Studies on the glycosylation of pyrrolo[2,3-d] pyrimidines with 1-O-acetyl-2,3,5-tri-O-benzoyl -β-D-ribofuranose: The formation of regioisomers during toyocamycin and 7-deazainosine syntheses

Article abstract of DOI:10.1080/15257770903091953

Glycosylation of silylated 4-amino-6-bromo-5-cyano-7H-pyrrolo[2,3-d] pyrimidine (9) with 1-O-acetyl-2,3,5-tri-O-benzoyl - d-ribofuranose (10) under "one-pot" glycosylation conditions (MeCN, TMSOTf) yielded the N-7 isomer 11 together with the N-1 compound 13 (ratio = 2:1). When the same conditions were applied to 4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine (21) the N-3 isomer 22 was the only glycosylation product formed in almost quantitative yield.

Full text of DOI:10.1080/15257770903091953

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Studies on the Glycosylation of
Pyrrolo[2,3-d] Pyrimidines with 1-
O-Acetyl-2,3,5-Tri-O-Benzoyl-β-
D-Ribofuranose: The Formation of
Regioisomers During Toyocamycin and 7-
Deazainosine Syntheses
Peter Leonard a , Sachin A. Ingale a b , Ping Ding a b , Xin Ming a &
Frank Seela a b
a Laboratory of Bioorganic Chemistry and Chemical Biology , Center
for Nanotechnology , Münster , Germany
b Laboratorium für Organische und Bioorganische Chemie , Institut
für Chemie, Universität Osnabrück , Osnabrück , Germany
Published online: 29 Jul 2009.
To cite this article: Peter Leonard , Sachin A. Ingale , Ping Ding , Xin Ming & Frank Seela (2009)
Studies on the Glycosylation of Pyrrolo[2,3-d] Pyrimidines with 1-O-Acetyl-2,3,5-Tri-O-Benzoyl-β-
D-Ribofuranose: The Formation of Regioisomers During Toyocamycin and 7-Deazainosine Syntheses,
Nucleosides, Nucleotides and Nucleic Acids, 28:5-7, 678-694, DOI: 10.1080/15257770903091953
To link to this article: http://dx.doi.org/10.1080/15257770903091953
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Nucleosides, Nucleotides and Nucleic Acids, 28:678–694, 2009
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770903091953
STUDIES ON THE GLYCOSYLATION OF PYRROLO[2,3-d]
PYRIMIDINES WITH 1-O-ACETYL-2,3,5-TRI-O-
BENZOYL-β-D-RIBOFURANOSE: THE FORMATION OF
REGIOISOMERS DURING TOYOCAMYCIN AND 7-DEAZAINOSINE
SYNTHESES
Peter Leonard,1 Sachin A. Ingale,1,2 Ping Ding,1,2 Xin Ming,1 and
Frank Seela1,2
1Laboratory of Bioorganic Chemistry and Chemical Biology, Center for Nanotechnology,
Mu¨nster, Germany
2Laboratorium fu¨r Organische und Bioorganische Chemie, Institut fu¨r Chemie, Universita¨t
Osnabru¨ck, Osnabru¨ck, Germany
Glycosylation of silylated 4-amino-6-bromo-5-cyano-7H-pyrrolo[2,3-d]pyrimidine (9) with 1-O-
2
acetyl-2,3,5-tri-O-benzoyl-β-d-ribofuranose (10) under “one-pot” glycosylation conditions (MeCN,
TMSOTf) yielded the N-7 isomer 11 together with the N-1 compound 13 (ratio = 2:1). When the
same conditions were applied to 4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine (21) the N-3 isomer 22 was
the only glycosylation product formed in almost quantitative yield.
Keywords
Nucleosides; pyrrolo[2;3-d]pyrimidines; glycosylation; toyocamycin; 7-
deazainosine; NMR-spectra
INTRODUCTION
The natural occurrence and the extraordinary biological and pharma-
cological properties of 7-deazapurine nucleosides have been the reason for
studies on their synthesis, transformation, incorporation in nucleic acids,
and the evaluation of their biochemical properties.[1–3] These subjects have
already been treated in a number of reviews[4–12] (if not otherwise stated
Received 6 February 2009; accepted 28 May 2009.
In honor and in celebration on the occasion of the 70th birthday of Morris J. Robins, a good friend
and an outstanding scientist.
We thank Dr. Simone Budow and M.Sc. Suresh Pujari for reading the manuscript. Financial support
by ChemBiotech, Mu¨nster, Germany is gratefully acknowledged.
Address correspondence to Frank Seela, Laboratory of Bioorganic Chemistry and Chemi-
cal Biology, Center for Nanotechnology, Heisenbergstrasse 11, 48149 Munster, Germany. E-mail:
Frank.Seela@uni-osnabrueck.de; Seela@uni-muenster.de
678

Glycosylation of Pyrrolo[2,3-d] Pyrimidines
679
systematic numbering is used throughout the manuscript). Pyrrolo[2,3-
d]pyrimidine nucleosides are naturally occurring and have been isolated
as monomers and as constituents of nucleic acids.[4,13] Among them are
ribonucleosides such as tubercidin (1a) isolated from Streptomyces tubercidicus
[14] as well as its 5-substituted derivatives toyocamycin (1b) and sangivamycin
(1c) (Figure 1), which are produced by Streptomyces toyocaensis or other
Streptomyces strains.[15,16] Other pyrrolo[2,3-d]pyrimidine nucleosides have
been isolated from marine organisms, showing biological activity as metabo-
lites or antimetabolites; some of them carry halogens at C-5-position of the
pyrrolo[2,3-d]pyrimidine moiety such as 5ꢁ-deoxy-5-iodotubercidin (2).[17]
Pyrrolo[2,3-d]pyrimidine ribonucleosides are also found as constituents
of tRNA: Queuosine (4b) or archaeosine (4c) represent 7-subsituted 7-
deazaguanine ribonucleosides, which are formed by post-modification of
tRNA.[18] The parent compound 7-deazaguanosine (4a) does not occur
in nature. It was synthesized in our laboratory in 1981.[19] Other natu-
rally occurring pyrrolo[2,3-d]pyrimidine nucleoside antibiotics have been
isolated, including mycalisines A (3a) and B (3b),[20,21] cadeguomycin
(4d),[22] the antibiotic AB-116 (kanagawamicin, 5),[23] and dapiramicin (6)
(Figure 1).[24–26] Echiguanines A and B (7a,b) which can act as kinase
FIGURE 1

680
P. Leonard et al.
inhibitors have been isolated from Streptomyces[27] and were synthesized
chemically,[28] 7-deazainosine (8) has been isolated from the ascidian
Aplidium pantherinum[29] and was prepared in our laboratory as well as by
others.[30, 31]
Considerable work has been done in the development of methods
for the chemical synthesis of pyrrolo[2,3-d]pyrimidine nucleosides related
to tubercidin (1a)[32,33] and its derivatives such as toyocamycin (1b) as
well as 7-deazainosine (8).[30,31,34] Different to purine nucleosides, the
synthesis by electrophilic attack of a sugar cation on the nitrogen of the
pyrrolo[2,3-d]pyrimidines affects the aromatic character of the pyrrole sys-
tem. Consequently, the pyrrole nitrogen is rather inert against glycosylation
with the result that the reaction might be directed into the pyrimidine
moiety[35] or takes place at the pyrrole carbons.[36,37] Glycosylation re-
actions performed on pyrrolo[2,3-d]pyrimidines under acidic conditions
results in poor yields when the pyrrole moiety is not functionalized.[35–38]
The development of the stereoselective nucleobase anion glycosylation
and/or using activated ribo sugar derivatives (ribofuranosyl halides) made
pyrrolo[2,3-d]pyrimidine 2ꢁ-deoxyribonucleosides easily accessible, but in
the case ribonucleosides the reaction shows drawbacks as ortho amides
are formed in many cases due to neighbour-group participation of sugar
acyl protecting groups at the 2-position.[39–43] The current work focuses
on the outcome of the glycosylation of the silylated nucleobases of toy-
ocamycin (1b) and 7-deazainosine (8) with 1-O-acetyl-2,3,5-tri-O-benzoyl-d-
ribofuranose (10) in an “one-pot” reaction employing TMSOTf as catalyst
and MeCN as solvent.
RESULTS AND DISCUSSION
1. Glycosylation of 4-amino-6-bromo-5-cyano-7H-pyrrolo
[2,3-d]pyrimidine (9) with 1-O-acetyl-2,3,5-tri-O-
benzoyl-β-D-ribofuranose (10)
Earlier, the synthesis of toyocamycin (1b) was described by the labo-
ratories of Bobek[44] and Townsend.[38,45] Both authors used 4-amino-6-
bromo-5-cyano-7H-pyrrolo[2,3-d]pyrimidine (9) for the glycosylation and
1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (10) as sugar component.
Bobek employed a sequential silylation protocol with hexamethyldisi-
lazane followed by trimethylsilyl chloride. The glycosylation of the silylated
nucleobase was performed in dichloroethane with trimethylsilyl trifluo-
romethanesulfonate (TMSOTf) as catalyst at 80◦C for 18 h resulting in a
yield of 88% of compound 11. Townsend described a “one-pot” procedure
in which N ,O-bis(trimethylsilyl)acetamide (BSA) was used as silylating
agent, TMSOTf as catalyst and acetonitrile as solvent. Here, the reaction
time was significantly shorter (3 hours at 80◦C) and the yield was somewhat

Glycosylation of Pyrrolo[2,3-d] Pyrimidines
681
lower (75%). Both authors described compound 11 as the only reaction
product.
We performed the same reaction at exactly the same conditions as
described by Townsend. For this purpose, 4-amino-6-bromo-5-cyano-7H-
pyrrolo[2,3-d]pyrimidine (9) was prepared as described.[46a–c] Nucleobase
9 was silylated by the addition of 2 equivalents of BSA in dry acetonitrile at
room temperature. Then, 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (10,
1 equivalent) and trimethylsilyl trifluoromethanesulfonate (3 equivalents)
were added resulting in a clear yellow solution which was heated at 80◦C for
3 hours. The formation of two main products (RF 0.45, 0.64) was indicated
by TLC (solvent CH2Cl2/EtOAc). Both compounds were separated by flash
chromatrography and the slower migrating compound was characterized
1
as compound 11 by comparison of the H-NMR spectra according to data
taken from the literature.[44,45] In our hands, compound 11 was isolated
in 51% yield. Another compound, tentatively assigned as compound 13
was obtained in 25% (ratio = 2:1). The reaction was repeated several
times under the same conditions to confirm a 2:1 ratio for the formation
of the nucleosides 11 and 13. Next, compounds 11 and 13 were treated
with saturated methanolic ammonia furnishing the nucleoside 12 and the
tentatively assigned 14 in 82% and 70% yield, respectively (Scheme 1). The
formation of two regioisomeric glycosylation products was supported by a
work of Bobek[47] on the same base 9, but using an azido sugar in the
glycosylation reaction. Two glycosylation products were obtained and their
structures were assigned to N-7 and N-1 isomers.
SCHEME 1

682
P. Leonard et al.
SCHEME 2
For debromination, the protected compounds 11 and 13 were refluxed
in hot ethanol for 3 h with ammonium formate and 10% Pd/C to give the
dehalogenated compounds 17 and 15. Toyocamycin (1b) and the tenta-
tively assigned isomer 16 were formed after debenzoylation in methanolic
ammonia (Scheme 2). All compounds were characterized by 1H- and
13C- NMR spectra and elemental analyses. However, the structures of 16
and its precursors are still ambiguous. For assignment, 13C-NMR spectra
(Table 1) were measured and coupling constants (Table 2) were determined
from gated-decoupled spectra. The signal for the C-2 was unambiguously
1
assigned based on the J (C-2, H-C-2) coupling (>200 Hz). Furthermore,
3
the C-2 carbon of nucleoside 16 shows a J (C-2, H-C-1ꢁ) coupling (3.8
Hz) to the anomeric proton giving a clear indication that the sugar is
attached to the pyrimidine moiety. The C-4 signal is assigned by the 3J (C-4,
H-C-2) coupling (>11 Hz) to H-C-2. The C-4a signal appears as a singlet
in case of the brominated nucleosides 12 and 14. After removal of the
3
bromine atom new couplings are observed to the H-C-6. C-4a shows a J
2
(C-4a, H-C-6) coupling (4.5 Hz) (compound 16). For the C-5 carbon a
J
(C-5, H-C-6) coupling (10.9 Hz) (compound 16) is observed and the C-6
1
carbon gives a J (C-6, H-C-6) coupling (188 Hz). The C-7a carbon shows
a complex splitting pattern in all nucleosides due to a variety of proximal
3
protons. Here, J couplings are possible to either H-C-1ꢁ, H-C-2 or H-C-6
(Table 2).
From Table 1, it is apparent that all C-2 carbon signals are shifted
upfield by about 10 ppm in the case of the N-1 isomers (13, 14, 15, 16)
compared to the N-7 glycosylated compounds (11, 12, 17, 1b). Similarly, a
downfield shift of about 10 ppm is observed for C-6 while the signal of C-4

683

684
P. Leonard et al.
TABLE 2 Coupling constants JC,H [Hz] of pyrrolo[2,3-d]pyrimidine nucleosidesa,b
12
14
16
C(2)
C(2)
C(4)
C(4a)
C(5)
C(6)
C(7a)
1J(C2, H-C2)
3J(C2, H-C1ꢁ)
3J(C4, H-C2)
3J(C4a, H-C6)
2J(C5, H-C6)
1J(C6, H-C6)
3J(C7a, H-C1ꢁ) or
3J(C7a, H-C2) or
3J(C7a, H-C6)
1J(C1ꢁ, H-C1ꢁ)
1J(C2ꢁ, H-C2ꢁ)
1J(C3ꢁ, H-C3ꢁ)
1J(C4ꢁ, H-C4ꢁ)
1J(C5ꢁ, H-C5ꢁ)
3J(CN, H-C6)
211
n.d.
11.6
s
s
s
202
—
11.1
s
s
s
210
3.8
12.0
4.5
10.9
188
m
m
6.7
5.5
164
149
150
147
139
s
C(1ꢁ)
C(2ꢁ)
C(3ꢁ)
C(4ꢁ)
C(5ꢁ)
C≡N
171
149
147
148
140
s
169
149
149
148
140
1.4
aMeasured in DMSO-d6 at 298 K.
bSystematic numbering. s = singlet. m = multiplet.
n.d. = not determined.
stays almost unaffected. According to observations made on other isomeric
pyrrolo[2,3-d]pyrimidine nucleosides, N-7 was established as glycosylation
site for the sugar residues linked to the pyrrole moiety and N-1 for the
isomers with the sugar attached to the pyrimidine system.[43,48] In both
series of isomers, the removal of the bromine substituent (15, 17) induces
a downfield shift for the C-6 (ca. 10 ppm) and an upfield shift of C-5
(Table 1). In addition, the amino group of the isonucleosides (13–16) shows
1
two signals for their exchangeable protons in the H-NMR spectrum. This
indicates the nonequivalence of these protons; a hindered rotation has been
reported for N-1 alkylated pyrrolo[2,3-d]pyrimidines.[49] Analogously, the
structure of the N-1 compound was assigned to formula 16. This structure
was further evidenced by single crystal x-ray analysis which is published
elsewhere.[50]
Next, UV-data were measured. From Table 3, it is obvious that a change
of the glycosylation position causes changes in the UV-spectra. When the
UV-spectra of the N-1 nucleosides 14 and 16 are compared to their N-7
counterparts 12 and 1b (toyocamycin), an additional maximum around 312
nm appears, a finding which was already reported for other pyrrolo[2,3-
d]pyrimidines with a functionalized pyrrole moiety (compounds 27, 28[48]).
The formation of the N-1 isomer in the course of glycosylation
is in line with methylation experiments performed in our labora-
tory on the tubercidin base 18 treated under neutral conditions with
MeI in dimethylacetamide.[51] In this case, two regiosiomeric methyla-
tion products—the N-3 isomer 20a and the N-1 derivative 19a were
obtained (Scheme 3). Analogously, neutral alkylation conditions with

Glycosylation of Pyrrolo[2,3-d] Pyrimidines
685
TABLE 3 UV data of pyrrolo[2,3-d]pyrimidine nucleosidesa
Cpd (λ
12[38]
1b
)
Wavelength [nm] Extinction coefficient (ε)
max
284
288(sh)
231
278
219
250
282
313
259
220
260
285
312
230
260
278
313
216
272
292
261
18300
9800
9300
15100
25400
6900
9900
7000
9100
25700
11000
12200
9600
13500
11300
12900
6200
22600
8700
10000
8000
27[48]
8
14
16
28[48]
23
aMeasured in methanol.
SCHEME 3

686
P. Leonard et al.
isopentenylbromide in HMPA were employed for the synthesis of the
7-deazapurine derivatives of naturally occurring triacanthine 19b,[49]
(Scheme 3), showing similar results. The different outcome of the gly-
cosylation reaction performed on the toyocamycin base 9 employing the
ribo sugar 10 is the result of the electron-withdrawing character of the
pyrrole substituents which changes the nucleophilic character of the ring
nitrogens. Consequently, N-7 becomes the most nucleophilic site whereas
N-1 is still nucleophilic enough to form the side product 13. N-3 has lost its
nucleophilicity due to the influence of the pyrrole substituents.
2. Glycosylation of 4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine (21)
with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (10)
The outcome of an “one-pot” glycosylation changes when
4-hydroxypyrrolo[2,3-d]pyrimidine (21) is used. Now, an exclusive
glycosylation at N-3 is observed leading to the protected derivative 22 in
quantitative yield which was deblocked in methanolic ammonia furnishing
23 (Scheme 4). This compound was already prepared under HgO catalysis
resulting in a significant lower yield at the glycosylation step (25%)[52]; a
similar outcome has been reported for a related derivative.[53] Nucleoside
25 (pyrroloC)[54] is also formed in almost quantitative yield when the
nucleobase 24 is used and the “one-pot” glycosylation is employed (Scheme
4). The deprotected nucleoside 26 is highly fluorescent and is introduced as
fluorescence reporter in single- and double-stranded oligonucleotides.[54]
SCHEME 4

Glycosylation of Pyrrolo[2,3-d] Pyrimidines
687
A number of 4,5-halogenated pyrrolo[2,3-d]pyrimidine ribonucleosides
were prepared by the “one-pot” glycosylation using TMSOTf/BSA.[55]
Also, nucleobase anion glycosylation was successful for the synthesis of
6-halogenated derivatives reported by Kazimierczuk[41] and Anderson.[48]
CONCLUSION
The 4-amino-7H-pyrrolo[2,3-d]pyrimidines such as 9 form the N-7 iso-
mer 11 as main product with the N-1 derivatives as minor component (13),
when “one-pot” glycosylation conditions (MeCN, silylated base, TMSOTf)
are employed. The corresponding 4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine
(21) or 2-hydroxy-7H-pyrrolo[2,3-d]pyrimidine (24) give the N-3 isomers
almost exclusively. A selective N-7 glycosylation is only accomplished with
5-substituted 4-chloro-7H-pyrrolo[2,3-d]pyrimidines,[55] or 4-phthalimido
derivatives[56] bearing electron-withdrawing substituents at C-5 (e.g., halo-
gens) while in the absence of electron-withdrawing substituents the
reaction fails. Here, isoproylidene-protected halogenoses have to be used
and nucleobase anion glycosylation has to be employed.[42,43] The glycosy-
lation reaction is selective when pyrrole precursors[57] are used instead of
pyrrolo[2,3-d]pyrimidines.
EXPERIMENTAL PART
General
All chemicals were purchased from Acros (Geel, Belgium), Fluka
(Taufkirehen, Germany), or Sigma-Aldrich (Sigma-Aldrich Chemie GmbH,
Deisenhofen, Germany). Solvents were of laboratory grade. Thin layer
chromatography (TLC): aluminium sheets, silica gel 60 F254 (0.2 mm;
Merck, Darmstadt, Germany). Flash column chromatography (FC): silica
gel 60 (VWR, Darmstadt, Germany) at 0.4 bar; sample collection with
an Ultra Rac II (Bromma, Sweden) fractions collector (LKB Instruments,
Sweden). UV spectra: U-3200 spectrometer (Hitachi, Tokyo, Japan); NMR
spectra: Avance-DPX-300 spectrometer (Bruker, Rheinstetten, Germany), at
1
300 MHz for H and 13C; δ in ppm relative to Me4Si as internal standard.
The J values are given in Hz. Elemental analyses were performed by
Mikroanalytisches Laboratorium Beller (Go¨ttingen, Germany).
4-Amino-6-bromo-5-cyano-7H-pyrrolo[2,3-d]pyrimidine (9): Compound
9 was prepared as described.[46] Analytical data: TLC (SiO2, CH2Cl2/MeOH
9:1): Rf 0.57. 1H-NMR (DMSO-d6): 8.22 (s, 1H, H-C(2)); 7.21 (s, 2H, NH2).
Analytical data are identical with those obtained earlier.[46]
4-Amino-5-cyano-7H-pyrrolo[2,3-d]pyrimidine (9a): Compound 9a was
prepared as described.[46] TLC (SiO2, CH2Cl2/MeOH 9:1): Rf 0.4. 1H-NMR

688
P. Leonard et al.
(DMSO-d6): 8.16 (s, 1H, H-C(2)); 8.09 (s, 1H, H-C(6)); 6.60 (s, 2H, NH2).
Analytical data are identical with those obtained earlier.[46]
Glycosylation of 4-amino-6-bromo-5-cyano-7H-pyrrolo[2,3-d]pyrimidine
(9) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (10): The glycosy-
lation was performed as described earlier by Townsend et al.[45] Com-
pound 9 (2.4 g, 10 mmol) was suspended in dry acetonitrile. N ,O-
Bis(trimethylsilyl)acetamide (4.1 g, 2.9 ml, 20 mmol) was added and the
mixture was stirred for 15 minutes. Then, 1-O-acetyl-2,3,5-tri-O-benzoyl-β-d-
ribofuranose (5.0 g, 10 mmol) and trimethylsilyl trifluoromethanesulfonate
(6.7 g, 5.4 ml, 30 mmol) were added. Within 10 minutes, the suspension
became a clear yellow solution. This solution was heated at 80◦C for 3 h,
cooled and extracted with ethyl acetate. The organic layer was washed with
saturated bicarbonate solution and brine, dried, evaporated and applied to
FC (silica gel, column 20 × 5 cm, CH2Cl2→CH2Cl2/EtOAc 4:1). After flash
chromatography (FC) two main zones were obtained. The fast migrating
zone furnished compound 13 (25%) and the slower migrating zone fur-
nished compound 11 (51%).
4-Amino-6-bromo-5-cyano-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-7H-
pyrrolo[2,3-d]pyrimidine (13): From the faster migrating zone compound
13 (1.7g, 25%) was isolated as colorless foam. TLC (SiO2, CH2Cl2/EtOAc
4:1): Rf 0.64. UV (MeOH): λmax 315 (ε 8200), 283 (ε 4900), 266 (ε 12900),
231 (ε 53700). 1H-NMR (DMSO-d6): 8.79 (bs, 1H, NH), 8.69 (s, 1H,
H-C(2)), 7.91, 7.64, 7.46 (3m, 16H, arom.H, NH), 6.63 (d, J = 2.4, 1H,
H-C(1ꢁ)), 6.31 (m, 2H, H-C(2ꢁ), H-C(3ꢁ)), 4.79 (m, 3H, H-C(4ꢁ), H-C(5ꢁ)).
Anal. Calc. for C33H24BrN5O7 (682.48): C 58.08, H 3.54, N 10.26; found C
58.10, H 3.65, N 10.20.
4-Amino-6-bromo-5-cyano-7-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-7-
pyrrolo[2,3-d]pyrimidine (11): From the slower migrating zone compound
11 (3.5g, 51%) was isolated as colorless foam. TLC (SiO2, CH2Cl2/EtOAc
1
4:1): Rf 0.45. H-NMR (DMSO-d6): 8.16 (s, 1H, H-C(2)), 7.90, 7.85, 7.45
(3m, 15H, arom.H), 7.12 (s, 2H, NH2), 6.61 (m, H-C(1ꢁ)), 6.43 (m, 2H,
H-C(2ꢁ), H-C(3ꢁ)), 4.87 (m, 2H, H-C(5ꢁ)), 4.60 (m, 1H, H-C(4ꢁ)). Analytical
data are identical to those reported earlier.[45]
4-Amino-5-cyano-7-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-7H-pyrrolo
[2,3-d]pyrimidine (17): The compound was prepared according to a
procedure published earlier[45] with 11 (1.0 g, 1.46 mmol) and ammonium
formate (1.0 g, 15 mmol) and 10% Pd on activated charcoal. After FC
(column 20 × 5 cm, CH2Cl2→CH2Cl2/EtOAc 4:1) compound 17 (750
mg, 85%, Lit.[45]: 85%) was obtained as colorless foam. TLC (SiO2,
1
CH2Cl2/EtOAc 4:1): Rf 0.25. H-NMR (DMSO-d6): 8.52 (s, 1H, H-C(6)),
8.17 (s, 1H, H-C(2)), 7.92, 7.86, 7.46 (3m, 15H, arom.H), 6.99 (s, 2H, NH2),
6.61 (d, J = 4.6, 1H, H-C(1ꢁ)), 6.33 (t, J = 4.7, 1H, H-C(2ꢁ)), 6.18 (t, J = 5.8,
1H, H-C(3ꢁ)), 4.85 (m, 2H, H-C(5ꢁ)), 4.67 (m, 1H, H-C(4ꢁ)). Analytical data
are identical to those reported earlier.[45]

Glycosylation of Pyrrolo[2,3-d] Pyrimidines
689
4-Amino-6-bromo-5-cyano-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]
pyrimidine (14): Compound 13 (1.0 g, 1.47 mmol) was stirred in MeOH
saturated with ammonia (50 ml) overnight. The solvent was evaporated and
the residual foam was adsorbed on silica gel (20 g) and applied to FC (silica
gel, column 15 × 5 cm, CH2Cl2→CH2Cl2/MeOH 95:5). Evaporation of the
main zone afforded 14 (380 mg, 70%) as colorless foam. Recrystallisation
from MeOH furnished colorless crystals. m.p.: 195–198◦C, dec. TLC (SiO2,
CH2Cl2/MeOH 95:5): Rf 0.20. UV (MeOH): λmax 285 (ε 19000); (Lit.[38]
1
284 (ε 18300)). H-NMR (DMSO-d6): 8.20 (s, 1H, H-C(2)), 7.08 (s, 2H,
NH2), 5.93 (d, J = 6.5, 1H, H-C(1ꢁ)), 5.46 (d, J = 6.1, 1H, HO-C(2ꢁ)), 5.33
(m, 1H, HO-C(3ꢁ)), 5.25 (d, J = 4.7, 1H, HO-C(5ꢁ)), 5.05 (d, J = 6.1, 1H,
H-C(2ꢁ)), 4.21 (d, J = 2.7, H-C(3ꢁ)), 3.97 (d, J = 2.9, 1H, H-C(4ꢁ)), 3.70,
3.54 (2m, 2H, H-C(5ꢁ)). Analytical data are identical to those reported
earlier.[38]
4-Amino-5-cyano-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine
(toyocamycin, (1b)): As described earlier[45] with compound 17 (0.6 g, 1
mmol) and saturated methanolic ammonia (50 ml). Compound 1b was
obtained as colorless solid (240 mg, 82%). TLC (SiO2, CH2Cl2/MeOH 9:1)
1
Rf 0.35. H-NMR (DMSO-d6): 8.45 (s, 1H, H-C(2)), 8.22 (s, 1H, H-C(6)),
6.92 (s, 2H, NH2), 6.05 (d, J = 5.6, 1H, H-C(1ꢁ)), 5.48 (d, J = 6.0, 1H,
HO-C(2ꢁ)), 5.22 (m, 2H, HO-C(3ꢁ), HO-C(5ꢁ)), 4.36 (d, J = 6.1, H-C(2ꢁ)),
4.09 (d, J = 2.7, 1H, H-C(3ꢁ)), 3.92 (d, J = 3.5, 1H, H-C(4ꢁ)), 3.62 (m, 2H,
H-C(5ꢁ)). Analytical data are identical to those reported earlier.[38,44,45]
4-Amino-5-cyano-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-7H-pyrrolo
[2,3-d] pyrimidine (15): Compound 13 (1.32 g, 1.9 mmol) was suspended
in EtOH (40 ml). Then, ammonium formate (1.0 g, 15 mmol) and 10%
Pd on activated charcoal (100 mg) was added and the solution was stirred
for 3 hours under reflux. The solution was filtrated through a bed of Celite
and the Celite was washed with hot EtOH (2 × 50 ml). The solvent of the
filtrate was evaporated and the remaining residue was dissolved in CH2Cl2,
adsorbed on silica gel (25 g) and applied to FC (silica gel, column 20 × 5
cm, CH2Cl2→CH2Cl2/EtOAc 4:1). Evaporation of the main zone furnished
compound 15 (960 mg, 82%) as colorless foam. TLC (SiO2, CH2Cl2/EtOAc
4:1): Rf 0.50. UV (MeOH): λmax 314 (ε 6500), 283 (ε 12200), 268 sh (ε
1
10200), 231 (ε 44700). H-NMR (DMSO-d6): 8.69 (s, 2H, H-C(2), NH),
7.90, 7.62, 7.45 (3m, 17H, arom.H, H-C(6), NH), 6.61 (m, 1H, H-C(1ꢁ)),
6.42 (m, 2H, H-C(2ꢁ), H-C(3ꢁ)), 4.80 (m, 3H, H-C(4ꢁ), H-C(5ꢁ)). Anal Calc.
for C33H25N5O7 (603.58): C 65.67, H 4.17, N 11.60; found C 65.58, H 4.18,
N 11.52.
4-Amino-6-bromo-5-cyano-1-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]
pyrimidine (14): Compound 13 (600 mg, 0.88 mmol) was suspended in
saturated methanolic ammonia (50 ml) and the mixture was stirred for 12
hours. The solvent was evaporated and the foamy residue was adsorbed
on silica gel (25 g) and applied to FC (silica gel, column 20 × 5 cm,

690
P. Leonard et al.
CH2Cl2→CH2Cl2/MeOH 95:5). Evaporation of the main zone afforded 14
as amorphous solid (250 mg, 77%). TLC (SiO2, CH2Cl2/MeOH 9:1): Rf
0.22. UV (MeOH): λmax 312 (ε 9600), 285 (ε 12200), 260 (ε 11000), 220
1
(ε 25700). H-NMR (DMSO-d6): 8.79 (s, 1H, H-C(2)), 8.57 (bs, 1H, NH),
7.39 (bs, 1H, NH), 6.07 (d, J = 4.3, 1H, H-C(1ꢁ)), 5.62 (d, J = 5.5, 1H,
HO-C(2ꢁ)), 5.49 (m, 1H, HO-C(3ꢁ)), 5.22 (d, J = 5.1, 1H, HO-C(5ꢁ)), 4.45
(m, 1H, H-C(2ꢁ)), 4.13 (m, 1H, H-C(3ꢁ)), 4.02 (m, 1H, H-C(4ꢁ)), 3.77, 3.61
(2m, 2H, H-C(5ꢁ)). Anal Calc. for C12H12BrN5O4 (370.16): C 38.94, H 3.27,
N 18.92; found C 38.85, H 3.30, N, 18.81.
4- Amino- 5-cyano- 1- (β-D-ribofuranosyl)- 7H- pyrrolo [2,3-d] pyrimidine
(16): Compound 15 (750 mg, 1.2 mmol) was suspended in saturated
methanolic ammonia (50 ml). The solution was stirred for 12 hours, then
the solvent was evaporated and the remaining residue was adsorbed on silica
gel (25 g). FC (silica gel, column 15 × 4 cm, CH2Cl2→CH2Cl2/MeOH 95:5)
furnished compound 16 (300 mg, 82%) as colorless solid. Crystallisation
from MeOH gave colorless crystals: m.p.: 189–192◦C, dec. TLC (SiO2,
CH2Cl2/MeOH 9:1): Rf 0.41. UV (MeOH): λmax 313 (ε 6200), 278 (ε
1
12900), 260 (ε 11300), 230 (ε 13500). H-NMR (DMSO-d6): 8.73 (s, 1H,
H-C(2)), 8.49 (bs, 1H, NH), 7.85 (s, 1H, H-C(6)), 7.20 (bs, 1H, NH), 6.23
(m, 1H, H-C(1ꢁ)), 6.02 (d, J = 5.5, 1H, HO-C(2ꢁ)), 5.60 (d, J = 5.8, 1H,
HO-C(3ꢁ)), 5.21 (d, J = 4.5, 1H, HO-C(5ꢁ)), 4.65 (m, 1H, H-C(2ꢁ)), 4.10 (m,
2H, H-C(3ꢁ)), H-C(4ꢁ)), 3.60 (m, 2H, H-C(5ꢁ)). Anal Calc. for C12H13N5O4
(291.26): C 49.48, H 4.50, N 24.04; found C 49.49, H 4.61, N 23.90.
3-(2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl)-3,7-dihydro-4H-pyrrolo[2,3-
d]pyrimidin-4-one (22): To a suspension of 3,7-dihydro-4H-pyrrolo[2,3-
d]pyrimidin-4-one (21) (220 mg, 1.63 mmol) in dry acetonitrile,
N ,O-bis(trimethylsilyl)acetamide (1.6 g, 1.1 ml, 4.43 mmol) was added
and the mixture stirred for 10 minutes at room temperature Then,
1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (10) (1.34 g, 2.65 mmol)
and trimethylsilyl trifluoromethanesulfonate (430 mg, 0.35 ml, 1.79
mmol) were introduced. The mixture was stirred for another 15 minutes
at room temperature During this time the suspension became a clear
yellow solution. This solution was heated at 80◦C for 3h in a preheated
oil-bath. The solution was cooled and diluted with ethyl acetate. The
organic layer was washed with saturated bicarbonate solution and brine,
dried, evaporated and applied to FC (silica gel, column 20 × 5 cm,
CH2Cl2/acetone 15:1). From FC one main zone was obtained. The solvent
was evaporated and the title compound 22 was obtained as colorless foam
(920 mg, 98%). TLC (SiO2, CH2Cl2/EtOAc 4:1): Rf 0.4. UV (MeOH): λmax
1
262 (ε 18000), 228 (ε 84000). H-NMR (DMSO-d6): 12.11 (s, 1H, NH),
8.33 (s, 1H, H-C(2)), 8.04–7.42 (4m, 15H, arom. H), 7.13 (d, J = 2.8, 1H,
H-C(6)), 6.55 (d, J = 2.8, 1H, H-C(5)), 6.38 (d, J = 2.3, 1H, H-C(1ꢁ)), 6.12
(m, 2H, H-C(2ꢁ), H-C(3ꢁ)), 4.73 (m, 3H, H-C(4ꢁ), H-C(5ꢁ)). Anal Calc. for

Glycosylation of Pyrrolo[2,3-d] Pyrimidines
691
C32H25N3O8 (579.56): C 66.32, H 4.35, N 7.25; found C 66.24, H 4.19, N
7.19.
3- (β-D-Ribofuranosyl)- 3,7- dihydro- 4H-pyrrolo [2,3-d]pyrimidin-4-one
(23): Compound 22 (1.08 g, 1.86 mmol) was suspended in saturated
methanolic ammonia (40 ml) and the mixture was stirred for 12 hours.
The solvent was evaporated and the residual foam was adsorbed on silica
gel (20 g) and applied to FC (silica gel, column 15 × 5 cm, CH2Cl2/MeOH
20:1→CH2Cl2/MeOH 4:1). Evaporation of the main zone afforded 23 (410
mg, 82%) as colorless foam. TLC (SiO2, CH2Cl2/MeOH 9:1): Rf 0.20. UV
(MeOH): λmax 261 (ε 16000). 1H-NMR (DMSO-d6): 11.87 (s, 1H, NH), 8.43
(s, 1H, H-C(2)), 7.07 (d, J = 2.9, 1H, H-C(6)), 6.48 (m, 2H, H-C(5)), 6.15
(d, J = 4.7, 1H, H-C(1ꢁ)), 5.38 (d, J = 5.5, 1H, HO-C(3ꢁ)), 5.14 (t, J =
5.0, 1H, HO-C(5ꢁ)), 5.11 (d, J = 6.9, 1H, HO-C(2ꢁ)), 4.13 (m, 2H, H-C(2ꢁ),
H-C(3ꢁ)), 3.91 (m, 1H, H-C(4ꢁ)), 3.68, 3.61 (2m, 2H, H-C(5ꢁ)). Anal Calc.
for C11H13N3O5 (267.24): C 49.44, H 4.90, N 15.72; found C 49.53, H 4.82,
N 15.61.
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