The total synthesis of moenomycin A

Article abstract of DOI:10.1021/ja065907x

Moenomycin A is the only known natural antibiotic that inhibits bacterial cell wall synthesis by binding to the transglycosylases that catalyze formation of the carbohydrate chains of peptidoglycan. We report here the total synthesis of moenomycin A using

Full text of DOI:10.1021/ja065907x

Published on Web 11/04/2006
The Total Synthesis of Moenomycin A
James G. Taylor,† Xuechen Li,† Markus Oberthu¨r,† Wenjiang Zhu,† and Daniel E. Kahne*,†,‡
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138, and
Department of Biological Chemistry and Molecular Biology, HarVard Medical School, Boston, Massachusetts 02115
Received August 14, 2006; E-mail: kahne@chemistry.harvard.edu
Scheme 1. Construction of BC, EF, and BCEF Oligosaccharidesa
Moenomycin A (1) is a potent antibiotic that inhibits bacterial
cell wall synthesis by binding to the transglycosylases that catalyze
formation of the carbohydrate chains of peptidoglycan.1 Moeno-
mycin is the only natural product inhibitor known to directly bind
to these enzymes. Its distinctive mechanism of action is matched
by its unusual structure. Moenomycin A consists of a highly func-
tionalized pentasaccharide attached via a unique phosphoglycerate
linkage to a polyprenyl chain. Many approaches to the synthesis
of moenomycin fragments and derivatives have been reported over
the past 30 years, primarily by Welzel and co-workers, but the total
synthesis of moenomycin A has not been accomplished.2 We report
here the first total synthesis of moenomycin A.
The moenomycin pentasaccharide presents a number of synthetic
challenges. Electron-withdrawing groups on several of the mono-
saccharides make them poor glycosyl donors and/or acceptors.
Many of the glycosidic bonds must also be formed to sterically
hindered alcohols. For example, the B ring galacturonamide is a
deactivated donor owing to the electron-withdrawing C6 position,3
and the C4 hydroxyls of the C and E rings of moenomycin are
sterically hindered and particularly unreactive in glycosylation
reactions.4 The stability of the diverse functional groups is also a
concern. The F ring contains both an amide and a carbamate, which
a Conditions: (a) Tf2O, DTBMP, ADMB, CH2Cl2, -78 to 0 °C, 75%;
are potentially reactive under glycosylation conditions, and the A
(b) mCPBA, CH2Cl2, -78 to 0 °C, 70%; (c) Tf2O, DTBMP, ADMB,
CH2Cl2, -42 °C, 84%; (d) Bu2BOTf, BH3·THF, THF, -60 °C, 83%; (e)
ring is sensitive to both oxidation5 and hydrogenation6 procedures.
Tf2O, DTBMP, ADMB, CH2Cl2, -60 °C, 50%. DTBMP ) 2,6-di-tert-
butyl-4-methylpyridine, ADMB ) 4-allyl-1,2-dimethoxybenzene
disaccharide 6 regioselectively and stereoselectively in 75% yield
using the standard sulfoxide glycosylation protocol, which involves
adding triflic anhydride to the glycosyl sulfoxide prior to adding
the acceptor.9 Disaccharide 6 was then oxidized to sulfoxide 7.
Unlike the BC linkage, none of the other glycosidic bonds were
formed using the standard glycosylation conditions. In the case of
the EF â-1,2 linkage, we observed that benzenesulfinic ester
Our synthetic approach involved constructing the BCEF tetra-
formation on the C2 hydroxyl of F ring 5 led to significant loss of
saccharide from the BC and EF disaccharide fragments, followed
the glycosyl acceptor.10 PhSOTf is generated during sulfoxide
by attachment of the D ring. The synthesis of the protected BCEF
glycosylations and is known to activate glycosyl sulfoxides.11
tetrasaccharide 10 is shown in Scheme 1. Because preliminary
Benzenesulfinic ester formation was presumed to be a downstream
investigations into the synthesis of the BC disaccharide revealed
byproduct resulting from the reaction of PhSOTf with glycosyl
that the A ring would not survive the glycosylation conditions, the
sulfoxides. Using 4-allyl-1,2-dimethoxybenzene (ADMB) to scav-
C6 position of the B ring 2 was protected as an ester to allow for
enge PhSOTf12 and changing the order of reagent addition during
late stage attachment of the A ring. The C2 amine of the C ring
the reaction (inverse addition)13 suppressed benzenesulfinic ester
acceptor 3 was protected with a tetrachlorophthaloyl (TCP) group7
as reports have demonstrated that this bulky protecting group
enables regioselective glycosylation at C4 in the presence of an
formation, and the EF disaccharide 8 was obtained in 84% yield.
The 4,6-(p-methoxylbenzylidene) group was then regioselectively
opened14 to afford 9.
unprotected C3 hydroxyl.8 In addition, the TCP protecting group
Coupling of the EF and BC disaccharide fragments also required
allows for neighboring group participation at C2, providing
the inverse addition protocol because the BC glycosyl donor decom-
â-stereochemical control during formation of the subsequent CE
glycosidic linkage. The glycosylation of 2 with 3 afforded BC
posed under the standard activation conditions. Inverse addition
decreases decomposition because the oxacarbenium ion is generated
slowly in the presence of the acceptor alcohol, which traps the
reactive intermediate before it reacts with other species.13 Thus,
† Harvard University.
‡ Harvard Medical School.
9
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J. AM. CHEM. SOC. 2006, 128, 15084-15085
10.1021/ja065907x CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Completion of the Synthesisa
a Conditons: (a) Ac2O, Py, 93%; (b) DDQ, CH2Cl2/pH 7 buffer, 79%; (c) Phenyl 2,3,4,6-tetra-O-benzyl-1-thio-â-D-glucopyranoside S-oxide, Tf2O, DTBMP,
ADMB, propionitrile, -78 °C, 76%; (d) NH3 in IPA/ CH2Cl2; (e) ethylenediamine, EtOH, 60 °C; (f) Ac2O, EtOH; (g) Ac2O, Py, 66% four steps; (h) H2,
Pd(OH)2/C, MeOH; (i) Ac2O, Py, 63% two steps; (j) BF3·Et2O, CH2Cl2, 97%; (k) 2-amino-3-hydroxy-2-cyclopenten-1-one hydrochloride, HATU, DIPEA,
CH2Cl2/DMF, 55%; (l) NaOH, THF, 80%; (m) Ac2O, Py, 78%; (n) H2NNH2·HOAc, 75%; (1) 2-Chloro-1,3,2-benzodioxaphosphorin-4-one, CH3CN, 85%;
(2) Py, 4 Å MS, methyl (R)-3-hydroxy-2-[(2Z,6E,13E)-3,8,8,14,18-pentamethyl-11-methylene-nonadeca-2,6,13,17-tetraen-1-yloxy]propanoate, 1-adaman-
tanecarbonyl chloride, then NMM/CCl4/Py/CH3CN/H2O (1:2.5:6:1:1), 62%; (3) 0.1 N LiOH, THF/H2O (1:1), then AcOH, 47%.18
when donor 7 was added to a solution containing triflic anhydride
and acceptor 9, tetrasaccharide 10 was obtained stereoselectively
in 50% yield. The free hydroxyl on the C ring was then acetylated
followed by removal of the PMB ether with DDQ to give 11
(Scheme 2).
previously,19 should enable the construction of most glycosidic
linkages.
Acknowledgment. Support for this work was provided by the
National Institutes of Health (Grant GM66174).
The final glycosylation involved forming a â-1,6 linkage between
a D ring sulfoxide and tetrasaccharide 11. To avoid introducing a
hindered, electron-withdrawing ester group on the C2 position of
the D ring donor, we chose to form this glycosidic linkage with
solvent control using propionitrile, which is known to give high
â-stereoselectivity in glycosylations.9,15 As before, benzenesulfinic
ester byproducts dominated the reaction in the absence of a PhSOTf
scavenger. When the reaction was carried out using the scavenger
ADMB and inverse addition, pentasaccharide 12 was obtained in
76% yield with complete â-stereoselectivity.
Supporting Information Available: Experimental procedures and
spectral data for numbered compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) van Heijenoort, J. Glycobiology 2001, 11, 25R-36R and references
therein.
(2) For a review of previous synthetic efforts toward moenomycin A see
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4763-4766.
Completion of the moenomycin pentasaccharide synthesis re-
quired protecting group removal and installation of the 2-amino-
3-hydroxy-2-cyclopenten-1-one (A ring) chromophore and F ring
amide and carbamate. Selective conversion of the phenyl ester and
phenyl carbonate of 12 into the desired carboxamide and carbamate,
respectively, was accomplished using NH3 in IPA/CH2Cl2. The TCP
protecting groups were then removed with ethylenediamine and
the liberated amines were acylated in situ to give 13. Hydrogenation
of the benzyl groups using Pd(OH)2/C in MeOH and acetylation
of the hydroxyls gave 14. Removal of the TMSE groups with BF3,16
followed by coupling of the A ring17 using HATU, and global
deprotection with NaOH afforded the fully deprotected penta-
saccharide 15. The identity of 15 was confirmed by correlation with
the natural pentasaccharide obtained through degradation of moeno-
mycin A. Peracetylation of 15 followed by selective deprotection
of the anomeric acetate with H2NNH2·HOAc gave 16. Coupling of
16 to the moenocinyl glycerate unit and deprotection, using our
published procedure,18 afforded moenomycin A (1).
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This synthesis of moenomycin A is both efficient and flexible,
allowing for variants of the antibiotic to be constructed in order to
probe its mechanism of action. Each glycosidic linkage was
synthesized stereoselectively using the sulfoxide glycosylation
reaction. Two sets of reaction conditions were employed depending
on the reactivity of the donor-acceptor pair. The sulfoxide
activation conditions described here, along with those described
696.
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