2-Deoxy-L-ribose from an L-arabinono-1,5-lactone

Article abstract of DOI:10.1016/S0957-4166(02)00738-3

A practical synthesis of 2-deoxy-L-ribose from L-arabinose depends on the efficient reduction by iodide of a triflate α to a lactone. The X-ray crystal structure of 3,4-O-isopropylidene-L-arabinono-1,5-lactone is reported.

Full text of DOI:10.1016/S0957-4166(02)00738-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2667–2672
2
-Deoxy-
L
-ribose from an -arabinono-1,5-lactone
L
a
a
b
c
Alistair J. Stewart, Richard M. Evans, Alexander C. Weymouth-Wilson, Andrew R. Cowley,
c
a,
David J. Watkin and George W. J. Fleet *
a
Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford OX1 3QY, UK
b
CMS Chemicals, 9 Milton Park, Abingdon, Oxford OX14 4RR, UK
c
Chemical Crystallography Laboratory, Oxford University, 9 Parks Road, Oxford OX1 3QU, UK
Received 1 October 2002; accepted 5 November 2002
Abstract—A practical synthesis of 2-deoxy-L-ribose from L-arabinose depends on the efficient reduction by iodide of a triflate a
to a lactone. The X-ray crystal structure of 3,4-O-isopropylidene-L-arabinono-1,5-lactone is reported. © 2002 Published by
Elsevier Science Ltd.
1
0
1. Introduction
derivatives of deoxyribose 2p. A practical procedure
for the synthesis of 2-deoxy- -ribose 2 from a readily
L
The majority of antiviral drugs are nucleoside ana-
logues. -Nucleosides are recognised by virus-encoded
accessible arabinopyranose derivative that avoids radi-
cal deoxygenation is needed.
L
or bacterial enzymes–but not by host enzymes–and
have a better profile of good antiviral activity combined
1
with minimal host toxicity. 3TC (Lamivudine) was the
2
. Results and discussion
first
apy against HIV and HBV. Further examples of
nucleosides, such as -thymidine, possessing potent
antiviral activity have identified a need for an efficient
L-nucleoside approved for use in combination ther-
2
L
-
This paper reports a procedure in which the C-2 OH
group of an arabinono-lactone is converted to a triflate
and subsequently removed by reduction by iodide.
L
synthesis of homochiral 2-deoxy-
starting materials.
L
-ribose 2 from cheap
The kinetic monoacetonide of -arabinose 4 is readily
L
available in high yield by treatment of arabinose with
dimethoxypropane in DMF in the presence of a cata-
lyst of p-toluenesulfonic acid. Treatment of the lactol
Although -ascorbic acid 3 has been used as a starting
L
3,4
material, the majority of syntheses of 2 start from
-arabinose 1 in which all that is needed is the removal
of the OH function at C-2 (Scheme 1). The classic
11
L
4
with bromine in dichloromethane in the presence of
5
sodium carbonate formed the crystalline lactone 5 in
7
procedure via the formation of
L-arabinal is experi-
21
21
5% yield (Scheme 2), [h]D −29.2 (c 1.01, CHCl ), [h]
3 D
mentally challenging on a large scale. In all the other
syntheses, it is necessary to form either a protected
pyranose 1p or furanose 1f of arabinose in which only
C-2 OH is free. Access to suitably protected derivatives
−91.5 (c 1.93, MeOH); the oxidation previously
reported by silver carbonate on Celite proceeded in a
much lower yield and with a very different specific
12
6
rotation [h] −1 (c 3.0, CHCl ). The 1,5-lactone 5 has
of 1f usually requires a number of manipulations, and
D
3
also been formed from treatment of
L-arabinono-1,4-
almost all the procedures utilise radical deoxygenations
1
3
7
,8
lactone in 16% yield as a foam; although the NMR
data for 5 closely matches the literature data, again the
specific rotation of the sample was very different from
in the reductive step. In contrast arabinopyranose
derivatives 1p with C-2 OH free are relatively easily
formed. However, nucleophilic substitution of leaving9
groups at C-2 of arabinose is fraught with problems
and again it is necessary to use Barton radical deoxy-
genation procedures to produce protected pyranose
21
D
14
that previously reported, [h]
−9.8 (c 1.8, MeOH).
Accordingly the structure of the hydroxylactone 5 was
firmly established by X-ray crystallographic analysis
(
Fig. 1). The lactone ring in 5 adopts a ‘boat’ confor-
mation with C-2 and C-5 occupying the ‘bow’ positions
and the C-2 OH. The hydroxyl group occupies an axial
*
0
Corresponding author.
957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00738-3

2
668
A. J. Stewart et al. / Tetrahedron: Asymmetry 13 (2002) 2667–2672
Scheme 1.
Scheme 2. Reagents and conditions: (i) Br , Na CO , CH Cl ; (ii) Tf O, pyridine, CH Cl ; (iii) LiI·3H O, MeCOEt, 80°C; (iv)
2
2
3
2
2
2
2
2
2
DIBALH, CH Cl , −50°C; (v) CF COOH:H O.
2
2
3
2
1
6
position. The molecules are linked by hydrogen bonds
formed between the hydroxyl group and the carbonyl O
7 has been previously prepared by the oxidation of
17
the enantiomer of the lactols 8.
of a neighbouring molecule (O(2)···O(1)% 2.722(2) A) to
,
form infinite chains running parallel to the crystallo-
graphic b axis (Fig. 2).
Reduction of the deoxylactone 7 with diisobutylalu-
minum hydride (DIBALH) gave the lactols 8 in 66%
isolated yield, with no over reduction. Subsequent treat-
ment of 8 with 0.4% trifluoroacetic acid in water gave
efficient deprotection to the target 2-deoxy- -ribose 2.
It is likely that on a larger scale, the DIBALH-hydroly-
sis sequence will proceed in an overall excellent yield.
Esterification of free hydroxyl group in 5 by treatment
with trifluoromethanesulfonic (triflic) anhydride in
dichloromethane in the presence of pyridine gave the
corresponding triflate in 93% yield. Reaction of the
triflate 6 with lithium iodide hydrate in butanone gave
L
the deoxygenated lactone
reduction may proceed by S 2 displacement of the
7 in 70% yield. The
N
1
5
triflate group in 6 by iodide, followed by further nucle-
ophilic attack by iodide on the ribo-iodo function to
produce iodine and an enolate which on protonation
gives the deoxylactone 7 (Scheme 3). The enantiomer of
3. Conclusion
2-Deoxy-3,5-di-O-toluoyl-a-
D-erythro-pentofuranosyl
chloride 10 is one of the most commonly used precur-

A. J. Stewart et al. / Tetrahedron: Asymmetry 13 (2002) 2667–2672
2669
23
Figure 1. Thermal ellipsoid plot (ORTEP-3 ) at 40% probability of 3,4-O-isopropylidene-
L
-arabinono-1,5-lactone 5.
4
. Experimental
Proton nuclear magnetic resonance spectra (l ) were
H
recorded on a Bruker DPX 400 (400 MHz) or Bruker
DPX 200 (200 MHz) spectrometer, and were calibrated
according to the chemical shift of residual protons in
13
the deuterated solvent. C NMR spectra (l ) were
C
recorded on a Bruker DPX 400 (100.6 MHz) or Bruker
DPX 200 (50.3 MHz) spectrometer and were calibrated
using chemical shift of the deuterated solvent. Chemical
shifts (l) are quoted in ppm and coupling constants (J)
in Hz. The following abbreviations are used to denote
multiplicities: s, singlet; d, doublet; dd, double-doublet;
ddd, double-double-doublet; t, triplet; q, quartet; dt,
double-triplet; quint, quintuplet; m, multiplet; br,
broad; a, apparent. Infrared spectra were recorded on a
Perkin–Elmer 1750 FT IR spectrophotometer using
−
1
thin films on NaCl plates and peaks are given in cm .
Low-resolution mass spectra were recorded either on a
VG platform atmospheric pressure chemical ionisation
(
APCI), Micromass GCT spectrometer (GC–MS) or a
Micromass LCT spectrometer (ESI). High-resolution
mass spectra (HRMS) were recorded on a Micromass
VG Autospec 500 OAT (CI, NH ) spectrometer. Opti-
3
cal rotations were measured on a Perkin–Elmer 241
polarimeter with a path length of 1 dm, concentrations
(c) are quoted in g/100 ml. Elemental analyses were
performed by the microanalysis service of the Inorganic
Chemistry Laboratory (Oxford). Melting points (mp)
were measured on a Kofler hot-block apparatus and are
uncorrected. Thin-layer chromatography (TLC) was
carried out on aluminium sheets coated with 60F254
silica from Merck, and plates were developed using
either a spray of vanillin (8 g/l) in 95% ethanol contain-
ing 1% (v/v) sulfuric acid or 0.2% w/v cerium(IV)sulfate
and 5% ammonium molybdate in 2 M sulfuric acid and
subsequent heating. Flash chromatography was carried
out using Sorbsil C60 40/60 silica. Solvents were used
as supplied (HPLC grade) and commercially available
reagents were used as supplied. Hexane refers to
petroleum ether boiling in the range 60–80°C. 3,4-O-
Figure 2. Crystal stacking of 3,4-O-isopropylidene-
binono-1,5-lactone 5.
L-ara-
sors for the synthesis of a wide variety of deoxyribonu-
cleosides usually with an excellent selectivity for the
formation of the required b-anomers 11 (Scheme 4) by
Vorbr u¨ ggen and other coupling procedures. The a-
chlorofuranose form 10 is efficiently established from
18
the unprotected 2-deoxy- -ribose 9.
D
This paper reports an efficient but non-optimised pro-
cedure for the synthesis of 2-deoxy- -ribose 2 which is
an intermediate likely to be of value in the generation
of new -nucleosides by analogous procedures to those
indicated for the -series in Scheme 4.
L
L
D

2
670
A. J. Stewart et al. / Tetrahedron: Asymmetry 13 (2002) 2667–2672
Scheme 3.
Scheme 4.
Isopropylidene-
L
-arabinopyranose 4 was prepared by
-arabinose as previously
4.2. 3,4-O-Isopropylidene-2-O-trifluoromethanesulfonyl-
-arabinono-1,5-lactone 6
the kinetic acetonation of
L
L
1
2
described.
Triflic anhydride (14.1 mL, 0.08 mol) was added to a
stirred solution of the hydroxylactone 5 (12.98 g, 0.07
mol) in dichloromethane (200 mL) and pyridine (6.79
mL, 0.08 mol) maintaining the temperature between
4.1. 3,4-O-Isopropylidene- -arabinono-1,5-lactone 5
L
Bromine (10.3 mL, 0.2 mol) was added dropwise over
0 min to a stirred suspension of sodium carbonate
21.2 g, 0.2 mol) in a solution of 3,4-O-isopropylidene-
-arabinopyranose (25 g, 0.13 mol) in
−
10 and −20°C over 30 min. After 2.5 h, TLC analysis
ethyl acetate:hexane, 2:3) indicated a new product (Rf
.43). The reaction mixture was diluted with
3
(
(
0
L
4
dichloromethane (400 mL), washed with water (350
mL) and the aqueous layer further extracted with
dichloromethane (3×150 mL). The combined organic
extracts were dried (magnesium sulfate), filtered and
concentrated in vacuo (co-evaporated with toluene); the
residue was purified using flash chromatography (ethyl
acetate:hexane, 2:3) to afford the triflate 6 (21.0 g, 93%)
dichloromethane (160 mL) at room temperature. The
reaction mixture was stirred for a further 5 h when
TLC analysis (ethyl acetate:hexane, 9:1) indicated a
major product (R 0.46). Nitrogen was bubbled through
the solution for 30 min to remove excess unreacted
f
bromine; the suspension filtered through celite
2
0
(
dichloromethane as eluant). The filtrate was washed
as a white solid, mp 88–89°C; [h] +24.5 (c 1.04,
D
−
1
with sodium thiosulfate solution (0.5 M Na S O , 200
CHCl ); w
(film): 1773 (CꢀO) cm ; l (CDCl , 400
2
2
3
3
max
H
3
mL); the aqueous extract was re-extracted with
dichloromethane (3×300 mL). The combined organic
extracts were dried with magnesium sulfate, filtered and
concentrated in vacuo to yield a yellow oil. This oil was
purified using column chromatography (ethyl ace-
tate:hexane, 2:3, preabsorbed from ethyl acetate) to
MHz): 1.41, 1.53 (2×3H, 2×s, C(CH ) ), 4.27 (1H, ddd,
3 2
H-5%), 4.65 (1H, m, H-3, H-4, H-5), 5.23 (1H, d, J2,3
5.77 Hz, H-2); lC (CDCl , 100 MHz): 24.4, 26.4
3
(C(C
6
H
3
)
), 67.0 (C-5), 70.1 (C-4), 74.4 (C-3), 80.0 (C-2),
13.1 (C6 (CH ) ), 163.1 (C-1); m/z (APCI +ve): 321
+
2
1
3 2
(
M+H , 75%). Found: C, 33.64; H, 3.42; C H F O S
9 11 3 7
requires C, 33.75; H, 3.46.
yield 3,4-O-isopropylidene-
L
-arabinono-1,5-lactone
5
(
18.3 g, 75%) as a white crystalline solid; mp 94–95°C
1
2
21
12
4.3. 2-Deoxy-3,4-O-isopropylidene-
L
-ribono-1,5-lactone
{
Lit. 95–97°C}; [h]D −29.2 (c 1.01, CHCl ) {Lit.
3
7
[
h]D −1 (c 3.0, CHCl )}; w
(film): 3429 (OH), 1754
max
3
−
1
(
2
CꢀO) cm ; l (CDCl , 400 MHz): 1.39, 1.53 (2×3H,
H
3
The triflate 6 (5.19 g, 0.016 mol) and lithium iodide
trihydrate (19 g, 0.10 mol) were dissolved in butanone
×s, C(CH ) ), 3.38 (1H, d, J
3.46 Hz, 2-OH), 4.13
3
2
OH,2
(
1H, dd, J5,5% 11.38 Hz, J4,5% 8.24 Hz, H-5%), 4.36 (1H,
dd, J2,3 6.19 Hz, J3,4 7.23 Hz, H-3), 4.44 (1H, dd, J2,OH
.36 Hz, J2,3 5.95 Hz, H-2), 4.51 (1H, ddd, J4,5 5.24 Hz,
(
140 mL) and the reaction mixture heated at 80°C.
After 24 h, TLC analysis (ethyl acetate:hexane, 2:1)
3
indicated no remaining starting material (R 0.53) and a
single new product (R 0.24). The reaction mixture was
f
J4,5% 7.8 Hz, J3,4 7.23 Hz, H-4), 4.59 (1H, dd, J5,5% 11.06
f
Hz, J4,5 5.11 Hz, H-5); lC (CDCl , 100 MHz): 24.8,
2
(
3
concentrated in vacuo, diluted with ethyl acetate (200
mL) and washed with 0.5 M sodium thiosulfate solu-
tion (150 mL) to remove the iodine. The aqueous
extracts were further extracted with ethyl acetate (2×80
mL); the combined organic extracts were dried (magne-
7.1 (C(C6 H ) ), 67.3 (C-5), 70.5 (C-4), 70.7 (C-2), 77.7
3 2
C-3), 112.2 (C
89 (M+H , 100%). Found: C, 51.06; H, 6.42; C H O
6
(CH ) ), 172.1 (C-1); m/z (APCI +ve):
3
2
+
1
8 12 5
requires C, 51.06; H, 6.43.

A. J. Stewart et al. / Tetrahedron: Asymmetry 13 (2002) 2667–2672
2671
sium sulfate), filtered and concentrated in vacuo to yield
a light orange solid. This residue was purified using
column chromatography (ethyl acetate:hexane, 2:1) to
stirred at room temperature. After 20 min, TLC analysis
(ethyl acetate) indicated formation of a new product (Rf
0.0) and no remaining starting material. This material
was identical to an authentic sample of 2, provided by
CMS Chemicals.
yield 2-deoxy-3,4-O-isopropylidene-
L-ribono-1,5-lactone
19
7
(1.93 g, 70%) as a white solid; mp 118–120°C [Lit. for
2
3
enantiomer 118–119°C]; [h] +148.1 (c 1.03, CHCl3)
D
1
9
22
D
[
Lit. for enantiomer [h] −146.8 (c 0.62, CHCl )]; w
film): 1742 (CꢀO) cm ; l (CDCl , 400 MHz): 1.34,
4.6. X-Ray crystal data
3
max
−
1
(
1
H
3
.45 (2×3H, 2×s, C(CH ) ), 2.53 (1H, dd, J 15.96 Hz,
A large single crystal of the lactone 5, cut to give a
fragment having dimensions approximately 0.16×0.18×
0.52 mm, was mounted on a glass fibre using perfluoro-
polyether oil and cooled rapidly to 150 K in a stream of
cold nitrogen using an Oxford Cryosystems
CRYOSTREAM unit. Diffraction data were measured
using an Enraf–Nonius Kappa CCD diffractometer
(graphite-monochromated Mo Ka radiation, u=0.71073
3
2
2,2%
J2%,3 3.76 Hz, H-2%), 2.53 (1H, dd, J2,2% 15.95 Hz, J2,3 2.49
Hz, H-2), 4.13 (1H, dd, J5,5% 12.95 Hz, J4,5% 1.87 Hz, H-5%),
4.41 (1H, dd, J5,5% 12.98 Hz, J4,5 1.2 Hz, H-5), 4.49 (1H,
m, H-4), 4.74 (1H, m, H-3); l (CDCl , 100 MHz): 24.0,
C
3
2
5.9 (C(C6 H ) ), 34.7 (C-2), 67.7 (C-5), 71.2 (C-4), 71.5
3 2
(
C-3), 109.4 (C6 (CH ) ), 169.6 (C-1); m/z (APCI +ve): 173
3 2
+ +
(
M+H , 100%). GC–MS: 190 (M+NH , 100%). Found:
4
A
,
). Intensity data were processed using the DENZO-
C, 55.78; H, 6.99; C H O requires C, 55.81; H, 7.02.
8
12
4
20
SMN package. Examination of the systematic absences
of the intensity data showed the space group to be either
P2 or P2 /m. The structure was solved in the space
4.4. 2-Deoxy-3,4-O-isopropylidene-L-ribose 8
1
1
2
1
group P2 using the direct-methods program SIR-92,
1
Diisobutylaluminum hydride (12.9 ml, 1.0 M in toluene,
2.87 mmol) was added dropwise to the deoxylactone 7
which located all non-hydrogen atoms. Subsequent full-
1
matrix least-squares refinement was carried out using the
(
1.58 g, 9.19 mmol) in dichloromethane (40 ml) at −50°C.
22
CRYSTALS program suite.
Coordinates and
After 15 min, TLC analysis (ethyl acetate/hexane 2:1)
anisotropic thermal parameters of all non-hydrogen
atoms were refined. The hydroxyl hydrogen atom was
located in a difference Fourier map and its coordinates
and isotropic thermal parameter subsequently refined.
Other hydrogen atoms were positioned geometrically
after each cycle of refinement. A 3-term Chebychev
polynomial weighting scheme was applied. Refinement
converged satisfactorily to give R=0.0284, wR=0.0378.
Crystal structure data has been deposited at the Cam-
bridge Crystallographic Data Centre CCDC 194890.
indicated the loss of starting material (R 0.2) and the
f
formation of a major product (R 0.3). Saturated aqueous
f
potassium sodium tartrate (40 ml) and dichloromethane
(
80 ml) were added and the reaction stirred vigorously
for a further 12 h. The organic layer was separated from
the aqueous layer. The aqueous layer was then further
extracted (dichloromethane, 2×50 ml), the organic frac-
tions combined, dried (magnesium sulfate) and concen-
trated in vacuo. The resulting residue was then purified
by flash chromatography (ethyl acetate/hexane 2:1) to
yield the protected deoxy -ribose 8 (1.05 g, 66%) as a
L
clear, colourless oil. Both anomers were collected in a
ratio of 3:1 and are referred to as major and minor,
respectively. l (200 MHz, CDCl ): 1.33 (s, 3H, C(CH ) ,
H
3
3 2
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2
3 2
1
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.5. 2-Deoxy- -ribose 2
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4. The difference in [h] for 5 between that observed in CHCl
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3
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1
1
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