The synthesis of (9S)-9-alkyl-9-hydroxyerythromycin a derivatives and their ketolides

Article abstract of DOI:10.1016/j.tetlet.2005.02.162

A short, concise synthesis of a novel series of (9S)-9-alkyl-9- hydroxyerythromycin A derivatives and their corresponding ketolides, is described. The key chemical transformation is a stereoselective addition of organomagnesium or organolithium agents to the 9-position of the suitably protected macrolide templates 8 and 13.

Full text of DOI:10.1016/j.tetlet.2005.02.162

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2731–2735
The synthesis of (9S)-9-alkyl-9-hydroxyerythromycin A
derivatives and their ketolides
Eugene B. Grant,* Jesse M. Weiss, Shawn Branum, Stuart Hayden, Sigmond Johnson,
Deodialsingh Guiadeen, William V. Murray and Mark J. Macielag
Antimicrobial Agents Research, Johnson & Johnson Pharmaceutical Research & Development, L.L.C.,
1000 Route 202, PO Box 300, Raritan, NJ 08869, USA
Received 15 February 2005; revised 25 February 2005; accepted 28 February 2005
Abstract—A short, concise synthesis of a novel series of (9S)-9-alkyl-9-hydroxyerythromycin A derivatives and their corresponding
ketolides, is described. The key chemical transformation is a stereoselective addition of organomagnesium or organolithium agents
to the 9-position of the suitably protected macrolide templates 8 and 13.
Ó 2005 Elsevier Ltd. All rights reserved.
The macrolide antibiotic erythromycin A (1) has
enjoyed widespread use in the treatment of respiratory
N
tract infections. Recently, its clinical efficacy has been
reduced by antibiotic resistance, particularly in the
important respiratory pathogen, Streptococcus pneumo-
niae.1 The primary mechanisms of resistance in S. pneu-
moniae are removal of the macrolide from the cytosol
via efflux, and alteration of the macrolide binding site
by ribosomal methylation.2,3 The need for new, more
effective macolide antibiotics has grown as the preva-
lence of erythromycin-resistant S. pneumoniae has
increased.
N
O
N
N
OH
O
HO
OH
OH
O
O
N
O
O
O
O
O
O
11
OH
6
12
O
N
O
O
3
OMe
O
O
O
OH
Telithromycin
Erythromycin A
Telithromycin (2)4 is the first of a new generation of
semi-synthetic macrolide antibiotics, known as—the
ketolides, to reach the market. Most S. pneumoniae clini-
cal isolates are susceptible to telithromycin, including
strains resistant to erythromycin due to efflux and/or
ribosomal methylation. Replacement of the cladinose
sugar of erythromycin A with the 3-ketone functionality
of telithromycin prevents induction of ribosomal meth-
ylation and endows the macrolide-derived core with
activity against organisms resistant due to efflux. How-
ever, this single structural change was insufficient to
provide a therapeutic agent; two additional synthetic
(1)
(2)
O
N
H
N
O
O
O
11
OH
6
12
N
O
O
3
O
O
O
Cethromycin
(3)
modifications were required.5 Optimal antimicrobial
activity was achieved when the 11,12-cyclic carbamate
and the attached aromatic side chain were introduced.
The function of the carbamate is not well understood,
although it may restrict the conformation of telithro-
mycin at the ribosomal binding site.6 In contrast the
Keywords: Stereoselective organometallic addition; Macrolides;
Ketolides.
*
Corresponding author. Tel.: +1 90 8218 6589; fax: +1 90 8203 8109;
e-mail: egrant@prdus.jnj.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.162

2732
E. B. Grant et al. / Tetrahedron Letters 46 (2005) 2731–2735
aromatic side chain has been shown by structural studies
to bind to domain II of the bacterial ribosome and
anchor the macrolide core to the peptide exit tunnel in
domain V.7 The related ketolide, cethromycin (3), has
a similar microbiological profile as telithromycin but is
distinguished from telithromycin by the attachment of
the aryl alkyl group to the C6-position, and by the pres-
ence of an unsubstituted C11,C12-cyclic carbamate.
Structural studies have demonstrated that the aromatic
side chains of 2 and 3 bind to a similar region of the bac-
terial ribosome.7
of the acidic functionalities of the macrolide were
blocked. To that end, macrolide derivative 8, with a ter-
tiary 11,12-cyclic carbamate, was chosen as the model
electrophile in a parallel survey of organolithium and
Grignard reagents. The synthesis of 8 was accomplished
from commercially available clarithromycin (7) by a
route analogous to that described by Baker et al.
(Scheme 2).11 Reaction of 8 with 5 equiv of an organo-
metallic reagent, such as allylmagnesium bromide, butyl-
lithium, lithium trimethylsilylacetylide, phenyllithium,
methyl magnesium bromide, or methyllithium, at
ꢀ78 °C in tetrahydrofuran led only to recover starting
material or a complex mixture of products. When the
reaction was conducted at 0 °C, only methyllithium
afforded an isolable quantity of addition product 9.
Methyl magnesium bromide, lithium trimethylsilylacet-
ylide, and phenyllithium either cleaved the cladinose
sugar or removed the 20-acetyl protecting group, with
no detectable addition to the ketone carbonyl, even
at elevated temperatures.
Alternatively, synthetic modification of the C9-ketone
could lead to ketolides with improved microbiological
properties.8 An NMRstudy of the conformations of 2
suggested the C9-ketone is in close proximity to the
C11-position. Thus, C9-substituents may occupy a simi-
lar region of conformational space as the telithromycin
C11-side chain.9 Although a number of nitrogen-based
nucleophiles having low steric requirements have been
incorporated into the C9-position of erythromycin A
to give oximino, imino, or amino derivatives,8 there is
little precedent in the literature for functionalization of
the 9-position of the erythronolide ring with a carbon
substituent. In fact, the only successful approach
reported to date involves the stereoselective addition
of cyanide to the cyclic thiocarbonate 5 derived from
9,9-dihydroerythromycin A to afford 6 (Scheme 1).10 Di-
rect addition of organometallic reagents to the C9-car-
bonyl of erythromycin A or B has been reported to
give unidentifiable products.10
NMRanalysis of the tertiary alcohol product from the
methyllithium reaction revealed selective addition of
the nucleophile to the 9-position to afford 9.12 Despite
our best efforts at optimization, however, the product
could be isolated in only 6% yield after acid hydrolysis
to 10. The clean conversion of 8 to 9 was hampered
by side reactions, such as loss of protecting groups as
well as difficulties in isolation due to cleavage of the
cladinose sugar upon chromatography.
Nevertheless, 10 could be readily converted to the corre-
sponding ketolide 12 in 50% overall yield by a three-step
sequence involving re-acetylation of the 20-hydroxy
We reasoned that it might be possible to add carbon
nucleophiles directly to the C9-carbonyl group if most
O
OH
S
OH
OH
OH
O
9
OH
HO
HO
OH
OH
Reference 10
O
N
O
O
N
O
O
O
O
O
O
O
O
OMe
OMe
OH
OH
1
4
a
S
CN
O
O
C
O
R
OH
O
OH
O
R
HO
HO
OH
OH
OH
b
O
N
O
N
O
O
O
O
O
O
O
OMe
OMe
OH
OH
6
5
Scheme 1. Reagents and conditions: (a) thiocarbonyldiimidazole, K2CO3; (b) KCN.

E. B. Grant et al. / Tetrahedron Letters 46 (2005) 2731–2735
2733
O
O
O
N
O
O
HO
O
OH
OH
OAc
Reference 11
O
O
N
O
O
N
O
O
O
O
O
O
O
O
MeO
MeO
OH
OTMS
Clarithromycin
7
8
HO
HO
O
O
O
O
a
N
N
O
O
d, e
OR1
OH
O
O
N
O
O
N
O
OR
O
O
O
O
R = L-cladinose, R1 = H
R = R1 = H
9
12
b
c
10
R = H, R1 = Ac
11
Scheme 2. Reagents and conditions: (a) MeLi (4 equiv); (b) 10% aqueous HCl, 6% yield over two steps; (c) acetic anhydride, Et3N, CH2Cl2; (d) Dess–
Martin periodinane, CH2Cl2; (e) MeOH.
group to afford 11, Dess–Martin oxidation of the
3-hydroxyl to the ketone,12 and tranesterification of
the 20-acetyl protecting group with methanol.13
sponding 3-hydroxyl derivative 15b–e resulting from
partial cleavage of the cladinose sugar. On the other
hand, lithium trimethylsilylacetylide (Table 1, entry 4)
provided the addition product 14a exclusively.
The poor outcome in the reaction of organometallic re-
agents with 8 might be due to the severe steric environ-
ment in the region of the C9-carbonyl. To help relieve
steric congestion, secondary carbamate 13, prepared
by a similar procedure as for 8,11 was chosen as the elec-
trophilic partner in the addition reaction (Scheme 3).
Reaction of 13 with organolithium or Grignard reagents
(5 equiv) in tetrahydrofuran at temperatures ranging
from 0 to 25 °C afforded a modest to good yield of addi-
tion product in select cases (see Table 1, entries 4–6, 8,
11, 13).14 In contrast to the tertiary carbamate 8, reac-
tion of methyllithium with 13 led only to decomposition
(entry 1), whereas methylmagnesium chloride (entry 5)
and methylmagnesium bromide (entry 6) afforded a
moderate to good yield of the corresponding addition
product. Although ethynylmagnesium bromide (entry
15) did not add to the C9-carbonyl group, lithium
trimethylsilylacetylide (entry 4) was sufficiently nucleo-
philic to undergo efficient addition. Sterically encum-
bered nucleophiles, such as phenyllithium (entry 2) or
phenylmagnesium bromide (entry 10), failed to yield
the desired product. In addition to the results in Table
1, 13 was resistant to alkylation by allyl trimethylsilane
both in the presence of boron trifluoride etherate or
under indium promoted Barbier conditions.15 Although
several Grignard reagents underwent successful addition
to 13 (Table 1, entries 5, 6, 8, 11, 13), the alkylated prod-
ucts 14b–e also contained various amounts of the corre-
Complete removal of the cladinose sugar could be
effected by treatment with aqueous HCl during reaction
work-up. Conversion of 15a–e to the corresponding
ketolides 18a–e was accomplished as before, by selective
protection of the 20-hydroxy group with acetic anhy-
dride to give 16a–e, oxidation with Dess–Martin period-
inane to provide 17a–e, and removal of the 20 acetate
protecting group (Scheme 3).
Since only one diastereomer was observed in the NMR
spectra of 18a–e, the remaining uncertainty concerned
the absolute stereochemistry of the newly formed ter-
tiary alcohol. Treatment of 18b with CDI in the presence
of sodium hydride in tetrahydrofuran at 0 °C rapidly
provided 19 as the sole product. The formation of oxaz-
inone 19 from 18b could only occur if addition of the
nucleophile had occurred from the a or bottom face of
the macrolide ring (Scheme 4). Given that Baker et al.
had established the absolute stereochemistry of 11,12-
cyclic carbamate 13 as 11R,11 the absolute stereochemis-
try of tertiary alcohols 14a–e must be 9S. Thus carbon-
based nucleophiles attack the C9-carbonyl group from
the same face of the macrolactone ring as sodium boro-
hydride16 in the reduction of erythromycin A to 4.
In summary, we have achieved the first successful addi-
tion of organometallic reagents to the 9-oxo-group of an

2734
E. B. Grant et al. / Tetrahedron Letters 46 (2005) 2731–2735
O
O
O
NH
O
O
HO
O
OH
OH
OAc
Reference 11
O
O
N
O
O
N
O
O
O
O
O
O
O
O
MeO
MeO
HO R2
NH
OH
7
OTMS
13
O
O
O
OR1
a
d
O
O
N
O
OR O
R = L-cladinose, R1 = H
R = R1 = H
14a-e
15a-e
b
c
R = H, R1 = Ac
HO R2
NH
16a-e
O
O
R2 = a* =
O
OR1
CH3
b =
O
O
N
c = CH2CH3
O
O
O
CH2Ph
d =
e =
R1 = OAc
R1 = H
17a-e
18a-e
e
Scheme 3. Reagents and conditions: (a) R2M (see Table 1); (b) 20% aqueous HCl; (c) acetic anhydride, Et3N, CH2Cl2; (d) Dess–Martin periodinane,
CH2Cl2; (e) MeOH.
Table 1. Nucleophiles and results of reaction with 13
O
HO
NH
O
R3M
Resulta
O
Entry
O
N
O
O
1
2
3
MeLi
PhLi
BuLi
Decomposition
Decomposition
Decomposition
O
O
a
OAc
OAc
O
O
N
O
O
N
18ab 67%
O
O
O
4
O
O
O
Si
Li
5
6
7
8
MeMgCl
MeMgBr
MeMgI
18b 54%
18b 71%
13c
18b
19
Scheme 4. Reagents and condition: (a) NaH, CDI, THF, 25 °C.
EtMgBr
18c 76%
9
Si
13c
MgBr
ate reactivity. Finally, the stereochemistry of the newly
formed tertiary alcohol was unambiguously established
as 9S by formation of oxazinone 19. The antibacterial
activity of ketolides 12 and 18a–e will be reported
elsewhere.
10
11
PhMgBr
PhCH2MgBr
13c
18d 52%
13c
12
13
14
15
MgBr
MgBr
18e 60%
13c
BuMgBr
13
MgBr
a Yields are for conversion of 13 to 18.
References and notes
b Trimethylsilyl group is removed in a separate deprotection reaction;
see Ref. 14.
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2001, 14, 367–381.
c Loss of protecting groups was noted.
erythromycin A-derived macrolide. Success was realized
by employing suitably protected macrolide templates 8
and 13 and carbon-based nucleophiles of the appropri-

E. B. Grant et al. / Tetrahedron Letters 46 (2005) 2731–2735
2735
2. (a) Nakajima, Y. J. Infect. Chemother. 1999, 5, 61–71; (b)
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and a pressure equalization-dropping funnel was charged
with 14 (156.3 g, 0.176 mol) in anhydrous THF (2 L). The
mixture was cooled to 0 °C and treated dropwise with a
solution of lithium trimethylsilylacetylide in THF (0.5 M,
1408 mL, 0.704 mol) over a 20-min period. The ice bath
was removed and the reaction was stirred overnight at
25 °C. The reaction mixture was treated with saturated
aqueous NH4Cl (1 L) and then transferred to a 12-L
separatory funnel. After an additional amount of NH4Cl
(4 L) was added, the organic phase was isolated, washed
with additional NH4Cl (3 L) and concentrated to dryness
to afford 238 g of a brownish foam. This foam was
dissolved in anhydrous THF (1.1 L) and acidified with
20% HCl (1.0 L) over a 30-min period. The reaction was
allowed to stir for 1 h, and then it was treated with
concentrated NH4OH (1.5 L) and diluted with EtOAc
(1.0 L). The mixture was transferred to a 12-L separatory
funnel, diluted with an additional amount of EtOAc
(1.0 L), and the organic phase was isolated. The aqueous
phase was extracted with EtOAc (1.0 L) and the combined
organic phase was concentrated to dryness to afford
163.9 g of light brown foam. This crude material was
dissolved in MeOH (1.6 L) and K2CO3 (188 g) was added
to the resulting solution. After the reaction was stirred for
1 h, it was concentrated to dryness and then diluted with
EtOAc (3.0 L) and H2O (3.0 L). The organic phase was
isolated and concentrated to dryness to afford 149.8 g of
crude product, which was purified by crystallization from
EtOAc to afford 84.7 g (75%) of 15a. 1H NMR(400 MHz;
CDCl3) d 5.50 (s, 1H), 5.11 (d, 1H, J = 9 Hz), 4.70 (br s,
1H), 4.50 (d, 1H, J = 8 Hz), 3.90–3.80 (m, 3H), 3.53 (m,
1H), 3.23 (dd, 1H, J = 7.6, 10.3 Hz), 3.10 (s, 3H), 2.73 (dd,
1H, J = 7, 10 Hz), 2.58 (s, 1H), 2.51–2.48 (m, 1H), 2.24 (s,
6H), 2.0–1.85 (m, 3H), 1.70–1.48 (m, 4H), 1.4–1.2 (m,
22H), 1.10 (d, 3H, J = 4 Hz), 0.87 (dd, 3H, J = 7, 11 Hz);
MS (m/z) 641 (M+H).
12. For a more detailed description see: Qiu, Y.-L.; Phan, L.
T.; Or, Y. S. US 6774115.
13. All new compounds were characterized by NMRand mass
spectral methods.
14. Representative synthesis: Example 15a: A 5-L four-neck
flask equipped with an overhead mechanical stirrer, a
thermocouple controller, a nitrogen inlet/outlet adapter,
15. Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55, 11149–11176.
16. Faghih, R.; Buytendorp, M.; Stephens, R.; Hardy, D.;
Plattner, J.; Lartey, P. J. Antibiot. 1990, 43, 1334–1336.