Effective anomerisation of 2′-deoxyadenosine derivatives during disaccharide nucleoside synthesis

Article abstract of DOI:10.1081/NCN-200040627

The formation of a disaccharide nucleoside (11) by O3′-glycosylation of 5′-O-protected 2′-deoxyadenosine or its N⁶-benzoylated derivative has been observed to be accompanied by anomerisation to the corresponding α-anomeric product (12). The latter reaction can be explained by instability of the N-glycosidic bond of purine 2′- deoxynucleosides in the presence of Lewis acids. An independent study on the anomerisation of partly blocked 2′-deoxyadenosine has been carried out. Additionally, transglycosylation has been utilized in the synthesis of 3′-O-β-D-ribofuranosyl-2′-deoxyadenosines and its α-anomer.

Full text of DOI:10.1081/NCN-200040627

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Effective Anomerisation of 2′‐Deoxyadenosine
Derivatives During Disaccharide Nucleoside Synthesis
Irina V. Gulyaeva a , Kari Neuvonen b , Harri Lönnberg b , Andrei A. Rodionov a , Elena V.
Shcheveleva a , Georgii V. Bobkov a , Ekaterina V. Efimtseva a & Sergey N. Mikhailov a
a Engelhardt Institute of Molecular Biology , Russian Academy of Sciences , Vavilov St. 32,
Moscow, 119991, Russia
b Department of Chemistry , University of Turku , Turku, FIN‐20014, Finland
Published online: 17 Aug 2006.
To cite this article: Irina V. Gulyaeva , Kari Neuvonen , Harri Lönnberg , Andrei A. Rodionov , Elena V. Shcheveleva , Georgii
V. Bobkov , Ekaterina V. Efimtseva & Sergey N. Mikhailov (2004) Effective Anomerisation of 2′‐Deoxyadenosine Derivatives
During Disaccharide Nucleoside Synthesis, Nucleosides, Nucleotides and Nucleic Acids, 23:12, 1849-1864, DOI: 10.1081/
NCN-200040627
To link to this article: http://dx.doi.org/10.1081/NCN-200040627
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 23, No. 12, pp. 1849–1864, 2004
Effective Anomerisation of 2’-Deoxyadenosine
Derivatives During Disaccharide
Nucleoside Synthesis
Irina V. Gulyaeva,1 Kari Neuvonen,2 Harri Lo¨nnberg,2
Andrei A. Rodionov,1 Elena V. Shcheveleva,1
Georgii V. Bobkov,1 Ekaterina V. Efimtseva,1 and Sergey N. Mikhailov1,
*
1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences,
Moscow, Russia
2Department of Chemistry, University of Turku, Turku, Finland
ABSTRACT
The formation of a disaccharide nucleoside (11) by O3’-glycosylation of 5’-O-
protected 2’-deoxyadenosine or its N6-benzoylated derivative has been observed to
be accompanied by anomerisation to the corresponding a-anomeric product (12).
The latter reaction can be explained by instability of the N-glycosidic bond of purine
2’-deoxynucleosides in the presence of Lewis acids. An independent study on the
anomerisation of partly blocked 2’-deoxyadenosine has been carried out. Additionally,
transglycosylation has been utilized in the synthesis of 3’-O-b-D-ribofuranosyl-2’-
deoxyadenosines and its a-anomer.
Key Words: Disaccharide nucleosides; Synthesis; Anomerisation; 2’-Deoxyadenosine
derivatives.
*
Correspondence: Sergey N. Mikhailov, Engelhardt Institute of Molecular Biology, Russian
Academy of Sciences, Vavilov St. 32, Moscow 119991, Russia; Fax: +7-095-135-1405;
E-mail: smikh@eimb.ru.
1849
DOI: 10.1081/NCN-200040627
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com
Copyright D 2004 by Marcel Dekker, Inc.

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Gulyaeva et al.
INTRODUCTION
Disaccharide nucleosides belong to an important group of natural substances found
in tRNAs and poly(ADP-ribose), or characterised as antibiotics and other physiologically
active compounds.[1,2] To date about a hundred disaccharide nucleosides have been
isolated from various natural sources.[3] These compounds contain an extra carbohydrate
residue linked to one of the nucleoside hydroxyl groups via an O-glycosidic bond. The
presence of an O- and N-glycosidic bond in disaccharide nucleosides makes their
properties similar to those of both carbohydrates and nucleosides.
Disaccharide nucleosides have been prepared either by coupling of an
appropriately blocked disaccharide with a heterocyclic base or by condensation of a
protected nucleoside with a monosaccharide using classical procedures of O- and N-
glycosylation.[4,5] The use of a natural nucleoside as a starting material simplifies the
synthesis. Many examples of the formation of an O-glycosidic bond between a partially
protected nucleoside and sugar have been reviewed.[2] In several cases side reactions
occur and substantial amounts of by-products are formed. During the past decade, the
scope and limitations of nucleoside O-glycosylation have been examined.[1,2] As part of
our investigations, we now present our recent results on the O-ribosylation reaction of
2’-deoxyadenosine derivatives.
RESULTS AND DISCUSSION
A simple and effective method for the preparation of 2’-O-(b-D-ribofuranosyl)nucleo-
sides starting from readily available 3’,5’-O-blocked N-acylribonucleosides and 1-O-
acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose (2) preactivated with tin tetrachloride in 1,2-
dichloroethane, has been recently developed.[6–8] The condensation proceeds by
stereospecific formation of the b-D-glycosidic bond and gives a high yield. Several other
fully acylated monosaccharide derivatives of D- and L-arabinofuranoses, D-erythrofur-
anose and D-ribopyranose have been successfully used in the same reaction.[9] This
general methodology has additionally been extended to the synthesis of pyrimidine 3’-O-
(b-D-ribofuranosyl)-2’-deoxynucleosides.[10] The coupling of 5’-O-(tert-butyldiphenyl-
silyl)thymidine (1a) with fully acylated sugar (2) in the presence of tin tetrachloride
under standard conditions (1,2-dichloroethane, 0°C, under nitrogen) gave the desired
product (3) in 79% yield[10] (Scheme 1). After deblocking, disaccharide nucleoside 4
was obtained without difficulties. It has been, however, shown that O-glycosylation of
purine 2’-deoxynucleosides results in a complex mixture of products.[10] Therefore we
now report on a detailed investigation of this condensation reaction, including structural
studies of the main products and mechanistic considerations of their formation.
Two nucleoside substrates, viz. 5’-O-(tert-butyldiphenylsilyl)-2’-deoxyadenosine (1c)
and its N6-benzoyl derivative (1b), were tested in the O-ribosylation reaction (Scheme 1).
The starting materials (1b,c) were prepared by selective silylation[11,12] of N6-benzoyl-2’-
deoxyadenosine[13] and 2’-deoxyadenosine, respectively. Condensation of 1b with a
small excess of 2, activated with tin tetrachloride in 1,2-dichloroethane for 1.5 h at 0°C
under nitrogen, gave a complex mixture of products. Prolonged treatment resulted in
darkening of the reaction mixture and lowered the yield of the disaccharide nucleoside.
After standard work-up and silica gel column chromatography, two main products were
isolated: nucleoside tetra-O-benzoate 5b[14,15] (39%) and disaccharide nucleoside 7b

Disaccharide Nucleoside Synthesis
1851
Scheme 1.
(12%). The same condensation with 1c resulted in formation of nucleoside tri-O-
benzoate 5c (31%) and disaccharide nucleoside 6c (18%). Deprotection with
tetrabutylammonium fluoride in THF gave the desilylated products (8c, 9b) and, after
subsequent treatment with ammonia in methanol, the free disaccharide nucleosides 11
1
and 12 were obtained. The H NMR spectra of the disaccharide nucleosides (Tables 1
and 2) indicated the presence of two furanose residues linked by a b-glycosidic bond
(J1’,2’ < 0.5 Hz). The principal difference was observed in J1’,2’a and J1’,2’b of the
nucleoside moiety. For b-series, the sum of these coupling constants is greater than that
for the corresponding a-nucleosides[16,17] (Table 2). The assignment of anomeric

1852
Gulyaeva et al.

Disaccharide Nucleoside Synthesis
1853

1854
Gulyaeva et al.
Table 3. NOE-data (%) of compounds 11 and 12 upon irradiation
of 1’-H.a
Nucleoside moietyb
b-Anomer 11
a-Anomer 12
H-4’
H-3’
H-2’a
H-2’b
2.1
c
c
3.6
0.9
5.0
aThe NOE enhancements expressed as percentage integrated with
respect to the irradiated spin (set to À100%).
bH2’a and H2’b were assigned as up (pro-S) and down (pro-R)
protons respectively.
cIntensity enhancement less than 0.5%.
configuration was based on NOE difference spectroscopy.[18] Saturation of H-1’ of the
b-anomer (11) resulted in a characteristic NOE (2.1%) at the H-4’, while no effect was
observed at the signal H-3’ of the nucleoside moiety[18] (Table 3). With both anomers,
the NOE effects on H-2’a and H-2’b signals were in agreement with the published
data:[18] the cis oriented protons exhibited a greater enhancement. As the table shows, the
a-anomer (12) exhibited only a weak enhancement at H-3’. With a-2’-deoxynucleosides,
the corresponding enhancement at H-3’ has been reported to be less then 1%.[18] In
addition, 11 had a negative Cotton effect on the B2u band, similarly to natural 2’-
deoxyadenosine, while 12 exerted a positive effect.
In order to determine the number of major products formed upon the O-
ribosylation of 2’-deoxyadenosines 1b and 1c and to quantify their yields, a HPLC
analysis was carried. The products obtained by the condensation of 1b with 2 in the
presence of tin tetrachloride under the above-mentioned conditions were isolated by
extraction with methylene chloride and the blocking groups were removed. According
to HPLC analysis, the mixture consisted of adenine, adenosine 10 and disaccharide
nucleosides 12 and 11, and several unidentified UV absorbing products. The ratio of
10:12:11 was 51:13:3. Similar products, but with predominant formation of the
b-anomer (11) were formed upon the analogous condensation of 1c with 2. The ratio of
10:12:11 was 39:4:31. It should be noted that in both cases the main product was
adenosine 10.
The formation of adenosine (10) and the a-anomer (12) as the main by-products
may be attributed to instability of the N-glycosidic bond of purine nucleosides (1b,c
and/or those in disaccharide 6b) in the presence of a Lewis acid. Previously it has been
shown that analogous condensation of N6-benzoyl-2’,3’-di-O-acyladenosines with 2
results in formation of the desired disaccharide together with substantial amounts
of nucleoside 5b and a trisaccharide.[15] It is known that the N-glycosidic bond of
N6-acylated 2’-deoxyadenosine is in acid less stable than that of its unprotected
derivative.[19,20] This may explain the predominant cleavage of the N-glycosidic bond
during ribosylation of 1b.
To get a deeper insight into the anomerisation process, we decided to examine the
behavior of 1b in the presence of tin tetrachloride in 1,2-dichloroethane. It was shown
that the reaction was completed in about 1 h at 0°C. According to TLC, 1b (Rf = 0.30 in
methylene chloride—ethanol 95:5) was converted to its a-anomer (13; Rf = 0.47) and

Disaccharide Nucleoside Synthesis
1855
N6-benzoyladenine. Prolonged treatment resulted in decomposition of nucleosides and
exclusive formation of N6-benzoyladenine. The yield of 13 was increased up to 50% by
addition of N6-benzoyladenine to the reaction mixture. The separation of 13 was easily
achieved by silica gel column chromatography. Stepwise deblocking of 13 gave 14 and
finally 15. The UV and CD spectra of 15 were consistent with the literature data.[21]
Much more drastic conditions were needed for the previously described[21]
anomerisation of fully acylated pyrimidine 2’-deoxyribonucleosides, viz. heating in
acetonitrile in the presence of bis(trimethylsilyl)acetamide (BSA) and trimethylsilyl
trifluoromethanesulfonate (TMSOTf) for 2–3 h at 70°C. a-2’-Deoxyriboadenosine was
synthesised by transglycosylation under similar conditions.[21] It should be mentioned
that the separation of the anomeric mixtures was rather complicated and the yields of
a-2’-deoxyribonucleosides ranged from 27 to 51%.[21]
To learn more about the mechanism of anomerisation, the stability of the 3’-O-
trimethylsilyl derivative 1d in the presence of tin tetrachloride in 1,2-dichloroethane
was investigated. The compound turned out to be stable for 3 h at 0°C. It may be
concluded that the presence of unprotected 3’-OH group destabilised the N-glycosidic
bond of 1b. Evidently the anomerisation took place with nucleoside 1b but not with
disaccharide 6b. It is known that tin tetrachloride may form complexes with nitrogen
atoms of heterocyclic bases and with hydroxyl groups.[22,23] The proposed mechanism
for the anomerisation is depicted in Scheme 2. For steric reasons, the complex of the
b-anomer presumably is less stable than that of the a-anomer and the equilibrium is
shifted towards the more stable product.
Scheme 2.

1856
Gulyaeva et al.
Preparation of the desired compounds from a disaccharide building block was also
attempted. Unfortunately condensation of methyl 5-O-toluoyl-2-deoxy-D-erythro-
pentofuranoside (5-O-toluoyl-2-deoxy-D-ribofuranoside) with 2 in the presence of tin
tetrachloride in 1,2-dichloroethane resulted in only decomposition of the starting
material, which may be taken as an indication of instability of 3-O-unprotected 2-
deoxy-D-ribofuranosides under the reaction conditions.
Preparation of 3’-O-(b-D-ribofuranosyl)-2’-deoxyadenosine (11) was additionally
attempted by the previously described method of transglycosylation.[24] Easily available
3’-O-glycosylated thymidine (3) was chosen as the glycosyl donor and N6-benzoyl-
adenine as the glycosyl acceptor. The reaction catalysed by trimethylsilyl triflate gave a
mixture of a- (7b) and b-anomers (6b) (Scheme 1). This mixture was difficult to
separate by silica gel column chromatography, due to rather similar Rf values of 6b and
7b, but after removal of the 5’-O-silyl groups, the separation could be carried out
without difficulties and 8b and 9b were obtained in 22% and 45% yields, respectively.
Subsequent saponification gave the free anomeric disaccharide nucleosides (11, 12).
The NMR spectra (Tables 1 and 2) of disaccharide nucleosides are rather
complicated due to the presence of two ribofuranose residues. Chemical shifts of H1’,
H2’ and H3’ of the ribose moiety and H1’, H2’a and H2’b of the 2-deoxyribose residue
along with the corresponding coupling constants could be calculated directly from the
NMR spectra. The other protons were assigned by comparison with the 1H NMR
spectra of related disaccharide nucleosides[7,10,15] and making use of double resonance
and COSY spectra. With a-anomers, the chemical shifts of H1’ and H4’ of the 2-
deoxyribose residue are located in a lower field than with b-anomers (Table 1). The
13C NMR spectra were analyzed in the similar fashion using 1H–13C correlation
spectra. An upfield shift of C1’ of the 3’-O-ribosyl residue to 105–107 ppm is typical
for b-linked disaccharide nucleosides.[7,10,15]
In summary, the facile anomerization of 2’-deoxyadenosine derivatives during
disaccharide nucleoside synthesis can be explained by the instability of the protected
purine nucleosides in the presence of Lewis acids. Consistent with this, trans-
glycosylation has been successfully used for the preparation of 3’-O-(b-D-ribofur-
anosyl)-2’-deoxyadenosine and its a-anomer (12).
EXPERIMENTAL PART
NMR spectra were recorded on a Bruker AMX 400 or a JEOL JNM-L-400
spectrometer at 298 K. The deuterium of the solvent was used as a lock signal and the
chemical shifts were measured relative to the solvent signals. The 2D homonuclear
H,H-correlation experiments were acquired using double quantum filtered COSY. The
2D heteronuclear one-bond correlation experiments were acquired using carbon
detected CH-shift correlation with partial homonuclear decoupling in the f1 dimension.
The spectral widths of 2D spectra were optimised from ID spectra. NOE difference
experiments were acquired using saturation times of 6–8 sec and the reported
enhancements were expressed as percentage integrated with respect to the irradiated
spin (set to À100%). Prior to NOE measurements, samples were deoxygenated by
nitrogen bubbling. The UV spectra were recorded on a Cary-300 UV/VIS spectro-
photometer (Varian) and the CD spectra on a JASCO J-715 spectropolarimeter. The

Disaccharide Nucleoside Synthesis
1857
liquid secondary ion mass spectra (FAB-LSIMS, Cs+ ion bombardment) were recorded
on a VG Zab Autospec mass spectrometer (VG Analytical, Manchester, UK) using
positive-ion mode and a polyethylene glycol matrix. Column chromatography was
performed on silica gel (0.063–0.200 mm, Merck). TLC was carried out on Kieselgel
260 F (Merck) using UV-detection and the following solvent systems (compositions
expressed as v/v): methylene chloride (A), methylene chloride—ethanol 95:5 (B),
methylene chloride—ethanol 9:1 (C), methylene chloride—ethanol 7:3 (D) and isopro-
panol—aq. ammonia—water 7:1:2 (E).
5’-O-(tert-Butyldiphenylsilyl)-N6-benzoyl-2’-deoxyadenosine (1b). To a solution
of N6-benzoyl-2’-deoxyadenosine (10 mmol) and imidazole (10 mmol) in dry pyridine
(20 ml), tert-butyldiphenylsilyl chloride (11 mmol) was added and the solution was
kept at 20°C for 3–5 h, i. e. until the reaction was complete according to TLC. The
solution was evaporated to dryness, the residue was dissolved in methylene chloride
and the organic layer was washed with water, 10% aqueous solution of sodium
bicarbonate and again with water. The organic layer was dried with Na2SO4, filtered,
evaporated to dryness and evaporated with toluene. The residue was purified by silica
gel chromatography using eluent B. Yield (4.45 g, 75%) as a foam; Rf 0.3 (B); dH(400
MHz; CDCl3) 1.05 (9 H, s, t-Bu), 2.57 (1 H, ddd, J2’b1’ 6.5, J2’b,3’ 3.7, J2’b,2’a À13.4, H-
2’b), 2.79 (1 H, ddd, J2’a,1’ 6.5, J2’a,3’ 6.2, H-2’a), 2.88 (1 H, br s,OH), 3.84 (1 H, dd,
J5’a,4’ 4.0, J5’a,5’b À11.2, H-5’a), 3.93 (1 H, dd, J5’b,4’ 5.0, H-5’b), 4.12(1 H, ddd, J4’,3’
2.8, H-4’), 4.76 (1 H, m, H-3’), 6.49 (1 H, t, H-1’), 7.33–8.03 (15 H, m, Bz, Ph), 8.20
(1 H, s, H-2), 8.74 (1 H, s, H-8), 9.21 (1 H, br s, NH); dC(100 MHz; CDCl3) 19.20
(SiCMe3), 26.91 (Me3), 40.44 (C-2’), 63.89 (C-5’), 72.05 (C-3’), 84.59 (C-1’), 87.14 (C-
4’), 123.23 (C-5), 127.86, 128.82, 129.97, 132.73, 133.72, 135.45, 135.52, (Bz, Ph),
141.29 (C-8), 149.47 (C-4), 151.28 (C-2), 152.62 (C-6), 164.66 (C = O). LSIMS
(FAB): [C33H33N5O5Si + H+] requires 594.2536, found 594.2540.
5’-O-tert-Butyldiphenylsilyl-2’-deoxyadenosine (1c). Compound 1c was prepared
from 2’-deoxyadenosine as described above for 1b. The residue obtained by evaporation
of the reaction solution to dryness was, however, dissolved in ethyl acetate instead of
methylene chloride and the product was purified by recrystallisation from a mixture of
methylene chloride—hexane 1:1, not by chromatography. Yield (4.1 g, 84%); Rf 0.11
(B); mp 138–140°C (from methylene chloride—hexane); dH(400 MHz; CDCl3) 1.06 (9
H, s, t-Bu), 2.53 (1 H, ddd, J2’b,1’ 6.5, J2’b,3’ 3.8, J2’b,2’a À13.3, H-2’b), 2.75 (1 H, ddd,
J2’a,1’ 6.5, J2’a,3’ 6.4, H-2’a), 3.08 (1 H, br s, OH), 3.85 (1 H, dd, J5’a,4’ 4.1, J5’a,5’b À11.1,
H-5’a), 3.91 (1 H, dd, J5’b,4’ 4.7, H-5’b), 4.08 (1 H, ddd, J4’,3’ 3.5, H-4’), 4.73 (1 H, m, H-
3’), 5.79 (2 H, br s, NH2), 6.46 (1 H, t, H-1’), 7.20–7.70 (10 H, m, Bz), 8.02 (1 H, s, H-
2), 8.30 (1 H, s, H-8); dC(100 MHz; CDCl3) 19.23 (SiCMe3), 26.93 (Me3), 40.52 (C-2’),
63.98 (C-5’), 72.07 (C-3’), 84.22 (C-1’), 86.96 (C-4’), 123.21 (C-5), 127.86, 129.98,
132.78, 135.51 (Ph), 138.80 (C-8), 148.50 (C-4), 152.97 (C-2), 155.40 (C-6). LSIMS
(FAB): [C26H31N5O3Si + H+] requires 490.2274, found 490.2270.
N6-benzoyl-9-[5-O-tert-butyldiphenylsilyl-3-O-(2,3,5-tri-O-benzoyl-b-D-ribofur-
anosyl)-2-deoxy-a-D-erythro-pentofuranosyl]adenine 7b. To a cold solution (0°C) of
1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose 2 (605 mg, 1.2 mmol) in 1,2-
dichloroethane (15 ml) under nitrogen, tin tetrachloride (0.18 ml, 1.5 mmol) was

1858
Gulyaeva et al.
added and the solution was kept at 0°C for 10 min. Nucleoside 1b (594 mg, 1 mmol)
was added and the resulting solution was kept for 1.5 h at 0°C. Then 10% aqueous
solution of sodium bicarbonate (10 ml) was added and the suspension was stirred for
20 min at 0°C. The suspension was diluted with methylene chloride (20 ml), filtered
through Hyflo Super Cel, the organic layer was separated, washed with water (15 ml),
dried over Na2SO4, filtered and evaporated to dryness. The residue was applied onto a
silica gel column (50 g). The column was washed with system A, and then eluted with
a mixture of methylene chloride—ethanol 99:1 to give N6-benzoyladenosine 2,3,5-
tri-O-benzoate (5b)[14,15] (266 mg, 39%) as a foam. Rf 0.72 (B). Further elution with
the same system yielded 7b (125 mg, 12%) as a foam. Rf 0.63 (B). LSIMS (FAB):
[C59H55N5O11Si + H+] requires 1038.3745, found 1038.3738.
9-[5-O-tert-Butyldiphenylsilyl-3-O-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)-2-de-
oxy-b-D-erythro-pentofuranosyl]adenine 6c. An analogous condensation of 2 (605
mg, 1.2 mmol) with 1c (490 mg, 1 mmol) in the presence of tin tetrachloride (0.18 ml,
1.5 = mmol) in 1,2-dichloroethane (15 ml) for 3 h at 0°C, followed by silica gel
chromatography (50 g) using a mixture of methylene chloride—ethanol 98:2 as an
eluent, gave 6c (170 mg, 18%) as a foam. Rf 0.51 (B); dC(100 MHz; CDCl3) 19.14
(SiCMe3), 26.83 (Me3), 38.17 (C-2’ dAdo), 63.47, 64.68 (C-5’ dAdo, C-5’ Rib), 72.06
(C-3’ Rib), 75.72 (C-2’ Rib), 78.19, 79.34 (C-3’ dAdo, C-4’ Rib), 84.71, 85.03 (C-1’
dAdo, C-4’ dAdo), 104.86 (C-1’ Rib), 119.86 (C-5), 127.79, 128.39, 128.52, 128.80,
129.54, 129.74, 129.91, 132.58, 133.27, 133.59, 135.47 (Bz, Ph), 139.77 (C-8), 149.22
(C-4), 150.14 (C-2), 154.07 (C-6), 165.15, 165.35, 166.09 (C = O). LSIMS (FAB):
[C52H51N5O10Si + H+] requires 934.3483, found 934.3478.
Further elution with the same system yielded adenosine 2’,3’,5’-tri-O-benzoate (5c)
(180 mg, 31%) as a foam. Rf 0.46 (B); dH(400 MHz; CDCl3) 4.72 (1 H, dd, J5’a,4’ 4.4,
J5’a,5’b À12.1, H-5’a), 4.83 (1 H, ddd, J4’,3’ 5.0, J4’,5’b 3.1, H-4’), 4.90 (1 H, dd, H-5’b),
6.28 (1 H, dd, J3’,2’ 5.9, H-3’), 6.36 (2 H, br s, NH2), 6.38 (1 H, dd, J2’,1’ 5.0, H-2’),
6.43 (1 H, d, H-1’), 7.34–7.59 (9 H, m, Bz), 7.93–8.10 (7 H, m, H-2, Bz), 8.24 (1 H,
s, H-8); dC(100 MHz; CDCl3) 63.57 (C-5’), 71.48 (C-3’), 74.05 (C-2’), 80.71 (C-4’),
86.96 (C-1’), 119.91 (C-5), 128.48, 128.77, 129.39, 129.79, 129.82, 133.34, 133.62,
133.70 (Bz), 139.08 (C-8), 149.68 (C-4), 153.08 (C-2), 155.69 (C-6), 165.11, 165.26,
166.12 (C = O).
N6-Benzoyl-9-[3-O-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)-2-deoxy-a-D-erythro-
pentofuranosyl]adenine (9b). Nucleoside 7b (104 mg, 0.10 mmol) was dissolved
in tetrahydrofuran (0.5 ml) and 0.5 M tetrabutylammonium fluoride trihydrate in
tetrahydrofuran (0.28 ml) was added. The solution was kept for 45 min at 20°C,
evaporated to dryness, coevaporated with chloroform (2 ml) and applied onto a silica
gel column (10 g). The column was washed with system A and eluted with a
mixture of methylene chloride-ethanol 97:3 to give 9b (64 mg, 80%) as a foam. Rf
O.32 (B). dC(100 MHz; CDCl3) 39.19 (C-2’ dAdo), 62.50, 64.32 (C-5’ dAdo, C-5’
Rib), 71.89 (C-3’ Rib), 75.72 (C-2’ Rib), 78.29, 79.47 (C-3’ dAdo, C-4’ Rib), 85.09,
85.98 (C-1’ dAdo, C-4’ dAdo), 105.10 (C-1’ Rib), 122.81 (C-5), 128.38, 129.77,
132.59, 133.21, 133.48, 133.62 (Bz), 141.47 (C-8), 149.52 (C-4), 151.27 (C-2), 152,61
(C-6), 165.30, 166.02 (C = O). LSIMS (FAB): [C43H37N5O11+ H+] requires 800.2567,
found 800.2574.

Disaccharide Nucleoside Synthesis
1859
9-[3-O-(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyl)-2-deoxy-b-D-erythro-pentofuta-
nosyl]adenine (8c). An anlogous desilylation of 6c (100 mg, 0.107 mmol) gave 8c
(57 mg, 77%) as a foam. Rf 0.29 (B); dC(100 MHz; CDCl3) 38.61 (C-2’ dAdo), 63.65,
64.84 (C-5’ dAdo, C-5’ Rib), 71.99 (C-3’ Rib), 75.96 (C-2’ Rib), 79.51, 81.30 (C-3’
dAdo, C-4’ Rib), 87.20, 87.86 (C-1’ dAdo, C-4’ dAdo), 105.68 (C-1’ Rib), 120.91 (C-5),
128.41, 128.53, 128.83, 129.75, 129.80, 132.58, 133.41, 133.53, 133.62 (Bz), 140.48
(C-8), 148.82 (C-4), 152.09 (C-2), 156.04 (C-6), 165.29, 165.44, 166.20 (C = O).
LSIMS (FAB): [C36H33N5O10+ H+] requires 696.2305, found 696.2311
9-(3-O-b-D-ribofuranosyl-2-deoxy-b-D-erythro-pentofuranosyl)adenine (11).
A
solution of nucleoside 8c (97 mg, 0.14 mmol) in 5 M ammonia in methanol (5 ml) was
kept for 3 days at 20°C and then evaporated to dryness in vacuo. The residue was
partitioned between methylene chloride (5 ml) and water (10 ml), and the water layer
was washed with methylene chloride (2 Â 5 ml). The aqueous layer was evaporated
and purified on a Silasorb C-18 reversed-phase HPLC column (10 Â 150 mm, 13 mm)
by isocratic elution with 5% acetonitrile in 0.01 M triethylammonium acetate at a flow
rate of 4 ml  minÀ1. The main UV absorbing peak (tR=10.0 min) was desalted on the
same column, washed initially with water and eluted with 20% aq. acetonitrile. The
fraction was evaporated and freeze-dried to give 11 (43 mg, 81%). Rf 0.12 (D), 0.81
(E); CD (water): lmax 262 nm (De À 0.85). lmax (H2O) 261 (pH 7–13) (e 14400), 259
nm (pH 2) (e 14000). dC(100 MHz; D2O) 38.55 (C-2’ dAdo), 62.55 (C-5’ dAdo), 63.48
(C-5’ Rib), 71.46 (C-3’ Rib), 75.38 (C-2’ Rib), 78.87 (C-3’ dAdo), 83.72 (C-4’ Rib),
85.58 (C-1’ dAdo), 86.25 (C-4’ dAdo), 107.26 (C-1’ Rib), 119.64 (C-5), 141.00 (C-8),
149.04 (C-4), 153.13 (C-2), 156.21 (C-6). LSIMS (FAB): [C15H21N5O5+ H+] requires
384.1519, found 384.1526.
9-(3-O-b-D-Ribofuranosyl-2-deoxy-a-D-erythro-pentofuranosyl) adenine (12).
Analogous debenzoylation of 9b (104 mg, 0.13 mmol) gave 12 (39 mg, 79%). Rf 0.09
(D), 0.78 (E); CD (water): lmax 261 nm (De + 3.80). lmax (H20) 261 nm (pH 7–13) (e
14300), 259 nm (pH 2) (e 14000). dC(100 MHz; D2O) 39.78 (C-2’ dAdo), 62.52 (C-5’
dAdo), 63.40 (C-5’ Rib), 71.50 (C-3’ Rib), 75.43 (C-2’ Rib), 79.22 (C-3’ dAdo), 83.43
(C-4’ Rib), 86.77 (C-1’ dAdo), 88.32 (C-4’ dAdo), 107.49 (C-1’ Rib), 119.36 (C-5),
141.13 (C-8), 148.63 (C-4), 153.14 (C-2), 155.84 (C-6). LSIMS (FAB):
[C15H21N5O7+ H+] requires 384.1519, found 384.1515.
O-Ribosylation of 5’-O-(tert-butyldiphenylsilyl)-N6-benzoyl-2’-deoxyadenosine
(1b). To a cold solution (0°C) of 2 (303 mg, 0.6 mmol) in 1,2-dichloroethane (7 ml)
under nitrogen, tin tetrachloride (0.084 ml, 0.72 mmol) was added and the solution was
kept for 10 min at 0°C. After addition of nucleoside 1b (297 mg, 0.5 mmol), the
solution was kept for 1.5 h at 0°C. Then 10% aqueous solution of sodium bicarbonate
(10 ml) was added and the suspension was stirred for 20 min at 0°C. The suspension
was diluted with methylene chloride (10 ml), filtered through Hyflo Super Cel, the
organic layer was separated, washed with water (2 Â 10 ml), dried and evaporated to
dryness. The residue (550 mg) was co-evaporated with tetrahydrofuran (3 ml), and
dissolved in tetrahydrofuran (1.5 ml), 0.5 M tetrabutylammonium fluoride trihydrate in
tetrahydrofuran (1.3 ml) was added. After 45 min at 20°C, water (0.5 ml) and Dowex-
50 (Na+ form; 0.7 ml) were added, and the mixture was stirred for 30 min at 20°C. The

1860
Gulyaeva et al.
resin was filtered off and washed with ethyl acetate and the filtrate was washed with
water (2 Â 10 ml). The organic layer was dried over Na2SO4, evaporated to dryness.
The residue was dissolved in 5 mol dmÀ3 ammonia in methanol (10 ml), kept for 3 days
at 20°C and concentrated to dryness in vacuo. The residue was partitioned between
methylene chloride (10 ml) and water (30 ml), and the aqueous layer was washed with
methylene chloride (2 Â 10 ml). The aqueous layer was concentrated to dryness. The
total yield 54% was estimated by UV spectra (A260 4000 o.u.). The mixture was
analysed by reversed-phase HPLC on a Nucleosil C-18 column (4 Â 250 mm, 5 mm)
using a concentration gradient 0–15% of acetonitrile in 0.05 M sodium acetate pH 4.2,
the flow rate was 1 ml  minÀ1. The following UV absorbing (254 nm) peaks
were observed: tR (integral in %, assignment), 9.40 min (4.8%, adenine), 11.46 min
(5.5%, unidentified), 12.96 min (51.0%, adenosine 10), 13.82 min (9.4%, benzamide),
14.30 min (13.0%, 12), 15.57 min (11.9%, unidentified), 17.63 min (2.9%, 11), 18.57
min (1.4%, unidentified). The concentration ratio of 10:12:11 was 51:13:3.
O-Ribosylation of 5’-O-(tert-butyldiphenylsilyl)-2’-deoxyadenosine (1c). The
condensation of 2 (303 mg, 0.6 mmol) with 1c (245 mg, 0.5 mmol) in the presence of
tin tetrachloride (0.084 ml, 0.72 mmol) in 1,2-dichloroethane (7 ml) was performed
analogously. According to the UV spectra (A260 3900 o.u.), the total yield was 52%. The
mixture was analysed analogously as with 1b. The following UV absorbing (254 nm)
peaks were observed: tR in min (integral in %, assignment), 9.40 min (4.1%, adenine),
10.15 min (3.8%, unidentified), 12.97 min (38.6%, adenosine 10), 13.89 min (6.5%,
benzamide), 14.30 min (4.3%, 12), 15.52 min (1.3%, unidentified), 16.11 min (10.3%,
unidentified), 17.68 min (31.0%, 11). The concentration ratio of 10:12:11 was 39:4:31.
N6-Benzoyl-9-[3-O-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)-2-deoxy-b-D-erythro-
pentofuranosyl]adenine (8b) and N6-benzoyl-9-[3-O-(2,3,5-tri-O-benzoyl-b-D-ribo-
furanosyl)-2-deoxy-a-D-erythro-pentofuranosyl]adenine (9b). A mixture of 3 (925
mg, 1 mmol), N6-benzoyladenine (478 mg, 2 mmol) and BSA (1.23 ml, 5 mmol) in dry
acetonitrile (6 ml) was refluxed for 10 min and 0.5 M trimethylsilyl triflate (0.6 ml, 1.2
mmol) in 1,2-dichloroethane was added. After refluxing for 2.5 h, the mixture was
cooled to 20°C, diluted with methylene chloride (70 ml) and washed with 10% aqueous
solution of sodium bicarbonate (20 ml). The organic layer was washed with water
(2 Â 10 ml), dried over Na2SO4 and evaporated to dryness. The residue (1.15 g) could
be partly separated on silica gel in system A to give 6b (79 mg) Rf 0.68 (B), the
mixture of 6b and 7b (515 mg) and 7b (183 mg). The mixture of 6b and 7b was
dissolved in tetrahydrofuran (2 ml) and 0.5 M tetrabutylammonium fluoride trihydrate
in tetrahydrofuran (2.6 ml) was added. The solution was kept for 45 min at 20°C,
evaporated to dryness, coevaporated with chloroform (10 ml) and applied onto a silica
gel column (30 g). The column was washed with system A and eluted with a mixture
of methylene chloride—ethanol 97:3 to give 8b (176 mg, 22%) as a foam. Rf 0.49 (B).
dC(100 MHz; CDCl3) 38.61 (C-2’ dAdo), 63.38, 64.76 (C-5’ dAdo, C-5’ Rib), 71.94 (C-
3’ Rib), 75.89 (C-2’ Rib), 79.52, 81.86 (C-3’ dAdo, C-4’ Rib), 86.99, 87.60 (C-1’ dAdo,
C-4’ dAdo), 105.62 (C-1’ Rib), 124.32 (C-5), 127.89, 128.38, 128.52, 128.77, 129.69,
129.74, 132.77, 133.38, 133.50, 133.59 (Bz), 142.78 (C-8), 149.81 (C-4), 152.60 (C-2),
152.04 (C-6), 164.62, 165.25, 165.40, 166.16 (C = O).
Further elution with system B gave 9b (362 mg 45%) as a foam. Rf 0.32 (B).

Disaccharide Nucleoside Synthesis
1861
N6-Benzoyl-9-(5’-O-tert-butyldiphenylsilyl-2’-deoxy-a-D-erythro-pentofuranosy-
fladenine (13). N6-Benzoyladenine (120 mg, 0.5 mmol) was suspended in 1,2-
dichloroethane (10 ml), tin tetrachloride (0.16 ml, 1.37 mmol) was added and the
solution was kept for 10 min at 0°C. After addition of nucleoside 1b (297 mg,
0.5 mmol), the mixture was kept for 1 h at 0°C. Then 10% aqueous solution of sodium
bicarbonate (15 ml) was added and the suspension was stirred for 20 min at 0°C. The
suspension was diluted with methylene chloride (20 ml) and filtered through Hyflo
Super Cel. The organic layer was separated, washed with water (15 ml), dried over
Na2SO4, filtered and evaporated to dryness. The residue was applied onto silica gel
column (20 g). The column was washed with system A, and then eluted with a mixture
of methylene chloride—ethanol 98:2 to give 13 (149 mg, 50%) as a foam. Rf 0.47 (B);
dH(400 MHz; CDCl3) 1.02 (9 H, s, t-Bu), 2.59 (1 H, dd, J2’b1’ 1.6, J2’b,2’a À14.9, H2’b),
3.09(1 H, ddd, J2’a,1’ 8.2, J2’a,3’ 7.6, H-2’a), 3.78 (1 H, dd, J5’a,4’ 3.0, J5’a,5’b À11.3, H-
5’a), 3.82 (1 H, dd, J5’b,4’ 3.2, H-5’b), 4.53 (1 H, dd, H-4’), 4.65 (1 H, d, H-3’), 6.32 (1
H, dd, H-1’), 7.29-8.01 (15 H, m, Bz, Ph), 8.43 (1 H, s, H-2), 8.78 (1 H, s, H-8), 9.42(1
H, br s, NH); dC(100 MHz; CDCl3) 19.16 (SiCMe3), 26.76 (Me3), 41.32 (C-2’), 65.11
(C-5’), 73.02 (C-3’), 87.18 (C-1’), 90.54 (C-4’), 123.10 (C-5), 127.72, 127.87, 128.83,
129.93, 129.99, 132.74, 132.94, 133.26, 135.53, (Bz, Ph), 143.24 (C-8), 149.63 (C-4),
150.06 (C-2), 151.96 (C-6), 164.82 (C = O). LSIMS (FAB): [C33H35N5O4Si + h+]
requires 594.2536, found 594.2532.
9-(2-Deoxy-a-D-erythro-pentofuranosyl)adenine (15). A solution of protected
nucleoside 13 (100 mg, 0.17 mmol) in 5 mol dmÀ 3 methanolic ammonia (5 ml) was
kept for 3 days at 20°C and then evaporated to dryness in vacuo. The residue was
crystallized from a mixture of methylene chloride—hexane 1:1 to give 9-(5’-O-tert-
butyldiphenylsilyl-a-D-erythro-pentofuranosyl)adenine (14). Rf 0.22 (B); mp 113–
115°C (from methylene chloride—hexane); dH(400 MHz; DMSO-d6) 1.02 (9 H, s, t-Bu),
2.39 (1 H, ddd, J2’b,1’ 2.8, J2’b,3’ 1.0, J2’b,2’a À14.3, H-2’b), 2.78 (1 H, ddd, J2’a,1’ 7.8, J2’a,3’
6.8, H-2’a), 3.70 (1 H, dd, J5’a,4’ 4.0, J5’a,5’b À11.2, H-5’a), 3.74(1 H, dd, J5’b,4’ 3.4, H-5’b),
4.28 (1 H, ddd, J4’,3’ 2.9, H-4’), 4.45 (1 H, dddd, J3’,OH 4.7, H-3’), 5.85 (1 H, d, OH), 6.39
(1 H, dd, H-1’), 7.29 (2 H, br s, NH2), 7.43–7.69 (10 H, m, Bz), 8.17(1 H, s, H-2), 8.40(1
H, s, H-8); dC(100 MHz; DMSO-d6) 18.74 (SiCMe3), 25.60 (Me3), 40.42 (C-2’), 64.22
(C-5’), 70.74 (C-3’), 83.72 (C-1’), 87.93 (C-4’), 118.90 (C-5), 127.88, 129.86, 132.70,
135.05 (Ph), 139.57 (C-8), 148.86 (C-4), 152.39 (C-2), 156.01 (C-6).
The residue (14) was evaporated with tetrahydrofuran (3 ml), dissolved in
tetrahydrofuran (1 ml) and 0.5 M tetrabutylammonium fluoride trihydrate in
tetrahydrofuran (0.48 ml) was added. After 45 min at 20°C, water (0.5 ml) and
Dowex-50 (Na+ form; 0.5 ml) were added, and the mixture was stirred for 30 min at
20°C. The resin was filtered off and washed with water. The filtrate was washed with
ethyl acetate (3 Â 5 ml) and evaporated in vacuo. The residue was purified on a
Silasorb C-18 semi-preparative reversed-phase HPLC column (10 Â 250 mm, 13 mm)
by isocratic elution with 5% acetonitrile in 0.01 M triethylammonium acetate at a flow
rate of 4 ml  minÀ 1. The peak eluted at tR=6.0 min was collected and concentrated.
The residue was desalted on the same column, washed initially with water and eluted
with 20% aq. acetonitrile. The main fraction was evaporated and freeze-dried to give
15 (22 mg, 51%). CD (water): lmax 262 nm (De + 0.35). lmax (H2O) 261 nmn (pH 7–
13) (e 14600), 260 nm (pH 2) (e 14300). Rf 0.28 (D). dH(400 MHz; D2O) 2.49(1 H, dd,

1862
Gulyaeva et al.
J2’b.1’ 1.2, J2’b,2’a À14.0, H-2’b), 2.90 (1 H, ddd, J2’a,1’ 8.0, J2’a,3’ 7.2, H-2’a), 3.67 (1 H,
dd, J5’a,4’ 5.2, J5’a,5’b À12.4, H-5’a), 3.74 (1 H, dd, J5’b,4’ 3.6, H-5’b), 4.35 (1 H, ddd,
J4’,3’ 2.4, H-4’), 4.51(1 H, dd, H-3’), 6.36 (1 H, dd, H-1’), 8.07 (1 H, s, H-2), 8.29 (1 H,
s, H-8); dC(100 MHz; D2O) 39.23 (C-2’), 61.33 (C-5’), 70.90 (C-3’), 84.78 (C-1’), 87.23
(C-4’), 118.36 (C-5), 140.48 (C-8), 147.63 (C-4), 151.85 (C-2), 154.94 (C-6). LSIMS
(FAB): [C10H13N5O3+ H+] requires 252.1096, found 252.1094.
Attempt of anomerization of N,O-bis(trimethylsilyl)-5’-O-tert-butyldiphenylsilyl-
N6-benzoyl-2-deoxyadenosine (1d). A solution of nucleoside 1b (297 mg, 0.5 mmol),
BSA (0.25 ml, 1mmol) in 1,2-dichloroethane (7 ml) was refluxed for 10 min. After cooling
to 0°C, tin tetrachloride (0.12 ml, 1 mmol) was added and the solution was kept for
3 h at 0°C. Then 10% aqueous solution of sodium bicarbonate (15 ml) was added and
the suspension was stirred for 20 min at 0°C. According to TLC, no changes were
observed. The suspension was diluted with methylene chloride (20 ml) and filtered
through Hyflo Super Cel. The organic layer was separated, washed with water (15 ml),
dried over Na2SO4, filtered and evaporated to dryness. The residue was dissolved in 5 M
methanolic ammonia (5 ml) and kept for 3 days at 20°C, and then evaporated to
dryness in vacuo. The residue was dissolved in ethyl acetate (30 ml) and washed with
water (10 ml). The organic layer was dried with Na2SO4, filtered and evaporated to
dryness. According to TLC and NMR spectroscopy, the product was identical with
nucleoside 1c.
ACKNOWLEDGMENTS
Authors thank the Russian Foundation for Basic Research and the Academy of
Finland for financial support.
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Received April 28, 2004
Accepted August 25, 2004