Acceptor-dependent stereoselective glycosylation: 2′-CB glycoside-mediated direct β-D-arabinofuranosylation and efficient synthesis of the octaarabinofuranoside in mycobacterial cell wall

Article abstract of DOI:10.1021/ol0510668

(Chemical Equation Presented) A reliable and generally applicable direct method for the stereoselective β-arabinofuranosylation employing a 2′-carboxybenzyl arabinofuranoside as the glycosyl donor has been established. The acyl-protective group on glycosy

Full text of DOI:10.1021/ol0510668

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3263-3266
Acceptor-Dependent Stereoselective
Glycosylation: 2 -CB
Glycoside-Mediated Direct
-Arabinofuranosylation and Efficient
Synthesis of the Octaarabinofuranoside
in Mycobacterial Cell Wall
Yong Joo Lee, Kyunghoon Lee, Eun Hye Jung, Heung Bae Jeon,* and
Kwan Soo Kim*
′
â
-D
Center for BioactiVe Molecular Hybrids and Department of Chemistry,
Yonsei UniVersity, Seoul 120-749, Korea
kwan@yonsei.ac.kr; hbj@yonsei.ac.kr
Received May 9, 2005
ABSTRACT
A reliable and generally applicable direct method for the stereoselective
â
-arabinofuranosylation employing a 2
′
-carboxybenzyl arabinofuranoside
as the glycosyl donor has been established. The acyl-protective group on glycosyl acceptors is essential for the
â-stereoselectivity. The
power of the present acceptor-dependent glycosylation method was demonstrated by the efficient synthesis of the octaarabinofuranoside in
arabinogalactan and lipoarabinomannan found in mycobacterial cell wall.
The development of efficient and stereoselective glycosyl-
ation methodologies1 has attracted a great deal of attention
in recent years due to the biological significance of many
complex oligosaccharides and glycoconjugates.2 The selec-
tion of proper glycosyl donors is one of the crucial factors
that determines the efficiency and stereoselectivity of gly-
cosylations. Although several efficient glycosyl donors such
as glycosyl trichloroacetimidates,3 thioglycosides,4 glycosyl
sulfoxides,5 glycals,6 n-pentenyl glycosides,7 and glycosyl
fluorides8 are available, the stereospecific formation of certain
glycosyl linkages such as â-D-mannopyranosyl and â-D-
arabinofuranosyl linkages still poses a great challenge.
(3) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem. 1994,
50, 21-123.
(4) Garegg, P. J. AdV. Carbohydr. Chem. Biochem. 1997, 52, 179-205.
(5) (a) Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J. Am. Chem.
Soc. 1989, 111, 6881-6882. (b) Gildersleeve, J.; Pascal, R. A., Jr.; Kahne,
D. J. Am. Chem. Soc. 1998, 120, 5961-5969.
(6) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl.
1996, 35, 1380-1419.
(7) Fraser-Reid, B.; Madsen, R. In PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker: New York, 1997; pp 339-356.
(8) Shimizu, M.; Togo, H.; Yokoyama, M. Synthesis 1998, 799-822.
(1) (a) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531. (b)
Boons, G.-J. Contemp. Org. Synth. 1996, 173-200. (c) Davis, B. G. J.
Chem. Soc., Perkin Trans. 1 2000, 2137-2160.
(2) (a) Varki, A. Glycobiology 1993, 3, 97-130. (b) Dwek, R. A. Chem.
ReV. 1996, 96, 683-720. (c) Dwek, R. A.; Butters, T. D. Chem. ReV. 2002,
102, 283-284.
10.1021/ol0510668 CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/28/2005

Several strategies for the stereoselective â-mannopyranosyl-
ation have been developed in recent years,9 whereas reliable,
direct methods for the construction of â-arabinofuranosyl
linkages have not yet been established. Thioarabinofurano-
sides have been used as glycosyl donors for the synthesis of
pentaarabinofuranosides and hexaarabinofuranosides contain-
ing â-D-arabinofuranosyl linkages,10 but they are not gener-
ally applicable for â-arabinofuranosylation with a range of
glycosyl acceptors (â/R e 4.5:1).11 Indirect methods such
as the internal aglycon delivery method12 and Lowary’s
method employing 2,3-anhydrolyxofuranosyl glycosides13
have been utilized as alternatives for the synthesis of â-D-
arabinofuranosides. Direct methods for the construction of
the â-arabinofuranosyl linkage would be more efficient and
practical than indirect methods. An added impetus to develop
efficient methods for the preparation of â-oligoarabinofura-
nosides comes from their presence in arabinogalactan and
immunogenic lipoarabinomannan found in mycobacterial cell
walls. Clearly, the synthesis of these oligoarabinofuranosides
could greatly contribute to the development of new thera-
peutic agents against tuberculosis and other mycobacterial
infections.14 We have previously introduced 2′-carboxybenzyl
(CB) glycosides as glycosyl donors for â-mannopyranosyl-
ation15 and 2-deoxy-â-glucopyranosylation.16 We applied this
CB glycoside methodology to the direct construction of the
â-arabinofuranosyl linkage and herein report a generally
applicable and highly stereoselective method for â-arabino-
furanosylation, in which the stereoselectivity is achieved by
properly choosing protective groups on the glycosyl accep-
tors. We also report the synthesis of an octaarabinofuranoside
found in mycobacterial arabinogalactan and lipoarabinoman-
nan14 by employing this acceptor-dependent â-arabinofura-
nosylation method.
Scheme 1. Synthesis of CB Arabinofuranoside 4a
a TFA ) trifluoroacetic acid, Bn ) benzyl, Bz ) benzoyl.
way of the D-arabinofuranosyl chloride by the following
sequence: (i) hydrolysis of 1 with HCl in acetic acid, (ii)
acetylation of the resulting anomeric OH with acetic
anhydride-pyridine to give acetate 5, (iii) anomeric chlo-
rination of 5 with HCl gas in methylene chloride, and (iv)
coupling of the resulting crude arabinofuranosyl chloride17
with 2 in the presence of HgBr2 and Hg(CN)2 in acetonitrile.
Selective hydrogenolysis of the benzyl ester functionality in
BCB arabinofuranoside 3 was readily achieved in the
presence of ammonium acetate to afford the desired CB
arabinoside 4 in 89% yield. CB 3,5-di-O-benzoyl-2-O-
benzylarabinofuranoside 6 was also prepared in like fashion
(see Supporting Information).
Glycosylations of various acceptors with the arabinofura-
nosyl donor 418 were carried out by dropwise addition of a
diluted solution of 1.5 equiv of Tf2O in CH2Cl2 to a solution
of 1.0 equiv of 4, 1.5 equiv of the acceptor, and 3.0 equiv
of 2,6-di-tert-butyl-4-methylpyridine (DTBMP) in CH2Cl2
at -78 °C. The reaction mixture was stirred for an additional
1 h at -78 °C and allowed to warm over 1 h to 0 °C. The
result of the glycosylation was unprecedented and exciting
in terms of the stereochemistry of products. Thus, reaction
of the donor 4 with acceptor 7 having benzoyl-protective
groups afforded â-disaccharide 21 almost exclusively (â/R
) 99:1) in 97% yield (entry 1 in Table 1), while the same
reaction with acceptor 12 having benzyl-protective groups
gave a mixture of R- and â-disaccharides 26 (â/R ) 7:1)
(entry 6). Further examples clearly showed that the protective
group of glycosyl acceptors was the crucial factor determin-
ing the outcome of the stereochemistry in glycosylations with
4. Regardless of pyranoses or furanoses and of primary
alcohols or secondary alcohols, glycosylations of acceptors
having benzoyl-protective groups, 8-11, with the donor 4
afforded â-disaccharides either exclusively or predominantly
CB tri-O-benzyl-D-arabinofuranoside 4 was efficiently
prepared from methyl tri-O-benzyl-D-arabinofuranoside 1.
Treatment of 1 with acetyl bromide in trifluoroacetic acid
and subsequent coupling of the resulting crude arabinofura-
nosyl bromide with benzyl 2-(hydroxymethyl) benzoate (2)
afforded 2′-(benzyloxycarbonyl)benzyl (BCB) tri-O-benzyl-
D-arabinofuranoside 3 (R/â ) 4:1) as shown in Scheme 1.
The pure R-anomer of 3 could also be prepared from 1 by
(9) (a) Gridley, J. J.; Osborn, H. M. I. J. Chem. Soc., Perkin Trans. 1
2000, 1471-1491. (b) Crich, D. In Glycochemistry: Principles, Synthesis,
and Applications; Wang, P. G., Bertozzi, C. R., Eds.; Marcel Dekker: New
York, 2001; pp 53-75.
(10) (a) Mereyala, H. B.; Hotha, S.; Gurjar, M. K. Chem. Commun. 1998,
685-686. (b) D’Souza, F. W.; Lowary, T. L. Org. Lett. 2000, 2, 1493-
1495. (c) Yin, H.; D’Souza, F. W.; Lowary, T. L. J. Org. Chem. 2002, 67,
892-903.
(11) Yin, H.; Lowary, T. L. Tetrahedron Lett. 2001, 42, 5829-5832.
(12) (a) Bamhaoud, T.; Sanchez, S.; Prandi, J. Chem. Commun. 2000,
659-660. (b) Sanchez, S.; Bamhaoud, T.; Prandi, J. Tetrahedron Lett. 2000,
41, 7447-7452.
(13) Gadikota, R. R.; Callam, C. S.; Wagner, T.; Fraino, B. D.; Lowary,
T. L. J. Am. Chem. Soc. 2003, 125, 4155-4165.
(14) (a) Brennan, P. J.; Nikaido, H. Annu. ReV. Biochem. 1995, 64, 29-
63. (b) Chatterjee, D. Curr. Opin. Chem. Biol. 1997, 1, 579-588. (c)
Lowary, T. L. In Glycoscience: Chemistry and Chemical Biology; Fraser-
Reid, B., Tatsuta, K., Thieme, J., Eds.; Springer-Verlag: Berlin, 2001; pp
2005-2080.
(15) Kim, K. S.; Kim, J. H.; Lee, Y. Joo; Lee, Y. Jun; Park, J. J. Am.
Chem. Soc. 2001, 123, 8477-8481.
(16) Kim, K. S.; Park, J.; Lee, Y. J.; Seo, Y. S. Angew. Chem., Int. Ed.
2003, 42, 459-462.
(17) Subramaniam, V.; Lowary, T. L. Tetrahedron 1999, 55, 5965-
5976.
(18) Regardless of the anomeric stereochemistry of 4, pure R-anomer,
or a mixture of R- and â-anomers (4:1), the yield and the stereochemistry
of the arabinofuranoside produced in the glycosylation were virtually
identical.
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Org. Lett., Vol. 7, No. 15, 2005

Table 1. Glycosylation with CB Arabinofuranosides 4 and 6
1
a Determined after isolation. b Determined by HPLC using Nova-Pak C18 column. c Determined by H NMR.
(â/R > 20:1) in high yields (entries 2-5), whereas the
â-stereoselectivity in glycosylations of acceptors having
benzyl-protective groups, 13-16, with the donor 4 was much
less pronounced (â/R < 11:1) (entries 7-10). We also
examined the influence of other protective groups in the
glycosyl acceptor on the stereochemistry of the glycosylation
product. Glycosylations of acceptor 17, having acetyl groups,
and of acceptor 18, having a benzylidene group, with the
donor 4 afforded predominantly â-disaccharides 31 (â/R )
38:1) and 32 (â/R ) 40:1), respectively (entries 11 and 12).
On the other hand, the glycosylation of acceptor 19 having
two isopropylidene groups with the donor 4 afforded a
mixture of R- and â-disaccharides 33 (â/R ) 6.1:1) (entry
13). Glycosylation of hindered alcohol 20 with 4 afforded
only â-arabinofuranoside 34 (entry 14), whereas glycosyla-
tions of primary alcohols, 1-octanol, and 2 with 4 gave
Org. Lett., Vol. 7, No. 15, 2005
3265

mixtures of R- and â-arabinofuranosides (entries 15 and 16).
Glycosylations with the CB dibenzoylarabinofuranoside 6
as a donor, however, were not as stereoselective as with 4
(entries 17-19).
Scheme 2. Synthesis of Octaarabinofuranoside 52a
We have applied this acceptor-dependent â-arabinosylation
method to the synthesis of octaarabinofuranoside 52. BCB
and CB arabinoside building blocks 39, 40, and 41 were
readily prepared from known compounds in a method similar
to that for the BCB and CB arabinosides 3 and 4 (Supporting
Information). Reaction of CB arabinofuranosyl donor 39 and
acceptor 10 under the standard glycosylation conditions
afforded R-arabinofuranosyl disaccharide 42 in 84% yield,
and subsequent removal of the levulinyl group of 42 with
hydrazine gave alcohol 43 as shown in Scheme 2. Repetitive
glycosylation of the disaccharide 43 as an acceptor with the
arabinofuranosyl donor 39 gave R-trisaccharide 44, which
was converted into the trisaccharide acceptor 45 by removal
of its levulinyl group with hydrazine. Glycosylation of the
diol 41 with 2 equiv of the glycosyl donor 40 afforded
R-trisaccharide 46 in 84% yield without any problems.
Deprotection of the two levulinyl groups in 46 with hydrazine
gave diol 47, in which the benzoyl group was utilized as the
protective group for acceptor-dependent â-arabinofuranosyl-
ation in the next step. The crucial double â-arabinofurano-
sylation of diol 47 with 3.7 equiv of the arabinofuranosyl
donor 4 proceeded smoothly under the standard conditions
to afford pentaarabinofuranoside 48 in 82% yield with
complete â-selectivity. No R-glycosides were detected at all
in the reaction mixture. The latent BCB arabinofuranoside
48 was converted into the active CB arabinoside 49. Coupling
of the pentaarabinofuranosyl donor 49 and the triarabino-
furanosyl acceptor 45 afforded protected octaarabinofura-
noside 50 in 83% yield. Debenzoylation of 50 with sodium
methoxide followed by hydrogenolysis of the resulting
partially benzyl-protected octaarabinfuranoside 51 afforded
the desired octaarabinofuranoside 52.
a Bz ) benzoyl, Lev ) levulinyl.
In conclusion, we have established a reliable and generally
applicable direct method for the stereoselective â-arabino-
furanosylation employing a CB tri-O-benzylarabinoside as
the glycosyl donor. The acyl-protective group on glycosyl
acceptors was essential for the â-stereoselectivity. The power
of the present acceptor-dependent glycosylation method was
demonstrated by the efficient synthesis of the octaarabino-
furanoside in arabinogalactan and the lipoarabinomannan
found in mycobacterial cell wall.
Acknowledgment. This work was supported by a grant
from the Korea Science and Engineering Foundation through
Center for Bioactive Molecular Hybrids (CBMH).
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0510668
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