (3H, d,
J ) 6.6 Hz), 1.13 (3H, d, J ) 6.6 Hz), 1.09 (3H, d, J ) 6.9 Hz),
0.88 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 219.2 (C-9), 206.0
(C-3), 169.8 (C-1), 132.3, 129.9, 129.4, 127.9, 124.3, 113.8,
102.7, 78.3, 78.2, 76.0, 74.3, 70.3, 69.4, 69.1, 65.9, 64.3, 55.2,
50.6, 45.4, 45.3, 40.2 (NMe2), 38.7, 37.7, 31.5, 28.4, 21.9, 21.2,
20.3, 18.1, 16.5, 14.6, 13.0, 12.3, 10.9. Anal. (C39H61NO11) C,
H, N.
6-O-(F or m ylm eth yl) Ketolid e 18. Ozone was passed
through a -78 °C solution of compound 14 (2.87 g, 4.0 mmol)
in dichloromethane (100 mL) for 45 min. The reaction mixture
was then flushed with nitrogen for 10 min. Dimethyl sulfide
(1.2 mL, 16 mmol) was added and the reaction mixture was
stirred for 30 min at 0 °C. The reaction mixture was concen-
trated to give white foam whose spectrum was consistent with
that of the corresponding N-oxide of 18. The N-oxide and
triphenylphosphine (3.44 g, 12.0 mmol) were dissolved in THF
(30 mL) and heated to 55 °C for 3.5 h. The mixture was
concentrated and purified by column chromatography (silica
gel, 1:1 acetone/hexane) to give 18 (1.29 g, 52%) as a white
1
solid: MS m/z (FAB) 616 (M + H)+; H NMR (CDCl3) δ 9.43
(1H, m), 5.15 (1H, m), 4.88 (1H, m), 4.45 (1H, m), 4.10-4.39
(3H, m), 3.85-4.00 (2H, m), 3.45-3.65 (3H, m), 2.95-3.25 (3H,
m), 2.90 (1H, m), 2.65 (1H, m), 2.47 (1H, m), 2.26 (6H, s), 1.90-
2.10 (2H, m), 1.50-1.68 (3H, m), 1.53 (3H, s), 1.41 (3H, s), 1.40
(3H, d, J ) 7.8 Hz), 1.10-1.30 (12H, m), 0.85 (3H, t, J ) 7.5
Hz); 13C NMR (CDCl3) δ 220.0 (C-9), 213.0 (CHO), 206.0 (C-
3), 174.8 (C-1), 103.0 (C-1′), 84.6, 78.4, 78.1, 76.0, 74.3, 70.3,
69.6, 69.0, 65.9, 65.6, 50.9, 45.8, 45.0, 40.2 (NMe2), 38.5, 37.9,
31.6, 28.3, 22.0, 21.4, 20.7, 18.2, 16.4, 14.6, 13.3, 12.2, 10.5.
6-O-(2-Am in oeth yl) Ketolid e 19i. To a methanol solution
(10 mL) of 18 (170 mg, 0.276 mmol) was added ammonium
acetate (212 mg, 2.76 mmol), and the mixture was cooled to 0
°C. Sodium cyanoborohydride (34 mg, 0.553 mmol) was added
and the reaction mixture was stirred at room temperature for
24 h. The reaction mixture was taken up in ethyl acetate,
washed with aqueous 5% sodium carbonate, aqueous 2% tris-
(hydroxymethyl)aminomethane, and brine, dried over sodium
6-O-[3-(4′-Ch lor oph en yl)-2-pr open yl] Ketolide 16c. Com-
pound 16c was prepared according to the procedures described
for the preparation of 16a , by replacing iodobenzene with
1-chloro-4-iodobenzene. Compound 16c (309 mg, 58%) was
1
obtained as a white solid: MS m/z (FAB) 724 (M + H)+; H
NMR (CDCl3) δ 7.39, (2H, d, J ) 8.4 Hz), 7.27 (2H, d, J ) 8.4
Hz), 6.58 (1H, d, J ) 15.6), 6.02 (1H, m), 5.16 (1H, m), 4.49
(1H, d, J ) 3.3 Hz), 4.36 (1H, d, J ) 7.2 Hz), 3.96 (1H, q, J )
6.6 Hz), 3.93 (1H, m), 3.78 (1H, m), 3.62 (2H, m), 3.38 (1H, br
s), 3.30 (1H, m), 3.20 (2H, m), 3.05 (1H, m), 2.63 (1H, m), 2.49
(1H, m), 2.26 (6H, s), 1.98 (1H, m), 1.85 (1H, m), 1.65 (2H, m),
1.50 (1H, m), 1.43 (3H, d, J ) 7.8 Hz), 1.41 (3H, s), 1.35 (3H,
d, J ) 6.9 Hz), 1.26 (3H, s), 1.25 (3H, d, J ) 6.6 Hz), 1.13 (3H,
d, J ) 6.6 Hz), 1.10 (3H, d, J ) 6.9 Hz), 0.87 (3H, t, J ) 7.5
Hz); 13C NMR (CDCl3) δ 219.6 (C-9), 206.0 (C-3), 169.8 (C-1),
139.6, 135.5, 131.3, 128.5, 127.9, 127.3, 102.7 (C-1′), 78.4, 78.2,
75.9, 74.2, 70.3, 69.5, 69.2, 65.9, 64.1, 50.6, 45.4, 45.3, 40.2

Erythromycin Derivatives with C-6 Aryl Groups
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4149
sulfate, filtered, and concentrated. Chromatography on silica
gel (90:10:0.5 dichloromethane/methanol/ammonia) gave 19i
(90 mg, 53%) as a white solid: MS m/z (FAB) 617 (M + H)+;
1H NMR (CDCl3) δ 5.21 (1H, dd, J ) 10.5, 3.3 Hz), 4.43 (1H,
d, J ) 3.6 Hz), 4.38 (1H, d, J ) 7.2 Hz), 3.80-4.00 (2H, m),
3.63 (1H, m), 3.05-3.40 (5H, m), 2.88 (1H, m), 2.65 (2H, m),
2.47 (2H, m), 2.27 (6H, s), 1.80-2.10 (2H, m), 1.40-1.70 (3H,
m), 1.45 (3H, d, J ) 7.8 Hz), 1.36 (3H, s), 1.20-1.32 (9H, m),
1.16 (3H, d, J ) 6.6 Hz), 1.13 (3H, d, J ) 6.9 Hz), 0.85 (3H, t,
J ) 7.5 Hz); 13C NMR (CDCl3) δ 217.0 (C-9), 206.3 (C-3), 170.6
(C-1), 102.7 (C-1′), 78.9, 78.5, 75.1, 74.9, 70.3, 69.4, 67.8, 65.9,
63.1, 50.8, 45.8, 44.9, 41.7, 40.3 (NMe2), 38.8, 38.2, 28.4, 22.2,
21.3, 20.7, 19.2, 16.6, 14.9, 12.8, 12.4, 10.9.
0.85 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 217.8 (C-9), 206.2
(C-3), 170.6 (C-1), 149.7, 148.2, 123.3, 102.5 (C-1′), 78.9, 78.4,
75.0, 74.9, 70.2, 69.5, 68.4, 65.9, 61.7, 52.4, 50.7, 48.7, 45.7,
44.8, 40.2(NMe2), 39.2, 38.5, 38.2, 28.4, 21.8, 21.3, 20.6, 18.7,
16.6, 14.6, 12.6, 12.2, 10.7. Anal. (C37H61N3O10) C, H, N.
6-O-[2-(4′-Qu in olylm eth yla m in o)eth yl] Ketolid e 19vii.
To a solution of 19i (90 mg, 0.15 mmol) in methanol (2 mL)
were added 4-quinolinecarboxaldehyde (23 mg, 0.15 mmol),
acetic acid (8.6 µl, 0.15 mmol), and sodium cyanoborohydride
(9.4 mg, 0.15 mmol), and the reaction mixture was stirred for
15 h at room temperature. The reaction mixture was taken
up in ethyl acetate and washed with aqueous 5% sodium
carbonate, aqueous 2% tris(hydroxymethyl)aminomethane,
and brine. The organic phase was dried over sodium sulfate,
filtered, and concentrated. Chromatography on silica gel (90:
10:0.5 dichloromethane/methanol/ammonia) gave 19vii (32
mg, 28%) as an off-white solid. MS m/z (FAB) 758 (M + H)+;
1H NMR (CDCl3) δ 8.90 (1H, d, J ) 4.5 Hz), 8.13 (1H, d, J )
7.8 Hz), 7.96 (1H, d, J ) 8.4 Hz), 7.72 (1H, m), 7.57 (1H, m),
7.55 (1H, d, J ) 4.5 Hz), 5.15 (1H, dd, J ) 10.5, 3.3 Hz), 4.45
(1H, d, J ) 3.6 Hz), 4.36 (1H, d, J ) 7.2 Hz), 4.25 (2H, br s),
3.90-4.00 (2H, m), 3.62 (1H, m), 3.10-3.40 (5H, m), 2.95 (1H,
m), 2.40-2.70 (4H, m), 2.26 (6H, s), 1.85-2.05 (2H, m), 1.50-
1.70 (3H, m), 1.44 (3H, d, J ) 7.8 Hz), 1.35 (3H, s), 1.29 (3H,
d, J ) 6.3 Hz), 1.27 (3H, s), 1.24 (3H, d, J ) 6.3 Hz), 1.16 (3H,
d, J ) 6.6 Hz), 1.15 (3H, d, J ) 6.9 Hz), 0.82 (3H, t, J ) 7.5
Hz); 13C NMR (CDCl3) δ 218.0 (C-9), 206.2 (C-3), 170.6 (C-1),
150.4, 150.3, 148.0, 146.2, 130.1, 130.0, 129.4, 126.7, 122.8,
118.2, 102.5 (C-1′), 78.9, 78.3, 75.0, 74.9, 70.2, 69.5, 68.4, 65.9,
61.5, 50.7, 49.3, 48.9, 45.7, 44.8, 40.2(NMe2), 38.5, 38.2, 28.4,
21.9, 21.3, 20.6, 18.7, 16.6, 14.7, 12.6, 12.2, 10.7.
2′,4′′-O-Dia cetyl-6-O-a llyl-12-O-a cylim id a zolyl Er yth -
r om ycin A (22). To a stirred solution of 6-O-allylerythromycin
11 (8.93 g, 11.6 mmol) and DMAP (0.35 g, 2.87 mmol) in
methylene chloride (45 mL) was added acetic anhydride (6.85
mL, 62.1 mmol) dropwise over 10 min. The reaction mixture
was stirred at room temperature for 1 h. The mixture was
diluted with an additional 50 mL of methylene chloride,
washed with 5% sodium bicarbonate and brine, and dried over
sodium sulfate. The corresponding 2′,4′′-O-diacetate of 11 was
obtained as a white solid (9.10 g, 92%) after recrystallization
from ethyl acetate/hexane.
6-O-[2-(Ben zyla m in o)eth yl] Ketolid e 19ii. To a 0 °C
solution in methanol (10 mL) of 18 (123 mg, 0.200 mmol) was
added acetic acid (114 µl, 2.00 mmol) and benzylamine (218
µl, 2.00 mmol), and the mixture was stirred for 10 min. Sodium
cyanoborohydride (24.8 mg, 0.400 mmol) was added and the
reaction mixture was stirred at room temperature for 16 h.
Additional sodium cyanoborohydride (24.8 mg, 0.400 mmol)
was added and stirring was continued for 24 h. The reaction
mixture was taken up in ethyl acetate, washed with aqueous
5% sodium carbonate, aqueous 2% tris(hydroxymethyl)ami-
nomethane, and brine, dried over sodium sulfate, filtered, and
concentrated. Chromatography on silica gel (95:5:0.5 dichlo-
romethane/methanol/ammonia) followed by a second chroma-
tography (50:50:0.5 acetone/hexanes/triethylamine) gave 19ii
(82 mg, 58%) as a white foam: MS m/z (FAB) 707 (M + H)+;
1H NMR (CDCl3) δ 7.20-7.40 (5H, m), 5.06 (1H, dd, J ) 10.5,
3.3 Hz), 4.38 (1H, d, J ) 3.6 Hz), 4.36 (1H, d, J ) 7.2 Hz),
3.90-4.00 (2H, m), 3.74 (2H, m), 3.61 (1H, m), 3.38 (1H, br s),
3.30 (2H, m), 3.24 (1H, br s), 3.16 (1H, m), 3.08 (1H, m), 2.86
(1H, m), 2.63 (1H, m), 2.40-2.53 (3H, m), 2.26 (6H, s), 1.80-
2.00 (2H, m), 1.66 (1H, m), 1.57 (1H, m), 1.50 (1H, m), 1.43
(3H, d, J ) 7.8 Hz), 1.32 (3H, s), 1.29 (3H, d, J ) 6.3 Hz), 1.27
(3H, s), 1.24 (3H, d, J ) 6.3 Hz), 1.16 (3H, d, J ) 6.6 Hz), 1.12
(3H, d, J ) 6.9 Hz), 0.80 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3)
δ 216.6 (C-9), 206.3 (C-3), 170.5 (C-1), 139.0, 128.6, 128.3,
126.9, 102.4 (C-1′), 78.9, 78.4, 75.1, 74.8, 70.2, 69.4, 67.8, 65.9,
61.7, 53.2, 50.7, 48.2, 45.6, 44.8, 40.2 (NMe2), 38.8, 38.0, 28.3,
21.9, 21.3, 20.6, 18.8, 16.6, 14.6, 12.6, 12.3, 10.7.
6-O-[2-(P h en eth yla m in o)eth yl] Ketolid e 19iii. To a 0 °C
solution in methanol (10 mL) of 18 (123 mg, 0.200 mmol) was
added acetic acid (114 µL, 2.00 mmol) and phenethylamine
(251 µL, 2.00 mmol), and the mixture was stirred for 10 min.
Sodium cyanoborohydride (24.8 mg, 0.400 mmol) was added
and the reaction mixture was stirred for 16 h at room
temperature. The reaction mixture was taken up in ethyl
acetate, washed with aqueous 5% sodium carbonate, aqueous
2% tris(hydroxymethyl)aminomethane, and brine, dried over
sodium sulfate, filtered, and concentrated. Chromatography
on silica gel (90:10:0.5 dichloromethane/methanol/ammonia)
gave the title compound (60 mg, 42%) as a white foam: MS
To a -40 °C solution under nitrogen in THF (30 mL) of the
diacetate prepared above (4.84 g, 5.64 mmol) was added
sodium hexamethyldisilazide (1.0 M in THF, 7.05 mL, 7.05
mmol), and the resulting white suspension was stirred for 40
min. A solution of carbonyldiimidazole (3.65 g, 22.56 mmol)
in THF (30 mL) and DMF (20 mL) was added dropwise over
30 min at -40 °C, and then the cold bath was removed and
the reaction mixture was stirred for 24 h. The reaction mixture
was taken up in ethyl acetate, washed with aqueous 5%
sodium bicarbonate and brine, dried over sodium sulfate,
filtered, and concentrated to give 22 (6.32 g, crude) as a white
foam, which was used without further purification.
1
m/z (FAB) 721 (M + H)+; H NMR (CDCl3) δ 7.16-7.35 (5H,
m), 5.21 (1H, dd, J ) 10.5, 3.3 Hz), 4.40 (1H, d, J ) 3.6 Hz),
4.36 (1H, d, J ) 7.2 Hz), 3.80-4.00 (2H, m), 3.62 (1H, m),
3.00-3.45 (6H, m), 2.75-3.00 (5H, m), 2.40-2.65 (4H, m), 2.26
(6H, s), 1.80-2.10 (2H, m), 1.66 (1H, m), 1.57 (1H, m), 1.50
(1H, m), 1.43 (3H, d, J ) 7.8 Hz), 1.33 (3H, s), 1.29 (3H, d, J
) 6.3 Hz), 1.27 (3H, s), 1.25 (3H, d, J ) 6.3 Hz), 1.16 (3H, d,
J ) 6.6 Hz), 1.12 (3H, d, J ) 6.9 Hz), 0.85 (3H, t, J ) 7.5 Hz).
Anal. (C39H64N2O10) C, H, N.
2′,4′′-O-Dia cetyl-6-O-a llyl-11,12-cycloca r ba m a te Er yth -
r om ycin A (23). To a solution of 22 (6.32 g, crude) in
acetonitrile (100 mL) and water (10 mL) was added 28%
aqueous ammonia, and the mixture was stirred at room
temperature for 4 days. The solvent was evaporated and the
residue was taken up in ethyl acetate. The resulting solution
was washed with aqueous 5% sodium bicarbonate and brine,
dried over sodium sulfate, filtered, and concentrated. The
crude product was purified by column chromatography (silica
gel, 1:1 acetone/hexane) to give 23 (3.88 g, 78% in two steps)
as a white solid: MS m/z (FAB) 883 (M + H)+; HRMS (FAB)
m/z 883.5164, calcd for C45H75N2O15 883.5162; 1H NMR (CDCl3)
δ 5.72 (1H, m), 5.64 (1H, br s), 5.15 (2H, m), 5.04 (1H, dd, J )
6.6, 2.4 Hz), 4.96 (1H, d, J ) 4.5 Hz), 4.66-4.80 (3H, m), 4.30
(1H, m), 3.89 (1H, m), 3.78 (2H, m), 3.68 (1H, s), 3.64 (1H, d,
J ) 6.0 Hz), 3.35 (3H, s), 2.90 (2H, m), 2.73 (1H, m), 2.56 (1H,
m), 2.42 (1H, d, J ) 15 Hz), 2.28 (6H, s), 2.10 (3H, s), 2.05
(3H, s), 2.00 (3H, s), 1.90 (2H, m), 1.25-1.77 (6H, m), 1.42 (3H,
s), 1.38 (3H, s), 1.22 (3H, d, J ) 6.6 Hz), 1.10-1.20 (12H, m),
0.96 (3H, d, J ) 7.0 Hz), 0.87 (3H, t, J ) 7.5 Hz); 13C NMR
6-O-[2-(4′-P yr id ylm eth yla m in o)eth yl] Ketolid e 19vi.
Compound 19vi (120 mg, 85%) was prepared according to the
procedures for the preparation of 19iii, replacing phenethy-
lamine with 4-(aminomethyl)pyridine: MS m/z (FAB) 708 (M
1
+ H)+; H NMR (CDCl3) δ 8.56 (2H, d, J ) 6.0 Hz), 7.35 (2H,
d, J ) 6.0 Hz), 5.13 (1H, dd, J ) 10.5, 3.3 Hz), 4.42 (1H, d, J
) 3.6 Hz), 4.37 (1H, d, J ) 7.2 Hz), 3.90-4.00 (2H, m), 3.77
(2H, m), 3.62 (1H, m), 3.43 (1H, br s), 3.10-3.40 (5H, m), 2.90
(1H, m), 2.63 (1H, m), 2.40-2.55 (3H, m), 2.26 (6H, s), 1.85-
2.05 (2H, m), 1.50-1.70 (3H, m), 1.43 (3H, d, J ) 7.8 Hz), 1.35
(3H, s), 1.29 (3H, d, J ) 6.3 Hz), 1.27 (3H, s), 1.24 (3H, d, J )
6.3 Hz), 1.16 (3H, d, J ) 6.6 Hz), 1.14 (3H, d, J ) 6.9 Hz),

4150 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Ma et al.
(CDCl3) δ 217.4 (C-9), 175.7 (C-1), 170.3 (CH3CO), 169.9 (CH3-
CO), 158.2 (carbamate), 134.5, 118.1, 99.6 (C-1′), 95.9 (C-1′′),
83.9, 79.2, 79.1, 78.4, 77.7, 75.6, 72.7, 72.1, 67.2, 65.6, 63.3,
63.1, 57.4, 49.2, 45.2, 44.6, 40.7 (NMe2), 38.9, 38.1, 37.3, 35.1,
31.2, 30.8, 22.4, 21.5, 21.1, 20.9, 20.8, 18.4, 18.2, 15.4, 13.8,
13.4, 10.5, 9.0.
mmol) was added dropwise over 5 min and stirred for an
additional 10 min at this temperature. A solution of the above
product (8.10 g, 11.9 mmol) in CH2Cl2 (60 mL) was introduced
dropwise over 30 min. After the mixture was stirred for 30
min at -10 to -5 °C, Et3N (1.99 mL, 14.3 mmol) was added
over 5 min and stirred for an additional 45 min before the
mixture warmed up to room temperature. The reaction mix-
ture was taken up in EtOAc and washed with 5% Na2CO3 and
brine. The organic phase was dried (Na2SO4) and concentrated.
The crude product was purified by column chromatography
(silica gel, 50:50:0.5 acetone/hexane/triethylamine) to give 26
(8.07 g 99%) as a white solid: MS m/z (FAB) 681 (M + H)+;
1H NMR (CDCl3) δ 5.61 (1H, br s), 5.55 (1H, m), 5.05-5.15
(3H, m), 4.74 (1H, dd, J ) 10.2, 7.5 Hz), 4.45 (1H, d, J ) 7.2
Hz), 4.32 (1H, d, J ) 3.6 Hz), 3.91 (1H, q, J ) 6.6 Hz), 3.88
(1H, br s), 3.62 (2H, m), 3.38 (1H, m), 3.16 (1H, m), 2.95 (1H,
m), 2.50-2.80 (3H, m), 2.27 (6H, s), 2.25 (1H, m), 2.04 (3H, s),
2.00 (3H, s), 1.95 (1H, m), 1.50-1.80 (3H, m), 1.53 (3H, s), 1.35
(3H, d, J ) 6.6 Hz), 1.32 (3H, s), 1.25 (3H, d, J ) 6.0 Hz), 1.23
(3H, d, J ) 6.9 Hz), 1.16 (3H, d, J ) 6.6 Hz), 1.13 (3H, d, J )
6.9 Hz), 0.88 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 216.8
(C-9), 205.3 (C-3), 169.7 (C-1), 169.5 (CH3CO), 157.9 (carbam-
ate), 134.3, 118.3, 100.3 (C-1′), 83.6, 78.4, 77.1, 75.1, 71.5, 69.0,
64.6, 63.3, 57.8, 50.7, 45.3, 45.0, 40.6 (NMe2), 38.6, 37.3, 30.6,
22.6, 21.3, 21.0, 20.1, 18.2, 14.4, 13.8, 13.6, 13.5, 10.5. Anal.
(C35H56N2O11) C, H, N.
6-O-[3-(3′-Qu in olyl)-2-p r op en yl]-11,12-cycloca r b a m -
a te Er yth r om ycin A (25s). To a solution of 23 (3.53 g, 4.00
mmol), palladium(II) acetate (135 mg, 0.60 mmol), and tri(o-
tolyl)phosphine (365 mg, 1.20 mmol) in acetonitrile (40 mL)
were added 3-bromoquinoline (0.831 mL, 6.12 mmol) and
triethylamine (1.15 mL, 8.26 mmol), and the mixture was
cooled to -78 °C and degassed. The reaction mixture was
warmed to 60 °C for 0.5 h and stirred at 100 °C for 20 h.
Additional palladium(II) acetate (90 mg, 0.40 mmol), and tri-
(o-tolyl)phosphine (122 mg, 0.40 mmol), 3-bromoquinoline
(0.543 mL, 4.00 mmol), and triethylamine (0.836 mL, 6.00
mmol) were added, and the mixture was stirred at 100 °C for
an additional 8 h under nitrogen. The reaction mixture was
taken up in ethyl acetate, washed twice with aqueous 5%
sodium bicarbonate, once with aqueous 2% tris(hydroxy-
methyl)aminomethane, and once with brine, dried over sodium
sulfate, filtered, and concentrated. The crude mixture was
purified by flash column chromatography on silica gel (1:1
acetone/hexane) to give the coupling product (2.85 g, 71%) as
an off-white solid: MS m/z (APCI)+ 1010 (M + H)+.
6-O-Allyl-11,12-cycloca r ba m a te Ketolid e 27. Compound
27 (89%) was obtained by stirring 26 in methanol for 24 h
followed by chromatography (silica gel, 95:5:0.5 methylene
chloride/methanol/ammonia): MS m/z (APCI) 639 (M + H)+;
HRMS (APCI) m/z 639.3854, calcd for C33H55N2O10 639.3857;
1H NMR (CDCl3) δ 5.60 (1H, br s), 5.55 (1H, m), 5.05-5.15
(3H, m), 4.38 (1H, d, J ) 7.2 Hz), 4.34 (1H, d, J ) 3.6 Hz),
3.95 (1H, q, J ) 6.6 Hz), 3.88 (1H, br s), 3.62 (2H, m), 3.40
(1H, m), 3.18 (2H, m), 2.95 (1H, m), 2.61 (1H, m), 2.48 (1H,
m), 2.27 (6H, s), 1.96 (1H, m), 1.50-1.80 (4H, m), 1.53 (3H, s),
1.39 (3H, d, J ) 6.9 Hz), 1.36 (3H, s), 1.34 (3H, d, J ) 6.0 Hz),
1.26 (3H, d, J ) 6.6 Hz), 1.17 (3H, d, J ) 6.6 Hz), 1.12 (3H, d,
J ) 6.9 Hz), 0.88 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 216.9
(C-9), 205.3 (C-3), 169.5 (C-1), 157.9 (carbamate), 134.4, 118.3,
102.8 (C-1′), 83.7, 78.4, 77.1, 76.1, 70.2, 69.5, 65.9, 64.6, 57.8,
50.8, 45.9, 45.1, 40.2 (NMe2), 38.9, 37.3, 28.3, 22.6, 21.3, 20.2,
18.2, 14.4, 13.8, 13.6, 10.6. Anal. (C33H54N2O10) C, H, N.
6-O-Allyl-2′-O-ben zoyl-12-O-acylim idazolyl Ketolide 28.
To a stirred 0 °C solution of 13 (73.5 g, 102 mmol) and
carbonyldiimidazole (CDI) (83.0 g, 512 mmol) in THF (1200
mL) was added LiH (1.71 g, 205 mmol) in small portions. The
reaction mixture was stirred at room temperature for 7 days.
The mixture was diluted with ethyl acetate, washed with 5%
sodium bicarbonate and brine, dried over sodium sulfate, and
concentrated. The crude product was purified by column
chromatography (silica gel, 3:7 acetone/hexane) to give inter-
mediate 28 (51.1 g, 68%) as a white solid: 1H NMR (CDCl3) δ
8.12 (1H, m), 8.03 (2H, dd, J ) 8.4, 1.5 Hz), 7.54 (1H, m), 7.44
(2H, m), 7.39 (1H, m), 7.08 (1H, m), 6.65 (1H, br s), 5.72 (2H,
m), 5.10 (1H, dd, J ) 15, 1.8 Hz), 5.01 (2H, m), 4.55 (1H, d,
J ) 7.5 Hz), 4.19 (1H, d, J ) 4.8 Hz), 3.95 (1H, m), 3.82 (1H,
m), 3.66 (1H, q, J ) 6.6 Hz), 3.55 (1H, m), 3.43 (1H, m), 3.03
(1H, m), 2.86 (1H, m), 2.26 (6H, s), 1.86 (3H, s), 1.76 (3H, s),
1.61 (3H, s), 1.36 (3H, d, J ) 6.9 Hz), 1.29 (3H, d, J ) 6.0 Hz),
1.20 (3H, br s), 1.11 (3H, d, J ) 6.6 Hz), 0.88 (3H, t, J ) 7.5
Hz).
To a stirred solution of the above coupling product (2.53 g,
2.50 mmol) in methanol (50 mL) was added 2 N sodium
hydroxide solution (7.5 mL, 15 mmol), and the mixture was
stirred at room temperature for 24 h. The reaction mixture
was taken up in ethyl acetate, washed with aqueous 5%
sodium bicarbonate and brine, and dried over sodium sulfate.
The crude mixture was purified by flash column chromatog-
raphy on silica gel (10:1:0.05 methylene chloride/methanol/
ammonia) to give 25 (1.42 g, 61%) as an off-white solid: MS
m/z (APCI)+ 926 (M + H)+; HRMS (FAB) m/z 926.5397, calcd
for C50H76N3O13 926.5378; 1H NMR (CDCl3) δ 9.06 (1H, d, J )
1.8 Hz), 8.25 (1H, d, J ) 1.8 Hz), 8.06 (1H, d, J ) 7.8 Hz),
7.82 (1H, d, J ) 7.8 Hz), 7.63 (1H, m), 7.50 (1H, m), 6.65 (1H,
d, J ) 15.6 Hz), 6.41 (1H, dt, J ) 15.6, 6.6 Hz), 5.60 (1H, br
s), 4.95 (1H, d, J ) 4.8 Hz), 4.85 (1H, dd, J ) 9.0, 2.4 Hz),
4.49 (1H, d, J ) 7.8 Hz), 4.22 (1H, m), 4.03 (2H, m), 3.90 (1H,
d, J ) 7.8 Hz), 3.89 (1H, m), 3.87 (1H, s), 3.53 (2H, m), 3.34
(3H, s), 3.20 (1H, dd, J ) 9.3, 6.6 Hz), 3.06 (1H, t, J ) 9.0 Hz),
2.80-3.00 (2H, m), 2.63 (1H, m), 2.46 (1H, m), 2.39 (1H, d, J
) 15.0 Hz), 2.31 (6H, s), 2.21 (1H, d, J ) 9.0 Hz), 1.55-2.00
(6H, m), 1.50 (3H, s), 1.43 (1H, m), 1.41 (3H, s), 1.33 (3H, d, J
) 6.6 Hz), 1.27 (3H, s), 1.25 (3H, d, J ) 6.6 Hz), 1.23 (3H, d,
J ) 6.9 Hz), 1.17 (3H, s), 1.13 (3H, s), 1.12 (3H, d, J ) 6.3
Hz), 0.74 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 217.5 (C-9),
175.7 (C-1), 157.5 (carbamate), 149.9, 147.2, 132.0, 129.5,
129.4, 128.7, 128.5, 128.0, 127.6, 126.2, 102.2 (C-1′), 95.7 (C-
1′′), 83.4, 79.2, 77.9, 77.4, 75.7, 72.4, 70.5, 68.4, 65.6, 65.3, 64.6,
57.4, 49.1, 44.8, 44.5, 39.9 (NMe2), 39.6, 38.4, 36.9, 34.4, 28.3,
22.0, 21.0, 20.6, 18.3, 18.1, 14.9, 13.3, 13.0, 10.2, 8.5.
2′-O-Acetyl-6-O-allyl-11,12-cyclocar bam ate Ketolide 26.
To a stirred suspension of 23 (69.0 g, 78.2 mmol) in ethanol
(200 mL) and water (400 mL), was added 1 N HCl (400 mL,
0.400 mol) dropwise over 20 min, and a clear solution was
obtained. The solution was stirred at room temperature for
72 h. More HCl (4 N, 100 mL, 0.4 mol) was added to the
reaction mixture and the mixture was stirred for an additional
48 h. The mixture was neutralized with 4 N NaOH and the
precipitate was collected by filtration to give a white solid,
35.56 g. The filtrate was extracted with ethyl acetate (2 × 400
mL), and the organic phase was washed with 5% sodium
carbonate and brine, dried over sodium sulfate, and concen-
trated to give an additional 21.58 g of white solid. The
combined crude material was purified by column chromatog-
raphy (silica gel, 50:50:0.5 acetone/hexane/triethylamine) to
give 25.64 g (48%) of the 3-OH intermediate. MS m/z (APCI)+
683 (M + H)+.
6-O-Allyl-2′-O-ben zoyl-11,12-cycloca r ba m a te Ketolid e
29. To a stirred solution of 28 (1.19 g, 1.50 mmol) in CH3CN
(20 mL) and THF (2 mL) was added aqueous 28% ammonia
(2 mL). The mixture was stirred at room temperature for 48
h and diluted with EtOAc (50 mL). The organic solution was
washed with 5% Na2CO3 and brine, dried over Na2SO4, and
concentrated. Column chromatography (silica gel, 3:7 acetone/
hexane) gave 29 (565 mg, 51%) and 30 (356 mg, 32%), both as
white solids. 29: MS m/z (APCI) 743 (M + H)+; 1H NMR
(CDCl3) δ 8.02 (2H, dd, J ) 7.8, 1.2 Hz), 7.56 (1H, m), 7.43
(2H, m), 5.56 (1H, br s), 5.54 (1H, m), 5.05-5.15 (3H, m), 4.58
(1H, d, J ) 7.2 Hz), 4.32 (1H, d, J ) 3.6 Hz), 3.82 (1H, br s),
NCS (2.37 g, 17.8 mmol) was dissolved in CH2Cl2 (80 mL)
and cooled to -10 °C under nitrogen. Me2S (1.52 mL, 20.8

Erythromycin Derivatives with C-6 Aryl Groups
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4151
3.78 (1H, q, J ) 6.6 Hz), 3.64 (2H, m), 3.37 (1H, m), 3.05 (1H,
m), 2.85 (2H, m), 2.56 (1H, m), 2.27 (6H, s), 1.94 (1H, m), 1.80
(1H, m), 1.40-1.60 (3H, m), 1.43 (3H, s), 1.35 (3H, s), 1.30 (3H,
d, J ) 6.9 Hz), 1.29 (3H, d, J ) 6.0 Hz), 1.12 (3H, d, J ) 6.3
Hz), 1.08 (3H, d, J ) 6.6 Hz), 0.98 (3H, d, J ) 6.9 Hz), 0.88
(3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 216.9 (C-9), 205.4 (C-
3), 169.4 (C-1), 165.2 (PhCO), 157.9 (carbamate), 134.3, 132.8,
130.5, 129.7, 128.3, 118.3, 100.6 (C-1′), 83.6, 78.4, 77.1, 75.3,
71.9, 69.2, 64.6, 63.5, 57.7, 50.7, 45.3, 45.1, 40.7 (NMe2), 38.5,
37.2, 31.5, 22.6, 21.1, 20.2, 18.3, 14.4, 14.1, 13.6, 13.5, 10.5.
69.5, 65.9, 64.7, 62.4, 50.9, 45.8, 45.3, 40.2 (NMe2), 38.9, 38.7,
32.1, 28.3, 22.6, 21.1, 20.5, 18.9, 14.7, 14.5, 14.1, 13.8, 13.7,
10.5.
11-N-[2-(N,N-Dim eth ylam in o)eth yl]-11,12-cyclocar bam -
a te Ketolid e 38s. Following the procedure for the preparation
of 35s, compound 38s was obtained in 20% yield: MS m/z
(APCI) 837 (M + H)+; 1H NMR (CDCl3) δ 9.02 (1H, d, J ) 2.4
Hz), 8.15 (1H, d, J ) 2.4 Hz), 8.06 (1H, m), 7.82 (1H, m), 7.66
(1H, m), 7.52 (1H, m), 6.57 (1H, d, J ) 16.2 Hz), 6.30 (1H, dt,
J ) 16.2, 6.0 Hz), 5.25 (1H, dd, J ) 9.6, 2.7 Hz), 4.47 (1H, d,
J ) 5.1 Hz), 4.34 (1H, d, J ) 7.2 Hz), 3.97 (1H, q, J ) 6.6 Hz),
3.90 (1H, m), 3.70 (2H, m), 3.25 (1H, m), 3.19 (2H, m), 2.95
(1H, m), 2.72 (1H, m), 2.60 (1H, m), 2.47 (2H, m), 2.26 (6H, s),
2.15-2.30 (2H, m), 2.12 (6H, s), 2.00 (1H, m), 1.40-1.80 (4H,
m), 1.52 (3H, s), 1.42 (3H, s), 1.41 (3H, d, J ) 6.9 Hz), 1.38
(3H, d, J ) 6.3 Hz), 1.20 (3H, d, J ) 6.0 Hz), 1.16 (3H, d, J )
6.0 Hz), 1.08 (3H, d, J ) 6.6 Hz), 0.85 (3H, t, J ) 7.5 Hz).
6-O-Allyl Tr icyclic Ketolid e 39. To a stirred solution of
28 (385 mg, 0.485 mmol) in CH3CN (10 mL) was added
ethylenediamine (291 mg, 4.85 mmol). The mixture was stirred
at room temperature for 60 h and diluted with EtOAc (50 mL).
The organic solution was washed with 5% Na2CO3 and brine,
dried over Na2SO4, and concentrated. The crude mixture was
then dissolved in MeOH (5 mL) and HOAc (60 µL, 1.00 mmol)
and stirred at room temperature for 48 h. The mixture was
diluted with EtOAc (50 mL) and washed with 5% Na2CO3 and
brine, dried over Na2SO4, and concentrated. Column chroma-
tography (silica gel, 95:5:0.5 CH2Cl2/MeOH/ammonia) gave 39
(126 mg, 40%) as an off-white solid: MS m/z (APCI) 664 (M +
H)+; HRMS (FAB) m/z 664.4173, calcd for C35H58N3O9 664.4173;
1H NMR (CDCl3) δ 5.65 (1H, m), 5.13 (1H, m), 5.02 (1H, m),
4.40 (1H, d, J ) 4.2 Hz), 4.34 (1H, d, J ) 7.5 Hz), 3.92 (1H, q,
J ) 6.6 Hz), 3.72 (2H, m), 3.58 (1H, m), 3.20 (2H, m), 2.85
(1H, m), 2.47 (1H, m), 2.27 (6H, s), 1.95 (1H, m), 1.40-1.70
(4H, m), 1.51 (3H, s), 1.40 (3H, d, J ) 6.9 Hz), 1.38 (3H, s),
1.34 (3H, d, J ) 6.0 Hz), 1.24 (3H, d, J ) 6.3 Hz), 1.22 (3H, d,
J ) 6.6 Hz), 1.05 (3H, d, J ) 6.9 Hz), 0.87 (3H, t, J ) 7.5 Hz);
13C NMR (CDCl3) δ 205.3 (C-3), 180.8 (C-9), 170.0 (C-1), 156.1
(carbamate), 137.1, 116.6, 103.0 (C-1′), 81.7, 79.4, 77.1, 76.1,
70.3, 69.5, 65.9, 64.8, 60.3, 50.8, 49.4, 46.0, 43.1, 42.0, 40.2
(NMe2), 38.5, 36.4, 31.5, 28.3, 22.4, 21.3, 20.4, 20.2, 14.7, 13.6,
13.0, 10.5.
11,12-Cycloca r ba za te Ketolid e 35s. To a stirred solution
of 28 (793 mg, 1.00 mmol) in CH3CN (10 mL) and THF (1 mL)
was added aqueous 85% hydrazine (0.5 mL). The mixture was
stirred at room temperature for 96 h and diluted with EtOAc
(50 mL). The organic phase was washed with 5% Na2CO3 and
brine, dried over Na2SO4, and concentrated. Column chroma-
tography (silica gel, 95:5:0.5 CH2Cl2/MeOH/ammonia) gave 31
(as 2′-OH, 341 mg, 52%) as an off-white solid: MS m/z (APCI)
654 (M + H)+.
Heck coupling of 31 and 3-bromoquinoline was conducted
according to the procedure described for the preparation of 25s.
Compound 35s was obtained in 40% yield after column
chromatography (silica gel, 95:5:0.5 CH2Cl2/MeOH/ammo-
nia): MS m/z (APCI) 781 (M + H)+; HRMS (FAB) m/z
781.4371, calcd for C42H61N4O10 781.4388; 1H NMR (CDCl3) δ
9.02 (1H, d, J ) 2.4 Hz), 8.12 (1H, d, J ) 2.4 Hz), 8.06 (1H,
m), 7.80 (1H, m), 7.66 (1H, m), 7.52 (1H, m), 6.58 (1H, d, J )
16.2 Hz), 6.31 (1H, dt, J ) 16.2, 6.0 Hz), 5.08 (1H, m), 4.45
(1H, d, J ) 5.1 Hz), 4.36 (1H, d, J ) 7.2 Hz), 3.98 (1H, q, J )
6.6 Hz), 3.95 (1H, m), 3.86 (1H, m), 3.56 (1H, m), 3.20 (3H,
m), 2.79 (1H, m), 2.53 (1H, m), 2.29 (6H, s), 1.96 (1H, m), 1.40-
1.80 (4H, m), 1.50 (3H, s), 1.48 (3H, s), 1.43 (3H, d, J ) 6.9
Hz), 1.41 (3H, d, J ) 6.6 Hz), 1.15-1.25 (6H, m), 1.08 (3H, d,
J ) 6.6 Hz), 0.86 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 216.7
(C-9), 205.0 (C-3), 170.1 (C-1), 149.3, 147.8, 132.5, 129.9, 129.3,
129.2, 128.7, 128.5, 128.1, 128.0, 126.9, 124.9, 103.0 (C-1′),
80.9, 79.1, 77.6, 76.8, 70.2, 69.5, 66.0, 64.6, 62.9, 50.9, 45.8,
45.0, 40.2 (NMe2), 39.5, 38.8, 31.6, 28.5, 22.6, 22.4, 21.1, 20.5,
18.6, 14.6, 14.3, 13.9, 13.6, 10.4. Anal. (C42H60N4O10) C, H, N.
11-N-Meth oxy-11,12-cycloca r ba m a te Ketolid e 36s. Fol-
lowing the procedure for the preparation of 35s, compound 36s
was obtained in 30% yield: MS m/z (APCI) 796 (M + H)+; 1H
NMR (CDCl3) δ 9.02 (1H, d, J ) 2.4 Hz), 8.08 (1H, d, J ) 2.4
Hz), 8.06 (1H, m), 7.79 (1H, m), 7.66 (1H, m), 7.52 (1H, m),
6.61 (1H, d, J ) 16.2 Hz), 6.43 (1H, dt, J ) 16.2, 6.0 Hz), 5.18
(1H, dd, J ) 9.6, 2.7 Hz), 4.40 (1H, d, J ) 5.1 Hz), 4.30 (1H,
d, J ) 7.2 Hz), 4.12 (1H, q, J ) 6.6 Hz), 4.03 (1H, m), 3.93
(1H, m), 3.60 (3H, s), 3.52 (1H, m), 3.18 (2H, m), 3.05 (1H,m),
2.93 (1H, m), 2.46 (2H, m), 2.27 (6H, s), 1.94 (1H, m), 1.40-
1.80 (4H, m), 1.53 (6H, s), 1.41 (3H, d, J ) 6.9 Hz), 1.38 (3H,
d, J ) 6.6 Hz), 1.23 (3H, d, J ) 6.0 Hz), 1.16 (3H, d, J ) 6.0
Hz), 1.14 (3H, d, J ) 6.6 Hz), 0.90 (3H, t, J ) 7.5 Hz); 13C
NMR (CDCl3) δ 211.8 (C-9), 203.8 (C-3), 170.1 (C-1), 156.2,
149.0, 147.4, 132.4, 130.4, 129.7, 129.1, 128.1, 127.9, 127.8,
126.8, 103.9 (C-1′), 81.3, 80.8, 78.6, 70.2, 69.5, 65.8, 64.8, 63.0,
62.0, 50.9, 46.2, 41.3, 40.2 (NMe2), 39.6, 38.3, 28.2, 22.7, 21.1,
17.1, 15.1, 14.4, 13.5, 11.0, 10.4.
6-O-[3-(3′-Qu in olyl)-2-p r op en yl] Tr icyclic Ketolid e 40s.
To a solution of 39 (663 mg, 1.00 mmol), palladium(II) acetate
(50 mg, 0.20 mmol), and tri(o-tolyl)phosphine (120 mg, 0.40
mmol) in acetonitrile (5 mL) were added 3-bromoquinoline
(0.270 mL, 2.00 mmol) and triethylamine (0.280 mL, 2.00
mmol). The mixture was cooled to -78 °C and degassed. The
reaction mixture was then warmed to 60 °C for 0.5 h and
stirred at 80 °C for 18 h. The reaction mixture was taken up
in ethyl acetate, washed twice with aqueous 5% sodium
bicarbonate, once with aqueous 2% tris(hydroxymethyl)ami-
nomethane, and once with brine, dried over sodium sulfate,
filtered, and concentrated. The crude mixture was purified by
flash column chromatography on silica gel (95:5:0.5 CH2Cl2/
MeOH/ammonia) to give 40s (486 mg, 62%) as an off-white
solid: MS m/z (APCI) 791 (M + H)+; HRMS (FAB) m/z
1
791.4590, calcd for C44H63N4O9 791.4595; H NMR (CDCl3) δ
11-N-Meth yl-11,12-Cycloca r ba m a te Ketolid e 37s. Fol-
lowing the procedure for the preparation of 35s, compound 37s
was obtained in 35% yield: MS m/z (APCI) 780 (M + H)+; 1H
NMR (CDCl3) δ 9.02 (1H, d, J ) 2.4 Hz), 8.12 (1H, d, J ) 2.4
Hz), 8.06 (1H, m), 7.81 (1H, m), 7.66 (1H, m), 7.52 (1H, m),
6.57 (1H, d, J ) 16.2 Hz), 6.24 (1H, dt, J ) 16.2, 6.0 Hz), 4.98
(1H, dd, J ) 9.6, 2.7 Hz), 4.47 (1H, d, J ) 5.1 Hz), 4.35 (1H,
d, J ) 7.2 Hz), 3.97 (1H, q, J ) 6.6 Hz), 3.92 (1H, m), 3.80
(1H, m), 3.55 (1H, m), 3.25 (1H, m), 3.18 (2H, m), 2.85 (3H, s),
2.70 (1H, m), 2.47 (1H, m), 2.27 (6H, s), 1.97 (1H, m), 1.40-
1.80 (4H, m), 1.53 (3H, s), 1.46 (3H, s), 1.43 (3H, d, J ) 6.9
Hz), 1.38 (3H, d, J ) 6.3 Hz), 1.20 (3H, d, J ) 6.0 Hz), 1.18
(3H, d, J ) 6.0 Hz), 1.05 (3H, d, J ) 6.6 Hz), 0.87 (3H, t, J )
7.5 Hz); 13C NMR (CDCl3) δ 215.3 (C-9), 205.1 (C-3), 170.0 (C-
1), 157.2, 149.5, 134.3, 132.5, 129.8, 129.6, 129.2, 129.1, 128.8,
127.9, 127.8, 126.8, 103.1 (C-1′), 82.3, 79.1, 77.9, 76.7, 70.2,
9.00 (1H, d, J ) 2.4 Hz), 8.13 (1H, d, J ) 2.4 Hz), 8.07 (1H, d,
J ) 8.4 Hz),), 7.80 (1H, d, J ) 8.4 Hz), 7.66 (1H, m), 7.52 (1H,
m), 6.63 (1H, d, J ) 16.2 Hz), 6.40 (1H, dt, J ) 16.2, 6.0 Hz),
5.02 (1H, dd, J ) 10.2, 2.7 Hz), 4.48 (1H, d, J ) 5.1 Hz), 4.36
(1H, d, J ) 7.2 Hz), 4.03 (1H, m), 3.98 (1H, q, J ) 6.6 Hz),
3.83 (1H, m), 3.60-3.80 (4H, m), 3.55 (1H, m), 3.21 (2H, m),
3.08 (1H, m), 2.86 (1H, m), 2.48 (1H, m), 2.27 (6H, s), 1.96
(1H, m), 1.50-1.70 (4H, m), 1.52 (3H, s), 1.49 (3H, s), 1.43 (3H,
d, J ) 6.9 Hz), 1.40 (3H, d, J ) 6.6 Hz), 1.23 (3H, d, J ) 6.6
Hz), 1.18 (3H, d, J ) 6.0 Hz), 1.09 (3H, d, J ) 6.6 Hz), 0.86
(3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 205.3 (C-3), 170.3 (C-
1), 155.9, 149.5, 147.6, 132.4, 130.9, 129.6, 129.2, 129.1, 128.4,
128.1, 127.9, 126.8, 124.9, 103.0 (C-1′), 81.6, 79.6, 77.1, 76.4,
70.2, 69.5, 66.0, 64.5, 60.3, 50.9, 49.2, 46.1, 43.0, 41.6, 40.2
(NMe2), 38.5, 36.5, 28.4, 22.3, 21.2, 20.4, 20.1, 14.7, 13.8, 13.0,
10.9, 10.4. Anal. (C44H62N4O9‚H2O) C, H, N.

4152 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Ma et al.
6-O-[3-(3′-Qu in olyl)-2-p r op en yl]-11,12-cycloca r b a m -
a te Ketolid e 41s: Gen er a l P r oced u r e. A mixture of 26 (2.72
g, 4.00 mmol), palladium(II) acetate (224 mg, 1.00 mmol), tri-
(o-tolyl)phosphine (608 mg, 2.00 mmol), 3-bromoquinoline (1.08
mL, 8.00 mmol), and triethylamine (1.11 mL, 8.00 mmol) in
acetonitrile (20 mL) was flushed with nitrogen and sealed in
a pressure tube. The reaction mixture was stirred at 50 °C for
1 h and then at 90 °C for 48 h. The reaction mixture was taken
up in ethyl acetate, washed with aqueous 5% sodium bicarbon-
ate and brine, dried over sodium sulfate, filtered, and concen-
trated. The crude mixture was purified by flash column
chromatography on silica gel (50:50:0.5 acetone/hexane/tri-
ethylamine) to give 2′-OAc-41s (2.62 g, 81%) as a white solid:
MS m/z (ESI) 808 (M + H)+; HRMS (FAB) m/z 808.4381, calcd
for C44H62N3O11 808.4379; 1H NMR (CDCl3) δ 9.02 (1H, d, J )
2.4 Hz), 8.16 (1H, d, J ) 2.4 Hz), 8.06 (1H, d, J ) 8.4 Hz),),
7.82 (1H, d, J ) 8.4 Hz), 7.64 (1H, m), 7.52 (1H, m), 6.56 (1H,
d, J ) 16.2 Hz), 6.17 (1H, dt, J ) 16.2, 6.0 Hz), 5.50 (1H, br
s), 5.98 (1H, dd, J ) 9.0, 3.0 Hz), 4.74 (1H, dd, J ) 10.8, 7.8
Hz), 4.44 (1H, d, J ) 7.2 Hz), 4.38 (1H, d, J ) 3.6 Hz), 3.93
(1H, q, J ) 6.6 Hz), 3.91 (1H, br s), 3.84 (1H, m), 3.70 (1H, m),
3.55 (1H, m), 3.20 (1H, m), 2.98 (1H, m), 2.50-2.70 (2H, m),
2.24 (6H, s), 2.03 (3H, s), 1.90 (1H, m), 1.71 (2H, m), 1.55 (1H,
m), 1.49 (3H, s), 1.41 (3H, s), 1.40 (3H, d, J ) 6.9 Hz), 1.26
(3H, d, J ) 6.6 Hz), 1.18 (3H, d, J ) 6.6 Hz), 1.15 (3H, d, J )
6-O-[3-(3′-P yr id yl)-2-p r op en yl]-11,12-cycloca r b a m a t e
Ketolid e 41d . Compound 41d was prepared as white solid in
36% yield according to the general procedure for the prepara-
1
tion of 41s: MS m/z (ESI) 716 (M + H)
+; H NMR (CDCl3) δ
8.56 (1H, d, J ) 2.4 Hz), 8.43 (1H, dd, J ) 4.8, 1.8 Hz), 7.70
(1H, ddd, J ) 8.4, 2.4, 1.8 Hz), 7.23 (1H, dd, J ) 8.4, 4.8 Hz),
6.40 (1H, d, J ) 15.6 Hz), 6.15 (1H, dt, J ) 15.6, 6.0 Hz), 5.74
(1H, br s), 5.22 (1H, dd, J ) 9.0, 3.0 Hz), 4.39 (1H, d, J ) 6.6
Hz), 4.38 (1H, d, J ) 3.6 Hz), 3.95 (1H, q, J ) 6.6 Hz), 3.94
(1H, br s), 3.90 (1H, m), 3.60 (2H, m), 3.18 (2H, m), 3.04 (1H,
m), 2.62 (1H, m), 2.47 (1H, m), 2.27 (6H, s), 1.50-2.20 (5H,
m), 1.55 (3H, s), 1.42 (3H, d, J ) 7.8 Hz), 1.35 (3H, d, J ) 6.9
Hz), 1.34 (3H, s), 1.25 (3H, d, J ) 6.3 Hz), 1.20 (3H, d, J ) 6.6
Hz), 1.13 (3H, d, J ) 6.0 Hz), 0.88 (3H, t, J ) 7.5 Hz); 13C
NMR (CDCl3) δ 217.5 (C-9), 205.6 (C-3), 170.1 (C-1), 158.2,
148.1, 148.0, 132.5, 128.8, 128.5, 123.3, 102.7 (C-1′), 83.7, 78.2,
77.2, 75.5, 70.2, 69.5, 65.9, 62.2, 58.2, 50.7, 45.3, 45.1, 40.2
(NMe2), 38.8, 37.3, 32.9, 28.2, 22.5, 21.3, 20.4, 18.4, 14.7, 13.7,
13.6, 10.4.
6-O-[3-(5′-Th ien o[2′,3′-b]p yr id yl)-2-p r op en yl]-11,12-cy-
cloca r ba m a te Ketolid e 41f. Compound 41f was prepared as
a white solid in 10% yield according to the general procedure
for the preparation of 41s: MS m/z (ESI) 772 (M + H)+; HRMS
(FAB) m/z 772.3862, calcd for C40H57N3O10S 772.3843; 1H NMR
(CDCl3) δ 8.62 (1H, d, J ) 2.0 Hz), 8.19 (1H, d, J ) 1.6 Hz),
7.49 (1H, d, J ) 6.0 Hz), 7.27 (1H, d, J ) 6.0 Hz), 6.52 (1H, d,
J ) 15.6 Hz), 6.08 (1H, dt, J ) 16.0, 6.8 Hz), 5.48 (1H, br s),
4.91 (1H, dd, J ) 9.2, 3.2 Hz), 4.40 (1H, d, J ) 4.8 Hz), 4.37
(1H, d, J ) 7.2 Hz), 4.02-3.51 (5H, m), 3.26-2.82 (3H, m),
2.65 (1H, m), 2.49 (1H, m), 2.27 (6H, s), 2.00-0.86 (26H, m)
0.81 (3H, t, J ) 7.6 Hz); 13C NMR (CDCl3) δ 217.2 (C-9), 205.3
(C-3), 169.5 (C-1), 157.4, 136.5, 133.7, 128.6, 127.8, 126.5,
125.5, 102.9 (C-1′), 83.5, 78.4, 77.7, 76.4, 70.2, 69.5, 65.9, 64.3,
58.2, 50.9, 46.2, 45.1, 40.2 (NMe2), 39.1, 37.3, 28.2, 22.8, 21.1,
20.3, 18.1, 14.4, 14.1, 13.7, 10.8. Anal. (C39H58N2O10) C, H, N.
6.0 Hz), 1.12 (3H, d, J ) 6.6 Hz), 0.81 (3H, t, J ) 7.5 Hz); 13
C
NMR (CDCl3) δ 217.3 (C-9), 205.3 (C-3), 169.7, 169.6, 157.6,
149.7, 147.7, 132.5, 130.0, 129.6, 129.2, 129.1, 128.4, 128.0,
126.7, 100.4 (C-1′), 83.4, 78.7, 77.6, 75.5, 71.5, 69.1, 64.3, 63.4,
58.2, 50.9, 45.7, 45.1, 40.6 (NMe2), 38.8, 37.3, 30.6, 22.6, 21.3,
20.9, 20.1, 18.1, 14.3, 13.8, 13.7, 10.6. Anal. (C44H61N3O11
0.5H2O) C, H, N.
‚
The product obtained above (1.477 g, 1.830 mmol) was
heated to reflux in MeOH (20 mL) for 2 h. After the solvent
was evaporated, the crude product was purified by column
chromatography (silica gel, 95:5:0.5 CH2Cl2/MeOH/ammonia)
to give 41s (1.138 g, 81%) as a white solid: MS m/z (ESI) 766
(M + H)+; HRMS (FAB) m/z 766.4301, calcd for C42H60N3O10
6-O-[3-(6′-Th ien o[3′,2′-b]p yr id yl)-2-p r op en yl]-11,12-cy-
cloca r ba m a te Ketolid e 41g. Compound 41g was prepared
as a white solid in 50% yield according to the general procedure
1
for the preparation of 41s: MS m/z (ESI) 773 (M + H)+; H
1
766.4279; H NMR (CDCl3) δ 9.03 (1H, d, J ) 2.4 Hz), 8.18
NMR (CDCl3) δ 8.73 (1H, d, J ) 1.8 Hz), 8.32 (1H, d, J ) 1.8
Hz), 7.69 (1H, d, J ) 5.4 Hz), 7.51 (1H, dd, J ) 5.4, 0.6 Hz),
6.53 (1H, d, J ) 15.9 Hz), 6.10 (1H, dt, J ) 15.9, 6.6 Hz), 5.46
(1H, br s), 4.92 (1H, dd, J ) 9.0, 3.3 Hz), 4.38 (2H, m), 3.97
(1H, q, J ) 6.6 Hz), 3.92 (1H, br s), 3.83 (1H, m), 3.68 (2H, m),
3.57 (2H, m), 3.19 (1H, m), 2.96 (1H, m), 2.64 (1H, m), 2.49
(1H, m), 2.27 (6H, s), 1.88 (1H, m), 1.58-1.81 (4H, m), 1.50
(3H, s), 1.48-1.09 (19H, m), 0.84 (3H, t, J ) 7.5 Hz); 13C NMR
(CDCl3) δ 217.45 (C-9), 205.3 (C-3), 169.7 (C-1), 157.7, 155.4,
146.9, 169.7, 157.7, 155.4, 146.9, 133.4, 130.7, 129.8, 127.9,
124.9, 102.9 (C-1′), 83.5, 78.7, 77.6, 76.6, 70.2, 69.5, 65.9, 64.3,
58.2, 50.9, 46.3, 45.1, 40.2 (NMe2), 39.1, 37.3, 28.3, 22.6, 21.1,
20.3, 18.1, 14.4, 14.3, 13.7, 10.8. Anal. (C39H58N2O10) C, H, N.
(1H, d, J ) 2.4 Hz), 8.05 (1H, d, J ) 8.4 Hz), 7.83 (1H, d, J )
8.4 Hz), 7.64 (1H, m), 7.52 (1H, m), 6.57 (1H, d, J ) 15.6 Hz),
6.17 (1H, dt, J ) 15.6, 6.0 Hz), 5.47 (1H, br s), 4.93 (1H, dd, J
) 9.0, 3.0 Hz), 4.39 (1H, d, J ) 4.2 Hz), 4.35 (1H, d, J ) 6.6
Hz), 3.95 (1H, q, J ) 6.6 Hz), 3.90 (1H, br s), 3.82 (1H, m),
3.70 (1H, m), 3.54 (1H, m), 3.43 (1H, br s), 3.18 (1H, m), 3.16
(1H, m), 2.96 (1H, m), 2.62 (1H, m), 2.43 (1H, m), 2.25 (6H, s),
1.85 (1H, m), 1.80 (1H, m), 1.70 (1H, m), 1.63 (1H, m), 1.50
(1H, m), 1.48 (3H, s), 1.43 (3H, s), 1.39 (3H, d, J ) 6.9 Hz),
1.37 (3H, d, J ) 6.6 Hz), 1.15 (3H, d, J ) 6.6 Hz), 1.12 (3H, d,
J ) 6.0 Hz), 1.10 (3H, d, J ) 6.6 Hz), 0.78 (3H, t, J ) 7.5 Hz);
13C NMR (CDCl3) δ 217.3 (C-9), 205.3 (C-3), 169.6, 169.6, 157.6,
149.7, 147.6, 132.4, 129.9, 129.6, 129.2, 129.0, 128.5, 128.0,
126.7, 102.9 (C-1′), 83.5, 78.7, 77.5, 76.4, 70.2, 69.5, 65.8, 64.3,
58.1, 50.8, 46.2, 45.0, 40.2 (NMe2), 39.1, 37.3, 28.2, 22.6, 21.1,
20.2, 18.0, 14.4, 14.1, 13.6, 10.6. Anal. (C42H59N3O10) C, H, N.
6-O-[3-(5′-Ben zim id a zolyl)-2-p r op en yl]-11,12-cycloca r -
ba m a te Ketolid e 41h . Compound 41h was prepared as a
white solid in 9% yield according to the general procedure for
the preparation of 41s: MS m/z (ESI) 755 (M + H)+; HRMS
(FAB) m/z 755.4224, calcd for C40H59N4O10 755.4231; 1H NMR
(CDCl3) δ 7.96 (1H, s), 7.55-7.70 (2H, m), 7.44 (1H, d, J ) 5.4
Hz), 6.55 (1H, d, J ) 15.6 Hz), 5.95 (1H, dt, J ) 15.6, 6.0 Hz),
5.50 (1H, br s), 4.85 (1H, br s), 4.39 (1H, d, J ) 4.2 Hz), 4.38
(1H, d, J ) 6.6 Hz), 4.00 (1H, s), 3.95 (1H, q, J ) 6.6 Hz), 3.82
(1H, m), 3.60 (2H, m), 3.20 (2H, m), 2.94 (1H, m), 2.65 (1H,
m), 2.48 (1H, m), 2.27 (6H, s), 1.85 (1H, m), 1.50-1.80 (4H,
m), 1.48 (3H, s), 1.42 (3H, s), 1.40 (3H, d, J ) 6.9 Hz), 1.39
(3H, d, J ) 6.6 Hz), 1.22 (3H, d, J ) 6.6 Hz), 1.13 (3H, d, J )
6-O-[3-P h en yl-2-p r op en yl]-11,12-cycloca r ba m a te Keto-
lid e 41a . Compound 41a was prepared as a white solid in 94%
yield according to the general procedure for the preparation
of 41s: MS m/z (ESI) 715 (M + H)+; HRMS (FAB) m/z
715.4168, calcd for C39H59N2O10 715.4190; 1H NMR (CDCl3) δ
7.45 (1H, d, J ) 7.2 Hz), 7.15-7.35 (4H, m), 6.42 (1H, d, J )
15.6 Hz), 5.96 (1H, dt, J ) 15.6, 6.0 Hz), 5.32 (1H, br s), 4.88
(1H, dd, J ) 9.0, 3.0 Hz), 4.38 (1H, d, J ) 4.2 Hz), 4.37 (1H,
d, J ) 6.6 Hz), 3.95 (1H, q, J ) 6.6 Hz), 3.92 (1H, br s), 3.80
(1H, m), 3.70 (2H, m), 3.20 (2H, m), 2.96 (1H, m), 2.62 (1H,
m), 2.45 (1H, m), 2.27 (6H, s), 1.89 (1H, m), 1.50-1.80 (4H,
m), 1.48 (3H, s), 1.42 (3H, s), 1.41 (3H, d, J ) 6.9 Hz), 1.39
(3H, d, J ) 6.6 Hz), 1.22 (3H, d, J ) 6.6 Hz), 1.13 (3H, d, J )
6.0 Hz), 1.11 (3H, d, J ) 6.6 Hz), 0.78 (3H, t, J ) 7.5 Hz); 13
C
NMR (CDCl3) δ 217.1 (C-9), 205.3 (C-3), 169.3 (C-1), 157.6,
141.2, 134.4, 124.2, 121.6, 103.0 (C-1′), 83.8, 78.4, 77.8, 76.5,
70.3, 69.5, 65.9, 64.3, 58.3, 50.9, 46.3, 45.0, 40.2 (NMe2), 39.1,
37.3, 28.3, 22.8, 21.2, 20.3, 18.1, 14.5, 14.3, 13.7, 10.7.
6.0 Hz), 1.11 (3H, d, J ) 6.6 Hz), 0.84 (3H, t, J ) 7.5 Hz); 13
C
NMR (CDCl3) δ 217.2 (C-9), 205.3 (C-3), 169.5 (C-1), 157.4,
136.5, 133.7, 128.6, 127.8, 126.5, 125.5, 102.9 (C-1′), 83.5, 78.4,
77.7, 76.4, 70.2, 69.5, 65.9, 64.3, 58.2, 50.9, 46.2, 45.1, 40.2
(NMe2), 39.1, 37.3, 28.2, 22.8, 21.1, 20.3, 18.1, 14.4, 14.1, 13.7,
10.8. Anal. (C39H58N2O10) C, H, N.
6-O-[3-(1′-Na p h t h yl)-2-p r op en yl]-11,12-cycloca r b a m -
a te Ketolid e 41i. Compound 41i was prepared as white solid
in 97% yield according to the general procedure for the
preparation of 41s: MS m/z (ESI) 765 (M + H)+; HRMS (FAB)

Erythromycin Derivatives with C-6 Aryl Groups
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4153
m/z 765.4356, calcd for C43H61N2O10 765.4326; 1H NMR (CDCl3)
δ 8.20 (1H, d, J ) 7.5 Hz), 7.70-7.90 (3H, m), 7.40-7.50 (3H,
m), 7.22 (1H, d, J ) 15.6 Hz), 6.04 (1H, dt, J ) 15.6, 6.0 Hz),
5.30 (1H, br s), 5.05 (1H, dd, J ) 9.0, 3.0 Hz), 4.42 (1H, J )
6.6 Hz), 4.40 (1H, d, J ) 4.2 Hz), 3.96 (1H, q, J ) 6.6 Hz),
3.93 (1H, br s), 3.90 (1H, m), 3.50-3.70 (2H, m), 3.20 (2H, m),
2.96 (1H, m), 2.65 (1H, m), 2.55 (1H, m), 2.30 (6H, s), 1.50-
1.80 (5H, m), 1.50 (3H, s), 1.46 (3H, s), 1.42 (3H, d, J ) 6.9
Hz), 1.41 (3H, d, J ) 6.6 Hz), 1.20 (3H, d, J ) 6.6 Hz), 1.15
(3H, d, J ) 6.0 Hz), 1.10 (3H, d, J ) 6.6 Hz), 0.85 (3H, t, J )
7.5 Hz); 13C NMR (CDCl3) δ 217.2 (C-9), 205.5 (C-3), 169.8 (C-
1), 157.3, 134.0, 133.7, 130.0, 128.7, 128.5, 128.1, 126.7, 125.9,
125.7, 125.6, 125.5, 123.7, 123.5, 102.8 (C-1′), 83.4, 78.6, 77.4,
76.6, 70.2, 69.4, 66.1, 64.5, 58.2, 50.9, 46.0, 45.2, 40.2 (NMe2),
39.1, 37.4, 28.6, 22.6, 21.1, 20.4, 18.1, 14.6, 14.1, 13.7, 10.6.
Anal. (C43H60N2O10) C, H, N.
(C-9), 205.5 (C-3), 169.9 (C-1), 157.3, 150.1, 148.5, 134.4, 132.0,
130.0, 129.4, 129.3, 128.4, 124.0, 120.9, 102.9 (C-1′), 83.4, 78.7,
77.4, 76.6, 70.2, 69.5, 66.0, 64.4, 58.2, 50.9, 46.1, 45.1, 40.2
(NMe2), 39.0, 37.4, 28.4, 22.5, 21.2, 20.4, 18.2, 14.5, 14.1, 13.7,
10.5. Anal. (C42H59N3O10) C, H, N.
6-O-[3-(5′-Isoqu in olyl)-2-p r op en yl]-11,12-cycloca r ba m -
a te Ketolid e 41m . Compound 41m was prepared as a white
solid in 31% yield according to the general procedure for the
preparation of 41s: MS m/z (ESI) 766 (M + H)+; HRMS (FAB)
m/z 766.4301, calcd for C42H60N3O10 766.4279; 1H NMR (CDCl3)
δ 9.23 (1H, s), 8.55 (1H, d, J ) 6.0 Hz), 8.21 (1H, d, J ) 8.4
Hz), 7.97 (2H, m), 7.90 (1H, d, J ) 7.8 Hz), 7.63 (1H, dd, J )
6.3, 6.0 Hz), 7.14 (1H, d, J ) 15.6 Hz), 6.08 (1H, dt, J ) 15.6,
6.0 Hz), 5.28 (1H, br s), 5.00 (1H, dd, J ) 9.0, 3.0 Hz), 4.42
(1H, d, J ) 2.4 Hz), 4.41 (1H, d, J ) 6.6 Hz), 3.97 (1H, q, J )
6.6 Hz), 3.90 (1H, br s), 3.90 (1H, m), 3.70 (1H, m), 3.61 (1H,
m), 3.20 (2H, m), 2.97 (1H, m), 2.65 (1H, m), 2.48 (1H, m),
2.29 (6H, s), 1.89 (1H, m), 1.50-1.80 (4H, m), 1.48 (3H, s), 1.46
(3H, s), 1.43 (3H, d, J ) 6.9 Hz), 1.41 (3H, d, J ) 6.6 Hz), 1.20
(3H, d, J ) 6.0 Hz), 1.14 (3H, d, J ) 6.6 Hz), 1.10 (3H, d, J )
6.6 Hz), 0.85 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 217.4
(C-9), 205.4 (C-3), 169.8 (C-1), 157.3, 153.1, 143.1, 133.7, 133.2,
130.0, 129.8, 128.1, 127.5, 127.3, 127.2, 116.4, 102.8 (C-1′),
83.4, 78.7, 77.4, 76.5, 70.2, 69.6, 65.9, 64.4, 58.2, 50.9, 46.1,
45.1, 40.2 (NMe2), 39.0, 37.3, 28.3, 22.5, 21.2, 20.4, 18.1, 14.5,
14.1, 13.6, 10.6. Anal. (C42H59N3O10) C, H, N.
6-O-[3-(4′-Isoqu in olyl)-2-p r op en yl]-11,12-cycloca r ba m -
a te Ketolid e 41j. Compound 41j was prepared as a white solid
in 33% yield according to the general procedure for the
preparation of 41s: MS m/z (ESI) 766 (M + H)+; HRMS (FAB)
m/z 766.4271, calcd for C42H60N3O10 766.4279; 1H NMR (CDCl3)
δ 9.18 (1H, s), 8.71 (1H, s), 8.21 (1H, d, J ) 8.4 Hz), 7.97 (1H,
d, J ) 8.4 Hz), 7.74 (1H, m), 7.61 (1H, m), 7.08 (1H, d, J )
15.6 Hz), 6.12 (1H, dt, J ) 15.6, 6.0 Hz), 5.28 (1H, br s), 5.07
(1H, dd, J ) 9.0, 3.0 Hz), 4.42 (1H, d, J ) 6.6 Hz), 4.41 (1H,
d, J ) 4.2 Hz), 3.96 (1H, q, J ) 6.6 Hz), 3.88 (1H, br s), 3.90
(1H, m), 3.70 (1H, m), 3.62 (1H, m), 3.20 (2H, m), 2.96 (1H,
m), 2.65 (1H, m), 2.52 (1H, m), 2.29 (6H, s), 1.89 (1H, m), 1.50-
1.80 (4H, m), 1.47 (3H, s), 1.46 (3H, s), 1.41 (3H, d, J ) 6.9
Hz), 1.39 (3H, d, J ) 6.6 Hz), 1.22 (3H, d, J ) 6.6 Hz), 1.13
(3H, d, J ) 6.0 Hz), 1.10 (3H, d, J ) 6.6 Hz), 0.85 (3H, t, J )
7.5 Hz); 13C NMR (CDCl3) δ 217.2 (C-9), 205.4 (C-3), 169.9 (C-
1), 157.3, 152.1, 140.7, 133.6, 130.6, 130.4, 128.0, 127.7, 127.0,
126.9, 122.8, 102.8 (C-1′), 83.4, 78.7, 77.3, 76.6, 70.2, 69.4, 66.0,
64.4, 58.2, 50.9, 46.0, 45.1, 40.2 (NMe2), 39.0, 37.3, 28.5, 22.5,
21.2, 20.4, 18.2, 14.5, 14.0, 13.7, 10.5. Anal. (C42H59N3O10) C,
H, N.
6-O-[3-(4′-Qu in olyl)-2-p r op en yl]-11,12-cycloca r b a m -
a te Ketolid e 41k . Compound 41k was prepared as an off-
white solid in 24% yield according to the general procedure
for the preparation of 41s: MS m/z (ESI) 766 (M + H)+; HRMS
(FAB) m/z 766.4299, calcd for C42H60N3O10 766.4279; 1H NMR
(CDCl3) δ 8.92 (1H, d, J ) 4.2 Hz), 8.18 (1H, d, J ) 7.8 Hz),
8.10 (1H, d, J ) 7.8 Hz), 7.70 (1H, m), 7.63 (1H, d, J ) 4.2
Hz), 7.55 (1H, m), 7.17 (1H, d, J ) 15.0 Hz), 6.12 (1H, dt, J )
15.0, 6.0 Hz), 5.39 (1H, br s), 5.05 (1H, dd, J ) 9.0, 3.0 Hz),
4.41 (1H, d, J ) 4.4 Hz), 4.39 (1H, d, J ) 6.6 Hz), 3.97 (1H, q,
J ) 6.6 Hz), 3.87 (1H, br s), 3.90 (1H, m), 3.75 (1H, m), 3.60
(1H, m), 3.20 (2H, m), 2.98 (1H, m), 2.65 (1H, m), 2.47 (1H,
m), 2.27 (6H, s), 1.90 (1H, m), 1.50-1.80 (4H, m), 1.49 (3H, s),
1.46 (3H, s), 1.43 (3H, d, J ) 6.9 Hz), 1.41 (3H, d, J ) 6.6 Hz),
1.18 (3H, d, J ) 6.6 Hz), 1.16 (3H, d, J ) 6.0 Hz), 1.13 (3H, d,
J ) 6.6 Hz), 0.86 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 217.6
(C-9), 205.4 (C-3), 169.9 (C-1), 157.4, 150.3, 142.2, 133.1, 130.1,
129.1, 127.2, 126.4, 126.2, 123.4, 117.4, 102.9 (C-1′), 83.4, 78.9,
77.4, 76.6, 70.2, 69.6, 65.9, 64.2, 58.2, 50.9, 46.2, 45.1, 40.2
(NMe2), 39.0, 37.4, 28.2, 22.5, 21.2, 20.4, 18.1, 14.5, 14.1, 13.6,
10.5.
6-O-[3-(8′-Qu in olyl)-2-p r op en yl]-11,12-cycloca r b a m -
a te Ketolid e 41n . Compound 41n was prepared as a white
solid in 16% yield according to the general procedure for the
preparation of 41s: MS m/z (ESI) 766 (M + H)+; HRMS (FAB)
m/z 766.4282, calcd for C42H60N3O10 766.4279.
6-O-[3-(2′-Na p h t h yl)-2-p r op en yl]-11,12-cycloca r b a m -
a te Ketolid e 41o. Compound 41o was prepared as a white
solid in 61% yield according to the general procedure for the
preparation of 41s: MS m/z (ESI) 765 (M + H)+; 1H NMR
(CDCl3) δ 7.60-7.85 (4H, m), 7.69 (1H, m), 7.38-7.45 (2H, m),
6.57 (1H, d, J ) 15.3 Hz), 6.04 (1H, dt, J ) 15.3, 6.0 Hz), 5.40
(1H, br s), 4.95 (1H, dd, J ) 9.0, 3.3 Hz), 4.3-4.45 (2H, m),
3.96 (1H, q, J ) 6.6 Hz), 3.95 (1H, br s), 3.84 (1H, m), 3.50-
3.70 (2H, m), 3.20 (2H, m), 2.96 (1H, m), 2.64 (1H, m), 2.56
(1H, m), 2.30 (6H, s), 1.50-1.80 (5H, m), 1.49 (3H, s), 1.43 (3H,
d, J ) 6.0 Hz), 1.42 (3H, d, J ) 6.6 Hz), 1.41 (3H, s), 1.19 (3H,
d, J ) 6.6 Hz), 1.13 (3H, d, J ) 6.0 Hz), 1.11 (3H, d, J ) 6.6
Hz), 0.83 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 217.2 (C-9),
205.4 (C-3), 169.6 (C-1), 157.5, 134.4, 134.1, 133.6, 133.0, 128.3,
128.1, 127.6, 126.6, 126.1, 126.0, 125.7, 123.6, 102.8 (C-1′),
83.5, 78.5, 77.7, 76.5, 70.2, 69.4, 66.1, 64.4, 58.2, 50.9, 46.2,
45.1, 40.2 (NMe2), 39.1, 37.4, 28.6, 22.7, 21.1, 20.3, 18.1, 14.5,
14.1, 13.7, 10.7.
6-O-[3-(2′-Qu in olyl)-2-p r op en yl]-11,12-cycloca r b a m -
a te Ketolid e 41p . Compound 41p was prepared as an off-
white solid in 14% yield according to the general procedure
for the preparation of 41s: MS m/z (ESI) 766 (M + H)+; HRMS
(FAB) m/z 766.4286, calcd for C42H60N3O10 766.4279.
6-O-[3-(4′-Isoqu in olyl)-2-p r op en yl]-11,12-cycloca r ba m -
a te Ketolid e 41q. Compound 41q was prepared as a white
solid in 30% yield according to the general procedure for the
preparation of 41s: MS m/z (ESI) 766 (M + H)+; 1H NMR
(CDCl3) δ 8.79 (1H, dd, J ) 4.2, 1.8 Hz), 8.03 (1H, dd, J ) 7.8,
1.8 Hz), 7.93 (1H, s), 7.72 (2H, s), 7.25 (1H, dd, J ) 7.8, 4.2
Hz), 6.56 (1H, d, J ) 15.6 Hz), 6.08 (1H, dt, J ) 15.6, 6.0 Hz),
5.35 (1H, br s), 4.92 (1H, dd, J ) 9.0, 3.0 Hz), 4.38 (1H, d, J )
6.6 Hz), 4.34 (1H, d, J ) 4.2 Hz), 3.88 (1H, q, J ) 6.6 Hz),
3.84 (1H, br s), 3.79 (1H, m), 3.61 (1H, m), 3.57 (1H, m), 3.32
(1H, m), 3.16 (1H, m), 2.92 (1H, m), 2.88 (1H, m), 2.52 (6H, s),
1.50-1.90 (5H, m), 1.42 (3H, s), 1.30-1.35 (6H, m), 1.10-1.23
(6H, m), 1.08 (3H, d, J ) 6.6 Hz), 1.04 (3H, d, J ) 6.0 Hz),
0.78 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 217.2 (C-9), 205.4
(C-3), 169.6 (C-1), 157.5, 150.5, 148.6, 137.8, 135.7, 132.9,
128.1, 127.9, 127.8, 124.0, 120.7, 102.0 (C-1′), 83.4, 78.5, 77.5,
76.4, 69.7, 68.5, 66.4, 64.2, 58.2, 50.8, 46.0, 45.1, 40.3 (NMe2),
38.9, 37.3, 29.6, 22.6, 20.9, 20.2, 18.0, 14.5, 14.0, 13.6, 10.6.
6-O-[3-(5′-Qu in olyl)-2-p r op en yl]-11,12-cycloca r b a m -
a te Ketolid e 41l. Compound 41l was prepared as a white solid
in 78% yield according to the general procedure for the
preparation of 41s: MS m/z (ESI) 766 (M + H)+; HRMS (FAB)
m/z 766.4281, calcd for C42H60N3O10 766.4279; 1H NMR (CDCl3)
δ 8.92 (1H, dd, J ) 4.5, 1.8 Hz), 8.57 (1H, d, J ) 8.4 Hz), 8.04
(1H, d, J ) 8.4 Hz), 7.82 (1H, d, J ) 7.2 Hz), 7.72 (1H, m),
7.43 (1H, m), 7.15 (1H, d, J ) 15.6 Hz), 6.08 (1H, dt, J ) 15.6,
6.0 Hz), 5.34 (1H, br s), 5.03 (1H, dd, J ) 9.0, 3.0 Hz), 4.42
(1H, d, J ) 3.6 Hz), 4.41 (1H, d, J ) 7.2 Hz), 3.96 (1H, q, J )
6.6 Hz), 3.91 (1H, br s), 3.90 (1H, m), 3.70 (1H, m), 3.62 (1H,
m), 3.20 (2H, m), 2.98 (1H, m), 2.65 (1H, m), 2.52 (1H, m),
2.28 (6H, s), 1.89 (1H, m), 1.50-1.80 (4H, m), 1.49 (3H, s), 1.46
(3H, s), 1.42 (3H, d, J ) 6.9 Hz), 1.41 (3H, d, J ) 6.6 Hz), 1.20
(3H, d, J ) 6.6 Hz), 1.16 (3H, d, J ) 6.0 Hz), 1.12 (3H, d, J )
6.6 Hz), 0.85 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 217.4
6-O-[3-(6′-Qu in olyl)-2-p r op en yl]-11,12-cycloca r b a m -
a te Ketolid e 41r . Compound 41r was prepared as a white

4154 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Ma et al.
solid in 77% yield according to the general procedure for the
preparation of 41s: MS m/z (ESI) 766 (M + H)+; HRMS (FAB)
m/z 766.4288, calcd for C42H60N3O10 766.4279; 1H NMR (CDCl3)
δ 8.84 (1H, dd, J ) 4.2, 1.2 Hz), 8.15 (1H, d, J ) 7.5 Hz), 8.07
(1H, d, J ) 7.5 Hz), 7.93 (1H, dd, J ) 8.4, 1.2 Hz), 7.79 (1H,
s), 7.36 (1H, dd, J ) 8.4, 4.2 Hz), 6.58 (1H, d, J ) 15.6 Hz),
6.12 (1H, dt, J ) 15.6, 6.0 Hz), 5.42 (1H, br s), 4.92 (1H, dd, J
) 9.0, 3.0 Hz), 4.41 (1H, d, J ) 4.2 Hz), 4.39 (1H, d, J ) 7.2
Hz), 3.96 (1H, q, J ) 6.6 Hz), 3.94 (1H, br s), 3.85 (1H, m),
3.70 (1H, m), 3.57 (1H, m), 3.20 (2H, m), 2.96 (1H, m), 2.65
(1H, m), 2.48 (1H, m), 2.26 (6H, s), 1.50-1.90 (5H, m), 1.48
(3H, s), 1.40-1.45 (9H, m), 1.20 (3H, d, J ) 6.0 Hz), 1.15 (3H,
d, J ) 6.6 Hz), 1.12 (3H, d, J ) 6.0 Hz), 0.82 (3H, t, J ) 7.5
Hz); 13C NMR (CDCl3) δ 217.4 (C-9), 205.4 (C-3), 169.6 (C-1),
157.5, 150.0, 148.1, 136.1, 134.9, 132.7, 129.8, 128.5, 127.5,
127.4, 126.0, 121.3, 102.9 (C-1′), 83.5, 78.6, 77.7, 76.5, 70.2,
69.5, 65.9, 64.3, 58.2, 50.9, 46.4, 45.1, 40.2 (NMe2), 39.1, 37.3,
28.3, 22.7, 21.1, 20.2, 18.1, 14.4, 14.3, 13.7, 10.7. Anal.
(C42H59N3O10) C, H, N.
50.8, 46.2, 45.0, 40.1 (NMe2), 38.9, 37.3, 28.2, 22.5, 21.1, 20.1,
18.0, 14.3, 14.1, 13.6, 13.5, 10.5.
6-O-[3-(6′-Cin n olyl)-2-p r op en yl]-11,12-cycloca r b a m -
a te Ketolid e 41w . Compound 41w was prepared as a white
solid in 27% yield according to the general procedure for the
preparation of 41s: MS m/z (ESI) 767 (M + H)+; 1H NMR
(CDCl3) δ 9.25 (1H, d, J ) 5.7 Hz), 9.45 (1H, d, J ) 8.7 Hz),
8.07 (1H, dd, J ) 9.3, 2.1 Hz), 7.84 (1H, dd, J ) 5.7, 0.6 Hz),
7.76 (1H, d, J ) 1.2 Hz), 6.61 (1H, d, J ) 15.9 Hz), 6.23 (1H,
dt, J ) 16.2, 6.6 Hz), 5.46 (1H, br s), 4.86 (1H, dd, J ) 9.0, 3.3
Hz), 4.40 (1H, d, J ) 5.1 Hz), 4.36 (1H, d, J ) 7.5 Hz), 3.97
(1H, q, J ) 6.6 Hz), 3.87 (1H, br s), 3.85 (1H, m), 3.72 (1H, m),
3.57 (1H, m), 3.49 (1H, m), 3.18 (2H, m), 2.96 (1H, m), 2.65
(1H, m), 2.50 (1H, m), 2.28 (6H, s), 1.20-1.90 (5H, m), 1.49
(3H, s), 1.44 (3H, s), 1.43 (3H, s), 1,40 (3H, s), 1.20 (3H, d, J )
7.2 Hz), 1.15 (3H, d, J ) 7.2 Hz), 1.13 (3H, d, J ) 6.6 Hz),
0.79 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 217.7 (C-9), 205.4
(C-3), 169.7 (C-1), 157.6, 150.6, 145.4, 139.4, 131.8, 130.7,
130.1, 128.9, 124.3, 122.6, 103.3 (C-1′), 83.5, 78.9, 77.6, 76.5,
70.2, 69.5, 65.9, 64.1, 58.0, 50.9, 46.5, 45.0, 40.2 (NMe2), 39.0,
37.4, 37.3, 30.9, 28.3, 22.6, 21.3, 21.2, 20.2, 18.1, 14.5, 14.4,
13.7, 10.8. Anal. (C41H58N4O10) C, H, N.
6-O-[3-(6′-Qu in a zolyl)-2-p r op en yl]-11,12-cycloca r ba m -
a te Ketolid e 41x. Compound 41x was prepared as an off-
white solid in 39% yield according to the general procedure
for the preparation of 41s: MS m/z (APCI) 767 (M + H)+;
HRMS (FAB) m/z 767.4236, calcd for C41H59N4O10 767.4231;
1H NMR (CDCl3) δ 9.38 (1H, s), 9.27 (1H, s), 8.15 (1H, d, J )
6.9 Hz), 8.02 (1H, d, J ) 6.9 Hz), 7.88 (1H, s), 6.61 (1H, d, J
) 15.6 Hz), 6.16 (1H, dt, J ) 15.6, 6.0 Hz), 5.45 (1H, br s),
4.87 (1H, dd, J ) 9.2, 3.2 Hz), 4.41 (1H, d, J ) 4.5 Hz), 4.37
(1H, d, J ) 7.8 Hz), 3.97 (1H, q, J ) 6.6 Hz), 3.89 (1H, br s),
3.83 (1H, m), 3.73 (1H, m), 3.56 (1H, m), 3.19 (2H, m), 2.96
(1H, m), 2.66 (1H, m), 2.47 (1H, m), 2.26 (6H, s), 1.20-1.90
(6H, m), 1.49 (3H, s), 1.45 (3H, s), 1.42 (3H, d, J ) 6.9 Hz),
1,41 (3H, d, J ) 6.3 Hz), 1.20 (3H, d, J ) 6.0 Hz), 1.15 (3H, d,
J ) 6.3 Hz), 1.12 (3H, d, J ) 6.0 Hz), 0.80 (3H, t, J ) 7.5 Hz);
13C NMR (CDCl3) δ 217.5 (C-9), 205.2 (C-3), 169.6 (C-1), 160.1,
157.5, 154.9, 149.7, 136.4, 132.2, 131.7, 128.9, 128.5, 125.3,
124.8, 102.9 (C-1′), 83.4, 78.7, 77.5, 76.4, 70.2, 69.5, 65.8, 64.0,
58.0, 50.8, 46.4, 45.0, 40.1 (NMe2), 38.9, 37.3, 28.2, 22.6, 21.1,
6-O-{3-[3′-(1,8-Na p h th yr id yl)]-2-p r op en yl}-11,12-cyclo-
ca r ba m a te Ketolid e 41t. Compound 41t was prepared as a
white solid in 11% yield according to the general procedure
for the preparation of 41s: MS m/z (ESI) 767 (M + H)+; HRMS
(ESI) m/z 767.4227, calcd for C41H59N4O10 767.4231; 1H NMR
(CDCl3) δ 9.22 (1H, d, J ) 2.4 Hz), 8.05 (1H, dd, J ) 3.6, 2.4
Hz), 8.20-8.25 (2H, m), 7.46 (1H, dd, J ) 8.4, 3.6 Hz), 7.79
(1H, s), 7.36 (1H, dd, J ) 8.4, 4.2 Hz), 6.58 (1H, d, J ) 15.6
Hz), 6.23 (1H, dt, J ) 15.6, 6.0 Hz), 5.52 (1H, br s), 4.94 (1H,
dd, J ) 9.0, 3.0 Hz), 4.40 (1H, d, J ) 4.5 Hz), 4.38 (1H, d, J )
7.8 Hz), 3.96 (1H, q, J ) 6.6 Hz), 3.90 (1H, br s), 3.85 (1H, m),
3.73 (1H, m), 3.57 (1H, m), 3.20 (2H, m), 2.97 (1H, m), 2.65
(1H, m), 2.52 (1H, m), 2.29 (6H, s), 1.20-1.90 (6H, m), 1.50
(3H, s), 1.43 (3H, s), 1.42 (3H, d, J ) 6.9 Hz), 1.40 (3H, d, J )
6.3 Hz), 1.20 (3H, d, J ) 6.0 Hz), 1.15 (3H, d, J ) 6.3 Hz),
1.14 (3H, d, J ) 6.0 Hz), 0.81 (3H, t, J ) 7.5 Hz).
6-O-{3-[3′-(1,6-Na p h th yr id yl)]-2-p r op en yl}-11,12-cyclo-
ca r ba m a te Ketolid e 41u . Compound 41u was prepared as
a white solid in 73% yield according to the general procedure
1
for the preparation of 41s: MS m/z (ESI) 767 (M + H)+; H
NMR (CDCl3) δ 9.28 (1H, s), 9.22 (1H, d, J ) 2.4 Hz), 8.69
(1H, d, J ) 6.0 Hz), 8.30 (1H, d, J ) 2.4 Hz), 7.89 (1H, d, J )
6.0 Hz), 6.58 (1H, d, J ) 15.6 Hz), 6.25 (1H, dt, J ) 15.6, 6.0
Hz), 5.53 (1H, br s), 4.91 (1H, dd, J ) 9.2, 3.2 Hz), 4.41 (1H,
d, J ) 4.5 Hz), 4.36 (1H, d, J ) 7.8 Hz), 3.97 (1H, q, J ) 6.6
Hz), 3.88 (1H, br s), 3.85 (1H, m), 3.74 (1H, m), 3.57 (1H, m),
3.49 (1H, m), 3.18 (2H, m), 2.98 (1H, m), 2.65 (1H, m), 2.46
(1H, m), 2.26 (6H, s), 1.20-1.90 (5H, m), 1.50 (3H, s), 1.44 (3H,
s), 1.43 (3H, d, J ) 6.9 Hz), 1,41 (3H, d, J ) 6.3 Hz), 1.18 (3H,
d, J ) 6.0 Hz), 1.15 (3H, d, J ) 6.3 Hz), 1.13 (3H, d, J ) 6.0
Hz), 0.81 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 217.4 (C-9),
205.2 (C-3), 169.6 (C-1), 157.6, 154.0, 153.0, 149.5, 146.4, 131.7,
131.2, 130.1, 128.9, 123.5, 121.8, 102.9 (C-1′), 83.4, 78.8, 77.4,
76.4, 70.2, 69.5, 65.8, 64.1, 58.0, 50.8, 46.4, 45.0, 40.1 (NMe2),
38.9, 37.3, 28.2, 22.5, 21.1, 20.1, 18.0, 14.3, 14.2, 13.5, 10.6.
Anal. (C41H58N4O10) C, H, N.
20.2, 18.0, 14.3, 14.2, 13.6, 13.5, 10.7. Anal. (C41H58N4O10
0.5H2O) C, H, N.
‚
6-O-[3-(6′-Qu in oxa lyl)-2-p r op en yl]-11,12-cycloca r ba m -
a te Ketolid e 41y. Compound 41y was prepared as an off-
white solid in 69% yield according to the general procedure
for the preparation of 41s: MS m/z (ESI) 767 (M + H)+; HRMS
(ESI) m/z 767.4221, calcd for C41H59N4O10 767.4231; 1H NMR
(CDCl3) δ 8.82 (1H, d, J ) 2.4 Hz), 8.77 (1H, d, J ) 2.4 Hz),
8.00-8.10 (3H, m), 6.65 (1H, d, J ) 16.2 Hz), 6.16 (1H, dt, J
) 16.2, 6.0 Hz), 5.39 (1H, br s), 4.97 (1H, dd, J ) 9.2, 3.2 Hz),
4.42 (1H, d, J ) 4.5 Hz), 4.39 (1H, d, J ) 7.8 Hz), 3.97 (1H, q,
J ) 6.6 Hz), 3.88 (1H, br s), 3.85 (1H, m), 3.72 (1H, m), 3.59
(1H, m), 3.45 (1H, m), 3.20 (2H, m), 2.97 (1H, m), 2.66 (1H,
m), 2.47 (1H, m), 2.28 (6H, s), 1.20-1.90 (6H, m), 1.49 (3H, s),
1.45 (3H, s), 1.43 (3H, d, J ) 6.6 Hz), 1,43 (3H, d, J ) 6.6 Hz),
1.20 (3H, d, J ) 6.0 Hz), 1.15 (3H, d, J ) 6.6 Hz), 1.12 (3H, d,
J ) 6.6 Hz), 0.85 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 217.4
(C-9), 205.3 (C-3), 169.7 (C-1), 157.6 (carbamate), 145.2, 144.4,
143.5, 143.0, 138.7, 132.1, 129.7, 129.3, 127.8, 127.5, 102.9 (C-
1′), 83.4, 78.7, 77.5, 76.5, 70.2, 69.6, 65.9, 64.2, 58.0, 50.9, 46.4,
45.1, 40.2 (NMe2), 39.0, 37.4, 28.2, 22.6, 21.2, 20.3, 18.1, 14.4,
14.3, 13.7, 13.6, 10.7. Anal. (C41H58N4O10) C, H, N.
6-O-{3-[7′-(1,4,5-Tr ia za n a p h th yl)]-2-p r op en yl}-11,12-cy-
cloca r ba m a te Ketolid e 41z. Compound 41z was prepared
as an off-white solid in 12% yield according to the general
procedure for the preparation of 41s: MS m/z (ESI) 768 (M +
H)+; 1H NMR (CDCl3) δ 9.34 (1H, d, J ) 2.5 Hz), 8.98 (1H, d,
J ) 2.4 Hz), 8.92 (1H, d, J ) 2.4 Hz), 8.46 (1H, d, J ) 2.5 Hz),
6.65 (1H, d, J ) 16.5 Hz), 6.38 (1H, dt, J ) 16.5, 6.0 Hz), 5.46
(1H, br s), 4.98 (1H, dd, J ) 9.2, 3.2 Hz), 4.41 (1H, d, J ) 4.5
Hz), 4.38 (1H, d, J ) 7.8 Hz), 3.97 (1H, q, J ) 6.6 Hz), 3.88
(1H, m), 3.85 (1H, br s), 3.75 (1H, m), 3.58 (2H, m), 3.18 (2H,
m), 2.97 (1H, m), 2.66 (1H, m), 2.48 (1H, m), 2.27 (6H, s), 1.20-
6-O-{3-[3′-(1,5-Na p h th yr id yl)]-2-p r op en yl}-11,12-cyclo-
ca r ba m a te Ketolid e 41v. Compound 41v was prepared as a
white solid in 61% yield according to the general procedure
1
for the preparation of 41s: MS m/z (ESI) 767 (M + H)+; H
NMR (CDCl3) δ 9.17 (1H, d, J ) 2.4 Hz), 8.94 (1H, d, J ) 4.0
Hz), 8.37 (1H, d, J ) 2.4 Hz), 8.36 (1H, d, J ) 8.0 Hz), 7.57
(1H, dd, J ) 8.0, 4.0 Hz), 6.62 (1H, d, J ) 15.6 Hz), 6.32 (1H,
dt, J ) 15.6, 6.0 Hz), 5.48 (1H, br s), 5.00 (1H, dd, J ) 9.2, 3.2
Hz), 4.41 (1H, d, J ) 4.5 Hz), 4.37 (1H, d, J ) 7.8 Hz), 3.97
(1H, q, J ) 6.6 Hz), 3.87 (1H, br s), 3.86 (1H, m), 3.74 (1H, m),
3.57 (1H, m), 3.47 (1H, m), 3.19 (2H, m), 2.98 (1H, m), 2.67
(1H, m), 2.47 (1H, m), 2.28 (6H, s), 1.20-1.90 (5H, m), 1.50
(3H, s), 1.45 (3H, s), 1.42 (3H, d, J ) 6.9 Hz), 1,41 (3H, d, J )
6.3 Hz), 1.19 (3H, d, J ) 6.0 Hz), 1.14 (3H, d, J ) 6.3 Hz),
1.12 (3H, d, J ) 6.3 Hz), 0.84 (3H, t, J ) 7.5 Hz); 13C NMR
(CDCl3) δ 217.2 (C-9), 205.2 (C-3), 169.7 (C-1), 157.6, 151.3,
150.1, 143.9, 143.0, 136.9, 133.6, 133.1, 130.4, 129.1, 123.7,
102.9 (C-1′), 83.4, 78.8, 77.3, 76.4, 70.1, 69.5, 65.8, 64.1, 58.1,

Erythromycin Derivatives with C-6 Aryl Groups
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4155
Surveillance Study. Antimicrob. Agents Chemother. 1999, 43,
1901-1908. (b) Thornsberry, C.; Ogilvie, P. T.; Holley, H. P.;
Sahm, D. F. Survey of Susceptibilities of Streptococcus pneu-
moniae, Haemophilus influenzae, and Moraxella catarrhalis
Isolates to 26 Antimicrobial Agents: A Prospective U. S. Study.
Antimicrob. Agents Chemother. 1999, 43, 2612-2623. (c) Barry,
A. L. Antimicrobial Resistance Among Clinical Isolates of
Streptocuccus pneumoniae in North America. Am. J . Med. 1999,
107, 28S-33S. (d) Tomasz, A. New Faces of an Old Pathogen:
Emergence and Spread of Multidrug-Resistant Streptococcus
pneumoniae. Am. J . Med. 1999, 107, 55S-59S.
1.90 (6H, m), 1.50 (3H, s), 1.44 (3H, s), 1.42 (3H, d, J ) 6.6
Hz), 1,41 (3H, d, J ) 6.6 Hz), 1.20 (3H, d, J ) 6.0 Hz), 1.16
(3H, d, J ) 6.6 Hz), 1.12 (3H, d, J ) 6.6 Hz), 0.84 (3H, t, J )
7.5 Hz); 13C NMR (CDCl3) δ 217.5 (C-9), 205.3 (C-3), 169.8 (C-
1), 157.7 (carbamate), 153.5, 150.7, 146.9, 146.3, 138.5, 134.4,
134.3, 132.0, 128.3, 102.9 (C-1′), 83.5, 79.0, 77.4, 76.5, 70.2,
69.5, 65.9, 64.1, 58.2, 50.9, 46.4, 45.1, 40.2 (NMe2), 39.0, 37.4,
28.3, 21.2, 20.2, 18.1, 14.4, 14.2, 14.1, 13.7, 13.6, 10.6.
6-O-[3-(3′-Qu in olyl)pr opyl]-11,12-cyclocar bam ate Keto-
lid e 42s. To a solution of 41s (230 mg, 0.300 mmol) in MeOH
(10 mL) under nitrogen atmosphere was added 10% Pd-C
catalyst (50 mg). The mixture was stirred under hydrogen
atmosphere (balloon pressure) for 18 h. The catalyst was
removed by filtration and the filtrate was concentrated.
Column chromatography (silica gel, 95:5:0.5 CH2Cl2/MeOH/
ammonia) of the crude product provided 42s (218 mg, 95%)
as a white solid: MS m/z (APCI) 768 (M + H)+; HRMS (ESI)
m/z 768.4437, calcd for C42H62N3O10 768.4435; 1H NMR (CDCl3)
δ 8.78 (1H, d, J ) 2.4 Hz), 8.06 (1H, d, J ) 8.5 Hz), 7.99 (1H,
d, J ) 2.4 Hz), 7.82 (1H, d, J ) 8.5 Hz), 7.63 (1H, m), 7.51
(1H, m), 5.75 (1H, br s), 5.20 (1H, dd, J ) 9.5, 2.5 Hz), 4.36
(2H, m), 3.94 (2H, m), 3.59 (1H, m), 3.18 (4H, m), 3.05 (1H,
m), 2.96 (1H, m), 2.72 (2H, m), 2.64 (1H, m), 2.52 (1H, m),
2.29 (6H, s), 1.97 (1H, m), 1.85 (1H, m), 1.50-1.70 (4H, m),
1.56 (3H, s), 1.42 (3H, d, J ) 8.0 Hz), 1.32 (3H, d, J ) 7.0 Hz),
1.26 (3H, s), 1.20 (3H, d, J ) 6.5 Hz), 1.18 (3H, d, J ) 7.0 Hz),
1.13 (3H, d, J ) 7.0 Hz), 0.85 (3H, t, J ) 7.5 Hz); 13C NMR
(CDCl3) δ 217.6 (C-9), 205.5 (C-3), 170.1 (C-1), 158.2 (carbam-
ate), 152.1, 146.8, 134.2, 134.0, 129.1, 128.4, 128.3, 127.5,
126.4, 102.6 (C-1′), 83.7, 78.2, 77.0, 75.5, 70.2, 69.4, 66.0, 61.9,
58.4, 50.6, 45.2, 40.2 (NMe2), 38.9, 37.3, 29.7, 29.0, 28.5, 22.6,
(2) Doern, G. V.; Brueggemann, A. B.; Huynh, H.; Wingert, E.;
Rhomberg, P. Antimicrobial Resistance with Streptococcus pneu-
moniae in the United States, 1997-1998. Emerging Infect. Dis.
1999, 5, 757-765.
(3) (a) Doern, G. V.; Pfaller, M. A.; Kugler, K.; Freeman, J .; J ones,
R. N. Prevalence of Antimicrobial Resistance Among Respiratory
Tract Streptococcus pneumoniae in North America: 1997 Results
from the SENTRY Antimicrobial Surveillance Program. Clin.
Infect. Dis. 1998, 27, 764-770. (b) Doern, G. V.; J ones, R. N.;
Pfaller, M. A.; Kugler, K.; The SENTRY Participants Group.
Haemophilus influenzae and Moraxella catarrhalis from Patients
with Community-Acquired Respiratory Tract Infections: Anti-
microbial Susceptibility Patterns from the SENTRY Antimicro-
bial Surveillance Program (United States and Canada, 1997).
Antimicrob. Agents Chemother. 1999, 43, 385-389.
(4) (a) Ma, Z.; Clark, R. F.; Wang, S.; Nilius, A. M.; Flamm, R. K.;
Or, Y. S. 39th Interscience Conference on Antimicrobial Agents
and Chemotherapy, San Francisco, CA, 1999; Abstr. F2133. (b)
Or, Y. S.; Clark, R. F.; Wang, S.; Chu, D. T. W.; Nilius, A. M.;
Flamm, R. K.; Mitten, M.; Ewing, P.; Alder, J .; Ma, Z. Design,
Synthesis, and Antimicrobial Activity of 6-O-Substituted Ke-
tolides Active against Resistant Respiratory Tract Pathogens.
J . Med. Chem. 2000, 43, 1045-1049. (c) Clark, R. F.; Ma, Z.;
Wang, S.; Griesgraber, G.; Tufano, M.; Yong, H.; Leping, L.;
Zhang, X.; Nilius, A. M.; Chu, D. T. W.; Or, Y. S. Bioorg. Med.
Chem. Lett. 2000, 10, 815.
(5) (a) Bryskier, A. J .; Butzler, J .-P.; Neu, H. C.; Tulkens, P. M.
Macrolides. Chemistry, Pharmacology and Clinical Uses; Arnette
Blackwell: Paris, 1993. (b) Chu, D. T. W. Recent Developments
in 14- and 15-Membered Macrolides. Expert Opin. Invest. Drugs
1995, 4, 65-94.
(6) (a) Nakajima, Y. Mechanism of Bacterial Resistance to Macrolide
Antibiotics. J . Infect. Chemother. 1999, 5, 61-74. (b) Weisblum,
B. Macrolide Resistance. Drug Resist. Updates 1998, 1, 29-41.
(c) Amsden, G. W. Pneumococcal Macrolide ResistancesMyth
or Reality. J . Antimicrob. Chemother. 1999, 44, 1-6. (d) Irizarry,
L. M.; Porter, B.; Lenroot, R.; Alexov, M.; Massic, L. Macrolide-
Resistant Streptococcus pneumoniae: Epidemiology, Mechanism
of Resistance, Acquisition and Clinical Implication. Recent Res.
Dev. Antimicrob. Agent Chemother. 1999, 3, 511-521.
21.2, 20.3, 18.4, 14.7, 13.7, 13.6, 13.0, 10.6. Anal. (C42H61N3O10
C, H, N.
)
6-O-[2-(3′-Qu in olyl)cyclop r op ylm eth yl]-11,12-cycloca r -
ba m a te Ketolid e 43s. To an ice-cold solution of CH2N2 in
ether (0.64 M, 3.12 mL, 2.00 mmol) was introduced a solution
of 41s (153 mg, 0.200 mmol) in CH2Cl2 (5 mL) under nitrogen
atmosphere. Pd(OAc)2 (2.0 mg, 0.01 mmol) was added and the
reaction mixture was stirred for 30 min. Additional CH2N2
ether solution (0.64 M, 3.12 mL, 2.00 mmol) was added and
the mixture was allowed to warm to room temperature over
50 min. The solvent was evaporated and the crude product
was purified by column chromatography (silica gel, 95:5:0.5
CH2Cl2/MeOH/ammonia) to give 43s (100 mg, 64%) as a
mixture of diastereomers (60:40 ratio): MS m/z (ESI) 780 (M
+ H)+; HRMS (ESI) m/z 780.4446, calcd for C43H62N3O10
(7) Roberts, M. C.; Sutcliffe, J .; Courvalin, P.; J ensen, L. B.; Rood,
J .; Seppala, H. Nomenclature for Macrolide and Macrolide-
Lincosamide-Streptogramin B Resistance Determinants. An-
timicrob. Agents Chemother. 1999, 43, 2823-2830.
1
780.4435; H NMR (CDCl3) δ 8.99 (isomer 1, 1H, d, J ) 2.4
(8) (a) Ma, Z.; Nemoto, P. A. Discovery and Development of Ketolides
as a New Generation of Macrolide Antimicrobial Agents. Curr.
Med. Chem. Anti-infect. Agents 2002, in press. (b) Resek, J . E.;
Wang, X. C.; Bhatia, A. V. Highlights of Recent Research on the
Synthesis of Ketolide Antibiotics. Curr. Opin. Drug Discov. Dev.
2000, 3, 807-817. (c) Chu, D. T. W. Recent Developments in
Macrolides and Ketolides. Curr. Opin. Microbiol. 1999, 2, 467-
474. (d) Bryskier, A. Novelties in the Field of Macrolides. Expert
Opin. Invest. Drugs 1997, 6, 1697-1709. (e) Bryskier, A. New
Research in Macrolides and Ketolides since 1997. Expert Opin.
Invest. Drugs 1999, 8, 1171-1194. (f) Wu, Y. J . Highlights of
Semi-Synthetic Developments from Erythromycin A. Curr.
Pharm. Des. 2000, 6, 181.
(9) (a) Baker, W. R.; Clark, J . D.; Stephens, R. L.; Kim, K. H.
Modification of Macrolide Antibiotics. Synthesis of 11-Deoxy-
11-(carboxyamino)-6-O-methylerythromycin A 11,12-(Cyclic Es-
ters) via an Intramolecular Michael Reaction of O-Carbamates
with an R,â-Unsaturated Ketone. J . Org. Chem. 1988, 53, 2340-
2345. (b) Fernandes, P. B.; Baker, W. R.; Freiberg, L. A.; Hardy,
D. J .; McDonald E. J . New Macrolides Active against Strepto-
coccus pyogenes with Inducible or Constitutive Type of Mac-
rolide-Lincosamide-Streptogramin B Resistance. Antimicrob.
Agents Chemother. 1989, 33, 78-81.
(10) (a) Agouridas, C.; Benedetti, Y.; Denis, A.; Le Martret, O.;
Chantot, J . F. Ketolides: A New Distinct Class of Macrolide
Antibacterials. Synthesis and Structural Characterization of RU
004. 35th Interscience Conference on Antimicrobial Agents and
Chemotherapy, San Francisco, CA, 1995; Abstr. F157. (b)
Agouridas, C.; Denis, A.; Auger, J .; Benedetti, Y.; Bonnefoy, A.;
Bretin, F.; Chantot, J .; Dussarat, A.; Fromentin, C.; D’Ambrieres,
S. G.; Lachaud, S.; Laurin, P.; Le Martret, O.; Loyau, V.; Tessot,
N. Synthesis and Antibacterial Activity of Ketolides (6-O-Methyl-
3-Oxoerythromycin Derivatives): A New Class of Antibacterials
Hz), 8.95 (isomer 2, 1H, d, J ) 2.4 Hz), 8.05 (isomer 1, 1H, d,
J ) 7.8 Hz), 8.03 (isomer 2, 1H, d, J ) 7.8 Hz), 7.76 (isomers
1 and 2 together, 1H, m), 7.70 (isomer 1, 1H, d, J ) 2.4 Hz),
7.74 (isomer 2, 1H, d, J ) 2.4 Hz), 7.62 (isomers 1 and 2, 1H,
m), 7.50 (isomers 1 and 2, 1H, m), 5.52 (isomer 1, 1H, br s),
5.72 (isomer 2, 1H, br s), 5.16 (isomers 1 and 2, 1H, m), 4.37
(isomers 1 and 2, 2H, m), 3.94 (isomers 1 and 2, 3H, m), 3.60
(isomers 1 and 2, 1H, m), 3.45 (isomers 1 and 2, 1H, m), 3.18
(isomers 1 and 2, 2H, m), 3.05 (isomers 1 and 2, 1H, m), 2.63
(isomers 1 and 2, 2H, m), 2.46 (isomers 1 and 2, 1H, m), 2.26
(isomers 1 and 2, 6H, s), 1.20-2.00 (9H, m), 1.52 (isomer 1,
3H, s), 1.56 (isomer 2, 1H, s), 1.10-1.45 (isomers 1 and 2, 18
H, m), 0.86 (isomer 1, 3H, t, J ) 7.5 Hz), 0.88 (isomer 2, 3H,
t, J ) 7.5 Hz). Anal. (C43H61N3O10) C, H, N.
Ack n ow led gm en t. We acknowledge the support of
the Abbott Process Research Department for providing
research intermediates, the Structural Chemistry De-
partment for structural characterization, and the Clini-
cal Microbiology Department for in vitro and in vivo
testing.
Refer en ces
(1) (a) J acobs, M. R.; Bajaksouzian, S.; Zilles, A.; Lin, G.; Pankuch,
G. A.; Appelbaum, P. C. Susceptibilities of Streptococcus pneu-
moniae and Haemophilus influenzae to 10 Oral Antimicrobial
Agents Based on Pharmacodynamic Parameters: 1997 U. S.

4156 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Ma et al.
Highly Potent Against Macrolide Resistant and Susceptible
Respiratory Pathogens. J . Med. Chem. 1998, 41, 4080-4100. (c)
Denis, A.; Agouridas, C.; Auger, J .-M.; Benedetti, Y.; Bonnefoy,
A.; Bretin, F.; Chantot, J .-F.; Dussarat, A.; Fromentin, C.;
D’Ambrieres, S. G.; Lachaud, S.; Laurin, P.; Martret, O. L.;
Loyau, V.; Tessot, N.; Pejac, J .-M.; Perron, S. Synthesis and
Antibacterial Activity of HMR 3647. A New Ketolide Highly
Potent against Erythromycin-Resistant and Susceptible Patho-
gens. Bioorg. Med. Chem. Lett. 1999, 9, 3075-3080.
(19) Morimoto, S.; Matsunaga, T.; Adachi, T.; Kashimura, M.; Asaka,
T.; Sota, K.; Watanabe, Y.; Sekiuchi, K. Preparation of Eryth-
romycin A Derivatives. European Patent EP 272110 A2, 1988.
(20) Corey, E. J .; Kim, C. U. New and Highly Effective Method for
the Oxidation of Primary and Secondary Alcohols to Carbonyl
Compounds. J . Am. Chem. Soc. 1972, 94, 7586-7587.
(21) For a recent review on Heck coupling reaction, see Cabri, W.;
Candiani, I. Recent Developments and New Perspectives in the
Heck Reaction. Acc. Chem. Res. 1995, 28, 2-7.
(11) Asaka, T.; Kashimura, M.; Misawa, Y.; Ono, T.; Suzuki, K.;
Yoshida, T.; Akashi, T.; Yokoo, C.; Nagate, T.; Morimoto, S. New
Macrolide Antibiotics, TE-802: Synthesis and Biological Proper-
ties. 35th Interscience Conference on Antimicrobial Agents and
Chemotherapy, San Francisco, CA, 1995; Abstr. F176.
(22) Louie, J .; Hartwig, J . F. A Route to Pd0 from PdII Metallacycles
in Amination and Cross-Coupling Chemistry. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2359-2361.
(23) Capobianco, J . O.; Cao, Z. S.; Shortridge, V. D.; Ma, Z.; Flamm,
R. K.; Zhong, P. Studies of the Novel Ketolide ABT-773:
Transport, Binding to Ribosomes, and Induction of Protein
Synthesis in Streptococcus pneumoniae. Antimicrob. Agents
Chemother. 2000, 44, 1562-1567.
(24) (a) Shortridge, V. D.; Doern, G. V.; Brueggemann, A. B.; Beyer,
J . M.; Flamm, R. K. Prevalence of Macrolide Resistance Mech-
anisms in Streptococcus pneumoniae Isolates from a Multicenter
Antibiotic Resistance Surveillance Study Conducted in the
United States in 1994-1995. Clin. Infect. Dis. 1999, 29, 1186-
1188. (b) Shortridge, V. D.; Flamm, R. K.; Ramer, N.; Beyer, J .;
Tanaka, S. K. Novel Mechanism of Macrolide Resistance in
Streptococcus pneumoniae. Diagn. Microbiol. Infect. Dis. 1996,
26, 73-78.
(25) (a) Hansen, L. H.; Mauvais, P.; Douthwaite, S. The Macrolide-
Ketolide Antibiotic Binding Site Is Formed by Structures in
Domain II and V of 23S Ribosomal RNA. Mol. Microbiol. 1999,
31, 623-631. (b) Xiong, L.; Shah, S.; Mauvais, P.; Mankin, A. S.
A Ketolide Resistance Mutation in Domain II of 23S rRNA
Reveals the Proximity of Hairpin 35 to the Peptidyl Transferase
Center. Mol. Microbiol. 1999, 31, 633-639. (c) Douthwaite, S.;
Hansen, L. H.; Mauvais, P. Macrolide-Ketolide Inhibition of
MLS-Resistant Ribosome Is Improved by Alternative Drug
Interaction with Domain II of 23S rRNA. Mol. Microbiol. 2000,
36, 183-193. (d) Vester, B.; Douthwaite, S. Macrolide Resistance
Conferred by Base Substitutions in 23S rRNA. Antimicrob.
Agents Chemother. 2001, 45, 1-12.
(12) (a) Elliott, R. L.; Pireh, D.; Griesgraber, G.; Nilius, A. M.; Ewing,
P. J .; Bui, M. H.; Raney, P. M.; Flamm, R. K.; Kim, K.; Henry,
R. F.; Chu, D. T. W.; Plattner, J . J .; Or, Y. S. Anhydrolide
Macrolides. 1. Synthesis and Antibacterial Activity of 2,3-
Anhydro-6-O-Methyl-11,12-Carbamate Erythromycin A Ana-
logues. J . Med. Chem. 1998, 41, 1651-1659. (b) Griesgraber,
G.; Kramer, M. J .; Elliott, R. L.; Nilius, A. M.; Ewing, P. J .;
Raney, P. M.; Bui, M.-H.; Flamm, R. K.; Chu, D. T. W.; Plattner,
J . J .; Or, Y. S. Anhydrolide Macrolides. 2. Synthesis and Anti-
bacterial Activity of 2,3-Anhydro-6-O-Methyl-11,12-Carbazate
Erythromycin A Analogues. J . Med. Chem. 1998, 41, 1660-1670.
(13) Asaka, T.; Kashimura, M.; Manaka, A.; Tanikawa, T.; Ishii, T.;
Sugimoto, T.; Suzuki, K.; Sugiyama, H.; Akashi, T.; Saito, H.;
Adachi, T.; Morimoto, S. Structure-Activity Studies Leading to
Potent Acylides: 3-O-Acyl-5-O-desosaminylerythromycin-11,12-
carbamates. 39th Interscience Conference on Antimicrobial
Agents and Chemotherapy, San Francisco, CA, 1999; Abstr.
F2159.
(14) Su, W. G.; Smyth, K. T.; Rainville, J . P.; Kaneko, T.; Sutcliffe,
J . A.; Brennan, L. A.; Duignan, J . M.; Girard, A. E.; Finegan, S.
M.; Cimochoski, C. R. Erythromycylamine 4′′-Carbamate Anti-
bacterail Agents: Synthesis and Biological Evaluation Resulting
in Discovery of CP-544372. 38th Interscience Conference on
Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998;
Abstr. F123.
(15) (a) Awan, A.; Brennan, R. J .; Regan, A. C.; Barber, J . Confor-
mational Analysis of the Erythromycin Analogues Azithromycin
and Clarithromycin in Aqueous Solution and Bound to Bacterial
Ribosomes. J . Chem. Soc., Chem. Commun. 1995, 1653-1654.
(b) Bertho, G.; Ladam, P.; Gharbi-Benarous, J .; Delaforge, M.;
Girault, J .-P. Solution Conformation of Methylated Macrolide
Antibiotics Roxithromycin and Erythromycin Using NMR and
Molecular Modeling. Ribosome-Bound Conformation Determined
by TRNOE and Formation of Cytochrome P450-Metabolite
Complex. Int. J . Biol. Macromol. 1998, 22, 103-127. (c) Bertho,
G.; Gharbi-Benarous, J .; Delaforge, M.; Girault, J .-P. Transferred
Nuclear Overhauser Effect Study of Macrolide-Ribosome In-
teractions: Correlation between Antibiotic Activities and Bound
Conformations. Bioorg. Med. Chem. 1998, 6, 209-221. (d) Awan,
A.; Brennan, R. J .; Regan, A. C.; Barber, J . The Conformation
of the Macrolide Antibiotics Erythromycin A, Azithromycin and
Clarithromycin in Aqueous Solution: A 1H NMR Study. J . Chem.
Soc., Perkin Trans. 2 2000, 1645-1652.
(26) (a) Ban, N.; Nissen, P.; Hansen, J .; Moore, P. B.; Steitz, T. A.
The Complete Atomic Structure of the Large Ribosomal Subunit
at 2.4 Å Resolution. Science 2000, 289, 905-920. (b) Nissen, P.;
Hansen, J .; Ban, N.; Moore, P. B.; Steitz, T. A. The Structural
Basis of Ribosome Activity in Peptide Bond Synthesis. Science
2000, 289, 920-930.
(27) (a) Shuker, S. B.; Hajduk, P. J .; Meadows, R. P.; Fesik, S. W.
Discovering High-Affinity Ligands for Proteins: SAR by NMR.
Science 1996, 274, 1531-1534. (b) Hajduk, P. J .; Meadows, R.
P.; Fesik, S. W. Discovering High-Affinity Ligands for Proteins.
Science 1997, 278, 497-499. (c) Kessler, H. Structure-Activity
Relationships by NMR: A New Procedure for Drug Discovery
by a Combinatorial-Rational Approach. Angew. Chem., Int. Ed.
Engl. 1997, 36, 829-831. (d) Sucheck, S. J .; Wong, A. L.; Koeller,
K. M.; Boehr, D. D.; Draker, K.; Sears, P.; Wright, G. D.; Wong,
C.-H. Design of Bifunctional Antibiotics that Target Bacterial
rRNA and Inhibit Resistance-Causing Enzymes. J . Am. Chem.
Soc. 2000, 122, 5230-5231.
(28) (a) Allen, N. E. Macrolide Resistance in Staphylococcus aureus:
Inducers of Macrolide Resistance. Antimicrob. Agents Chemo-
ther. 1977, 11, 669-674. (b) Pestka, S.; Vince, R.; LeMahieu,
R.; Weiss, F.; Fern, L.; Unowsky, J . Induction of Erythromycin
Resistance in Staphylococcus aureus by Erythromycin Deriva-
tives. Antimicrob. Agents Chemother. 1976, 9, 128-130.
(29) Mitten, M.; Meulbroek, J .; Paige, L.; Alder, J .; Ewing, P.;
Mollson, K. W.; Nilius, A. M.; Flamm, R. K.; Ma, Z.; Or, Y. S.
Efficacies of ABT-773 and HMR-3647 against Respiratory
Pathogens Causing Acute Systemic Infections in Mice and Lung
Infections in Rats. 39th Interscience Conference on Antimicrobial
Agents and Chemotherapy, San Francisco, CA, 1999; Abstr.
F2150.
(16) Harris, D. R.; McGeachin, S. G.; Mills, H. H. The Structure and
Stereochemistry of Erythromycin A. Tetrahedron Lett. 1965,
679-685.
(17) (a) Bertho, G.; Gharbi-Benarous, J .; Delaforge, M.; Lang, C.;
Parent, A.; Girault, J .-P. Conformational Analysis of Ketolide,
Conformations of RU 004 in Solution and Bound to Bacterial
Ribosomes. J . Med. Chem. 1998, 41, 3373-3386. (b) Evrard-
Todeschi, N.; Gharbi-Benarous, J .; Gaillet, C.; Verdier, L.;
Bertho, G.; Lang, C.; Parent, A.; Girault, J .-P. Conformations
in Solution and Bound to Bacterial Ribosomes of Ketolides, HMR
3647 (Telithromycin) and RU 72366: A New Class of Highly
Potent Antibacterials. Bioorg. Med. Chem. 2000, 8, 1579-1597.
(18) Mosamune, S.; Bates, G. S.; Corcoran, J . W. Macrolides. Recent
Progress in Chemistry and Biochemistry. Angew. Chem., Int. Ed.
Engl. 1977, 16, 585-607.
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