Synthesis of novel 4′-substituted 16-membered ring macrolide antibiotics derived from leucomycins

Article abstract of DOI:10.1016/j.bmcl.2003.10.028

A series of novel 4′-substituted 16-membered ring macrolides was synthesized by the cleavage of the mycarose sugar and subsequent modification of 4′-hydroxyl group. This new class of macrolides antibiotics is acid stable. The synthetic methodology described here is expected to find application in the synthesis of new generation of macrolides that target the emerging bacterial resistance.

Full text of DOI:10.1016/j.bmcl.2003.10.028

Bioorganic & Medicinal Chemistry Letters 14 (2004) 519–521
Synthesis of novel 40-substituted 16-membered ring macrolide
antibiotics derived from leucomycins
Zhaolin Wang,* Tianying Jian, Ly T. Phan and Yat Sun Or
Enanta Pharmaceuticals, Inc., 500 Arsenal Street, Watertown, MA 02472, USA
Received 18 June 2003; accepted 2 October 2003
Abstract—A series of novel 40-substituted 16-membered ring macrolides was synthesized by the cleavage of the mycarose sugar and
subsequent modification of 40-hydroxyl group. This new class of macrolides antibiotics is acid stable. The synthetic methodology
described here is expected to find application in the synthesis of new generation of macrolides that target the emerging bacterial
resistance.
# 2003 Elsevier Ltd. All rights reserved.
Macrolide antibiotics have been widely used to treat
1
Herein, we report the synthesis of a series of novel
40-substituted 16-membered ring macrolides derived
from members of the leucomycin complex.
bacterial infections for the past 50years. They are
considered as the preferred therapeutic agents for the
treatment of upper and lower respiratory tract infec-
tions due to their safety and efficacy.2 Macrolides exert
potent antibacterial effect by selectively binding to the
50S subunit of the bacterial ribosome and inhibition of
the protein synthesis.3 Recent published crystal struc-
tures of the bacterial ribosomal complexed with macro-
lides have demonstrated that they bind in the
polypeptide exit tunnel to block the elongating poly-
peptide.4 As a large family of both natural and semi-
synthetic antibiotics, macrolides are classified according
to the size of the lactone ring consisting of 12–16 atoms
and to the number and type of sugars attached. Ery-
thromycin A (Fig. 1) and its derivatives, which have a
fourteen membered lactone ring, are the most com-
monly used macrolides. However, erythromycin-resis-
tant bacterial strains have become increasingly
prevalent over the past decade.5 The sixteen membered
ring macrolides of leucomycins, such as josamycin and
kitasamycin (Fig. 1), constitute another important class
of clinically useful antibiotics.6 These sixteen membered
ring macrolides offer some advantages over 14-mem-
bered erythromycin derivatives, such as gastrointestinal
tolerance and activity against resistance-expressing
strains.7 However, little research has been done to
improve their acid stability and antibacterial activity.8
Our approach to improve the acid stability of leucomy-
cins is to remove the mycarose sugar and modify the
40-hydroxyl group. Josamycin, one of the members of
leucomycins, was used as a model compound for this
study. Scheme 1 outlines the synthesis of 40-carbamates
of josamycin. Oxidation of josamycin 1 with chromic
oxide converted the 9-hydroxyl group to the 9-ketone
group. Protection of the 20-hydroxyl group of 2 with an
acetyl group generated 3. Hydrolysis of the 40-mycarose
group of 3 in 0.3 M HCl gave the corresponding
40-hydroxyl compound 4. Reaction of 4 with various
isocyanates followed by deprotection of the 20-acetate
with methanol at room temperature proceeded
smoothly to afford the desired products 6 in yields
ranging from 46–50%.
* Corresponding author at present address: 88 Kingsbury Street,
Wellesley, MA 02481, USA. Tel.: +1-781-235-0842; fax: +1-781-
235-0842; e-mail: zhaolinwang@comcast.net
Figure 1. Structures of erythromycin A, clarithromycin and members
of the leucomycins.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.10.028

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Z. Wang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 519–521
Scheme 4. (a) PhCH2SO2Cl, Py, ꢁ40 ꢀC, 3 h (93%); (b) NaI, 2-buta-
none, 80 ꢀC, 1 h (85%); (c) n-Bu3SnH, AIBN, benzene, 80 ꢀC, 2 h
(37%); (d) TFA, CH3CN, rt 16 h; (e) MeOH, rt, 16 h (74% in two
steps).
In order to verify if the 40-hydroxyl is important for the
antibiotic activity, a 40-deoxy analogue 16 was prepared
as outlined in Scheme 4. Sulfonate ester 13 was gener-
ated by the reaction of 9 with sulfonyl chloride. The
displacement of the sulfonate 13 by NaI provided com-
pound 14. The treatment of 14 with tributyltin hydride
and AIBN gave the deoxy analogue 15. The deprotec-
tion of 15 with TFA to remove the acetal group fol-
lowed by methanol deprotection to remove the 20-acetyl
generated the final product 16. The 40-deoxy compound
16 showed significant lost in antibacterial activity,
highlighting the importance of 40-substitutions.
Scheme 1. (a) CrO3, Py/H2O, rt, 3 h (46%); (b) Ac2O, Py, rt, 16 h
(100%); (c) 0.3 M HCl, rt, 16 h (79%); (d) R-N¼C¼O, Et3N, CH2Cl2,
rt, 5–16 h (46–50%); (e) MeOH, rt (100%).
Conversion of the trichloroacetyl carbamate 7 to the
corresponding amide 8 is achieved by alkaline hydro-
lysis with sodium bicarbonate in methanol as outlined
in Scheme 2.
The recent high-resolution X-ray co-crystal structures of
the bacterial ribosome and macrolides have revealed
their detailed interactions at the atomic level. It is
showed in the co-crystal structures of the 50S ribosomal
subunit from Haloarcula marismortui in complex with
carbomycin A that the mycarose sugar at the 40-position
extends up the peptide exit tunnel toward the peptidyl
transferase center (PTC).4 Since carbomycin A has a
very similar structure to leucomycins, the crystal struc-
tures imply that leucomycins interfere more directly
with the activity of the PTC than erythromycin A in
which there is no attachment at the 40-position. There-
fore, replacing the acid labile mycarose sugar of leuco-
mycins with other substituents would improve their acid
stability and may increase their binding interactions
with the ribosome as well.
The synthesis of an allyl ether is described in Scheme 3.
Protection of the aldehyde group of 4 with acetyl chlo-
ride in methanol gave 9. Palladium-catalyzed reaction of
compound 9 with allyl-t-butyl carbonate provided 10 in
83% yield. Heck reaction of 10 with 3-bromoquinoline
generated enol ether 11 as the major product and sub-
sequent deprotection in methanol gave the final
compound 12.
Scheme 2. (a) NaHCO3, MeOH, rt, 0.5 h; (b) MeOH, rt, 12 h (56% in
two steps).
The new 16-membered macrolide antibiotics were tested
against resistant bacterial strains (Streptococcus pyo-
genes 1323 and Streptococcus pneumoniae 7701)9 and
compound 12 showed enhanced MIC activity.10
In conclusion, the synthesis of a novel series of 40-sub-
stituted leucomycin derivatives has been described. The
synthetic routes demonstrated here are useful for fur-
ther diverse modifications in the development of new
macrolide antibiotics to overcome resistant pathogens.
Acknowledgements
Scheme 3. (a) Acetyl chloride, MeOH, 12 h (74%); (b) ally t-butyl
carbonate, Pd2(dba)3, dppb, THF, 65 ꢀC, 2 h (83%); (c) 3-bromoqui-
noline, Pd(OAc)2, P(o-Tol)3, Et3N, CH3CN, 80 ꢀC, 16 h (43%); (d)
HCl, CH3CN, rt, 16 h; (e) MeOH, rt, 16 h (74% in two steps).
We thank Theresa Haley and Alex Polemeropoulos of
Enanta Pharmaceuticals for determining the MIC
values of new macrolides.

Z. Wang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 519–521
521
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