Synthetic studies toward the preparation of (4R,5R)-(-)-3-[(benzyloxy) methyl]-4,5-O-isopropylidene-cyclopenten-2-one: An important synthetic intermediate for carbanucleosides

Article abstract of DOI:10.1016/j.tetasy.2004.11.069

The carbocyclic compound (4R,5R)-(-)-3-[(benzyloxy)methyl]-4,5-O- isopropylidene-2-cyclopentenone 1 is an important synthetic intermediate to access a variety of carbanucleosides. Herein, synthetic studies that lead to this valuable compound employing ine

Full text of DOI:10.1016/j.tetasy.2004.11.069

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 425–431
Synthetic studies toward the preparation of (4R,5R)-(ꢀ)-
3-[(benzyloxy)methyl]-4,5-O-isopropylidene-cyclopenten-2-one:
an important synthetic intermediate for carbanucleosides
´
´
Eleonora Elhalem, Marıa J. Comin, Julieta Leitofuter, Guadalupe Garcıa-Lin˜ares
and Juan B. Rodriguez*
´ ´ ´
Departamento de Quımica Organica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellon 2,
Ciudad Universitaria, C1428EHA Buenos Aires, Argentina
Received 7 November 2004; accepted 19 November 2004
Available online 22 December 2004
Abstract—The carbocyclic compound (4R,5R)-(ꢀ)-3-[(benzyloxy)methyl]-4,5-O-isopropylidene-2-cyclopentenone 1 is an important
synthetic intermediate to access a variety of carbanucleosides. Herein, synthetic studies that lead to this valuable compound employ-
ing inexpensive D-ribose as the chiral source are presented.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
In spite of having at hand many synthetic methods for
the preparation of these intermediates, most of them
suffer from some disadvantages such as low overall
yields, partial racemization, numerous synthetic steps,
and nonviable scale up preparations that make these
processes impractical from the synthetic point of view.
Very recently, Jeong et al. solved this problem to some
extent by a new excellent and elegant synthetic approach
that allows a straightforward access to these com-
pounds.10 With this strategy, that employs D-ribose as
a chiral starting material, it is possible to obtain the
respective silyl ether and trityl derivatives of compound
1, namely, compounds 2–4, respectively, in very good
yields.10 On the other hand, the benzyl protecting group
has been widely used in nucleoside chemistry and pre-
sents some advantages over silyl and trityl protecting
groups, such as stability in acidic media and facile re-
moval.16 However, this strategy does not work when
the benzyl protecting group is required to protect the
hydroxymethyl group (compound 1). This failure is
due to one of the key steps for this method, which is
the facial diastereoselectivity exhibited by synthetic
intermediate 9a toward the attack of a Grignard reagent
onto the corresponding carbonyl group. The presence of
bulky groups like tert-butyldiphenylsilyl or trityl moiety
block more efficiently the Si face of the carbonyl group
of compounds 9b–d than the benzyl ether does. There-
fore, in the presence of these bulky groups, the preferred
side for nucleophilic attack in compounds 9b–d is the Re
face of the carbonyl moiety. With the appropriate
In common with conventional nucleosides, their corre-
sponding isosteric analogues carbanucleosides display
a wide range of biological properties especially as anti-
viral and antitumor agents.1–6 The title compound
(4R,5R)-(ꢀ)-3-[(benzyloxy)methyl]-4,5-O-isopropylid-
ene-2-cyclopentenone 1,7,8 and other closely related
compounds such as 2,9 3,9 4,9,10 5,11 6,7,8,12 7,11,13 and
14,15 are versatile synthetic intermediates that have been
used for the preparation of a significant number of car-
bocyclic nucleosides (Fig. 1).
8
RO
O
RO
OH
O
O
O
O
1, R = Bn
6, R = Bn
2, R = TBDMS
3, R = TBDPS
4, R = Tr
7, R = MOM
8, R = t-Bu
5, R = MOM
Figure 1.
*
Corresponding author. Tel.: +54 11 4 576 3346; fax: +54 11 4 576
3385; e-mail: jbr@qo.fcen.uba.ar
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.069

426
E. Elhalem et al. / Tetrahedron: Asymmetry 16 (2005) 425–431
stereochemistry, the resulting dienes 10a–d are able to be
converted into the desired carbocyclic rings (12a–d) by a
Grubbs ring closure metathesis reaction17 (Scheme 1).
of D-ribono-1,4-lactone presents a number of difficulties
in terms of the introduction of the benzyl group to pro-
tect the primary alcohol at the C-5 position that are
associated with lactone ring opening. In fact, we experi-
enced these problems during the total synthesis of nepla-
nocin C and neplanocin F employing 1 as synthetic
intermediate.8,20 Consequently, a large scale and reliable
method for the preparation of 1 is still lacking. In this
work we report a straightforward access to 1 from read-
ily available and inexpensive D-ribose.
HO
RO
RO
O
a
RO
HO
+
O
O
O
O
O
O
10a, R = Bn
9a, R = Bn
11a, R = Bn
10b, R = TBDMS
10c, R = TBDPS
10d, R = Tr
9b, R = TBDMS
9c, R = TBDPS
9d, R = Tr
11b, R = TBDMS
11c, R = TBDPS
11d, R = Tr
2. Results and discussion
The synthesis of 28 was successfully carried out starting
from readily available and inexpensive D-ribose as the
chiral source. This compound treated with acetone in
the presence of sulfuric acid21,22 followed by addition
of allylic alcohol afforded, via a Fischer glycosidation
reaction, the desired allyl 2,3-O-isopropylidene-b-D-
ribofuranoside 18 in 96% yield in a one-pot procedure.
Nuclear magnetic resonance analysis of 18 indicated
the b-configuration of the furanosic form for this com-
pound. The anomeric proton appeared as a broad sin-
glet at 5.12 ppm in the proton NMR spectrum, while
the anomeric carbon was observed at 108.0 ppm in the
corresponding 13C NMR spectrum. The protection of
the free primary hydroxyl group at C-5 in compound
18 as a benzyl ether derivative was conducted by treat-
ment with benzyl bromide and sodium hydride in
N,N-dimethylformamide at 0 ꢁC23 to give 19 in 61%
yield. Allyl group cleavage was conducted in three steps:
(a) isomerization of the allyl moiety to form the corre-
sponding enol ether;24 (b) oxidative double bond cleav-
age to produce the respective formyl glycoside; (c)
removal of the formyl group to obtain the free sugar.
Therefore, on reaction with potassium tert-butoxide in
methyl sulfoxide at 100 ꢁC 19 was converted into iso-
merized product 20 in 92% yield, which treated with
ozone in methylene chloride at ꢀ78 ꢁC followed by addi-
tion of triphenylphosphine25 afforded compound 21 in
95% yield. The resulting formyl glycoside was removed
by treatment with methanolic triethylamine to produce
22 in theoretical yield. Hydrolysis of prop-1-en-1-yl gly-
coside 20 was also attempted either by hydrolysis in mild
acidic conditions,26 or by the use of iodine.27 Neither of
these methods was effective in terms of the reaction
yield. Deprotection of the anomeric center was more
efficiently performed by the use of palladium chloride
in methanol.28 Therefore, on reaction with palladium
chloride compound 19 was straightforwardly converted
into free sugar 22 in 72% yield. Kinetics for this reaction
was a critical point in this transformation because long
reaction times led to isopropylidene cleavage as well.
The optimum reaction time was 4 h at room tempera-
ture. This strategy straightforwardly allowed access to
sugar 22 with the free anomeric center. As mentioned
before, it is not possible to protect the C-5 position as
a benzyl ether without previous glycoside formation
due to undesired lactol ring-opening provoked by ben-
zylation procedures. Compound 22 treated with lithium
aluminum hydride afforded the corresponding alditol 23
in 88% yield, which was regioselectively protected by
b
c
HO
RO
RO
+
BnO
O
OH
HO
O
O
O
O
O
13a, R = Bn
12a, R = Bn
1, R = Bn
13b, R = TBDMS
13c, R = TBDPS
13d, R = Tr
12b, R = TBDMS
12c, R = TBDPS
12d, R = Tr
2, R = TBDMS
3, R = TBDPS
4, R = Tr
Scheme 1. Reagents and conditions: (a) CH2CHMgBr, THF, ꢀ78 ꢁC,
1 h; (b) Grubbs catalyst, CH2Cl2, rt, 2 d; (c) PDC, MS, DMF, rt, 18 h.
The high diastereoselectivity exhibited by 9b with vinyl
magnesium bromide has also been observed by Chu
et al.18,19 The benzyl ether derivative 10a is obtained
by this protocol in only 17% yield,10 therefore this pro-
cess is not viable from the synthetic point of view. In
addition, Jacobson et al. have described another inter-
esting synthetic approach to obtain 1 starting from
5-O-benzyl-1-O-tert-butyldiphenylsilyl-2,3-O-isopropyl-
iden-D-ribose (compound 14) as advanced starting mate-
rial. This strategy uses also a Grubbs reaction as the key
step. However, this article suffers from some discrepan-
cies about the origin of the chiral starting material 14. In
spite of being mentioned in the main text and the corre-
sponding scheme that 14 is prepared from D-ribono-1,4-
lactone 15 in four synthetic steps, the authors cite the
work of Ohira et al. that uses 5-O-trityl-2,3-O-isopropyl-
iden-D-ribose 16 as the starting material, which in turn,
is readily available from D-ribose 17 (Fig. 2).9 In any
case, if compound 16 is employed, the trityl protecting
group should be replaced by the benzyl ether. The use
O
O
RO
HO
OH
OTBDPS
HO
OH
O
O
15
14, R = Bn
16, R = Tr
Figure 2.

E. Elhalem et al. / Tetrahedron: Asymmetry 16 (2005) 425–431
427
treatment with one equivalent of tert-butylchlorodiphen-
ylsilane dissolved in N,N-dimethylformamide in the
presence of imidazole to give the corresponding silyl
ether derivative 24 exclusively in almost quantitative
yield (Scheme 2).
cleavage by treatment with tetrabutyl ammonium fluo-
ride in acetonitrile at room temperature afforded the
respective pentitol 27 in 97% yield. On treatment with
methyl sulfoxide/oxalyl chloride under Swern reaction
conditions, 27 was converted into aldehyde 28 in 100%
yield. This compound treated with vinylmagnesium bro-
mide produced the desired allylic alcohol 29 as a diaste-
reomeric mixture. NMR analysis of 29 indicated the
presence of two diastereomers with the diagnostic sig-
nals for the vinylic proton bonded to the hydroxylated
carbon: a double double of doublets centered at
5.76 ppm and coupling constants of 16.7, 10.5, 5.7 Hz,
respectively, for the major isomer and a double double
of doublets centered at 6.00 ppm and coupling constants
of 16.1, 10.5, 5.7 Hz, respectively, for the minor isomer
Once the tert-butyldiphenylsilyl ether 24 was at hand, a
somewhat analogous strategy outlined by Jacobson
et al. was followed.12 This compound underwent Swern
oxidation29 by treatment with oxalyl chloride and
methyl sulfoxide at ꢀ70 ꢁC followed by addition of tri-
ethylamine to produce the expected keto derivative 25.
Treatment of keto derivative 25 with methyltriphenyl-
phosphonium bromide and n-butyllithium at 0 ꢁC gave
rise to corresponding alkene 26 that after silyl ether
OBn
OH
O
O
O
OH
O
O
c
HO
a
b
O
O
O
O
HO
OH
O
O
18
17
19
BnO
O
OH
BnO
BnO
f
O
O
O
O
O
e
d
H
O
O
O
O
22
21
20
OBn
O
BnO
BnO
O
OTBDPS
OH
OH
OH
OTBDPS
i
h
g
O
O
O
O
O
25
OBn
23
24
BnO
BnO
OTBDPS
OH
O
O
O
l
k
j
O
O
O
O
26
27
28
BnO
OBn
O
BnO
O
O
OH
OH
O
O
O
O
29
1
30
Scheme 2. Reagents and conditions: (a) i. H2SO4, acetone, 0 ꢁC, 2 h, ii. allylic alcohol, rt, 3 d, 96%; (b) BnBr, NaH, DMF, 0 ꢁC, 3 h, 61%; (c) tBuOK,
DMSO, 100 ꢁC, 16 h, 92%; (d) O3, CH2Cl2, ꢀ78 ꢁC ! PPh3, rt, 95%; (e) MeOH, NEt3, rt, 16 h, 100%; (f) LiAlH4, THF, rt, 2 h, 88%; (g) TBDPSCl,
imidazole, DMF, rt, 16 h, 98%; (h) i. (ClCO)2, DMSO, CH2Cl2, ꢀ70 ꢁC, ii. NEt3, 5 min, 100%; (i) [PPh3CH3]+Brꢀ, n-BuLi, THF, 0 ꢁC, 30 min ! 25,
rt, 16 h, 92%; (j) (n-Bu)4NF, MeCN, rt, 2 h, 97%; (k) i. (ClCO)2, DMSO, CH2Cl2, ꢀ70 ꢁC, ii. NEt3, 5 min, 98%; (l) vinyl magnesium bromide, THF,
ꢀ78 ꢁC, 8%.

428
E. Elhalem et al. / Tetrahedron: Asymmetry 16 (2005) 425–431
(data not shown). However the desired transformation
occurred in very low yield employing either a commer-
cial tetrahydrofuran solution of vinylmagnesium bro-
mide or a freshly prepared Grignard reagent from
vinyl bromide, and, unexpectedly, the isolated main
product turned out to be the reduction product alcohol
27. The problems associated to this synthetic step
could be to some extent overcome with the use of a
recently prepared tetrahydrofuran solution of vinylli-
thium. Efforts aimed at optimizing the addition of vinyl
lithium or vinyl magnesium bromide onto 28 are
currently being pursued in our laboratory. Conversion
of 29 into 1 is direct and could be carried out by Jacob-
son protocol.
4.2. Allyl 2,3-O-isopropylidene-b-D-ribofuranoside 18
A mixture of D-ribose 17 (10.09 g, 67.2 mmol) in acetone
(300 mL) cooled at 0 ꢁC was treated with concentrated
sulfuric acid (4.0 mL) dropwise. The reaction mixture
was stirred at room temperature for 2 h. Then, allylic
alcohol (10.0 mL) was added and the mixture was stir-
red at room temperature for 3 days. The reaction was
quenched by addition of ammonium hydroxide until
pH = 7.0. The resulting ammonium sulfate was filtered
off and the solvent was evaporated. The residue was
purified by column chromatography (silica gel) eluting
with a mixture of hexane–EtOAc (9:1) to afford
14.81 g (96% yield) of pure compound 18 as a colorless
23
oil: Rf 0.45 (hexane–EtOAc, 3:2); ½aŠ ¼ ꢀ69:9 (c 0.8,
D
CHCl3); 1H NMR (500 MHz, CDCl3) d 5.85 (dddd,
J = 17.4, 10.4, 6.1, 5.5 Hz, 1H, CH2CH@CH2), 5.31
(dq, J = 17.6, 1.5 Hz, 1H, CH2CH@CHtransH), 5.24
(dq, J = 10.3, 1.3 Hz, 1H, CH2CH@CHHcis), 5.12 (br
s, 1H, H-1), 4.85 (d, J = 5.9 Hz, 1H, H-3), 4.63 (d,
J = 5.9 Hz, 1H, H-2), 4.42 (t, J = 2.8 Hz, 1H, H-4),
4.24 (ddt, J = 12.7, 5.4, 1.4 Hz, 1H, CHaHCH@CH2),
4.07 (ddt, J = 12.7, 5.9, 1.4Hz, 1H, CHHbCH@CH2),
3.53 (dt, J = 12.6, 2.5 Hz, 1H, H-5a), 3.47 (ddd,
J = 12.5, 10.5, 3.4 Hz, 1H, H-5b), 3.16 (dd, J = 10.4,
2.8 Hz, 1H, OH), 1.49 (s, 3H, CH3), 1.32 (s, 3H, CH3);
13C NMR (125 MHz, CDCl3) d 133.1 (CH2CH@CH2),
118.3 (CH2CH@CH2), 112.1 (C(CH3)2), 108.0 (C-1),
88.5 (C-4), 86.0 (C-2), 81.5 (C-3), 69.0 (CH2CH@CH2),
64.0 (C-5), 26.4 (CH3), 24.7 (CH3). Anal. Calcd for
C11H18O5: C, 57.38; H, 7.88. Found: C, 57.51; H, 7.98.
3. Conclusions
In conclusion, the formal synthesis of the key intermedi-
ate 1 is presented with a full characterization of all the
respective intermediates until keto derivative 28 that
were not available in the literature. The novelty in this
synthetic approach was the facile access to free sugar
22, in which it was possible to modify the oxidation state
of the anomeric center.
4. Experimental
4.1. General methods
Unless otherwise noted, chemicals were commercially
available and used without further purification. Air
and/or moisture sensitive reactions were carried out un-
der a dry argon atmosphere in flame dried glassware.
Solvents were distilled before use. Methylene chloride
was distilled from phosphorus pentoxide and stored
over freshly activated 3 A molecular sieves; methyl sulf-
oxide was distilled from calcium hydride and stored over
˚
freshly activated 3 A molecular sieves, and tetrahydrofu-
4.3. Allyl 5-O-benzyl-2,3-O-isopropylidene-b-D-ribofur-
anoside 19
A solution of compound 18 (14.81 g, 64.3 mmol) in
anhydrous N,N-dimethylformamide (25 mL) cooled at
0 ꢁC was treated with benzyl bromide (9.6 mL,
80.7 mmol) under argon atmosphere. Then, a 60% so-
dium hydride dispersion (3.76 g, 94.1 mmol) was added
portionwise over 15 min while the temperature was
maintained at 0 ꢁC. The reaction mixture was stirred
at 0 ꢁC for 3 h. The reaction was quenched by addition
of a saturated aqueous solution of ammonium chloride
(150 mL). The mixture was extracted with methylene
chloride (3 · 75 mL), and the combined organic layers
were washed with brine (5 · 75 mL), dried (Na2SO4),
and the solvent was evaporated. The residue was puri-
fied by column chromatography (silica gel) using hex-
ane–EtOAc (19:1) as eluent to give 12.52 g of pure 19
˚
ran was distilled from sodium benzophenone ketyl.
Anhydrous N,N-dimethylformamide was used as sup-
plied from Aldrich.
Nuclear magnetic resonance spectra were recorded using
a Bruker AM-500 spectrometer. Chemical shifts are re-
ported in parts per million (d) relative to tetramethyl-
silane. The 1H NMR spectra are referenced with
respect to the residual CHCl3 proton of the solvent
CDCl3 at 7.26 ppm. 13C NMR spectra were fully decou-
pled and are referenced to the middle peak of the solvent
CDCl3 at 77.0 ppm. Melting points were determined
using a Fisher–Johns apparatus and are uncorrected.
Column chromatography separations were run using
E. Merck silica gel (Kieselgel 60, 230–400 mesh). Analyt-
ical thin layer chromatography was performed employ-
ing 0.2 mm coated commercial silica gel plates (E.
Merck, DC-Plastikfolien, Kieselgel 60 F254) and was
visualized by 254 nm UV or by immersion into an ethan-
olic solution of 5% H2SO4. Elemental analyses were per-
formed by Atlantic Microlab, Norcross, Georgia. The
results were within 0.4% of the theoretical values ex-
cept where otherwise stated.
(61% yield) as a colorless oil: Rf 0.37 (hexane–EtOAc,
23
D
9:1); ½aŠ ¼ ꢀ15:3 (c 1.8, CHCl3); 1H NMR
(500 MHz, CDCl3) d 7.34 (m, 5H, Ph), 5.84 (m,
1H, CH2CH@CH2), 5.24 (dq, J = 17.3, 1.6 Hz, 1H,
CH2CH@CHtransH), 5.16 (dq, J = 10.3, 1.5 Hz, 1H,
CH2CH@CHHcis), 5.11 (s, 1H, H-1), 4.69 (dd, J = 5.9,
0.7 Hz, 1H, H-3), 4.62 (d, J = 5.9 Hz, 1H, H-2), 4.56
(d, J = 12.1 Hz, 1H, OCHbHPh), 4.52 (d, J = 11.8 Hz ,
1H, OCHaHPh), 4.40 (distorted t, J = 7.2 Hz,
1H, H-4), 4.13 (ddt, J = 13.0, 5.1, 1.4 Hz, 1H,
CHaHCH@CH2), 3.93 (ddt, J = 13.0, 6.1, 1.4Hz, 1H,
CHHbCH@CH2), 3.53 (dd, J = 9.7, 6.8 Hz, 1H, H-5a),
3.47 (dd, J = 9.7, 8.1 Hz, 1H, H-5b), 1.48 (s, 3H, CH3),

E. Elhalem et al. / Tetrahedron: Asymmetry 16 (2005) 425–431
429
1.31 (s, 3H, CH3); 13C NMR (125 MHz, CDCl3) d 138.0
(Ph), 133.8 (CH2CH@CH2), 128.4 (Ph), 127.7 (Ph),
117.3 (CH2CH@CH2), 112.4 (C(CH3)2), 107.3 (C-1),
85.3 (C-2), 85.2 (C-4), 82.2 (C-3), 73.3 (OCH2Ph), 71.2
(C-5), 67.9 (CH2CH@CH2), 26.5 (CH3), 25.0 (CH3).
Anal. Calcd for C18H24O5: C, 67.48; H, 7.55. Found:
C, 67.69; H, 7.56.
(C-2), 81.7 (C-3), 73.3 (OCH2Ph), 70.2 (C-5), 26.4
(CH3), 25.0 (CH3).
4.6. 5-O-Benzyl-2,3-O-isopropylidene-a,b-D-ribofuranose
22
Method A. A solution of compound 21 (4.49 g,
14.6 mmol) in methanol (20 mL) was treated with trieth-
ylamine (0.5 mL). The reaction mixture was stirred at
room temperature overnight. The solvent was evapo-
rated and the product was purified by column chroma-
tography (silica gel) employing a mixture of hexane–
EtOAc (9:1) to yield 4.08 g (100% yield) of pure 22
4.4. Z-Prop-1-en-1-yl 5-O-benzyl-2,3-O-isopropylidene-b-
D-ribofuranoside 20
A solution of compound 19 (9.72 g, 30.3 mmol) in
methyl sulfoxide (10 mL) was treated with potassium
tert-butoxide (1.36 g, 12.1 mmol) under argon atmo-
sphere, and the reaction mixture was stirred at 100 ꢁC
for 16 h. The mixture was partitioned between water
(50 mL) and methylene chloride (50 mL). The aqueous
layer was extracted with methylene chloride
(2 · 50 mL). The combined organic layers were washed
with brine (5 · 100 mL), dried (MgSO4), and the solvent
was evaporated. The residue was purified by column
chromatography eluting with hexane–EtOAc (99:1) to
as a colorless oil: Rf 0.49 (hexane–EtOAc, 7:3);
23
D
½aŠ ¼ ꢀ2:92 (c 2.0, CHCl3); 1H NMR (500 MHz,
CDCl3) d 7.40–7.27 (m, 5H, Ph), 5.29 (s, 1H, H-1),
5.27 (s, 1H, H-1, a-anomer), 4.73 (d, J = 5.9 Hz, 1H,
H-3), 4.64 (d, J = 11.6 Hz, 1H, OCHaHPh), 4.57 (d,
J = 11.6 Hz, 1H, OCHHbPh), 4.50 (d, J = 5.9 Hz, 1H,
H-2), 4.38 (dist t, J = 2.2 Hz, 1H, H-4), 3.66 (dd,
J = 10.0, 2.5 Hz, 1H, H-5a), 3.59 (dd, J = 10.0, 2.3 Hz,
1H, H-5b), 1.48 (s, 3H, CH3), 1.31 (s, 3H, CH3); 13C
NMR (125 MHz, CDCl3) d 136.1 (Ph), 128.4 (Ph),
128.1 (Ph), 112.0 (C(CH3)2), 103.8 (C-1), 100.7 (C-1 a-
anomer), 87.6 (C-4), 85.6 (C-2), 82.0 (C-3), 74.1
(OCH2Ph), 71.1 (C-5), 26.5 (CH3), 24.9 (CH3). Anal.
Calcd for C15H20O5: C, 64.27; H, 7.19. Found: C,
64.10; H, 7.25.
afford 8.91 g (92% yield) of pure compound 20 as a col-
23
D
orless oil: Rf 0.37 (hexane–EtOAc, 9:1); ½aŠ ¼ ꢀ21:8 (c
1
1.1, CHCl3); H NMR (500 MHz, CDCl3) d 7.33 (m,
5H, Ph), 6.08 (dq, J = 6.4, 1.7 Hz, 1H, CH@CHCH3),
5.26 (s, 1H, H-1), 4.75 (d, J = 6.2 Hz, 1H, H-3), 4.72
(d, J = 5.9 Hz, 1H, H-2), 4.58 (d, J = 12.1 Hz, 1H,
OCHHaPh), 4.50 (d, J = 12.1 Hz, 1H, OCHHbPh),
4.53 (distorted pentet, J = 6.8 Hz, 1H, CH@CHCH3),
4.40 (distorted t, J = 7.1 Hz, 1H, H-4), 3.50 (dd,
J = 9.9, 6.4 Hz, 1H, H-5a), 3.47 (dd, J = 9.9, 8.0 Hz,
1H, H-5b), 1.50 (dd, J = 6.7, 1.7Hz, 3H, CH@CHCH3),
1.49 (s, 3H, CH3), 1.33 (s, 3H, CH3); 13C NMR
(50 MHz, CDCl3) d 141.4 (CH@CHCH3), 137.9 (Ph),
128.4 (Ph), 127.7 (Ph), 112.6 (C(CH3)2), 108.0 (C-1),
103.4 (CH@CHCH3), 85.7 (C-4), 85.0 (C-2), 82.2 (C-
3), 73.4 (OCH2Ph), 70.7 (C-5), 26.4 (CH3), 25.0 (CH3),
9.4 (CH@CHCH3). Anal. Calcd for C18H24O5: C,
67.48; H, 7.55. Found: C, 67.24; H, 7.45.
Method B. A solution of compound 19 (162 mg,
0.51 mmol) in methanol (10 mL) was treated with palla-
dium chloride as catalyst (3.0 mg). The reaction mixture
was stirred at room temperature for 4 h. The mixture
was filtered through a Celite bed. The solvent was evap-
orated and the residue was purified by column chroma-
tography (silica gel) eluting with hexane–EtOAc (19:1)
to afford 42 mg of 22 and 69 mg of unreacted starting
material 19 (72% yield).
4.7. 5-O-Benzyl-2,3-O-isopropylidene-D-ribitol 23
A solution of compound 22 (936 mg, 3.3 mmol) in anhy-
drous tetrahydrofuran (18 mL) was treated with lithium
aluminum hydride (507 mg, 13.4 mmol) and the reaction
mixture was stirred at room temperature for 2 h. The
reaction was quenched with ethyl acetate (1.0 mL).
The mixture was partitioned between an aqueous satu-
rated solution of sodium potassium tartrate (100 mL)
and methylene chloride (100 mL). The organic layer
was washed with the tartrate solution (3 · 70 mL) and
water (2 · 70 mL). The solvent was dried (MgSO4) and
evaporated. The residue was purified by column chro-
matography (silica gel) eluting with hexane–EtOAc
(4:1) to afford 815 mg (88% yield) of pure compound
4.5. Formyl 5-O-benzyl-2,3-O-isopropylidene-b-D-ribo-
furanoside 21
To a solution of compound 20 (5.64 g, 17.6 mmol) in
anhydrous methylene chloride (50 mL) cooled at
ꢀ78 ꢁC was bubbled ozone until the reaction mixture
turned blue. Then, triphenylphosphine (9.30 g,
35.2 mmol) was added and the mixture was allowed to
warm to room temperature. The solvent was evaporated
and the residue was purified by column chromatography
(silica gel) eluting with hexane–EtOAc (9:1) to afford
4.69 g (95% yield) of pure compound 21 as a colorless
1
oil: Rf 0.29 (hexane–EtOAc, 4:1); H NMR (500 MHz,
23 as a white solid: Rf 0.29 (hexane–EtOAc, 1:1); mp
23
D
64–65 ꢁC; ½aŠ ¼ þ26:3 (c 2.6, CHCl3); 1H NMR
CDCl3) d 7.99 (s, 1H, OCHO), 7.34 (m, 5H, Ph), 6.27
(s, 1H, H-1), 4.79 (d, J = 5.9 Hz, 1H, H-3), 4.72 (d,
J = 5.9 Hz, 1H, H-2), 4.55 (mAB, 2H, OCH2Ph), 4.50
(dist t, J = 6.2 Hz, 1H, H-4), 3.57 (dd, J = 10.0, 5.7 Hz,
1H, H-5a), 3.48 (dd, J = 10.0, 7.3 Hz, 1H, H-5b), 1.51
(s, 3H, CH3), 1.34 (s, 3H, CH3); 13C NMR (125 MHz,
CDCl3) d 159.5 (OCHO), 137.7 (Ph), 128.4 (Ph), 127.6
(Ph), 113.1 (C(CH3)2), 102.6 (C-1), 86.8 (C-4), 85.2
(500 MHz, CDCl3) d 7.34 (m, 5H, Ph), 4.59 (mAB,
2H, OCH2Ph), 4.35 (dt, J = 7.7, 5.5 Hz, 1H, H-2), 4.10
(dd, J = 9.7, 5.8 Hz, 1H, H-3), 3.96 (m, 1H, H-4), 3.88
(ddd, J = 11.8, 7.7, 5.0 Hz, 1H, H-1a), 3.80 (m, 1H, H-
1b), 3.76 (dd, J = 9.6, 3.0 Hz, 1H, H-5a), 3.57 (dd,
J = 9.6, 6.7 Hz, 1H, H-5b), 3.00 (m, 1H, OH), 2.97 (m,
1H, OH), 1.39 (s, 3H, CH3), 1.34 (s, 3H, CH3); 13C

430
E. Elhalem et al. / Tetrahedron: Asymmetry 16 (2005) 425–431
NMR (125 MHz, CDCl3) d 137.8 (Ph), 128.5 (Ph), 127.8
(Ph), 108.6 (C(CH3)2), 85.6 (C-2)*, 82.0 (C-3)*, 73.5
(OCH2Ph), 71.7 (C-5), 68.7 (C-4), 60.8 (C-1), 27.8
(CH3), 25.3 (CH3). Anal. Calcd for C15H22O5: C,
63.81; H, 7.85. Found: C, 64.04; H, 8.12.
5a,b), 4.41–4.34 (m, 2H, OCH2Ph, H-2), 3.78 (dd,
J = 11.6, 4.6 Hz, 1H, H-1a), 3.71 (dd, J = 11.4, 4.1 Hz,
1H, H-1b), 1.55 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.04
(s, 9H, C(CH3)3). 13C NMR (125 MHz, CDCl3) d
205.2 (C-4), 137.3 (Ph), 135.7 (Ph), 135.6 (Ph), 133.2
(Ph), 133.0 (Ph), 129.7 (Ph), 128.4 (Ph), 127.8 (Ph),
127.7 (Ph), 109.7 (C(CH3)2), 79.7 (C-3), 78.5 (C-2),
74.1 (C-5), 73.2 (OCH2Ph), 61.9 (C-1), 26.9 (C(CH3)3),
26.7 (CH3), 24.6 (CH3), 19.2 (C(CH3)3).
4.8. 1-O-tert-Butyldiphenylsilyl-5-O-benzyl-2,3-O-isoprop-
ylidene-D-ribitol 24
To a solution of compound 23 (1.59 g, 5.63 mmol) in
anhydrous dimethylformamide (10 mL) was added
imidazole (844 mg, 12.4 mmol) and tert-butyldiphenyl
chlorosilane (1.61 g, 6.83 mmol) and the reaction mix-
ture was stirred at room temperature overnight. The
mixture was partitioned between water (100 mL) and
methylene chloride (100 mL). The aqueous phase was
reextracted with methylene chloride (100 mL), and the
combined organic layers were washed with brine
(5 · 100 mL), dried (MgSO4), and the solvent was evap-
orated. The residue was purified by column chromato-
graphy (silica gel) eluting with hexane–EtOAc (19:1) to
4.10. (2S,3R)-1-O-tert-Butyldiphenylsilyl-5-O-benzyl-2,3-
O-isopropylidene-4-C-methylene-D-erythro-pentitol 26
A suspension of methyltriphenylphosphonium bromide
(19.32 g, 54.1 mmol) in anhydrous tetrahydrofuran
(70 mL) at 0 ꢁC was added n-butyllithium (1.6 M in hex-
ane; 28.3 mL, 45.3 mmol) dropwise under argon atmo-
sphere. The mixture was stirred at 0 ꢁC for 30 min.
Then, was added a solution of compound 25 (3.08 g,
5.9 mmol) in tetrahydrofuran (10 mL), and the reaction
mixture was stirred at room temperature overnight. The
solvent was evaporated and the residue was purified by
column chromatography (silica gel) eluting with hex-
ane–EtOAc (97:3) to afford 2.794 g (92% yield) of pure
compound 26 as a colorless oil: Rf 0.28 (hexane–EtOAc,
give 2.858 g (98% yield) of pure compound 24 as a col-
23
D
orless oil: Rf 0.47 (hexane–EtOAc, 4:1); ½aŠ ¼ ꢀ4:2 (c
1
3.2 CHCl3); H NMR (500 MHz, CDCl3) d 7.68 (m,
4H, Ph), 7.46–7.28 (m, 11H, Ph), 4.65 (d, J = 12.3 Hz,
1H, OCHaHPh), 4.61 (d, J = 12.2 Hz, 1H, OCHHbPh),
4.34 (m, 1H, H-2), 4.29 (dd, J = 9.3, 5.7 Hz, 1H, H-3),
4.07 (m, 1H, H-4), 3.90 (dd, J = 10.8, 8.3 Hz, 1H, H-
1a), 3.79 (dd, J = 10.1, 2.3 Hz, 1H, H-5a), 3.72 (d,
J = 3.4 Hz, 1H, OH), 3.67 (dd, J = 11.0, 4.1 Hz, 1H,
H-1b), 3.65 (dd, J = 10.0, 5.6 Hz, 1H, H-5b), 1.31 (s,
3H, CH3), 1.30 (s, 3H, CH3), 1.07 (s, 9H, C(CH3)3);
13C NMR (125 MHz, CDCl3) d 138.5 (Ph), 135.6 (Ph),
132.5 (Ph), 132.4 (Ph), 128.3 (Ph), 127.9 (Ph), 127.7
(Ph), 127.5 (Ph), 108.5 (C(CH3)2), 77.4 (C-2)*, 76.9 (C-
3)*, 73.5 (OCH2Ph), 71.8 (C-5), 69.0 (C-4), 62.9 (C-1),
27.9 (CH3), 26.9 (C(CH3)3), 25.4 (CH3), 19.1
(C(CH3)3). Anal. Calcd for C31H40O5Si: C, 71.50; H,
7.74. Found: C, 71.69; H, 7.76. *Signal attribution
may be interchanged.
23
D
1
9:1); ½aŠ ¼ ꢀ36:9 (c 1.0, CHCl3); H NMR (500 MHz,
CDCl3) d 7.65 (m, 4H, Ph), 7.42–7.28 (m, 11H, Ph), 5.35
(s, 1H, C@CHaH), 5.24 (s, 1H, C@CHHb), 4.81 (d,
J = 5.9 Hz, 1H, H-3), 4.50 (d, J = 11.6 Hz, 1H,
OCHaHPh), 4.40 (d, J = 11.6 Hz, 1H, OCHHbPh),
4.33 (q, J = 6.0 Hz, 1H, H-2), 4.06 (d, J = 12.5 Hz, 1H,
H-5a), 3.99 (d, J = 12.5 Hz, 1H, H-5b), 3.64 (dd,
J = 10.5, 6.4 Hz, 1H, H-1a), 3.49 (dd, J = 10.5, 5.5 Hz,
1H, H-1b), 1.40 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.02
(s, 9H, C(CH3)3); 13C NMR (125 MHz, CDCl3) d
140.8 (C-4), 138.2 (Ph), 135.7 (Ph), 135.6 (Ph), 133.5
(Ph), 133.3 (Ph), 129.6 (Ph), 128.4 (Ph), 127.6 (Ph),
127.6 (Ph), 113.7 (C@CH2), 107.8 (C(CH3)2), 78.3 (C-
3), 76.9 (C-2), 72.1 (OCH2Ph), 71.8 (C-5), 63.5 (C-1),
27.6 (CH3), 26.8 (C(CH3)3), 25.3 (CH3), 19.1 (C(CH3)3).
4.9. (2S,3S)-1-O-tert-Butyldiphenylsilyl-5-O-benzyl-2,3-
O-isopropylidene-4-keto-D-erythro-pentitol 25
4.11. (2S,3R)-5-O-Benzyl-2,3-O-isopropylidene-4-C-
methylene-D-erythro-pentitol 27
To a solution of oxalyl chloride (1.12 mL, 12.93 mmol)
in anhydrous methylene chloride (10 mL) cooled at
ꢀ70 ꢁC under argon atmosphere was added methyl sulf-
oxide (2 mL). The mixture was stirred at ꢀ70 ꢁC for
5 min, then alcohol 24 (3.06 g, 5.88 mmol) in methylene
chloride (10 mL) was added and the reaction was stirred
for 15 min. Triethylamine (5.5 mL) was then added and
the mixture was stirred for an additional 5 min. The
mixture was allowed to warm to room temperature
and water (50 mL) was added. The aqueous phase was
reextracted with methylene chloride (50 mL). The com-
bined organic layers were washed with brine
(4 · 50 mL), dried (MgSO4), and the solvent was evapo-
rated to afford 3.05 g (100% yield) of pure compound 25
as a colorless oil, which was used in the next step with-
A solution of the compound 26 (2.62 g, 5.07 mmol) in
acetonitrile (30 mL) was added tetrabutyl ammonium
fluoride (1.0 M in tetrahydrofuran, 7.0 mL, 7.0 mmol)
and the resulting mixture was stirred at room tempera-
ture for 2 h. The solvent was evaporated and the prod-
uct was purified by column chromatography (silica gel)
eluting with hexane–EtOAc (9:1) to afford 1.37 g (97%
yield) of pure compound 27 as a colorless oil: Rf 0.26
23
1
(hexane–EtOAc, 4:1); ½aŠ ¼ ꢀ49:0 (c 2.0 CHCl3); H
D
NMR (500 MHz, CDCl3) d 7.32 (m, 5H, Ph), 5.44 (s,
1H, C@CHaH), 5.31 (s, 1H, C@CHHb), 4.72 (d,
J = 6.4 Hz, 1H, H-3), 4.53 (mAB, 2H, OCH2Ph), 4.27
(q, J = 6.4 Hz, 1H, H-2), 4.03 (d, J = 11.6 Hz, 1H, H-
5a), 3.98 (d, J = 11.6 Hz, 1H, H-5b), 3.51 (ddd,
J = 11.4, 6.1, 5.2 Hz, 1H, H-1a), 3.43 (dd, J = 11.4, 6.0,
5.4 Hz, 1H, H-1b), 2.36 (t, J = 6.1 Hz, 1H, OH), 1.49
(s, 3H, CH3), 1.38 (s, 3H, CH3); 13C NMR (125 MHz,
CDCl3) d 140.0 (C-4), 137.3 (Ph), 128.4 (Ph), 127.8
out further purification: Rf 0.42 (hexane–EtOAc, 4:1);
23
½aŠ ¼ ꢀ34:1 (c 2.3, CHCl3); 1H NMR (500 MHz,
D
CDCl3) d 7.68 (m, 4H, Ph), 7.38–7.27 (m, 11H, Ph),
4.70 (d, J = 8.0 Hz, 1H, H-3), 4.49–4.46 (m, 2H, H-

E. Elhalem et al. / Tetrahedron: Asymmetry 16 (2005) 425–431
431
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(Ph), 127.7 (Ph), 115.0 (C@CH2), 107.9 (C(CH3)2), 77.9
(C-3), 76.6 (C-2), 72.9 (OCH2Ph), 71.8 (C-5), 61.9 (C-1),
27.7 (CH3), 25.2 (CH3).
4.12. (2S,3R)-5-O-Benzyl-2,3-O-isopropylidene-1-keto-4-
C-methylene-D-erythro-pentose 28
6. Rodriguez, J. B.; Comin, M. J. Mini Rev. Med. Chem.
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To a solution of oxalyl chloride (0.75 mL, 8.6 mmol) in
anhydrous methylene chloride (10 mL) cooled at ꢀ70 ꢁC
under argon atmosphere was added methyl sulfoxide
(1.5 mL). The mixture was stirred at ꢀ70 ꢁC for 5 min,
then compound 27 (1.09 g, 3.92 mmol) in methylene
chloride (10 mL) was added and the reaction was stirred
for 15 min. Triethylamine (4.0 mL) was then added and
the mixture was stirred for an additional 5 min. The
mixture was allowed to warm to room temperature
and water (50 mL) was added. The aqueous phase was
reextracted with methylene chloride (50 mL). The com-
bined organic layers were washed with brine
(4 · 50 mL), dried (MgSO4), and the solvent was evapo-
rated. The residue was purified by column chromatogra-
phy (silica gel) employing a mixture of hexane–EtOAc
(9:1) to afford 1.059 g (98% yield) of pure compound
28 as a colorless oil: Rf 0.44 (hexane–EtOAc, 3:2);
23
D
½aŠ ¼ ꢀ44:5 (c 1.5, CHCl3) 1H NMR (500 MHz,
CDCl3) d 9.46 (d, J = 2.7 Hz, 1H, H-1), 7.33 (m, 5H,
Ph), 5.41 (s, 1H, C@CHaH), 5.28 (t, J = 1.1 Hz, 1H,
C@CHHb), 4.93 (d, J = 7.4 Hz, 1H, H-3), 4.53 (d,
J = 12.0 Hz, 1H, OCHHaPh), 4.49 (d, J = 11.9 Hz, 1H,
OCHHbPh), 4.46 (dd, J = 7.4, 2.8 Hz, 1H, H-2), 4.02
(mAB, 2H, H-5), 1.63 (s, 3H, CH3), 1.44 (s, 3H, CH3);
13C NMR (125 MHz, CDCl3) d 200.2 (C-1), 139.1 (C-
4), 137.7 (Ph), 128.4 (Ph), 127.8 (Ph), 127.7 (Ph), 114.9
C@CH2), 110.5 (C(CH3)2), 81.6 (C-2), 77.6 (C-3), 72.3
(OCH2Ph), 71.4 (C-5), 27.1 (CH3), 25.3 (CH3).
19. Chu, C. K.; Jin, Y. H.; Baker, R. O.; Huggins, J. Bioorg.
Med. Chem. Lett. 2003, 13, 9–12.
20. Comin, M. J.; Leitofuter, J.; Rodriguez, J. B. Tetrahedron
2002, 58, 3129–3136.
Acknowledgements
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´
Thanks are owned to Fundacion Antorchas, the
National Research Council of Argentina (grant PIP
635/98) and the Universidad de Buenos Aires (grant
X-252) for financial support.
23. Marquez, V. E.; Russ, P.; Alonso, R.; Sidiqqui, M. A.;
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