A simple and efficient synthesis of 2-deoxy-L-ribose from 2-deoxy-D-ribose

Article abstract of DOI:10.1055/s-2006-950401

An efficient synthesis of 2-deoxy-L-ribose was achieved without chromatography starting from its enantiomer 2-deoxy-D-ribose in more than 30% overall yield. An unexpected product, 2-deoxy-xylose, was obtained under slightly different reaction conditions a

Full text of DOI:10.1055/s-2006-950401

2498
LETTER
A Simple and Efficient Synthesis of 2-Deoxy-L-ribose from 2-Deoxy-D-ribose
2
-Deoxy-
L
-
ribose
fr
om 2-Deoxy
J
-
D
-ribosei, Meili Pang, Jie Han, Suihan Feng, Xiaotian Zhang, Yuxin Ma, Jiben Meng*
Department of Chemistry, Nankai University, Tianjin 300071, P. R. of China
Fax +86(22)23502230; E-mail: mengjiben@nankai.edu.cn
Received 15 May 2006
deoxy-D-ribose without the use of either expensive
Abstract: An efficient synthesis of 2-deoxy-L-ribose was achieved
without chromatography starting from its enantiomer 2-deoxy-D-ri-
bose in more than 30% overall yield. An unexpected product, 2-
deoxy-xylose, was obtained under slightly different reaction condi-
reagents or chromatographic techniques. The starting
compound for our synthesis is 2-deoxy-D-ribose, which
can be easily prepared from D-glucose,5 and is also avail-
tions and isolated with partial racemization. The structure of the able commercially and is inexpensive. Compared to the
scalemic 2-deoxy-xylose was confirmed by X-ray crystallography.
reported procedures, this route is one of the shortest
synthetic sequences (Scheme 1).
Key words: synthesis, deoxyribose, enantiomer
The first step was to protect the aldehyde group of 2-
deoxy-D-ribose (1) by selectively converting 1 into the
corresponding pyranoside 3, rather than the furanoside 2,
through the procedures reported by Deriaz et al.6 and
Crotti et al.7 The obtained pyranoside 3 was a mixture of
The use of L-nucleosides and their analogues as pharma-
ceuticals has increased dramatically due to their good an-
tiviral activities and generally lower toxicity.1 In addition,
oligonucleotides composed of 2-deoxy-L-ribose show
better resistance to digestion by certain nucleases.2
Recently, it was reported that 2-deoxy-L-ribose and its
analogues enhance apoptosis and suppress the growth of
tumors, and thus show some promise for antitumor thera-
py.3 Therefore, efficient and practical preparative meth-
ods for L-nucleosides and carbohydrates are much needed.
To date, several syntheses of 2-deoxy-L-ribose have been
reported.4 In these syntheses, either lengthy synthetic
routes were required, or expensive or highly toxic re-
agents were used, although a few of the reports addressed
some of these issues. Herein, we describe a simple
synthetic protocol to produce 2-deoxy-L-ribose from 2-
1
a- and b-anomers (a:b = 1:3), as measured by H NMR
spectroscopy. Compound 3 was then fully tosylated to
give 4 in 82% yield, and 4 was subsequently treated with
potassium benzoate under reflux in DMF. To our surprise,
the presence of a small amount of water in DMF played a
critical role in the stereochemistry of the SN2 reactions at
the C3 and C4 positions.
When 4 was reacted with potassium benzoate in refluxing
anhydrous DMF, dibenzoate 7, in partially racemized
form, was isolated in 50% yield.8 The dibenzoate 7 could
be converted into the scalemic 2-deoxy-xylose (9) in two
steps in an overall yield of 83%.8,9 The structure of 9 was
1
O
CHO
H3C
S
Cl
2
3
4
H
H
H
H
HO
O
O
1% HCl/MeOH
85%
O
O
OH
OH
OCH3
OCH3
OCH3
HO
HO
TsO
TsO
pyridine
82%
OH
CH2OH
5
2
3
4
1
α:β = 1:3
2-deoxy-D-ribose
PhCOO
HO
HO
COOK
HO
O
O
O
NH3
MeOH
PhCOOH
OCH3
OCH3
OH
anhydrous DMF, reflux, 20 h
50%
H2O, reflux
PhCOO
HO
9: 2-deoxy-xylose
83% (two steps)
7
8
(mixture of DL, αβ)
(mixture of DL, αβ)
mixture of DL
)
4
HO
COOK
PhCOO
HO
HO
PhCOO
HO
O
O
O
O
NH3
MeOH
46% (two steps)
PhCOOH
OH
OCH3
OCH3
+
HO
OCH3
HO
H2O, reflux
95%
DMF, H2O, reflux, 20 h
12
10
11
2-deoxy-
L
-ribose
α:β = 3:1
Scheme 1 Synthesis of 2-deoxy-L-ribose and 2-deoxy-xylose
SYNLETT 2006, No. 15, pp 2498–2500
1
8
.0
9
.2
0
0
6
Advanced online publication: 08.09.2006
DOI: 10.1055/s-2006-950401; Art ID: W10106ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
2-Deoxy-L-ribose from 2-Deoxy-D-ribose
2499
first positively identified by X-ray crystallography and is configuration at C3 and C4. Therefore, 2-deoxy-D-ribose
shown in Figure 1.10 By comparing the specific rotation was successfully converted into its enantiomer. This
value of 9 ([a]20D +0.6, c 1.00, H2O) with that of 2-deoxy- mechanistic explanation about the stereochemistry was
D-xylose in the same solvent and concentration fully supported by the obtained physical and spectroscop-
([a]22D –2.0, c 1.00, H2O),9a it was concluded that 9 ic data for 7–12.
existed as a mixture of 2-deoxy-D-xylose and 2-deoxy-L-
xylose with low optical purity.
O
Ph
O
OCH3
OCH3
C
O
O
Ph
O
+
TsO
OCH3
+
COO–
O
Ph
O
4
O
C
O
6
H2O
O
TsO
5
O
O
Ph
Ph
O
+
O
+
Ph
OCH3
H2O
O
or
OCH3
OCH3
+
O
O
O
PhCOO–
PhCOO–
PhCOO
HO
O
PhCOO
PhCOO
OCH3
Figure 1 The structure of 2-deoxy-xylose (9), showing 30% proba-
bility displacement ellipsoids and the atom labeling scheme.
OOCPh
O
O
OCH3
+
H3CO
+
HO
O
OOCPh
PhCOO
OCH3
7
When the substitution reaction of 4 with potassium
benzoate was run in water-containing DMF, a mixture of
the two mono-benzoylated compounds was obtained (10),
which were further converted into pyranoside 11 through
methanolysis in 46% yield over the two steps. The
anomeric mixture of 11 was readily deprotected to give
the final product 12 in 95% yield.11 The physical and
spectroscopic data of compound 12 were consistent with
those obtained from authentic 2-deoxy-L-ribose, suggest-
ing that product 12 was the desired 2-deoxy-L-ribose with
high optical purity. Thus, this multi-step procedure consti-
tuted a simple and straightforward preparative method for
2-deoxy-L-ribose.
10
Scheme 2 Mechanistic explanation for the formation of 7 and 10
under anhydrous and water-containing conditions.
In conclusion, a simple and efficient synthesis of 2-deoxy-
L-ribose was successfully developed from 2-deoxy-D-ri-
bose. This method carried some obvious advantages such
as being simple and efficient, there being no need for
chromatographic purification or the use of expensive
reagents. After further optimization, it could become a
practical method for a large-scale synthesis of 2-deoxy-L-
ribose. It was also demonstrated that 2-deoxy-xylose
could be prepared in good yield from 2-deoxy-D-ribose,
though in low optical purity.
The stereochemical outcome of this synthetic protocol
may be interpreted in terms of regioselective nucleophilic
attack after neighboring-group participation, as illustrated
in Scheme 2. When 4 was refluxed with potassium ben-
zoate in DMF, the first substitution of TsO– readily oc-
curred at either C3 or C4 with inversion of configuration
at this center. This gave a regioisomeric mixture of mono-
benzoylated species 5, in which the benzoate group was in
a favored position to nucleophilically attack the carbon of
the remaining tosylate, and consequently, form the inter-
mediate acylonium ion 6. Under anhydrous conditions, 6
is subsequently attacked at either C3 or C4 by the relative-
ly bulky benzoate anion to produce the dibenzoate 7, with
inversion of configuration of the attacked carbon. In the
presence of water, however, 6 is preferentially attacked at
the benzoyl carbon by the small nucleophile water, to give
10 with the retention of configuration of C3 and C4. As a
result, the net stereochemical change was the inversion of
Acknowledgment
We thank the National Natural Science Foundation of China (grant
no. 20490210, 20372039). We also thank Prof. Zhengjie He
(Department of Chemistry, Nankai University) and Prof. Qizheng
Yao (School of Pharmacy, China Pharmaceutical University) for
their valuable suggestions.
References and Notes
(1) (a) Schinazi, R. F.; Gosselin, G.; Faraj, A.; Korba, B. E.;
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LETTER
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between H2O (70 mL) and CH2Cl2 (70 mL), and the aqueous
layer was separated and washed again with CH2Cl2 (50 mL).
The resulting aqueous solution was saturated with benzoic
acid and heated at reflux for 1 h. After cooling to r.t., CHCl3
(25 mL) was added, and the aqueous layer separated and
washed again with CHCl3 (25 mL). The aqueous layer was
concentrated to dryness and recrystallized from acetone–
EtOAc (1:1) to give 2-deoxy-xylose (9) as white crystals
(1.6 g, 83%). Single crystals suitable for X-ray diffraction
measurements were obtained from acetone–EtOAc by slow
evaporation at r.t. Analytical data: mp 77–78 °C; [a]20D +0.6
(c 1.00, H2O); 1H NMR (300 MHz, DMSO-d6): d = 6.47 (d,
J = 6.6 Hz, 1 H), 4.84 (dd, J1 = 4.6 Hz, J2 = 4.8 Hz, 2 H),
4.59–4.53 (m, 1 H), 3.68–3.62 (dd, J1 = J2 = 5.0 Hz, 1 H),
3.33–3.27 (m, 1 H), 3.19–3.10 (m, 1 H), 2.98–2.91 (m, 1H),
1.93–1.87 (dddd, J1 = J2 = J3 = J4 = 2.0 Hz, 1 H), 1.31–1.20
(m, 1 H); ESI-MS: m/z = 179 [M + HCOO–]; Anal. Calcd for
C5H10O4: C, 44.77; H, 7.52. Found: C, 45.02; H, 7.33.
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(10) CCDC 293775 contains the supplementary crystallographic
data and collection parameters for 9. These data can be
obtained free of charge via ww.ccdc.cam.ac.uk/conts/
retrieving.html.
(11) Typical procedure for 2-deoxy-l-ribose: To a solution of 4
(10 g, 0.022 mol) in DMF (30 mL) was added H2O (5 mL)
and potassium benzoate (25 g, 0.16 mol), and the mixture
was heated at reflux with stirring for 6 h. The resulting
mixture was concentrated and stirred with H2O (50 mL) and
CH2Cl2 (30 mL), filtered, and the aqueous layer of the filtrate
was separated and extracted with CH2Cl2 (30 mL). The
organic layers were combined and treated with Na2CO3 and
evaporated to a syrup (mixture 10). This material was
dissolved in MeOH (60 mL), the solution saturated with
NH3, and stirred at r.t. for 24 h. After evaporation, the
residual syrup was partitioned between H2O (20 mL) and
CH2Cl2 (20 mL), and the aqueous layer was separated and
washed again with CH2Cl2 (20 mL) before being evaporated
to dryness and the residue recrystallized from Et2O to give
mixture 11 as a white solid (1.9 g, 46%). The solid was
heated at reflux in a saturated aqueous solution of benzoic
acid (80 mL) for 1 h. After cooling to r.t., CHCl3 (30 mL)
was added, and the aqueous layer separated and washed
again with CHCl3 (20 mL) before being concentrated to give
a colorless syrup. The syrup was treated with a small amount
of acetone–isopropanol (7:1) and refrigerated for about a
week to give 2-deoxy-L-ribose (12) as a white powder
(1.6 g, 95%). Data: mp 74–76 °C; [a]20D +53 (c 1.00, H2O);
1H NMR (300 MHz, D2O): d = 5.47–5.13 (m, 1 H), 4.22–
3.42 (m, 4 H), 2.29–1.50 (m, 2 H); ESI-MS: m/z = 179
[M+HCOO–] (weak); Anal. Calcd for C5H10O4: C, 44.77; H,
7.52. Found: C, 44.61; H, 7.75.
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(8) Typical procedure for 2-deoxy-xylose: To a solution of 4
(10 g, 0.022 mol) in DMF (30 mL) was added potassium
benzoate (30 g, 0.19 mol), and the mixture was heated at
reflux with stirring for 10 h. The resulting mixture was
concentrated and stirred with H2O (50 mL) and CH2Cl2
(30 mL), filtered, and the aqueous layer of the filtrate was
separated and extracted with CH2Cl2 (30 mL). The combined
organic layers were evaporated to dryness and the residue
recrystallized from EtOH–H2O to give 7 as white crystals
(3.9 g, 50%). This material was dissolved in MeOH (60 mL),
the solution was saturated with NH3, and stirred at r.t. for
24 h. After evaporation, the residual syrup was partitioned
Synlett 2006, No. 15, 2498–2500 © Thieme Stuttgart · New York