Bronsted acid-promoted glycosylations of disaccharide glycal substructures of the saccharomicins

Article abstract of DOI:10.1021/ol901923x

An acid-promoted glycosylate and alkynol cycloisomerization sequence provided direct access to the 2-deoxytrisaccharide corresponding to the fucose-saccharosamine-digitoxose substructure of saccharomicin B. In the course of this work, the absolute stereochemistry of the repeating fucose- saccharosamine disaccharide of saccharomicins was also confirmed.

Full text of DOI:10.1021/ol901923x

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4850-4853
Brønsted Acid-Promoted Glycosylations
of Disaccharide Glycal Substructures of
the Saccharomicins
Bradley R. Balthaser and Frank E. McDonald*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
fmcdona@emory.edu
Received August 18, 2009
ABSTRACT
An acid-promoted glycosylation and alkynol cycloisomerization sequence provided direct access to the 2-deoxytrisaccharide corresponding
to the fucose-saccharosamine-digitoxose substructure of saccharomicin B. In the course of this work, the absolute stereochemistry of the
repeating fucose-saccharosamine disaccharide of saccharomicins was also confirmed.
The heptadecasaccharide antibiotics saccharomicins A and
B were first isolated from the actinobacteria Saccharothrix
espanaensis (Figure 1) and were found to have activity
against a wide array of Gram-positive and Gram-negative
bacteria. Cross resistance was not observed with many other
antibiotics, including vancomycin, piperacillin, or ciprof-
loxacin.1
terminal D-fucose (fuc-1) attached to the aglycon,2 as well as a
synthesis of saccharosamine glycal via tungsten-catalyzed
alkynol cycloisomerization,3 we now report the synthesis of a
protected form of the fucose-saccharosamine disaccharide (3)
present in several sectors of saccharomicins, specifically fuc-
3/sac-2, fuc-5/sac-4, fuc-8/sac-7, and fuc-12/sac-11. In ad-
dition, we demonstrate the viability of Brønsted acid-pro-
moted glycosylations to form 2-deoxyglycosides correspond-
ing to the trisaccharides fuc-8/sac-7/rha-6 and the fuc-12/
sac-11/rha-10 of saccharomicin A as well as fuc-12/sac-11/
dig-10 of saccharomicin B.
The saccharomicins possess several structural features of
interest as synthetic targets. In addition to the 2-deoxysugar
digitoxose (dig, Figure 1), the rare pyranosides saccharosamine
(sac) and 4-epi-vancosamine (eva) are 2,6-dideoxysugars bear-
ing 3-amino and 3-methyl substituents. On the basis of our
earlier work that established the absolute stereochemistry of the
(2) Pletcher, J. M.; McDonald, F. E. Org. Lett. 2005, 7, 4749.
(3) Cutchins, W. W.; McDonald, F. E. Org. Lett. 2002, 4, 749.
(4) (a) Schmidt, R. R.; Wegmann, B.; Jung, K.-H. Liebigs Ann. Chem.
1991, 121. (b) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem.
1994, 50, 21.
(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) Singh, M. P.; Petersen, P. J.; Weiss, W. J.; Kong, F.; Greenstein,
M. Antimicrob. Agents Chemother. 2000, 44, 2154.
(5) The identity of glycosides 6 and 7 was confirmed by X-ray
crystallography (Supporting Information).
10.1021/ol901923x CCC: $40.75
Published on Web 09/25/2009
 2009 American Chemical Society

Figure 1. Saccharomicins A and B.
Although the stereochemistry of fucose-1 in saccharo-
micins was established as the D-isomer,2 we chose to
prepare fragments and develop methods based on the
antipodal structures, due to the ready availability of
L-fucose. Thus, our synthesis began with the resolution
of racemic ꢀ-lactam 5 by glycosylation with the L-fucose-
derived trichloroacetimidate 4 (Scheme 1).4 The success
of this transformation was particularly sensitive to tem-
perature, so that temperatures below -45 °C favored
orthoester formation, whereas temperatures above 0 °C
produced a greater proportion of the R-glycoside anomers.
After acetate ester removal and selective protection of the
cis-diols as acetonide esters, the diastereomers 6 and 7
were chromatographically separated.5
Scheme 1. Preparation of Fucose-Saccharosamine Disaccharide Glycals 11-12 and 14-15
Org. Lett., Vol. 11, No. 21, 2009
4851

Scheme 2. Synthesis of Disaccharides ent-3 and 16
Scheme 3. Acid-Promoted Glycosylations of Disaccharide 15 with Rhamnose Acceptor 17
The acidic protons of the fucosyl C2-hydroxyl and the
conversion to the disaccharide glycal 14. The N-Alloc
alkene may have coordinated with tungsten carbonyl,9 as
N-benzyloxycarbonyl and N-butoxycarbonyl-protected sub-
strates are considerably more reactive in alkynol cycloi-
somerizations.3,10
terminal alkyne of compound 6 were protected to provide
compound 8 bearing TBS ether and TMS-alkyne. From
ꢀ-lactam 8, sequential addition of methyl and hydride
nucleophiles3 afforded the secondary alcohol 9, although
stereoselective hydride addition was achieved only with the
chiral oxazaborolidine reagent.6,7 Two protocols for protec-
tive group manipulations were explored to diminish basicity
of the nitrogen substituent for the alkynol cycloisomerization
step. Originally, we first removed the para-methoxyphenyl
(PMP) substituent from 9 and formed the acetamide, fol-
lowed by desilylations with tetrabutylammonium difluorot-
riphenyl-silane and acetic acid.8 Subsequently, we observed
that desilylations proceeded more cleanly from compound
9, followed by oxidative removal of the PMP substituent
and N-acylation.
As the methyl glycoside of a peracetylated derivative of
the fucose-saccharosamine disaccharide (3) had been re-
ported as a degradation product arising from acidic metha-
nolysis of saccharomicins, we sought to prepare the antipode
of this compound to conclusively establish the absolute
stereochemistry of the natural product-derived material.1a
Acidic methanolysis of disaccharide glycal 11 was ac-
companied by acetonide removal, and acetylation of the
hydroxyl groups of fucose provided a mixture of ent-3 and
the ꢀ-anomer, 16 (Scheme 2). After chromatographic separa-
tion of the anomers, the minor R-anomer ent-3 matched the
spectroscopic data provided for the antipode of this structure,
thus confirming that the fucose and saccharosamine sugars
in the repeating unit of the natural product saccharomicins
both possessed D-stereochemistry.11 Furthermore, the major
ꢀ-anomer of 16 was also characterized by X-ray crystal-
lography, thus unambiguously establishing the structure of
our synthetic material.12,13
Tungsten-catalyzed alkynol cycloisomerization of com-
pound 10 proceeded efficiently to afford the disaccharide
glycal 11, and O-acetylation of the fucosyl 2-hydroxyl
gave compound 12. With an eye to facile late-stage
deprotection of the amino substituent, we also prepared
substrate 13 bearing an N-allyloxycarbonyl (Alloc) protec-
tive group. In this case, the alkynol cycloisomerization
reaction was noticeably slower, and a relatively high
loading of tungsten carbonyl was required for complete
Having previously established a viable acid-catalyzed
glycosylation of a disaccharide glycal in our synthesis of
(6) (a) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611. (b)
Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(7) A variety of substrate-controlled reduction methods gave poor
stereoselectivity; see Supporting Information for a summary of these results.
The (R)-diastereomer was produced in approximately 5% yield in the
oxazaborolidine reduction and was recycled by IBX oxidation to the methyl
ketone.
(8) (a) Evans, C. M.; Kirby, A. J. J. Chem. Soc., Perkin Trans. II 1984,
1269. (b) Hecker, S. J.; Heathcock, C. H. J. Am. Chem. Soc. 1986, 108,
4586. (c) Desilylation with tetrabutylammonium fluoride in the presence
of acetic acid gave byproducts consistent with hydration of the alkyne,
possibly from 5-exo-cyclization of the alkynyl alcohol and hydrolysis of
the exocyclic enol ether, whereas the desilylation with tetrabutylammonium
difluorotriphenylsilane afforded good yields of alkynyl alcohol 10.
(9) (a) Barluenga, J.; Die´guez, A.; Rodr´ıguez, F.; Fanana´s, F. J.; Sordo,
T.; Campomanes, P. Chem.sEur. J. 2005, 11, 5735. (b) Katz, T. J. Angew.
Chem., Int. Ed. 2005, 44, 3010. (c) Fuchibe, K.; Iwasawa, N. Chem.sEur.
J. 2003, 9, 905.
(10) Davidson, M. H.; McDonald, F. E. Org. Lett. 2004, 6, 1601.
(11) We thank Drs. Fangming Kong and Guy T. Carter (Wyeth
Research) for providing 1H and 13C NMR spectra of compound 3
(Supporting Information).
(12) We thank Drs. Rui Cao and Kenneth I. Hardcastle (Emory
University) for solving the crystal structure of compound 16 (Supporting
Information).
(13) The L-fucosyl-D-saccharosamine diastereomer of 16 has also been
prepared by a similar protocol beginning with compound 7 (Supporting
Information).
4852
Org. Lett., Vol. 11, No. 21, 2009

Scheme 4
.
Acid-Promoted Glycosylation of Disaccharide 15 with Alkynyl Alcohol 19 and Cycloisomerization to
Digitoxose-Terminated Trisaccharide 22
digitoxin,14 we explored the glycosylation of glycal 15 with
the D-rhamnose acceptor 17. In initial experiments, the yield
of trisaccharide 18 was diminished by competitive hydration
of the glycal due to adventitious water. However, excellent
yields of 18 were obtained when the glycosylation was
conducted in the presence of molecular sieves (Scheme 3).
The optimized transformation required excess camphorsul-
fonic acid due to the mildly basic nature of the molecular
sieves. Glycosylation occurred with complete stereoselec-
tivity trans to the C3-acetamido substituent.15
Building on the concept of acyclic alkynyl alcohols as
glycosyl acceptors,14,16 we subsequently explored the gly-
cosylation of disaccharide 15 with alkynyl alcohol 19 as the
precursor to digitoxose (Scheme 4). In this case, the glycoside
20 was generated in excellent yield and with high stereose-
lectivity for the ꢀ-anomer. After removal of the ester
protective groups, the alkynyl alcohol substrate 21 underwent
cycloisomerization to the trisaccharide glycal 22, although
this transformation required stoichiometric tungsten carbonyl
due to the N-Alloc substituent.
In summary, this work has confirmed the structure of
the repeating fucose-saccharosamine disaccharide of
saccharomicins and has provided insight into the viability
of Brønsted acid-promoted glycosylations with this dis-
accharide to provide 2-deoxyglycoside trisaccharide sub-
structures observed in the saccharomicins.
Acknowledgment. This work was initially supported by
the National Institutes of Health, grant CA-59703.
Supporting Information Available: Experimental pro-
cedures and characterization and spectral data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) McDonald, F. E.; Reddy, K. S. Angew. Chem., Int. Ed. 2001, 40,
3653.
(15) These results are consistent with anchimeric assistance from the
N-carbonyl substituent at C3. For examples of glycosylations trans- to C3-
ester substituents, see: (a) Tsai, T. Y. R.; Jin, H.; Wiesner, K. Can. J. Chem.
1984, 62, 1403. (b) Komarova, B. S.; Tsvetkov, Y. E.; Knivel, Y. A.;
Za¨hringer, U.; Pier, G. B.; Nifantiev, N. E. Tetrahedron Lett. 2006, 47,
3583. (c) Chiba, S.; Kitamura, M.; Narasaka, K. J. Am. Chem. Soc. 2006,
128, 6931.
OL901923X
(16) McDonald, F. E.; Wu, M. Org. Lett. 2002, 4, 3979.
Org. Lett., Vol. 11, No. 21, 2009
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