β-glycosides of 2,3-diazido-2,3-dideoxy-D-mannose, a synthetic precursor of a rare bacterial cell-wall building unit

Article abstract of DOI:10.1021/ol0058893

(Formula presented) 2,3-Diazido-2,3-dideoxy-β-D-mannopyranoside derivatives were synthesized in order to prepare β-glycosides of 2,3-diacetamido-2,3-dideoxy-D-mannuronic acid, a rare moiety of bacterial oligosaccharides. A direct glycosyl donor, 4,6-di-O-

Full text of DOI:10.1021/ol0058893

ORGANIC
LETTERS
2000
Vol. 2, No. 13
1839-1842
â-Glycosides of
2,3-Diazido-2,3-dideoxy-D-mannose, a
Synthetic Precursor of a Rare Bacterial
Cell-Wall Building Unit†
,‡,§,|
Zolta´n Szurmai,*
Daniel Charon‡
Ja´nos Ra´ko´,§ Ka´roly AÄ goston,§ Alain Danan,‡ and
Equipe “Endotoxines” du C.N.R.S. (U.R.A. 1116), UniVersite´ de Paris-Sud,
Centre d'Etudes Pharmaceutiques, 92296 Chaˆtenay-Malabry, France, and
Institute of Biochemistry, Faculty of Sciences, UniVersity of Debrecen, P.O. Box 55,
H-4010 Debrecen, Hungary
szurmaiz@tigris.klte.hu
Received April 4, 2000
ABSTRACT
2,3-Diazido-2,3-dideoxy-â-D-mannopyranoside derivatives were synthesized in order to prepare â-glycosides of 2,3-diacetamido-2,3-dideoxy-
D-mannuronic acid, a rare moiety of bacterial oligosaccharides. A direct glycosyl donor, 4,6-di-O-acetyl-2,3-diazido-2,3-dideoxy-r-D-mannopyranosyl
bromide, was prepared, and its synthetic capacity was tested in glycosylation reactions. An indirect route was also elaborated: 3-azido-3-
deoxy-â-D-glucopyranosides were converted into â-D-mannopyranosides. The cis vicinal diazido function successfully tolerated the conditions
of mild acidic hydrolysis, tritylation, Jones oxidation, TEMPO oxidation, acetolysis, and bromination with TiBr4.
2,3-Diacetamido-2,3-dideoxy-D-mannuronic acid is a con-
stituent of the cell-wall of microorganisms1,2 where it is
linked by a â-glycosidic bond to another monosaccharide
unit. To prepare bacterial oligosaccharides containing this
rare mannuronic unitsbearing in mind the difficulties
inherent in 1,2-cis glycosylationsswe investigated the
synthetic methods which would lead to a 2,3-diacetamido-
â-mannosidic linkage.
Despite the fact that many new highly effective glycosy-
lation methods have been elaborated over the past two
decades,3-6 â-mannosylation is still a challenge in carbohy-
drate chemistry.7,8 2-Acetamido-2-deoxy-â-mannosides as
natural compounds have been synthesized rather frequently,9-13
† Dedicated to Professor Andra´s Lipta´k on the occasion of his 65th
birthday.
‡ Universite´ de Paris-Sud.
§ University of Debrecen.
| Address correspondence to this author at the University of Debrecen.
Fax: (36)-52-512913.
(7) Kaji, E.; Lichtenthaler, F. W. Trends Glycosci. Glycotechnol. 1993,
5, 121-142.
(1) Caroff, M.; Lebbar, S.; Szabo´, L. XIVth International Carbohydrate
Symposium, Stockholm, Sweden, 1988; Abstract A 22.
(2) Knirel, Y. A.; Vinogradov, E. V.; Shashkov, A. S.; Dmitrijev, B.
A.; Kochetkov, N. K. Carbohydr. Res. 1982, 104, C4-C7.
(3) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155-173.
(4) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212-235.
(5) Sinay¨, P. Pure Appl. Chem. 1991, 63, 519-528.
(6) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531.
(8) Barresi, F.; Hindsgaul, O. Modern Methods in Carbohydrate Syn-
thesis; Khan, S. H., O′Neill, R. A., Eds.; Harwood Academic Publishers:
1996; pp 251-276.
(9) David, S.; Malleron, A.; Dini, C. Carbohydr. Res. 1989, 188, 193-
200.
(10) Paulsen, H.; Lorentzen, J. P. Carbohydr. Res. 1984, 133, C1-C4.
Paulsen, H.; Lorentzen, J. P. Carbohydr. Res. 1986, 150, 63-90.
10.1021/ol0058893 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/01/2000

but to our best knowledge, there is no method in the literature
for the preparation of â-linked 2,3-diacetamido-manno
derivatives. For this reason, we report the synthesis and the
synthetic capacity of 4,6-di-O-acetyl-2,3-diazido-2,3-dideoxy-
R-D-mannopyranosyl bromide, a halide capable of forming
1,2-cis glycosides. On the other hand, we show an indirect
route via 3-azido-3-deoxy-â-D-glucopyranosides, which have
been converted into the target compounds.
For the synthesis of 2,3-diacetamido-2,3-dideoxy-â-D-
mannopyranoside derivatives, mannosyl bromide 8 was
prepared as a “direct” glycosyl donor. The key compound
in the reaction sequence was methyl 2,3-diazido-4,6-O-
benzylidene-2,3-dideoxy-R-D-mannopyranoside (1) which
was synthesized from methyl R-D-glucopyranoside on a
relatively large scale according to the slightly modified
method of Guthrie and Murphy.14,15
7 with TiBr4 (2 equiv) in dry CH2Cl2 at room temperature
gave glycosyl donor 8. The potentiality of uronide 5 to lead
to uronyl donor was actively tested but without success;
therefore only bromide 8 was used as glycosyl donor. The
reaction of bromide 8 with methanol, 9-decen-1-ol, and
2-propanol in the presence of Ag-silicate in dry CH2Cl2
exclusively yielded â-anomers (9, 10, and 11), respectively.
The â-anomeric configurations were clearly demonstrated
by the [R]D values and the NMR data. In the 13C NMR
spectra, the JC-1,H-1 values were in the range of 157-158
Hz, respectively.
Surprisingly, when the HgBr2 promoter was used in dry
CH2Cl2, and either methanol or 2-propanol was present in
excess, the observed â:R ratios were 20:1 and 10:1 (by TLC),
respectively. The reaction of compound 8 with 2-propanol
in the presence of Hg(CN)2 still gave the â-mannoside (11)
as the main product. These experiments showed that the
coupling of bromide 8 with reactive aglycons yielded mainly
â-mannosides. If the promoters were effective enough and
the nucleophiles were present in extremely high quantities,
the reaction had an SN2 character producing 1,2-cis glycosidic
linkages. Decreasing the activity of the promoters [Ag-silicate
f HgBr2 f Hg(CN)2] the â:R selectivity also decreased
(Scheme 2).
Compound 1 was hydrolyzed, and the resulting methyl
2,3-diazido-2,3-dideoxy-R-D-mannopyranoside (2) was con-
ventionally acetylated into 3. Compound 1 was also con-
verted in three steps (via 2) into methyl (methyl 4-O-acetyl-
2,3-diazido-2,3-dideoxy-R-D-mannopyranosid)uronate (5) by
Jones oxidation of the corresponding 6-O-trityl derivative
1
(4).16 The structure of 5 was ascertained by its H NMR
spectrum in which the singlet of COOMe (3.77 ppm) and
the doublet of H-5 were clearly identified. With the aim of
obtaining a derivative of diamino mannuronic acid, which
could be a convenient acceptor for further glycosylation, the
diol (2) was selectively oxidized at the C-6 hydroxy group
with sodium hypochlorite and catalytic amounts of 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) under phase transfer
conditions.17 The free acid (6) was obtained crystalline with
an isolated yield of 73%. Upon esterification with methanol
and subsequent acetylation, it led to 5, identical with the
product obtained by Jones oxidation (Scheme 1).
Scheme 2a
Scheme 1a
a (a) Ac2O, H2SO4, 80%; (b) TiBr4, CH2Cl2, 90%; (c) Ag-silicate,
CH2Cl2, 76-82%; (d) HgBr2, CH2Cl2, 4 Å, 70-79%; (e) Hg(CN)2,
toluene/MeNO2, 33%.
The availability of bromide 8 was tested by its reaction
with 13,18 as a model compound, using different promoters.
a (a) 60% AcOH, 94%; (b) Py, Ac2O, 91%; (c) Py, TrCl; (d) Py,
Ac2O, 55% for two steps; (e) CrO3, H2SO4, CH2Cl2/acetone; (f)
Bu4NBr, MeI, CH2Cl2/H2O, 79% for two steps; (g) TEMPO,
NaOCl, 73%; (h) MeOH, H+, resin; (i) Py, Ac2O, 94% for two
steps.
(12) Classon, B.; Garegg, P. J.; Oscarson, S.; Tide´n, A.-K. Carbohydr.
Res. 1991, 216, 187-196.
(13) Kaji, E.; Lichtenthaler, F. W.; Osa, Y.; Takahashi, K.; Matsui, E.;
Zen, S. Chem. Lett. 1992, 707-710.
(14) Guthrie, R. D.; Murphy, D. J. Chem. Soc. 1965, 5288-5294 .
(15) Guthrie, R. D.; Murphy, D. J. Chem. Soc. 1965, 6956-6960.
(16) Steffan, W.; Vogel, C.; Kristen, H. Carbohydr. Res. 1990, 204, 109-
120.
(17) Davis, N. J.; Flitsch, S. L. J. Chem. Soc., Perkin Trans. 1 1994,
359-368.
(18) Chittenden, G. J. F.; Buchanan, J. G. Carbohydr. Res. 1969, 11,
379-385.
Acetolysis of the glycosidic methyl group in compound 3
afforded the corresponding 1-O-acetate (7). The reaction of
(11) Micheli, E.; Nicotra, F.; Panza, L.; Ronchetti, F.; Toma, L.
Carbohydr. Res. 1985, 139, C1-C3.
1840
Org. Lett., Vol. 2, No. 13, 2000

Ag-silicate or HgBr2 yielded a mixture of the corresponding
disaccharides (14 and 15), with opposite â:R selectivity (7:2
and 1:2). In the case of Ag-triflate, only the R-disaccharide
(15) was obtained in 80% yield. The configurations of the
interglycosidic linkages were determined by the [R]D values
and NMR data. The JC-1′,H-1′ values were 173 Hz for the
R-disaccharide (15) and 162 Hz for the â-one (14) (Scheme
3).
prepared from D-glucose in a five-step reaction sequence.
Acidic hydrolysis (f 16) followed by conventional acety-
lation (f 17) and then bromination with TiBr4 (2 equiv)
gave R-bromide 18, which was reacted with methanol and
unreactive glucose derivative 19 to give compounds 20 and
21, separately. The donor’s neighboring-group-active acyloxy
substituent on C-2 governed the stereospecific formation of
the â-D-glucosides. In the case of compound 19, the highly
effective silver triflate promoter assured that disaccharide
21 would be obtained in high yield. Deacylation (20 f 22
and 21 f 23) followed by isopropylidenation (22 f 24 and
23 f 25) yielded the key 2-OH compounds, suitable for
changing the configurations on C-2. Thus, compounds 24
and 25 were reacted with trifluoromethanesulfonic anhydride
and then converted into the diazido â-mannosides (24 f 26
f 28 and 25 f 27 f 29) in good yields (Scheme 5). All
Scheme 3a
Scheme 5a
a (a) Ag-silicate, CH2Cl2, â:R ) 7:2; (b) HgBr2, CH2Cl2, 4 Å
â:R ) 1:2; (c) AgOTf, CH2Cl2/toluene, 4 Å only R.
From the above results it is predictable that mannosyl
bromide 8 cannot be used as a glycosyl donor to undertake
the stereoselective synthesis of complex oligosaccharides.
However, it can be of great use in preparing the simple
glycosides of 2,3-diacetamido-2,3-dideoxy-D-mannuronic
acid.
To overcome the difficulties inherent in the “direct”
method, an “indirect” synthetic route was also elaborated
(Scheme 4). According to the literature, 3-azido-3-deoxy-
1,2:5,6-di-O-isopropylidene-R-D-glucofuranose (16)19 was
a (a) 2,2-Dimethoxypropane, pTsOH, 85-92%; (b) Py, Tf2O; (c)
NaN3, DMF, 78-84% for two steps.
compounds gave satisfactory microanalytical and/or spec-
troscopic data.20
(19) Brimacombe, J. S.; Bryan, J. G. H.; Husain, A.; Stacey, M.; Tolley,
M. S. Carbohydr. Res. 1967, 3, 318-324.
(20) Compound 3: mp 83 °C (from EtOH); [R]D +111.7° (c 0.80 CHCl3);
1H NMR (CDCl3) δ 4.77 (s, 1 H, H-1), 3.43 (s, 3 H, OMe); 13C NMR δ
98.1 (C-1, JC-1, H-1 172 Hz). Compound 5: mp 100-101 °C (EtOH); [R]D
+122.1° (c 0.63 CHCl3); 1H NMR (CDCl3) δ 4.88 (d, 1 H, J1,2 ) 2.9 Hz,
H-1), 4.24 (d, 1 H, J4, 5 8.3 Hz, H-5), 3.77 (s, 3 H, COOMe), 3.48 (s, 3 H,
OMe). Compound 7: [R]D +59.3° (c 0.77 CHCl3); 1H NMR (CDCl3) δ
6.10 (d, 0.62 H, J1,2 ) 1 Hz, H-1R), 5.80 (bs, 0.38 H, H-1â). Compound
8: 1H NMR (CDCl3) δ 6.42 (d, 1 H, J1,2 ) 1.4 Hz, H-1), 2.16 and 2.10
(2s, each 3 H, 2 OAc). Compound 9: mp 115-117 °C (from EtOH); [R]D
-67.2° (c 0.95 CHCl3); 1H NMR (CDCl3) δ 4.56 (s, 1 H, H-1), 3.51 (s, 3
H, OMe); 13C NMR δ 101.0 (C-1, JC-1,H-1 ) 158 Hz). Compound 10:
Scheme 4a
1
[R]D -63.5° (c 0.70 CHCl3); H NMR (CDCl3) δ 4.62 (s, 1 H, H-1); 13C
NMR δ 100.08 (C-1, JC-1,H-1 ) 158 Hz). Compound 11: [R]D -86.4° (c
0.57 CHCl3); 1H NMR (CDCl3) δ 4.71 (d, 1 H, J1,2 < 1 Hz, H-1); 13C
NMR δ 98.17 (C-1, JC1, H-1 ) 157 Hz). Compound 14: [R]D -11° (c 0.60
CHCl3); 1H NMR (CDCl3) δ 4.79 (bs, 1 H, H-1′), 4.59 (d, 1 H, J1,2 ) 7.8
Hz, H-1); 13C NMR δ 99.60 (C-1, JC-1,H-1 ) 161 Hz) and 99.15 (C-1′,
JC-1′,H-1′ ) 162 Hz). Compound 15: [R]D +106° (c 0.28 CHCl3); 1H NMR
(CDCl3) δ 4.98 (bs, 1 H, H-1′), 4.63 (d, 1 H, J1,2 ) 8.1 Hz, H-1); 13C
NMR δ 98.87 (C-1, JC-1,H-1 ) 61 Hz), 93.03 (C-1′, JC-1′,H-1′ ) 173 Hz).
Compound 18: 1H NMR (CDCl3) δ 6.63 (d, 1 H, J1,2 ) 3.9 Hz, H-1); 13
C
NRM δ 87.00 (C-1), 61.27 (C-3), 60.88 (C-6). Compound 20: [R]D -15.4°
(c 0.41 CHCl3); 1H NMR (CDCl3) δ 4.39 (d, 1 H, J1,2 ) 7.8 Hz, H-1), 3.50
(s, 3 H, OMe). Compound 21: [R]D -4.5° (c 0.24 CHCl3); 1H NMR
(CDCl3) δ 4.57 (d, 1 H, J1,2 ) 3.7 Hz, H-1), 4.38 (d, 1 H, J1′,2′ ) 8.1 Hz,
H-1′), 3.37 (s, 3 H, OMe); 13C NMR δ 100.25 (C-1′) 98.43 (C-1), 67.43
(C-6), 64.17 (C-3′), 61.70 (C-6′), 55.43 (OMe). Compound 24: [R]D -19.8°
(c 0.50 CHCl3); 1H NMR (CDCl3) δ 4.28 (d, 1 H, J1,2 ) 7.3 Hz, H-1), 3.56
a (a) Py, Ac2O, 94%; (b) TiBr4, CH2Cl2, 91%, %; (c) HgBr2,
CH2Cl2, 4 Å, 92%; (d) AgOTf, CH2Cl2/toluene, 4 Å, 88%; (e)
NaOMe, MeOH, 84-88%.
Org. Lett., Vol. 2, No. 13, 2000
1841

In summary, it is obvious that both synthetic routes have
their advantages and disadvantages. In the case of the direct
one, different â-glycosides can be prepared using the same
donor (8). Unfortunately, unreactive aglycons with high
stereoselectivity cannot be mannosylated in good yields.
From this point of view, the indirect9,11,12,21-26 route is more
useful; the gluco-donor’s (18) neighboring-group-active
substituent on C-2 allows the stereospecific construction of
the â-glycosidic linkages. The crucial step of this sequence,
namely changing the configuration of C-2, has been suc-
cessfully carried out by nucleophilic substitution reactions.
The only disadvantage is that the complete reaction sequence
has to be accomplished for every target compound. The
carboxylic function of the mannuronic moiety is introduced
at a later stage of the synthesis by the Pt-O2 system,10
TEMPO oxidation,17 or Jones oxidation, as was successfully
shown for the conversion of methyloside 2 into methyl
uronate 5.
Acknowledgment. The authors thank Dr. Ladislas Szabo´,
Dr. Patricia Szabo´, Dr. La´szlo´ Szila´gyi, and Mrs. Michelle
Mondange for their interest and help. Financial support from
the French Government and, in part, from the Hungarian
National Foundation (OTKA T015543) is gratefully
acknowledged.
(s, 3 H, OMe); 13C NRM δ 104.32 (C-1), 64.61 (C-3), 62.07 (C-6), 57.41
(OMe). Compound 25: [R]D +17.9° (c 0.18 CHCl3); 1H NMR (CDCl3) δ
4.53 (d, 1 H, J1,2 ) 3.7 Hz, H-1), 4.48 (d, 1 H, J1′,2′ ) 7.0 Hz, H-1′), 3.34
(s, 3 H, OMe); 13C NMR δ 103.67 (C-1′) 98.26 (C-1), 68.41 (C-6), 64.62
(C-3′), 61.94 (C-6′), 55.29 (OMe). Compound 28: [R]D -53.9° (c 0.20
OL0058893
(21) Bore´n, H. B.; Ekborg, G.; Eklind, K.; Garegg, P. J.; Pilotti, Å.;
Swahn, C. G. Acta Chem. Scand. 1973, 27, 2639-2644.
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A. Y.; Klimov, E. M.; Bayramova, N. E.; Torgov, V. I. Carbohydr. Res.
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(24) Liu, K. K.-C.; Danishefsky, S. J. J. Org. Chem. 1994, 59, 1892-
1894.
1
CHCl3); H NMR (CDCl3) δ 4.54 (d, 1 H, J1,2 ) 1.4 Hz, H-1), 3.57 (s, 3
H, OMe), 1.54 and 1.43 (2 s, each 3 H, 2Me); 13C NMR δ 101.55 (C-1,
JC-1,H-1 ) 159 Hz), 100.36 (Me-C-Me), 62.01 (C-6), 63.30 and 60.56 (C-
2,3), 57.31 (OMe), 28.91 and 18.98 (2Me). Compound 29: [R]D -18.6° (c
1
0.29 CHCl3); H NMR (CDCl3) δ 4.68 (d, 1 H, J1,2 ) 3.4 Hz, H-1), 4.53
(bs, 1 H, H-1′), 3.46 (s, 3 H, OMe), 1.53 and 1.47 (2s, each 3 H, 2Me); 13
C
NMR δ 100.61 (C-1′, JC-1′,H-1′ ) 160 Hz), 100.07 (Me-C-Me), 98.31 (C-
1, JC-1,H-1 ) 171 Hz), 68.02 (C-6), 61.82 (C-6′), 63.47 and 60.28 (C-
2′and C-3′), 55.39 (OMe), 28.91 and 18.95 (2Me).
(25) Alais, J.; David, S. Carbohydr. Res. 1990, 201, 69-77.
(26) Gu¨nther, W.; Kunz, H. Carbohydr. Res. 1992, 228, 217-241.
1842
Org. Lett., Vol. 2, No. 13, 2000