Preparative route to glucuronyl donors bearing temporary protecting group at O-3 via 6,3-lactonisation by Bz2O or Piv2O

Article abstract of DOI:10.1016/S0008-6215(01)00272-5

Heating of non-substituted β-D-glucopyranuronic acids in the presence of pivalic or benzoic anhydride in DMF gives 4-O-monoacylated or 2,4-di-O-acylated 6,3-lactones that can be easily transformed into corresponding methyl uronates bearing free OH-groups at C-2 and C-3 or C-3 only, respectively. This method was used for preparation of selectively 3-O-protected glucuronyl donors of thioglycoside and trichloracetimidate types.

Full text of DOI:10.1016/S0008-6215(01)00272-5

Carbohydrate Research 336 (2001) 309–313
www.elsevier.com/locate/carres
Note
Preparative route to glucuronyl donors bearing
temporary protecting group at O-3 via 6,3-lactonisation
by Bz2O or Piv2Oꢀ
Andrei V. Kornilov, Elena V. Sukhova, Nikolay E. Nifantiev*
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, 119991 Moscow
B-334, Russia
Received 28 August 2001; accepted 18 October 2001
Abstract
Heating of non-substituted b-D-glucopyranuronic acids in the presence of pivalic or benzoic anhydride in DMF
gives 4-O-monoacylated or 2,4-di-O-acylated 6,3-lactones that can be easily transformed into corresponding methyl
uronates bearing free OH-groups at C-2 and C-3 or C-3 only, respectively. This method was used for preparation of
selectively 3-O-protected glucuronyl donors of thioglycoside and trichloracetimidate types. © 2001 Elsevier Science
Ltd. All rights reserved.
Keywords: Glucuronic acid; Lactonisation; Regioselectivity; Glucuronyl donors
The glucuronyl blocks which carry free or
selectively substituted OH-group at C-3 are
necessary for the preparation of a variety of
oligosaccharides, particularly HNK-1 anti-
genic structures.1–4 Such blocks can be pre-
pared via regoiselective O-acylation of
respective intermediate stannylidene deriva-
tives.2,3 Another method1,4,5 consists of treat-
ment of glucopyranuronosides with Ac2O
followed by subsequent methanolysis of the
corresponding 6,3-lactone formed to give 3-
monohydroxy 2,4-di-O-acetylated glucurono-
sides.
The latter method is effective but gives
products which are not often optimal for fur-
ther synthetic applications, particularly for
preparation of glucuronyl donors because the
2-O-acetylated ones are less effective reagents
as compared with 2-O-pivaloylated6,7 or 2-O-
benzoylated8 compounds. In this paper we
describe the lactonisation of glucopyra-
nouronosides 1 and 29 in the presence of Bz2O
and Piv2O as a key step in syntheses of 2,4-di-
O-benzoylated and pivaloylated glucuronopy-
ranosyl derivatives bearing unsubstituted or
temporary protected HO-group at C-3. The
starting acid 1 was obtained by treatment of
ethyl[methyl(2,3,4-tri-O-acetyl-1-thio-b- -
D
ꢀ Synthesis of oligosaccharides related to HNK-1 antigen,1
Part 4.
* Corresponding author. Fax: +7-095-1358784.
E-mail address: nen@ioc.ac.ru (N.E. Nifantiev).
glucopyranosyl)uronate]8 with LiOH in
aqueous THF and purified by ion-exchange
chromatography.
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(01)00272-5

310
A.V. Kornilo6 et al. / Carbohydrate Research 336 (2001) 309–313
the H-4 signal (l 5.26 and 4.94 ppm, respec-
tively) in the H NMR spectra.
The known conditions for lactonisation of
1
glucuronic acid glycosides in acetic anhydride
which was also used as a solvent5 are not
acceptable for treatment with Bz2O or Piv2O.
We found that the DMF is the optimal sol-
vent for such reactions and their result de-
pends on the amount of acylating agents and
reaction conditions used. Particularly, heating
of the acids 1 and 2 in presence of 20–25
equivalents of Bz2O gave the mixture of 4-O
and 2,4-di-O-benzoylated lactones. In con-
trast, lactonisation of the acid 2 under the
same conditions but with six equivalents of
Bz2O resulted in the formation of the
The most effective procedure developed for
preparation of 2,4-di-O-acylated derivatives
includes three steps: (1) Lactonisation of an
acid in DMF under heating at 80–85 °C for
3–9 h with either benzoic (20–25 equivalents)
or pivalic anhydride (38 equivalents); (2) com-
plete O-acylation by addition of Py and
DMAP at rt with the formation of peracylated
6,3-lactone of the common structure 7; (3)
methanolysis of the lacton ring in the presence
of anhydrous AcONa (Scheme 1).
Such treatment of compounds 1 and 2 gave
the 2,4-di-O-benzoylated derivatives 8, 10 and
2,4-di-O-pivaloated 14 in 64, 64% and 60%
overall yields, respectively, that coincided with
the efficiency of the preparation of respective
2,4-di-O-acetylated derivatives with the use of
Ac2O.5 The presence of acyl groups at O-4
and O-2 in the products 8, 10 and 14 was
confirmed by the low-field shift values of H-4
(l 5.44, 5.50, 5.08 ppm) and H-2 signals (l
5.32, 5.26, 4.89 ppm) in contrast to the high-
field values of H-3 (l 4.17, 4.18, 3.78 ppm,
monobenzoylated product
3
only. 4-O-
Monoacylated lactone 4 was also formed ex-
clusively during lactonisation of acid 2 with 39
equivalents of Piv2O even under heating up to
9 h.
Without purification, the lactones 3 and 4
were subjected to sodium acetate catalysed
methanolysis to give the 2,3-diols 5 and 6 in
69 and 59% overall yields, respectively. The
presence of ester group at O-4 in diols 5 and 6
was followed from the low-field position of
Scheme 1. Reagents and conditions: (a) Bz2O (20–25 equiv), DMF, 85 °C, 4 h; (b) Bz2O, Py, DMAP, DMF, 36 h, rt; (c) MeOH,
anhyd AcONa, DMF; (d) Ac2O, Py; (e) PdCl2, MeOH, 2 h; (f) CCl3CN, K2CO3, CH2Cl2, −5 °C; (g) Bz2O (6 equiv) or Piv2O
(38 equiv), 85 °C, DMF, 3 h; (h) Piv2O, Py, DMAP, DMF, 36 h, rt.

A.V. Kornilo6 et al. / Carbohydrate Research 336 (2001) 309–313
311
1
respectively) in H NMR spectra. Compound
Anal. Calcd for C8H14O6S: C, 40.33; H, 5.92.
Found: C, 40.39; H, 5.96.
10 contained a small quantity of aromatic
impurities difficult to separate by flash chro-
matography and subsequent crystallisation.
Therefore it was characterised as 3-O-acetate
11. The monohydroxy compound 8 was also
acetylated to give the compound 9.
The glycoside 11 was deallylated with PdCl2
in MeOH10 to give the hemicetal 12, which
was then treated with CCl3CN and K2CO3 to
afford the glucuronyl trichloroacetimidate 13
in 58% overall yield. Compounds 9 and 13
were synthesised for the use as glucuronyl-
donor blocks with a temporary acetyl group
by O-3 which is selectively removable by mild-
acid methanolysis.11
In conclusion, lactonisation of the O- and
S-pyranosides of glucuronic acid in the pres-
ence of benzoic or pivalic anhydride and sub-
sequent methanolysis leads to the respective
2,4-di-O- or 4-O-monoacylated derivatives de-
pending on conditions used. The 4-O-acylated
lactones are the convenient precursors for
derivatives of glucopyranuronosides bearing
different blocking groups at O-2, O-3 and
O-4.
Allyl [methyl(4-O-benzoyl-i- -glucopyran-
D
osyl)uronate] (5).—The solution of acid 29 (80
mg, 0.34 mmol) was treated with Bz2O (463
mg, 2.05 mmol) in 3 mL DMF at 75 °C
during 3 h and the mixture was diluted with
EtOAc (20 mL), washed with satd aq
NaHCO3 (40 mL), filtered through cotton
wool and concentrated. The residue was dried,
then dissolved in anhyd MeOH (5 mL), anhyd
NaOAc (16 mg, 0.24 mmol) was added and
the mixture was kept for 20 h at rt. The
mixture was deionised with cation-exchange
resin KU-2 (H+) during 0.5 h, the resin was
filtered off and washed with MeOH (20 mL),
filtrates were combined and evaporated.
Column chromatography of the residue (1:2
EtOAc–petroleum ether) gave 5 (83 mg, 69%)
1
as a syrup: [h]D –17° (c 1, CHCl3); H NMR
(CDCl3): l 5.93 (m, 1 H, OCH2CHꢀCH2),
5.39–5.14 (m, 2 H, OCH2CHꢀCH2), 5.26 (dd,
1 H, J3,4 9.5, J4,5 9.9 Hz, H-4), 4.45 (d, 1 H,
J1,2 7.4 Hz, H-1), 4.43–4.32 and 4.20–4.13
(2m, 2 H, OCH2CHꢀCH2), 4.07 (d, 1 H, H-5),
3.86 (dd, 1 H, J2,3 9.2 Hz, H-3), 3.60 (dd, 1 H,
H-2), 3.60 (s, 3 H, CO2CH3). Anal. Calcd for
C17H18O8: C, 58.29; H, 5.18. Found: C, 58.33;
H, 5.24.
1. Experimental
Allyl [methyl(4-O-pi6aloyl-i- -glucopyran-
D
osyl)uronate] (6).—The solution of acid 2 (245
mg, 1.05 mmol) in DMF (8 mL) was treated
with Piv2O (8 mL, 39.43 mmol), and then with
anhyd MeOH (10 mL) and anhyd NaOAc (32
mg, 0.48 mmol) as described for 5. Column
For description of general experimental
procedures, see Ref. 1.
Ethyl
acid) (1).—To a solution of ethyl[methyl-
(2,3,4-tri-O-acetyl-1-thio-b- -glucopyranosyl)-
(1-thio-i- -glucopyranosyluronic
D
D
uronate]8 (620 mg, 1.65 mmol) in 16.5 mL
(10:1) THF–water, LiOH (2 M, 5 mL) was
added at −10 °C, the reaction mixture was
allowed to attain rt during 5 h. Cation-ex-
change resin KU-2 (H+) (4 mL) and MeOH
(10 mL) were added, the mixture was kept for
0.5 h and the resin was filtered off. The resin
was washed with MeOH (20 mL) and the
filtrate was evaporated. Ion-exchange chro-
matography and subsequent freeze-drying re-
sulted in amorphous 1 (370 mg, 94%): [h]D
chromatography
(1:2
EtOAc–petroleum
ether) gave 6 (205 mg, 59%) as a syrup: [h]D
1
−50° (c 1, CHCl3); H NMR (CDCl3): l 5.90
(m, 1 H, OCH2CHꢀCH2), 5.33–5.15 (m, 2 H,
OCH2CHꢀCH2), 4.94 (dd, 1 H, J3,4 9.5, J4,5 9.9
Hz, H-4), 4.38 (d, 1 H, J1,2 7.5 Hz, H-1),
4.36–4.30 and 4.19–4.03 (2m,
2
H,
OCH2CHꢀCH2), 3.94 (d, 1 H, H-5), 3.68 (dd,
1 H, J2,3 9.1 Hz, H-3), 3.66 (s, 3 H, CO2CH3),
3.52 (dd, 1 H, H-2). Anal. Calcd for C15H24O8:
C, 54.21; H, 7.28. Found: C, 54.19; H, 7.15.
1
Ethyl
[methyl(2,4-O-benzoyl-1-thio-i- -
D
−35° (c 1, CH3OH); H NMR (CD3OD): l
glucopyranosyl)uronate] (8).—To a solution of
1 (65 mg, 0.27 mmol) in DMF (5 mL), Bz2O
(1.53 g, 6.83 mmol) was added and the reac-
tion mixture was kept at 85 °C for 3 h. Pyri-
4.40 (d, 1 H, J1,2 9.1 Hz, H-1), 3.75 (d, 1 H,
J4,5 8.8 Hz, H-5), 3.49 (br.t, 1 H, H-4), 3.37 (t,
1 H, J2,3=J3,4 8.5 Hz, H-3), 3.20 (dd, 1 H,
H-2), 2.65 (m, SCH2CH3), 1.25 (t, SCH2CH3).

312
A.V. Kornilo6 et al. / Carbohydrate Research 336 (2001) 309–313
mmol), then with pyridine (5 mL), DMAP (84
mg, 0.69 mmol), and finally with MeOH (2
mL) and anhyd NaOAc (10 mg, 0.15 mmol)
as described for 8. Column chromatography
(1:2 EtOAc–petroleum ether) gave 10 (381
mg), which was then acetylated with Ac2O (2
mL) in Py (2 mL) at 20 °C for 24 h. The
solution was coevaporated with toluene (2×
10 mL) and the residue was subjected to
column chromatography (1:2 EtOAc–
petroleum ether) and subsequent crystallisa-
tion gave 11 (415 mg, 61%) as needles: mp
176–177 °C (1:2 EtOAc–petroleum ether);
dine (3 mL) and DMAP (17 mg, 0.34 mmol)
were added at rt and the solution was kept for
36 h, diluted with EtOAc (20 mL) and washed
with 1 M H2SO4 (20 mL), satd aq NaHCO3
(50 mL), and satd aq NaCl (10 mL), filtered
through cotton wool, evaporated and coevap-
orated with toluene (10 mL), dried and dis-
solved in anhyd MeOH (2 mL). To this
solution the anhyd NaOAc (10 mg, 0.15
mmol) was added and the mixture was kept
for 12 h at rt. Cation-exchange resin KU-2 (2
mL) was added to a solution for 0.5 h and
filtered off. The resin was washed with MeOH
(20 mL) and the filtrates were combined and
concentrated. Column chromatography of the
residue (1:2 EtOAc–petroleum ether) and sub-
sequent crystallisation gave 8 (80 mg, 64%) as
needles: mp 164–166 °C (EtOAc–petroleum
1
[h]D −3° (c 1, CHCl3); H NMR (CD3OD): l
5.78 (m, 1 H, OCH2CHꢀCH2), 5.68 (dd, 1 H,
J2,3 9.1, J3,4 9.3 Hz, H-3) 5.59 (t, 1 H, J4,5 9.3
Hz, H-4), 5.43 (dd, 1 H, J1,2 7.4 Hz, H-2),
5.29–5.01 (m, 2 H, OCH2CHꢀCH2), 4.85 (d, 1
H, H-1), 4.45–4.33 and 4.20–4.05 (2m, 2 H,
OCH2CHꢀCH2), 4.29 (d, 1 H, H-5), 3.70 (s, 3
H, CO2CH3), 1.85 (s, 3 H, COCH3). MALDI-
TOF-MS: Calcd for [M+Na]+: 521.5.
Found: 521.1. Anal. Calcd for C26H26O10: C,
62.65; H, 5.26. Found: C, 62.59; H, 4.98.
1
ether); [h]D −11° (c 1, CHCl3); H NMR
(CDCl3): l 5.44 (t, 1 H, J3,4 9.6 Hz, H-4), 5.32
(t, 1 H, J2,3 9.4 Hz, H-2), 4.71 (d, 1 H, J1,2 9.9
Hz, H-1), 4.20 (d, 1 H, J4,5 9.9 Hz, H-5), 4.17
(t, 1 H, H-3), 3.66 (s, 3 H, CO2CH3), 2.75 (m,
SCH2CH3), 1.23 (t, SCH2CH3). MALDI-
TOF-MS: Calcd for [M+Na]+: 483.5.
Found: 483.1. Anal. Calcd for C23H24O8S: C,
59.92; H, 5.27; S, 6.80. Found: C, 59.99; H,
5.25; S, 6.96.
Methyl
glucopyranosyl
(3-O-acetyl-2,4-O-benzoyl-h-
D
-
trichloroacetimidate)uronate
(13).—Palladium chloride (25.8 mg, 0.15
mmol) was added to a solution of 11 (207 mg,
0.42 mmol) in anhyd MeOH (10 mL). The
reaction mixture was stirred for 2 h at rt and
filtered through a Celite layer, and evapo-
rated. The residue was diluted with of EtOAc
(20 mL), washed with satd aq NaHCO3 (50
mL), filtered through cotton wool, concen-
trated and then filtered through a pad of silica
gel to give 135 mg of 12 as amorphous foam.
Hemicetal 12 was treated with trichloroace-
tonitrile (295 mL, 2.95 mmol) and K2CO3 (200
mg, 1.43 mmol) in anhyd CH2Cl2 (2 mL)
under dry argon at −5 °C for 2.5 h and the
mixture was concentrated. Column chro-
matography of the residue (1:3 EtOAc–
petroleum ether+1% Et3N) gave amorphous
13 (151 mg, 58%): [h]D +61° (c 0.5, CHCl3);
1H NMR (CDCl3): l 8.70 (s, 1 H, NH), 6.85
(d, 1 H, J1,2 3.6 Hz, H-1), 6.04 (t, 1 H,
J2,3=J3,4 10.0 Hz, H-3), 5.58 (dd, 1 H, J4,5
10.2 Hz, H-4), 5.46 (dd, 1 H, H-2), 4.67 (d, 1
H, H-5), 3.68 (s, 3 H, CO2CH3), 1.90 (s, 3 H,
COCH3).
Ethyl [methyl(3-O-acetyl-2,4-O-benzoyl-1-
thio-i- -glucopyranosyl)uronate] (9).—Glu-
D
curonide 8 (60 mg, 0.13 mmol) was acetylated
in a mixture of Py (2 mL) and Ac2O (2 mL) at
20 °C during 24 h. The mixture was coevapo-
rated with toluene (10 mL) and dried. Column
chromatography of the residue (1:2 EtOAc–
petroleum ether) and subsequent crystallisa-
tion gave 3-O-acetate 9 (63 mg, 94%) as
needles: mp 207–209 °C (EtOAc–petroleum
1
ether); [h]D −9° (c 0.6, CHCl3); H NMR: l
5.70 (t, 1 H, J3,4 9.4 Hz, H-3), 5.55 (t, 1 H, J4,5
9.6 Hz, H-4), 5.42 (t, 1 H, J2,3 9.0 Hz, H-2),
4.78 (d, 1 H, J1,2 9.0 Hz, H-1), 4.26 (d, 1 H,
H-5), 3.70 (s, 3 H, CO2CH3), 2.78 (m,
SCH2CH3), 1.25 (t, SCH2CH3). MALDI-
TOF-MS: Calcd for [M+Na]+: 525.5.
Found: 524.9. Anal. Calcd for C25H26O9S: C,
59.75; H, 5.21. Found: C, 59.82; H, 5.21.
Allyl [methyl(3-O-acetyl-2,4-O-benzoyl-i-
D
-glucopyranosyl)uronate] (11).—The solution
of acid 2 (320 mg, 1.37 mmol) in DMF (15
mL) was treated with Bz2O (6.19 g, 27.4

A.V. Kornilo6 et al. / Carbohydrate Research 336 (2001) 309–313
313
Allyl [methyl(2,4-O-pi6aloyl-i-
D
-glucopy-
dation for Basic Research (Projects No. 00-03-
32815a, 01-03-33059 and 01-03-06139). We
thank Dr L.O. Kononov for useful discussion.
ranosyl)uronate] (14).—Acid 2 (123 mg, 0.52
mmol) was treated with Piv2O (4 mL, 19.72
mmol) in DMF (4 mL) for 9 h, then with Py
(4 mL) and DMAP (16.7 mg, 0.34 mmol) for
36 h and finally with anhyd MeOH (2 mL)
and anhyd NaOAc (10 mg, 0.15 mmol) as
described for 8 and subjected to column chro-
matography (1:3 EtOAc–petroleum ether)
and subsequent crystallisation to give 14 (123
mg, 60%) as needles: mp 120–121 °C (1:3
EtOAc–petroleum ether); [h]D −48° (c 1,
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1
CHCl3); H NMR (CDCl3): l 5.81 (m, 1 H,
OCH2CHꢀCH2), 5.29–5.14 (m,
2
H,
OCH2CHꢀCH2), 5.08 (dd, 1 H, J3,4 9.2, J4,5 9.8
Hz, H-4), 4.89 (dd, 1 H, J1,2 7.7, J2,3 9.2 Hz,
H-2), 4.55 (d, 1 H, H-1), 4.38–4.28 and 4.10–
4.00 (2m, 2 H, OCH2CHꢀCH2), 3.97 (d, 1 H,
H-5), 3.78 (t, 1 H, H-3), 3.72 (s, 3 H,
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Acknowledgements
This work was supported by GlycoSence
AG (Jena, Germany) and the Russian Foun-