1,2,5-Ortho esters of D-arabinose as versatile arabinofuranosidic building blocks. Concise synthesis of the tetrasaccharidic cap of the lipoarabinomannan of Mycobacterium tuberculosis

Article abstract of DOI:10.1039/b000873g

1,2,5-ortho esters of D-arabinose were found to be ideally suited building blocks for the stereoselective formation of and β arabinofuranosidic linkages after nucleophilic opening of the orthoester with oxygen and sulfur nucleophiles; the tetrasaccharidic cap of the lipoarabinomannan of Mycobacterium tuberculosis was then synthesized in a highly convergent manner.

Full text of DOI:10.1039/b000873g

1,2,5-ortho esters of -arabinose as versatile arabinofuranosidic building
D
blocks. Concise synthesis of the tetrasaccharidic cap of the lipoarabinomannan
of Mycobacterium tuberculosis
Toufiq Bamhaoud,a Sylvie Sanchezb and Jacques Prandi*b
a Laboratoire de Chimie Organique et Bioorganique, Université Chouaib Doukkali, BP 20, El Jadida, Maroc
b Institut de Pharmacologie et de Biologie Structurale du CNRS, 205 route de Narbonne, 31077 Toulouse, France.
E-mail: prandi@ipbs.fr
Received (in Cambridge, UK) 1st February 2000, Accepted 7th March 2000
Published on the Web 31st March 2000
1,2,5-ortho esters of
D-arabinose were found to be ideally
suited building blocks for the stereoselective formation of a
and b arabinofuranosidic linkages after nucleophilic open-
ing of the orthoester with oxygen and sulfur nucleophiles;
the tetrasaccharidic cap of the lipoarabinomannan of
Mycobacterium tuberculosis was then synthesized in a highly
convergent manner.
Lipoarabinomannans (LAMs) are highly antigenic polysacchar-
idic compounds isolated from the cell wall of various species of
mycobacteria.1 They share common structural features, a
phosphatidyl myo-inositol anchor and a mannan core substi-
tuted by an arabinan domain, exclusively composed of
arabinofuranosidic units.1 At the ends of this arabinan domain,
are found b- -arabinofuranosides substituted on position 5 by
D-
D
small motifs, called caps, variable on the mycobacterial
species.2–5 Strong modulations of the biological properties of
the LAMs were observed for LAMs isolated from different
species of mycobacteria and these variations have been
tentatively correlated to the structure of these caps.2,4–8
In light of the importance of these motifs for the biological
properties of the LAMs in relation with the immunopathoge-
nicity of M. tuberculosis, we now report the expeditious
synthesis of 1 (Scheme 1) the major tetrasaccharide found at the
ends of the LAMs of M. tuberculosis and M. bovis BCG in a
form suitable for further conjugation with a protein.9 Orthoe-
sters 3 and 11 were found to be highly versatile precursors for
the elaboration of the two different arabinofuranosidic rings and
the construction of the crucial b-arabinofuranosidic linkage.
The result is a rapid and convergent synthesis of 1.
Scheme 1 Reagents and conditions: i, NaH, BnBr, DMF, room temp., 1 h,
82%; ii, 5 equiv. methyl 9-hydroxynonanoate, 0.1 equiv. SnCl4, MS 4
Å, CH2Cl2, room temp., 15 min, 76%; iii, 1.1 equiv. EtSH, 0.1 equiv. SnCl4,
MS 4 Å, CH2Cl2, 218 °C, 30 min, 80%; iv, 1.5 equiv. ButPh2SiCl, 1.5
equiv. imidazole, DMF, room temp., 1 h, 92%; v, 0.1 equiv. MeONa,
MeOH, room temp., 79%; vi, 2.5 equiv. BEMP, 2.5 equiv. p-MeOBnBr,
MeCN, 0 °C to room temp., 1 h, 70%. vii, NaH, BnBr, DMF, room temp.,
1 h, 90%; viii, 5 equiv. HOCH2(CH2)7C(O)OMe, 2 equiv. SnCl4, MS 4 Å,
CH2Cl2, room temp., 3 h, then MeONa, MeOH, room temp., 1 h, 60%; ix,
1.5 equiv. ButCOCl, 0.1 equiv. DMAP, pyridine, 0 °C, 1.5 h, 80%.
3-O-benzyl 1,2,5-benzylidene -arabinofuranose 3 was read-
D
ily obtained in 82% yield from the 1,2,5-benzylidene
D
-
arabinofuranose 2 {[a]D 228 (c 0.94, CHCl3) lit.10 +28 for
the enantiomer} after treatment with benzyl bromide and
sodium hydride in dimethylformamide (Scheme 1). SnCl4
catalyzed opening of orthoester 3 with 5 equiv. of methyl
25
proved to be more difficult than for 3. 2 Equiv. of SnCl4 at room
temperature were necessary to bring the reaction of 11 with
methyl 9-hydroxynonanoate to completion and a mixture of
2-O- and 5-O-dichloroacetyl a-arabinofuranosides was ob-
tained. a-Arabinofuranoside 12 was isolated in 60% yield after
deacylation with sodium methoxide. Selective pivaloylation of
the primary hydroxy group of 12 (0 °C, ButCOCl, DMAP,
pyridine) gave alcohol 13 ready for glycosylation (80%).
Opening of 11 with ethanethiol was also obtained with 1.2
equiv. of EtSH and 0.2 equiv. SnCl4 at 0 °C, deacylation of the
mixture of dichloroacetates as above gave 9 in 64% overall
yield from 11. Selective silylation of the primary position of 9
with TBDPSCl and imidazole afforded 73% of the previously
prepared 7. Finally, the 4-methoxybenzyl group was introduced
on the 2-position of 7 with 2.5 equiv. of 4-methoxybenzyl
bromide16 and 2.5 equiv. of 2-tert-butylimino-2-diethylamino-
1,3-dimethylperhydro-1,3,2-diazaphosphorine17 (BEMP) in
acetonitrile to give thioarabinofuranoside 8 in 70% yield.
Coupling of the arabinofuranosidic units and elaboration of
the b-arabinofuranosidic linkage were accomplished according
to Ogawa’s internal aglycon delivery approach.14,18 Reaction of
1.1 equiv. of 8 with 13 and 1.5 equiv. of 2,3-dichloro-
9-hydroxynonanoate9 in CH2Cl2 gave the 2-O-benzoyl-a-
-
D
arabinofuranoside 4 as the only isolated product in 76% yield.
Complete regio- and stereo-selectivity were observed for the
double orthoester opening11 and none of the isomeric 5-O-
benzoyl arabinofuranosidic compound was observed with this
catalyst. In an analogous manner, ethyl 2-O-benzoyl-3-O-
benzyl-1-thio-a- -arabinofuranoside 5 was obtained in 80%
D
yield from the opening of 3 with 1.1 equiv. of ethanethiol under
SnCl4 catalysis, once again with complete stereocontrol of the
orthoester opening.12,13 Unmasking of the hydroxy group on the
2-position of the arabinofuranosidic ring of thioglycoside 5 for
later attachment of the p-methoxybenzyl tether14 was carried
out in two steps and gave alcohol 7 in 73% overall yield
(Scheme 1).
We also looked at the reactions of 3-O-benzyl 1,2,5-di-
chloroethylidene
(BnBr, NaH, DMF) from known compound 10, prepared in only
two steps from
-arabinose.15 As was expected from electronic
D-arabinofuranose 11, available in 90% yield
D
factors, nucleophilic opening of the orthoester function of 11
DOI: 10.1039/b000873g
Chem. Commun., 2000, 659–660
This journal is © The Royal Society of Chemistry 2000
659

mixture on the H-1B anomeric center. This mixture could not be
separated at this stage, so the ester groups were removed with
0.5 M sodium methoxide solution in methanol (75%) and the
mixture of triols was chromatographed to give pure 23.
Hydrogenolysis of the benzyl groups [H2, Pd(OH)2/C, MeOH]
gave the target compound 127 in 65% yield.
In conclusion, orthoester derivatives of arabinose and
mannose were used for the efficient synthesis of 1, the
tetrasaccharidic cap of the lipoarabinomannan of M. tuberculo-
sis, via a convergent route using minimal protecting groups
manipulation and selective anomeric activation. Both a- and b-
arabinofuranosides were obtained with complete stereocontrol
from 3-O-benzyl-1,2,5-orthoesters of -arabinose. Extension of
D
this methodology to the elaboration of other complex poly-
arabinofuranosidic structures and synthesis of neoantigens from
1 for biological evaluation are currently under way.
Scheme 2 Reagents and conditions: i, 1.1 equiv. 8, 1 equiv. 13, 1.5 equiv.
DDQ, MS 4 Å, CH2Cl2, 0 °C to room temp., 2.5 h, 84%; ii, 1.2 equiv. IDCP,
MS 4 Å, CH2Cl2, room temp., 1.5 h, 73%; iii, Ac2O, pyridine, room temp.,
then 1.2 equiv. Bun4NF, THF, room temp., 0.5 h, 75%, 2 steps; iv, 1.5 equiv.
PhSeH, MS 4 Å, cat. HgBr2, MeCN, room temp., 2 h, 75% ; v, 5.5 equiv.
EtSH, MS 4 Å, cat. HgBr2, MeCN, room temp., 48 h, 79% ; vi, MeONa,
MeOH, room temp., 16 h, 91% ; vii, 1 equiv. 18, 1.1 equiv. 20, 1.1 equiv.
NIS, 0.1 equiv. TMSOTf, MS 4 Å, CH2Cl2, 218 °C to room temp.,
71%.
Notes and references
1 D. Chatterjee and K. H. Khoo, Glycobiology, 1998, 8, 113.
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3 D. Chatterjee, K. Lowell, B. Rivoire, M. R. McNeil and P. J. Brennan,
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139, 2649.
5 M. Gilleron, N. Himoudi, O. Adam, P. Constant, A. Venisse, M. Rivière
and G. Puzo, J. Biol. Chem., 1997, 272, 117.
6 A. Vercellone, J. Nigou and G. Puzo, Front. Biosci., 1998, 3, e149.
7 P. A. Sieling, D. Chatterjee, S. A. Porcelli, T. I. Prigozy, R. J.
Mazzaccaro, Y. Soriano, B. R. Bloom, M. B. Brenner, M. Kronenberg,
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9 R. U. Lemieux, D. R. Bundle and D. A. Baker, J. Am. Chem. Soc., 1975,
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10 N. K. Kochetkov, A. Y. Khorlin, A. F. Bochkov and I. G. Yazlovetskii,
Izv. Akad. Nauk. SSSR, Ser. Khim., 1966, 1966; A. F. Bochkov, Y. V.
Voznyi, V. N. Chernetskii, V. M. Dashunin and A. V. Rodionov, Izv.
Akad. Nauk. SSSR, Ser. Khim., 1975, 348.
11 N. K. Kochetkov, A. F. Bochkov and I. G. Yazlovetsky, Carbohydr.
Res., 1969, 9, 49.
12 Other catalysts gave mixtures of isomeric 2-O- and 5-O-benzoylated
arabinofuranosides. For a related orthoester opening, see ref. 13.
13 F. Nakatsuko, H. Kamitakahara and M. Hori, J. Am. Chem. Soc., 1996,
118, 1677.
14 Y. Ito and T. Ogawa, Angew. Chem., Int. Ed. Engl., 1994, 33, 1765; A.
Dan, Y. Ito and T. Ogawa, J. Org. Chem., 1995, 60, 4680.
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1994, 35, 9233.
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41; C. H. Gotfredsen, J. P. Jacobsen and J. Wengel, Tetrahedron Lett.,
1994, 35, 6941.
18 For other approaches to the synthesis of b-arabinofuranosides, see: H. B.
Mereyala, S. Hotha and M. K. Gurjar, Chem. Commun., 1998, 685; J.
Désiré and J. Prandi, Carbohydr. Res., 1999, 317, 110.
19 P. Smid, G. A. de Ruiter, G. A. Van der Marel, F. M. Rombouts and J. H.
Van Boom, J. Carbohydr. Chem., 1991, 10, 833.
5,6-dicyano-1,4-benzoquinone in CH2Cl2 gave the mixed acetal
14 in 84% isolated yield after chromatography (Scheme 2).
Intramolecular glycosylation was promoted with 1.2 equiv. of
iodonium dicollidine perchlorate (IDCP)19 in CH2Cl2 and gave
a rewarding 73% yield of the b-linked disaccharide 15 as the
only isolated product. The b-(d) configuration of the new
1
anomeric center was firmly established from the H and 13C
NMR data (dH-1A 5.15, JH-1A,H-2A 4.5 Hz; dC-1A 101.48).20
Acetylation (acetic anhydride, pyridine) and silyl ether depro-
tection with tetrabutylammonium fluoride in tetrahydrofuran
gave the diarabinofuranoside 16 ready for further elongation
(75% from 15).
The dimannosidic glycosyl donor 21 was efficiently obtained
from orthoester 1721 taking advantage of the higher reactivity of
selenoglycosides over thioglycosides towards activation.22,23
17 was first opened with 1.5 equiv. of selenophenol24 under
HgBr2 catalysis and gave (a-selenoglycoside 18 in 75% yield
(Scheme 2). The known thioglycoside 19,25 obtained in 79%
from 17 after HgBr2-promoted ethanethiol opening, was
deacetylated (MeONa, MeOH) to give glycosyl acceptor 20 in
91% yield. Selective activation of selenoglycoside 18 with 1.1
equiv. of N-iodosuccinimide (NIS) and 10% trimethylsilyl
trifluoromethanesulfonate (TMSOTf),26 and coupling with 1.1
equiv. of thioglycoside 20 in CH2Cl2 at 218 °C gave the
expected a-linked dimannosidic compound 21 in 71% yield
with complete control of the new anomeric center. 21 was
isolated in slightly lower yield (64%) when the original silver
trifluoromethanesulfonate/potassium carbonate combination22
was used as promoter for the glycosylation of 20 with 18.
Final coupling was done by glycosylation of disaccharide 16
with 1.5 equiv. of thiodisaccharide 21 under NIS/catalytic
TMSOTf activation (Scheme 3). A 70% yield of tetra-
saccharidic compounds 22 was obtained as a 4:1 a,b anomeric
20 K. Bock and C. Pedersen, Adv. Carbohydr. Chem. Biochem., 1983, 41,
27; R. C. Beier and B. P. Mundy, J. Carbohydr. Chem., 1984, 3, 253.
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24 W. H. H. Gunther, J. Org. Chem., 1966, 31, 1202.
25 T. Peters, Liebigs Ann. Chem., 1991, 135.
26 G. H. Veeneman, S. H. Van Leeuwen, H. Zuurmond and J. H. Van
Boom, J. Carbohydr. Chem., 1991, 9, 783.
25
27 Selected data for 1. [a]D +18 (c 0.44, water); 1H NMR (500 MHz,
Scheme 3 Reagents and conditions: i, 1 equiv. 16, 1.5 equiv. 21, 1.7 equiv.
NIS, 0.15 equiv. TMSOTf, MS 4 Å, CH2Cl2, 215 °C, 1 h, 70%; ii, 0.5 M
MeONa, MeOH, room temp., 5 h, 75%; iii, H2, Pd(OH)2/C, MeOH, room
temp., 1 h, 65%.
D2O, 293 K): d 5.16 (d, 1H, J 1.7 Hz, H-1B), 5.11 (d, 1H, J 4.5 Hz, H-1A),
5.10 (d, 1H, J 2 Hz, H-1), 5.02 (d, 1H, J 2 Hz, H-1BA). 13C NMR (125.72
MHz, D2O, 293 K) d 106.09 (C-1), 103.01 (C-1BA), 101.05 (C-1A), 98.86
(C-1B), 87.48 (C-2), 80.40 (C-2B), 76.67 (C-2A).
660
Chem. Commun., 2000, 659–660