The synthesis of [(β-D-ribofuranosyloxy)-methyl]nucleosides

Article abstract of DOI:10.1081/NCN-120030722

The coupling reaction of acetoxymethoxy ribofuranoside 4 with nucleic acid bases 5a-f to synthesize novel (ribofuranosyloxy)methyl uracil, thymine, cytosine, adenine, guanine derivatives 6a-g respectively in preference to the expected formation of natural nucleosides 2′,3′,5′ -tri-O-benzoyl uridine, methyluridine, cytidine, adenosine and guanosine 7a-g is described. Detailed study of these reactions catalysed by Lewis acids TMSOTf and SnCl₄ is described. TMSOTf exhibited selectivity for the formation of ribofuranosyloxy methyl derivatives 6a-g rather than 7a-g. Reason for formation of 6a-g is explained by HSAB principle.

Full text of DOI:10.1081/NCN-120030722

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The Synthesis of
[(β‐d‐Ribofuranosyloxy)‐methyl]nucleosides
Dr. Hari Babu Mereyala a & Sreeman Kumar Mamidyala a
a Gas Based Chemicals and Processes Division , Indian Institute of Chemical Technology ,
Tarnaka, Hyderabad, 500 007, India
Published online: 07 Feb 2007.
To cite this article: Dr. Hari Babu Mereyala & Sreeman Kumar Mamidyala (2004) The Synthesis of
[(β‐d‐Ribofuranosyloxy)‐methyl]nucleosides, Nucleosides, Nucleotides and Nucleic Acids, 23:4, 655-669, DOI: 10.1081/
NCN-120030722
To link to this article: http://dx.doi.org/10.1081/NCN-120030722
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 23, No. 4, pp. 655–669, 2004
The Synthesis of [(b-D-Ribofuranosyloxy)-
methyl]nucleosides
*
Hari Babu Mereyala and Sreeman Kumar Mamidyala
Gas Based Chemicals and Processes Division, Indian Institute of
Chemical Technology, Tarnaka, Hyderabad, India
ABSTRACT
The coupling reaction of acetoxymethoxy ribofuranoside 4 with nucleic acid bases
5a–f to synthesize novel (ribofuranosyloxy)methyl uracil, thymine, cytosine, adenine,
guanine derivatives 6a–g respectively in preference to the expected formation of
natural nucleosides 2’,3’,5’-tri-O-benzoyl uridine, methyluridine, cytidine, adenosine
and guanosine 7a–g is described. Detailed study of these reactions catalysed by Lewis
acids TMSOTf and SnCl4 is described. TMSOTf exhibited selectivity for the
formation of ribofuranosyloxy methyl derivatives 6a–g rather than 7a–g. Reason for
formation of 6a–g is explained by HSAB principle.
Key Words: Acetoxymethoxy; Methyluridine; Cytidine; Adenosine; Guanosine.
*
Correspondence: Dr. Hari Babu Mereyala, Deputy Director, Speciality, Gas Based Chemicals and
Processes Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India;
Fax: +91-040-716-0387 or +91-040-716-0757; E-mail: mereyalahb@rediffmail.com.
655
DOI: 10.1081/NCN-120030722
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com
Copyright D 2004 by Marcel Dekker, Inc.

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INTRODUCTION
The Vorbruggen[1–7] modification of Hilbert–Johnson reaction[8] of persilylated
heterocyclic bases with peracylated sugars in presence of Friedel–Crafts catalysts has
become a standard synthetic method for preparation of natural nucleosides routine-
ly in high yields. The reaction of silylated pyrimidines and purines with 1-O-acetyl-
2,3,5-tri-O-benzoyl-b-D-ribofuranoside is known to proceed via a stable electrophilic
1,2-a-acyloxonium intermediate.[9–13] The various mechanisms of all these synthetic
methods of nucleoside synthesis have been earlier studied, carefully reviewed[14,15] and
discussed.[16]
In this report we describe our experiments aimed at the concept of fine-tuning
the acetoxymethoxyglycosyl derivative a to generate glycosyloxy carbocation b and
capture it by nucleic acid bases B to achieve synthesis of novel glycosyloxymethyl
nucleosides d (Scheme 1). Glycosyloxy carbocation b has a tendency to fragment
further to the thermodynamically more stable ‘glycosyl cation c’ and form the natural
nucleoside e when captured by B. The results of this fundamentally new approach might
have some significance in developing newer themes in carbohydrate chemistry.[17–20]
The key acetoxymethoxy substrate a required to illustrate the above concept was
elegantly synthesized from 1-O-acetyl-2,3,5-tri-O-benzoyl-a/b-D-ribofuranoside
(1)[21,22] by initial reaction with propargyl alcohol, BF3.Et2O in CHCl3 at room
temperature to isolate propynyl ribofuranoside derivative 2[23] (Scheme 2). Compound
2 on further reaction with a catalytic amount of Hg (OCOCF3)2 in acetone-H2O (2:1) at
room temperature gave the corresponding keto derivative 3. Baeyer–Villiger oxidation
of keto compound 3 with m-CPBA in CHCl3 gave 1-[(2,3,5-tri-O-benzoyl-b-D-
ribofuranosyloxy)methyl]acetate (4) as a crystalline solid, mp 71°C in 42% overall
1
yield starting from 1.[24] Compound 4 was characterized by H NMR (the methylene
protons at d 5.36, d 5.42 as an AB type quartet, J = 7.5 Hz and H-1 at d 5.56 as a
singlet) and 13C NMR (the methylene carbon at d 84.7 and C-1 at d 103.9).
In order to study the potential of the envisaged concept a Vorbruggen modified
Hilbert–Johnson reaction of 4 with bis(trimethylsilyl) uracil (5a), bis(trimethysilyl)-
thymine (5b) and bis(trimethylsilyl) cytosine (5c)[25] was affected (Scheme 3) with the
Friedel–Crafts catalyst Sn(IV)Cl/CHCl3 at room temperature for 4–6 h. It resulted in
the formation of a mixture of ribofuranosyloxymethyl uracil 6a, -thymine 6b, -cytosine
6c derivatives (24–30% yield) along with the corresponding natural nucleosides
Scheme 1. Mechanism proposed for the formation of [(b-D-ribofuranosyloxy)methyl]nucleosides.

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Scheme 2. Synthesis of acetoxymethoxy ribofuranoside 4.
2’,3’,5’-tri-O-benzoyluridine, 5-methyluridine, and cytidine (7a–c respectively, 45–47%
yield) (Table 1, entries i,iii,v).
The mixture of ribofuranosyl derivatives 6a–c and 7a–c was separated by column
1
chromatography and characterized by H NMR spectra as 1-[2,3,5-tri-O-benzoyl-b-D-
ribofuranosyloxy)methyl]uracil (6a), 1-[(2,3,5-tri-O-benzoyl-b-D-ribofuranosyloxy)
methyl]thymine (6b), 1-[(2,3,5-tri-O-benzoyl-b-D-ribofuranosyloxy)methyl]cytosine
(6c) respectively (the methylene protons at d 5.10–5.15 (1 H) and d 5.36–5.40 (1 H)
as an AB type quartet, J = 10 Hz and H-1’ at d 5.50–5.60 as a singlet) and 13C NMR
(the methylene carbon at d 78.0–80.0 and C-1 at d 104.2–104.7). Unambiguous
assignment of structure for 6a–c was accomplished after hydrolysis (NaHCO3/MeOH)
to isolate 8a–c respectively, characterized (Scheme 3) as 1-[(-b-D-ribofuranosyloxy)-
methyl]uracil (8a), 1-[(-b-D-ribofuranosyloxy)methyl]thymine (8b) and 1-[(-b-D-ribo-
1
furanosyloxy)methyl]cytosine (8c) respectively by H NMR (the methylene protons at d
5.20–5.27 (1 H) and d 5.35–5.40 (1 H) as an AB type quartet J = 10 Hz and H-1’ at d
5.20–5.22 as a singlet) and 13C NMR (the methylene carbon at d 82.5–83.5 and C-1’ at
d 105.2–106.0).
The differentiation of N-1 alkylation from N-3 of 8a–c was readily accomplished
by comparison of ultraviolet spectra of the compounds in neutral vs 0.1 N alkali.[26–28]
They were characterized as N-1alkylation products as they showed less than a 2-mm
shift. Natural nucleosides 7a–c were characterized as 2’,3’,5’-tri-O-benzoyluridine (7a),
5-methyluridine (7b) and cytidine (7c) respectively (Scheme 3) by comparison of their
1H NMR spectral data and melting point with those reported in literature.[29] Formation
of compounds 6a–c and 7a–c can be explained from the capture of oxymethyl
carbocation b and ribofuranosyl cation c respectively by the base B (a–c) (Scheme 1).
In order to drive the reaction towards the formation of 6 alone, we have studied the
replacement of SnCl4 by the weaker Friedel–Crafts catalyst (CH3)3SiOSO3CF3
(TMSOTf) to perform the coupling reaction.[30] Thus, reaction of 4 with 5a (entry
ii) and 5b (entry iv) was carried out with TMSOTf/CHCl3 at reflux temperature (3–5 h)
to isolate 6a and 6b respectively in high yield, and formation of 7a and 7b was not
observed (Table 1). The generality of the reaction was studied for coupling of 4 with
cytosine derivative 5c under similar reaction conditions, resulting in the isolation of 6c
and 7c in a ratio of 1:1 respectively (Table 1, entry vi) indicating moderate selectivity,

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Scheme 3. Synthesis of [(b-D-ribofuranosyloxy)methyl]nucleosides.
probably due to the higher basicity of cytosine.[31,32] In order to achieve the selective
formation of 6c, coupling of 4 with bis(trimethylsilyl)-N4-benzoylcytosine (5d)[33] was
attempted, resulting in the isolation of N4-benzoyl-1-[(2,3,5-tri-O-benzoyl-b-D-ribofu-
ranosyloxy)methyl]cytosine (6d) and N4-2,3,5-tetra-O-benzoyl cytidine (7d) in a ratio
of 3:1 respectively (entry vii). Thus, use of the N4-benzoyl derivative of cytosine in the
coupling reaction has resulted in the isolation of the desired product 6d in higher yield.
In order to establish the generality of the reaction, coupling of 1 with bis(tri-
methylsilyl)-N6-benzoyladenine (5e)[34] was carried out in SnCl4/MeCN at room
temperature to isolate 6e and 7e respectively, in a ratio of 1:2 (entry viii) (Scheme 3).
A similar observation was made in the coupling of 4 with 5a–c. Compound 6e was
characterized analogously to 6a–c. In order to assign the regiochemistry, 6e was
hydrolyzed (NaHCO3/methanol) to 9-[(-b-D-ribofuranosyloxy)methyl]adenine (8e) and
characterized by an 1H NMR spectrum analogous to natural nucleosides from the
appearance of H-2 and H-8 protons at d 8.25 and d 8.20, respectively, indicating it to
be the N9 isomer.[35] Natural nucleoside 7e was characterized as N6,2,3,5-tetra-O-
benzoyladenosine (7e) by comparison of its 1H NMR spectrum, melting point and
optical rotation with that reported in literature[29] and was found to be the N9
regioisomer. In order to enhance the formation of 6e, coupling of 4 with 5e was studied

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Mereyala and Mamidyala
by use of a weaker catalyst (TMSOTf) in solvents such as CHCl3 (entry xi, xii) and
MeCN (entry ix, x) at room temperature to reflux temperature. The best result was
the formation of a mixture of 6e and 7e respectively (Table 1), in a ratio 1.3:1 in
MeCN at room temperature (entry ix). The observed moderate selectivity in this
reaction needs to be studied in detail. The scope and utility of the coupling reaction was
also examined for the preparation of ribofuranosyloxymethyl guanine derivatives in view
of their importance as pharmacologically active compounds such as acyclovir,[36,37]
ganciclovir[38,39] and penciclovir.[40] Coupling of 4 and N2-acetyl-tris(trimethylsilyl)-
guanine (5f)[41] in SnCl4/MeCN at room temperature gave 6f,6g:7f,7g (a ratio of 1:1.6,
entry xiii) while at reflux temperature coupling resulted in the formation of the undesired
nucleosides in larger amount (a ratio of 1:7.8, entry xiv). Reactions by change of solvent
and catalyst was attempted to enhance the selective formation of 6f,6g. Thus, coupling of
4 with 5f in TMSOTf/MeCN at room temperature gave 6f,6g:7f,7g in a ratio of 1:2.7
(entry xv), and at reflux temperature it changed to 1:1.8 (entry xvi). The change of
solvent to 1,2-dichloroethane and reaction at reflux temperature has exhibited the desired
selectivity and resulted in the formation of 6f,6g in 57% isolated yield (entry xvii), while
formation of 7f,7g was not observed. TMSOTf was found to be the suitable catalyst for
preparation of ribofuranosyloxymethyl derivatives 6a–g. Compounds 6f,6g and 7f,7g
were found to be a mixture of N9/N7 regiosiomers, 6f,6g were characterized analogously
to 6a–c. In order to assign the regiochemistry[42–44] 6f,6g were hydrolyzed to 8f,8g
respectively (Scheme 3) and unambiguously characterized[42–44] by the 1H and 13C NMR
as 9-[(-b-D-ribofuranosyloxy)methyl] guanine (8f) (the H-8 at d 7.75 as a singlet, NH2 at d
6.55; C-5 at d 116.4, C-8 at d 137.7 and C-4 at d 151.2) and 7-[(-b-D-ribofuranosylox-
y)methyl]guanine (8g) (the H-8 at d 8.0 as singlet, NH2 at d 6.20; C-5 at d 105.7, C-8 at d
145.0 and C-4 at d 161.0) respectively.[42–44] N2-Acetyl-9-(2,3,5-tri-O-benzoy-b-D-
ribofuranosyl)guanine (7f) and N2-acetyl-7-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl) gua-
nine (7g) were characterized as N9 and N7 linked natural nucleosides respectively by
comparison of their 1H NMR spectra and melting point with that reported in
literature.[29,42–44]
Formation of regiosiomers N9 (6f and 7f) and N7 (6g and 7g) was studied by
change of solvent (MeCN,1,2-dichloroethane), temperature (room temperature, reflux)
and catalyst (Sn(IV)Cl, TMSOTf). From these experiments it was observed that in the
formation of regioisomers 6f,6g and 7f,7g respectively, the N7 isomer predominated
over N9 in SnCl4 under kinetically controlled conditions, where as under thermo-
dynamic conditions no such selectivity was observed in SnCl4 or TMSOTf. The lack of
regioselectivity observed in the present study is ascrobed to the difference in reactivity
of donors 4 and 1, bearing the acetoxymethoxy and the acetyl leaving group
respectively. Attempted isomerisation[35,45] of N7 isomer 6g in TMSOTf/MeCN at
reflux temperature resulted in the decomposition, and formation of 6f (N9 isomer) or
natural nucleosides 7f and 7g was not observed.
We have earlier reported[24] that acetoxymethoxy glycopyranosides a couple with
alcohols (sugar and simple alcohols) to form O-glycosides due to the capture of
glycosyl cation c, while formation of products resulting from the capture of
glycosyloxymethyl carbocation b was not observed. In the present study we have
shown that coupling with nitrogen bases lead to the formation of products by capture of
intermediate b in preference to c. The reason for selectivity appears to be according to
the HSAB principle.[46–48] The glycosyl cation c is a hard acid and couples with hard

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bases[31,32,49] (alcohols, cytosine and adenine), where as carbocation b is a borderline
soft acid and is captured by soft base[31,32,49] (uracil, thymine and guanine).
In summary synthesis of novel ribofuranosyloxymethyl uracil, thymine, cytosine,
adenine and guanine was achieved by fine tuning of the acetoxymethoxy leaving group
of ribofuranoside. Application of this method for the synthesis of other glycosyl
derivatives is under investigation.
EXPERIMENTAL
1H NMR spectra were recorded using the following instruments: at 200 MHz on a
Varian Gemini, at 300 MHz on a Bruker Avance; at 400 MHz on a Varian Unity; at
500 MHz on a Varian Inova, with tetramethyl silane as internal standard for solutions
in deuteriochloroform. J values are given Hz. 13C NMR spectra were taken with Varian
Gemini (50 MHz), Bruker Avance (75 MHz) spectrometer with CDCl3 as internal
standard (C 77.0) for solutions in deuteriochloroform, DMSO-d6 (C 39.7) for solutions
in deuterio dimethyl sulfoxide, dioxane (C 67.3) for solutions in deuterated water.
Optical rotations were measured with a JASCO DIP-370 instrument. Melting points
were determined by using Fischer–John’s melting point apparatus and are uncorrected.
IR spectra were taken with a Perkin–Elmer 1310 spectrometer. UV spectra were
recorded on a Shimadzu UV 160A spectrometer. Organic solutions were dried over
anhydrous Na2SO4.
A Typical Procedure for Coupling of Ribofuranoside Derivative 4 with Nucleic
Acid Bases 5a–f (Method A: SnCl4 or Method B: Trimethylsilyltrifluoromethane
sulfonate (TMSOTf) (1.2–2.0 mmol, 0.5N in CHCl3 or MeCN or 1,2-dichloro-
ethane). To a solution (20 ml) of ribofuranoside derivative 4 (1.0 mmol) and silylated
nucleic acid bases 5a–f (1.2 mmol) at 0°C was added the catalyst under nitrogen
atmosphere. The reaction mixture was stirred at room temperature for 4–18 h or reflux
temperature for 1–6 h, progress of the reaction was monitored by TLC. After
completion of the reaction it was neutralized with saturated aqueous NaHCO3 solution
and filtered through a celite pad. The filtrate was extracted into CHCl3 (30 ml), organic
phase was separated, washed with brine, dried over anhydrous Na2SO4 and the solvent
was removed under reduced pressure to obtain a residue. The residue was separated by
column chromatography [SiO2, 60–120 mesh, ethyl acetate:chloroform] to isolate the
title compounds 6a–g and 7a–g.
2-Propynyl 2,3,5-Tri-O-benzoyl-b-D-ribofuranoside (2). To a solution of 1-O-
acetyl-2,3,5-tri-O-benzoyl-a/b-D-ribofuranoside (1) (20.0g, 39.7 mmol) in dry CHCl3 (200
mL) was added propargyl alcohol (2.8 mL, 47.6 mmol) and BF3.Et2O (6 mL, 47.6 mmol) at
0°C. The reaction mixture was stirred at room temperature for 5 h. After completion of the
reaction, anhydrous K2CO3 (6.0 g) was added, stirred for further 30 min., filtered, and the
residue was washed with CHCl3 (50 mL). The filtrate was transferred to a separating
funnel, washed with water (100 mL Â 2) and brine (100 mL). The organic phase was
separated, dried (Na2SO4) and concentrated to obtain a residue. The residue was chro-
matographed [SiO2; hexane–ethyl acetate (9:1)] to isolate the title compound 2 (13.3 g,

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68%) as a crystalline solid. mp 56°C; [a]D 12.4 (c 1.0, CHCl3); IR (KBr) nmax 3277, 3238,
2954, 2884, 2108, 1731, 1717, 1604, 1485, 1392, 1261, 1170, 1123, 1093, 1031 and 954
1
cmÀ1; H NMR (200 MHz; CDCl3) d 2.41 (1H, t, CꢀCH), 4.25, 4.35 (2H, AB quartet,
J = 9.3 Hz, CH2–CꢀC), 4.52 (1H, dd, J = 13.0, 6.0 Hz, H5), 4.60–4.80 (2H, m, 4H, H5’),
5.48 (1H, s, H1), 5.72 (1H d, J = 4.6 Hz, H2), 5.90 (1H dd, J = 3.7 Hz, H3), 7.25–8.25
(15H, m, aromatic); 13C NMR (50 MHz; CDCl3) d 54.5 (HCꢀC–), 64.5 (C5), 72.1 (C4),
75.7 (C3), 75.9 (O–CH2–C), 78.3 (HCꢀC–), 79.4 (C2), 103.4 (C1), 128–135 (aromatic),
165.03, 165.77 and 166.06 (C=O,ester); FAB-MS m/z: 523 [M+ + Na]; Anal.Calcd for
C29H24O8: C,69.59; H, 4.83. Found: C, 69.42; H, 4.78.
2-(Oxopropoxy) 2,3,5-Tri-O-benzoyl-b-D-ribofuranoside (3). To a solution of
2-propynyl 2,3,5-tri-O-benzoyl-b-D-ribofuranoside (2) (13.0 g, 26 mmol) in acetone:
H2O (200 mL, 2:1) was added Hg(OCOCF3)2 (2.21 g, 5.18 mmol). The reaction
mixture was stirred at room temperature for 6h. After completion of the reaction, acetone
was evaporated, the resulting residue was dissolved in ethyl acetate (200 mL), washed
with 10% aqueous KI solution (100 mL Â 2), 20% aqueous hypo solution (100 mL Â 2)
and brine (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated
to obtain the title compound 3 (12.9 g, 96%) as a solid. mp 75°C; [a]D 3.1 (c 1.0, CHCl3);
IR (KBr) nmax 2977, 2953, 2885, 2870, 2830, 1731, 1715, 1584, 1446, 1308, 1262, 1108,
1
1046, 1015 and 708 cmÀ1; H NMR (200 MHz; CDCl3) d 2.10 (3H, s, CH3), 4.10, 4.24
(2H, AB type quartet, J = 10.0 Hz, OCH2C), 4.52 (1H, dd, J = 13.0, 6.0 Hz, H5), 4.60–
4.80 (2H, m, H4,H5’), 5.30 (1H, s, H1), 5.80 (1H, d, J = 4.7 Hz, H2), 5.90 (1H, dd,
J = 3.7 Hz, H3), 7.20–8.25 (15H, m, aromatic); 13C NMR (50 MHz; CDCl3) d 26.3 (CH3),
64.3 (C5), 71.9 (C4), 72.3 (OCH2C), 75.3 (C3), 79.5 (C2), 105.1(C1), 125–135
(aromatic), 165.0, 165.2 and 165.1; (C=O,ester); FAB-MS m/z: 541 [M+ + Na]; Anal.
calcd for C29H26O9:C, 67.17; H, 5.05. Found: C, 67.37; H, 5.18.
1-[(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyloxy)methyl]acetate (4). To a solution
of 2-(oxopropoxy)2,3,5-tri-O-benzoyl-b-D-ribofuranoside (3) (12.0g, 23.2 mmol) in dry
CHCl3 (120 mL) was added m-CPBA (9.6 g, 55.6 mmol). The reaction mixture was
stirred at room temperature for 12h. After completion of the reaction, the reaction
mixture was diluted with CHCl3 (150 mL), washed with saturated aqueous NaHCO3
solution (150 mL Â 3, water (150 mL), brine (150 mL) and dried (Na2SO4). The
solvent was concentrated to give a residue which was purified by silica gel
chromatogrpahy (SiO2, hexane:ethyl acetate, 9:1) to obtain the title compound 4 as a
white solid. mp 71°C; [a]D 8.0 (c 1.0, CHCl3); UV lmax (MeOH) nm: 274; IR (KBr)
nmax 3062, 3015, 2938, 1752, 1731, 1604, 1430, 1261, 1107, 1046, 1015 and 708 cmÀ1
;
1H NMR (200 MHz; CDCl3) d 2.10 (3H, s, CH3), 4.54 (1H, dd, J = 13.0, 4.65 Hz, H5),
4.66–4.86 (2H, m, H4,H5’), 5.36, 5.42 (2H, AB type quartet, J = 7.5 Hz, OCH2O),
5.56 (1H, s, H1), 5.75 (1H, d, J = 6.5 Hz, H2), 5.90 (1H, dd, J = 4.4 Hz, H3), 7.20–
8.20 (15H, m, aromatic); 13C NMR (50 MHz; CDCl3) d 20.8 (CH3) 64.4 (C5), 71.9
(C4), 75.4 (C3), 79.5 (C2), 84.7 (OCH2O), 103.9 (C1), 125–135 (aromatic), 165.0,
165.2 and 170.1 (C=O, ester); FAB-MS m/z: 535 [M+ + H]; Anal. calcd for
C29H26O10:C, 65.16; H, 4.90. Found: C, 65.27; H, 5.11.
1-[(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyloxy)methyl]uracil (6a). Prepared
according to method B (2.24 mmol) by reacting 4 (1.0 g, 1.87 mmol) and 5a (0.57 g,

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2.24 mmol) in CHCl3 (40 mL) at reflux for 3 h to isoltate the title compound as a pale
yellow solid (1.07 g, 98.1% yield). mp 78–80°C; [a]D 16.0 (c 1.0, CHCl3); UV lmax
(MeCN) nm: 259; IR (KBr) nmax 3062, 2107, 1723, 1677, 1446, 1262, 1154, 1086,
1015, 816 and 692 cmÀ1; 1H NMR (200 MHz; CDCl3) d 4.60 (1H, dd, J = 13.0, 5.5 Hz,
H5’), 4.60–4.80 (2H, m, H4’,H5@), 5.14, 5.38 (2H, AB type quartet, J = 10.0 Hz,
OCH2N), 5.50 (1H, s, H1’), 5.62 (1H, d, J = 5.6 Hz, H2’), 5.65 (1H, d, J = 5.5 Hz, H5),
5.82 (1H, dd, J = 4.0 Hz, H3’), 7.18 (1H, d, H6), 7.20–8.20 (15H, m, aromatic), 9.0
(1H, br s, NH); 13C NMR (50 MHz; CDCl3) d 64.3 (C5’), 71.7 (C4’), 74.5 (C3’), 75.5
(C2’), 78.0 (OCH2N), 103.0 (C5), 104.5 (C1’), 127–135 (aromatic), 143.5 (C6), 150.0
(C=O, C2), 163.5 (C=O, C4), 165.0, 165.3 and 166.0 (C=O, ester); FAB-MS m/z: 609
[M+ + Na]; Anal calcd for C31H26O10N2:C, 63.48; H, 4.47; N, 4.78 Found: C, 63.37; H,
4.36; N, 4.67.
1-[(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyloxy)methyl]thymine (6b). Prepared
according to method B (2.22 mmol) by reacting 4 (1.0 g, 1.87 mmol) and 5b (0.6 g,
2.22 mmol) in CHCl3 (40 mL) at reflux for 4 h to isoltate the title compound as a white
crystalline solid (0.88 g, 78.6% yield). mp 82-84°C; [a]D 41.0 (c 1.0, CHCl3); UV lmax
(MeOH) nm: 266; IR (KBr) nmax 3176, 2970, 1721, 1684, 1369, 1307, 1269, 1092,
1
1062 and 1031 cmÀ1; H NMR (200 MHz; CDCl3) d 1.90 (3H, s, CH3), 4.50 (1H, dd,
J = 14.0, 6.5 Hz, H5’), 4.60–4.80 (2H, m, H4’,H5@), 5.10,5.36 (2H, AB type quartet,
J = 10.0 Hz, OCH2N), 5.50 (1H, s, H1’), 5.70 (1H, d, J = 5.0 Hz, H2’), 5.80 (1H, dd,
J = 4.0 Hz, H3’), 6.98 (1H, s, H6), 7.20–8.20 (15H, m, aromatic), 8.50 (1H, br s, NH);
13C NMR (50 MHz; CDCl3) d 12.2 (CH3), 64.6 (C5’), 74.5 (C4’), 76.0 (C3’), 78.0
(C2’), 80.0 (OCH2N), 104.7 (C1’), 111.5 (C5), 127–135 (aromatic), 151.0 (C=O,C2)
164.0 (C=O,C4) 164.8, 165.0 and 165.8 (C=O,ester); FAB-MS m/z: 601 [M+ + H];
Anal. cacld for C32H28O18N2:C, 63.99; H, 4.70; N, 4.66. Found: C, 64.17; H,
4.62; N, 4.59.
1-[(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyloxy)methyl]cytosine (6c). Prepared
according to method A (6.74 mmol) by reacting 4 (3.0 g, 5.61 mmol) and 5a (1.71
g, 6.74 mmol) in CHCl3 (30 mL) at room temperature for 6 h to isolate after
chromatographic separation (ethyl acetate:chloroform, 2:1) 7c (1.47 g, 47.4% yield)) as
a crystalline solid mp 180–82°C (lit.13 mp 182–83°C) and the title compound 6c (0.96 g,
29.5% yield) as a white crystalline solid. mp 178–181°C; [a]D 29.0 (c 1.0, CHCl3);
UV lmax (MeOH) nm: 271; IR (KBr) nmax 3336, 3200, 1728, 1664, 1616, 1488, 1370,
1
1264, 1088 and 1040 cmÀ1; H NMR (200 MHz; CDCl3) d 4.50 (1H, dd, J = 13.0,
J = 5.0 Hz, H5’), 4.60–4.80 (2H, m, H4’,H5@), 5.15, 5.40 (2H, AB type quartet,
J = 10.0 Hz, OCH2N), 5.60 (1H, s, H1’), 5.70 (d, J = 5.0 Hz, H2’), 5.85 (1H,dd,
J = 3.0 Hz, H3’), 5.95 (1H,d, J = 7.5 Hz, H5), 7.15–8.15 (16H, m, H6, aromatic); 13C
NMR (50 MHz; CDCl3) d 64.7 (C5’), 72.1 (C4’), 75.5 (C2’), 76.5 (C3’), 79.5 (OCH2N),
104.2 (C1’), 128–135 (aromatic), 144.6 (C6), 156.1 (C4), 165.1 (C=O,C2) 165.4,
166.0, 166.1 (C=O,ester); FAB-MS m/z: 586 [M+ + H]; Anal. cald for C31H27O9N3: C,
63.58; H, 4.65; N, 7.18. Found: C, 63.41; H, 4.59; N, 7.12.
N4Benzoyl-1-[(2,3,5-tri-O-benzoyl-b-D-ribofuranosyloxy)methyl]cytosine (6d).
Prepared according to method B (1.11 mmol) by reacting 4 (0.5 g, 0.93 mmol) and
5d (0.4 g, 1.11 mmol) in CHCl3 (20 mL) at reflux temperature for 4 h to isoltate after

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chromatographic separation (ethylacetate:chloroform, 2:1) 7d (0.1 g, 17.0% yield) as a
crystalline solid mp 205–7°C (lit.13 mp 206.5–208°C) and the title compound 6d
(0.33 g, 52.0% yield) as a white crystalline solid. mp 126–128°C; [a]D 9.0 (c 1.0,
CHCl3); UV lmax (MeCN) nm: 258; IR (KBr) nmax 3062, 2915, 1723, 1662, 1604,
1
1530, 1454, 1307, 1270, 1100, 1046, 970, 815 and 692 cmÀ1; H NMR (200 MHz;
CDCl3) d 4.50 (1H, dd, J = 13.0, 5.0 Hz, H5’), 4.55–4.75 (2H, m, H4’,H5@), 5.20, 5.50
(2H, AB type quartet, J = 10.0 Hz, OCH2N), 5.60 (1H, s, H1’), 5.65 (1H, d, J = 5.0 Hz,
H2’), 5.70–5.90 (1H, m, H3’), 7.20–8.15 (17H, m, H5,H6,aromatic); FAB-MS m/z:
690 [M+ + H]; Anal. calcd for C38H31O10N3:C, 66.18; H, 4.53; N, 6.09. Found: C,
66.31; H, 4.48; N, 6.02.
N6-Benzoyl-9-[(2,3,5-tri-O-benzoyl-b-D-ribofuranosyloxy)methyl]adenine (6e).
Prepared according to method B (3.7 mmol) by reacting 4 (1.0 g, 1.87mmol) and 5a
(0.86 g, 2.24 mmol) in MeCN (40 mL) at room temperature for 16 h to isoltate after
chromatographic separation (ethyl acetate:chloroform, 2:1) 7e (0.44 g, 34.9% yield)) as
a crystalline solid mp 89–91°C (lit.13 mp 88–92°C) and the title compound 6e (0.6 g,
45.4% yield) as a yellowish solid. mp 113–116°C; [a]D 7.0 (c 1, CHCl3); UV lmax
(MeCN) nm: 277; IR (KBr) nmax 3323, 3085, 1723, 1616, 1508, 1446, 1323, 1261,
1
1062, 1015 and 708 cmÀ1; H NMR (200 MHz; CDCl3) d 4.50 (1H, dd, J = 14.0,
5.0 Hz, H5’), 4.65–4.90 (2H, m, H4’,H5@), 5.50 (1H, s, H1’), 5.60–6.00 (4H, m,
OCH2N,H2’,H3’), 7.20–8.20 (21H, m, H8, aromatic), 8.80 (1H,s, H2), 9.00 (1H, br s,
NH); 13C NMR (50 MHz; CDCl3) d 45.2 (C5’), 64.3 (C4’), 75.3 (C2’), 81.1 (OCH2N),
104.0 (C1’), 122.1 (C5),125–135 (aromatic) 143.0 (C8), 149.7 (C4), 152.0 (C2),
153.1 (C6), 164.8, 165.0, 165.3, 166.0 (C=O,ester); FAB-MS m/z: 714 [M+ + H];
Anal. cacld for C39H31O9N5:C, 65.68; H, 4.37; N, 9.82. Found: C, 63.81; H, 4.21;
N, 9.72.
N2-Acetyl-9-[(2,3,5-tri-O-benzoyl-b-D-ribofuranosyloxy)methyl]guanine (6f)
N2-Acetyl-7-[(2,3,5-tri-O-benzoyl-b-D-ribofuranosyloxy)methyl]guanine (6g). Pre-
pared according to method B (2.24 mmol) by reacting 4 (1.0 g, 1.87 mmol) and 5f
(0.91 g, 2.24 mmol) in 1,2-dichloroethane (40 mL) at reflux temperature for 2 h to
isoltate after chromatographic separation (ethyl acetate:chloroform, 3:1) the title
compound 6f (0.38 g, 29.7% yield) as a white crystalline solid. mp 125–127°C; [a]D
42.0 (c 1, CHCl3); UV lmax (MeCN) nm: 281; IR (KBr) nmax 3170, 3046, 2923, 1730,
1
1677, 1600, 1554, 1430, 1338, 1261, 1077, 1000 and 692 cmÀ1; H NMR (200 MHz;
CDCl3) d 2.38 (3H, s, Ac), 4.60–4.85 (3H,m, H4’,H5’,H5@), 5.50 (1H,s, H1’), 5.45–
5.65 (2H, AB type quartet, J = 10.0 Hz, OCH2N), 5.60–5.80 (2H, m, H2’,H3’), 7.15–
8.00 (15H, m, aromatic), 10.42 (1H, br s, NH), 12.00 (1H, br s, NH); FAB-MS m/z:
668 [M++ H]; Anal. cacld for C34H29O10N5:C, 61.16; H, 4.38; N, 10.4. Found: C,
61.28; H, 4.27; N, 10.32.; followed by (6g) (0.34 g, 27% yield) as a white crystalline
solid. mp 225–228°C; [a]D À 30.0 (c 1, CHCl3); UV lmax (MeCN) nm: 266; IR (KBr)
nmax 3300, 2930, 2861, 1715, 1685, 1616, 1385, 1315, 1261, 1092, 1046, 1030 and
692 cmÀ 1 1H NMR (200 MHz; CDCl3) d 2.20 (3H, s, Ac), 4.20–4.80 (3H, m,
;
H4’,H5’,H5@), 5.65 (1H, s, H1’), 5.70–6.08 (4H, m, OCH2N, H2’,H3’), 7.20–8.20 (15H,
m, aromatic), 11.50 (1H, br s, NH), 12.20 (1H,br s, NH); FAB-MS m/z: 668 [M+ + H];
Anal cacld for C34H29O10N5:C, 66.16; H, 4.38; N, 10.49. Found: C, 66.01; H,
4.29; N, 10.33.

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1-[(b-D-Ribofuranosyloxy)methyl]uracil (8a). To a solution of 6a (0.9g, 1.53
mmol) in methanol (18 mL) was added a catalytic amount of NaHCO3 (0.1 g) and
refluxed for 3 h. After completion of the reaction the reaction mixture was neutralized
with IR 120 H+ resin, filtered, washed with methanol (10 mL) and filtrate was
evaporated to a residue. The residue was dissolved in water (25 mL) washed with
chloroform (25 mL), the water phase was concentrated to isolate the title compound as
a white solid in 93% yield (0.39 g), mp 113–115°C; [a]D 144.0 (c 1.0, H2O); UV lmax
(H2O) nm: 260, (0.1N, NaOH) 261; IR (KBr) nmax 3370, 3046, 2830, 2315, 1685,
1
1446, 1262, 1054, 953 and 815 cmÀ1; H NMR (400 MHz; D2O) d 3.60 (1H, dd,
J = 10.0,5.5 Hz, H5’), 3.80 (1H, dd, J = 4.0 Hz, H5@), 4.05 (1H, m, H3’), 4.12 (1H, d,
J = 5.5 Hz, H2’), 5.22 (1H, s, H1’), 5.27, 5.40 (2H, AB type quartet, J = 11.0 Hz,
OCH2N), 5.90 (1H, d, J = 5.5 Hz, H5), 7.80 (1H, d, H6); 13C NMR (50 MHz; D2O) d
63.0 (C5’), 71.0 (C4’), 75.0 (C3’), 75.5 (C2’), 83.5 (OCH2N), 102.5 (C5), 106.0 (C1’),
146.5 (C6), 152.25 (C=O,C2), 166.5 (C=O,C4); FAB-MS m/z: 275 [M+ + H]; Anal.
calcd for C10H14O7N7:C, 43.80; H, 5.15; N, 10.22. Found: C, 43.67; H, 5.11; N, 10.25.
1-[(b-D-Ribofuranosyloxy)methyl]thymine (8b). To a solution of 6b (0.7g,
1.16 mmol) in methanol (14 mL) was added a catalytic amount of NaHCO3 (0.08 g)
and refluxed for 3 h. to isolate by the work up described for 8a the title compound as a
white crystalline solid in 98.5% yield (0.33 g). mp 188–190°C; [a]D À22.0 (c 1.0,
MeOH); UV lmax (MeOH) nm: 265, (0.1N NaOH) 266; IR (Neat) nmax 3400, 2953, 1693,
1677, 1362, 1330, 1260, 1076 and 1030 cmÀ1; 1H NMR (200 MHz; D2O) d 1.90 (3H, s,
CH3), 3.60 (1H, dd, J = 14.0, 6.5 Hz, H5’), 3.80 (1H, dd, J = 4.0 Hz, H5@), 3.90–4.30 (2H,
m, H3’,H4’), 5.20 (1H, s, H1’), 5.25, 5.35 (2H, AB type quartet, J = 10.0 Hz, OCH2N),
7.60 (1H, s, H6), 8.00 (1H, br s, NH); 13C NMR (50 MHz; D2O) d 10.7 (CH3), 62.2 (C5’),
70.1 (C4’), 74.0 (C3’), 74.4 (C2’), 82.6 (OCH2N), 105.2 (C1’), 110.6 (C5), 141.3 (C6),
151.5 (C=O,C2), 166.1 (C=O,C4); FAB-MS m/z: 311 [M+ + Na]; Anal calcd for
C11H16O7N2:C, 45.83, H, 5.60, N, 9.2. Found: C, 45.91; H, 5.52; N, 9.13.
1-[(b-D-Ribofuranosyloxy)methyl]cytosine (8c). To a solution of 6c (0.9g,
1.5 mmol) in methanol (18 mL) was added a catalytic amount of NaHCO3 (0.1 g)
and refluxed for 3 h. to isolate by the work up described for 8a the title compound as a
white crystalline solid in 75 % yield (0.31 g) as a white solid. mp 146°C; [a]D 16.0 (c
1, MeOH); UV lmax (MeOH) nm: 268, (0.1N NaOH) 270; IR (Neat) nmax 3446, 1662,
1
1500, 1384, 1200 and 731 cmÀ1; H NMR (200 MHz; D2O) d 3.60 (1H,dd, J = 13.0,
5.0 Hz, H5’), 3.80 (1H,dd, J = 3.0 Hz, H5@), 3.90–4.30 (3H, m, H2’,H3’,H4’), 5.20 (1H,
s, H1’), 5.20, 5.40 (1H, AB type quartet, J = 10.0 Hz,OCH2N), 6.15 (1H,d, J = 7.5 Hz,
H5), 7.70 (1H,d, H6); 13C NMR (50 MHz; D2O) d 62.1 (C5’), 70.1 (C4’), 74.0 (C3’),
76.0 (C2’), 82.5 (OCH2N), 105.2 (C1’), 146.0 (C6), 156.6 (C4), 165.5 (C=O,C2); FAB-
MS m/z: 274 [M+ + H]; Anal. calcd for C10H15O6N2:C, 43.95; H, 5.53; N, 15.38.
Found: C, 43.81; H, 5.45; N, 15.22.
9-[(b-D-Ribofuranosyloxy)methyl]adenine (8e). To a solution of 6e (0.4g,
0.56 mmol) in methanol (8 mL) was added a catalytic amount of NaHCO3 (0.05 g)
and refluxed for 5 h. to isolate by the work up described for 8a the title compound as a
white crystalline solid in 83.2% yield (0.14 g). mp 155–158°C; [a]D À 34.0 (c 1,
DMSO); UV lmax (H2O) nm: 259; IR ?KBr) nmax 3308, 1670, 1685, 1600, 140.8, 1370,

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1
1285, 1123, 1062, 1023, 962, 800 and 722 cmÀ1; H NMR (200 MHz;DMSO-d6) d
3.20–4.00 (6H,m, H2’,H3’,H4’,H5’,H5@,OH), 4.75 (1H, br s, OH), 4.90 (1H, s, H1’),
5.10 (1H, br s, OH), 5.55, 5.70 (2H,AB type quartet, J = 10.0 Hz, OCH2N)), 7.25 (2H,
br s, NH2), 8.20 (1H, s, H8), 8.25 (1H,s, H2); 13C NMR (50 MHz; DMSO-d6) d
62.6(C5’), 68.6(C4’), 70.6(C3’), 74.5 (C2’), 84.1 (OCH2N), 105.1 (C1’), 118.6 (C5),
141.5 (C8), 149.6 (C4), 153.0 (C2), 156.0 (C6); FAB-MS m/z: 298 [M+ + H]; Anal.
calcd for C11H15O5N5:C, 44.44; H, 5.09; N, 23.56. Found: C, 44.51; H, 5.01; N, 23.44.
9-[(b-D-Ribofuranosyloxy)methyl]guanine (8f). To a solution of 6f (0.3g,
0.44 mmol) in methanol (6 mL) was added a catalytic amount of NaHCO3 (0.05 g)
and refluxed for 3 h. to isolate by the work up described for 8a the title compound as a
white crystalline solid in 78.5% yield (0.11 g). mp 260–262°C; [a]D À4.0 (c 0.5,
DMSO); UV lmax (H2O) nm: 252; IR (KBr) nmax 3353, 3200, 2970, 2892, 2762, 1692,
1646, 1600, 1523, 1477, 1168, 1015, 984, 790, 692 and 570 cmÀ1; 1H NMR (300 MHz;
DMSO-d6) d 3.25–3.60 (2H, m, H5’, H5@), 3.64 (1H, s, H2’), 3.65–4.00 (2H, m,
H3’,H4’), 4.65 (1H, s, OH), 4.88 (1H, s, OH), 4.90 (1H, s, H1’), 5.14 (1H, s, OH), 5.35,
5.45 (2H, AB type quartet, J = 10.0 Hz, OCH2N), 6.55 (2H, br s, NH2), 7.75 (1H, s,
H8), 10.70 (1H, br s, NH); 13C NMR (50 MHz; DMSO-d6) d 62.5 (C5’), 68.1 (C4’),
70.5 (C3’), 74.3 (C2’), 84.0 (OCH2N), 104.7 (C1’), 116.4 (C5), 137.7 (C8), 151.2 (C4),
153.9 (C2), 156.7 (C6); FAB-MS m/z: 314 [M+ + H]; Anal. calcd for C11H15O6N5:C,
42.17; H, 4.83; N, 22.36. Found: C, 42.26; H, 4.72; N, 22.2.
7-[(b-D-Ribofuranosyloxy)methyl]guanine (8g). To a solution of 6g (0.3g,
0.44 mmol) in methanol (6 mL) was added a catalytic amount of NaHCO3 (0.05 g)
and refluxed for 5 h. to isolate by the work up procedure described for 8a the title
compound as a white crystalline solid in 93% yield (0.13 g). mp 264°C (decomposed);
[a]D 24.0 (c 0.5, DMSO); UV lmax (H2O) nm: 285; IR (KBr) nmax 3315, 3154, 2915,
1
1661, 1538, 1454, 1370, 1210, 1092 and 1030 cmÀ1; H NMR (500 MHz; DMSO-d6)
d 3.20–3.60 (2H, m, H5’,H5@), 3.70 (1H, s, H2’), 3.75–3.95 (2H, m, H3’,H4’), 4.60
(1H, s, OH), 4.80 (1H, s, OH), 4.90 (1H, s, H1’), 5.00 (1H, s, OH), 5.60, 5.65 (2H, AB
type quartet, J = 10.0 Hz, OCH2N), 6.20 (2H, br s, NH2), 8.00 (1H, s, H8), 10.90 (1H,
br s, NH); 13C NMR (75 MHz; DMSO-d6) d 63.4 (C5’), 71.4 (C4’), 72.3 (C3’), 75.3
(C2’), 84.8 (OCH2N), 105.7 (C1’), 106.4 (C5), 145.0 (C8), 154.0 (C2), 155.3 (C6),
161.0 (C4); FAB-MS m/z: 314 [M+ + H]; Anal. calcd for C11H15O6N5:C, 42.17; H,
4.83; N, 22.36. Found: C, 42.24; H, 4.71; N, 22.19.
ACKNOWLEDGMENT
MSK thanks Council for Scientific and Industrial Research, New Delhi for the
financial assistance in the form of a Senior Research Fellowship.
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Received May 9, 2003
Accepted December 31, 2003

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