Addition of difluorocarbene to 3′,4′-unsaturated nucleosides: Synthesis of 2′-deoxy analogues with a 2-oxabicyclo[3.1.0]hexane framework

Article abstract of DOI:10.1021/jo061965p

Treatment of protected 2′-deoxy-3′,4′-unsaturated nucleosides derived from adenosine and uridine with difluorocarbene [generated from bis(trifluoromethyl)mercury and sodium iodide] gave fused-ring 2,2-difluorocyclopropane compounds. Stereoselective α-face

Full text of DOI:10.1021/jo061965p

Addition of Difluorocarbene to 3′,4′-Unsaturated Nucleosides:
Synthesis of 2′-Deoxy Analogues with a 2-Oxabicyclo[3.1.0]hexane
Framework1
Ireneusz Nowak, John F. Cannon, and Morris J. Robins*
Department of Chemistry and Biochemistry, Brigham Young UniVersity, ProVo, Utah 84602-5700
morris_robins@byu.edu
ReceiVed September 22, 2006
Treatment of protected 2′-deoxy-3′,4′-unsaturated nucleosides derived from adenosine and uridine with
difluorocarbene [generated from bis(trifluoromethyl)mercury and sodium iodide] gave fused-ring 2,2-
difluorocyclopropane compounds. Stereoselective R-face addition to the dihydrofuran ring resulted from
hindrance by the protected â-anomeric nucleobases. A protected uracil compound was converted smoothly
into the cytosine derivative via a 4-(1,2,4-triazol-1-yl) intermediate. Removal of the protecting groups
gave new difluorocyclopropane-fused nucleoside analogues. The solid-state conformation of the nearly
2
planar furanosyl ring in the uracil compound had a shallow E pucker, and a more pronounced E
1
conformation was present in the furanosyl ring of the cytosine derivative.
Introduction
receptors7 have been demonstrated with such constrained
nucleoside analogues. Syntheses of carbocyclic nucleoside
analogues require multiple steps, and the resulting surrogates
lack a furanosyl oxygen atom (O4′), which affects hydrogen
bond accepting as well as anomeric and gauche effects.
Very recently, Simmons-Smith cyclopropanation of enol
ether B (derived from L-xylose) was used to prepare a
2-oxabicyclo[3.1.0]hexane-based precursor for nucleoside ana-
logue A8 (Figure 1). We had anticipated9 that electron-rich
alkenes derived from nucleoside enol ethers such as D would
undergo addition of difluorocarbene to produce 2-oxabicyclo-
Nucleosides constitute a steadily growing family of small
molecules with demonstrated therapeutic potential. A variable
that adds complexity to interpretations of structure-activity
relationships with nucleoside analogues is their inherent flex-
ibility. Various conformational forms of naturally occurring
nucleosides are in rapid equilibrium. Furanosyl rings have
pseudorotational mobility, and relationships were defined for
two extreme forms of ring pucker [i.e., the north (N) and south
(S) pseudorotational ranges].2 Conformational preferences are
determined by the interplay of anomeric, gauche, and steric
effects.3 Design and synthesis of conformationally restricted
nucleoside analogues has been pursued to probe enzyme
preferences for the N versus S (or other) forms. Marquez and
co-workers have shown that ring-fused cyclopropane-cyclo-
pentane rings provide carbocyclic bicyclo[3.1.0]hexane scaffolds
that can be constrained in either N4 or S5 ranges. Selectivities
for binding with several enzymes6 and subtypes of adenosine
(4) Choi, Y.; Moon, H. R.; Yoshimura, Y.; Marquez, V. E. Nucleosides,
Nucleotides Nucleic Acids 2003, 22, 547-557.
(5) Ezzitouni, A.; Marquez, V. E. J. Chem. Soc., Perkin Trans. 1 1997,
1073-1078.
(6) (a) Marquez, V. E.; Ezzitouni, A.; Russ, P.; Siddiqui, M. A.; Ford,
H.; Feldman, R. J.; Mitsuya, H.; George, C.; Barchi, J. J., Jr. J. Am. Chem.
Soc. 1998, 120, 2780-2789. (b) Marquez, V. E.; Russ, P.; Alonso, R.;
Siddiqui, M. A.; Hernandez, S.; George, C.; Nicklaus, M. C.; Dai, F.; Ford,
H. HelV. Chim. Acta 1999, 82, 2119-2129.
(7) (a) Jacobson, K. A.; Ji, X.-D.; Li, A.-H.; Melman, N.; Siddiqui,
M. A.; Shin, K.-J.; Marquez, V. E.; Ravi, R. G. J. Med. Chem. 2000, 43,
2196-2203. (b) Kim, H. S.; Ravi, R. G.; Marquez, V. E.; Maddileti, S.;
Wihlborg, A.-K.; Erlinge, D.; Malsmjo, M.; Bojer, J. L.; Harden, T. K.;
Jacobson, K. A. J. Med. Chem. 2002, 45, 208-218.
(8) Gagneron, J.; Gosselin, G.; Mathe´, C. J. Org. Chem. 2005, 70, 6891-
6897.
(1) Nucleic Acid Related Compounds. 141. Paper 140: Zhong, M.;
Robins, M. J. J. Org. Chem. 2006, 71, 8901-8906.
(2) (a) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1972, 94, 8205-
8212. (b) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1973, 95, 2333-
2344.
(3) Thibaudeau, C.; Chattopadhaya, J. In Stereoelectronic Effects in
Nucleosides and Their Structural Implications; Uppsala University Press:
Uppsala, Sweden, 1999.
(9) Nowak, I.; Cannon, J. F.; Robins, M. J. Org. Lett. 2004, 6, 4767-
4770.
10.1021/jo061965p CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/16/2006
532
J. Org. Chem. 2007, 72, 532-537

Synthesis of 2′-Deoxy Analogues
with adventitious HF). Therefore, we generated difluorocarbene
(carbenoid) from the inexpensive and readily prepared bis-
(trifluoromethyl)mercury13 (CAUTION)14 and sodium iodide
in THF at 60 °C.
Cyclopropylcarbinyl-allylcarbinyl rearrangements that occur
upon generation of radicals vicinal to such cyclopropane rings15
preclude radical-mediated removal of the 2′-hydroxyl group at
later stages in the synthesis. Protection of N3 of (2′,5′ and 3′,5′)-
bis-O-TBSuridine16 by 4-methoxybenzylation,17 and treatment
of the resulting mixture of (2′,5′ and 3′,5′)-bis-O-TBS-3-(4-
methoxybenzyl)uridines (2a/2b) (1:1) with NaH/CS2 and MeI
gave a 2′-enhanced mixture of xanthates 3a/3b (4:1). Equilibra-
tion of TBS groups between O2′ and O3′ under basic conditions
is well-known, and migration to the more basic O3′ is
thermodynamically favored. The 3a/3b mixture was subjected
to Barton deoxygenation, and 4a was isolated by chromatog-
raphy (52% yield for 3 steps) (Scheme 1).
FIGURE 1. 2-Oxabicyclo[3.1.0]hexane analogues.
TBS groups were removed18 from 4a, which was converted
into 5′-O-TBS derivative 6a (76% for two steps). Replacement
of a secondary hydroxyl group by iodide (I2/Ph3P/imidazole)19
usually proceeds with inversion of configuration. However, such
treatment of 6a gave a mixture of inverted product 7a and
epimer 7b (2.4:1, 81%). Diastereomers 7a and 7b had closely
similar properties, but both isomers were separated and char-
acterized after removal of the TBS groups with NH4F/MeOH.18
Participation of O2 on the uracil ring might have contributed
to formation of the doubly inverted isomer 7b.
We had reported syntheses of 3′,4′-unsaturated nucleoside
containing an oxygen atom at C2′ by elimination of H4′ and
iodide from C3′ with AgOAc/pyridine and DBN/benzene.20
However, treatment of the 7a/7b mixture by either of these
procedures resulted in predominant or exclusive elimination of
H2′/H2′′ to give the 2′,3′-unsaturated isomer 8a. In contrast,
heating 7a/7b in a solution of DABCO in benzene at reflux
gave 8a/8b (1:2, 99% total). It is noteworthy that no cis-
elimination of H4′ and iodide (and neither cis- nor trans-
elimination of H2′/H2′′ and iodide) was observed with the
erythro isomer 7b, which was recovered from the reaction
mixture.
Because separation of 8a/8b was found to be impractical,
we treated the mixture with (CF3)2Hg and NaI in THF at 60
°C. Adducts were not formed with the less reactive 2′,3′-alkene
8a, whereas the electron-rich enol ether 8b underwent addition
of difluorocarbene under these mild conditions. Deprotection
of the mixture (NH4F/MeOH) and chromatography allowed
separation of the major adduct 9 (65%) from the 2′,3′-alkene,
minor adduct, and other byproducts. Benzoylation of 9 gave
10 (99%), excess CAN in CH3CN/H2O at reflux removed the
4-methoxybenzyl group to give 11 (82%), and debenzoylation
[3.1.0]hexane nucleosides analogues, C, that would resemble
2′-deoxynucleosides with a difluoromethylene bridge spanning
the C3′-C4′ bond. Isosteric replacement of hydrogen by fluorine
(with the accompanying stereoelectronic effects) could contrib-
ute insights for correlations of sugar ring conformation restraint
and biological activity. The potent electron-withdrawing effects
of fluorine might enhance stability against acid- and enzyme-
catalyzed glycosyl bond hydrolysis, and fluorine-substituted
analogues usually exhibit increased lipophilicity and altered
protein binding. We now report syntheses of the adenine,
cytosine, and uracil 2′-deoxy analogues, C, of 3′,4′-difluoro-
methylene insertion compounds derived from adenosine and
uridine.
Results and Discussion
We recently developed mild methods for the synthesis of
compounds with difluorocyclopropane fused with rings contain-
ing nitrogen or oxygen by addition of difluorocarbene to
enamines9 or vinyl ethers.10 The ultimate goal was synthesis of
nucleoside analogues whose furanosyl rings were conforma-
tionally restricted by fusion with a difluorocyclopropane ring.
Reported procedures in fluorine chemistry usually employed
conditions that are incompatible with the sensitivity of glycosyl
bonds, and functional groups (including 3-NH of uracil and
6-NH2 of adenine)10 in nucleoside derivatives can interact
unfavorably with organometallic-based reagents. Suitable pro-
tection of the base and sugar components allowed successful
addition of difluorocarbene [generated from Seyferth’s reagent
(PhHgCF3)] to the vinyl ether of 4′,5′-unsaturated nucleosides,
and good to high yields of spirodifluorocyclopropane products
were obtained.10 With the present analogues, interference by
oxygen-containing groups vicinal to the 3′,4′ carbon-carbon
double bond during addition of difluorocarbene (possibly
associated with mercury/iodine species) was precluded by prior
C2′ deoxygenation. Seyferth’s reagent is convenient to use, but
its preparation is expensive and somewhat involved and
dangerous.11 Dolbier’s reagent (trimethylsilyl fluorosulfonyldi-
fluoroacetate, TFDA) is moisture sensitive, and generation of
CF2 required heating TFDA with sodium fluoride at g90 °C12
(3′,4′-unsaturated nucleosides would decompose upon heating
(12) Tian, F.; Kruger, V.; Bautista, O.; Duan, J.-X.; Li, A.-R.; Dolbier,
W. R., Jr.; Chen, Q.-Y. Org. Lett. 2000, 2, 563-564.
(13) Knunyants, I. L.; Komissarov, Y. F.; Dyatkin, B. L.; Lantseva,
L. T. IzV. Acad. Nauk SSSR, Ser. Khim. 1973, 943-944.
(14) CAUTION: (CF3)2Hg is volatile and toxic, and should be used
only by experienced research personnel with appropriate safety precautions.
(15) Tian, F.; Dolbier, W. R., Jr. Org. Lett. 2000, 2, 835-837.
(16) Samano, V.; Robins, M. J. Synthesis 1991, 283-288.
(17) Danishefsky, S. J.; DeNinno, S. L.; Chen, S-h.; Boisvert, L.;
Barbachyn, M. J. Am. Chem. Soc. 1989, 111, 5810-5818.
(18) Zhang, W.; Robins, M. J. Tetrahedron Lett. 1992, 33, 1177-1180.
(19) (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.
(10) Nowak, I.; Robins, M. J. J. Org. Chem. 2006, 71, 8876-8883.
(11) (a) Seyferth, D.; Hopper, S. P. J. Org. Chem. 1972, 37, 4070-
4075. (b) Seyferth, D.; Hopper, S. P.; Murphy, G. J. J. Organomet. Chem.
1972, 46, 201-209.
(20) Robins, M. J.; Jones, R. A.; Mengel, R. J. Am. Chem. Soc. 1976,
98, 8213-8217.
J. Org. Chem, Vol. 72, No. 2, 2007 533

Nowak et al.
SCHEME 1a
SCHEME 2a
a Reagents and conditions: (a) (i) NaH/CS2/DMF/0 °C, (ii) MeI; (b)
Bu3SnH/AIBN/toluene/90 °C; (c) NH4F/MeOH/65 °C; (d) TBSCl/pyridine;
(e) Ph3P/I2/imidazole/toluene/70 °C; (f) DABCO/benzene/80 °C; (g)
(CF3)2Hg/NaI/THF/60 °C; (h) TFA/H2O/0 °C.
deoxygenation gave 16 (62%), which was desilylated and then
selectively protected at O5′ to give 17 (69% for 2 steps).
Treatment of 17 with Ph3P/I2/imidazole gave crystalline 18
(74%), whose structure was confirmed by X-ray analysis.23
Formation of the single stereoisomer contrasts with our results
with 6a f 7a/7b, and also with a report24 in which a 1:3
epimeric mixture of iodides was obtained with an analogue
lacking protection at N6. Epimerization by iodide displacement
of iodide at C3′ was invoked with that unprotected analogue,24
and neighboring group participation (by O2 of the uracil moiety)
might also occur in the 6a f 7a/7b transformation. The
enhanced solubility of 17 in toluene [resulting from masking
the amino group as a 6-(2,5-dimethypyrrol-1-yl) moiety] might
limit epimerization by reducing reaction times at elevated
temperatures.
a Reagents and conditions: (a) PMBCl/K2CO3/DMF; (b) (i) NaH/CS2/
DMF/0 °C, (ii) MeI; (c) Bu3SnH/AIBN/toluene/90 °C; (d) NH4F/MeOH/
65 °C; (e) TBSCl/pyridine; (f) Ph3P/I2/imidazole/toluene/70 °C; (g) DABCO/
benzene/80 °C; (h) (CF3)2Hg/NaI/THF/60 °C; (i) PhCOCl/Et3N/DCM; (j)
CAN/CH3CN/H2O/70 °C; (k) NH3/MeOH/60 °C; (l) POCl3/1,2,4-triazole/
Et3N/CH3CN; (m) NH3/H2O/1,4-dioxane; (n) NH3/MeOH.
(NH3/MeOH) gave the 2′-deoxyuridine analogue 12 (86%).
Treatment of 11 with POCl3/1,2,4-triazole/Et3N/CH3CN21 gave
the 4-(1,2,4-triazol-1-yl) intermediate (93%), which was sub-
jected to ammonolysis (NH3/H2O/dioxane) and debenzoylation
(NH3/MeOH) to give 2′-deoxycytidine analogue 13. Purification
[Dowex 1 × 2 (OH-)] and acidification (HBr/H2O) gave the
crystalline hydrobromide salt of 13 (60% for 3 steps).
A parallel approach was used for the synthesis of adenine
analogue 22 (Scheme 2), but differences are noteworthy. We
made TBS derivatives of the 6-(2,5-dimethylpyrrol-1-yl)purine
nucleosides 14a and 14b to overcome difficulties encountered
with other 6-amino protecting groups22 in the presence of
organomercury reagents. In contrast with the uridine derivatives
2a/2b, treatment of 14a/14b with NaH/CS2 and MeI gave highly
predominant formation of the 2′-xanthate 15 (86%), presumably
resulting from enhanced migration of the TBS group to the more
basic O3′ and attack of the O2′ anion on CS2. Barton
DABCO in refluxing benzene converted 18 into a mixture
of elimination products 19/20 (1:2, 97% total), which is in
harmony with the parallel reaction with 7a. The desired
regioisomer 20 was isolated and subjected to (CF3)2Hg/NaI at
60 °C to give the diastereomeric difluorocyclopropanes 21a/
21b (∼9:1, 51% total). Treatment of 21a/21b with TFA/H2O
(9:1) effected hydrolytic cleavage of both the 2,5-dimethylpyr-
role ring and the TBS ether. 19F NMR chemical shifts and
(21) Divakar, K. J.; Reese, C. B. J. Chem. Soc., Perkin Trans. 1 1982,
1171-1176.
(22) Nowak, I.; Robins, M. J. Org. Lett. 2003, 5, 3345-3348.
(23) Zhong, M.; Nowak, I.; Cannon, J. F.; Robins, M. J. J. Org. Chem.
2006, 71, 4216-4221.
(24) Yu, D.; d’Alarcao, M. J. Org. Chem. 1989, 54, 3240-3242.
534 J. Org. Chem., Vol. 72, No. 2, 2007

Synthesis of 2′-Deoxy Analogues
Experimental Section26
2′-Deoxy-3-(4-methoxybenzyl)uridine (5) and 5′-O-TBS-3′-
deoxy-3-(4-methoxybenzyl)uridine (6b). (A) Dried K2CO3 (11.3
g, 82.0 mmol) and then 4-methoxybenzyl chloride (12.8 g, 11.4
mL, 82.0 mmol) were added to a stirred solution of a mixture16 of
3′,5′-bis-O-TBS-uridine (1a) and 2′,5′-bis-O-TBS-uridine (1b) (19.3
g, 41.0 mmol) in DMF (60 mL), and stirring was continued at
ambient temperature overnight. Volatiles were removed in vacuo,
and the residue was chromatographed (hexanes f EtOAc/hexanes,
1:3) to give a 1:1 mixture of 3′,5′-bis-O-TBS-3-(4-methoxybenzyl)-
uridine (2a) and 2′,5′-bis-O-TBS-3-(4-methoxybenzyl)uridine (2b)
as a colorless oil (22.8 g, 94%). (B) NaH (1.8 g, 76.9 mmol) and
then CS2 (3.8 mL, 4.9 g, 65.4 mmol) were added to an ice-cold
solution of the 2a/2b in DMF (100 mL), and the solution was stirred
at 0 °C for 1.5 h. MeI (7.1 mL, 16.2 g, 115.3 mmol) was added,
and stirring was continued for 0.5 h. Volatiles were evaporated in
vacuo, the residue was partitioned [EtOAc (200 mL)/H2O (200
mL)], and the aqueous phase was extracted with EtOAc (2 × 200
mL). The combined organic phase was dried (MgSO4), and volatiles
were evaporated to give a mixture of xanthates 3a/3b (4:1; 24.1 g,
92%). (C) A deoxygenated solution of this material in toluene (100
mL) was heated to 90 °C, and a solution of AIBN (600 mg, 3.5
mmol) and Bu3SnH (15.0 mL, 16.2 g, 55.5 mmol) in toluene (20
mL) was added slowly (20 min). Heating and stirring were
continued for an additional 30 min, and volatiles were evaporated
in vacuo. The residue was chromatographed (hexanes f EtOAc/
hexanes, 1:20) to give 3′,5′-bis-O-TBS-2′-deoxy-3-(4-methoxyben-
zyl)uridine (4a) (∼12.2 g, 60%) and 2′,5′-bis-O-TBS-3′-deoxy-3-
(4-methoxybenzyl)uridine (4b) (∼3.1 g, 15%) contaminated with
tin-containing impurities. (D) A solution of 4a (6.5 g, 11.3 mmol)
and NH4F (2.5 g, 67.6 mmol) in MeOH (200 mL) was refluxed
with stirring for 12 h, and volatiles were evaporated. Chromatog-
raphy (EtOAc) gave 5 (3.7 g, 94%). Purification by recrystallizations
(EtOAc) gave a colorless powder: mp 133-135 °C; UV max 222,
264 nm (ꢀ 19 000, 13 200), min 217, 240 nm (ꢀ 18 700, 6500); 1H
NMR (CD3OD) δ 2.12-2.21 (m, 1H), 2.31 (ddd, J ) 3.4, 5.9,
13.7 Hz, 1H), 3.71 (dd, J ) 3.4, 13.2 Hz, 1H), 3.76 (s, 3H), 3.77
(dd, J ) 3.4, 13.2 Hz, 1H), 3.91-3.93 (m, 1H), 4.37 (dt, J ) 3.4,
5.9 Hz, 1H), 5.00 (s, 2H), 5.78 (d, J ) 8.4 Hz, 1H), 6.28 (t, J )
6.6 Hz, 1H), 6.83 (d, J ) 8.8 Hz, 2H), 7.32 (d, J ) 8.8 Hz, 2H),
7.98 (d, J ) 8.4 Hz, 1H); 13C NMR (CD3OD) δ 41.6, 44.7, 55.8,
62.8, 72.2, 87.6, 89.0, 102.2, 114.8, 130.4, 131.1, 140.7, 152.4,
160.6, 165.0; FAB-MS m/z 371 ([M + Na+] 100%); HRMS
(C17H20N2O6Na) calcd 371.1219, found 371.1208. (E) Deprotection
of 4b (1.7 g, 2.9 mmol) with NH4F (0.6 g, 16.2 mmol) as described
for 4a f 5 was followed by treatment with 1.1 equiv of TBSCl in
pyridine, evaporation to dryness, and chromatography (EtOAc/
hexanes, 1:6 f 1:2) to give 6b (0.9 g, 70%) as a pale-yellow oil:
UV max 222, 264 nm (ꢀ 19 000, 13 200), min 217, 240 nm (ꢀ
FIGURE 2. X-ray crystal structure of 12.
FIGURE 3. X-ray crystal structure of 13‚HBr.
couplings of the microcrystalline major isomer 22 (54%) were
parallel with those of the major uracil 12 and cytosine 13
analogues.
X-ray Structures. Crystals of 12 and 13‚HBr were suitable
for X-ray analysis. The nearly planar furanosyl ring25 in 12 (νmax
) 10.1°) has a pseudorotation-cycle angle of P ) 159.8° (a
2
shallow E conformational preference), and the rotation angle
of the base about the glycosyl bond is in the anti range (ø )
-148.1°) (Figure 2). The furanosyl moiety in 13‚HBr has a
larger maximum puckering amplitude (νmax ) 25.3°), P )
135.6° (1E conformation range), and the base rotation also is
anti (ø ) -138.7°) (Figure 3). Thus, changes in the nucleobase
and charge (hydrobromide salt) caused only minimal alterations
in preferred conformations of these constrained 2-oxabicyclo-
[3.1.0]hexane nucleoside analogues.
In summary, we have synthesized a new class of 2-oxabicyclo-
[3.1.0]hexane-based nucleosides that are conformationally re-
stricted by a difluoromethylene bridge spanning the C3′-C4′
bond. Addition of difluorocarbene (carbenoid) to vinyl ethers
within 3′,4′-unsaturated nucleosides derived from adenosine and
uridine gave the target structures. Electron-withdrawing effects
of two fluorine atoms â to the furanosyl ring oxygen (O4′) in
these compounds are expected to confer stability under condi-
tions that result in chemical or enzymatic cleavage of naturally
occurring nucleosides. Solid-state conformations of the uracil
(2E) and cytosine (1E) analogues were similar, with a less
puckered furanosyl ring in the former. Synthesis of other types
of difluorocyclopropane-fused nucleoside analogues and col-
laborative biological testing results will be reported separately.
1
18 700, 6500); H NMR (CD3OD) δ 0.08 (s, 3H), 0.09 (s, 3H),
0.90 (s, 9H), 1.88 (ddd, J ) 1.5, 5.4, 13.2 Hz, 1H), 2.08-2.14 (m,
1H), 3.68 (dd, J ) 1.5, 11.7 Hz, 1H), 3.76 (s, 3H), 3.81 (s, 1H),
4.11 (dd, J ) 1.5, 11.7 Hz, 1H), 4.35 (d, J ) 4.4 Hz, 1H), 4.51-
4.55 (m, 1H), 5.00 (d, J ) 13.7 Hz, 1H), 5.07 (d, J ) 13.7 Hz,
1H), 5.69 (s, 1H), 5.71 (d, J ) 8.3 Hz, 1H), 6.60 (d, J ) 8.8 Hz,
2H), 7.42 (d, J ) 8.8 Hz, 2H), 8.03 (d, J ) 7.8 Hz, 1H); 13C NMR
(CD3OD) δ -5.6, -5.5, 18.4, 25.8, 31.9, 43.4, 55.2, 62.9, 77.4,
82.0, 94.0, 100.9, 113.6, 128.9, 130.6, 137.8, 151.4, 159.0, 162.8;
FAB-MS m/z 495 ([M + Na+] 100%); HRMS (C23H34N2O6SiNa)
calcd 495.2084, found 495.2103.
1-(5-O-TBS-2,3-dideoxy-3-iodo-â-D-threo-pentofuranosyl)-3-
(4-methoxybenzyl)uracil (7a) and 5′-O-TBS-2′,3′-dideoxy-3′-
iodouridine (7b). A solution of 5 (3.7 g, 10.6 mmol) and TBSCl
(1.8 g, 11.7 mmol) in pyridine (10 mL) was stirred at ambient
temperature for 1.5 h. Volatiles were evaporated, and the residue
was chromatographed (EtOAc/hexanes, 1:6 f1:2) to give 5′-O-
(25) (a) Sun, G.; Voigt, J. H.; Filippov, I. V.; Marquez, V. E.; Nicklaus,
M. C. J. Chem. Inf. Comput. Sci. 2004, 44, 1752-1762 and references
quoted therein. (b) Altona-Sundaralingam pseudorotational parameters were
calculated by the Pseudo-Rotational Online Service and Interactive Tool
(PROSIT) available at http://cactus.nci.nih.biv/prosit.
(26) General experimental details are in the Supporting Information.
J. Org. Chem, Vol. 72, No. 2, 2007 535

Nowak et al.
TBS-2′-deoxy-3-(4-methoxybenzyl)uridine (6a) (4.0 g, 81%) as a
pale yellow oil: FAB-MS m/z 463 ([M + H+] 10%), 307 (100%);
HRMS (C23H35N2O6Si) calcd 463.2264, found 463.2249.
EtOAc) to give crystalline material (1.03 g, 86%) that was
recrystallized (MeOH) to give 12: mp 168-170 °C dec; UV max
259 nm (ꢀ 9900), min 229 nm (ꢀ 2700); 1H NMR (CD3OD) δ 2.44-
2.53 (m, 2H), 2.78 (dd, J ) 7.8, 13.7 Hz, 1H), 3.89 (d, J ) 13.2
Hz, 1H), 4.06 (dd, J ) 3.4, 13.2 Hz, 1H), 5.72 (d, J ) 8.3 Hz,
1H), 6.10-6.16 (m, 1H), 7.81 (d, J ) 8.3 Hz, 1H); 19F NMR (CD3-
OD) δ 135.7 (dd, J ) 15.0, 164.5 Hz, 1F), 151.0 (d, J ) 164.5 Hz,
1F); 13C NMR (CD3OD) δ 28.9 (t, J ) 12.2 Hz), 32.7, 58.5, 74.4
(t, J ) 11.1 Hz), 90.9 (dd, J ) 3.3, 7.9 Hz), 103.4, 114.8 (dd, J )
295.3, 303.7 Hz), 142.9, 152.0, 166.2; MS m/z 260 ([M+] 3%),
229, 202, 158, 138 (100%); HRMS (C10H10F2N2O4) calcd 260.0608,
found 260.0602. Anal. Calcd for C10H10F2N2O4: C, 46.16; H, 3.87;
N 10.77. Found: C, 46.23; H, 4.11; N 11.06.
Ph3P (9.1 g, 34.6 mmol), imidazole (4.7 g, 69.3 mmol), and
iodine (8.8 g, 34.6 mmol) were added to a stirred solution of 6a
(8.0 g, 17.3 mmol) in toluene (200 mL) under N2. Stirring was
continued, and the mixture was heated at 70 °C for 2 h and then
cooled to ambient temperature. The clear supernatant was decanted,
concentrated, and chromatographed (EtOAc/hexanes, 1:4) to give
the threo/erythro epimers 7a/7b (2.4:1; 8.1 g, 81%). See the
Supporting Information for separation and characterization of the
deprotected epimers.
1-[5-O-Benzoyl-2,3-dideoxy-3,4-C-(difluoromethylene)-â-D-
erythro-pentofuranosyl]-3-(4-methoxybenzyl)uracil (10). (A) A
solution of 7a/7b (8.0 g, 13.9 mmol) and DABCO (6.0 g, 53.6
mmol) in benzene (200 mL) was stirred at reflux for 6 h,
concentrated, and deposited on silica gel. Chromatography (EtOAc/
hexanes, 1:20 f 1:3) gave unreacted 7b (2.2 g, 28%) plus a 1:2
mixture of 1-(5-O-TBS-2,3-dideoxy-â-D-glycero-pent-2-enofura-
nosyl)-3-(4-methoxybenzyl)uracil (8a) and (R)-2-[(tert-butyldi-
methylsilyloxy)methyl]-5-[3-(4-methoxybenzyl)uracil-1-yl]-4,5-di-
hydrofuran (8b) (total: 4.4 g, 71%). (B) Powdered NaI (3.0 g, 20.0
mmol) was stirred and heated (170 °C, oil bath) under vacuum for
1 h in a flask (250 mL) equipped with a Teflon valve. The bath
was allowed to cool to ambient temperature, and a mixture of 8a/
8b (1.47 g, 3.3 mmol) and then (CF3)2Hg13,14 (1.7 g, 5.0 mmol) in
dried THF (10 mL) was injected through a septum (under N2). The
reaction mixture was heated at 60 °C for 1 h, and volatiles were
evaporated. Column chromatography (EtOAc/hexanes, 1:4 f 1:1)
gave a mixture of unreacted 8a plus 5′-O-TBS-2′,3′-dideoxy-3′,4′-
C-(difluoromethylene)-â-D-erythro-pentofuranosyl]-3-(4-methoxy-
benzyl)uracil. A solution of the mixture (1.40 g) and NH4F (0.4 g,
10.8 mmol) in MeOH (25 mL) was refluxed overnight. Volatiles
were evaporated, and the residue was chromatographed (EtOAc/
hexanes, 1:4 f 2:1) to give 1-[2,3-dideoxy-3,4-C-(difluorometh-
ylene)-â-D-erythro-pentofuranosyl]-3-(4-methoxybenzyl)uracil (9)
(470 mg, 65%). (C) Et3N (0.5 mL, 0.4 g, 3.9 mmol) and BzCl (0.3
mL, 0.4 g, 2.6 mmol) were added to a stirred solution of 9 (470
mg, 1.2 mmol) in CH2Cl2 (5 mL), and stirring was continued for
1 h. Volatiles were evaporated, and the residue was chromato-
graphed (EtOAc/hexanes, 1:6 f EtOAc) to give 1-[5-O-benzoyl-
2,3-dideoxy-3,4-C-(difluoromethylene)-â-D-erythro-pentofuranosyl]-
3-(4-methoxybenzyl)uracil (10) (590 mg, 99%): UV max 227, 260
nm (ꢀ 25 500, 10 000), min 212, 248 nm (ꢀ 17 700, 8700); 1H NMR
(CDCl3) δ 2.30-2.36 (m, 1H), 2.50 (dd, J ) 7.3, 14.2 Hz, 1H),
2.85 (dd, J ) 7.8, 11.2 Hz, 1H), 3.76 (s, 3H), 4.80-4.87 (m, 2H),
4.95 (d, J ) 13.7 Hz, 1H), 4.98 (d, J ) 13.7 Hz, 1H), 5.56 (d, J )
8.3 Hz, 1H), 6.12-6.15 (m, 1H), 6.81 (d, J ) 8.3 Hz, 2H), 7.29
(d, J ) 8.3 Hz, 1H), 7.40 (d, J ) 8.8 Hz, 2H), 7.47 (t, J ) 7.6 Hz,
2H), 7.61 (t, J ) 7.3 Hz, 1H), 8.04 (d, J ) 8.3 Hz, 2H); 19F NMR
(CDCl3) δ 135.7 (dd, J ) 15.0, 166.6 Hz, 1F), 155.0 (d, J ) 166.6
Hz, 1F); 13C NMR (CDCl3) δ 28.0 (t, J ) 12.2 Hz), 32.1, 43.5,
55.1, 59.8, 70.3 (t, J ) 11.4 Hz), 89.7 (d, J ) 4.1 Hz), 102.8,
111.9 (dd, J ) 296.8, 305.2 Hz), 113.6, 128.6, 128.7, 129.1, 129.6,
130.7, 133.7, 137.2, 150.3, 159.1, 162.1, 165.9; FAB-MS m/z 507
([M + Na+] 100%), 485 (100%); HRMS (C25H22F2N2O6Na) calcd
507.1344, found 507.1333.
1-[2,3-Dideoxy-3,4-C-(difluoromethylene)-â-D-erythro-pento-
furanosyl]cytosine Hydrobromide (13‚HBr). Et3N (7.28 mL, 3.86
g, 38.2 mmol) was added dropwise to a stirred, cooled (∼0 °C)
mixture of POCl3 (1.11 mL, 1.77 g, 11.54 mmol), 1,2,4-triazole
(3.80 g, 55.1 mmol), and MeCN (32.8 mL). A solution of 11 (1.92
g, 5.25 mmol) in MeCN (20.5 mL) was added, and stirring was
continued at ambient temperature for 2 h. Et3N (5.08 mL, 3.70 g,
36.6 mmol) and H2O (2.05 mL) were added, and stirring was
continued for 10 min. Volatiles were evaporated, and the residue
was partitioned [ice-cold, saturated NaHCO3/H2O (60 mL)//CH2-
Cl2 (60 mL)]. The aqueous phase was extracted (CH2Cl2, 60 mL),
and the combined organic phase was washed (brine, 100 mL) and
dried (MgSO4). Evaporation of volatiles gave 1-[5-O-benzoyl-2,3-
dideoxy-3,4-C-(difluoromethylene)-â-D-erythro-pentofuranosyl]-4-
(1,2,4-triazol-1-yl)pyrimidin-2-one (2.04 g, 93%) as colorless
crystals, which were dissolved in 1,4-dioxane (30 mL) and stirred
with a solution of NH3/H2O (30%, 10 mL) at ambient temperature
for 12 h. Volatiles were evaporated and the residue was dissolved
and filtered through silica gel (EtOAc/MeOH, 2:1). Volatiles were
evaporated, and the residue was stirred in NH3/MeOH (14%, 10
mL) at 80 °C for 90 min. Volatiles were evaporated and the residue
was dissolved in H2O and applied to a column of Dowex 1 × 2
(OH-) resin (in H2O). Elution (H2O) and evaporation of volatiles
from UV-active fractions gave 1-[2,3-dideoxy-3,4-C-(difluoro-
methylene)-â-D-erythro-pentofuranosyl]cytosine (13) (520 mg,
60%) as a pale-yellow oil that was dissolved in MeOH (10 mL)
and 48% HBr/H2O (1 mL) was added. Volatiles were evaporated,
and the residue was recrystallized (MeOH) to give 13‚HBr as
colorless crystals: mp 170-174 °C dec; UV max 280 nm (ꢀ
1
11 400), min 245 nm (ꢀ 3000); H NMR (CD3OD) δ 2.51-2.64
(m, 2H), 2.86 (dd, J ) 7.8, 13.7 Hz, 1H), 3.91 (d, J ) 13.2 Hz,
1H), 4.10 (dd, J ) 3.4, 13.2 Hz, 1H), 6.09-6.13 (m, 1H), 6.15 (d,
J ) 7.8 Hz, 1H), 8.26 (d, J ) 7.8 Hz, 1H); 19F NMR (CD3OD) δ
136.1 (dd, J ) 15.0, 164.5 Hz, 1F), 152.0 (d, J ) 164.5 Hz, 1F);
13C NMR (CD3OD) δ 28.9 (t, J ) 12.2 Hz), 33.3, 58.3, 75.3 (t, J
) 11.2 Hz), 92.3 (br s), 95.2, 114.5 (dd, J ) 294.5, 302.9 Hz),
147.0, 148.3, 161.5; FAB-MS m/z 282 ([M + Na+] 90%), 239,
237 (100%); HRMS (C10H11F2N3O3Na) calcd 282.0666, found
282.0678.
9-[3,5-Bis-O-TBS-2-O-(thiomethoxythiocarbonyl)-â-D-ribo-
furanosyl]-6-(2,5-dimethylpyrrol-1-yl)purine (15). NaH (1.42 g,
59.3 mmol) and then CS2 (3.0 mL, 3.8 g, 50.4 mmol) were added
to a cold (ice/water bath) stirred solution of 14a/14b22 (17.0 g, 29.7
mmol) in DMF (100 mL). Stirring was continued for 1.5 h at ∼0
°C, MeI (5.5 mL, 12.6 g, 89.0 mmol) was added, and stirring was
continued for 0.5 h. Volatiles were evaporated in vacuo (<50 °C),
the residue was partitioned (EtOAc/H2O), the aqueous phase was
extracted (EtOAc, 3 × 100 mL), and the combined organic phase
was dried (MgSO4). Volatiles were evaporated, and the residue was
chromatographed (EtOAc/hexanes, 1:20 f 1:4) to give xanthate
15 (17.0 g, 86%). Recrystallizations of a sample (toluene/hexanes)
gave colorless needles: mp 158-160 °C; UV max 283 nm (ꢀ
1-[2,3-Dideoxy-3,4-C-(difluoromethylene)-â-D-erythro-pento-
furanosyl]uracil (12). (A) CAN (8.5 g, 15.5 mmol) in H2O (18
mL) was added to a solution of 10 (1.9 g, 3.9 mmol) in CH3CN
(180 mL), the mixture was heated at 70 °C for 1.5 h, and H2O was
added. The diluted reaction mixture was extracted with EtOAc (5
× 50 mL), and the combined organic phase was concentrated and
deposited on silica gel. Chromatography (EtOAc/hexanes, 1:4 f
2:1) gave 1-[5-O-benzoyl-2,3-dideoxy-3,4-C-(difluoromethylene)-
â-D-erythro-pentofuranosyl]uracil (11) (1.17 g, 82%). (B) A solution
of 11 (1.68 g, 4.6 mmol) in NH3/MeOH (14%, 20 mL) in a sealed
flask was heated at 60 °C overnight. Volatiles were evaporated,
and the residue was chromatographed (EtOAc/hexanes, 1:3 f
1
20 200), min 248 nm (ꢀ 4700); H NMR (CDCl3) δ 0.06 (s, 3H),
0.10 (s, 3H), 0.12 (s, 3H), 0.13 (s, 3H), 0.89 (s, 9H), 0.95 (s, 9H),
2.21 (s, 6H), 2.56 (s, 3H), 3.82 (dd, J ) 2.4, 11.7 Hz, 1H), 3.97
(dd, J ) 2.9, 11.7 Hz, 1H), 4.23-4.25 (m, 1H), 4.96 (dd, J ) 2.9,
536 J. Org. Chem., Vol. 72, No. 2, 2007

Synthesis of 2′-Deoxy Analogues
4.9 Hz, 1H), 5.98 (s, 2H), 6.44 (t, J ) 5.4 Hz, 1H), 6.51 (d, J )
5.9 Hz, 1H), 8.36 (s, 1H), 8.92 (s, 1H); 13C NMR (CDCl3) δ -5.6,
-5.5, -5.1 (2C), 13.5, 17.9, 18.3, 19.2, 25.6, 25.9, 62.4, 70.3, 82.6,
85.6, 86.8, 108.8, 128.9, 129.6, 143.4, 150.2, 152.3, 153.2, 215.0;
FAB-MS m/z 686 ([M + Na+] 67%), 664, 451 (100%), 421, 343,
291; HRMS (C30H49N5O6S2Si2Na) calcd 686.2662, found 686.2669.
9-[5-O-TBS-2-deoxy-â-D-erythro-pentofuranosyl]-6-(2,5-di-
methylpyrrol-1-yl)purine (17). A solution of 15 (17.0 g, 25.6
mmol) in dried toluene (50 mL) was deoxygenated (N2) and heated
with stirring at 100 °C. A solution of Bu3SnH (14.0 mL, 15.0 g,
51.3 mmol) and AIBN (0.8 g, 4.9 mmol) in dried toluene (20 mL)
was added over 40 min, and stirring was continued at 100 °C for
20 min. Volatiles were evaporated, and the residue was chromato-
graphed (hexanes f EtOAc/hexanes, 1:6) to give 9-[3,5-bis-O-
TBS-2-deoxy-â-D-erythro-pentofuranosyl]-6-(2,5-dimethylpyrrol-
1-yl)purine (16) (8.8 g, 62%) as an orange oil, which was dissolved
in MeOH (100 mL). NH4F (3.4 g, 91.5 mmol) was added, the
solution was stirred at reflux overnight, and volatiles were
evaporated. The residue was chromatographed (EtOAc) to give 9-[2-
deoxy-â-D-erythro-pentofuranosyl]-6-(2,5-dimethylpyrrol-1-yl)pu-
rine (5.2 g, 93%) as an orange oil, which was dissolved in pyridine
(14 mL). TBS-Cl (2.63 g, 17.4 mmol) was added, and the solution
was stirred for 1 h. Volatiles were evaporated in vacuo, and the
residue was chromatographed (EtOAc/hexanes, 1:6 f EtOAc) to
give 17 (5.0 g, 71%) as an orange oil: UV max 283 nm (ꢀ 12 200),
and purification (PTLC; EtOAc/hexanes, 1:3) gave 19: 1H NMR
(CDCl3) δ 0.026 (s, 3H), 0.031 (s, 3H), 0.86 (s, 9H), 2.19 (s, 6H),
3.81-3.91 (m, 2H), 5.12-5.16 (m, 1H), 5.97 (2H), 6.10-6.12 (m,
1H), 6.44-6.46 (m, 1H), 7.23-7.25 (m, 1H), 8.38 (s, 1H), 8.94
(s, 1H); 13C NMR (CDCl3) δ -5.5, -5.4, 13.5, 18.5, 25.9, 64.6,
88.0, 88.4, 108.8, 125.1, 128.8, 129.7, 135.0, 143.5, 150.0, 152.3,
153.3; MS m/z 448 ([M + Na+] 100%), 426 (50%); HRMS
(C22H31N5O2SiNa) calcd 448.2145, found 448.2150. Enol ether 20
was obtained as a pale yellow oil: UV max 283 nm (ꢀ 11 800),
1
min 246 nm (ꢀ 3800); H NMR (CDCl3) δ 0.08 (s, 3H), 0.10 (s,
3H), 0.90 (s, 9H), 2.21 (s, 6H), 3.03-3.06 (m, 1H), 4.41-4.48
(m, 1H), 4.23-4.31 (m, 2H), 5.17 (s, 1H), 5.98 (s, 2H), 6.96 (dd,
J ) 2.9, 9.3 Hz, 1H), 8.27 (s, 1H), 8.94 (s, 1H); 13C NMR (CDCl3)
δ -5.4 (2C), 13.5, 18.3, 25.7, 36.8, 58.2, 84.3, 95.2, 108.9, 128.5,
129.7, 142.1, 150.2, 152.5, 152.7, 157.0; MS m/z 425 ([M+] 55%),
213 (100%); HRMS (C22H31N5O2Si) calcd 425.2247, found 425.2249.
9-[2,3-Dideoxy-3,4-C-(difluoromethylene)-â-D-erythro-pento-
furanosyl]adenine (22). Treatment of 20 (2.5 g, 5.9 mmol) in dried
THF (25 mL) with the reagent prepared from NaI (5.3 g, 35.3
mmol) and (CF3)2Hg13,14 (3.0 g, 8.8 mmol) (according to the
procedure described for 7a f 8) gave a mixture that was deposited
on silica gel and chromatographed (EtOAc/hexanes, 1:10 f 1:7).
The eluted red oil contained a mixture of 9-[5-O-TBS-2,3-dideoxy-
3,4-C-(difluoromethylene)-â-D-erythro-pentofuranosyl]-6-(2,5-di-
methylpyrrol-1-yl)purine (21a) and 9-[5-O-TBS-2,3-dideoxy-3,4-
C-(difluoromethylene)-R -L-erythro-pentofuranosyl]-6-(2,5-dimeth-
ylpyrrol-1-yl)purine (21b) (∼9:1; 1.43 g, 51%), which was dissolved
in cold (∼0 °C) TFA/H2O (9:1, 20 mL) and stirred at ∼0 °C for 3
h. Volatiles were evaporated in vacuo (<30 °C), saturated NaHCO3/
H2O (20 mL) was added, the mixture was extracted (EtOAc, 4 ×
50 mL), the organic phase was combined, and volatiles were
evaporated. Chromatography of the resulting red oil (EtOAc/MeOH,
20:1) gave 22 (460 mg, 54%) as a syrup that was crystallized
(MeOH) to give 22 as an analytically pure white powder: mp 188-
190 °C dec; UV max 259 nm (ꢀ 14 000), min 227 nm (ꢀ 2500); 1H
NMR (CD3OD) δ 2.66 (dd, J ) 6.1, 14.9 Hz, 1H), 2.91-3.02 (m,
2H), 3.89 (d, J ) 13.2 Hz, 1H), 4.03 (dd, J ) 3.4, 13.2 Hz, 1H),
6.38 (t, J ) 6.1 Hz, 1H), 8.20 (s, 1H), 8.32 (s, 1H); 19F NMR
(CD3OD) δ 135.1 (dd, J ) 15.0, 164.5 Hz, 1F), 152.0 (d, J )
164.5 Hz, 1F); 13C NMR (CD3OD) δ 29.5 (t, J ) 12.6 Hz), 33.4,
58.9, 74.9 (t, J ) 11.4 Hz), 90.5, 103.4, 114.8 (dd, J ) 294.5,
302.9 Hz), 120.7, 141.2, 150.2, 154.1, 157.6; MS m/z 283 ([M+]
3%), 226, 135; HRMS (C11H11F2N5O2) calcd 283.0880, found
283.0890. Anal. Calcd for C11H11F2N5O2: C, 46.65; H, 3.91; N
24.73. Found: C, 46.43; H, 4.05; N, 24.80.
1
min 245 nm (ꢀ 3800); H NMR (CDCl3) δ 0.09 (s, 6H), 0.90 (s,
9H), 2.19 (s, 6H), 2.53-2.58 (m, 1H), 2.67-2.73 (m, 1H), 3.16
(br s, 1H), 3.85 (dd, J ) 3.9, 11.2 Hz, 1H), 3.90 (dd, J ) 3.9, 11.2
Hz, 1H), 4.09-4.10 (m, 1H), 4.62-4.66 (m, 1H), 5.94 (s, 2H),
6.60 (t, J ) 6.3 Hz, 1H), 8.45 (s, 1H), 8.91 (s, 1H); 13C NMR
(CDCl3) δ -5.5, -5.4, 13.4, 18.3, 25.9, 41.1, 63.3, 72.0, 84.6, 87.4,
108.9, 129.0, 129.6, 143.4, 150.0, 152.1, 153.0; FAB-MS m/z 443
([M+] 100%); HRMS (C22H33N5O3Si) calcd 443.2352, found
443.2360.
9-[5-O-TBS-2,3-dideoxy-3-iodo-â-D-threo-pentofuranosyl]-6-
(2,5-dimethylpyrrol-1-yl)purine (18). Ph3P (3.9 g, 14.9 mmol),
imidazole (2.0 g, 29.8 mmol), and iodine (3.8 g, 15.0 mmol) were
added to a stirred solution of 17 (2.2 g, 5.0 mmol) in toluene (70
mL) under N2. The mixture was stirred and heated at 70 °C for 2
h, and allowed to cool to ambient temperature. The clear supernatant
was decanted, concentrated, and chromatographed (EtOAc/hexanes,
1:4) to give 18 (2.0 g, 74%). Recrystallizations (CH2Cl2/MeOH)
gave colorless needles: mp 116-118 °C dec; UV max 283 nm (ꢀ
1
13 500), min 245 nm (ꢀ 4400); H NMR (CDCl3) δ 0.13 (s, 3H),
0.14 (s, 3H), 0.89 (s, 9H), 0.91 (s, 9H), 2.21 (s, 6H), 3.10 (dt, J )
4.6, 14.6 Hz, 3H), 3.33 (dt, J ) 6.9, 14.6 Hz, 1H), 3.73-3.76 (m,
1H), 3.91 (dd, J ) 4.4, 10.7 Hz, 1H), 4.09 (dd, J ) 4.9, 10.7 Hz,
1H), 4.54-4.58 (m, 1H), 5.98 (s, 2H), 6.50 (dd, J ) 4.7, 7.0 Hz,
1H), 8.62 (s, 1H), 8.90 (s, 1H); 13C NMR (CDCl3) δ -5.3 (2C),
13.5, 18.2, 20.0, 25.9, 43.8, 67.8, 82.7, 84.5, 108.9, 129.0, 129.7,
143.4, 150.1, 152.1, 152.8; FAB-MS m/z 553 ([M+] 30%); HRMS
(C22H32IN5O2Si) calcd 553.1329, found 553.1360.
Acknowledgment. We gratefully acknowledge pharmaceuti-
cal company unrestricted gift funds (M.J.R.), NIH Grant
GM29332, and Brigham Young University for support of this
work.
Supporting Information Available: General experimental
details, separation and characterization of the products of depro-
tection of 7a/7b, NMR spectra of compounds for which elemental
analyses were not obtained, and CIF data for the crystal structures
of 12 (code number XL519) and 13‚HBr (code number XL528).
This material is available free of charge via the Internet at
http://pubs.acs.org.
9-(5-O-TBS-2,3-dideoxy-â-D-glycero-pent-2-enofuranosyl)-6-
(2,5-dimethylpyrrol-1-yl)purine (19) and (R)-2-[(tert-Butyldi-
methylsilyloxy)methyl]-5-[6-(2,5-dimethylpyrrol-1-yl)purin-9-
yl]-4,5-dihydrofuran (20). A solution of 18 (2.7 g, 4.9 mmol) and
DABCO (3.0 g, 26.8 mmol) in benzene (60 mL) was stirred and
heated at 80 °C under N2 for 14 h, allowed to cool to ambient
temperature, and concentrated. Filtration through silica (EtOAc/
hexanes, 1:3) gave a mixture of 19/20 (1:2; 2.0 g, 97%). Separation
JO061965P
J. Org. Chem, Vol. 72, No. 2, 2007 537