β-selective arabinofuranosylation using a 2,3-o-xylylene-protected donor

Article abstract of DOI:10.1021/ol101520q

Reported is a novel stereoselective β-arabinofuranosylation that makes use of a conformationally restricted 2,3-O-xylylene-protected arabinofuranosyl donor. Optimization of the reaction conditions showed that factors including the structure of the accepto

Full text of DOI:10.1021/ol101520q

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3686-3689
ꢀ-Selective Arabinofuranosylation Using
a 2,3-O-Xylylene-Protected Donor
Akihiro Imamura and Todd L. Lowary*
Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry,
The UniVersity of Alberta, Gunning-Lemieux Chemistry Centre,
Edmonton, Alberta T6G 2G2, Canada
tlowary@ualberta.ca
Received July 2, 2010
ABSTRACT
Reported is a novel stereoselective ꢀ-arabinofuranosylation that makes use of a conformationally restricted 2,3-O-xylylene-protected arabinofuranosyl
donor. Optimization of the reaction conditions showed that factors including the structure of the acceptor alcohol, substrate concentration, and
protecting group on O-5 of the donor affect the stereochemical outcome of the glycosylation. To demonstrate the utility of the methodology, the
synthesis of an oligosaccharide fragment from the mycobacterial cell wall polysaccharide lipoarabinomannan was carried out.
The development of stereoselective glycosylation methods
has attracted significant attention given the essential role
of carbohydrates in biology.1 To date, many innovative
glycosylation methodologies have been developed;2 how-
ever, most of these address the preparation of pyranose
glycosides.3 In contrast, studies on stereoselective fura-
nosylation have been more limited.4 There is nevertheless
a need for methods that enable the preparation of furano-
sides in a stereoselective manner, given the critical role
that glycoconjugates containing these residues play in the
life cycle of a number of microorganisms.4,5
Furanose-containing glycans are particularly important in
Mycobacterium tuberculosis, the organism that causes tu-
berculosis (TB). This disease has received increasing atten-
tion due to the emergence of drug-resistant strains of the
bacterium.6 The M. tuberculosis cell wall consists largely
of two furanose-rich polysaccharides, the mycolyl-arabi-
nogalactan-peptidoglycan (mAGP) complex, and lipoarabi-
nomannan (LAM).7 Common to both is an arabinan domain
containing D-arabinofuranose (Araf) residues. At the termini
of these arabinan chains is a branched structure with two
ꢀ-Araf residues (Figure 1). In LAM, O-5 of these ꢀ-Araf
residues is often further capped with other species,
including short R-(1f2)-linked oligomannosides as shown
in Figure 1.8
(1) Essentials of Glycobiology, 2nd ed.; Varki, A., Cummings, R. D.,
Esko, J. D., Freeze, H. H., Stanley, P., Bertozzi, C. R., Hart, G. W., Etzler,
M. E., Eds.; Cold Spring Harbor Laboratory Press: New York, 2009.
(2) (a) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 2. (b)
Carmona, A. T.; Moreno-Vargas, A. J.; Robina, I. Curr. Org. Synth. 2008,
5, 33. (c) PreparatiVe Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel
Dekker, Inc.: New York, 1997.
(3) (a) Demchenko, A. V. Synlett 2003, 9, 1225. (b) Gridley, J. J.;
Osborn, H. M. I. J. Chem. Soc., Perkin Trans. 1 2000, 1471. (c) Bongat,
A. F. G.; Demchenko, A. V. Carbohydr. Res. 2007, 342, 374. (d) Hou, D.;
Lowary, T. L. Carbohydr. Res. 2009, 344, 1911. (e) Ando, H.; Imamura,
A. Trends Glycosci. Glycotechnol. 2004, 16, 293.
The synthesis of mAGP and LAM fragments is essential
to provide materials for investigations that will lead to the
(4) For reviews, see: (a) Lowary, T. L. Curr. Opin. Chem. Biol. 2003,
7, 749. (b) Peltier, P.; Euzen, R.; Daniellou, R.; Nugier-Chauvin, C.;
Ferrie`res, V. Carbohydr. Res. 2008, 343, 1897.
(7) Kaur, D.; Guerin, M. E.; Skovierova, H.; Brennan, P. J.; Jackson,
M. AdV. Appl. Microbiol. 2009, 69, 23.
(5) Richards, M. R.; Lowary, T. L. ChemBioChem 2009, 10, 1920.
(6) Chiang, C.; Yew, W. W. Int. J. Tuberc. Lung Dis. 2009, 13, 304.
(8) Briken, V.; Porcelli, S. A.; Besra, G. S.; Kremer, L. Mol. Microbiol.
2004, 53, 391.
10.1021/ol101520q  2010 American Chemical Society
Published on Web 07/19/2010

the conformation of the ring is locked with a 2,3-O-xylylene
group (6-8, Scheme 1).14,15 It was anticipated13 that
oxacarbenium ions generated from these thioglycosides
would adopt conformations favoring ꢀ-Araf formation. We
report here the methodology using this new donor type and
its application to the synthesis of a mycobacterial arabinan
fragment.
Scheme 1. Preparation of 2,3-O-Xylylene-Protected Donors
Figure 1. (A) Terminal structure of LAM arabinan. (B) Examples
of conformationally locked thioglycosides 1 and 2 used for the
stereoselective synthesis of ꢀ-Araf residues.11
The 2,3-O-xylylene-protected donors were readily prepared
as illustrated in Scheme 1. Thioglycoside 316 was deacylated,
and then a TBDPS group was introduced on O-5 to afford 4
in excellent yield over two steps. Incorporation of the
xylylene group was achieved upon treatment with R,R′-
dibromo-o-xylene and NaH in DMF, and subsequent removal
of the TBDPS group gave 5 in 58% yield from 4.17 The
2,3-O-xylylene-protected donors used in this study (6-8)
were efficiently prepared from 5 under standard conditions.
We first explored the use of 6 in coupling reactions with
alcohols 9-16 (Table 1). All glycosylations were promoted
with the NIS-AgOTf promotor system18 in CH2Cl2. The
identification of new drug targets and vaccines for treating
and preventing TB.9 A challenge in the synthesis of structures
of this type is stereoselectively introducing the ꢀ-Araf
linkages.4a Several innovative approaches for synthesizing
these linkages have therefore been reported, including both
direct10,11 and indirect12 methods. Among the direct methods,
the use of conformationally locked donors such as 3,5-O-
di-t-butylsilylene- and 3,5-O-tetra-i-propyldisiloxane-pro-
tected thioglycosides (1 and 2, respectively) has shown
particular promise.11
The design of 1 and 2 was inspired by Woerpel and co-
workers’ studies on the stereoselectivity of nucleophilic
attack onto five-membered ring oxacarbenium ions.13 It has
been proposed11a that the high stereocontrol seen in reactions
with 1 and 2 arises because attack of the alcohol onto a rigid
oxacarbenium ion intermediate is favored from the face
leading to the ꢀ-glycoside.
Despite the power of this approach, the tethering of the
conformationally restricting group between O-3 and O-5
complicates the synthesis of structures in which O-5 of the
ꢀ-Araf residues is further modified (see Figure 1A). We
therefore envisioned an approach to these targets in which
1
product stereochemistry was confirmed by H NMR spec-
troscopy in CDCl3. For the R-anomer, J1,2 is ∼2.0 Hz, while
for the ꢀ-anomer, J1,2 is ∼5.0 Hz.
The effect of acceptor concentration on reaction stereo-
selectivity19 was examined first. The glycosylations at
relatively low concentration (0.1 M, entry 2) and low
concentration (0.03 M, entry 3) proceeded smoothly and
afforded the octyl glycoside 17 in excellent yield with slight
ꢀ-selectivity. The reaction showed no selectivity when
performed at high concentration (1.0 M, entry 1).
Next, coupling reactions were performed at various
temperatures. Increasing the reaction temperature (Table 1
entry 4) did not improve the ꢀ-selectivity, and when the
(9) Umesiri, F. E.; Sanki, A. K.; Boucau, J.; Ronning, D. R.; Sucheck,
S. J. Med. Res. ReV. 2010, 30, 290.
(10) (a) Lee, Y. J.; Lee, K.; Jung, E. H.; Jeon, H. B.; Kim, K. S. Org.
Lett. 2005, 7, 3263. (b) Ishiwata, A.; Akao, H.; Ito, Y.; Sunagawa, M.;
(14) Biasing the conformation of a pyranose ring with a cis-butenyl linker
has been reported, but the use of this species in glycosylation reactions has
not. Cao, Y.; Kasai, Y.; Bando, M.; Kawagoe, M.; Yamada, H. Tetrahedron
Kusunose, N.; Kashiwazaki, Y. Bioorg. Med. Chem. 2006, 14, 3049
.
(11) (a) Zhu, X.; Kawatkar, S.; Rao, Y.; Boons, G.-J. J. Am. Chem.
Soc. 2006, 128, 11948. (b) Crich, D.; Pedersen, C. M.; Bowers, A. A.;
Wink, D. J. J. Org. Chem. 2007, 72, 1553. (c) Wang, Y.; Maguire-Boyle,
S.; Dere, R. T.; Zhu, X. Carbohydr. Res. 2008, 343, 3100. (d) Ishiwata,
A.; Akao, H.; Ito, Y. Org. Lett. 2006, 8, 5525. (e) Joe, M.; Bai, Y.; Nacario,
2009, 65, 2574.
(15) It should be noted that a glycosylation with a 2,3-di-O-tetra-i-
propyldisiloxane-protected arabinofuranose thioglycoside has been reported
(ref 11d); the R/ꢀ selectivity was ∼ 1:2.5.
(16) Callam, C. S.; Gadikota, R. R.; Lowary, T. L. J. Org. Chem. 2001,
66, 4549.
R. C.; Lowary, T. L. J. Am. Chem. Soc. 2007, 129, 9885
.
(12) (a) De´sire´, J.; Prandi, J. Carbohydr. Res. 1999, 317, 110. (b)
Ishiwata, A.; Munemura, Y.; Ito, Y. Eur. J. Org. Chem. 2008, 4250. (c)
Gadikota, R. R.; Callam, C. S.; Wagner, T.; Fraino, B. D.; Lowary, T. L.
J. Am. Chem. Soc. 2003, 125, 4155.
(17) The purification of the product after the introduction of the xylylene
group was difficult. However, removal of the TBDPS group made it easier
to separate 5 from other reaction byproducts.
(18) Konradsson, P.; Udodong, U. E.; Fraser-Reid, B. Tetrahedron Lett.
1990, 31, 4313.
(13) (a) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A.
J. Am. Chem. Soc. 1999, 121, 12208. (b) Larsen, C. H.; Ridgway, B. H.;
Shaw, J. T.; Smith, D. M.; Woerpel, K. A. J. Am. Chem. Soc. 2005, 127,
10879.
(19) (a) Chao, C.-S.; Li, C.-W.; Chen, M.-C.; Chang, S.-S.; Mong, K.-
K. T. Chem.sEur. J. 2009, 15, 10972. (b) Ishiwata, A.; Sakurai, A.; Du¨rr,
K.; Ito, Y. Bioorg. Med. Chem. 2010, 18, 3678.
Org. Lett., Vol. 12, No. 16, 2010
3687

stereoselectivity (entries 10 and 11). On the other hand, the
glycosylation of arabinofuranosyl acceptor 16 containing a
free C-2 hydroxyl group (entry 12) afforded the ꢀ-glycoside
in excellent yield and stereoselectivity (8.6:1 ꢀ/R ratio). This
result is of particular significance because the ꢀ-Araf-(1f2)-
R-Araf fragment is a motif present in mycobacterial arabinan.
At 0 °C, the ꢀ-selectivity of the reaction between 6 and 16
was notably reduced (entry 13). The sensitivity of the
stereoselectivity on the structure of the acceptor is unclear,
but these findings are consistent with work reported by other
groups on the synthesis of ꢀ-arabinofuranosides.10-12
Optimization of the reaction conditions for the synthesis
of the ꢀ-Araf-(1f2)-R-Araf motif was next examined (Table
2) using 16 and 6-8. The effect of solvent was studied first.
Table 1. Glycosidation of 6 with Various Acceptors
Table 2. Glycosylation of 16 with Donors 6-8
a Combined yield of R- and ꢀ-isomers. b The use of 1,2-dichloroethane
as the solvent afforded the product in 99% yield with a 1.4:1 ꢀ:R ratio.
a Activator system: A, NIS-AgOTf; B, BSP-Tf2O; C, NIS-BF3 · OEt2.
b Solvent: T, toluene; P, propionitrile; D, CH2Cl2; M, CH2Cl2-
CH3CN-CH3CH2CN (1:2:1). c Combined yield of R and ꢀ isomers. d After
3 h, AgOTf (0.15 equiv) was added. e After 2 h, TESOTf (0.20 equiv) was
added. f When carried out at -60 °C under the same conditions, the product
was obtained in 95% yield and 12.6:1 R:ꢀ selectivity.
reaction was conducted at low temperature (-45 °C), the
stereoselectivity was reversed (1:5.7 ꢀ/R ratio (entry 5)). This
was also observed when other simple alcohols such as
cyclohexanol (10) and t-butanol (11) were used as the
acceptor (entries 6 and 7).
Glycosidations at -45 °C with various carbohydrate
acceptors were also examined. Reaction with primary alco-
hols 12 and 13 (entries 8 and 9) afforded predominantly the
ꢀ-glycoside. When secondary alcohol 14 was used, a slight
decrease in ꢀ-stereoselectivity was observed, while reaction
with the hindered secondary alcohol 15 showed little
In toluene, the desired disaccharide 24 was formed in
excellent yield but with moderate stereoselectivity; in pro-
pionitrile, a 1:1 R:ꢀ ratio was obtained (entries 1 and 2).
Mong and co-workers have reported that a mixture of
CH2Cl2-CH3CN-EtCN (1:2:1) enhances ꢀ-selectivity in
3688
Org. Lett., Vol. 12, No. 16, 2010

pyranose glycosylations.19a However, in this reaction (entry
3), the R-glycoside was obtained as the major product. These
results suggest that, unlike pyranose systems,20 the use of
nitrile solvents does not enhance ꢀ-selectivity, at least using
this donor.
Scheme 2. Synthesis of a Heptasaccharide Fragment in LAM
Other activator systems were also examined. The coupling
of 6 and 16 promoted by 1-benzenesulfinyl piperidine and
triflic anhydride (BSP-Tf2O, entry 4)21 gave the best
ꢀ-selectivity, but the product yield decreased considerably.
Interestingly, replacement of AgOTf as the acid catalyst with
BF3 · OEt2 (entry 5) led to the inversion of the stereoselec-
tivity, suggesting that the presence of the triflate ion may be
crucial to the ꢀ-selectivity, but the origin of this effect is
unknown and requires further study.
Finally, we studied the effect of the O-5 protecting group
in the donor. Glycosylation of 16 with 7, which has an
electron-withdrawing benzoyl group on O-5 (entry 6),
reduced the ꢀ-selectivity. In contrast with 8, which has a
more electron-rich p-methoxybenzyl (PMB) group on O-5
(entry 7), the ꢀ-selectivity was significantly increased (12.6:1
ꢀ/R ratio). Although the effect of the O-5 protecting group
on reaction stereoselectivity is not clear at present, a similar
effect has been previously reported.10b,22 In summary, this
optimization study indicates that the best results are obtained
with donor 8, using NIS-AgOTf activation in CH2Cl2 at
-45 °C.
Having optimized the formation of the ꢀ-Araf-(1f2)-R-
Araf motif, we targeted the synthesis of a fragment of
mycobacterial LAM (35, Scheme 2). The synthesis started
from diol 2723 and thioglycoside 28.23 Treatment of these
compounds with NIS-AgOTf afforded R-arabinofuranosyl
trisaccharide 29 in excellent (91%) yield. Subsequent de-
benzoylation with NaOCH3 gave trisaccharide 30 in 84%
yield. Glycosylation of 30 with 8 was conducted under the
optimized reaction conditions described above to afford
pentasaccharide 31 in 65% yield; the minor glycoside
isomers formed in this reaction were neither isolated nor
characterized. Next, exposure of 31 to DDQ provided a
79% yield of pentasaccharide diol 32. Final glycosylation
of 32 with 3324 afforded heptasaccharide 34 in 73% yield.
The stereochemistry of the mannopyranosides was con-
firmed by the magnitude of the JC1,H1 for these residues.
The value obtained for both rings (174 Hz) supports
R-configuration.25 Finally, debenzoylation of 34 and
subsequent hydrogenolysis of benzyl and xylylene groups
furnished the desired target 35 in 80% yield over the two
steps.
introduction of the ꢀ-Araf moiety with high selectivity and
the product of this reaction can easily be converted into
derivatives possessing the capping motifs.8
In conclusion, a novel direct method for ꢀ-selective arabino-
furanosylation employing a 2,3-O-xylylene-protected Araf donor
has been developed. It was found that the glycosylation
stereoselectivity was dependent on the reaction conditions, and
in particular, the use of a 5-O-PMB-type donor was essential.
The methodology was easily applied to the synthesis of a
fragment of mannose-capped mycobacterial LAM.
Acknowledgment. This work was supported by the
University of Alberta, The National Sciences and Engineer-
ing Research Council of Canada, and the Alberta Ingenuity
Centre for Carbohydrate Science. A.I. thanks the Uehara
Foundation for a postdoctoral fellowship.
Supporting Information Available: Experimental data
Although syntheses of mannose-capped LAM structures
have been reported,26 only a few have contained the ꢀ-Araf
residues.26c-e The methodology described here is ideal for
the synthesis of targets of this type as it allows the
1
and H and 13C NMR spectra for all previously unreported
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL101520Q
(20) Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett. 1984,
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(21) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015.
(22) Liu, C.; Richards, M. R.; Lowary, T. L. J. Org. Chem. 2010,
accepted for publication.
(26) (a) Ho¨lemann, A.; Stocker, B. L.; Seeberger, P. H. J. Org. Chem.
2006, 71, 8071. (b) Fraser-Reid, B.; Lu, J.; Jayaprakash, K. N.; Lo´pez,
J. C. Tetrahedron: Asymmetry 2006, 17, 2449. (c) Marotte, K.; Sanchez,
S.; Bamhaoud, T.; Prandi, J. Eur. J. Org. Chem. 2003, 3587. (d) Bamhaoud,
T.; Sanchez, S.; Prandi, J. Chem. Commun. 2000, 659. (e) Subramaniam,
V.; Lowary, T. L. Tetrahedron 1999, 55, 5965. (f) Cao, B.; Williams, S. J.
Nat. Prod. Rep. 2010, 27, 919.
(23) Yin, H.; D’Souza, F. W.; Lowary, T. L. J. Org. Chem. 2002, 67,
892.
(24) Joe, M.; Lowary, T. L. Unpublished investigations.
(25) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293.
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