7-Functionalized 7-deazapurine ribonucleosides related to 2-aminoadenosine, guanosine, and xanthosine: Glycosylation of pyrrolo[2,3-d]pyrimidines with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose

Article abstract of DOI:10.1021/jo0516640

The Silyl-Hilbert-Johnson reaction as well as the nucleobase-anion glycosylation of a series of 7-deazapurines has been investigated, and the 7-functionalized 7-deazapurine ribonucleosides were prepared. Glycosylation of the 7-halogenated 6-chloro-2-pival

Full text of DOI:10.1021/jo0516640

7-Functionalized 7-Deazapurine Ribonucleosides Related to
2-Aminoadenosine, Guanosine, and Xanthosine: Glycosylation of
Pyrrolo[2,3-d]pyrimidines with
1-O-Acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose
Frank Seela* and Xiaohua Peng
Laboratorium fu¨r Organische und Bioorganische Chemie, Institut fu¨r Chemie, UniVersita¨t Osnabru¨ck,
Barbarastr. 7, D-49069 Osnabru¨ck, Germany, and Center for Nanotechnology (CeNTech),
GieVenbecker Weg 11, 48149 Mu¨nster, Germany
frank.seela@uni-osnabrueck.de
ReceiVed August 8, 2005
The Silyl-Hilbert-Johnson reaction as well as the nucleobase-anion glycosylation of a series of 7-de-
azapurines has been investigated, and the 7-functionalized 7-deazapurine ribonucleosides were prepared.
Glycosylation of the 7-halogenated 6-chloro-2-pivaloylamino-7-deazapurines 9b-d with 1-O-acetyl-
2,3,5-tri-O-benzoyl-D-ribofuranose (5) gave the â-D-nucleosides 11b-d (73-75% yield), which were
transformed to a number of novel 7-halogenated 7-deazapurine ribonucleosides (2b-d, 3b-d, and 4b-d)
related to guanosine, 2-aminoadenosine, and xanthosine. 7-Alkynyl derivatives (2e-i, 3e-h, or 4g) have
been prepared from the corresponding 7-iodonucleosides 2d, 3d, or 4d employing the palladium-catalyzed
Sonogashira cross-coupling reaction. The 7-halogenated 2-amino-7-deazapurine ribonucleosides with a
reactive 6-chloro substituent (18b-d) were synthesized in an alternative way using nucleobase-anion
glycosylation performed on the 7-halogenated 2-amino-6-chloro-7-deazapurines 13b-d with 5-O-[(1,1-
dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-R-D-ribofuranosyl chloride (17). Compounds
18b-d have been converted to the nucleosides 19b-d carrying reactive substituents in the pyrimidine
moiety. Conformational analysis of selected nucleosides on the basis of proton coupling constants and
using the program PSEUROT showed that these ribonucleosides exist in a preferred S conformation in
solution.
Introduction
mycin (1b), and sangivamycin (1c; Scheme 1), exhibit a broad
spectrum of biological activity (purine numbering is used
throughout the general section).1,2 The frequent natural occur-
rences and the biological properties of this class of compounds
have promoted ample studies toward the synthesis, biological
activity, and incorporation in oligonucleotides as well as the
Several naturally occurring 7-deazapurine (pyrrolo[2,3-d]-
pyrimidine) ribonucleosides, such as tubercidin (1a), toyoca-
* To whom correspondence should be addressed. Phone: +49(0)541 969
2791. Fax: +49(0)541 969 2370.
10.1021/jo0516640 CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/01/2005
J. Org. Chem. 2006, 71, 81-90
81

Seela and Peng
SCHEME 1. Structures of Nucleosides 1-4
chemically designed analogues.3-7 The 7 position of 7-dea-
zapurine is an ideal site for modifications that may lead to
increasing antiviral activity,1,8 to the introduction of reporter
groups, to the modification of interference RNA, or to the
enhancement of DNA or RNA duplex stability by substituents
of moderate size, such as alkynyl residues or halogens.4,7
Moreover, halogen-functionalized derivatives can be converted
into biologically useful analogues by displacement reactions9-14
or cross-coupling chemistry.15-20 Thus, an efficient synthetic
accessibility of the 7-functionalized 7-deazapurine ribonucleo-
sides is of importance.
Considerable efforts have been expended in the development
of methods for the chemical synthesis of the 7-deazapurine
nucleosides related to tubercidin3,6c or 7-deazaguanosine.6a,b
Different from the purine nucleoside, the synthesis by electro-
philic glycosylation performed on the 7-deazapurines destroys
the aromatic character of the pyrrole system. Consequently, the
pyrrole nitrogen is rather inert against glycosylation with the
result that the reaction is directed into the pyrimidine moiety21a
or takes place at the pyrrole carbons.21b,c Therefore, the
glycosylation reaction performed under acid-catalyzed condi-
tions resulted in poor yields.21,22 The development of stereose-
lective nucleobase-anion glycosylation made 7-deazapurine 2′-
deoxyribonucleosides easily accessible.23,24 This method was
later applied to the synthesis of the 7-deazapurine ribonucleo-
sides by using ribofuranosyl halides.25-27 Unfortunately, ortho
amides are formed by neighbor group participation when the
sugar contains an acyl protecting group at the 2 position.25,27a,b
This was circumvented when the nucleobase-anion glycosyl-
ation of a 7-deazapurine base was performed with a sugar halide
protected at the 2,3-cis diol with an isopropylidene residue.27c
By this means, 6-chloro- or 2-amino-6-chloro-7-deazapurine
ribonucleosides were prepared under regio- and stereoselective
control in good yield.10,27a,28 As we became interested in the
(1) Suhadolnik, R. J. Pyrrolopyrimidine Nucleosides in Nucleoside
Antibiotics; Wiley-Interscience: New York, 1970; pp 298-353 (and
references therein).
(2) Kasai, H.; Ohashi, Z.; Harada, F.; Nishimura, S.; Oppenheimer, N.
J.; Crain, P. F.; Liehr, J. G.; von Minden, D. L.; McCloskey, J. A.
Biochemistry 1975, 14, 4198-4208.
(3) Revankar, G. R.; Robins, R. K. In Pyrrolo[2,3-d]pyrimidine (7-
Deazapurine) Nucleosides in Chemistry of Nucleosides and Nucleotides;
Townsend, L. B., Ed.; Plenum Press: New York, 1991; pp 200-247 (and
references therein).
(4) Seela, F.; Peng, X.; Li, H. J. Am. Chem. Soc. 2005, 127, 7739-
7751.
(5) Li, H.; Peng, X.; Seela, F. Bioorg. Med. Chem. Lett. 2004, 14, 6031-
6034.
(6) (a) Seela, F.; Hasselmann, D. Chem. Ber. 1980, 113, 3389-3393.
(b) Saito, Y.; Kato, K.; Umezawa, K. Tetrahedron 1998, 54, 4251-4266.
(c) Tolman, R. L.; Robins, R. K.; Townsend, L. B. J. Am. Chem. Soc. 1968,
90, 524-526. (d) Watanabe, S.; Ueda, T. Nucleosides Nucleotides 1982,
1, 191-203. (e) Watanabe, S.; Ueda, T. Nucleosides Nucleotides 1983, 2,
113-125.
(7) (a) Seela, F.; Peng, X. In Base-modified oligodeoxyribonucleotides:
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, 2005; pp 4.25.1-
4.25.24. (b) Seela, F.; Peng, X. In Synthesis and properties of 7-substituted
7-deazapurine (pyrrolo[2,3-d]pyrimidne) 2′-deoxyribonucleosides 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, 2005; pp
1.10.1-1.10.20.
(8) (a) Kazlauskas, R.; Murphy, P. T.; Wells, R. J.; Baird-Lambert, J.
A.; Jamieson, D. D. Aust. J. Chem. 1983, 36, 165-170. (b) Bergstrom, D.
E.; Brattesani, A. J.; Ogawa, M. K.; Reddy, P. A.; Schweickert, M. J.;
Balzarini, J.; De Clercq, E. J. Med. Chem. 1984, 27, 285-292.
(9) Ve´liz, E. A.; Beal, P. A. J. Org. Chem. 2001, 66, 8592-8598.
(10) Seela, F.; Soulimane, T.; Mersmann, K.; Ju¨rgens, T. HelV. Chim.
Acta 1990, 73, 1879-1887.
(11) van der Wenden, E. M.; von Frijtag Drabbe Ku¨nzel, J. K.; Mathoˆt,
R. A. A.; Danhof, M.; IJzerman, A. P.; Soudijn, W. J. Med. Chem. 1995,
38, 4000-4006.
(12) Gupta, V.; Kool, E. T. Chem. Commun. 1997, 1425-1426.
(13) Janeba, Z.; Francom, P.; Robins, M. J. J. Org. Chem. 2003, 68,
989-992.
(14) Seela, F.; Peng, X. Synthesis 2004, 1203-1210.
(15) Matsuda, A.; Shinozaki, M.; Yamaguchi, T.; Homma, H.; Nomoto,
R.; Miyasaka, T.; Watanabe, Y.; Abiru, T. J. Med. Chem. 1992, 35, 241-
252.
(16) Van Aerschot, A. A.; Mamos, P.; Weyns, N. J.; Ikeda, S.; De Clercq,
E.; Herdewijn, P. A. J. Med. Chem. 1993, 36, 2938-2942.
(17) Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q. J. Am.
Chem. Soc. 1999, 121, 6090-6091.
(18) Lakshman, M. K.; Hilmer, J. H.; Martin, J. Q.; Keeler, J. C.; Dinh,
Y. Q. V.; Ngassa, F. N.; Russon, L. M. J. Am. Chem. Soc. 2001, 123, 7779-
7787.
(19) Ve´liz, E. A.; Stephens, O. M.; Beal, P. A. Org. Lett. 2001, 3, 2969-
2972.
(20) Seela, F.; Zulauf, M. Synthesis 1996, 726-730.
(21) (a) Tolman, R. L.; Tolman, G. L.; Robins, R. K.; Townsend, L. B.
J. Heterocycl. Chem. 1970, 7, 799-806. (b) Girgis, N. S.; Michael, M. A.;
Smee, D. F.; Alaghamandan, H. A.; Robins, R. K.; Cottam, H. B. J. Med.
Chem. 1990, 33, 2750-2755. (c) Seela, F.; Debelak, H. J. Org. Chem. 2001,
66, 3303-3312.
(22) Tolman, R. L.; Robins, R. K.; Townsend, L. B. J. Am. Chem. Soc.
1969, 91, 2102-2108.
(23) (a) Winkeler, H.-D.; Seela, F. J. Org. Chem. 1983, 48, 3119-3122.
(b) Seela, F.; Westermann, B.; Bindig, U. J. Chem. Soc., Perkin Trans. 1
1988, 697-702.
(24) Kazimierczuk, Z.; Cottam, H. B.; Revankar, G. R.; Robins, R. K.
J. Am. Chem. Soc. 1984, 106, 6379-6382.
(25) Seela, F.; Lu¨pke, U.; Hasselmann, D. Chem. Ber. 1980, 113, 2808-
2813.
(26) Kazimierczuk, Z.; Revankar, G. R.; Robins, R. K. Nucleic Acids
Res. 1984, 12, 1179-1192.
(27) (a) Zhang, L.; Zhang, Y.; Li, X.; Zhang, L. Bioorg. Med. Chem.
2002, 10, 907-912. (b) Ramasamy, K.; Robins, R. K.; Revankar, G. R. J.
Heterocycl. Chem. 1987, 24, 863-868. (c) Wilcox, C. S.; Otoski, R. M.
Tetrahedron Lett. 1986, 27, 1011-1014.
82 J. Org. Chem., Vol. 71, No. 1, 2006

Glycosylation of Pyrrolo[2,3-d]pyrimidines
SCHEME 2. Glycosylation of Compound 6 with Sugar
Derivative 5
7-functionalized 7-deazapurine ribonucleosides, nucleobase-
anion glycosylation was applied to the synthesis of such
derivatives. However, it appeared that this protocol exhibited
drawbacks for the synthesis of the 7-functionalized 7-deazapu-
rine ribonucleosides, such as low coupling yields (Supporting
Information) and a large consumption of nucleobases. This
stimulated us to investigate the classical Silyl-Hilbert-Johnson
reaction performed under Vorbru¨ggen conditions in more detail.
Commercially available 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribo-
furanose was used as the sugar component.
As previous work was concerned with the synthesis of the
7-deazapurine ribonucleosides related to tubercidin, this paper
mainly focuses on the 7-functionalized 7-deazapurine ribo-
nucleosides, such as the 7-deazaguanosines (2b-d), the 2-amino-
7-deazaadenosines (3b-d), and the 7-deazaxanthosines (4b-
d; Scheme 1). Two synthetic methods, nucleobase-anion
glycosylation and Silyl-Hilbert-Johnson glycosylation, are
compared. A rapid and efficient synthesis of 2-pivaloylamino-
6,7-dihalogenated 7-deazapurine ribonucleosides is described.
The resulting ribonucleosides were used in various displacement
reactions to yield compounds 2b-d, 3b-d, and 4b-d. Among
those, the 7-iodo compounds 2d, 3d, or 4d are particularly useful
as intermediates for introducing alkynyl or aminoalkynyl groups
via the Pd-catalyzed Sonogashira cross-coupling reaction.
mixture of the N(2)-monoglycosylated nucleoside 7 and the
N(2)-bis-glycosylated compound 8 (Scheme 2). The structural
assignment of compounds 7 and 8 was made on the basis of 1H
and 13C NMR spectra (Supporting Information). The 1H NMR
spectrum of the nucleoside 7 shows two N-H signals, a singlet
at 11.46 ppm corresponding to the proton at N(9), and a doublet
at 8.24 ppm corresponding to the proton at N(2). The spectrum
of the nucleoside 8 shows two sets of sugar signals and only
Results and Discussion
This manuscript focuses on glycosylation reactions performed
on the 7-deazapurines (pyrrolo[2,3-d]pyrimidines) with two
different ribose derivatives, namely, 1-O-acetyl-2,3,5-tri-O-
benzoyl-D-ribofuranose (5) and 5-O-[(1,1-dimethylethyl)dim-
ethylsilyl]-2,3-O-(1-methylethylidene)-R-D-ribofuranosyl chlo-
ride. The 7-deazapurines are functionalized at the 2, 6, and 7
positions. The exocyclic amino group is protected or nonpro-
tected, depending on the protocol of the glycosylation reaction.
The glycosylation protocols were altered (nucleobase-anion
glycosylation vs Silyl-Hilbert-Johnson reaction) and the
reaction conditions were changed to provide reliable and
convenient procedures for the preparation of the 7-halogenated
7-deazapurine ribonucleosides. Although it will be shown that
the Silyl-Hilbert-Johnson glycosylation can be applied ef-
ficiently to the 7-deazapurines with various substituents at
different positions, reactive groups (e.g., halogen substituents)
being present in the pyrimidine moiety are displaced during
subsequent deprotection of the sugar or the base moiety. In these
particular cases, it is still advisable to employ nucleobase-anion
glycosylation with isopropylidene-protected sugar derivatives.
This will be discussed in the second part of the manuscript,
and examples will be given.
Glycosylation of the Nucleobases 9b-d with 1-O-Acetyl-
2,3,5-tri-O-benzoyl-D-ribofuranose (5). Earlier, it has been
shown for the 7-deazapurines nonfunctionalized at the 7 or 8
position that the acid-catalyzed glycosylation is directed to the
pyrrole carbons.21b,c To prevent the unwanted side reaction, the
2-amino-7,8-dimethyl-7-deazapurine (6) was employed at first
in the glycosylation studies. The coupling reaction of the base
6 with the sugar 5 was performed in dichloroethane using
trimethylsilyl trifluoromethanesulfonate (TMSOTf) as the cata-
lyst. Although the reaction proceeded smoothly, it resulted in a
1
one for the base moiety; the H NMR spectrum of compound
8 did not show a proton signal at 8.24 ppm, which is observed
for nucleoside 7. This confirms that the sugar is not attached
directly to the nucleobase but is linked to the exocyclic amino
group. After treatment of 7 and 8 with NH3/MeOH, glycosylic
bond cleavage was observed.
Therefore, the 2-amino group was protected with a sterically
demanding pivaloyl residue (see compounds 9b-d; Scheme
3).14,29 The nucleobases were silylated with hexamethyldisila-
zane (HMDS), and the subsequent glycosylation was performed
in dichloroethane with the sugar 5 using TMSOTf as the catalyst.
Only the glycosylation of the 7-iodo compound 9d with the
sugar 5 afforded the â-D-nucleoside 11d (45% yield, Supporting
Information). The glycosylation of the 7-chloro or 7-bromo
functionalized nucleobases 9b,c with 5 failed.
Recently, N,O-bis(trimethylsilyl)acetamide (BSA) as the
silylating reagent, CH3CN as the solvent, and TMSOTf as the
catalyst were employed for the synthesis of 7-fluoro-7-deazaad-
enosine, following the modified Vorbru¨ggen procedure.30,31
Thus, the glycosylation of 9b-d with the sugar 5 was performed
under the same conditions. Nevertheless, the glycosylation
reaction did not take place at room temperature. Therefore, the
reaction was performed at different temperatures and reaction
times. When the reaction was carried out at temperatures higher
than 60 °C, the sugar decomposed and the glycosylation yield
was low even when a large excess of the sugar component was
consumed. Consequently, the temperature of the reaction was
varied. It was found that, within a temperature range of 40-60
°C and using a twofold excess of the sugar component, the
conditions were optimal and the nucleobases were completely
(29) Peng, X.; Seela, F. Org. Biomol. Chem. 2004, 2, 2838-2846.
(30) (a) Vorbru¨ggen, H. Acc. Chem. Res. 1995, 28, 509-520. (b)
Vorbru¨ggen, H.; Ruh-Pohlenz, C. Org. React. 2000, 55, 1-630. (c)
Lukevics, E.; Zablocka, A. In Nucleoside Synthesis Organosilicon Methods;
Ellis Horwood: New York, 1991.
(31) Wang, X.; Seth, P. P.; Ranken, R.; Swayze, E. E.; Migawa, M. T.
Nucleosides, Nucleotides Nucleic Acids 2004, 23, 161-170.
(28) (a) Ramasamy, K.; Imamura, N.; Robins, R. K.; Revankar, G. R.
Tetrahedron Lett. 1987, 28, 5107-5110. (b) Ramasamy, K.; Imamura, N.;
Robins, R. K.; Revankar, G. R. J. Heterocycl. Chem. 1988, 25, 1893-
1898. (c) Rosemeyer, H.; Seela, F. HelV. Chim. Acta 1988, 71, 1573-
1585.
J. Org. Chem, Vol. 71, No. 1, 2006 83

Seela and Peng
SCHEME 3. Synthesis of Nucleosides 11b-d
SCHEME 4. Structures of Nucleobases 9-13
Conversion of Compounds 11b-d to the 7-Deazaguanine
Ribonucleosides (2b-d), to the 2-Amino-7-deazaadenine
Analogues (3b-d), and to the 7-Deazaxanthine Derivatives
(4b-d). The 6- or 7-halogenated 2-amino-7-deazapurine nu-
cleosides are useful intermediates for further manipulations using
nucleophilic displacement reactions or palladium-catalyzed
cross-coupling chemistry.10,14,20,28 So, the transformation of the
6,7-dihalogenated 2-pivaloylamino-7-deazapurine ribonucleo-
sides 11b-d to several new 6,7-functionalized 2-amino-7-
deazapurine ribonucleosides was studied. The 2,6-diamino
ribonucleosides 3b-d were obtained from compounds 11b-d
when treated with aq NH3 (120 °C, 24 h, autoclave). Compounds
11b-d were converted also to the 4-methoxy derivatives 14b-d
(0.5 M NaOMe, reflux, Supporting Information). The guanosine
analogues 2b-d became accessible from compounds 14b-d
(Scheme 5). The intermediately formed 4-methoxy nucleosides
14b-d were converted to 7-deazaxanthine nucleosides 4b-d
(Scheme 6).
consumed within 24 h (TLC, CH2Cl2/MeOH, 99:1). This
protocol afforded the highest glycosylation yields of the
protected â-D-ribonucleosides 11b-d (73-75%) when the
nucleobases 9b-d were employed (Scheme 3). Then, com-
pounds 11b-d were transformed to a series of ribonucleosides,
namely, the guanosine analogues 2b-d, the 2-amino-7-dea-
zaadenosines 3b-d, and the 7-deazaxathosine derivatives 4b-
d, by nucleophilic displacement reactions. This will be discussed
in the next section.
Surprisingly, we were not able to perform the glycosylation
under the same reaction conditions with compound 9a not
functionalized at the 7 position using the same protected
ribofuranose 5. Also, the glycosylation of nucleobase 12
protected at the 2-amino group with an acetyl residue or the
2-amino unprotected nucleobases 13a-d failed (Scheme 4). Up
to now, we have no good explanation for this finding. However,
it seems likely that the electron-withdrawing 7-halogen sub-
stituents change the reactivity of the pyrrole nitrogens signifi-
cantly, which might affect silylation as well as glycosylation.
Next, the deamination of compounds 14b-d or 14a10 with
NaNO2/AcOH was performed, resulting in the formation of the
nucleosides 15a-d (Scheme 6). Two methods, Me3SiCl/NaI
in CH3CN or aq NaOH,32 were employed for the demethylation
(15a-d f 4a-d). Compound 15a was demethylated to give
7-deazaxanthosine 4a with Me3SiCl/NaI/CH3CN (90% yield).
However, this method cannot be applied to the conversion of
the 7-halogenated nucleosides 15b-d to 7-deazaxanthosine
analogues 4b-d. When compounds 15b,c were treated with
Me3SiCl/NaI/CH3CN, the 7-chloro or 7-bromo substituent was
SCHEME 5. Transformation of Intermediates 11b-d to the Nucleosides 2b-d and 3b-d
84 J. Org. Chem., Vol. 71, No. 1, 2006

Glycosylation of Pyrrolo[2,3-d]pyrimidines
SCHEME 6. Transformation of 14a-d to the
7-Deazaxanthosine Derivatives 4a-d
partially displaced by iodine. Demethylation of 15d with
Me3SiCl/NaI/CH3CN resulted in deiodination, and a mixture
of 4a,d (3:2) was formed. This was confirmed by H and 13C
1
FIGURE 1. Reverse-phase HPLC (RP-18) profiles of (A) reaction
products obtained after demethylation of 15d using Me3SiCl/NaI; (B)
a mixture of nucleosides 4a,d and the reaction products of the
demethylation. The nucleoside mixtures were analyzed by reverse-phase
HPLC at 260 nm on an RP-18 column (200 × 10 cm). Gradient: 0-20
min 100% A, 20-40 min 0-65% B in A, and 40-60 min 65-0% B
in A. Flow rate ) 0.7 mL/min [A, 0.1 M (Et3NH)OAc (pH 7.0)/MeCN,
95:5; B, MeCN].
1
NMR spectra as well as by HPLC. Both H and 13C NMR
spectra of the reaction products show two sets of nucleoside
signals that correspond to the signals of pure 4a,d, respectively.
Furthermore, the HPLC profile of the reaction shows two
product peaks that were identified using an artificial mixture
of pure nucleosides 4a,d (Figure 1). To avoid the unwanted
side reactions occurring during demethylation of 15b-d, the
reaction was performed under alkaline conditions (2 N NaOH,
reflux, 48 h). This resulted in a clean conversion of 15b-d to
the 7-deazaxanthosine derivatives 4b-d (74-78% yield).
Palladium-Catalyzed Sonogashira Cross-Coupling Reac-
tion. The introduction of alkynyl or aminoalkynyl side chains
to the purine constituents of DNA or RNA has a major impact
on their structure and stability,33 their resistance to enzymatic
degradation,34 or an increased sensitivity of oligonucleotide
detection by MALDI-TOF spectrometry.35a,b Also, the prepara-
tion of amino-functionalized oligonucleotides and their labeling
with reporter groups has become an important tool of nucleic
acid sequencing and diagnostics. The 7-iodo derivatives (2d,
3d, and 4d) of the 7-deazapurine ribonucleosides are particularly
valuable intermediates for introducing alkynyl or aminoalkynyl
groups because they can be used as starting materials in Pd-
catalyzed cross-coupling reactions.20 Thus, the 7-iodo-7-dea-
zapurine ribonucleosides 2d, 3d, and 4d were employed as
precursors in the palladium-catalyzed Sonogashira cross-
coupling reaction, yielding a number of novel 7-alkynyl or
aminoalkynyl 7-deazapurine ribonucleosides 2e-i, 3e-h, or 4g
(Scheme 7). The coupling reaction was performed in anhydrous
DMF with tetrakis(triphenylphosphine)palladium(0), copper(I)
iodide, and triethylamine under argon and resulted in 50-92%
yields of the alkynyl derivatives (Supporting Information).
Glycosylation of the Nucleobases 13b-d with 5-O-[(1,1-
Dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-r-
D-ribofuranosyl Chloride (17). As described above, the
7-functionalized 7-deazapurine ribonucleosides related to 2-ami-
noadenosine, guanosine, and xanthosine became easily acces-
sible by using the 2-pivaloylamino nucleosides 11b-d as
precursors. However, the pivaloyl group of compounds 11b-d
is rather stable against hydrolysis and cannot be removed under
mild basic conditions. Thus, nucleosides with labile residues at
the 6 position of the pyrimidine moiety, such as a chloro
substituent, cannot be prepared from these intermediates.
Consequently, nucleobase-anion glycosylation was employed
for the preparation of the 7-substituted 2-amino-6-chloro-7-
deazapurine ribonucleosides.
It was found that the nucleobase-anion glycosylation of
2-pivaloylamino-7- deazapurines 9b-d with the halogenose 17
did not occur. Also, 2-acetyl-protected nucleobase 12 gave a
rather low yield (8%, Supporting Information). It is likely that
the nucleophilicity of the pyrrole nitrogen is reduced when the
2-amino group is protected. Regarding the regioselectivity of
the halogenation of the 2-amino-7-deazapurines, the protection
of the 2-amino group is absolutely necessary.14 As the trifluo-
roacetyl group is stable enough for such purposes and can be
removed rather easily, we selected this group for the protection
of compound 13a. The latter was treated with trifluoroacetic
anhydride in pyridine to give the protected derivative 16
(Scheme 8, Supporting Information). The regioselective 7-io-
dination of 16 with N-iodosuccinimide in CH2Cl2 followed by
deprotection with NH3/MeOH yielded the 7-iodo derivative 13d
(Supporting Information).
Next, the glycosylation of 13d with 5-O-[(1,1-dimethylethyl)-
dimethylsilyl]-2,3-O-(1-methylethylidene)-R-D-ribofuranosyl chlo-
ride (17)27c,28c was performed in CH3CN with a twofold excess
of powdered KOH and 0.1 equiv of tris[2-(2-methoxyethoxy)]-
ethylamine (TDA-1) under stirring at room temperature. The
desired nucleoside, 18d, was obtained in 50% yield. Subsequent
deprotection of 18d with 90% CF3COOH at room temperature
afforded the ribonucleoside 19d (90% yield). Encouraged by
the successful synthesis of nucleoside 19d, we then applied this
protocol to the preparation of the 7-chlorinated and 7-brominated
analogues. Nucleobase-anion glycosylation of 13b,c (Support-
ing Information) with sugar chloride 17 yielded 18b,c in 48-
51% yield. Deprotection of the nucleosides 18b,c under the
conditions described for 18d resulted in nearly quantitative
(32) Seela, F.; Shaikh, K. HelV. Chim. Acta 2004, 87, 1325-1332.
(33) (a) Seela, F.; Zulauf, M. Chem.sEur. J. 1998, 4, 1781-1790. (b)
Seela, F.; Zulauf, M. J. Chem. Soc., Perkin Trans. 1 1999, 479-488. (c)
Buhr, C. A.; Wagner, R. W.; Grant, D.; Froehler, B. C. Nucleic Acids Res.
1996, 24, 2974-2980. (d) Balow, G.; Mohan, V.; Lesnik, E. A.; Johnston,
J. F.; Monia, B. P.; Acevedo, O. L. Nucleic Acids Res. 1998, 26, 3350-
3357. (e) He, J.; Seela, F. Nucleic Acids Res. 2002, 30, 5485-5496.
(34) Rosemeyer, H.; Ramzaeva, N.; Becker, E.-M.; Feiling, E.; Seela,
F. Bioconjugate Chem. 2002, 13, 1274-1285.
(35) (a) Gut, I. G.; Beck, S. Nucleic Acids Res. 1995, 23, 1367-1373.
(b) Wenzel, T.; Fro¨hlich, T.; Strassburger, K.; Richter, S.; Bimmler, J.;
Franke, C.; Thomas, I.; Kostrzewa, M. Nucleosides, Nucleotides Nucleic
Acids 2001, 20, 883-887. (c) Seela, F.; Bussmann, W. Nucleosides
Nucleotides 1985, 4, 391-394.
J. Org. Chem, Vol. 71, No. 1, 2006 85

Seela and Peng
SCHEME 7. Synthesis of the 7-Alkynyl-7-Deazapurine Nucleosides (2e-i)a
a Reagents and conditions: (a) HCtCR, anhydrous DMF, Pd(0)(PPh3)4, CuI, Et3N; (b) MeOH, K2CO3.
SCHEME 8. Halogenation and Nucleobase-Anion Glycosylation
yields of compounds 19b,c. The moderate glycosylation yield
of the 7-halogenated bases 13b-d with 17 is caused by the
low solubility of compounds 13b-d. Also, the electron-
withdrawing property of the halogen atoms might reduce the
electron-donating ability of the 7-deazapurine (pyrrolo[2,3-d]-
pyrimidine) anion and decrease its nucleophilicity.
nucleosides 2-4 were measured by spectrophotometric titra-
tion36 (pH 1.5-13.5) at 220-350 nm (Supporting Information).
As shown in Table 2, the pKa values of the 7-halogenated
compounds 2b-d, 3b-d, and 4b-d are lower than those of
the corresponding nonfunctionalized nucleosides 2a, 3a, and
4a, while the 7-alkynyl nucleosides 2f,g show very similar pKa
values as the parent compounds.
A conformational analysis of the sugar moieties of nucleo-
sides 2b, 3c, and 4b,c was performed next on the basis of
proton-proton coupling constants using the program PSEUROT
(version 6.3).37a,b The default electronegativity values described
in the manual PSEUROT 6.3 were used.37a The parameters A
and B were taken from the published work of Altona and co-
workers.37c In the PSEUROT program, a minimization of the
All compounds were characterized by 1H NMR (Experimental
Section and Supporting Information) and 13C NMR spectra
(Table 1) as well as by elemental analysis (Experimental
Section). All nucleosides are assigned as â-D-anomers from the
1H and 13C NMR spectra, referring to earlier work.10,28c,35c The
assignments of the 13C NMR chemical shifts are made according
to related compounds.10,14,32 Compared to the nonfunctionalized
compound, the C-7 signal is shifted upfield about 13 ppm upon
bromination (2c, 3c, 4c, and 15c), about 50 ppm upon iodination
(2d, 3d, 4d, and 15d), and 4 ppm upon alkynylation, but the
signal is shifted downfield upon chlorination (about 3 ppm for
2b, 3b, 4b, and 15b).
Physical Properties of 7-Deazapurine Ribonucleosides
(pKa Values and Sugar Ring Conformation). The pKa values
and the conformational parameters of nucleosides can affect base
pairing and duplex stability. Therefore, particular ribonucleosides
were selected for data determination. The pKa values of
(36) Albert, A.; Serjeant, E. P. The Determination of Ionization Constants;
Chapman and Hall, Ltd.: London, 1971; pp 44-64.
(37) (a) Van Wijk, L.; Haasnoot, C. A. G.; de Leeuw, F. A. A. M.;
Huckriede, B. D.; Westra Hoekzema, A. J. A.; Altona, C. PSEUROT,
Version 6.3; Leiden Institute of Chemistry, Leiden University: Leiden, The
Netherlands, 1999. (b) Thibaudeau, C.; Chattopadhyaya, J. Stereoelectronic
effects in nucleosides and nucleotides and their structural implications;
Uppsala University Press: Uppsala, Sweden, 1999; pp 55-135. (c)
Mikhailopulo, I. A.; Pricota, T. I.; Sivets, G. G.; Altona, C. J. Org. Chem.
2003, 68, 5897-5908.
86 J. Org. Chem., Vol. 71, No. 1, 2006

Glycosylation of Pyrrolo[2,3-d]pyrimidines
TABLE 1. 13C NMR Chemical Shifts of the 7-Deazapurine Ribonucleosides 2-19a
C(2)d
C(2)
C(4)d
C(6)
C(4a)
C(5)
C(5)
C(7)
C(6)
C(8)
C(7a)d
C(4)
compdb,c
C(1′)
C(2′)
C(3′)
C(4′)
C(5′)
2a10
2b
2c
152.6
153.0
152.9
152.6
159.7
160.2
160.0
159.7
150.8
150.5
151.1
150.3
152.3
152.3
151.7
159.8
159.7
159.4
159.3
160.8
160.5
160.2
159.5
159.4
159.1
159.5
159.4
159.0
158.7
157.4
157.6
158.0
157.9
157.1
157.2
157.5
159.6
158.4
158.7
158.9
150.6
151.4
151.5
162.7
162.8
162.8
164.0
163.8
163.8
163.8
150.7
151.1
151.8
150.5
150.9
151.5
100.2
97.1
98.1
99.8
96.5
93.4
94.5
96.5
99.7
96.5
97.3
99.1
110.0
111.4
113.2
95.0
96.3
98.7
98.5
96.7
98.2
100.4
105.0
106.1
108.1
104.9
106.0
108.0
102.3
106.2
90.3
117.3
114.3
116.7
122.0
118.3
115.0
117.5
123.0
118.4
115.3
117.5
122.9
125.9
129.4
128.3
116.6
119.1
124.4
121.2
118.3
120.8
125.9
120.8
123.3
128.7
120.4
122.9
128.4
151.2
150.4
150.8
151.2
152.8
152.3
152.7
153.2
138.4
138.2
140.1
139.0
150.5
151.1
151.2
153.7
154.2
154.7
e
152.4
152.3
e
152.5
152.9
153.3
153.4
153.7
154.1
86.1
85.6
85.6
85.6
86.9
85.7
85.8
85.8
85.5
85.7
85.7
85.7
87.6
88.0
87.5
85.6
85.6
85.6
85.0
86.6
86.5
86.6
88.4
88.4
88.5
85.7
85.8
85.7
73.7
73.6
73.6
73.6
73.7
73.4
73.4
73.3
74.0
74.2
74.0
74.1
71.2
71.5
71.2
73.5
73.5
73.4
73.7
73.8
73.8
73.7
80.4
80.5
80.5
73.6
73.6
73.6
70.6
70.4
70.4
70.5
70.8
70.5
70.5
70.6
70.7
70.6
70.6
70.6
73.9
74.1
73.8
70.5
70.5
70.5
70.6
70.5
70.5
70.5
83.6
83.7
83.7
70.4
70.4
70.5
84.6
84.7
84.7
84.7
84.7
84.7
84.7
84.7
89.3
89.2
89.1
89.1
79.2
79.4
79.1
84.7
84.8
84.7
85.0
85.1
85.1
85.1
86.2
86.2
86.1
85.0
85.0
85.0
61.8
61.5
61.5
61.5
62.0
61.6
61.6
61.7
61.4
61.3
61.3
61.3
63.6
63.8
63.6
61.5
61.5
61.5
61.5
61.4
61.4
61.4
63.3
63.4
63.4
61.4
61.4
61.4
2d
55.1
3a10
3b
100.1
103.2
87.4
3c
3d
4a
4b
4c
4d
52.3
103.1
107.3
91.1
56.3
103.4
88.1
54.0
103.2
87.2
51.7
99.4
103.4
87.3
52.0
103.3
87.8
53.7
103.1
87.5
53.3
11b
11c
11d
14b
14c
14d
15a
15b
15c
15d
18b
18c
18d
19b
19c
19d
a Measured in d6-DMSO. b First heading row ) systematic numbering. c Second heading row ) purine numbering. d Tentative. e Not detected.
3
TABLE 2. pKa Values of the 7-Deazapurine Ribonucleosides 2-4a
compd wavelengthb (nm) pKa compd wavelengthb (nm) pKa
TABLE 3. JH,H Coupling Constant of the Sugar Moieties and
Conformer Population of the Ribonucleosides Guanosine (G), 2b, 3c,
and 4b,ca
2a
2b
2c
2d
2f
304
304
304
304
307
305
285
10.2
9.7
9.8
3b
3c
3d
4a
4b
4c
4d
285
285
287
260
260
260
260
4.9
4.8
4.9
6.5
6.0
6.1
6.1
3JH,H [HZ]
pseudorotational parametersb
compd 1′,2′ 2′,3′ 3′,4′ %S %N PS (deg) PN (deg) rms (Hz)
9.7
Gc
2b
3c
4b
4c
6.00 5.20 3.60 66 34
5.96 5.33 3.59 66 34
6.30 5.39 3.00 69 31
6.32 5.64 2.70 69 31
6.16 5.56 2.82 70 30
141.3
137.8
186.9
198.1
196.5
-13.4
-20.8
56.3
76.3
67.5
0.000
0.000
0.000
0.000
0.000
10.1
10.2
5.7
2g
3a
a Measured in phosphate buffer (7.8 g NaH2PO4‚H2O in 500 mL H2O)
from pH 1.5 to pH 13.5. b Wavelength with the most significant absorbance
change.
a Measured in D2O. b ΨN (deg) ) 32 and ΨS (deg) ) 35 were fixed
during the final minimization. c Electronegativities are taken from PSEUROT,
version 6.3; parameters A and B are taken from Altona et al.;37c and
experimental coupling constants are taken from Chattopadhyaya et al.38e
differences between the experimental and the calculated cou-
plings is accomplished by a nonlinear Newton-Raphson
minimization; the quality of the fit is expressed by the root-
mean-square (rms) difference. This procedure presupposes the
existence of a two-state N/S equilibrium (Figure 2). The input
contained the following coupling constants: J(H1′,H2′),
J(H2′,H3′), and J(H3′,H4′). During the iterations, the puckering
amplitudes of both conformers were constrained. The coupling
constants J(H1′,H2′), J(H2′,H3′), and J(H3′,H4′) and the pseu-
dorotational parameters are shown in Table 3. For detailed
procedures of the PSEUROT calculation, refer to refs 29 and
37b.
According to Table 3, it is apparent that the 7-halogenated
7-deazapurine ribonucleosides show a preferred S conformer
population in solution, which is similar to the corresponding
2′-deoxyribonucleosides.14,29,32 This is also in line with the sugar
conformation of tubercidin (1a) and toyocamycin (1b) found
in the crystalline state adopting an S-type pucker.38a-d Compared
to the 2-amino-7-deazaadenosine derivative 3c or the 7-deaza-
xanthosine analogues 4b,c, 7-deazaguanine ribonucleoside 2b
shifts the N / S equilibrium toward the N conformation (Table
3). Our data are similar to those of the corresponding canonical
purine ribonucleosides described by Chattopadhyaya and co-
workers.38e This suggests that purine or the 7-deazapurine
ribonucleosides prefer the S conformation in solution while the
N conformation is found for pyrimidine ribonucleosides (such
(38) (a) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1972, 94,
8205-8212. (b) Stroud, R. M. Acta Crystallogr., Sect. B 1973, 29, 690-
696. (c) Abola, J.; Sundaralingam, M. Acta Crystallogr., Sect. B 1973, 29,
697-703. (d) Prusiner, P.; Sundaralingam, M. Acta Crystallogr., Sect. B
1978, 34, 517-523. (e) Plavec, J.; Tong, W.; Chattopadhyaya, J. J. Am.
Chem. Soc. 1993, 115, 9734-9746.
FIGURE 2. N and S conformers of ribonucleosides.
J. Org. Chem, Vol. 71, No. 1, 2006 87

Seela and Peng
as cytidine)38e or for purine ribonucleosides with the 5′-hydroxyl
groups being phosphorylated, as reported by Altona and
Sundaralingam.38a
moieties of nucleosides 2b, 3c, and 4b,c disclose that these
ribonucleosides prefer the S conformation in aq solution.
Experimental Section
4,5-Dichloro-2-pivaloylamino-7-[(2,3,5-tri-O-benzoyl)-â-D-ri-
bofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (11b). General Pro-
cedure for the Preparation of 11b-d. Into a stirred suspension
of 4,5-dichloro-2-pivaloylamino-7H-pyrrolo[2,3-d] pyrimidine14 (9b,
574 mg, 2.0 mmol) in anhydrous MeCN (14 mL) was added BSA
(97%, 0.6 mL, 2.41 mmol) at room temperature. After stirring for
5 min, TMSOTf (0.50 mL, 2.59 mmol) was added and 1-O-acetyl-
2,3,5-tri-O-benzoyl-D-ribofuranose43 (5; 2.02 g, 4.0 mmol) was
introduced in three portions (once per 8 h). In total, the reaction
was stirred at 50 °C (oil bath) for 24 h, cooled to room temperature,
and diluted with CH2Cl2 (50 mL). The solution was washed with
aqueous saturated NaHCO3 and brine, dried over Na2SO4, and
evaporated under reduced pressure to give a syrup, which was
applied to flash chromatography (FC) on silica gel (column 4 ×
12 cm, solvent CH2Cl2). The main zone afforded compound 11b
as a yellowish foam (1.07 g, 73%). TLC (silica gel, CH2Cl2/MeOH,
99:1): Rf 0.30. UV (MeOH): λmax 231 nm (ꢀ 48 100), 254 nm (ꢀ
34 500), 275 nm (ꢀ 8800), 281 nm (ꢀ 8700). 1H NMR (DMSO-d6,
250 MHz): δ 1.19 (s, 9H, 3Me), 4.61-4.86 [m, 3H, H-C(4′),
H-C(5′)], 6.35-6.38 and 6.41-6.44 [2m, 2H, H-C(3′), H-C(2′)],
6.52 [d, J ) 3.7 Hz, 1H, H-C(1′)], 7.42-7.49 (m, 6H, aromatic),
7.63-7.65 (m, 3H, aromatic), 7.88-7.96 (m, 6H, aromatic), 8.03
[s, 1H, H-C(6)], 10.39 (s, 1H, NH). Anal. Calcd for C37H32Cl2N4O8
(731.58): C, 60.74; H, 4.41; N, 7.66. Found: C, 60.72; H, 4.30;
N, 7.65.
5-Bromo-4-chloro-2-pivaloylamino-7-[(2,3,5-tri-O-benzoyl)-
â-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (11c). Com-
pound 11c was prepared as described for 11b using 5-bromo-4-
chloro-2-pivaloylamino-7H-pyrrolo[2,3-d] pyrimidine14 (9c, 663 mg,
2.0 mmol) and 5 (2.02 g, 4.0 mmol). Compound 11c was obtained
as a pale yellow foam (1.17 g, 75%). TLC (silica gel, CH2Cl2/
MeOH, 99:1): Rf 0.30. UV (MeOH): λmax 232 nm (ꢀ 48 200), 254
nm (ꢀ 34 600), 275 nm (ꢀ 8200), 281 nm (ꢀ 8100). 1H NMR
(DMSO-d6, 250 MHz): δ 1.16 (s, 9H, 3Me), 4.60-4.84 [m, 3H,
H-C(4′), H-C(5′)], 6.34-6.37 and 6.42-6.47 [2m, 2H, H-C(3′),
H-C(2′)], 6.50 [d, J ) 3.6 Hz, 1H, H-C(1′)], 7.40-7.49 (m, 6H,
aromatic), 7.62-7.65 (m, 3H, aromatic), 7.86-7.93 (m, 6H,
aromatic), 8.01 [s, 1H, H-C(6)], 10.38 (s, 1H, NH). Anal. Calcd
for C37H32ClBrN4O8 (776.03): C, 57.27; H, 4.16; N, 7.22. Found:
C, 57.57; H, 4.01; N, 7.08.
Conclusion
According to the literature, the synthesis of the 7-deazapurine
ribonucleosides is accomplished with difficulties.21a,39 This
results from the reactivity differences of the pyrrole versus the
imidazole systems. While imidazole nitrogens are easily attacked
by electrophilic sugar cations, the free electron pair of the
pyrrole nitrogen is rather inert, as its electron pair is part of the
aromatic π system. Even though a number of methods have
been developed for the synthesis of the 7-deazapurine ribo-
nucleosides using activated sugar halides such as the chloromer-
cury salt procedure,40 fusion reactions,22,39 the indoline-indole
method,41 the Wittenburg procedure,21a,42 the nucleobase-anion
glycosylation,25-27 and so forth, the outcome of these procedures
is disappointing.3 The glycosylation was directed into the
pyrimidine moiety,21a takes place at the pyrrole carbons,21b,c or
resulted in poor yields.22,40,41
In the present investigation it was observed that the TMSOTf-
catalyzed glycosylation of the 7-deazapurines with the ribosugar
5 depends strongly on the silylation reagent,31 the substituents
of the base moiety, and a carefully selected temperature. As a
result of the inertness of the pyrrole nitrogen, the silylating step
becomes important. When the silylation was carried out with
BSA in MeCN and the glycosylation was performed in the same
solution (one-pot reaction), the yields were generally high. This
was not the case in the two-step protocolssilylation with
HMDS/(NH4)2SO4 and the removal of the reagent by distillation
(first step), followed by the glycosylation in dichloroethane
(second step). The two-step procedure even failed in some cases.
To avoid the exocyclic amino group competing with the pyrrole
nitrogen in the glycosylation reaction, a bulky group was
provided for the protection of the 2-amino group (9b-d).
Electron-withdrawing substituents (such as halogens) on the
7-deazapurine moiety facilitate the glycosylation reaction;
7-deazapurines without 7-substituents resist glycosylation. A
temperature range of 40-60 °C was optimal; higher tempera-
tures caused extensive decomposition of the sugar. When all
parameters were carefully chosen, the synthesis of the 7-func-
tionalized 7-deazapurine ribonucleosides became efficient. Gly-
cosylation of the 2-pivaloylamino-6,7-dihalogenated 7-deazapu-
rines 9b-d with the sugar 5 afforded the â-D-nucleosides
11b-d in excellent yields (73-75%). The 7-deazaguanosine
analogues 2b-d, the 2-amino-7-deazaadenosines 3b-d, and the
7-deazaxanthosine derivatives 4b-d were prepared from 11b-d
by nucleophilic displacement reactions. The 7-iodo compounds
2d, 3d, or 4d were converted to the 7-alkynyl or 7-aminoalkynyl
derivatives (2e-i, 3e-h, or 4g) by palladium-catalyzed cross-
coupling chemistry. Conformational analysis of the sugar
4-Chloro-5-iodo-2-pivaloylamino-7-[(2,3,5-tri-O-benzoyl)-â-
D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (11d). As de-
scribed for 11b, compound 11d was prepared from 4-chloro-5-
iodo-2-pivaloylamino-7H-pyrrolo[2,3-d] pyrimidine14 (9d, 757 mg,
2.0 mmol) and 5 (2.02 g, 4.0 mmol). Compound 11d was obtained
as a yellowish foam (1.2 g, 73%). TLC (silica gel, CH2Cl2/MeOH,
99:1): Rf 0.30. UV (MeOH): λmax 230 nm (ꢀ 48 000), 253 nm (ꢀ
34 600), 273 nm (ꢀ 9300), 283 nm (ꢀ 9300). 1H NMR (DMSO-d6,
250 MHz): δ 1.18 (s, 9H, 3Me), 4.62-4.85 [m, 3H, H-C(4′),
H-C(5′)], 6.33-6.37 [m, 1H, H-C(3′)], 6.44-6.48 [m, 1H,
H-C(2′)], 6.52 [d, J ) 3.7 Hz, 1H, H-C(1′)], 7.42-7.47 (m, 6H,
aromatic), 7.62-7.64 (m, 3H, aromatic), 7.89-7.94 (m, 6H,
aromatic), 8.06 [s, 1H, H-C(6)], 10.34 (s, 1H, NH). Anal. Calcd
for C37H32ClIN4O8 (823.03): C, 54.00; H, 3.92; N, 6.81. Found:
C, 54.14; H, 4.30; N, 6.63.
(39) Tolman, R. L.; Robins, R. K.; Townsend, L. B. J. Heterocycl. Chem.
1967, 4, 230-238.
5-Chloro-7-(â-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-
2,4-diamine (3b). General Procedure for the Preparation of 3b-
d. A suspension of 11b (732 mg, 1.0 mmol) in dioxane (30 mL)
and 25% aq NH3 (70 mL) was introduced into an autoclave and
stirred at 120 °C for 24 h. The volume of the clear solution was
reduced to 10 mL and kept in the refrigerator for 24 h, affording
(40) Bobek, M.; Whistler, R. L.; Bloch, A. J. Med. Chem. 1972, 15,
168-171.
(41) Ektova, L. V.; Tolkachev, V. N.; Kornveits, M. Z.; Preobrazhen-
skaya, M. N. Bioorg. Khim. 1978, 4, 1250-1255.
(42) (a) Wittenburg, E. Chem. Ber. 1968, 101, 1095-1114. (b) Sharma,
M.; Bloch, A.; Bobek, M. Nucleosides Nucleotides 1993, 12, 643-648. (c)
Townsend, L. B.; Tolman, R. L.; Robins, R. K.; Milne, G. H. J. Heterocycl.
Chem. 1976, 13, 1363-1364. (d) Lu¨pke, U.; Seela, F. Chem. Ber. 1979,
112, 3526-3529. (e) Lu¨pke, U.; Seela, F. Chem. Ber. 1979, 112, 799-
806.
(43) Recondo, E. F.; Rinderknecht, H. HelV. Chim. Acta 1959, 42, 1171-
1173.
88 J. Org. Chem., Vol. 71, No. 1, 2006

Glycosylation of Pyrrolo[2,3-d]pyrimidines
colorless needles (287 mg, 91%), mp ) 238 °C (H2O, decomposi-
tion). TLC (silica gel, CH2Cl2/MeOH, 9:1): Rf 0.20. UV (MeOH):
(s, 3H, OMe), 4.04-4.05 [m, 1H, H-C(3′)], 4.27-4.29 [m, 1H,
H-C(2′)], 5.11-5.29 [m, 3H, OH-C(5′), OH-C(3′), OH-C(2′)],
5.93 [d, J ) 6.1 Hz, 1H, H-C(1′)], 6.37 [d, J ) 3.5 Hz, 1H,
H-C(5)], 7.22 [d, J ) 3.5 Hz, 1H, H-C(6)], 11.39 (s, 1H, NH).
Anal. Calcd for C12H15N3O6 (297.26): C, 48.48; H, 5.09; N, 14.14.
Found: C, 48.56; H, 5.12; N, 14.08.
λmax 228 nm (ꢀ 34 800), 268 nm (ꢀ 16 200), 289 nm (ꢀ 9600). Anal.
Calcd for C11H14ClN5O4 (315.71): C, 41.85; H, 4.47; N, 22.18.
Found: C, 41.45; H, 4.35; N, 21.99.
5-Bromo-7-(â-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-
2,4-diamine (3c). Compound 3c was prepared from 11c (512 mg,
0.66 mmol) as described for 3b, affording colorless crystals (200
mg, 84%), mp ) 238 °C (H2O, decomposition). TLC (silica gel,
CH2Cl2/MeOH, 9:1): Rf 0.20. UV (MeOH): λmax 229 nm (ꢀ
32 900), 269 nm (ꢀ 11 100), 289 nm (ꢀ 9000). Anal. Calcd for
C11H14BrN5O4 (360.16): C, 36.68; H, 3.92; N, 19.44. Found: C,
36.87; H, 3.78; N, 19.34.
5-Chloro-1,7-dihydro-4-methoxy-7-(â-D-ribofuranosyl)-2H-
pyrrolo[2,3-d]pyrimidin-2-amine (15b). By an identical procedure
as described for 15a, the deamination of 14b (331 mg, 1.0 mmol)
was performed yielding colorless needles of 15b (279 mg, 84%),
mp ) 219 °C (H2O, decomposition). TLC (silica gel, CH2Cl2/
MeOH, 5:1): Rf 0.57. UV (MeOH): λmax 229 nm (ꢀ 22 700), 285
1
nm (ꢀ 6200). H NMR (DMSO-d6, 250 MHz): δ 3.51-3.62 [m,
2H, H-C(5′)], 3.86-3.87 [m, 1H, H-C(4′)], 3.98 (s, 3H, OMe),
4.04-4.05 [m, 1H, H-C(3′)], 4.26-4.28 [m, 1H, H-C(2′)], 5.10-
5.12 [m, 2H, OH-C(5′), OH-C(3′)], 5.32 [d, J ) 5.9 Hz, 1H,
OH-C(2′)], 5.97 [d, J ) 6.2 Hz, 1H, H-C(1′)], 7.44 [s, 1H,
H-C(6)], 11.62 (s, 1H, NH). Anal. Calcd for C12H14ClN3O6
(331.71): C, 43.45; H, 4.25; N, 12.67. Found: C, 43.29; H, 4.15;
N, 12.52.
5-Iodo-7-(â-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-2,4-
diamine (3d). Compound 11d (1.14 g, 1.39 mmol) was converted
to 3d as described for 3b, affording colorless crystals (500 mg,
89%), mp ) 236 °C (H2O, decomposition). TLC (silica gel, CH2Cl2/
MeOH, 9:1): Rf 0.20. UV (MeOH): λmax 231 nm (ꢀ 35 000), 269
nm (ꢀ 11 200), 289 nm (ꢀ 9800). Anal. Calcd for C11H14IN5O4 (407.
16): C, 32.45; H, 3.47; N, 17.20. Found: C, 32.59; H, 3.51; N,
17.36.
2-Amino-5-chloro-7-(â-D-ribofuranosyl)-3,7-dihydro-4H-pyr-
rolo[2,3-d]pyrimidin-4-one (2b). General Procedure for the
Preparation of 2b-d. Compound 14b (149 mg, 0.45 mmol) was
dissolved in 2 N NaOH (40 mL) and 1,4-dioxane (6 mL). The
mixture was stirred under reflux for 3 h. After neutralization with
2 N HCl, the volume was reduced by 50%. The solution was applied
to a Serdolit AD-4 column (3 × 12 cm, resin 0.1-0.2 mm). Salt
was removed by elution with H2O (150 mL), and the product was
eluted with H2O/i-PrOH (9:1, 500 mL). The fractions containing
compound 2b were combined; the solvent was evaporated to about
50 mL. Crystallization occurred overnight affording colorless
crystals (114 mg, 80%), mp > 290 °C (H2O, decomposition). TLC
(silica gel, CH2Cl2/MeOH, 5:1): Rf 0.22. UV (MeOH): λmax 220
nm (ꢀ 22 400), 263 nm (ꢀ 12 600), 287 nm (ꢀ 6900). Anal. Calcd
for C11H13ClN4O5 (316.70): C, 41.72; H, 4.14; N, 17.69. Found:
C, 41.92; H, 4.46; N, 17.52.
2-Amino-5-bromo-3,7-dihydro-7-(â-D-ribofuranosyl)-4H-pyr-
rolo[2,3-d]pyrimidin-4-one (2c). Compound 14c (199 mg, 0.53
mmol) was converted to 2c as described for 2b, affording colorless
crystals (163 mg, 85%), mp > 290 °C (H2O, decomposition). TLC
(silica gel, CH2Cl2/MeOH, 5:1): Rf 0.23. UV (MeOH): λmax 222
nm (ꢀ 26 000), 262 nm (ꢀ 12 300), 287 nm (ꢀ 8200). Anal. Calcd
for C11H13BrN4O5 (361.15): C, 36.58; H, 3.63; N, 15.51. Found:
C, 37.02; H, 3.82; N, 15.11.
2-Amino-5-iodo-3,7-dihydro-7-(â-D-ribofuranosyl)-4H-pyrrolo-
[2,3-d]pyrimidin-4-one (2d). Nucleoside 2d was prepared from
14d (422 mg, 1.0 mmol) as described for 2b, affording colorless
crystals (355 mg, 87%), mp > 239 °C (H2O, decomposition) TLC
(silica gel, CH2Cl2/MeOH, 5:1): Rf 0.28. UV (MeOH): λmax 266
nm (ꢀ 12 000), 287 nm (ꢀ 8200). Anal. Calcd for C11H13IN4O5
(408.15): C, 32.37; H, 3.21; N, 13.73. Found: C, 32.58; H, 3.19;
N, 13.67.
1,7-Dihydro-4-methoxy-7-(â-D-ribofuranosyl)-2H-pyrrolo[2,3-
d]pyrimidin-2-amine (15a). General Procedure for the Prepara-
tion of 15a-d. To a solution of 14a (297 mg, 1.0 mmol) in a
mixture of glacial acetic acid and H2O (v/v, 1:7, 60 mL) was added
a solution of NaNO2 (170 mg, 2.46 mmol) in H2O (2.0 mL)
dropwise while stirring at room temperature. The stirring was
continued for 30 min, and the pH of the yellow solution was
adjusted to 7.0 with 25% aq NH3. The solution was applied to a
Serdolit AD-4 column (4 × 20 cm, resin 0.1-0.2 mm). Salt was
removed by washing with H2O (200 mL), and the product was
eluted with H2O/MeOH (1:1, 300 mL). The volume of the combined
fractions was reduced to about 20%, thereby forming colorless
needles (220 mg, 74%), mp ) 203 °C (H2O, decomposition). TLC
(silica gel, CH2Cl2/MeOH, 5:1): Rf 0.53. UV (MeOH): λmax 223
nm (ꢀ 26 000), 288 nm (ꢀ 6900). 1H NMR (DMSO-d6, 250 MHz):
δ 3.50-3.64 [m, 2H, H-C(5′)], 3.87-3.89 [m, 1H, H-C(4′)], 3.95
5-Bromo-1,7-dihydro-4-methoxy-7-(â-D-ribofuranosyl)-2H-
pyrrolo[2,3-d]pyrimidin-2-amine (15c). For the preparation of 15c,
compound 14c (375 mg, 1.0 mmol) was treated as descibed for
15a, yielding colorless crystals (327 mg, 87%), mp ) 220 °C (H2O,
decomposition). TLC (silica gel, CH2Cl2/MeOH, 5:1): Rf 0.57. UV
1
(MeOH): λmax 226 nm (ꢀ 23 600), 287 nm (ꢀ 6400). H NMR
(DMSO-d6, 250 MHz): δ 3.44-3.62 [m, 2H, H-C(5′)], 3.85-
3.87 [m, 1H, H-C(4′)], 3.98 (s, 3H, OMe), 4.04-4.05 [m, 1H,
H-C(3′)], 4.26-4.28 [m, 1H, H-C(2′)], 5.10-5.12 [m, 2H, OH-
C(5′), OH-C(3′)], 5.32 [br s, 1H, OH-C(2′)], 5.97 [d, J ) 6.2
Hz, 1H, H-C(1′)], 7.48 [s, 1H, H-C(6)], 11.62 (s, 1H, NH). Anal.
Calcd for C12H14BrN3O6 (376.16): C, 38.32; H, 3.75; N, 11.17.
Found: C, 38.43; H, 3.86; N, 11.23.
1,7-Dihydro-5-iodo-4-methoxy-7-(â-D-ribofuranosyl)-2H-pyr-
rolo[2,3-d]pyrimidin-2-amine (15d). Compound 15d was obtained
by the deamination of 14d (422 mg, 1.0 mmol) in the same way as
described for 15a, affording colorless needles (364 mg, 86%), mp
) 220 °C (H2O, decomposition). TLC (silica gel, CH2Cl2/MeOH,
5:1): Rf 0.57. UV (MeOH): λmax 229 nm (ꢀ 23 500), 287 nm (ꢀ
1
6200). H NMR (DMSO-d6, 250 MHz): δ 3.55-3.58 [m, 2H,
H-C(5′)], 3.86-3.87 [m, 1H, H-C(4′)], 3.97 (s, 3H, MeO), 4.03-
4.05 [m, 1H, H-C(3′)], 4.26-4.28 [m, 1H, H-C(2′)], 5.08-5.11
[br d, 2H, OH-C(5′), OH-C(3′)], 5.30 [d, J ) 5.8 Hz, 1H, OH-
C(2′)], 5.94 [d, J ) 5.1 Hz, 1H, H-C(1′)], 7.48 [s, 1H, H-C(6)],
11.52 (s, 1H, NH). Anal. Calcd for C12H14IN3O6 (423.16): C, 34.06;
H, 3.33; N, 9.93. Found: C, 33.98; H, 3.40; N, 9.87.
7-(â-D-Ribofuranosyl)-1,3,7-trihydro-2H,4H-pyrrolo[2,3-d]py-
rimidin-2,4-dione (4a). To a suspension of 15a (148 mg, 0.50
mmol) in MeCN was added NaI (113 mg, 0.75 mmol) and Me3SiCl
(99 µL, 0.78 mol) at room temperature while stirring. Stirring was
continued for 1 h. The precipitated product was filtered and washed
with MeCN to give 4a as a colorless solid (127 mg, 90%). TLC
(silica gel, CH2Cl2/MeOH, 5:1): Rf 0.38. UV (0.1 M NaH2PO4 in
H2O): λmax 219 nm (ꢀ 24 600), 252 nm (ꢀ 10 400), 281 nm (ꢀ 7300).
Anal. Calcd for C11H13N3O6 (283.24): C, 46.65; H, 4.63; N, 14.84.
Found: C, 46.54; H, 4.48; N, 14.81.
5-Chloro-7-(â-D-ribofuranosyl)-1,3,7-trihydro-2H,4H-pyrrolo-
[2,3-d]pyrimidin-2,4-dione (4b). General Procedure for the
Preparation of 4b-d. A solution of compound 15b (200 mg, 0.60
mmol) in 2 N NaOH (40 mL) and 1,4-dioxane (6 mL) was stirred
under reflux for 48 h. After neutralization with 2 N HCl and
reducing the volume to 1/3, the solution was applied to a Serdolit
AD-4 column (3 × 12 cm, resin 0.1-0.2 mm). The column was
washed with H2O (150 mL) to remove the salt, and the product
was eluted with MeOH (200 mL). The fractions containing
compound 4b were combined, the volume was reduced to 20% of
its original value, and compound 4b was crystallized from H2O as
colorless crystals (143 mg, 75%), mp ) 240 °C (H2O, decomposi-
tion). TLC (silica gel, CH2Cl2/MeOH, 5:1): Rf 0.40. UV (0.1 M
J. Org. Chem, Vol. 71, No. 1, 2006 89

Seela and Peng
NaH2PO4 in H2O): λmax 220 nm (ꢀ 24 800), 255 nm (ꢀ 10 500),
286 nm (ꢀ 6400). Anal. Calcd for C11H12ClN3O6 (317.68): C, 41.59;
H, 3.81; N, 13.23. Found: C, 41.15; H, 4.08; N, 13.20.
applied to 18d employing 13d (2.36 g, 8.0 mmol) and freshly
prepared 17, resulting in a pink foam (1.16 g, 50%). TLC (silica
gel, CH2Cl2/MeOH, 99:1): Rf 0.17. UV (MeOH): λmax 244 nm (ꢀ
29 700), 268 nm (ꢀ 3700), 324 nm (ꢀ 4900). 1H NMR (DMSO-d6,
500 MHz): δ 0.00 (s, 6H, Me2Si), 0.84 (s, 9H, t-BuSi), 1.31 and
1.51 (2s, 6H, 2Me), 3.65-3.70 [m, 2H, H-C(5′)], 4.09-4.12 [m,
1H, H-C(4′)], 4.90-4.95 [m, 1H, H-C(3′)], 5.08-5.12 [m, 1H,
H-C(2′)], 6.12 [d, J ) 2.0 Hz, 1H, H-C(1′)], 6.92 (s, 2H, NH2),
7.51 [s, 1H, H-C(6)]. Anal. Calcd for C20H30ClIN4O4Si (580.92):
C, 41.35; H, 5.21; N, 9.64. Found: C, 41.16; H, 5.39; N, 9.60.
2-Amino-4,5-dichloro-7-(â-D-ribofuranosyl)-7H-pyrrolo[2,3-
d]pyrimidine (19b). General Procedure for the Preparation of
19b-d. A solution of 18b (979 mg, 2.0 mmol) in 90% aq CF3-
OOH solution (5 mL) was stirred for 1 h at room temperature. The
mixture was evaporated, and traces of CF3OOH were removed by
coevaporation with MeOH. The residue was crystallized from
MeOH, yielding colorless crystals (630 mg, 94%), mp ) 185 °C.
TLC (silica gel, CH2Cl2/MeOH, 9:1): Rf 0.29. UV (MeOH): λmax
241 nm (ꢀ 27 500), 267 nm (ꢀ 3200), 324 nm (ꢀ 4600). Anal. Calcd
for C11H12Cl2N4O4 (335.14): C, 39.42; H, 3.61; N, 16.72. Found:
C, 39.43; H, 3.76; N, 16.33.
2-Amino-5-bromo-4-chloro-7-(â-D-ribofuranosyl)-7H-pyrrolo-
[2,3-d]pyrimidine (19c). Compound 18c (902 mg, 1.69 mmol) was
converted to the nucleoside 19c as described for 19b, yielding
colorless crystals (603 mg, 94%), mp ) 180 °C (MeOH). TLC
(silica gel, CH2Cl2/MeOH, 9:1): Rf 0.29. UV (MeOH): λmax 242
nm (ꢀ 27 600), 268 nm (ꢀ 3100), 325 nm (ꢀ 4500). Anal. Calcd for
C11H12BrClN4O4 (379.59): C, 34.80; H, 3.19; N, 14.76. Found:
C, 34.90; H, 3.24; N, 14.44.
2-Amino-4-chloro-5-iodo-7-(â-D-ribofuranosyl)-7H-pyrrolo-
[2,3-d]pyrimidine (19d). Compound 19d was prepared from 18d
(999 mg, 1.72 mmol) as described for 19b, affording colorless
crystals (660 mg, 90%), mp ) 180 °C (MeOH). TLC (silica gel,
CH2Cl2/MeOH, 9:1): Rf 0.30. UV (MeOH): λmax 244 nm (ꢀ
26 700), 268 nm (ꢀ 3500), 324 nm (ꢀ 4400). Anal. Calcd for C11H12-
ClIN4O4(426.59): C, 30.97; H, 2.84; N, 13.13. Found: C, 31.22;
H, 3.00; N, 13.02.
5-Bromo-7-(â-D-ribofuranosyl)-1,3,7-trihydro-2H,4H-pyrrolo-
[2,3-d]pyrimidin-2,4-dione (4c). Compound 4c was prepared from
15c (188 mg, 0.5 mmol) as described for 4b, yielding colorless
crystals (141 mg, 78%), mp ) 220 °C (H2O, decomposition). TLC
(silica gel, CH2Cl2/MeOH, 5:1): Rf 0.40. UV (0.1 M NaH2PO4 in
H2O): λmax 222 nm (ꢀ 24 000), 256 nm (ꢀ 10 200), 285 nm (ꢀ 6500).
Anal. Calcd for C11H12BrN3O6 (362.13): C, 36.48; H, 3.34; N,
11.60. Found: C, 36.54; H, 3.46; N, 11.54.
5-Iodo-7-(â-D-ribofuranosyl)-1,3,7-trihydro-2H,4H-pyrrolo-
[2,3-d]pyrimidin-2,4-dione (4d). The preparation of 4d followed
the protocol described for 4b employing 15d (351 mg, 0.83 mmol).
Colorless crystals of 4d were obtained (251 mg, 74%), mp ) 230
°C (H2O, decomposition). TLC (silica gel, CH2Cl2/MeOH, 5:1):
Rf 0.40. UV (0.1 M NaH2PO4 in H2O): λmax 224 nm (ꢀ 21 800),
258 nm (ꢀ 9700), 285 nm (ꢀ 6800). Anal. Calcd for C11H12IN3O6
(409.13): C, 32.29; H, 2.96; N, 10.27; I, 31.02. Found: C, 32.41;
H, 3.12; N, 10.20; I, 30.74.
4,5-Dichloro-7-{5′-O-[(1,1-dimethylethyl)dimethylsilyl]-2′,3′-
O-(1-methylethylidene)-â-D-ribofuranosyl}-7H-pyrrolo[2,3-d]py-
rimidin-2-amine (18b). General Procedure for the Preparation
of 18b-d. A suspension of powdered KOH (760 mg, 13.57 mmol)
and TDA-1 (0.2 mL, 0.63 mmol) in MeCN (100 mL) was stirred
for 10 min at room temperature. Compound 13b (1.62 g, 7.98
mmol) was added, and the stirring was continued for 1 h. Then,
freshly prepared 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-
methylethylidene)-R-D-ribofuranosyl chloride27c,28c (17, 1.29 mg,
4.0 mmol, calculated on the basis of 100% yield of 17) was added
to the stirred suspension, and the stirring was continued for 20 h at
room temperature. Insoluble material was filtered off, the filtrate
was evaporated to dryness, and the residue was applied to FC (silica
gel, column 5 × 12 cm, elution with CH2Cl2). The fractions
containing the desired material were collected and evaporated to
dryness to give compound 18b as a colorless foam (0.99 g, 51%).
TLC (silica gel, CH2Cl2/MeOH, 99:1): Rf 0.17. UV (MeOH): λmax
1
240 nm (ꢀ 29 000), 265 nm (ꢀ 3700), 324 nm (ꢀ 5000). H NMR
(DMSO-d6, 500 MHz): δ 0.00 (s, 6H, Me2Si), 0.84 (s, 9H, t-BuSi),
1.33 and 1.53 (2s, 6H, 2Me), 3.70-3.76 [m, 2H, H-C(5′)], 4.11-
4.14 [m, 1H, H-C(4′)], 4.94-4.96 [dd, J ) 3.3, 6.1 Hz, 1H,
H-C(3′)], 5.13-5.14 [dd, J ) 2.1, 6.1 Hz, 1H, H-C(2′)], 6.14 [d,
J ) 2.1 Hz, 1H, H-C(1′)], 7.03 (s, 2H, NH2), 7.48 [s, 1H, H-C(6)].
Anal. Calcd for C20H30Cl2N4O4Si (489.45): C, 49.08; H, 6.18; N,
11.45. Found: C, 49.47; H, 6.05; N, 11.18.
Acknowledgment. We thank Prof. Igor Mikhailopulo and
Dr. Hong Li for the calculations of the pseudorotational
parameters, Dr. Helmut Rosemeyer and Dr. Xiaomei Zhang for
the measurement of the NMR spectra, Dr. Peter Leonard for
supplying us with compounds 12 and 13a, and Mrs. Xin Ming
for the preparation of compound 4a. We also appreciate the
assistance of Miss Simone Budow and Mrs. Elisabeth Michalek
during the preparation of the manuscript. Financial support by
Roche Diagnostics GmbH, Germany, is gratefully acknowl-
edged.
5-Bromo-4-chloro-7-{5′-O-[(1,1-dimethylethyl)dimethylsilyl]-
2′,3′-O-(1-methylethylidene)-â-D-ribofuranosyl}-7H-pyrrolo[2,3-
d]pyrimidin-2-amine (18c). The procedure described for 18b was
applied to 18c using 13c (1.98 g, 8.0 mmol) and freshly prepared
17 (1.29 g, 4.0 mmol), yielding a yellowish foam (1.03 g, 48%).
TLC (silica gel, CH2Cl2/MeOH, 99:1): Rf 0.17. UV (MeOH): λmax
Supporting Information Available: The synthesis and char-
acterization for compounds 6-8 and 12; the procedures for the
glycosylation of 8 with sugar chloride 17; experimental details of
the Pd-catalyzed cross-coupling reaction of 2d, 3d, and 4d;
characterization of compounds 2e-i, 3e-h, and 4g; the synthesis
and characterization of compounds 14b-d from 11b-d; the
synthesis and characterization of the 7-halogenated bases 13b-d;
tables of 1H NMR data; and pKa measurements of compounds 2-4.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
241 nm (ꢀ 29 200), 267 nm (ꢀ 3600), 324 nm (ꢀ 4900). H NMR
(DMSO-d6, 250 MHz): δ 0.00 (s, 6H, Me2Si), 0.84 (s, 9H, t-BuSi),
1.32 and 1.52 (2s, 6H, 2Me), 3.71-3.77 [m, 2H, H-C(5′)], 4.09-
4.15 [m, 1H, H-C(4′)], 4.93-4.96 [dd, J ) 3.4, 6.2 Hz, 1H,
H-C(3′)], 5.11-5.15 [dd, J ) 2.1, 6.2 Hz, 1H, H-C(2′)], 6.14 [d,
J ) 2.1 Hz, 1H, H-C(1′)], 7.00 (s, 2H, NH2), 7.51 [s, 1H, H-C(6)].
Anal. Calcd for C20H30BrClN4O4Si (533.93): C, 44.99; H, 5.66;
N, 10.49. Found: C, 45.46; H, 5.76; N, 10.76.
4-Chloro-7-{5′-O-[(1,1-dimethylethyl)dimethylsilyl]-2′,3′-O-(1-
methylethylidene)-â-D-ribofuranosyl}-5-iodo-7H-pyrrolo[2,3-d]-
pyrimidin-2-amine (18d). The procedure described for 18b was
JO0516640
90 J. Org. Chem., Vol. 71, No. 1, 2006