7-Functionalized 7-deazapurine β-d and β-l-ribonucleosides related to tubercidin and 7-deazainosine: glycosylation of pyrrolo[2,3-d]pyrimidines with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-d or β-l-ribofuranose

Article abstract of DOI:10.1016/j.tet.2007.06.107

Several 7-functionalized 7-deazapurine ribonucleosides were prepared. Glycosylation of 7-halogenated 6-chloro-7-deazapurines with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-d-ribofuranose or 1-O-acetyl-2,3,5-tri-O-benzoyl-β-l-ribofuranose gave the protected β-d-nuc

Full text of DOI:10.1016/j.tet.2007.06.107

Tetrahedron 63 (2007) 9850–9861
7-Functionalized 7-deazapurine b-D and b-L-ribonucleosides
related to tubercidin and 7-deazainosine: glycosylation
of pyrrolo[2,3-d]pyrimidines with 1-O-acetyl-
2,3,5-tri-O-benzoyl-b-D or b-L-ribofuranose
a,b
Frank Seelaa,b, and Xin Ming
*
aLaboratory of Bioorganic Chemistry and Chemical Biology, Center for Nanotechnology, Heisenbergstrasse 11,
48149 Mu€nster, Germany
bLaboratorium fu€r Organische und Bioorganische Chemie, Institut fu€r Chemie, Universita€t Osnabru€ck, Barbarastrasse 7,
49069 Osnabru€ck, Germany
Received 9 May 2007; revised 26 June 2007; accepted 28 June 2007
Available online 17 July 2007
Abstract—Several 7-functionalized 7-deazapurine ribonucleosides were prepared. Glycosylation of 7-halogenated 6-chloro-7-deazapurines
with 1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose or 1-O-acetyl-2,3,5-tri-O-benzoyl-b-L-ribofuranose gave the protected b-D-nucleo-
sides 8c–e (53–62%) and the b-L-nucleosides 9b–e (57–72%), which were transformed to 7-halogenated 7-deazapurine ribonucleosides re-
lated to tubercidin and 7-deazainosine. 7-Alkynyl derivatives (1f,g) and (2f,g) were obtained from the 7-iodo nucleosides 1e and 2e employing
the palladium-catalyzed Sonogashira cross-coupling reaction. Within the series of 7-deazaadenosine (tubercidin) analogues and 7-deazaino-
sine derivatives physical data such as pKa values, chromatographic mobilities, 13C NMR chemical shifts were determined and correlated to
each other.
Ó 2007 Elsevier Ltd. All rights reserved.
R
N
NH2
4a
R
N
1. Introduction
O
R
N
NH2
N
3
1
HN
5
7
7
9
5
N
N
Pyrrolo[2,3-d]pyrimidine (7-deazapurine) ribonucleosides
are naturally occurring. Because of their widespread bio-
logical activities they received attention as antiviral and
anticancer reagents.1,2 Among the monomeric molecules
are tubercidin (1a) and its 7-substituted derivatives, toyoca-
mycin (1h) and sangivamycin (1i), which were isolated from
Streptomyces strains (purine numbering is used throughout
Section 2) (Fig. 1). 7-Halogenated analogues such as 50-de-
oxy-7-iodotubercidin were detected in marine organisms.3
7-Deazapurine ribonucleosides were found as constituents
of tRNA: queuosine and archaeosine represent 7-substituted
7-deazaguanine ribonucleosides, which are formed by the
post-modification of a nucleic acid.2,4 Other naturally occur-
ring 7-deazapurine nucleoside antibiotics were isolated,
including mycalisines A and B,5 cadeguomycin,6 the
antibiotic AB-116 (kanagawamicin) and dapiramicin.7–9 7-
Deazainosine has been isolated from the ascidian Aplidium
pantherinum.10 As the shape of the 7-deazapurines closely
N
1
7a
O
N
3
O
O
HO
HO
OH
HO
OH
HO
OH
HO
OH
systematic numbering
purine numbering
1a: R = H
b: R = F
c: R = Cl
d: R = Br
e: R = I
2a: R = H
b: R = F
c: R = Cl
d: R = Br
e: R = I
3a: R = H
b: R = F
c: R = Cl
d: R = Br
e: R = I
f : R =
g: R =
C C CH3
C C NPhth
O
C
f: R =
g: R =
C C CH3
C C CH2 NH
CF3
h: R = CN
i: R = CONH2
Figure 1. Structures of nucleosides 1–3.
resembles that of purines, they are used as substitutes for
the canonical constituents of DNA and RNA.
Keywords: Halogenated 7-deazapurines; ‘One-pot’ glycosylation; Ribo-
nucleosides; Cross-coupling; pKa Values.
* Corresponding author. Tel.: +49 (0)251 53406 500; fax: +49 (0)251 53406
587; e-mail: frank.seela@uni-osnabrueck.de
URL: http://www.seela.net
Recent developments in RNA chemistry and biology such
as the discovery of the catalytic function of RNA or RNA
interference have focused the interest of base modified
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.107

F. Seela, X. Ming / Tetrahedron 63 (2007) 9850–9861
9851
ribonucleosides.11,12 The frequent occurrence and biological
properties of this class of compounds have prompted ample
studies toward the synthesis, biological activities, and
incorporation in oligonucleotides as well as of chemically
designed analogues.13–21 In many cases these 7-deazapur-
ines are functionalized at the 7-position. Halogen-function-
alized derivatives can present biological activity or can be
used for further manipulations22–25 such as cross-coupling
chemistry.26–31
group at the 2-position with no or little formation of the
expected N-9 nucleosides.45–47 This was circumvented when
the nucleobase anion glycosylation of a 7-deazapurine
base was performed with a sugar halide protected at the
20,30-cis diol with benzyl residues or an isopropylidene moi-
ety.45–52 While benzyl protected sugars lead to anomeric
mixture of nucleosides,17,47 the usage of 1-chloro-2,3-O-
isopropylidene-5-O-tert-butyldimethylsilyl-a-D-ribofuranose
gives the b-D-anomers exclusively.45,46,48–52 However,
glycosylation of the 7-substituted derivatives did not work
satisfactorily.33 As we wanted to use the commercially
available 1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose
or 1-O-acetyl-2,3,5-tri-O-benzoyl-b-L-ribofuranose as a
sugar component for glycosylation, we went back to the
silylation of the nucleobase. We and others have already
shown that the application of the Wittenburg protocol (silyl-
ated base, sugar bromide, and mercuric oxide in benzene or
other solvents) results in mixtures of isomeric glycosylation
products with very little of the N-7 glycosylated pyrrolo[2,3-
d]pyrimidine.32,53 As an alternative the silyl-Hilbert–
Johnson reaction54 was employed. This reaction is usually
performed as a two-step protocol (i) silylation of the nucleo-
base in the presence of ammonium sulfate and (ii) glycosyl-
Earlier work demonstrated that 7-deazapurines resist glyco-
sylation when 1-O-acetyl-2,3,5-tri-O-benzoylribofuranose
was employed in the glycosylation reaction.13,32 Thus, an
efficient protocol for the synthesis of 7-deazapurine ribonu-
cleosides is indispensable. Recent work on 7-functionalized
7-deazapurine ribonucleosides focused on the preparation of
nucleosides related to guanosine, xanthosine, and purine-
2,6-diamine.33 The present manuscript investigates the
synthesis of 7-halogenated 7-deazapurine ribonucleosides
related to adenosine and inosine. In particular, the synthesis
of 7-deazaadenosines 1c–e, their b-L-enantiomers 3b–e as
well as 7-deazainosines 2b–e will be described. The work
reports on the further functionalization of the 7-iodo deriva-
tives by the Sonogashira cross-coupling reaction (1f,g and
2f,g) and studies the influence of the 7-substituents on the
physical properties.
ation with an acylated ribosugar derivative in the presence
55,56
€
of a Friedel–Crafts catalyst (Vorbruggen conditions).
However, also under these conditions a glycosylation of
the pyrrole nitrogen was not observed.33
2. Results and discussion
In addition to the above synthetic methods a so called ‘one-
pot’ protocol of the silyl-Hilbert–Johnson reaction was
described.33 This ‘one-pot’ protocol was used by Wolfe for
the synthesis of 20-C-methyl-b-D-ribonucleosides.57 In this
procedure, the nucleobase was silylated with BSA (N,O-
bis(trimethylsilyl)acetamide) in MeCN and glycosylated
with 20-C-methyl-1,2,3,5-tetra-O-benzoyl-D-ribofuranose
in the presence of SnCl4. Later, Ding employed the same
procedure for the synthesis of toyocamycin derivatives and
7-deazainosine derivatives.58 Here, MeCN was used as a sol-
vent, and TMSOTf (trimethylsilyl trifluoromethanesulfo-
2.1. Glycosylation of the 7-deazapurines 4b–e with
1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose (6)
or 1-O-acetyl-2,3,5-tri-O-benzoyl-b-L-ribofuranose (7)
Considerable effort has been expended in the development
of methods for the synthesis of 7-deazapurine ribonucleo-
sides including tubercidin and 7-deazainosine. Mizuno
et al. reported on the 7-deazainosine (2a) synthesis using
an amino functionalized pyrimidine derivative and a pro-
tected sugar aldehyde as starting materials to form a Schiff
base as intermediate yielding 7-deazainosine in a multi-
step procedure.34 Robins and co-workers synthesized 4-
chloro-7-(b-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine by
chlorination of 7-deazainosine which was obtained from
the naturally occurring tubercidin by chemical deamina-
tion.35 With this intermediate, halogenated compounds
such as 1c–e and 2d were prepared in low overall yields.36
A protocol involving 1,2,3,5-tetra-O-acetyl-b-D-ribofuranose
for the glycosylation of a toyocamycin precursor was
reported by Townsend, another group employed the fusion
reaction which resulted in low yields as well.37,38 Overall,
it was shown that the pyrrole nitrogen is rather inert to
glycosylation with the result that the reaction is directed
into the pyrimidine moiety,32 takes place at the more nucleo-
philic pyrrole carbons39,40 or results in poor yields.
€
nate) as glycosylation catalyst (Vorbruggen conditions).
The nucleobases were silylated and directly glycosylated
in one step. Townsend applied this procedure for the synthe-
sis of toyocamycin.59
We used the ‘one-pot’ method for the synthesis of the 7-
deazaadenosine analogues 1c–e, and the 7-deazainosine
nucleosides 2b–e as well as the b-L-nucleosides 3b–e. The
nucleobases 4b–e60,61 were silylated with 1.2 equiv of
BSA in anhydrous MeCN at room temperature and then
reacted with 1.2 equiv of 1-O-acetyl-2,3,5-tri-O-benzoyl-
b-D-ribofuranose (6) or 1-O-acetyl-2,3,5-tri-O-benzoyl-b-L-
ribofuranose (7) in the presence of TMSOTf (trimethylsilyl
trifluoromethanesulfonate) at 80 ꢀC (Scheme 1). This
afforded the glycosylated intermediates 8b–e and 9b–e in
the b-D and the b-L series. It was found that 1.2 equiv of
TMSOTf led to completion of the reaction within 1 h result-
ing in 53–72% yields of the glycosylation products 8b–e and
9b–e. This is different from the reaction conditions applied
for the more sensitive 7-halogenated 2-amino-6-chloro-7-
deazapurines, which required 40–50 ꢀC, with 24 h reaction
time.33 We were not able to perform the glycosylation under
the same reaction conditions with the same protected ribo-
furanoses 6 and 7 using the non-fuctionalized 4a which is
The development of the stereoselective nucleobase anion
glycosylation made 7-deazapurine 20-deoxyribonucleosides
easily accessible.41–43 Later on, this protocol was applied
to 7-deazapurine ribonucleosides’ synthesis, using activated
ribosugar derivatives (ribofuranosyl halides).44–52 Unfortu-
nately, ortho amides are formed by neighboring group
participation when the sugar contains an acyl protecting

9852
F. Seela, X. Ming / Tetrahedron 63 (2007) 9850–9861
O
R
N
Cl
N
BzO
OAc
OBz
N
BzO
6
CH3CN, TMSOTf
O
BzO
8b: 65%60
c: 62%
BzO
OBz
d: 53%
8b-e
e: 59%
R
Cl
N
R
Cl
BSA
MeCN
N
N
N
N
H
N
R
N
Cl
O
SiMe3
OBz
AcO
4b-e
N
5b-e
BzO
OBz
N
7
O
CH3CN, TMSOTf
OBz
9b: 68%
c: 72%
d: 64%
e: 57%
BzO
OBz
9b-e
b: R = F
c: R = Cl
d: R = Br
e: R = I
Scheme 1. Glycosylation performed on compounds 4 with the sugar derivatives 6 and 7.
not bearing an electron-withdrawing substituent at the 7-po-
sition. Bio and co-workers reported a similar observation for
4a employing 20-C-methyl-1,2,3,5-tetra-O-benzoyl-D-ribo-
furanose in the glycosylation reaction.62 It is obvious that
the electron-withdrawing character of the 7-halogeno sub-
stituents is a prerequisite for a successful glycosylation
employing the common sugar derivative, most probably
such conditions are already required for a successful silyla-
tion. In the case of nucleobases not functionalized at the 7-
position the isopropylidene protected sugar has to be
used.45,46,48–52 The other option would be the synthesis of
bromo or iodo compounds followed by reductive removal
of halogen.
employed for the substitution of the 6-methoxy group to
an oxo group: Me3SiCl/NaI in CH3CN or aq NaOH solution
(Scheme 2).33,64 Compounds 10b–d were demethylated
with Me3SiCl/NaI/CH3CN, while demethylation of 10e
with Me3SiCl/NaI/CH3CN resulted in partial deiodination
thereby forming a mixture of 2a and 2e, which was con-
firmed by NMR spectra. Both the 1H and 13C NMR spectra
of the reaction product show two sets of nucleoside signals
which correspond to the signals of 2a and 2e, respectively.
When compounds 10b–d were treated with Me3SiCl/NaI/
CH3CN, the 7-fluoro, 7-chloro, and 7-bromo substituents
were not affected, which was different from the correspond-
ing 7-deazaxanthosine derivatives.33,64 In the case of 7-halo-
genated 7-deazaxanthosines, the 7-chloro and the 7-bromo
substituents were partially displaced by an iodo substituent.
Regarding the characteristics of the nucleoside structures we
performed a single crystal X-ray analysis on 7-fluorotuberci-
din (1b), which was synthesized by Wang and co-workers.60
Both, the glycosylation position (N-9) and the anomeric con-
figuration (b-D) were confirmed.63 The 13C NMR chemical
shifts of the synthesized nucleosides will be discussed later.
The enantiomeric character of the b-L-nucleosides was
16
L-fluorotubercidin 3b
14
12
10
8
1
deduced from their identical H and 13C NMR spectra; the
6
4
assignment to the L-series is deduced from the L-sugar
used for the glycosylation. The CD spectra and the spatial
mirror images are diagnostic for the enantiomeric character
(Fig. 2).
2
0
-2
-4
-6
-8
-10
-12
2.2. Synthesis of the 7-halogenated 7-deazaadenosines
1b–e and 7-deazainosines 2b–e
-14
-16
D-fluorotubercidin 1b
The ribonucleosides 2b–e were prepared from the intermedi-
ates 8b–e. Deprotection of 8b–e in 0.5 M NaOMe/MeOH at
room temperature afforded the deblocked nucleosides 10b–e
under simultaneous displacement of the 6-chloro substituent
to a 6-methoxy group (Cl/OCH3). Two protocols were
220
240
260
280
300
320
340
wavelength [nm]
Figure 2. The CD spectra of nucleosides 1b and 3b measured in MeOH
(c¼4ꢁ10ꢂ4 M).

F. Seela, X. Ming / Tetrahedron 63 (2007) 9850–9861
9853
R
N
O
N
TMSI
NaI
HN
MeCN
OMe
R
N
2b: 94%
c: 89%
d: 81%
N
O
MeONa
MeOH
HO
N
O
HO
OH
10b: 68%
c: 93%
HO
R
N
Cl
N
2b-d
d: 86%
e: 90%
HO
10b-e
OH
N
I
O
HN
O
BzO
R
N
NH2
N
2N NaOH
N
O
BzO
8b-e
OBz
2e: 91%
HO
N
N
O
NH3/MeOH
HO
OH
1c: 70%
d: 61%
e: 71%
HO
2e
HO
OH
1c-e
b: R = F
c: R = Cl
d: R = Br
e: R = I
Scheme 2. Transformation of the intermediates 8b–e to the nucleosides 1c–e and 2b–e.
To avoid the unwanted side reaction occurring on 10e, the
nucleophilic OMe/OH displacement was performed under
alkaline conditions (2 N aq NaOH, reflux 1.5 h). This re-
sulted in a clean exchange of the methoxy group under for-
mation of 2e (91% yield). In another series of experiments,
compounds 8c–e were converted into the 7-halogenated tu-
bercidin derivatives 1c–e, employing methanolic ammonia
in an autoclave (120 ꢀC, overnight). The corresponding b-L
enantiomers 9b–e were converted by the same procedure
as described for the b-D nucleosides 8b–e, yielding the 7-
halogenated b-L-tubercidin derivatives 3b–e (Scheme 3).
this type of reaction yielding the 7-alkynyl and amino-
alkynyl 7-deazapurine ribonucleosides 1f,g and 2f,g. The
reaction was performed in anhydrous DMF with tetra-
kis(triphenylphosphine)palladium(0), copper(I)iodide, and
triethylamine under nitrogen and resulted in 68–81% yields
of the alkynyl derivatives (Scheme 4).
NH2
NH2
I
Pd(PPh3)4
CuI
R
N
N
N
Et3N
DMF
1f: 69%
g: 81%
N
N
O
N
O
HO
HO
The introduction of alkynyl or aminoalkynyl side chains to
purine constituents of DNA or RNA has a major impact on
the oligonucleotide structure and stability,65–69 e.g., resis-
tance against enzymatic degradation,70 or an increased
sensitivity of oligonucleotide detection by MALDI-TOF
spectrometry.71,72 The 7-iodo-substituted derivatives 1e
and 2e are particularly valuable intermediates for introduc-
ing alkynyl or aminoalkynyl side chains since they can be
used as starting materials in Pd-catalyzed cross-coupling
reactions.31 Thus, they were employed as precursors in
HO
OH
HO
OH
1f: R = C C CH3
g: R = C C CH2
O
N
O
O
N
O
R
I
Pd(PPh3)4
CuI
HN
HN
Et3N
N
DMF
N
N
R
NH2
2f: 68%
g: 69%
O
R
N
O
Cl
N
HO
HO
N
N
HO
OH
N
HO
OH
N
NH3/MeOH
O
3b: 90%
c: 75%
d: 73%
e: 77%
2f: R = C C CH3
g: R = C C CH2 NH C CF3
O
OH
O
OBz
HO
OH
BzO
OBz
Scheme 4. Synthesis of 7-alkynyl-7-deazapurine nucleosides.
9b-e
3b-e
b: R = F
c: R = Cl
d: R = Br
e: R = I
2.3. Physical properties of the 7-functionalized
7-deazapurine nucleosides
All compounds were characterized by UV–vis spectra
(Table 1 and Section 4). The UV spectra of compounds
Scheme 3. Transformation of the intermediates 9b–e to the b-L-nucleosides
3b–e.

9854
F. Seela, X. Ming / Tetrahedron 63 (2007) 9850–9861
Table 1. UV data of 7-substituted 7-deazapurine ribonucleosidesa
(a)
1,8
1,6
1,4
1,2
1,0
0,8
Compound
lmax
(nm)
3
Compound
lmax
(nm)
3
1a44
1b
1c
1d
1e
270
281
281
281
284
237
280
280
11,900
9700
9900
3b
3c
3d
3e
279
280
281
284
10,200
9500
9200
7900
9600
8000
1f
12,500
8800
10,700
pKa = 4.42
1g
2a
2b
2c
2d
259
264
264
265
9100
7500
8100
8400
2e
2f
2g
266
271
270
7500
9800
12,000
2
3
4
5
6
7
8
9
10
a
Measured in MeOH.
pH value
(b)
1,25
1,20
1,15
1,10
1,05
1,00
0,95
0,90
0,85
1a–g, 2a–g, and 3b–e were measured in methanol. Table 1
indicates that the 7-halogeno and 7-alkynyl substituents in-
duce a bathochromic shift compared to the corresponding
non-functionalized nucleosides 1a and 2a. In the series of
the 7-substituted tubercidin derivatives 1, the wavelength
maximum was shifted 11 nm in the case of the fluoro, chloro,
and bromo derivatives 1b–d and 14 nm for the iodo deriva-
tive 1e, while in the case of the alkynyl side chains, the shift
is about 10 nm for 1f and 1g. For the iodo derivative of
nucleoside 1e a stronger shift is found. In the 7-deazainosine
series 2, the UV bathochromic shift is only 5 nm for the fluo-
ro and chloro derivatives, 6 nm for the bromo derivative, and
7 nm for the iodo compound. In contrast to the halogeno
compounds the alkynyl side chains induce a bathochromic
shift of about 12 nm. Here, the wavelength shift for the
halogeno compounds is moderate compared to the series
of compounds 1, while the bathochromic shifts for alkynyl
substituted compounds are almost the same as for the halo-
geno series 1. For the series of b-L compounds 3b–e, the
shifts are comparable to their b-D counterparts.
pKa = 9.73
4
6
8
10
12
pH Value
Figure 3. Absorbance change of compounds 1b (a) and 2b (b) as a function
of pH values measured at 226 nm.
Earlier, a series of 7-deaza-20-deoxyadenosine derivatives
were reported showing fluorescence.75 Therefore, it was of
interest to investigate this matter on 7-(alkynyl)-7-deaza-
adenosine and 7-(alkynyl)-7-deazainosine. Only the 7-pro-
pynyl-7-deazaadenosine exhibited significant fluorescence
(Fig. 4). The same large Stokes shift (90 nm) with an emis-
sion at 370 nm was observed when the compound was
The pKa values of the nucleosides can strongly affect the
base pairing properties and duplex stability of oligonucleo-
tides.73 Therefore, the pKa values of nucleosides 1a–f and
2a–e were measured by spectrophotometric titration74 (pH
1.5–13.5) at 200–350 nm. As shown in Table 2, the pKa
values of the 7-halogenated compounds 1b–e, 2b–e as
well as the 7-alkynyl nucleoside 1f are lower than those of
the corresponding non-functionalized nucleosides 1a and
2a (Fig. 3). These pKa changes result from the electron-with-
drawing character of the 7-substituents including halogens
as well as alkynyl groups making deprotonation more favor-
able and protonation more difficult.
300
λEx = 280 nm
λEm = 370 nm
250
200
150
100
50
Table 2. pKa Values of the 7-deazapurine ribonucleosidesa
Compound Wavelength pKa
(nm)
Compound Wavelength pKa
(nm)
1a
1b
1c
1d
1e
1f
226
226
232
234
239
241
5.33 2a
226
220
220
223
226
10.21
4.42 2b
4.24 2c
4.29 2d
4.42 2e
4.50
9.73
9.33
9.41
9.93
0
220 240 260 280 300 320 340 360 380 400 420 440 460 480 500
wavelength [nm]
a
Determination according to the spectrophotometric titration at indicated
wavelength.
Figure 4. Fluorescence spectrum of the 7-propynyl-7-deazaadenosine 1f in
MeOH (c¼10ꢂ5 M).

F. Seela, X. Ming / Tetrahedron 63 (2007) 9850–9861
9855
irradiated at 280 nm for 1f as observed for its 20-deoxyribo
derivative.75a None of the 7-deazainosine derivatives were
fluorescent.
lipophilicity were evaluated by HPLC experiments per-
formed on a hydrophobic column (RP-18 (250ꢁ10 mm))
(Fig. 6) and were compared with the calculated log P values
(Table 4). According to Table 4 and compared to non-func-
tionalized nucleoside 1a, the log P values are increased for
the halogenated derivatives and an even stronger increase
is found for the alkynyl modified derivatives 1f,g. For 1f,g,
the log P values increase from ꢂ0.36ꢃ0.46 for 1a to
0.98ꢃ0.60 and 2.51ꢃ0.65, respectively. These values are
closely matched to the retention times (Fig. 6) attained
from the reversed-phase HPLC experiments. The retention
times of nucleosides are 8.8 min for the non-functionalized
nucleoside 1a, 13.5 min for the fluoro derivative 1b,
34.9 min for the alkynyl modified derivative 1g.
The nucleosides and the intermediates were characterized by
1H and 13C NMR spectra. The 13C NMR data are summa-
rized in Table 3. Assignments of the 13C NMR chemical
shifts were made according to the gated-decoupled 13C
NMR spectra and referring to the earlier literature.76,77 Table
3 shows that the 7-substituted compounds exhibited a charac-
teristic shift of C-7 induced by the various substituents.
Compared to the non-functionalized nucleosides 1a and
2a, the C-7 signals are downfield shifted about 43 ppm for
the fluoro derivatives 1b and 2b, while the chloro derivatives
1c and 2c show a downfield shift of only about 3 ppm. On the
other hand, the bromo and iodo substituents induce an up-
field shift of 12 ppm for 1d and 2d and 48 ppm for 1e and
2e. This trend is also observed for the bases 4a–e78 and other
heterocycle ring systems such as 5-halogenated uracil deriv-
atives.79 The alkynyl side chains also induce an upfield shift,
but the effects are weaker than for the bromo and iodo
derivatives. It is in the range of 5 ppm for 1f,g and 2f,g.
In Figure 5, the chemical shifts observed for the 7-deaza-
7-haloinosine at C-7 and C-8 carbon position are plotted
against the substituent electronegativity (Ex) values of
Shoolery and Dailey.80 d (13C) of C-7 is increasing, with
increasing electronegativity of the substituents. At position
C-8, two bonds away from the substituent, the substituent
effect is lower relative to that of C-7. Additionally, d (13C)
signals are observed to decrease linearly with increasing
electronegativity (Ex) (Fig. 5).
160
140
C-7
F
Cl
120
I
Br
Cl
100
80
C-8
Br
F
60
I
40
2,4
2
,6
2,
8
3
,0
3,
2
3
,4
3,
6
3,8
4,
0
4,2
Electronegativity of the Subsitituents
Due to the introduction of various substituents into the
7-position of the 7-deazapurine moiety, the lipophilic
character of the nucleosides is changed. The differences in
Figure 5. Plot ofthe13C chemicalshiftattheindicatedcarbonpositionversus
substituent electronegativity (Ex), for 7-halogenated 7-deazainosines.
Table 3. 13C NMR chemical shifts of 7-deazapurine ribonucleosidesa
Compound
C(2)b
C(2)c
C(4)b
C(5)b
C(6)b
C(4)c
C(7)b
C(5)c
C(8)b
C(6)c
C(10)
C(20)
C(30)
C(40)
C(50)
C(7a)c
C(4a)c
1a51
1b
1c
1d
1e
1f
1g
2a
2b
2c
2d
2e
2f
2g
3b
3c
151.5
152.8
152.7
152.4
152.0
152.5
153.1
147.8
144.8
145.1
144.9
144.7
144.8
145.1
153.0
152.7
152.4
151.9
151.6
151.6
151.5d
151.1d
149.9
146.3
149.2
149.6
150.2
149.4
150.0
143.8
143.7
146.9
147.3
147.8
147.2
147.5
146.4
149.2
149.6
150.2
147.5
150.6
151.1d
151.8d
103.1
92.5
99.9
101.1
103.3
102.4
102.7
108.4
97.4
106.5
106.0
108.1
107.6
107.6
92.8
157.5
155.9
156.8
156.9
157.2
157.6
157.8
158.2
156.3
157.1
157.2
157.8
157.5
157.4
156.0
156.8
157.0
157.2
161.5
162.1
162.2
162.3
99.5
142.6
102.7
86.8d
51.9
95.6
94.3
102.5
144.9
104.9
90.4
55.4
99.8
98.2
142.8
102.6
86.8d
51.9
141.4
102.7
86.6
122.3
104.4
119.3
121.8
127.2
125.9
123.7
121.1
103.7
118.2
120.6
125.8
124.7
118.1
104.7
119.2
121.8
127.2
107.2
121.8
124.2
129.4
87.6
86.5
86.8
86.7d
86.9
87.2
86.4
87.0
86.5
86.7
86.7
86.8
86.9
86.9
86.7
86.7
86.7d
86.8
86.5
86.8
86.8
86.8
73.7
73.9
74.0
73.9
73.9
73.9
74.3
74.3
74.3
74.4
74.4
74.4
74.4
74.5
74.1
73.9
73.9
73.9
74.1
74.2
74.2
74.1
70.8
70.6
70.5
70.5
70.5
70.6
70.6
70.6
70.4
70.5
70.4
70.5
70.5
70.4
70.8
70.5
70.5
70.5
70.5
70.4
70.4
70.5
85.1
85.0
85.2
85.2
85.2
85.2
85.6
85.1
85.3
85.3
85.3
85.3
85.2
85.2
85.2
85.2
85.2
85.2
85.2
85.3
85.3
85.3
61.9
61.7
61.6
61.5
61.6
61.6
61.9
61.6
61.4
61.4
61.4
61.4
61.4
61.3
61.8
61.5
61.5
61.6
61.5
61.4
61.4
61.4
99.9
3d
3e
10b
10c
10d
10e
101.1
103.2
95.0
102.7
104.1
106.7
51.4
a
Measured in DMSO-d6.
Purine numbering.
Systematic numbering.
Tentative.
b
c
d

9856
F. Seela, X. Ming / Tetrahedron 63 (2007) 9850–9861
data were determined which shed light into the behavior of
tubercidin and 7-deazainosine analogues.
4. Experimental part
4.1. General
All chemicals were purchased from ACROS, Fluka or
Sigma–Aldrich (Sigma–Aldrich Chemie GmbH, Deisen-
hofen, Germany). Solvents were of laboratory grade. TLC:
aluminum sheets, silica gel 60 F254 (0.2 mm, VWR Interna-
tional, Darmstadt, Germany); flash column chromatography
(FC): silica gel 60 (VWR International, Darmstadt,
Germany) at 0.4 bar; solvent systems for TLC and FC:
cyclohexane/ethyl acetate 10:1 (A), cyclohexane/ethyl
acetate 3:1 (B), CH2Cl2/MeOH 20:1 (C), CH2Cl2/MeOH
9:1 (D), CH2Cl2/MeOH 6:1 (E); sample collection with
a MultiRac fraction collector (LKB Instruments Sweden).
Reverse-phase HPLC was carried out on a 250ꢁ10 mm
RP-18 LiChrosorb column (Merck) with a Merck–Hitachi
HPLC pump (model 655 A-12) connected with a variable
wavelength monitor (model 655-A), a controller (model
L-5000), and an integrator (model D-2000). UV spectra:
U-3200 UV–vis spectrophotometer (Hitachi, Japan); CD
spectra: Jasco J-600A spectropolarimeter (Jasco, Japan).
NMR spectra: Avance-DPX-250 or AMX–500 spectrometer
(Bruker, Rheinstetten, Germany); d values in parts per
million relative to Me4Si as internal standard (1H and 13C),
J values in hertz. Melting points were determined by a
Figure 6. Reversed-phase HPLC profile of an artificial mixture of the
nucleosides 1a–g. Column, RP-18 (250ꢁ10 mm); gradient: 0 min 100%
B, after 10 min 5% A, after 20 min 15% A, after 25 min 20% A, after
30 min 30% A, after 35 min 15% A in B; A¼MeCN, B¼0.1 M (Et3NH)OAc
buffer, pH¼7.0.
Table 4. log P Values and retention times of 7-functionalized tubercidin
derivatives
Compound
log P Value
Retention
time (min)
€
Linstrom apparatus and are not corrected. Element analyses
were performed by Mikroanalytisches Laboratorium Beller,
€
Gottingen, Germany.
1a
1b
1c
1d
1e
1f
ꢂ0.36ꢃ0.46
ꢂ0.30ꢃ0.55
0.24ꢃ0.49
0.42ꢃ0.55
0.68ꢃ0.55
0.98ꢃ0.60
2.51ꢃ0.65
8.8
13.5
20.4
21.7
24.0
25.6
34.9
4.1.1. 4,5-Dichloro-7-[(2,3,5-tri-O-benzoyl)-b-D-ribofur-
anosyl]-7H-pyrrolo[2,3-d]pyrimidine (8c). N,O-Bis(tri-
methylsilyl)acetamide (BSA, 0.55 mL, 2.2 mmol) was added
to a stirred suspension of 4,5-dichloro-7H-pyrrolo[2,3-d]-
pyrimidine61 (376 mg, 2.0 mmol) in dry acetonitrile
(15 mL). After stirring at rt for 10 min, 1-O-acetyl-2,3,5-
tri-O-benzoyl-b-D-ribofuranose (1.13 g, 2.24 mmol) was
added, followed by the addition of trimethylsilyl trifluoro-
methanesulfonate (0.42 mL, 2.17 mmol). The reaction mix-
ture was stirred at rt for 15 min after which the flask was
transferred to a preheated oil bath at 80 ꢀC. After stirring
for 1 h at 80 ꢀC, the reaction mixture was cooled to rt and
diluted with EtOAc (75 mL). The organic phase was sequen-
tially washed with aq satd NaHCO3 and brine, dried
(Na2SO4), and concentrated to provide the crude nucleoside.
Purification by flash column chromatography (FC) (column
10ꢁ5 cm, A) provided 8c as a colorless foam (780 mg,
62%). TLC (silica gel, B): Rf 0.46. UV (MeOH): lmax 228
1g
3. Conclusion
Although a number of methods have been developed for the-
synthesis of the 7-deazapurine ribonucleosides using acti-
vated sugar halides, the outcome of the products of the
fusion reaction, nucleobase anion glycosylation, and other
procedures is disappointing. The glycosylation is directed
into the pyrimidine moiety,32 takes place at the more nucleo-
philic pyrrole carbons,39,40 or results in poor yields. The pres-
ent investigation shows that the TMSOTf-catalyzed ‘one-pot’
glycosylation reaction is an efficient method for the synthesis
of 7-functionalized-7-deazapurines. Electron-withdrawing
substituents (such as halogens) on the 7-deazapurine moiety
facilitate the glycosylation reaction. 7-Deazapurines without
7-substituents resist glycosylation.
1
(68,100), 274 (6100). H NMR (DMSO-d6) d: 8.63 (s, H–
C(2)); 8.29 (s, H–C(6)); 8.00–7.84 (m, arom, H); 7.65 (m,
arom, H); 7.54–7.40 (m, arom, H); 6.72 (d, J¼4.90 Hz, H–
C(10)); 6.30 (t, J¼5.74 Hz, J¼5.29 Hz, H–C(20)); 6.13 (t,
J¼5.55 Hz, J¼5.76 Hz, H–C(30)); 4.88–4.64 (m, H–C(40),
H–C(50)). Anal. Calcd for C32H23Cl2N3O7 (632.45): C
60.77, H 3.67, N 6.64; found: C 60.65, H 3.58, N 6.60.
The glycosylation products 8c–e and their b-L-enantiomers
9b–e were obtained in yields of 53–72%. From the interme-
diates, the tubercidin analogues 1b–e, the b-L-enantiomers
3b–e, and 7-deazainosine analogues 2b–e were obtained.
The palladium-catalyzed cross-coupling chemistry afforded
7-alkynyl or 7-aminoalkynyl derivatives. They can be used
for reporter group attachment in protocols of RNA-sequenc-
ing and detection within single or double-stranded oligoribo-
nucleotides. Apart from these synthetic aspects, physical
4.1.2. 4,5-Dichloro-7-[(2,3,5-tri-O-benzoyl)-b-L-ribofur-
anosyl]-7H-pyrrolo[2,3-d]pyrimidine (9c). As described
for 8c with N,O-bis(trimethylsilyl)acetamide (BSA,

F. Seela, X. Ming / Tetrahedron 63 (2007) 9850–9861
9857
0.67 mL, 2.70 mmol), 4,5-dichloropyrrolo[2,3-d]pyrimidine61
(461 mg, 2.45 mmol), dry acetonitrile (12 mL), 1-O-acetyl-
2,3,5-tri-O-benzoyl-b-L-ribofuranose (1.40 g, 2.78 mmol),
and trimethylsilyl trifluoromethanesulfonate (0.50 mL,
2.59 mmol) yielding 9c as colorless foam (1.12 g, 72%).
TLC (silica gel, B): Rf 0.46. UV (MeOH): lmax 228
4.88–4.66 (m, H–C(40), H–C(50)). Anal. Calcd for
C32H23BrClN3O7 (676.90): C 56.78, H 3.42, N 6.21; found:
C 56.98, H 3.50, N 5.99.
4.1.6. 4-Chloro-5-iodo-7-[(2,3,5-tri-O-benzoyl)-b-D-ribo-
furanosyl]-7H-pyrrolo[2,3-d]pyrimidine (8e). As de-
scribed for 8c with N,O-bis(trimethylsilyl)acetamide (BSA,
0.11 mL, 0.44 mmol), 5-chloro-4-iodo-7H-pyrrolo[2,3-d]-
pyrimidine61 (112 mg, 0.40 mmol), dry acetonitrile (5 mL),
1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose (222 mg,
0.44 mmol), and trimethylsilyl trifluoromethanesulfonate
(0.081 mL, 0.42 mmol) affording 8e as colorless foam
(171 mg, 59%). TLC (silica gel, B): Rf 0.46. UV (MeOH):
1
(65,200), 273 (6400). H NMR (DMSO-d6) d: 8.63 (s, H–
C(2)); 8.30 (s, H–C(6)); 8.00–7.84 (m, arom, H); 7.63 (m,
arom, H); 7.54–7.40 (m, arom, H); 6.73 (d, J¼4.49 Hz, H–
C(10)); 6.30 (t, J¼5.13 Hz, J¼5.00 Hz, H–C(20)); 6.13 (t,
J¼5.24 Hz, J¼5.58 Hz, H–C(30)); 4.87–4.65 (m, H–C(40),
H–C(50)). Anal. Calcd for C32H23Cl2N3O7 (632.45): C
60.77, H 3.67, N 6.64; found: C 60.95, H 3.75, N 6.53.
1
lmax 230 (61,000), 272 (5800). H NMR (DMSO-d6) d:
4.1.3. 4-Chloro-5-fluoro-7-[(2,3,5-tri-O-benzoyl)-b-L-ribo-
furanosyl]pyrrolo[2,3-d]pyrimidine (9b). As described for
8c with N,O-bis(trimethylsilyl)acetamide (BSA, 0.68 mL,
2.74 mmol), 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine60
(390 mg, 2.27 mmol), dry acetonitrile (12 mL), 1-O-acetyl-
2,3,5-tri-O-benzoyl-b-L-ribofuranose (1.40 g, 2.78 mmol),
and trimethylsilyl trifluoromethanesulfonate (0.53 mL,
2.74 mmol) yielding 9b as colorless foam (950 mg, 68%).
TLC (silica gel, B): Rf 0.46. UV (MeOH): lmax 227
8.60 (s, H–C(2)); 8.30 (s, H–C(6)); 8.00–7.83 (m, arom,
H); 7.65 (m, arom, H); 7.52–7.43 (m, arom, H); 6.71 (d,
J¼4.87 Hz, H–C(10)); 6.29 (t, J¼5.81 Hz, J¼5.19 Hz, H–
C(20)); 6.14 (t, J¼5.54 Hz, J¼5.85 Hz, H–C(30)); 4.87–
4.64 (m, H–C(40), H–C(50)). Anal. Calcd for C32H23ClIN3O7
(723.90): C 53.09, H 3.20, N 5.80; found: C 53.13, H 3.16,
N 5.85.
4.1.7. 4-Chloro-5-iodo-7-[(2,3,5-tri-O-benzoyl)-b-L-ribo-
furanosyl]pyrrolo[2,3-d]pyrimidine (9e). As described
for 8c with N,O-bis(trimethylsilyl)acetamide (BSA,
0.55 mL, 2.22 mmol), 5-chloro-4-iodo-7H-pyrrolo[2,3-d]-
pyrimidine61 (559 mg, 2.00 mmol), dry acetonitrile (15 mL),
1-O-acetyl-2,3,5-tri-O-benzoyl-b-L-ribofuranose (1.13 g,
2.24 mmol), and trimethylsilyl trifluoromethanesulfonate
(0.45 mL, 2.33 mmol) affording 9e as colorless foam
(830 mg, 57%). TLC (silica gel, B): Rf 0.46. UV (MeOH):
1
(62,000), 273 (6500). H NMR (DMSO-d6) d: 8.63 (s, H–
C(2)); 8.12 (s, H–C(6)); 8.00–7.84 (m, arom, H); 7.65 (m,
arom, H); 7.54–7.40 (m, arom, H); 6.73 (m, H–C(10)); 6.29
(d, J¼3.25 Hz, H–C(20)); 6.12 (d, J¼3.64 Hz, H–C(30));
4.87–4.62 (m, H–C(40), H–C(50)). Anal. Calcd for
C32H23ClFN3O7 (615.99): C 62.39, H 3.76, N 6.82; found:
C 62.51, H 3.86, N 6.72.
1
4.1.4. 5-Bromo-4-chloro-7-[(2,3,5-tri-O-benzoyl)-b-D-
ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (8d). As
described for 8c with N,O-bis(trimethylsilyl)acetamide
(BSA, 0.55 mL, 2.22 mmol), 4-bromo-5-chloro-7H-pyrrolo-
[2,3-d]pyrimidine61 (465 mg, 2.00 mmol), dry acetonitrile
(12 mL), 1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose
(1.13 g, 2.24 mmol), and trimethylsilyl trifluoromethanesul-
fonate (0.40 mL, 2.07 mmol) yielding 8d as colorless foam
(723 mg, 53%). TLC (silica gel, B): Rf 0.46. UV (MeOH):
lmax 230 (60,000), 274 (5700). H NMR (DMSO-d6) d:
8.60 (s, H–C(2)); 8.30 (s, H–C(6)); 8.00–7.84 (m, arom,
H); 7.63 (m, arom, H); 7.55–7.40 (m, arom, H); 6.71 (d,
J¼4.61 Hz, H–C(10)); 6.29 (t, J¼5.53 Hz, J¼5.09 Hz, H–
C(20)); 6.14 (t, J¼5.39 Hz, J¼5.45 Hz, H–C(30)); 4.86–
4.64 (m, H–C(40), H–C(50)). Anal. Calcd for C32H23ClIN3O7
(723.90): C 53.09, H 3.20, N 5.80; found: C 52.88, H 3.28,
N 5.95.
1
lmax 230 (59,800), 273 (6000). H NMR (DMSO-d6) d:
4.1.8. 5-Fluoro-4-methoxy-7-(b-D-ribofuranosyl)-7H-
8b60
8.62 (s, H–C(2)); 8.32 (s, H–C(6)); 8.00–7.84 (m, arom,
H); 7.65 (m, arom, H); 7.54–7.40 (m, arom, H); 6.72
(d, J¼4.83 Hz, H–C(10)); 6.30 (t, J¼4.50 Hz, J¼6.72 Hz,
H–C(20)); 6.13 (t, J¼5.80 Hz, J¼5.69 Hz, H–C(30));
4.88–4.66 (m, H–C(40), H–C(50)). Anal. Calcd for
C32H23BrClN3O7 (676.90): C 56.78, H 3.42, N 6.21; found:
C 56.70, H 3.30, N 6.24.
pyrrolo[2,3-d]pyrimidine
(10b).
Compound
(643 mg, 1.04 mmol) was dissolved in 0.5 M NaOCH3
(20 mL). The solution was stirred overnight and then evapo-
rated, the residue was applied to FC (column 10ꢁ5 cm, C),
yielding 10b as colorless solid (213 mg, 68%). TLC (silica
gel, D): Rf 0.39. UV (MeOH): lmax 220 (17,600), 278
1
(5400). H NMR (DMSO-d6) d: 8.47 (s, H–C(2)); 7.67 (s,
H–C(6)); 6.21 (d, J¼5.50 Hz, H–C(100)); 5.52 (d,
J¼1.14 Hz, OH–C(20)); 5.40 (d, J¼3.90 Hz, OH–C(30));
5.20 (m, OH–C(50)); 4.33 (d, J¼3.24 Hz, H–C(20)); 4.08
(m, OCH3–C(4), H–C(30)); 3.91 (d, J¼2.34 Hz, H–C(40));
3.59 (m, H–C(50)). Anal. Calcd for C12H14FN3O5
(299.26): C 48.16, H 4.72, N 14.04; found: C 48.27, H
4.61, N 13.98.
4.1.5. 5-Bromo-4-chloro-7-[(2,3,5-tri-O-benzoyl)-b-L-
ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (9d). As de-
scribed for 8c with N,O-bis(trimethylsilyl)acetamide (BSA,
0.55 mL, 2.2 mmol), 4-bromo-5-chloro-7H-pyrrolo[2,3-d]-
pyrimidine61 (465 mg, 2.00 mmol), dry acetonitrile
(12 mL), 1-O-acetyl-2,3,5-tri-O-benzoyl-b-L-ribofuranose
(1.13 g, 2.24 mmol), and trimethylsilyl trifluoromethanesul-
fonate (0.40 mL, 2.07 mmol) affording 9d as colorless foam
(866 mg, 64%). TLC (silica gel, B): Rf 0.46. UV (MeOH):
4.1.9. 5-Chloro-4-methoxy-7-(b-D-ribofuranosyl)-7H-
pyrrolo[2,3-d]pyrimidine (10c). Compound 8c (700 mg,
1.11 mmol) was dissolved in 0.5 M NaOCH3 (20 mL). The
solution was stirred overnight and evaporated. The residue
was applied to FC (column 20ꢁ5 cm, C), yielding 10c
as colorless solid (325 mg, 93%). TLC (silica gel, D):
Rf 0.42. UV (MeOH): lmax 222 (22,700), 279 (6700).
1
lmax 228 (61,600), 273 (5900). H NMR (DMSO-d6) d:
8.62 (s, H–C(2)); 8.31 (s, H–C(6)); 8.00–7.84 (m, arom,
H); 7.63 (m, arom, H); 7.54–7.40 (m, arom, H); 6.72
(d, J¼4.90 Hz, H–C(10)); 6.30 (t, J¼5.41 Hz, J¼5.71 Hz,
H–C(20)); 6.13 (t, J¼5.47 Hz, J¼5.78 Hz, H–C(30));

9858
F. Seela, X. Ming / Tetrahedron 63 (2007) 9850–9861
1H NMR (DMSO-d6) d: 8.47 (s, H–C(2)); 7.86 (s, H–C(6));
6.16 (d, J¼5.64 Hz, H–C(10)); 5.40 (d, J¼5.90 Hz, OH–
C(20)); 5.19 (d, J¼4.40 Hz, OH–C(30)); 5.10 (m, OH–
C(50)); 4.35 (m, H–C(20)); 4.06 (m, OCH3–C(4), H–C(30));
3.91 (m, H–C(40)); 3.61 (m, H–C(50)). Anal. Calcd for
C12H14ClN3O5 (315.71): C 45.65, H 4.47, N 13.31; found:
C 45.78, H 4.56, N 13.19.
(d, J¼4.72 Hz, OH-(50)); 4.35 (m, H–C(20)); 4.06 (m,
H–C(30)); 3.88 (m, H–C(40)); 3.58 (m, H–C(50)).
4.1.14. 4-Amino-5-iodo-7-(b-D-ribofuranosyl)-7H-pyr-
rolo[2,3-d]pyrimidine (1e). As described for 1c with 8e
(830 mg, 1.15 mmol), methanolic ammonia (70 mL) afford-
ing 1e as brown solid. Crystallization from MeOH gave
brownish needles of 1e (320 mg, 71%). Mp 215 ꢀC (lit.
216–217 ꢀC).36 TLC (silica gel, E) Rf 0.41. UV (MeOH):
lmax 284 (8000). 1H NMR (DMSO-d6) d: 8.10 (s, H–
C(2)); 7.67 (s, H–C(6)); 6.68 (s, NH2–C(4)); 6.02 (d,
J¼6.19 Hz, H–C(10)); 5.33 (d, J¼6.20 Hz, OH–C(20));
5.19 (d, J¼5.30 Hz, OH–C(30)); 5.14 (d, J¼4.60 Hz, OH–
C(50)); 4.35 (m, H–C(20)); 4.06 (m, H–C(30)); 3.88 (m,
H–C(40)); 3.59 (m, H–C(50)).
4.1.10. 5-Bromo-4-methoxy-7-(b-D-ribofuranosyl)-7H-
pyrrolo[2,3-d]pyrimidine (10d). As described for 10b
with 8d (672 mg, 0.99 mmol) and 0.5 M NaOCH3
(20 mL); 10d was obtained as colorless solid (307 mg,
86%). TLC (silica gel, D): Rf 0.42. UV (MeOH): lmax 223
1
(19,900), 280 (5900). H NMR (DMSO-d6) d: 8.46 (s, H–
C(2)); 7.89 (s, H–C(6)); 6.15 (d, J¼5.93 Hz, H–C(10));
5.40 (d, J¼6.26 Hz, OH–C(20)); 5.19 (d, J¼4.64 Hz, OH–
C(30)); 5.10 (t, J¼5.25 Hz, J¼4.92 Hz, OH–C(50)); 4.35
(m, H–C(20)); 4.06 (m, OCH3–C(4), H–C(30)); 3.91 (m, H–
C(40)); 3.61 (m, H–C(50)). Anal. Calcd for C12H14BrN3O5
(360.16): C 40.02, H 3.92, N 11.67; found: C 39.89, H
3.84, N 11.75.
4.1.15. 5-Fluoro-3,7-dihydro-7-(b-D-ribofuranosyl)-
4H-pyrrolo[2,3-d]pyrimidin-4-one (2b). To a suspension
of 10b (145 mg, 0.48 mmol) and NaI (374 mg, 2.49 mmol)
in MeCN (15 mL), chlorotrimethylsilane (0.32 mL,
2.49 mmol) was added. The suspension was stirred at rt
for 3 h, evaporated to dryness, and the residue was applied
to FC (column 20ꢁ5 cm, E), yielding 2b as colorless solid
(130 mg, 94%). TLC (silica gel, E) Rf 0.27. UV (0.1 M
NaH2PO4 buffer): lmax 217 (17,000), 265 (6600). 1H NMR
(DMSO-d6) d: 12.12 (s, H–N(3)); 7.92 (s, H–C(2)); 7.34
(s, H–C(6)); 6.05 (d, J¼5.65 Hz, H–C(10)); 5.37 (d,
J¼5.92 Hz, OH–C(20)); 5.15 (d, J¼4.3 Hz, OH–C(30));
5.04 (t, J¼5.32 Hz, J¼4.92 Hz, OH–C(50)); 4.23 (m,
H–C(20)); 4.05 (m, H–C(30)); 3.87 (m, H–C(40)); 3.56 (m,
H–C(50)). Anal. Calcd for C11H12FN3O5 (285.23): C
46.32, H 4.24, N 14.73; found: C 46.06, H 4.13, N 14.56.
4.1.11. 5-Iodo-4-methoxy-7-(b-D-ribofuranosyl)-7H-pyr-
rolo[2,3-d]pyrimidine (10e). As described for 10b with 8e
(713 mg, 0.98 mmol) and 0.5 M NaOCH3 (20 mL) affording
10e as colorless solid (359 mg, 90%). Crystallization from
MeOH gave colorless needles of 10e. Mp 211–212 ꢀC
(dec) (lit. 212–213 ꢀC).46 TLC (silica gel, D): Rf 0.45. UV
1
(MeOH): 226 (21,200), 282.5 (5540). H NMR (DMSO-
d6) d: 8.44 (s, H–C(2)); 7.88 (s, H–C(6)); 6.13 (d,
J¼6.16 Hz, H–C(10)); 5.38 (d, J¼6.29 Hz, OH–C(20));
5.17 (d, J¼4.66 Hz, OH–C(30)); 5.10 (t, J¼5.37 Hz,
J¼5.25 Hz, OH–C(50)); 4.37 (m, H–C(20)); 4.07 (m,
OCH3–C(4), H–C(30)); 3.90 (d, J¼3.12 Hz, H–C(40)); 3.63
(m, H–C(50)).
4.1.16. 5-Chloro-3,7-dihydro-7-(b-D-ribofuranosyl)-4H-
pyrrolo[2,3-d]pyrimidin-4-one (2c). As described for 2b
with 10c (161 mg, 0.51 mmol), NaI (229 mg, 1.53 mmol),
chlorotrimethylsilane (0.20 mL, 1.53 mmol), and MeCN
(10 mL) affording 2c as colorless solid (137 mg, 89%).
TLC (silica gel, E) Rf 0.33. UV (0.1 M NaH2PO4): lmax
4.1.12. 4-Amino-5-chloro-7-(b-D-ribofuranosyl)-7H-pyr-
rolo[2,3-d]pyrimidine (1c). Compound 8c (900 mg,
1.42 mmol) was dissolved in methanolic ammonia (satu-
rated with NH3 at 0 ꢀC, 100 mL) and placed in an autoclave.
The reaction mixture was heated at 120–130 ꢀC overnight.
The mixture was then cooled and the solvent was evaporated
to provide the crude nucleoside. Purification by FC (silica
gel, D) provided 1c as colorless solid. Crystallization from
MeOH gave colorless needles of 1c (299 mg, 70%). Mp
226 ꢀC (lit. 226–228 ꢀC).36 TLC (silica gel, E) Rf 0.34. UV
1
220 (16,800), 266 (7600). H NMR (DMSO-d6) d: 12.14
(s, NH–C(3)); 7.95 (s, H–C(2)); 7.54 (s, H–C(6)); 6.02 (d,
J¼5.32 Hz, H–C(10)); 5.38 (m, OH–C(20)); 5.16 (m, OH–
C(30)); 5.06 (m, OH–C(50)); 4.27 (m, H–C(20)); 4.06 (m,
H–C(30)); 3.88 (m, H–C(40)); 3.57 (m, H–C(50)). Anal. Calcd
for C11H12ClN3O5 (301.68): C 43.79, H 4.01, N 13.93;
found: C 43.90, H 4.05, N 13.99.
1
(MeOH): 281 (9800). H NMR (DMSO-d6) d: 8.09 (s, H–
C(2)); 7.67 (s, H–C(6)); 6.69 (s, NH2–C(4)); 6.02 (d,
J¼6.07 Hz, H–C(10)); 5.33 (d, J¼6.24 Hz, OH–C(20));
5.17 (m, OH–C(30)); 5.13 (d, J¼4.48 Hz, OH–C(50)); 4.35
(m, H–C(20)); 4.05 (m, H–C(30)); 3.88 (m, H–C(40)); 3.57
(m, H–C(50)).
4.1.17. 5-Bromo-3,7-dihydro-7-(b-D-ribofuranosyl)-4H-
pyrrolo[2,3-d]pyrimidin-4-one (2d). As described for 2b
with 10d (130 mg, 0.36 mmol), NaI (162 mg, 1.08 mmol),
chlorotrimethylsilane (0.15 mL, 1.17 mmol), and MeCN
(10 mL) affording 2d as colorless solid (101 mg, 81%).
Recrystallization from MeOH gave 2d as colorless needles.
Mp 225–226 ꢀC (dec) (lit. 254.5–255 ꢀC, from water).36
TLC (silica gel, E) Rf 0.36. UV (0.1 M NaH2PO4): lmax
4.1.13. 4-Amino-5-bromo-7-(b-D-ribofuranosyl)-7H-pyr-
rolo[2,3-d]pyrimidine (1d). As described for 1c with 8d
(756 mg, 1.12 mmol), methanolic ammonia (saturated with
NH3 at 0 ꢀC, 100 mL) affording 1d as colorless solid. Crys-
tallization from MeOH gave colorless needles of 1d
(237 mg, 61%). Mp 232 ꢀC (lit. 231–232 ꢀC).36 TLC (silica
1
222 (16,200), 267 (7700). H NMR (DMSO-d6) d: 12.13
(s, NH–C(3)); 7.95 (s, H–C(2)); 7.57 (s, H–C(6)); 6.01 (d,
J¼5.95 Hz, H–C(10)); 5.38 (d, J¼4.95 Hz, OH–C(20)); 5.15
(m, OH–C(30)); 5.06 (m, OH–C(50)); 4.28 (m, H–C(20));
4.05 (m, H–C(30)); 3.87 (m, H–C(40)); 3.57 (m, H–C(50)).
1
gel, E) Rf 0.38. UV (MeOH): lmax 281 (9200). H NMR
(DMSO-d6) d: 8.10 (s, H–C(2)); 7.65 (s, H–C(6)); 6.79 (s,
NH2–C(4)); 6.05 (d, J¼6.01 Hz, H–C(10)); 5.32 (d,
J¼6.22 Hz, OH–C(20)); 5.15 (d, J¼5.42 Hz, OH-(30)); 5.11
4.1.18. 3,7-Dihydro-5-iodo-7-(b-D-ribofuranosyl)-4H-
pyrrolo[2,3-d]pyrimidin-4-one (2e). Compound 10e

F. Seela, X. Ming / Tetrahedron 63 (2007) 9850–9861
9859
(260 mg, 0.64 mmol) was dissolved in 2 N NaOH (20 mL).
The solution was refluxed for 1.5 h, and then neutralized
with diluted HCl. Purification by FC (silica gel, D) provided
2e as colorless solid (230 mg, 91%). Recrystallization from
MeOH gave 2e as colorless needles. Mp 224–225 ꢀC (dec).
TLC (silica gel, E) Rf 0.36. UV (0.1 M NaH2PO4): lmax 226
(800 mg, 1.11 mmol), methanolic ammonia (saturated with
NH3 at 0 ꢀC, 100 mL) yielding 3e as brownish solid
(333 mg, 77%). Recrystallization from MeOH gave brown-
ish needles. Mp 221–223 ꢀC (dec). TLC (silica gel, E) Rf
0.41. Mp UV (MeOH): lmax 284 (7900). 1H NMR
(DMSO-d6) d: 8.10 (s, H–C(2)); 7.67 (s, H–C(6)); 6.69 (s,
NH2–C(4)); 6.02 (d, J¼5.8 Hz, H–C(10)); 5.32 (d,
J¼6.13 Hz, OH–C(20)); 5.17 (m, OH–C(30)); 5.14 (m,
OH–C(50)); 4.36 (m, H–C(20)); 4.06 (m, H–C(30)); 3.88
(m, H–C(40)); 3.59 (m, H–C(50)). Anal. Calcd for
C11H13IN4O4 (392.15): C 33.69, H 3.34, N 14.29; found:
C 34.01, H 3.23, N 14.49.
1
(14,300), 274 (7200). H NMR (DMSO-d6) d: 12.13 (s,
NH–C(3)); 7.94 (s, H–C(2)); 7.57 (s, H–C(6)); 5.98 (d, J¼
6.07 Hz, H–C(10)); 5.37 (m, OH–C(20)); 5.09 (m, OH–C(30));
4.28 (m, H–C(20)); 4.04 (m, H–C(30)); 3.87 (m, H–
C(40)); 3.55 (m, H–C(50)). Anal. Calcd for C11H12IN3O5
(393.13): C 33.61, H 3.08, N 10.69; found: C 33.52, H
3.01, N 10.62.
4.1.23. 4-Amino-5-propynyl-7-(b-D-ribofuranosyl)-7H-
pyrrolo[2,3-d]pyrimidine (1f). A suspension of 4-amino-
5-iodo-7-b-D-ribofuranosyl-7H-pyrrolo[2,3-d]pyrimidine (1e,
300 mg, 0.77 mmol),36 Pd(O)(PPh3)4 (251 mg, 0.22 mmol),
and CuI (80.6 mg, 0.42 mmol) were thoroughly purged
with N2. DMF (2 mL) was added, the solution was purged
with N2 for another 10 min. Et3N (0.46 mL, 3.3 mmol)
was added, followed by propyne gas cooled in ice bath for
20 min. The solution was sealed and stirred at rt for 18 h.
After evaporation, the residue was purified by FC (silica
gel, C) to give 1f as yellowish solid (160 mg, 69%). TLC
(silica gel, E) Rf 0.38. UV (MeOH): lmax 237 (12,500),
280 (8800). 1H NMR (DMSO-d6) d: 8.09 (s, H–C(2)); 7.65
(s, H–C(6)); 6.67 (s, NH2–C(4)); 6.00 (d, J¼6.00 Hz, H–
C(10)); 5.31 (d, J¼5.95 Hz, OH–C(20)); 5.21 (m, OH–C(30));
5.11 (d, J¼3.14 Hz, OH–C(50)); 4.36 (m, H–C(20)); 4.07
(m, H-(30)); 3.89 (m, H-(40)); 3.63 (m, H–C(50)); 2.08 (s,
CH3–C(5)). Anal. Calcd for C14H16N4O4 (304.30): C
55.26, H 5.30, N 18.41; found: C 55.12, H 5.31, N 18.38.
4.1.19. 4-Amino-5-fluoro-7-(b-L-ribofuranosyl)-7H-pyr-
rolo[2,3-d]pyrimidine (3b). Compound 9b (480 mg,
0.78 mmol) was dissolved in methanolic ammonia (satu-
rated with NH3 at 0 ꢀC, 70 mL), placed in autoclave, and
stirred at 120–130 ꢀC overnight. The reaction mixture was
then cooled and the solvent evaporated to provide the crude
nucleoside. FC (silica gel, D) provided 3b as colorless solid
(200 mg, 90%). Recrystallization from MeOH gave 3b as
colorless needles. Mp 220–221 ꢀC (dec). TLC (silica gel,
E) Rf 0.25. UV (MeOH): lmax 279 (10,200). 1H NMR
(DMSO-d6) d: 8.07 (s, H–C(2)); 7.36 (s, H–C(6)); 7.03 (s,
NH2–C(4)); 6.07 (d, J¼5.9 Hz, H–C(10)); 5.32 (d, J¼
6.32 Hz, OH–C(20)); 5.14 (m, OH–C(30), OH–C(50)); 4.30
(m, H–C(20)); 4.06 (m, H–C(30)); 3.86 (m, H–C(40)); 3.59
(m, H–C(50)). Anal. Calcd for C11H13FN4O4 (284.24): C
46.48, H 4.61, N 19.71; found: C 46.60, H 4.53, N 19.63.
4.1.20. 4-Amino-5-chloro-7-(b-L-ribofuranosyl)-7H-pyr-
rolo[2,3-d]pyrimidine (3c). As described for 3b with 9c
(566 mg, 0.89 mmol), methanolic ammonia (saturated with
NH3 at 0 ꢀC, 100 mL) yielding 3c as colorless solid
(201 mg, 75%). Recrystallization from MeOH gave 3c as
colorless needles. Mp 228–230 ꢀC (dec). TLC (silica gel,
E) Rf 0.34. UV (MeOH): lmax 280 (9500). 1H NMR
(DMSO-d6) d: 8.09 (s, H–C(2)); 7.59 (s, H–C(6)); 6.90 (s,
NH2–C(4)); 6.04 (d, J¼5.9 Hz, H–C(10)); 5.34 (d,
J¼6.17 Hz, OH–C(20)); 5.17 (d, J¼4.72 Hz, OH–C(30));
5.13 (d, J¼3.99 Hz, OH–C(50)); 4.32 (m, H–C(20)); 4.06
(m, H–C(30)); 3.87 (m, H–C(40)); 3.56 (m, H–C(50)). Anal.
Calcd for C11H13ClN4O4 (300.70): C 43.94, H 4.36, N
18.63; found: C 43.73, H 4.40, N 18.69.
4.1.24. 4-Amino-5-(phthalimido-1-propynyl)-7-(b-D-
ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (1g). A sus-
pension of 4-amino-5-iodo-7-b-D-ribofuranosyl-7H-pyrrolo-
[2,3-d]pyrimidine (1e, 588 mg, 1.50 mmol),36 Pd(O)(PPh3)4
(472 mg, 0.41 mmol), CuI (158 mg, 0.83 mmol), Et3N
(0.90 mL, 6.46 mmol), and 4-phthalimido-1-propyne
(1.23 g, 6.5 mmol) in anhydrous DMF (5 mL) was stirred
under N2 at rt for 3 h. After evaporation, the residue was pu-
rified by FC (silica gel, C) to give 1g as yellowish solid
(546 mg, 81%). Mp 217–220 ꢀC (MeOH) (dec). TLC (silica
gel, D) Rf 0.42. UV (MeOH): lmax 217 (40,800), 280
1
(10,700). H NMR (DMSO-d6) d: 8.10 (s, H–C(2)); 7.90
(m, arom, H); 7.76 (s, H–C(6)); 6.83 (s, NH2–C(4)); 6.00
(d, J¼5.99 Hz, H–C(10)); 5.31 (d, J¼6.21 Hz, OH–C(20));
5.17 (t, J¼5.34 Hz, J¼5.01 Hz, OH–C(30)); 5.09 (d,
J¼4.42 Hz, OH–C(50)); 4.69 (s, CH2–C(5)); 4.33 (m,
H–C(20)); 4.05 (m, H-(30)); 3.87 (m, H-(40)); 3.52 (m,
H–C(50)). Anal. Calcd for C22H19N5O6 (449.42): C 58.80,
H 4.26, N 15.58; found: C 58.69, H 4.66, N 15.28.
4.1.21. 4-Amino-5-bromo-7-(b-L-ribofuranosyl)-7H-pyr-
rolo[2,3-d]pyrimidine (3d). As described for 3b with 9d
(815 mg, 1.20 mmol), methanolic ammonia (saturated with
NH3 at 0 ꢀC, 100 mL) affording 3d as colorless solid
(304 mg, 73%). Recrystallization from MeOH gave color-
less needles. Mp 224–225 ꢀC (dec). TLC (silica gel, E) Rf
1
0.38. UV (MeOH): lmax 281 (9200). H NMR (DMSO-d6)
d: 8.10 (s, H–C(2)); 7.65 (s, H–C(6)); 6.80 (s, NH2–C(4));
6.04 (d, J¼6.0 Hz, H–C(10)); 5.32 (d, J¼6.16 Hz, OH–
C(20)); 5.14 (d, J¼5.78 Hz, OH–C(30)); 5.11 (d,
J¼4.67 Hz, OH–C(50)); 4.35 (m, H–C(20)); 4.06 (m, H–
C(30)); 3.88 (m, H–C(40)); 3.60 (m, H–C(50)). Anal. Calcd
for C11H13BrN4O4 (345.15): C 38.28, H 3.80, N 16.23;
found: C 37.99, H 3.83, N 16.24.
4.1.25. 3,7-Dihydro-5-propynyl-7-(b-D-ribofuranosyl)-
4H-pyrrolo[2,3-d]pyrimidin-4-one (2f). 3,7-Dihydro-
5-iodo-7-b-D-ribofuranosyl-4H-pyrrolo[2,3-d]pyrimidin-4-
one (2e, 195 mg, 0.49 mmol), Pd(O)(PPh3)4 (162 mg,
0.14 mmol), CuI (52.1 mg, 0.27 mmol) were thoroughly
purged with N2. DMF (2 mL) was added, the solution was
purged with N2 for 10 min. Et3N (0.3 mL, 2.13 mmol) was
added, followed by condensed propyne gas cooled in ice
for 20 min. The solution was sealed and stirred at rt for
18 h. After evaporation, the residue was purified by FC
4.1.22. 4-Amino-5-iodo-7-(b-L-ribofuranosyl)-7H-pyr-
rolo[2,3-d]pyrimidine (3e). As described for 3b with 9e

9860
F. Seela, X. Ming / Tetrahedron 63 (2007) 9850–9861
10. Kim, J.; Pordesimo, E. O.; Toth, S. I.; Schmitz, F. J. J. Nat.
Prod. 1993, 56, 1813.
11. Doudna, J. A.; Cech, T. R. Nature 2002, 418, 222.
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S. E.; Mello, C. C. Nature 1998, 391, 806.
13. Revankar, G. R.; Robins, R. K. Pyrrolo[2,3-d]pyrimidine (7-
deazapurine) Nucleosides in Chemistry of Nucleosides and
Nucleotides; Townsend, L. B., Ed.; Plenum: New York, NY,
1991; pp 200–247 and references cited therein.
14. Seela, F.; Peng, X.; Li, H. J. Am. Chem. Soc. 2005, 127, 7739.
15. Li, H.; Peng, X.; Seela, F. Bioorg. Med. Chem. Lett. 2004, 14,
6031.
(silica gel, D), yielding 2f as colorless solid (101 mg, 68%).
TLC (silica gel, E) Rf 0.38. UV (MeOH): lmax 227 (17,700),
271 (9800). H NMR (DMSO-d6) d: 12.07 (s, NH–C(3));
7.91 (s, H–C(2)); 7.58 (s, H–C(6)); 5.99 (d, J¼5.42 Hz,
H–C(10)); 5.36 (d, J¼5.82 Hz, OH–C(20)); 5.15 (d,
J¼3.85 Hz, OH–C(30)); 5.06 (m, OH–C(50)); 4.27 (m, H–
C(20)); 4.07 (m, H–C(30)); 3.87 (m, H–C(40)); 3.58 (m, H–
C(50)); 2.01 (s, CH3–C(5)). Anal. Calcd for C14H15N3O5
(305.29): C 55.08, H 4.95, N 13.76; found: C 54.81, H
5.05, N 13.70.
1
4.1.26. 3,7-Dihydro-7-(b-D-ribofuranosyl)-5-[3-(trifluoro-
acetamido)propynyl]-4H-pyrrolo [2,3-d]pyrimidin-
4-one (2g). 3,7-Dihydro-5-iodo-7-b-D-ribofuranosyl-4H-
pyrrolo[2,3-d] pyrimidin-4-one (2e, 200 mg, 0.51 mmol),
Pd(O)(PPh3)4 (68 mg, 0.058 mmol), CuI (26.4 mg,
0.14 mmol) were thoroughly purged with N2. DMF (2 mL)
was added, the solution was purged with N2 for 10 min.
Et3N (0.15 mL, 1.06 mmol) was added, followed by 2,2,2-
trifluoro-N-(prop-2-ynyl)acetamide (0.90 g, 5.92 mmol).81
The solution was sealed and stirred at rt for 20 h. After evap-
oration, the residue was purified by FC (silica gel, C) to give
2g as yellow solid (146 mg, 69%). TLC (silica gel, E) Rf
16. Seela, F.; Hasselmann, D. Chem. Ber. 1980, 113, 3389.
17. Saito, Y.; Kato, K.; Umezawa, K. Tetrahedron 1998, 54, 4251.
18. Tolman, R. L.; Robins, R. K.; Townsend, L. B. J. Am. Chem.
Soc. 1968, 90, 524.
19. Watanabe, S.; Ueda, T. Nucleosides Nucleotides 1982, 1, 191.
20. Watanabe, S.; Ueda, T. Nucleosides Nucleotides 1983, 2, 113.
21. (a) Seela, F.; Peng, X. Base-Modified Oligodeoxy-
ribonucleotides: Using Pyrrolo [2,3-d]pyrimidines to Replace
Purines in Current Protocols in Nucleic Acid Chemistry;
Beaucage, S. L., Bergstrom, D. E., Glick, G. D., Jones, R. A.,
Eds.; John Wiley & Sons: New York, NY, 2005; pp 4.25.1–
4.25.24; (b) Seela, F.; Peng, X. Synthesis and Properties
of 7-Substituted 7-Deazapurine (pyrrolo[2,3-d]pyrimidine)
20-Deoxyribonucleosides in Current Protocols in Nucleic Acid
Chemistry; Bergstrom, D. E., Glick, G. D., Jones, R. A., Eds.;
John Wiley & Sons: New York, NY, 2005; pp 1.10.1–1.10.20.
1
0.38. UV (MeOH): lmax 227 (18,100), 270 (12,000). H
NMR (DMSO-d6) d: 12.31 (s, NH–C(3)); 10.12 (s, NH–
C(5)); 7.97 (s, H–C(2)); 7.73 (s, H–C(6)); 6.03 (m,
H–C(10)); 5.39 (d, J¼3.35 Hz, OH–C(20)); 5.18 (m, OH–
C(30)); 5.09 (m, OH–C(50)); 4.29 (m, CH2–C(5), H–C(20));
4.08 (m, H–C(30)); 3.90 (m, H–C(40)); 3.79 (m, H–C(50)).
Anal. Calcd for C16H15F3N4O6 (416.31): C 46.16, H 3.63,
N 13.46; found: C 45.86, H 3.75, N 13.30.
ꢀ
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24. Gupta, V.; Kool, E. T. Chem. Commun. 1997, 1425.
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We thank Dr. H. Rosemeyer, Dr. X. Zhang for the measure-
ment of the NMR spectra. Financial support by Roche Diag-
nostics GmbH and ChemBiotech, Germany, is gratefully
acknowledged.
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