Facile synthesis of β- And α-arabinofuranosides and application to cell wall motifs of M. tuberculosis

Article abstract of DOI:10.1021/ol400931p

Propargyl 1,2-orthoesters of arabinose are exploited for the synthesis of 1,2-trans furanosides; easily accessible 1,2-trans ribofuranosides are converted to challenging 1,2-cis-arabinofuranosides by oxidoreduction. Utility of these protocols was demonstrated by the successful synthesis of major structural motifs present in the cell surface of Mycobacterium tuberculosis. Key furanosylations were carried out under gold-catalyzed glycosidation conditions.

Full text of DOI:10.1021/ol400931p

ORGANIC
LETTERS
2013
Vol. 15, No. 10
2466–2469
Facile Synthesis of β- and
r‑Arabinofuranosides and Application
to Cell Wall Motifs of M. tuberculosis
Shivaji A. Thadke, Bijoyananda Mishra, and Srinivas Hotha*
Department of Chemistry, Indian Institute of Science Education and Research,
Pune 411 008, India
s.hotha@iiserpune.ac.in
Received April 4, 2013
ABSTRACT
Propargyl 1,2-orthoesters of arabinose are exploited for the synthesis of 1,2-trans furanosides; easily accessible 1,2-trans ribofuranosides are
converted to challenging 1,2-cis-arabinofuranosides by oxidoreduction. Utility of these protocols was demonstrated by the successful synthesis
of major structural motifs present in the cell surface of Mycobacterium tuberculosis. Key furanosylations were carried out under gold-catalyzed
glycosidation conditions.
Tuberculosis (TB) has plagued mankind for centuries
and still continues to kill more than two million lives every
year globally.1,2 Mycobacterium tuberculosis (Mtb) is the
etiological agent, and pioneering efforts from the Brennan
group highlighted two major carbohydrate epitopes viz.
lipoarabinomannan (LAM) and arabinogalactan (AG) in
the cell surface of Mtb.3 Both LAM and AG have an
oligoarabinofuranoside which is highly characteristic to
the Mtb cell wall. The xenobiotic nature of arabinofur-
anose is noteworthy since inhibitors of biosynthetic path-
ways for oligomerization of arabinofuranoses could offer
opportunities for the development of novel therapeutics.
Indeed, ethambutol, an antitubercular drug, has been
shown to arrest the biosynthesis of arabinan.4 Specificity
and the xenobiotic nature of arabinofuranosides coupled
with the challenge in synthesizing 1,2-trans (or R-) and
1,2-cis (or β-) arabinofuranosides has attracted many to
develop strategies.5,6 Motifs AÀC are the structural con-
stituents present in the arabinan part of Mtb (Figure 1);
arabinan is ligated to the oligomeric chain of galactofur-
anoses through a 1f5 trans linkage.3 Among the host of
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(4) (a) Lee, R. E.; Mikusova, K.; Brennan, P. J.; Besra, G. S. J. Am.
Chem. Soc. 1995, 117, 11829–11831. (b) Alderwick, L. J.; Birch, H. L.;
Mishra, A. K.; Eggeling, L.; Besra, G. S. Biochem. Soc. Trans. 2007, 35,
1325–1328.
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1934. (b) Mereyala, H. B.; Hotha, S.; Gurjar, M. K. Chem. Commun.
1998, 685–686. (c) D’Souza, F. W.; Lowary, T. L. Org. Lett. 2000, 2,
1493–1495. (d) Yin, H.; D’Souza, F. W.; Lowary, T. L. J. Org. Chem.
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Fraino, B.; Lowary, T. L. J. Am. Chem. Soc. 2003, 125, 4155–4165. (f)
Jayaprakash, K. N.; Lu, J.; Fraser-Reid, B. Angew. Chem., Int. Ed. 2005,
44, 5894–5898. (g) Callam, C. S.; Gadikota, R. R.; Krien, D. M.;
Lowary, T. L. J. Am. Chem. Soc. 2003, 125, 13112–13119. (h) Desire,
J.; Prandi, J. Carbohydr. Res. 1999, 317, 110–118. (i) Lee, Y. J.; Lee, K.;
Jung, E. H.; Jeon, H. B.; Kim, K. S. Org. Lett. 2005, 7, 3263–3266. (j)
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(1) (a) Ginsberg, A. M.; Spigelman, M. Nat. Med 2007, 13, 290–294.
(b) Zhang, Y. Annu. Rev. Pharmacol. Toxicol. 2005, 45, 529–564.
(2) (a) Gandhi, N. R.; Moll, A.; Sturm, A. W.; Pawinski, R.;
Govender, T.; Lalloo, U.; Zeller, K.; Andrews, J.; Friedland, G. Lancet
2006, 368, 1575–1580. (b) Samandari, T.; Agizew, T. B.; Nyirenda, S.;
Tedla, Z.; Sibanda, T.; Shang, N.; Mosimaneotsile, B.; Motsamai, O. I.;
Bozeman, L.; Davis, M. K.; Talbot, E. A.; Moeti, T. L.; Moffat, H. J.;
Kilmarx, P. H.; Castro, K. G.; Wells, C. D. Lancet 2011, 377, 1588–98.
(c) WHO Report. Global tuberculosis control-surveilance, planning,
financing; World Health Organization: Geneva, 2004. (d) Chiang, C.-Y.;
Yew, W. W. Int. J. Tuberc. Lung Dis. 2009, 13, 304–311.
(6) (a) Joe, M.; Bai, Y.; Nacario, R. C.; Lowary, T. L. J. Am. Chem.
Soc. 2007, 129, 9885–9901. (b) Ishiwata, A.; Ito, Y. J. Am. Chem. Soc.
2011, 133, 2275–2291. (c) Fraser-Reid, B.; Lu, J.; Jayaprakash, K. N.;
Lopez, J. C. Tetrahedron: Asymm. 2006, 17, 2449–2463. (d) Lu, J.;
Fraser-Reid, B. Chem. Commun. 2005, 862–864.
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H. R.; Brennan, P. J. Biochem. 1995, 34, 4257–4266. (b) Lee, A.; Wu,
S. W.; Scherman, M. S.; Torrelles, J. B.; Chatterjee, D.; McNeil, M. R.;
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r
10.1021/ol400931p
Published on Web 05/09/2013
2013 American Chemical Society

product in diminished yield, whereas HAuCl4 and AuBr3
showed the required 1,2-trans disaccharide in almost com-
parative yield to that of AuCl3; however, HAuCl4 is found
to be more hygroscopic, and thus, AuCl3 was chosen for
further reactions.8 Optimized reaction conditions were
then applied on variety of aglycons comprising aliphatic
(2b), aromatic (2c), steroidal (2d), amino acid (2e), and
carbohydratederived aglycons (2fÀj), and gratifyingly, the
corresponding 1,2-trans arabinofuranosides (3bÀj) were
obtained in high yields (Scheme 1).8
Identification of a practical procedure for 1,2-trans
arabinofuranosides prompted us to look at the utility of
our gold catalysis repertoire to 1,2-cis furanosides which
are renowned for their synthetic difficulty. For a long time,
biochemists thought that β-arabinofuranosides are obtained
from β-ribofuranosides by epimerization at the C-2 position.9
Figure 1. Mtb cell wall motifs AÀC and the strategy.
glycosyl donors,5a thio-,5bÀe n-pentenyl,5a,f trichloroacet-
amidates,5g,6 1,2,5-orthoester,5h and n-pentenyl orthoesters6d
are investigated for the synthesis of arabinofuranosides.
Recent independent synthetic efforts from the Lowary6a
and Ito6b groups culminated in the synthesis of docosaar-
abinofuranoside (22-mer) with 4 1,2-cis and 18 1,2-trans
glycosidic linkages. An octadodecamer fragment of LAM
in the protected form has been synthesized by Fraser-
Reid’s group.6c,d However, among the two linkages, stereo-
selective synthesis of 1,2-cis furanosides isstill a formidable
task and notoriously difficult.
Scheme 1. Propargyl 1,2-Orthoesters for R-Arabinofuranosides
From our laboratory, a gold-catalyzed transglycosida-
tion by the activation of propargyl (or methyl) glycosides
was identified;7aÀc subsequently, propargyl 1,2-ortho-
esters were observed to give 1,2-trans glycopyranosides at
room temperature.7d,e Gold-catalyzed glycosidation was
tested on many substrates and noticed to facilitate synthe-
sis of biomimitics and glycopolypeptides in an advanta-
geous manner.7 Thus, 1,2-trans arabinofuranosides can
also be envisaged in a facile manner through a propargyl
1,2-orthoester strategy (Figure 1).
Accordingly, the propargyl 1,2-orthoester of arabino-
furanose 1a was synthesized8 and subjected to standard
gold-catalyzed glycosidation conditions7c (AuCl3/4 A MS
˚
powder/CH2Cl2/25 °C) with model aglycon 2a to observe
1,2-trans furanoside 3a, orthoester 4, and the propargyl
arabinofuranoside (5) in 1 h (Scheme 1).8 Interestingly,
orthoester 4 got converted into the required furanoside 3a
in 2 h. Further studies with other alkyne activators (RuCl3,
PdCl2) and Lewis acids (AgOTf, TMSOTf) illustrated the
importance of AuCl3 since RuCl3 and PdCl2 failed to
activate the orthoester (Table S1, Supporting Information).
Addition of Et3N arrested the furanosylation indicating in
situ generation of Brønsted acid. Propargyl glycoside5 was
the only identified product when the reaction was carried
out in anhydrous CH2Cl2.HCl which indicated
that Brønsted acid alone is not sufficient.8 AuCl gave the
In addition, chemistry of pyranosides10a,b has a long
precedence of oxidoreduction strategy for the conversion
of 1,2-trans to 1,2-cis pyranosides; however, a parallel
approach in furanosides is rare except for a report of
oxidoreduction strategy on a more substituted L-arabino-
furanosyl system by de Oliviera et al.10c The biochemical
approach of Mtb and many examples in pyranosides is
sufficiently enticing to investigate the chemical conversion
(9) (a) Manina, G.; Pasca, M. R.; Buroni, S.; De Rossi, E.; Riccardi,
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G. Curr. Med. Chem. 2010, 17, 3099–3108. (b) Trefzer, C.; Skovierova,
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H.; Buroni, S.; Bobovska, A.; Nenci, S.; Molteni, E.; Pojer, F.; Pasca,
(7) (a) Hotha, S.; Kashyap, S. J. Am. Chem. Soc. 2006, 128, 9620–
9621. (b) Vidadala, S. R.; Hotha, S. Chem. Commun. 2011, 47, 9906–
9908. (c) Vidadala, S. R.; Gayatri, G.; Sastry, G. N.; Hotha, S. Chem.
Commun. 2011, 47, 9906–9908. (d) Hotha, S.; Sureshkumar, G. Tetra-
hedron Lett. 2007, 48, 6564–6568. (e) Sureshkumar, G.; Hotha, S. Chem.
Commun. 2008, 4282–4284. (f) Vidadala, S. R.; Thadke, S. A.; Hotha, S.
J. Org. Chem. 2009, 74, 9233–9236. (g) Pimpalpalle, T. M.; Vidadala,
S. R.; Hotha, S.; Linker, T. Chem. Commun. 2011, 47, 10434–10436. (h)
Pati, D.; Shaikh, A. Y.; Das, S.; Nareddy, P. K.; Swamy, M. J.; Hotha,
S.; Gupta, S. S. Biomacromolecules 2012, 13, 1287–1295.
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M. R.; Makarov, V.; Cole, S. T.; Riccardi, G.; Mikusova, K.; Johnsson,
K. J. Am. Chem. Soc. 2012, 134, 912–915. (c) Batt, S. M.; Jabeen, T.;
Bhowruth, V.; Quill, L.; Lund, P. A.; Eggeling, L.; Alderwick, L. J.;
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Futterer, K.; Besra, G. S. Proc. Nat. Acad. Sci. U.S.A. 2012, 109, 11354–
11359.
(10) (a) Boren, H. B.; Ekborg, G.; Eklind, K.; Garegg, P. J.; Pilotti,
A.; Swahn, C. G. Acta Chem. Scand. 1973, 27, 2639–2644. (b) Ekborg,
G.; Lindberg, B.; LØnngren, J. Acta Chem. Scand. 1972, 26, 3287–3292.
(c) de Oliveira, M. T.; Hughes, D. L.; Nepogodiev, S. A.; Field, R. A.
Carbohydr. Res. 2008, 343, 211–220.
(8) See the Supporting Information.
Org. Lett., Vol. 15, No. 10, 2013
2467

Scheme 2. Conversion of β-Ribofuranosides to β-Arabinofuranosides
Figure 2. Representative UPLC trace for the conversion of
β-Ribf substrate 7c to β-Araf product 9c.
those of 9c were found at δ 98.0, 102.4 ppm in the 13C
1
NMR spectrum (Scheme 2).11 In addition, JCÀH values
further confirmed as anomeric linkages of 7c were observed
1
at 171, 176 Hz whereas JCÀH values of both 1,2-cis
linkages of 9c were noticed at 174 and 183 Hz.8
Identification of facile protocols for 1,2-cis and 1,2-trans
arabinofuranosides inspired to synthesize major arabinan
structural motifs A-C of Mtb. n-Pentenyl group was
selectedatthereducingend amongmany otherpossibilities
since propargyl orthoesters can be orthogonally activated
in the presence of aglycons containing n-pentenyl moiety.7e
In addition, n-pentenyl group serves as a protecting group
at the anomeric postion and acts as a leaving group when
required.
of 1,2-trans (or β-) ribofuranosides to 1,2-cis (or β-)
arabinofuranosides. β-Ribofuranosides shall be easily ac-
cessed by the above delineated propargyl 1,2-orthoester
strategy. To evaluate, a suitably protected propargyl 1,2-
orthoester of ribofuranose was required. Accordingly,
ribofuranosyl donor 1b was synthesized from D-ribose
and subjected to the aforementioned gold catalyzed gly-
cosidation with a panel of aglycons (2b,d,f,kÀm) to obtain
corresponding β-ribofuranosides (6aÀf) in very good yields
(Scheme 2).8 Subsequently, all ribofuranosides 6aÀf in
Accordingly, n-pentenyl glycoside (3b) was saponified
ꢁ
under Zemplen conditions and the primary hydroxyl
ꢁ
parallel were saponified under Zemplen conditions (NaOMe,
group was protected as silyl ether using TBDPSCl to
obtain compound 10. Per-O-benzylation with NaH/BnBr
in DMF followed by deprotection of a silyl group using
TBAF in THF gave the required aglycon 11 in good yield.
The key 1,2-trans arabinofuranosylation with propargyl
MeOH) to 7aÀf and oxidized with DessÀMartin period-
inane in CH2Cl2 at 25 °C to the respective 2-ribulofura-
noses (8aÀf) in greater than 90% yields. Crude residues
of 2-ribulofuranoses 8aÀf were subsequently subjected to
NaBH4 reduction in CH3OH to observe complete conver-
sion to 1,2-cis-arabinofuranosides 9aÀf (Scheme 2).8
Conversion of β-ribofuranoside to β-arabinofuranoside
was monitored by UPLCÀMS using a model β-ribofur-
anoside7c. Initially, standards ofβ-ribf (7c) and β-araf (9c)
were injected to find two well-separated peaks at tR 8.48
min for β-ribf and tR 9.93 min for β-araf (Figure 2).
Crude residue of oxidation reaction was noticed to contain
hydrated gem-diol (tR = 6.30 min) in addition to the
required ketone (tR = 17.45 min) and the remaining
starting material (8%).
˚
1,2-orthoester 1a under AuCl3/4 A MS powder/CH2Cl2/
25 °C for 2 h gave the disaccharide 12, which is also the
protected form of motif C present in the Mtb cell wall.
Conversion of disaccharide 12 to tetrasaccharide demands
free hydroxyl groups at the C-3 and C-5 postions on the
nonreducing furanoside. Accordingly, disaccharide 12 was
converted to aglycon 13 in three steps. Protection of C-3,
C-5 hydroxyl groups with Cl(i-Pr)2SiOSi(i-Pr)2Cl in pyr-
idine and conversion of C-2 OH to benzyl ether under
standard conditions afforded a fully protected disacchar-
ide which was further subjected to desilylation reaction
with TBAF to obtain the aglycon 13 in good yields. In
parallel, glycosyl donor 1c was synthesized from pro-
pargyl 1,2-orthoester 1a by saponification and benzylation
(Scheme 3). Gold-catalyzed furanosylation between agly-
con 13 and 2 equiv of propargyl 1,2-orthoester 1c as
furanosyl donor resulted in the isolation of a fully protected
tetrasaccharide (which is a fully protected form of motif B)
that was converted to diol 14 using NaOMe in MeOH.
Fortunately, NaBH4 reduction gave an 8:92 ratio of
7c:9c which clearly showed that the reduction took place in
a diastereoselective manner. Conversion of ribofuranose
to arabinofuranose was confirmed as anomeric carbons of
disaccharides 7c were noticed at δ 97.9, 107.8 ppm whereas
(11) (a) Mizutani, K.; Kasai, R.; Nakamura, M.; Tanaka, O. Carbo-
hydr. Res. 1989, 185, 27–38. (b) Imamura, A.; Lowary, T. Trends
Glycosci. Glycotech. 2011, 23, 134–152.
2468
Org. Lett., Vol. 15, No. 10, 2013

Scheme 3. Synthesis of Arabinan Motifs of M. tuberculosis
The next challenge was to convert the tetrasaccharide 14
to the hexaarabinofuranosyl motif A for which the above
identified chemical method for β-arabinofuranosylation
can be employed. Thus, the gold-catalyzed furanosyla-
tion between aglycon 14 and 2 molar equiv ribofura-
nosyl donor 1b was carried out to obtain the hexa-
furanoside in 62% yield. Subsequent saponification
around 173À177 Hz, and that of the other two 1,2-cis
linkages were found around 183 Hz of hexasaccharide 16,
1
whereas all JCÀH values of compound 15 were noticed
between 173 and 176 Hz only (Scheme 3).8
Inconclusion, propargyl 1,2-orthesterswereexploitedto
synthesize 1,2-trans and 1,2-cis furanosides in a stereose-
lective fashion. Utility of thus-identified arabinofuranosy-
lation protocols was demonstrated by the successful
synthesis of major structural motifs present in the cell wall
of Mycobacterium tuberculosis. Essentially, key furanosy-
lations for1,2-trans and 1,2-cis glycosides wereachieved by
exploiting salient features of gold catalysis and propargyl
1,2-orthoesters.
ꢁ
under Zemplen conditions resulted in aglycon 15 that
was oxidized with DessÀMartin periodinane to give
the 2-ulose derivative. NaBH4-mediated stereoselective
reduction of the 2-ulose derivative gave the hexaarabi-
nofuranoside 16 with two 1,2-cis and four 1,2-trans
linkages (Scheme 3).
Conversion of ribofuranose-containing hexasaccharide
to hexasaccharide with all arabinofuranosyl residues is
confirmed by its anomeric 13C NMR spectral signatures.
The six anomeric carbons of compound 15 are observed as
a single set between δ 105.6À107.5 ppm, whereas those
carbons were noticed as two sets in the hexaarabonofur-
ansyl compound 16. The two carbons linked in 1,2-cis
fashion are identified at δ 101.7 and 102.0 ppm, and the
remaining four 1,2-trans anomeric carbons were observed
between δ 105.5 and 106.7 ppm (Scheme 3).11 Further-
more, 1JCÀH values for four 1,2-trans linkages were noticed
Acknowledgment. S.H. thanks the DST, New Delhi, for
a SwarnaJayanthi Fellowship, and S.A.T. thanks CSIR
and B.M. thanks UGC for financial support.
Supporting Information Available. Experimental pro-
cedures, spectroscopic data, and spectral charts. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 10, 2013
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