Synthesis and antibacterial activity of C12 des-methyl ketolides

Article abstract of DOI:10.1016/j.bmcl.2006.05.104

Synthesis of C₁₂ des-methyl ketolide is developed featuring an intramolecular epoxide formation/elimination process to establish the C₁₂ stereocenter. These ketolides are potent against several key respiratory pathogens, including er

Full text of DOI:10.1016/j.bmcl.2006.05.104

Bioorganic & Medicinal Chemistry Letters 16 (2006) 4692–4696
Synthesis and antibacterial activity of C12 des-methyl ketolides
Xiaodong Lin,* Alice C. Rico, Daniel T. Chu, Georgia L. Carroll, Lynn Barker,
Ribhi Shawar, Manoj C. Desai and Jacob J. Plattner
Small Molecule Drug Discovery, Biopharma Research, Chiron Corporation, 4560 Horton Street, Emeryville, CA 94608, USA
Received 14 April 2006; revised 26 May 2006; accepted 30 May 2006
Available online 19 June 2006
Abstract—Synthesis of C12 des-methyl ketolide is developed featuring an intramolecular epoxide formation/elimination process to
establish the C12 stereocenter. These ketolides are potent against several key respiratory pathogens, including erythromycin resistant
erm- and mef-containing strains of Streptococcus pneumoniae.
Ó 2006 Elsevier Ltd. All rights reserved.
Macrolide antibiotics such as erythromycin A (Fig. 1)
are potent against several key respiratory pathogens
including Staphylococcus aureus and Streptococcus pneu-
moniae. They have been widely used for the treatment of
bacterial respiratory tract infections for many years. The
second generation of macrolides, including clarithromy-
cin1 and azithromycin,2 was developed to overcome the
problems associated with acid instability of erythromy-
cin.3 These compounds displayed better pharmacokinet-
ic properties as well as a broader spectrum of activity.
of macrolide known as ketolides (telithromycin6 and
cethromycin (ABT-773)7) has been developed. Ketolides
differ from other macrolides in that the C3 cladinose su-
gar of erythromycin A is replaced with a C3 ketone
group. Additionally, a heterocycle is tethered to the
macrolide core, introducing an additional binding con-
tact with the target ribosome.
In our laboratories, we sought to develop novel keto-
lides with in vitro and in vivo potency against resistant
strains. These ketolides are novel in that they have a
C12 modified macrocycle core. Using chemical synthesis
we have been able to access C12 hydrogen (des-methyl)8a
and other alkyl groups8,9 in place of the natural C12
methyl of erythromycin derived macrocycles. In this pa-
per, we wish to report the synthesis of C12 des-methyl
macrolide core, conversion of the core to ketolide deriv-
atives, and in vitro activities of the resulting ketolides.
Macrolides exert their antibacterial activity by reversibly
binding to the 23S ribosomal RNA in the 50S subunit of
ribosomes in order to block protein synthesis.4 Recently,
macrolide resistant pathogens with two main resistant
mechanisms, active efflux of the drug (mef gene) and tar-
get site modification (erm gene), have emerged.5 To
overcome the resistant pathogens, a third generation
O
O
R
N
O
N
HO
O
HO
N
N
OH
3
N
O
N
12
6
HO
O
21
12
O
O
21
O
O
O
O
O
O
O
O
1
3
O
O
1
OH
erythromycin A; R=H
clarithromycin; R=CH3
telithromycin
Figure 1. Clinically utilized macrolides.
Keywords: Macrolide; Ketolide; Antibacterial.
*
Corresponding author. Tel.: +1 510 923 7752. fax: +1 510 923 3360; e-mail: xiaodong_lin@chiron.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.05.104

X. Lin et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4692–4696
4693
including Mitsunobu reaction and intermolecular SN2-
type reaction with the mesylate of 2, did not yield any
desired product. It appears that the C12 secondary alco-
hol and its mesylate are not reactive toward intermolec-
ular SN2-type reactions, probably because the site is too
crowded. Hence we sought to invert the C12 alpha
hydroxy via an intramolecular reaction.
O
O
N
O
O
N
BzO
BzO
H
a, b
O
O
O
O
HO
O
O
O
O
O
O
O
O
O
O
O
O
OBz
OBz
1
2
Converting the C12 hydroxyl group to mesylate followed
by hydrolysis of the cyclic acetonide using acetic acid
yielded diol 3. Treatment of 3 with cesium carbonate
gave the C11AC12 epoxide 4 with inversion of stereocen-
ter at C12. To confirm the stereochemistry of compound
4, the benzoyl protecting group at C-20of the desosamine
was removed to grow the crystal and a structure was
determined by X-ray diffraction.13 To complete the syn-
thesis, C9 was oxidized and the resulting ketone was sub-
jected to basic conditions which allowed deprotonation
and b-elimination, resulting in enone 5. Deprotonation
with sodium hydride in the presence of carbonyldiimi-
dazole gave C12 imidazole carbamate, which upon reac-
tion with excess ammonia yielded C11AC12 cyclic NH
carbamate. Acidic hydrolysis of the cladinose and subse-
quent Corey–Kim oxidation of C3-hydroxy to C3-keto
then gave ketolide 6. The X-ray crystal diffraction of 6
unambiguously confirmed the stereochemistry of the
C12 des-methyl ketolide.13
c, d
OH
OH
OH
O
N
BzO
O
O
H
O
N
BzO
MsO
H
O
O
e
O
O
O
O
O
O
O
O
O
O
O
OBz
OBz
4
3
f, g
O
O
O
H
O
N
O
N
N
HO
H
BzO
BzO
O
H
h, i, j, k
O
O
O
O
O
O
O
O
O
O
O
O
OBz
Scheme 212 illustrates a more concise sequence for
synthesizing C12 des-methyl ketolide analogs with dif-
ferent heterocycles tethered to the carbamate nitrogen.
Thus, mesylate formation of 2 was followed by hydro-
lysis of both C3 cladinose and cyclic acetonide with
hydrochloric acid. The subsequent oxidation using
Dess–Martin periodinane oxidized both C3 and C9
hydroxy groups to afford diketone 7. Treatment of 7
5
6
Scheme 1. Reagents and conditions: (a) p-TsOH, O3, DCM/MeOH,
ꢀ78 °C, 10 min; then Me2S, ꢀ78 °C, 10 min; then Et3N, ꢀ78 to 25 °C,
85%; (b) NaBH4, EtOH, 25 °C, 17 h; (c) MsCl, DMAP, Et3N, DCM,
0 °C, 30 min; (d) HOAc, ACN, H2O, 65 °C, 16 h, 83% over three steps;
(e) Cs2CO3, ACN, 25 °C, 22 h; (f) Dess–Martin periodinane, DCM,
0–25 °C, 6 h, 96% over two steps; (g) DBU, acetone, 25 °C, 6 h; (h)
CDI, NaH, THF, ꢀ15–0 °C, 2 h; (i) NH4OH, THF, ACN, 50 °C, 22 h,
63% over three steps; (j) 3 M HCl (aq), ACN, 25 °C, 26 h, 92%; (k)
N-chlorosuccinimide, Me2S, DCM, ꢀ20 °C, 40 min; then Et3N,
ꢀ20–0 °C, 30 min, 75%.
O
O
O
N
BzO
H
O
N
H
BzO
O
O
HO
OH
a, b, c
Synthetic modifications of erythromycin have been pur-
sued by numerous investigators in order to prepare
chemical derivatives with improved biological profiles.
More recently, modifications involving the C11 and C12
hydroxyl groups have been extensively explored,10
which, in conjunction with modifications of C3 cladinose
moiety, eventually yielded the recently approved keto-
lide telithromycin. However, there are few examples of
chemical modifications to erythronolides at C12 and,
especially, with regard to the C12AC21 bond.11
MsO
O
O
O
O
O
O
O
O
O
O
O
OBz
2
7
d
O
O
Het
N
O
O
N
O
BzO
N
HO
H
HO
O
e, f, g
H
We have previously reported the efficient synthesis of a
suitably protected C12AC21 exocyclic alkenyl macrolide
1 from erythromycin A.9 As shown in Scheme 1,12 ozon-
olysis of the tosylate salt of 1 yielded C12-keto macro-
lide. Hydride reduction of the C12-keto group then
afforded C12 des-methyl macrolide core 2, with unde-
sired and unnatural C12 alpha hydroxy configuration.
The stereochemistry at C12 was determined based upon
X-ray diffraction of the crystals of 2.13 Efforts to deliver
hydride from the bottom face were not fruitful. Several
attempts to invert the alpha hydroxyl group at C12,
O
O
O
O
O
O
O
O
O
O
8
9: Het=tethered heterocycle
Scheme 2. Reagents and conditions: (a) MsCl, DMAP, Et3N, CH2Cl2,
0 °C, 30 min; (b) 3 M HCl (aq), ACN, 25 °C, 14 h, 88% over two steps;
(c) Dess–Martin periodinane, CH2Cl2, 0–4 °C, 48 h, 77%; (d) DBU,
acetone, 25 °C, 15 h, 72%; (e) NaH, CDI, THF, ꢀ15–0 °C, 25 min; (f)
Het-amine, ACN, 75 °C, 40 h, 43–84% over two steps; (g) MeOH,
70 °C, 22 h, 42–79%.

4694
X. Lin et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4692–4696
with DBU in acetone allowed epoxide formation,
deprotonation at C10, and elimination/epoxide opening
to occur in one pot. The resulting enone 8 was trans-
formed to C12 imidazole carbamate, which upon reac-
tion with an excess of side-chain amine and
deprotection of the desosamine benzoate by heating
in methanol yielded final ketolide analogs 9. The C12
des-methyl ketolides (9a–9u) prepared and reported
are illustrated in Figure 2. The heteroaryl side-chain
amines incorporated into the ketolides were synthe-
sized as described previously.9
concentration (MIC) in lg/mL as determined by the
Broth microdilution method.15
The data in Tables 1 and 2 indicate that, in general, C12
des-methyl ketolides possess similar potency as telithro-
mycin against most pathogens in vitro. Most of the C12
des-methyl ketolides are potent against the mef and erm
gene-containing S. pneumoniae strains that clarithromy-
cin is not active against. The overall activity spectrum of
the C12 des-methyl ketolides can be attenuated by the
nature of the heterocycle tethered to the C11, C12 carba-
mate. All of the heterocyclic moieties on the C12 des-
methyl ketolides reported here are tethered to the C11
attached nitrogen via a four-atom spacer. The heterocy-
clic moieties can be divided into 5,6-membered unfused
bi-heteroaryl or 5,6- and 6,6-fused heteroaromatic bicy-
clic systems.
The structural assignments of the final ketolides were
supported by NMR comparison to analog 6, of which
the crystal structure was obtained, and its 20-hydroxy
derivative. Additionally, for compound 9g, which has
the same alkyl tethered group off the cyclic carbamate
as telithromycin, the 1H NMR peaks for the macrocycle
core, excluding resonances for the C12 methyl or hydro-
gen group, are practically identical to those of
telithromycin.14
Among the 5,6-membered biaryl heterocycle analogs
(Table 1), compound 9g contains the same pyridyl
imidazole moiety as telithromycin. Although 9g
showed very similar potency as telithromycin against
most pathogens tested, it was not potent against E.
faecalis_bc11148-2. This is also seen for clarithromycin
and seems a general trend for most of C12 des-methyl
ketolides with a few exceptions (Tables 1 and 2).
Changing the pyridyl to phenyl ring, compound 9f
showed much improved potency against two mef-con-
taining resistant strains (vs 9g and teli). Replacing the
imidazole ring with thiophene, analogs 9d and 9e
showed weaker activity against erm-containing and
H. influenzae strains. The three thiazole-containing
analogs (9a–c) all showed improved potency against
E. faecalis_bc11148-2 (vs 9g). However, they also suf-
fered from poor potency against erm strain. Similar
potency profile change was also observed with 9i
and 9j, analogs having substitution ortho to nitrogen
of the pyridine ring. Compound 9a was the least po-
tent among all analogs. Adding gem-dimethyl group
off the alpha carbon of the carbon chain linker result-
ed in much improved potency against E. faecal-
is_bc11148-2 (9h vs 9g). The most interesting
observation is from compounds 9k and 9l, containing
2-fluoropyridine and 2-chloropyridine, respectively.
Although 9k showed decreased potency against resis-
tant strains, compound 9l showed much improved
potency vs 9g and an activity profile comparable to
telithromycin.
To evaluate the antibacterial activity, the C12 des-methyl
ketolides were assayed in a primary panel against a
number of strains of Staphylococcus aureus, Staphylococ-
cus epidermidis, Enterococcus faecalis, Streptococcus
pyogenes, Streptococcus pneumoniae, and Haemophilus
influenzae. Included among the strains of S. pneumoniae
were erythromycin resistant strains containing mef
and erm genes. Telithromycin and clarithromycin
were used for comparison in all assays. The in vitro anti-
bacterial activity is reported as the minimum inhibitory
O
Het
O
N
O
N
HO
O
H
O
O
O
O
O
Het:
V
R2
W
Y
Z
9f: W=C,R1=R2=H
N
9g: W=N,R1=R2=H
9a: V=Y=Z=C,W=N,X=S
9b: V=Y=C,W=N,X=S,Z=CNH2
9c: V=Y=N,W=Z=C,X=S
9d: V=W=Y=C, X=S,Z=N
9e: V=W=C,X=S,Y=Z=N
W
X
N
9h: W=N, R1=CH3,R2=H
9i: W=N,R1=H,R2=OCH3
9j: W=N,R1=H,R2=CH3
9k: W=N,R1=H,R2=F
9l: W=N,R1=H,R2=Cl
R1
R1
Table 2 summarizes data of fused biaryl heterocycle
analogs. Among three aza-benzimidazole compounds,
adding gem-dimethyl group off the alpha carbon of the
carbon chain linker once again resulted in much im-
proved potency against E. faecalis_bc11148-2 (9o vs
9m and 9n). The 4-azaindole (9q)- and 4-aminoindole-
(9r) containing analogs had potency better than the in-
dole analog 9p. All three compounds had improved
potency against mef strains compared to telithromycin,
especially 9q. The three quinoline-containing derivatives
differ by the position of carbon chain linker which influ-
enced the potency profile as well. For example, 9s, with
linker ortho to the nitrogen, had improved activity
against E. faecalis_bc11148-2 (vs 9g) as well as mef
N
X
9s
W
9m: W=Y=N,X=C,R=H
9n: W=X=N,Y=C,R=H
9o: W=X=N,Y=C,R=CH3
9p: W=X=Y=C,R=H
Y
N
N
R
R
9q: W=Y=C,X=N,R=H
9r: W=Y=C,X=CNH2,R=H
9t
N
9u
Figure 2. Structures of C12 des-methyl ketolides.

X. Lin et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4692–4696
Table 1. In vitro antibacterial activity [MIC (lg/mL)] of C12 des-methyl ketolidesa
4695
Strains
9a
9b
9c
9d
0.2
50
9e
9f
9g
9h
9i
9j
9k
9l
S. aureus_29213
S. aureus_33591
0.78
>50
0.78
0.4
>50
0.4
0.2
>50
0.2
0.1
0.2
>50
0.2
0.2
>50
0.1
0.2
>50
0.78
0.2
>50
0.1
0.2
>50
0.1
0.2
>50
0.2
0.2
>50
0.2
0.2
>50
0.1
S. epidermidis_14990
S. epidermidis f50654
E. faecalis_29212
0.2
0.1
0.4
0.4
0.2
0.2
0.2
60.05
>50
0.2
0.1
0.2
0.1
0.1
0.1
0.2
60.05
6.25
0.2
0.1
0.78
60.05
25
0.2
60.05
0.4
60.05 60.05
3.13 25
E. faecalis_bc11148-2
S. pyogenes_8668
S. pneumo_49619
6.25
0.2
3.13
>50
>50
1.56
60.05
60.05
60.05
60.05
0.4
3.13
60.05
60.05
60.05
60.05
50
60.05
60.05
60.05
60.05
50
60.05 60.05
60.05 60.05
60.05 60.05
60.05 60.05
25
0.78
0.1
60.05
60.05
60.05
60.05
60.05
60.05
60.05
60.05
0.78
60.05
60.05
60.05
60.05
0.2
60.05
60.05
60.05
60.05
50
60.05
60.05
60.05
0.2
60.05
60.05
60.05
60.05
0.4
60.05
60.05
60.05
25
S. pneumo_297-749
S. pneumo_280-962
S. pneumo_Erm 6849
S. pneumo_Mef 5654
S. pneumo_Mef S 3427
H. influenzae_49247
H. influenzae_2762
6.25 >50
12.5
1.56
0.1
0.78
0.4
0.1
0.4
60.05
12.5
0.2
1.56
0.2
1.56
0.2
0.78
0.1
1.56
0.4
0.78
0.78
0.78
0.1
60.05
6.25
1.56
60.05
3.13
nd
12.5
3.13
6.25
1.56
12.5
6.25
0.78
3.13
1.56
6.25
1.56
3.13
1.56
3.13
0.78
6.25
1.56
3.13
3.13
a nd, not determined.
Table 2. In vitro antibacterial activity [MIC (lg/mL)] of C12 des-methyl ketolidesa
Strains
9m
0.2
>50
0.2
9n
9o
9p
9q
9r
9s
9t
9u
teli
0.1–0.2
>50
clari
0.4–0.78
>50
S. aureus_29213
S. aureus_33591
0.4
>50
0.4
0.2
>50
0.1
0.4
>50
0.2
0.2
>50
0.4
0.2
>50
0.4
0.4
>50
0.4
>50
0.1
>50
S. epidermidis_14990
S. epidermidis f50654
E. faecalis_29212
0.2
0.2
0.2
0.4
0.1
0.1
0.1–0.2
0.1–0.2
60.05–0.1
0.4
0.2–0.4
0.2–0.4
0.78–1.56
0.4
60.05
50
0.4
0.1
0.1
60.05
0.4
0.1
0.4
0.1
0.78
60.05
6.25
60.05
3.13
0.1
60.05
>50
E. faecalis_bc11148-2
S. pyogenes_8668
>50
1.56 >50
6.25
12.5
60.05
60.05
60.05
60.05
0.4
>50
60.05
60.05
60.05
60.05
0.78
60.05
60.05
60.05
60.05
0.78
60.05
60.05
60.05
60.05
6.25
60.05
60.05
60.05
60.05
6.25
60.05
60.05
60.05
60.05
0.2
60.05
0.1
60.05
60.05
60.05
60.05
25
60.05
60.05
60.05
60.05
6.25
60.05
60.05
60.05
60.05
60.05
>50
S. pneumo_49619
S. pneumo_297-749
S. pneumo_280-962
S. pneumo_Erm 6849
S. pneumo_Mef 5654
S. pneumo_Mef S 3427
H. influenzae_49247
H. influenzae_2762
60.05
60.05
60.05
25
60.05
60.05
0.1–0.4
0.4–0.78
0.1–0.2
3.13–6.25
0.4–1.56
0.78
3.13
1.56
0.2
0.2
0.78
0.2
0.2
0.1
6.25–12.5
60.05
3.13
0.4
3.13
0.2
6.25
60.05
6.25
60.05
1.56
60.05
3.13
60.05
3.13
0.1
60.05
1.56
3.13–6.25
6.25–12.5
0.78–3.13
6.25
1.56
nd
nd
1.56
nd
0.78
1.56
nd
nd
a nd, not determined; teli, telithromycine; clari, clarithromycin.
strains (vs teli), but lost potency against erm strain.
Compound 9u had better potency than telithromycin
against mef and H. influenzae strains.
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j.bmcl.2006.05.104.
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13. 3D pictures of the crystal structures are provided in
Supporting Information. The deposition numbers are
CCDC 609190-609192 at the Cambridge Crystallographic
Data Centre.
14. Spectral data of compound 9g and 20-hydroxy derivative
of 6 are reported in Supporting Information.
15. NCCLS. Methods for Dilution Antimicrobial Susceptibil-
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