Functionalization of Guanosine and 2′-Deoxyguanosine at C6: A Modified Appel Process and SNAr Displacement of Imidazole

Article abstract of DOI:10.1081/NCN-120027823

Treatment of sugar-protected 2-N-trityl derivatives of guanosine and 2′-deoxyguanosine with imidazole/triphenylphosphine/iodine/ethyldiisopropylamine gives the corresponding 6-(imidazol-1-yl)-2-(tritylamino)purine nucleosides. S _NAr displacement of the imidazole moiety with nucleophiles provides 2-amino-6-substituted-purine nucleosides and 2′-deoxynucleosides.

Full text of DOI:10.1081/NCN-120027823

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Functionalization of Guanosine and
2′‐Deoxyguanosine at C6: A Modified Appel Process
and SNAr Displacement of Imidazole
Zlatko Janeba a , Xiaoyu Lin a & Morris J. Robins a
a Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah,
84602‐5700, USA
Version of record first published: 01 Jun 2007.
To cite this article: Zlatko Janeba, Xiaoyu Lin & Morris J. Robins (2004): Functionalization of Guanosine and
2′‐Deoxyguanosine at C6: A Modified Appel Process and SNAr Displacement of Imidazole , Nucleosides, Nucleotides and
Nucleic Acids, 23:1-2, 137-147
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 23, Nos. 1 & 2, pp. 137–147, 2004
Functionalization of Guanosine and 2’-Deoxyguanosine
at C6: A Modified Appel Process and SNAr
Displacement of Imidazoley,#
*
Zlatko Janeba, Xiaoyu Lin, and Morris J. Robins
Department of Chemistry and Biochemistry, Brigham Young University,
Provo, Utah, USA
ABSTRACT
Treatment of sugar-protected 2-N-trityl derivatives of guanosine and 2’-deoxyguano-
sine with imidazole/triphenylphosphine/iodine/ethyldiisopropylamine gives the
corresponding 6-(imidazol-1-yl)-2-(tritylamino)purine nucleosides. SNAr displace-
ment of the imidazole moiety with nucleophiles provides 2-amino-6-substituted-
purine nucleosides and 2’-deoxynucleosides.
Key Words: 2-Amino-6-substituted-purine nucleosides and 2’-deoxynucleosides;
2’-Deoxyguanosine derivatives; Guanosine derivatives; Guanine nucleoside
modifications.
yIn honor and celebration of the 70th birthday of Professor Leroy B. Townsend.
#This paper is: Nucleic Acid Related Compounds, 122. Paper 121 is Ref. [1].
*
Correspondence: Morris J. Robins, Department of Chemistry and Biochemistry, Brigham
Young University, Provo, UT 84602-5700, USA; Fax: (801) 422-0153; E-mail: morris_robins@
byu.edu.
137
DOI: 10.1081/NCN-120027823
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com
Copyright D 2004 by Marcel Dekker, Inc.

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Janeba, Lin, and Robins
INTRODUCTION
Studies on the synthesis of nucleosides and nucleotides with modified bases have
been pursued for many years, but the field remains very active. Significant new
biological effects continue to be discovered with these compounds, including unnatural
base pairing and medicinal activities, especially as antiviral and anticancer agents.
Base-sugar coupling procedures provide access to varied bases on a given sugar
analogue. However, such approaches often produce isomeric mixtures, and anomers
usually are formed with sugar derivatives lacking an anchimeric C2 participating group.
Modifications of naturally occurring nucleosides avoid these complications and can be
employed to give good yields of regio- and stereochemically pure products.
Recently, several leaving groups at C6 of purines have been employed for
modification of nucleosides and 2’-deoxynucleosides. These have included elaboration
of an amino function into a (1,2,4-triazol-4-yl) leaving group[2] for direct transformation
of 6-aminopurine compounds, halo-deoxygenation[3–6] for substitution of 6-oxopurine
derivatives, and diazotization-halodediazoniation for indirect functionalization of
aminopurine analogues.[7–11] Conversions of hypoxanthine and/or guanine compounds
into 6-O-(pentafluorophenyl),[12] 6-pyridyl,[13] and 6-O-(2,4,6-triisopropylbenzenesul-
fonyl)[5] derivatives, and further activation of the hindered sulfonates by SNAr
displacements to provide quaternary amine salts,[14,15] have been used for transforma-
tions of 2’-deoxy- and/or inosine and guanosine derivatives. Enhanced interest in such
nucleobase modifications has been stimulated by recent studies on palladium-promoted
C–N bond formation at C6 of purine 2’-deoxy- and nucleoside derivatives, which has
proven to be especially useful for SNAr reactions with less nucleophilic aromatic
amines.[16–19]
We developed a modified Appel[20,21] protocol [imidazole/Ph3P/I2/EtN(iPr)2] for
introduction of the 6-(imidazol-1-yl) group into inosine and 2’-deoxyinosine.[22] Ve´liz
and Beal reported conversions of inosine and guanosine derivatives into the cor-
responding 6-bromo- and 2-amino-6-bromopurine compounds. However, their Appel
reagent system (NBS/HMPT) was too acidic for the more sensitive 2’-deoxynucleoside
derivatives, and glycosyl cleavage occurred.[6] In contrast, our combination [imidazole/
Ph3P/I2/EtN(iPr)2] provided a mild and highly efficient transformation of sugar-
protected 2’-deoxyinosine, as well as inosine, into the 6-(imidazol-1-yl)purine com-
pounds, which were converted into 6-substituted-purine 2’-deoxy- and nucleosides in
high yields by SNAr displacements with nitrogen, oxygen, and sulfur nucleophiles.[22]
The serious limitation of our protocol was its failure to convert analogous 2’-deoxy-
and guanosine derivatives into 2-amino-6-(imidazol-1-yl)purine compounds. We now
report circumvention of this limitation with 2-N-trityl derivatives of sugar-protected
guanosine and 2’-deoxyguanosine.
RESULTS AND DISCUSSION
Preliminary results with sugar-protected guanosine derivatives indicated that side
reactions occurred with the 2-amino group and our Appel reagent combination.[23]
Protection of the 2-amino function with common electron-withdrawing (acetyl,

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139
benzoyl, or pivaloyl) or electron-donating (N,N-dimethylaminomethylene) groups gave
derivatives that did not undergo clean reactions to produce the 6-(imidazol-1-yl)
compounds. However, treatment of 5’-O-(tert-butyldimethylsilyl)-2’,3’-O-isopropyli-
dene-2-N-tritylguanosine (2) [prepared in 87% yield by protection of 2’,3’-O-
isopropylideneguanosine (1) (Scheme 1) with TBDMSCl and then TrCl] with
imidazole/Ph3P/I2/EtN(iPr)2 in hot toluene gave 9-[5-O-(tert-butyldimethylsilyl)-2,3-
O-isopropylidene-b-D-ribofuranosyl]-6-(imidazol-1-yl)-2-(tritylamino)purine (ꢀ 89%).
The steric bulk of the trityl group might be a significant factor in the success of this
amino-protection strategy. Deprotection of this material (TFA/H2O) gave 2-amino-6-
(imidazol-1-yl)-9-(b-D-ribofuranosyl)purine (3) (82% from 2). SNAr displacement
reactions of 3 with nitrogen and oxygen nucleophiles proceeded more readily than with
its protected derivative, but less readily than with the 6-(imidazol-1-yl)purine
nucleosides without a 2-amino substituent.[22]
Treatment of 3 with Dowex 1 Â 2 (OHÀ) resin (pre-soaked in MeOH) in MeOH at
ambient temperature gave 2-amino-6-methoxy-9-(b-D-ribofuranosyl)purine (4a) (93%),
and Me2NH/H2O at ambient temperature converted 3 into 2-amino-6-(dimethylamino)-
9-(b-D-ribofuranosyl)purine (4b) (88%). However, SNAr displacement of imidazole
from 3 with neat benzylamine was sluggish. This reaction was not complete after
heating at 100°C for 48 h, and byproduct formation was problematic (TLC). Addition
of DBU to the reaction mixture increased the rate, and 2-amino-6-(benzylamino)-9-(b-
D-ribofuranosyl)purine (4c) (82%) was obtained after 39 h at 100°C. Such SNAr
displacements can be executed with 2-amino-6-chloro-[3–5] or the more reactive 2-
amino-6-bromopurine[6] analogues, and the preparation of our 6-(imidazol-1-yl)
derivatives requires tritylation and detritylation. However, these protection/deprotection
steps are essentially quantitative, and the imidazol-1-yl substituent is stable under tin
radical-mediated reaction conditions that are compromised by the presence of bromo or
chloro groups.
Preliminary experiments with 2-N-trityl derivatives of 2’-deoxyguanosine revealed
that the glycosyl bond was too acid sensitive for efficient detritylation. Treatment of
Scheme 1. Reagents: (a) (i) TBDMSCl/DMAP/Et3N/pyridine; (ii) TrCl/Et3N/pyridine. (b) (i)
Imidazole/I2/Ph3P/EtN(iPr)2/toluene; (ii) TFA/H2O (9:1). (c) Dowex 1 Â 2 (OHÀ)/MeOH (for 4a),
Me2NH/H2O (for 4b), and PhCH2NH2/DBU (for 4c).

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Janeba, Lin, and Robins
3’,5’-di-O-acetyl-2’-deoxyguanosine[24] (5) (Scheme 2) with mono- and dimethoxytrityl
chloride gave the 3’,5’-di-O-acetyl-2-N-MMTr (6a) (97%) and 2-N-DMTr (6b) (95%)
derivatives.[25] Treatment of 6a and 6b with imidazole/Ph3P/I2/EtN(iPr)2 followed by
extraction of the reaction mixtures with EtOAc and detritylation with 80% AcOH/H2O/
dioxane[26] (55°C for MMTr; ambient temperature for DMTr) gave 2-amino-9-(3,5-di-
O-acetyl-2-deoxy-b-D-erythro-pentofuranosyl)-6-(imidazol-1-yl)purine (7) as a white
foam. Purification of 7 was not straightforward, and SNAr displacements with such
protected derivatives had been found to proceed less readily. Deacetylation of 7 (NH3/
MeOH) was effected to give the crystalline 2-amino-9-(2-deoxy-b-D-erythro-pentofu-
ranosyl)-6-(imidazol-1-yl)purine (8) (56% from 6a; 58% from 6b). Preparation of the
2-amino-6-chloropurine 2’-deoxy analogue by our modified deoxychlorination proce-
dure[4,5] requires stringent conditions, and the convenient deoxybromination method-
ology of Ve´liz and Beal fails with 2’-deoxynucleosides.[6]
Treatment of 8 with Dowex 1 Â 2 (OHÀ) in MeOH at ambient temperature gave
2-amino-9-(2-deoxy-b-D-erythro-pentofuranosyl)-6-methoxypurine (9a) (61%), and
Me2NH/H2O at 50°C gave 2-amino-9-(2-deoxy-b-D-erythro-pentofuranosyl)-6-
(dimethylamino)purine (9b) (59%). Benzylamine/DBU at 100°C gave 2-amino-6-(benzyl-
amino)-9-(2-deoxy-b-D-erythro-pentofuranosyl)purine (9c) (76%).
In summary, the modified Appel combination of imidazole/Ph3P/I2/EtN(iPr)2 in
hot toluene, which we developed for C6 functionalization of sugar-protected 2’-
deoxyinosine and inosine derivatives, failed to give the corresponding 2-amino-6-
(imidazol-1-yl) compounds with guanine nucleoside analogues. Protection of the
guanine 2-amino group with trityl, MMTr, or DMTr gives derivatives that undergo near
quantitative conversions into the 2-N-(trityl or substituted-trityl)-6-(imidazol-1-yl)
analogues. Deprotection provides 2-amino-6-(imidazol-1-yl)purine compounds that
undergo SNAr reactions with nitrogen and oxygen nucleophiles to give 2-amino-6-
substituted-purine nucleosides and 2’-deoxynucleosides in excellent to good yields.
This provides a new approach for modification of the readily available guanosine and
2’-deoxyguanosine.
Scheme 2. Reagents: (a) RCl/EtN(iPr)2/pyridine. (b) (i) Imidazole/I2/Ph3P/EtN(iPr)2/toluene;
(ii) 80% AcOH/(dioxane/H2O, 4:1). (c) NH3/MeOH. (d) Dowex 1 Â 2 (OHÀ)/MeOH (for 9a),
Me2NH/H2O (for 9b), and PhCH2NH2/DBU (for 9c).

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Functionalization of Guanosine at C6
141
EXPERIMENTAL SECTION
Uncorrected melting points were determined with a capillary tube apparatus. UV
spectra were determined with solutions in MeOH unless otherwise noted. NMR spectra
1
were obtained with solutions in Me2SO-d6 (Me4Si internal), H at 300 MHz and 13C at
75 MHz unless otherwise noted. High-resolution mass spectra (MS) were determined
under FAB conditions (glycerol or thioglycerol matrix) unless otherwise noted. Reagent
grade chemicals were used, and solvents were distilled before use. Toluene was dried
over and distilled from CaH2. TLC was performed with silica G plates with UV254
indicator (Sorbent Technologies), and MeOH/CH2Cl2 (1–15%) solvent systems. Merck
Kieselgel 60 (230-400 mesh) and Dowex 1 Â 2 (OHÀ) were used for column
chromatography. Method 1 (nucleoside/Dowex 1 Â 2 (OHÀ)/MeOH) is described for
3 ! 4a, method 2 (nucleoside/MMTrCl or DMTrCl/EtN(iPr)2/pyridine) is described for
5 ! 6a, and method 3 [(i) nucleoside/imidazole/Ph3P/I2/EtN(iPr)2; (ii) AcOH/H2O/
dioxane; (iii) NH3/MeOH] is described for 6a ! 8.
5’-O-(tert-Butyldimethylsilyl)-2’,3’-O-isopropylidene-2-N-tritylguanosine (2).
TBDMSCl (7.54 g, 50.0 mmol), DMAP (40 mg, 0.32 mmol), and Et3N (10.0 mL,
7.26 g, 0.072 mol) were added to a stirred suspension of 2’,3’-O-isopropylidenegua-
nosine (10.4 g, 32.4 mmol) in pyridine (120 mL). Stirring was continued for 24 h, and
volatiles were evaporated in vacuo. Pyridine (150 mL), trityl chloride (32 g, 0.11 mol),
and Et3N (16 mL, 11.6 g, 0.11 mol) were added to the residue, and the suspension was
stirred for 24 h. Volatiles were evaporated and the residue was partitioned (H2O/
CH2Cl2). The aqueous phase was extracted (CH2Cl2, 5 Â 15 mL), and the combined
organic phase was washed (brine) and dried (Na2SO4). Volatiles were evaporated, and
the residue was chromatographed (MeOH/CH2Cl2, 1 ! 3%) to give a yellow solid
foam. This material was recrystallized (toluene) to give 2 (19.13 g, 87%) as a white
powder: mp 215–217°C; UV max 279 nm (sh, e 12 600), 261 nm (e 14 900), 255 (sh,
1
e 13 800); H NMR (CDCl3) d 0.004, 0.017 (2 Â s, 2 Â 3H), 0.86 (s, 9H), 1.24, 1.47
(2 Â s, 2 Â 3H), 3.58 (d, J = 4.4 Hz, 2H), 4.17 (dt, J = 2.5, 4.4 Hz, 1H), 4.46 (dd,
J = 2.4, 6.1 Hz, 1H), 4.69 (dd, J = 2.6, 6.1 Hz, 1H), 5.40 (d, J = 2.6 Hz, 1H), 7.06–
7.25 (m, 9H), 7.33 (s, 1H), 7.35–7.48 (m, 6H), 7.65, 11.50 (2 Â bs, 2 Â 1H); 13C
NMR (CDCl3) d –5.17, –5.25, 18.5, 25.9, 26.1, 27.5, 63.6, 71.2, 81.2, 83.9, 86.6, 90.9,
113.7, 118.1, 126.8, 127.8, 129.2, 136.2, 144.7, 150.1, 151.4, 158.8; HRMS m/z
680.3271 [MH+ (C38H46N5O5Si) = 680.3268].
2-Amino-6-(imidazol-1-yl)-9-( -D-ribofuranosyl)purine (3). Imidazole (1.05 g,
0.015 mol) and 2 (2.05 g, 0.003 mol) were added to a stirred slurry of Ph3P (3.86 g,
0.015 mol), I2 (3.75 g, 0.015 mol), and EtN(iPr)2 (5.2 mL, 3.86 g, 0.030 mol) in
freshly distilled toluene (80 mL). Stirring was continued at 95°C for 40 min. Volatiles
were evaporated, and EtOAc (100 mL) was added. The solid was filtered, and volatiles
were evaporated. The residue was chromatographed (EtOAc/hexanes, 10 ! 30%) to
give a white solid foam (1.94 g). A solution of this material in TFA/H2O (9:1) was
stirred at 0°C for 40 min. Volatiles were evaporated, and H2O was added. Solids were
filtered, and the filtrate was evaporated. The residue was chromatographed (MeOH/
CH2Cl2, 1 ! 6%) to give 3 (824 mg, 82%). Recrystallization (MeOH) gave 3 as a

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Janeba, Lin, and Robins
white solid: mp 179–182°C; UV max 321 nm (e 9600), 251 nm (sh, e 9200), 227 nm
1
(e 30 200); H NMR d 3.56 (dd, J = 4.0, 11.8 Hz, 1H), 3.67 (dd, J = 4.0, 11.8 Hz,
1H), 3.93 (‘‘dd’’, J = 3.9, 7.5 Hz, 1H), 4.15 (‘‘dd’’, J = 4.0, 4.4 Hz, 1H), 4.52 (dd,
J = 5.1, 5.5 Hz, 1H), 4.89–5.71 (m, 3H), 5.88 (d, J = 5.5 Hz, 1H), 7.17–7.31 (m, 1H),
8.20–8.33 (m, 1H), 8.47 (s, 1H), 8.90–9.08 (m, 1H); 13C NMR d 61.3, 70.3, 73.6,
85.4, 86.6, 115.2, 117.3, 129.6, 136.6, 141.1, 145.1, 155.9, 160.0; HRMS m/z 334.1258
[MH+ (C13H16N7O4) = 334.1264]. Anal. Calcd for C13H15N7O4: C, 45.61; H, 4.71; N,
28.64. Found: C, 45.63; H, 4.83; N, 28.44.
2-Amino-6-methoxy-9-( -D-ribofuranosyl)purine (4a).[3] Method 1. A suspen-
sion of 3 (72.2 mg, 0.217 mmol) and Dowex 1 Â 2 (OH–) resin (4 ml, pre-soaked in
MeOH) in MeOH (5 ml) was stirred at ambient temperature for 27 h. The mixture
was filtered, and volatiles were evaporated from the filtrate. The residue was
dissolved (H2O) and chromatographed [Dowex 1 Â 2 (OH–); MeOH/H2O, increasing
gradient] to give 4a (60 mg, 93%) as a white powder. Recrystallization (MeOH/Et2O)
gave an analytical sample (recovery 75%): mp 120°C (softening); UV (H2O) max 280
1
nm (e 8500), 248 nm (e 8900); H NMR d 3.53 (ddd, J = 4.1, 5.9, 12.0 Hz, 1H), 3.63
(ddd, J = 4.3, 5.0, 12.0 Hz, 1H), 3.89 (‘‘dd’’, J = 3.9, 7.6 Hz, 1H), 3.96 (s, 3H),
4.07–4.13 (m, 1H), 4.46 (‘‘dd’’, J = 6.0, 11.1 Hz, 1H), 5.10 (dd, J = 5.4, 5.8 Hz,
1H), 5.14 (d, J = 4.6 Hz, 1H), 5.41 (d , J = 6.1 Hz, 1H), 5.78 (d, J = 6.0 Hz, 1H),
6.46 (bs, 2H), 8.17 (s, 1H); 13C NMR d 53.2, 61.4, 70.4, 73.5, 85.2, 86.5, 114.0,
138.0, 154.1, 159.8, 160.7; HRMS m/z 320.0964 [MNa+ (C11H15N5O5Na) =
320.0971]. Anal. Calcd for C11H15N5O5: C, 44.44; H, 5.09; N, 23.56. Found: C,
44.19; H, 5.32; N, 23.45.
2-Amino-6-(dimethylamino)-9-( -D-ribofuranosyl)purine (4b).[3,27] A solution
of 3 (49 mg, 0.15 mmol) in 40% Me2NH/H2O (2 ml) was stirred at ambient temperature
for 48 h. The solution was concentrated and chromatographed [Dowex 1 Â 2 (OHÀ),
H2O/MeOH]. The residue was recrystallized (MeOH) to give 4b (40 mg, 88%) as white
1
pellets: mp 200–202°C; UV (H2O) max 284 nm (e 15 000), 229 nm (e 18 200); H
NMR d 3.36 (bs, 6H), 3.47–3.69 (m, 2H), 3.89 (‘‘dd’’, J = 3.4, 6.7 Hz, 1H), 4.09
(‘‘dd’’, J = 4.5, 7.8 Hz, 1H), 4.47 (‘‘dd’’, J = 6.0, 11.1 Hz, 1H), 5.12 (d, J = 4.6 Hz,
1H), 5.34–5.39 (m, 2H), 5.75 (d, J = 6.1 Hz, 1H), 5.80 (bs, 2H), 7.94 (s, 1H); 13C NMR
d 37.7, 61.6, 70.6, 73.3, 85.3, 86.8, 113.9, 135.0, 152.5, 154.7, 159.3; HRMS m/z
311.1474 [MH+ (C12H19N6O4) = 311.1468].
2-Amino-6-(benzylamino)-9-( -D-ribofuranosyl)purine (4c).[28] A solution of 3
(65 mg, 0.195 mmol) and DBU (0.30 mL, 305 mg, 2 mmol) in benzylamine (2.5 mL)
was stirred at 100°C for 40 h. Volatiles were evaporated in vacuo, and AcOH/H2O was
added. The neutralized mixture was filtered, and the filtrate was concentrated and
chromatographed [Dowex 1 Â 2 (OHÀ), H2O/MeOH] to give 4c (63 mg, 82%) as a
glass. Recrystallization (MeOH/Et2O) gave material: mp ꢀ120°C (softening); UV max
1
284 nm (e 14 800), 261 nm (e 10 200), 252 nm (sh, e 9100); H NMR d 3.52 (ddd,
J = 3.7, 6.9, 12.0 Hz, 1H), 3.63 (ddd, J = 3.8, 4.5, 12.0 Hz, 1H), 3.90 (‘‘dd’’, J = 3.3,
6.5 Hz, 1H), 4.05–4.13 (m, 1H), 4.51 (‘‘dd’’, J = 6.0, 11.1 Hz, 1H), 4.64 (bs, 2H), 5.12
(d, J = 4.4 Hz, 1H), 5.33–5.47 (m, 2H), 5.73 (d, J = 6.1 Hz, 1H), 5.82 (bs, 2H), 7.16–
7.36 (m, 5H), 7.88 (bs, 1H), 7.93 (s, 1H); 13C NMR d 42.5, 61.7, 70.7, 73.2, 85.5, 86.9,

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Functionalization of Guanosine at C6
143
113.6, 126.5, 127.2, 128.1, 136.1, 140.5, 150.9, 154.9, 160.0; HRMS m/z 395.1493
[MNa+ (C17H20N6O4Na) = 395.1443].
3’,5’-Di-O-acetyl-2’-deoxy-2-N-(mono-p-methoxytrityl)guanosine (6a). Method
2. A solution of 5 (1.76 g, 5.0 mmol) in pyridine (75 mL) was treated with MMTrCl
(4.63 g, 15.0 mmol) and EtN(iPr)2 (2.6 mL, 1.94 g, 15.0 mmol) under Ar at room
temperature for 15 h. MeOH (2.5 mL) was added, and the mixture was stirred for 30
min. Volatiles were evaporated in vacuo, and toluene was added and evaporated
(3 Â 30 mL) from the residue. The oil was dissolved in CH2Cl2 (100 mL), and washed
(H2O, 2 Â 30 mL). The organic phase was dried (Na2SO4), and volatiles were
evaporated. The residue was chromatographed (MeOH/CH2Cl2, 0 ! 5%) to give 6a
(3.02 g, 97%) as a white solid: mp 212–216°C; UV max 278 nm (e 18 400), 261 nm (e
1
20 600), 234 nm (sh, e 21 500); H NMR d 1.87–1.89 (m, 1H), 2.02 (s, 3H), 2.11 (s,
3H), 2.15–2.17 (m, 1H), 3.72 (s, 3H), 4.02–4.03 (m, 2H), 4.09–4.10 (m, 1H), 5.06–
5.07 (m, 1H), 5.61–5.63 (m, 1H), 6.72–6.74 (m, 2H), 7.11–7.33 (m, 13H), 7.58 (bs,
1H), 11.33 (bs, 1H); 13C NMR d 21.0, 21.2, 36.7, 55.3, 63.7, 70.7, 74.8, 82.2, 84.9,
113.3, 118.4, 126.9, 128.0, 129.0, 130.4, 135.7, 136.8, 144.9, 150.2, 151.4, 158.5,
158.8, 170.3, 170.6; HRMS (EI) m/z 623.2384 [M+ (C34H33N5O7) = 623.2380].
3’,5’-Di-O-acetyl-2’-deoxy-2-N-(di-p-methoxytrityl)guanosine (6b).[25] Treat-
ment of 5 (1.76 g, 5.0 mmol) with DMTrCl (5.1 g, 15.0 mmol) by method 2 gave
6b (3.12 g, 95%) as a slightly yellow solid foam: mp 134–137°C; UV max 278 nm (e
17 100), 261 nm (e 18 100), 234 nm (e 25 600); 1H NMR d 1.92–1.94 (m, 1H), 2.03 (s,
3H), 2.11 (s, 3H), 2.21–2.24 (m, 1H), 3.72 (s, 6H), 4.02–4.07 (m, 2H), 4.10–4.12 (m,
1H), 5.08–5.09 (m, 1H), 5.66–5.67 (m, 1H), 6.72–6.75 (m, 4H), 7.12–7.30 (m, 10H),
7.46 (bs, 1H), 11.14 (bs, 1H); 13C NMR d 20.9, 21.1, 36.7, 55.3, 63.7, 70.4, 74.8, 82.2,
84.9, 113.3, 118.3, 126.9, 128.0, 128.8, 130.2, 135.7, 136.9, 145.1, 150.3, 151.4, 158.4,
170.3, 170.6; HRMS (EI) m/z 653.2491 [M+ (C35H35N5O8) = 653.2486].
2-Amino-9-(2-deoxy- -D-erythro-pentofuranosyl)-6-(imidazol-1-yl)purine
(8). Method 3. (i) Imidazole (782 mg, 11.5 mmol) and 6a (1.43 g, 2.3 mmol) were
added to a stirred slurry of Ph3P (2.99 g, 11.5 mmol), I2 (2.92 g, 11.5 mmol), and
EtN(iPr)2 (3 mL, 2.2 g, 17 mmol) in freshly distilled toluene (70 mL). Stirring under
Ar was continued at 80°C for 2 h. Volatiles were evaporated, and EtOAc (100 mL) was
added. The solid was filtered, and volatiles were evaporated from the filtrate.
Chromatography of the residue (MeOH/CH2Cl2, 0 ! 5%) gave a white solid foam. (ii)
This material was dissolved in 80% AcOH/(dioxane/H2O, 4:1) (50 mL), and the
solution was stirred at 55°C for 3 h. Volatiles were evaporated, and the residue was
dissolved in CH2Cl2 (100 mL). The solution was washed (NaHCO3/H2O, H2O) and
dried (Na2SO4). Volatiles were evaporated, and the residue was chromatographed
1
(MeOH/CH2Cl2, 0 ! 8%) to give 7 (813 mg) as a white foam: H NMR (500 MHz) d
2.02 (s, 3H), 2.10 (s, 3H), 2.50–2.56 (m, 1H), 3.05–3.08 (m, 1H), 4.21–4.31 (m, 3H),
5.34–5.36 (m, 1H), 6.30–6.33 (m, 1H), 6.92 (bs, 2H), 7.20 (s, 1H), 8.23 (s, 1H), 8.42
(s, 1H), 8.91 (s, 1H); HRMS m/z 402.1542 [MH+ (C17H20N7O5) = 402.1526]. (iii) NH3/
MeOH (10 mL, saturated at 0°C) was added to a solution of crude 7 (813 mg) in
MeOH (10 mL) in a pressure tube, and the sealed vessel was heated at 70°C for 3 h.
Volatiles were evaporated, and the residue was chromatographed (MeOH/CH2Cl2,

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Janeba, Lin, and Robins
5 ! 15%) and recrystallized (MeOH/EtOAc) to give 8 (407 mg, 56% from 6a) as
white crystals: mp 202°C; UV max 321 nm (e 10 200), 251 nm (sh, e 10 700), 226 nm
1
(e 33 600); H NMR (500 MHz) d 2.27–2.31 (m, 1H), 2.62–2.67 (m, 1H), 3.52–3.61
(m, 2H), 3.84–3.87 (m, 1H), 4.397–4.403 (m, 1H), 4.98 (‘‘t’’, J = 5.6 Hz, 1H), 5.32–
5.33 (m, 1H), 6.29 (t, J = 6.8, 1H), 6.86 (bs, 2H), 7.19 (s, 1H), 8.23 (s, 1H), 8.43 (s,
1H), 8.92 (s, 1H); 13C NMR d (125 MHz) d 39.4, 61.6, 70.6, 82.8, 87.8, 115.2, 117.1,
130.0, 136.6, 140.8, 145.1, 155.5, 159.9; HRMS (EI) m/z 317.1239 [M+
(C13H15N7O3) = 317.1236]. Anal. Calcd for C13H15N7O3: C, 49.21; H, 4.76; N,
30.90. Found: C, 49.14; H, 4.84; N, 30.90.
Treatment of 6b (1.53 g, 2.34 mmol) by method 3 [(ii) AcOH/(dioxane/H2O, 4:1)
(50 mL) at ambient temperature] gave 8 (430 mg, 58%) as white crystals: mp 200–
1
201°C; UV and H and 13C NMR spectra were identical to those of 8 prepared from 6a.
2-Amino-9-(2-deoxy- -D-erythro-pentofuranosyl)-6-methoxypurine (9a).[13,29]
Treatment of 8 (80 mg, 0.252 mmol) by method 1 gave 9a (34 mg, 61%) as a
glass, which was recrystallized (EtOH/EtOAc) to give white crystals (29 mg, 52%): mp
1
142°C; UV (H2O) max 280 nm (e 10 100), 248 nm (e 10 500); H NMR (500 MHz) d
2.21 (ddd, J = 2.9, 5.9, 13.2 Hz, 1H), 2.56–2.59 (m, 1H), 3.47–3.52 (m, 1H), 3.54–
3.58 (m, 1H), 3.816–3.821 (m, 1H), 3.95 (s, 3H), 4.347–4.352 (m, 1H), 5.00 (‘‘t’’,
J = 5.5 MHz, 1H), 5.27–5.28 (m, 1H), 6.21 (t, J = 6.8 Hz, 1H), 6.46 (bs, 2H), 8.08 (s,
1H); 13C NMR (125 MHz) d 39.5, 53.2, 61.7, 70.8, 82.7, 87.6, 113.9, 137.7, 153.8,
159.8, 160.7; HRMS m/z 304.1006 [MNa+ (C11H15N5 O4Na) = 304.1022].
2-Amino-9-(2-deoxy- -D-erythro-pentofuranosyl)-6-(dimethylamino)purine
(9b).[30] A solution of 8 (90 mg, 0.284 mmol) in 40% Me2NH/H2O (3 mL) was
stirred at 50°C for 16 h. Volatiles were evaporated, and the residue was chro-
matographed (preparative silica gel TLC plate; MeOH/CH2Cl2, 1:9) to give 9b (49 mg,
1
59%) as a glass: UV (H2O) max 284 nm (e 15 000), 229 nm (e 18 600); H NMR (500
MHz) d 2.17 (ddd, J = 2.7, 6.1, 12.9 Hz, 1H), 2.52–2.57 (m, 1H), 3.36 (bs, 6H), 3.48–
3.52 (m, 1H), 3.55–3.59 (m, 1H), 3.81–3.83 (m, 1H), 4.345–4.350 (m, 1H), 5.21 (‘‘t’’,
J = 5.4 Hz, 1H), 5.27–5.28 (m, 1H), 5.81 (bs, 2H), 6.18–6.21 (m, 1H), 7.93 (s, 1H);
13C NMR (125 MHz) d 37.6, 39.4, 61.9, 70.9, 82.8, 87.6, 113.9, 134.6, 152.3, 154.7,
159.3; HRMS (EI) m/z 294.1433 [M+ (C12H18N6O3) = 294.1440].
2-Amino-6-(benzylamino)-9-(2-deoxy- -D-erythro-pentofuranosyl)purine (9c).
A solution of 8 (57 mg, 0.180 mmol) and DBU (0.3 mL, 305 mg, 2 mmol) in
benzylamine (2.5 mL) was stirred at 100°C for 48 h. Volatiles were evaporated in
vacuo, and AcOH/H2O was added. Volatiles were evaporated from the neutrallized
solution, and EtOH was added and evaporated (2 Â 5 mL). The residue was chro-
matographed (preparative silica gel TLC plate; MeOH/CH2Cl2, 1:9) to give 9c (49 mg,
1
76%) as a glass: UV max 284 nm (e 14 700), 261 nm (e 9900); H NMR (500 MHz) d
2.18 (ddd, J = 2.4, 5.9, 12.7 Hz, 1H), 2.58–2.63 (m, 1H), 3.51–3.53 (m, 1H), 3.58–
3.60 (m, 1H), 3.84–3.85 (m, 1H), 4.358–4.362 (m, 1H), 4.64 (s, 2H), 5.28 (s, 2H), 5.85
(bs, 2H), 6.19 (t, J = 6.8 Hz, 1H), 7.18–7.21 (m, 1H), 7.26–7.34 (m, 4H), 7.88 (bs,
1H), 7.94 (s, 1H); 13C NMR (125 MHz) d 39.4, 42.5, 62.0, 71.1, 83.1, 87.7, 113.6,
126.5, 127.2, 128.1, 135.7, 140.5, 150.7, 154.9, 160.1; HRMS m/z 379.1486 [MNa+
(C17H20N6O3Na) = 379.1495].

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145
ACKNOWLEDGMENTS
We are grateful for Graduate Research Fellowships from Brigham Young
University (X.L.) and pharmaceutical company gift funds (M.J.R.) for financial support.
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Received August 7, 2003
Accepted October 6, 2003

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