Synthesis of 2′,3′-dideoxy-2′-trifluoromethyl-N-azanucleosides

Article abstract of DOI:10.1135/cccc20021267

The trifluoromethylation of (Z)/(E)-tert-butyl (4S)-4-(2′-ethoxycarbonyl-2′-bromoprop-1′-enyl)-2,2- dimethyloxazolidine-3-carboxylate (4), which is derived from chiral serine aldehyde, yields α-trifluoromethyl-α,β-unsaturated ester 1. Compound 1 is used as a key intermediate for the synthesis of a number of 2′,3′-dideoxy-2′-trifluoromethyl-N-azanucleosides.

Full text of DOI:10.1135/cccc20021267

2′,3′-Dideoxy-2′-trifluoromethyl-N-azanucleosides
1267
SYNTHESIS OF 2′,3′-DIDEOXY-2′-TRIFLUOROMETHYL-N-AZANUCLEOSIDES
a,
b
b
Feng-Ling QING *, Jiang YU and Xiang-Kai FU
a
College of Chemistry and Chemical Engineering, Donghua University, 1882 West Yanan Lu,
Shanghai 200051, China; e-mail: flq@pub.sioc.ac.cn
College of Chemistry and Chemical Engineering, Southwest Normal University, Beibei,
Chongqing, 400715, China
b
Received March 19, 2002
Accepted July 25, 2002
Dedicated to the memory of Professor Miloš Hudlický.
Th e trifluorom eth ylation of (Z)/(E)-tert-butyl (4S)-4-(2′-eth oxycarbon yl-2′-brom oprop-1′-en yl)-
2,2-dim eth yloxazolidin e-3-carboxylate (4), wh ich is derived from ch iral serin e aldeh yde,
yields α-trifluorom eth yl-α,β-un saturated ester 1. Com poun d 1 is used as a key in term ediate
for th e syn th esis of a n um ber of 2′,3′-dideoxy-2′-trifluorom eth yl-N-azan ucleosides.
Keyw ord s: Trifluorom eth ylation ; α-Trifluorom eth yl-α,β-un saturated ester; Nucleosides;
Azan ucleosides; Am in osugars; An tivirals; Fluorin ated com poun ds.
Th e n eed for n ew an tiviral an d an tican cer agen ts h as led to th e discovery of
a class of m odified n ucleosides1. In particular, sugar-m odified derivatives
h ave proved to be of curren t in terest for th e use of can cer an d viral ch em o-
th erapy2. Azan ucleosides, in wh ich th e pyran ose or furan ose rin g oxygen is
replaced by n itrogen , are an im portan t class of m odified n ucleosides3. Th e
in troduction of a fluorin e atom in to th e sugar m oiety of som e n ucleosides
resulted in com poun ds with a broad spectrum of an tiviral an d an tican cer
activity4. Sin ce fluorin e an d trifluorom eth yl groups h ave sim ilar in ductive
effects, σ = 0.5 an d 0.45, respectively, we were in terested in in corporation a
trifluorom eth yl group at th e 2′ position of th e sugar rin g. Alth ough
m on ofluorin ated5 an d gem-difluorin ated6 sugar n ucleosides h ave been
widely studied, on ly a few trifluorom eth ylated sugar n ucleosides h ave been
reported, wh ich is probably due to th e sh ortcom in gs of existin g syn th etic
m eth ods. To our kn owledge, th ere is n o report on th e fluorin ated
azan ucleoside. In th is article, we describe a n ovel an d gen eral route to
2′,3′-dideoxy-2′-trifluorom eth yl-N-azan ucleosides.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)
doi:10.1135/cccc20021267

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Qing, Yu, Fu:
RESULTS AND DISCUSSION
α-Trifluorom eth yl-α,β-un saturated ester 1, prepared from ch iral serin e alde-
h yde7 2 (Sch em e 1), was used as th e key in term ediate for th e preparation of
2′,3′-dideoxy-2′-trifluorom eth yl-N-azan ucleosides. Th e Wittig reaction of al-
deh yde 2 with ylide 3 provided th e Z isom er of α-brom o-α,β-un saturated
ester 4 as th e m ajor product (Z : E = 92 : 8) in 93% yield. Th e treatm en t of 4
with FSO2CF2CO2Me an d CuI in DMF/HMPA gave a 76 : 24 m ixture of Z-
an d E-1 in 62% isolated yield8.
CO2C2H5
CHO
NBoc
Br
NBoc
Br
CO2C2H5
PPh3
O
O
+
2
3
4, Z : E = 92 : 8
FSO2CF2CO2CH3
CuI, DMF/HMPA
CO2C2H5
CF3
O
NBoc
1, Z : E = 76 : 24
SCHEME 1
Due to difficulties in separation of (Z)-1 an d (E)-1 isom ers, th e m ixture
was directly used in th e n ext reaction (Sch em e 2). Hydrogen ation of 1 in
the presence of 10% Pd/C afforded 5 as a mixture of the C-2 epimers (syn : anti =
3.9 : 1, determ in ed by 19F NMR spectrum ) in 95% yield. Treatm en t of 5
with citric acid in m eth an ol at 60 °C provided alcoh ol 6 in 58% yield.
Protection of the hydroxyl group with tert-butyldimethylsilyl chloride (TBDMSCl)
CO2C2H5
H2, Pd/C
CO2C2H5
Citric acid / MeOH
CO2C2H5
CF3
CF3
NBoc
CF3
NHBoc
O
O
HO
6
1
5
TBDMSCl
Pyridine / CH2Cl2
Boc
Boc
N
TBDMSO
TBDMSO
CO2C2H5
CF3
N
TBDMSO
DIBAL-H
OH
OH
+
NBoc
CH2Cl2, -78 oC
CF3
CF3
7
8a
8b
SCHEME 2
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2′,3′-Dideoxy-2′-trifluoromethyl-N-azanucleosides
1269
gave 7 in 92% yield. Th e cyclized acetal 8a an d 8b were obtain ed via in tra-
m olecular n ucleoph ilic addition by reduction of com poun d 7 with diiso-
butylalum in u m h ydride (DIBAL-H) in an h ydrou s CH2Cl2 at –78 °C.
Com poun ds 8a an d 8b were separated in a ratio of 4.6 : 1 by colum n ch ro-
m atograph y on silica gel. 8a was th e sin gle α an om er an d used for th e syn -
th esis of 2′,3′-dideoxy-2′-trifluorom eth yl-N-azan ucleosides, wh ereas 8b was
a m ixture of α an d β an om ers.
Th e acetylation of 8a with acetic an h ydride in CH2Cl2 yielded th e sin gle
α an om eric acetate 9. Couplin g of 9 with silylated uracil an d th ym in e un -
der Vorbruggen con dition s9 (glycosylation reaction ) provided exclusively
th e α an om ers 10 an d 11, respectively (Sch em e 3). Th e rem oval of th e silyl
group with TBAF gave 2′,3′-dideoxy-2′-trifluorom eth yl-N-azan ucleosides 12
Boc
N
Boc
N
TBDMSO
TBDMSO
OH
OAc
Ac2O / DMAP
CF3
CF3
8a
9
silylated uracil
or
TMSOTf
silylated thymine
R
R
O
O
Boc
N
Boc
HO
TBDMSO
N
N
NH
TBAF
N
NH
O
O
CF3
CF3
12, R = H
10, R = H
13, R = CH3
11, R = CH3
SCHEME 3
an d 13. Sim ilarly, 9 was con den sed with silylated cytosin e afforded a 2 : 1
m ixture of α an d β an om er of 14 (Sch em e 4). Th e α an d β an om er of 14
could n ot be separated. Ben zoylation of th e am in o group of 14, followed by
rem oval of th e silyl group gave 15 an d 16, wh ich were readily separated by
colum n ch rom atograph y on silica gel. Treatm en t of 15 an d 16 with a
saturated solution of am m onium in m ethanol afforded 2′,3′-dideoxy-2′-tri-
fluoromethyl-N-azan ucleosides 17 an d 18, respectively.
Th e con figuration assign m en ts of th e an om eric cen ter were m ade on th e
basis of 1D an d 2D NMR spectroscopy. Th e con figuration of th e CF3 was as-
sign ed m ain ly by 19F NMR spectrum , in wh ich th e CF3 at lower field was as-
sign ed as th e α-trifluorom eth yl isom er an d th e on e at h igh er field were
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Qing, Yu, Fu:
NH2
Boc
N
Boc
N
TBDMSO
TBDMSO
OAc
N
N
silylated cytosine
TMSOTf
O
CF3
CF3
9
14
(PhCO)2O
NHBz
Boc
N
TBDMSO
N
N
O
CF3
TBAF
NHBz
NHBz
N
Boc
Boc
N
HO
HO
N
N
N
N
+
O
O
CF3
CF3
15
16
satd NH3/MeOH
satd NH3/MeOH
NH2
NH2
Boc
N
Boc
HO
HO
N
N
N
N
N
O
O
CF3
CF3
17
18
SCHEME 4
assign ed as th e β isom er. Th is assign m en t was furth er con firm ed by th e
NOESY experim en t of 17 an d 18 (Fig. 1). Com poun ds 12, 13, 17, an d 18
are a class of “reverse n ucleosides” 10, en an tiom ers of n orm al n ucleosides.
NH2
NH2
Boc
N
F3C
Boc
N
F3C
H
N
H
N
HO
N
H
N
HO
O
H
O
H
H
17
18
FIG. 1
NOE correlation from NOESY spectra of 17 an d 18
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2′,3′-Dideoxy-2′-trifluoromethyl-N-azanucleosides
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EXPERIMENTAL
1H NMR spectra were recorded on eith er a Bruker AM300 (300 MHz) or a Bruker AM400
(400 MHz) spectrom eter, with TMS as in tern al stan dard.19F NMR spectra were recorded on
eith er an EM-360L (56.4 MHz) or a Bruker AM300 (282 MHz) spectrom eter, with CF3COOH
as th e extern al stan dard an d upfield is positive. Ch em ical sh ifts are given in ppm (δ-scale),
couplin g con stan ts (J) in Hz. IR spectra (waven um bers in cm –1) were recorded on
a
Sh im adzu IR-440 Spectrom eter. Th e m ass spectra were recorded on a Fin n igan -MAT-8430
m ass spectrom eter usin g EI ion ization at 70 eV.
Eth yl (Z)/(E)-2-Brom o-3-[(S)-3-(tert-butoxycarbon yl)-2,2-dim eth yloxazolidin -4-yl]-
acrylate (4)
A solution of triph en ylcarbeth oxybrom om eth ylen eph osph oran e (3; 37.5 g, 87.7 m m ol) an d
(S)-Garn er’s aldeh yde 2 (20.0 g, 87.7 m m ol) in dich lorom eth an e (350 m l) was h eated un der
reflux with stirrin g for 24 h . After th e solven t was rem oved, th e residue was refluxed for
30 m in with a m ixture of h exan e–eth yl acetate (6 : 1, 100 m l). Th e procedure was repeated
th ree tim es, th e com bin ed extracts were filtered, an d th e filtrate was con cen trated to yield a
yellow oil. Th e oil was purified by colum n ch rom atograph y on silica gel (h exan e– eth yl acetate
20 : 1) to give 30.9 g (93%) of (Z)/(E)-4 (92 : 8, by 1H NMR) as a ligh t am ber oil. 1H NMR
(300 MHz,CD3COCD3): 7.26 (d, J = 7.8, 0.93 H); 6.77 (d, J = 7.8, 0.07 H); 5.11–4.76 (m , 1 H);
4.71–4.29 (m , 3 H); 3.87–3.80 (m , 1 H); 1.59–1.30 (m , 18 H). IR (th in film ): 2 982, 1 705, 1
616. MS, m/z: 380 (M+ + 1, 1), 57 (100). For C15H24BrNO5 (378.3) calculated: 47.63% C,
6.40% H, 3.70% N; foun d: 47.44% C, 6.505% H, 3.78% N.
Eth yl (Z)/(E)-3-[(S)-3-(tert-Butoxycarbon yl)-2,2-dim eth yloxazolidin -4-yl]-2-(trifluorom eth yl)-
acrylate (1)
To a solution of 4 (24.9 g, 66.1 m m ol) in an h ydrous DMF (210 m l) an d HMPA (35 m l) was
added CuI (3.16 g, 16.5 m m ol). Th en th e m ixture was h eated to 75 °C, an d a solution of
FSO2CF2CO2Me (26.4 m l, 231.5 m m ol) in DMF (35 m l) was added via syrin ge over a period
of 12 h . After stirrin g at 75 °C for 30 h , th e reaction m ixture was treated with saturated
aqueous NH4Cl an d was filtered. Th e filtrate was extracted with dieth yl eth er. Th en organ ic
layer was wash ed with brin e, dried over Na2SO4 an d con cen trated. Th e residue was purified
by colum n ch rom atograph y on silica gel (h exan e–eth yl acetate 25 : 1) to give a m ixture of
14.1 g (62%) of (Z)/(E)-1 (76 : 24, by 19F NMR) as an am ber oil. 1H NMR (300 MHz,
CD3COCD3): 7.21 (d, J = 8.7, 0.67 H); 6.94 (d, J = 8.4, 0.33 H); 5.19–4.97 (m , 1 H); 4.36–4.26
(m , 3 H); 3.91–3.85 (m , 1 H); 1.61–1.20 (m , 18 H). 19F NMR (56.4 MHz, CDCl3): –18.0 (s,
2.27 F); –12.5 (s, 0.73 F). IR (th in film ): 2 984, 1 735, 1 710. MS, m/z: 380 (M+ + 1, 2), 57
(100). For C16H24F3NO5 (367.4) calculated: 52.31% C, 6.59% H, 3.81% N; foun d: 52.42% C,
6.58% H, 4.07% N.
Eth yl 3-[(S)-3-(tert-Butoxycarbon yl)-2,2-dim eth yloxazolidin -4-yl]-2-(trifluorom eth yl)-
propan oate (5)
10% of Pd/C (1.46 g, 1.37 m m ol) was added to a solution of (Z)/(E)-1 (7.20 g, 19.62 m m ol)
in eth yl acetate (150 m l) at room tem perature un der 1 atm of h ydrogen . After stirrin g for 5 h ,
th e reaction m ixture was filtered, an d th e solven t was rem oved to give th e crude oil. Th is oil
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Qing, Yu, Fu:
was purified by colum n ch rom atograph y on silica gel (h exan e–eth yl acetate 10 : 1) to afford
6.88 g (95%) of 5 as a colorless oil. 1H NMR (300 MHz, CD3COCD3): 4.24–4.28 (m , 2 H);
4.02–4.06 (m , 2 H); 3.77 (m , 1 H); 3.44 (m , 1 H); 2.19 (m , 2 H); 1.28–1.55 (m , 18 H). 19F NMR
(282 MHz, CD3COCD3): –13.7 (d, J = 8.2); –12.9 (d, J = 8.4). IR (th in film ): 2 984, 2 941,
2 881, 1 749, 1 702. MS, m/z: 370 (M+ + 1, 2); 254 (60), 57 (100). For C16H26F3NO5 (369.4)
calculated: 52.02% C, 7.10% H, 3.79% N; foun d: 52.22% C, 7.14% H, 3.88% N.
Eth yl 4-[(tert-Butoxycarbon yl)am in o]-5-h ydroxy-2-(trifluorom eth yl)pen tan oate (6)
A m ixture of 5 (6.93 g, 18.8 m m ol), 5% aqueous citric acid solution (50 m l) an d m eth an ol
(100 m l) was stirred at 60 °C for 4 h . Th en th e solven t an d water were rem oved un der re-
duced pressure. Th e residue was purified by colum n ch rom atograph y on silica gel (h exan e–
eth yl acetate 3 : 1) to give 3.58 g (58%) of th e alcoh ol 6 as a colorless oil. 1H NMR (300
MHz, CD3COCD3): 4.19–4.34 (m , 2 H); 3.39–3.63 (m , 4 H); 2.23 (m , 1 H); 1.88 (m , 1 H);
1.24–1.41 (m , 12 H). 19F NMR (282 MHz, CD3COCD3): –13.3 (d, J = 8.4); –13.0 (d, J = 8.2).
IR (th in film ): 3 385, 2 983, 2 940, 1 748, 1 691. MS, m/z: 330 (M+ + 1, 5), 230 (56), 57 (100).
For C13H22F3NO5 (329.3): 47.41% C, 6.73% H, 4.25% N; foun d: 47.46% C, 6.76% H, 4.20% N.
Eth yl 4-[(tert-Butoxycarbon yl)am in o]-5-(tert-butyldim eth ylsilyloxy)-2-(trifluorom eth yl)-
pen tan oate (7)
To
a solution of th e alcoh ol 6 (3.54 g, 10.76 m m ol) in CH2Cl2 (40 m l) was added
tert-butyldim eth ylsilyl ch loride (3.23 g, 21.52 m m ol) an d im idazole (2.19 g, 32.28 m m ol).
After bein g stirred for 2 h at room tem perature, th e reaction m ixture was poured on to water.
Th e organ ic layer was wash ed with brin e, dried over an h ydrous Na2SO4 an d con cen trated to
give a yellowish oil. Th e oil was purified by colum n ch rom atograph y on silica gel (h exan e–
eth yl acetate 8 : 1) to give 4.37 g (92%) of com poun d 7. 1H NMR (300 MHz, CD3COCD3):
4.24 (q, J = 7.1, 2 H); 3.59–3.69 (m , 3 H); 3.44 (m , 1 H); 2.20 (m ,1 H); 1.90 (m , 1 H); 1.41 (s,
9 H); 1.28 (t, J = 7.1, 3 H); 0.91 (s, 9 H); 0.09 (s, 6 H). 19F NMR (282 MHz, CD3COCD3):
–13.2 (s); –13.9 (s). IR (th in film ): 3 448, 3 382, 2 980, 2 959, 2 933, 2 861, 1 750, 1 720. MS,
m/z: 444 (M+ + 1, 3), 344 (82), 57 (100). For C19H36F3NO5Si: (443.6) calculated: 51.44% C,
8.18% H, 3.16% N; foun d: 51.23% C, 8.15% H, 3.10% N.
tert-Butyl (2R,3S,5R)-2-Hydroxy-5-[(tert-butyldim eth ylsilyloxy)m eth yl]-3-(trifluorom eth yl)-
pyrrolidin e-1-carboxylate (8a) an d
tert-Butyl (2R,3R,5R)-2-Hydroxy-5-[(tert-butyldim eth ylsilyloxy)m eth yl]-3-(trifluorom eth yl)-
pyrrolidin e-1-carboxylate (8b)
A solution of 7 (4.35 g, 9.19 m m ol) in an h ydrous dich lorom eth an e (100 m l) was cooled to
–78 °C, an d a 1.0 M solution of DIBAL-H in cycloh exan e (29.46 m l, 29.46 m m ol) was added
dropwise over a period of 1 h . Th e reaction m ixture was stirred at –78 °C for 3 h . Th en th e
reaction was quen ch ed by th e slow addition of m eth an ol below –70 °C, un til n o m ore gas
elution occurred. Th e m ixture was th en allowed to warm to room tem perature, 1 M HCl (100
m l) was added, an d th e m ixture was stirred for 1 h . Th e aqueous layer was extracted with
eth er. Th e organ ic layers were com bin ed, wash ed with saturated NaHCO3 an d brin e, dried
over Na2SO4, an d con cen trated to give a yellowish oil. Th e oil was purified by colum n
ch rom atograph y on silica gel (h exan e–eth yl acetate 10 : 1) to give 2.56 g (64%) of 8a as an
am ber oil an d 0.60 g (15%) of 8b as an am ber oil.
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2′,3′-Dideoxy-2′-trifluoromethyl-N-azanucleosides
1273
8a: 1H NMR (300 MHz, CD3COCD3): 5.59 (d, J = 3.0, 1 H); 4.02 (br, 1 H); 3.83 (dd, J =
9.3, 4.3, 1 H); 3.68 (br, 1 H); 3.02 (m , 1 H); 2.76–2.27 (m , 1 H); 2.20–2.10 (m , 1 H); 1.47 (s,
9 H); 0.92 (s, 9 H); 0.11 (s, 6 H). 19F NMR (282 MHz, CD3OD): –10.5 (s).
8b: 1H NMR (300 MHz, CD3COCD3): 5.61 (br, 0.93 H); 5.51 (d, J = 3.3, 0.07 H); 3.97–4.04
(m , 1 H); 3.85 (m , 1 H); 3.74 (m , 1 H); 2.97 (m , 1 H); 2.20–2.34 (m , 2 H); 1.49 (s, 0.63 H);
1.46 (s, 8.37 H); 0.92 (s, 8.37 H); 0.91 (s, 0.63 H); 0.11 (s, 5.58 H); 0.08 (s, 0.42 H). 19F NMR
(282 MHz, CD3OD): –15.7 (s). IR (th in film ): 3 443, 2 959, 2 933, 2 861, 1 688. MS, m/z: 402
(M+ + 3, 5), 57 (91), 282 (100). For C17H32F3NO4Si (399.5) calculated: 51.10% C, 8.07% H,
3.51% N; foun d: 51.21% C, 8.18% H, 3.54% N.
tert-Butyl (2R,3S,5R)-2-(Acetyloxy)-5-[(tert-butyldim eth ylsilyloxy)m eth yl]-3-(trifluorom eth yl)-
pyrrolidin e-1-carboxylate (9)
To a solution of 8a (2.54 g, 6.37 m m ol) in an h ydrous CH2Cl2 (60 m l), DMAP (80 m g, 0.64
m m ol) an d acetic an h ydride (4.0 m l, 38.2 m m ol) were added, an d th e resultin g solution was
stirred at room tem perature overn igh t. Th e reaction m ixture was poured in to a saturated
aqueous NaHCO3 solution an d stirred for 25 m in . Th e organ ic layers were wash ed with
brin e, dried over Na2SO4, an d con cen trated to give a ligh t am ber oil. Th e oil was purified by
colum n ch rom atograph y on silica gel (h exan e–eth yl acetate 8 : 1) to give com poun d 9 (93%)
as an am ber oil. 1H NMR (300 MHz, CD3COCD3): 6.66 (d, J = 1.2, 1 H); 4.02–4.00 (m , 1 H);
3.80 (br, 2 H); 3.21 (m , 1 H); 2.36 (m , 1 H); 2.22 (m , 1 H); 2.01 (s, 3 H); 1.42 (s, 9 H); 0.91
(s, 9 H); 0.09 (s, 6 H). 19F NMR (282 MHz, CD3OD): –10.4 (s). IR (th in film ): 2 960, 2 933,
2 860, 1 759, 1 715. MS, m/z: 442 (M+ + 1, 6), 441 (M+, 13), 73 (38), 57 (100). For C19H34F3NO5Si
(441.6) calculated: 51.68% C, 7.76% H, 3.20% N; foun d: 51.46% C, 7.86% H, 3.20% N.
tert-Butyl (2S,3S,5R)-5-[(tert-Butyldim eth ylsilyloxy)m eth yl]-2-[5-m eth yl-2,4-dioxo-
3,4-dih ydropyrim idin -1(2H)-yl]-3-(trifluorom eth yl)pyrrolidin e-1-carboxylate (11)
To a stirred solution of com poun d 9 (0.31 g, 0.705 m m ol) an d th ym in e (0.25 g, 1.97 m m ol)
in an h ydrous aceton itrile (20 m l) was added N,O-bis(trim eth ylsilyl)acetam ide (1.35 m l, 4.09
m m ol). Th e reaction m ixture was stirred un der reflux for 30 m in . After coolin g to 0 °C,
trim eth ylsilyl triflate (0.35 m l, 1.68 m m ol) was added dropwise an d th e solution was stirred
at room tem perature for 16 h . Th e reaction m ixture was quen ch ed with cold saturated aque-
ous NaHCO3 an d th e resultin g m ixture was extracted with dich lorom eth an e. Th e com bin ed
extract was wash ed with brin e, dried over Na2SO4, an d con cen trated to give a yellow oil. Th e
oil was purified by colum n ch rom atograph y on silica gel (h exan e–eth yl acetate 3.5 : 1) to give
0.27 g (69%) of 11 as a wh ite foam . 1H NMR (300 MHz, CD3COCD3): 7.34 (s, 1 H); 6.33 (d,
J = 7.5, 1 H); 4.16–4.12 (m , 2 H); 3.92 (dd, J = 11.9, 4.3, 1 H); 3.48 (m , 1 H); 2.42–2.30 (m ,
2 H); 1.88 (s, 3 H); 1.37 (s, 9 H); 0.97 (s, 9 H); 0.20 (s, 6 H). 19F NMR (282 MHz, CD3OD):
–11.2 (d, J = 8.0). IR (KBr): 3 207, 3 065, 2 959, 2 860, 1 696. MS, m/z: 224 (100), 57 (82).
For C22H36F3N3O5Si (507.6) calculated: 52.05% C, 7.15% H, 8.28% N; foun d: 52.19% C,
7.23% H, 8.23% N.
tert-Butyl (2S,3S,5R)-5-[(tert-Butyldim eth ylsilyloxy)m eth yl]-2-[2,4-dioxo-
3,4-dih ydropyrim idin -1(2H)-yl]-3-(trifluorom eth yl)pyrrolidin e-1-carboxylate (10)
Com poun d 10 (0.38 g, 76%) was prepared as a wh ite foam from com poun d 9 (0.50 g, 1.125
m m ol) usin g th e sam e con dition s as for 11. 1H NMR (300 MHz, CD3COCD3): 7.92 (d, J =
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8.1, 1 H); 6.19 (d, J = 6.2, 1 H); 5.48 (d, J = 8.1, 1 H); 4.07 (dd, J = 10.6, 2.3, 1 H); 3.98–3.94
(m , 1 H); 3.69 (dd, J = 10.6, 2.0, 1 H); 3.24 (m , 1 H); 2.22–2.17 (m , 2 H); 1.21 (s, 9 H); 0.78
(s, 9 H); 0.01 (s, 6 H). 19F NMR (282 MHz, CD3OD): –11.1 (d, J = 8.0). IR (KBr): 3 212, 3 066,
2 959, 2 934, 2 861, 1 698, 1 635. MS, m/z: 497 (M+ + 4, 3), 119 (68), 91 (100). For
C
21H34F3N3O5Si (493.6) calculated: 51.10% C, 6.94% H, 8.51% N; foun d: 50.88% C, 6.855 H,
8.36% N.
tert-Butyl (2S,3S,5R)-5-(Hydroxym eth yl)-2-[5-m eth yl-2,4-dioxo-3,4-dih ydropyrim idin -
1(2H)-yl]-3-(trifluorom eth yl)pyrrolidin e-1-carboxylate (13)
A stirred solution of protected n ucleoside 11 (0.23 g, 0.45 m m ol) in an h ydrous THF was
treated with a 1.0 M solution of TBAF in THF (0.92 m l, 0.92 m m ol) at room tem perature.
After stirrin g for 1 h , th e solven t was rem oved an d th e residue was purified by colum n ch ro-
m atograph y on silica gel (h exan e–eth yl acetate 1 : 2.5) to give 0.18 g (97%) of 13 as a wh ite
foam . 1H NMR (300 MHz, CD3OD): 8.45 (s, 1 H); 6.52 (d, J = 7.0, 1 H); 4.30–4.24 (m , 2 H);
3.87 (dd, J = 11.9, 2.9, 1 H); 3.59 (m , 1 H); 2.49–2.42 (m , 2 H); 2.08 (s, 3 H); 1.58 (s, 9 H).
19F NMR (282 MHz, CD3OD): –8.6 (d, J = 8.0). IR (KBr): 3 473, 3 204, 3 064, 2 982, 1 695.
MS, m/z: 168 (62), 57 (100). For C16H22F3N3O5 (393.4) calculated: 48.85% C, 5.64% H,
10.68% N; foun d: 48.895 C, 5.85% H, 10.57% N.
tert-Butyl (2S,3S,5R)-5-(Hydroxym eth yl)-2-[2,4-dioxo-3,4-dih ydropyrim idin -1(2H)-yl]-
3-(trifluorom eth yl)pyrrolidin e-1-carboxylate (12)
Com poun d 12 (193 m g, 95%) was prepared as a wh ite foam from com poun d 11 (254 m g,
0.51 m m ol) usin g th e sam e con dition s as for com poun d 13. 1H NMR (300 MHz, CD3OD):
8.57 (d, J = 8.1, 1 H); 6.53 (d, J = 7.0, 1 H); 5.92 (d, J = 8.1, 1 H); 4.20–4.14 (m , 2 H); 3.87
(dd, J = 10.9, 1.8, 1 H); 3.65 (m , 1 H); 2.53–2.50 (m , 2 H); 1.60 (s, 9 H). 19F NMR (282 MHz,
CD3OD): –8.6 (d, J = 8.0). IR (KBr): 3 480, 3 063, 2 982, 1 694. MS, m/z: 380 (M+ + 1, 3), 57
(88), 168 (100). For C15H20F3N3O5 (379.3) calculated: 47.49% C, 5.31% H, 11.08% N; foun d:
47.63% C, 5.03% H, 10.82% N.
tert-Butyl (2RS,3S,5R)-2-[4-Am in o-2-oxopyrim idin -1(2H)-yl]-5-[(tert-butyldim eth ylsilyloxy)-
m eth yl]-3-(trifluorom eth yl)pyrrolidin e-1-carboxylate (14)
Com poun d 14 (193 m g, 95%) was prepared as a wh ite foam from com poun d 9 (254 m g,
0.51 m m ol) an d cytosin e (179 m g, 1.61 m m ol) usin g th e sam e con dition s as for com poun d 11.
tert-Butyl (2R,3S,5R)-2-[4-(Ben zoylam in o)-2-oxopyrim idin -1(2H)-yl]-5-(h ydroxym eth yl)-
3-(trifluorom eth yl)pyrrolidin e-1-carboxylate (15) an d
tert-Butyl (2S,3S,5R)-2-[4-(Ben zoylam in o)-2-oxopyrim idin -1(2H)-yl]-5-(h ydroxym eth yl)-
3-(trifluorom eth yl)pyrrolidin e-1-carboxylate (16)
To a stirred solution of com poun d 14 (0.28 g, 0.580 m m ol) in dry dich lorom eth an e (20 m l)
was added ben zoic an h ydride (0.17 g, 0.765 m m ol). Th e reaction m ixture was stirred at
room tem perature for 30 h . Th e solven t was rem oved an d th e residue was purified by col-
um n ch rom atograph y on silica gel (dich lorom eth an e–MeOH 60 : 1) to afford 0.31 g (91%)
of N4-ben zoylated n ucleoside as an am ber oil. Th en treatm en t of th is com poun d with TBAF
un der th e reaction con dition s for com poun d 11 gave separated com poun ds 15 an d 16.
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15: 1H NMR (300 MHz, CD3COCD3): 8.16 (d, J = 8.0, 1 H); 8.06 (m , 1 H); 7.70–7.36 (m ,
5 H); 6.78 (d, J = 7.3, 1 H); 4.42 (m , 1 H); 3.96–3.86 (m , 2 H); 3.74–3.63 (m , 1 H); 2.64–2.52
(m , 1 H); 2.42–2.35 (m , 1 H); 1.29 (s, 9 H). IR (KBr): 3 341, 2 978, 2 982, 2 931, 1 706, 1 626,
1 560, 1 486, 1 371. MS, m/z: 482 (M+ – 1, 1), 105 (96), 57(100).
16: 1H NMR (300 MHz, CD3COCD3): 8.83 (d, J = 7.5, 1 H); 8.17–8.14 (m , 2 H); 7.70–7.36
(m , 4 H); 6.47 (br, 1 H); 4.22–4.15 (m , 2 H); 3.77 (dd, J = 11.0, 1.9, 1 H); 3.53 (m , 1 H); 2.48
(m , 1 H); 2.41–2.33 (m , 1 H); 1.36 (s, 9 H).
tert-Butyl (2S,3S,5R)-2-[4-Am in o-2-oxopyrim idin -1(2H)-yl]-5-(h ydroxym eth yl)-
3-(trifluorom eth yl)pyrrolidin e-1-carboxylate (18)
A solution of th e protected com poun d 16 (91 m g, 0.188 m m ol) in MeOH (10 m l) was
treated with saturated m eth an olic am m on ia (25 m l) an d th e reaction m ixture was stirred at
room tem perature for 4 h . After rem oval of th e volatile m aterials, th e residue was purified
by colum n ch rom atograph y on silica gel (dich lorom eth an e–MeOH 8 : 1) to afford 65 m g
(92%) of 18. 1H NMR (300 MHz, CD3OD): 8.48 (d, J = 7.1, 1 H); 6.54 (br, 1 H); 6.09 (d, J =
7.1, 1 H); 4.28–4.25 (m , 2 H); 3.87 (dd, J = 11.0, 1.9, 1 H); 3.57 (m , 1 H); 2.55–2.43 (m , 2 H);
1.57 (s, 9 H). 19F NMR (282 MHz, CD3OD): –8.8 (d, J = 6.0). IR (KBr): 3 349, 3 212, 2 980,
1 614, 1 527, 1 493, 1 370. MS, m/z: 379 (M+, 1), 377 (M+ – 2, 0.28), 42 (66), 56 (100).
tert-Butyl (2R,3S,5R)-2-[4-Am in o-2-oxopyrim idin -1(2H)-yl]-5-(h ydroxym eth yl)-
3-(trifluorom eth yl)pyrrolidin e-1-carboxylate (17)
Com p ou n d 17 (51 m g, 90%) as a ligh t am ber foam was p rep ared from com p ou n d 15
(65 m g, 0.13 m m ol) usin g th e sam e con dition s as for com poun d 18. 1H NMR (300 MHz,
CD3OD): 7.69 (d, J = 7.2, 1 H); 6.84 (d, 7.3, 1 H); 6.13 (d, J = 7.2, 1 H); 4.49 (m , 1 H); 4.06
(dd, J = 7.2, 4.2, 1 H); 3.92 (m , 1 H); 3.81 (dd, J = 11.4, 2.3, 1 H); 2.62 (m , 1 H); 2.48–2.43
(m , 1 H); 1.53 (s, 9 H). 19F NMR (282 MHz, CD3COCD3): –13.2 (d, J = 8.0).
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