Chiral synthesis of 4-[1-(2-deoxy-β-L-ribofuranosyl)] derivatives of 2-substituted 5-fluoroaniline: "Cytosine replacement" analogues of deoxy-β-L-cytidine

Full text of DOI:10.1021/jo000510b

9214
J . Org. Chem. 2000, 65, 9214-9219
potent antiviral activity against human immunodefi-
Ch ir a l Syn th esis of
ciency virus (HIV) and hepatitis B virus (HBV), and lower
4-[1-(2-Deoxy-â-L-r ibofu r a n osyl)]
toxicity, in comparison to the D enantiomers.5,9
Der iva tives of 2-Su bstitu ted
Nonpolar hydrophobic isosteres of â-D-pyrimidine nu-
cleosides which retain close structural, steric, and iso-
electronic relationships to the natural base, which are
not likely to form hydrogen bonds, have been reported
by Kool et al.10 In this regard, the 2,4-difluoro-5-meth-
ylphenyl isostere (â-D-1) was designed as an unnatural
mimic of thymidine (â-D-2). Furthermore, the 5′-tri-
5-F lu or oa n ilin e: “Cytosin e Rep la cem en t”
An a logu es of Deoxy-â-L-cytid in e
Zhi-Xian Wang,† Leonard I. Wiebe,† J an Balzarini,‡
Erik De Clercq,‡ and Edward E. Knaus*,†
Faculty of Pharmacy and Pharmaceutical Sciences,
University of Alberta, Edmonton, Alberta, Canada T6G
2N8, and Rega Institute for Medical Research,
Minderbroedersstraat 10, Leuven B-3000, Belgium
Received April 4, 2000
In tr od u ction
L-Thymidine (L-TdR), a substrate for herpes simplex
virus type 1 thymidine kinase (HSV-1 TK), reduces
HSV-1 multiplication in HeLa cells. HSV-1 TK phosphor-
ylates the L and D enantiomers of TdR to their corre-
sponding monophosphates (MPs) with identical efficacy.1
Similar results have been observed for the L-TdR ana-
logues 5-iodo-2′-deoxyuridine (L-IUdR) and (E)-5-(2-bro-
movinyl)-2′-deoxyuridine (L-BVUdR), whose D enanti-
omers are potent, but cytotoxic, antiherpetic drugs. The
approximately 1000-fold lower cytotoxicity of L-IUdR and
L-BVUdR, relative to the D enantiomers, is due to the
fact that L-IUdR lacks affinity for cellular TK and that
phosphate of â-D-1 (â-D-1-TP) was selectively inserted
opposite adenine (A) into replicating DNA strands by the
Klenow fragment (KF, exo- mutant) of Escherischia coli
DNA polymerase 1 with an efficacy (Vmax/Km) only 40-
fold lower than that for â-D-2-TP.11 These results indi-
cated that the 2,4-difluoro-5-methylphenyl moiety of
â-D-1 is isoelectronic with the thymine base which it
replaces and is utilized by KF polymerase.12-14 It was
envisaged that the structurally related 4-(2-substituted
5-fluoroaniline)-â-L-nucleoside mimics (13a ,b), which are
hybrids of the C-aryl (â-D-1) and deoxycytidine nucleo-
sides (â-L-3a ,b), may have interesting biological activ-
ity.1,2 We now report the synthesis of the 4-[1-(2-deoxy-
â-L-ribofuranosyl)] derivatives of 2-substituted-5-fluoro-
anilines (â-L-13a ,b), which were designed as unnatural
C-aryl 2′-deoxy-â-L-cytidine mimics.
L-IUdRMP and L-BVUdRMP, in contrast to their
D
enantiomers, do not inhibit thymidylate synthase (TS).2
Thus, the viral TK enzyme, but not human cytosolic TK,
lacks enantioselectivity for natural â-D- and unnatural
â-L-nucleosides. Consequently, L-nucleosides have at-
tracted the attention of medicinal chemists due to their
unique potency, mechanism of action, and toxicity pro-
file.3 Some representative L-cytidine analogues such as
2′,3′-dideoxy-3′-thia-â-L-cytidine (3TC, Lamivudine),4,5
2′,3′-dideoxy-3′-thia-â-L-5-fluorocytidine (L-FTC),6 and
2′,3′-dideoxy-â-L-5-fluorocytidine (L-FddC)7,8 have shown
promising antiviral activity. 3TC and L-FTC exhibit more
* To whom correspondence should be addressed. Tel: (780) 492-
5993. Fax: (780) 492-1217. E-mail: eknaus@pharmacy.ualberta.ca.
† University of Alberta.
Resu lts a n d Discu ssion
‡ Rega Institute for Medical Research.
The Heck-type coupling reaction constitutes a simple,
yet direct, method to form a C-C bond between a suitably
protected glycal and an activated iodo- or trifluoro-
methanesulfonate-substituted aryl (heteroaryl) reagent,
to prepare the â-anomer of nucleosides in reasonable
yields.15 In this study, the Heck coupling reaction is a
key method for the synthesis of unnatural deoxy-â-L-
cytidine mimics, as illustrated in Scheme 1.
(1) Spadari, S.; Maga, G.; Focher, F.; Ciarrocchi, G.; Manservigi, R.;
Arcamone, F.; Capobianco, M.; Carcuro, A.; Colonna, F. Iotti, S.;
Garbesi, A. J . Med. Chem. 1992, 35, 4214-4220.
(2) Spadari, S.; Ciarrocchi, G.; Focher, F.; Verri, A.; Maga, G.;
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Pharmacol. 1995, 47, 1231-1238.
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Res. 1998, 40, 19-44.
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tional Conference on AIDS; Montreal, Canada, J une 4-9, 1989;
Philadelphia Science Group: Philadelphia, 1990; Paper no. T.C.O.I.,
p 515.
(9) Chang, C. N.; Doong, S. L.; Zhou, J . H.; Beach, J . W.; J eong, L.
S.; Chu, C. K.; Tsai, C. H.; Cheng, Y.-C.; Liotta, D.; Schinazi, R. F. J .
Biol. Chem. 1992, 267, 13938-13942.
(5) Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis, R.;
Cannon, D.; J eong, L. S.; Beach, J . W.; Choi, W.-B.; Yeola, S.; Liotta,
D. C. Antimicrob. Agents Chemother. 1992, 36, 672-676.
(6) Furman, P. A.; Davis, M.; Liotta, D. C.; Paff, M.; Frick, L. W.;
Nelson, D. J .; Dornsife, R. E.; Wurster, J . A.; Wilson, L. J .; Fyfe, J . A.;
Tuttle, J . V.; Miller, W. H.; Condreay, L.; Averett, D. R.; Schinazi, R.
F.; Painter, G. R. Antimicrob. Agents Chemother. 1992, 36, 2686-2692.
(7) Lin, T.-S.; Luo, M.-Z.; Liu, M.-C.; Pai, S. B.; Dutschman, G. E.;
Cheng, Y.-C. J . Med. Chem. 1994, 37, 798-803.
(10) Schweitzer, B. A.; Kool, E. T. J . Org. Chem. 1994, 59, 7238-
7242.
(11) Moran, S.; Ren, R. X.-F.; Kool, E. T. Proc. Natl. Acad. Sci. U.S.A.
1997, 94, 10506-10511.
(12) Moran, S.; Ren, R. X.-F.; Rumney, S.; Kool, E. T. J . Am. Chem.
Soc. 1997, 119, 2056-2057.
(13) Morales, J . C.; Kool, E. T. Nature Struct. Biol. 1998, 5, 950-
(8) Gosselin, G.; Schinazi, R. F.; Sommadossi, J .-P.; Mathe, C.;
Bergogne, M.-C.; Aubertin, A.-M.; Kirn, A.; Imbach, J .-L. Antimicrob.
Agents Chemother. 1994, 38, 1292-1297.
954.
(14) Guckian, K. M.; Krugh, T. R.; Kool, E. T. Nature Struct. Biol.
1998, 5, 954-959.
10.1021/jo000510b CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/30/2000

Notes
J . Org. Chem., Vol. 65, No. 26, 2000 9215
Sch em e 1
The L-ribose derivatives 5 and 6 were prepared by
derivative 4 was oxidized by PDC in CH2Cl2, and the
resulting ketone was reduced stereoselectively using
NaBH4 to afford a mixture of the desired ribose deriva-
tives 5 (68%) and 6 (28%). Chu et al.16 reported that the
use of EtOAc-EtOH (1:2) as solvent prevented cleavage
of a benzoyl group, although in our hands the diol 6 was
produced using the same reaction conditions. The diol 6
was also readily prepared by treatment of 5 with NaOMe
in MeOH. Reaction of 6 with benzyl bromide in THF in
the presence of NaH gave the 3,5-di-O-benzyl L-ribose
derivative 7a . Careful treatment of the 5-O-(p-chloroben-
zoyl) L-ribose derivative 5 with benzyl bromide and NaH
in dry THF afforded the 5-O-(p-chlorobenzoyl)-3-benzyl
L-ribose derivative 7b in 87% yield.
adapting reported procedures.16 Ketalization of L-xylose,
in acetone in the presence of anhydrous CuSO4 and a
catalytic amount of concentrated H2SO4, followed by
selective hydrolysis with 0.1 N HCl afforded 1,2-O-
isopropylidene-R-xylofuranose.17 Selective protection of
the 5-OH using p-Cl-Bz-Cl in pyridine-CH2Cl2 at 0 °C
gave 4. The 3-OH substituent of the pentofuranose
(15) (a) Hsieh, H.-P.; McLaughlin, L. W. J . Org. Chem. 1995, 60,
5356-5359. (b) Daves, G. D. Acc. Chem. Res. 1990, 23, 201-206. (c)
Hacksell, U.; Daves, G. D. J . Org. Chem. 1983, 48, 2870-2876. (d)
Outten, R. A.; Daves, G. D. J . Org. Chem. 1989, 54, 29-35. (e) Farr,
R. N.; Daves, G. D. J . Carbohydr. Chem. 1990, 23, 653-660. (f) Farr,
R. N.; Kwok, D.-I.; Daves, G. D. J . Org. Chem. 1992, 57, 2093-2100.
(g) Zhang, H. C.; Daves, G. D. J . Org. Chem. 1992, 57, 4690-4696. (h)
Coleman, R. S.; Madaras, M. L. J . Org. Chem. 1998, 63, 5700-5703.
(16) Ma, T.; Pai, S. B.; Zhu, Y. L.; Lin, J . S.; Shanmuganathan, K.;
Du, J .; Wang, C.; Kim, H.; Newton, M. G.; Cheng, Y. C.; Chu, C. K. J .
Med. Chem. 1996, 39, 2835-2843.
Although numerous attempts have been made to
prepare furanose glycals, two reactions have been the
most useful in the carbohydrate field. For example,
Garegg and Samuelsson have found that action of the
iodine-triphenylphosphine-imidazole reagent on a vic-
(17) Baker, B. R.; Schaub, R. E. J . Am. Chem. Soc. 1955, 77, 5900-
5905.

9216 J . Org. Chem., Vol. 65, No. 26, 2000
Notes
diol produced an unstable vic-diiodide that underwent
an iodine-elimination reaction to afford the corresponding
unsaturated sugar.18 The second reaction is related to the
Corey and Hopkins dideoxygenation procedure,19 where
the action of 1,3-dimethyl-2-phenyl-1,3,2-diazaphospho-
lidine (DMPD) on a vic-diol thiocarbonate was shown to
result in elimination to afford the olefin product, which
has been used for the synthesis of enofuranosides20 and
furanoid glycals.21 We adapted a method related to the
Garegg and Samuelsson procedure18 to prepare the
ribofuranoid glycals 8a and 8b.
The 1,2-O-isopropylidenyl group in 7a and 7b was
readily removed by treatment with 80% aqueous AcOH
at 100 °C. The resulting vic-diols were treated directly
with the iodine-triphenylphosphine-imidazole reagent
in dry CH2Cl2 at 25 °C to afford the desired ribofuranoid
glycals 8a and 8b in 45 and 62% yields, respectively.
Garegg and Samuelsson performed similar reactions at
reflux temperature in toluene for several hours to prepare
unsaturated sugars.18 In our study, the starting material
(7a ,b) immediately disappeared after addition of the
reagent, to yield the corresponding glycal (8). This
observation, which is identical with a report by Diaz et
al.,21 is attributed to the higher reactivity of the hydroxyl
group at the anomeric position.
F igu r e 1. NOE determinations of the conformation and
configuration of 2,5-difluoro-4-[1-(2-deoxy-â-L-ribofuranosyl)]-
aniline (13b) in MeOH-d4 at 22 °C.
cific reduction apparently involves initial coordination of
the borohydride reagent with the C-5′ hydroxyl and
hydride delivery from the hindered â-face of the carbo-
hydrate ring.15f The configuration and conformation of
13b were analyzed by nuclear Overhauser enhancement
The Heck coupling reaction of 3-fluoro-4-iodoaniline
(9a ) or 2,5-difluoro-4-iodoaniline (9b) with glycal 8a or
8b in the presence of palladium(II) acetate, Ph3As, and
Et3N in dry MeCN at 70 °C,22 afforded 10a (57%) or 10b
(71%). A variety of methods were investigated to convert
the benzyl enol ether (10) to the ketone (12). Thus,
hydrogenation of 10b using 10% Pd on C and H2 gas in
THF, or EtOH, gave a complex mixture of products.
Treatment of 10b with TMSI gave the 5-O-(p-chloroben-
zoyl)-protected ketone in low yield (25%), and subsequent
reduction of this ketone with NaB(OAc)3H slowly pro-
duced a mixture of two C-3 OH isomers. Treatment of
10a , or 10b, with BCl3 in CH2Cl2 at -78 °C also did not
give the desired ketone, even though the starting com-
pound was completely consumed. The instability of
compounds 10a ,b is probably due to the high reactivity
of the sugar ring oxygen atom, which is located at an
allylic and benzylic position that makes it susceptible to
attack by acid, resulting in sugar ring opening. It was
therefore anticipated that the decomposition of 10a , or
10b, could be prevented if the reaction was performed
under basic conditions. Accordingly, the Pd on C cata-
lyzed hydrogenation of 10a in anhydrous EtOH contain-
ing several drops of Et3N at 60 °C afforded the hydroxy
ketone 12a in 61% yield. The 5-(p-chlorobenzoyl) group
of 10b was readily removed by treatment with NaOMe
in MeOH, and the resulting benzyl enol ether (11) was
converted to the hydroxy ketone 12b in quantitative yield
upon Pd on C catalyzed hydrogenation in anhydrous
EtOH in the presence of several drops of Et3N at 60 °C.
Subsequent reduction of the hydroxy ketones 12a ,b with
1
(NOE) H NMR difference spectroscopy (see Figure 1).
Selective irradiation of the H-4′ signal resulted in an
enhancement of the H-1′ signal (2.5%) and irradiation of
the H-2′′ signal gave a 6.3% enhancement of the H-1′
signal, which support the assignment of the â-configu-
ration.22
The C-6 hydrogen of the 4-amino-2,5-difluoro-
phenyl moiety is oriented in the direction of the sugar
ring, since NOE enhancements of the C-6 hydrogen were
observed upon selective irradiation of H-1′ (1.6%), H-2′
(2.8%), and the CH2OH (1.1%) signals.
Replacement of the natural cytosine base moiety in â-L-
3a , or â-L-3b, by an unnatural aryl isostere such as a
2-substituted 5-fluoroaniline ring system could confer
new properties that may be useful in the design of a novel
class of third-generation C-aryl deoxy-â-L-cytidine mim-
ics. These mimics offer a number of potential advantages,
such as resistance to pyrimidine phosphorylases due to
the absence of a glycosyl bond, decreased host cell toxicity
due to their inability to inhibit TS, and resistance to
deamination (inactivation) by deoxycytidine deaminase.
The ability of â-L-13a and â-L-13b to inhibit the
proliferation of murine leukemia cells (L1210/0), murine
mammary carcinoma cells (FM3A/0), and human T-
lymphocyte cells (Molt4/C8, CEM/O) in cell cultures by
50% (IC50 ( SEM) were evaluated using a previously
reported procedure.23 In these assays 13a and 13b
provided negligible (IC50: 300-400 µM), or no (IC50
>
22
NaB(AcO)3H in dry MeCN afforded the target deoxy-
500 µM), inhibition of L1210/0 (IC50 ) 402 ( 138 µM
(13a ) and 451 ( 10 µM (13b)), FM3A/0 (IC50 > 500 µM
(13a ,b)), Molt 4/C8 (IC50 ) 297 ( 45 µM (13a ) and > 500
µM (13b)), or CEM/0 (IC50 ) 406 ( 133 µM (13a ) and >
500 µM (13b)) cell proliferation. In addition 13a ,b did
not protect (EC50 > 250 µM) human T-lymphocytes (CEM
â-L-cytidine C-nucleoside mimics (13a ,b). This stereospe-
(18) Garegg, J .; Samuelsson, B. Synthesis 1979, 813-814.
(19) Corey, E. J .; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 1979-
1982.
(20) Chu, C. K.; Bhadti, V. S.; Doboszewski, B.; Gu, Z. P.; Kosugi,
Y.; Pullaiah, K. C.; van Rogy, P. J . Org. Chem. 1989, 54, 2217-2225.
(21) Diaz, R. R.; Melgarejo, C. R.; Cubero, I. I.; Lopez-Espinosa, M.
T. P. Carbohydr. Res. 1997, 300, 375-380.
(22) Walker, J . A.; Chen, J . J .; Hinkley, J . M.; Wise, D. S.; Townsend,
L. B. Nucleosides & Nucleotides 1997, 16, 1999-2012.
(23) De Clercq, E.; Balzarini, J .; Torrence, P. F.; Mertes, M. P.;
Schmidt, C. L.; Shugar, D.; Barr, P. J .; J ones, A. S.; Verhelst, G.;
Walker, R. T. Mol. Pharmacol. 1981, 19, 321-330.

Notes
J . Org. Chem., Vol. 65, No. 26, 2000 9217
dissolved in EtOAc; this solution was passed through a silica
gel pad, and the pad was washed with EtOAc. Removal of the
solvent from the filtrate gave a residue that was recrystallized
from hexanes-ether to give 5 (15.8 g, 56%) as white crystals.
Removal of the solvent from the mother liquor gave a residue
that was purified via flash chromatography (hexanes-EtOAc,
2:1 to 1:2 v/v) to provide additional 5 (3.4 g, 12%) and 6 (4.5 g,
28%), affording 19.2 g of 5 (68% total yield).
Com p ou n d 5: white crystals; mp 136-138 °C; 1H NMR
(CDCl3) δ 7.98 (d, J ) 8.5 Hz, 2H), 7.40 (d, J ) 8.5 Hz, 2H), 5.84
(d, J ) 4.0 Hz, 1H), 4.68 (dd, J ) 12.2, 2.4 Hz, 1H), 4.60 (dd, J
) 5.2, 4.0 Hz, 1H), 4.43 (dd, J ) 12.2, 5.5 Hz, 1H), 4.07 (ddd, J
) 8.8, 5.8, 2.4 Hz, 1H), 3.93 (m, 1H), 2.60 (br s, 1H, D2O
exchangeable), 1.58 (s, 3H), 1.37 (s, 3H); 13C NMR (CDCl3) δ
165.43, 139.55, 131.09, 128.66, 128.29, 112.80, 104.10, 78.50,
78.30, 72.28, 63.72, 26.54, 26.49. Anal. Calcd for C15H17ClO6: C,
54.81; H, 5.21. Found: C, 54.68; H, 5.15.
cells) against the cytopathogenicity induced by human
immunodeficiency viruses (HIV-1, HIV-2).24
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. 1H NMR
(300 MHz), 13C NMR (75.5 MHz), and 19F NMR (282.4 MHz)
spectra were recorded with TMS (δ 0), CDCl3 (δ 77) or DMSO-
d6 (δ 39.5), and external C6F6 (δ 0) as reference standards,
respectively. NOE studies were performed under steady-state
conditions using the Bruker NOE DIFF.AU software program
(signal to noise ratio of 136 for a single pulse). MeOH-d4 was
dried using molecular sieves (type 3A, 1.6 mm pellets) and
degassed by passage of dry argon at 22 °C just prior to use.
Elemental analyses were performed by the MicroAnalysis
Service Laboratory, Department of Chemistry, University of
Alberta. Silica gel 60 (E. Merck Co.) was employed for all silica
gel column flash chromatography separations. All reagents were
purchased from the Aldrich Chemical Co.
Com p ou n d 6: white crystals; mp 87-89 °C (lit.16 mp 86-87
1
°C); H NMR (CDCl3) δ 5.76 (d, J ) 3.7 Hz, 1H), 4.54 (dd, J )
4.9, 3.7 Hz, 1H), 3.96 (dd, J ) 8.8, 4.9 Hz, 1H), 3.89 (dd, J )
12.2, 2.4 Hz, 1H), 3.82 (ddd, J ) 8.8, 3.3, 2.4 Hz, 1H), 3.69 (dd,
J ) 12.2, 3.3 Hz, 1H), 3.2 (br s, 2H, D2O exchangeable), 1.53 (s,
3H), 1.33 (s, 3H); 13C NMR (CDCl3) δ 113.13, 104.37, 81.09,
79.25, 71.35, 61.23, 26.93 (2C).
1,2-O-Isop r op ylid en e-r-L-r ibofu r a n ose (6). NaOMe (1.9 g,
35 mmol) was added to a suspension of 5 (8.5 g, 25.8 mmol) in
MeOH (50 mL) at 25 °C, and the resulting mixture was stirred
at 25 °C for 30 min. The reaction was quenched with solid NH4-
Cl, and the mixture was diluted with ether (150 mL), filtered,
and washed with ether. Removal of the solvent from the filtrate
gave a residue that was purified via flash chromatography
(hexanes-EtOAc, 1:1 to 1:2 v/v) to give the diol 6 (4.81 g, 98%)
as white crystals. The melting point and NMR spectral data for
6 were identical with those listed above.
5-O-(p -Ch lor ob en zoyl)-1,2-O-isop r op ylid en e-r-L-xylo-
fu r a n ose (4). A mixture of L-xylose (24.5 g, 0.163 mol), dry
CuSO4 (50 g, 0.341 mol), and concentrated H2SO4 (2 mL) in
acetone (200 mL) was stirred at 25 °C for 24 h. The mixture
was filtered, and the solid was washed with acetone. The filtrate
was neutralized with concentrated NH4OH, and the resulting
white solid was removed by suction filtration. Removal of the
solvent in vacuo from the filtrate gave a syrup that was treated
with aqueous 0.1 N HCl (150 mL) for 1 h at 25 °C, during which
time the reaction mixture turned to a clear solution. The reaction
was quenched with solid NaHCO3 to a pH of 7.5. The solution
was washed with ether once, and the aqueous fraction was
evaporated in vacuo to yield a pale yellow syrup, which was
dissolved in CHCl3 (100 mL) prior to drying (Na2SO4). Filtration,
and removal of the solvent in vacuo, afforded a pale yellow syrup
(30.5 g, 98%). p-Chlorobenzoyl chloride (20.1 mL, 0.158 mol) was
added dropwise over 30 min to an ice-cold solution of this syrup
(30 g, 0.158 mol) and pyridine (27 mL) in dry CH2Cl2 (130 mL).
The resulting mixture was stirred at 0 °C for 1 h and washed
with aqueous 1 N HCl and saturated NaHCO3, prior to drying
the organic fraction (Na2SO4). After filtration, and removal of
the solvent in vacuo, the residue obtained was recrystallized
from ether to afford white crystals (37 g). The product remaining
in the mother liquor was purified by flash chromatography
(hexanes-EtOAc, 5:1 to 2:1 v/v) to give additional product (4.5
g), providing the title compound 4 (41.5 g, 80%) as white
crystals: mp 102-104 °C; 1H NMR (CDCl3) δ 7.99 (d, J ) 8.5
Hz, 2H), 7.43 (d, J ) 8.5 Hz, 2H), 5.96 (d, J ) 3.7 Hz, 1H), 4.77
(dd, J ) 12.8, 8.8 Hz, 1H), 4.59 (d, J ) 3.7 Hz, 1H), 4.5-4.4 (m,
2H), 4.19 (br s, 1H), 3.16 (br s, 1H, D2O exchangeable), 1.51 (s,
3H), 1.33 (s, 3H); 13C NMR (CDCl3) δ 166.10, 139.84, 131.10,
128.70, 127.87, 111.83, 104.79, 85.17, 78.46, 74.64, 62.14, 26.76,
26.13. Anal. Calcd for C15H17ClO6: C, 54.81; H, 5.21. Found: C,
54.72; H, 5.28.
5-O-(p-Ch lor oben zoyl)-1,2-O-isopr opyliden e-r-L-r ibofu r a-
n ose (5) a n d 1,2-O-Isop r op ylid en e-r-L-r ibofu r a n ose (6).
PDC (30.7 g, 0.0816 mol) and Ac2O (42.3 mL, 0.449 mol) were
added to a solution of 4 (41 g, 0.125 mol) in dry CH2Cl2 (350
mL), and the resulting solution was stirred at reflux for 2 h.
After the mixture was cooled to 25 °C, the solvent was removed
in vacuo, and the residue obtained was dissolved in EtOAc (50
mL). The mixture was filtered through a silica gel pad, and the
pad was washed with EtOAc-hexane (1:1 v/v). The solvent from
the filtrate was removed in vacuo, and the residue was coevapo-
rated with toluene (2 × 50 mL). The residue was recrystallized
from hexanes-EtOAc to afford 5-O-(p-chlorobenzoyl)-1,2-O-
isopropylidene-R-L-erythro-pentofuranos-3-ulose (35 g, 87%) as
white crystals, mp 104-105 °C.
3,5-Di-O-b en zyl-1,2-O-isop r op ylid en e-r-L-r ib ofu r a n ose
(7a ). The diol 6 (4.8 g, 25 mmol) was added in aliquots to an
ice-cold suspension of NaH (60% in mineral oil, 2.4 g, 60 mmol)
in dry THF (80 mL) with stirring under argon, and the resulting
mixture was stirred at 0 °C for 30 min, prior to addition of benzyl
bromide (7.3 mL, 60 mmol). After the reaction mixture was
stirred at 0 °C for 1 h, and then at 25 °C for 12 h, the reaction
was quenched with solid NH4Cl. The reaction mixture was
diluted with ether (100 mL), and the mixture was washed with
water and brine, prior to drying the organic fraction (Na2SO4).
After filtration and removal of the solvent in vacuo, the residue
obtained was purified via flash chromatography (hexanes-ether,
1:0 to 1:1 v/v) to afford 7a (8.65 g, 92%) as a colorless oil: 1H
NMR (CDCl3) δ 7.4-7.2 (m, 10H), 5.79 (d, J ) 4.0 Hz, 1H), 4.76
(d, J ) 11.9 Hz, 1H), 4.60 (d, J ) 7.0 Hz, 1H), 4.56 (d, J ) 7.0
Hz, 1H), 4.58 (m, 1H), 4.52 (d, J ) 11.9 Hz, 1H), 4.22 (ddd, J )
9.2, 4.0, 2.1 Hz, 1H), 3.89 (dd, J ) 9.2, 4.3 Hz, 1H), 3.80 (dd, J
) 11.3, 2.1 Hz, 1H), 3.60 (dd, J ) 11.3, 4.0 Hz, 1H), 1.63 (s, 3H),
1.39 (s, 3H); 13C NMR (CDCl3) δ 138.08, 137.67, 128.25, 128.18,
127.82, 127.76, 127.54, 127.42, 112.73, 104.13, 77.43, 77.38,
73.44, 72.14, 68.28, 26.78, 26.59.
5-O-(p-Ch lor oben zoyl)-3-O-ben zyl-1,2-O-isop r op ylid en e-
r-L-r ibofu r a n ose (7b). Compound 5 (13.14 g, 40 mmol) and
benzyl chloride (7.2 mL, 60 mmol) were added in aliquots to an
ice-cold suspension of NaH (60% in mineral oil, 1.8 g, 45 mmol)
in dry THF (50 mL) with stirring under argon. The reaction
mixture was stirred at 0 °C for 30 min and then at 25 °C for 5
h. Solid NH4Cl (5 g) was added to quench the reaction, and the
mixture was stirred for another 10 min. The reaction mixture
was diluted with ether (200 mL) and washed with water (150
mL). The aqueous fraction was extracted with ether (2 × 100
mL), and the combined organic extracts were washed with
saturated aqueous NH4Cl and brine prior to drying (Na2SO4).
After filtration, and removal of the solvent in vacuo, the residue
obtained was purified via flash chromatography (hexanes-
EtOAc, 10:1 v/v) to give 7b (14.49 g, 87%) as white crystals: mp
84-85 °C; 1H NMR (CDCl3) δ 7.89 (d, J ) 8.2 Hz, 2H), 7.5-7.3
(m, 7H), 5.81 (d, J ) 3.7 Hz, 1H), 4.85 (d, J ) 11.9 Hz, 1H),
4.6-4.7 (m, 2H), 4.59 (d, J ) 11.9 Hz, 1H), 4.45-4.35 (m, 2H),
3.79 (dd, J ) 8.8, 4.3 Hz, 1H), 1.67 (s, 3H), 1.44 (s, 3H); 13C NMR
(CDCl3) δ 165.16, 139.39, 137.23, 131.01, 128.54, 128.41, 128.28,
128.02, 127.93, 113.08, 104.20, 77.56, 76.96, 76.33, 72.11, 63.35,
NaBH4 (3.27 g, 86 mmol) was added in aliquots to a stirred
solution of the above ketone (28 g, 85.76 mmol) in anhydrous
EtOH (100 mL) and EtOAc (100 mL) at 0 °C; the mixture was
stirred at 0 °C for 1 h and then neutralized with dilute AcOH.
Removal of the solvent in vacuo gave a residue that was
(24) Balzarini, J .; Naesens, L.; Slachmuylders, J .; Niphuis, H.;
Rosenberg, L.; Holy´, A.; Schellekens, H.; De Clercq, E. AIDS 1991, 5,
21-28.

9218 J . Org. Chem., Vol. 65, No. 26, 2000
Notes
26.77, 26.54. Anal. Calcd for C22H23ClO6: C, 63.08; H, 5.53.
Found: C, 62.89; H, 5.37.
4:1 v/v) followed by recrystallization from hexanes-ether gave
10b (0.81 g, 71%) as pale yellow needles: mp 137-138 °C; IR
1
1,4-An h yd r o-3,5-d i-O-b en zyl-2-d eoxy-L-er yth r o-p en t -1-
en itol (8a ). A solution of 7a (4.63 g, 12.5 mmol) in 80% aqueous
AcOH (80 mL) was stirred at 100 °C for 5 h. Removal of the
solvent in vacuo gave a residue that was coevaporated with
toluene once. The residue was dissolved in EtOAc (100 mL) and
treated with solid NaHCO3. Filtration and removal of the solvent
in vacuo afforded the diol as a colorless syrup, which was used
directly in the subsequent reaction.
(NaCl) 3479, 3365, 1721, 1666, 1643 cm-1; H NMR (CDCl3) δ
7.88 (d, J ) 8.5 Hz, 2H), 7.36 (d, J ) 8.5 Hz, 2H), 7.33 (br s,
5H), 7.02 (dd, J ) 11.3, 6.4 Hz, 1H), 6.43 (dd, J ) 10.7, 7.2 Hz,
1H), 6.03 (m, 1H), 5.03 (m, 1H), 4.93 (d, J ) 5.5 Hz, 2H), 4.89
(m, 1H), 4.63 (dd, J ) 11.9, 2.7 Hz, 1H), 4.55 (dd, J ) 11.9, 4.0
Hz, 1H), 3.75 (br s, 2H, D2O exchangeable); 13C NMR (CDCl3) δ
165.43, 156.25 (d, J ) 240.6 Hz), 154.24, 147.2 (d, J ) 235.3
Hz), 139.21, 135.72, 135.21 (dd, J ) 15.4, 11.0 Hz), 131.00,
128.50, 128.41, 128.19, 127.41, 118.61 (dd, J ) 16.0, 5.5 Hz),
113.96 (dd, J ) 21.9, 6.0 Hz), 103.10 (dd, J ) 27.5, 3.3 Hz), 96.29,
Triphenylphosphine (7.22 g, 27.5 mmol) and imidazole (7.52
g, 110.6 mmol) were added in aliquots to a well-stirred solution
of iodine (7.0 g, 27.5 mmol) in dry CH2Cl2 (100 mL) at 25 °C,
during which time the reaction mixture turned to a pale yellow.
The above diol in dry CH2Cl2 (20 mL) was added to the reaction
mixture, which immediately changed color to brown. After it was
stirred at 25 °C for 10 min, Et3N (5 mL) was added to the
mixture, and the reaction mixture was concentrated to half-
volume before dilution with hexane (100 mL). The mixture was
passed through a silica gel pad that was washed with a large
volume of hexanes-ether (1:1 v/v) and then ether. The solvents
from the combined organic eluants were removed, and the
residue obtained was purified via flash chromatography (hex-
anes-ether, 6:1 v/v, the silica gel was treated with 1% Et3N in
hexane before packing the column to avoid on-column decom-
position of the glycal 8a ) to afford the glycal 8a (1.65 g, 45%) as
a colorless syrup: 1H NMR (CDCl3) δ 7.4-7.2 (m, 10H), 6.62 (d,
J ) 2.7 Hz, 1 H), 5.20 (dd, J ) 2.7, 2.1 Hz, 1H), 4.75-4.60 (m,
2H), 4.61 (d, J ) 4.0 Hz, 2H), 4.56 (s, 2H), 3.59 (dd, J ) 9.9, 6.1
Hz, 1H), 3.46 (d, J ) 9.9, 5.3 Hz, 1H); 13C NMR (CDCl3) δ 150.20,
138.26, 137.83, 128.30, 128.27, 127.72, 127.61, 127.57, 127.48,
100.53, 84.81, 82.68, 73.38, 69.89, 69.55.
1,4-An h yd r o-5-O-(p-ch lor oben zoyl)-3-O-ben zyl-2-d eoxy-
L-er yth r o-p en t-1-en itol (8b). A solution of 7b (5.25 g, 12.5
mmol) in 80% aqueous AcOH (80 mL) was stirred at 100 °C for
4 h. Removal of the solvent in vacuo gave a residue that was
coevaporated with toluene once; the residue was dissolved in
EtOAc (100 mL) and treated with solid NaHCO3. Filtration, and
removal of the solvent, afforded the diol as a colorless syrup,
which was used directly in the subsequent reaction.
Triphenylphosphine (7.22 g, 27.5 mmol) and imidazole (7.52
g, 110.6 mmol) were added in aliquots to a well-stirred solution
of iodine (7.0 g, 27.5 mmol) in dry CH2Cl2 (100 mL) at 25 °C;
the reaction was completed and the product purified as described
for the preparation of 8a above to afford the glycal 8b (2.55 g,
62%) as a colorless syrup: 1H NMR (CDCl3) δ 7.97 (d, J ) 8.8
Hz, 2H), 7.43 (d, J ) 8.8 Hz, 2H), 7.4-7.25 (m, 5H), 6.63 (dd, J
) 2.7, 0.8 Hz, 1H), 5.27 (dd, J ) 2.7, 2.4 Hz, 1H), 4.79 (td, J )
5.5, 3.0 Hz, 1H), 4.72 (ddd, J ) 3.0, 2.4, 0.8 Hz, 1H), 4.56 (s,
2H), 4.35 (d, J ) 5.5 Hz, 2H); 13C NMR (CDCl3) δ 165.32, 150.45,
139.68, 137.95, 131.09, 128.77, 128.45, 128.16, 127.74, 100.70,
83.57, 82.52, 69.79, 64.70. Anal. Calcd for C19H17ClO4: C, 66.19;
H, 4.97. Found: C, 66.24; H, 4.91.
79.97, 78.31 (d, J ) 2.2 Hz), 72.60, 65.06. Anal. Calcd for C25H20
-
ClF2NO4: C, 63.63; H, 4.27; N, 2.97. Found: C, 63.41; H, 4.00;
N, 2.86.
3-F lu or o-4-(â-L-glycer op en t ofu r a n -3-u los-1-yl)a n ilin e
(12a ). Pd on C (10% w/w, 0.1 g) was added to a solution of 10a
(0.38 g, 0.936 mmol) in dry EtOH (6 mL) and Et3N (0.05 mL),
and the resulting mixture was stirred at 60 °C under 1 atm of
H2 gas for 8 h. After filtration, and removal of the solvent in
vacuo, the residue was purified via flash chromatography
(hexanes-EtOAc, 1:1 v/v) to give the hydroxy ketone 12a (0.13
g, 61%) as pale yellow crystals: mp 132-133 °C; IR (NaCl) 3446,
1
3364, 3220, 1752, 1635 cm-1; H NMR (CDCl3) δ 7.20 (dd, J )
8.5, 8.2 Hz, 1H), 6.39 (dd, J ) 8.5, 2.1 Hz, 1H), 6.30 (dd, J )
12.5, 2.1 Hz, 1H), 5.22 (dd, J ) 11.0, 6.0 Hz, 1H), 3.90 (t, J )
3.0 Hz, 1H), 3.78 (d, J ) 3.0 Hz, 2H), 3.62 (br s, 3H, D2O
exchangeable), 2.70 (dd, J ) 18.1, 6.0 Hz, 1H), 2.48 (dd, J )
18.1, 11.0 Hz, 1H); 13C NMR (CDCl3) δ 214.2, 161.26 (d, J )
243.9 Hz), 148.61 (d, J ) 9.9 Hz), 128.39 (d, J ) 6.6 Hz), 115.4
(d, J ) 14.5 Hz), 110.74 (d, J ) 2.2 Hz), 101.68 (d, J ) 25.3 Hz),
82.32, 72.1, 61.05, 43.87. Anal. Calcd for C11H12FNO3: C, 58.66;
H, 5.37; N, 6.22. Found: C, 58.29; H, 5.30; N, 6.15.
4-(5-(H yd r oxym e t h yl)-4-(b e n zyloxy)-2,5-d ih yd r o-â-L-
fu r a n -2-yl)-2,5-d iflu or oa n ilin e (11). NaOMe (0.16 g, 3 mmol)
was added to a suspension of 10b (0.8 g, 1.75 mmol) in dry
MeOH (30 mL) with stirring, and the reaction mixture was
stirred at 25 °C for 1.5 h, during which time the reaction mixture
changed to a clear solution. The reaction was quenched with
solid NH4Cl, and then ether (100 mL) was added. After filtration,
and removal of the solvent in vacuo, the residue obtained was
purified via flash chromatography (hexanes-EtOAc, 2:1 v/v) to
give 11 (0.465 g, 90%) as a yellow syrup: IR (NaCl) 3465, 3362,
1
3224, 1663, 1645, 1518 cm-1; H NMR (CDCl3) δ 7.45-7.3 (m,
5H), 7.05 (dd, J ) 11.3, 6.4 Hz, 1H), 6.45 (dd, J ) 11.0, 7.3 Hz,
1H), 6.03 (m, 1H), 4.95 (d, J ) 3.1 Hz, 2H), 4.79 (m, 1H), 4.76
(m, 1H), 3.80 (d, J ) 3.4, 2H); 13C NMR (CDCl3) δ 156.25 (d, J
) 240.6 Hz), 155.39, 147.6 (d, J ) 235.1 Hz), 135.85, 135.57 (dd,
J ) 15.4, 11.0 Hz), 128.53, 128.19, 127.42, 118.41 (dd, J ) 16.0,
5.5 Hz), 114.22 (dd, J ) 22.0, 5.5 Hz), 103.20 (dd, J ) 28.6, 3.3
Hz), 95.53, 82.33, 77.88 (d, J ) 3.3 Hz), 72.53, 62.95. Anal. Calcd
for C18H17F2NO3: C, 64.85; H, 5.14; N, 4.20. Found: C, 64.55;
H, 5.21; N, 3.98.
4-(5-((Ben zyloxy)m eth yl)-4-(ben zyloxy)-2,5-d ih yd r o-â-L-
fu r a n -2-yl)-3-flu or oa n ilin e (10a ). A freshly dried 100 mL
round-bottom flask was charged with palladium acetate (0.1 g,
0.364 mmol) and triphenylarsine (0.4 g, 1.33 mmol) under argon.
Dry MeCN (15 mL) was added, and the yellow suspension was
stirred at 25 °C for 30 min. A solution of the glycal 8a (0.592 g,
2 mmol), 9a (0.592 g, 2.5 mmol), and Et3N (0.6 mL) in MeCN
(10 mL) was added with stirring, and the resulting solution was
stirred at 70 °C for 24 h. The solvents were removed in vacuo,
and the residue was purified via flash chromatography (hex-
anes-EtOAc, 3:1 v/v) to give 10a (0.46 g, 57%) as a yellow
2,5-D iflu o r o -4-(â-L -g ly c e r o p e n t o fu r a n -3-u lo s -1-y l)-
a n ilin e (12b). Et3N (3 drops) and 10% Pd on C (0.1 g) were
added to a solution of 11 (0.42 g, 1.42 mmol) in dry EtOH (10
mL) with stirring, and the resulting mixture was stirred at 60
°C under 1 atm of H2 gas for 2 h. After filtration, and removal
of the solvent in vacuo, the residue was purified via flash
chromatography (hexanes-EtOAc, 1.5:1 to 1:1 v/v) to give the
hydroxy ketone 12b (0.33 g, 96%) as a colorless syrup: IR (NaCl)
3465, 3368, 3231, 1758, 1649, 1522 cm-1 1H NMR (CDCl3) δ
;
7.14 (dd, J ) 11.3, 6.4 Hz, 1H), 6.48 (dd, J ) 11.3, 7.3 Hz, 1H),
5.29 (dd, J ) 11.0, 5.8 Hz, 1H), 4.0 (t, J ) 3.3 Hz, 1H), 3.95 (d,
J ) 3.3 Hz, 2H), 3.92 (br s, 2H, D2O exchangeable), 2.84 (dd, J
) 18.0, 5.8 Hz, 1H), 2.49 (dd, J ) 18.0, 11.0 Hz, 1H), 2.47 (br s,
1H, D2O exchangeable); 13C NMR (CDCl3) δ 213.41, 156.45 (dd,
J ) 240.6, 2.2 Hz), 147.47 (dd, J ) 235.1, 2.2 Hz), 135.83 (dd, J
) 15.4, 12.1 Hz), 115.41 (dd, J ) 16.9, 5.5 Hz), 113.5 (dd, J )
22.0, 5.5 Hz), 103.3 (dd, J ) 27.5, 4.4 Hz), 82.0, 71.76, 61.40,
44.10. Anal. Calcd for C11H11F2NO3: C, 54.32; H, 4.56; N, 5.76.
Found: C, 54.61; H, 5.05; N, 5.51.
3-F lu or o-4-[1-(2-d eoxy-â-L-r ibofu r a n osyl)]a n ilin e (13a ).
NaB(OAc)3H (0.26 g, 1.2 mmol) was added in one aliquot to an
ice-cold solution of 12a (0.09 g, 0.3 mmol) in dry MeCN (5 mL)
with stirring under argon. After the mixture was stirred at 0
°C for 1.5 h, the reaction was quenched with MeOH (2 mL), and
1
syrup: IR (NaCl) 3471, 3368, 3229, 1664, 1630 cm-1; H NMR
(CDCl3) δ 7.45-7.2 (m, 11H), 6.35-6.3 (m, 2H), 6.10 (dd, J )
3.3, 1.2 Hz), 4.93 (br s, 3H), 4.83 (br s, 1H), 4.63 (d, J ) 3.7 Hz,
2H), 3.85 (dd, J ) 10.7, 2.4 Hz), 3.74 (dd, J ) 10.7, 4.9 Hz, 1H),
3.7 (br s, 2H, D2O exchangeable); 13C NMR (CDCl3) δ 160.95 (d,
J ) 243.9 Hz), 154.81, 147.67 (d, J ) 11.0 Hz), 138.43, 136.15,
129.63 (d, J ) 5.5 Hz), 128.41, 128.12, 127.98, 127.56, 127.34,
127.25, 119.16 (d, J ) 13.2 Hz), 110.72, 101.30 (d, J ) 25.3 Hz),
96.40, 81.49, 73.25, 72.27, 71.46.
4-[5-(((p-Ch lor oben zoyl)oxy)m eth yl)-4-(ben zyloxy)-2,5-
d ih yd r o-â-L-fu r a n -2-yl]-2,5-d iflu or oa n ilin e (10b). Reaction
of 8b with 9b, using the method described for the preparation
of 10a above, and purification of the product (hexanes-EtOAc,

Notes
J . Org. Chem., Vol. 65, No. 26, 2000 9219
the solvents were removed in vacuo. The residue was purified
via flash chromatography (hexanes-EtOAc, 1:2 to 0:1 v/v) to give
13a (0.075 g, 83%) as a pale yellow syrup, which was recrystal-
lized from EtOH to give pale yellow crystals (0.020 g, 22%): mp
182-184 °C; [R]27D -27.6° (c 0.17, MeOH); UV (MeOH) λmax 243.1
nm (ꢀ 11 156), 288.5 (ꢀ 1757); 1H NMR (DMSO-d6) δ 7.10 (dd, J
) 8.8, 8.5 Hz, 1H), 6.34 (d, J ) 8.5 Hz, 1H), 6.25 (d, J ) 13.2
Hz, 1H), 5.31 (s, 2H, D2O exchangeable), 5.06 (dd, J ) 10.4, 5.5
Hz, 1H), 5.0 (d, J ) 4.0 Hz, 1H, D2O exchangeable), 4.69 (t, J )
5.5 Hz, 1H, D2O exchangeable), 4.14 (m, 1H), 3.69 (m, 1H), 3.41
(m, 2H), 1.94 (dd, J ) 12.6, 5.5 Hz, 1H), 1.78 (ddd, J ) 12.6,
10.4, 5.5 Hz, 1H); 13C NMR (DMSO-d6) δ 160.52 (d, J ) 241.7
Hz), 149.74 (d, J ) 12.1 Hz), 128.12, 114.91 (d, J ) 14.3 Hz),
109.73, 99.62 (d, J ) 27.5 Hz), 87.05, 72.83, 72.30 (d, J ) 8.8
Hz), 62.41 (d, J ) 8.8 Hz), 41.76 (d, J ) 3.3 Hz); 19F NMR
165 °C; [R]27 -42.8° (c 0.26, MeOH); UV (MeOH) λmax 237.3
D
nm (ꢀ 12 656), 289.2 (ꢀ 3663); 1H NMR (MeOH-d4) δ 7.09 (dd, J
) 12.2, 6.7 Hz, 1H), 6.47 (dd, J ) 11.9, 7.6 Hz, 1H), 5.25 (dd, J
) 10.4, 5.2 Hz, 1H), 4.21 (m, 1H), 3.92 (m, 1H), 3.63 (m, 2H),
2.10 (dd, J ) 12.5, 5.2 Hz, 1H), 1.91 (ddd, J ) 12.5, 10.4, 5.5
Hz, 1H); 13C NMR (DMSO-d6) δ 155.53 (d, J ) 238.4 Hz), 146.61
(d, J ) 232.9 Hz), 136.58 (dd, J ) 15.4, 12.1 Hz), 115.26 (dd, J
) 16.5, 5.5 Hz), 112.95 (dd, J ) 20.9, 6.6 Hz), 101.69 (dd, J )
27.5, 4.4 Hz), 87.17, 72.22, 72.14, 62.20, 42.02. Anal. Calcd for
C11H13F2NO3: C, 53.88; H, 5.34; N, 5.71. Found: C, 53.64; H,
5.36; N, 5.60.
Ack n ow led gm en t. We are grateful to the Canadian
Institutes of Health Research (Grant. No. MOP-14480)
for financial support of this research and to the Alberta
Heritage Foundation for Medical Research for a fellow-
ship to Z.-X.W. Work done at the Rega Institute was
supported by the Fonds voor Wetenschappelijk Onder-
zoek (FWO)-Vlaanderen (Krediet no. 9.0104.98) and the
Geconcerteerde Onderzoeksacties (GOA)-Vlaamse Ge-
meenschap contract no. 2000/12. We thank Ann Absillis,
Anita Camps, Frieda De Meyer, Lizette van Berckelaer,
Lies Vandenheurck, and Anita Van Lierde for excellent
technical assistance.
(DMSO-d6) δ 46.03 (dd, J ) 12.2, 9.2 Hz). Anal. Calcd for C11H14
-
FNO3: C, 58.14; H, 6.21; N, 6.16. Found: C, 58.08; H, 6.42; N,
6.09.
2,5-Diflu or o-4-[1-(2-deoxy-â-L-r ibofu r an osyl)]an ilin e (13b).
NaB(OAc)3H (1.1 g, 5.2 mmol) was added in one portion to an
ice-cold solution of 12b (0.31 g, 1.275 mmol) in dry MeCN (15
mL) with stirring under argon. After stirring at 0 °C for 2 h,
the reaction was quenched with MeOH (5 mL), and the solvents
were removed in vacuo. The residue was purified via flash
chromatography (hexanes-EtOAc, 1:2 to 0:1 v/v) to give 13b
(0.26 g, 84%) as a pale yellow solid, which was recrystallized
from ether to give pale yellow crystals (0.21 g, 68%): mp 163-
J O000510B