Synthesis of novel 3'-C-methyl-apionucleosides: An asymmetric construction of a quaternary carbon by claisen rearrangement

Article abstract of DOI:10.1016/S0008-6215(00)00005-7

The synthesis of 2,3-dideoxy-3-C-(hydroxymethyl)-3-C-glycero-tetrofuranosyl nucleosides was accomplished in high enatiomeric purity (98.5% ee) via [3,3]-sigmatropic Claisen rearrangement of (E)(S)-5-benzyloxy-1-tert-butyldimethylsilanyloxy-4-methyl-pent-3 -en-2-ol prepared from 2,3-O-isopropylidene-D-glyceraldehyde. The synthesized nucleosides were assayed against human immunodeficiency virus (HIV) and hepatitis B virus in human peripheral blood mononuclear (PBM) and 2.2.15 cells, respectively. 6-Amino-9-[2,3-dideoxy-3-C-(hydroxymethyl)-3-C-methyl-β-D-glycer o-tetrofuranosyl]-2-fluoropurine shows moderate antiviral activity (EC₅₀ = 2.55 μM) against HIV-1 strains and 6-amino-9-[3-deoxy-3-C-(hydroxymethyl)-3-methyl-α-D-glycero-tetr ofuranosyl]-2-fluoropurine exhibits potent anti-HIV activity EC₅₀ = 0.073 μM) with significant cytotoxity (IC₅₀ = 1.0 μM). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(00)00005-7

www.elsevier.nl/locate/carres
Carbohydrate Research 328 (2000) 37–48
Synthesis of novel 3%-C-methyl-apionucleosides: an
asymmetric construction of a quaternary carbon by
Claisen rearrangement
Joon H. Hong a, Mu-Yun Gao a, Yongseok Choi a, Yung-Chi Cheng b,
Raymond F. Schinazi c, Chung K. Chu a,*
a Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The Uni6ersity of Georgia, Athens,
GA 30602, USA
b Department of Pharmacology, Yale Uni6ersity School of Medicine, New Ha6en, CT 06510, USA
c Emory Uni6ersity School of Medicine/VA Medical Center, Decatur, GA 30033, USA
Received 6 October 1999; accepted 8 December 1999
Abstract
The synthesis of 2,3-dideoxy-3-C-(hydroxymethyl)-3-C-methyl-
plished in high enatiomeric purity (98.5% ee) via [3,3]-sigmatropic Claisen rearrangement of (E)(S)-5-benzyloxy-1-
tert-butyldimethylsilanyloxy-4-methyl-pent-3-en-2-ol prepared from 2,3-O-isopropylidene- -glyceraldehyde. The
D-glycero-tetrofuranosyl nucleosides was accom-
D
synthesized nucleosides were assayed against human immunodeficiency virus (HIV) and hepatitis B virus in human
peripheral blood mononuclear (PBM) and 2.2.15 cells, respectively. 6-Amino-9-[2,3-dideoxy-3-C-(hydroxymethyl)-3-
C-methyl-b-
D
-glycero-tetrofuranosyl]-2-fluoropurine shows moderate antiviral activity (EC50=2.55 mM) against
HIV-1 strains and 6-amino-9-[3-deoxy-3-C-(hydroxymethyl)-3-methyl-a-
D
-glycero-tetrofuranosyl]-2-fluoropurine ex-
hibits potent anti-HIV activity (EC50=0.073 mM) with significant cytotoxity (IC50=1.0 mM). © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: Apionucleosides; Claisen rearrangement; Anti-HIV activity
as they represent a new class of compounds and
exhibit significant biological activity. Further-
more, more fundamental modifications of pen-
tofuranose moiety, such as isonucleosides and
apionucleosides, have been reported to be com-
patible with antiviral activities [6]. In attempts
to find new lead compounds with improved bi-
ological activity, we have synthesized a number
of apionucleosides with several substituents at
the 3%-position. Previously, we reported an effi-
cient synthetic method of 3%-fluoro-substituted
apionucleosides using the Claisen rearrange-
ment reaction in a communication [7]. In this
paper we focus on the synthesis of 3%-C-methyl-
substituted apionucleoside analogues.
1. Introduction
Emerging drug-resistant virus strains as well
as toxicity are major problems in antiviral
chemotherapy [1,2]. Therefore, a number of
structurally modified nucleosides have been
synthesized to overcome these drawbacks.
Among the compounds synthesized, 4%-cyan-
othymidine [3], 4%-azidothymidine [4] and 4%-
fluoronucleosides [5] are of particular interest
* Corresponding author. Tel.: +1-706-5425379; fax: +1-
706-5425381.
E-mail address: dchu@rx.uga.edu (C.K. Chu).
0008-6215/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(00)00005-7

38
J.H. Hong et al. / Carbohydrate Research 328 (2000) 37–48
It is well known that the Claisen rearrange-
quaternary carbon ethyl ester 7 in 66% yield.
The enantioselectivity (98.5% ee) of the reac-
tion was determined by using a chiral HPLC
[18]. The double bond of 7 was then ozonized
into aldehyde 8 and subsequently reduced us-
ing DIBAL-H in toluene at −78 °C to yield
lactol 9 in 47% yield in two steps. The apiose
lactol 9 was acetylated in pyridine to yield the
key intermediate 10 as a glycosyl donor
(Scheme 1). For the preparation of the cy-
tosine derivatives 19 and 20, compound 10
was condensed with per-O-trimethylsilyl-N4-
benzoylcytosine using trimethylsilyl trifluoro-
methanesulfonate (TMSOTf) as the catalyst in
1,2-dichloroethane (DCE) to give protected
nucleosides 11 and 12 (2:3=b,a ratio, deter-
mined by NMR spectroscopy) as an anomeric
mixture, which is readily separated by silica
gel column chromatography. Compounds 11
and 12 were separately treated with methano-
lic ammonia and subsequently debenzylated
using catalytic hydrogenolysis to obtain the
desired final nucleosides 19 and 20, respec-
tively (Scheme 2). The stereochemical assign-
ment was determined on the basis of 1D and
2D NOE experiments. Compound 10 was also
ment has been widely employed in synthetic
organic chemistry with a high degree of 1,3-
chirality transmission [7]. However, few exam-
ples of 4%-C-alkyl nucleosides [8] or 4%-C-alkyl
carbocyclic nucleosides [9] have been reported
to date in the literature. The scarcity of exam-
ples of 4%-alkyl-substituted nucleosides may be
due to the synthetic difficulties for elaborating
a necessary quaternary carbon center. The
synthesis of the quaternary carbon stereocen-
ter has frequently been a difficult task since a
large number of natural products possess the
quaternary carbon [10]. The methodology for
the elaboration of the quaternary carbon
stereocenter has been extensively discussed in
the literature [11], such as aldol reactions [12],
Michael reactions [13], palladium-catalyzed al-
lylation [14], Heck reactions [15], cycloaddi-
tion reactions [16], and sigmatropic rearrange-
ments [17]. Recently, we published a method
of the synthesis for 3%-C-methyl-4%-thio-api-
onucleosides [18]. Herein, we wish to report
the full account of the synthesis of 3%-C-
methyl-apionucleosides.
condensed
with
corresponding
per-O-
trimethylsilyl-N4-benzoyl-5-fluorocytosine us-
ing TMSOTf as a catalyst in 1,2-dichloro-
ethane to yield the corresponding nucleosides
13 and 14 as an anomeric mixture, which was
readily separated by preparative thin-layer
chromatography (TLC). To obtain the final
nucleosides, compounds 13 and 14 were sub-
jected to the methanolic ammonia and subse-
quently debenzylated using the same con-
ditions as those used for cytosine nucleosides.
In the preparation of thymine and uracil nu-
cleosides, the glycosyl donor 10 was con-
densed with the corresponding persilylated
uracil and thymine using the similar Vorbru¨g-
gen reaction conditions [21] to yield protected
nucleosides 15–18, respectively. Each nu-
cleoside was debenzylated under the same cat-
alytic hydrogenolysis conditions as the
cytosine nucleosides, followed by purification
and separation using preparative TLC to ob-
tain compounds 23–26, respectively. The syn-
thesis of adenine and inosine nucleosides was
carried out by condensation of compound 10
with silylated 6-chloropurine using TMSOTf
2. Results and discussion
2,3-O-Isopropylidene-
[19] was prepared from 1,2:5,6-di-O-isopropyl-
idene- -mannitol and was subjected to the
Wittig reaction with ethoxycarbonyl ethyli-
dene(triphenyl)phosphorane in dichloro-
D
-glyceraldehyde (1)
D
methane to give the a,b-unsaturated ethyl es-
ter 2 [20]. Compound 2 was reduced by di-
isobutylaluminum hydride (DIBAL-H) in
dichloromethane to give allylic alcohol 3 in
97% yield. The hydroxyl group of compound
3 was protected by treatment with sodium
hydride and benzyl bromide to give com-
pound 4. The isopropylidene group of com-
pound 4 was hydrolyzed to diol 5 using 2 N
HCl in 1,4-dioxane. The primary hydroxy
group of 5 was selectively protected with a
tert-butyldimethysilyl group to yield com-
pound 6 in 92% yield under mild reaction
conditions. Johnson–Claisen rearrangement
of compound 6 with triethyl orthoacetate at
135 °C in the presence of catalytic amounts of
propionic acid yielded the g,d-unsaturated

J.H. Hong et al. / Carbohydrate Research 328 (2000) 37–48
39
methods for the synthesis of 33 and 34
(Scheme 2).
as a catalyst in dichloroethane to give pro-
tected 6-chloropurine derivatives 27 and 28 as
an anomeric mixture (Scheme 2). In the prepa-
ration of adenine derivatives, the anomeric
mixture was treated with ammonia in
methanol in a steel bomb at 80–90 °C, fol-
lowed by preparative TLC separation and
debenzylation to obtain 31 and 32. The stereo-
chemical assignment of these nucleosides was
also made similarly to the cytosine nucleosides
(1D and 2D NOE experiments). The inosine
derivatives 33 and 34 were obtained by the
treatment of 6-chloropurine analogues with
2-mercaptoethanol and sodium methoxide in
methanol by deprotection with dissolving
metal (Birch conditions) [22]. For the synthe-
sis of the guanine derivative, compound 10
was condensed with silylated 6-chloro-2-
fluoropurine using TMSOTf as the catalyst in
dichloroethane to give protected 6-chloro-2-
fluoropurine derivatives 29 and 30 as an
anomeric mixture. Without separation, this
anomeric mixture was subjected to aminolysis
to give 2-amino-6-chloro- and 6-chloro-2-
fluoropurine analogues, which were converted
to guanine derivatives 35 and 36 and 2-
fluoroadenine derivatives 37 and 38, by similar
The synthesized nucleosides were assayed
against HIV and hepatitis B virus in PBM and
2.2.15 cells, respectively. It was found that
compound 37 shows moderate activity against
HIV (EC50=2.55 mM). Interestingly, com-
pound 38 shows good activity as well as a
significant toxicity (EC50 =0.073 mM, IC50=
1.0 mM in PBM cells). However, none of these
compounds showed any significant anti-HBV
activity up to 100 mM.
3. Experimental
General methods.—Melting points (mp)
were determined on a Mel-Temp II apparatus
1
and are uncorrected. H NMR spectra were
recorded on a 400 AMX spectrometer for 400
MHz, with Me4Si as internal standard. Chem-
ical shifts (l) are reported in parts per million
(ppm), and signals are reported as s (singlet),
d (doublet), t (triplet), q (quartet), m (multi-
plet), br s (broad singlet) or br d (broad
doublet). Mass spectra were measured on a
Micromass Autospec high-resolution mass
Scheme 1. Reagents: (a) ethoxycarbonyl ethylidene(triphenyl)phosphorane, CH2Cl2, 0 °C; (b) Dibal-H, toluene, −78 °C; (c) BnBr,
NaH, THF; (d) 2 N HCl; (e) TBDMSCl, imidazole, CH2Cl2; (f) Triethyl orthoacetate, propionic acid, 135 °C; (g) O3–DMS,
MeOH, −78 °C; (h) Dibal-H, toluene, −78 °C; (i) (Ac)2O, pyridine.

40
J.H. Hong et al. / Carbohydrate Research 328 (2000) 37–48
Scheme 2. Reagents: (a) silylated bases, TMSOTf, ClCH2CH2Cl; (b) (i) NH3–MeOH and 20% Pd(OH)2/C, cyclohexane, MeOH
for 19–22; (ii) 20% Pd(OH2/C, cyclohexane, MeOH for 23–26; (c) (i) NH3–MeOH, 90 °C and 20% Pd(OH)2/C, cyclohexane,
MeOH for 31 and 32 or NSCH2OH, NaOMe, MeOH, reflux and Na/THF, −78 °C for 33 and 34; (ii) NH3–DME and
HSCH2CH2OH, NaOMe, MeOH, reflux and Na–THF, −78°C for 35 and 36; (iii) NH3–DME and 20% Pd(OH)2/C;
cyclohexane, MeOH for 37 and 38.
The residue was triturated with small amounts
of cold diethyl ether to precipitate
triphenylphosphine oxide. n-Hexane was
added to this triturated mixture. The resulting
suspension was kept in the refrigerator for 1 h
to precipitate additional product. The resulting
solid (triphenylphosphine oxide) was filtered
off with the aid of Celite and the solvent was
evaporated under reduced pressure. The
residue was purified by silica gel column chro-
matography (23:1 hexane–EtOAc) to give
compound 2 as a liquid (19.7 g, 79%); [h]D26
spectrometer. Optical rotations were per-
formed on a Jasco DIP-370 Digital Polarime-
ter. TLC was performed on Uniplates (silica
gel) purchased from Analtech Co. Silica Gel G
(TLC) grade\440 mesh was used for vacuum
flash column chromatography. UV spectra
were obtained on a Beckman DU 650 spec-
trophotometer. Elemental analyses were per-
formed by Atlantic Microlab, Inc., Norcross,
GA.
Ethyl (E)(S)-3-(2,2-dimethyl[1,3]dioxolane-
4-yl)-2-methylacrylate (2).—A solution of car-
bethoxyethylidene triphenylphosphorane (47.0
g, 129.7 mmol) in CH2Cl2 (150 mL) was added
dropwise to a solution of 1 (15.5 g, 117.4
mmol) in CH2Cl2 (300 mL) at 0 °C. The sol-
vent was evaporated under reduced pressure.
1
+19.1° (c 3.9, CHCl3); H NMR (CDCl3): l
6.70 (dd, J 1.4, 8.1 Hz, l H), 4.85 (q, J 7.5 Hz,
1 H), 4.23–4.15 (m, 3 H), 3.63 (t, J 7.7 Hz, 1
H), 1.90 (d, J 1.2 Hz, 3 H), 1.46, 1.42 (s, s, 3
H, 3 H), 1.30 (t, J 7.1 Hz, 3 H).

J.H. Hong et al. / Carbohydrate Research 328 (2000) 37–48
41
(E)(S) - 4 - (3 - Hydroxy - 2 - methylpropenyl)-
2,2-dimethyl[1,3]dioxolane (3).—DIBAL-H
(21.2 g, 80.9 mmol) in 1,4-dioxane (100 mL), 2
N HCl (200 mL) was added, and the mixture
was stirred at rt for 2 h. After the reaction
mixture was neutralized with solid NaHCO3,
the solvent was evaporated under reduced
pressure and co-evaporated twice with EtOH.
The residue was dissolved in CH2Cl2 and dried
over anhyd MgSO4. The solid was filtered off
with the aid of Celite, and the filtrate was
concentrated under reduced pressure. The
residue was purified by silica gel column chro-
matography (1:2 hexane–EtOAc) to give 5
(170.0 mL, 1 M solution in hexane) was added
dropwise at −78 °C under argon to a solu-
tion of 2 (18.0 g, 84.1 mmol) in CH2Cl2 (365
mL). After stirring for 30 min under the same
conditions, the reaction mixture was quenched
by a slow addition of MeOH (200 mL) and
stirred for another 3 h. The resulting solid was
filtered off with the aid of Celite and the
solvent was evaporated under reduced pres-
sure. The residue was purified by silica gel
column chromatography (3:2 hexane–EtOAc)
to give 3 (14.0 g, 97%); [h]2D3 +12.7° (c 5.4,
CHCl3); 1H NMR (CDCl3): l 5.41 (ddd, J 8.6,
2.8, 1.3 Hz, 1 H), 4.77 (m, 1 H), 4.01 (dd, J
5.4, 2.2 Hz, 1 H), 3.96 (s, 2 H), 3.48 (t, J 8.0
Hz, 1 H), 1.67 (d, J 0.8 Hz, 3 H), 1.33, 1.32 (s,
s, 3 H, 3 H).
1
(15.2 g, 85%); [h]2D6 +9.2° (c 7.2, CHCl3); H
NMR (CDCl3): l 7.35–7.26 (m, 5 H, phenyl
H), 5.47 (d, J 8.3 Hz, 1 H), 4.52–4.48 (m, 3
H), 3.90 (s, 2 H), 3.58 (d, J 10.8 Hz, 1 H), 3.48
(dd, J 10.3, 8.0 Hz, 1 H), 1.74 (s, 3 H); 13C
NMR (CDCl3): l 138.06, 137.15, 128.41,
128.21, 127.75, 75.13, 72.17, 69.08, 66.15,
14.49; Anal. Calcd for C13H18O3: C, 70.21; H,
8.19. Found: C, 70.24; H, 8.16.
(E)(S)-4-(3-Benzyloxy-2-methylpropenyl)-
2,2-dimethyl[1,3]dioxolane (4).—Sodium hy-
dride (3.9 g, 97.5 mmol 60% in oil) was
washed twice with anhyd pentane. Anhydrous
THF (200 mL) was added to the mixture, and
a solution of compound 3 (14.0 g, 81.5 mmol)
in tetrahydrofuran (THF) (100 mL) was
slowly added, and then stirred for 30 min
under nitrogen. Benzyl bromide (89.5 mmol,
15.3 g) was then added slowly with stirring for
3 h under nitrogen at room temperature (rt).
A satd NH4Cl soln was slowly added to
quench the excess sodium hydride, and the
mixture was extracted twice with diethyl ether.
The organic extract was dried over anhyd
MgSO4 and filtered. The filtrate was concen-
trated under reduced pressure. The residue
was purified by silica gel column chromatog-
raphy (15:1 hexane–EtOAc) to give 4 (21.2 g,
(E)(S) - 5 - Benzyloxy - 1 - tert - butyldimethyl-
silanyloxy-4-methylpent-3-en-2-ol (6).—Imi-
dazole (2.0 g, 30.0 mmol) was added to a
solution of compound 5 (3.3 g, 15.0 mmol) in
CH2Cl2 (100 mL), and the mixture was then
cooled to −10 °C. To this reaction mixture a
solution of tert-butyldimethylsilyl chloride
(2.3 g, 15.2 mmol) in CH2Cl2 (50 mL) was
slowly added. The reaction solvent was evapo-
rated under reduced pressure. The residue was
extracted twice with diethyl ether and water.
The combined organic layer was dried over
anhyd MgSO4, filtered, and concentrated un-
der reduced pressure. The residue was purified
by silica gel column chromatography (10:1
hexane–EtOAc) to give compound 6 (4.6 g,
92%); [h]2D5 +15.8° (c 6.5, CHCl3); H NMR
1
1
99%); [h]2D6 +10.9° (c 6.0, CHCl3); H NMR
(CDCl3): l 26–7.17 (m, 5 H), 5.36 (d, J 8.2
Hz, 1 H), 4.40–4.36 (m, 3 H), 3.83 (s, 2 H),
3.51 (dd, J 10.1, 3.6 Hz, 1 H), 3.35 (t, J 9.9
Hz, 1 H), 1.66 (s, 3 H), 0.83 (s, 9 H), 0.02 (s,
6 H); 13C NMR (CDCl3): l 138.24, 136.85,
128.31, 127.63, 127.56, 127.51, 127.41, 75.27,
71.83, 68.85, 66.58, 25.90, 25.84, 14.42, 5.35,
5.42; Anal. Calcd for C19H32O3Si·0.6H2O: C,
65.70; H, 9.39. Found: C, 65.68; H, 9.28.
(CDCl3): l 7.34–7.25 (m, 5 H), 5.52 (dd, J
7.4, 1.0 Hz, 1 H), 4.83 (m, 1 H), 4.48 (s, 2 H),
4.09 (dd, J 7.9, 5.9 Hz, 1 H), 3.92 (s, 2 H),
3.54 (t, J 8.1 Hz, 1 H), 1.75 (s, 3 H), 1.43, 1.40
13
(s, s, 3 H, 3 H); C NMR (CDCl3): l 138.47,
138.33, 128.65, 127.96, 127.88, 124.68, 109.29,
76.99, 75.37, 72.78, 72.24. 69.60, 27.06, 26.27,
14.60; HRMS Calcd for [M+H]+: 263.1647;
found: 263.1624. Anal. Calcd for C16H22O3·
0.1C6H14: C, 73.52; H, 8.64. Found: C, 73.71;
H, 8.51.
Ethyl
(E)(S)-3-benzyloxymethyl-6-tert-
butyldimethylsilanyloxy - 3 - methylhex - 4 - enate
(7).—A mixture of allylic alcohol 6 (6.8 g,
202.4 mmol), triethyl orthoacetate (100 mL),
and catalytic amounts of propionic acid (131.1
(E)(S) - 5 - Benzyloxy - 4 - methylpent - 3 - ene-
1,2-diol (5).—To a solution of compound 4

42
J.H. Hong et al. / Carbohydrate Research 328 (2000) 37–48
mL) was heated to 135 °C in a Claisen appara-
tus for 4 h under nitrogen. The reaction mix-
ture was cooled to rt and distilled off in
vacuo. The resulting residue was purified by
silica gel column chromatography (30:1 hex-
ane–EtOAc) to give 7 (5.4 g, 65.4%); [h]D25
silica gel column chromatography (2:1 hex-
1
ane–EtOAc) to give 9 (2.4 g, 67.2%): H
NMR (CDCl3): l 7.38–7.28 (m, 5 H), 5.52 (t,
J 2.6 Hz, 0.3 H), 5.40 (m, 0.7 H), 4.69–4.49
(m, 2 H), 4.01–3.58 (m, 2 H), 3.38–3.19 (m, 2
H), 2.10–1.63 (m, 2 H), 1.23, 1.06 (s, s, 3 H).
1 - O - Acetyl - 3 - C - (benzyloxymethyl) - 2,3-
1
−9.7° (c 9.9, CHCl3); H NMR (CDCl3): l
7.30–7.21 (m, 5 H), 5.72 (dd, J 15.9, 0.9 Hz, 1
H), 5.51 (dt, J 10.1, 5.1 Hz, 1 H), 4.45 (s, 1
H), 4.09 (d, J 5.1 Hz, 2 H), 4.02 (q, J 7.1 Hz,
2 H), 3.32 (d, J 8.9 Hz, 1 H), 3.27 (d, J 8.6 Hz,
1 H), 2.39 (s, 2 H), 1.17 (t, J 7.1 Hz, 3 H), 1.12
(s, 3 H), 0.84 (d, J 0.6 Hz, 9 H), 0.06 (s, 6 H);
13C NMR (CDCl3): l 171.78, 138.63, 135.11,
128.23, 127.88, 127.38, 76.68, 73.21, 64.10,
59.94, 42.15, 39.49, 25.94, 22.10, 18.38, 14.25,
−5.12; MS (m/z): 277 [M+H]+. Anal. Calcd
for C23H38O4Si: C, 67.94; H, 9.42. Found: C,
68.06; H, 9.34.
dideoxy-3-C-methyl- -glycero-tetrofuranose
D
(10).—To a solution of compound 9 (2.4 g,
10.8 mmol) in pyridine (73 mL), Ac2O (1.65 g,
16.2 mmol) was slowly added, and the mixture
was stirred overnight under nitrogen. The pyr-
idine was evaporated under reduced pressure
and co-evaporated with toluene three times.
The residue was dissolved in EtOAc and suc-
cessively washed with 0.01 N HCl, satd
NaHCO3 soln, and brine. The extract was
dried over Na2SO4 and filtered. The filtrate
was concentrated under reduced pressure. The
residue was purified by silica gel column chro-
matography (6:1 hexane–EtOAc) to give 10
(2.3 g, 89.2%): 1H NMR (CDCl3): l 7.37–7.28
(m, 5 H), 6.28 (dd, J 5.4, 2.4 Hz, 0.4 H), 6.26
(dd, J 5.7, 1.6 Hz, 0.6 H), 4.55 (s, 1.2 H), 4.53
(d, J 1.4 Hz, 0.8 H), 3.96–3.63 (m, 2 H), 3.42
(s, 0.8 H), 3.27 (dd, J 19.8, 11.2 Hz, 1.2 H),
2.22 (dd, J 14.0, 5.9 Hz, 0.8 H), 2.06, 2.00 (s,
s, 3 H), 1.75 (dd, J 13.9, 1.7 Hz, 1.2 H), 1.25,
1.19 (s, s, 3 H).
General procedure for condensation of ace-
tate 10 with bases.—N4-benzoylcytosine (602
mg, 2.8 mmol), anhyd HMDS (40 mL), and a
catalytic amount of (NH4)2SO4 were refluxed
to a clear solution, and the solvent was dis-
tilled off under anhyd conditions. The residue
was dissolved in anhyd CH2Cl2 (10 mL). To
this mixture, a solution of 10 (369.3 mg, 1.4
mmol) in dry dichloroethane (10 mL) and
Me3SiOTf (0.5 mL, 2.8 mmol) was added, and
the resulting mixture was stirred at rt for 2 h.
The reaction mixture was quenched with 5 mL
of satd NaHCO3 and stirred for 10 min. The
resulting solid was filtered through a Celite
pad, and the filtrate was extracted twice with
CH2Cl2. The combined organic layers were
dried over anhyd Na2SO4, filtered, and con-
centrated under reduced pressure. The residue
was purified and separated by preparative
TLC (3:2:1 hexane–EtOAc–MeCN) to give
11 (259 mg, 44%) and 12 (211 mg, 36%).
Ethyl (R)-3-benzyloxymethyl-3-methyl-4-
oxobutyrate (8).—A solution of compound 7
(14.8 g, 36.5 mmol) in MeOH (220 mL) was
cooled down to −78 °C, and ozone gas was
then bubbled into the reaction mixture until a
blue color persisted for an additional 5 min.
The reaction mixture was degassed with nitro-
gen, and methyl sulfide (13.4 mL, 183 mmol)
was slowly added at −78 °C. The mixture
was stirred for 3 h at rt under nitrogen. The
mixture was concentrated under reduced pres-
sure, and the residue was purified by silica gel
column chromatography (8:1 hexane–EtOAc)
to give 8 as a colorless oil (6.8 g, 70.3%); [h]D24
1
−5.4° (c 4.0, CHCl3); H NMR (CDCl3): l
9.65 (s, 1 H), 7.36–7.27 (m, 5 H), 4.49 (s, 2
H), 4.10 (q, J 7.1 Hz, 2 H), 3.54 (d, J 9.0 Hz,
2 H), 2.81 (d, J 5.9, 1 H), 2.58 (d, J 5.8 Hz, 1
H), 1.22 (t, J 7.1 Hz, 3 H), 1.17 (s, 3 H).
3 - C - (Benzyloxymethyl) - 2,3 - dideoxy - 3 - C-
methyl- -glycero-tetrofuranose (9).—To a so-
D
lution of compound 8 (4.1 g, 15.5 mmol) in
toluene (100 mL), 1 M solution of DIBAL-H
(33.5 mL, 33.5 mmol) in toluene was added
dropwise at −78 °C under nitrogen, and the
mixture was then stirred for 30 min at
−78 °C. The reaction mixture was quenched
with MeOH (33.5 mL), and the temperature
was increased to rt. After stirring at rt for 3 h,
the resulting solid was removed by filtration,
and the filtrate was concentrated under re-
duced pressure. The residue was purified by

J.H. Hong et al. / Carbohydrate Research 328 (2000) 37–48
43
N4 -Benzoyl-1-[3-C-(benzyloxymethyl)-2,3-
(dd, J 13.9, 6.7 Hz, 1 H), 2.01 (dd, J 13.9, 6.0
13
Hz, 1 H), 1.11 (s, 3 H); C NMR (CDCl3): l
dideoxy-3-C-methyl-i- -glycero-tetrofura-
D
nosyl]cytosine (11) and N4-benzoyl-1-[3-C-
(benzyloxymethyl)-2,3-dideoxy-3-C-methyl-h-
152.45, 152.11, 139.25, 137.47, 132.84, 128.78,
128.11, 127.45, 127.41, 87.48, 76.84, 75.47,
73.94, 44.17, 43.58, 22.04. 14: [h]2D5 −41.1° (c
2.1, CHCl3); UV (MeOH) umax 256.5, 324.5
D
-glycero-tetrofuranosyl]cytosine
(12).—11:
[h]2D4 +77.2° (c 0.9% CHCl3); UV (MeOH)
1
1
nm; H NMR (CDCl3): l 8.29 (d, J 7.5 Hz, 1
umax 259.5, 301.5 nm; H NMR (CDCl3): l
H), 7.63–7.26 (m, 10 H), 5.97 (t, J 6.4 Hz, 1
H), 4.55 (s, 2 H), 4.09, 3.79 (d, d, J 8.7, 8.7
Hz, 2 H), 3.34 (d, J 8.6 Hz, 2 H), 2.68 (dd, J
13.9, 6.5 Hz, 1 H), 1.72 (dd, J 13.9, 6.2 Hz, 1
H), 1.11 (s, 3 H); 13C NMR (CDCl3): l
152.14, 151.24, 137.44, 132.97, 129.93, 128.47,
127.46, 127.54, 124.44, 124.26, 88.50, 77.66,
75.10, 73.41, 44.07, 43.50, 21.66.
7.92–7.27 (m, 12 H), 6.11 (t, J 6.2 Hz, 1 H),
4.48, 4.44 (d, d, J 12.2, 11.8 Hz, 2 H), 4.16 (d,
J 8.4 Hz, 1 H), 3.78 (d, J 8.5 Hz, 1 H), 3.28,
3.25 (d, d, J 8.8, 8.8 Hz, 2 H), 2.52 (dd, J 13.4,
6.6 Hz, 1 H), 2.03 (dd, J 13.7, 5.4 Hz, 1 H),
1.21 (s, 3 H); 13C NMR (CDCl3): l 161.97,
143.93, 137.84, 133.19, 129.10, 128.49, 127.86,
127.67, 127.44, 95.80, 88.82, 77.81, 74.87,
73.33, 43.85, 43.60, 29.70, 22.80; HRMS
Calcd for [M+H]+: 420.1923; found:
420.1931. 12: [h]D25 −38.6° (c 0.2, CHCl3): UV
(MeOH) umax 258.5, 304.5 nm; 1H NMR
(CDCl3): l 8.02 (d, J 7.4 Hz, 1 H), 7.62 (d, J
7.4 Hz, 1 H), 7.90–7.30 (m, 10 H), 6.01 (t, J
6.3 Hz, 1 H), 4.56 (s, 2 H), 4.16 (d, J 8.6 Hz,
1 H), 3.80 (d, J 8.6 Hz, 1 H), 3.39 (d, J 8.8
Hz), 3.33 (d, J 8.8 Hz, 1 H), 2.81 (dd, J 14.0,
6.7 Hz, 1 H), 1.75 (dd, J 14.0, 5.7 Hz, 1 H),
1.15 (s, 3 H); 13C NMR (CDCl3): l 162.16,
143.43, 138.10, 133.22, 129.16, 128.44, 127.69,
127.53, 89.42, 77.94, 75.17, 73.38, 44.11, 44.04,
29.70, 21.60; HRMS Calcd for [M+H]+:
420.1923; found: 420.1748.
1-[3-C-(Benzyloxymethyl)-2,3-dideoxy-3-C-
methyl-i- -glycero-tetrofuranosyl]uracil (15)
D
and 1-[3-C-(benzyloxymethyl)-2,3-dideoxy-3-
C - methyl - h - - glycero - tetrofuranosyl]uracil
D
(16).—Silylated uracil (prepared from uracil
(254 mg, 2.3 mmol), anhyd HMDS (10 mL),
and a catalytic amount of (NH4)2SO4) was
reacted with 10 (300 mg, 1.1 mmol) and
Me3SiOTf (0.4 mL, 2.3 mmol) in dry
dichloroethane (20 mL) at rt for 2 h under
nitrogen. After a workup similar to that of 11
and 12, purification by silica gel column chro-
matography (15:1 CHCl3–MeOH) gave 15
and 16 as inseparable anomeric mixtures (354
1
mg, 99%): H NMR (CDCl3): l 7.56 (d, J 7.2
N4 - Benzoyl - 1 - [3 - C - (benzyloxymethyl)-
Hz, 0.5 H), 7.50 (d, J 7.2, 0.5 Hz), 7.38–7.28
(m, 5 H), 6.03 (t, 6.7 Hz, 1 H), 5.64 (d, d, J
7.2, 7.2 Hz, 1 H), 4.51 (s, 1 H), 3.96, 3.58 (d,
d, J 8.2, 8.2 Hz, 1 H), 3.30, 3.32 (s, s, 2 H),
2.11 (m, 1 H), 1.80 (m, 1 H), 1.13, 1.15 (2s, 3
H).
2,3-dideoxy-3-C-methyl-i- -glycero-tetrofura-
D
nosyl]5-fluorocytosine (13) and N4-benzoyl-1-
[3-C-(benzyloxymethyl)-2,3-deoxy-3-methyl-
h -
D
- glycero - tetrofuranosyl]5 - fluorocytosine
(14).—Silylated N4-benzoyl-5-fluorocytosine,
which was prepared from N4-benzol-5-fluoro-
cytosine (644 mg, 1.4 mmol), anhyd HMDS
(10 mL), and a catalytic amount of (NH4)2-
SO4, was reacted with 10 (243 mg, 0.9 mmol)
and Me3SiOTf (0.5 mL, 2.8 mmol) in dry
dichloroethane (20 mL) at rt for 2 h under
nitrogen. After a workup similar to that for 11
and 12, purification by preparative TLC
(60:12:5 hexane–EtOAc–MeCN) gave 13 (238
mg, 30%) and 14 (193 mg, 24%): 13: [h]D25
+68.9° (c 2.1, CHCl3); UV (MeOH) umax
1-[3-C-(Benzyloxymethyl)-2,3-dideoxy-3-C-
methyl - i -
(17) and
D
- glycero - tetrofuranosyl]thymine
1-[3-C-(benzy-loxymethyl)-2,3-
dideoxy-3-C-methyl-h- -glycero-tetrofura-
D
nosyl]thymine (18).—Silylated thymine (pre-
pared from thymine (484 mg, 3.8 mmol), an-
hyd HMDS (20 mL), and a catalytic amount
of (NH4)2SO4) were reacted with 10 (508 mg,
1.9 mmol) and Me3SiOTf (0.7 mL, 3.8 mmol)
in dry dichloroethane (20 mL) at rt for 2 h
under nitrogen. After a workup similar to that
of 11 and 12, purification by silica gel column
chromatography (5:1 CHCl3 –MeOH) gave 17
and 18 as an inseparable anomeric mixture
1
257.5, 326.5 nm; H NMR (CDCl3): l 8.22 (d,
J 7.4 Hz, 1 H), 7.64–7.25 (m, 10 H), 6.01 (t, J
6.7 Hz, 1 H), 4.44 (s, 2 H), 4.05, 3.65 (d, d, J
8.6, 8.6 Hz, 2 H), 3.24 (d, J 8.6 Hz, 2 H), 2.25
1
(632 mg, 99.5%): H NMR (CDCl3): l 7.57,

44
J.H. Hong et al. / Carbohydrate Research 328 (2000) 37–48
Hz, 1 H), 1.01 (s, 3 H); 13C NMR (DMSO-d6):
l 164.37, 164.29, 153.86, 139.60, 92.63, 92.58,
92.53, 85.45, 74.45, 64.91, 64.78, 43.57, 43.55,
40.52, 19.38; HRMS Calcd for [M+H]+:
226.1192; found: 226.1196. Anal. Calcd for
C10H15N3O3: C, 53.32; H, 6.71; N, 18.66.
Found: C, 53.30; H, 6.71; N, 18.62.
7.59 (s, s, 1 H), 6.04, 6.11 (t, t, J 7.4, 7.4 Hz,
1 H), 4.99, 5.04 (t, t, J 5.2, 5.4 Hz, 1 H, D2O
exchangeable), 3.81, 3.83 (s, s, 2 H), 3.37–3.41
(m, 2 H), 2.30–2.33 (m, 1 H), 1.861.88 (s, s, 3
H), 1.76–1.79 (m, 1 H), 1.14, 1.11 (s, s, 3 H).
1-[2,3-Dideoxy-3-C-(hydroxymethyl)-3-C-
methyl - i -
D
- glycero - tetrofuranosyl]cytosine
1-[2,3-Dideoxy-3-C-(hydroxymethyl)-3 -C-
(19).—Compound 11 (258.7mg, 0.6 mmol)
was treated with satd methanolic ammonia at
rt overnight. The solvent was evaporated un-
der reduced pressure. After purification by
silica gel column chromatography (15:
CHCl3–MeOH, 192.3 mg, 99%), cytosine ana-
logue (192.3 mg, 0.6 mmol) was refluxed with
Pd(OH)2/C (135.5 mg) in MeOH (38.9 mL)
and cyclohexene (10.1 mL) overnight. The
reaction mixture was filtered and evaporated.
The residue was purified by silica gel column
chromatography (5:1 CHCl3–MeOH) to give
compound 19 (105 mg, 77.1%): mp 177–
179 °C; [h]2D6 +77.8° (c 0.3, MeOH); UV
(H2O) umax 271.5 nm (m 10,800) (pH 7), 276.5
nm (m 18,800) (pH 2), 270.5 nm (m 17,000) (pH
11); 1H NMR (DMSO-d6): l 7.61 (d, J 7.5 Hz,
1 H), 7.18 (br d, 2 H, D2O exchangeable), 6.04
(t, J 6.7 Hz, 1 H), 5.74 (d, J 7.5 Hz, 1 H), 4.88
(t, J 6.2 Hz, 1 H, D2O exchangeable), 3.96,
3.50 (d, d, J 8.2, 8.2 Hz, 2 H), 3.35 (d, J 7.9
Hz, 2 H), 2.00 (dd, J 13.2, 6.6 Hz, 1 H), 1.77
(dd, J 13.2, 7.2 Hz, 1 H), 1.07 (s, 3 H); 13C
NMR (DMSO-d6): l 169.02, 168.95, 168.88,
158.51, 144.14, 144.09, 97.42, 97.37, 97.32,
89.63, 79.65, 69.61, 69.49, 48.21, 45.09, 25.58;
HRMS Calcd for [M+H]+: 226.1192; found:
226.1187. Anal. Calcd for C10H15N3O3·
0.4H2O: C, 51.67; H, 6.79; N,18.06. Found: C,
51.60; H, 6.65; N, 18.04.
methyl-i- -glycero-tetrofuranosyl]-5-fluoro-
D
cytosine (21).—Compound 13 (93 mg, 0.2
mmol) was also converted into compound 21
(28.9 mg, 36.9%) by a method similar to that
of 19: mp 181–183 °C; [h]2D5 +214.9° (c 0.2,
MeOH); UV (H2O) umax 281.5 nm (m 7950)
(pH 7), 290.0 nm (m 9440) (pH 2), 280.0 nm (m
1
7920) (pH 11); H NMR (MeOH-d4): l 7.77
(d, J 6.3 Hz, 1 H), 5.93 (t, J 6.4 Hz, 1 H),
3.99, 3.57 (d, d, J 8.5, 8.5 Hz, 2 H), 3.21, (d,
J 1.3 Hz, 2 H), 2.14 (dd, J 13.5, 7.0 Hz, 1 H),
1.82 (dd, J 13.5, 6.5 Hz, 1 H), 1.06 (s, 3 H);
13C NMR (MeOH-d4): l 159.65, 159.51,
156.46, 126.29, 125.97, 89.27, 78.06, 68.13,
67.96, 43.33, 22.46; HRMS Calcd for [M+
H]+: 244.1097; found: 244.1098. Anal. Calcd
for C10H14FN3O3·0.4EtOH: C, 49.50; H, 6.26;
N, 16.05. Found: C, 49.35; H, 5.97; N, 15.95.
1-[2,3-Dideoxy-3-C-(hydroxymethyl)-3-C-
methyl-h- -glycero-tetrofuranosyl]-5-fluoro-
D
cytosine (22).—Compound 14 (158 mg, 0.4
mmol) was converted into compound 22 (26.9
mg, 37.7%) by a method similar to that of 19:
mp 190–192 °C; [h]2D3 −48.2° (c 0.3, MeOH);
UV (H2O) umax 280.5 nm (m 8530) (pH 7),
289.5 nm (m 11,300) (pH 2), 280.5 nm (m 7200)
(pH 11); 1H NMR (MeOH-d4): l 7.85 (d, J 6.5
Hz, 1 H), 5.93 (t, J 6.4 Hz, 1 H), 3.96, 3.83 (d,
d, J 8.6, 8.5 Hz, 2 H), 3.47, 3.43 (d, d, J 10.9,
10.8, 2 H), 2.53 (dd, J 13.7, 6.5 Hz, 1 H), 1.70
(dd, J 13.7, 6.5 Hz, 1 H), 1.11 (s, 3 H); 13C
NMR (MeOH-d4): l 159.68, 159.64, 156.47,
126.27, 125.95, 89.84, 77.78, 68.18, 43.80,
20.87; HRMS Calcd for [M+H]+: 244.1097;
1-[2,3-Dideoxy-3-C-(hydroxymethyl)-3-C-
methyl - h -
D
- glycero - tetrofuranosyl]cytosine
(20).—Compound 12 (211 mg, 0.5 mmol) was
converted into compound 20 (83 mg, 72.3%)
by a similar method to that of 19: mp 199–
201 °C; [h]2D6 −48.4° (c 0.2, MeOH); UV
(H2O) umax 270.5 nm (m 7740) (pH 7), 279.5 nm
found:
244.1096.
Anal.
Calcd
for
C10H14FN3O3·0.4MeOH: C, 48.74; H, 5.62; N,
16.40. Found: C, 48.93; H, 5.88; N, 16.13.
1-[2,3-Dideoxy-3-C-(hydroxymethyl)-3-C-
1
(m 8730) (pH 2), 271.5 nm (m 9100) (pH 11); H
NMR (DMSO-d6): l 7.65 (d, J 7.4 Hz, 1 H),
7.14 (br d, 2 H, D2O exchangeable), 5.95 (t, J
6.7 Hz, 1 H), 5.74 (d, J 7.3 Hz, 1 H), 4.92 (t,
J 5.5 Hz, 1 H, D2O exchangeable), 3.80, 3.71
( d, d, J 8.2, 8.2 Hz, 2 H), 3.33 (s, 2 H), 2.31
(dd, J 13.3, 6.6 Hz, 1 H), 1.56 (dd, J 13.3, 6.9
methyl-i-
and 1-[2,3-deoxy-3-C-(hydroxymethyl)-3-C-
methyl-h- -glycero-tetrafuranosyl]uracil (24).
D
-glycero-tetrofuranosyl]uracil (23)
D
—Compound 15 and 16 (354 mg, 1.1 mmol)
was refluxed with Pd(OH)2/C (499 mg) in
MeOH (143 mL) and cyclohexene (37 mL)

J.H. Hong et al. / Carbohydrate Research 328 (2000) 37–48
45
HRMS Calcd for [M+H]+: 241.1188; found:
241.1176. Anal. Calcd for C11H16N2O2: C,
54.99; H, 6.71; N, 11.66. Found: C, 54.84; H,
overnight. The reaction mixture was filtered
and evaporated. The residue was purified and
separated by preparative TLC (30:1 CHCl3–
MeOH) to give 23 (74.1 mg, 29.2%) and 24
(82.3 mg, 32.5%). 23: mp 122–124 °C; [h]D27
−4.0° (c 0.5, MeOH); UV (H2O) umax 261.5
nm (m 8470) (pH 7), 263.5 nm (m 8110) (pH 2),
6.62; N, 11.57. 26: mp 154–156 °C; [h]D23
+
25.5° (c 0.5, MeOH); UV (H2O) umax 266.0 nm
(m 8700) (pH 7), 268.5 nm (m 9210) (pH 2),
1
280.0 nm (m 8540) (pH 11); H NMR (DMSO-
1
d6): l 11.28 (s, 1 H, D2O exchangeable), 7.50
(s, 1 H), 6.06 (t, J 7.1 Hz, 1 H), 4.92 (t, J 5.3
Hz, 1 H, D2O exchangeable), 3.98, 3.49 (d, d,
J 8.2, 8.2 Hz, 2 H), 3.31 (s, 2 H), 1.92 (m, 2
H), 1.79 (s, 3 H), 1.07 (s, 3 H); 13C NMR
(DMSO-d6): l 164.14, 150.75, 136.27, 109.84,
85.53, 76.68, 66.55, 45.14, 40.78, 22.41, 12.52;
HRMS Calcd for [M+H]+: 241.1188; found:
241.1198. Anal. Calcd for C11H16N2O2: C,
54.99; H, 6.71; N, 11.66. Found: C, 55.02; H,
6.71; N, 11.64.
262.5 nm (m 8000) (pH 11); H NMR (MeOH-
d4): l 7.62 (d, J 8.0 Hz, 1 H), 5.91 (t, J 6.7 Hz,
1 H), 5.62 (d, J 8.1 Hz, 1 H), 3.84, 3.75 (d, d,
J 8.5, 8.4 Hz, 2 H), 3.37, 3.34 (d, d, J 8.8, 10.8
Hz, 2 H), 2.36 (dd, J 13.6, 6.6 Hz, 1 H), 1.69
(dd, J 13.7, 6.8 Hz, 1 H), 1.04 (s, 3 H); 13C
NMR (MeOH-d4): l 164.76, 150.49, 140.40,
100.75, 87.35, 76.02, 66.44, 44.58, 41.20, 18.99;
Anal. Calcd for C10H14N2O4: C, 53.09; H,
6.24; N, 12.38. Found: C, 52.80; H, 6.27; N,
12.23; HRMS Calcd for [M+H]+: 227.1032;
found: 227.1040. 24: mp 134–136 °C; [h]D26
+17.0° (c 0.9, MeOH); UV (H2O) umax 261.0
(m 8695) (pH 7), 261.5 (m 9212) (pH 2), 260.0 (m
9-[3-C-(Benzyloxymethyl)-2,3-dideoxy-3-C-
methyl - i - - glycero - tetrofuranosyl]6 - chloro-
D
purine (27) and 9-[3-C-(benzyloxymethyl)-2,3-
dideoxy-3-C-methyl-h- -glycero-tetrofuran-
D
1
8539) (pH 11); H NMR (MeOH-d4): l 7.64
osyl]6-chloropurine (28).—Silylated 6-chlorop-
urine (prepared from 6-chloropurine (410.5
mg, 2.7 mmol), anhyd HMDS (23 mL), and a
catalytic amount of (NH4)2SO4) was reacted
with 10 (351.0 mg, 1.3 mmol) and Me3SiOTf
(0.5 mL, 2.7 mmol) in dry dichloroethane (20
mL) at rt for 2 h under nitrogen. After a
similar workup to that of 11 and 12, purifica-
tion by silica gel column chromatography (3:1
hexane–EtOAc) gave 27 and 28 (295.3 mg,
62.0%) as an inseparable anomeric mixture:
1H NMR (CDCl3): l 8.75, 8.72 (s, s, 1 H),
8.40, 8.26 (s, s, 1 H), 7.38–7.19 (m, 5 H), 6.45,
6.29 (d, d, t, J 7.2, 5.7 Hz, 1 H), 4.60, 4.53 (s,
s, 2 H) 4.19, 4.02 (d, d, J 8.5, 8.5 Hz, 2 H),
3.76, 3.56 (d, d, J 9.5, 9.5 Hz, 2 H), 2.69 (dd,
J 14.2, 5.8 Hz, 1 H), 2.37 (dd, J 13.8, 7.2 Hz,
1 H), 2.09–1.98 (m, 2 H), 1.25, 1.11 (s, s, 3
H); HRMS Calcd for [M+H]+: 359.1275;
found: 329.1310.
(d, J 8.1 Hz, 1 H), 6.00 (t, J 6.7 Hz, 1 H), 5.62
(d, J 8.1 Hz, 1 H), 3.97, 3.55 (d, d, J 8.4, 8.4
Hz, 2 H), 3.37 (s, 2 H), 2.06 (dd, J 13.5, 6.6
Hz, 1 H), 1.91 (dd, J 13.4, 6.8 Hz, 1 H), 1.07
(s, 3 H); 13C NMR (MeOH-d4): l 166.74,
152.59, 142.47, 102.93, 88.75, 78.49, 68.31,
46.58, 42.97, 22.89; HRMS Calcd for [M+
H]+: 227.1032; found: 227.1046. Anal. Calcd
for C10H14N2O4: C, 53.09; H, 6.24; N, 12.38.
Found: C, 53.13; H, 6.26; N, 12.28.
1 -[2,3-Dideoxy-3-C-(hydroxymethyl)-3-C-
methyl - i -
D
- glycero - tetrofuranosyl]thymine
(25) and 1-[3-deoxy 3-C-(hydroxymethyl)-3-C-
methyl - h - - glycero - tetrofuranosyl]thymine
D
(26).—Compounds 25 (185 mg, 44.9%) and
26 (196 mg, 47.7%) were obtained from 17
and 18 (566 mg, 1.7 mmol) by a similar
method to that of 23 and 24. 25: mp 172–
174 °C; [h]2D3 +7.9° (c 0.4, MeOH); UV (H2O)
umax 265.5 nm (m 10,100) (pH 7), 268.0 nm (m
9-[3-C-(Benzyloxymethyl)-2,3-dideoxy-3-C-
1
9840) (pH 2), 268.0 nm (m 6680) (pH 11); H
methyl-i-
2-fluoropurine
loxymethyl)-2,3-dideoxy-3-C-methyl-h-
D
-glycero-tetrofuranosyl]-6-chloro-
NMR (DMSO-d6): l 11.31(s, 1 H, D2O ex-
changeable), 7.58 (s, 1 H), 6.04 (t, J 7.4 Hz, 1
H), 4.99 (t, J 5.2 Hz, 1 H, D2O exchangeable),
3.81 (s, 2 H), 3.37 (s, 2 H), 2.31 (dd, J 13.3,
6.5 Hz, 1 H), 1.86 (s, 3 H), 1.76 (dd, J 13.1,
6.5 Hz, 1 H), 1.14 (s, 3 H): 13C NMR
(DMSO-d6): l 167.27, 153.84, 139.66, 113.03,
89.19, 79.12, 69.54, 48.45, 44.01, 23.70, 15.59;
(29)
and
9-[3-C-(benzy-
-gly-
D
cero - tetrofuranosyl] - 6 - chloro - 2 - fluoropurine
(30).—Silylated 6-chloro-2-fluoropurine (pre-
pared from 6-chloro-2-fluoropurine (432 mg,
2.8 mmol), anhyd HMDS (20 mL), and a
catalytic amount of (NH4)2SO4) was reacted
with 10 (500 mg, 1.9 mmol) and Me3SiOTf

46
J.H. Hong et al. / Carbohydrate Research 328 (2000) 37–48
1
2), 260.0 nm (m 16,100) (pH 11); H NMR
(DMSO-d6): l 8.52 (s, 1 H), 8.33 (s, 1 H), 7.44
(br s, 2 H, D2O exchangeable), 6.43 (t, J 6.8
Hz, 1 H), 5.14 (t, J 5.3 Hz, 1 H, D2O ex-
changeable), 4.06, 4.01 (d, d, J 8.2, 8.1 Hz, 2
H), 3.51 (s, 2 H), 2.57 (dd, J 7.0, 1.2 Hz, 1 H),
(0.5 mL, 2.8 mmol) in dry dichloroethane (20
mL) at rt for 2 h under nitrogen. After a
similar workup to that of 11 and 12, purifica-
tion by silica gel column chromatography (5:1
hexane–EtOAc) gave 29 and 30 (396 mg,
1
56%) as an inseparable anomeric mixture: H
13
2.44 (dd, J 7.0, 1.8 Hz, 1 H),1.35 (s, 3 H); C
NMR (MeOH-d4): l 8.59, 8.57 (s, s, 1 H),
7.54–7.27 (m, 5 H), 6.35, 6.28 (t, t, J 6.3, 6.6
Hz, 1 H), 4.51–4.48 (m, 2 H), 4.21, 3.91 (m, 2
H), 3.35–3.33 (m, 2 H), 2.70–2.58 (m, 1 H),
2.43–2.30 (m, 1 H), 1.13, 1.15 (s, s, 3 H).
9-[2,3-Dideoxy-3-C-(hydroxymethyl)-3-C-
NMR (DMSO-d6): l 159.53, 159.46, 155.98,
152.57, 142.93, 122.76, 87.95, 78.73, 69.60,
69.47, 48.89, 48.87, 23.34; HRMS Calcd for
[M+H]+: 250.1304; found: 250.1278. Anal.
Calcd for C11H15N5O2: C, 53.00; H, 6.07; N,
28.10. Found: C, 53.13; H, 6.13; N, 28.03.
1-[2,3-Dideoxy-3-C-(hydroxymethyl)-3-C-
methyl - i -
D
- glycero - tetrofuranosyl]adenine
(31).—Anomeric mixtures 27 and 28 (200.0
mg, 0.6 mmol) were treated with satd
methalonic ammonia for 15 h at 90 °C in a
steel bomb. After removal of the solvent, the
residue was purified by preparative TLC (10:1
CHCl3–MeOH) to give the b isomer (55.9 mg,
29.5%) and the a isomer (59.7 mg, 31.6%).
The b isomer (71.0 mg, 0.2 mmol) was
refluxed with Pd(OH)2/C (46.4 mg) in MeOH
(10.4 mL) and cyclohexene (3.2 mL)
overnight. The reaction mixture was filtered,
and the solvent was evaporated. The residue
was purified by silica gel column chromatog-
raphy (5:1 CHCL3 –MeOH) to give 31 (32.4
mg, 62.1%) as a white solid: mp 217–219 °C;
[h]2D5 −55.4° (c 0.2, DMF); UV (H2O) umax
259.0 nm (m 14,100) (pH 7), 258.0 (m 21,300)
(pH 2), 260.0 nm (m 16,700) (pH 11); 1H NMR
(DMSO-d6): l 8.41 (s, 1 H), 8.24 (s, 1 H), 7.36
(br s, 2 H, D2O exchangeable), 6.42 (t, J 6.9
Hz, 1 H), 5.06 (t, J 5.2 Hz, 1 H, D2O ex-
changeable), 4.14, 3.64 (d, d, J 8.2, 8.2 Hz, 2
H), 3.56 (d, J 10.3 Hz, 2 H), 2.62 (dd, J 13.2,
6.9 Hz, 1 H), 2.25 (dd, J 13.2, 7.2 Hz, 1 H),
methyl - i -
thine (33) and 1-[2,3-dideoxy-3-C-(hydroxy-
methyl)-3- C -methyl-h- -glycero -tetrofura-
D
- glycero - tetrofuranosyl]hypoxan-
D
nosyl] hypoxanthine (34).—The anomeric mix-
ture of 27 and 28 (177 mg, 0.5 mmol) was
refluxed with MeOH (8.5 mL, 2.0 mmol),
CH3ONa (2.6 mL, 2.0 mmol), and 2-mercap-
toethanol (0.13 mL, 2.0 mmol) for 3 h. The
solvent was removed under reduced pressure.
The residue was purified by preparative TLC
to give an anomeric mixture (137.1 mg,
82.1%), which was dissolved in anhyd THF (2
mL) and cooled down to −78 °C in a Dewar
flask. Around 3 mL of ammonia gas was
collected in the reaction mixture. To this reac-
tion mixture, small particles of sodium metal
were added until a blue color appeared at
−78 °C under nitrogen. When the blue color
started to appear, the reaction mixture was
immediately quenched with MeOH (disap-
pearance of color) and elevated in temperature
to rt to remove the ammonia gas. The reaction
mixture was neutralized with AcOH until the
pH was around 7.5. The solvent was removed
under reduced pressure. The residue was
purified by preparative TLC (5:1 CHCl3–
MeOH) to give 33 (19.6 mg, 23.6%) and 34
(22.6 mg, 18.6%). 33: mp 178–180 °C; [h]D28
−21.2° (c 0.2, MeOH); UV (H2O) umax 248.5
nm (m 10,800) (pH 7), 249.0 nm (m 12,300) (pH
13
1.23 (s, 3 H); C NMR (DMSO-d6): l 159.52,
159.46, 156.03, 152.64, 142.50, 122.58, 87.84,
79.60, 69.64, 69.52, 48.87, 48.85, 25.60;
HRMS Calcd for [M+H]+: 250.1304; found:
250.1292. Anal. Calcd for C11H15N5O2: C,
53.00; H, 6.07; N, 28.10. Found: C, 52.88; H,
6.09; N, 27.95.
1
2), 255.0 nm (m 10,500) (pH 11); H NMR
9-[2,3-Dideoxy-3-C-(hydroxymethyl)-3-C-
(MeOH-d4): l 8.18 (s, 1 H), 7.95 (s, 1 H), 6.30
(t, J 6.8 Hz, 1 H), 4.10, 3.90 (d, d J 8.4, 8.4
Hz, 2 H), 3.51, 3.38 (d, d, J 10.9, 10.9 Hz, 2
H), 2.48 (dd, J 13.6, 6.5 Hz, 1 H), 2.20 (dd, J
13.5, 7.2 Hz, 1 H), 1.15 (s, 3 H); HRMS Calcd
for [M+H]+: 251.1144; found: 251.1122.
Anal. Calcd for C11H14N4O3: C, 52.79; H,
methyl - h -
D
- glycero - tetrofuranosyl]adenine
(32).—The a isomer (89.7 mg, 0.3 mmol)
obtained from 27 and 28 was converted into
32 (41.3 mg, 57.9%): mp 158–160 °C; [h]D28
+33.5° (c 1.1, MeOH); UV (H2O) umax 260.0
nm (m 11,800) (pH 7), 257.5 nm (m 14,400) (pH

J.H. Hong et al. / Carbohydrate Research 328 (2000) 37–48
47
220 °C; [h]2D6 +25.7° (c 0.3, MeOH); UV
(H2O) umax 253.0 nm (m 13,100) (pH 7), 254.5
nm (m 12,000) (pH 2), 262.0 nm (m 12,700) (pH
5.64; N, 22.39. Found: C, 52.08; H, 6.00; N,
21.92. 34: mp 170–173 °C; [h]2D6 +40.5° (c 0.3,
MeOH); UV (H2O) umax 249.0 nm (m 12,500)
(pH 7), 249.0 nm (m 13,600) (pH 2), 255.5 nm
1
11); H NMR (MeOH-d4): l 7.77(s, 1 H), 6.03
1
(m 12,300) (pH 11); H NMR (MeOH-d4): l
(t, J 6.8 Hz, 1 H), 3.86, 3.81 (d, d, J 8.5, 8.4
Hz, 2 H), 3.39, 3.33 (d, d, J 6.7, 6.7 Hz, 2 H),
2.36 (dd, J 13.4, 7.0 Hz, 1 H), 2.24 (dd, J 13.6,
6.7 Hz, 1 H), 1.12 (s, 3 H); HRMS Calcd for
[M+H]+: 266.1253; found: 266.1255. Anal.
Calcd for C11H15N5O3·1.0H2O·0.2MeOH: C,
46.44; H, 4.77; N, 24.18. Found: C, 46.66; H,
5.10; N, 24.18.
8.12 (s, 1 H), 7.95 (s, 1 H), 6.21 (t, J 6.8 Hz,
1 H), 3.92, 3.87 (d, d, J 8.4, 8.5 Hz, 2 H), 3.44,
3.38 (d, d, J 10.8, 10.9 Hz, 2 H), 2.46 (dd, J
13.7, 7.0 Hz, 1 H), 2.30 (dd, J 13.7, 6.6 Hz, 1
H), 1.14 (s, 3 H); HRMS Calcd for [M+H]+:
251.1144; found: 251.1125. Anal. Calcd for
C11H14N4O3·0.3MeOH: C, 52.03; H, 5.83; N,
21.48. Found: C, 51.96; H, 5.64; N, 21.26.
9-[2,3-Dideoxy-3-C-(hydroxymethyl)-3-C-
6 - Amino - 9 - [2,3 - dideoxy - 3 - C - (hydroxy-
methyl)-3-C-methyl-i- -glycero-tetrofuran-
D
osyl]-2-fluoropurine (37) and 6-amino-9-[2,3-
dideoxy-3-C-(hydroxymethyl)-3-C-methyl-h-
methyl-i-
and 9-[2,3-deoxy-3-C-(hydroxymethyl)-3-C-
methyl - h - - glycero - tetrofuranosyl]guanine
D-glycero-tetrofuranosyl]guanine (35)
D
- glycero - tetrofuranosyl] - 2 - fluoropurine
D
(38).—A mixture of 6-amino-2-fluoro-purine
analogues (96.0 mg, 0.3 mmol) in EtOH (10
ml) was treated with palladium-on-charcoal
(50 mg) and stirred overnight under an atmo-
sphere of hydrogen. After checking for the
complete disappearance of the starting materi-
als, the reaction mixture was filtered and con-
centrated. The residue was purified and
separated by preparative TLC (10:1 CHCl3–
MeOH) to give 37 (26.7 mg, 37.2%) and 38
(30.5 mg, 42.4%). 37: mp 208–210 °C; [h]D26
−32.2° (c 0.6, MeOH); UV (H2O) umax 261.0
nm (m 22,900) (pH 7), 261.0 nm (m 22,400) (pH
(36).—Ammonia gas was slowly bubbled into
the mixture of 29 and 30 (280 mg, 0.7 mmol)
in ethylene glycol dimethyl ether (DME, 45
mL) for 24 h. The solvent was removed under
reduced pressure. The residue was purified by
preparative TLC to give 2-amino-6-chloro-
purine analogues as an inseparable anomeric
mixture (120.5 mg, 32.2%) and 6-amino-2-
fluoro-purine analogues as an inseparable
anomeric mixture (48.2 mg, 13.5%). The 2-
amino-6-chloropurine analogues (66.2 mg, 0.2
mmol) were refluxed with MeOH (3.5 mL),
CH3ONa (0.9 mL, 0.7 mmol), and 2-mercap-
toethanol (0.05 mL, 0.7 mmol) for 18 h. After
concentration of the mixture, the residue was
purified by preparative TLC to give guanine
analogues (44.2 mg, 70.4%) as an inseparable
anomeric mixture, which was debenzylated by
the dissolving metal method similar to that of
33 and 34 to give 35 (22.5 mg, 8.6% from 29
and 30) and 36 (26.2 mg, 10.0% from 29 and
30). 35: mp 231–233 °C; [h]2D7 −43.7° (c 0.2,
MeOH); UV (H2O) umax 253.0 nm (m 12,600)
(pH 7), 253.5 nm (m 10,200) (pH 2), 262.5 nm
1
2), 261.0 nm (m 23,300) (pH 11); H NMR
(MeOH-d4): l 8.15 (s, 1 H), 6.19 (t, J 6.8 Hz,
1 H), 4.08 (d, J 8.4 Hz, 1 H), 3.58 (d, J 8.4 Hz,
1 H), 3.53, 3.49 (d, d, J 10.9, 10.9 Hz, 2 H),
2.47 (dd, J 13.6, 6.5 Hz, 1 H), 2.17 (dd, J 13.6,
7.2 Hz, 1 H), 1.13 (s, 3 H); HRMS Calcd for
[M+H]+: 268.1210; found: 268.1231. Anal.
Calcd for C11H14FN5O2·0.2MeOH: C, 49.04;
H, 5.45; N, 25.43. Found: C, 49.06; H, 5.50;
N, 25.08. 38: mp 200–202 °C; [h]2D6 +21.5° (c
0.2, MeOH); UV (H2O) umax 261.5 nm (m
20,600) (pH 7), 261.5 nm (m 21,100) (pH 2),
261.5 nm (m 20,500) (pH 11); 1H NMR
(MeOH-d4): l 8.08 (s, 1 H), 6.10 (t, J 6.7 Hz,
1 H), 3.88, 3.84 (d, d, J 8.4, 8.4 Hz, 2 H), 3.43,
3.38 (d, d, J 11.0, 11.0 Hz, 2 H), 2.42 (dd, J
13.9, 7.4 Hz, 1 H), 2.31 (dd, J 13.8, 6.6 Hz, 1
H), 1.14 (s, 3 H); HRMS Calcd for [M+H]+:
268.1210; found: 268.1232. Anal. Calcd for
C11H14FN5O2·1.3MeOH: C, 47.79; H, 5.96; N,
22.67. Found: C, 47.40; H, 5.50; N, 23.04.
1
(m 11,000) (pH 11); H NMR (MeOH-d4): l
7.83 (s, 1 H), 6.11 (t, J 6.9 Hz, 1 H), 4.04, 3.52
(d, d, J 8.4, 8.3 Hz, 2 H), 3.48 (d, J 2.7 Hz, 2
H), 2.40 (dd, J 13.5, 6.8 Hz, 1 H), 2.10 (dd, J
13.3, 7.2 Hz, 1 H), 1.14 (s, 3 H); HRMS Calcd
for [M+H]+: 266.1253; found: 266.1259.
Anal.
Calcd
for
C11H15N5O3·1.0H2O·
0.4MeOH: C, 47.88; H, 5.60; N, 24.94. Found:
C, 48.06; H, 5.22; N, 24.58. 36: mp 218–

48
J.H. Hong et al. / Carbohydrate Research 328 (2000) 37–48
Takeuchi, T. Matsumoto, K. Suzuki, J. Am. Chem. Soc.,
Acknowledgements
120 (1998) 11633–11644. (f) A.G.H. Wee, Q. Yu, Tetra-
hedron, 54 (1998) 13435–13448.
This research was supported by US Public
Health Service Research Grants (AI 33655
and AI 323521) from the National Institutes
of Health and the Department of Veterans
Affairs.
[11] For reviews on construction of quaternary carbon see:
(a) S.F. Martin, Tetrahedron, 36 (1980) 419–460. (b) K.
Fuji, Chem. Re6., 93 (1993) 2037–2066. (c) E.J. Corey,
A. Guzman-Perez, Angew. Chem., Int. Ed. Engl., 37
(1998) 388–401.
[12] (a) C. Agami, J. Levisalles, C. Puchot, J. Chem. Soc.,
Chem. Commun., (1985) 441–442. (b) M. Braun, H.
Sacha, D. Galle, S. Baskaran, Pure Appl. Chem., 68
(1996) 561–564.
[13] (a) M. Sawamura, H. Hamashima, Y. Ito, J. Am. Chem.
Soc., 114 (1992) 8295–8296. (b) J.C.F. Alves, A.B.C.
Simas, P.R.R. Costa, J. d’Angelo, Tetrahedron: Asym-
metry, 8 (1997) 1963–1966. (c) D. Desmaele, K. Mek-
ouar, J. d’Angelo, J. Org. Chem., 62 (1997) 3890–3901.
[14] (a) B.M. Trost, R. Radinov, E.M. Grenzer, J. Am.
Chem. Soc., 119 (1997) 7879–7880. (b) S.Y. Cho, M.
Shibasaki, Tetrahedron: Asymmetry, 9 (1998) 3751–
3754.
[15] (a) A. Ashimori, L.E. Overman, J. Org. Chem., 57
(1992) 4571–4572. (b) S. Honzawa, T. Mizutani, M.
Shibasaki, Tetrahedron Lett., 40 (1999) 311–314. (c) A.
Ashimori, B. Bachand, L.E. Overman, D.J. Poon, J.
Am. Chem. Soc., 120 (1998) 6477–6487.
[16] (a) S.E. Denmark, L.R. Marcin, J. Org. Chem., 62
(1997) 1675–1686. (b) J.D. Winkler, M. Doherty, Tetra-
hedron Lett., 39 (1998) 2253–2256. (c) C. Palomo, J.M.
Aizpurua, J.M. Garcia, R. Galarza, M. Legido, R.
Urchegui, P. Roman, A. Luque, L. Server Carrio, A.
Linden, J. Org. Chem., 62 (1997) 2070–2079.
[17] (a) P. Schubert, S. Morris, Aldrichim. Acta, 26 (1993)
17–29. (b) H. Frauenrath, in G. Helmchen, R.W. Hoff-
mann, J. Mulzer, E. Schaumann (Eds.), Houben-Weyl,
Methoden den Organischen Chemie, Thieme, 1995, pp.
3301–3689. (c) U. Kazmaier, Liebigs Ann. Recl., (1997)
285–295.
References
[1] E. De Clercq, Med. Res. Re6., 16 (1996) 125–157.
[2] E. De Clercq, AIDS Res. Hum. Retro6ir., 8 (1992)
119–137.
[3] C. Oyang, H.Y. Wu, E.B. Fraser-Smith, K.A.M.
Walker, Tetrahedron Lett., 33 (1992) 37–40.
[4] H. Maag, R.M. Rydzewski, M.J. McRoberts, D. Crow-
ford-Ruth, J.P.H. Verheyden, E.J. Prisbe, J. Med.
Chem., 35 (1992) 1440–1451.
[5] I.D. Jenkins, J.P.H. Verheyden, J.G. Moffatt, J. Am.
Chem. Soc., 98 (1976) 3346–3357.
[6] (a) V. Nair, T.S. Jahnke, Antimicrob. Agents Chemother.,
39 (1995) 1017–1029. (b) V. Nair, L.B. Zintek, T.B.
Sells, D.F. Purdy, G.S. Jeon, Anti6iral Res., 23 (1994)
38.
[7] (a) J.H. Hong, K. Lee, Y. Choi, C.K. Chu, Tetrahedron
Lett., 39 (1998) 3443–3446. For reviews on Claisen and
related sigmatropic rearrangements see: (b) P.A. Bartlett,
Tetrahedron, 36 (1980) 3–72. (c) S. Blechert, Synthesis,
(1989) 71–82. (d) F.E. Ziegler, Chem. Re6., 88 (1988)
1423–1452. (e) P. Wipt, in B.M. Trost, I. Flemming
(Eds.), Comprehensi6e Organic Synthesis, Vol. 5, Perga-
mon, New York, 1991, pp. 827–873.
[8] (a) B.H. Lipshutz, S. Sharma, S.H. Dimock, J.R. Beh-
ling, Synthesis, (1992) 191–195. (b) A. Arnone, P.
Bravo, M. Frigerio, F. Viani, G. Salani, C. Zappala`, J.
Chem. Res., (S) (1997) 458–459. (c) N. Nguyen-Ba, W.
Brown, N. Lee, B. Zacharie, Synthesis, (1998) 759–762.
[9] M.I. Nieto, J.M. Blanco, O. Caaman˜o, F. Ferna´ndez, X.
Garc´ıa-Mere, J. Balzarini, E. Padalko, J. Neyts, E. De
Clercq, Nucleosides Nucleotides, 17 (1998) 1255–1266.
[10] (a) J.C. Alves, A.B.C. Simas, P.R.R. Costa, J. d’Angelo,
Tetrahedron: Asymmetry, 8 (1997) 1963–1966. (b) S.
Faure, O. Piva, Synlett, (1998) 1414–1416. (c) N. Ya-
mazaki, T. Ito, C. Kibayashi, Tetrahedron Lett., 40
(1999) 739–742. (d) Y. Kita, S. Akai, H.J. Fujioka, Syn.
Org. Chem. Jpn., 56 (1998) 963–974. (e) T. Saito, T.
Suzuki, M. Morimoto, C. Akiyama, T. Ochiai, K.
[18] J.H. Hong, M.-Y. Gao, C.K. Chu, Tetrahedron Lett., 40
(1999) 231–234.
[19] B. Hafele, V. Jager, Liebigs Ann. Chem., 317 (1987)
85–87.
[20] (a) H. Nemoto, A. Satoh, M. Ando, K. Fukumoto, J.
Chem. Soc., Chem. Commun., 15 (1990) 1001–1002. (b)
A.B. Smith III, Q. Lin, K. Nakayama, A.M. Boldi, C.S.
Brook, M, D. McBriar, W.H. Moser, M. Sobukawa, L.
Zhuang, Tetrahedron Lett., 38 (1997) 8675–8678.
[21] H. Vorbru¨ggen, G. Ho¨fle, Chem. Ber., 114 (1981) 1256–
1268.
[22] U.O. Cheriyan, K.K. Ogilvie, Nucleosides Nucleotides, 1
(1982) 233–237.