Synthesis of trans-Configurated Spacered Nucleoside Analogues Comprising a Difluorocyclopropane Moiety

Article abstract of DOI:10.1515/znb-2003-1010

A novel class of trans-configurated difluorinated cyclopropanoic nucleoside analogues containing a methylene spacer between the cyclopropane ring and the heterocycle has been prepared. Some of these compounds showed weak anti-HIV activity in preliminary s

Full text of DOI:10.1515/znb-2003-1010

Synthesis of trans-Configurated Spacered Nucleoside Analogues
Comprising a Difluorocyclopropane Moiety
Rene´ Csuk and Leo Eversmann
Institut fu¨r Organische Chemie, Martin-Luther-Universita¨t Halle-Wittenberg,
Kurt-Mothes-Straße 2, D-06120 Halle (Saale), Germany
Reprint requests to Prof. Dr. R. Csuk. E-mail: csuk@chemie.uni-halle.de
Z. Naturforsch. 58b, 997 – 1004 (2003); received August 8, 2003
A novel class of trans-configurated difluorinated cyclopropanoic nucleoside analogues containing
a methylene spacer between the cyclopropane ring and the heterocycle has been prepared. Some of
these compounds showed weak anti-HIV activity in preliminary screenings.
Key words: Nucleoside Analogues, Cyclopropanes
Introduction
Thus, commercially available (E)-1,4-dibromo-but-
2-ene (1) was acetylated using anhydrous potassium
acetate in glacial acetic acid [11] to afford 2. Since
the mono-deacetylation with potassium carbonate in
methanol [12] failed to give excellent yields especially
for large scale preparations, a different route had to be
established. Chemoenzymatic routes have been used in
the past very successfully for different hydrolyses re-
actions. Several lipases, esterases, amidases and pro-
teases were screened on a small scale; among these
the esterase from porcine liver (PLE) showed a high
selectivity and an excellent reaction rate. Using pH-
stat-conditions at pH = 7 the chemoenzymatic mono-
deacetylation of 2 yielded 83% of the monoacetate (E)-
4-hydroxy-2-butenyl acetate (3). Reaction of 3 with
benzyl bromide / sodium hydride [13] gave the benzyl
ether 4. Reaction of 4 with sodium chlorodifluoroace-
tate in dry diglyme at 190 – 200 ◦C gave the racemic di-
fluorocyclopropane 5 together with unreacted starting
material 4. The chromatographic separation of these
two compounds failed under many different condi-
tions. Thus, a different strategy had to be applied:
Treatment of the mixture 4/5 under Zemple´n condi-
tions with a catalytic amount of sodium methoxide in
methanol led to a deacetylation reaction affording a
mixture of 6 and 7 that was easily separated by column
chromatography. Re-acetylation of 6 gave 4.
Fluorinated carbocyclic nucleoside analogues are
regarded as most promising candidates for a success-
ful therapy against viruses. During our own efforts
towards the development of cyclopropanoic nucleo-
side analogues, we became interested in the synthesis
of compounds showing a trans relationship between
the hydroxymethyl moiety and the methylene spacered
heterocycle.
Thus, a difluorinated, trans configurated and suit-
ably substituted cyclopropane seemed to be the
best suited starting material for such an approach.
Geminal difluorinated cyclopropanes have previ-
ously been prepared by the addition of difluoro-
carbenes to nucleophilic olefins using either phenyl(tri-
fluoromethyl)mercury [1 – 3] or bromodifluoromethyl-
phosphonium bromide in the presence of cesium or
potassium fluoride [4 – 6] or by the thermal decompo-
sition of sodium chlorodifluoroacetate [7 – 10].
Results and Discussion
A suitable precursor has previously been synthe-
sized by Taguchi et al. [10] by a sequence of reactions
starting from [(E)-4-(benzyloxy)-2-butenyl]oxy(tert-
butyl)dimethylsilane whose thermal reaction with
sodium chlorodifluoroacetate yielded the correspond-
ing difluorocyclopropane that was subsequently sub-
jected to a de-silylation reaction. The yields of this ap-
proach were only moderate and thus another approach
to a suitable starting material was called for.
The trans-configurated difluorocyclopropane 6 is
well characterized by its 19F NMR spectrum. Whereas
for the corresponding cis-analogue 8 the difference
in the chemical shifts of the two fluorine substituents
|∆F−1,F−2| = 25.4 ppm is rather large, for the trans-
c
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R. Csuk – L. Eversmann · Synthesis of trans-Configurated Spacered Nucleoside Analogues
Table 1. Characteristic NMR data for compounds 8 (cis)
and 6 (trans)
Nucleus
C-1
δ(ppm) 8
28.35
δ (ppm) 6
28.79
|∆(δ8 −δ6)|
0.44
C-2
C-3
113.78
24.83
114.23
26.44
0.45
1.61
C-4
55.58
59.06
3.48
C-5
62.58
65.97
3.39
F-1
F-2
−124.0
−149.60
25.6
−138.90
−140.53
1.63
14.9
9.07
|∆(δF−1 −δF−2)|
yields, the same strategy seemed not to be suited for
the synthesis of the adenine as well as for the 5-fluoro-
uracil analogue due to functional group incompatibil-
ity. Thus, intermediate 6 was allowed to react with
3-benzoyl-5-fluoro-uracil under Mitsunobu conitions
with TPP and diisopropyl azodicarboxylate (DIAD) to
afford 73% of 14 whose treatment with a solution of
dry ammonia in methanol gave 81% of debenzoylated
15. Hydrogenolysis of 15 in the presence of Pearlman’s
catalyst and cyclohexene finally gave 16.
Reaction of 6 with 6-chloro-purine/TPP/DEAD in
1,4-dioxane gave 73% of 17 whose ammonolysis
(75 ◦C, 3.6 MPa) in an autoclave gave 71% of the corre-
sponding 6-amino-purine 18. Transfer-hydrogenolysis
of 18 with cyclohexene and Pearlman’s catalyst af-
forded 78% of the adenosine analogue 19.
Scheme 1. Reactions: a) KOAc/Ac2O; b) PLE, pH =
7.0; c) BnBr, NaH; d) ClF2CCO2Na, 190 – 200 ◦C,
diglyme; e) NaOMe (cat.) in MeOH; f) H2, Pd/C,
MeOH; g) pyridine/Ac2O; h) DEAD, TPP, N3-benzoyl-
thymine; i) KOH/MeOH; j) DEAD, TPP, N3-benzoyl-
uracil; k) DIAD, TPP, N3-benzoyl-5-fluoro-uracil; l) NH3,
MeOH; m) Pearlman’s catalyst, MeOH, cyclohexene; n) 6-
chloro-purine, DEAD, TPP; o) NH3, 75 ◦C, 3.6 Mpa.
analogue 6 |δF−1,F−2| = 1.5 ppm is small. In the
13C NMR spectrum of 6 the signal for the carbon bear-
ing the geminal fluoro substituents is found as a dou-
blet of doublet with 1JC,F = 286.7 and 1JC,F = 285.9 Hz.
Characteristic NMR parameters for 8 and 6 are com-
piled in Table 1.
Hydrogenolysis of 5 using Pd/C in methanol af-
forded 9. Reaction of 9 under Mitsunobu condi-
tions [13] with 3-benzoyl-thymine, triphenylphos-
phane (TPP) and diethyl azodicarboxylate (DEAD) in
dry 1,4-dioxane afforded 52% of the thymine ana-
logue 10 whose treatment with potassium hydroxide
in methanol gave 63% of 11.
Again, 19F NMR spectroscopy can be used quite
efficiently to distinguish between cis and trans con-
figurated difluorocyclopropanes as exemplified for the
cis- and trans-adenosine analogues 19 and 20, respec-
tively. Thus, whereas for cis-20 the signals of the two
difluoro substituents are found at δ = −124.38 and
δ = −151.45 ppm, for the trans-configurated 19 an
AB-spin system is observed (δ = −136.92 and δ =
−138.56 ppm, JAB = 164.5 Hz).
Compounds 11, 13, 16 and 19 have been tested for
anti-HIV activity but only weak to moderate activity
was observed.
In an analogous manner from the reaction of 9 with
TPP/DEAD/3-benzoyl-uracil 12 was obtained whose
deprotection with potassium hydroxide in methanol af-
forded 62% of the target molecule 13 as a white solid.
Experimental Section
General: Melting points are uncorrected (Leica hot stage
microscope), optical rotations were obtained using a Perkin-
Elmer 341 polarimeter (1 cm micro cell), NMR spectra (in-
Although this approach allowed the synthesis of the
thymine and the uracil analogues with fair to good ternal Me4Si) were recorded using the Varian spectrometers
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R. Csuk – L. Eversmann · Synthesis of trans-Configurated Spacered Nucleoside Analogues
999
Gemini 200, Gemini 2000 or Unity 500 (δ given in ppm, J 4.7 Hz, CH2OAc), 4.52 (s, 2 H, CH2-Ph), 4.02 (d, J = 4.7 Hz,
in Hz, internal Me4Si for 1H and 13C NMR spectra, inter- CH2OBn), 2.07 (s, 3 H, CH3). – 13C NMR (125 MHz,
nal CCl3F was used for 19F NMR spectra, C’ correspond to CDCl3): δ = 170.5 (s, CO), 138.03 (s, Cq-phenyl), 130.83
the atoms of the heterocycle), IR spectra (film or KBr pel- (d, CH=), 128.31 (d, phenyl), 127.62 (d, phenyl), 127.55 (d,
let) on a Perkin-Elmer FT-IR spectrometer Spectrum 1000, CH=), 72.30 (t, CH2-ph), 69.66 (t, OCH2), 64.12 (t, CH2-
MS spectra were taken on a Intectra GmbH AMD 402 (elec- OAc), 20.78 (q, CH3). – MS (EI, 70 eV): m/z (%) = 221 (6),
tron impact, 70 eV) or on a Finnigan MAT TSQ 7000 instru- 220 (13), 160 (6), 105 (46), 92 (20), 91 (100). – Analysis for
ment (electrospray, voltage 4.5 kV, sheath gas nitrogen); for C13H16O3 (220.27): calcd. C 70.89, H 7.32; found C 70.85,
elemental analysis a Foss-Heraeus Vario EL instrument was H 7.38.
used; tlc was performed on silica gel (Merck 5554, detection
( )-(1 SR, 3 SR)-trans-[3-Benzyloxymethyl-2,2-difluoro-
cyclopropyl]methylacetate (( )-5)
by UV absorption or by treatment with a solution of 10%
sulfuric acid, ammonium molybdate and cerium(IV)) sulfate
followed by gentle heating.
A solution of 4 (3.6 g, 16.4 mmol) in dry diglyme (5 ml)
was heated to 190 ◦C. A solution of sodium chlorodifluoro-
acetate (27.3 g, 179 mmol) in dry diglyme (47 ml) was
(E)-Butene-1,4-diol monoacetate (3)
In a pH-stat equipment a mixture of 2 (146.0 g, 0.85 mol) added at this temperature over a period of 60 minutes. Af-
in water (2000 ml) was stirred at pH = 7 in the presence of ter keeping the reaction at 190 ◦C for an additional 15 min-
PLE (Boehringer-Mannheim, 10 × 200 µl) for 5 days keep- utes it was cooled to room temperature, poured into ice
ing the pH constant at 7.0 by the addition of 1 N sodium water and the aqueous solution was extracted with hexane
hydroxide (amount: 855 ml). The reaction mixture was ex- (4 × 100 ml). The combined organic layers were washed
tracted with ethyl acetate (7 × 400 ml), the combined or- with brine, dried (MgSO4), the solvents evaporated under re-
ganic phases were dried and the solvent evaporated. The duced pressure and the remaining brown oil was subjected
crude product was purfied by chromatography (silica gel, to column chromatography (silica gel, ethyl acetate/hexane
hexane/ethyl acetate 4:1) to afford pure 3 (91.8 g, 83.1%) as 1:8) to afford 5 (2.97 g, 67%) as a colorless oil contami-
a colorless liquid. – nD = 1.4523. – RF (ethyl acetate/hexane nated with some starting material that was easily separated
1:4) 0.14. – IR (film): ν = 3410s, 3015w, 2945m, 2875m, in the next reaction step; an analytical pure sample of com-
2360w, 1740s, 1450m, 1385s, 1365s, 1240s, 1090s, 1025s pound 5 was prepared by deacetylation (vide infra), chro-
cm−1. – 1H NMR (400 MHz, CDCl3): δ = 5.90 (dtt, J = matography (silica gel, ethyl acetate/hexane 1:2 → 1:1 and
15.6, 4.5, 1.2 Hz, 1 H, −CH=C), 5.80 (dtt, J = 15.6, 5.8, re-acetylation (pyridine, acetic anhydride). – RF (ethyl ac-
1.2 Hz, −CH=C), 4.55 (m, 2 H, CH2-OAc), 4.15 (dq, J = etate/hexane 1:8) 0.18. – IR (film): ν = 3030w, 2865m,
5.0, 1.2 Hz, 2 H, CH2O), 2.16 (br s, 1 H, OH), 2.05 (s, 3 H, 1745s, 1670w, 1485s, 1455s, 1390s, 1370s, 1325m, 1230s,
CH3). – 13C NMR (50 MHz, CDCl3): δ = 172.10 (s, CO), 1195s, 1100s, 1025s cm−1. – 1H NMR (200 MHz, CDCl3):
134.82 (d, CH=C), 125.95 (d, CH=C), 65.29 (t, CH2OH), δ = 7.35 – 7.24 (m, 5 H, phenyl), 4.35 and 4.47 (AB system,
63.42 (t, CH2-OAc), 21.75 (q, CH3). – MS (EI, 70 eV): JAB = 11.9 Hz, 2 H, CH2-phenyl), 4.25 – 4.02 (m, 2 H, CH2-
3
m/z (%) = 112 (1), 100 (1), 99 (1), 70 (35), 69 (12), 61 (12), OAc), 3.65 (dd, JH,H = 5.7, 5.1 Hz, 2 H, CH2-OBn), 2.03
43 (100). – Analysis for C6H10O3 (130.14): calcd. C 55.37, (s, 3 H, CH3), 1.86 – 1.73 (m, 3JH,H = 5.7, 5.1 Hz, 2 H, 1-H,
H 7.74; found C 55.21, H 7.82.
3-H). – 13C NMR (50 MHz, CDCl3): δ = 170.82 (s, C=O),
137.88 (s, Cq-phenyl), 128.50 (d, Cortho-phenyl), 127.84 (d,
Cmeta-phenyl), 127.67 (d, Cpara-phenyl), 113.78 (dd, 1JC,F
=
(E)-4-(benzyloxy)-2-butenyl acetate (4)
286.7, 286.7 Hz, CF2), 72.62 (t, CH2-phenyl), 65.75 (t, CH2-
To a suspension of sodium hydride (24.0 g, 60%) in dry
dioxane (350 ml) at 0 ◦C a solution of 3 (62 g, 0.476 mol) in
dioxane (100 ml) was slowly added; stirring was continued
at room temperature for 30 min until the evolution of hydro-
gen had ceased. The reaction mixture was cooled to 0 ◦C and
benzyl bromide (86 g, 0.5 mol) was slowly added within 1 h.
After stirring for 12 h at room temperature and usual work-
up followed by chromatography (silica gel, hexane/ethyl ac-
etate 8:1 → 3:2) 4 (91.72 g, 87.4%) was obtained as an
oil. – nD = 1.5083. – RF (ethyl acetate/hexane 1:3) 0.40. –
IR (film): ν = 3090w, 3065w, 3030w, 2940w, 2855m, 2360w,
2340w, 1740s, 1605w, 1495w, 1455m, 1380m, 1365s, 1235s,
1105s, 1025s cm−1. – 1H NMR (400 MHz, CDCl3): δ =
3
OBn), 60.53 (dt, JC,F = 2.4 Hz, CH2-OAc), 26.85 (virt dt,
2
2JC,F = 10.5 Hz, C-3), 25.39 (virt dt, JC,F = 10.8 Hz, C-
1), 20.80 (q, CH3). – 19F NMR (188 MHz, CDCl3): δ =
3
−139.92 (virt t, JF,H = 7.3 Hz, 2 F). – MS (EI, 70 eV):
m/z (%) = 270 (1), 227 (1), 209 (1), 180 (1), 163 (1), 160
(2), 144 (7), 107 (7), 105 (8), 92 (10), 91 (100), 65 (14), 43
(53). – Analysis for C14H16O3F2 (270.28): calcd. C 62.21,
H 5.97; found C 61.82, H 6.16.
( )-(1 SR, 3 SR)-[3-Benzyloxymethyl-2,2-difluorocyclo-
propyl]methanol (( )-6)
A solution of 5 (2.97 g, 11.0 mmol) in methanol (7 ml)
7.30 (m, 5 H, phenyl), 5.87 (m, 2 H, CH=), 4.60 (d, J = was treated with catalytic amounts of sodium methoxide.
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R. Csuk – L. Eversmann · Synthesis of trans-Configurated Spacered Nucleoside Analogues
After 90 minutes the reaction was complete and the reaction 51 (9), 43 (100). – Analysis for C7H10O3F2 (180.10): calcd.
mixture was neutralized by the addition of 10% aqueous hy- C 46.67, H 5.59; found C 46.66, H 5.61.
drochloric acid. The solvent was evaporated and the residue
suspended in water (10 ml). The resulting suspension was ex-
tracted with ethyl acetate (4×50 ml), the combined organic
layers were washed with brine, dried (MgSO4), and the sol-
vents were evaporated. The remaining crude oil was purified
by column chromatography (silica gel, ethyl acetate/hexane
1:2 → 1:1) to afford 6 (2.16 g, 58% yield from 4) as a
colorless oil. – RF (ethyl acetate/hexane 1:1) 0.40. – UV/vis
(methanol): λmax (lg ε) = 263 nm (2.21). – IR (film): ν =
3400s, 3065w, 3030m, 2875s, 1485s, 1455s, 1365s, 1320w,
1265s, 1185s, 1095s, 1015s cm−1. – 1H NMR (200 MHz,
CDCl3): δ = 7.40 – 7.24 (m, 5 H, H-phenyl), 4.55 and 4.48
(AB system, JAB = 11.9 Hz, 2 H, CH2-phenyl), 3.67 – 3.60
(m, 2 H, CH2-OH), 3.59 – 3.48 (m, 2 H, CH2-OBn), 2.30 (br
s, 1 H, OH), 1.82 – 1.59 (m, 2 H, 1-H, 3-H). – 13C NMR
(50 MHz, CDCl3): δ = 137.67 (s, Cq-phenyl), 128.46 (d,
( )-3-Benzoyl-1-[(1 SR, 3 R)-3-acetoxymethyl-2,2-difluoro-
cyclopropylmethyl]-5-methyl-1,2,3,4-tetrahydro-2,4-pyr-
imidinedione (( )-10)
The reaction was performed using the same conditions as
described for 17 using 9 (0.28 g, 1.56 mmol), triphenylphos-
phane (0.8 g, 3.04 mmol), N3-benzoylthymine (0.60 g,
2.61 mmol), 1,4-dioxane (7 ml) and DEAD (0.49 ml,
3.02 mmol) in 1,4-dioxane (20 ml). Evaporation of the sol-
vents and purification by column chromatography (silica
gel, ethyl acetate/hexane 1:2) gave 10 (0.50 g, 82%) as an
oil. – RF (ethyl acetate) 0.63. – UV/vis (MeOH): λmax1
(lg ε) = 254 nm (4.26), λmax2 (lg ε) = 283 nm, (3.91). – IR
(film): ν = 3340w, 3070w, 2960w, 1750m, 1700m, 1650s,
1600s, 1485m, 1440m, 1365m, 1320m, 1245m, 1200m,
1180m, 1120w, 1040m, 1015m cm−1. – 1H NMR (200 MHz,
CDCl3): δ = 7.94 – 7.89 (m, 2 H, Hortho), 7.67 – 7.61 (m,
Cortho-phenyl), 127.86 (d, Cmeta-phenyl), 127.76 (d, Cpara
-
1
phenyl), 114.23 (dd, JC,F = 286.7, 285.9 Hz, CF2), 72.72
(t, CH2-phenyl), 65.97 (dt, 3JC,F = 3.9 Hz, CH2-OBn), 59.06
(dt, 3JC,F = 5.4 Hz, CH2-OH), 28.79 (virt dt, 2JC,F = 10.0 Hz,
1 H, Hpara), 7.53 – 7.27 (m, 2 H, Hmeta), 7.10 (s, 1 H, 6’-H),
2
4.23 – 4.03 (m, 3 H, CH2-OAC H-CH’N), 3.56 (dd, JH,H
=
3
−14.5 Hz, JH,H = 6.9 Hz, 1 H, H’-CHN), 2.09 – 1.84 (m,
7 H, 1-H, 3-H, 2×CH3). – 13C NMR (50 MHz, CDCl3): δ =
170.68 (s, C=O (Ac)), 168.71 (s, C=O (Bz)), 162.87 (s, C-
2’), 149.78 (s, C-4’), 139.47 (d, C-6’), 135.07 (s, Cq-phenyl),
131.44 (d, Cpara-phenyl), 130.33 (d, Cortho-phenyl), 129.12
(d, Cmeta-phenyl), 113.29 (dd, 1JC,F = 289.0, 289.0 Hz, CF2),
111.28 (s, C-5’), 59.82 (dt, 3JC,F = 4.6 Hz, CH2-OAc), 45.52
(dt, 3JC,F = 3.8 Hz, CH2-N), 26.21 (virt dt, 2JC,F = 10.8 Hz,
2
C-1), 26.44 (virt dt, JC,F = 10.8 Hz, C-3). – 19F NMR
(188 MHz, CDCl3): δ = −138.90 and −140.53 (AB sys-
tem, JAB = 165.6 Hz, FA and FB). – MS (EI, 70 eV):
m/z (%) = 228 (6), 107 (14), 91 (100), 79 (4), 65 (5). – Anal-
ysis for C12H14O2F2 (228.24): calcd. C 63.14, H 6.13; found
C 62.60, H 6.09.
( )-(1 SR, 3 SR)-[3-Acetoxymethyl-2,2-difluorocyclopropyl]
methanol (( )-9)
2
C-3), 25.80 (virt dt, JC,F = 10.4 Hz, C-1), 20.56 (q, CH3
(Ac)), 12.30 (q, 5’-CH3). – 19F NMR (188 MHz, CDCl3):
δ = −138.30 and −139.85 (AB system, JAB = 164.4 Hz,
FA and FB). – MS (EI, 70 eV): m/z (%) = 392 (10), 364
(12), 333 (5), 322 (11), 305 (13), 277 (10), 262 (15), 183 (8),
105 (100), 77 (36). – Analysis for C19H18N2O5F2 (440.15):
calcd. C 57.16, H 5.02, N 6.76; found C 57.35, H 4.97,
N 6.91.
To a solution of 5 (0.49 g, 1.81 mmol) in methanol
(30 ml) was added a catalytic amount of palladium on char-
coal (10%). The resulting heterogeneous reaction mixture
was subjected to a hydrogenation at 0.3 – 0.5 MPa in an au-
toclave. The reaction was observed by tlc. After completion
of the reaction the catalyst was filtered off. After evaporation
of all volatiles the title compound 9 (0.29 g, 89%) was ob-
tained as a clear oil. – RF (ethyl acetate/hexane 1:2) 0.20. –
IR (film): ν = 3435m, 2960w, 2895w, 1740s, 1485s, 1390s,
1370s, 1325m, 1240s, 1190s, 1135m, 1040s, 1015s cm−1. –
1H NMR (400 MHz, CDCl3): δ = 4.21 – 4.16 (m, 1 H, H-
( )-1-[(1 SR, 3 SR)-2,2-Difluoro-3-hydroxymethyl-cyclopro-
pylmethyl]-5-methyl-1,2,3,4-tetrahydro-2,4-pyrimidinedione
[ = 9-(3-hydroxymethyl-2,2-difluoro-cyclopropylmethyl)-
thymine] (( )-11)
2
3
CH’OAc), 4.04 (ddd, JH,H = −11.9 Hz, JH,H = 7.4 Hz,
4JF,H = 1.8 Hz, 1 H, H’-CHOAc), 3.69 (m, 2 H, CH2-OH),
A solution of 10 (0.44 g, 1.12 mmol) and potassium hy-
2.08 (br s, 1 H, OH), 2.05 (s, 3 H, CH3), 1.81 – 1.74 (m, droxide (0.18 g, 3.2 mmol) in methanol (25 ml) was stirred
2 H, cyclopr.). – 13C NMR (100 MHz, CDCl3): δ = 171.20 at room temperature for 3 hours. After neutralization by hy-
(s, C=O), 113.96 (dd, 1JC,F = 287.2, 287.2 Hz, CF2), 60.44 drochloric acid (10%) all volatiles were removed in vacuo
3
3
(dt, JC,F = 5.0 Hz, CH2-OH), 58.87 (dt, JC,F = 5.0 Hz, and the remaining oil was subjected to column chromato-
CH2-OAc), 28.86 (virt dt, 2JC,F = 10.4 Hz, C-1), 25.13 (virt graphy (silica gel, ethyl acetate) to afford 11 (0.18 g, 63%)
2
dt, JC,F = 10.8 Hz, C-3), 20.64 (q, CH3). – 19F NMR as a white solid. – M. p.: 157 – 161 ◦C. – RF (ethyl acetate)
(188 MHz, CDCl3): δ = −139.49 and −141.01 (AB system, 0.25. – UV/vis (methanol): λmax (lg ε) = 271 nm, 3.92. –
JAB = 164.5 Hz, FA and FB). – MS (EI, 70 eV): m/z (%) = IR (KBr): ν = 3500m, 3165w, 3030m, 2830w, 1710s, 1665s,
163 (1), 149 (1), 100 (2), 91 (5), 90 (16), 77 (13), 64 (4), 1480m, 1420m, 1360m, 1315w, 1265m, 1240m, 1225m,
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R. Csuk – L. Eversmann · Synthesis of trans-Configurated Spacered Nucleoside Analogues
1001
1200m, 1160m, 1130w, 1105w, 1045m cm−1. – 1H NMR [ = 9-(3-hydroxymethyl-2,2-difluoro-cyclopropylmethyl)-
(400 MHz, CD3OD): δ = 7.41 (d, 4JH,H = 1.2 Hz, 1 H, 6’-H), uracil] (( )-13)
3.99 – 3.94 (m, 1 H, H-CH’N), 3.76 (dd, 2JH,H = −15.4 Hz,
A solution of 12 (0.45 g, 1.19 mmol) and potassium hy-
droxide (0.47 g, 8.4 mmol) in methanol (20 ml) was stirred at
room temperature overnight. After neutralization by diluted
hydrochloric acid (10%) and filtration the filtrate was evapo-
rated under reduced pressure and the remaining oil was sub-
jected to column chromatography (silica gel, ethyl acetate
→ ethyl acetate/methanol 9:1) to afford 13 (0.17 g, 62%)
as a white solid. – M. p.: 192 – 199 ◦C. – RF (ethyl acetate)
0.20. – UV/vis (methanol): λmax (lg ε) = 265 nm (3.96). – IR
(KBr): ν = 3410s, 3155m, 3015s, 2970m, 2890m, 2825m,
2530s, 2270s, 1760m, 1680s, 1630s, 1480s, 1460s, 1430s,
1405m, 1375s, 1360s, 1315m, 1270s, 1255s, 1245s, 1205s,
1190m, 1175m, 1140m, 1115m, 1070w, 1040s, 1025m,
1000s cm−1. – 1H NMR (200 MHz, CD3OD): δ = 7.56
3
3JH,H = 7.4, 1 H, H’-CHN), 3.59 (virt d, JH,H = 6.8 Hz,
2 H, CH2-OH), 1.98 – 1.89 (m, 2 H, 1-H, 3-H), 1.86 (d,
4JH,H = 1.2, 3 H, CH3). – 13C NMR (100 MHz, CD3OD):
δ = 167.03 (s, C-2’), 153.16 (s, C-4’), 142.74 (d, C-6’),
1
116.06 (dd, JC,F = 288.0, 285.5 Hz, CF2), 111.62 (2, C-
5’), 58.92 (dt, 3JC,F = 5.0 Hz, CH2-OH), 46.15 (dt, JC,F
=
3
5.0 Hz, CH2-N), 30.67 (virt dt, 2JC,F = 10.2 Hz, C-3), 26.43
(virt dt, JC,F = 10.6 Hz, C-1), 12.13 (q, CH3). – 19F NMR
2
(188 MHz, CD3OD): δ = −135.95 and −138.41 (AB system,
JAB = 164.5 Hz, FA and FB). – MS (EI, 70 eV): m/z (%) = 246
(58), 229 (71), 215 (100), 196 (16), 172 (27), 149 (33), 139
(40), 126 (42), 96 (62). – HRMS calcd. for C10H12N2O3F2:
246.0816; found: 246.0816.
3
3
(d, JH,H = 7.8 Hz, 1 H, 6’-H), 5.66 (d, JH,H = 7.8 Hz,
1 H, 5’-H), 4.11 – 3.97 (m, 1 H, H-CH’N), 3.83-3.66 (m,
1 H, H’-CHN), 3.61 – 3.58 (m, 2 H, CH2-OH), 2.03 – 1.82
(m, 2 H, 1-H, 3-H). – 13C NMR (100 MHz, CD3OD): δ =
166.43 (s, C-2’), 152.55 (s, C-4’), 146.49 (d, C-6’), 115.54
( )-3-Benzoyl-1-[(1 SR, 3 R)-3-acetoxymethyl-2,2-difluoro-
cyclopropylmethyl]-1,2,3,4-te trahydro-2,4-pyrimidinedione
(( )-12)
The reaction was performed under the conditions as de-
scribed for 17 using 9 (0.37 g, 2.0 mmol), triphenylphos-
phane (1.50 g, 5.70 mmol), N3-benzoyluracil (0.60 g,
2.78 mmol), 1,4-dioxane (10 ml) and DEAD (0.58 ml,
5.5 mmol) in 1,4-dioxane (17 ml). After evaporation of
the solvents purification by column chromatography (silica
gel, ethyl acetate/hexane 1:1) gave 12 (0.45 g, 59%) as an
oil. – RF (ethyl acetate/hexane 3:7) 0.26. – IR (film): ν =
3090w, 2965w, 1750s, 1705s, 1670s, 1600s, 1565m, 1485s,
1440s, 1385s, 1370s, 1320s, 1245s, 1140m, 1100m, 1045s,
1
(dd, JC,F = 287.9, 287.9 Hz, CF2), 102.22 (d, C-5’), 58.43
3
3
(dt, JC,F = 4.9 Hz, CH2-OH), 46.00 (dt, JC,F = 4.9 Hz,
CH2-N), 30.24 (virt dt, 2JC,F = 9.6 Hz, C-3), 25.90 (virt dt,
2JC,F = 10.8 Hz, C-1). – 19F NMR (188 MHz, CD3OD):
δ = −136.12 and −138.55 (AB system, JAB = 164.5 Hz,
FA and FB). – HRMS calcd. for C9H10N2O3F2: 232.0659;
found: 232.0659. – Analysis for C9H10N2O3F2 (232.18):
calcd. C 46.56, H 4.34, N 12.07; found C 46.41, H 4.43,
N 12.12.
1015s cm−1. – H NMR (200 MHz, CDCl3): δ = 7.90 (m,
1
( )-3-Benzoyl-1-[(1 SR, 3 SR)-3-benzyloxymethyl-2,2-di-
fluorocyclopropylmethyl]-5-fluoro-1,2,3,4-tetrahydro-2,4-
pyrimidinedione ((pm)-14)
2 H, Hortho), 7.65 (m, 1 H, Hpara), 7.48 (m, 2 H, Hmeta), 7.24
3
3
(d, JH,H = 8.0 Hz, 1 H, 6’-H), 5.81 (d, JH,H = 8.0 Hz,
1 H, 5’-H), 4.21 – 4.02 (m, 3 H, CH2-OAC H-CH’N), 3.58
2
3
(dd, JH,H = −14.6 Hz, JH,H = 7.8, 1 H, H’-CHN), 2.03
(s, 3 H, CH3), 2.09 – 1.84 (m, 2 H, 1-H, 3-H). – 13C NMR
(50 MHz, CDCl3): δ = 170.77 (s, C=O (Ac)), 168.41 (s,
C=O (Bz)), 162.09 (s, C-2’), 149.77 (s, C-4’), 143.48 (d, C-
6’), 135.22 (s, Cq-phenyl), 131.33 (d, Cpara-phenyl), 130.44
(d, Cortho-phenyl), 129.25 (d, Cmeta-phenyl), 113.50 (CF2),
102.76 (d, C-5’), 59.83 (dt, 3JC,F = 3.9 Hz, CH2-OAc), 45.97
(dt, 3JC,F = 4.6 Hz, CH2-N), 26.35 (virt dt, 2JC,F = 10.8 Hz,
C-3), 25.80 (virt dt, 2JC,F = 10.8 Hz, C-1), 20.67 (q, CH3). –
19F NMR (188 MHz, CDCl3): δ = −138.32 and -139.91 (AB
system, JAB = −165.4 Hz, FA and FB); MS (EI, 70 eV):
m/z (%) = 378 (18), 350 (21), 319 (13), 308 (8), 291 (24),
290 (12), 277 (10), 171 (8), 106 (22), 105 (100%). – Anal-
ysis for C18H16N2O5F2 (444.13): calcd. C 57.15, H 4.23,
N 7.40; found C 57.08, H 4.56; N 7.30.
The reaction was performed according to the Mitsunobu
reaction as described for the preparation of compound 17
using 6 (0.53 g, 2.33 mmol), triphenylphosphane (1.22 g,
4.66 mmol), N3-benzoyl-5-fluorouracil (1.10 g, 4.66 mmol),
1,4-dioxane (4 ml) and DIAD (0.90 ml, 4.66 mmol) in 1,4-
dioxane (20 ml). After stirring overnight the solvent was
evaporated, the residue was purified by column chromatog-
raphy (silica gel, ethyl acetate/hexane 1:2) and 14 (0.76 g,
73%) was obtained as a colorless oil. – RF (ethyl ac-
etate/hexane 1:2) 0.30. – UV/vis (methanol): λmax1 (lg ε) =
259 nm (4.30), λmax2 (lg ε) = 287 nm (3.97). – IR (film):
ν = 3435w, 3095w, 2865w, 1755s, 1711m, 1665s, 1600w,
1475m, 1450m, 1410w, 1180m, 1105m, 1075w, 1010w
cm−1. – 1H NMR (200 MHz, CDCl3): δ = 7.92 – 7.87 (m,
2 H, Hortho-phenyl), 7.69 (m, 1 H, Hpara-phenyl), 7.50 –
7.42 (m, 2 H, Hmeta-phenyl), 7.37 - 7.26 (m, 6 H, H-phenyl,
Bn), 6’-H), 4.53 and 4.47 (AB system, JAB = −11.9 Hz,
2 H, CH2-phenyl), 4.26 – 4.15 (m, 1 H, H-CH’N), 3.68 –
( )-1-[(1 SR, 3 SR)-2,2-Difluoro-3-hydroxymethyl-cyclo-
propylmethyl]-1,2,3,4-te trahydro-2,4-pyrimidinedione
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R. Csuk – L. Eversmann · Synthesis of trans-Configurated Spacered Nucleoside Analogues
3.43 (m, 3 H, H’-CHN, CH2-OBn), 1.96 – 1.76 (m, 2 H, ( )-1-[(1 SR, 3 SR)-2,2-Difluoro-3-hydroxymethyl-cyclo-
1-H, 3-H). – 13C NMR (50 MHz, CDCl3): δ = 167.18 (s, propylmethyl]-5-fluoro-1,2,3,4-tetrahydro-2,4-pyrimidine-
2
C=O (Bz)), 156.20 (d, JC,F = 26.9 Hz, C-4’), 148.56 (s, dione [ = 9-(3-hydroxymethyl-2,2-difluoro-cyclopropylme-
1
C-2’), 140.34 (d, JC,F = 241.6 Hz, C-5’), 137.55 (s, Cq- thyl)fluorouracil] (( )-16)
phenyl, Bn)), 135.55 (s, Cq-phenyl, Bz)), 131.07 (d, Cpara
-
Removal of the benzyl group was performed by treat-
ing 15 (0.38 g, 1.11 mmol) with cyclohexene (17 ml) and
Pearlman’s catalyst (0.87 g, 20%) in refluxing methanol
(19 ml) for 4 hours. After column chromatography (sil-
ica gel, ethyl acetate) 16 (0.1 g, 36%) was obtained as a
phenyl, Bz)), 130.66 (d, Cortho-phenyl, Bz)), 129.36 (d,
Cmeta-phenyl, Bz)), 128.65 (d, Cortho-phenyl, Bn)), 128.07
(d, Cmeta-phenyl, Bn)), 127,86 (dd, 2JC,F = 33.6 Hz, C-6’),
1
127.73 (d, Cpara-phenyl, Bn)), 113.55 (dd, JC,F = 290.9,
3
285.5 Hz, CF2), 73.04 (t, CH2-phenyl), 65.19 (dt, JC,F
=
◦
white solid. – M. p.: 187 C. – RF (ethyl acetate) 0.44. –
3.7 Hz, CH2-OBn), 46.01 (dt, 3JC,F = 5.0 Hz, CH2-N), 27.55
(virt dt, 2JC,F = 10.6 Hz, C-3), 25.05 (virt dt, 2JC,F = 11.0 Hz,
C-1). – 19F NMR (188 MHz, CDCl3): δ = −137.65 and
−139.60 (AB system, JAB = 168.1 Hz, FA and FB), −165.16
(s, 5’-F); MS (EI, 70 eV): m/z (%) = 339 (69), 233 (31), 194
(5), 143 (5), 105 (100), 91 (19), 77 (21). – HRMS calcd. for
C23H22O4N2F3: 428.1548; found: 428.1548. – Analysis for
C23H22O4N2F3 (428.15): calcd. C 64.48, H 5.18, N 5.64;
found C 64.41, H 5.13, N 5.37.
UV/vis (methanol): λmax (lg ε) = 276 nm (3.95). – IR
(KBr): ν = 3415w, 3025w, 2840w, 1695m, 1665w, 1470w,
1390w, 1375w, 1315w, 1265w, 1240w, 1170w, 1120w,
1040w cm−1. – 1H NMR (400 MHz, CD3OD): δ = 7.81 (d,
3JF,H = 6.2 Hz, 1 H, H-C(6’)), 3.96 (ddd, 2JH,H = −14.7 Hz,
4
3JH,H = 7.8 Hz, JF,H = 2.2 Hz, 1 H, H-CH’N), 3.79 (ddd,
4
2JH,H = 14.7 Hz, 3JH,H = 7.1 Hz, JF,H = 1.0 Hz, 1 H, H’-
CHN), 3.60 (dddd, 2JH,H = -12.1 Hz, 3JH,H = 7.6 Hz, 4JF,H
=
1.3, 0.2 Hz, 1 H, H-CH’OH), 3.58 (dddd, 2JH,H = -12.1 Hz,
3JH,H = 7.2 Hz, 4JF,H = 2.7, 1.3 Hz, H’-CHOH), 1.96 (ddddd,
3JF,H = 14.1, 0.2 Hz, 3JH,H = 7.9, 7.1, 7.0 Hz, 1 H, 1-H), 1.94
( )-1-[(1 SR, 3 SR)-3-Benzyloxymethyl-2,2-difluorocyclo-
propylmethyl]-5-fluor o-1,2,3,4-tetrahydro-2,4-pyrimidine-
dione (( )-15)
3
3
(ddddd, JF,H = 14.6 Hz, 0.2 Hz, JH,H = 7.6, 7.2, 7.0 Hz,
1 H, 3-H). – 13C NMR (100 MHz, CD3OD): δ = 160.02 (d,
2JC,F = 26.2 Hz, C-4’), 151.70 (s, C-2’), 141.97 (d, 1JC,F
=
A solution of 14 (0.70 g, 1.63 mmol) in methanol (27 ml)
was treated with ammonium hydroxide (13 ml) for 3 hours.
The volatiles were evaporated and the remaining oil was
subjected to column chromatography (silica gel, ethyl ac-
etate/hexane 1:1) to give 15 (0.45 g, 81%) as a white solid. –
M. p.: 114 – 116 ◦C. – RF (ethyl acetate/hexane 1:1) 0.28. –
UV/vis (methanol): λmax (lg ε) = 276 nm (3.92). – IR (KBr):
ν = 3400w, 3165w, 3070m, 2845m, 1690s, 1660s, 1475m,
1440w, 1415w, 1390m, 1370m, 1340m, 1315w, 1250s,
1240s, 1210m, 1180m, 1100m, 1075w, 1045m, 1030w,
1020w cm−1. – 1H NMR (200 MHz, CDCl3): δ = 8.73 (br s,
1 H, NH), 7.39 – 7.26 (m, 6 H, H-phenyl, Bn), H-C(6’)), 4.53
and 4.46 (AB system, JAB = −11.9 Hz, 2 H, CH2-phenyl),
4.22 – 4.10 (m, 1 H, H-CH’N), 3.66 – 3.41 (m, 3 H, H’-CHN,
CH2-OBn), 1.91 – 1.77 (m, 2 H, 1-H, 3-H). – 13C NMR
(100 MHz, CDCl3): δ = 157.39 (d, 2JC,F = 26.5 Hz, C-4’),
149.82 (s, C-2’), 140.72 (d, 1JC,F = 239.1 Hz, C-5’), 137.58
(s, Cq-phenyl, Bn)), 128.55 (d, Cortho-phenyl, Bn)), 128.00
233.8 Hz, C-5’), 130.80 (dd, 2JC,F = 33.9 Hz, C-6’), 115.97
(dd, 1JC,F = 288.4, 285.5 Hz, CF2), 58.86 (dt, 3JC,F = 4.9 Hz,
CH2-OH), 46.56 (dt, 3JC,F = 5.4 Hz, CH2-N), 30.76 (virt dt,
2JC,F = 10.2 Hz, C-3), 26.30 (virt dt, 2JC,F = 10.7 Hz, C-1). –
19F NMR (188 MHz, CD3OD): δ = −135.90 and −138.40
(AB system, JAB = 164.5 Hz, FA and FB), −167.68 (s, 5’-
F). – MS (EI, 70 eV): m/z (%) = 250 (26), 233 (40), 219
(100), 200 (33), 176 (20), 167 (2), 156 (24), 153 (36), 143
(50), 130 (54), 128 (11), 120 (9), 113 (11), 103 (11), 100
(61), 91 (19), 87 (24), 77 (24), 71 (7), 59 (6). – HRMS calcd.
for C9H9O3N2F3: 250.0565; found: 250.0565. – Analysis
for C9H9O3N2F3 (250.06): calcd. C 43.21, H 3.63, N 11.20;
found C 43.01, H 3.41, N 11.02.
( )-[(1 SR, 3 SR)-(3-Benzyloxymethyl-2,2-difluorocyclo-
propyl)-methyl]-6-chloro-9H-purine (( )-17)
2
(dd, JC,F = 33.2 Hz, C-6’), 127.95 (d, Cmeta-phenyl, Bn)),
To a mixture of 6 (0.44 g, 1.93 mmol), triphenylphos-
1
127.66 (d, Cpara-phenyl, Bn)), 113.62 (dd, JC,F = 290.5, phane (0.85 g, 3.24 mmol) and 6-chloropurine (0.45 g,
3
285.5 Hz, CF2), 72.81 (t, CH2-phenyl), 65.26 (dt, JC,F
=
2.91 mmol) in dry 1,4-dioxane (20 ml) a solution of DEAD
3.7 Hz, CH2-OBn), 45.78 (dt, 3JC,F = 5.0 Hz, CH2-N), 27.33 (0.53 ml, 3.22 mmol) in dioxane (10 ml) was added drop-
(virt dt, 2JC,F = 10.6 Hz, C-3), 24.89 (virt dt, 2JC,F = 10.8 Hz, wise at room temperature over a period of 2 hours. The
C-1). – 19F NMR (188 MHz, CDCl3): δ = −137.84 and reaction mixture was stirred overnight, the solvent evap-
−139.78 (AB system, JAB = 164.5 Hz, FA and FB), −166.26 orated and the remaining yellowish oil purified by col-
(s, 5’-F). – MS (EI, 70 eV): m/z (%) = 340 (18), 234 (87), umn chromatography (silica gel, ethyl acetate/hexane 2:3)
214 (97), 143 (32), 130 (28), 107 (11), 100 (17), 91 (100), 85 to afford 17 (0.51 g, 73%) as an oil. – RF (ethyl acetate)
(46). – HRMS calcd. for C16H15O3N2F3: 340.1035; found: 0.30. – IR (film): ν = 3065w, 3030w, 2865w, 1725w, 1595s,
340.1035. – Analysis for C16H15O3N2F3 (340.10): calcd. 1565s, 1485s, 1455m, 1440m, 1425m, 1405s, 1365m, 1335s,
C 56.47, H 4.44; N 8.23; found C 56.22, H 4.19, N 8.12.
1260m, 1210s, 1180m, 1150m, 1095m, 1020m cm−1. –
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R. Csuk – L. Eversmann · Synthesis of trans-Configurated Spacered Nucleoside Analogues
1003
1H NMR (400 MHz, CDCl3): δ = 8.70 (s, 1 H, 2’-H), CH2-N), 31.03 (virt dt, 2JC,F = 10.2 Hz, C-3), 26.97 (virt dt,
8.22 (s, 1 H, 8’-H), 7.31 – 7.15 (m, 5 H, H-phenyl), 4.48 – 2JC,F = 10.6 Hz, C-1). – 19F NMR (188 MHz, CD3OD): δ =
2
4.29 (m, 4 H, CH2-phenyl, CH2-N), 3.58 (ddd, JH,H
=
−136.92 and −138.56 (AB system, JAB = 164.5 Hz, FA and
3
4
−10.4, JH,H = 7.0, JF,H = 1.6, 1 H, H-CH’OBn), 3.46 – FB). – MS (EI, 70 eV): m/z (%) = 255 (16), 199 (100), 183
3.41 (m, 1 H, H’-CHOBn), 2.06m – 1.93 (m, 2 H, H-1),
3-H). – 13C NMR (100 MHz, CDCl3): δ = 153.22 (s, C-
6’), 152.85 (d, C-2’), 152.34 (s, C-4’), 145.78 (d, C-8’),
138.50 (s, Cq-phenyl), 129.58 (d, Cortho-phenyl), 129.00 (d,
Cmeta-phenyl), 128.60 (d, Cpara-phenyl), 115.00 (s, C-5’),
(63), 149 (49), 77 (74). – HRMS calcd. for: C10H11N5OF2:
255.0931; found: 255.0931. – Analysis for C10H11N5OF2
(255.09): calcd. C 47.06; H 4.34, N 27.44; found C 47.23,
H 4.11, N 27.20.
1
114.32 (dd, JC,F = 289.7, 286.3 Hz, CF2), 73.84 (t, CH2-
( )-9-[(1 SR, 3 SR)-(3-Benzyloxymethyl-2,2-difluoro-
cyclopropyl)methyl]-9H-6-purinamine (( )-21)
3
phenyl), 66.07 (dt, JC,F = 3.3 Hz, CH2-OBn), 42.28 (dt,
3JC,F = 5.0 Hz, CH2-N), 28.85 (virt dt, JC,F = 10.6 Hz,
2
Treatment of compound 17 (0.78 g, 2.14 mmol ) with
an excess of liquid ammonia in an autoclave at 75 ◦C and
40 bar resulted after evaporation of the volatiles and col-
umn chromatography (silica gel, ethyl acetate) in the for-
mation of 18 (0.52 g, 71%) that was isolated as a white
solid. – M. p. 148 – 149 ◦C. – RF (ethyl acetate) 0.10. –
UV/vis (methanol): λmax (lg ε) = 263 nm (4.22). – IR (KBr):
ν = 3295m, 3122m, 2860w, 1670m, 1600m, 1480m, 1415m,
1360w, 1310m, 1245m, 1210m, 1170w, 1115m, 1075m,
1020w cm−1. – 1H NMR (400 MHz, CD3OD): δ = 8.21
(s, 1 H, 2’-H), 8.17 (s, 1 H, 8’-H), 7.29 – 7.10 (m , 5 H,
C-3), 26.63 (virt dt, JC,F = 10.8 Hz, C-1). – 19F NMR
2
(188 MHz, CDCl3): δ = −138.86 and −139.92 (AB system,
JAB = 164.5 Hz, FA and FB). – MS (EI, 70 eV): m/z (%) =
364 (1), 277 (5), 258 (19), 238 (100), 223 (57), 203 (4),
181 (7), 167 (11), 155 (15), 91 (73). – HRMS calcd. for:
C17H15N4OClF2: 364.0902; found: 364.0902. – Analysis for
C17H15N4OClF2 (364.78): calcd. C 55.97, H 4.14, N 15.36;
found C 55.83, H 4.27, N 15.43.
( )-[(1 SR, 3 SR)-3-[(6-Amino-9H-9-purinylmethyl)-2,2-di-
fluorocyclopropyl]methanol [ = 9-(3-hydroxymethyl-2,2-di-
fluoro-cyclopropylmethyladenine] (( )−19)
2
3
H-phenyl), 4.49 (dd, JH,H = −14.7 Hz, JH,H = 6.2 Hz,
1 H, H-CH’N), 4.33 – 4.12 (m, 3 H, H’-CHN, CH2-phenyl),
2
3
To a solution of 18 (0.45 g, 1.3 mmol) in methanol (50 ml) 3.60 (dd, JH,H = −10.7 Hz, JH,H = 6.8 Hz, H-CH’OBn),
were added cyclohexene (40 ml ) and Pearlman’ catalyst 3.47 – 3.41 (m, 1 H, H’-CHOBn), 2.24 – 2.10 (m, 2 H, 1-
H, 3-H). – 13C NMR (100 MHz, CD3OD): δ = 157.07 (s,
(0.34 g, 20% ) and the reaction mixture was heated un-
der reflux for 26 hours. After filtration and evaporation of C-6’), 153.63 (d, C-2’), 150.45 (s, C-4’), 142.03 (d, C-8’),
the volatiles the resulting crude product was subjected to 138.92 (s, Cq-phenyl), 129.04 (d, Cortho-phenyl), 128.34 (d,
Cmeta-phenyl), 128.17 (d, Cpara-phenyl), 119.74 (s, C-5’),
19:1) to afford 19 (0.26 g, 78%) as a white solid. – M. p. 115.21 (dd, JC,F = 287.2, 286.7 Hz, CF2), 72.95 (t, CH2-
column chromatography (silica gel, ethyl acetate/methanol
1
◦
205 – 214 C. – RF (ethyl acetate/methanol 19:1) 0.30. – phenyl), 66.10 (t, CH2-OBn), 41.18 (t, CH2-N), 28.32 (virt
2
2
dt, JC,F = 10.4 Hz, C-3), 27.11 (virt dt, JC,F = 10.8 Hz,
UV/vis (methanol): λmax (lg ε) = 263 (4.13). – IR (KBr):
ν = 3345m, 3100m, 1670m, 1600m, 1575w, 1480w, 1415w, C-1). – 19F NMR (188 MHz, CD3OD): δ = −136.62 and
1305w, 1250m, 1195w, 1045w, 1010w cm−1. – 1H NMR −137.37 (AB system, JAB = 164.5 Hz, FA and FB). – MS
(EI, 70 eV): m/z (%) = 345 (2), 296 (2), 254 (2), 239 (11),
(400 MHz, CD3OD): δ = 8.24 (s, 1 H, 2’-H), 8.19 (s, 1
2
3
H, 8’-H), 4.41 (ddd, JH,H = −15.0 Hz, JH,H = 7.7 Hz, 224 (6), 219 (100), 204 (8), 192 (3), 148 (9), 135 (25), 108
4JH,H = 1.6 Hz, 1 H, H-CH’N), 4.38 (ddd, 2JH,H = −15.0 Hz, (4), 91 (28). – Analysis for C17H17N5OF2 (345.14): calcd.
3JH,H = 7.9 Hz, 4JH,H = 1.6 Hz, 1 H, H’-CHN), 3.58 (dddd,
C 59.10, H 4.93, N 20.29; found C 59.34, H 4.85, N 20.00.
3
4
2JH,H = −12.0 Hz, JH,H = 7.8 Hz, JH,H = 1.6, 0.8 Hz,
2
3
1 H, H-CH’OH), 3.56 (dddd, JH,H = −12.0 Hz, JH,H
=
Acknowledgements
4
6.8 Hz, JF,H = 2.9, 1.4 Hz, 1 H, H’-CHOH), 2.13 (ddddd,
4JF,H = 13.9, 0.2 Hz, 3JH,H = 7.8, 7.7, 6.7 Hz, 1 H, 3-H), 2.01
(ddddd, 3JF,H = 14.8, 0.1 Hz, 3JH,H = 7.8, 6.8, 6.7 Hz, 1 H,
1-H). – 13C NMR (100 MHz, CD3OD): δ = 156.87 (s, C-6’),
153.05 (d, C-2’), 150.86 (s, C-4’), 142.79 (d, C-8’), 120.13
Financial support by the European Communities (SC1*-
CT92-0780) and the Fonds der Chemischen Industrie is
gratefully acknowledged. We like to thank Dr. R. Kluge for
the ESI-MS measurements, Dr. D. Stro¨hl for numerous NMR
spectra and Mr. M. Klawonn for performing initial experi-
ments for the synthesis of 3.
1
(s, C-5’), 115.82 (dd, JC,F = 288.0, 285.9 Hz, CF2), 58.79
(dt, JC,F = 5.0 Hz, CH2-OH), 41.78 (dt, JC,F = 5.4 Hz,
3
3
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R. Csuk – L. Eversmann · Synthesis of trans-Configurated Spacered Nucleoside Analogues
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