Fluorinated pyrrolo[2,3-d]pyrimidine nucleosides: 7- Fluoro-7-deazapurine 2′-deoxyribofuranosides and 2′-deoxy-2′-fluoroarabinofuranosyl derivatives

Article abstract of DOI:10.1055/s-2006-942400

The syntheses of 7-deaza-7-fluoro-2′-deoxyadenosine (1a), 7-deaza-7-fluoro- 2′-deoxyinosine (3a) and 7-deaza-7-fluoro-2′- deoxyguanosine (3c) as well as of the 2′-deoxy-2′- fluoroarabinofuranosyl derivatives 1b, 3b are described. Starting materials were 6

Full text of DOI:10.1055/s-2006-942400

PAPER
2005
Fluorinated Pyrrolo[2,3-d]pyrimidine Nucleosides: 7- Fluoro-7-deazapurine
2¢-Deoxyribofuranosides and 2¢-Deoxy-2¢-fluoroarabinofuranosyl Derivatives
FluorinatedPy
r
rrolo[2,3
a
-
d
]pyrimid
n
ine
N
ucleosi
k
des Seela,*a,b Kuiying Xu,a,b Padmaja Chittepua,b
a
Laboratorium für Organische und Bioorganische Chemie, Institut für Chemie, Universität Osnabrück, Barbarastr. 7, 49069 Osnabrück,
Germany
b
Center for Nanotechnology (CeNTech), Gievenbecker Weg 11, 48149 Münster, Germany
Fax +49(541)9692370; E-mail: Frank.Seela@uni-osnabrueck.de
Received 19 January 2006; revised 3 February 2006
the favorable properties of pyrrolo[2,3-d]pyrimidine nu-
cleosides with the well documented pharmaceutical be-
haviors of fluorine substitution. Thus, fluorine
substituents were introduced into 7-deazapurine nucleo-
Abstract: The syntheses of 7-deaza-7-fluoro-2¢-deoxyadenosine
(1a), 7-deaza-7-fluoro- 2¢-deoxyinosine (3a) and 7-deaza-7-fluoro-
2¢-deoxyguanosine (3c) as well as of the 2¢-deoxy-2¢-fluoroarabino-
furanosyl derivatives 1b, 3b are described. Starting materials were
6-chloro-7-fluoro-7-deazapurine
(4-chloro-5-fluoropyrrolo[2,3- sides.
d]pyrimidine, 4b) and 2-pivaloylamino-6-chloro-7-fluoro-7-deaza-
purine (2-pivaloylamino-4-chloro-5-fluoropyrrolo[2,3-d]pyrimi-
dine, 6). Nucleobase anion glycosylation of 4b or 6 with the
halogenoses 7 or 9 furnished the protected b-D-nucleosides 8, 10
and 11, which were converted to compounds 1a, 1b by ammonoly-
sis and to 2a–c by sodium methoxide treatment. The 2¢-deoxy-
inosine derivatives 3a, 3b and the guanosine analogue 3c were
obtained from 2a–c. Conformational analysis of the nucleosides 1a,
1b was performed in solution and in the solid state. Single-crystal
X-ray analyses showed that the sugar moiety of 1a exhibits the S-
conformation (P = 164.8°, t = 40.1°). In solution the 2¢-fluoro sub-
stituents shift the sugar conformation slightly towards N.
From the steric point of view, the presence of a fluorine
atom in a nucleoside does not lead to a significant pertur-
bation to the shape of the molecule because of the small
van der Waals radius of 1.47 Å.12 At the same time, the
fluorine atom has the highest electronegativity (3.98 vs
3.44 of oxygen). As a result, the incorporation of the
fluorine atom in a nucleobase give rise to changes in the
electronic state of the heterocyclic moiety, and the pres-
ence in the sugar part leads to conformational changes.
This paper reports on the stereoselective synthesis and
properties of 7-deaza-7-fluoro-2¢-deoxyadenosine (7-fluo-
ro-2¢-deoxytubercidin, 1a), 7-deaza-7-fluoro-2¢-deoxy-
inosine (3a), and 7-deaza-7-fluoro-2¢-deoxyguanosine
(3c), in addition to 2¢-deoxy-2¢-fluoroarabinonucleosides
1b–3b with the fluorine atom in the 7-position are de-
scribed (Figure 1).
Key words: fluorine, glycosylations, pyrrolo[2,3-d]pyrimidines,
nucleosides, sugar conformation
Fluorine-substituted analogues of the nucleic acid compo-
nents have become established as antiviral, antitumor, and
antifungal agents. Important compounds of this class of
nucleosides contain the fluorine atom at the C-2¢ position
of the sugar moiety, but the most active compounds such
as 5-fluorouridine have the fluorine atom at the base. As
pyrrolo[2,3-d]pyrimidine nucleosides represent structural
mimics of the parent purine compounds, they are useful as
structural probes in DNA diagnostics as well as in anti-
sense technology. The 7-position of 7-deazapurine system
is supposed to be a matching position to the 5-position of
pyrimidines. Recently, the 7-fluoro derivative of tuberci-
din was prepared which exhibits reduced cytotoxicity
compared to the parent tubercidin.1 Some halogenated 7-
deazapurine (pyrrolo[2,3-d]pyrimidine) nucleosides have
gained attention since some of them, such as 7-iodotuber-
cidin,2–4 2¢-deoxy-2¢-fluoroarabinotubercidin5 and 2-ami-
no-2¢-deoxy-2¢-fluoroarabinotubercidin,6,7 exhibit a broad
spectrum of biological activity (purine numbering is used
throughout the general section). Furthermore, 7-haloge-
nated 7-deazapurine nucleosides can stabilize the DNA
duplex structures.8–11 We were interested in combining
OMe
NH2
F
5
F
4
4a
3 N
N
6
R1
HO
N
N
N
7
7a
N
1
O
O
R
R2
HO
HO
2a: R1 = R2 = H
HO
1a: R = H
b: R = F
b: R1 = H, R2 = F
c: R1 = NH2, R2 = H
systematic numbering
O
F
6
1
5
7
Cl
R
HN
R1
HO
8
N 9
4
N
N
3
O
N
N
R2
H
HO
3a: R1 = R2 = H
4a: R = H
b: R = F
c: R = Cl
d: R = Br
e: R = I
b: R1 = H, R2 = F
c: R1 = NH2, R2 = H
SYNTHESIS 2006, No. 12, pp 2005–2012
x
x.
x
x
.
2
0
0
6
purine numbering
Advanced online publication: 17.05.2006
DOI: 10.1055/s-2006-942400; Art ID: T00806SS
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Compounds 1–4

2006
F. Seela et al.
PAPER
7-Halogenated 7-deazapurine nucleosides can be pre- glycosylation reaction was obtained from 1-acetyl-2,3,5-
pared by the halogenation of an appropriately protected tri-O-benzoyl-b-D-ribofuranose by a three-step procedure
nucleoside or the nucleobase which is glycosylated after- as described in the literature.20–22 Stereochemical control
wards.13,14 The electrophilic fluorination of heterocycles of the 2¢-deoxy-2¢-arabinofluoronucleoside synthesis pro-
is usually carried out with fluorine gas or acetyl hypofluo- ceeds in a similar way to that of 2¢-deoxyribonucleosides.
rites.15 However, milder conditions were expected to Glycosylation of 4b with bromosugar 9 resulted in the ex-
work on the electron-rich 7-position of 7-deazpurines. In clusive formation of the protected b-D-nucleoside 10.
the case of 7-deazapurine nucleosides the fluorination re- Treatment with aqueous ammonia removed the protecting
sulted in decomposition by using various electrophilic groups and displaced the 6-chloro substituent to an amino
fluorinating conditions.1 Thus, the fluorination was per- group to form nucleoside 1b. With sodium methoxide
formed on the base level. Among the different fluorina- treatment 10 was converted to the 6-methoxy compound
tion reagents Selectfluor16 proved to be the most 2b. Usually, the conversion of methoxy derivatives to the
promising reagent as 6-chloro-7-fluoro-7-deazapurine corresponding inosine analogues is performed in reflux-
(4b) was already prepared by this way.1
ing aqueous 2 N NaOH at elevated temperature. However,
in the case of 2b, decomposition took place after pro-
longed treatment. Thus, the reaction time was limited to
one hour to give compound 3b (Scheme 2).
Next, compound 4b was employed in the stereoselective
nucleobase-anion glycosylation17,18 using 2-deoxy-3,5-di-
O-(p-toluoyl)-a-D-erythro-pentofuranosyl chloride (7).19
The reaction was performed in acetonitrile with powdered
KOH and TDA-1 {tris[2-(2-methoxyethoxy)eth-
yl]amine}as catalyst. The protected nucleoside 8 was iso-
lated in 67% yield without formation of the a-D-anomer
(Scheme 1). Deprotection of compound 8 with 25% aque-
ous ammonia (120 °C) resulted in the removal of the tolu-
oyl groups and a simultaneous conversion of the 6-chloro
substituent to an amino group resulting in 1a. When the
deprotection was performed in NaOMe/MeOH, it resulted
in the formation of the methoxy nucleoside 2a. Treatment
of 2a with 2 N aqueous NaOH yielded the 2¢-deoxy-
inosine analogue 3a (83% yield). In all cases the fluorine
substituent was not displaced. A selective removal of the
sugar protecting groups without displacement of the 6-
chloro substituent was not successful.
Cl
F
N
MeCN,
KOH, TDA-1
N
N
O
BzO
+
F
4b
Br
O
F
62%
BzO
BzO
9
BzO
10
NH3⋅H2O, dioxane
120 °C,16 h
1b
2b
72%
10
NaOMe,
MeOH
2 N NaOH
37%
3b
97%
Cl
F
Scheme 2
N
MeCN,
KOH, TDA-1
O
N
N
For the synthesis of the related nucleosides with a 2-ami-
no function, the preparation started from 2-amino-6-chlo-
ro-7-deazapurine. Compound 5 with a bulky pivaloyl
protecting group was selected to direct the electrophilic
fluorination to the 7-position as it was observed for other
halogenation reactions.9,14,23–25 Selectfluor was chosen as
a fluorination reagent. However, only traces of the desired
product were formed under condition used for compound
4b. Consequently, the reaction temperature was decreased
from 80 to 50 °C and the concentration of acetic acid as
well as the reaction time was reduced. Under these opti-
mized conditions (50–60 °C, 25 min and 10% acetic acid)
compound 6 was obtained in 30% yield (Scheme 3).
4b
+
TolO
Cl
67%
O
TolO
TolO
TolO
7
8
NH3⋅H2O
1a
2a
89%
8
NaOMe/
MeOH
2 N NaOH
83%
3a
86%
Tol = 4-methylbenzoyl
TDA-1 = tris[2-(2-methoxyethoxy)ethyl]amine
Cl
Cl
F
Scheme 1
MeCN, AcOH
50 °C, 25 min
N
N
+
Selectfluor
30%
N
N
In a similar way as described above, the 2-deoxy-2-fluo-
ro-b-D-arabinonucleosides 1b, 2b, 3b, were prepared
(Scheme 2). 3,5-Di-O-benzoyl-2-deoxy-2-fluoro-a-D-ar-
abinofuranosyl bromide (9) which was employed in the
PivHN
N
PivHN
N
H
H
5
6
Scheme 3
Synthesis 2006, No. 12, 2005–2012 © Thieme Stuttgart · New York

PAPER
Fluorinated Pyrrolo[2,3-d]pyrimidine Nucleosides
2007
Compound 6 was converted to the nucleoside 11 by nucle- is 1.43 higher than that of 2-halogenated derivatives. This
obase-anion glycosylation with 2-deoxy-3,5-di-O-(p- results from the electron-withdrawing effect of the 7-halo-
toluoyl)-a-D-erythro-pentofuranosyl chloride (7), similar gen substituents reducing the basicity of 7-deaza-2¢-
to that of compound 4b. The protected nucleoside 11 deoxyadenosine. However, the differences among the ha-
which was obtained in 64% yield was treated with 0.5 N logenated derivatives are small. The situation is different
NaOMe in MeOH (2 h) under reflux resulting in the re- for the deprotonation of the corresponding inosine deriv-
moval of both the toluoyl and pivaloyl groups; also the 6- atives. Here, an increasing electronegativity of the halo-
chloro group was displaced by the methoxy function to gen substituents increases the acidity of the nucleobase.
give compound 2c. Next, the methoxy compound 2c was
converted to the 7-fluorinated 2¢-deoxyguanosine deriva-
tive 3c in aqueous 2 N NaOH at elevated temperature
In nucleosides, the most populated conformations of the
furanose ring are N(C-3¢-endo) and S(C-2¢-endo). These
conformations depend on the various gauche and anomer-
(Scheme 4).
ic effects.31 In 2'-deoxyribonucleosides, the 5¢-OH and the
3¢-OH groups prefer a gauche orientation resulting in an
Cl
F
S-sugar pucker. In the case of the 2¢-deoxy-2¢-fluoro-b-D-
arabinonucleosides containing a modified nucleobase the
N
situation is more complex due to the strong gauche effect
MeCN,
KOH, TDA-1
N
PivHN
TolO
N
O
of the highly electronegative F-atom and the anomeric-ef-
fect induced by the modified base. In order to study the ef-
fect of the fluorine substitution on the base and the sugar
moiety the conformational analysis of the nucleosides 1a,
1b, 3a, and 3b was performed using the PSEUROT pro-
gram (version 6.3)32 and employing updated values for the
substituent electronegativity constants.33 In this program,
a minimization of the difference between the experimen-
tal and calculated couplings are accomplished by a nonlin-
ear 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 in the solution. The program calculates
TolO
6
+
O
Cl
64%
TolO
TolO
11
7
NaOMe,
MeOH
2 N NaOH
70%
3c
2c
11
87%
Scheme 4
The nucleosides and the intermediates were characterized
1
13
19
by H, C and F NMR spectroscopy as well as by ele-
mental analysis or mass spectra. To confirm the anomeric
configuration of 1a–c, 1H-NOE spectra was measured for
compound 1a. Irradiation of H-8 resulted in NOE effects
at H-1¢ (1.7%) and Hb-2¢ (4.4%); no NOE was observed
for Ha-2¢, which proved the b-D conformation. The 13C
NMR data are summarized in Table 1. Assignments of
the 13C NMR chemical shifts are made according to the
gate-decoupled 13C NMR spectra and referring to the ear-
lier literature.26,27 Table 1 also shows that the halogens at
the 7 position change the chemical shift of the C-7 in 6-
chloro-7-deazapurine. Compared to the non-functional-
3
3
the best fits of the JH,H and JF,H experimental coupling
constants to the five conformational parameters: the phase
angles (PS and PN) and puckering amplitudes (YS and YN)
of the S- and N-conformers, and the population of the S-
type conformer (XS; XS + XN = 1).
The input contained the following 1H NMR coupling con-
stants: JH-1¢,H-2¢, JH-1¢,H-2¢¢, JH-2¢,H-3¢, JH-2¢¢,H-3¢, JH-3¢,H-4¢, JH-1¢,F-2¢
,
1
J
H-3¢,F-2¢. They were taken from well-resolved H NMR
3
spectra measured in D2O. The use of the both JH,H and
3JH,F coupling constants permits a detailed conformational
analysis of the pentofuranose ring (Table 4).
ized 6-chloro-7-deazapurine 4a the C-7 signal of the 7- From Table 4 it is apparent that all nucleosides are in the
fluoro derivative 4b is shifted downfield (40 ppm) while N ' S equilibrium in solution showing a preferred S pop-
the 7-chloro25 base 4c shows a downfield shift of only 3 ulation. The values of the 7-fluorinated 2¢-deoxytuberci-
ppm. The other halogens induce an upfield shift (4d26,
din (1a) show a population of 70% S and 30% N, which is
Dd = ca. 13 ppm; 4e28 Dd = ca. 50 ppm). This trend is also almost the same as the other halogenated 2¢-deoxytuberci-
observed in other ring systems such as 5-halogenated din derivatives (30% N for chloro, 29% N for bromo and
uracil derivatives.29
29% N for iodo).34 Furthermore, no change was observed
when the nucleoside was changed from adenosine ana-
logue 1a (30% N) to the inosine derivative 3a (30% N).
However, in the case of the 2¢-fluoroarabino nucleosides
the N-population is increased from 33% in 1b to 40% in
3b. These values are similar to what were observed in 7-
halogenated 2-amino-7-deazapurine 2¢-fluoroarabino nu-
cleosides (34–37% N).35 Moreover, it can be seen that the
presence of a fluorine atom on 2¢-arabino position of the
7-deazapurine nucleosides 1b, 3b does not change the
sugar conformation strongly compared to the 2¢-deoxynu-
cleosides 1a, 3a. This is different to the pyrazolo[3,4-
The fluorine position 7 or 8 was assigned from the cou-
pling constants (Table 2) as well as on the basis of the
crystal structure. JF,C-7 has a value of about 250 Hz, show-
ing a 1J coupling, whereas JF,C-8 and JF,C-5 have values of
about 25 and 15 Hz, respectively, as 2J coupling constants
(Table 2). Gated-decoupled 13C NMR for 4b showed
1JH,C-2 = 209.3 Hz, 1JH,C-8 = 192.2 Hz and 2JH,C-7 = 6.8 Hz.
The pKa values of the various nucleosides are summarized
in Table 3. For the protonation of the nucleoside, the pKa
value of 7-deaza-2¢-deoxyadenosine (2¢-deoxytubercidin)
Synthesis 2006, No. 12, 2005–2012 © Thieme Stuttgart · New York

2008
F. Seela et al.
PAPER
Table 1 13C NMR Chemical Shifts (d) of Nucleosides and Precursorsa
Productb,c C-2
C-2
C-4
C-6
C-4a
C-5
C-5
C-7
C-6
C-8
C-7a
C-4
C-1¢
C-2¢)
C-3¢
C-4¢
C-5¢
4a
4b
4c
4d
4e
6
150.0
150.4
148.5
149.9
150.2
150.7
152.0e
149.1
149.2
155.8
155.8
161.4
161.4
156.3
156.2
147.8e
162.1e
156.9e
116.6
105.4
112.6
113.6
115.7
102.2
106.7
106.6
92.3
98.9
128.3
111.2
126.1
128.6
133.8
109.7
111.3
112.5
103.9
105.3
107.2
108.2
103.4
105.0
107.9
101.2
99.5
151.8
146.8
150.5
151.5
151.4
148.5e
146.5
146.6
145.8
146.0
147.0
147.0
143.1
143.1
150.9e
150.3e
147.6e
–
–
–
–
–
151.1
151.1
150.9
150.4
147.9e
151.5
151.8
152.7
152.9
151.6
151.7
144.8
145.0
152.0e
160.0e
153.0e
139.7
101.6
85.8
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
51.5
–
–
–
–
–
140.2
140.4
140.5
142.6
140.6
141.4
142.1
144.9
144.7
142.2
142.9
145.6
–
–
–
–
–
8
83.5
81.7
82.4
80.4
82.7
80.8
82.6
80.9
84.0
81.8
81.8
36.1
93.3
74.7
76.1
70.9
72.5
70.8
72.2
70.8
72.2
74.8
70.9
70.9
81.4
78.0
87.2
82.7
87.4
82.8
87.4
82.8
82.3
86.9
87.0
64.0
63.7
61.9
60.3
61.8
60.2
61.8
60.1
64.0
62.0
61.9
10
1a
1b
2a
2b
3a
3b
11f
2c
3c
d
–
92.1
95.8
d
95.0
–
94.7
95.7
d
97.3
–
97.3
95.6
37.8
104.4
87.5
d
–
d
89.9
–
a Measured in DMSO-d6.
b Systematic numbering.
c Purine numbering.
d Superimposed by DMSO.
e Tentative.
f Measured in CDCl3.
AMX-500 spectrometers (Bruker); d values in ppm relative to
Me4Si as internal standard. J values are in Hz. Elemental analyses
were performed by the Mikroanalytisches Laboratorium Beller,
Göttingen, Germany. ESI-TOF mass spectra were performed on a
micrOTOF Bruker Daltonics spectrometer in electropositive mode.
d]pyrimidine 2¢-fluoroarabinonucleosides showing a pre-
dominant N-conformer population.36 It is the result of the
combined influence of the gauche effect of the 2¢-fluoro
atom and the anomeric effect of the nucleobase with the N
atom next to the glycosylation site.36
4-Chloro-5-fluoro-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimi-
dine (6)
The single crystal X-ray analysis of compound 1a con-
firms the b-D configuration of the nucleoside.37 Further-
more, the crystal structures for 1a is characterized by the
anti orientation of the glycosylic bond with a O4¢–C1¢–
N9–C4 torsion angle of c = –101.1°. The sugar ring has
the C(2¢)-endo-C(3¢)-exo (2T3) conformation, S-type with
P = 164.8°, t = 40.1°. The preferred population in the so-
lution is also S (30% N and 70% S).
4-Chloro-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimidine (5;14 1.01
g, 4 mmol) and Selectfluor (2.13 g, 6.0 mmol) were placed in a
round-bottom flask, followed by the addition of anhyd MeCN (40
mL) and AcOH (4 mL). The mixture was then heated at 50 °C for
25 min under N2. The mixture was cooled by ice-water and diluted
with CH2Cl2 (120 mL). The organic layer was washed with 5% aq
NaHCO3. The inorganic layer was separated and extracted with
CH2Cl2 (2 × 50 mL). The combined organic layers were dried
(Na2SO4) and filtered. The filtrate was evaporated; the residue was
adsorbed on silica gel and applied on the top of a silica gel column
(4 × 12 cm). Elution with CH2Cl2–MeOH (200:1) afforded 6 as col-
orless foam (0.32 g, 30%); Rf = 0.11 (CH2Cl2–MeOH, 40:1).
All chemicals were purchased from ACROS, Fluka, or Sigma-Ald-
rich. Solvents were distilled from technical grade. Petroleum ether
(PE) used had bp 40–60 °C. TLC: aluminum sheets, silica gel 60
F
254 (0.2 mm, VWR International). Flash chromatography (FC): 0.4
1H NMR (250 MHz, DMSO-d6): d = 1.22 (s, 9 H, 3 CH3), 7.52 (m,
bar, silica gel 60 (VWR International, Darmstadt, Germany). Mp:
Linström apparatus, not corrected. UV spectra: U-3200 UV/Vis
spectrometer (Hitachi, Japan). NMR spectra: Avance DPX 250 or
1 H, H-6), 10.13 (br s, 1 H, CONH), 12.21 (br s, 1 H, H-7).
19F NMR (235 MHz, DMSO-d6): d = –167.07 (F-5).
Synthesis 2006, No. 12, 2005–2012 © Thieme Stuttgart · New York

PAPER
Fluorinated Pyrrolo[2,3-d]pyrimidine Nucleosides
2009
Table 2 13C,19F Coupling Constants of the Fluorinated Compoundsa,b
Compound
C-5,F-7
13.8
14.6
14.3
14.5
15.8
15.7
15.5
15.3
12.4
10.1
14.9
16.7
14.3
C-7,F-7
246.1
245.6
249.6
249.3
248.1
245.3
246.5
246.7
247.8
247.5
247.3
246.5
246.1
C-8,F-7
25.6
25.8
26.9
25.1
28.4
30.2
26.7
27.6
27.1
30.0
26.6
27.2
27.2
C-1¢,F-2¢
C-2¢,F-2¢
C-3¢,F-2¢
C-4¢,F-2¢
4b
6
–
–
–
–
–
–
–
–
8
–
–
–
–
10
1a
1b
2a
2b
3a
3b
11c
2c
3c
16.4
–
191.8
28.3
–
5.4
–
–
16.9
–
191.8
22.6
–
5.3
–
–
17.0
–
192.2
22.9
–
5.8
–
–
16.7
–
192.3
23.0
–
5.6
–
–
–
–
–
–
–
–
–
–
a Measured in DMSO-d6.
b Purine numbering.
c Measured in CDCl3.
Table 3 pKa Values of the Nucleosidesa
b
c
Nucleoside
pKa
Nucleoside
pKa
2¢-deoxyadenosine
3.65
5.08
4.43
4.16
4.18
4.23
4.30
1.70
1.89
2¢-deoxyinosine
9.07
9.84
9.22
9.52
9.64
9.81
9.30
7-deaza-2¢-deoxyadenosine
7-deaza-2¢-deoxyinosine
7-deaza-7-fluoro-2¢-deoxyadenosine (1a)
7-bromo-7-deaza-2¢-deoxyadenosine
7-chloro-7-deaza-2¢- deoxyadenosine
7-deaza-7-iodo-2¢- deoxyadenosine
7-deaza-2¢,7-difluoro-2¢-deoxyarabinoadenosine (1b)
7-deaza-2¢-deoxyguanosine
7-deaza-7-fluoro-2¢-deoxyinosine (3a)
7-deaza-7-chloro-2¢-deoxyinosine
7-deaza-7-bromo-2¢-deoxyinosine
7-deaza-7-iodo-2¢-deoxyinosine
7-deaza-2¢,7-difluoro-2¢-deoxyarabinoinosine (3b)
7-deaza-2¢-deoxyguanosine
10.2
9.9
7-deaza-7-fluoro-2¢-deoxyguanosine (3c)
7-deaza-7-fluoro-2¢-deoxyguanosine (3c)
a Measured by spectrophotometric titration (pH 1.5–12.5) at 220–350 nm.30,
b Protonation.
c Deprotonation.
MS (ESI-TOF): m/z calcd for C11H13ClFN4O [M + 1]+: 271.08;
found: 271.08; m/z calcd for C11H12ClFN4O + Na [M + Na]+:
293.06; found: 293.06.
4-Chloro-7-[2-deoxy-3,5-di-O-(p-toluoyl)-b-D-erythro-pento-
furanosyl]-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (8)
To a suspension of powdered KOH (85%, 0.94 g, 14.3 mmol) in
MeCN (50 mL), were added TDA-1 (0.18 mL, 0.57 mmol) and
compound 4b1 (700 mg, 4.08 mmol). After the mixture was kept
stirring for 5 min, compound 719 (2.07 g, 5.32 mmol) was added in
15 min, and the stirring was continued for 20 min. Insoluble mate-
rial was filtered off, the precipitate was washed with MeCN, and the
filtrate was evaporated to dryness. The residue was applied to FC
UV (MeOH): lmax (e) = 244 (29300), 282 (5200), 302 nm (4900).
Anal. Calcd for C11H12ClFN4O (270.69): C, 48.81; H, 4.47. Found:
C, 50.16; H, 4.62.
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2010
F. Seela et al.
PAPER
3
Table 4 JH,H Coupling Constant of the Sugar Moiety and Conformer Population of Nucleosidesa
Product 3JH,H (Hz)
1¢,2¢
3JH,F (Hz)
1¢F
Pseudorotational Parameters
1¢,2¢¢
6.55
–
2¢,3
2¢¢,3¢
3.15
–
3¢,4¢
3.50
4.76
3.61
5.13
3¢F
–
2¢F
–
%N
30
%S
70
67
70
60
Ps (°)
150.7
127.8
152.5
131.1
ys (°)
33.0
43.0
27.8
41.0
1a
1b
3a
3b
7.30
3.02
6.82
3.92
6.30
3.26
6.65
3.54
–
17.1
–
18.9
–
51.7
–
33
6.49
–
3.39
–
30
16.2
18.8
51.7
40
a Measured in D2O.
(silica gel, column 4 × 10 cm), and eluted with PE–EtOAc (8:1).
The main zone was collected and condensed to a colorless solid,
which was crystallized from MeOH to give colorless crystals of 8
(1.43 g, 67%); mp 114 °C; Rf = 0.2 (PE–EtOAc, 6:1).
1H NMR (250 MHz, DMSO-d6): d = 2.37 (s, 3 H, CH3), 2.40 (s, 3
H, CH3), 2.73–2.80 (m, 1 H, H-2¢), 2.01–3.12 (m, 1 H, H-2¢), 4.48–
4.63 (m, 3 H, H-4¢, H-5¢), 5.75 (m, 1 H, H-3¢), 6.80 (t, 1 H, J = 6.9
Hz, H-1¢), 7.28–7.96 (m, 8 H, 2 C6H4), 8.01 (s, 1 H, H-6), 8.69 (s,
1 H, H-2).
J = 5.4 Hz, 5¢-OH), 5.30 (d, 1 H, J = 3.8 Hz, 3¢-OH), 6.65 (t, 1 H,
J = 6.2 Hz, H-1¢), 7.63 (s, 1 H, H-6), 8.43 (s, 1 H, H-2).
19F NMR (235 MHz, DMSO-d6): d = –167.68 (F-5).
UV (MeOH): lmax (e) = 277 nm (6500).
Anal. Calcd for C12H14FN3O4 (283.26): C, 50.88; H, 4.98; N, 14.83.
Found: C, 50.78; H, 5.06; N, 14.80.
7-(2-Deoxy-b-D-erythro-pentofuranosyl)-3,7-dihydro-5-fluoro-
4H-pyrrolo[2,3-d]pyrimidin-4-one (3a)
19F NMR (235 MHz, DMSO-d6): d = –169.38 (F-5).
A solution of 2a (140 mg, 0.49 mmol) in aq 2 N NaOH (2.5 mL) was
refluxed for 3 h. After cooling to r.t., the mixture was neutralized
with 1 N AcOH. The mixture was evaporated to dryness which was
applied to FC (silica gel, column 2 × 10 cm) and eluted with
CH2Cl2–MeOH (15:1) to yield a colorless solid. Recrystallization
from MeOH afforded 3a as colorless crystals (110 mg, 83%); mp
211 °C; Rf = 0.33 (CH2Cl2–MeOH, 10:1).
1H NMR (250 MHz, DMSO-d6): d = 2.14–2.19 (m, 1 H, H-2¢),
2.30–2.41 (m, 1 H, H-2¢), 3.50–3.52 (m, 2 H, H-5¢), 3.67–3.70 (m,
1 H, H-4¢), 4.29 (m, 1 H, H-3¢), 4.94 (m, 1 H, 5¢-OH), 5.29 (m, 1 H,
3¢-OH), 6.52 (t, 1 H, J = 6.5 Hz, H-1¢), 7.30 (s, 1 H, H-6), 7.91 (s, 1
H, H-2), 12.11 (br s, 1 H, NH).
UV (MeOH): lmax (e) = 230 (55900), 276 nm (8100).
Anal. Calcd for C27H23ClFN3O5 (523.94): C, 61.89; H, 4.42; N,
8.02. Found: C, 61.72; H, 4.36; N, 8.00.
4-Amino-7-(2-deoxy-b-D-erythro-pentofuranosyl)-5-fluoro-7H-
pyrrolo[2,3-d]pyrimidine (1a)
A suspension of compound 8 (1.43 g, 2.73 mmol) in 25% aq
NH4OH (100 mL) was introduced into an autoclave and stirred at
120 °C for 24 h. The clear solution was evaporated and the residue
was subjected to FC (silica gel, column 5 × 10 cm), and eluted with
CH2Cl2–MeOH (10:1). The main zone was collected and condensed
to a colorless solid, which was crystallized from MeOH–CH2Cl2 to
yield colorless crystals of 1a (654 mg, 89%); mp 165 °C; Rf = 0.17
(CH2Cl2–MeOH, 10:1).
19F NMR (235 MHz, DMSO-d6): d = –166.07 (F-5).
UV (MeOH): lmax (e) = 263 (7400), 275 nm (7200).
1H NMR (250 MHz, DMSO-d6): d = 2.13–2.17 (m, 1 H, H-2¢),
2.38–2.44 (m, 1 H, H-2¢), 3.47–3.57 (m, 2 H, H-5¢), 3.79–3.80 (m,
1 H, H-4¢), 4.32 (m, 1 H, H-3¢), 5.01 (t, 1 H, J = 5.3 Hz, 5¢-OH), 5.26
(d, 1 H, J = 3.9 Hz, 3¢-OH), 6.55 (t, 1 H, J = 6.6 Hz, H-1¢), 7.00 (br
s, 2 H, NH2), 7.34 (s, 1 H, H-6), 8.07 (s, 1 H, H-2).
Anal. Calcd for C11H12FN3O4 (269.23): C, 49.07; H, 4.49; N, 15.61.
Found: C, 48.89; H, 4.59; N, 15.35.
4-Chloro-7-[2-deoxy-3,5-di-O-(p-toluoyl)-b-D-erythro-pento-
furanosyl]-5-fluoro-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimi-
dine (11)
19F NMR (235 MHz, DMSO-d6): d = –167.95 (F-5).
To a suspension of powdered KOH (85%, 105 mg, 1.6 mmol) in
MeCN (10 mL), were added TDA-1 (0.02 mL, 0.05 mmol) and
compound 6 (135.5 mg, 0.5 mmol). After stirring the mixture for 5
min, compound 719 (252.5 mg, 0.65 mmol) was added within 5 min
and the stirring was continued for 20 min. Insoluble material was
filtered off, the precipitate was washed with MeCN, and the filtrate
was evaporated to dryness. The residue was applied to FC (silica
gel, column 2 × 10 cm) and eluted with PE–EtOAc (4:1). The com-
bined fractions were evaporated to give 11 as colorless solid (200
mg, 64%); Rf = 0.25 (cyclohexane–EtOAc, 3:1).
1H NMR (250 MHz, CDCl3): d = 1.35 (s, 9 H, 3 CH3), 2.42 (s, 3 H,
CH3), 2.44 (s, 3 H, CH3), 2.78–2.82 (m, 1 H, H-2¢), 2.91–2.97 (m, 1
H, H-2¢), 4.54–4.70 (m, 3 H, H-5¢, H-4¢), 5.74–5.77 (m, 1 H, H-3¢),
6.77 (t, 1 H, J = 6.8 Hz, H-1¢), 6.99 (d, J = 2.4 Hz, 1 H, H-6), 7.18–
7.99 (m, 8 H, 2 C6H4), 8.17 (s, 1 H, NHPiv).
UV (MeOH): lmax (e) = 276 nm (10700).
Anal. Calcd for C11H13FN4O3 (268.24): C, 49.25; H, 4.88; N, 20.89.
Found: C, 49.19; H, 4.87; N, 20.76.
7-(2-Deoxy-b-D-erythro-pentofuranosyl)-5-fluoro-4-methoxy-
7H-pyrrolo[2,3-d]pyrimidine (2a)
Compound 8 (220 mg, 0.42 mmol) was suspended in 0.2 N NaOMe
in MeOH (50 mL). The mixture was kept stirring at r.t. for 12 h. The
mixture was evaporated and applied to FC (silica gel, column 2 × 10
cm), and eluted with CH2Cl2–MeOH (20:1). The main zone was
collected and condensed to a colorless solid, which was recrystal-
lized from MeOH to give 2a as colorless crystals (102 mg, 86%);
mp 112 °C; Rf = 0.67 (CH2Cl2–MeOH, 10:1).
1H NMR (250 MHz, DMSO-d6): d = 2.17–2.24 (m, 1 H, H-2¢),
2.39–2.44 (m, 1 H, H-2¢), 3.45–3.59 (m, 2 H, H-5¢), 3.81–3.82 (m,
1 H, H-4¢), 4.05 (s, 3 H, OCH3), 4.34 (m, 1 H, H-3¢), 4.97 (t, 1 H,
19F NMR (235 MHz, CDCl3): d = –166.85 (F-5).
UV (MeOH): lmax (e) = 243 (58800), 274 nm (7500).
Synthesis 2006, No. 12, 2005–2012 © Thieme Stuttgart · New York

PAPER
Fluorinated Pyrrolo[2,3-d]pyrimidine Nucleosides
2011
Anal. Calcd for C32H32ClFN4O6 (623.07): C, 61.69; H, 5.18; N,
8.99. Found: C, 61.66; H, 5.10; N, 9.03.
plied to FC (silica gel, column 4 × 10 cm), eluted with PE–EtOAc
(7:1). The main zone was collected and condensed to a colorless sol-
id, which was crystallized from MeOH to give colorless crystals of
10 (0.74 g, 61.7%); mp 144 °C; Rf = 0.55 (PE–EtOAc, 3:1).
1H NMR (250 MHz, DMSO-d6): d = 4.67–4.78 (m, 3 H, H-4¢, H-5¢),
5.76 (m, 1 H, H-2¢), 5.87 (m, 1 H, H-3¢), 6.95 (d, J = 14.89 Hz, 1 H,
H-1¢), 7.85 (s, 1 H, H-6), 7.47–7.75, 7.97–8.10 (m, 10 H, 2 C6H5),
8.76 (s, 1 H, H-2).
2-Amino-7-(2-deoxy-b-D-erythro-pentofuranosyl)-5-fluoro-4-
methoxy-7H-pyrrolo[2,3-d]pyrimidine (2c)
Compound 11 (140 mg, 0.22 mmol) was dissolved in 0.5 N NaOMe
in MeOH (4 mL), and the mixture was stirred under reflux for 2 h.
TLC monitoring showed completion of the reaction. The mixture
was evaporated and applied to a silica gel column, eluted with
CH2Cl2–MeOH (30:1–20:1) to form 2c as a colorless solid (50 mg,
87%); Rf = 0.34 (CH2Cl2–MeOH, 10:1).
19F NMR (235 MHz, DMSO-d6): d = –169.61 (F-5), –199.11 (dt,
2JF,H-2¢ = 49.4 Hz, 3JF,H-3¢ = 21.17, 3JF,H-1¢ = 18.82 Hz, F-2¢).
1H NMR (250 MHz, DMSO-d6): d = 2.03–2.09 (m, 1 H, H-2¢),
2.23–2.30 (m, 1 H, H-2¢), 3.45–3.50 (m, 2 H, H-5¢), 3.74 (m, 1 H,
H-4¢), 4.27 (m, 1 H, H-3¢), 4.91 (t, J = 5.5 Hz, 5¢-OH), 5.22 (d,
J = 1.80 Hz, 1 H, 3¢-OH), 6.42 (m, 3 H, H-1¢, NH2), 7.00 (br s, 1 H,
H-6).
UV (MeOH): lmax (e) = 228 (48200), 276 nm (8200).
Anal. Calcd for C25H18ClF2N3O5 (513.88): C, 58.43; H, 3.53; N,
8.18. Found: C, 58.58; H, 3.67; N, 8.05.
4-Amino-7-(2-deoxy-2-fluoro-b-D-arabinofuranosyl)-5-fluoro-
7H-pyrrolo[2,3-d] pyrimidine (1b)
19F NMR (235 MHz, DMSO-d6): d = –167.94 (F-5).
A suspension of compound 10 (2.2 g, 4.28 mmol) in a mixture of
25% aq NH4OH (150 mL) and dioxane (20 mL) was heated at
120 °C for 16 h in an autoclave. The mixture was then cooled and
evaporated to dryness. The residue was subjected to FC (silica gel,
column 5 × 15 cm), and eluted with CH2Cl2–MeOH (9:1) to yield
colorless solid. Crystallization from MeOH afforded 1b as colorless
crystals (0.88 g, 72%); mp 200 °C; Rf = 0.18 (CH2Cl2–MeOH,
10:1).
1H NMR (250 MHz, DMSO-d6): d = 3.56–3.68 (m, 2 H, H-5¢), 3.75
(m, 1 H, H-4¢), 4.34 (m, 1 H, H-3¢), 5.00 (t, J = 5.55 Hz, 1 H, 5¢-
OH), 5.10 (dt, JF,2¢ = 52.85 Hz, 1 H, H-2¢), 5.89 (d, 1 H, J = 4.35 Hz,
3¢-OH), 6.56 (d, J = 3.37 Hz, 1 H, H-1¢), 7.04 (br s, 2 H, NH2), 7.23
(s, 1 H, H-6), 8.08 (s, 1 H, H-2).
UV (MeOH): lmax (e) = 264 (8900), 287 nm (6100).
Anal. Calcd for C12H15FN4O4 (298.27): C, 48.32; H, 5.07; N, 18.78.
Found: C, 48.46; H, 5.05; N, 18.62.
2-Amino-7-(2-deoxy-b-D-erythro-pentofuranosyl)-3,7-dihydro-
5-fluoro-4H-pyrrolo[2,3-d]pyrimidin-4-one (3c)
Compound 2c (60 mg, 0.20 mmol) was dissolved in aq 2 N NaOH
(5 mL) and refluxed for 2 h. The mixture was cooled and neutralized
with 1 N AcOH and evaporated to dryness. The residue was applied
to a silica gel column and eluted with CH2Cl2–MeOH (10:1) to ob-
tain the desired product 3c as a colorless solid (40 mg, 70.5%); Rf =
0.12 (CH2Cl2–MeOH, 10:1).
1H NMR (250 MHz, DMSO-d6): d = 2.00–2.07 (m, 1 H, H-2¢),
2.19–2.30 (m, 1 H, H-2¢), 3.45–3.47 (m, 2 H, H-5¢), 3.73 (m, 1 H,
H-4¢), 4.25 (m, 1 H, H-3¢), 4.91 (m, 1 H, 5¢-OH), 5.22 (m, 1 H, 3¢-
OH), 6.32 (m, 1 H, H-1¢), 6.43 (s, 2 H, NH2), 6.81 (s, 1 H, H-6),
10.60 (br s, 1 H, NH).
19F NMR (235 MHz, DMSO-d6): d = –168.30 (F-5), –199.68 (dd,
2JF,H-2¢ = 52.9 Hz, 3JF,H-3¢ = 21.7, 3JF,H-1¢ = 16.13 Hz, F-2¢).
UV (MeOH): lmax (e) = 278 nm (10000).
Anal. Calcd for C11H12F2N4O3 (286.23): C, 46.16; H, 4.23; N,
19.57. Found: C, 46.00; H, 4.31; N, 19.51.
19F NMR (235 MHz, DMSO-d6): d = –167.89 (F-5).
UV (MeOH): lmax (e) = 261 nm (10700).
7-(2-Deoxy-2-fluoro-b-D-arabinofuranosyl)-5-fluoro-4-meth-
oxy-7H-pyrrolo[2,3-d]pyrimidine (2b)
MS (ESI-TOF): m/z calcd for C11H14FN4O4 [M + 1]+: 285.10;
found: 285.10; m/z calcd for C11H13FN4O4 + Na [M + Na]+: 307.08;
found: 307.08.
Compound 10 (0.3 g, 0.58 mmol) was suspended in 0.2 N NaOMe
in MeOH (35 mL), the suspension was stirred at r.t. for 12 h, and the
formed solution was neutralized with AcOH. The mixture was
evaporated and applied to FC (silica gel, column 2 × 10 cm) and
eluted with CH2Cl2–MeOH (12:1) to yield 2b as colorless solid
(0.17 g, 97%); Rf = 0.53 (CH2Cl2–MeOH, 9:1).
1H NMR (250 MHz, DMSO-d6): d = 3.58–3.66 (m, 2 H, H-5¢), 3.79
(m, 1 H, H-4¢), 4.07 (s, 3 H, OCH3), 4.34 (m, J3¢,F = 20.01 Hz, 1 H,
H-3¢), 5.06 (t, J = 5.00 Hz, 1 H, 5¢-OH), 5.29 (dt, JF,2¢ = 50.02 Hz, 1
H, H-2¢), 5.92 (d, 1 H, J = 5.00 Hz, 3¢-OH), 6.67 (dd, J1¢,2¢ = 3.9 Hz,
1 H, H-1¢), 7.54 (s, 1 H, H-6), 8.46 (s, 1 H, H-2).
Anal. Calcd for C11H13FN4O4 (284.24): C, 46.48; H, 4.61; N, 19.71.
Found: C, 46.59; H, 4.51; N, 19.41.
1-Bromo-2-deoxy-2-fluoro-3,5-di-O-benzoyl-a-D-arabinofura-
nose (9)20
To a solution of 1,3,5-tri-O-benzoyl-2-fluoro-a-D-arabinofuranose
(1.0 g, 2.15 mmol) in CH2Cl2 (5 mL), was added a 30% HBr solu-
tion in AcOH (1.2 mL). The mixture was stirred at r.t. for 16 h and
evaporated to dryness. The oily residue was redissolved in CH2Cl2
(20 mL), the solution washed with H2O (5 mL) and aq sat. NaHCO3
solution (5 mL), and dried (Na2SO4). Concentration gave a viscous
syrup which was further dried under high vacuum for 18 h at r.t. The
colorless syrup 9 (840 mg, 92%) was used in the next step without
purification.
19F NMR (235 MHz, DMSO-d6): d = –168.11 (F-5), –199.93 (dt,
2JF,H-2' = 52.9, 3JF,H-3¢ = 21.7, 3JF,H-1¢ = 16.13 Hz, F-2¢).
UV (MeOH): lmax (e) = 276 nm (6700).
Anal. Calcd for C12H13F2N3O4 (301.25): C, 47.84; H, 4.35; N,
13.95. Found: C, 48.00; H, 4.46; N, 13.85.
4-Chloro-7-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-b-D-arabino-
furanosyl)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (10)
7-(2-Deoxy-2-fluoro-b-D-arabinofuranosyl)-3,7-dihydro-5-fluo-
ro-4H-pyrrolo[2,3-d]pyrimidin-4-one (3b)
To a stirred suspension of 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyri-
midine (4b; 0.4 g, 2.33 mmol) in anhyd MeCN (17 mL), powdered
KOH (85%, 0.61 g, 9.24 mmol) was added. After the mixture was
stirred for 10 min at r.t., the phase-transfer catalyst TDA-1 (0.12
mL, 0.38 mmol) was added. The stirring was continued for another
15 min, and then a solution of bromo sugar 9 (1.38 g, 3.26 mmol) in
MeCN (20 mL) was added in portions. After stirring for another 10
min, the mixture was filtered. The filtrate was concentrated and ap-
A solution of 2b (140 mg, 0.46 mmol) in aq 2 N NaOH (2.8 mL)
was refluxed for 1 h. After cooling to r.t., the mixture was neutral-
ized with 1 N AcOH. The mixture was evaporated to dryness and
applied to a silica gel column, elution with CH2Cl2–MeOH (15:1)
gave a colorless solid which was recrystallized from MeOH to give
colorless crystals of 3b (50 mg, 37%); Rf = 0.34 (CH2Cl2–MeOH,
10:1).
Synthesis 2006, No. 12, 2005–2012 © Thieme Stuttgart · New York

2012
F. Seela et al.
PAPER
1H NMR (250 MHz, DMSO-d6): d = 3.36–3.62 (m, 2 H, H-5¢), 3.78
(m, 1 H, H-4¢), 4.37 (m, 1 H, H-3¢), 5.01 (t, 1 H, 5¢-OH), 5.23, 5.02
(dt, JF,2¢ = 52.95 Hz, 1 H, H-2¢), 5.91 (d, 1 H, 3¢-OH), 6.50 (dd,
J1¢,F = 16.93 Hz, J1¢,2¢ = 3.42 Hz, 1 H, H-1¢), 7.36 (s, 1 H, H-6), 7.93
(s, 1 H, H-2), 12.13 (br s, 1 H, NH).
(14) Seela, F.; Peng, X. Synthesis 2004, 1203.
(15) Erian, A. W. J. Heterocycl. Chem. 2001, 38, 793.
(16) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.;
Wong, C.-H. Angew. Chem. Int. Ed. 2005, 44, 192.
(17) Winkeler, H.-D.; Seela, F. J. Org. Chem. 1983, 48, 3119.
(18) Seela, F.; Westermann, B.; Bindig, U. J. Chem. Soc., Perkin
Trans. 1 1988, 697.
19F NMR (235 MHz, DMSO-d6): d = –166.67 (F-5), –200.10 (dt,
2JF,H-2¢ = 52.94 Hz, 3JF,H-3¢ = 21.17, 3JF,H-1¢ = 16.17 Hz, F-2¢).
(19) Hoffer, M. Chem. Ber. 1960, 93, 2777.
(20) Howell, H. G.; Brodfuehrer, P. R.; Brundidge, S. P.;
Benigni, D. A.; Sapino, C. Jr. J. Org. Chem. 1988, 53, 85.
(21) Gudmundsson, K. S.; Freeman, G. A.; Drach, J. C.;
Townsend, L. B. J. Med. Chem. 2000, 43, 2473.
(22) Tann, C. H.; Brodfuehrer, P. R.; Brundidge, S. P.; Sapino, C.
Jr.; Howell, H. G. J. Org. Chem. 1985, 50, 3644.
(23) Taylor, E. C.; Kuhnt, D.; Shih, C.; Rinzel, S. M.; Grindey,
G. B.; Barredo, J.; Jannatipour, M.; Moran, R. G. J. Med.
Chem. 1992, 35, 4450.
UV (MeOH): lmax (e) = 263 (6000), 275 nm (5900).
Anal. Calcd for C11H11F2N3O4 (287.22): C, 46.00; H, 3.86; N,
14.63. Found: C, 45.88; H, 3.95; N, 14.58.
Acknowledgment
We thank Dr. Helmut Rosemeyer, Dr. Xiaomei Zhang and Simone
Budow for the measurement of the NMR spectra and Dr. Hong Li
for the calculation of the pseudorotational parameters. We grateful-
ly acknowledge financial support by Idenix Pharmaceuticals, Cam-
bridge, US.
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