The beta-fluorine effect. Electronic versus steric effects in radical deoxygenations of fluorine-containing pentofuranose nucleosides.

Article abstract of DOI:10.1021/jo020428b

Stereoselective pyramidalization of free radicals by a vicinal fluorine substituent, the beta-fluorine effect, was invoked to rationalize a 77:23 anti/syn ratio of 2-deuterio-1-fluorocyclopentanes obtained by radical reduction of trans-2-fluoro-1-bromocyclopentane with tributyltin deuteride (Dolbier, W. R., Jr.; Bartberger, M. D. J. Org. Chem. 1995, 60, 4984-4985). We have evaluated analogous reductions of the four possible stereoisomers of some adenine 2'(3')-fluoro-3'(2')-O-phenoxythiocarbonyl nucleoside derivatives. In all cases, the steric effect of adenine on the beta face directs deuterium transfer from the stannane to C2'(C3') on the alpha face of the furanose ring. However, the beta-fluorine effect enhances ratios of deuterium transfer anti to the vicinal fluorine substituent.

Full text of DOI:10.1021/jo020428b

Th e â-F lu or in e Effect. Electr on ic Ver su s Ster ic Effects in Ra d ica l
Deoxygen a tion s of F lu or in e-Con ta in in g P en tofu r a n ose
Nu cleosid es
Stanislaw F. Wnuk,*,† Dania R. Companioni,† Vladimir Neschadimenko,‡,§ and
Morris J . Robins*,‡
Department of Chemistry, Florida International University, Miami, Florida 33199, and Department of
Chemistry and Biochemistry, Brigham Young University, Provo, Utah, 84602
wnuk@fiu.edu
Received J une 24, 2002
Stereoselective pyramidalization of free radicals by a vicinal fluorine substituent, the â-fluorine
effect, was invoked to rationalize a 77:23 anti/syn ratio of 2-deuterio-1-fluorocyclopentanes obtained
by radical reduction of trans-2-fluoro-1-bromocyclopentane with tributyltin deuteride (Dolbier, W.
R., J r.; Bartberger, M. D. J . Org. Chem. 1995, 60, 4984-4985). We have evaluated analogous
reductions of the four possible stereoisomers of some adenine 2′(3′)-fluoro-3′(2′)-O-phenoxythiocar-
bonyl nucleoside derivatives. In all cases, the steric effect of adenine on the â face directs deuterium
transfer from the stannane to C2′(C3′) on the R face of the furanose ring. However, the â-fluorine
effect enhances ratios of deuterium transfer anti to the vicinal fluorine substituent.
In tr od u ction
from solvent was enhanced by a â-fluorine substituent,
and especially when fluorine and the xanthate ester
group were trans.5 Reduction of (3′,5′-bis-O-silyl-2′-keto
or 2′,5′-bis-O-silyl-3′-keto)nucleosides with sodium boro-
hydride6a or sodium triacetoxyborohydride6b,c also gave
products from predominant attack at the R-face. The
above results demonstrate that steric effects (i.e., pref-
erential delivery of hydrogen or hydride anti to the
heterocylic base in nucleosides) play a major role in the
stereochemical outcome of such reactions.
Dolbier and Bartberger observed anti selectivity
(77:23) with tributyltin hydride-mediated reduction of
â-fluorocyclopentyl radicals (A, Figure 1).7 Other steric
effects on the selectivity of deuterium transfer were
precluded in that unsubstituted ring system. Effects of
a vicinal fluoro substituent on the diastereoselectivity of
deuterium transfer were attributted to anti versus syn
pyramidalization of radicals in the transition state.7 A
â-oxygen effect on radical deoxygenation of thionocar-
bonate esters was examined and found to be indirect
rather than stereoelectronic.8
Stereoselectivity in free radical reactions is an area of
considerable interest.1,2 We have shown that radical
deoxygenation of 2′-O-phenoxythiocarbonyl (PTC) esters
of 3′,5′-bis-O-silyl-protected adenosine (or its arabino
epimer) with tributyltin deuteride gave 2′(R/S)-deuterio-
2′-deoxy derivatives (∼88:12). This indicated that deu-
terium transfer from the bulky tributylstannane to a C2′
radical occurrred with pronounced stereoselectivity at the
less hindered R-face (ribo).3 Ishido and co-workers found
even greater stereoselectivity (as high as 99:1) for tri-
ethylborane-initiated stannane-4a or tris(trimethylsilyl)-
silane-mediated4b deuterium transfers with 2′-O-PTC
esters or 2′-bromo-2′-deoxynucleosides at low tempera-
tures. Marquez and co-workers reported that radical-
mediated deoxygenations of nucleoside xanthate esters
with dilauroyl peroxide/(2-propanol-d8 or diglyme-d14
)
also showed preference for the R-face of nucleoside
derivatives.5 They noted that abstraction of deuterium
* To whom correspondence should be addressed. Fax: (305) 348-
3772.
We now report competition between steric and â-
fluorine effects, including the impact of fluorine regio-
and stereochemistry, on radical deoxygenations of 2′(3′)-
O-phenoxythiocarbonyl (PTC) esters of fluoropentofura-
nosyl-adenine nucleosides. One product, the glycosyl-
† Florida International University.
‡ Brigham Young University.
§ Present address: Amersham Pharmacia Biotech, Piscataway, NJ .
(1) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions. Concepts, Guidelines, and Synthetic Applications; VCH:
New York, 1996.
(2) Bouvier, J .-P.; J ung, G.; Liu, Z.; Guerin, B.; Guindon, Y. Org.
Lett. 2001, 3, 1391-1394.
(6) (a) Hansske, F.; Madej, D.; Robins, M. J . Tetrahedron 1984, 40,
125-135. (b) Robins, M. J .; Samano, V.; J ohnson, M. D. J . Org. Chem.
1990, 55, 410-412. (c) Robins, M. J .; Sarker, S.; Samano, V.; Wnuk,
S. F. Tetrahedron 1997, 53, 447-456.
(3) Robins, M. J .; Wilson, J . S.; Hansske, F. J . Am. Chem. Soc. 1983,
105, 4059-4065.
(4) (a) Kawashima, E.; Aoyama, Y.; Sekine, T.; Miyahara, M.;
Radwan, M. F.; Nakamura, E.; Kainosho, M.; Kyogoku, Y.; Ishido, Y.
J . Org. Chem. 1995, 60, 6980-6986. (b) Kawashima, E.; Uchida, S.;
Miyahara, M.; Ishido, Y. Tetrahedron Lett. 1997, 42, 7369-7372.
(5) Siddiqui, M. A.; Driscoll, J . S.; Abushanab, E.; Kelley, J . A.;
Barchi, J . J ., J r.; Marquez, V. E. Nucleosides Nucleotides Nucleic Acids
2000, 19, 1-12.
(7) Dolbier, W. R., J r.; Bartberger, M. D. J . Org. Chem. 1995, 60,
4984-4985.
(8) (a) Crich, D.; Beckwith, A. L. J .; Chen, C.; Yao, Q.; Davison, I.
G. E.; Longmore, R. W.; Anaya de Parrodi, C.; Quintero-Cortes, L.;
Sandoval-Ramirez, J . J . Am. Chem. Soc. 1995, 117, 8757-8768. (b)
Beckwith, A. L. J .; Crich, D.; Duggan, P. J .; Yao, Q. Chem. Rev. 1997,
97, 3273-3312.
10.1021/jo020428b CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/16/2002
8794
J . Org. Chem. 2002, 67, 8794-8797

The â-Fluorine Effect
TABLE 1. Ra tios of Deu ter iu m Su bstitu tion w ith
Ra d ica l Deoxygen a tion of 2′(3′)-O-P TC Der iva tives of
F lu or op en tofu r a n osyla d en in e Nu cleosid esa ,b
ratio of
2′(3′)-O-PTC-3′(2′)-fluoro 2′/2′′(3′/3′′)-deuterio F/D diastereotopic
substrate
epimers
excess (de)
5, 2′-fluoro-ribo
7 (3′R/ S, 64:36)
8 (3′R/ S, 64:36)
9 (3′R/ S, 93:7)
10 (3′R/ S, 92:8)
17 (2′R/ S, 15:85)
18 (2′R/ S, 14:86)
19 (2′R/ S, 7:93)
20 (2′R/ S, 7:93)
28
syn
85
anti
71
syn
86
F IGURE 1. Structure of the pyramidalized â-fluorocyclopen-
tyl radical intermediate (A) postulated to rationalize the anti
stereoselectivity for deuterium transfer with tributyltin hy-
dride.7
6, 2′-fluoro-arabino
15, 3′-fluoro-ribo
16, 3′-fluoro-xylo
SCHEME 1a
anti
a
Averages of duplicate experiments determined by 1H NMR
(H2′/2" or H3′/3") analysis. b Radical reduction of 5′-O-monomethox-
ytrityl analogues of 15 and 16 gave the same ratios of deuterio
epimers [3′-F-ribo (2′R/ S, 15:85) and 3′-F-xylo (2′R/ S, 8:92)].13
epimers 9; 15 gave 5′-O-TBDMS-2′,3′-dideoxy-2′(R/S)-
deuterio-3′-fluoroadenosine (17), and 16 gave the 2′(R/
S)-deuterio-3′-fluoro-threo epimers 19. Ratios of deute-
rium epimers were determined by 1H NMR and were
consistent with those determined with 5′-O-monometh-
oxytrityl derivatives13 (Table 1). Compounds 7, 9, 17, and
19 were desilylated (NH4F/MeOH)14 to give 8,9,10 10,9,10
a
Key: (a) TBDMS-Cl/imidazole/DMF; (b) PTC-Cl/DMAP/
MeCN; (c) Bu3SnD/AIBN/toluene/85 °C; (d) NH4F/MeOH/∆.
1
18,9 and 20,9 respectively, with H NMR data as reported
SCHEME 2a
except for simplification of multiplets and ∼50% reduc-
tion in intensities of signals for H3′,3′′ (8 and 10) or
H2′,2′′ (18 and 20). 1H-1H and 1H-19F coupling constants
in spectra of 8, 10, 18, and 20 were consistent with
experimental9,10 and calculated15 values for other fluorodi-
deoxynucleosides and had compatible magnitude reduc-
tions for coupling with 2H. Epimeric ratios were deter-
mined more easily with some ofthe deprotected derivatives.
The data in Table 1 indicate that stereoselectivity for
deuterium abstraction by a pentofuranosyl radical with
a â-fluoro substituent is dominated by the steric influence
of the heterocyclic base. In all cases, the major product
has deuterium on the R face (trans to the base on the â
face) independent of the position or orientation of the
fluorine atom. However, comparison of the data for
conversion of 5 f 7 (3′R/S, 64:36; syn F/D de 28) versus
that for 6 f 9 (3′R/S, 93:7; anti F/D de 86) shows that
the orientation of the â-fluorine relative to the radical
center can have a significant effect on deuterium transfer
stereochemistry. A less pronounced but parallel trend
was observed for deuterium abstraction with 3′-fluoro-
nucleosides (15 f 17 (syn F/D de 70) versus 16 f 19
(anti F/D de 86)).16
a
Key: (a) TBDMS-Cl/imidazole/DMF; (b) PTC-Cl/DMAP/
MeCN; (c) Bu3SnD/AIBN/toluene/85 °C; (d) NH4F/MeOH/∆.
stablized 9-(2,3-dideoxy-2-fluoro-â-D-threo-pentofurano-
syl)adenine, is an inhibitor of HIV.9-11
Resu lts a n d Discu ssion
The methodology of Pankiewicz and co-workers12 was
employed to prepare 2′-deoxy-2′-fluoroadenosine (1) and
its arabino epimer 3 (Scheme 1), and 3′-deoxy-3′-fluoro-
adenosine (11) and its xylo epimer 13 (Scheme 2).
Silylation (O5′) of fluoro nucleosides 1, 3, 11, and 13
(TBDMS-Cl) gave 2, 4, 12, and 14, which were treated
with PTC-Cl to give 5′-O-TBDMS-2′-deoxy-2′-fluoro-3′-
O-PTC-adenosine (5) and its arabino epimer 6, and
5′-O-TBDMS-3′-deoxy-3′-fluoro-2′-O-PTC-adenosine (15)
and its xylo epimer 16, respectively.
Con clu sion s
It is clear that steric effects are decisive for determi-
nation of the stereoslectivity of transfer of deuterium
Treatment of 5 with tributyltin deuteride gave 5′-O-
TBDMS-2′,3′-dideoxy-3′(R/S)-deuterio-2′-fluoroadeno-
sine (7), and 6 gave the 3′(R/S)-deuterio-2′-fluoro-threo
(13) Neschadimenko, V. V. Ph.D. Dissertation, Brigham Young
University, Provo, Utah, 1999.
(14) Zhang, W.; Robins, M. J . Tetrahedron Lett. 1992, 33, 1177-
(9) Herdewijn, P.; Pauwels, R.; Baba, M.; Balzarini, J .; De Clercq,
E. J . Med. Chem. 1987, 30, 2131-2137.
1180.
(15) Thibaudeau, C.; Plavec, J .; Chattopadhyaya, J . J . Org. Chem.
1998, 63, 4967-4984.
(10) Marquez, V. E.; Tseng, C. K.-H.; Mitsuya, H.; Aoki, S.; Kelley,
J . A.; Ford, H., J r.; Roth, J . S.; Broder, S.; J ohns, D. G.; Driscoll, J . S.
J . Med. Chem. 1990, 33, 978-985.
(16) The greater R stereoselectivity for radical reduction of 15
compared to that of 5 probably results from the larger steric effect of
the heterocyclic base at C2′ relative to C3′. Reductions of ketonucleo-
sides with NaBH4,6a or especially with NaB(OAc)3H,6b,c are known to
give products from predominant attack by the hydride reagent at the
less hindered R face of the sugar ring. Such reductions proceed with
significantly greater stereoselectivity at C2′ than at C3′.
(11) Takamatsu, S.; Maruyama, T.; Katayama, S.; Hirose, N.; Naito,
M.; Izawa, K. J . Org. Chem. 2001, 66, 7469-7477.
(12) (a) Pankiewicz, K, W.; Krzeminski, J .; Ciszewski, L. A.; Ren,
W.-Y.; Watanabe, K. A. J . Org. Chem. 1992, 57, 553-559. (b) Pank-
iewicz, K. W. Carbohydr. Res. 2000, 327, 87-105.
J . Org. Chem, Vol. 67, No. 25, 2002 8795

Wnuk et al.
J ) 7.6 Hz, 2H), 8.16 (s, 1H), 8.40 (s, 1H); 19F NMR δ -199.19
(dt, J ) 18.0, 51.0 Hz).
from tributyltin hydride to fluoropentofuranosyl radicals
generated from these adenine nucleoside derivatives. In
all cases, deuterium abstraction occurs at the less
hindered R face of the sugar ring trans to the heterocyclic
base. However, this R face stereoselectivity is enhanced
by the anti effect of a vicinal fluorine substituent with
an arabino or xylo orientation (on the â face of the ring).
A smaller anti effect is still apparent with a vicinal
fluorine on the R face (ribo orientations). Complex stereo-
electronic/steric interactions might be involved with these
furanose rings that have electronegative (F, O, N) sub-
stituents.
5′-O-(ter t-Bu tyld im eth ylsilyl)-2′,3′-d id eoxy-3′(R/S)-d eu -
ter io-2′-flu or oa d en osin e (7). Procedure C. A solution of 5
(17 mg, 0.32 mmol), AIBN (1.2 mg, 0.007 mmol), and Bu3SnD
(17.4 µL, 18 mg, 0.064 mmol) in toluene (1 mL) was deoxy-
genated (Ar) for 30 min and then heated for 3 h at 85 °C.
Volatiles were evaporated, and the residue was chromato-
graphed (EtOAc) to give 7 (3′R/S, ∼64:36; 8.5 mg, 67%) with
data as reported10 except for the following: 1H NMR δ 2.23
(dd, J ) 5.1, 19.3 Hz, 0.36H), 2.49 (ddd, J ) 4.0, 10.7, 42.3
Hz, 0.64H), 4.60 (dt, J ) 2.6, 10.6 Hz, 1H), 5.42 (dd, J ) 3.7,
51.5 Hz, 1H), 6.33 (d, J ) 16.5 Hz, 1H); 19F NMR δ -181.04
(ddd, J ) 16.5, 42.0, 51.5 Hz); MS m/z 369 (MH+).
2′,3′-Did eoxy-3′(R/S)-d eu ter io-2′-flu or oa d en osin e (8).
Procedure D. NH4F (100 mg, 2.7 mmol) was added to a stirred
solution of 7 (3′R/S, ∼64:36; 15 mg, 0.04 mmol) in MeOH (2
mL), and stirring was continued for 26 h at reflux. Volatiles
were evaporated, and the residue was chromatograhed (5 f
10% MeOH/CHCl3) to give 8 (3′R/S, ∼64:36; 6 mg, 60%) with
data as reported9,10 except for the following: 1H NMR (MeOH-
d4) δ 2.30 (dd, J ) 5.4, 19.5 Hz, 0.36H), 2.53 (ddd, J ) 4.3,
9.7, 38.2 Hz, 0.64H), 4.53-4.57 (m, 1H), 5.52 (dd, J ) 4.2, 52.0
Hz, 1H), 6.30 (d, J ) 16.8 Hz, 1H); 19F NMR (MeOH-d4) δ
-182.62 (ddd, J ) 16.0, 38.0, 52.0 Hz); MS m/z 255 (MH+).
9-[5-O-(ter t-Bu tyldim eth ylsilyl)-2,3-dideoxy-3(R/S)-deu -
ter io-2-flu or o-â-D-th r eo-pen tofu r an osyl]aden in e (9). Treat-
ment of 6 (10 mg, 0.02 mmol) using procedure C gave 9 (3′R/
S, ∼93:7; 6.5 mg, 90%) with data as reported10 except for the
following: 1H NMR δ 2.46 (dd, J ) 3.4, 26.8 Hz, 0.93H), 2.58
(br d, J ) 30.0 Hz, 0.07H), 4.30 (“q”, J ) 5.1 Hz, 1H), 5.30 (dt,
J ) 2.6, 53.6 Hz, 1H), 6.34 (dd, J ) 3.2, 18.1 Hz, 1H); 19F NMR
δ -188.04 (dt, J ) 23.0, 53.0 Hz); MS m/z 369 (MH+). Our 1H
NMR spectrum of 9 is in agreement with that of 9-[5-O-
benzoyl-2,3-dideoxy-3(R/S)-deuterio-2-fluoro-â-D-threo-pento-
furanosyl]-6-methoxypurine (3′R/S, ∼89:11) obtained by deox-
ygenation of the 3′-xanthate with lauroyl peroxide/2-propanol-
d8.5
Exp er im en ta l Section
1H (Me4Si) (400 MHz) and 19F (CCl3F) (376.4 MHz) NMR
spectra were determined with solutions in CDCl3 unless
otherwise noted. Mass spectra (MS) were obtained by atmo-
spheric pressure chemical ionization (APCI) techniques. Re-
agent-grade chemicals were used, and solvents were dried by
reflux over and distillation from CaH2 under an argon atmo-
sphere. Merck kieselgel 60-F254 was used for TLC, and Merck
kieselgel 60 (230-400 mesh) was used for column chromatog-
raphy.
5′-O-(ter t-Bu t yld im et h ylsilyl)-2′-d eoxy-2′-flu or oa d e-
n osin e (2). Procedure A. TBDMS-Cl (63 mg, 0.44 mmol) and
imidazole (43 mg, 0.66 mmol) were added to 112a (59 mg, 0.22
mmol) in dried DMF (3 mL) at ambient temperature, and the
solution was stirred overnight. H2O (1.0 mL) was added;
volatiles were evaporated, and the residue was partitioned
(EtOAc//NH4Cl/H2O). The organic layer was washed (brine),
dried (Na2SO4), evaporated, and column chromatographed (5
f 10% MeOH/CHCl3) to give 2 (59 mg, 70%): 1H NMR δ 0.14
(s, 6H), 0.93 (s, 9H), 3.93 (dd, J ) 2.5, 11.7 Hz, 1H), 4.09 (dd,
J ) 2.4, 11.7 Hz, 1H), 4.19-4.25 (m, 1H), 4.72 (ddd, J ) 4.4,
6.5, 17.5 Hz, 1H), 5.45 (ddd, J ) 2.2, 4.2, 52.9 Hz, 1H), 6.02
(dd, J ) 2.2, 15.0 Hz, 1H), 6.28 (br s, 2H), 8.23 (s, 1H), 8.38 (s,
1H); 19F NMR δ -204.33 (dt, J ) 16.0, 53.0 Hz); MS m/z 384
(MH+). Anal. Calcd for C16H26FN5O3Si (383.5): C, 50.11; H,
6.83; N, 18.26. Found: C, 50.33; H, 6.99; N, 18.01.
9-[2,3-Dideoxy-3(R/S)-deu ter io-2-flu or o-â-D-th r eo-pen to-
fu r a n osyl]a d en in e (10). Treatment of 9 (3′R/ S, ∼93:7; 12.5
mg, 0.035 mmol) using procedure D gave 10 (3′R/S, ∼92:8; 5
mg, 60%) with data as reported9,10 except for the following:
1H NMR (MeOH-d4) δ 2.30 (“dt”, J ) 4.2, 27.2 Hz, 0.92H), 2.55
(“dt”, J ) 6.8, 31.0 Hz, 0.08H), 4.27 (“q”, J ) 5.2 Hz, 1H), 5.29
9-[5-O-(ter t-Bu t yld im et h ylsilyl)-2-d eoxy-2-flu or o-â-D-
a r a bin ofu r a n osyl]a d en in e (4). Treatment of 310,12a (40 mg,
0.15 mmol) using procedure A gave 410 (36.5 mg, 64%): 19F
NMR δ -198.02 (dt, J ) 17.0, 51.0 Hz).
(dt, J ) 2.7, 54.1 Hz, 1H), 6.26 (dd, J ) 3.5, 16.8 Hz, 1H); 19
F
NMR (MeOH-d4) δ -182.62 (ddd, J ) 17.0, 27.0, 54.0 Hz); MS
m/z 255 (MH+).
5′-O-(ter t-Bu t yld im et h ylsilyl)-2′-d eoxy-2′-flu or o-3′-O-
(p h en oxyth ioca r bon yl)a d en osin e (5). Procedure B. PTC-
Cl (21.5 µL, 27 mg, 0.15 mmol) was added dropwise to a stirred
solution of 2 (39 mg, 0.1 mmol) and DMAP (55 mg, 0.45 mmol)
in MeCN (3 mL). Stirring was continued for 5 h, and volatiles
were evaporated. The residue was partitioned (EtOAc/H2O),
and the organic layer was washed (0.1 M HCl/H2O, NaHCO3/
H2O, brine) and dried (Na2SO4). Volatiles were evaporated, and
the residue was chromatographed (30% hexanes/EtOAc f
EtOAc) to give 5 (35 mg, 66%): 1H NMR δ 0.15 (s, 6H), 0.95
(s, 9H), 3.98 (dd, J ) 2.0, 11.8 Hz, 1H), 4.11 (dd, J ) 1.8, 11.7
Hz, 1H), 4.59-4.63 (m, 1H), 5.77 (“dt”, J ) 3.9, 51.7 Hz, 1H),
5.90 (br s, 2H), 6.04 (“dt”, J ) 5.6, 13.1 Hz, 1H), 6.47 (dd, J )
3.2, 15.0 Hz, 1H), 7.15 (d, J ) 8.5 Hz, 2H), 7.35 (t, J ) 7.3 Hz,
1H), 7.47 (t, J ) 7.8 Hz, 2H), 8.20 (s, 1H), 8.39 (s, 1H); 19F
NMR δ -205.26 (dt, J ) 14.0, 51.0 Hz); MS m/z 520 (MH+).
Anal. Calcd for C23H30FN5O4SSi (519.7): C, 53.16; H, 5.82; N,
13.48. Found: C, 52.88; H, 5.61; N, 13.77.
9-[5-O-(ter t-Bu tyld im eth ylsilyl)-2-d eoxy-2-flu or o-3-O-
(ph en oxyth iocar bon yl)-â-D-ar abin ofu r an osyl]aden in e (6).
Treatment of 4 (36 mg, 0.094 mmol) using procedure B gave
610 (28 mg, 57%): 1H NMR δ 0.15 (s, 6H), 0.96 (s, 9H), 3.95
(dd, J ) 4.7, 11.0 Hz, 1H), 4.02 (dd, J ) 4.8, 10.7 Hz, 1H),
4.39-4.44 (m, 1H), 5.57 (dd, J ) 2.8, 49.6 Hz, 1H), 6.01 (dd, J
) 2.6, 15.6 Hz, 1H), 5.73 (br s, 2H), 6.59 (dd, J ) 2.6, 22.0 Hz,
1H), 7.16 (d, J ) 7.6 Hz, 2H), 7.36 (t, J ) 7.3 Hz, 1H), 7.47 (t,
5′-O-(ter t-Bu t yld im et h ylsilyl)-3′-d eoxy-3′-flu or oa d e-
n osin e (12). Treatment of 1117 (80 mg, 0.3 mmol) using
procedure A gave 12 (76 mg, 67%): 1H NMR δ -0.02 (s, 3H),
0.04 (s, 3H), 0.79 (s, 9H), 3.83-3.87 (m, 2H), 4.58 (dt, J ) 2.8,
26.4 Hz, 1H), 4.74 (ddd, J ) 4.5, 7.0, 24.7 Hz, 1H), 5.19 (dd, J
) 4.4, 54.5 Hz, 1H), 5.86 (br s, 2H), 6.02 (d, J ) 7.2 Hz, 1H),
8.08 (s, 1H), 8.33 (s, 1H); 19F NMR δ -199.45 (dt, J ) 26.0,
54.0 Hz); MS m/z 384 (MH+). Anal. Calcd for C16H26FN5O3Si
(383.5): C, 50.11; H, 6.83; N, 18.26. Found: C, 49.89; H, 6.99;
N, 18.03.
9-[5-O-(ter t-Bu t yld im et h ylsilyl)-3-d eoxy-3-flu or o-â-D-
xylofu r a n osyl]a d en in e (14). Treatment of 1318 (45 mg, 0.17
mmol) using procedure A gave 14 (44.5 mg, 69%): 1H NMR δ
0.11 (s, 6H), 0.91 (s, 9H), 4.03 (dd, J ) 6.1, 10.2 Hz, 1H), 4.08
(dd, J ) 6.4, 10.5 Hz, 1H), 4.56 (dtd, J ) 3.3, 5.9, 26.8 Hz,
1H), 4.66 (dt, J ) 1.7, 15.4 Hz, 1H), 5.16 (ddd, J ) 2.0, 2.9,
51.2 Hz, 1H), 5.93 (br s, 2H), 6.01 (d, J ) 1.5 Hz, 1H), 7.99 (s,
1H), 8.31 (s, 1H); 19F NMR δ -203.72 (ddd, J ) 16.0, 26.0,
50.0 Hz); MS m/z 384 (MH+). Anal. Calcd for C16H26FN5O3Si
(383.5): C, 50.11; H, 6.83; N, 18.26. Found: C, 50.01; H, 6.72;
N, 18.08.
(17) Battistini, C.; Giordani, A.; Ermoli, A.; Franceschi, G. Synthesis
1990, 900-905.
(18) Robins, M. J .; Fouron, Y.; Mengel, R. J . Org. Chem. 1974, 39,
1564-1570.
8796 J . Org. Chem., Vol. 67, No. 25, 2002

The â-Fluorine Effect
5′-O-(ter t-Bu t yld im et h ylsilyl)-3′-d eoxy-3′-flu or o-2′-O-
(p h en oxyth ioca r bon yl)a d en osin e (15). Treatment of 12 (24
mg, 0.062 mmol) using procedure B gave 15 (24 mg, 74%): 1H
NMR δ 0.16 (s, 6H), 0.96 (s, 9H), 3.93 (dd, J ) 2.5, 11.5 Hz,
1H), 4.01 (dd, J ) 1.6, 11.4 Hz, 1H), 4.59 (dt, J ) 1.7, 25.8 Hz,
1H), 5.61 (dd, J 4.3, 54.1 Hz, 1H), 5.98 (br s, 2H), 6.28 (ddd, J
) 4.3, 7.6, 20.7 Hz, 1H), 6.60 (d, J ) 7.2 Hz, 1H), 7.07 (d, J )
7.6 Hz, 2H), 7.3 (t, J ) 7.3 Hz, 1H), 7.41 (t, J ) 7.6 Hz, 2H),
8.20 (s, 1H), 8.42 (s, 1H); 19F NMR δ -199.24 (ddd, J ) 21.0,
procedure D gave 18 (2′R/S, ∼14:86; 2.8 mg, 81%) with data
as reported9 except for the following: 1H NMR (MeOH-d4) δ
2.66 (dd, J ) 5.4, 20.6 Hz, 0.14H), 2.94 (ddd, J ) 4.3, 9.3, 40.8
Hz, 0.86H), 4.38 (dt, J ) 2.7, 27.3 Hz, 1H), 5.40 (dd, J ) 4.6,
53.6 Hz, 1H), 6.43 (d, J ) 9.4 Hz, 1H); 19F NMR (MeOH-d4) δ
-173.44 (ddd, J ) 28.0, 41.0, 53.0 Hz); MS m/z 255 (MH+).
9-[5-O-(ter t-Bu tyldim eth ylsilyl)-2,3-dideoxy-2(R/S)-deu -
t er io-3-flu or o-â-D-th r eo-p en t ofu r a n osyl]a d en in e (19).
Treatment of 16 (8.6 mg, 0.017 mmol) using procedure C gave
19 (2′R/S, ∼7:93; 3 mg, 65%): 1H NMR δ 0.11 (s, 6H), 0.93 (s,
9H), 2.72 (d, J ) 15.4 Hz, 0.93H), 2.85 (br d, J ) 44.0 Hz,
0.07H), 3.99 (dd, J ) 5.9, 10.2 Hz, 1H), 4.04 (dd, J ) 7.1, 10.1
Hz, 1H), 4.20 (dddd, J ) 2.5, 6.0, 7.2, 28.6 Hz, 1H), 5.36 (dd,
J ) 2.0, 53.4 Hz, 1H), 5.79 (br s, 2H), 6.56 (s, 1H), 8.13 (s,
1H), 8.34 (s, 1H); 19F NMR δ -193.82 (ddd, J ) 22.0, 27.0,
54.0 Hz); MS m/z 369 (MH+). Anal. Calcd for C16H25DFN5O2-
Si (368.5): C, 52.15; H, 6.84; N, 19.00. Found: C, 52.07; H,
6.99; N, 18.71.
9-[2,3-Dideoxy-2(R/S)-deu ter io-3-flu or o-â-D-th r eo-pen to-
fu r a n osyl]a d en in e (20). Treatment of 19 (2′R/ S, ∼7:93; 4
mg, 0.011 mmol) using procedure D gave 20 (2′R/S, ∼7:93; 2.7
mg, 98%) with data as reported9 except for the following: 1H
NMR (MeOH-d4) δ 2.75 (dd, J ) 1.4, 21.3 Hz, 0.93H), 2.96
(dd, J ) 7.1, 45.9 Hz, 0.07H), 4.26 (dtd, J ) 2.7, 6.4, 29.2 Hz,
1H), 5.42 (dd, J ) 2.6, 54.1 Hz, 1H), 6.59 (d, J ) 1.4 Hz, 1H);
19F NMR (MeOH-d4) δ -194.91 (ddd, J ) 27.0, 22.0, 54.0 Hz);
MS m/z 255 (MH+).
26.0, 54.0 Hz); MS m/z 520 (MH+). Anal. Calcd for C23H30
-
FN5O4SSi (519.7): C, 53.16; H, 5.82; N, 13.48. Found: C, 53.35;
H, 5.95; N, 13.09.
9-[5-O-(ter t-Bu tyld im eth ylsilyl)-3-d eoxy-3-flu or o-2-O-
(p h en oxyth ioca r bon yl)-â-D-xylofu r a n osyl]a d en in e (16).
Treatment of 14 (44 mg, 0.12 mmol) using procedure B gave
16 (30 mg, 50%): 1H NMR δ 0.14 (s, 6H), 0.95 (s, 9H), 3.99-
4.09 (m, 2H), 4.49 (dtd, J ) 3.0, 7.5, 28.5 Hz, 1H), 5.39 (dd, J
) 2.6, 49.8 Hz, 1H), 5.73 (br s, 2H), 6.09 (d, J ) 13.3 Hz, 1H),
6.50 (s, 1H), 7.15 (d, J ) 7.5 Hz, 2H), 7.36 (t, J ) 7.8 Hz, 1H),
7.46 (t, J ) 7.8 Hz, 2H), 8.09 (s, 1H), 8.40 (s, 1H); 19F NMR δ
-199.19 (dt, J ) 18.0, 51.0 Hz); MS m/z 520 (MH+). Anal.
Calcd for C23H30FN5O4SSi (519.7): C, 53.16; H, 5.82; N, 13.48.
Found: C, 53.44; H, 6.09; N, 13.21.
5′-O-(ter t-Bu tyld im eth ylsilyl)-2′,3′d id eoxy-2′(R/S)-d eu -
ter io-3′-flu or oa d en osin e (17). Treatment of 15 (17.5 mg,
0.034 mmol) using procedure C gave 17 (2′R/S, ∼15:85; 6.5
mg, 54%) with data as reported19 except for the following: 1H
NMR δ 2.73 (ddd, J ) 8.7, 4.8, 39.1 Hz, 0.85H), 2.82 (dd, J )
4.2, 18.8 Hz, 0.15H), 4.44 (dt, J ) 3.3, 26.4 Hz, 1H), 5.36 (dd,
J ) 4.6, 53.5 Hz, 1H), 6.55 (d, J ) 8.9 Hz, 1H); 19F NMR δ
-176.95 (ddd, J ) 26.6, 37.7, 52.7 Hz); MS m/z 369 (MH+).
2′,3′-Did eoxy-2′(R/S)-d eu ter io-3′-flu or oa d en osin e (18).
Treatment of 17 (2′R/S, ∼15:85; 5 mg, 0.014 mmol) using
Ack n ow led gm en t. We thank Florida International
University and Brigham Young University for support.
D.R.C. was sponsored by an MBRS RISE program (NIH/
NIGMS; R25 GM61347).
(19) Maguire, A. R.; Meng, W.; Roberts, S. M.; Willetts, A. J . J .
Chem. Soc., Perkin Trans. 1 1993, 15, 1795-1808.
J O020428B
J . Org. Chem, Vol. 67, No. 25, 2002 8797