Synthesis of differently protected 1-C-methyl-ribofuranoses intermediates for the preparation of biologically active 1'-C-methyl-ribonucleosides

Article abstract of DOI:10.1080/07328300802217848

Starting from D-ribose, differently protected 1-C-methyl-D-ribofuranoses have been prepared as intermediates for the synthesis of variously modified 1'-C-methyl-ribonucleosides, a class of compounds potentially endowed with interesting biological activity.

Full text of DOI:10.1080/07328300802217848

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Synthesis of Differently Protected
1‐C‐Methyl‐Ribofuranoses Intermediates
for the Preparation of Biologically Active
1′‐C‐Methyl‐Ribonucleosides
Laura Alessandrini a , Silvana Casati a , Pierangela Ciuffreda a , Roberta
Ottria a & Enzo Santaniello b
a Dipartimento di Scienze Precliniche LITA Vialba, Università degli Studi di
Milano – Via G. B. Grassi , Milano, Italy
b Dipartimento di Medicina, Chirurgia e Odontoiatria, Università degli Studi
di Milano – Via A. di Rudinì , Milano, Italy
Published online: 24 Jul 2008.
To cite this article: Laura Alessandrini , Silvana Casati , Pierangela Ciuffreda , Roberta Ottria & Enzo
Santaniello (2008) Synthesis of Differently Protected 1‐C‐Methyl‐Ribofuranoses Intermediates for the
Preparation of Biologically Active 1′‐C‐Methyl‐Ribonucleosides, Journal of Carbohydrate Chemistry, 27:5,
332-344, DOI: 10.1080/07328300802217848
To link to this article: http://dx.doi.org/10.1080/07328300802217848
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Journal of Carbohydrate Chemistry, 27:332–344, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300802217848
Synthesis of Differently
Protected 1-C-Methyl-
Ribofuranoses
Intermediates for the
Preparation of Biologically
Active 10-C-Methyl-
Ribonucleosides
Laura Alessandrini,1 Silvana Casati,1 Pierangela Ciuffreda,1
Roberta Ottria,1 and Enzo Santaniello2
1
`
Dipartimento di Scienze Precliniche LITAVialba, Universita degli Studi di Milano – Via
G. B. Grassi, Milano, Italy
2
`
Dipartimento di Medicina, Chirurgia e Odontoiatria, Universita degli Studi di Milano –
`
Via A. di Rudinı, Milano, Italy
Starting from D-ribose, differently protected 1-C-methyl-D-ribofuranoses have been
prepared as intermediates for the synthesis of variously modified 10-C-methyl-ribonu-
cleosides, a class of compounds potentially endowed with interesting biological activity.
Keywords 1-C-Methyl-D-ribofuranoses, 1-Deoxy-psicofuranoses, D-Ribonolactone,
Tetrapropylammonium perruthenate
INTRODUCTION
Synthetic nucleosides with modifications in the carbohydrate or base moiety
are often characterized by anticancer[1] or antiviral[2–4] activity. In this
respect, 40 years ago it was recognized that modifications at the 10-position
of adenosine, as in psicoadenosine (Fig. 1), “prevent deamination, while
Received April 22, 2008; accepted May 20, 2008.
Address correspondence to Pierangela Ciuffreda, Dipartimento di Scienze
`
Precliniche LITA Vialba, Universita degli Studi di Milano – Via G. B. Grassi, 74-20157
Milano, Italy. E-mail: pierangela.ciuffreda@unimi.it
332

Synthesis of 1-C-Methyl-Ribofuranoses
333
Figure 1: Structure of 1’-C-substituted nucleosides, 1-deoxypsicofuranose derivatives, and
D-ribonolactone.
permitting good growth inhibitory activity.”[5] Therefore, “modifications at this
position, although chemically difficult, appear to be desirable.”[5]
Due to this synthetic difficulty, only a few 10-C-substituted nucleosides have
been prepared so far[6–9] and new promising biological activity for this class of
compounds has been recently disclosed.[10] For our project related to the syn-
thesis of analogues of 10-C-methyl-adenosine,[11,12] gram quantities of 1-deox-
ypsicofuranoses were required (Fig. 1).
RESULTS AND DISCUSSION
Synthesis of Differently Protected D-Ribonolactone
Derivatives from D-Ribose
D-Ribonolactone would represent the ideal starting material for this syn-
thesis, but its high price is not adequate to large-scale preparations. For this
reason, D-ribose has been chosen as the alternative starting material as
already proposed for the preparation of kilogram scale of a few D-ribonolactone
derivatives.[13,14]
We have tried classical oxidations including the reactions with permanga-
nate[13] or pyridinium chlorochromate[15] and the reagent of choice was tetra-
propylammonium perrhuthenate (TPAP) under catalytic conditions with
N-methylmorpholine N-oxide (NMMO) as co-oxidant.[16] This oxidizing
system, previously applied to the synthesis of lactones from pyranoses and fur-
anoses protected as benzyl and allyl ethers,[17] allowed a nearly quantitative
transformation (95% of recovered purified product) of protected D-ribofura-
noses 2, 3b, and 4 to the corresponding lactones 5, 6, and 7 (Sch. 1).
The preparation of lactone 6 started from the reaction of D-ribose (1a) with
benzaldehyde in the presence of zinc chloride.[18] 2,3-Benzylidene derivative 3a
was obtained as an endo/exo mixture of the phenyl group of the benzylidene
moiety, the b-anomer prevailing over the a-one (8:1 ratio).[19] 1H NMR

L. Alessandrini et al.
334
Scheme 1: Synthesis of protected D-ribonolactones 5, 6, and 7.
analysis of the two products purified by flash chromatography showed that the
less polar product corresponds to the b-anomer, characterized by signals of
H-C(1) (doublets at 5.53 and 5.56 ppm) coupled with H-C(2) (J , 1 Hz). The
more polar product corresponds to the a-anomer, characterized by signals of
H-C(1) (doublets at 5.96 and 5.98 ppm) coupled with H-C(2) (J ¼ 3.7 Hz).
Compound 3a was utilized as a crude a/b mixture, silylated to ribofuranose
3b, which was then oxidized with TPAP/NMMO to lactone 6 (3:1 exo/endo,
overall yield from D-ribose 51%). The endo (or R) configuration for the phenyl
group of the major isomer of compound 6 was assigned by analysis of the
NOE experiment. Saturation of the benzylidene proton resulted in NOEs of
H-C(2) and H-C(3) signals, whereas H-C(4) was not affected. As a complemen-
tary result, in the minor isomer the irradiation of the benzylidene proton led to
H-C(4) signal enhancement and the configuration exo (or S) was assigned.
We have also synthesized 2,3,5-tribenzyl-D-ribono-1,4-lactone 7, consider-
ing that the corresponding 1-C-methyl-ribofuranose 10 could be a useful
intermediate for the synthesis of 10-C-methyl-adenosine. 2,3,5-Tri-O-benzyl-
D-ribofuranose (4) was prepared from 1-O-methyl-ribofuranose (1b) essentially
as described in the literature[20] and quantitatively oxidized to lactone 7 using
TPAP/NMMO (Sch. 1).
Synthesis of 1-C-methyl-ribofuranoses
Reaction of protected D-ribonolactones with organometallic reagents is a
well-known methodology for the synthesis of C-nucleosides.[21] It has been
reported that ribonolactone 5 reacts with methyllithium at low temperature to

Synthesis of 1-C-Methyl-Ribofuranoses
335
afford the corresponding 1-deoxy-psicofuranose 8, as only one anomer.[6,7,11]
Opening of the ribonolactone to the corresponding methyl ketone and
related formation of a tertiary alcohol reported for other lactones[22] were not
observed in the case of lactone 5.[23] We have verified that 8 presents only
the a-OH and have not observed the formation of other competing side
products. Under the same conditions, the methylation of 2,3-benzylidene
lactone 6[11] afforded a mixture of unidentified products along with 1-deoxypsico-
furanose 9 that could only be isolated in 38% yield. Compound 9 is an endo/exo
mixture of the anomer that presents the methyl group in the a position, as
evidenced by NOE experiments in which irradiation of methyl group at C-1 led
to H-C(5) enhancement. In the 1H NMR spectrum of compound 9 we observed
two signals corresponding to the 1-methyl at 1.62 ppm (exo) and 2.38 ppm
(endo). The downshift of the signal at 2.38 ppm in the endo-9 can be explained
by the influence of the vicinal phenyl group at the same side of the methyl group.
Finally, we examined the methylation of lactone 7 and obtained compound
10 in good yield (91% of purified product) as an anomeric mixture (1 a-CH3:3.5
b-CH3 ratio, as determined by NMR analysis) with no evidence for other side
products (Sch. 2).
Acetylation of 1-C-methyl-ribofuranoses
The synthesis of 10-C-methyl-nucleosides required the acetylation of
1-deoxy-psicofuranoses before the coupling with the base.[6,7,9,11] The
Scheme 2: Methylation of lactones 5, 6, and 7.

L. Alessandrini et al.
336
Scheme 3: Acetylation of 1-C-methyl-ribofuranoses 8, 9, and 10.
acetylation of compound 8 has been studied in detail and it has been demon-
strated that, starting from an anomerically pure 8, an a/b mixture of acetate
11 is formed (a-anomer 28%, b-anomer 58%).[11]
The acetylation of anomerically pure 9 yielded an equimolar mixture of
four acetyl derivatives 12, a-acetate (endo/exo), and b-acetate (endo/exo)
with a small amount of acyclic compounds, and this discourages from the use
of this intermediate for 10-C-methyl-nucleosides synthesis. Under the same
conditions of acetylation, 1-deoxy-psicofuranose 10 afforded only one product
(60% yield) that did not correspond to the expected cyclic acetate 14. 1H
NMR analysis of the isolated product showed resonances of H-C(5) at
5.32 ppm and of H-C(3) at 4.05 ppm, consistent with an acyclic structure.
1
The singlet at 2.14 ppm in the H NMR spectrum and the signal at 208.19 in
the 13C NMR spectrum suggested that a methyl ketone was present in the
structure. Furthermore, the resonance at 169.76 ppm in the 13C NMR indi-
cated the presence of an acetate and the structure of acyclic ketohexose was
proposed for the product 13 (Sch. 3).
CONCLUSIONS
We have investigated the preparation of a few 1-C-methyl-ribofuranoses
starting from D-ribose (1a), which was transformed in the corresponding

Synthesis of 1-C-Methyl-Ribofuranoses
337
derivatives 2, 3b, and 4. The oxidation of these compounds to the corresponding
lactones 5, 6, and 7 has been quantitatively achieved with TPAP under catalytic
conditions with NMMO as co-oxidant. The methylation of lactones 5 and 7 sat-
isfactorily afforded 1-C-methyl-ribofuranoses 8 and 10, whereas the yield of 1-C-
methyl-ribofuranose 9 from lactone 6 was low. The acetates 11, 12, and 14 are
key intermediates for the synthesis of 10-C-methyl-nucleosides. Under
standard acetylating conditions the 3,4-O-benzylidene derivative 9 gave the
acetate mixture 12 in low yields and an open form was the only product
obtained from the benzyl derivative 10. Only the acetate of 3,4-O-isopropyli-
dene-1-C-methyl-ribofuranose 11 could be prepared in satisfactory yield.[12] In
light of our results, starting from 1a, only the synthetic pathway leading to
the acetates 11 is suitable for the synthesis of 10-C-methyl-nucleosides.
EXPERIMENTAL
General
Melting points were recorded on a Stuart Scientific SMP3 instrument and
are uncorrected. Optical rotations were measured on a Perkin-Elmer 241
polarimeter using sodium lamp at 589 nm in CHCl3.1H NMR spectra were
recorded at 303 K on Bruker AM-500 spectrometer operating at 500.13 and
125.76 MHz for 1H and 13C, respectively, equipped with an Aspect 3000
1
computer, a process control, and an array processor. The H NMR chemical
shifts are reported in parts per million, using as reference the signal for
residual solvent protons (7.24 for CDCl3), and coupling constants (J) are
given in Hertz. In the 13C NMR spectra the residual solvent signal was used
as an internal reference (CDCl3, triplet at d ¼ 77.23 ppm). All assignments
were confirmed with the aid of two-dimensional 1H,1H (COSYGPQF)
or 1H,13C (INV4GPQF) or 1H,13C (INV4GPLRNDQF) experiments using
standard Bruker pulse programs. Mass spectra were recorded on Finnigan
LCQ-Deca (Termoquest) in ESI positive-ion mode, KV 5.00, 2258C, 15 V.
The progress of all reactions and column chromatography were monitored
by TLC (Silica Gel 60 F254 precoated plates with fluorescent indicator, Merck).
Purification of products was achieved by flash chromatography using
silica gel 60 (230–400 mesh, Merck). 2,3,5-Tri-O-benzyl-D-ribofuranose
(4),[20] 6-O-(tert-butyldimethylsilyl)-3,4-O-isopropylidene-1-deoxy-D-psicofura-
nose (8), and 2-O-acetyl-6-O-(tert-butyldimethylsilyl)-3,4-O-isopropylidene-1-
deoxy-D-psicofuranose (11)[11] were prepared according to literature and
verified by NMR and ESI-MS.
2,3-O-Benzylidene-a/b-D-ribofuranose (3a)
A mixture of D-ribose 1a (1.0 g, 6.6 mmol), ZnCl2 (0.83 g, 6.1 mmol), and
benzaldehyde (4.5 mL, 45.0 mmol) was stirred for 18 h. Aqueous 40%

L. Alessandrini et al.
338
NaHSO3 (75 mL) was added, the mixture stirred for 15 min, and, after evapor-
ation at reduced pressure, the residue was treated with CH2Cl2 (120 mL). The
resulting slurry was stirred vigorously for 1 h and filtered and the filtrate evap-
orated. The residue was purified by flash chromatography (petroleum ether/
ethyl acetate, 6:4) and two products were separated corresponding to
a-anomer (Rf 0.125 in petroleum ether/ethyl acetate, 6:4) and b-anomer
(Rf 0.375 in petroleum ether/ethyl acetate, 6:4) (1:8) of the endo/exo mixture
of title compound (64% yield).[19]
b-3a: 0.90 g; 1H NMR endo d ¼ 7.45–7.44 (m, 5H, Ph), 5.80 (s, 1H, H-CPh), 5.56
(d, J , 1, 1H, H-1), 4.90 (d, J ¼ 6.2 Hz, 1H, H-2), 4.68 (d, J ¼ 6.2 Hz, 1H, H-3),
4.58–4.57 (m, 1H, H-4), 3.82–3.75 (m, AB part of ABX system, 2H, H-5a,b)
ppm; exo d ¼ 7.39–7.36 (m, 5H, Ph), 5.97 (s, 1H, H-CPh), 5.53 (d, J , 1, 1H,
H-1), 4.98 (d, J ¼ 5.6 Hz, 1H, H-2), 4.69 (d, J ¼ 5.6 Hz, 1H, H-3), 4.53–4.50
(m, 1H, H-4), 3.82–3.75 (m, AB part of ABX system, 2H, H-5a,b) ppm.
a-3a: 0.11 g; 1H NMR endo d ¼ 7.47–7.44 (m, 5H, Ph), 6.0 (s, 1H, H-CPh), 5.96
(d, J ¼ 3.7, 1H, H-1), 4.63 (dd, J ¼ 3.7 Hz, J ¼ 5.3 Hz, 1H, H-2), 4.09 (dd,
J ¼ 5.3 Hz, J ¼ 8.4 Hz, 1H, H-3), 3.97 (dd, J ¼ 2.7 Hz, J ¼ 12.1 Hz, 1H,
H-5a), 3.91 (ddd, J ¼ 2.7 Hz, J ¼ 2.7 Hz, J ¼ 8.4 Hz, 1H, H-4), 3.73 (dd,
J ¼ 2.7 Hz, J ¼ 12.1 Hz, 1H, H-5b) ppm; exo d ¼ 7.41–7.38 (m, 5H, Ph), 6.18
(s, 1H, H-CPh), 5.98 (d, J ¼ 3.7, 1H, H-1), 4.71 (dd, J ¼ 3.7 Hz, J ¼ 5.3 Hz,
1H, H-2), 4.11 (dd, J ¼ 5.3 Hz, J ¼ 8.4 Hz, 1H, H-3), 3.97 (dd, J ¼ 2.7 Hz,
J ¼ 12.1 Hz, 1H, H-5a), 3.91 (ddd, J ¼ 2.7 Hz, J ¼ 2.7 Hz, J ¼ 8.4 Hz, 1H,
H-4), 3.73 (dd, J ¼ 2.7 Hz, J ¼ 12.1 Hz, 1H, H-5b) ppm.
5-O-(tert-Butyldimethylsilyl)-2,3-O-benzylidene-a/b-D-ribofuranose (3b)
To a solution of the a/b mixture of 3a (1.0 g, 4.2 mmol) in dry CH2Cl2
(50 mL) under N2, triethylamine (0.64 mL, 4.6 mmol), DMAP (0.05 g,
0.42 mmol) in dry CH2Cl2 (5 mL) and tert-butyldimethylsilylchloride (0.69 g,
4.6 mmol) in dry CH2Cl2 (30 mL) were sequentially added. The mixture was
stirred at rt for 5 h and treated with 1M HCl solution to acidic pH, then with
NaHCO3 and H2O to pH 7.0. The solution was dried on Na2SO4 and evaporated
under reduced pressure to give crude a/b mixture of 3b (0.90 g, 83% yield,
endo/exo).[24]
1
b-3b: H NMR endo d ¼ 7.54–7.51 (m, 2H, Ph), 7.43–7.38 (m, 3H, Ph), 5.79
(s, 1H, H-CPh), 5.47 (d, J , 1, 1H, H-1), 4.82 (d, J ¼ 5.0 Hz, 1H, H-2), 4.64
(d, J ¼ 5.0 Hz, 1H, H-3), 4.54 (dd, J ¼ 2.4 Hz, J ¼ 2.4 Hz, 1H, H-4), 3.88–
3.82 (m, AB part of ABX system, 2H, H-5a,b), 0.98 (s, 9H, SiC(CH3)3), 0.18
(s, 3H, SiCH3), 0.16 (s, 3H, SiCH3) ppm; exo d ¼ 7.50–7.48 (m, 2H, Ph),
7.54–7.51 (m, 2H, Ph), 6.00 (s, 1H, H-CPh), 5.44 (d, J , 1, 1H, H-1), 4.92
(d, J ¼ 5.0 Hz, 1H, H-2), 4.66 (d, J ¼ 5.0 Hz, 1H, H-3), 4.49 (dd, J ¼ 2.4 Hz,

Synthesis of 1-C-Methyl-Ribofuranoses
339
J ¼ 2.4 Hz, 1H, H-4), 3.84–3.78 (m, AB part of ABX system, 2H, H-5a,b) 0.97
(s, 9H, SiC(CH3)3), 0.19 (s, 3H, SiCH3), 0.18 (s, 3H, SiCH3) ppm.
1
a-3b: H NMR endo d ¼ 7.52–7.48 (m, 2H, Ph), 7.43–7.38 (m, 3H, Ph), 6.02
(s, 1H, H-CPh), 5.88 (d, J ¼ 4.6, 1H, H-1), 4.50 (dd, J ¼ 4.6 Hz, J ¼ 4.8 Hz,
1H, H-2), 4.25 (dd, J ¼ 4.8 Hz, J ¼ 5.3 Hz, 1H, H-3), 3.95–3.90 (m, m 1H,
H-4), 3.76–3.69 (m, AB part of ABX system, 2H, H-5a,b), 0.97 (s, 9H,
SiC(CH3)3), 0.18 (s, 3H, SiCH3), 0.16 (s, 3H, SiCH3) ppm; exo d ¼ 7.62–7.58
(m, 2H, Ph), 7.43–7.38 (m, 3H, Ph), 6.17 (s, 1H, H-CPh), 5.91 (d, J ¼ 4.6, 1H,
H-1), 4.61 (dd, J ¼ 4.6 Hz, J ¼ 4.8 Hz, 1H, H-2), 4.23 (dd, J ¼ 4.8 Hz,
J ¼ 5.3 Hz, 1H, H-3), 3.92–3.87 (m, 1H, H-4), 3.72–3.66 (m, AB part of ABX
system, 2H, H-5a,b), 0.98 (s, 9H, SiC(CH3)3), 0.19 (s, 3H, SiCH3), 0.15 (s, 3H,
SiCH3) ppm.
General Procedure for the Tetrapropylammonium
Perruthenate (TPAP) Oxidation
A solution of ribofuranose derivative (5.0 mmol) in dry CH2Cl2 (40 mL)
with NMMO (1.17 g, 10.0 mmol) and molecular sieves (2.5 g) was stirred at
rt and TPAP (0.175 g, 0.5 mmol) was added. After 30 min of stirring, the oxi-
dation was complete and was filtered on a celite pad that was then washed
with CH2Cl2. The filtrate was evaporated under reduced pressure to give the
crude product.
5-O-(tert-Butyldimethylsilyl)-2,3-O-isopropylidene-D-ribono-1,4-lactone (5)
Colorless crystals (1.44 g, 95%); mp 69–718C [lit.[25] 69–708C]; [a]D20 –48.7
(c ¼ 1.00, CHCl3) f[13][a]D20 –46.6 (c ¼ 0.80, CHCl3)g; H NMR: d ¼ 4.76–4.72
1
(m, 2H, H-2 and H-3), 4.61 (ddd, J ¼ 1.0 Hz, J ¼ 1.9 Hz, J ¼ 5.6 Hz, 1H,
H-4), 3.91 (dd, J ¼ 1.9 Hz, J ¼ 11.3 Hz, 1H, H-5a), 3.82 (dd, J ¼ 1.0 Hz,
J ¼ 11.3 Hz, 1H, H-5b), 1.49 (s, 3H, CH3), 1.40 (s, 3H, CH3), 0.89 (s, 3H,
SiC(CH3)3), 0.09 (s, 3H, SiCH3), 0.07 (s, 3H, SiCH3) ppm. 13C NMR
(500 MHz; CDCl3, 258C): d ¼ 174.17 (C55O), 112.99 (Cquat), 82.31 (C-4), 78.47
(C-3), 75.79 (C-2), 62.98 (C-5), 26.78 (CCH3), 25.76 (SiC(CH3)3), 25.58
(CCH3), 18.19 (SiC(CH3)3), –5.62 (SiCH3), –5.77 (SiCH3) ppm. M/z 320
(M þ NH3)þ.
5-O-(tert-Butyldimethylsilyl)-2,3-O-benzylidene-D-ribono-1,4-lactone (6)
Colorless syrup (1.66 g, 95%, endo/exo 3:1).
1
endo-6: H NMR d ¼ 7.49–7.47 (2H, m, Ph), 7.43–7.41 (m, 3H, Ph), 5.99
(s, 1H, PhCH), 4.90–4.87 (m, 2H, H-2 and H-3), 4.77–4.76 (ddd, J , 1.0 Hz,
J ¼ 1.3 Hz, J ¼ 2.0 Hz 1H, H-4), 3.96 (dd, J ¼ 2.0 Hz, J ¼ 11.3 Hz, 1H, H-5a),
3.87 (dd, J ¼ 1.3 Hz, J ¼ 11.3 Hz, 1H, H-5b), 0.93 (s, 9H, SiC(CH3)3), 0.12
(s, 3H, SiCH3), 0.11 (s, 3H, SiCH3) ppm. 13C NMR: d ¼ 172.95 (C55O), 135.29

L. Alessandrini et al.
340
(PhC), 130.06 (PhCH), 128.52 (PhCH), 126.85 (PhCH), 106.57 (PhCH), 81.61
(C-3), 80.08 (C-2), 75.91 (C-4), 63,17 (C-5), 25.79 (SiC(CH3)3), 18.22
(SiC(CH3)3), –5.58 (SiCH3), –5.72 (SiCH3) ppm. M/z 373 (M þ Na), 723
(M þ M þ Na).
exo-6: 1H NMR d ¼ 7.51–7.48 (2H, m, Ph), 7.43–7.42 (m, 3H, Ph), 5.98 (s, 1H,
PhCH), 4.99 (d, J ¼ 5.7 Hz, 1H, H-2), 4.82–4.80 (m, 2H, H-3 and H-4), 3.94 (dd,
J ¼ 2.0 Hz, J ¼ 11.4 Hz, 1H, H-5a), 3.87 (dd, J ¼ 1.2 Hz, J ¼ 11.4 Hz, 1H,
H-5b), 0.91 (s, 9H, SiC(CH3)3), 0.11 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3) ppm.
13C NMR: d ¼ 173.05 (C55O), 135.70 (PhC), 130.05 (PhCH), 128.49 (PhCH),
126.47 (PhCH), 104.60 (PhCH), 84.13 (C-3), 77.86 (C-2), 76.42 (C-4), 63,18
(C-5), 25.77 (SiC(CH3)3), 18.21 (SiC(CH3)3), –5.62 (SiCH3), –5.72 (SiCH3)
ppm. M/z 373 (M þ Na), 723 (M þ M þ Na).
2,3,5-O-Tribenzyl-D-ribono-1,4-lactone (7)
Colorless crystals (1.98 g, 95%); mp 53–548C [lit.[26] 54–558C]; [a]D20 þ73.6
(c ¼ 1.00, CHCl3) flit.[27] [a]D20 þ74.1 (c ¼ 2.00, CHCl3)g; H NMR: d ¼ 7.45–
1
7.30 (m, 13H, Ph), 7.24–7.17 (m, 2H, Ph), 4.98 (d, J ¼ 11.9 Hz, 1H, CHHPh),
4.78 (d, J ¼ 11.9 Hz, 1H, CHHPh), 4.73 (d, J ¼ 11.9 Hz, 1H, CHHPh), 4.60
(d, J ¼ 11.9 Hz, 1H, CHHPh), 4.57 (ddd, J ¼ 1.6 Hz, J ¼ 2.4 Hz, J ¼ 2.7 Hz,
1H, H-4), 4.52 (d, J ¼ 11.0 Hz, 1H, CHHPh), 4.45 (d, J ¼ 5.9 Hz, 1H, H-2),
4.44 (d, J ¼ 11.0 Hz, 1H, CHHPh), 4.14 (dd, J ¼ 5.9 Hz, J ¼ 1.6 Hz, 1H, H-3),
3.69 (dd, J ¼ 2.7 Hz, J ¼ 11.0 Hz, 1H, H-5a), 3.59 (dd, J ¼ 2.4 Hz,
J ¼ 11.0 Hz, 1H, H-5b) ppm. 13C NMR: d ¼ 173.74 (C55O), 137.30 (PhCH2),
137.19 (PhCH2), 173.01 (PhCH2), 128.54 (PhCH2), 128.28 (PhCH2), 128.14
(PhCH2), 128.08 (PhCH2), 128.02 (PhCH2), 127.63 (PhCH2), 81.82 (C-4),
75.43 (C-3), 73.78 (CH2), 73.68 (C-2), 72.76 (CH2), 72.42 (CH2), 68.80 (C-5)
ppm. M/z 441 (M þ Na).
General Procedure for the Methylation of D-Ribonolactone
Derivatives
To a stirred solution of 1.6 M methyllithium in diethyl ether (2.13 mL) at
–708C under argon atmosphere, a solution of D-ribonolactone derivative
(2.0mmol) in anhydrous diethyl ether (20 mL) was added dropwise. After 1 h
the mixture was warmed to 08C, treated with 10% aqueous NH4Cl (20 mL)
and extracted with diethyl ether (3 ꢀ 20 mL). The combined organic solutions
were washed with ice-cold water (2 ꢀ 15 mL) and dried over anhydrous
Na2SO4. Removal of the solvent under reduced pressure and purification of
the residue by flash chromatography (petroleum ether/ethyl acetate, 9:1)
afforded required 1-deoxy-psicofuranoside.

Synthesis of 1-C-Methyl-Ribofuranoses
341
6-O-(tert-Butyldimethylsilyl)-3,4-O-benzylidene-1-deoxy-D-psicofuranose (9)
Colorless syrup (0.28 g, 38%, 3:1 endo/exo).
1
endo-9: H NMR d ¼ 7.53–7.50 (m, 2H, Ph), 7.43–7.40 (m, 3H, Ph), 5.94
(s, 1H, PhCH), 4.76 (d, 1H, J ¼ 5.1 Hz, H-3), 4.25 (dd, J ¼ 5.1 Hz, J ¼ 7.1 Hz,
1H, H-4), 3.85 (dd, J ¼ 6.0 Hz, J ¼ 6.0 Hz, 1H, H-6a), 3.79–3.75 (m, 2H, H-5
and H-6b), 2.38 (s, 3H, CH3), 0.93 (s, 9H, SiC(CH3)3), 0.11 (s, 3H, SiCH3),
0.10 (s, 3H, SiCH3) ppm.
exo-9: 1H NMR d ¼ 7.52–7.49 (m, 2H, Ph), 7.44–7.40 (m, 3H, Ph), 5.92 (s, 1H,
PhCH), 5.05 (dd, 1H, J ¼ 1.3 Hz, J ¼ 5.1 Hz, H-4), 4.57 (d, J ¼ 5.1 Hz, 1H,
H-3), 4.41 (ddd, J ¼ 1.3 Hz, J ¼ 1.9 Hz, J ¼ 1.9 Hz, 1H, H-5), 3.90–3.80
(m, 2H, H-6a and H-6b), 1.62 (s, 3H, CH3), 0.97 (s, 9H, SiC(CH3)3), 0.19
(s, 3H, SiCH3), 0.18 (s, 3H, SiCH3) ppm.
3,4,6-Tribenzyl-1-deoxy-D-psicofuranose (10)
Colorless syrup (0.79 g, 91%, anomeric mixture 1: 3.5 ratio);[28] major
isomer: 1H NMR d ¼ 7.43–7.35 (m, 15H, Ph), 4.73 (d, J ¼ 11.5 Hz, 1H,
CHHPh), 4.62 (d, J ¼ 11.5 Hz, 1H, CHHPh), 4.67–4.61 (AB system, 2H,
CH2Ph), 4.57 (d, J ¼ 12.0 Hz, 1H, CHHPh), 4.52 (d, J ¼ 12.0 Hz, 1H,
CHHPh), 4.35 (ddd, J ¼ 2.2 Hz, J ¼ 3.5 Hz, J ¼ 4.8 Hz, 1H, H-5), 4.04 (dd,
J ¼ 2.2 Hz, J ¼ 5.1 Hz, 1H, H-4), 3.76 (d, J ¼ 5.1 Hz, 1H, H-3), 3.54 (dd,
J ¼ 3.5 Hz, J ¼ 10.4 Hz, 1H, H-6a), 3.48 (dd, J ¼ 4.8 Hz, J ¼ 10.4 Hz, 1H,
1
H-6b), 1.51 (s, 1H, CH3) ppm. minor isomer: H NMR d ¼ 7.34–7.27 (m, 15H,
Ph), 4.80 (d, J ¼ 11.8 Hz, 1H, CHHPh), 4.75 (d, J ¼ 11.8 Hz, 1H, CHHPh),
4.58 (d, J ¼ 11.0 Hz, 1H, CHHPh), 4.50 (d, J ¼ 11.0 Hz, 1H, CHHPh), 4.46–
4.40 (AB system, 2H, CH2Ph), 4.31–4.29 (m, 1H, H-5), 4.01 (dd, J ¼ 2.4 Hz,
J ¼ 4.4 Hz, 1H, H-4), 3.84 (d, J ¼ 4.4 Hz, 1H, H-3), 3.68 (dd, J ¼ 2.6 Hz,
J ¼ 10.4 Hz, 1H, H-6a), 3.65 (dd, J ¼ 3.0 Hz, J ¼ 10.4 Hz, 1H, H-6b), 1.58
(s, 1H, CH3) ppm.
General Procedure for the Acetylation of 1-Deoxy-D-
psicofuranoses
To a solution of 1-deoxy-psicofuranose (1.0 mmol) and DMAP (5 mg,
0.04 mmol) in pyridine (2 mL), acetic anhydride (0.11 mL, 1.0 mmol) was
added dropwise and the reaction was stirred at rt for 5 h. Ice-cold water
(5 mL) was then added and the aqueous phase was extracted with CHCl3
(3 ꢀ 3 mL). The combined organic layers were washed with a cold saturated
NaHCO3 solution (3 ꢀ 3 mL), dried over anhydrous Na2SO4, and evaporated
under reduced pressure.
5-O-Acetyl-3,4,6-tri-O-benzyl-1-deoxy-D-psicose (13)
From 3,4,6-tribenzyl-1-deoxy-D-psicofuranose (10), compound 13 was
purified by flash chromatography (petroleum ether/ethyl acetate, 8:2);

L. Alessandrini et al.
342
colorless syrup (0.29 g, 60%); [a]2D0 þ 0.0 (c ¼ 1.00, CHCl3); 1H NMR d ¼ 7.36–
7.24 (m, 15H, Ph), 5.32 (ddd, J ¼ 4.0 Hz, J ¼ 4.0 Hz, J ¼ 6.8 Hz, 1H, H-5), 4.65
(d, J ¼ 11.9 Hz, 1H, CHHPh), 4.62–4.59 (AB system, 2H, CH2Ph), 4.60
(d, J ¼ 11.9 Hz, 1H, CHHPh), 4.56 (d, J ¼ 12.0 Hz, 1H, CHHPh), 4.48
(d, J ¼ 12.0 Hz, 1H, CHHPh), 4.21 (dd, J ¼ 4.0 Hz, J ¼ 6.8 Hz, 1H, H-4), 4.05
(d, J ¼ 4.0 Hz, 1H, H-3), 3.78–3.72 (m, 2H, H-6a,b), 2.14 (s, 3H, COCH3),
2.05 (s, 3H, OCOCH3) ppm. 13C NMR: d ¼ 208.19 (C55O), 169.76 (C55O),
138.03 (PhC), 137.44 (PhC), 137.26 (PhC), 128.48 (PhCH), 128.42 (PhCH),
128.07 (PhCH), 127.99 (PhCH), 127.90 (PhCH), 127.74 (PhCH), 127.69
(PhCH), 83.41(C-3), 78.43 (C-4), 73.25 (CH2), 73.17 (CH2), 72.92 (CH2), 71.35
(C-5), 68.14 (C-6), 27.15 (OCOCH3), 21.15 (1-CH3) ppm. M/z 499 (M þ Na).
Anal. Calcd for C29H32O6: C, 73.09; H, 6.67. Found: C, 73.22; H, 6.74.
ACKNOWLEDGMENTS
`
This work has been financially supported by Universita degli Studi di Milano
(Fondi FIRST).
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