Synthesis of 3′-deoxynucleosides with 2-oxabicyclo[3.1.0]hexane sugar moieties: Addition of difluorocarbene to a 3′,4′-unsaturated uridine derivative and 1,2-dihydrofurans derived from D- and L-xylose

Article abstract of DOI:10.1021/jo062614d

(Chemical Equation Presented) Syntheses of 3′-deoxy analogues of adenosine, cytidine, and uridine with a 2,2-difluorocyclopropane ring fused at C3′-C4′ are described. Treatment of a 2′,5′-protected- 3′,4′-unsaturated derivative of uridine with difluorocar

Full text of DOI:10.1021/jo062614d

Synthesis of 3′-Deoxynucleosides with 2-Oxabicyclo[3.1.0]hexane
Sugar Moieties: Addition of Difluorocarbene to a 3′,4′-Unsaturated
Uridine Derivative and 1,2-Dihydrofurans Derived from D- and
L-Xylose1
Ireneusz Nowak and Morris J. Robins*
Department of Chemistry and Biochemistry, Brigham Young UniVersity, ProVo, Utah 84602-5700
morris_robins@byu.edu
ReceiVed December 19, 2006
Syntheses of 3′-deoxy analogues of adenosine, cytidine, and uridine with a 2,2-difluorocyclopropane
ring fused at C3′-C4′ are described. Treatment of a 2′,5′-protected-3′,4′-unsaturated derivative of uridine
with difluorocarbene [generated from (CF3)2Hg and NaI] gave a diastereomeric mixture of the 3′,4′-
difluoromethylene compounds (R-L-arabino/â-D-ribo, ∼5:4). The limited stereoselectivity for addition at
the â face results from competitive steric hindrance by an allylic 4-methoxybenzyloxy group at C2′ on
the R face and a homoallylic nucleobase at C1′ on the â face. Protected uracil derivatives were converted
into their cytosine counterparts via 4-(1,2,4-triazol-1-yl) intermediates. Treatment of 1,2-dihydrofurans
derived from D- and L-xylose with difluorocarbene resulted in stereospecific addition at the â face (anti
to the 1,2-O-isopropylidene group on the R face). Glycosylations with activated enantiomeric sugar
derivatives with the fused difluorocyclopropane ring on the â face gave protected adenine nucleosides,
whereas attempted glycosylation with an R-fused derivative gave multiple products. Removal of base-
and sugar-protecting groups gave new difluoromethylene-bridged nucleoside analogues.
Introduction
unsaturated derivatives occurred readily to give the spirodif-
luorocyclopropyl compounds A. The fused-ring nucleosides B
Attachment of fluorine atoms on sugar moieties of nucleoside
analogues can impart potent anticancer2 and antiviral3 activity.
Deoxy- and deoxofluorination procedures, as well as nucleo-
philic substitution of leaving groups by fluoride, provide
straightforward routes for generation of CF and CF2 groups.4
The small size and powerful electronegativity of fluorine can
cause significant alterations of stereoelectronic effects, which
restrict conformational equilibria of nucleosides5 and stabilize
glycosyl bonds.6 We recently described syntheses of the
difluoromethylene-bridged nucleoside analogues A7 and B8 by
addition of difluorocarbene to enol ethers derived from adeno-
sine and uridine. Difluorocarbene addition to the 5′-deoxy-4′,5′-
(1) Nucleic Acid Related Compounds. 143. Paper 142: Nowak, I.;
Robins, M. J. J. Org. Chem., publisher online Mar. 3, 2007, http://dx.doi.org/
10.1021/jo062544a.
(2) (a) Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. J. Org.
Chem. 1988, 53, 2406-2409. (b) Schy, W. E.; Hertel, L. W.; Kroin, J. S.;
Bloom, L. B.; Goodman, M. F.; Richardson, F. C. Cancer Res. 1993, 53,
4582-4587.
(3) Marquez, V. E.; Lim, B. B.; Barchi, J. J.; Nicklaus, M. C. In
Nucleosides and Nucleotides as Antitumor and AntiViral Agents; Chu, C.
K., Baker, D. C., Eds.; Plenum: New York, 1993; pp 265-284.
(4) Pankiewicz, K. W. Carbohydr. Res. 2000, 327, 87-105.
(fluorinated 2′-deoxy analogues of C9) were obtained by addition
of CF2 to 2′,3′-dideoxy-3′,4′-unsaturated compounds. Effects
of gem-difluoro substitution on the acidities of O2′ and O5′ or
(5) Thibaudeau, C.; Kumar, A.; Bekiroglu, S.; Matsuda, A.; Marquez,
V. E.; Chattopadhyaya, J. J. Org. Chem. 1998, 63, 5447-5462 and
references cited therein.
(6) York, J. L. J. Org. Chem. 1981, 46, 2171-2173.
(7) Nowak, I.; Robins, M. J. J. Org. Chem. 2006, 71, 8876-8883.
10.1021/jo062614d CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/27/2007
J. Org. Chem. 2007, 72, 3319-3325
3319

Nowak and Robins
SCHEME 1a
a Reagents and conditions: (a) PMB-Cl/NaH/DMF/0 °C; (b) NH4F/MeOH/65 °C; (c) TBS-Cl/pyridine; (d) I2/Ph3P/imidazole/toluene/75 °C; (e) DABCO/
benzene/70 °C; (f) (CH3)2Hg/NaI/THF/75 °C; (g) CAN/MeCN/H2O; (h) Ac2O/pyridine; (i) CAN/MeCN/H2O/70 °C; (j) NH3/H2O/1,4-dioxane; (k) 1,2,4-
triazole/POCl3/Et3N/MeCN.
other properties of D relative to those of C9 might result in
altered biological responses that accrued from differences in
phosphorylation, protein binding, etc. We now report addition
of CF2 [generated from NaI and (CF3)2Hg10 (Caution)11] to a
uridine-derived 2′-O-TBS-3′-deoxy-3′,4′-unsaturated nucleoside,
which gave the uracil bicyclo[3.1.0]hexane analogue D and its
3′,4′-difluoromethylene-bridged diastereomer. Uracil to cytosine
conversions via 4-(1,2,4-triazol-1-yl) intermediates12 proceeded
smoothly. Addition of CF2 to the 2′-O-TBS enol ether derived
from uridine was sluggish, and addition to a 2′-deoxy compound
derived from adenosine was more difficult than that with a
uridine-derived analogue.8 Therefore, D- and L-xylose were
converted into protected 1,2-dihydrofurans that were subjected
to addition of CF2. Activated derivatives of the enantiomeric
adducts were coupled with adenine to provide purine bicyclo-
[3.1.0]hexane analogues.
observed in alkylations of 1a/1b with methyl iodide or allyl
bromide. Spontaneous crystallization of 2 allowed its separation
by filtration of the desilylation reaction mixture; treatment of 2
with DAST gave the 5′-deoxy-5′-fluoro derivative (verified by
19F NMR14), which confirmed the presence of the 5′-CH2OH
group. The 2′-O-PMB compound 4 eluted more rapidly than
its 3′-O-PMB isomer 3, which facilitated chromatographic
purification of 4 (3 could be purified by rechromatography of
overlapping fractions).
Protection of 4 with TBS-Cl/pyridine gave the 5′-O-TBS-3-
N,2′-O-di(PMB) derivative 6 (77%), which was treated with I2/
PPh3/imidazole.15 The stereochemically inverted iodide 7 (84%)
was isolated exclusivelysin contrast to the epimeric mixture
obtained with a 2′-deoxy analogue.8 Apparently, stereoelectronic
effects and/or anchimeric assistance by the 2′-O-PMB group
exerted greater control than “double SN2 displacement” by
iodide or participation by O2 of the nucleobase. Regioselective
elimination of HI (7 f 8) proceeded smoothly with DABCO
in hot benzene or toluene.8 The 1H NMR spectrum of enol ether
8 (96%) had no peaks corresponding to the 2′,3′-unsaturated
structure 8′ (both 2′,3′- and 3′,4′-unsaturated isomers were
produced with the 2′-deoxy analogue8). The allylic 2′-O-(PMB)
group diminished the rate of addition of difluorocarbene to the
double bond of 8 (∼20-fold compared to that of the 2′-deoxy
analogue). The R-L-arabino16 diastereomer 9a (46%) was the
major product, which was separated from the â-D-ribo16 isomer
10a (37%) by chromatography. The â/R face selectivity (9a/
Results and Discussion
A mixture of 2′,5′- and 3′,5′-di[O-(tert-butyldimethylsilyl)]-
3-(4-methoxybenzyl)uridines8 (1a/1b, 1:1) was alkylated [NaH/
4-methoxybenzyl chloride (PMB-Cl)/DMF/0 °C]. Desilylation
(NH4F/MeOH13) gave 3-N,2′,3′-di-O-tri(PMB)uridine (2, 18%),
3-N,3′-O-di(PMB)uridine/3-N,2′-O-di(PMB)uridine (3/4, 1:2;
59%), and 3-N-(PMB)uridine (5, 16%). The apparent intermo-
lecular transfer of TBS groups between secondary alcohol
functions (resulting in the formation of 2 and 5) was not
(8) Nowak, I.; Cannon, J. F.; Robins, M. J. J. Org. Chem. 2007, 72,
532-537.
(14) The 19F NMR spectrum had a triplet of doublets at 57.0 ppm (2J )
3
47.3 Hz, J ) 33.6 Hz).
(9) Gagneron, J.; Gosselin, G.; Mathe´, C. J. Org. Chem. 2005, 70, 6891-
6897.
(15) (a) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1
1980, 2866-2869. (b) Garegg, P. J.; Johansson, R.; Ortega, C.; Samuelsson,
B. J. Chem. Soc., Perkin Trans. 1 1982, 681-683.
(16) For consistency with nucleoside nomenclature, the difluoromethylene
bridge is considered to be a C-substituent on C3′ and C4′ (i.e., the orientation
of the 5′-CH2OH group is used to assign the D- or L-configuration). However,
the -CF2- moiety on C4′ has a higher C-I-P priority than -CH2OH.
Therefore, configurations in the 9 “L-arabino” series are 3′R,4′R and those
in the 10 “D-ribo” series are 3′S,4′S.
(10) Knunyants, I. L.; Komissarov, Y. F.; Dyatkin, B. L.; Lantseva, L.
T. IzV. Acad. Nauk SSSR, Ser. Khim. 1973, 943-944.
(11) Caution: (CF3)2Hg is volatile and toxic, and should be used only
by experienced research personnel with appropriate safety precautions.
(12) Divakar, K. J.; Reese, C. B. J. Chem. Soc., Perkin Trans. 1 1982,
1171-1176.
(13) Zhang, W.; Robins, M. J. Tetrahedron Lett. 1992, 33, 1177-1180.
3320 J. Org. Chem., Vol. 72, No. 9, 2007

Synthesis of 3′-Deoxynucleosides
SCHEME 2a
a Reagents and conditions: (a) DBU/toluene/80 °C; (b) (CF3)2Hg/NaI/THF/70 °C; (c) AcOH/Ac2O/H2SO4; (d) adenine/SnCl4/CH3CN/80 °C; (e) NH3/
H2O/1,4-dioxane.
10a, 5:4) was low, presumably resulting from competing steric
hindrance by the allylic (PMB-O) substituent at C2′ and the
homoallylic [(3-N-(PMB)uracil] group at C1′. Treatment of 9a
(and 10a) with CAN in aqueous acetonitrile at ambient
temperature cleaved both of the 5′-O-TBS17 and 2′-O-(PMB)
ethers to give 9b (and 10b). Acetylation gave 9c (72%, two
steps) [and 10c (59%, two steps)]. Treatment of 9c (and 10c)
with CAN in aqueous acetonitrile at 70 °C18 removed the 3-N-
(PMB) group, and aqueous ammonia in 1,4-dioxane converted
the diacetylated intermediates 9d (and 10d) into the target uracil
nucleosides 9e (48%, two steps) [and 10e (67%, two steps)].
Treatment of 10d with phosphoryl chloride/1,2,4-triazole/
triethylamine12 gave 4-(1,2,4-triazol-1-yl) derivative 10f (90%)
in high yield, whereas the analogous conversion of 9d to 9f
(46%) produced several byproducts. Intermediates 9f and 10f
were subjected to ammonolysis (NH3/H2O/1,4-dioxane) and
chromatography (Dowex 1 × 2 [OH-]) to give the cytosine
nucleosides 9g (77%) and 10g (61%, isolated as the HBr salt).
We next focused on the synthesis of adenine analogues. The
slow rate of addition of CF2 to 8, which gave nearly equal
amounts of diastereomers 9a and 10a, and the large excess of
(CF3)2Hg needed to drive analogous additions with adenine
nucleosides7 prompted another approach. Coupling of adenine
with a sugar derivative containing a preformed difluorocyclo-
propane ring circumvents addition of CF2 to an adenosine-
derived enol ether. Coupling also might be applicable with other
base analogues, and enhanced stereoselectivity might be attained
by addition of CF2 to a suitably functionalized precursor.
Treatment of the known D-xylose triflate derivative 1119
(Scheme 2) with DBU in hot toluene gave 5-O-benzoyl-1,2-
O-isopropylidene-R-D-glycero-pent-3-enofuranose (12). Dias-
tereoselective addition of CF2 to the â face of enol ether 12,
opposite to the R-oriented isopropylidene group, gave the
tricyclic difluorocyclopropane 13 (86%). Treatment of 13 with
AcOH/Ac2O/H2SO4 gave an anomeric mixture of the 1,2-di-
O-acetyl derivatives 14 (55%). We employed a benzoyl ester
for protection of O5, rather than a benzyl ether,9 because partial
cleavage of a benzylic ether and acetylation occurred under the
acidic acetolysis conditions. Adenine and 14 were coupled
(SnCl4 catalysis20) to give 15 in low yield (33%), and depro-
tection gave the adenine nucleoside R-L-16 (Scheme 2). Because
the enantiomers of 2′,3′-dideoxy-3′-thiacytidine (3TC) have
significantly different anti-HIV and toxicity effects,21 and D-
and L-xylose are commercially available, we prepared the
enantiomer R-D-16 by the same sequence.
We attempted to apply the coupling approach for synthesis
of the â-D diastereomer. Gagneron et al.9 reported a synthesis
of compound C beginning with an unfluorinated analogue of
the enantiomer of 13. Their acid-catalyzed solvolysis of the
isopropylidene group gave a product that was functionalized at
O2 and subjected to SN2 inversion at C2 (xylo to ribo). However,
solvolysis of our difluoro analogue under acidic conditions gave
mixtures of epimers and byproducts without a cyclopropane ring.
The powerful electron-withdrawing effect of the CF2 group
affects the ease of formation and stability of oxocarbenium ions,
and fluorine-carbon bonds in difluorocyclopropanes are sus-
ceptible to solvolysis because electron pairs on fluorine atoms
stabilize R-carbocationic character. Products derived from allylic
carbocation rearrangements are formed by ring opening of
difluorocyclopropanes at the bond proximal to the CF2 group
when positive character is generated at positions R to the
cyclopropane ring (whereas bond cleavage is distal to the CF2
group with radical character at R positions).22 Problems also
were encountered with attempted SN2 inversions at C2 of an
isolated minor component. Stereoelectronic effects result in
major differences in the reactivity and stability of such diaster-
eomers.
Compounds 9e and 9g were obtained in crystalline forms
suitable for X-ray analysis. The sugar moiety in 9e (Figure 1)
has a conformation in the 1E (P ) 113.9°) range and a maximum
puckering amplitude (νmax) of 29.6°. The rotational conformation
about the glycosyl bond (ø ) -115.0°) is in the anti range. In
contrast, the furanosyl ring in 9g (Figure 2) is almost flat (νmax
) 6.2°) with a weak preference for the 2E (P ) 338.2°) range,
and the rotation about the glycosyl bond is shifted significantly
(ø ) -171.6°). The nature of the base (uracil or cytosine) and/
or crystal-packing forces seriously affected the pucker (and
especially amplitude) of the furanosyl ring and base rotation in
these conformationally restricted analogues.
In summary, we have synthesized new nucleoside analogues
with 2-oxabicyclo[3.1.0]hexane sugar moieties that have a
difluorocyclopropyl ring fused at C3′-C4′. Addition of difluo-
(17) Hwu, J. R.; Jain, M. L.; Tsai, F.-Y.; Tsay, S.-C.; Balakumar, A.;
Hakimelahi, G. H. J. Org. Chem. 2000, 65, 5077-5088.
(18) Danishefsky, S. J.; DeNinno, S. L.; Chen, S.-h.; Boisvert, L.;
Barbachyn, M. J. J. Am. Soc. Chem. 1989, 111, 5810-5818.
(19) Molina, J.; Maslen, H. L.; Simons, C. Nucleosides, Nucleotides,
Nucleic Acids 2001, 20, 981-983.
(21) Skalski, V.; Chang, C.-N.; Dutschman, G.; Cheng, Y.-C. J. Biol.
Chem. 1993, 268, 23234-23238.
(22) Dolbier, W. R., Jr.; Battiste, M. A. Chem. ReV. 2003, 103, 1071-
1098.
(20) Saneyoshi, M.; Satoh, E. Chem. Pharm. Bull. 1979, 27, 2518-2521.
J. Org. Chem, Vol. 72, No. 9, 2007 3321

Nowak and Robins
1H), 4.02 (d, J ) 5.6 Hz, 1H), 4.18-4.22 (m, 2H), 4.34, 4.49 (2
× d, J ) 11.2 Hz, 2H), 4.58, 4.71 (2 × d, J ) 11.7 Hz, 2H), 4.96,
5.04 (2 × d, J ) 13.7 Hz, 2H), 5.65 (d, J ) 8.3 Hz, 1H), 5.72 (d,
J ) 3.4 Hz, 1H), 6.75, 6.85, 6.86, 7.21, 7.22, 7.47 (6 × m, 6 ×
2H), 7.45 (d, J ) 8.3 Hz, 1H); 13C NMR (CDCl3) δ 43.4, 55.18
(2C), 55.24, 61.2, 71.5, 71.9, 74.3, 77.6, 83.1, 91.7, 101.6, 113.6,
113.7, 113.8, 128.2, 129.2, 129.38, 129.45, 130.1, 130.8, 139.3,
150.6, 159.1, 159.36, 159.42, 162.6; FAB-MS m/z 627 ([M + Na+],
100); HRMS (C33H36N2O9Na) calcd 627.2318, found 627.2319.
The filtrate was concentrated and chromatographed. Elution with
EtOAc/hexanes (1:1) f EtOAc gave 3-N,3′-O-di-(4-methoxyben-
zyl)uridine (3) and 3-N,2′-O-di-(4-methoxybenzyl)uridine (4) (1:
2; 19.2 g, 59%). Rechromatography of overlapping fractions
allowed separation of 3 and 4.
FIGURE 1. X-ray crystal structure of 9e.
3: 1H NMR (CDCl3) δ 2.69 (br s, 2H), 3.77, 3.78 (2 × s, 2 ×
3H), 3.77-3.82 (m, 1H), 3.98 (d, J ) 12.2 Hz, 1H), 4.04-4.07
(m, 1H), 4.19-4.26 (m, 2H), 4.63, 4.67 (2 × d, J ) 11.7 Hz, 2H),
4.98, 5.02 (2 × d, J ) 13.7 Hz, 2H), 5.65 (d, J ) 8.3 Hz, 1H),
5.71 (d, J ) 3.9 Hz, 1H), 6.74, 6.84, 7.15, 7.46 (4 × m, 4 × 2H),
7.42 (d, J ) 8.3 Hz, 1H); 13C NMR (CDCl3) δ 43.6, 55.17, 55.25,
61.8, 72.7, 72.8, 76.6, 83.0, 94.0, 102.1, 113.6, 114.0, 128.66,
128.70, 129.8, 130.8, 139.8, 151.0, 159.0, 159.7, 162.6; FAB-MS
m/z 307 (100), 485 ([M + H+], 32); HRMS (C25H29N2O8) calcd
485.1918, found 485.1917.
4: 1H NMR (CDCl3) δ 2.75 (br s, 2H), 3.64 (dd, J ) 2.4, 12.2
Hz, 1H), 3.77, 3.82 (2 × s, 2 × 3H), 3.90 (dd, J ) 2.0, 12.2 Hz,
1H), 4.11-4.12 (m, 1H), 4.24, 4.41 (2 × t, J ) 5.1 Hz, 2 × 1H),
4.57, 4.60 (2 × d, J ) 11.2 Hz, 2 × 2H), 4.99, 5.03 (2 × d, J )
13.7 Hz, 2H), 5.55 (d, J ) 3.9 Hz, 1H), 5.74 (d, J ) 8.3 Hz, 1H),
6.82, 6.90, 7.27, 7.43 (4 × m, 4 × 2H), 7.39 (d, J ) 8.3 Hz, 1H);
13C NMR (CDCl3) δ 43.4, 55.1 (2C), 61.0, 68.4, 72.1, 79.6, 84.9,
90.0, 101.7, 113.6, 113.8, 128.67, 128.72, 129.9, 130.7, 138.9,
150.7, 159.0, 159.5, 162.6; FAB-MS m/z 485 ([M + H+], 100);
HRMS (C25H29N2O8) calcd 485.1918, found 485.1920.
Further elution of the original column (EtOAc/MeOH, 2:1) gave
3-N-(4-methoxybenzyl)uridine (5) (4.0 g, 16%): 1H NMR (CD3-
OD) δ 3.73 (dd, J ) 2.9, 12.2 Hz, 1H), 3.75 (s, 3H), 3.84 (dd, J )
2.4, 12.2 Hz, 1H), 3.98-4.01 (m, 1H), 4.11-4.16 (m, 2H), 5.01
(s, 2H), 5.78 (d, J ) 8.3 Hz, 1H), 5.92 (d, J ) 3.9 Hz, 1H), 6.82,
7.32 (2 × m, 2 × 2H), 8.02 (d, J ) 8.3 Hz, 1H); 13C NMR (CD3-
OD) δ 44.7, 55.8, 62.1, 71.1, 75.9, 86.2, 91.7, 102.2, 114.7, 130.3,
131.2, 140.9, 152.6, 160.6, 164.9; FAB-MS m/z 321 (100), 387
([M + Na+], 42); HRMS (C17H20N2O7Na) calcd 387.1168, found
387.1155.
FIGURE 2. X-ray crystal structure of 9g.
rocarbene to a 3′,4′ vinyl ether derived from uridine gave nearly
equal amounts of the â-D-ribo16 and R-L-arabino16 diastereomers,
which were converted into uracil and cytosine nucleoside
analogues. Differences in ring puckering and base orientation
were observed in X-ray crystal structures of a conformationally
restricted uracil and cytosine â-D-ribofuranosyl pair. Addition
of CF2 to 3,4 enol ethers derived from the D and L enantiomers
of 1,2-O-isopropylidene-R-xylofuranose gave adducts with the
difluoromethylene bridge anti to the isopropylidene group.
Acetolysis gave 1,2-di-O-acetyl derivatives, which underwent
coupling with adenine to give the enantiomeric R-L-arabino-
furanosyl nucleoside analogues. Acid-catalyzed methanolysis
of the isopropylidene compounds gave mixtures containing
epimerized and cyclopropane ring-opened byproducts, which
thwarted attempts to obtain the adenine â-D-ribofuranosyl
analogues.
5′-O-(tert-Butyldimethylsilyl)-3-N,2′-O-di(4-methoxybenzyl)-
uridine (6). TBS-Cl (1.52 g, 10.1 mmol) was added to a stirred
solution of 4 (4.15 g, 9.2 mmol) in pyridine (20 mL), and stirring
was continued for 1 h. Volatiles were evaporated, and the residue
was chromatographed (EtOAc/hexanes, 1:6 f 1:2) to give 6 (4.23
g, 77%) as a colorless oil: UV max 225, 266 nm (ꢀ 23 900, 9900),
1
min 213, 245 nm (ꢀ 19 500, 4900); H NMR (CDCl3) δ 0.08 (s,
Experimental Section23
6H), 0.90 (s, 9H), 2.59 (d, J ) 6.8 Hz, 1H), 3.77, 3.78 (2 × s, 2
× 3H), 3.78-3.84, 3.98-4.03 (2 × m, 2 × 2H), 4.11-4.17 (m,
1H), 4.70, 4.77 (2 × d, J ) 13.7 Hz, 2 × 1H), 5.06 (s, 2 H), 5.63
(d, J ) 7.8 Hz, 1H), 6.07 (d, J ) 2.4 Hz, 1H), 6.75, 6.85, 7.18,
7.49 (4 × d, J ) 8.8 Hz, 4 × 2H), 7.86 (d, J ) 7.8 Hz, 1H); 13C
NMR (CDCl3) δ -5.8, -5.7, 18.3, 25.8, 43.3, 55.0, 55.1, 61.4,
67.8, 71.5, 80.2, 84.5, 87.5, 101.4, 113.6, 113.8, 128.5, 129.0, 129.8,
130.6, 137.5, 150.7, 159.0, 159.5, 162.4; FAB-MS m/z 599 ([M +
H+], 100), 541, 461; HRMS (C31H43N2O8Si) calcd 599.2788, found
599.2795.
3-N,2′-O-Di-(4-methoxybenzyl)uridine (4). NaH (3.2 g, 133
mmol) and PMB-Cl (10.1 mL, 11.6 g, 74.3 mmol) were added to
an ice-cold solution of 1a/1b7 (1:1; 40.0 g, 67.6 mmol) in DMF
(120 mL), and the suspension was stirred for 1.5 h at ∼0 °C.
Volatiles were evaporated in vacuo, and the residue was partitioned
(H2O, 200 mL/EtOAc, 200 mL). The aqueous phase was extracted
(EtOAc, 2 × 200 mL), and the combined organic phase was dried
(MgSO4) and evaporated to give a yellow oil. NH4F (6.0 g, 162
mmol) and MeOH (500 mL) were added, and the mixture was
stirred at reflux for 20 h and then cooled to 0 °C. Crystalline
material was filtered, washed with cold MeOH (50 mL), and dried
to give 3-N,2′,3′-di-O-tri-(4-methoxybenzyl)uridine 2 (7.2 g,
18%): 1H NMR (CDCl3) δ 2.60 (br s, 1H), 3.68 (d, J ) 12.2 Hz,
1H), 3.78, 3.79, 3.80 (3 × s, 3 × 3H), 3.94 (dd, J ) 2.4, 12.2. Hz,
1-[5-O-(tert-Butyldimethylsilyl)-3-deoxy-3-iodo-2-O-(4-meth-
oxybenzyl)-â-D-xylofuranosyl]-3-(4-methoxybenzyl)uracil (7). A
stirred solution of 6 (4.0 g, 6.8 mmol) in toluene (130 mL) was
treated with PPh3 (3.7 g, 14.1 mmol), imidazole (1.9 g, 28.3 mmol),
and I2 (3.6 g, 14.1 mmol) under N2. The mixture was heated at 75
°C for 2.5 h, and cooled to ambient temperature. The clear
supernatant was decanted and concentrated. Chromatography
(EtOAc/hexanes, 1:9 f 1:3) gave 7 (4.0 g, 84%). An analytically
(23) Experimental details are in the Supporting Information.
3322 J. Org. Chem., Vol. 72, No. 9, 2007

Synthesis of 3′-Deoxynucleosides
pure sample was obtained by crystallization (MeOH) as colorless
blocks: mp 96-98 °C; UV max 226, 265 nm (ꢀ 25 700, 11 200),
min 214, 245 nm (ꢀ 22 600, 6800); 1H NMR (CDCl3) δ 0.10, 0.11
(2 × s, 2 × 3H), 0.90 (s, 9H), 3.76, 3.77 (2 × s, 2 × 3H), 3.78
(dd, J ) 4.9, 10.7 Hz, 1H), 3.88 (q, J ) 4.4 Hz, 1H), 3.98 (dd, J
) 3.9, 10.7 Hz, 1H), 4.33-4.36 (m, 2H), 4.63 (d, J ) 13.7 Hz,
1H), 4.71, 5.09 (2 × d, J ) 13.7 Hz, 2 × 1H), 5.66 (d, J ) 8.3 Hz,
1H), 5.92 (d, J ) 3.9 Hz, 1H), 6.73 (d, J ) 8.7 Hz, 2H), 6.83,
7.15, 7.48 (3 × d, J ) 8.8 Hz, 3 × 2H), 7.62 (d, J ) 8.3 Hz, 2H);
13C NMR (CDCl3) δ -5.7, -5.4, 18.0, 25.1, 25.7, 43.2, 54.80,
54.85, 67.0, 72.0, 79.8, 86.4, 88.7, 101.3, 113.3, 113.5, 128.5, 128.7,
129.5, 130.5, 137.5, 150.5, 158.8, 159.3, 161.9; FAB-MS m/z 731
([M + Na+] 100%), 711, 605; HRMS (C31H41IN2O7SiNa) calcd
731.1625, found 731.1626.
(EtOAc/hexanes, 1:4 f EtOAc) gave 9b (3.6 g, 97%). This material
was dissolved in pyridine (10 mL) and Ac2O (5 mL), and the
solution was stirred for 17 h at ambient temperature. Volatiles were
evaporated in vacuo, and the residue was chromatographed (EtOAc/
hexanes, 1:2 f EtOAc) to give 9c as a yellow oil (3.12 g, 72%):
UV max 223, 259 nm (ꢀ 13 300, 8800), min 216, 240 nm (ꢀ 12 800,
5800); 1H NMR (CDCl3) δ 2.02, 2.08 (2 × s, 2 × 3H), 2.39 (d, J
) 15.1 Hz, 1H), 3.69 (s, 3H), 4.37-4.45 (m, 2H), 4.86, 4.99 (2 ×
d, J ) 13.7 Hz, 2 × 1H), 5.20 (d, J ) 6.3 Hz, 1H), 5.78 (d, J )
8.3 Hz, 1H), 6.47 (d, J ) 6.3 Hz, 1H), 6.74 (d, J ) 8.8 Hz, 2H),
7.19 (d, J ) 8.3 Hz, 1H), 7.30 (d, J ) 8.8 Hz, 2H); 19F NMR
(CDCl3) δ 129.3 (dd, J ) 15.0, 170.9 Hz, 1F), 149.7 (d, J ) 170.9
Hz, 1F); 13C NMR (CDCl3) δ 20.3, 20.6, 33.3 (t, J ) 12.1 Hz),
43.8, 55.1, 59.4, 68.0 (t, J ) 11.9 Hz), 74.7, 95.5 (d, J ) 3.7 Hz),
103.6, 110.4 (t, J ) 297.7 Hz), 113.6, 128.5, 130.3, 136.0 (d, J )
7.3 Hz), 150.7, 159.0, 161.8, 169.4, 170.3; FAB-MS m/z 503 ([M
+ Na+] 100%); HRMS (C22H22F2N2O8Na) calcd 503.1245, found
503.1242.
1-[2,5-Di-O-acetyl-3-deoxy-3,4-C-(difluoromethylene)-â-D-ri-
bofuranosyl]-3-(4-methoxybenzyl)uracil (10c). Treatment of 10a
(7.4 g, 11.6 mmol) according to the procedure described for 9a f
9b f 9c gave 10c as a yellow oil (3.28 g; 59%, two steps). UV
max 223, 258 nm (ꢀ 13 600, 8 800), min 217, 240 nm (ꢀ 13 100,
5 800); 1H NMR (CDCl3) δ 2.03, 2.05 (2 × s, 2 × 3H), 2.69 (dd,
J ) 14.6, 7.0 Hz, 1H), 3.70 (s, 3H), 4.37 (dd, J ) 13.2, 1.8 Hz,
1H), 4.51 (d, J ) 13.2 Hz, 1H), 4.92, 4.96 (2 × d, J ) 13.6 Hz, 2
× 1H), 5.50 (d, J ) 3.7 Hz, 1H), 5.71 (d, J ) 8.0 Hz, 1H), 5.74
(m, 1H), 6.75 (d, J ) 8.4 Hz, 2H), 7.03 (d, J ) 8.0 Hz, 1H), 7.33
(d, J ) 8.4 Hz, 2H); 19F NMR (CDCl3) δ 133.6 (dd, J ) 14.9,
170.9 Hz, 1F), 148.7 (d, J ) 170.9 Hz, 1F); 13C NMR (CDCl3) δ
20.57, 20.63, 33.1 (t, J ) 12.6 Hz), 43.6, 55.2, 59.7, 71.6 (t, J )
11.5 Hz), 77.4, 96.7, 102.8, 111.5 (dd, J ) 294.5, 306.7 Hz), 113.7,
128.4, 130.6, 139.6, 150.4, 159.1, 162.0, 170.2, 170.5; FAB-MS
m/z 481 ([M + H+] 100%); HRMS (C22H23F2N2O8) calcd 481.1422,
found 481.1418.
1-[3-Deoxy-3,4-C-(difluoromethylene)-â-D-ribofuranosyl]u-
racil (10e). A solution of CAN (12.3 g, 22.5 mmol) in H2O (15
mL) was added to a stirred solution of 10c (2.7 g, 5.63 mmol) in
CH3CN (150 mL), and stirring was continued at 70 °C for 1.5 h.
H2O was added, the mixture was extracted (EtOAc, 3 × 100 mL),
and volatiles were evaporated in vacuo from the combined organic
phase. The residue was chromatographed (EtOAc/hexanes, 1:3 f
EtOAc) to give crude 1-[2,5-di-O-acetyl-3-deoxy-3,4-C-(difluo-
romethylene)-â-D-ribofuranosyl]uracil (10d, 1.5 g). This material
was added to a stirred solution of 1,4-dioxane (18 mL) and 30%
NH3/H2O (5 mL), and stirring was continued overnight. Volatiles
were evaporated, and the residue was dissolved (H2O, 20 mL) and
applied to a column of Dowex 1 × 2 (OH-) resin (in H2O). Elution
[H2O f MeOH f AcOH/MeOH (1:10)] and evaporation of
volatiles from UV-absorbing fractions gave 10e (740 mg; 48%, 2
steps) as a yellow syrup. An analytically pure sample was obtained
after several recrystallizations (EtOH): mp 180-182 °C; UV max
259 nm (ꢀ 9600), min 229 nm (ꢀ 2800); 1H NMR (CD3OD) δ 2.43
(d, J ) 16.6 Hz, 1H), 3.89 (d, J ) 13.2 Hz, 1H), 3.98 (dd, J )
13.2, 2.9 Hz, 1H), 4.52 (d, J ) 6.3 Hz, 1H), 5.79 (d, J ) 7.8 Hz,
1H), 6.33 (d, J ) 6.3 Hz, 1H), 7.48 (d, J ) 7.8 Hz, 1H); 19F NMR
(CD3OD) δ 129.7 (dd, J ) 16.0, 168.7 Hz, 1F), 148.9 (d, J )
168.7 Hz, 1F); 13C NMR (CD3OD) δ 36.2 (t, J ) 11.4 Hz), 59.1,
72.2 (t, J ) 11.8 Hz), 76.1, 98.6 (d, J ) 4.6 Hz), 104.0, 113.6 (t,
J ) 296.0 Hz), 141.3 (d, J ) 6.9 Hz), 152.4, 165.8; EI-MS m/z
276 ([M+] 2%); HRMS (C10H10F2N2O5) calcd 276.0557, found
276.0563. Anal. Calcd for C10H10F2N2O5: C, 43.49; H, 3.65; N
10.14. Found: C, 43.31; H, 3.86; N 9.96.
1-[5-O-(tert-Butyldimethylsilyl)-3-deoxy-2-O-(4-methoxyben-
zyl)-â-D-glycero-pent-3-enofuranosyl]-3-(4-methoxybenzyl)u-
racil (8). A stirred solution of 7 (4.0 g, 5.6 mmol) and DABCO
(2.0 g, 17.9 mmol) in benzene (50 mL) was refluxed for 20 h and
concentrated. Chromatography (EtOAc/hexanes, 1:6 f 1:3) gave
8 (3.2 g, 96%) as a pale yellow oil: UV max 226, 265 nm (ꢀ 27 700,
1
11 200), min 214, 245 nm (ꢀ 24 500, 7300); H NMR (CDCl3) δ
0.09 (s, 6H), 0.90 (s, 9H), 3.76 (s, 3H), 3.79 (s, 3H), 4.23, 4.26 (2
× d, J ) 13.7 Hz, 2 × 1H), 4.46 (s, 1H), 4.59, 4.72, 5.07, 5.09 (4
× d, J ) 13.7 Hz, 4 × 1H), 5.17 (s, 1H), 5.71 (d, J ) 8.3 Hz, 1H),
6.45 (s, 1H), 6.82, 6.85 (2 × d, J ) 8.8 Hz, 2 × 2H), 7.10 (d, J )
8.3 Hz, 1H), 7.22, 7.48 (2 × d, J ) 8.8 Hz, 2 × 2H); 13C NMR
(CDCl3) δ -5.61, -5.57, 18.1, 25.6, 43.5, 55.0, 58.0, 70.4, 85.0,
90.8, 98.9, 102.2, 113.6, 113.7, 128.8, 129.3, 129.5, 129.6, 130.6,
136.5, 150.2, 159.0, 159.3, 162.2, 162.4; FAB-MS m/z 603 ([M +
Na+] 100%); HRMS (C31H40N2O7SiNa) calcd 603.2502, found
603.2509.
1-[5-O-(tert-Butyldimethylsilyl)-3-deoxy-3,4-C-(difluorometh-
ylene)-2-O-(4-methoxybenzyl)-r-L-arabinofuranosyl]-3-(4-meth-
oxybenzyl)uracil16 (9a) and 1-[5-O-(tert-Butyldimethylsilyl)-3-
deoxy-3,4-C-(difluoromethylene)-2-O-(4-methoxybenzyl)-â-D-
ribofuranosyl]-3-(4-methoxybenzyl)uracil16 (10a). Powdered NaI
(30.0 g, 200 mmol) was stirred and heated (170 °C, oil bath) under
vacuum for 1 h in a flask (500 mL) equipped with a Teflon valve,
then allowed to cool to ambient temperature. (CF3)2Hg (17.4 g,
50.8 mmol) in dried THF (50 mL) and 8 (15.0 g, 25.4 mmol) were
injected through a septum (under N2). The reaction mixture was
heated at 70 °C for 24 h, and volatiles were evaporated. Chroma-
tography (EtOAc/hexanes, 1:9 f 1:6) gave 9a (7.4 g, 46%): 1H
NMR (CDCl3) δ 0.09, 0.11 (2 × s, 2 × 3H), 0.93 (s, 9H), 2.27 (d,
J ) 15.6 Hz, 1H), 3.74, 3.76 (2 × s, 2 × 3H), 3.87 (d, J ) 12.7
Hz, 1H), 4.04-4.08 (m, 2H), 4.40, 4.50 (2 × d, J ) 12.2 Hz, 2H),
5.02, 5.07 (2 × d, J ) 13.7 Hz, 2H), 5.68, 7.03 (2 × d, J ) 8.3
Hz, 2 × 1H), 6.51 (d, J ) 6.3 Hz, 1H), 6.68, 6.82, 7.06 7.49 (4 ×
m, 4 × 2H); 19F NMR (CDCl3) δ 129.5 (dd, J ) 15.0, 168.7 Hz,
1F), 148.8 (d, J ) 168.8 Hz, 1F); FAB-MS m/z 631 ([M + H+]
40%), 121 (100%); HRMS (C32H41F2N2O7Si) calcd 631.2645, found
631.2654.
Further elution of the column with EtOAc/hexanes (1:1) gave
10a (6.0 g, 37%): 1H NMR (CDCl3) δ 0.05, 0.06 (2 × s, 2 × 3H),
0.88 (s, 9H), 2.27 (dd, J ) 6.8, 14.6 Hz, 1H), 3.75-3.80 (m, 1H),
3.760, 3.764 (2 × s, 2 × 3H), 4.11 (dd, J ) 3.4, 12.2 Hz, 1H),
4.44-4.54 (m, 3H), 5.03, 5.05 (2 × d, J ) 13.7 Hz, 2H), 5.69 (d,
J ) 7.8 Hz, 1H), 5.97-6.00 (m, 1H), 6.74, 6.83, 7.11, 7.48 (4 ×
m, 4 × 2H), 7.29 (d, J ) 7.8 Hz, 1H); 19F NMR (CDCl3) δ 133.3
(dd, J ) 15.0, 170.9 Hz, 1F), 147.6 (d, J ) 170.9 Hz, 1F); FAB-
MS m/z 653 ([M + Na+] 10%), 141 (100%); HRMS (C32H40F2N2O7-
SiNa) calcd 653.2465, found 653.2468.
1-[2,5-Di-O-acetyl-3-deoxy-3,4-C-(difluoromethylene)-r-L-
arabinofuranosyl]-3-(4-methoxybenzyl)uracil (9c). A solution of
CAN (15.4 g, 28.1 mmol) in H2O (20 mL) was added to a stirred
solution of 9a (6.0 g, 9.4 mmol) in CH3CN (200 mL). Stirring was
continued at ambient temperature for 2.5 h, H2O was added, and
the solution was extracted (EtOAc, 3 × 100 mL). The combined
organic phase was concentrated in vacuo, and chromatography
1-[3-Deoxy-3,4-C-(difluoromethylene)-r-L-arabinofuranosyl]-
uracil (9e). Treatment of 9c (3.1 g, 6.46 mmol) with CAN followed
by ammonolysis (as described for 10c f 10e) gave 9e (1.19 g;
67%, 2 steps) as a colorless oil. Purification by PTLC (EtOAc/
MeOH, 7:1) gave 9e: UV max 259 nm (ꢀ 9600), min 229 nm (ꢀ
1
3000); H NMR (Me2CO-d6) δ 2.65 (dd, J ) 6.8, 16.2 Hz, 1H),
J. Org. Chem, Vol. 72, No. 9, 2007 3323

Nowak and Robins
3.84 (d, J ) 13.2 Hz, 1H), 4.01 (dd, J ) 13.2, 3.4 Hz, 1H), 5.10-
5.13 (m, 1H), 5.70 (d, J ) 8.3 Hz, 1H), 5.84 (dd, J ) 2.4, 4.9 Hz,
1H), 7.74 (d, J ) 8.3 Hz, 1H); 19F NMR (Me2CO-d6) δ 132.8 (dd,
J ) 168.7, 17.1 Hz, 1F), 146.4 (d, J ) 168.7 Hz, 1F); 13C NMR
(Me2CO-d6) δ 32.6 (t, J ) 11.7 Hz), 58.2, 73.9 (t, J ) 11.2 Hz),
76.8, 94.5 (d, J ) 5.5 Hz), 103.5, 114.8 (dd, J ) 292.2, 306.9 Hz),
142.6, 151.5, 164.2; FAB-MS m/z 277 ([M + H+] 60%), 140
(100%); HRMS (C10H11F2N2O5) calcd 277.0636, found 277.0651.
1-[3-Deoxy-3,4-C-(difluoromethylene)-â-D-ribofuranosyl]cy-
tosine Hydrobromide (10g‚HBr). Et3N (6.17 mL, 4.49 g, 44.5
mmol) was added dropwise to a cooled (∼0 °C) stirred mixture of
1,2,4-triazole (3.22 g, 46.7 mmol), POCl3 (0.94 mL, 1.50 g, 9.8
mmol), and MeCN (28 mL). A solution of 10d (1.6 g, 4.4 mmol)
in MeCN (18 mL) was added, and stirring was continued for 2 h
at ambient temperature. Et3N (4.29 mL, 3.13 g, 30.9 mmol) and
H2O (1.7 mL) were added, and stirring was continued for 10 min.
Volatiles were evaporated at ambient temperature, and the residue
was partitioned [ice-cold, saturated NaHCO3/H2O (100 mL)//CH2-
Cl2 (100 mL)]. The aqueous phase was extracted (CH2Cl2, 100 mL),
and the combined organic phase was washed (brine, 50 mL) and
dried (MgSO4). Volatiles were evaporated to give 1-[2,5-di-O-
acetyl-3-deoxy-3,4-C-(difluoromethylene)-â-D-ribofuranosyl]-4-
(1,2,4-triazol-1-yl)pyrimidin-2-one (10f) (1.64 g, 90%) as a yellow
syrup: FAB-MS m/z 434 ([M + Na+] 100%); HRMS (C16H15F2N5O6-
Na) calcd 434.0879, found 434.0880.
NH3/H2O (30%, 6 mL) was added to a stirred solution of this
material in 1,4-dioxane (18 mL), and stirring was continued for 12
h at ambient temperature. Volatiles were evaporated, and the residue
was dissolved (H2O, 20 mL) and applied to a column of Dowex 1
× 2 (OH-) resin (in H2O). Elution [H2O, MeOH] and evaporation
of volatiles from UV-absorbing fractions gave 10g (870 mg) as a
yellow syrup. A solution of this material in MeOH was treated
with 5% HBr/H2O and volatiles were evaporated. The red residue
was chromatographed on silica gel (EtOAc f EtOAc/MeOH, 2:1),
and crystallized (EtOH) to give 10g‚HBr (870 mg, 61%) as a white
powder: mp 218-220 °C; UV max 278 nm (ꢀ 10 000), min 245
nm (ꢀ 4200); 1H NMR (CD3OD) δ 2.61 (d, J ) 15.1, 7.3 Hz, 1H),
3.88 (d, J ) 13.2 Hz, 1H), 3.98 (dd, J ) 13.2, 3.4 Hz, 1H), 4.97-
5.00 (m, 1H), 5.82 (dd, J ) 2.4, 4.4 Hz, 1H), 6.18, 8.13 (2 × d, J
) 7.8 Hz, 2 × 1H); 19F NMR (CD3OD) δ 133.1 (dd, J ) 15.0,
170.9 Hz, 1F), 147.2 (d, J ) 170.9 Hz, 1F); 13C NMR (CD3OD) δ
33.3 (t, J ) 11.8 Hz), 58.6, 75.2 (t, J ) 11.4 Hz), 77.9, 95.8, 96.1
(d, J ) 4.8 Hz), 114.7 (dd, J ) 291.4, 305.9 Hz), 147.3, 148.5,
161.5; EI-MS m/z 276 ([M + H+] 60%); HRMS (C10H12F2N3O4)
calcd 276.0796, found 276.0800. Anal. Calcd for C10H12-
BrF2N3O4: C, 33.73; H, 3.40; N, 11.80. Found: C, 33.77; H, 3.55;
N, 11.86.
1-[3-Deoxy-3,4-C-(difluoromethylene)-r-L-arabinofuranosyl]-
cytosine (9g). Et3N (6.95 mL, 5.05 g, 50.1 mmol) was added
dropwise to a cooled (∼0 °C) stirred mixture of 1,2,4-triazole (3.62
g, 52.5 mmol), POCl3 (1.06 mL, 1.69 g, 11.0 mmol), and MeCN
(31 mL). A solution of 1-[2,5-di-O-acetyl-3-deoxy-3,4-C-(difluo-
romethylene)-R-L-arabinofuranosyl]uracil 9d (1.8 g, 5.0 mmol) in
MeCN (20 mL) was added, and stirring was continued for 2 h at
ambient temperature. Et3N (4.83 mL, 3.52 g, 34.8 mmol) and H2O
(1.94 mL) were added, and stirring was continued for 10 min.
Volatiles were evaporated at ambient temperature, and the residue
was partitioned [ice-cold saturated NaHCO3/H2O (100 mL)//CH2-
Cl2 (100 mL)]. The aqueous phase was extracted (CH2Cl2, 100 mL),
and the combined organic phase was washed (brine, 50 mL) and
dried (MgSO4). Volatiles were evaporated to give a yellow oil (1.7
g). Chromatography (EtOAc/hexanes, 1:2 f 2:1) gave a mixture
of unidentified products (mainly two, 330 mg) and 1-[2,5-di-O-
acetyl-3-deoxy-3,4-C-(difluoromethylene)-R-L-arabinofuranosyl]-
4-(1,2,4-triazol-1-yl)pyrimidin-2-one (9f) (940 mg, 46%) as a
colorless syrup: FAB-MS m/z 434 ([M + Na+] 13%), 321, 239
(100%); HRMS (C16H15F2N5O6Na) calcd 434.0879, found 434.0880.
NH3/H2O (30%, 6 mL) was added to a stirred solution of this
material in 1,4-dioxane (18 mL), and stirring was continued for 12
h at ambient temperature. Volatiles were evaporated, and the residue
was dissolved (H2O, 20 mL) and applied to a column of Dowex 1
× 2 (OH-) resin (in H2O). Elution [H2O, MeOH (1 L)] and
evaporation of volatiles from UV-absorbing fractions gave a residue
that was chromatographed (EtOAc f EtOAc/MeOH, 10:1) to give
9g (490 mg, 77%) as colorless crystals: mp >250 °C dec; UV
max 242, 269 nm (ꢀ 8500, 8300), min 225, 257 nm (ꢀ 7100, 8000);
1H NMR (CD3OD) δ 2.40 (d, J ) 16.6 Hz, 1H), 3.89 (d, J ) 13.7
Hz, 1H), 3.96 (dd, J ) 13.7, 3.4 Hz, 1H), 4.56 (d, J ) 5.9 Hz,
1H), 5.93 (d, J ) 7.3 Hz, 1H), 6.36 (d, J ) 5.9 Hz, 1H), 7.54 (d,
J ) 7.3 Hz, 1H); 19F NMR (CD3OD) δ 130.0 (dd, J ) 17.1, 168.7
Hz, 1F), 148.9 (d, J ) 168.7 Hz, 1F); 13C NMR (CD3OD) δ 36.5
(t, J ) 11.8 Hz), 59.2, 72.8 (t, J ) 11.3 Hz), 77.2, 97.0, 100.1 (d,
J ) 5.3 Hz), 113.7 (t, J ) 296.0 Hz), 141.7 (d, J ) 6.1 Hz), 158.6,
167.7; EI-MS m/z 298 ([M + Na+] 60%), 242 (100%); HRMS
(C10H11F2N3O4Na) calcd 298.0615, found 298.0632. Anal. Calcd
for C10H11F2N3O4: C, 43.64; H, 4.03; N, 15.27. Found: C, 43.57;
H, 4.16; N, 15.33.
5-O-Benzoyl-3-deoxy-1,2-O-isopropylidene-3,4-C-(difluorom-
ethylene)-â-L-arabinofuranose (13). A solution of 5-O-benzoyl-
1,2-O-isopropylidene-3-O-triflyl-R-D-xylofuranose19 (11) (28.0 g,
62.2 mmol) and DBU (14.2 g, 13.9 mL, 93.3 mmol) in toluene
(100 mL) was stirred for 1 h at 80 °C. Volatiles were evaporated
in vacuo, and the residue was chromatographed (EtOAc/hexanes,
1:6) to give 5-O-benzoyl-1,2-O-isopropylidene-3-deoxy-R-D-glyc-
ero-pent-3-enofuranose (12) (15.0 g, 87%) as a colorless oil: 1H
NMR (CDCl3) δ 1.46, 1.49 (2 × s, 2 × 3H), 4.83-4.90 (m, 2H),
5.29-5.34 (m, 2H), 6.12 (d, J ) 5.4 Hz, 1H), 7.43-8.06 (m, 5H);
13C NMR (CDCl3) δ 27.5, 27.7, 58.8, 83.1, 100.5, 106.2, 112.0,
128.1, 129.2, 129.4, 133.0, 156.2, 165.3; FAB-MS m/z 277 ([M +
H+] 15%), 105 (100%); HRMS (C15H17O5) calcd 277.1076, found
277.1059.
A solution of NaI (39.1 g, 260.9 mmol) and (CF3)2Hg (22.1 g,
65.2 mmol) in THF (60 mL) was added to this material (15.0 g,
54.3 mmol), and the mixture was stirred and heated for 2 h at 70
°C in a sealed flask. The resulting brown solution was concentrated,
then chromatographed (EtOAc/hexanes, 1:6 f 1:2) to give 13 (17.5
g, 99%) as a pale yellow oil: 1H NMR (CDCl3) δ 1.35, 1.49 (2 ×
s, 2 × 3H), 2.58 (d, J ) 16.1 Hz, 1H), 4.73 (dd, J ) 2.9, 13.2 Hz,
1H), 4.83 (d, J ) 13.2 Hz, 1H), 4.88 (d, J ) 3.9 Hz, 1H), 5.76 (t,
J ) 3.9 Hz, 1H), 7.41-7.46 (m, 2H), 7.54-7.59 (m, 1H), 8.06-
8.10 (m, 2H); 19F NMR (CDCl3) δ 136.6 (dd, J ) 17.1, 173.0 Hz,
1F), 150.8 (d, J ) 173.0 Hz, 1F); 13C NMR (CDCl3) δ 27.3, 28.1,
32.6 (t, J ) 11.1 Hz), 60.0, 69.5 (t, J ) 11.1 Hz), 81.2, 108.4 (d,
J ) 7.6 Hz), 110.7 (dd, J ) 296.8, 302.1 Hz), 115.4, 128.3, 129.3,
129.8, 133.2, 156.1; FAB-MS m/z 349 ([M + Na+] 80%), 269
(100%); HRMS (C16H16F2O5Na) calcd 349.0864, found 349.0864.
1-[3-Deoxy-3,4-C-(difluoromethylene)-r-L-arabinofuranosyl]-
adenine (r-L-16). A mixture of 13 (15 g, 46 mmol), AcOH (138
mL), Ac2O (28 mL), and concentrated H2SO4 (4.5 mL) was stirred
for 8 h at ambient temperature. The solution was partitioned [EtOAc
(300 mL)/H2O (500 mL)], and the aqueous phase was extracted
(EtOAc, 2 × 200 mL). The combined organic phase was dried
(MgSO4), concentrated, and chromatographed (EtOAc/hexanes, 1:6
f 1:1) to give 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-3,4-C-(dif-
luoromethylene)-L-arabinofuranose (14) (9.4 g, 55%). SnCl4 (17.3
mL, 39.8 g, 152.4 mmol) was added to a cold (-20 °C) stirred
mixture of this material and adenine (6.86 g, 50.8 mmol) in dried
CH3CN (160 mL). The resulting clear, dark solution was stirred
and heated for 30 min at 80 °C, cooled to ambient temperature,
and washed with saturated NaHCO3/H2O. Volatiles were evaporated
from the organic layer, and the residue was chromatographed
(EtOAc f EtOAc/MeOH, 10:1) to give 9-(2-O-acetyl-5-O-benzoyl-
3-deoxy-3,4-C-(difluoromethylene)-R-L-arabinofuranosyl)adenine
(15) (3.71 g, 33%). A solution of this material (1.5 g, 3.37 mmol)
in 1,4-dioxane (20 mL) and NH3/H2O (30%, 5 mL) was stirred
overnight at ambient temperature. Volatiles were evaporated, and
the residue was chromatographed (Dowex 1 × 2 [OH-]; (MeOH
f AcOH/MeOH, 1:4)). UV-absorbing fractions were concentrated
3324 J. Org. Chem., Vol. 72, No. 9, 2007

Synthesis of 3′-Deoxynucleosides
and chromatographed on silica gel (EtOAc f EtOAc/MeOH, 10:
1) to give R-L-16 (740 mg, 73%): [R]24D -36.8° (c 0.57, MeOH);
UV max 259 nm (ꢀ 14 000), min 227 nm (ꢀ 2500); 1H NMR (CD3-
OD) δ 2.53 (d, J ) 16.1 Hz, 1H), 3.90 (d, J ) 13.2 Hz, 1H), 4.03
(dd, J ) 3.4, 13.2 Hz, 1H), 5.03 (s, J ) 6.3 Hz, 1H), 6.39 (d, J )
6.3 Hz, 1H), 8.215, 8.223 (2 × s, 2 × 1H); 19F NMR (CD3OD) δ
130.4 (dd, J ) 17.1, 166.6 Hz, 1F), 150.0 (d, J ) 166.6 Hz, 1F).
13C NMR (DMSO-d6) δ 34.9 (t, J ) 10.7 Hz), 57.4, 70.5 (t, J )
11.4 Hz), 73.8, 95.3 (d, J ) 6.1 Hz), 112.4 (dd, J ) 293.7, 299.1
Hz), 118.5, 138.6, 149.8, 153.1, 156.1; EI-MS m/z 299 ([M+] 7%),
242, 177, 148 (100%); HRMS (C11H11F2N5O3) calcd 299.0830,
found 299.0826.
of the enantiomers of compounds 11-16 were identical with those
described; R-D-16: [R]24 34.2° (c 0.38, MeOH).
D
Acknowledgment. We gratefully acknowledge NIH grant
GM29332, pharmaceutical company unrestricted gift funds
(M.J.R.), and Brigham Young University for support of this
work, and thank Professor John F. Cannon for determining the
X-ray crystal structures.
Supporting Information Available: General experimental
details, NMR spectra, X-ray CIF data for 9e (code XL555) and 9g
(code XL567). This material is available free of charge via the
Internet at http://pubs.acs.org.
1-[3-Deoxy-3,4-C-(difluoromethylene)-r-D-arabinofuranosyl]-
adenine (r-D-16). L-Xylose was subjected to the identical sequence
used for conversion of D-xylose to R-L-16. NMR and mass spectra
JO062614D
J. Org. Chem, Vol. 72, No. 9, 2007 3325