Comparison of Several Glucuronate Glycosyl Donors

Article abstract of DOI:10.1081/CAR-120026603

Methyl 3,4-di-O-benzyl-[(S)-1,2-O-(1-cyanoethylidene)]-α-D- glucopyranuronate (12), methyl 3,4-di-O-benzyl-[(S)-1,2-O-(1-ethoxyethylidene)]- α-D-glucopyranuronate (14), methyl 2-O-acetyl-3,4-di-O-benzyl-α-D- glucopyranuronate bromide (15), methyl (2-O-acetyl-3,4-di-O-benzyl-α-D- glucopyranosyl)uronate trichloroacetimidate (17), and methyl (2,3,4-tri-O-benzyl-α/β-D-glucopyranosyl)uronate trichloroacetimidate (30) were synthesized and used as glycosyl donors. Glycosylation reactions of 12 with (5-R)-2,3,4,5-tetrahydro-5-trityloxymethyl-2- furanone (32) and 14,15,17 with the corresponding (5-R)-2,3,4,5-tetrahydro-5- hydroxymethyl-2-furanone (31) provided the exclusively β-linked glucuronide 33 in 69%, 28%, 45%, and 71% yield, respectively. The coupling of donor 30 with acceptor 31 furnished the glucuronated lactone 35 in 70% yield with a surprisingly high content (20%) of the undesired α-linked sugar residue. The structure of 33 was proved by NMR and X-ray diffraction studies. In a model reaction a complete deprotection procedure of the glucuronic acid lactone conjugation was demonstrated.

Full text of DOI:10.1081/CAR-120026603

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Comparison of Several Glucuronate Glycosyl Donors
Anahit Pews‐Davtyan a , Alexander Pirojan b , Izabella Shaljyan b , Aida A. Awetissjan b ,
Helmut Reinke a & Christian Vogel a
a Department of Chemistry , University of Rostock , Albert‐Einstein‐Str. 3a, Rostock, 18059,
Germany
b Faculty for Chemisty, Institute of Organic Chemistry , Yerevan State University , I. A.
Manoogian St., Yerevan, 375049, Armenia
Published online: 02 Feb 2007.
To cite this article: Anahit Pews‐Davtyan , Alexander Pirojan , Izabella Shaljyan , Aida A. Awetissjan , Helmut Reinke &
Christian Vogel (2003) Comparison of Several Glucuronate Glycosyl Donors, Journal of Carbohydrate Chemistry, 22:9, 939-962,
DOI: 10.1081/CAR-120026603
To link to this article: http://dx.doi.org/10.1081/CAR-120026603
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 22, No. 9, pp. 939–962, 2003
Comparison of Several Glucuronate Glycosyl Donors
Anahit Pews-Davtyan,1 Alexander Pirojan,2 Izabella Shaljyan,2
Aida A. Awetissjan,2 Helmut Reinke,1 and Christian Vogel1,
*
1Department of Chemistry, University of Rostock, Rostock, Germany
2Faculty for Chemisty, Institute of Organic Chemistry,
Yerevan State University, Yerevan, Armenia
ABSTRACT
Methyl 3,4-di-O-benzyl-[(S)-1,2-O-(1-cyanoethylidene)]-a-D-glucopyranuronate (12),
methyl 3,4-di-O-benzyl-[(S)-1,2-O-(1-ethoxyethylidene)]-a-D-glucopyranuronate (14),
methyl 2-O-acetyl-3,4-di-O-benzyl-a-D-glucopyranuronate bromide (15), methyl (2-
O-acetyl-3,4-di-O-benzyl-a-D-glucopyranosyl)uronate trichloroacetimidate (17), and
methyl (2,3,4-tri-O-benzyl-a/b-D-glucopyranosyl)uronate trichloroacetimidate (30)
were synthesized and used as glycosyl donors. Glycosylation reactions of 12 with (5-
R)-2,3,4,5ꢀtetrahydro-5-trityloxymethyl-2-furanone (32) and 14,15,17 with the cor-
responding (5-R)-2,3,4,5-tetrahydro-5-hydroxymethyl-2-furanone (31) provided the
exclusively b-linked glucuronide 33 in 69%, 28%, 45%, and 71% yield, respectively.
The coupling of donor 30 with acceptor 31 furnished the glucuronated lactone 35 in
70% yield with a surprisingly high content (20%) of the undesired a-linked sugar
residue. The structure of 33 was proved by NMR and X-ray diffraction studies. In a
model reaction a complete deprotection procedure of the glucuronic acid lactone
conjugation was demonstrated.
Key Words: D-glucuronic acid derivatives; Orthoesters; Trichloroacetimidates;
Cyanoethylidene derivatives; Glycosylation; X-ray structures.
*
Correspondence: Christian Vogel, Department of Chemistry, University of Rostock, Albert-
Einstein-Str. 3a, 18059 Rostock, Germany; E-mail: christian.vogel@chemie.uni-rostock.de.
939
DOI: 10.1081/CAR-120026603
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright D 2003 by Marcel Dekker, Inc.

940
Pews-Davtyan et al.
INTRODUCTION
In a program directed towards the synthesis of biologically active lactone O-glu-
curonides, the development of new and more effective uronic acid glycosyl donors
became necessary. Two general strategies of synthesizing O-glucuronides have been
applied: the most commonly used glycosylation with readily accessible but sluggish acyl
glucuronate donors, or, rarely, glycosylation with more active benzyl or silyl ether
protected glucuronates.[2,3] Generally, the anchimeric assistance of an acyl substituent on
O-2 leads predominantly to the b-configuration, whereas stereochemical control of the
glycosylation by using ether protected intermediates is more complicated.[4] We now
report the application of several glucuronate glycosyl donors, potentially of value in both
strategies, bearing not only the participating O-2 acyl substituent but also the activating
benzyl ethers for protection of the remaining hydroxyl groups. As model substances for
highly sensitive lactones the commercially available (5-R)-2,3,4,5-tetrahydro-5-hy-
droxymethyl-2-furanone (31) and the corresponding (5-R)-2,3,4,5ꢀtetrahydro-5-trityl-
oxyethyl-2-furanone (32) were chosen.
RESULTS AND DISCUSSION
For the preparation of the orthoester 6, suitable as a potential intermediate for a
series of glucuronate glycosyl donors, it is possible to proceed from the acetylated
glucopyranose 1,2-orthoester 2. The latter one was synthesized by classical in situ
anomerization from the peracetylated a-D-glucopyranosyl bromide (1)[5] in the presence
of sym-collidine, ethanol and tetra-n-butylammonium bromide (Scheme 1).[6] After
Zemple´n deacetylation the more accessible primary hydroxyl group of 3 was se-
lectively protected as a tert-butyldimethylsilyl ether by a procedure of Sinay¨ et al.[7]
Scheme 1.

Comparison of Glucuronate Glycosyl Donors
941
Chromatographic purification provided the S-configured 1,2-O-(1-ethoxyethylidene)
derivative 4 in 87% yield. The benzylation of 4 with benzyl bromide and sodium
hydride in N,N-dimethylformamide (5, 71% yield), followed by cleavage of the silyl
ether bond with tetra-n-butylammonium fluoride trihydrate provided compound 6 (96%
yield). Temporary protection of the primary hydroxyl function was then taken over by a
simple O-6 acetylation of 6 to give 7 which is sufficiently stable in the following steps
for the synthesis of the cyanoethylidene derivative 9. For this purpose, the fully pro-
tected orthoester 7 was converted into the bromide 8 by a procedure of Lemieux et al.[8]
and then treated with carefully powdered sodium cyanide, tetra-n-butylammonium
bromide in dry acetonitrile[9] to provide the exo/endo mixture of 9 in 58% and 15%
yield, respectively.
1
X-Ray and H NMR studies[10] were employed to address the absolute configu-
ration of the cyano group in peracetylated 1,2-O-(1-cyanoethylidene)-a-D-glycopyra-
noses. From these results it could be concluded that for cyanoethylidene derivatives
with the cyano group in an exo-orientation (S-configuration), the proton signal for this
methyl group appeared downfield (d > 1.80 ppm) in comparison to those from a methyl
group in an exo-orientation (R-configuration; d < 1.80 ppm). Owing to the observed
values for 9exo [d 1.87 ppm, C(CN)CH3] and 9endo [d 1.76 ppm, C(CN)CH3], the
configurations of the 1,2-cis-fused five membered rings could be described as having
endo- and exo-cyanoethylidene groups, respectively. In order to simplify monitoring,
the exo-isomer 9exo was used exclusively, in the following reaction steps.
Gentle cleavage of the acetyl group was achieved with 0.28 M methanolic hy-
drochloric acid at room temperature to afford 10 in 69% yield.[11] The oxidation of the
partially protected compound 10 with the Jones reagent [chromium(VI)oxide–sulfuric
acid] was carried out in 1:5 dichloromethane-acetone,[12] and the resulting glucopyra-
nuronic acid 11 was treated with diazomethane to give the methyl ester 12 in 63%
yield (Scheme 2).
Shortening the preparation of 12 was achieved via the orthoester 14 which was
obtained by oxidation of 6 with the TEMPO/hypochlorite system[13] and subsequent
esterification under phase transfer condition in 65% yield.[14] Treatment of the glu-
curonate orthoester 14 with acetyl bromide in the presence of tetra-n-butylammonium
bromide[8] then provided the glycosyl bromide 15. In contrast to the formation of the
methyl 3,4-di-O-acetyl-1,2-O-[(1-exocyano)ethylidene]-a-D-glucopyranuronate that re-
quired drastic reaction conditions (an excess of silver cyanide in boiling xylene[15]) the
3,4-di-O-benzyl bromide 15 reacted smoothly with sodium cyanide, tetra-n-butyl-
ammonium bromide in dry acetonitrile at room temperature to give the desired cya-
noethylidene derivative 12 in 65% yield. Thus, the introduction of the benzyl ethers at
the O-3 and O-4 position instead of the acetyl groups increases the reactivity of the
bromide 15 significantly.[16,17] Surprisingly, the reaction was very stereoselective be-
cause no endo-configured cyanoethylidene derivative was observed. Comparing both
synthetic pathways for 12 with respect to the overall yield from 6, the latter (41%) is
more efficient than the first one (24%).
Starting from orthoester 14, a further glucuronate glycosyl donor was prepared.
Acid catalyzed hydrolysis of the orthoester[18] leads quantitatively to an a/b-mixture
(4:1) of 16. Treatment of this mixture with sodium hydride and trichloroacetonitrile[19]
in dry dichloromethane delivers after three hours at room temperature the benzylated a-
trichloroacetimidate 17 bearing an anchimeric acetyl group at position O-2 in excellent

942
Pews-Davtyan et al.
Scheme 2.
(94%) yield. Noteworthy, the quality of the sodium hydride sets the limits for the
introduction of the trichloroacetimidate function and in some cases appreciable amounts
of the b-isomer could be observed. Typically, the small coupling constant J1,2 of 3.5 Hz
1
for the a-anomer 17 and the considerable bigger one of 7.1 Hz for 17 in the H NMR
spectra illustrated the situation at the anomeric center.

Comparison of Glucuronate Glycosyl Donors
943
To avoid the crucial oxidation step during changing from glucose to the glucuronic
acid series, we established an alternative synthetic route starting from the glucuronolactone
18. Compound 18 was transformed, via the peracetylated glucopyranuronate 20, into
the methyl (glucopyranosyl bromide)uronate 21 by a procedure described by Bollen-
beck et al.[20] The NMR data for 20 are published herein.
The reaction of 21 with dry ethanol in the presence of sym-collidine and tetra-n-
butylammonium bromide provided the corresponding orthoester 22 in 90% yield. The
structure of the orthoester 22 is supported by the analytical data and by the NMR data.
1
The singlet at d 1.69 in the H NMR spectrum is assigned[21] to the endo-methyl group
at C-2 of the dioxolane ring and indicates that the synthesized orthoacetate is an exo-
isomer. Whereas deacetylation of 22 was achieved under Zemple´n conditions, subse-
quent benzylation of 23 in a basic medium led to b-elimination.[22] Until now, we have
not found conditions to avoid this undesired side reaction, even though a multitude of
benzylation procedures was tested. In most cases, the main product was the enopy-
ranuronate 24, whose synthesis on a preparative scale is described in the Experimental.
For the purpose of comparison, the glucuronate glycosyl donor 30, used by
Schmidt et al. for the synthesis of b-glucuronides,[19] was prepared by an alternative
route starting from a glucuronate precursor. Therefore, the bromide 21 was treated
with allyl alcohol in a mercuric salt promoted glycosylation to provide the allyl b-
glycoside 25 in excellent (97%) yield. The analytical data for 25 fully agree with
the proposed structure. Thus, the vicinal coupling constant value J1,2 = 7.7 Hz in the
1H NMR spectrum indicates clearly the stereochemistry at the anomeric center. Re-
moval of the acetyl groups of 25 was achieved with 0.28 M hydrochloric acid in
dry methanol in 90% yield. For activation of the hydroxyl groups, the obtained triol
26 was converted into the trimethylsilyl derivative 27 in 81% yield. However, the
reductive etherification of benzaldehyde with that alkoxytrimethylsilane[23] did not give
the desired benzylated glucuronate 28 whose preparation succeeded with benzyl bro-
mide in the presence of silver oxide. Strong exclusion of moisture is the fundamental
requirement in this step and the benzylated uronate 28 was obtained in 38% average
yield. After deallylation of compound 28 with the aid of palladium(II)chloride,[24] the
introduction of the trichloroacetimidate group at the anomeric center of 27 in the
presence of sodium hydride[19] furnished the trichloroacetimidate 30 as an a/b-mixture
in 58% and 14% yield, respectively. The quality of the sodium hydride had again a
strong influence on the outcome of the reaction with regard to both yield and ratio of the
1
a/b-anomers, which were separated by HPLC. Characteristic signals in the H NMR
spectra appeared at d 6.50 (d, 1H, J1,2 = 3.4 Hz) and at d 5.87 (d, 1H, J1,2 = 7.3 Hz) for
H-1 and in the 13C NMR spectra at d 93.96 and at d 98.02 for C-1 of 30 and 30 ,
respectively (Scheme 3).
For the comparative study, the glucuronate donors 14,15,17,30 were coupled with
the lactone 31 in a ratio of 1:1.1. The highest yields of the glucuronated lactones 33
and 35 were achieved with the trichloroacetimidates 17 (71%) and 30 (70%), respec-
tively, in the presence of boron trifluoride etherate. In contrast to the results of Schmidt
et al., who also applied the glycosyl donor 30 for the synthesis of b-D-glucopy-
ranosyluronates under comparable conditions,[19] lactone 35 contains a surprisingly
high content (20%) of the undesired a-coupled sugar residue,[25] whereas the anchi-
meric acetyl group at the O-2 position of the other donors guarantees the formation of
the b-glycosidic linkage on lactone 33 (Scheme 4).

944
Pews-Davtyan et al.
Scheme 3.
Comparable results afforded the tritylcyanoethylidene condensation[15] of the gly-
cosyl donor 12 with the tritylated lactone 32 providing 33 in 69% yield. In the case of
the bromide 15, the glycosylation of 31 with the aid of silver perchlorate in acetoni-
trile[26] gave a moderate yield of 45%. Surprisingly low was the yield of lactone
33 when the orthoester 14 was used as glycosyl donor. The two-stage glycosylation,

Comparison of Glucuronate Glycosyl Donors
945
Scheme 4.
involving re-esterification of the starting orthoester with the starting lactone 31 and
glycosylation with the resulting orthoester,[27,28] yielded 33 only in 28% (Figure 1).
The NMR data secure the b-glycosidic linkage between the glucuronate residue
and the lactone in compound 33. Thus, the stereochemistry of the glycosidic linkage
1
was assigned based on the large vicinal coupling constant J1,2 = 7.5 Hz in the H NMR
and on the resonance of C-1 at d 101.50 in the 13C NMR spectra. Additionally, the
X-ray diffraction studies were done to establish the structure of 33 and to gain

946
Pews-Davtyan et al.
Figure 1. An ORTEP diagram of compound 33. (Go to www.dekker.com to view this figure
in color.)
information on the conformation of the pyranose ring. The solid crystallizes in the
trigonal space group P31. The decision to assign P31 instead of the enantiomorphous
space group P32 could not be made on the basis of the absolute structure parameter
but was a result of considering the conformation of the precursor. The sugar ring adopts
an almost ideal 4C1 conformation, the puckering parameters are Q = 0.575(4) A,
˚
Y = 4.7(4)° and F = 357(6)°.
Next, a two-step saponification[29] was used for deesterification of 33. Therefore,
compound 33 was treated at first with sodium methoxide in methanol to provide
deacetylated 34 (75%), and then with lithium hydroxide in water-acetone to remove the
methyl ester group (37, 88%). Finally, the benzyl protective groups of 35 and 37 were
removed by hydrogenolysis over Pd-C to give the partially deprotected glucuronate 36,
still containing 20% of the a-anomer, and the fully deprotected pure b-anomeric glu-
cosyluronic acid derivative 38 in yields of 98% and 84%, respectively.
In conclusion, we synthesized several glucuronate derivatives potentially suitable as
glycosyl donors. The following glycosylation reactions provided b-linked glucuronides
of lactone 31, which was used as a model compound. The best yields and the best
stereoselectivity were obtained with the trichloroacetimidate 17 and with the cya-
noethylidene derivative 12. This result may be connected with the activation of the
donors by benzyl protective groups and the anchimeric effect of the acetyl group at the
O-2 position. It seems, that the glucuronate glycosyl donors 12 and 17 can compete with
methyl (ethyl 2-O-acetyl-3,4-di-O-benzyl-1-thio-b-D-glucopyranosid)uronate and with
methyl [ethyl 2-O-acetyl-3,4-O-(1,1,3,3-tetraisopropyl-1,3-disiloxane-1,3-diyl)-1-thio-b-
D-glucopyranosid]uronate prepared and used by S. Oscarson et al.[2,3] regarding both
accessibility and reaction capacity.

Comparison of Glucuronate Glycosyl Donors
EXPERIMENTAL
947
General methods. Melting points were determined with a Boetius micro appa-
ratus BHMK 05 (Rapido, Dresden) and are uncorrected. Optical rotations were mea-
sured for solutions in a 2-cm cell with an automatic polarimeter ‘‘GYROMAT’’ (Dr.
Kernchen Co.). NMR spectra were recorded with Bruker AC-250 or ARX-300 spec-
trometers, at 250 MHz or 300 MHz for 1H, and 62.9 MHz or 75.5 MHz for 13C,
respectively. Chemical shifts are given relative to the signal of internal standard tet-
ramethylsilane (d = 0). First order chemical shifts and coupling constants were obtained
from one-dimensional spectra, and assignment of proton resonances was based on
COSY experiments. For the X-ray structure determination, a crystal of 33 was checked
by a rotational photograph and a suitable reduced cell was found by the automatic cell
determination routine. The data collection was performed in routine o-scan, the
structure was solved by direct methods (Siemens SHELXTL, 1990, Siemens Analytical
X-ray Inst. Inc.) and refined by the full matrix least-squares method of Bruker
SHELXTL, Vers.5.10, Copyright 1997, Bruker Analytical X-ray Systems. All non-
hydrogen atoms were refined anisotropically. The hydrogens were put into theoretical
positions and refined using the riding model. Additional parameters are as follows:
˚
Siemens P4 diffractometer; radiation: l = 0.71073 A (Mo-Ka), graphite monochro-
mator; crystal size: 0.68 ꢁ 0.48 ꢁ 0.46 mm3; formula: C28H32O10; formula weight:
528.54; temperature: 293(2) K; crystal system: trigonal; space group: P31; unit cell
˚
˚
dimensions: a = b = 13.294(2) A, c = 13.412(2) A, a = b = 90°, g = 120°; volume:
3
3
˚
2052.7(5) A ; Z = 3; density (calculated): 1.283 Mg/m ; absorption coefficient: 0.097
mmꢀ1; F(000): 840; Y range for data collection: 2.33 to 21.99°; index ranges:
ꢀ12 ꢂ h ꢂ 12, ꢀ13 ꢂ k ꢂ 13, ꢀ14 ꢂ l ꢂ 14; reflections collected: 3719; indepen-
dent reflections: 3294; R(int) = 0.0358, completeness to Y = 21.99°, 98.6%; data/
restraints/parameters: 3294/1/344; goodness-of-fit on F2: 1.033; final R indices [I > 2s
(I)]: R1 = 0.0474, wR2 = 0.1221; R indices (all data): R1 = 0.0583, wR2 = 0.1322;
absolute structure parameter: ꢀ0.6(14); extinction coefficient: 0.017(2); largest diff.
˚
peak/hole: 0.164/ꢀ0.182 e.A-3. Crystallographic data (excluding structure factors) for
the structure 33 reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no. CCDC 147232. Copies
of the data can be obtained free of charge on application to The Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: Int.code +(1223) 336-033; e-mail:
deposit@ccdc.cam.ac.uk or via www.ccdc.cam.ac.uk/conts/retrieving.html.
Thin-layer chromatography (TLC) on precoated plates of silica gel (Merck, Silica
Gel 60, F254, 0.25 mm) was performed with the following solvent systems (v/v): (A)
9:1, (B) 7:1, (C) 4:1, (D) 3:1, (E) 2:1, (F) 1:1, (G) 1:2 heptane–ethyl acetate, (H) 12:1,
(I) 1:2 ethyl acetate–methanol, (J) 7:4:1, (K) 7:4:2 ethyl acetate–methanol–water. The
spots were made visible by spraying with methanolic 10% H2SO4 solution and charring
them for 3–5 min with a heat gun. Detection of benzyl derivatives was effected by UV
fluorescence. Preparative flash chromatography and HPLC was performed by elution
from columns of slurry-packed Silica Gel 60 (Merck, 40–63 mm) and Nucleosil 100-7
(Knauer, 7.0 mm), respectively, with the above solvent systems. All solvents and re-
agents were purified and dried according to standard procedures.[30] After classical
work up of the reaction mixtures, the organic layers as a rule, were dried over MgSO4,
and then concentrated under reduced pressure (rotary evaporator).

948
Pews-Davtyan et al.
6-O-tert-Butyldimethylsilyl-[(S)-1,2-O-(1-ethoxyethylidene)]- -D-glucopyranose
(4). Triethylamine (4.45 mL, 32.1 mmol), 4-dimethylaminopyridine (2.6 g, 21.4
mmol) and tert-butyldimethylsilyl chloride (4.2 g, 27.8 mmol) were added to a solution
of orthoester 3 (5.36 g, 21.4 mmol) in dry dichloromethane (50 mL). After stirring for
one hour at rt (TLC solvent G Rf 0.54), the solution was diluted with chloroform (50
mL) and heptane (200 mL), washed with cold sat aq NH4Cl (3 ꢁ 50 mL), sat aq
NaHCO3 (2 ꢁ 50 mL), water (2 ꢁ 50 mL), dried and concentrated. The residue was
purified by MPLC (eluent ethyl acetate gradient 25% ! 50% in heptane with 1%
[24]
triethylamine) to yield 4 (6.78 g, 87%) as an amorphous colorless solid: [a]D
+ 19.7
1
(c 1.0, chloroform); H NMR (CDCl3) d 0.05 [s, 6H, Si(CH3)2C(CH3)3], 0.86 [s, 9H,
Si(CH3)2(CH3)3], 1.14 [t, 3H, C(CH3)OCH2CH3], 1.64 [s, 3H, C(CH3)OCH2CH3], 2.99
(bs, 2H, 2 ꢁ OH), 3.52 [q, 2H, C(CH3)OCH2CH3], 3.66 (dd, 1H, J4,5 = 7.6 Hz, H-4),
3.72 (ddd, 1H, H-5), 3.77 (dd, 1H, J6,6’ = 10.8 Hz, J6,5 = 4.2 Hz, H-6), 3.87 (dd, 1H,
J6’,5 = 3.6 Hz, H-6’), 3.90 (dd, 1H, J3,4 = 5.4 Hz, H-3), 4.24 (t, 1H, J2,3 = 5.1 Hz, H-2),
5.72 (d, 1H, J1,2 = 5.1 Hz, H-1); 13C NMR (CDCl3) d ꢀ5.50 [Si(CH3)2C(CH3)3 two
signals are isochronic], 15.20 [C(CH3)OCH2CH3], 18.21 [Si(CH3)2C(CH3)3], 22.19
[C(CH3)OCH2CH3], 25.79 [Si(CH3)2C(CH3)3 three signals are isochronic], 58.61
[C(CH3)OCH2CH3], 64.17 (C-6), 70.22 (C-5), 72.49 (C-3), 73.05 (C-4), 76.76 (C-2),
97.62 (C-1), 121.01 [C(CH3)OCH2CH3].
Anal.Calcd for C16H32O7Si (364.51): C, 52.72; H, 8.85. Found: C, 52.49; H, 8.67.
3,4-Di-O-benzyl-6-O-tert-butyldimethylsilyl-[(S)-1,2-O-(1-ethoxyethylidene)]- -
D-glucopyranose (5). Sodium hydride (3.6 g, 119 mmol, 80% dispersion in oil) was
added to a stirred solution of compound 4 (6.2 g, 17 mmol) in dry N,N-dimethylform-
amide (60 mL) at 0°C. The solution was kept for 30 min at that temperature, and benzyl
bromide (10 mL, 85 mmol) was then added dropwise. The mixture was allowed to attain
rt and stirring was continued for further 2 h. When the reaction was complete (TLC
solvent D Rf 0.58), methanol (10 mL) was added at 0°C and after stirring for further 20
min, the mixture was diluted with chloroform (50 mL) and heptane (100 mL). The
organic layer was washed with water (4 ꢁ 50 mL), dried and concentrated. MPLC
purification of the residue (eluent gradient ethyl acetate 0%!10 % in heptane with 1%
[24]
triethylamine) afforded compound 5 (6.6 g, 71%) as a colorless syrup: [a]D
+ 22.7 (c
1.0, chloroform); 1H NMR (CDCl3) d 0.06 [s, 6H, Si(CH3)2C(CH3)3], 0.90 [s, 9H,
Si(CH3)2(CH3)3], 1.19 [t, 3H, C(CH3)OCH2CH3], 1.65 [s, 3H, C(CH3)OCH2CH3], 3.54
[dq, 2H, C(CH3)OCH2CH3], 3.64 (t, 1H, H-5), 3.72 (ddd, 1H, J4,5 = 9.3 Hz, H-4), 3.83
(dd, 2H, J6,5 = J6’,5 = 3.0 Hz, H-6, H-6’), 3.85 (dd, 1H, J3,4 = 3.6 Hz, H-3), 4.67
(ddd, 1H, J2,3 = 5.1 Hz, H-2), 4.53, 4.67 (2d, 2H, J = 11.3 Hz, CH2C6H5), 4.60, 4.71
(2d, 2H, J = 11.8 Hz, CH2C6H5), 5.74 (d, 1H, J1,2 = 5.6 Hz, H-1), 7.26–7.38 (m,
10H, 2 ꢁ CH2C6H5); 13C NMR (CDCl3) d ꢀ5.24, ꢀ5.12 [Si(CH3)2C(CH3)3], 15.37
[C(CH3)OCH2CH3], 18.39 [Si(CH3)2C(CH3)3], 22.23 [C(CH3)OCH2CH3], 25.98 [Si-
(CH3)2C(CH3)3], 58.55 [C(CH3)OCH2CH3], 62.74 (C-6), 72.04 (C-5), 72.06, 73.35
(2 ꢁ CH2C6H5), 74.63 (C-4), 76.59 (C-2), 79.72 (C-3), 97.96 (C-1), 120.94 [C(CH3)-
OCH2CH3], 127.79, 127.88, 128.00, 128.03, 128.41, 128.45, 137.87, 138.27 (2 ꢁ
CH2C6H5, four signals are isochronic).
Anal.Calcd for C30H44O7Si (544.76): C, 66.14; H, 8.14. Found: C, 66.41; H, 8.22.
3,4-Di-O-benzyl-[(S)-1,2-O-(1-ethoxyethylidene)]- -D-glucopyranose (6). Tet-
rabutylammonium fluoride trihydrate (1.32 g, 4.2 mmol) was added to a solution of

Comparison of Glucuronate Glycosyl Donors
949
compound 5 (1.68 g, 3.0 mmol) in tetrahydrofuran (25 mL). After stirring for 30 min at
rt (TLC solvent F Rf 0.57), the reaction mixture was diluted with chloroform (70 mL)
and heptane (140 mL), and the organic layer was washed with water (5 ꢁ 50 mL),
dried and concentrated. MPLC purification of the residue (eluent solvent C with 1%
[24]
triethylamine) provided 6 (1.24 g, 96 %) as a colorless syrup: [a]D
+ 35.2 (c 1.0,
1
chloroform); H NMR (CDCl3) d 1.20 [t, 3H, C(CH3)OCH2CH3], 1.68 [s, 3H, C(CH3)-
OCH2CH3], 2.20 (bs, 1H, OH), 3.53 [q, 2H, C(CH3)OCH2CH3], 3.63 (dd, 1H,
J4,5 = 0.8 Hz, H-4), 3.68 (m, 1H, H-6), 3.69 (m, 1H, H-5), 3.80 (m, 1H, H-6’), 3.90
(t, 1H, J3,4 = 3.4 Hz, H-3), 4.43 (ddd, 1H, J2,3 = 5.3 Hz, H-2), 4.44, 4.58 (2d, 2H,
J = 11.5 Hz, CH2C6H5), 4.57, 4.67 (2d, 2H, J = 12.0 Hz, CH2C6H5), 5.72 (d, 1H,
J1,2 = 5.0 Hz, H-1), 7.27–7.40 (m, 10H, 2 ꢁ CH2C6H5); 13C NMR (CDCl3) d 15.38
[C(CH3)OCH2CH3], 21.41 [C(CH3)OCH2CH3], 58.89 [C(CH3)OCH2CH3], 62.57 (C-
6), 70.66 (C-5), 71.95, 72.64 (2 ꢁ CH2C6H5), 74.88 (C-2), 75.14 (C-4), 77.76 (C-3),
97.49 (C-1), 120.96 [C(CH3)OCH2CH3], 127.99, 128.08, 128.11, 128.48, 128.55, 137.51,
137.77 (2 ꢁ CH2C6H5, five signals are isochronic).
Anal.Calcd for C24H30O7 (430.49): C, 66.96; H, 7.02. Found: C, 67.19; H, 7.12.
6-O-Acetyl-3,4-di-O-benzyl-[(S)-1,2-O-(1-ethoxyethylidene)]- -D-glucopyranose
(7). Acetic anhydride (6.3 mL) was added dropwise to a solution of compound 6 (1.29 g,
3.0 mmol) in dry pyridine (10 mL) under an atmosphere of argon at 0°C. After stirring
overnight at rt (TLC solvent E Rf 0.43), methanol (2 mL) was added dropwise at 0°C and
after 30 min, the mixture was poured into ice–water (200 mL). The aqueous layer was
extracted with chloroform (2 ꢁ 50 mL), the combined extracts were diluted with heptane
(200 mL), and the organic layer was washed successively with sat aq NH4Cl (3 ꢁ 50 mL),
water (2 ꢁ 50 mL), sat aq NaHCO3 (2 ꢁ 50 mL), water (2 ꢁ 50 mL), dried and con-
centrated. The crude material was purified by HPLC (eluent solvent C with 1% triethy-
lamine) to yield 7 (1.13 g, 80%) as a colorless syrup: [a]D[25] +39.7 (c 1.0, chloroform); 1H
NMR (CDCl3) d 1.20 [t, 3H, C(CH3)OCH2CH3], 1.68 [s, 3H, C(CH3)OCH2CH3], 2.10 (s,
3H, OCOCH3), 3.54 [q, 2H, C(CH3)OCH2CH3], 3.58 (m, 1H, H-4), 3.86 (m, 1H, J5,6 = 2.6
Hz, J5,6’ = 4.8 Hz, H-5), 3.92 (t, 1H, J3,4 = 3.6 Hz, H-3), 4.19 (dd, 1H, J6,6’ = 11.9 Hz,
H-6), 4.27 (dd, 1H, H-6’), 4.39, 4.60 (2d, 2H, J = 11.8 Hz, CH2C6H5), 4.44 (ddd, 1H,
J2,3 = 5.2 Hz, H-2), 4.61, 4.72 (2d, 2H, J = 11,6 Hz, CH2C6H5), 5.71 (d, 1H, J1,2 = 5.3 Hz,
H-1), 7.28–7.40 (m, 10H, 2ꢁCH2C6H5); 13C NMR (CDCl3) d 15.19 [C(CH3)OCH2CH3],
20.64 (OCOCH3), 21.36 [C(CH3)OCH2CH3], 58.67 [C(CH3)OCH2CH3], 63.52 (C-6),
68.37 (C-5), 71.75, 72.30 (2 ꢁ CH2C6H5), 74.77 (C-4), 74.81 (C-2), 77.75 (C-3), 97.35
(C-1), 120.86 [C(CH3)OCH2CH3], 127.81, 127.91, 127.98, 128.17, 128.29, 128.37, 137.37
(2 ꢁ CH2C6H5, five signals are isochronic), 170.57 (OCOCH3).
Anal.Calcd for C26H32O8 (472.53): C, 66.09; H, 6.82. Found: C, 65.92; H, 6.74.
2,6-Di-O-acetyl-3,4-di-O-benzyl- -D-glucopyranosyl bromide (8). Acetyl bro-
mide (0.83 mL, 11.2 mmol) was added to a stirred mixture of compound 7 (2.66 g, 5.6
˚
mmol), tetraethylammonium bromide (0.59 g, 2.8 mmol), and molecular sieves (4 A,
3.0 g) in dry dichloromethane (20 mL). After stirring for 30 min at rt (TLC solvent E
Rf 0.44), the reaction mixture was poured into a stirred ice-cold solution of sat aq
NaHCO3 (500 mL), chloroform (100 mL), and heptane (200 mL). The organic layer
was separated, washed with water (2 ꢁ 50 mL), dried and concentrated. The crude
bromide 8 (2.74 g, 96%) isolated as a light-yellow syrup was used immediately for the
next step without further purification.

950
Pews-Davtyan et al.
6-O-Acetyl-3,4-di-O-benzyl-[1,2-O-(1-cyanoethylidene)]- -D-glucopyranose (9).
The heterogeneous mixture of glucosyl bromide 8 (2.74 g, 5.4 mmol), carefully pow-
dered sodium cyanide (2.64 g, 54 mmol), and tetrabutylammonium bromide (0.87 g,
2.7 mmol) in dry acetonitrile (15 mL) was stirred at rt for 20 h in the dark followed by
TLC. The mixture was then diluted with heptane (120 mL) and chloroform (60 mL),
washed successively with water (4 ꢁ 50 mL), aq 5% KHSO4 (2 ꢁ 50 mL), water
(2 ꢁ 50 mL), sat aq NaHCO3 (2 ꢁ 50 mL), water (2 ꢁ 50 mL), dried, and concen-
trated. The residue was dissolved in ethyl acetate (10 mL), and the resulting solution
was filtered through a thin layer of silica gel and concentrated. The crude material was
purified by MPLC (eluent ethyl acetate gradient 10%!25% in heptane).
6-O-Acetyl-3,4-di-O-benzyl-[(S)-1,2-O-(1-cyanoethylidene)]-a-D-glucopyranose
[24]
(9exo). (1.41 g, 58%, TLC solvent E Rf 0.43), colorless crystals: mp 87–89°C; [a]D
1
+20.6 (c 1.0, chloroform); H NMR (CDCl3) d 1.87 [s, 3H, C(CN)CH3], 2.02 (s, 3H,
OCOCH3), 3.55 (ddd, 1H, J4,5 = 9.6 Hz, H-4), 3.79 (ddd, 1H, J5,6 = 2.7 Hz, J5,6’ = 5.2
Hz, H-5), 3.96 (t, 1H, J3,4 = 2.9 Hz, H-3), 4.16 (dd, 1H, J6,6’ = 12.2 Hz, H-6), 4.25 (dd,
1H, H-6’), 4.35, 4.53 (2d, 2H, J = 11.6 Hz, CH2C6H5), 4.48 (ddd, 1H, J2,3 = 3.2 Hz, H-2),
4.58, 4.70 (2d, 2H, J = 11.7 Hz, CH2C6H5), 5.78 (d, 1H, J1,2 = 5.2 Hz, H-1), 7.21–7.41
(m, 10H, 2 ꢁ CH2C6H5); 13C NMR (CDCl3) d 20.75 (OCOCH3), 24.55 [C(CN)CH3],
63.42 (C-6), 68.63 (C-5), 72.06, 72.26 (2 ꢁ CH2C6H5), 74.72 (C-4), 74.98 (C-2), 75.95
(C-3), 97.94 (C-1), 98.58 [C(CN)CH3], 116.94 [C(CN)CH3], 128.14, 128.36, 128.52,
128.68, 136.94 (2 ꢁ CH2C6H5, seven signals are isochronic), 170.70 (OCOCH3).
Anal.Calcd for C25H27O7N (453.49): C, 66.21; H, 6.00; N, 3.09. Found: C, 66.05;
H, 5.92; N, 3.12.
6-O-Acetyl-3,4-di-O-benzyl-[(R)-1,2-O-(1-cyanoethylidene)]- -D-glucopyranose
[24]
(9endo). (0.36 g, 15%, TLC solvent E Rf 0.40), colorless syrup: [a]D
+ 70.9 (c 1.0,
1
chloroform); H NMR (CDCl3) d 1.76 [s, 3H, C(CN)CH3], 2.01 (s, 3H, OCOCH3), 3.51
(dd, 1H, J4,5 = 9.6 Hz, H-4), 4.05 (m, 1H, H-5), 4.23 (d, 1H, J3,4 = 8.1 Hz, H-3), 4.28
(m, 1H, H-6), 4.31 (m, 1H, H-6’), 4.36 (t, 1H, J2,3 = 5.5 Hz, H-2), 4.56, 4.72 (2d, 2H,
J = 11.4 Hz, CH2C6H5), 4.80, 4.86 (2d, 2H, J = 11.6 Hz, CH2C6H5), 5.65 (d, 1H,
J1,2 = 4.9 Hz, H-1), 7.23–7.40 (m, 10H, 2 ꢁ CH2C6H5); 13C NMR (CDCl3) d 20.78
(OCOCH3), 24.40 [C(CN)CH3], 62.87 (C-6), 71.17 (C-5), 73.39, 74.28 (2 ꢁ CH2C6H5),
74.11 (C-4), 80.12 (C-2), 80.28 (C-3), 99.01 (C-1), 99.11 [C(CN)CH3], 117.81 [C(CN)-
CH3], 128.02, 128.14, 128.48, 128.53, 137.49 (2 ꢁ CH2C6H5, seven signals are iso-
chronic), 170.53 (OCOCH3).
Anal.Calcd for C25H27O7N (453.49): C, 66.21; H, 6.00; N, 3.09. Found: C, 66.04;
H, 5.91; N, 3.20.
3,4-Di-O-benzyl-[(S)-1,2-O-(1-cyanoethylidene)]- -D-glucopyranose (10). Meth-
anolic HCl (0.28 M, 60 mL, prepared by adding 1.2 mL acetyl chloride to 60 mL ice-cold
dry methanol) was added to a solution of 9exo (1.05 g, 2.3 mmol) in dry dichloromethane
(20 mL) and the mixture was stirred for 15 h at rt (TLC solvent F Rf 0.46). The solution
was made neutral by addition of PbCO3/Pb(OH)2 (5 g). The lead salts were filtered off
and washed with dry methanol. The filtrate and washings were passed through a thin
layer of silica gel and concentrated. The residue was purified by MPLC (eluent ethyl
acetate gradient 0% ! 50% in heptane) to yield 10 (0.65 g, 69%) as colorless crystals:

Comparison of Glucuronate Glycosyl Donors
951
[26]
1
mp 114–115°C; [a]D
+ 12.8 (c 1.0, chloroform); H NMR (CDCl3) d 1.84 [s, 3H,
C(CN)CH3], 3.61–3.66 (m, 3H, H-4, H-5, H-6), 3.78 (m, 1H, H-6’), 3.93 (ddd, 1H,
J3,4 = 2.8 Hz, H-3), 4.39, 4.51 (2d, 2H, J = 11.6 Hz, CH2C6H5), 4.44 (ddd, 1H, J2,3 = 5.3
Hz, H-2), 4.54, 4.64 (2d, 2H, J = 11.8 Hz, CH2C6H5), 5.77 (d, 1H, J1,2 = 5.5 Hz, H-1),
7.21–7.40 (m, 10H, 2 ꢁ CH2C6H5); 13C NMR (CDCl3) d 24.30 [C(CN)CH3], 62.18 (C-
6), 70.71 (C-5), 71.84, 72.24 (2 ꢁ CH2C6H5), 74.53 (C-4), 74.86 (C-2), 75.77 (C-3),
97.72 (C-1), 98.35 [C(CN)CH3], 116.77 [C(CN)CH3], 127.80, 127.85, 127.92, 128.04,
128.29, 128.43, 136.75, 137.21 (2 ꢁ CH2C6H5, four signals are isochronic).
Anal.Calcd for C23H25NO6 (411.45): C, 67.14; H, 6.12; N, 3.40. Found: C, 67.19;
H, 6.20; N, 3.31.
Methyl 3,4-di-O-benzyl-[(S)-1,2-O-(1-ethoxyethylidene)]- -D-glucopyranuronate
(14). To a solution of orthoester 6 (861 mg, 2 mmol) in dichloromethane (20 mL)
were added 2,2,6,6-tetramethylpiperidine 1-oxide (TEMPO, 3.9 mg, 0.025 mmol), aq
5% NaHCO3 (10 mL), KBr (48 mg, 0.4 mmol) and tetrabutylammonium chloride (14
mg, 0.05 mmol). After a few minutes, a solution of aq NaOCl (13% active chlorine, 12
mL), sat aq NaHCO3 (5 mL) and sat aq NaCl (10 mL) was added at 0°C. The mixture
was stirred vigorously for an additional 30 min at rt followed by TLC (solvent F).
NaHCO3 (1.5 g), tetrabutylammonium bromide (645 mg, 2.0 mmol) and methyl iodide
(0.5 mL, 8.0 mmol) were then added and the resulting mixture was stirred vigorously
overnight (TLC solvent E Rf 0.44). Chloroform (30 mL) and heptane (100 mL) were
added and the organic layer was washed with water (3 ꢁ 50 mL), dried and concen-
trated. The purification of the residue by HPLC (eluent solvent A with 1% Et3N)
[24]
1
yielded 14 (595 mg, 65%) as a colorless syrup: [a]D
+ 19.4 (c 1.0, chloroform); H
NMR (CDCl3) d 1.18 [t, 3H, C(CH3)OCH2CH3], 1.68 [s, 3H, C(CH3)OCH2CH3], 3.53
[q, 2H, C(CH3)OCH2CH3], 3.69 (s, 3H, OCH3), 3.91 (m, 1H, H-4), 3.93 (m, 1H, H-3),
4.30 (m, 1H, H-5), 4.36 (m, 1H, H-2), 4.53, 4.62 (2d, 2H, J = 11.60 Hz, CH2C6H5),
4.54, 4.60 (2d, 2H, J = 12.0 Hz, CH2C6H5), 5.79 (d, 1H, J1,2 = 4.6 Hz, H-1), 7.24–7.36
(m, 10H, 2 ꢁ CH2C6H5); 13C NMR (CDCl3) d 15.28 [C(CH3)OCH2CH3], 22.43 [C-
(CH3)OCH2CH3], 52.40 (OCH3), 58.51 [C(CH3)OCH2CH3], 71.14 (C-5), 72.13, 72.79
(2 ꢁ CH2C6H5), 75.50 (C-4), 75.71 (C-2), 76.80 (C-3), 96.77 (C-1), 122.15 [C(CH3)-
OCH2CH3], 127.91, 128.02, 128.38, 128.49, 137.41, 137.65 (2 ꢁ CH2C6H5, six signals
are isochronic), 170.16 (C-6).
Anal.Calcd for C25H30O8 (458.50): C, 65.49; H, 6.59. Found: C, 65.28; H, 6.71.
Methyl 2-O-acetyl-3,4-di-O-benzyl- -D-glucopyranosyluronate bromide (15).
Acetyl bromide (0.3 mL, 4.0 mmol) was added to a mixture of compound 14 (367 mg,
0.8 mmol), tetraethylammonium bromide (84 mg, 0.4 mmol), and molecular sieves
˚
(4 A, 0.5 g) in dry dichloromethane (5 mL) at ambient temperature. After stirring for
2 h (TLC solvent E Rf 0.46), chloroform (25 mL) and heptane (50 mL) were added and
the resulting organic layer was washed with ice–water (2 ꢁ 50 mL), sat aq NaHCO3
(2 ꢁ 50 mL), ice–water (2 ꢁ 50 mL), dried and concentrated. The crude bromide 15
(380 mg, 96%) obtained as a light-yellow syrup was used immediately for the next step
without further purification.
Methyl 3,4-di-O-benzyl-[(S)-1,2-O-(1-cyanoethylidene)]- -D-glucopyranuronate
(12). Via 10. Jones reagent (3.8 mL, prepared by adding 720 mg chromium(VI) oxide

952
Pews-Davtyan et al.
to 3.6 mL 3.5 M sulfuric acid) was added dropwise to a solution of compound 10 (0.5
g, 1.2 mmol) in acetone (5 mL) and dichloromethane (1 mL) at 0°C. After stirring for
15 h at rt, ethanol was added (10 mL) and the solution was filtered. The neutralization
of the filtrate was realized by addition of NaHCO3 (1.5 g). The salts were filtered off
and the filtrate was concentrated. After dissolving the residue in chloroform (7 mL), the
resulting solution was treated with Dowex 50 [H+] resin to reach pH 2–3, then filtered
and concentrated to dryness. The obtained syrupy 3,4-di-O-benzyl-[(S)-1,2-O-(1-cya-
noethylidene]-a-D-glucopyranuronic acid (11) was dissolved in dichloromethane (5 mL)
and a solution of diazomethane in ether (ca. 10 mL) was added dropwise until the
yellow color of the reaction mixture persisted (TLC solvent E Rf 0.45). The excess of
diazomethane was destroyed by addition of acetic acid ( 3 mL) and the solution was
then poured in water (50 mL). The layers were separated and the organic layer was
washed with water (2 ꢁ 50 mL), sat aq NaHCO3 (2 ꢁ 50 mL), water (2 ꢁ 50 mL),
dried and concentrated. The purification of the residue by HPLC (solvent C) gave the
ester 12 (0.34 g, 63%) as a colorless syrup.
Via 15. The heterogeneous mixture of bromide 15 (400 mg, 0.8 mmol), carefully
powdered sodium cyanide (780 mg, 16 mmol) and tetrabutylammonium bromide (130
mg, 0.4 mmol) in dry acetonitrile (8 mL) was vigorously stirred for 4 d under an argon
atmosphere at rt in the dark (TLC solvent E Rf 0.45). The reaction mixture was then
diluted with heptane (100 mL) and chloroform (50 mL), washed successively with
water (4 ꢁ 50 mL), aq 15% NaHSO4 (2 ꢁ 50 mL), water (2 ꢁ 50 mL), sat aq
NaHCO3 (2 ꢁ 50 mL), water (2 ꢁ 50 mL), dried and concentrated. The residue was
dissolved in ethyl acetate (10 mL), the solution was filtered through a thin layer of
silica gel and concentrated. The crude material was purified by HPLC to yield ex-
[24]
clusively the pure exo-isomer 12 (230 mg, 65%) as a syrup: [a]D
ꢀ 6.3 (c 1.0,
1
chloroform); H NMR (CDCl3) d 1.88 [s, 3H, C(CN)CH3], 3.72 (s, 3H, OCH3), 4.05
(dd, 1H, J4,5 = 7.6 Hz, H-4), 4.06 (m, 1H, H-3), 4.22 (d, 1H, H-5), 4.43 (m, 1H, H-2),
4.50, 4.55 (2d, 2H, J = 11.5 Hz, CH2C6H5), 4.52, 4.58 (2d, 2H, J = 11.9 Hz,
CH2C6H5), 5.86 (d, 1H, J1,2 = 4.9 Hz, H-1) 7.24–7.39 (m, 10H, 2 ꢁ CH2C6H5); 13C
NMR (CDCl3) d 24.84 [C(CN)CH3], 52.58 (OCH3), 70.79 (C-5), 72.21, 72.62 (2 ꢁ
CH2C6H5), 75.00 (C-3), 75.21 (C-4), 75.45 (C-2), 97.04 (C-1), 99.37 [C(CN)CH3],
116.84 [C(CN)CH3], 127.99, 128.05, 128.29, 128.46, 128.63, 129.79, 136.84, 137.34
(2 ꢁ CH2C6H5, four signals are isochronic), 169.49 (C-6); CI mass spectrum (isobu-
tane): m/z 439 (M+).
Anal.Calcd for C24H25NO7 (439.46): C, 65.59; H, 5.73; N, 3.19. Found: C, 65.72;
H, 5.56; N, 3.16.
Methyl 2-O-acetyl-3,4-di-O-benzyl-D-glucopyranuronate (16). To a solution of
orthoester 14 (1.83 g, 4.0 mmol) in 1.4-dioxane (40 mL) was added aq 60% acetic acid
(80 mL). After stirring at rt for 1 h (TLC solvent F Rf 0.39), the solution was co-
evaporated with toluene (5 ꢁ 50 mL). The residue was purified by HPLC (eluent
1
solvent E) to provide crystalline 16 (1.68 g, 98%, 4:1 ratio of the a,b anomers ): H
NMR of 16 (CDCl3) d 2.01 (s, 3H, OCOCH3), 3.69 (s, 3H, OCH3), 3.83 (dd, 1H,
J4,5 = 9.5 Hz, H-4), 4.05 (dd, 1H, J3,4 = 8.8 Hz, H-3), 4.48 (d, 1H, H-5) 4.61, 4.72 (2d,
2H, J = 11.0 Hz, CH2C6H5), 4.75, 4.76 (2d, 2H, J = 9.7 Hz, CH2C6H5), 4.85 (dd, 1H,
J2,3 = 9.7 Hz, H-2), 5.44 (d, 1H, J1,2 = 3.6 Hz, H-1) 7.20–7.37 (m, 10H, 2 ꢁ CH2C6H5);
13C NMR (CDCl3) d 20.84 (OCOCH3), 52.52 (OCH3), 70.44 (C-5), 72.97 (C-2), 75.04,

Comparison of Glucuronate Glycosyl Donors
953
75.42 (2 ꢁ CH2C6H5), 78.81 (C-3), 79.19 (C-4), 90.72 (C-1), 127.65, 127.76, 127.89,
127.98, 128.03, 128.42, 137.74, 138.24 (2 ꢁ CH2C6H5, four signals are isochronic),
169.74 (OCOCH3), 170.28 (C-6).
Anal.Calcd for C23H26O8 (430.45): C, 64.18; H, 6.08. Found: C, 64.02; H, 6.05.
Methyl (2-O-acetyl-3,4-di-O-benzyl- -D-glucopyranosyl)uronate trichloroace-
timidate (17). A suspension of sodium hydride in oil (70%, 19.2 mg, 0.56 mmol) was
added to a solution of compound 16 (340 mg, 0.8 mmol) and trichloroacetonitrile (0.8
mL, 8.0 mmol) in dry dichloromethane (8 mL).The mixture was stirred for 3 h at rt (TLC
solvent F Rf 0.61), filtered then through a thin layer of silica gel and evaporated. The
crude product was purified by HPLC (eluent solvent B) to yield 17 (430 mg, 94%) as
[26]
1
colorless syrup: [a]D
+ 68.4 (c 1.0, chloroform); H NMR (CDCl3) d 1.93 (s, 3H,
OCOCH3), 3.72 (s, 3H, OCH3), 3.94 (dd, 1H, J4,5 = 10.0 Hz, H-4), 4.11 (t, 1H, J3,4 = 9.6
Hz, H-3), 4.43 (d, 1H, H-5), 4.63, 4.76 (2d, 2H, J = 10.7 Hz, CH2C6H5), 4.82, 4.87 (2d,
2H, J = 11.3 Hz, CH2C6H5), 5.09 (dd, 1H, J2,3 = 9.9 Hz, H-2), 6.54 (d, 1H, J1,2 = 3.5 Hz,
H-1), 7.23–7.38 (m, 10H, 2 ꢁ CH2C6H5), 8.64 [s, 1H, O(C NH)CCl3]; 13C NMR
(CDCl3) d 20.51 (OCOCH3), 52.66 (OCH3), 71.81 (C-5), 72.65 (C-4), 75.51 (2 ꢁ
CH2C6H5), 78.77 (C-3), 78.95 (C-2), 90.79 [O(C NH)CCl3], 93.57 (C-1), 127.89,
128.09, 128.22, 128.44, 128.49, 137.42, 137.99 (2 ꢁ CH2C6H5, five signals are iso-
chronic), 160.74 [O(C NH)CCl3], 168.66 (OCOCH3), 168.86 (C-6); CI mass spectrum
(isobutane): m/z 413 (M-trichloroacetimidate+, 100%).
Anal.Calcd for C25H26NO8Cl3 (574.84): C, 52.23; H, 4.56; N, 2.44. Found: C,
52.38; H, 4.69; N, 2.57.
The quality of the sodium hydride has a strong influence on the outcome of the
reaction. In some cases, the yield was remarkably lower and the formation of the
1
b-anomer was observed: H NMR of 17 (CDCl3) d 1.92 (s, 3H, OCOCH3), 3.71 (s,
3H, OCH3), 3.77 (t, 1H, J3,4 = 8.5 Hz, H-3), 4.04 (dd, 1H, J4,5 = 9.8 Hz, H-4), 4.15 (d,
1H, H-5), 4.63, 4.77 (2d, 2H, J = 11.1 Hz, CH2C6H5), 4.69, 4.79 (2d, 2H, J = 11.6 Hz,
CH2C6H5), 5.28 (dd, 1H, J2,3 = 8.5 Hz, H-2), 5.83 (d, 1H, J1,2 = 7.1 Hz, H-1), 7.21–
7.36 (m, 10H, 2 ꢁ CH2C6H5), 8.66 [s, 1H, O(C NH)CCl3]; 13C NMR of 17 (CDCl3)
d 20.69 (OCOCH3), 52.63 (OCH3), 71.60 (C-5), 74.88 (C-4), 74.67, 75.00 (2 ꢁ
CH2C6H5), 78.51 (C-3), 81.43 (C-2), 90.83 [O(C NH)CCl3], 95.96 (C-1), 127.89,
127.93, 128.01, 128.10, 128.45, 137.43, 137.74 (2 ꢁ CH2C6H5, five signals are iso-
chronic), 160.98 [O(C NH)CCl3], 168.31 (OCOCH3), 168.96 (C-6).
Methyl 1,2,3,4-tetra-O-acetyl- -D-glucopyranuronate (20). 1H NMR (CDCl3) d
1.96, 1.97, 2.05 (3s, 12H, 4 ꢁ OCOCH3), 3.80 (s, 3H, OCH3), 4.14 (d, 1H, H-5), 5.08
(dd, 1H, J2,3 = 8.8 Hz, H-2), 5.17 (t, 1H, J4,5 = 9.3 Hz, H-4), 5.22 (dd, 1H, J3,4 = 12.7
Hz, H-3), 5.71 (d, 1H, J1,2 = 8.1 Hz, H-1); 13C NMR (CDCl3) d 20.44, 20.52, 20.74
(4 ꢁ OCOCH3), 52.99 (OCH3), 68.87 (C-2), 70.09 (C-3), 71.75 (C-4), 72.90 (C-5),
91.29 (C-1), 166.79 (C-6), 168.80, 169.15, 169.39, 169.86 (4 ꢁ OCOCH3).
Methyl 3,4-di-O-acetyl-[(S)-1,2-O-(1-ethoxyethylidene)]- -D-glucopyranuronate
(22). Dry ethanol (1.3 mL, 21.8 mmol), sym-collidine (2 mL, 15.3 mmol) and tetra-
butylammonium bromide (0.46 g, 1.39 mmol) were added to a mixture of bromide 21
˚
(5.5 g, 13.9 mmol) and molecular sieves (4A, 0.5 g) in dry acetonitrile (8 mL). After
stirring overnight (TLC solvent F Rf 0.57) at 40°C under an atmosphere of argon, the

954
Pews-Davtyan et al.
precipitated sym-collidine hydrobromide was filtered off and the filtrate was passed
through a layer of silica gel. The solution was then diluted with chloroform (50 mL) and
heptane (100 mL), washed with ice–water (5 ꢁ 50 mL), dried and concentrated. The
purification of the residue by MPLC (eluent solvent B with 1% Et3N) yielded 22 (4.7 g,
[26]
1
90%) as a colorless syrup: [a]D
+ 11.5 (c 1.0, chloroform); H NMR (CDCl3) d 1.13
[t, 3H, C(CH3)OCH2CH3], 1.69 [s, 3H, C(CH3)OCH2CH3], 2.04, 2.05 (2s, 6H, 2 ꢁ
OCOCH3), 3.49 [q, 2H, C(CH3)OCH2CH3], 3.72 (s, 3H, OCH3), 4.27 (m, 1H, H-2), 4.27
(d, 1H, H-5), 5.09 (ddd, 1H, J4,5 = 7.5 Hz, H-4), 5.18 (t, 1H, J3,4 = 2.6 Hz, H-3), 5.81 (d,
1H, J1,2 = 4.6 Hz, H-1); 13C NMR (CDCl3) d 15.17 [C(CH3)OCH2CH3], 20.71 (2 ꢁ
OCOCH3), 21.53 [C(CH3)OCH2CH3], 52.72 (OCH3), 58.87 [C(CH3)OCH2CH3], 68.18
(C-4),68.37(C-3),68.98(C-5),72.81(C-2),96.01(C-1),122.24[C(CH3)OCH2CH3],168.91
(2 ꢁ OCOCH3),169.38(C-6).
Anal.Calcd for C15H22O10 (362.33): C, 49.72; H, 6.12. Found: C, 49.85; H, 6.07.
Methyl [(S)-1,2-O-(1-ethoxyethylidene)]- -D-glucopyranuronate (23). A meth-
anolic sodium methoxide solution (0.5 M, 0.7 mL) was added to a solution of compound
22 (900 mg, 2.5 mmol) in dry methanol (15 mL). After stirring for 1 h at ambient
temperature under an atmosphere of argon (TLC solvent G Rf 0.25), the solution was
concentrated. The residue was dissolved in ethyl acetate, filtered through a layer of
silica gel and concentrated. The purification of the crude material by MPLC (eluent
solvent F with 1% Et3N) afforded 23 (670 mg, 95%) as a colorless syrup: [a]D[26] + 19.7
1
(c 1.0, chloroform); H NMR (CDCl3) d 1.16 [t, 3H, C(CH3)OCH2CH3), 1.69 [s, 3H,
C(CH3)OCH2CH3], 3.54 [q, 2H, C(CH3)OCH2CH3], 3.78 (s, 3H, OCH3), 3.92 (dd, 1H,
J4,5 = 6.7 Hz, H-4), 4.09 (t, 1H, J3,4 = 4.5 Hz, H-3), 4.27 (t, 1H, J2,3 = 4.2 Hz, H-2),
4.29 (d, 1H, H-5), 5.82 (d, 1H, J1,2 = 4.0 Hz, H-1); 13C NMR (CDCl3) d 15.17
[C(CH3)OCH2CH3], 23.07 [C(CH3)OCH2CH3], 52.69 (OCH3), 58.64 [C(CH3)OCH2CH3],
70.02 (C-4), 70.53(C-3), 73.43(C-5), 77.27 (C-2), 96.24 (C-1), 122.35 [C(CH3)OCH2CH3],
170.88 (C-6).
Anal.Calcd for C11H18O8 (278.25): C, 47.48; H, 6.52. Found: C, 47.33; H, 6.50.
Methyl 3-O-benzyl-[(S)-1,2-O-(1-ethoxyethylidene)]-4-deoxy-L-threo-hex-4-eno-
˚
pyranuronate (24). Molecular sieves (4 A, 0.5 g) were added to a solution of com-
pound 23 (0.56 g, 2.0 mmol) in dry N,N-dimethylformamide (20 mL) and the mixture
was stirred for 15 min at ambient temperature. After cooling to ꢀ20°C, dry silver oxide
(0.93 g, 4.0 mmol) and dry potassium iodide (0.33 g, 2.0 mmol) were added under an
atmosphere of argon. A solution of benzyl bromide (0.71 mL, 6.0 mmol) in dry N,N-
dimethylformamide (2 mL) was then added dropwise to the vigorously stirred reaction
mixture during 30 min at ꢀ20°C. After stirring for 2 h at that temperature (TLC solvent
F Rf 0.56), the mixture was filtered through bed of silica gel and the filtrate was diluted
with chloroform (50 mL) and heptane (100 mL). The organic layer was washed with
ice–water (2 ꢁ 50 mL), aq 10% sodium thiosulphate (3 ꢁ 50 mL), brine (2 ꢁ 50 mL),
ice–water (2 ꢁ 50 mL), dried and concentrated. The crude material was purified by
HPLC (eluent solvent A) to provide compound 24 (0.55 g, 78 %) as a colorless syrup:
[a]D[24] + 140.2 (c 1.0, chloroform); 1H NMR (CDCl3) d 1.17 [t, 3H, C(CH3)OCH2CH3],
1.54 [s, 3H, C(CH3)OCH2CH3], 3.55 [q, 2H, C(CH3)OCH2CH3], 3.79 (s, 3H, OCH3), 4.17
(dd, 1H, J3,4 = 4.9 Hz, H-3), 4.50 (m, J2,3 = 1.8 Hz, 1H, H-2), 4.55, 4.63 (2d, 2H, J = 11.6
Hz, CH2C6H5), 5.73 (d, 1H, J1,2 = 4.0 Hz, H-1), 6.24 (dd, 1H, H-4), 7.27–7.34 (m, 5H,

Comparison of Glucuronate Glycosyl Donors
955
CH2C6H5); 13C NMR (CDCl3) d 14.97 [C(CH3)OCH2CH3], 24.43 [C(CH3)OCH2CH3],
52.52 (OCH3), 57.95 [C(CH3)OCH2CH3], 67.31 (C-3), 70.96 (CH2C6H5), 77.39 (C-2),
96.15 (C-1), 107.32 (C-4), 123.06 [C(CH3)OCH2CH3], 127.82, 128.02, 128.48, 137.11
(CH2C6H5), 143.07 (C-5), 162.14 (C-6).
Anal.Calcd for C25H30O8 (458.50): C, 65.49; H, 6.59. Found: C, 65.28; H, 6.71.
Methyl (allyl 2,3,4-tri-O-acetyl- -D-glucopyranosid)uronate (25). Mercuric
cyanide (3.46 g, 13.7 mmol) and mercuric bromide (0.49 g, 1.37 mmol) were added to a
solution of bromide 21 (10.9 g, 27.4 mmol) in dry allyl alcohol (56 mL). The mixture
was stirred for 15 h at ambient temperature under an atmosphere of argon (TLC solvent
G Rf 0.43) and then concentrated. The residue was dissolved in a solution of chloroform
(50 mL) and heptane (100 mL). The resulting solution was washed with ice–water
(4 ꢁ 50 mL), aq 1 N potassium iodide (3 ꢁ 50 mL), ice–water (2 ꢁ 50 mL), dried and
concentrated. The residue was purified by crystallization from ethyl acetate–heptane
[24]
(1:4) to provide 25 (10.0 g, 97%) as colorless crystals: mp 134–135°C; [a]D
ꢀ 40.2
(c 1.0, chloroform); 1H NMR (CDCl3) d 1.97, 2.05 (2s, 9H, 3 ꢁ OCOCH3), 3.72 (s, 3H,
OCH3), 3.97 (d, 1H, H-5), 4.06, 4.33 (2m, 2H, OCH2CH CH2), 4.57 (d, 1H, J1,2 = 7.7
Hz, H-1), 5.00 (m, 1H, H-2), 5.21 (m, 1H, J4,5 = 9.6 Hz, H-4), 5.22 (m, 1H, H-3), 5.15–
5.27 (m, 2H, OCH2CH CH2), 5.79 (m, 1H, OCH2CH CH2); 13C NMR (CDCl3) d
20.52, 20.64 (3 ꢁ OCOCH3 one signal is isochronic), 52.93 (OCH3), 69.41 (C-4), 70.12
(OCH2CH CH2), 71.17 (C-2), 72.04 (C-3), 72.56 (C-5), 99.45 (C-1), 117.88 (OCH2-
CH CH2), 133.06 (OCH2CH CH2), 167.29 (C-6), 169.29, 169.42, 170.17 (3 ꢁ
OCOCH3).
Anal.Calcd for C16H22O10 (374.34): C, 51.34; H, 5.92. Found: C, 51.39; H, 5.98.
Methyl (allyl -D-glucopyranosid)uronate (26). Compound 25 (2.27 g, 6 mmol)
was dissolved in methanolic HCl (0.28 N, 184 mL, prepared by adding 4.3 mL acetyl
chloride to 180 mL ice-cold dry methanol) and the solution was stirred for 10 h at rt
(TLC solvent H Rf 0.48). The solution was then neutralized with solid NaHCO3,
filtered through a thin layer of alkaline alumina, concentrated and dried in high vacuum
[25]
to give analytically pure 26 (1.34, 90%) as a colorless amorphous solid: [a]D
ꢀ 60.0
1
(c 1.0, chloroform); H NMR (CDCl3) d 3.45 (m, 1H, H-2), 3.53 (m, 1H, H-3), 3.68
(m, 1H, J4,5 = 9.6 Hz, H-4), 3.75 (s, 3H, OCH3), 3.83 (d, 1H, H-5), 4.06, 4.30 (m, 2H,
OCH2CH CH2), 4.34 (d, 1H, J1,2 = 7.3 Hz, H-1), 4.70 (brs, 3H, 3 ꢁ OH), 5.14, 5.25
(2m, 2H, OCH2CH CH2), 5.87 (m, 1H, OCH2CH CH2); 13C NMR (CDCl3) d 52.79
(OCH3), 70.52 (OCH2CH CH2), 71.34 (C-4), 72.83 (C-2), 74.67 (C-5), 75.54 (C-3),
101.76 (C-1), 118.30 (OCH2CH CH2), 133.68 (OCH2CH CH2), 169.72 (C-6).
Anal.Calcd for C10H16O7 (248.23): C, 48.38; H, 6.49. Found: C, 48.24; H, 6.52.
Methyl (allyl 2,3,4-tri-O-trimethylsilyl- -D-glucopyranosid)uronate (27). Hexa-
methyldisilazane (1.65 mL, 8 mmol) and trimethylsilyl chloride (0.5 mL, 4 mmol) were
˚
added to a mixture of 26 (496 mg, 2 mmol) and molecular sieves (4 A, 0.5 g) in dry
pyridine (25 mL). After stirring for 1 h at ambient temperature (TLC solvent E Rf 0.54),
the mixture was diluted with chloroform (25 mL) and heptane (50 mL) and filtered. The
filtrate was washed with ice–water (2 ꢁ 50 mL), sat aq NH4Cl (2 ꢁ 50 mL), sat aq
NaHCO3 (2 ꢁ 50 mL), ice–water (2 ꢁ 50 mL), dried and concentrated. The residue
was purified by HPLC (eluent solvent A) to provide 27 (0.76 g, 81%) as a colorless

956
Pews-Davtyan et al.
[24]
1
syrup: [a]D
ꢀ 13.9 (c 1.0, chloroform); H NMR (CDCl3) d 0.06, 0.10, 0.13 [3s, 9H,
3 ꢁ Si(CH3)3], 3.40 (m, 1H, H-2), 3.42 (m, 1H, H-3), 3.70 (m, 1H, J4,5 = 9.5 Hz, H-4),
3.75 (s, 3H, OCH3), 3.78 (d, 1H, H-5), 3.97, 4.32 (2m, 2H, OCH2CH CH2), 4.23 (d, 1H,
J1,2 = 7.0 Hz, H-1), 5.14, 5.23 (2m, 2H, OCH2CH CH2), 5.87 (m, 1H, OCH2CH CH2);
13C NMR (CDCl3) d 0.11, 0.76, 0.96, 1.23, 1.43 [3 ꢁ Si(CH3)3, four signals are iso-
chronic], 52.45 (OCH3), 70.52 (OCH2CH CH2), 73.33 (C-4), 75.45 (C-2), 76.42
(C-5), 78.57 (C-3), 102.65 (C-1), 117.89 (OCH2CH CH2), 133.88 (OCH2CH CH2),
169.39 (C-6).
Anal.Calcd for C19H40O7Si3 (464.77): C, 49.10; H, 8.67. Found: C, 49.01; H, 8.81.
Methyl (allyl 2,3,4-tri-O-benzyl- -D-glucopyranosid)uronate (28). Molecular
˚
sieves (4 A, 1 g) were added to a solution of carefully dried 27 (500 mg, 2 mmol) in
dry N,N-dimethylformamide (22 mL) under an atmosphere of argon. After stirring for
15 min, dry silver oxide (5.56 g, 24 mmol) and dry potassium iodide (1.66 g, 1.0
mmol) were added at ꢀ23°C. To the vigorously stirred mixture was then added benzyl
bromide (2.85 mL, 24 mmol) in dry N,N-dimethylformamide (2 mL) during 30 min at
the same temperature. After stirring for 8 h (TLC solvent E Rf 0.53) at that temper-
ature, the mixture was filtered through a layer of silica gel. The filtrate was then diluted
with chloroform (50 mL) and heptane (100 mL), washed with ice–water (2 ꢁ 50 mL),
aq 10% sodium thiosulphate (3 ꢁ 50 mL), brine (2 ꢁ 50 mL), ice–water (2 ꢁ 50 mL),
dried and concentrated. The crude material was purified by HPLC (eluent solvent A) to
[25]
provide 28 (0.39 g, 38%) as colorless crystals: mp 112–113°C; [a]D
ꢀ 5.4 (c 1.0,
chloroform); 1H NMR (CDCl3) d 3.53 (dd, 1H, J2,3 = 9.1 Hz, H-2), 3.67 (t, 1H,
J3,4 = 8.5 Hz, H-3), 3.72 (s, 3H, OCH3), 3.84 (dd, 1H, J4,5 = 9.6 Hz, H-4), 3.91 (d, 1H,
H-5), 4.12, 4.42 (2m, 2H, OCH2CH CH2), 4.51 (d, 1H, J1,2 = 7.8 Hz, H-1), 4.60, 4.72
(2d, 2H, J = 11.2 Hz, CH2C6H5), 4.77, 4.81 (2 bs, 2H, J = 12.5 Hz, CH2C6H5), 4.92,
4.94 (2d, 2H, J = 10.7 Hz, CH2C6H5), 5.21, 5.34 (2m, 2H, OCH2CH CH2), 5.93 (m,
1H, OCH2CH CH2), 7.20–7.39 (m, 15H, 3 ꢁ CH2C6H5); 13C NMR (CDCl3) d 52.32
(OCH3), 70.42 (OCH2CH CH2), 74.44 (C-5), 74.81, 74.95, 75.60 (3 ꢁ CH2C6H5),
79.22 (C-4), 81.73 (C-2), 83.79 (C-3), 102.82 (C-1), 117.51 (OCH2CH CH2), 133.62
(OCH2CH CH2), 127.56, 127.64, 127.72, 127.76, 127.88, 128.09, 128.28, 137.82,
138.21, 138.37 (3 ꢁ CH2C6H5, eight signals are isochronic), 168.94 (C-6); CI mass
spectrum (isobutane): m/z 517.6 (M–H+).
Anal.Calcd for C31H34O7 (518.60): C, 71.79; H, 6.61. Found: C, 71.95; H, 6.67.
Methyl 2,3,4-tri-O-benzyl-D-glucopyranuronate (29). Sodium acetate (496 mg,
6.1 mmol) and palladium(II)chloride (390 mg, 2.2 mmol) were added to a solution of 28
(287 mg, 0.55 mmol) in acetic acid–water (20:1, 14 mL) and the mixture was stirred for 12
h at 40°C (TLC solvent F Rf 0.43). After filtration through Celite, the solution was diluted
with chloroform (35 mL) and heptane (70 mL) and successively washed with ice–water
(2 ꢁ 50 mL), sat aq NaHCO3 (2 ꢁ 50 mL), ice–water (2 ꢁ 50 mL), dried and concen-
trated. The crude material was purified by HPLC (eluent solvent B) to give 29 (210 mg,
80%, 4:1 ratio of the a,b anomers ) as colorless crystals: 1H NMR of 29 (CDCl3) d 3.58
(dd, 1H, J2,3 = 9.0 Hz, H-2), 3.68 (s, 3H, OCH3), 3.73 (dd, 1H, J4,5 = 9.7 Hz, H-4), 3.97 (t,
1H, J3,4 = 9.0 Hz, H-3), 4.46 (d, 1H, H-5) 4.64, 4.75 (2d, 2H, J = 11.9 Hz, CH2C6H5), 4.72,
4.77 (2d, 2H, J = 10.7 Hz, CH2C6H5), 4.80, 4.88 (2d, 2H, J = 11.0 Hz, CH2C6H5), 5.19 (d,

Comparison of Glucuronate Glycosyl Donors
957
1H, J1,2 = 3.4 Hz, H-1) 7.20–7.35 (m, 15H, 3 ꢁ CH2C6H5); 13C NMR of 29 (CDCl3) d
52.54 (OCH3), 70.39 (C-5), 73.49, 75.07, 75.77 (3 ꢁ CH2C6H5), 79.17 (C-4), 79.26 (C-2),
80.77 (C-3), 91.63 (C-1), 127.80, 127.90, 128.00, 128.05, 128.18, 128.23, 128.46, 128.48,
128.61, 137.61, 137.87, 138.40 (3 ꢁ CH2C6H5, six signals are isochronic), 170.06 (C-6).
Anal.Calcd for C28H30O7 (478.54): C, 70.28; H, 6.32. Found: C, 70.14; H, 6.30.
Methyl (2,3,4-tri-O-benzyl-D-glucopyranosyl)uronate trichloroacetimidate (30).
The glucuronate 29 (479 g, 1.0 mmol) was converted into the trichloroacetimidate 30
as described by Schmidt et al.[19] The quality of the sodium hydride has a strong
influence on the outcome of the reaction with regard to both yield and ratio of the a,b-
anomers. The a,b-anomers were separated by HPLC (eluent solvent A).
Methyl (2,3,4-tri-O-benzyl- -D-glucopyranosyl)uronate trichloroacetimidate
[24]
(30 ). (360 mg, 58%, TLC solvent F Rf 0.61), colorless syrup: [a]D
+ 45.8 (c 1.0,
1
chloroform); H NMR (CDCl3) d 3.69 (s, 3H, OCH3), 3.78 (dd, 1H, J2,3 = 9.5 Hz, H-
2), 3.82 (dd, 1H, J4,5 = 10.0 Hz, H-4), 4.06 (t, 1H, J3,4 = 9.3 Hz, H-3), 4.41 (dd, 1H, H-
5), 4.58 (d, 1H, J = 11.0 Hz, CH2C6H5), 4.71 (d, 2H, J = 11.0 Hz, CH2C6H5), 4.82 (d,
2H, J = 11.0 Hz, CH2C6H5), 4.95 (d, 1H, J = 11.0 Hz, CH2C6H5), 6.50 (d, 1H,
J1,2 = 3.4 Hz, H-1), 7.20–7.35 (m, 15H, 3 ꢁ CH2C6H5), 8.65 [s, 1H, O(C NH)CCl3];
13C NMR (CDCl3) d 52.64 (OCH3), 74.52 (C-5), 73.11, 75.47, 75.84 (3 ꢁ CH2C6H5),
78.75 (C-2), 78.86 (C-4), 80.70 (C-3), 90.99 [O(C NH)CCl3], 93.96 (C-1), 127.73,
127.78, 127.91, 128.03, 128.08, 128.20, 128.44, 128.48, 137.63, 137.68, 138.32 (3 ꢁ
CH2C6H5, seven signals are isochronic), 161.05 [O(C NH)CCl3], 169.23 (C-6).
Anal.Calcd for C30H30Cl3NO7 (622.93): C, 57.84; H, 4.85; N, 2.25. Found: C,
58.06; H, 4.91; N, 2.40.
Methyl (2,3,4-tri-O-benzyl- -D-glucopyranosyl)uronate trichloroacetimidate
[24]
(30 ). (90 mg, 14%, TLC solvent F Rf 0.60), colorless crystals: mp 106°C; [a]D
1
+15.2 (c 1.0, chloroform); H NMR (CDCl3) d 3.70 (s, 3H, OCH3) 3.76 (m, 1H, H-2),
3.78 (m, 1H, J3,4 = 9.5 Hz, H-3), 3.92 (t, 1H, J4,5 = 9.5 Hz, H-4), 4.09 (d, 1H, J5,4 = 9.5
Hz, H-5), 4.60, 4,80 (2d, 2H, J = 11.1 Hz, CH2C6H5), 4.74, 4.92 (2d, 2H, J = 10.7 Hz,
CHC6H5), 4.78, 4.88 (2d, 2H, J = 10.4 Hz, CH2C6H5), 5.87 (d, 1H, J1,2 = 7.3 Hz, H-1),
7.20-7.34 (m, 15H, 3 ꢁ CH2C6H5), 8.72 [s, 1H, O(C NH)CCl3]; 13C NMR (CDCl3) d
52.64 (OCH3), 74.82 (C-5), 74.86, 75.06, 75.63 (3 ꢁ CH2C6H5), 78.74 (C-4), 80.43 (C-
3), 83.64 (C-2), 91.47 [O(C NH)CCl3], 98.02 (C-1), 127.80, 127.85, 127.92, 127.97,
128.02, 128.08, 128.19, 128.45, 128.58, 137.60, 137.66, 138.12 (3 ꢁ CH2C6H5, six
signals are isochronic), 160.91 [O(C NH)CCl3], 168.70 (C-6).
Anal.Calcd for C30H30Cl3NO7 (622.93): C, 57.84; H, 4.85; N, 2.25. Found: C,
57.76; H, 4.82; N, 2.31.
Methyl [(2-R)-2,3,4,5-tetrahydro-5-oxo-2-furylmethyl 2-O-acetyl-3,4-di-O-ben-
zyl- -D-glucopyranosid]uronate (33). Via 12 and 32. The cyanoethylidene deriva-
tive 12 (88 mg, 0.2 mmol) and (5-R)-tetrahydro-5-trityloxymethyl-2-furanone (32, 79
mg, 0.22 mmol, FLUKA 93461) were dissolved in dry dichloromethane (10 mL) and
the solvent then evaporated. The residue was dried under high vacuum for about 2
h and then dissolved in dry dichloromethane (3 mL, twice distilled over CaH2). Trityl

958
Pews-Davtyan et al.
perchlorate (7 mg, 0.02 mmol) was added and the mixture was stirred in the dark
under an inert atmosphere at rt. After 24 h followed by TLC (solvent G Rf 0.43), aq
pyridine (2% water, 0.2 mL) was added. The reaction mixture was then filtered,
diluted with heptane (40 mL) and chloroform (20 mL), washed with water (3 ꢁ 30
mL), dried and concentrated. The purification by HPLC (eluent solvent F) afforded
compound 33 (73 mg, 69%).
Via 14 and 31. A solution of orthoester 14 (229 mg, 0.5 mmol) and (5-R)-2,3,4,5-
tetrahydro-5-hydoxymethyl-2-furanone (31, 64 mg, 0.55 mmol, FLUKA 55621) in dry
1,2-dichloroethane (3 mL) was evaporated at atmospheric pressure by addition of
fresh solvent to keep the volume constant. When 10 mL of the solvent had been
distilled off, p- toluenesulfonic acid (1.1 mg, 6.7 mmol) in dry dichloroethane (1 mL)
was added, and the mixture was distilled under the same conditions until the for-
mation of the new orthoester was nearly complete (ca. 1 h) while 14 disappeared in
the TLC (solvent F). Pyridinium perchlorate (1.2 mg, 6.7 mmol) was then added and
the mixture was refluxed for 2 h (TLC solvent G Rf 0.43). The solution was treated
with pyridine (0.1 mL) and evaporated. The residue was purified by HPLC to give 33
(74 mg, 28%).
Via 15 and 31. Anhyd silver perchlorate (112 mg, 0.54 mmol) was added to a
stirred solution of bromide 15 (222 mg, 0.45 mmol) in dry acetonitrile (5 mL) at
ꢀ15°C. After 40 min, a solution of the lactone 31 (58 mg, 0.5 mmol) in dry acetonitrile
(2 mL) was added and stirring was continued at rt for 16 h (TLC solvent G Rf 0.43).
The reaction mixture was then neutralized with anhydr sodium carbonate, diluted with
chloroform (30 mL) and heptane (60 mL) and filtered. The organic layer was washed
with water (3 ꢁ 50 mL), dried and concentrated. The crude product was purified by
HPLC to give 33 (107 mg, 45%).
Via 17 and 31. A solution of boron trifluoride etherate (5.8 mL, 46 mmol) in dry
dichloromethane (0.5 mL) was added to a mixture of trichloroacetimidate 17 (161 mg,
˚
0.28 mmol), lactone 31 (36 mg, 0.31 mmol) and molecular sieves (4 A, 1 g) in dry
dichloromethane (5 mL) under an atmosphere of argon at ꢀ20°C. After stirring for 2 h
at that temperature (TLC solvent G Rf 0.43), the mixture was treated with anhyd
NaHCO3 (50 mg) and passed through a layer of silica gel. The filtrate was washed with
sat aq NaHCO3 (2 ꢁ 50 mL), water (2 ꢁ 50 mL), dried and concentrated. The crude
material was purified by HPLC to yield 33 (105 mg, 71%) as colorless crystals: mp
[24]
128°C (from ethyl acetate–heptane); [a]D
ꢀ 13.6 (c 1.0, chloroform); 1H NMR
(CDCl3) d 1.96 (s, 3H, OCOCH3), 2.22 (m, 2H, lactone: H-4, H-4’), 2.36, 2.61 (2m,
2H, lactone: H-3, H-3’), 3.64 (dd, 1H, J = 11.2 Hz, lactone: H-6), 3.66 (dd, 1H,
J3,4 = 11.1 Hz, H-3), 3.71 (s, 3H, OCH3), 3.86 (dd, 1H, J4,5 = 8.0 Hz, H-4), 3.90 (ddd,
1H, J5,4 = 9.7 Hz, H-5), 3.94 (dd, 1H, lactone: H-6’), 4.43 (d, 1H, J1,2 = 7.5 Hz, H-1),
4.62 (m, 1H, lactone: H-5), 4.59, 4.66 (2d, 2H, J = 11.8 Hz, CH2C6H5), 4.76, 4.77 (2d,
2H, J = 11.2 Hz, CH2C6H5), 5.04 (dd, 1H, J2,3 = 9.2 Hz, H-2), 7.20–7.34 (m, 10H,
2 ꢁ CH2C6H5); 13C NMR (CDCl3) d 20.65 (OCOCH3), 23.56 (lactone: C-4), 28.05
(lactone: C-3), 52.59 (OCH3), 71.18 (lactone: C-6), 72.37 (C-2), 74.44 (C-5), 75.08
(2 ꢁ CH2C6H5, two signals are isochronic), 77.78 (lactone: C-5), 79.24 (C-4), 81.79
(C-3), 101.50 (C-1), 127.87, 128.03, 128.46, 137.51, 137.81 (2 ꢁ CH2C6H5, seven
signals are isochronic), 168.68 (C-6), 169.80 (COCH3), 177.52 (lactone: C-2); CI mass
spectrum: m/z 527.6 (M–H+), 413 (M-lactone+, 100%).
Anal.Calcd for C28H32O10 (528.55): C, 63.63; H, 6.10. Found: C, 63.55; H, 6.17.

Comparison of Glucuronate Glycosyl Donors
959
Methyl [(2-R)-2,3,4,5-tetrahydro-5-oxo-2-furylmethyl 3,4-di-O-benzyl- -D-glu-
copyranosid]uronate (34). Methanolic sodium methoxide (0.5 M, 0.7 mL) was added
to a solution of 33 (158 mg, 0.3 mmol) in dry dichloromethane (2 mL) and dry
methanol (10 mL). After stirring for 4 h at ambient temperature (TLC solvent G Rf
0.35), the solution was neutralized with Dowex-50 (H+) resin, filtered and concentrated.
The purification of the residue by HPLC (eluent solvent F) afforded compound 34 (110
[24]
1
mg, 75%), as colorless crystals: mp 112°C; [a]D
ꢀ 23.5 (c 1.0, chloroform); H
NMR (CDCl3) d 2.22 (m, 2H, lactone: H-4, H-4’), 2.52 (m, 2H, H-3, H-3’), 3.57 (dd,
1H, J2,3 = 7.9 Hz, H-2), 3.58 (dd, 1H, J3,4 = 8.2 Hz, H-3), 3.72 (s, 3H, OCH3), 3.80
(dd, 1H, J4,5 = 8.0 Hz, H-4), 3.81 (d, 1H, lactone: H-6), 3.91 (d, 1H, J5,4 = 9.6 Hz,
H-5), 3.99 (dd, 1H, lactone: H-6’), 4.37 (d, 1H, J1,2 = 7.6 Hz, H-1), 4.59, 4.80 (2d, 2H,
J = 11.1 Hz, CH2C6H5), 4.68 (m, 1H, lactone: H-5), 4.83, 4.92 (2d, 2H, J = 11,3 Hz,
CH2C6H5), 7.20–7.40 (m, 10H, 2 ꢁ CH2C6H5); 13C NMR (CDCl3) d 23.73 (lactone:
C-4), 28.31 (lactone: C-3), 52.48 (OCH3), 70.96 (lactone: C-6), 73.96 (C-2), 74.41 (C-
5), 74.95, 75.16 (2 ꢁ CH2C6H5), 78.21 (lactone: C-5), 78.76 (C-4), 83.37 (C-3), 103.25
(C-1), 127.76, 127.84, 127.91, 128.36, 128.42, 137.61, 138.21 (2 ꢁ CH2C6H5, five
signals are isochronic), 168.87 (C-6), 177.42 (lactone: C-2).
Anal.Calcd for C26H30O9 (486.51): C, 64.18; H, 6.21. Found: C, 64.37; H, 6.36.
Methyl [(2-R)-2,3,4,5-tetrahydro-5-oxo-2-furylmethyl 2,3,4-tri-O-benzyl- -D-
glucopyranosid]uronate (35). A solution of boron trifluoride etherate (3.5 mL, 25
mmol) in dry dichloromethane (1.0 mL) was added to a mixture of trichloroacetimidate
˚
30 (95 mg, 0.15 mmol), lactone 31 (19 mg, 0.17 mmol) and molecular sieves (4 A, 1 g)
in dry dichloromethane (3 mL) under an atmosphere of argon at ꢀ20°C. After stirring
for 2 h at that temperature (TLC solvent F Rf 0.33), the mixture was treated with anhyd
NaHCO3 (50 mg) and passed through a layer of silica gel. The filtrate was washed with
sat aq NaHCO3 (2 ꢁ 50 mL), water (2 ꢁ 50 mL), dried and concentrated. The residue
was purified by HPLC (eluent solvent F) to provide compound 35 (61 mg, 70%,
1
containing ca. 20% of the a-anomer) as colorless syrup: H NMR of 35 (CDCl3) d 2.24
(m, 2H, lactone: H-4, H-4’), 2.50 (m, 2H, lactone: H-3, H-3’), 3.48 (dd, 1H, J2,3 = 8.7
Hz, H-2), 3.66 (t, 1H, J4,5 = 8.7 Hz, H-4), 3.71 (s, 3H, OCH3), 3.81 (dd, 1H, lactone:
H-6), 3.83 (dd, 1H, J3,4 = 9.0 Hz, H-3), 3.89 (d, 1H, J5,4 = 9.5 Hz, H-5), 3.99 (dd, 1H,
lactone: H-6’), 4.48 (d, 1H, J1,2 = 7.3 Hz, H-1) 4.56, 4.66 (2d, 2H, J = 11.00 Hz,
CH2C6H5), 4.67 (m, 1H, lactone: H-5), 4.77, 4.78 (2d, 2H, J = 11.4 Hz, CH2C6H5),
4.80, 4.89 (2d, 2H, J = 11.0 Hz, CH2C6H5), 7.17–7.35 (m, 15H, 3 ꢁ CH2C6H5); 13C
NMR of 35 (CDCl3) d 23.91 (lactone: C-4), 28.45 (lactone: C-3), 52.55 (OCH3), 70.52
(lactone: C-6), 74.35 (C-5), 74.86, 75.07, 75.71 (3 ꢁ CH2C6H5), 78.20 (lactone: C-5),
79.07 (C-3), 81.57 (C-2), 83.70 (C-4), 103.57 (C-1), 127.77, 127.81, 127.88, 127.93,
128.02, 128.09, 128.44, 128.56, 137.71, 137.95, 138.22 (3 ꢁ CH2C6H5, seven signals
are isochronic), 169.06 (C-6), 177.01 (lactone: C-2).
Anal.Calcd for C33H36O9 (576.64): C, 68.73; H, 6.29. Found: C, 68.61; H, 6.40.
Methyl [(2-R)-2,3,4,5-tetrahydro-5-oxo-2-furylmethyl -D-glucopyranosid]uro-
nate (36). To a solution of 35 (49 mg, 85 mmol) in ethyl acetate (2 mL) and ethanol
(3 mL) 10% was added palladium-on-charcoal (65 mg). The mixture was stirred in an
atmosphere of hydrogen at rt. When the reaction was complete (TLC solvent H Rf
0.20), the mixture was filtered over Celite, eluted successively with ethanol, and the

960
Pews-Davtyan et al.
combined filtrates were concentrated to yield compound 36 (26 mg, 98%, containing
1
20% of the a-anomer) as a colorless powder: H NMR of 36 (D2O) d 2.14, 2.37 (2 m,
2H, lactone: H-4, H-4’), 2.67 (m, 2H, lactone: H-3, H-3’), 3.36 (dd, 1H, J2,3 = 9.2 Hz,
H-2), 3.57 (dd, 1H, J3,4 = 9.2 Hz, H-3), 3.59 (dd, 1H, J4,5 = 8.6 Hz, H-4), 3.84 (s, 3H,
OCH3), 3.93, 4.01 (2dd, 2H, lactone: H-6, H-6’), 4.09 (dd, 1H, J5,4 = 9.4 Hz, H-5), 4.57
(d, 1H, J1,2 = 7.9 Hz, H-1), 4.88 (m, 1H, lactone: H-5); 13C NMR of 36 (D2O) d 25.74
(lactone: C-4), 31.26 (lactone: C-3), 55.90 (OCH3), 73.97 (lactone: C-6), 74.05 (C-4),
75.45 (C-2), 77.37 (C-5), 77.88 (C-3), 83.37 (lactone: C-5), 102.17 (C-1), 169.67 (C-6),
178.63 (lactone: C-2).
Anal.Calcd for C12H18O9 (306.26): C, 47.06; H, 5.92. Found: C, 47.20; H, 5.84.
(2-R)-2,3,4,5-Tetrahydro-5-oxo-2-furylmethyl 3,4-di-O-benzyl- -D-glucopyrano-
siduronic acid (37). Aq 1 M lithium hydroxide (3 mL) was added to a solution of 34
(107 mg, 0.22 mmol) in acetone (7 mL). After stirring for 3 h at ambient temperature
(TLC solvent J Rf 0.30), the solution was treated with Dowex-50 (H+) resin, filtered, and
successively coevaporated with toluene (3 ꢁ 5 mL), ethanol (3 ꢁ 5 mL), and chloro-
form (3 ꢁ 5 mL). The residue was purified by preparative TLC (eluent solvent K Rf
[24]
0.45) to afford compound 37 (91 mg, 88%) as colorless crystals: mp 133°C; [a]D
ꢀ
1
94.1 (c 1.0, methanol); H NMR (CD3OD) d 2.23 (m, 2H, lactone: H-4, H-4’), 2.56 (m,
2H, lactone: H-3, H-3’), 3.45 (dd, 1H, J2,3 = 8.5 Hz, H-2), 3.52 (dd, 1H, J4,5 = 9.1 Hz,
H-4), 3.79 (d, 1H, J5,4 = 9.0 Hz, H-5), 3.80 (dd, 1H, J3,4 = 8.6 Hz, H-3), 3.81, 3.95 (2dd,
2H, lactone: H-6, H-6’), 4.37 (d, 1H, J1,2 = 7.3 Hz, H-1), 4.67, 4.75 (2d, 2H, J = 10.7
Hz, CH2C6H5), 4.74 (m, 1H, lactone: H-5), 4.77, 4.91 (2d, 2H, J = 11.2 Hz, CH2C6H5),
7.18–7.36 (m, 10H, 2 ꢁ CH2C6H5); 13C NMR (CD3OD) d 24.69 (lactone: C-4), 29.26
(lactone: C-3), 71.78 (lactone: C-4), 75.32 (C-2), 75.50, 76.12 (2 ꢁ CH2C6H5), 78.81
(C-5), 80.91 (lactone: C-5), 81.95 (C-3), 85.79 (C-4), 104.63 (C-1), 128.38, 128.86,
129.04, 129.13, 129.19, 140.04, 140.34 (2 ꢁ CH2C6H5, five signals are isochronic),
176.23 (C-6), 180.26 (lactone: C-2); CI mass spectrum: m/z 473.2 (M + H+).
Anal.Calcd for C25H28O9 (472.49): C, 63.55; H, 5.97. Found: C, 63.29; H, 5.84.
(2-R)-2,3,4,5-Tetrahydro-5-oxo-2-furylmethyl -D-glucopyranosiduronic acid
(38). To a solution of compound 37 (38 mg, 0.08 mmol) in ethyl acetate (2 mL) and
ethanol (5 mL) was added 10% palladium-on-charcoal (20 mg). The mixture was
stirred in an atmosphere of hydrogen at rt. When the reaction was complete (TLC
solvent I Rf 0.26), the mixture was filtered over Celite, eluted successively with
ethanol, and the combined filtrates were concentrated. The residue was purified by
preparative TLC (eluent solvent K Rf 0.30). After concentration of the extracts, the
residue was dissolved in water and lyophilized to provide compound 38 (20 mg, 84%)
[24]
1
as a colorless powder: [a]D
ꢀ 9.7 (c 1.0, water); H NMR (CDCl3) d 2.20–2.45 (m,
4H, lactone: H-3, H-3’, H-4, H-4’), 3.34 (dd, 1H, J2,3 = 7.5 Hz, H-2), 3.50 (d, 1H,
J3,4 = 7.6 Hz, H-3), 3.51 (d, 1H, J4,5 = 7.9 Hz, H-4), 3.71 (d, 1H, J5,4 = 8.1 Hz, H-5),
3.82, 4.10 (2dd, 2H, lactone: H-6, H-6’), 4.49 (d, 1H, J1,2 = 7.5 Hz, H-1), 4.66 (m, 1H,
lactone: H-5); 13C NMR (D2O) d 24.02 (lactone: C-4), 29.46 (lactone: C-3), 71.87
(lactone: C-6), 72.82 (C-4), 73.90 (C-2), 74.01 (lactone: C-5), 76.57 (C-3), 76.98 (C-5),
103.35 (C-1), 172.58 (C-6), 183.06 (lactone: C-2).
Anal.Calcd for C11H16O9 (292.24): C, 45.21; H, 5.52. Found: C, 44.93; H, 5.44.

Comparison of Glucuronate Glycosyl Donors
ACKNOWLEDGMENTS
961
The authors are grateful to the Deutschen Forschungsgemeinschaft as well as the
Fonds der Chemischen Industrie for financial support.
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Received October 2, 2002
Revised August 26, 2003