First synthesis of methyl α-C-D-arabinofuranosyl-(1→5)-α-D-arabinofuranoside: The C-disaccharide segment of motif C of Mycobacterium tuberculosis

Article abstract of DOI:10.1016/S0040-4039(02)01760-4

The synthesis of C-analogue of the disaccharide 2 α-araf-(1→5)-araf, present in motif C of the arabino-galactan portion of Mycobacterium tuberculosis, has been described. The critical C-C bond formation reaction to couple both the furanosyl residues has b

Full text of DOI:10.1016/S0040-4039(02)01760-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7577–7579
First synthesis of methyl
a-C-
D
-arabinofuranosyl-(1“5)-a- -arabinofuranoside:
D
the C-disaccharide segment of motif C of
Mycobacterium tuberculosis
Mukund K. Gurjar,* Ravi Nagaprasad and C. V. Ramana
National Chemical Laboratory, Pune 411 008, India
Received 27 June 2002; revised 13 August 2002; accepted 22 August 2002
Abstract—The synthesis of C-analogue of the disaccharide 2 a-araf-(1“5)-araf, present in motif C of the arabino-galactan
portion of Mycobacterium tuberculosis, has been described. The critical CꢀC bond formation reaction to couple both the furanosyl
residues has been accomplished through nitro-aldol condensation. © 2002 Elsevier Science Ltd. All rights reserved.
The mycolic arabino-galactan (AG) complex present on
the cell wall surface of Mycobacterium tuberculosis has
unique structural features unknown in actinomycetes.1
The furanoside rings of AG complex are conformation-
ally more mobile (than pyranosides) and are largely
linked through primary hydroxyl groups.2 These char-
acteristics enable the crowded AG complex to adopt a
structure in which mycolic acids are closely arranged in
parallel arrays.3 The AG complex is critical for the
survival of M. tuberculosis. The hydrophobic AG com-
plex acts as a strong barrier for the passage of antibi-
otics into the cell and therefore, play an important role
in developing resistance of Mycobacteria to many
antibiotics.
extent resemble those of naturally occurring O-gly-
cosides. The C-glycosides serve as glycosyl regulators
and as synthetic ligands for probing cellular interac-
tions. To our knowledge, no attempts have yet been
made to synthesize C-analogues of any oligosaccharide
present in AG complex of M. tuberculosis. In continua-
tion of our interest in AG complex, we undertook the
first synthesis of a-C-
D
-araf-(1“5)-a-D-araf as a
methyl glycoside 2 which constitutes the C-analogue of
motif C oligosaccharide (Fig. 1).
The retrosynthetic scheme for 2 was based on the C–C
coupling reaction between two partners 4 and 5 via the
nitro-aldol condensation reaction (Scheme 1).
The drug ethambutol blocks the biosynthetic pathway
of arabinose.4 The inhibition of biosynthetic pathway,
involved in development of M. tuberculosis cells, is
considered as an attractive strategy for drug develop-
ment against M. tuberculosis. The oligosaccharides
present on various motifs of AG complex are struc-
turally elucidated and their synthesis from our group5
as well as from others6 have dominated the area in
recent years.
The synthesis of 4 was initiated from methyl 2,3-di-O-
benzyl-a-
-arabinofuranoside8 6 which was converted
D
into the 5-deoxy-5-iodo derivative 7. Replacement9 of
the iodine with a nitro group was accomplished with
NaNO2, phloroglucinol.monohydrate in DMSO
1
(Scheme 2). In the H NMR spectrum of 4, the distinc-
The C-linked glycosides7 of glycosyl compounds are
stable to both chemical and metabolic degradation. The
conformational features of C-glycosides to a large
* Corresponding author. Tel.: +91-20-5882456; fax: +91-5893614;
e-mail: gurjar@dalton.ncl.res.in
Figure 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01760-4

7578
M. K. Gurjar et al. / Tetrahedron Letters 43 (2002) 7577–7579
Scheme 1. Retrosynthetic analysis for the disaccharide 2.
Scheme 2. Reagents and conditions: (a) I2, imidazole, PPh3, C6H5CH3, D, 1.5 h (81%); (b) NaNO2, phoroglucinol.H2O, DMSO,
rt, 72 h (68%).
tive down-field shift of resonances due to methylene
protons at C-5 were observed. The 13C NMR spectrum
was consistent with the assigned structure.
The second component 5 was obtained from
cosamine-hydrochloride which was subjected to a dia-
zotization-mediated ring contraction reaction,
D-glu-
subsequent reduction and selective benzoylation to
afford the known10 dibenzoate derivative 8. The free
hydroxyl group of 8 was protected as benzyl ethers by
treatment with BnBr/Ag2O in CH2Cl2 followed by
debenzoylation with NaOMe in methanol to give the
dibenzyl derivative 10.
Scheme 3. Reagents and conditions: (a) BnBr, Ag2O, CH2Cl2,
rt, 10 h (86%); (b) NaOMe, MeOH, rt, 0.5 h (88%); (c) NaH
(1 equiv.), BnBr (1 equiv.), DMF, 0°C, 1.5 h (84%); (d)
(COCl)2, DMSO, CH2Cl2, −78°C, Et3N, 0.5 h (95%).
The selective protection of one of the hydroxymethyl
groups was performed with 1 equiv. of each NaH and
BnBr in DMF. Compound 10 being C2-symmetric,
afforded only one diastereomer 11. The free hydroxy-
methyl functionality in 11 was oxidized under Swern
conditions and the resulting aldehyde 5, being unstable,
was utilized for the next step without any delay
(Scheme 3).
The coupling reaction11 between 4 and 5 occurred in
the presence of catalytic KF in CH3CN to give a
diastereomeric mixture of 3 which was subjected to
three successive steps, i.e. dehydration, selective reduc-
tion of conjugated olefin and denitration with n-
Bu3SnH to give the penta-O-benzyl C-disaccharide 12.
Scheme 4. Reagents and conditions: (a) KF, 18-C-6, MeCN,
rt, 3.5 h (48%); (b) (i) Ac2O, Py., CHCl3, 12 h; (ii) NaBH4,
EtOH, CH2Cl2, rt, 2.5 h; (iii) Bu3SnH, AIBN, C6H5CH3, D, 1
h (44% in three steps); (c) Pd(OH)2, H2, rt, 1 atm, 24 h (74%).
The structure of 12 was fully scrutinized by spectro-
scopic and analytical examination.12 For example, the
1H NMR spectrum of 12 showed characteristic signals
due to two methylene groups, which serve as a linker
between two sugar moieties, between 2.57 (t) and 3.61
(m) ppm. The anomeric protons were located at l 3.77
(H-1%, dd) and l 4.89 (H-1, s). The 13C NMR spectrum
and elemental analysis of compound 12 were consistent
with the assigned structure. Finally hydrogenolysis of
12 in presence of Pd(OH)2 at normal temperature and
pressure gave the C-disaccharide 2 (Scheme 4), the
spectroscopic and elemental data for which was consis-
tent with the assigned structure.12
In summary, this report describes the first successful
synthesis of the C-oligosaccharide of motif C of M.
tuberculosis. The biological and structural implications
of this C-analogue will not be only interesting but
significant from a drug development point of view.

M. K. Gurjar et al. / Tetrahedron Letters 43 (2002) 7577–7579
7579
Acknowledgements
7. Dondoni, A.; Marra, A.; Mizuno, M.; Giovannini, P. P.
J. Org. Chem. 2002, 67, 4186–4199.
R.N. thanks CSIR for financial support in the form of
research fellowship.
8. (a) Glaudemans, C. P. I.; Fletcher, H. G., Jr. J. Am.
Chem. Soc. 1965, 87, 4636–4641; (b) Mikhailopulo, I. A.;
Sivets, G. G. Helv. Chim. Acta 1999, 82, 2052–2065; (c)
Yin, H.; Lowary, T. L. Tetrahedron Lett. 2001, 42, 5829–
5832.
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