β-arabinofuranosylation using 5- O -(2-quinolinecarbonyl) substituted ethyl thioglycoside donors

Article abstract of DOI:10.1021/ol401755e

A new β-stereoselective d- and l-arabinofuranosylation method has been developed employing 5-O-(2-quinolinecarbonyl) substituted arabinosyl ethyl thioglycosides as glycosyl donors. The approach allows a wide range of acceptor substrates to be used; the β-selectivity is good-to-excellent. Stereoselective synthesis of a mannose-capped octasaccharide portion from a mycobacterial cell wall polysaccharide was then carried out to demonstrate the utility of this methodology.

Full text of DOI:10.1021/ol401755e

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
β‑Arabinofuranosylation Using
5‑O‑(2-Quinolinecarbonyl) Substituted
Ethyl Thioglycoside Donors
Qiang-Wei Liu,† Hua-Chao Bin,† and Jin-Song Yang*,†,‡
Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of
Education, Department of Chemistry of Medicinal Natural Products, West China School
of Pharmacy, and State Key Laboratory of Biotherapy, West China Hospital,
Sichuan University, Chengdu 610041, China
yjs@scu.edu.cn
Received June 21, 2013
ABSTRACT
A new β-stereoselective D- and L-arabinofuranosylation method has been developed employing 5-O-(2-quinolinecarbonyl) substituted arabinosyl
ethyl thioglycosides as glycosyl donors. The approach allows a wide range of acceptor substrates to be used; the β-selectivity is good-to-excellent.
Stereoselective synthesis of a mannose-capped octasaccharide portion from a mycobacterial cell wall polysaccharide was then carried out to
demonstrate the utility of this methodology.
Arabinofuranose (Araf) is a very common structural
constituent of polysaccharides present in living organ-
isms.1 Both D- and L-arabinosides were found, with the
D-form being the major component of mycobacterial cell
walls, and the L-form being an important component of
the plant cell wall. β-Arabinofuranosides usually occur at
the nonreducing end of these polysaccharides and play
a crucial role in numerous biological events. For example,
β-(1f2)-D-arabinosides are found at the nonreducing ter-
minal ends of arabinogalactan (AG) and lipoarabinoman-
nan (LAM), two major biopolymers in mycobacterial
cell walls. Both AG and LAM are closely associated with
the survival and pathogenicity of mycobacteria, includ-
ing human pathogens Mycobacterium tuberculosis and
Mycobacterium leprae.1a,b On the other hand, plant-originated
arabinogalactans are modified with β-L-Araf residues
at the nonreducing termini and side chains.1c There is
evidence that these highly complex polysaccharides are
involved in the development and differentiation of plant
cells.2
Due to their biological relevance, the synthesis of
β-arabinofuranosides, especially the development of effective
β-arabinofuranosylating building blocks, has received con-
siderable attention.3 In contrast to R-arabinoside counter-
parts, which can be constructed in a straightforward manner
by participation of an acyl-type group on the 2-position, the
stereoselective formation of β-arabinofuranosidic linkages
is still a great challenge in carbohydrate chemistry. To date,
several elegant methods directed toward β-arabinofurano-
sides have been reported, including both direct4,5 and
indirect6 methods. Among the direct approaches, the use of
conformationally constrained donors such as 3,5-O-di-tert-
butylsilylene (DTBS)-, 3,5-O-tetraisopropyldisiloxanylidene
(3) For reviews on synthesis of Araf-containing oligosaccharides, see:
(a) Lowary, T. L. Curr. Opin. Chem. Biol. 2003, 7, 749. (b) Peltier, P.;
ꢀ
Euzen, R.; Daniellou, R.; Nugier-Chauvin, C.; Ferrieres, V. Carbohydr.
Res. 2008, 343, 1897. (c) Imamura, A.; Lowary, T. L. Trends Glycosci.
Glycotech. 2011, 23, 134. (d) Liang, X.-Y.; Deng, L.-M.; Yang, J.-S.
Chin. J. Org. Chem. 2013, 33, 245.
(4) (a) Lee, Y. J.; Lee, K.; Jung, E. H.; Jeon, H. B.; Kim, K. S. Org.
Lett. 2005, 7, 3263. (b) D’Souza, F. W.; Lowary, T. L. Org. Lett. 2000, 2,
1493. (c) Yin, H.-F.; D’Souza, F. W.; Lowary, T. L. J. Org. Chem. 2002,
67, 892. (d) Ishiwata, A.; Akao, H.; Ito, Y.; Sunagawa, M.; Kusunose,
N.; Kashiwazaki, Y. Bioorg. Med. Chem. 2006, 14, 3049. (e) Li, Y.;
Singh, G. T. Tetrahedron Lett. 2001, 42, 6615.
† West China School of Pharmacy.
‡ West China Hospital.
(1) (a) Lowary, T. L. In Glycoscience: Chemistry and Chemical
Biology; Fraser-Reid, B.; Tatsuta, K.; Thiem, J., Eds.; Springer: Berlin,
2001; p 2005. (b) Brennan, P. J. Tuberculosis 2003, 83, 91. (c) Ridley,
B. L.; O’Neill, M. A.; Mohnen, D. Phytochemistry 2001, 57, 929.
(2) Fincher, G. B.; Stone, B. A.; Clarke, A. E. Annu. Rev. Plant
Physiol. 1983, 34, 47.
r
10.1021/ol401755e
XXXX American Chemical Society

(TIPDS)-, and 2,3-O-xylylene protected thioglycosides has
shown special promise.5,6e Alternatively, 20-carboxybenzyl
(CB) glycoside4a and p-cresol thioglycoside4b,c methodolo-
gies have also been reported by Kim and Lowary, respec-
tively, to be effective for the direct β-arabinosylations.
Recently, Demchenko and co-workers developed a nov-
el hydrogen-bond-mediated aglycone delivery strategy
for stereoselective synthesis of oligosaccharides.7 The basic
concept of their strategy relies on the fact that the inter-
molecular hydrogen bonding interaction formed between
the donor and acceptor can directthe accessof the acceptor
to one specific face of the donor ring. Based on this
strategy, various pyranosides including challenging R-glu-
co-, β-manno-, and β-rhamnosides were stereoselectively
synthesized.
Here, we sought to apply the H-bonding-assisted
glycosylation approach to the construction of 1,2-cis-
β-arabinofuranosides.8 Thus, a set of Araf donors 1ꢀ3,
all carrying a directing group at the 5-position, were
designed (Scheme 1). The sp2-hybridized nitrogen within
the 5-O-substituents can function as a H-bond acceptor. It
is anticipated that, in a typical glycosylation process, the
acceptor is first tethered via a H-bond with an arabinosyl
donor to form A. Upon activation, the nucleophilic attack
of the acceptor on the anomeric center will occur prefer-
entially from the β-side of the resulting oxacarbenium ion
B, thereby leading to a β-linked Araf glycoside C. In this
Letter, we report the development of a new β-arabino-
furanosylation method using 5-O-(2-quinolinecarbonyl)
(Quin) substituted thioglycosides as glycosyl donors and
demonstrate the efficiency the method possesses through
the stereoselective synthesis of a mannose-capped octasac-
charide fragment from mycobacterial LAM.
Scheme 2. Preparation of Donors 1ꢀ3
The designed 5-O-substituted donors 1ꢀ3 were readily
made as illustrated in Scheme 2. The known thioglycoside
49 was treated with 2-picolinic acid to furnish thioglycoside 1
in 92% yield. Compound 1was then converted into trichloro-
acetimidate 2 through a two-step activation procedure
(Scheme 2, eq 1).10 The synthesis of ethyl thioglycoside
derivatives 3aꢀd began with regioselective 5-O-protection
of 511 as a TBDPS ether. The obtained 6 was in turn
subjected to 2,3-O-benzylation and followed by 5-O-desi-
lylation to provide alcohol 74d (65% yield for the two
steps). Esterification of 7 with a series of carboxylic acids in
CH2Cl2 gave the required 3aꢀd in excellent yields (eq 2).
With the donors 1ꢀ3 in hand, we first explored their
reactions with Araf alcohols 8ꢀ10 (Table 1). All glycosyla-
tions were run employing 1.3 equiv of the donor (5 mM) and
1 equiv of the acceptor in the presence of the NIS/TfOH
system or TMSOTf for thioglycoside (1and 3) and trichloro-
acetimidate (2) donors, respectively, in dry ClCH2CH2Cl.
The product stereochemistry was determined by 1H NMR
spectroscopy in CDCl3.12 For the R-anomer, JH1,H2 is
3
∼2.0 Hz, while, for the β-anomer, 3JH1,H2 is ∼5.0 Hz.
The effect of the anomeric leaving group of the donor
on the reaction outcome was examined first. As a result,
the glycosylations of 1, 2, and 3a all bearing a Pico
(2-pyridinecarbonyl) group on O-5 with model 3-OH accep-
tor 8 afforded disaccharide glycoside 11a with equally satis-
factory 1,2-cis stereoselectivity (β/R 10:1, Table 1, entries
1ꢀ3). Among the three donors tested, the ethyl thioglycoside
3a showed the highest reactivity in terms of reaction tem-
perature and time and generated an excellent 85% yield of
11a (entry 3).
Scheme 1. Design of Potential Glycosyl Donors for
β-Arabinofuranosylation
Next, the influence of the 5-O-directing group on reac-
tion stereoselectivity was studied. As shown in Table 1,
entries 4ꢀ7, the glycosylations of the diversely 5-substi-
tuted ethyl thioglycosides 3aꢀd with acceptors 9 and 10
(5) (a) Zhu, X.-M.; Kawatkar, S.; Rao, Y.; Boons, G.-J. J. Am. Chem.
Soc. 2006, 128, 11948. (b) Ishiwata, A.; Akao, H.; Ito, Y. Org. Lett. 2006,
8, 5525. (c) Crich, D.; Pedersen, C. M.; Bowers, A. A.; Wink, D. J. J. Org.
Chem. 2007, 72, 1553. (d) Joe, M.; Bai, Y.; Nacario, R. C.; Lowary, T. L.
J. Am. Chem. Soc. 2007, 129, 9885. (e) Wang, Y.-X.; Maguire-Boyle, S.;
Dere, R. T.; Zhu, X.-M. Carbohydr. Res. 2008, 343, 3100. (f) Imamura,
A.; Lowary, T. L. Org. Lett. 2010, 12, 3686.
(7) Yasomanee, J. P.; Demchenko, A. V. J. Am. Chem. Soc. 2012,
134, 20097.
(8) For a recent review on stereoselective glycosylation through an
intramolecular aglycone delivery (IAD) method, see: Ishiwata, A.; Lee,
Y. J.; Ito, Y. Org. Biomol. Chem. 2010, 8, 3596.
(9) Liang, X.-Y.; Bin, H.-C.; Yang, J.-S. Org. Lett. 2013, 15, 2834.
(10) Schmidt, R. R.; Jung, K.-H. In Preparative Carbohydrate Chem-
istry; Hanessian, S., Ed.; Dekker: New York, 1997; p 283.
(11) Hou, D.-J.; Taha, H. A.; Lowary, T. L. J. Am. Chem. Soc. 2009,
131, 12937.
(12) Mizutani, K.; Kasai, R.; Nakamura, M.; Tanaka, O.; Matsuura,
H. Carbohydr. Res. 1989, 185, 27.
(6) (a) Marotte, K.; Sanchez, S.; Bamhaoud, T.; Prandi, J. Eur. J.
Org. Chem. 2003, 3587. (b) Bamhaoud, T.; Sanchez, S.; Prandi, J. Chem.
Commun. 2000, 659. (c) Gadikota, R. R.; Callam, C. S.; Wagner, T.;
Fraino, B. D.; Lowary, T. L. J. Am. Chem. Soc. 2003, 125, 4155. (d)
Ishiwata, A.; Munemura, Y.; Ito, Y. Eur. J. Org. Chem. 2008, 4250. (e)
Ishiwata, A.; Ito, Y. J. Am. Chem. Soc. 2011, 133, 2275. (f) Thadke, S. A.;
Mishra, B.; Hotha, S. Org. Lett. 2013, 15, 2466.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Effect of Anomeric Leaving Group and 5-Participating
Group of Donors on Glycosylation Stereoselectivity
Table 2. Glycosylation of D- and L-3d with Various Acceptorsa
a For entries 1 and 3ꢀ7. b For entry 2. c Yield of the major β-isomer
unless otherwise noted. d Determined by 1H NMR of the corresponding
isomer mixture. e Yield of the inseparable mixture of R/β-isomers.
a Glycosylations were run with D-3d (for entries 1ꢀ10) or L-3d
molecular sieves (MS) in ClCH2CH2Cl at ꢀ30 f 0 °C for 2ꢀ3 h. b Yield
of the major β-isomer unless otherwise noted. c Determined by 1H NMR
of the corresponding isomer mixture. d Donor (2 equiv)/acceptor (1 equiv)
were used. e Yield of the inseparable mixture of R/β-isomers.
˚
(for entries 11ꢀ15), acceptor, NIS (2 equiv)/TfOH (0.2 equiv), 4 A
afforded the corresponding products in 44ꢀ90% yields and
with varying degrees of β-stereocontrol. A lower selectivity
(β/R 6.5:1) was observed in the reaction of 3a with 2-OH
acceptor 9 (entry 4 vs 3). The couplings of 5-O-Pyrim
(pyrimidine-4-carbonyl) and Pyra (2-pyrazinecarbonyl)
carrying 3b,c with 2- and 5-OH acceptors 9,10 displayed
slight selectivity (β/R 1.2:1 and 1.6:1, respectively, entries
5ꢀ6). Gratifyingly, the 5-O-Quin substituted 3d showed
strong stereocontrolling capability in the reaction with 9and
a great increase in selectivity (β/R 20:1) was obtained for the
product 14a (entry 7). Overall, the above optimization study
indicates that the best results are obtained with donor 3d,
using NIS/TfOH activation in ClCH2CH2Cl at ꢀ30 f 0 °C.
With the optimal reaction conditions, we then set out to
survey a variety of acceptors to establish the generality of
this 1,2-cis arabinofuranosylation reaction.
We were pleased to find that a broad range of sugar series
including arabinofuranose, gluco-, galacto-, and mannopyr-
anose alcohols as well as the common 1-adamantanol all
reacted very well with 3d, resulting in the corresponding
glycoside products 14aꢀj in high 87ꢀ95% yields as mainly
or exclusively the β-anomers (Table 2, entries 1ꢀ10). The
stereochemical outcome is dependent on the nature of the
acceptor. Reactions with primary acceptors 10, 16, 18, 20,
and 21 provided in general better 1,2-cis selectivities than
reactions with more hindered secondary and tertiary accep-
tors 9, 15, 17, 19, and 22 (entries 3, 4, 6, 8, and 9 vs 1, 2, 5, 7,
and 10). The sensitivity of the stereoselectivity on the struc-
ture of the acceptor is unclear, but these findings are con-
sistent with previous work reported by other groups on the
synthesis of β-arabinofuranosides.4ꢀ6 It is significant that
the 2-OH alcohols 9 and 15 were glycosylated (entries 1 and
2) in excellent yields (88ꢀ90%) and β/R ratios (20:1ꢀ25:1),
affording the biologically relevant β-D-Araf-(1f2)-R-D-Araf
disaccharides 14a,b, which correspond to the nonreducing
terminal structure of mycobacterial AG and LAM. Fur-
thermore, the high level of yields and selectivities achieved in
the couplings of alcohols 19 and 22 was also remarkable
(entries 7 and 10). These results clearly demonostrated the
high reactivity of 3d even with very unreactive acceptors.13
To extend this methodology to the stereoselective synthe-
sis of β-L-arabinofuranoside, we further investigated the
Org. Lett., Vol. XX, No. XX, XXXX
C

glycosylation of L-3d (see Supporting Information) with
different carbohydrate acceptors. It was found that D- and
L-Araf donors may exhibit different glycosylation be-
havior. For example, Boons et al. disclosed that the 3,5-
O-DTBS protectedL-thioarabinofuranosidegaveexcellent
β-stereocontrol in a variety of glycosylations.5a But the
analogous 3,5-O-DTBS protected D-thioarabinofurano-
side was proven by the Ito group to give lower β-selectivity
under the same activation conditions (NIS/AgOTf).5b The
origin of this difference is unclear at present.
Scheme 3. Synthesis of a Protected Octasaccharide Motif in
LAM
In this work, L-3d was verified to have similar reaction
properties as that of its enantiomer D-3d by a number
of glycosylations with glycosyl acceptors having either
primary or secondary hydroxyl groups (Table 2,
entries 11ꢀ15). Each coupling reaction was high yield-
ing (70ꢀ95%) and β-selective (β/R 10:1 to β only). Of
particular note are the high and complete β-selectivities
observed in 3- and 6-O-L-arabinofuranosylations of
the galactosyl acceptors 23 and 20 (entries 14 and 15,
respectively) as the obtained 1,3- and 1,6-β-linked
L-Araf-D-Galp disaccharides 14n,o represent the char-
acteristic substructures of plant arabinogalactans.
Utilizing the developed stereoselective arabinosylation
approach, we targeted the preparation of an octasacchar-
ide capping motif14 of mycobacterial LAM (24, Scheme 3).
Oligosaccharide 24 presents a particular synthetic chal-
lenge for it contains two 1,2-cis arabinofuranosidic bonds.
The synthesis began with disaccharide diol 256c and phenyl
thioglycoside 26.9 Treatment of both compounds with
Although there have been several syntheses of mannose-
capped LAM glycans,17 the efficient installation of the
internal β-Araf residue was rare.6a,b,17c,17d Our methodol-
ogy offers a practical access to such molecules since it not
only permits the introduction of the β-Araf linkage with
high selectivity but also facilitates further modification at
the 5-position.
In conclusion, a simple and versatile methodology to-
ward 1,2-cis selective D- and L-arabinofuranosylations
using 5-O-Quin equipped thioarabinosides D- and L-3d as
the donors has been uncovered. The approach was applied
successfully to the synthesis of a protected nonreducing
terminal octasaccharide derivative of the mycobacterial
cell wall.
NIS/TfOH yielded R-arabinofuranosyl tetrasaccharide
6c
ꢁ
27 in 85% yield. Subsequent debenzoylation via Zemplen
transesterification (NaOMe, MeOH) afforded 286c in 86%
yield. The key double coupling of 28 with 3 equiv of 3d
was run according to the aforementioned conditions to
give cleanly the bis-β-arabinosylated hexasaccharide 29 in
good yield. Otherpossiblestereoisomerswere notdetected.
Then, the Quin group was easily removed by means of
Acknowledgment. Financial support from the NSFC
(21172156, 21021001), the 973 program (2010CB833202),
and the Ministry of Education (NCET-08-0377,
20100181110082) is highly appreciated.
ꢁ
Zemplen reaction to liberate the 5-OHs of two β-Araf
moieties, delivering an 84% yield of 30. At last, coupling
between 30 and mannosyl donor 3115 at ꢀ78 °C for 1 h
produced the desired protected octasaccharide 24 in 91%
yield. The R-configuration of the newly formed manno-
pyranosides was confirmed by a combination of the
1JC1,H1 coupling constant and the chemical shift of the
anomeric carbon for these units.16
Supporting Information Available. Experimental de-
tails and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) A similar glycosylation between a 4-OH galactosyl acceptor and
a 2,3-O-xylylene-protected thioglycoside was reported by the Lowary
group. The reaction gave a quantitative yield but no selectivity; see ref 5f.
(14) Briken, V.; Porcelli, S. A.; Besra, G. S.; Kremer, L. Mol.
Microbiol. 2004, 53, 391.
ꢁ
(17) (a) Fraser-Reid, B.; Lu, J.; Jayaprakash, K. N.; Lopez, J. C.
ꢁ
ꢁ
Tetrahedron: Asymmetry 2006, 17, 2449. (b) Desire, J.; Prandi, J.
Carbohydr. Res. 1999, 317, 110. (c) Subramaniam, V.; Lowary, T. L.
Tetrahedron 1999, 55, 5965. (d) Cao, B.; Williams, S. J. Nat. Prod. Rep.
2010, 27, 919 and references cited therein.
(15) Brimble, M. A.; Kowalczyk, R.; Muir, V. J. Org. Biomol. Chem.
2008, 6, 112.
(16) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX