Synthesis of 3′-deoxy-3′-difluoromethyl azanucleosides from trans-4-hydroxy-L-proline

Article abstract of DOI:10.1021/jo050057+

Two strategies were tried to synthesize 3′-deoxy-3′- difluoromethyl azanucleosides. After the failure of the first route, the key intermediate 12 from trans-4-hydroxyproline 7 in 8 steps was stereoselectively prepared. The alcohol 12 was subjected to sele

Full text of DOI:10.1021/jo050057+

Synthesis of 3′-Deoxy-3′-difluoromethyl Azanucleosides from
trans-4-Hydroxy-L-proline
Xiao-Long Qiu§ and Feng-Ling Qing*,§,‡
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Science, 354 Fenglin Lu, Shanghai 200032, China, and College of Chemistry and Chemistry
Engineering, Donghua University, 1882 West Yanan Lu, Shanghai 200051, China
flq@mail.sioc.ac.cn
Received January 11, 2005
Two strategies were tried to synthesize 3′-deoxy-3′-difluoromethyl azanucleosides. After the failure
of the first route, the key intermediate 12 from trans-4-hydroxyproline 7 in 8 steps was
stereoselectively prepared. The alcohol 12 was subjected to selective protection, oxidation, and
difluoromethylenation to afford the fluorinated compound 18, whose hydrogenation was then
systematically investigated. After a series of transformations of protecting groups, the resultant
compounds 22 and 23 were oxidized to the desired lactams 24 and 25, which were successfully
utilized to synthesize our target molecules, 3′-deoxy-3′-difluoromethyl azanucleosides 33, 34a, 34b,
and 35.
Introduction
success in the fight against viral infection. For the last
two decades, some high biological nucleoside and nucleo-
side analogues have been synthesized, studied, and used.
For example, the 5-iodo-2′-deoxyuridine (IDU) was li-
censed as the first nucleoside antiviral, and the first
antiviral chemotherapeutic agent for use in humans.5 The
2′,3′-dideoxynucleosides (ddNs) have thus far proven to
be the most effective therapeutic agents against human
immunodeficiency virus (HIV)6 and hepatitis B virus
(HBV).7 3′-Azido-2′,3′-dideoxythymidine (AZT),8 2′,3′-
dideoxyinosine (DDI),9 and 2′,3′-dideoxycytidine (DDC)10
In general, nucleosides, consisting of both a base
moiety and a sugar moiety, are classified into two major
divisions, that is, N-nucleosides and C-nucleosides.1
N-Nucleosides feature a bond between the anomeric
carbon of the sugar moiety and the nitrogen of the base
moiety. C-Nucleosides have a bond between the anomeric
moiety and the carbon of the base moiety. Further, the
nucleosides, wherein carbon, sulfur, phosphorus, and
nitrogen substitute for the sugar ring oxygen, are com-
monly defined as carbocyclic nucleosides,2 thionucleo-
sides,3 phosphanucleosides,4 and azanucleosides,1 respec-
tively. Nucleosides and nucleoside analogues, known to
be DNA and RNA subunits, have achieved considerable
(2) For carbocyclic nucleoside reviews, see: (a) Crimmins, M. T.
Tetrahedron 1998, 54, 9229. (b) Borthwick, A. D.; Biggadike, K.
Tetrahedron 1992, 48, 571. (c) Agrofoglio, L.; Suhas, E.; Farese, A.;
Condom, R.; Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994,
50, 10611. (d) Marquez, V. E.; Lim, M.-U. Med. Res. Rev. 1986, 6, 1.
(e) Vine, R.; Akella, L. B. Med. Res. Rev. 1996, 52, 2789.
(3) Yokoyama, M. Synthesis 2000, 1637.
(4) Yamashita, M.; Kato, Y.; Suzuki, K.; Reddy, P. M.; Oshikawa,
T. Abstr. 29th Congress Heterocycl. Chem. 1998, 461.
(5) Kaufman, H. E. Proc. Soc. Exptl. Biol. Med. 1962, 109, 251.
* To whom correspondence should be addressed. Fax: 86-21-
64166128.
§ Shanghai Institute of Organic Chemistry.
‡ Donghua University.
(1) Yokoyama, M.; Momotake A. Synthesis 1999, 1541.
10.1021/jo050057+ CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/05/2005
3826
J. Org. Chem. 2005, 70, 3826-3837

Synthesis of 3′-Deoxy-3′-difluoromethyl Azanucleosides
SCHEME 1
have also been approved for the treatment of AIDS.
However, some nucleosides have shown limited stability,
high toxicity, and lower bioactivity, so development of
new antiviral and anticancer nucleoside analogues is
intensively demanded despite great improvements against
virus and cancer.
Recently, fluorinated nucleosides, containing fluorine
atom(s) or fluorine-containing groups in the sugar moiety
or the base moiety of nucleoside, have drawn increasing
attention due to the introduction of the fluorine atom(s)
into some nucleosides resulting in great improvement
of bioactivity and stability of the corresponding com-
pounds.11 Perhaps the best known of the fluorinated
nucleosides are 1-(2-deoxy-2-fluoro-â-D-arabinofuranosyl)-
thymine (FMAU),12 1-(2-deoxy-2-fluoro-â-D-arabinofura-
nosyl)-5-iodocytosine (FIAC),12b 1-(2-deoxy-2-fluoro-â-D-
arabinofuranosyl)-5-ethyluracil (FEAU),13 3′-deoxy-3′-
fluorothymidine (FLT),14 1-(2,3-dideoxy-2-fluoro-â-D-threo-
pentofuranosyl)cytosine (F-ddC),15 1-(2-deoxy-2-C-fluoro-
methyl-â-D-arabinofuranosyl)cytosine(SFDC),16 and 1-(2-
deoxy-2,2-difluoro-â-D-arabinofuranosyl)cytosine (Gem-
citabine),17 all of which have high antiherpes activity, as
well as antitumor activity in some cases. Although
monofluorinated, gem-difluorinated, and trifluoromethy-
lated sugar nucleosides, thionucleosides, and carbocyclic
nucleosides have been widely studied, only a few fluori-
nated azanucleosides have been reported.18 Difluoro-
methylated (CHF2-) and monofluoromethylated (CH2F-)
azanucleosides are attractive potential bioactive targets
because of the unique properties of the two groups and
azanucluosides. First, two groups have synthesized a
series of azanucleosides and some of azanucleosides have
proved active against human tumor cell lines.19 Second,
the CF2 and CHF groups have been proposed as reason-
able isosteric and isopolar replacements for neutral
oxygen, conferring phosphatase stability on nucleotide
phosphate moiety.20 Third, the CHF2 and CH2F groups
have been employed 21 as preferable replacements for CH3
in oligo(deoxyribonucleotide methyl phosphonate) due
to its ability to act as a hydrogen donor,22 potentially
allowing interaction with solvent and biological mol-
ecules. Fourth, replacements of the sugar ring oxygen of
a nucleoside by nitrogen could cause the effects of
biological significance. Besides the simple heteroatom
effect of nitrogen,23 nitrogen could bind with exceedingly
high affinity and specificity to a variety of base-exicision
DNA repair (BER) enzymes, which may suggest a transi-
tion-state model for the glycosyl transfer reaction leading
to base excision.24 On the basis of the above consideration
and our ongoing efforts to develop new antiviral and
anticancer agents, several difluoromethylated and mono-
fluoromethylated azanucleosides were prepared in our
group.18b,25 Here reported is our recent synthesis of
3′-deoxy-3′-difluoromethyl azanucleosides, starting from
natural, cheap, and commercially available trans-4-
hydroxy-L-proline.
(6) Parks, R. E., Jr.; Stoeckler, J. D.; Cambor, C.; Savarese, T. M.;
Crabtree, G. W.; Chu, S.-H. In Molecular Actions and Targets for
Cancer Chemothreapeutic Agents; Sartorelli, A. C., Lazo, J. S., Bertino,
J. R., Eds.; Academic Press: New York, 1981; p 229.
(7) (a) Secrist, J. A., III; Tiwari, K. N.; Riordan, J. M.; Montgomery,
J. A. J. Med. Chem. 1991, 34, 2361. (b) Tiwari, K. N.; Secrist, J. A.,
III; Montgomery, J. A. Nucleosides Nucleotides 1994, 13, 1819.
(8) Yoshimura, Y.; Endo, M.; Miura, S.; Sakata, S. J. Org. Chem.
1999, 64, 7912.
(9) Wang, P.; Hong, J. H.; Cooperwood, J. S.; Chu, C. K. Antiviral
Res. 1998, 40, 19.
(10) Young, R. J.; Shaw-Ponter, S.; Thomson, J. B.; Miller, J. A.;
Cumming, J. G.; Pugh, A. W.; Rider, P. Bioorg. Med. Chem. Lett. 1995,
5, 2599.
(11) For fluoronucleoside reviews, see: (a) Bergstrom, D. E.; Swar-
tling, D. J.; Libeman, J. F.; Greenberg, A.; Dolbier, W. R., Jr., Eds.
Flurorine Containing Moleculars, Structure, Reactivity, and Applica-
tions; VCH: New York, 1988; pp 259-308. (b) Herdewijn, P.; Van
Aerschot, A.; Kerremans, L. Nucleosides Nucleotides 1989, 8, 65. (c)
Pankiewicz, K. W.; Watanabe, K. A. J. Fluorine Chem. 1993, 64, 15.
(d) Pankiewicz, K. W. Carbohydr. Res. 2000, 327, 87.
(12) (a) Chu, C. K.; Ma, T.; Shanmuganathan, K.; Wang, C.; Xiang,
Y.; Pai, S. B.; Yao, G. Q.; Sommadossi, J. P.; Cheng, Y. C. Antimicrob.
Agents Chemother. 1995, 39, 979. (b) Watanabe, K. A.; Reichman, U.;
Hirota, K.; Lopez, C.; Fox, J. J. J. Med. Chem. 1979, 22, 21.
(13) Su, T.-L.; Watanabe, K. A.; Schinazi, R. F.; Fox, J. J. J. Med.
Chem. 1986, 29, 151.
(14) (a) Etzold, G.; Hintsche, R.; Kowollik, G.; Langen, P. Tetrahe-
dron 1971, 27, 2463. (b) Balzarini, J.; Baba, M.; Pauwels, R.; Herdewijn,
P.; De Clercq, E. Biochem. Pharmacol. 1988, 37, 2847.
(15) Okabe, M.; Sun, R.-C.; Zenchoff, G. B. J. Org. Chem. 1991, 56,
4392.
(16) Yoshimura, Y.; Saitoh, K.; Ashida, N.; Sakata, S.; Matsuda, A.
Bioorg. Med. Chem. Lett. 1994, 4, 721.
Results and Discussion
Attempt To Synthesize Target Molecules from
L-Pyroglutamic Acid. On the basis of retrosynthetic
analysis (Scheme 1), the target molecules A can be
reached from the fluorinated intermediate B, which could
be prepared from keto compound C via difluoromethyl-
enation followed by hydrogenation. Selective protection
of the two hydroxyl groups of D followed by oxidation of
the residual hydroxyl group would furnish the lactam C.
The alcohol D can be provided via dihydroxylation of the
lactam E, which could be conveniently synthesized from
L-pyroglutamic acid 1. It is noteworthy that the Boc-
protecting groups of target molecules A could not be
removed because the N-azanucleosides having a free NH
group have proved to be unstable.26
(19) (a) Peterson, M. L.; Vince, R. J. Med. Chem. 1991, 34, 2787. (b)
Eva Ng, K.-m.; Orgel, L. E. J. Med. Chem. 1989, 32, 1754.
(20) (a) Blackburn, G. M.; Eckstein, F.; Kent, D. E.; Perree, D.
Nucleosides Nucleotides 1985, 4, 165. (b) Bamford, M. J.; Coe, P. L.;
Walker, R. T. J. Med. Chem. 1990, 33, 2488.
(21) (a) Bergstrom, D. E.; Romo, E.; Shum, P. Nucleosides Nucle-
otides 1987, 6, 53. (b) Bergstrom, D. E.; Shum, P. W. J. Org. Chem.
1988, 53, 3953.
(22) Nelson, D. D., Jr.; Fraser, G. T.; Klemperer, W. Science 1987,
238, 1670.
(17) (a) Kotra, L. P.; Xiang, Y.; Newton, M. G.; Schinazi, R. F.;
Cheng, Y.-C.; Chu, C. K. J. Med. Chem. 1997, 40, 3635. (b) Hertel, L.
W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. J. Org. Chem. 1988, 53,
2406.
(18) (a) Qing, F.-L.; Yu, J.; Fu, X.-K. Collect. Czech. Chem. Commun.
2002, 67, 1267. (b) Qiu, X.-L.; Qing, F.-L. Synthesis 2004, 334.
(23) Akiba, K.-y. Yuki Gosei Kyokai Shi 1984, 42, 378.
(24) Scha¨rer, O. D.; Verdine, G. L. J. Am. Chem. Soc. 1995, 117,
10781.
(25) Qiu, X.-L.; Qing, F.-L. Bioorg. Med. Chem. 2005, 13, 277.
J. Org. Chem, Vol. 70, No. 10, 2005 3827

Qiu and Qing
SCHEME 2a
SCHEME 3
a Reagent and conditions: (a) (i) SOCl2, MeOH; (ii) NaBH4,
EtOH; (iii) TBDMSCl, DMAP, imidazole, CH2Cl2; (iv) t-Boc2O,
Et3N, DMAP, CH2Cl2; (b) (i) LiHMDS, THF, -78 °C then PhSeCl,
THF, -78 °C; (ii) H2O2, pyridine; (c) OsO4, 4-methylmorpholine
N-oxide monohydrate (NMNO), acetone-H2O, rt; (d) BzCl, pyri-
dine, DMAP, CH2Cl2, -78 then -10 °C; (e) Dess-Martin Oxidant,
CH2Cl2, rt.
resulting phenylselenyl derivative smoothly afforded the
alkene 9 in 63% yield over two steps.32 Then, reduction
of the compound 9 with LiAlH4 in Et2O at room temper-
ature gave the alcohol 10 in 89% yield. The protecting
group for the primary hydroxy group was a key point
because the diastereoselectivity of the following dihy-
droxylation was controlled by this protecting group. Thus,
the big-blocking-effect protecting group, tert-butyldi-
phenylsilyl, was utilized and the favorable alkene 11 was
provided in 82% yield. Dihydroxylation reaction was
carried out on compound 11 and the only isomer 12 was
obtained in 92% yield.
Selective protection of the hydroxyl groups in 12 was
studied. According to the previous reports33 and following
transformation, the tert-butyldimethylsilyl group would
be the appropriate protecting group. However, exposure
of compound 12 to TBDMSCl/imidazole at 0 °C in DMF
or CH2Cl2 only resulted in the recovery of the starting
material, even when catalytic DMAP was added (Scheme
5). Increasing the reaction temperature to room temper-
ature also gave the disappointing outcome and both the
expected product 13 and the protective compound 14
were isolated in 31% and 49% yield, respectively. Slightly
surprisingly, treatment of compound 12 with BzCl/
pyridine/DMAP at -10 °C for 24 h in CH2Cl2 gave the
acceptable result and the favorable compound 15 was
afforded in 70% yield along with isomer 16 in 17% yield
and recovery of 7% starting material.
Thus, according to our retrosynthetic analysis, the
lactam 2 was prepared from L-pyroglutamic acid over 4
steps in 42% yield (Scheme 2).27 Treatment of the
compound 2 with LiHMDS/PhSeCl in THF at -78 °C
followed by elimination of the resulting phenylselenyl
derivative with H2O2/pyridine smoothly gave the alkene
3 in 75% yield.28 Then, dihydroxylation of the compound
3 resulted in only isomer 4 in 62% yield along with
recovery of 30% starting material.29 Selective protection
of the two hydroxyl groups of 4 with BzCl afforded the
desired alcohol 5 in 85% yield and there are no other
products detected by TLC except a few starting materials.
Oxidation of the residual hydroxyl group in the compound
5 with the Dess-Martin oxidant was carried out; how-
ever, the reaction was very complicated and no expected
compound 6 was isolated. In our opinion, the special
structure of the desired compound 6 bearing a benzoyl-
protected hydroxy group between two keto groups was
responsible for the failure of the reaction. The compounds
containing this similar structure are unstable and prone
to racemization and isomerization.30
Synthesis of Target Molecules from trans-4-Hy-
droxy-L-proline. In view of the above failure, we
changed our synthetic strategy; the new synthetic strat-
egy is outlined in Scheme 3. In our opinion, the lactam
skeleton of the intermediate B could be constructed via
oxidation of the pyrrolidine F, which might be prepared
by difluoromethylenation of the keto G followed by
hydrogenation. Similarly to the first route, dihydroxyla-
tion of the alkene I followed by selective protection of the
resulting hydroxyl groups in H and oxidation of the
residual hydroxyl group could provide the keto G. The
intermediate I could be conveniently prepared from trans-
4-hydroxy-proline 7.
With compound 15 in hand, oxidation of the residual
hydroxy group with Dess-Martin oxidant in CH2Cl2 at
room temperature smoothly provided the keto 17 in 92%
yield (Scheme 6). Then, difluoromethylenation of the
carbonyl group with CF2Br2/Zn/HMPT in THF success-
fully afforded the fluorinated compound 18 in 83% yield.34
(30) (a) Roush, W. R.; Pfeifer, L. A. Org. Lett. 2000, 2, 859. (b) Jones,
R. C. F.; Begley, M. J.; Peterson, G. E.; Sumaria, S. J. Chem. Soc.,
Perkin Trans. 1 1990, 1959.
(31) (a) Greenwood, E. S.; Hitchcock, P. B.; Parsons, P. J. Tetrahe-
dron 2003, 59, 3307.
(32) (a) Goli, D. M.; Cheesman, B. V.; Hassan, M. E.; Lodaya, R.;
Slama, J. T. Carbohydr. Res. 1994, 259, 219. (b) Rueger, H.; Benn, M.
H. Can. J. Chem. 1982, 60, 2918. (c) Arakawa, Y.; Ohnishi, M.;
Yoshimura, N.; Yoshifuji, S. Chem. Pharm. Bull. 2003, 51, 1015. (d)
Schumacher, K. K.; Jiang, J.; Joullie´, M. M. Tetrahedron: Asymmetry
1998, 9, 47.
(33) (a) Tokuda, M.; Fujita, H.; Miyamoto, T.; Suginome, H. Tetra-
hedron 1993, 49, 2413. (b) Iida, H.; Yamazaki, N.; Kibayashi, C. J.
Org. Chem. 1986, 51, 1069. (c) Shi, S.-c.; Zeng, C.-m.; Lin, G.-q.
Heterocycles 1995, 41, 277. (d) Kang, S. H.; Choi, H.-w. J. Chem. Soc.,
Chem. Commun. 1996, 1521. (e) Ikota, N.; Inaba, H. Chem. Pharm.
Bull. 1996, 44, 587.
Although the protective ester 8 was first prepared from
trans-4-hydroxyproline 7 over three steps in 78% yield,31
treatment of the compound 8 with PhSeSePh/MeOH
under reflux conditions following elimination of the
(26) Altmann, K.-H. Tetrahedron Lett. 1993, 34, 7721.
(27) (a) Ikota, N. Chem. Pharm. Bull. 1992, 40, 1925. (b) Pickering,
L.; Malhi, B. S.; Coe, P. L.; Walker, R. T. Nucleosides Nucleotides 1994,
13, 1493.
(28) Frieman, B. A.; Bock, C. W.; Bhat, K. L. Heterocycles 2001, 55,
2099.
(29) Yoda, H.; Oguchi, T.; Takabe, K. T. Tetrahedron: Asymmetry
1996, 7, 2113.
(34) (a) Motherwell, W. B.; Tozer, M. J.; Ross, B. C. J. Chem. Soc.,
Chem. Commun. 1989, 1437. (b) Houlton, J. S.; Motherwell, W. B.;
Ross, B. C.; Tozer, M. J.; Williams, D. J.; Slawin, A. M. Tetrahedron
1993, 49, 8087.
3828 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of 3′-Deoxy-3′-difluoromethyl Azanucleosides
SCHEME 4a
TABLE 1. Hydrogenation of Compound 18
yield (%)
pressure
(atm)
time
solvent (h) 19 20
recovery
(%)
entry catalyst
1
2
3
4
5
6
7
8
9
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
1
MeOH
EtOAc
EtOAc
EtOAc
THF
17
24
24
17
17
7
11 <1
9
83
46
9
38
87
48
77
37
22
1
0
0
20
70
80
80
80
80
80
100
31 <1
41 12
27
7
THF
<1 <1
13 20
<4 13
EtOAc
dioxane
dioxane 65 <4 48
dioxane 31
7
7
10 Pd(OH)2/C
10 54
a Reagent and conditions: (a) (i) SOCl2, MeOH, 0 °C to room
temperature; (ii) Boc2O, CH2Cl2, Et3N, DMAP, rt; (iii) MsCl, Et3N,
DMAP, CH2Cl2, rt; (b) (i) PhSeSePh, MeOH, reflux; (ii) H2O2,
pyridine, rt.; (c) LiAlH4, Et2O, rt; (d) TBDPSCl, imidazole, DMAP,
CH2Cl2, rt; (e) OsO4, 4-methylmorpholine N-oxide monohydrate
(NMNO), acetone-H2O, rt.
with substitution of EtOAc for MeOH under the same
conditions (entry 2). Thus, 20 atm of H2 was used for this
reaction and after 24 h, compound 19 was afforded in
31% yield besides a small amount of compound 20 and
46% recovery of 18 (entry 3). When the hydrogen pressure
was increased to 70 atm, the yield of 19 was increased
to 41%. However, the decomposition was also obvious
with only 9% recovery of 18 (entry 4). The replacement
of EtOAc with THF did not give a better hydrogenation
outcome (entry 5). Pd(OH)2/C was also used as a catalyst
to investigate this reaction (entries 6-10). Using THF
as a solvent under 80 atm of H2 also gave a bad result
(entry 6). Besides 48% recovery of starting material,
compounds 19 and 20 were provided in 13% and 20%
yield, respectively, with utilization of EtOAc as solvent
(entry 7). When the reaction was carried out under 80
atm of H2 with dioxane as solvent, the main compound
20 was afforded in 13% yield after 7 h (entry 8).
Prolongation of reaction time to 65 h could increase the
yield of 20 to 48% (entry 9). Finally, when the hydrogen
pressure was added to 100 atm also with dioxane as
solvent, compounds 19 and 20 were furnished in 10% and
54% yield, respectively (entry 10). It was evident from
the above hydrogenation outcome that pressure and
solvent were two important points to the hydrogenation
of 18. Also obvious was that the catalysts Pd/C and
Pd(OH)2/C could give different stereoselectivity. That
was, diasteroisomer 19 was the main product with Pd/C
being used, and diastersoisomer 20 was provided as the
main product with Pd(OH)2/C as catalyst. In our opinion,
when Pd/C was used, the blocking effect of the substrate
induced the attack of hydrogen on the Re side of the
double bound, which resulted in the main product 19.
However, hydrogen mainly attacked the Si side to afford
the main product 20 with Pd(OH)2/C as catalyst, perhaps
due to the influence of the hydrogen bond between the
hydroxy group and the oxygen atoms of substrate.
Then, oxidation of compounds 19 and 20 with RuO2‚
xH2O/NaIO4 under ethyl acetate/water biphase condition
was carried out, respectively (Scheme 7). However, the
reactions were complicated and only a few expected
compounds were detected by TLC. Although many suc-
cessful examples about the oxidation of the pyrrolidine
substrates containing silyl group(s) to the corresponding
lactams with RuO2‚xH2O/NaIO4 were reported, Young et
al.36 reported that the tert-butyldiphenylsilyl group could
be oxidated to the tert-butylhydroxylphenylsilyl group by
SCHEME 5a
a Reagent and conditions: (a) TBDMSCl, DMAP, imidazole,
DMF, rt, 3 h; (b) BzCl, pyridine, CH2Cl2, -10 °C, 24 h.
SCHEME 6a
a Reagent and conditions: (a) Dess-Martin oxidant, CH2Cl2,
rt; (b) CF2Br2, HMPT, Zn, THF, reflux.
Although hydrogenations of similar substrates were
reported,35 hydrogenation of alkene 18 was still a chal-
lenge to us due to bulky block effects of the neighboring
groups. Thus, different solvents, catalysts, and hydrogen
pressure were used to investigate the hydrogenation
reaction (Table 1). Pd/C was first selected as catalyst
(entries 1-5). Hydrogenation of 18 in MeOH at room
temperature and 1 atm (H2) for 17 h gave a disappointing
outcome and the desired compounds 19 and 20 were
isolated in 11% and <1% yield, respectively, along with
recovery of 9% starting material (entry 1). The low yield
was attributed to the decomposition of 18 under proton
solvent. However, there was no reaction that occurred
(35) (a) Serafinowski, P. J.; Brown, C. A.; Barnes, C. L. Nucleosides
Nucleotides 2001, 20, 921. (b) Marcotte, S.; Gerard, B.; Pannecoucke,
X.; Feasson, C.; Quirion, J.-C. Synthesis 2001, 929.
(36) (a) Durand, X.; Hudhomme, P.; Khan, J. A.; Young, D. W. J.
Chem. Soc., Perkin Trans. 1 1996, 1131. (b) Durand, X.; Hudhomme,
P.; Khan, J. A.; Young, D. W. Tetrahedron Lett. 1995, 36, 1351.
J. Org. Chem, Vol. 70, No. 10, 2005 3829

Qiu and Qing
SCHEME 7a
treated with acetic anhydride to afford anomeric acetate
28 in 95% yield over two steps (Scheme 9). Similarly,
lactam 25 was transformated predominantly, but not
exclusively, into anomeric acetate 29a (55%) and 29b
(11%) under the same conditions. Coupling of 28 with
silylated uracil under Vorbru¨ggen conditions39 gave
mainly the R-anomer 30b in 67% yield along with the
â-anomer 30a in 7% yield. Silyl-protected azanucleosides
30a and 30b could be separated by column chromatog-
raphy. However, acetate 29a was condensed with sily-
lated uracil, as described for 28, to afford mainly â-ano-
mer 31a in 77% yield along with the R-anomer 31b in
13% yield. Coupling of acetate 29a with silylated thymine
gave â-anomer 32a and R-anomer 32b in 49% and 31%
yield, respectively. Finally, removal of the silyl protective
groups with TBAF in THF smoothly gave 3′-deoxy-3′-
difluoromethyl azanucleosides 33, 34a, 34b, and 35. The
opposite stereochemical outcome in coupling acetate 28
and 29a with silylated uracil could be elucidated from
Figure 1. That is, the silylated uracil mainly attacked
the less shielded Re side of the double bond in intermedi-
ate 28′, which resulted in the formation of R-anomer 30b.
However, the Si diastereoface of intermediate 29′ was
less shielded, which was mainly subjected to the attack
of silylated uracil to provide â-anomer 31a as the main
product.
a Reagent and conditions: (a) RuO2‚xH2O, NaIO4, EtOAc, H2O,
rt.
SCHEME 8a
a Reagent and conditions: (a) (i) TBAF, THF, rt; (ii) TBDMSCl,
imidazole, DMAP, CH2Cl2, rt; (b) (i) saturated NH3/MeOH, rt; (ii)
TBDMSCl, imidazole, DMAP, DMF, rt; (c) RuO2‚xH2O, NaIO4,
EtOAc, H2O, rt.
The stereochemical assignments of the silylated aza-
nucleosides were made on the base of 1D and 2D NMR
spectroscopy and X-ray crystallography. The configura-
RuO2‚xH2O/NaIO4. While no tert-butylhydroxylphenyl-
silyl-containing compound was isolated, it is our opinion
that the failures of the reactions were attributed to the
existence of the tert-butyldiphenylsilyl group.
1
tion of the anomeric center was assigned mainly by H
NMR, in which the anomers with H4′ at lower field were
assigned as the R-anomers and the ones at higher field
were assigned as the â-anomers on the base of the
deshielding effect of the base moiety (Figure 2).40 This
assignment was further confirmed by the NOESY experi-
ment of 30a, 30b, 31a, and 31b (Figure 2) as well as the
X-ray crystallography of 30a.
In summary, two strategies were used to synthesize
3′-deoxy-3′-difluoromethyl azanucleosides. After the fail-
ure of the first route, we stereoselectively prepared the
key intermediate 12 from trans-4-hydroxy-proline 7 in
eight steps. Alcohol 12 was subjected to selective protec-
tion, oxidation, and difluoromethylenation to afford the
fluorinated compound 18, whose hydrogenation was then
systematically investigated. After a series of transforma-
tions of protecting groups, the resultant compounds 22
and 23 were oxidized to the desired lactams 24 and 25,
which were successfully utilized to synthesize our target
molecules, 3′-deoxy-3′-difluoromethyl azanucleosides 33,
34a, 34b, and 35. Furthermore, work is in progress to
use the intermediates 24 and 25 for the synthesis of other
biologically potential active compounds. Antiviral and
cytotoxicity evaluations of compounds 33, 34a, 34b, and
35 are also currently in progress.
In view of the above failure and following transforma-
tion, we decided to replace the protecting groups of
hydroxy groups with tert-butyldimethylsilyl groups. Thus,
exposure of compound 20 to TBAF in THF followed by
protection of the resultant primary hydroxyl group with
the tert-butyldimethylsilyl group provided compound 21
in 75% yield over two steps (Scheme 8). The absolute
configuration of compound 21 was confirmed by X-ray.
Then, treatment of 21 with a saturated solution of
ammonia in methanol followed by protection of the
resultant hydroxyl group also with the tert-butyldimeth-
ylsilyl group smoothly afforded compound 23 in 86%
yield. Similarly, compound 22 was furnished from 19 in
60% yield over four steps. Next oxidation of the pyrroli-
dine 22 with RuO2‚xH2O/NaIO4 under ethyl acetate/water
biphase condition was carried out and the desired lactam
24 was provided in 40% yield after 16 h. However,
tertiary alcohol 26 was also isolated in 33% yield, which
resulted from the oxidation of the hydrogen atom in the
2′-C position of compound 22, just as reported by Ikota.37
Treatment of compound 23 with the same condition for
13.5 h gave the desired compound 25 and alcohol 27 in
54% and 2% yield, respectively, along with the 11%
recovery of starting material. Obviously from the yield
of alcohols 26 and 27, besides the electron effect,38 the
RuO4 oxidation procedure was also influenced by the
blocking effect. That is, the hydrogen atom in the 2′-C
position of compound 23 is more efficiently shielded than
that of compound 22, which directly resulted in the lower
yield of the byproduct 27 than that of 26.
Experimental Section
THF was distilled from sodium metal. CH2Cl2 and pyridine
were distilled from CaH2. All the melting points and optical
rotations are uncorrected. Chemical shifts (δ) of 1H NMR, 13
C
(38) Lee, D. G.; Van den Engh, M. Can. J. Chem. 1972, 50, 3129.
(39) (a) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber.
1981, 114, 1234. (b) Vorbru¨ggen, H.; Ho¨fle, G. Chem. Ber. 1981, 114,
1256.
(40) Chun, B. K.; Olgen, S.; Hong, J. H.; Newton, M. C.; Chu, C. K.
J. Org. Chem. 2000, 65, 685.
Lactam 24 was reduced by LiBEt3H in anhydrous THF
to provide exclusively â-anomeric isomer, which was then
(37) Ikota, N. Heterocycles 1993, 36, 2035.
3830 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of 3′-Deoxy-3′-difluoromethyl Azanucleosides
SCHEME 9a
a Reagent and conditions: (a) (i) LiBEt3H, THF, -78 °C; (ii) Ac2O, CH2Cl2, Et3N, DMAP, rt; (b) silylated uracil or thymine, N,O-
bis(trimethylsilyl)acetamide, TMSOTf, 0 °C to rt. (c) TBAF, THF, rt.
resulting mixture was stirred at room temperature for 4 days.
The reaction was quenched with H2O and the mixture was
extracted with CH2Cl2 (3 × 30 mL). The combined organic
phases were washed with brine and dried over anhydrous
Na2SO4. After filtration and removal of the solvent, the
resulting residue was purified by flash chromatography (hex-
ane/ethyl acetate, 2:3) to afford 4 as a white solid (219 mg,
62%) and the starting material (95 mg). Compound 4: mp
1
74-76 °C; [R]20 -10.6 (c 0.84, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 4.58 (d, J ) 4.8 Hz, 1H), 4.32 (d, J ) 4.8 Hz, 1H),
FIGURE 1. Explanation of the opposite stereochemical
outcome in the glycosylation reaction.
4.09 (br, 1H), 3.94 (dd, J ) 3.0, 2.4 Hz, 1H), 3.80 (d, J ) 10.2
Hz, 2H), 3.39 (br, 1H), 1.50 (s, 9H), 0.83 (s, 9H), 0.01, -0.01
(2s, 6H); 13C NMR (75.5 MHz, CDCl3) δ 173.9, 149.7, 83.6, 71.6,
69.3, 64.7, 61.8, 28.0, 25.8, 18.2, -5.6; IR (thin film) 3440, 2957,
1776, 1739, 1695, 1473, 1367, 1286 cm-1; MS (ESI) m/z 384.2
(M + Na+). Anal. Calcd for C16H31NO6Si: C, 53.18; H, 8.59;
N, 3.88. Found: C, 53.20; H, 8.53; N, 3.67.
(3R,4R,5R)-N-tert-Butoxycarbonyl-3-benzoyloxy-4-hy-
droxy-5-(tert-butyldimethylsiloxymethyl)pyrrolidin-2-
one (5). To a solution of compound 4 (213 mg, 0.59 mmol) and
DMAP (6 mg, 0.05 mmol) in CH2Cl2 (2 mL) and pyridine (2
mL) at -78 °C was added BzCl (71 µL, 0.61 mmol) dropwise.
The mixture was then warmed to -10 °C and stirred for 12 h.
The reaction was quenched with H2O (5 mL) and the resulting
mixture was extracted with CH2Cl2 (3 × 25 mL). The combined
organic phases were washed with 1 M citric acid and brine
and dried over anhydrous Na2SO4. After filtration and removal
of the solvent, the resulting residue was purified by flash
chromatography (hexane/ethyl acetate, 4:1) to afford 5 as a
FIGURE 2. Selective NOE correlation from NOESY spectra
oil (235 mg, 85%) and the starting material (8 mg). Compound
1
1
5: [R]20 -32.3 (c 0.78, CHCl3); H NMR (300 MHz, CDCl3) δ
of 30a, 30b, 31a, and 31b and H NMR data of H4′.
D
8.10 (d, J ) 8.4 Hz, 2H), 7.59 (t, J ) 7.5 Hz, 1H), 7.44 (t, J )
7.5 Hz, 1H), 5.92 (d, J ) 5.4 Hz, 1H), 4.57 (d, J ) 5.4 Hz, 1H),
4.19 (s, 1H), 4.04 (dd, J ) 2.7, 2.4 Hz, 1H), 3.86 (d, J ) 10.8
Hz, 1H), 2.66 (br, 1H), 1.54 (s, 9H), 0.90 (s, 9H), 0.08, 0.06 (2s,
6H); 13C NMR (75.5 MHz, CDCl3) δ 168.2, 165.2, 149.9, 133.6,
130.1, 128.8, 128.5, 83.6, 72.8, 69.1, 64.9, 61.7, 28.0, 25.8, 18.6,
-5.6; IR (thin film) 3486, 2957, 1789, 1728, 1603, 1473, 1371,
1309, 1258, 838 cm-1; MS (ESI) m/z 488.3 (M + Na+); ESI-
HRMS m/z 488.2072 (M + Na+, C23H35NO7Si required
488.2075).
NMR, and 19F NMR (CFCl3 as external standard and low field
is positive) spectra are reported in ppm, and coupling constants
(J) are in Hz.
Compounds 2 and 3 were prepared according to the litera-
ture procedure.27,28
(3R,4R,5R)-N-tert-Butoxycarbonyl-3,4-dihydroxy-5-(tert-
butyldimethylsiloxymethyl)pyrrolidin-2-one (4). To a
cooled solution of compound 3 (323 mg, 0.98 mmol) and
4-methylmorpholine N-oxide monohydrate (NMNO) (222 mg,
1.49 mmol) in acetone (15 mL) and H2O (4 mL) was added
OsO4 (0.50 mL, 0.1 M in toluene, 0.05 mmol) dropwise. The
(4R)-N-tert-Butoxycarbonyl-4-methylsulfonyloxy-l-pro-
line Methyl Ester (8). To a cooled solution of trans-4-hydroxy-
J. Org. Chem, Vol. 70, No. 10, 2005 3831

Qiu and Qing
L-proline 7 (10.00 g, 76.26 mmol) in anhydrous MeOH (100
mL) was added SOCl2 (6.5 mL, 89.06 mmol) dropwise. After
the mixture was refluxed for 2 h, it was cooled to room
temperature and stirred overnight. After the solvent was
removed in vacuo, the residue was washed twice with anhy-
drous Et2O to provide white solid (14.00 g). Then, to a cooled
solution of the above white solid (14.00 g) and DMAP (2.00 g,
16.39 mmol) in anhydrous CH2Cl2 (150 mL) was added Et3N
(25 mL), followed by a solution of Boc2O (19.0 mL, 88.79 mmol)
in CH2Cl2 (50 mL) dropwise. The mixture was warmed to room
temperature and stirred overnight. The reaction was quenched
with H2O and the aqueous layer was extracted with CH2Cl2.
The combined organic phases were washed with 1 M citric acid
and brine and dried over anhydrous Na2SO4. After filtration
and removal of the solvent, the resulting residue was purified
by flash chromatography (hexane/ethyl acetate, 1:1) to afford
a white solid (15.529 g), which was then solved in CH2Cl2 (250
mL). After the miture was cooled to 0 °C, DMAP (2.00 g, 16.39
mmol) and Et3N (13 mL) were added, followed by MsCl (7.3
mL, 94.32 mmol) dropwise. The mixture was stirred for 2 h
and H2O (50 mL) was added. The aqueous layer was extracted
with CH2Cl2. Then, the combined organic phases were washed
with brine and dried over anhydrous Na2SO4. After filtration
and removal of the solvent, the resulting residue was purified
by flash chromatography (hexane/ethyl acetate, 2:1) to afford
tion of 10 (6.72 g, 33.77 mmol) and imidazole (6.88 g, 101.18
mmol) in CH2Cl2 (130 mL) was added DMAP (420 mg, 3.44
mmol), followed by TBDPSCl (14 mL, 53.48 mmol) dropwise.
The mixture was then stirred overnight and the reaction was
quenched with H2O (50 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 20 mL). The combined organic phases were
washed with brine and dried over anhydrous Na2SO4. After
filtration and removal of the solvent, the resulting residue was
purified by flash chromatography (hexane/ethyl acetate,
15:1) to afford 11 as a white foam (12.10 g, 82%). [R]20D -90.1
1
(c 1.06, CHCl3); H NMR (300 MHz, CDCl3) δ 7.66-7.64 (m,
4H), 7.39-7.37 (m, 6H), 5.89-5.78 (m, 2H), 4.64-4.52 (2br,
1H), 4.29-3.99 (m, 2.4H), 3.85 (ddd, J ) 16.7, 3.0, 2.9 Hz, 1H),
3.69 (dd, J ) 6.3, 6.6 Hz, 0.6H), 1.48, 1.36 (2s, 9H), 1.00 (s,
9H), rotamers; 13C NMR (75.5 MHz, CDCl3) δ 154.0, 135.6,
129.6, 129.5, 128.7, 127.6, 126.2, 79.3 and 79.1, 65.5 and 65.3,
65.1, 63.7, 54.2 and 54.0, 28.5 and 28.4, 26.7, 19.3, 19.2,
rotamers; IR (thin film) 3073, 3051, 2860, 1960, 1741, 1701,
1627, 1590, 1402, 1114, 702 cm-1; MS (ESI) m/z 438.3 (M +
H+); ESI-HRMS m/z 438.2460 (M + H+, C26H36NO3Si required
438.2459).
(2R,3R,4S)-N-tert-Butyloxycarbonyl-3,4-dihydroxy-2-
(tert-butyldiphenylsiloxymethyl)pyrrolidine (12). To a 0
°C solution of 11 (10.00 g, 22.88 mmol) and 4-methylmorpho-
line N-oxide monohydrate (NMNO) (9.10 g, 67.41 mmol) in
acetone (250 mL) and H2O (60 mL) was added OsO4 (5.0 mL,
0.1 M in toluene, 0.5 mmol). The resulting mixture was
warmed to room temperature and stirred for 5 h. Then,
Na2SO3 (5.0 g) was added and after 30 min of stirring, the
mixture was extracted with EtOAc (3 × 100 mL). The
combined organic phases were washed with brine and dried
over anhydrous Na2SO4. After filtration and removal of the
solvent, the resulting residue was purified by flash chroma-
tography (hexane/ethyl acetate, 1:1) to afford 12 as a white
foam (9.65 g, 92%). [R]20D -30.5 (c 1.01, MeOH); 1H NMR (300
MHz, MeOH-d4) δ 7.64-7.61 (m, 4H), 7.42-7.35 (m, 6H),
4.40-4.30 (m, 2H), 4.08 (dd, J ) 3.9, 3.6 Hz, 0.48H), 3.88 (dd,
J ) 4.2, 4.5 Hz, 0.62H), 3.77-3.66 (m, 2H), 3.59-3.39 (m, 2H),
1.47, 1.28 (2s, 9H), 1.03, 1.02 (2s, 9H), rotamers; 13C NMR (75.5
MHz, MeOH-d4) δ 156.4, 136.6, 135.7, 135.6, 134.5, 134.4,
134.3, 131.0, 128.9, 81.1 and 80.9, 75.0 and 74.5, 71.3 and 70.8,
66.3 and 66.0, 63.8 and 63.0, 52.8 and 52.1, 28.9 and 28.8, 27.4,
20.1, rotamers; IR (thin film) 3395, 3073, 3051, 2932, 1698,
1670, 1590, 1427, 1113, 702 cm-1; MS (ESI) m/z 472.3 (M +
H+); ESI-HRMS m/z 494.2322 (M + Na+, C26H37NO5NaSi
required 494.2333).
(2R,3R,4S)-N-tert-Butyloxycarbonyl-4-tert-butyldi-
methylsilyloxy-3-hydroxy-2-(tert-butyldiphenylsiloxy-
methyl)pyrrolidine (13) and (2R,3R,4S)-N-tert-Butyloxy-
carbonyl-4-tert-butyldimethylsilyloxy-3-tert-butyldi-
methylsilyloxy-2-(tert-butyldiphenylsiloxymethyl)pyr-
rolidine (14). To a 0 °C solution of 12 (90 mg, 0.19 mmol)
and DMAP (3 mg, 0.02 mmol) in DMF (0.5 mL) was added
imidazole (68 mg, 0.49 mmol), followed by TBDMSCl (32 mg,
0.21 mmol). Then, the mixture was warmed to room temper-
ature and stirred for 3 h. EtOAc (40 mL) was added and the
resulting mixture was washed with brine (3 × 15 mL). The
organic phase was dried over anhydrous Na2SO4. After filtra-
tion and removal of the solvent, the resulting residue was
purified by flash chromatography (hexane/ethyl acetate,
10:1) to afford 13 as a white foam (35 mg, more polar, 31%)
and 14 as a white foam (65 mg, less polar, 49%). Compound
13: [R]24D -12.4 (c 1.32, acetone); 1H NMR (300 MHz, acetone-
d6) δ 7.70-7.68 (m, 4H), 7.46-7.42 (m, 6H), 4.60-4.55 (m, 1H),
4.33-4.29 (m, 1H), 4.12-3.88 (m, 1H), 3.84-3.71 (m, 2H),
3.64-3.52 (m, 1H), 3.47-3.35 (m, 2H), 1.47, 1.32 (2s, 9H), 1.07
(s, 9H), 0.93 (s, 9H), 0.15, 0.14 (2s, 6H), rotamers; 13C NMR
(75.5 MHz, acetone-d6) δ 155.4 and 155.2, 136.6, 136.5, 135.6,
134.6, 134.5, 134.4, 130.9, 128.9, 79.7, 75.5 and 74.9, 72.8 and
72.3, 66.2 and 66.1, 64.4 and 63.5, 52.8 and 52.4, 29.0 and 28.9,
27.6, 26.5, 20.1, 19.0, -4.3, rotamers; IR (thin film) 3439, 3073,
3053, 2956, 1699, 1681, 1590, 1409, 1113, 838 cm-1; MS (ESI)
8 as a white solid (19.317 g, 78%). [R]25D -48.4 (c 1.58, CHCl3)
1
(lit.31 [R]25 -50.7 (c 1.5 CHCl3)); H NMR (300 MHz, CDCl3)
D
δ 5.26 (br, 1H), 4.47-4.37 (m, 1H), 3.86-3.75 (m, 1H), 3.82 (s,
3H), 3.08 (s, 3H), 2.68-2.55 (m, 1H), 2.32-2.23 (m, 1H), 1.47,
1.42 (2s, 9H); MS (ESI) m/z 346.1 (M + Na+).
Methyl (2S)-N-tert-Butyloxycarbonyl-3,4-dehydropro-
linate (9). To a 0 °C solution of 8 (19.317 g, 59.80 mmol) and
PhSeSePh (11.222 g, 35.95 mmol) in MeOH (450 mL) was
added NaBH4 (3.0 g, 78.95 mmol) in several portions. Then,
the mixture was refluxed about 11 h and the solution was
removed in vacuo. H2O (100 mL) was added and the mixture
was extracted with Et2O (3 × 80 mL). The combined organic
was washed with brine and dried over anhydrous Na2SO4.
After filtration and removal of the solvent, the resulting
residue was purified by flash chromatography (hexane/ethyl
acetate, 2:1) to afford an oil (20.213 g), which was then resolved
in CH2Cl2 (320 mL) and pyridine (6.5 mL) and 30% aqueous
H2O2 (15 mL) were added. After about 2 h, H2O (100 mL) was
added. The organic layer was then washed with 1 M citric acid,
saturated aqueous Na2SO3, and brine and dried over anhy-
drous Na2SO4. After filtration and removal of the solvent, the
resulting residue was purified by flash chromatography (hex-
ane/ethyl acetate, 10:1) to afford 9 as a clear oil (8.57 g, 63%).
[R]20 -261.0 (c 1.11, CHCl3) (lit.32d [R]20 -131.0 (c 1.22,
D
D
CHCl3)); 1H NMR (300 MHz, CDCl3) δ 5.98-5.95 (m, 1H),
5.69-5.66 (m, 1H), 4.94-4.91 (m, 1H), 4.25-4.15 (m, 2H), 3.71,
3.70 (2s, 3H), 1.45, 1.39 (2s, 9H), rotamers; 13C NMR (75.5
MHz, CDCl3) δ 170.9 and 170.6, 153.8 and 153.3, 129.3 and
129.2, 124.7 and 124.6, 80.1, 66.5 and 66.2, 53.4 and 53.2, 52.1,
52.0 and 51.9, 28.3 and 28.2, rotamers.
(2S)-N-tert-Butyloxycarbonyl-2-hydroxymethyl-3-pyr-
roline (10). To a 0 °C solution of 9 (8.57 g, 37.75 mmol) in
anhydrous Et2O (200 mL) was added LiAlH4 (1.55 g, 41.2
mmol). The mixture was then warmed to room temperature
and stirred for 1 h. The reaction was quenched with H2O (50
mL) and the aqueous layer was extracted with Et2O (3 × 50
mL). The combined organic phases were washed with brine
and dried over anhydrous Na2SO4. After filtration and removal
of the solvent, the resulting residue was purified by flash
chromatography (hexane/ethyl acetate, 3:1 then 2:1) to afford
10 as a clear oil (6.72 g, 89%). [R]20 -107.8 (c 1.23, CHCl3)
D
(lit.31 [R]20D -107.2 (c 13.9, CHCl3)); 1H NMR (300 MHz, CDCl3)
δ 5.84 (br, 1H), 5.65 (br, 1H), 4.72 (br, 1H), 4.22-4.04 (m, 3H),
3.79-3.75 (dd, J ) 2.7, 2.4 Hz, 1H), 3.62-3.60 (br, 1H), 1.51,
1.49 (2s, 9H), rotamers.
(2S)-N-tert-Butyloxycarbonyl-2-(tert-butyldiphenylsi-
loxymethyl)-3,4-dehydropyrrolidine (11). To a 0 °C solu-
3832 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of 3′-Deoxy-3′-difluoromethyl Azanucleosides
m/z 608.3 (M + Na+), 586.3 (M + H+); ESI-HRMS m/z 586.3375
(M + H+, C32H52NO5Si2 required 586.3379). Compound 14:
[R]20D -5.5 (c 2.33, acetone); 1H NMR (300 MHz, acetone-d6) δ
7.73-7.70 (m, 4H), 7.45-7.42 (m, 6H), 4.45-4.39 (m, 2H),
3.95-3.76 (m, 3H), 3.51-3.34 (m, 2H), 1.45, 1.32 (2s, 9H), 1.08
(s, 9H), 0.92, 0.91 (2s, 18H), 0.17-0.12 (m, 12H), rotamers;
13C NMR (75.5 MHz, acetone-d6) δ 155.6 and 155.3, 136.4,
135.5, 134.4, 134.2, 134.0, 130.9, 130.8, 128.9, 128.8, 128.7,
79.6, 75.8 and 75.3, 72.5 and 72.0, 67.1 and 66.8, 63.9 and 63.1,
28.8, 28.7, 27.5, 26.5, 26.4, 20.0 and 19.9, 18.9, -3.8, -4.4,
-4.2, -4.2, -4.3, rotamers; IR (thin film) 2957, 2859, 1702,
1473, 1393, 1254, 1113, 837 cm-1; MS (ESI) m/z 722.5 (M +
Na+), 700.5 (M + H+); ESI-HRMS m/z 700.4245 (M + H+,
C38H66NO5Si3 required 700.4243).
131.1, 130.8, 130.1, 129.8, 129.0, 81.0, 74.0, 65.0, 64.2, 48.8,
28.8, 27.4, 20.0; IR (thin film) 3073, 2933, 1780, 1731, 1702,
1602, 1589, 1396, 1273, 1115, 709 cm-1; MS (ESI) m/z
574.3 (M + H+); ESI-HRMS m/z 596.2426 (M + Na+,
C33H39NO6NaSi required 596.2439).
(2S,4R)-N-tert-Butyloxycarbonyl-4-benzoyloxy-3-di-
fluoromethylenyl-2-(tert-butyldiphenylsiloxymethyl)-
pyrrolidine (18). To a -15 °C solution of 17 (2.149 g, 3.75
mmol) in THF (80 mL) was added HMPT (3.5 mL, 18.5 mmol)
followed by CF2Br2 (1.75 mL, 19.10 mmol). The mixture was
stirred at room temperature for 0.5 h and then Zn dust (1.20
g, 18.5 mmol) was added. The mixture was heated to reflux
for 0.5 h and cooled to room temperature. H2O (50 mL) and
Et2O (100 mL) were added. The aqueous phase was extracted
with Et2O (3 × 30 mL). The combined organic phases were
washed with saturated aqueous CuSO4 and brine and dried
over anhydrous Na2SO4. After filtration and removal of the
solvent, the resulting residue was purified by flash chroma-
tography (hexane/ethyl acetate, 25:1) to afford 18 as a white
foam (1.886 g, 83%). [R]20D +22.4 (c 1.0, acetone); 1H NMR (300
MHz, acetone-d6) δ 8.04 (d, J ) 7.5 Hz, 2H), 7.70-7.64 (m,
5H), 7.55-7.46 (m, 8H), 6.22 (br, 1H), 4.90 (br, 1H), 4.24-
3.92 (m, 3H), 3.79 (t, J ) 12.5 Hz, 1H), 1.47, 1.40 (2s, 9H),
1.08 (s, 9H), rotamers; 19F NMR (282 MHz, CDCl3) δ -84.17
to -84.38 (m, 1F), -84.64 to -84.89 (m, 1F); 13C NMR (75.5
MHz, acetone-d6) δ 166.5, 154.5 and 154.1, 153.3 (t, J ) 290.1
Hz) and 153.2 (t, J ) 288.8 Hz), 136.5, 136.4, 134.5, 131.1,
131.0, 130.6, 129.7, 129.0, 92.6 (t, J ) 21.2 Hz) and 91.9 (t, J
) 21.0 Hz), 80.7, 72.6 (d, J ) 6.6 Hz) and 72.0 (d, J ) 4.8 Hz),
65.3 and 64.2, 59.3, 55.1 and 54.6, 28.8, 27.4, 20.0, rotamers;
IR (thin film) 3073, 2933, 1961, 1772, 1724, 1702, 1602, 1580,
1474, 1403, 1278, 1265, 1174, 1106, 710 cm-1; MS (ESI) m/z
630.2 (M + Na+), 608.2 (M + H+); ESI-HRMS m/z 630.2453
(M + Na+, C34H39F2NO5NaSi required 630.2458).
(2R,3R,4S)-N-tert-Butyloxycarbonyl-4-benzoyloxy-3-
hydroxy-2-(tert-butyldiphenylsiloxymethyl)pyr-
rolidine (15) and (2R,3R,4S)-N-tert-Butyloxycarbonyl-
4-hydroxy-3-benzoyloxy-2-(tert-butyldiphenylsiloxy-
methyl)pyrrolidine (16). To a -78 °C solution of 12 (716
mg, 1.52 mmol) and DMAP (10 mg, 0.08 mmol) in CH2Cl2 (4.5
mL) was added pyridine (3.0 mL), followed by BzCl (176 µL,
1.52 mmol) dropwise. Then, the mixture was warmed to -10
°C and stirred for 24 h. The reaction was quenched with H2O
(10 mL) and the aqueous layer was extracted with CH2Cl2 (3
× 30 mL). The combined organic phases were washed with 1
M citric acid and brine and dried over anhydrous Na2SO4. After
filtration and removal of the solvent, the resulting residue was
purified by flash chromatography (hexane/ethyl acetate, 8:1)
to afford 15 as a white foam (614 mg, less polar, 70%) and 16
as a white foam (145 mg, more polar, 17%) and the starting
material (52 mg, 7%). Coumpound 15: [R]20 -26.3 (c 0.94,
D
acetone); 1H NMR (300 MHz, acetone-d6) δ 8.11-7.44 (m, 15H),
5.67-5.62 (m, 1H), 4.85-4.71 (m, 2H), 4.19-3.96 (m, 1H),
3.90-3.69 (m, 4H), 1.49-1.34 (m, 9H), 1.09, 1.08 (2s, 9H),
rotamers; 13C NMR (75.5 MHz, acetone-d6) δ 166.6, 155.2,
136.5, 134.1, 131.4, 130.8, 130.6, 129.5, 128.9, 79.9, 74.5 and
74.2, 73.5 and 72.9, 66.5 and 66.3, 64.0 and 63.1, 50.1 and 49.7,
28.9, 27.5, 20.0, rotamers; IR (thin film) 3434, 3073, 2933,
1964, 1725, 1699, 1677, 1603, 1589, 1275, 1114, 709 cm-1; MS
(ESI) m/z 598.2 (M + Na+), 576.2 (M + H+); ESI-HRMS m/z
598.2575 (M + Na+, C33H41NO6NaSi required 598.2595).
(2S,3S,4R)-N-tert-Butyloxycarbonyl-4-benzoyloxy-3-di-
fluoromethyl-2-(tert-butyldiphenylsiloxymethyl)pyr-
rolidine (19) and (2S,3R,4R)-N-tert-Butyloxycarbonyl-4-
benzoyloxy-3-difluoromethyl-2-(tert-butyldiphenylsi-
loxymethyl)pyrrolidine (20). Typical procedure: To a solu-
tion of 18 in solvent was added catalyst. Then, the mixture
was hydrogenated under different press. After filtration and
removal of the solvent, the resulting residue was purified by
flash chromatography (hexane/ethyl acetate, 25:1) to afford 19
as a white foam (less polar) and 20 as a white foam (more
polar). Compound 19: [R]20D -11.0 (c 0.22, acetone); 1H NMR
(300 MHz, acetone-d6) δ 8.09-8.06 (m, 2H), 7.73-7.45 (m,
13H), 6.41 (tt, J ) 55.7, 7.8 Hz, 1H), 6.10-6.04 (m, 1H), 4.29-
4.16 (m, 2H), 4.12-3.98 (m, 1H), 3.72 (t, J ) 12.9 Hz, 1H),
3.51 (dd, J ) 6.3, 6.0 Hz, 1H), 3.40-3.22 (m, 1H), 1.48, 1.32
(2s, 9H), 1.13 (s, 9H), rotamers; 19F NMR (282 MHz, acetone-
d6) δ -114.12 to -115.40 (m, 1F), -119.66 to -121.04 (ddd, J
) 313.8, 18.0, 19.0 Hz, 1F); 13C NMR (75.5 MHz, acetone-d6)
δ 166.5, 154.2, 136.6, 136.5, 134.4, 133.5, 131.1, 131.0, 130.8,
130.6, 129.6, 129.0, 117.7 (t, J ) 238.9 Hz), 80.5, 72.8 and
72.3, 64.3 and 63.4, 59.1 and 58.9, 52.5, 50.5 (t, J ) 21.1
Hz) and 49.7 (t, J ) 21.7 Hz), 28.8, 27.5, 19.8, rotamers; IR
(thin film) 3074, 2933, 1728, 1700, 1603, 1589, 1474, 1395,
1270, 1111 cm-1; MS (ESI) m/z 648.4 (M + K+), 632.2 (M +
Na+), 610.3 (M + H+); ESI-HRMS m/z 632.2622 (M + Na+,
Compound 16: [R]20 -16.0 (c 0.57, acetone); 1H NMR (300
D
MHz, acetone-d6) δ 8.09 (d, J ) 7.8 Hz, 2H), 7.72-7.39 (m,
13H), 5.73-5.68 (m, 1H), 4.76 (br, 1H), 4.60-4.58 (m, 1H),
4.21-3.85 (m, 3H), 3.77-3.55 (m, 2H), 1.49, 1.31 (2s, 9H), 1.05
(s, 9H), rotamers; 13C NMR (75.5 MHz, acetone-d6) δ 166.6,
155.2 and 154.9, 136.5, 134.1, 131.5, 130.9, 130.7, 129.5, 128.9,
79.9, 77.8 and 77.2, 70.1 and 69.5, 64.1 and 63.1, 63.6, 53.0
and 52.6, 28.8, 27.5, 20.0, rotamers; IR (thin film) 3441, 3073,
2933, 1725, 1699, 1679, 1603, 1589, 1473, 1276, 1114, 709
cm-1; MS (ESI) m/z 576.3 (M + H+); ESI-HRMS m/z 598.2584
(M + Na+, C33H41NO6NaSi required 598.2596).
(2R,4S)-N-tert-Butyloxycarbonyl-4-benzoyloxy-3-oxo-
2-(tert-butyldiphenylsiloxymethyl)pyrrolidine (17). To a
cooled solution of Dess-Martin oxidant (618 mg, 1.46 mmol)
in CH2Cl2 (6 mL) was added a solution of 15 (536 mg, 0.93
mmol) in CH2Cl2 (12 mL) dropwise. The mixture was warmed
to room temperature and stirred for 1.5 h. Then, the mixture
was cooled again and a solution of Na2S2O4 (1.0 g) and NaHCO3
(200 mg) in H2O (10 mL) was added dropwise. The resulting
mixture was stirred for about 0.5 h and the aqueous layer was
extracted with CH2Cl2 (3 × 30 mL). The combined organic
phases were washed with saturated aqueous NaHCO3 and
brine and dried over anhydrous Na2SO4. After filtration and
removal of the solvent, the resulting residue was purified by
flash chromatography (hexane/ethyl acetate, 10:1) to afford 17
C34H41F2NO5NaSi required 632.2614). Compound 20: [R]20
D
-14.4 (c 0.74, acetone); 1H NMR (300 MHz, acetone-d6) δ 8.06-
8.05 (m, 2H), 7.75-7.44 (m, 13H), 6.50 (td, J ) 55.8, 5.4 Hz,
1H), 5.82 (br, 1H), 4.36-4.14 (m, 2H), 4.03-3.91 (m, 1H),
3.83-3.69 (m, 2H), 3.58-3.41 (m, 1H), 1.41, 1.32 (2s, 9H), 1.08
(s, 9H), rotamers; 19F NMR (282 MHz, acetone-d6) δ -116.47
to -117.75 (ddd, J ) 293.1, 10.2, 10.7 Hz, 1F), -123.22 to
-124.62 (dddd, J ) 291.3, 55.8, 16.4, 16.9 Hz, 1F); 13C NMR
(75.5 MHz, acetone-d6) δ 166.1, 154.9 and 154.7, 136.3, 135.4,
134.4, 134.0, 130.8, 130.7, 130.4, 129.5, 128.8, 120.7, 117.5 (t,
J ) 240.6 Hz), 80.2 and 80.1, 73.8 and 73.5, 64.8 and 63.9,
58.8 (t, J ) 6.9 Hz), 53.9 and 53.3, 48.1 (t, J ) 21.4 Hz) and
47.3 (t, J ) 20.3 Hz), 28.6, 27.2, 19.9, rotamers; IR (thin film)
as a white foam (489 mg, 92%). [R]20 -30.8 (c 1.2, acetone);
D
1H NMR (300 MHz, acetone-d6) δ 8.11-8.07 (m, 2H), 7.72-
7.66 (m, 5H), 7.58-7.44 (m, 8H), 5.67 (dd, J ) 7.5, 7.8 Hz,
1H), 4.48-4.18 (m, 3H), 3.96 (t, J ) 10.2 Hz, 1H), 3.82 (t, J )
8.9 Hz, 1H), 1.55, 1.38 (2s, 9H), 1.07 (s, 9H); 13C NMR (75.5
MHz, acetone-d6) δ 207.3, 166.1, 155.0, 136.5, 134.8, 133.7,
J. Org. Chem, Vol. 70, No. 10, 2005 3833

Qiu and Qing
3073, 2933, 1728, 1700, 1602, 1589, 1473, 1394, 1270, 1113,
709 cm-1; MS (ESI) m/z 648.3 (M + K+), 632.2 (M +
Na+), 610.3 (M + H+); ESI-HRMS m/z 632.2628 (M + Na+,
C34H41F2NO5NaSi required 632.2614).
117.4 (t, J ) 239.6 Hz), 80.2 and 80.0, 73.7 and 73.4, 64.1 and
63.0, 58.9 and 58.7, 53.7 and 53.3, 48.1 (t, J ) 21.3 Hz) and
47.1 (t, J ) 21.4 Hz), 28.6 and 28.5, 26.3, 18.9, -5.2, -5.3,
rotamers; IR (thin film) 2956, 1718, 1695, 1602, 1584, 1474,
1403, 1280, 1122, 1086, 775 cm-1; MS (ESI) m/z 508.1 (M +
Na+), 486.2 (M + H+). Anal. Calcd for C24H37 F2NO5Si: C,
59.38; H, 7.63; N, 2.89. Found: C, 59.51; H, 7.85; N, 2.86.
(2S,3S,4R)-N-tert-Butyloxycarbonyl-4-tert-butyldi-
methylsiloxy-3-difluoromethyl-2-(tert-butyldimethylsi-
loxymethyl)pyrrolidine (22). To a 0 °C solution of 19 (460
mg, 0.76 mmol) in THF (20 mL) was added TBAF (0.76 mL, 1
M in THF, 0.76 mmol) dropwise. The mixture was warmed to
room temperature and stirred until the reaction was shown
to be complete by TLC. After removal of the solvent, the
resulting residue was purified by flash chromatography (hex-
ane/ethyl acetate, 3:1) to afford a clear oil (207 mg), which was
solved in CH2Cl2 (10 mL) and cooled to 0 °C. To the solution
was added DMAP (10 mg, 0.08 mmol) and imidazole (125 mg,
1.84 mmol), followed by a solution of TBDMSCl (138 mg, 0.91
mmol) in CH2Cl2 (2 mL). The mixture was warmed to room
temperature and stirred for 2 h. After removal of the solvent,
the resulting residue was purified by flash chromatography
(hexane/ethyl acetate, 4:1) to afford a clear oil (258 mg), which
was solved in MeOH (3.5 mL) and cooled to 0 °C. Then, to the
resulting solution was added a saturated solution of ammonia
in methanol (15 mL). The mixture was stirred at room
temperature for 28 h. After removal of the solvent, the
resulting residue was purified by flash chromatography (hex-
ane/ethyl acetate, 4:1) to afford a clear oil (180 mg), which was
solved in DMF (3 mL) and cooled to 0 °C. To the resulting
solution was added DMAP (40 mg, 0.33 mmol) and imidazole
(1.20 g, 17.6 mmol), followed by a solution of TBDMSCl (2.00
g, 13.27 mmol) in DMF (4 mL). The mixture was then stirred
for 2.5 h at room temperature. After removal of the solvent,
the resulting residue was purified by flash chromatography
(hexane/ethyl acetate, 50:1) to afford 22 as a clear oil (225 mg,
60%). [R]20D +6.1 (c 0.59, acetone); 1H NMR (300 MHz, acetone-
d6) δ 6.37-5.96 (m, 1H), 4.75 (q, J ) 7.5 Hz, 1H), 4.06-3.95
(m, 2H), 3.77-3.64 (m, 2H), 3.13 (dd, J ) 6.6, 6.9 Hz, 1H),
2.80-2.65 (m, 1H), 1.45 (s, 9H), 0.94, 0.89 (2s, 18H), 0.08 (s,
12H), rotamers; 19F NMR (282 MHz, acetone-d6) δ -113.24 to
-114.72 (m, 1F), -119.20 to -120.98 (dddd, J ) 294.3, 137.5,
11.6, 12.5 Hz, 1F); 13C NMR (75.5 MHz, acetone-d6) δ 154.2
and 153.9, 118.4 (t, J ) 240.1 Hz) and 118.3 (t, J ) 240.0 Hz),
80.0 and 79.9, 71.3 (d, J ) 3.5 Hz) and 70.7 (d, J ) 3.8 Hz),
62.7 and 61.6, 59.2 (t, J ) 9.3 Hz), 55.1, 53.4 (t, J ) 20.2 Hz)
and 52.7 (t, J ) 20.2 Hz), 28.8, 26.4, 26.2, 18.8, 18.6, -4.4,
-4.8, -5.2, -5.3, rotamers; IR (thin film) 2957, 2932, 1702,
1393, 1257, 1132, 1116, 838 cm-1; MS (ESI) m/z 496.3 (M +
H+); ESI-HRMS m/z 518.2917 (M + Na+, C23H47F2NO5NaSi2
required 518.2904).
(2S,3R,4R)-N-tert-Butyloxycarbonyl-4-tert-butyldi-
methylsiloxy-3-difluoromethyl-2-(tert-butyldimethylsi-
loxymethyl)pyrrolidine (23). To a solution of 21 (344 mg,
0.71 mmol) in MeOH (5 mL) at 0 °C was added a saturated
solution of ammonia in methanol (10 mL). The mixture was
stirred at room temperature for 6 h. After removal of the
solvent, the resulting residue was purified by flash chroma-
tography (hexane/ethyl acetate, 3:1) to afford a clear oil (250
mg), which was solved in DMF (7 mL) and cooled to 0 °C. To
the resulting solution was added DMAP (38 mg, 0.31 mmol)
and imidazole (600 mg, 8.82 mmol), followed by a solution of
TBDMSCl (1.04 g, 6.89 mmol) in DMF (1 mL). The mixture
was then stirred overnight at room temperature. After removal
of the solvent, the resulting residue was purified by flash
chromatography (hexane/ethyl acetate, 40:1) to afford 23 as a
clear oil (302 mg, 86%). [R]20D -20.4 (c 0.47, acetone); 1H NMR
(300 MHz, acetone-d6) δ 6.11 (td, J ) 56.7, 6.7 Hz, 1H), 4.57
(br, 1H), 4.13 (dd, J ) 9.9, 10.5 Hz, 1H), 3.98 (d, J ) 7.8 Hz,
1H), 3.72-3.53 (m, 2H), 3.27 (ddd, J ) 17.1, 3.6, 3.6 Hz, 1H),
2.92-2.85 (m, 1H), 1.46, 1.45 (2s, 9H), 0.90 (s, 18H), 0.14-
0.04 (m, 12H), rotamers; 19F NMR (282 MHz, acetone-d6) δ
-115.75 to -117.20 (m, 1F), -125.4 to -126.9 (m, 1F); 13C
NMR (75.5 MHz, acetone-d6) δ 155.0, 118.9 (t, J ) 238.1 Hz)
and 118.8 (t, J ) 238.3 Hz), 79.8 and 79.6, 72.0 (d, J ) 6.5
Hz) and 71.6 (d, J ) 5.4 Hz), 63.8 and 62.7, 58.8 (t, J ) 8.6
Hz), 56.4 and 55.8, 49.7 (t, J ) 21.1 Hz) and 48.7 (t, J ) 20.7
Hz), 28.8, 26.4, 26.2, 18.9, 18.7, -4.5, -5.0, -5.1, -5.2,
rotamers; IR (thin film) 2957, 1702, 1473, 1398, 1257, 1151,
1118, 837, 778 cm-1; MS (ESI) m/z 496.3 (M + H+); ESI-HRMS
m/z 518.2925 (M + Na+, C23H47F2NO5NaSi2 required 518.2904).
(5S,4S,3R)-N-tert-Butyloxycarbonyl-5-tert-butyldi-
methylsilyloxymethyl-4-difluoromethyl-3-(tert-butyldi-
methylsilyloxy)pyrolidin-2-one (24) and (2R,3R,4R)-N-
tert-Butyloxycarbonyl-4-tert-butyldimethylsiloxy-3-di-
fluoromethyl-2-(tert-butyldimethylsiloxymethyl)-2-hy-
droxypyrrolidine (26). To a solution of NaIO4 (330 mg, 1.54
mmol) in H2O (6 mL) was added RuO2‚xH2O (15 mg). The
mixture was stirred at room temperature for 5 min and a
solution of 22 (225 mg, 0.45 mmol) in EtOAc (6 mL) was added
dropwise. Then, the mixture was stirred at room temperature
for 16 h. H2O (20 mL) and EtOAc (20 mL) were added and the
aqueous layer was extracted with EtOAc (2 × 15 mL). The
combined organic phases were washed with brine and dried
over anhydrous Na2SO4. After filtration and removal of the
solvent, the resulting residue was purified by flash chroma-
tography (hexane/ethyl acetate, 60:1, then 10:1) to afford 24
as a clear oil (92 mg, less polar, 40%) and 26 as a clear oil (76
(2S,3R,4R)-N-tert-Butyloxycarbonyl-4-benzoyloxy-3-
difluoromethyl-2-(tert-butyldimethylsiloxymethyl)pyr-
rolidine (21). To a 0 °C solution of 20 (579 mg, 0.95 mmol) in
THF (25 mL) was added TBAF (0.95 mL, 1 M in THF, 0.95
mmol) dropwise. The mixture was warmed to room tempera-
ture and stirred for 4.5 h. After removal of the solvent, the
resulting residue was purified by flash chromatography (hex-
ane/ethyl acetate, 3:1) to afford a clear oil (280 mg), which was
solved in CH2Cl2 (20 mL) and cooled to 0 °C. To the solution
was added DMAP (26 mg, 0.21 mmol) and imidazole (373 mg,
5.48 mmol), followed by a solution of TBDMSCl (382 mg, 2.53
mmol) in CH2Cl2 (0.5 mL). The mixture was warmed to room
temperature and stirred overnight. After removal of the
solvent, the resulting residue was purified by flash chroma-
tography (hexane/ethyl acetate, 20:1) to afford 21 as a white
mg, more polar, 33%). Compound 24: [R]20 +18.7 (c 0.57,
D
acetone); 1H NMR (300 MHz, acetone-d6) δ 6.28 (td, J ) 55.6,
7.2 Hz, 1H), 4.72 (d, J ) 10.2 Hz, 1H), 4.32 (d, J ) 8.7 Hz,
1H), 4.10 (d, J ) 11.1 Hz, 1H), 3.86 (d, J ) 12.3 Hz, 1H), 2.95-
2.84 (m, 1H), 1.52 (s, 9H), 0.91, 0.90 (2s, 18H), 0.19-0.06 (m,
12H), rotamers; 19F NMR (282 MHz, acetone-d6) δ -115.06 to
-116.39 (dd, J ) 54.1, 54.4 Hz, 1F), -119.00 to -120.31 (m,
1F); 13C NMR (75.5 MHz, acetone-d6) δ 171.8 and 171.7, 150.6,
118.1 (t, J ) 239.0 Hz), 83.8, 72.5 and 72.4, 61.5, 56.6 and
56.5, 49.0 (t, J ) 22.1 Hz), 28.5, 26.5, 26.3, 19.0, 18.9, 1.6, -3.5,
-4.8, -5.3, rotamers; IR (thin film) 2955, 1789, 1771, 1714,
1473, 1165, 1019, 841 cm-1; MS (ESI) m/z 532.3 (M + Na+);
ESI-HRMS m/z 532.2702 (M + Na+, C23H45F2NO5NaSi2 re-
solid (344 mg, 75%). Mp 96-97 °C; [R]20 -27.2 (c 0.66,
D
acetone); 1H NMR (300 MHz, acetone-d6) δ 8.05 (d, J ) 7.2
Hz, 2H), 7.67 (t, J ) 7.2 Hz, 1H), 7.52 (t, J ) 7.5 Hz, 2H), 6.44
(td, J ) 55.7, 5.7 Hz, 1H), 5.73-5.69 (m, 1H), 4.27-4.12 (m,
2H), 3.93-3.55 (m, 3H), 3.32-3.16 (m, 1H), 1.47, 1.38 (2s, 9H),
0.94 (s, 9H), 0.12-0.09 (m, 6H), rotamers; 19F NMR (282 MHz,
acetone-d6) δ -116.85 to -118.10 (dd, J ) 56.4, 54.1 Hz, 1F),
-123.44 to -124.68 (m, 1F); 13C NMR (75.5 MHz, acetone-d6)
δ 166.1, 154.7, 134.4, 130.5, 129.5, 117.5 (t, J ) 239.4 Hz) and
quired 532.2697). Compound 26: [R]20 -3.9 (c 1.78, CHCl3);
D
1H NMR (300 MHz, acetone-d6) δ 6.43-6.01 (m, 1H), 5.25-
5.18 (m, 1H), 4.61 (dd, J ) 4.8, 5.1 Hz, 1H), 4.40 (d, J ) 5.1
Hz, 0.34H) and 4.44 (d, J ) 5.4 Hz, 0.66H), 4.16 (d, J ) 11.4
Hz, 0.66H) and 4.05 (d, J ) 11.1 Hz, 0.34H), 3.92 (d, J ) 8.7
3834 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of 3′-Deoxy-3′-difluoromethyl Azanucleosides
Hz, 1H), 3.72-3.62 (m, 1H), 2.98-2.81 (m, 1H), 1.48 (s, 9H),
0.93, 0.92 (2s, 18H), 0.13-0.07 (m, 12H), rotamers; 19F NMR
(282 MHz, acetone-d6) δ -112.39 to -114.31 (dddd, J ) 298.36,
174.00, 14.66, 12.69 Hz, 1F), -117.63 to -119.52 (dddd, J )
297.37, 168.14, 11.21, 13.32 Hz, 1F); 13C NMR (75.5 MHz,
benzene-d6) δ 154.0 and 153.8, 117.5 (t, J ) 240.1 Hz), 80.5,
80.2, 71.6 (d, J ) 9.2 Hz) and 70.9 (d, J ) 5.8 Hz), 61.2 and
60.2, 57.1 (d, J ) 9.1 Hz), 49.2 (t, J ) 21.5 Hz) and 48.2 (t, J
) 20.6 Hz), 28.5, 26.0, 25.7, 18.2, 18.1, -4.8, -5.0, -5.4, -5.6,
rotamers; IR (thin film) 3463, 2956, 1704, 1474, 1369, 1257,
1170, 1133, 839, 779 cm-1; MS (ESI) m/z 529.3 (M + NH4+);
HRMS-ESI m/z 534.2849 (M + Na+, C23H47F2NO5NaSi2 re-
quired 534.2853).
solvent, the resulting residue was purified by flash chroma-
tography (hexane/ethyl acetate, 25:1) to afford 28 as a clear
1
oil (95 mg, 95%). [R]20 -23.5 (c 1.5, acetone); H NMR (300
D
MHz, MeOH-d4) δ 6.27 (d, J ) 2.7 Hz, 1H), 6.20 (td, J ) 56.4,
7.4 Hz, 1H), 4.57-4.54 (m, 1H), 4.12-4.00 (m, 2H), 3.78-3.73
(m, 1H), 2.78-2.65 (m, 1H), 2.04 (s, 3H), 1.43 (s, 9H), 0.95,
0.87 (2s, 18H), 0.11, 0.10, 0.07, 0.05 (4s, 12H); 19F NMR (282
MHz, MeOH-d4) δ -114.00 to -115.28 (ddd, J ) 293.99, 11.28,
11.14 Hz, 1F), -117.32 to -118.55 (dd, J ) 60.07, 57.25 Hz,
1F); 13C NMR (75.5 MHz, MeOH-d4) δ 171.0, 154.9, 117.4 (t, J
) 239.3 Hz), 88.9 and 88.8, 82.6, 77.4, 61.6, 60.5 and 60.4,
54.4, 28.7, 26.5, 26.1, 21.5, 19.2, 18.7, -4.4, -4.9, -5.2, -5.5,
rotamers; IR (thin film) 2957, 1759, 1710, 1473, 1369, 1257,
1116, 1019, 840 cm-1; MS (ESI) m/z 576.3 (M + Na+); ESI-
HRMS m/z 576.2969 (M + Na+, C25H49F2NO6NaSi2 required
576.2959).
(5S,4R,3R)-N-tert-Butyloxycarbonyl-5-tert-butyldi-
methylsilyloxymethyl-4-difluoromethyl-3-(tert-butyldi-
methylsilyloxy)pyrolidin-2-one (25) and (2R,3S,4R)-N-
tert-Butyloxycarbonyl-4-tert-butyldimethylsiloxy-3-di-
fluoromethyl-2-(tert-butyldimethylsiloxymethyl)-2-hy-
droxypyrrolidine (27). Compounds 25 (260 mg, less polar,
54%) and 27 (10 mg, more polar, 2%) were prepared as clear
oils from compound 23 (465 mg, 0.94 mmol), using the same
conditions as described for compounds 24 and 26. Compound
25: [R]20D -7.8 (c 0.74, acetone); 1H NMR (300 MHz, acetone-
d6) δ 6.24 (td, J ) 55.3, 2.1 Hz, 1H), 4.91 (d, J ) 9.3 Hz, 1H),
4.33 (br, 1H), 4.10 (dd, J ) 2.7, 2.7 Hz, 1H), 3.79 (dd, J ) 1.8,
2.1 Hz, 1H), 3.11-2.96 (m, 1H), 1.52 (s, 9H), 0.94, 0.90 (2s,
18H), 0.21-0.07 (m, 12H), rotamers; 19F NMR (282 MHz,
acetone-d6) δ -126.03 to -127.26 (ddd, J ) 284.3, 9.7, 7.8 Hz,
1F), -127.79 to -131.08 (ddd, J ) 284.5, 26.6, 26.1 Hz, 1F);
13C NMR (75.5 MHz, acetone-d6) δ 171.6, 150.6, 116.6 (t, J )
240.1 Hz), 83.5, 71.4 and 71.3, 64.6, 55.5 (t, J ) 4.1 Hz), 44.5
(t, J ) 19.3 Hz), 28.3, 26.3, 26.2, 19.0, -4.2, -5.1, -5.3, -5.4,
rotamers; IR (thin film) 2957, 2932, 1801, 1772, 1720, 1473,
1370, 1311, 1258, 1158, 839, 781 cm-1; MS (ESI) m/z 548.3
(M + K+), 532.3 (M + Na+); ESI-HRMS m/z 532.2687 (M +
Na+, C23H45F2NO5NaSi2 required 532.2697). Compound 27:
[R]20D -25.1 (c 0.46, acetone); 1H NMR (300 MHz, acetone-d6)
δ 6.13 (td, J ) 56.7, 6.9 Hz, 1H), 5.25-5.19 (m, 1H), 4.23-
3.97 (m, 4H), 3.64 (dd, J ) 11.4, 9.9 Hz, 1H), 3.01-2.87 (m,
(2S,3R,4R,5S)-N-tert-Butyloxycarbonyl-2-acetyloxy-3-
tert-butyldimethylsilyloxyl-4-difluoromethyl-5-(tert-bu-
tyldimethylsilyloxymethyl)pyrrolidine (29a) and (2R,3R,-
4R,5S)-N-tert-Butyloxycarbonyl-2-acetyloxy-3-tert-
butyldimethylsilyloxyl-4-difluoromethyl-5-(tert-butyldi-
methylsilyloxymethyl)pyrrolidine (29b). Compounds 29a
(151 mg, 55%) and 29b (29 mg, 11%) were prepared as clear
oils from compound 25 (253 mg, 0.50 mmol), using the same
conditions as described for compound 28. Compound 29a:
[R]20D -16.1 (c 0.78, MeOH); 1H NMR (300 MHz, MeOH-d4) δ
6.39 (d, J ) 4.2 Hz, 1H), 6.17 (td, J ) 56.4, 6.1 Hz, 1H), 4.77-
4.72 (m, 1H), 4.11-4.00 (m, 2H), 3.62-3.53 (m, 1H), 2.70-
2.56 (m, 1H), 2.04 (s, 3H), 1.47, 1.42 (2s, 9H), 0.92, 0.88 (2s,
18H), 0.11-0.061 (m, 12H); 19F NMR (282 MHz, MeOH-d4) δ
-114.15 to -115.41 (m, 1F), -120.62 to -121.88 (m, 1F); 13C
NMR (75.5 MHz, MeOH-d4) δ 171.1, 154.5, 117.1 (t, J ) 240.2
Hz), 82.6, 71.5, 65.2, 64.4, 59.1 (t, J ) 5.1 Hz), 49.9 (t, J )
19.9 Hz), 28.6, 26.4, 26.2, 21.1, 19.2, 18.8, -5.0, -5.2; IR (thin
film) 2958, 2932, 1753, 1716, 1473, 1392, 1369, 1259, 1149,
1113, 839 cm-1; MS (ESI) m/z 592.3 (M + K+), 576.3 (M +
Na+); ESI-HRMS m/z 576.2960 (M + Na+, C25H49F2NO6NaSi2
required 576.2959). Compound 29b: [R]24 -42.5 (c 0.97,
D
1
MeOH); H NMR (300 MHz, MeOH-d4) δ 6.34 (dt, J ) 57.2,
1H), 1.46 (s, 9H), 0.92, 0.90 (2s, 18H), 0.16-0.10 (m, 12H); 19
F
8.1 Hz, 1H), 5.53-5.52 (br, 1H), 5.22 (t, J ) 5.4 Hz, 1H), 4.24-
3.85 (m, 2H), 3.66-3.55 (m, 1H), 2.98-2.85 (m, 1H), 2.05 (s,
3H), 1.49 (s, 9H), 1.0 (s, 18H), 0.18, 0.16, 0.09, 0.07 (4s, 12H);
19F NMR (282 MHz, MeOH-d4) δ -117.56 to -115.87 (m, 2F);
13C NMR (75.5 MHz, MeOH-d4) δ 171.6, 154.6, 117.8 (t, J )
239.4 Hz), 82.2, 72.4, 64.9, 63.5, 58.8 (t, J ) 5.8 Hz), 48.0 (t,
J ) 21.2 Hz), 28.8, 26.4, 26.4, 20.9, 19.2, 19.1, -4.4, -4.6, -4.8,
NMR (282 MHz, acetone-d6) δ -114.80 to -116.91 (ddd, J )
297.93, 53.30, 56.96 Hz, 1F), -124.67 to -124.06 (ddd, J )
437.1, 43.71, 20.59 Hz, 1F); 13C NMR (75.5 MHz, acetone-d6)
δ 154.7 and 154.3, 118.9 (t, J ) 236.2 Hz) and 118.7 (t, J )
238.0 Hz), 87.3, 80.5 and 80.4, 77.0 (d, J ) 8.3 Hz) and 76.4
(d, J ) 9.3 Hz), 63.3 and 62.0, 59.0 and 58.9, 47.0 (t, J ) 23.1
Hz) and 46.0 (t, J ) 21.5 Hz), 28.6, 26.4, 26.0, 19.0, 18.6, -4.7,
-5.1, -5.3, -5.4, rotamers; IR (thin film) 3441, 2958, 1705,
1473, 1392, 1368, 1257, 1105, 1058, 838, 779 cm-1; MS (ESI)
m/z 550.2 (M + K+), 534.3 (M + Na+); HRMS-ESI m/z 534.2853
(M + Na+, C23H47F2NO5NaSi2 required 534.2853).
-5.2; IR (thin film) 2958, 1755, 1713, 1473, 1397, 838 cm-1
;
MS (ESI) m/z 554.2 (M + H+); ESI-HRMS m/z 576.2963 (M +
Na+, C25H49F2NO6NaSi2 required 576.2959).
1-[(2R,3R,4S,5S)-N-tert-Butyloxycarbonyl-3-tert-bu-
tyldimethylsilyloxy-4-difluoromethyl-5-(tert-butyldi-
methylsilyloxymethyl)pyrrolidin-2-yl]uracil (30a) and
1-[(2S,3R,4S,5S)-N-tert-Butyloxycarbonyl-3-tert-butyldi-
methylsilyloxy-4-difluoromethyl-5-(tert-butyldimethyl-
silyloxymethyl)pyrrolidin-2-yl]uracil (30b). To a stirred
solution of 28 (95 mg, 0.17 mmol) and uracil (60 mg, 0.54
mmol) in anhydrous acetonitrile (8 mL) was added N,O-bis-
(trimethylsilyl)acetamide (0.30 mL, 0.91 mmol). The reaction
mixture was stirred under reflux for 30 min. After the mixture
was cooled to 0 °C, TMSOTf (0.08 mL, 0.38 mmol) was added
dropwise and the solution was stirred at room temperature
for a further 30 min. The reaction was quenched with cold
saturated aqueous NaHCO3 (2 mL) and the resulting mixture
was extracted with CH2Cl2 (3 × 15 mL). The combined organic
phases were washed with brine and dried over anhydrous
Na2SO4. After removal of the solvent, the resulting residue
was purified by flash chromatography (hexane/ethyl acetate,
7:1) to give two compounds, the less polar compound 30a (7
mg, 7%, white foam) and the more polar compound 30b (70
(2S,3R,4S,5S)-N-tert-Butyloxycarbonyl-2-acetyloxy-3-
tert-butyldimethylsilyloxyl-4-difluoromethyl-5-(tert-bu-
tyldimethylsilyloxymethyl)pyrrolidine (28). To a -78 °C
solution of 24 (92 mg, 0.18 mmol) in THF (5 mL) was added
LiBEt3H (0.45 mL, 1 M in THF, 0.45 mmol) dropwise. The
mixture was then stirred at -78 °C for 1 h and the reaction
was quenched with H2O (2 mL) at -78 °C. After the mixture
was warmed to room temperature, H2O (10 mL) was added
and the mixture was extracted with Et2O (3 × 15 mL). The
combined organic phases were washed with brine and dried
over anhydrous Na2SO4. After filtration and removal of the
solvent, the resulting residue was purified by flash chroma-
tography (hexane/ethyl acetate, 20:1) to afford a clear oil (92
mg), which was solved in CH2Cl2 (9 mL). Then, to this resulting
solution was added DMAP (17 mg, 0.14 mmol) and Et3N (0.97
mL, 6.9 mmol), followed by Ac2O (0.35 mL, 3.70 mmol)
dropwise. The mixture was stirred at room temperature for 2
h and the reaction was quenched with H2O (2 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The
combined organic phases were washed with brine and dried
over anhydrous Na2SO4. After filtration and removal of the
mg, 67%, white foam). Compound 30a: [R]25 -60.2 (c 0.30,
D
acetone); 1H NMR (300 MHz, acetone-d6) δ 10.09 (s, 1H), 7.98
(d, J ) 7.8 Hz, 1H), 6.24 (td, J ) 55.4, 6.5 Hz, 1H), 5.99 (d, J
J. Org. Chem, Vol. 70, No. 10, 2005 3835

Qiu and Qing
) 6.9 Hz, 1H), 5.71 (d, J ) 7.5 Hz, 1H), 4.65 (dd, J ) 6.6, 6.9
Hz, 1H), 4.19 (t, J ) 10.8 Hz, 2H), 3.87 (d, J ) 10.8 Hz, 1H),
3.16-2.98 (m, 1H), 1.36 (s, 9H), 1.00 (s, 9H), 0.86 (s, 9H), 0.21,
0.05, -0.07 (3s, 12H); 19F NMR (282 MHz, acetone-d6) δ
-114.75 to -116.14 (m, 1F), -117.48 to -118.79 (m, 1F);
13C NMR (100.0 MHz, acetone-d6) δ 163.2, 154.3, 151.8,
140.6, 117.1 (t, J ) 239.68 Hz), 103.1, 81.6, 75.1, 73.6, 63.3,
58.7, 49.0 (t, J ) 20.5 Hz), 28.3, 26.5, 25.9, 19.0, 18.2, -4.5,
-4.9, -5.1, -5.7; IR (thin film) 3202, 3071, 2958, 1699, 1635,
1463, 1370, 1259, 1164, 839 cm-1; MS (ESI) m/z 628.3 (M +
Na+), 606.3 (M + H+); ESI-HRMS m/z 606.3199 (M + H+,
were prepared as white foams from compound 29a (54 mg,
0.098 mmol) and thymine (38 mg, 0.30 mmol), using the same
conditions as described for compounds 30a and 30b. Com-
pound 32a: [R]20D -56.1 (c 0.49, acetone); 1H NMR (300 MHz,
acetone-d6) δ 10.06 (s, 1H), 7.64 (s, 1H), 6.27 (td, J ) 56.0, 3.6
Hz, 1H), 5.85 (br, 1H), 4.73 (t, J ) 5.4 Hz, 1H), 4.33 (d, J )
10.8 Hz, 1H), 4.25-4.22 (m, 1H), 3.83 (dd, J ) 2.1, 2.4 Hz,
1H), 2.84-2.81 (m, 1H), 1.88 (s, 3H), 1.39 (s, 9H), 0.98, 0.90
(2s, 18H), 0.19, 0.13 (2s, 12H); 19F NMR (282 MHz, acetone-
d6) δ -121.91 to -123.08 (dd, J ) 33.0, 54.71 Hz, 1F), -126.64
to -127.89 (m, 1F); 13C NMR (75.5 MHz, acetone-d6) δ 164.2,
155.0, 151.7, 136.2, 117.4 (t, J ) 239.8 Hz), 110.4, 81.8, 76.2,
75.2, 64.2, 59.0, 46.0 (t, J ) 20.6 Hz), 28.2, 26.5, 26.0, 19.2,
18.5, 12.9, -4.6, -4.8, -5.1, -5.2; IR (thin film) 3192, 3060,
2957, 2933, 1694, 1472, 1370, 1258, 1147, 1107, 838 cm-1; MS
(ESI) m/z 642.3 (M + Na+), 620.3 (M + H+); ESI-HRMS m/z
C27H50F2N3O6Si2 required 606.3201). Compound 30b: [R]20
D
+7.2 (c 0.65, acetone); 1H NMR (300 MHz, acetone-d6) δ 10.12
(s, 1H), 7.61 (d, J ) 8.1 Hz, 1H), 6.40 (d, J ) 6.6 Hz, 1H), 6.21
(td, J ) 55.5, 6.6 Hz, 1H), 5.60 (d, J ) 7.8 Hz, 1H), 4.95 (t, J
) 8.6 Hz, 1H), 4.30 (d, J ) 5.7 Hz, 1H), 4.20 (d, J ) 11.4 Hz,
1H), 3.68 (d, J ) 11.4 Hz, 1H), 3.11-2.95 (m, 1H), 1.37 (s,
9H), 0.97, 0.81 (2s, 18H), 0.13, 0.12, 0.10, 0.06 (4s, 12H); 19F
NMR (282 MHz, acetone-d6) δ -113.70 to -115.00 (ddd, J )
298.2, 12.1, 11.7 Hz, 1F), -117.73 to -119.03 (ddd, J ) 297.9,
13.0, 11.7 Hz, 1F); 13C NMR (75.5 MHz, acetone-d6) δ 163.2,
153.0, 151.9, 142.4, 118.0 (t, J ) 240.2 Hz), 102.1, 81.7, 71.6
and 71.5, 68.4, 60.3, 58.0 and 57.9, 50.5 (t, J ) 20.3 Hz), 28.4,
26.3, 25.9, 18.7, 18.2, -4.5, -5.0, -5.3, -5.5, rotamers; IR (thin
620.3363 (M + H+, C28H52F2N3O6Si2 required 620.3357).
1
Compound 32b: [R]20 -42.2 (c 0.61, acetone); H NMR (300
D
MHz, MeOH-d4) δ 7.25 (s, 1H), 6.26 (d, J ) 6.9 Hz, 1H),
6.12 (t, J ) 55.8 Hz, 1H), 4.88 (t, J ) 8.1 Hz, 1H), 4.56-4.30
(m, 2H), 3.48 (d, J ) 9.9 Hz, 1H), 2.96-2.77 (m, 1H), 1.85
(s, 3H), 1.33 (s, 9H), 0.94, 0.83 (2s, 18H), 0.12, 0.10, 0.09,
0.01 (4s, 12H); 19F NMR (282 MHz, MeOH-d4) δ -118.13 to
-119.38 (ddd, J ) 287.6, 9.3, 9.7 Hz, 1F), -124.4 to -125.7
(ddd, J ) 287.2, 24.3, 22.0 Hz, 1F); 13C NMR (75.5 MHz,
MeOH-d4) δ 116.3, 154.2, 152.8, 139.5, 117.0 (t, J ) 239.7
Hz), 110.2, 82.8, 71.9, 71.1, 63.7, 59.1, 48.7 (t, J ) 21.7 Hz),
28.5, 26.4, 26.1, 19.0, 18.7, 12.5, -5.0,-5.2, -5.3, -5.4; IR
(thin film) 3194, 3060, 2957, 2932, 2860, 1693, 1473, 1369,
1259, 1148, 838, 780 cm-1; MS (ESI) m/z 620.0 (M + H+); ESI-
HRMS m/z 642.3179 (M + Na+, C28H51F2N3O6NaSi2 required
642.3177).
film) 3190, 2958, 1701, 1629, 1368, 1259, 1137, 838, 780 cm-1
;
MS (ESI) m/z 628.3 (M + Na+), 606.3 (M + H+); ESI-HRMS
m/z 628.3025 (M + Na+, C27H49F2N3O6NaSi2 required 628.3020).
1-[(2R,3R,4R,5S)-N-tert-Butyloxycarbonyl-3-tert-bu-
tyldimethylsilyloxy-4-difluoromethyl-5-(tert-butyldi-
methylsilyloxymethyl)pyrrolidin-2-yl]uracil (31a) and
1-[(2S,3R,4R,5S)-N-tert-Butyloxycarbonyl-3-tert-butyldi-
methylsilyloxy-4-difluoromethyl-5-(tert-butyldimethyl-
silyloxymethyl)pyrrolidin-2-yl]uracil (31b). Compounds
31a (49 mg, less polar, 77%) and 31b (8 mg, more polar, 13%)
were prepared as white foams from compound 29a (58 mg,
0.10 mmol) and uracil (37 mg, 0.33 mmol), using the same
conditions as described for compounds 30a and 30b. Com-
pound 31a: [R]20D -43.0 (c 0.83, acetone); 1H NMR (300 MHz,
acetone-d6) δ 10.15 (s, 1H), 8.14 (d, J ) 8.4 Hz, 1H), 6.14 (td,
J ) 55.8, 5.1 Hz, 1H), 5.87 (br, 1H), 5.56 (d, J ) 7.2 Hz, 1H),
4.63-4.60 (m, 1H), 4.52 (d, J ) 10.8 Hz, 1H), 4.23 (d, J ) 7.5
Hz, 1H), 3.82 (d, J ) 11.1 Hz, 1H), 2.95-2.82 (m, 1H), 1.42 (s,
9H), 0.97, 0.91 (2s, 18H), 0.22-0.15 (m, 12H); 19F NMR (282
MHz, acetone-d6) δ -117.05 to -120.02 (m, 1F), -124.25 to
-126.31 (m, 1F); 13C NMR (75.5 MHz, acetone-d6) δ 163.7,
155.0, 151.9, 140.9, 117.9 (t, J ) 239.3 Hz), 102.1, 82.1, 76.9,
75.7, 63.1, 60.0, 46.0 (t, J ) 20.5 Hz), 28.4, 26.5, 26.2, 19.3,
18.7, -4.4, -5.0, -5.1, -5.3; IR (thin film) 2933, 1712, 1676,
1373, 1334, 1257, 1148, 1111, 836 cm-1; MS (ESI) m/z 628.3
(M + Na+), 606.2 (M + H+); ESI-MALDI m/z 628.3033 (M +
Na+, C27H49F2N3O6NaSi2 required 628.3020). Compound 31b:
[R]20D -48.7 (c 0.35, acetone); 1H NMR (300 MHz, acetone-d6)
δ 10.03 (s, 1H), 7.42 (d, J ) 5.7 Hz, 1H), 6.31-6.29 (br, 1H),
6.20 (t, J ) 55.2 Hz, 1H), 5.64 (d, J ) 6.9 Hz, 1H), 4.96 (t, J
) 8.1 Hz, 1H), 4.35 (br, 2H), 3.58-3.52 (m, 1H), 3.06-2.88
(m, 1H), 1.36 (s, 9H), 0.93, 0.86 (2s, 18H), 0.16, 0.12, 0.11, 0.06
(4s, 12H); 19F NMR (282 MHz, acetone-d6) δ -116.88 to
-118.10 (m, 1F), -122.99 to -124.31 (ddd, J ) 290.9, 18.9,
17.8 Hz, 1F); 13C NMR (75.5 MHz, acetone-d6) δ 163.4, 153.1,
151.8, 142.1, 116.7 (t, J ) 238.6 Hz), 101.4, 81.6, 71.5, 70.5,
63.3, 58.6, 48.2, 28.3, 26.2, 26.0, 18.6, 18.4, -5.0, -5.4; IR (thin
film) 3200, 3065, 2956, 2931, 2860, 1699, 1630, 1471, 1464,
1368, 1259, 1147, 839, 780 cm-1; MS (ESI) m/z 628.3 (M +
Na+), 606.3 (M + H+); ESI-HRMS m/z 606.3209 (M + H+,
C27H50F2N3O6Si2 required 606.3201).
1-[(2R,3R,4R,5S)-N-tert-Butyloxycarbonyl-3-hydroxy-
4-difluoromethyl-5-(hydroxymethyl)pyrrolidin-2-yl]-
uracil (33). To a 0 °C solution of 31a (40 mg, 0.066 mmol) in
THF (10 mL) was added TBAF (0.16 mL, 1 M in THF, 0.16
mmol) dropwise. The mixture was stirred at room temperature
for 1.5 h and the reaction was quenched with H2O (10 mL).
Then, the mixture was extracted with EtOAc (3 × 20 mL).
The combined organic phases were washed with brine and
dried over anhydrous Na2SO4. After removal of the solvent,
the resulting residue was purified by flash chromatography
(hexane/ethyl acetate, 1:2.5) to give 33 as a white foam (20
mg, 80%). [R]20 -87.4 (c 0.46, H2O); 1H NMR (300 MHz,
D
MeOH-d4) δ 8.35 (d, J ) 8.4 Hz, 1H), 6.21 (td, J ) 56.03, 3.3
Hz, 1H), 5.84 (br, 1H), 5.67 (d, J ) 5.7 Hz, 1H), 4.50 (br, 1H),
4.21-4.13 (m, 2H), 3.63 (d, J ) 11.1 Hz, 1H), 2.87-2.70 (m,
1H), 1.39 (s, 9H); 19F NMR (282 MHz, MeOH-d4) δ -119.87 to
-123.53 (m, 1F), -126.94 to -129.31 (m, 1F); 13C NMR (75.5
MHz, MeOH-d4) δ 166.3, 155.8, 152.7, 142.7, 117.8 (t, J ) 238.4
Hz), 102.3, 83.0, 77.2, 74.7, 62.2, 59.8, 46.3 (t, J ) 20.8 Hz),
28.5; IR (thin film) 3398, 2925, 2854, 1704, 1472, 1396, 1371,
1085, 808 cm-1; MS (ESI) m/z 777.3 (2M + Na+), 755.2 (2M +
H+), 400.0 (M + Na+); ESI-HRMS m/z 400.1282 (M + Na+,
C15H21F2N3O6Na required 400.1291).
1-[(2R,3R,4R,5S)-N-tert-butyloxycarbonyl-3-hydroxy-
4-difluoromethyl-5-(hydroxymethyl)pyrrolidin-2-yl]-
thymine (34a). Compound 34a (14 mg, 74%) was prepared
as a white foam from compound 32a (30 mg, 0.049 mmol),
using the same conditions as described for compound 33. [R]20
D
1
-78.5 (c 0.43, MeOH); H NMR (300 MHz, MeOH-d4) δ 8.26
(s, 1H), 6.20 (td, J ) 55.9, 3.6 Hz, 1H), 5.83 (br, 1H), 4.50-
4.47 (br, 1H), 4.23 (d, J ) 11.7 Hz, 1H), 4.13-4.10 (m, 1H),
3.65 (d, J ) 10.8 Hz, 1H), 2.87-2.72 (m, 1H), 1.86 (s, 3H),
1.39 (s, 9H); 19F NMR (282 MHz, MeOH-d4) δ -119.73 to
-123.38 (m, 1F), -126.87 to -129.15 (m, 1F); 13C NMR (75.5
MHz, MeOH-d4) δ 166.6, 155.9, 152.8, 138.6, 117.8 (t, J ) 239.5
Hz), 111.1, 83.1, 77.0, 74.6, 62.2, 59.9, 46.3 (t, J ) 20.9 Hz),
28.5, 12.4; IR (thin film) 3459, 3061, 3000, 2940, 1712, 1678,
1660, 1636, 1475, 1385, 1226, 1088, 773 cm-1; MS (ESI) m/z
430.3 (M + K+), 414.2 (M + Na+); ESI-HRMS m/z 414.1438
(M + Na+, C16H23F2N3O6Na required 414.1447).
1-[(2R,3R,4R,5S)-N-tert-Butyloxycarbonyl-3-tert-bu-
tyldimethylsilyloxy-4-difluoromethyl-5-(tert-butyldi-
methylsilyloxymethyl)pyrrolidin-2-yl]thymine (32a) and
1-[(2S,3R,4R,5S)-N-tert-Butyloxycarbonyl-3-tert-butyldi-
methylsilyloxy-4-difluoromethyl-5-(tert-butyldimethyl-
silyloxymethyl)pyrrolidin-2-yl]thymine (32b). Compounds
32a (30 mg, less polar, 49%) and 32b (19 mg, more polar, 31%)
3836 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of 3′-Deoxy-3′-difluoromethyl Azanucleosides
1-[(2S,3R,4R,5S)-N-tert-Butyloxycarbonyl-3-hydroxy-
4-difluoromethyl-5-(hydroxymethyl)pyrrolidin-2-yl]-
thymine (34b). Compound 34b (22 mg, 63%) was prepared
as a white foam from compound 32b (55 mg, 0.089 mmol),
4.22 (m, 1H), 4.10-4.00 (m, 1H), 3.60-3.52 (m, 1H), 2.80-
2.68 (m, 1H), 1.46, 1.36 (2s, 9H); 19F NMR (282 MHz, MeOH-
d4) δ -113.74 to -115.36 (m, 1F), -120.49 to -122.04 (m, 1F);
13C NMR (75.5 MHz, MeOH-d4) δ 166.3, 154.0, 152.9, 143.1,
118.7 (t, J ) 240.2 Hz), 102.2, 82.7, 70.9 and 70.8, 70.3, 60.3,
59.1, 50.2 (t, J ) 18.3 Hz), 28.5, rotamers; IR (thin film) 3589,
using the same conditions as described for compound 33. [R]20
D
1
-28.6 (c 0.79, MeOH); H NMR (300 MHz, MeOH-d4) δ 7.29
3523, 3318, 3043, 1702, 1660, 1631, 1481, 1389, 1240 cm-1
;
(s, 1H), 6.19-6.15 (br, 1H), 6.18 (td, J ) 56.1, 5.4 Hz, 1H),
4.54 (br, 1H), 4.36-4.26 (m, 1H), 4.21 (d, J ) 6.0 Hz, 1H), 3.48
(d, J ) 11.7 Hz, 1H), 2.95-2.79 (m, 1H), 1.87 (s, 3H), 1.34 (s,
9H); 19F NMR (282 MHz, MeOH-d4) δ -118.01 to -119.24 (dd,
J ) 15.3, 15.2 Hz, 1F), -124.54 to -125.84 (ddd, J ) 292.22,
15.23, 15.79 Hz, 1F); 13C NMR (75.5 MHz, MeOH-d4) δ 166.5,
154.5, 152.9, 140.1, 118.1 (t, J ) 238.4 Hz), 109.6, 82.6, 72.5,
70.0, 60.8, 60.2, 47.0, 28.5, 12.4; IR (thin film) 3396, 2928, 1691,
1477, 1370, 1264, 1145, 776 cm-1; MS (ESI) m/z 430.2 (M +
K+), 414.3 (M + Na+), 392.3 (M + H+); ESI-HRMS m/z
414.1439 (M + Na+, C16H23F2N3O6Na required 414.1447).
1-[(2S,3R,4S,5S)-N-tert-Butyloxycarbonyl-3-hydroxy-4-
difluoromethyl-5-(hydroxymethyl)pyrrolidin-2-yl]-
uracil (35). Compound 35 (36 mg, 85%) was prepared as a
white foam from compound 30b (68 mg, 0.11 mmol), using the
MS (ESI) m/z 777.3 (2M + Na+), 755.3 (2M + H+), 628.3 (M +
Na+), 400.2 (M + Na+); ESI-HRMS m/z 400.1293 (M + Na+,
C15H21F2N3O6Na required 400.1291).
Acknowledgment. We thank the National Natural
Science Foundation of China (Nos. 20325210 and
20472105), Ministry of Education of China, and Shang-
hai Municipal Scientific Committee for funding this
work.
Supporting Information Available: Crystallographic
data (CIF) and ORTEP drawing for the compounds 21 and 30a;
1
copies of H NMR and 13C NMR spectra of compounds 4, 5,
same conditions as described for compound 33. [R]25 +2.8 (c
D
and 8-35. This material is available free of charge via the
0.97, MeOH); 1H NMR (300 MHz, MeOH-d4) δ 7.56 (d, J )
7.5 Hz, 1H), 6.30 (d, J ) 6.3 Hz, 1H), 6.19 (td, J ) 55.9, 6.6
Hz, 1H), 5.70 (d, J ) 8.1 Hz, 1H), 4.88-4.82 (m, 1H), 4.25-
Internet at http://pubs.acs.org.
JO050057+
J. Org. Chem, Vol. 70, No. 10, 2005 3837