Angewandte
Chemie
DOI: 10.1002/anie.200805334
Natural Products
Total Synthesis of Azithromycin**
Hyoung Cheul Kim and Sung Ho Kang*
Azithromycin (1; see Scheme 1) is a semi-synthetic
15-membered macrolide antibiotic, which is derived
from erythromycin A by a sequence of oximation,
Beckmann rearrangement, reduction, and N-meth-
ylation.[1] Azithromycin is the first azalide on the
market and it displays the best antibacterial activity
among its family members. In comparison with
erythromycins, its beneficial properties stem from
its improved acid stability, increased oral bioavail-
ability, longer half-life, higher intracellular concen-
tration, and broader antibacterial activity.[2] The X-
ray crystal structure of a bacterial ribosome–macro-
lide complex suggests that azithromycin exerts
Scheme 1. Retrosynthetic analysis of azithromycin (1). TBS=tert-butyldimethyl-
silyl.
antimicrobial activity by binding to the growing peptide in
the trough of the 50S subunit to inhibit the protein biosyn-
thesis.[3] As azithromycin possesses a stereochemically com-
plex molecular architecture, similar to that of erythromy-
cin A, and excellent physiological properties, it was seen as a
great synthetic challenge by our research group. Moreover,
we have recently established a highly enantioselective desym-
metrization of 2-substituted glycerols,[4] which could be well
suited to elaborate the stereogenic quaternary centers
embedded in azithromycin. Herein, we report the first
asymmetric total synthesis of azithromycin 1.
tive yield (Scheme 2). After conversion of 7 into the
corresponding epoxide through mesylation in a one-pot
process, the generated epoxy benzoate was hydrolyzed,
oxidized[6] and treated with Et2Zn with the aid of the amino
alcohol ligand 8[7] to give an 11:1 separable mixture of the
desired R alcohol 9[8] and its diastereomeric S alcohol in 65%
combined overall yield from 7. The epoxy alcohol 9 was
derivatized into the diasteromeric epoxide 10 in 71% yield
along with 2–3% of its isomeric epoxide by reduction of the
epoxy group with Red-Al, silylation of the secondary hydroxy
group, and hydroxy-directing epoxidation. The epoxy group
of 10 was amenable to regioselective substitution using NaN3
A retrosynthetic disconnection of 1 at the lactone linkage
À
and the C9 N9a bond would provide the western amine
alcohol chain 2 and the eastern hydroxy carboxylic acid chain
3 (Scheme 1). Taking into consideration the previous synthe-
ses of erythromycins[5] and the synthetic efficiency needed for
azithromycin, the timing of the glycosylation steps appear to
be critical to achieve more effective glycosylations and
macrolactonization, and thus obviate extra protection/depro-
tection manipulation. Based on the retrosynthetic analysis, we
propose to append desosamine during the eastern chain
construction and cladinose after formation of the macrolide.
Our synthesis of azithromycin was initiated with the
preparation of 2 through the desymmetrization method,
asymmetric ethyl addition, and regioselective epoxide open-
ings. According to the plan, the triol 4 was desymmetrized
enantioselectively in the presence of the imine catalyst 5[4a] to
furnish the monobenzoate 7 with 91% ee in nearly quantita-
Scheme 2. Preparation of the amine 2. a) 5, BzCl, Et3N, THF, RT, 98%
(91% ee); b) MsCl, Et3N, CH2Cl2, À788C; then DBU, RT; c) K2CO3,
MeOH, RT, 69% (over 2 steps); d) SO3·Py, Et3N, DMSO, CH2Cl2, 08C;
e) 8, Et2Zn, toluene, RT, 86% (over 2 steps); f) Red-Al, THF, 08C;
g) TESCl, imidazole, DMF, RT; h) mCPBA, CH2Cl2, À508C, 71% (over
3 steps); i) NaN3, MgSO4, MeOCH2CH2OH, 1108C, 82%; j) TBSCl,
imidazole, DMF, RT, 90%; k) Ph3P, H2O, THF, RT, 87%; l) HF/
pyridine, THF, RT, 92%. Bz=benzoyl, DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, DMF=N,N-dimethylformamide, DMSO=dimethyl
sulfoxide, mCPBA=3-chloroperbenzoic acid, Ms=methanesulfonyl,
Py=pyridine, Red-Al=bis(2-methoxyethoxy)aluminum hydride, TES=
triethylsilyl.
[*] H. C. Kim, Prof. Dr. S. H. Kang
Department of Chemistry, School of Molecular Science (BK21),
KAIST, Daejeon 305-701 (Korea)
Fax: (+82)42-350-2810
E-mail: shkang@kaist.ac.kr
[**] This work was supported by a Korea Science and Engineering
Foundation (KOSEF) grant funded by the Korea government
(MOST; R01-2007-000-10051-0).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2009, 48, 1827 –1829
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1827