Electrophilic fluorination of 5-(cyanomethyl)imidazole-4-carboxylate nucleosides: Facile entry to 3-fluoro-3-deazaguanosine analogues

Article abstract of DOI:10.1055/s-2005-869869

A facile and efficient methodology is described for the synthesis of 3-fluoro-3-deazaguanosines based on a novel electrophilic fluorination of 5-(cyanomethyl)imidazole-4-carboxylate nucleosides. This general methodology can be readily applied to the synth

Full text of DOI:10.1055/s-2005-869869

1586
LETTER
Electrophilic Fluorination of 5-(Cyanomethyl)imidazole-4-carboxylate
Nucleosides: Facile Entry to 3-Fluoro-3-deazaguanosine Analogues
F
acile Entry to 3-F
a
luoro-3-de
n
dA
naloguesasamy Sakthivel,*1 P. Dan Cook
Biota Inc, 2232 Rutherford Rd, Carlsbad, CA, 92008, USA
Fax +1(858)6252433; E-mail: sakvel@hotmail.com
Received 28 March 2005
Abstract: A facile and efficient methodology is described for the
synthesis of 3-fluoro-3-deazaguanosines based on a novel electro-
philic fluorination of 5-(cyanomethyl)imidazole-4-carboxylate nu-
cleosides. This general methodology can be readily applied to the
synthesis of sugar-modified 3-fluoro-3-deazaguanosine analogues.
Key words: nucleosides, 3-deazaguanosine, 3-deazapurine, fluori-
nated nucleosides, electrophilic fluorination
The synthesis of organofluorine compounds has attracted
an enormous amount of interest in recent years because of
these compounds’ interesting biological properties.2 The
introduction of one or more fluorine atoms into biologi-
cally active compounds often affects their chemical prop-
erties and enhances, for example, their bioavailability and
bioactivity.3 Many fluorinated nucleoside analogues have
been synthesized and studied as potential inhibitors of en-
zymes and as therapeutics agents.4 Because of their inter-
esting base pairing properties, enzyme recognition, and
cellular uptake, the synthesis of novel fluorine-substituted
nucleosides is not only of major interest to researchers
interested in nucleoside chemistry5 but also to those
working on antisense oligonucleotides6 and siRNA thera-
peutics.7 It was reported4b quite recently that 2¢-C-methyl-
7-fluoro-7-deazaadenosine (1a), a nucleoside derivative
in which a C–F bond appears at the 7-position of 2¢-C-
methyladenosine (1b) or 2¢-C-methyl-7-deazaadenosine
(1c), inhibits the replication of hepatitis C virus (HCV)
with higher inhibitory potency (EC50 = 0.07 mM) than its
parent compounds 1b (EC50 = 0.25 mM) and 1c
(EC50 = 0.26 mM). 3-Deazaguanosine (3-deaza-G, 2a)8
display broad-spectrum antiviral and anticancer activities,
and 3¢-deoxyribonucleosides exhibit interesting antiviral,
antifungal, antibacterial, antiparasitic, and anticancer
properties.9 Furthermore, studies on the identification of
NS5B hepatitis C RNA-dependent RNA polymerase in-
hibitors have revealed that 3¢-deoxyguanosine (2b) and 2¢-
C-methylguanosine (2c) display potent anti-HCV activi-
ty.10 These findings warranted us to synthesize a series of
3-fluoro-3-deazaguanosine analogues, 3a–c, that combine
the 3-fluoro-3-deazaguanine heterocycle with the active
compounds’ ribosugar moieties (Figure 1).
Figure 1 Rationale for the synthesis of target fluorinated nucleo-
sides 3a–c.
Although Matsuda and coworkers11 first synthesized 3-F-
3-deaza-G (3a) in 1999, its biological properties have not
been well established.12 Perhaps, this may be due to the
complexity in the chemical synthesis. Moreover, the re-
ported multistep synthesis begins with 5-aminoimidazole-
4-carboxamideriboside (AICAR, 1d), which is not a
readily accessible starting material, especially for the syn-
theses of sugar-modified analogues of 3-F-3-deaza-G nu-
cleoside (Scheme 1). Even the syntheses of sugar-
modified AICAR derivatives, while possible, would be
challenging using existing methods.13 To simplify and
generalize the synthesis of 3-F-3-deaza-G nucleosides
with different sugar modifications, we envisioned the syn-
thesis depicted in Scheme 1, which uses as a key reaction
the electrophilic fluorination of 5-(cyanomethyl)imida-
zole-4-carboxylate nucleosides, which can be obtained in
large quantities by using a reported procedure. In this pa-
per, we report the most general, convenient, and facile
methodology to date for the synthesis of 3-F-3-deaza-G
nucleosides prepared through electrophilic fluorination.
Following reported procedures, we coupled the silylated
5-(cyanomethyl)imidazole-4-carboxylate14 (6) with two
different sugars, 1,2,3,5-tetra-O-benozyl-b-D-ribofura-
nose and 5-O-(4-methylbenzoyl)-3-deoxy-1,2-di-O-
acetyl-b-D-ribofuranose, in the presence of tin(IV) chlo-
ride to give the desired nucleosides 4a and 4b, respective-
ly.15 In contrast, the coupling reaction between 2-C-
methyl-1,2,3,5-tetra-O-benzoyl-b-D-ribofuranose16 and 6
SYNLETT 2005, No. 10, pp 1586–1590
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Advanced online publication: 07.06.2005
DOI: 10.1055/s-2005-869869; Art ID: S03705ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Facile Entry to 3-Fluoro-3-deazaguanosine Analogues
1587
Scheme 1 R = b-D-ribofuranosyl.
Scheme 2 Reagents and conditions: (i) for 4a and 4b: a) HMDS,
cat. ammonium sulphate, reflux; b) 1,2,3,5-tetra-O-benzoyl-D-ribo-
furanose or 1,2-O-diacetyl-5-O-(4-methylbenzoyl)-3-deoxy-D-ribo-
furanose, MeCN, Sn(IV)Cl4; for 4c: 1,2,3,5-tetra-O-benzoyl-2-C-
methyl-D-ribofuranose, MeCN, TMSOTf, DBU, 0 °C to r.t., 24 h; (ii)
a) NaH (95%), MeCN, 0 °C; b) SelectfluorTM, DMF, –45 °C.
in the presence of tin(IV) chloride did not yield any
glycosylated product. In addition, under Vorbrüggen
glycosylation conditions,17 this coupling reaction provid-
ed the undesired positional isomer 7c as the major product
in a 10:1 ratio with respect to the desired 4c.
we also isolated the difluorinated product 8c (ca. 5%,
Scheme 2).
Interestingly, when 6 and 2-C-methyl-1,2,3,5-tetra-O-
benzoyl-b-D-ribofuranose16 were reacted with trimethyl-
silyl trifluoromethanesulfonate (TMSOTf) in the presence
of 1,8-diazabicyclo[4,5,0]undec-7-ene (DBU) at room
temperature, the desired positional isomer 4c was formed
as the major product in a 3:1 ratio (82% combined yield).
The two positional isomers 4c and 7c were readily sepa-
rated by column chromatography on silica gel and we as-
signed their structures from analyses of 1H NMR spectra
(NOE experiments). It has been reported that the carban-
ion generated by sodium hydride at the methylene carbon
atom adjacent to the cyano group can react with various
alkyl halides.18 Under such conditions, one can perform
electrophilic fluorination of the generated carbanion using
readily available fluorine electrophiles.
In an effort to synthesize the desired 3-F-3-deaza-G 3a,
we made several attempts to cyclize the fluorinated prod-
uct 5a in one-pot reactions using reaction conditions that
have been reported20 for the synthesis of 3-deaza-G 9a
from 4a (Scheme 3). Unfortunately, one-pot ring-closure
reactions of 5a using methanolic NH3, liquid NH3, and
NH4OH provided complex mixtures of highly fluorescent
products. LC/Mass spectrometric analyses of the crude re-
action mixtures indicated neither the carboxamide inter-
mediate 11a nor the desired product 3a. Cyclization
reactions of compound 5a mediated by either HBr or hy-
drazine also failed to produce the corresponding ring-
closed products.21 We believe that electron-withdrawing
fluorine substituent in 5a causes trouble in the one-pot
ring-closure reaction. It has, however, been demonstrated
in the literature that the 5-(cyanomethyl)imidazole-4-car-
boxamide nucleoside analogues 2d and 10a undergo
smooth ring-closure reactions to give the 3-deaza-G ana-
logues 3a and 9a, respectively, under mild basic condi-
tions (5% aq Na2CO3 in EtOH).11,20a To proceed with this
type of ring-closure, we attempted to synthesize the car-
boxamide analogue 11a from the methyl ester 5a.
We reacted nucleoside 4a with sodium hydride (95%,
Aldrich) in anhydrous MeCN at 0 °C for one hour and
then cooled the resulting mixture to –45 °C. A solution of
1-(chloromethyl)-4-fluoro-1,4-diazonia bicyclo[2.2.2]oc-
tane bis(tetrafluoroborate) (Selectfluor) in DMF was
injected slowly into the mixture, which was then stirred at
–45 °C for 30 minutes. Quenching the reaction mixture
with 5% aqueous AcOH, followed by the usual workup,
gave the desired fluorinated product 5a in 60% yield as a
1:1 mixture of diastereoisomers.19 We were pleased by
this result because the fluorinated product 5a, after con-
version to its carboxamide derivative 11a, should provide
facile entry to the preparation of the 3-fluorinated 3-de-
azapurine nucleosides 3-F-3-deaza-G, 3-F-3-deaza-A,
and 3-F-3-deaza-2,6-diaminopurine.11 For the preparation
of 5a, the use of other commercially available F+ reagents
did not provide any advantages over the use of Select-
fluor. To generalize this electrophilic fluorination reac-
tion, we also fluorinated the 3¢-deoxy and 2¢-C-methyl
sugar-modified analogues 4b and 4c in a similar manner
to give 5b (1:1 dr, 65%) and 5c (1:1 dr, 67%), respec-
tively.19 In the case of the 2¢-C-methyl sugar analogue,
Unfortunately, when we reacted 5a with liquid NH3, com-
plete decomposition of the starting material occurred,
even at room temperature. Interestingly, however, upon
reaction with methanolic NH3 at room temperature for 48
hours, the fluorinated methyl ester 5a produced exclusive-
ly (Scheme 4) the imidomethoxy imidazolecarboxamide
analogue 12a (1:3 diastereoisomeric mixture, 75%
yield);22 the formation of carboxamide 11a was not de-
tected.23 When this reaction was stopped after 24 hours,
the products isolated from the mixture were 12a and the
intermediate 13a. Formation of 13a clearly indicates that
methanolic NH3 reacts first with the cyano group before it
Synlett 2005, No. 10, 1586–1590 © Thieme Stuttgart · New York

1588
K. Sakthivel, P. D. Cook
LETTER
Scheme 3 Reagents and conditions: (i) aq NH4OH, 80 °C or liquid
NH3, MeOH, aq NH4OH or liquid NH3, MeOH, 85 °C; (ii) 5%
Na2CO3 in aq EtOH, reflux; (iii) liquid NH3, r.t., 12 h. R = b-D-ribo-
furanosyl.
Scheme 5 Mechanism of ring-closure reaction.
In conclusion, we have successfully developed an effi-
cient strategy for the synthesis of 3-F-3-deaza-G nucleo-
sides by using electrophilic fluorination as the key
reaction. We have also demonstrated that this methodolo-
gy can be applied generally to the synthesis of a range of
modified sugar analogues of 3-F-3-deaza-G. The fluori-
nated products 5a–c are good intermediates that provide
facile entry to the preparation of 3-F-3-deaza-purine nu-
cleosides. Detailed synthetic applications of this strategy
and a study of the biological properties of the fluorinated
3-deazapurine nucleosides will be published in due
course.
reacts with the methyl ester unit. In a similar manner, we
also reacted compounds 5b and 5c with saturated metha-
nolic NH3 to give 12b (80%) and 12c (78%), respectively.
Treatment of compound 12a with 1 M triethylamine in
20% aqueous MeOH (60 °C, 8 h) led to a novel ring-clo-
sure reaction that gave 3-F-3-deaza-G 3a in 60% yield.24
1
We confirmed the structure of 3a by comparing its H
NMR, 13C NMR and UV spectra with those of a com-
pound reported by Matsuda and coworkers.11 To indicate
the generality of this synthetic methodology, we also suc-
cessfully cyclized the sugar-modified analogues 5b and
5c in a similar fashion to give the 3-F-3-deaza-G ana-
logues 3b (62%) and 3c (68%), respectively.25,26
Acknowledgment
The mechanism of these cyclization reactions may occur
through either of the two pathways illustrated in
Scheme 5. Nucleophilic addition of the carboxamide an-
ion (generated by the base) onto the methoxy imidate
could take place either by an SN2-type mechanism (path a)
or through a tetrahedral intermediate (path b). After the
nucleophilic attack, ring-closure products undergo base-
assisted tautomerization to give the desired products 3a–c.
We thank Drs. John Lambert and Susan M. Daluge for their support.
References
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Scheme 4 Reagents and conditions: (i) MeOH saturated with NH3
at 0 °C, r.t., 24–48 h; (ii) 1 M Et3N in 20% aq MeOH, 60 °C, 8 h.
Synlett 2005, No. 10, 1586–1590 © Thieme Stuttgart · New York

LETTER
Facile Entry to 3-Fluoro-3-deazaguanosine Analogues
1589
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(19) Compound 5a (diastereomers 1:1): 1H NMR (300 MHz,
CDCl3): d = 3.92 (s, 3 H, OCH3), 4.66–4.90 (m, 3 H, 4¢,
5¢,5¢¢-H), 5.90–6.06 (m, 2 H, 2¢,3¢-H), 6.48 (d, J = 6.7 Hz, 1
H, 1¢-H), 7.31–7.63 (m, 10 H, 9 Ar-H, Imi-2-H), 7.92–8.14
(m, 7 H, 6 × Ar-H, CHFCN). 19F NMR (282 MHz, CDCl3):
d (diastreomers) = –175.76 (d, JF-H = 43.6 Hz), –172.72 (d,
JF-H = 43.6 Hz). HRMS: m/z calcd for C33H26FN3O9 [MNa+]:
650.1551; found: 650.1550. ESI-MS: m/z = 650 [MNa+].
Compound 5b (diastereomers 1:1): 1H NMR (300 MHz,
CDCl3): d = 2.15 (s, 3 H, COCH3), 2.20–2.50 (m, 5 H, 3¢,3¢¢-
H, Tol-CH3), 3.94 (s, 3 H, OCH3), 4.53–4.75 (m, 3 H, 4¢,
5¢,5¢¢-H), 5.40–5.46 (m, 1 H, 2¢-H), 6.13–6.16 (m, 1 H, 1¢-H),
7.25 (m, 2 H, Ar-H), 7.41 (d, 1 H, J = 43.1 Hz, CHFCN),
7.86–7.98 (m, 3 H, 2 × Ar-H, Imi-2-H). 19F NMR (282 MHz,
CDCl3): d (diastreomers) = –176.41 (d, JF-H = 43.6 Hz),
–174.03 (d, JF-H = 43.6 Hz). HRMS: m/z calcd for
C22H22FN3O7 [MNa+]: 482.1334; found: 482.1333. ESI-MS:
m/z = 482 [MNa+].
Compound 5c (diastereomers 1:1): 1H NMR (300 MHz,
CDCl3): d = 1.58 (2 × s, 3 H, CH3), 3.98 (2 × s, 3 H, OCH3),
4.78–4.96 (m, 3 H, 4¢, 5¢,5¢¢-H), 5.75 (2 × d, 1 H, 3¢-H), 6.66
and 6.80 (2 × s, 1 H, 1¢-H), 7.26–7.62 (m, 10 H, 9 × Ar-H,
Imi-2-H), 7.80–8.19 and 8.20 (m, 7 H, 6 × Ar-H, CHFCN).
19F NMR (282 MHz, CDCl3): d (diastereomers) = –179.31
(d, JF-H = 41.6 Hz), –170.0 (d, JF-H = 41.6 Hz). HRMS: m/z
calcd for C34H28FN3O9 [MNa+]: 664.1707; found: 664.1704.
ESI-MS: m/z = 664 [MNa+].
(10) (a) Eldrup, A. B.; Allerson, C. R.; Bennet, C. F.; Bera, S.;
Bhat, B.; Bosserman, M.; Brooks, J.; Burlein, C.; Carrol, S.
S.; Cook, P. D.; Getty, K. L.; MacCoss, M.; McMasters, D.
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DMSO-d6): d = 3.45–3.70 (m, 5 H, 2¢, 3¢-H, OCH3), 3.85–
3.86 (m, 1 H, 4¢-H), 4.04–4.16 (m, 2 H, 5¢,5¢¢-H), 5.08–5.22
(m, 2 H, 3¢, 5¢¢-OH), 5.40 and 5.49 (2 × d, J = 4.1, 4.7 Hz, 1
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(12) However, synthesis and biological properties of 2,3-
difluoro-3-deaza-Ad, 3-F-3-deaza-Ad, 3-Br-3-deaza-G and
3-Cl-3-deaza-G were reported. See: Liu, M. C.; Luo, M. Z.;
Mozdziesz, D. E.; Lin, T. S.; Dutschman, G. E.; Gullen, E.
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H, 2¢-OH), 5.51 (d, J = 5.56 Hz, 1 H, 1¢-H), 7.17 (d, JH-F =
44.8 Hz, 0.3 H, CHF), 7.22 (d, JH-F = 44.8 Hz, 0.7 H, CHF),
7.40 and 7.60 (2 × br s, 2 H, NH2), 8.21 and 8.24 (2 × br s,
1 H, Imi-2H), 8.50 (br s, 1 H, NH). 19F NMR (282 MHz,
CDCl3): d (diastereomers) = –176.84 (d, JF-H = 43.6 Hz),
–173.84 (d, JF-H = 43.6 Hz). HRMS: m/z calcd for
(13) Minakawa, N.; Sasabuchi, Y.; Kiyosue, A.; Kojima, N.;
Matsuda, A. Chem. Pharm. Bull. 1996, 44, 288.
C12H17FN4O6 [MNa+] = 355.1030; found: 355.1034. ESI-
MS: m/z = 355 [MNa+].
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Beames, C. G. Jr. J. Org. Chem. 1963, 28, 3041.
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Am. Chem. Soc. 1975, 97, 2916. (b) Carrol, S. S.;
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(23) To our surprise, 5-imidomethoxy imidazole-4-carboxamide
riboside analogues similar to 12a have never been detected,
or proposed to form, during the cyclization reactions of 4a or
10a in basic alcoholic solutions. See ref. 11 and ref. 20.
(24) A similar ring-closure was also effected successfully when
using 5% Na2CO3 in EtOH, but, because of its high polarity,
we had difficulties in isolating the product from the
inorganic salt. Although the ring-closure reaction could also
be realized using several organic amine bases (DBU,
pyridine, N,N-diisopropylethylamine, etc.), we prefer to use
less volatile Et3N base.
(25) Although the conversions of the ring-closure reactions were
>80%, the high polarities of products 3a–c restricted their
isolated yields to only 60–68%.
(26) Compound 3b: UV (0.5 N NaOH): lmax = 287 nm (e 9400).
1H NMR (300 MHz, DMSO-d6): d = 1.80–1.88 (m, 1 H, 3¢-
H), 2.08–2.18 (m, 1 H, 3¢¢-H), 3.51–3.55 (m, 1 H, 5¢-H),
3.64–3.67 (m, 1 H, 5¢¢-H), 4.28–4.42 (m, 2 H, 4¢-H, 2¢-OH),
5.01 (t, 1 H, J = 5.3 Hz, 5¢-OH), 5.52 (br s, 2 H, NH2), 5.61
(d, J = 4.4 Hz, 1 H, 2¢-H), 5.78 (s, 1 H, 1¢-H), 8.04 (s, 1 H,
(17) Niedballa, U.; Vorbrüggen, H. J. J. Org. Chem. 1974, 39,
3654.
(18) Acevedo, O. L.; Andrews, R. S.; Cook, P. D. Nucleosides
Nucleotides 1993, 12, 403.
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1590
K. Sakthivel, P. D. Cook
LETTER
2-H), 10.44 (br s, 1 H, NH). 19F NMR (282 MHz, DMSO-
d6): d = –186.70. 13C NMR (75 MHz, DMSO-d6): d = 34.6,
62.9, 76.4, 81.7, 93.1 (d, J = 5.5 Hz), 122.2 (d, J = 215.0
Hz), 123.2, 132.1 (d, J = 9.0 Hz), 135.9 (d, J = 22.0 Hz),
137.6, 155.0. HRMS: m/z calcd for C11H14FN4O4 [MH+] =
285.0999; found: 285.0991; [MNa+]: 307.0819; found:
307.0809. ESI-MS: m/z = 285 [MH+].
Compound 3c: UV (H2O): lmax = 272 nm (e 8200), 310 nm
(e 7100). 1H NMR (300 MHz, DMSO-d6): d = 0.71 (s, 3 H,
CH3), 3.62–3.69 (m, 1 H, 5¢-H), 3.82–3.93 (m, 3 H, 3¢,4¢,5¢¢-
H), 5.15 (s, 1 H, 2¢-OH), 5.21–5.27 (m, 2 H, 3¢,5¢-OH), 5.54
(br s, 2 H, NH2), 5.77 (s, 1 H, 1¢-H), 8.24 (s, 1 H, 2-H), 10.46
(br s, 1 H, NH). 19F NMR (282 MHz, DMSO-d6): d =
–186.46. 13C NMR (75 MHz, DMSO-d6): d = 20.5, 59.7,
71.7, 79.5, 83.0, 93.3 (d, J = 7 Hz), 122.2 (d, J = 214 Hz),
122.9, 132.2 (d, J = 9 Hz), 135.9 (d, J = 22 Hz), 137.5,
155.0. HRMS: m/z calcd for C12H16FN4O5 [MH+]: 315.1105;
found: 315.1102; [MNa+]: 337.0924; found: 337.0920. ESI-
MS: m/z = 315 [MH+].
Synlett 2005, No. 10, 1586–1590 © Thieme Stuttgart · New York