A comprehensive glycosylation system for the elaboration of oligoarabinofuranosides

Article abstract of DOI:10.1016/S0040-4039(00)01273-9

1,2,5-Orthoesters of D-arabinose are key compounds for the construction of a glycosylation system that allows the stereoselective synthesis of any interglycosidic linkage between arabinofuranosidic units. Application to the synthesis of a pentaarabinofuranoside of the mycobacterial cell wall is also described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01273-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7447–7452
A comprehensive glycosylation system for the elaboration of
oligoarabinofuranosides
Sylvie Sanchez,a Toufiq Bamhaoudb and Jacques Prandia,*
aInstitut de Pharmacologie et de Biologie Structurale du CNRS, 205 route de Narbonne,
F-31077 Toulouse Cedex, France
bLaboratoire de Chimie Organique et Bioorganique, Universite´ Chouaib Doukkali, BP 20 El Jadida, Morocco
Received 15 June 2000; accepted 24 July 2000
Abstract
1,2,5-Orthoesters of D-arabinose are key compounds for the construction of a glycosylation system that
allows the stereoselective synthesis of any interglycosidic linkage between arabinofuranosidic units.
Application to the synthesis of a pentaarabinofuranoside of the mycobacterial cell wall is also described.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: glycosylation; arabinofuranoside; mycobacterium.
1. Introduction
Mycobacteria form a class of microorganisms where two major pathogens are found,
Mycobacterium leprae, the etiologic agent of leprosy and Mycobacterium tuberculosis, responsi-
ble for human tuberculosis. They make intensive use of
cell wall where it is found as homopolymers in the furanoside form with a-(1“5), a-(1“3) and
b-(1“2) linkages.1 As
-arabinose is not used by the human host, the biosynthetic pathway of
D
-arabinose for the construction of their
D
mycobacterial arabinans is a potential target for the development of new therapeutic agents
against tuberculosis and other mycobacterial infections.2 For this, small synthetic oligoarabino-
furanosides are powerful tools for the search and characterization of enzymatic activities and
their synthesis has prompted renewed interest in arabinofuranoside chemistry.3,4 Pursuing our
work on the construction of arabinofuranosides,5,6 we now present our preliminary results on a
comprehensive glycosylation system which allows the efficient elaboration of any possible
glycosidic linkage between arabinofuranosidic units.
* Corresponding author. Tel: +33 (0)5 61 17 54 85; fax: +33 (0)5 61 17 59 94; e-mail: prandi@ipbs.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01273-9

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2. Preparation of arabinofuranosidic donors and acceptors
In order to shorten the lengthy protection/deprotection sequences usually associated with
oligosaccharide synthesis, we looked for a common synthetic intermediate which could be easily
transformed into donors and acceptors. As the group on the carbon 2 of the donor controls the
stereoselectivity of the glycosylation reaction (see Fig. 1), this position had to be differentiated
from the others for the introduction of a participating group (a-donors) or of a p-methoxylbenzyl
group (b-donors).7 We also needed fast and regioselective access to partially protected acceptors.
Figure 1. Schematic representation of the formation of a diarabinofuranoside
1,2,5-Benzylidene
D
-arabinose (1),8 its 3-O-benzyl ether 26 and 3-O-benzyl-1,2,5-dichloroethyli-
dene
D
-arabinose (3)9,6 were submitted to acid-catalyzed ring opening with oxy-, thio- and
seleno-nucleophiles to obtain the corresponding a-glycosides 4–12 in good yields (see Fig. 2).
Figure 2. Compounds 1–12
Some representative results are summarized in Table 1.
For ring opening with alcohols, a fivefold excess of reagent had to be used to avoid
oligomerization of the orthoester,10 whereas for the other nucleophiles, only a slight excess (1.1–1.5
equiv.) of reagent was used. No significant influence of the Lewis acid was observed for the ring
opening of 2 provided that a strong acid was used (see Table 1). The use of HgBr2 as

7449
Table 1
Substratea
Nucleophile
Acid (equiv.)
Producta
Yieldb (%)
1
1
2
2
2
2
3
2
3
2
Octanol
SnCl4 (0.1)
SnCl4 (0.1)
SnCl4 (0.1)
BF3:OEt2 (0.15)
TMSOTf (0.1)
SnCl4 (0.1)
SnCl4 (2.0)
SnCl4 (0.1)
SnCl4 (0.2)
SnCl4 (0.1)
4
5
6
7
7
8
9
10
11
12
95
74
96
89
90
76
60
80
64
61
4-Pentenol
Methanol
Octanol
Octanol
HO(CH2)8C(O)OMe
HO(CH2)8C(O)OMe
EtSH
EtSH
PhSeH
a See Fig. 1 for structural formulas.
b Yields are for isolated, chromatographically homogeneous and analytically pure products.
promoter10 with compound 2 gave sluggish reactions and long reaction times. Opening of the
orthoester of the dichloroethylidene derivative 3 was found to be more difficult and gave lower
yields than for 1 and 2, but could be obtained with a higher amount of acid catalyst. The
successful opening of 2 with selenophenol gave access to selenoglycoside donors, which are
known to be selectively activated in the presence of thioglycosides.11 4-Pentenyl glycosides,
another type of donor,12 were also easily made from orthoester 2 and 4-pentenol.
Acceptors 13 and 14 were then obtained from 4 and 9 in 77 and 69% yields, respectively, by
selective protection of the primary position of the ring as a tert-butyldiphenylsilyl ether (Scheme
1). Monopivaloylation of 9 gave compound 156 in 80% yield.
Scheme 1. a: 1.4 equiv. TBDPSCl, imidazole, DMF, 0°C to rt, 1 h, 77%. b: 1.4 equiv. TBDPSCl, imidazole, DMF,
rt, 2 h, 69%. c: 1.5 equiv. tert-BuCOCl, 0.1 equiv. DMAP, pyridine, 0°C, 1.5 h, 80%. d: 1.5 equiv. TBDPSCl,
imidazole, DMF, rt, 1 h, 93%. e: 1.5 equiv. TBDPSCl, imidazole, DMF, rt, 3 h, 80%. f: 2.5 equiv. p-MeOPhCH2Br,
2.5 equiv. BEMP, 0°C to rt, acetonitrile, 2 h, 71%. g: 1.5 equiv. FMOC-Cl, pyridine, CH2Cl2, rt, 1 h, 82%. h: 1.3
equiv. tert-BuCOCl, DMAP, pyridine, 0°C to rt, 2.5 h, 65%. i: same as f, 67%

7450
Thioglycoside donors were also easily derived from the opening products of 2 and 3 with
ethanethiol. Silylation of 10 gave the a-donor 16 in 93% yield. Elaboration of donors from 11
is of particular interest: first, both a- and b-donors could be made in only two steps from 11,
and second, different a-directing groups could be introduced on 17 (or 20), which gave another
level of flexibility for the further elaboration of oligoarabinofuranosides. Monoprotection of the
primary position of 11 could be carried out with tert-butyldiphenylsilyl chloride (TBDPSCl) in
DMF to give 17 in 80% yield or with pivaloyl chloride in pyridine to give 20 in 65% yield.
Introduction of the p-methoxybenzyl group on 17 and 20 was effected as previously described5,6
with p-methoxybenzyl bromide and 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-
1,3,2-diazaphosphorine13 (BEMP) in acetonitrile and gave the b-donors 18 and 21 in 71 and 67%
yields, respectively. a-Donor 19 was obtained in 82% yield from the reaction of 17 with
9-fluorenylmethyl chloroformate (FMOC-Cl) and pyridine in CH2Cl2. It should be emphasized
that many of these compounds could be used as donors as well as acceptors depending on the
reaction conditions: for example, 5 is an acceptor on the 3 and 5 positions and an a-donor once
,
Scheme 2. a: 1.0 equiv. 13, 1.3 equiv. 16, 1.7 equiv. NIS, 0.1 equiv. TMSOTf, MS 4 A, CH2Cl2, 0°C, 1 h, 94%. b:
,
,
1.0 equiv. 18, 1.05 equiv. 7, 1.5 equiv. DDQ, MS 4 A, CH2Cl2, rt, 3 h, 53%; 1.2 equiv. IDCP, MS 4 A, CH2Cl2, rt,
,
1.5 h, then 5% DDQ in CH3CN/H2O 9/1, 79%. c: 1.0 equiv. 13, 1.2 equiv. 18, 1.5 equiv. DDQ, MS 4 A, CH2Cl2,
rt, 3.5 h; 1.3 equiv. IDCP, MS 4 A, CH2Cl2, 0°C to rt, 3 h, then 5% DDQ in CH3CN/H2O 9/1, 74% overall. d: 1.0
equiv. 4, 2.5 equiv. 19, 3.7 equiv. NIS, 0.25 equiv. TMSOTf, MS 4 A, CH2Cl2, 0°C to rt, 79%. e: Et3N/THF 1/4, rt,
9 h, 97%. f: 2.5 equiv. 18, 2.8 equiv. DDQ, MS 4 A, CH2Cl2, 0°C to rt, 75%; 2.7 equiv. IDCP, MS 4 A, CH2Cl2, rt,
22 h, then 1 equiv. DDQ in CH3CN/H2O 9/1, 23% (two steps). g: 6 equiv. NBu4F, THF, rt, 2 h; MeONa, MeOH,
rt, 18 h; H2, Pd/C, MeOH, rt, 2 h; 52% (three steps)
,
,
,
,

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these positions are protected (or glycosylated); thioglycosides 10, 11, 17 and 20 are donor
precursors, but may be used as acceptors versus selenoglycoside donors derived from 12.
3. Synthesis of oligoarabinofuranosides
With donors and acceptors in hand, the construction of oligoarabinosides was straightfor-
ward. a-Arabinofuranosides were obtained in good yield and complete stereocontrol14 from the
reaction of a-donors 16 or 19 with acceptors. For example, coupling of 16 with alcohol 13 under
N-iodosuccinimide/trimethylsilyl trifluoromethanesulfonate (NIS/TMSOTf) activation gave a-
disaccharide 22 in 94% yield (Scheme 2).
The formation of b-diarabinofuranosides was equally effective from the two-step reaction of
b-donor 18 with acceptors.7 The 1,5-linked b-diarabinofuranoside 23 was obtained from the
reaction of 18 with 7; and 24 was obtained stereochemically pure in 74% yield from the coupling
of 18 with 13. The 1,2-linked b-diarabinofuranoside has already been described from the
reaction of 15 with 18.6 Finally, the pentaarabinofuranoside 28, the terminal motif of the
mycobacterial arabinogalactan1 was assembled. Bis a-glycosylation of diol 4 with 2.5 equiv. of
donor 19 under NIS/TMSOTf activation gave in one step the trisaccharide 25 in 79% yield.
Selective deprotection of the FMOC groups with triethylamine in THF afforded diol 26
(quantitative yield), which was submitted to a bis-b-glycosylation7 with donor 18 to give the
pentaarabinofuranoside 27. Deprotection gave the desired compound 28 in only six steps from
the monosaccharidic building blocks.15
In conclusion, we have shown the synthetic potential of 1,2,5-orthoesters of
D-arabinose for
the preparation of various arabinofuranosidic building blocks which could be used for the
elaboration of complex oligoarabinofuranosides. Exploration of this system is currently being
actively pursued.
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