Synthesis of the saccharomicin fucose-aglycon conjugate and determination of absolute configuration

Article abstract of DOI:10.1021/ol051971s

(Chemical Equation Presented) Schmidt glycosylation of the appropriately protected 3,4-dihydroxycinnamate methyl ester with 2,3,4- triacetoxyfucopyranosyltrichloroacetimidate gives aryl glycoside in high yield and diastereoselectivity. 2-Sulfation of fuco

Full text of DOI:10.1021/ol051971s

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4749-4752
Synthesis of the Saccharomicin
Fucose Aglycon Conjugate and
−
Determination of Absolute Configuration
Joseph M. Pletcher and Frank E. McDonald*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
fmcdona@emory.edu
Received August 15, 2005
ABSTRACT
Schmidt glycosylation of the appropriately protected 3,4-dihydroxycinnamate methyl ester with 2,3,4-triacetoxyfucopyranosyltrichloroacetimidate
gives aryl glycoside in high yield and diastereoselectivity. 2-Sulfation of fucose, installation of taurine, and global deprotection of the remaining
protecting groups affords the fucose−aglycon conjugate of saccharomicin. This synthesis which arises from L-fucose also establishes the
absolute configuration of the reducing terminus of the saccharomicin oligosaccharide.
Saccharomicins A and B were isolated in 1998 by Kong and
co-workers from the antibiotic complex designated LL-
C19004, produced by the rare actinomycete Saccharothrix
espanaensis.1 This new class of antibiotics exhibits in vitro
and in vivo antibacterial activity against a panel of pathogenic
Gram-positive organisms, including strains of multiresistant
staphylococci and enterococci bacteria.2 The mechanism of
action is currently unclear, but studies suggest that the
saccharomicin oligosaccharide disrupts the bacterial cell
membrane, allowing for intracellular potassium leakage and
subsequent cell death. Although the saccharomicins have a
small therapeutic window with regard to lethal dosage, the
oligosaccharide backbone and its conformation appears to
be critical to the observed biological activity and may provide
a template for the design of future therapeutics. Aside from
the medicinal impetus for a study of the saccharomicins, their
molecular architectures present a myriad of synthetic chal-
lenges worthy of exploration and an opportunity for develop-
ment of new methods of chemical synthesis.
Chemical degradation and spectroscopic characterization
were the primary techniques used for structural elucidation
of saccharomicins A and B, revealing connectivity patterns
and relative configurations of all 17 sugars. However, the
absolute stereochemistry of each monosaccharide unit was
arbitrarily assigned based on their most abundant natural
forms and remains ambiguous. As a starting point, we sought
to synthesize the reported structures of degradation products
and compare their optical rotations to the naturally derived
materials, thereby providing information vital to the pursuit
of a stereoselective total synthesis.
(1) (a) Kong, F.; Zhao, N.; Siegel, M. M.; Janota, K.; Ashcroft, J. S.;
Koehn, F. E.; Borders, D. B.; Carter, G. T. J. Am. Chem. Soc. 1998, 120,
13301. (b) Shi, S. D.-H.; Hendrickson, C. L.; Marshall, A. G.; Siegel, M.
M.; Kong, F.; Carter, G. T. J. Am. Soc. Mass. Spectrom. 1999, 10, 1285.
(2) Singh, M. P.; Petersen, P. J.; Weiss, W. J.; Kong, F.; Greenstein, M.
Antimicrob. Agents Chemother. 2000, 44, 2154.
10.1021/ol051971s CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/14/2005

Figure 1. Structures of saccharomicins A and B (1, 2) and the fucose-aglycon conjugate 3 from mild acidic hydrolysis.
The fucose-aglycon conjugate (3) (Figure 1) was one of
two UV-active degradation products isolated from mild acid
hydrolysis, and although Kong and co-workers assigned a
D-configuration to the fucose, for convenience we chose to
prepare the antipode ent-3, containing readily available
L-fucose. The fucose-aglycon â-linkage led us to envision a
stereoselective glycosylation between an activated fucosyl
donor and a selectively protected cinnamic acid derivative.
Strategic protective group manipulations would then permit
selective installation of the 2′-sulfate and taurine moieties
of the degradation product 3.
Stereoselective glycosylations of several 3-protected de-
rivatives of 3,4-dihydroxycinnamate methyl ester 43 were
accomplished with the 2,3,4-tri-O-acetyl L-fucosyl trichlo-
roacetimidate 54 to give good yields of the â-fucosides 6
(Scheme 1). By way of contrast, the 1,2-glycal epoxide from
dimethyldioxirane epoxidation of 3,4-bis-O-TBS-fucal af-
forded the undesired R-glycoside as the major product under
a variety of conditions,5 consistent with precedents involving
glycosylation of phenols with glycal epoxides.6 We also
observed that the 3,4-acetonide-protected analogue of 5
was unreactive to glycosylation with phenolic nucleophile
4c.
As removal of the methyl ether of 6c (R ) Me) was
difficult to achieve in the presence of the glycosidic linkage,
the majority of our successful efforts stemmed from the
benzylic ether-protected glycosides 6a,b. Removal of acetate
protective groups and acid-catalyzed reaction of the resulting
triols with 2,2-dimethoxypropane7 afforded regioselective
protection of the cis-3′ and 4′-hydroxyls in 7a,b (Scheme
2). The remaining hydroxyl substituent at C2′ was then
converted into the sulfate esters 8a,b in excellent yield.
In the course of our synthetic work, we were concerned
about the eventual removal of protective groups in the
presence of potentially sensitive functional groups. We were
pleased to observe that the acetonide protective group could
be removed by acidic hydrolysis at several stages of this
synthesis. Although p-toluenesulfonic acid-catalyzed depro-
tection of 8a gave a 37% yield of 9 (accompanied with
byproducts resulting from hydrolysis of sulfate ester and/or
glycoside), Dowex 50WX8 ion-exchange resin provided a
74% isolated yield of 9. However, deprotection of the benzyl
Scheme 1. Synthesis of Phenolic Fucosides 6
(3) (a) Compounds 4a and 4b were prepared by Wadsworth-Emmons
olefination of the corresponding 3-protected derivative of 3,4-di-
hydroxybenzaldehyde (see the Supporting Information). (b) 4c: Gu, W.;
Jing, X.; Pan, X.; Chan, A. S. C.; Yang, T.-K. Tetrahedron Lett. 2000, 41,
6079.
(4) (a) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem. 1994,
50, 21. (b) Jiang, Z.-H.; Schmidt, R. R. Liebigs Ann. Chem. 1992, 9, 975.
(5) This unpublished work was conducted by Dr. Minglang Wu.
(6) Chiappe, C.; LoMoro, G.; Munforte, P. Tetrahedron 1997, 53, 10471.
(7) For acetonide protection in the presence of an aryl PMB-ether, see:
Trost, B. M.; Dudash, J., Jr.; Dirat, O. Chem. Eur. J. 2002, 8, 259.
4750
Org. Lett., Vol. 7, No. 21, 2005

Scheme 2. Protective Group Studies Associated with
Scheme 3. Introduction of Taurine and Removal of Protective
Regioselective Introduction of Sulfate Ester
Groups
partial hydrolysis of mixed anhydride 12, as some of the
carboxylic acid 11 was recovered albeit contaminated with
triethylammonium salts. Compound ent-3 was obtained pure
after C18 silica gel chromatography with slow elution H2O/
1
MeOH (9:1) and gives identical H and 13C NMR spectra
when compared to the naturally derived fucose-aglycon
ether of 8a or 9 was much more difficult. Despite precedents
which suggested that selective removal of the benzyl ether
might be achieved under transfer hydrogenation condi-
tions,8 all attempts at reductive debenzylation resulted in
concomitant saturation of the conjugated alkene functionality.
Other procedures for deprotection of benzyl ethers such as
conjugate.12
Optical rotation of the synthetic fucose-aglycon conjugate
ent-3 derived from L-fucose gave a positive sign of rota-
tion: [R]D ) +63 (c 0.22 in MeOH); [R]D ) +53 (c 0.26 in
H2O), whereas that of the naturally derived material was [R]D
) -60.1 (c 0.052 in H2O),13 indicating an absolute config-
uration of D-fucose in the saccharomicins. While D-fucose
is considerably more expensive than L-fucose, we note that
D-fucose glycal can be easily prepared using alkynyl alcohol
cycloisomerization methodology14 and can likely be incor-
porated in a projected synthesis of saccharomicin oligosac-
charides.
In conclusion, we have completed a short synthesis of
the fucose-aglycon substructure of saccharomicins,
which compares favorably to the enantiomer of compound
3 arising from acid-catalyzed degradation of saccharomi-
cins.
9
FeCl3 were incompatible with the glycosidic linkage.
Fortunately, the p-methoxybenzyl (PMBn) ether 8b was acid
labile and could be cleanly deprotected at the same time as
the removal of the acetonide to provide 10 in 76% isolated
yield, without significant cleavage of the glycosidic linkage
or sulfate ester.
Thus, the synthesis was successfully completed from the
PMBn-protected glycoside 8b, which was converted into the
carboxylic acid 11 by basic hydrolysis of the methyl ester
(Scheme 3). The taurine amide was then introduced by
employing the intermediacy of an isobutyl mixed anhydride
1210,11 to provide 13. This synthetic intermediate was diffi-
cult to purify from triethylammonium salts, but subse-
quent treatment with Dowex 50WX8 in water at room-
temperature affected removal of both the acetonide and
PMBn protecting groups to afford the saccharomicin fucose-
aglycon conjugate, as the L-enantiomer (ent-3). The modest
yield of ent-3 is attributed to incomplete formation and/or
Acknowledgment. We thank the National Institutes of
Health (CA 59703) for support of this research. We also
acknowledge use of shared instrumentation provided by
grants from the National Institutes of Health, National
Science Foundation, and the Georgia Research Alliance
(8) (a) Felix, A. M.; Heimer, E. P.; Lambros, T. J.; Tzougraki, C.;
Meienhofer, J. J. Org. Chem. 1978, 21, 4194. (b) Knapp, S.; Nandan, S. R.
J. Org. Chem. 1994, 59, 281. (c) Kawada, T.; Asano, R.; Hayashida, S.;
Sakuno, T. J. Org. Chem. 1999, 64, 9268.
(9) (a) Park, M. H.; Takeda, R.; Nakanishi, K. Tetrahedron Lett. 1987,
28, 3823. (b) Rodebaugh, R.; Debenham, J. S.; Fraser-Reid, B. Tetrahedron
Lett. 1996, 37, 5477.
(12) We thank Dr. Fangming Kong (Wyeth Research) for providing 1H
and 13C NMR spectra of 3.
(13) The optical rotation data (unpublished) was graciously provided by
Dr. Fangming Kong. In a private communication, he notes some uncertainty
with the magnitude of the rotations measured in his work, but the sign of
the rotation of 3 derived from naturally occurring saccharomicin is
consistently negative.
(10) Lebel, H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 9624.
(11) Attempted introduction of taurine by other methods, such as
dehydrative carbodiimide coupling of the carboxylic acid or acylation of
the corresponding acid chloride, were unsuccessful.
(14) (a) McDonald, F. E.; Reddy, K. S., D´ıaz, Y. J. Am. Chem. Soc.
2000, 122, 4304. (b) McDonald, F. E.; Reddy, K. S. Angew. Chem., Int.
Ed. 2001, 40, 3653. (c) McDonald, F. E.; Wu, M. Org. Lett. 2002, 4, 3979.
(d) Koo, B.; McDonald, F. E. Org. Lett. 2005, 7, 3621.
Org. Lett., Vol. 7, No. 21, 2005
4751

(NMR spectroscopy, mass spectrometry) as well as the
University Research Committee of Emory University (po-
larimeter). We are particularly appreciative to Dr. Fangming
Kong (Wyeth Research) for providing copies of NMR spectra
and unpublished data regarding the optical rotation of
compound 3.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL051971S
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