Concise chemoenzymatic synthesis of methyl d-2,3-dideoxyriboside

Article abstract of DOI:10.1016/j.tetasy.2010.05.039

The synthesis of methyl α- and β-d-2,3-dideoxyriboside from a non-carbohydrate source is presented. The source of chirality is the microbial oxidation of halobenzenes to produce cyclohexadienediols, which are transformed into the final product in five steps with high chemical and enantiomeric purity.

Full text of DOI:10.1016/j.tetasy.2010.05.039

Tetrahedron: Asymmetry 21 (2010) 969–972
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Concise chemoenzymatic synthesis of methyl D-2,3-dideoxyriboside
Juan C. Ramos a, Paula Bracco a, Mauro Mazzini a, José R. Fernández a,b, Daniela Gamenara a,
Gustavo A. Seoane a,
*
a Organic Chemistry Department, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay
b University of Santiago de Compostela, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of methyl
a- and b-D-2,3-dideoxyriboside from a non-carbohydrate source is presented.
Received 26 April 2010
Accepted 21 May 2010
Available online 19 June 2010
The source of chirality is the microbial oxidation of halobenzenes to produce cyclohexadienediols, which
are transformed into the final product in five steps with high chemical and enantiomeric purity.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
microbial oxidation of aromatics, have been extensively used in or-
ganic synthesis.43,44
20,30-Dideoxynucleosides and analogues are among the most
active agents against HIV, a causative agent for acquired immuno-
deficiency syndrome (AIDS), acting as nucleoside reverse transcrip-
tase inhibitors (NRTIs).1,2 In particular, 30-azido-30-deoxythymidine
(AZT),3–6 20,30-dideoxyinosine (ddI),3,4,6 20,30-didehydro-20-deoxy-
thymidine (D4T),7,8 and 20,30-dideoxycytidine (ddC)9,8 have been
approved for the treatment of AIDS.
2. Results and discussion
The first step of the sequence was the toluene dioxygenase-
mediated oxidation of halobenzenes to produce enantiopure cis-
diene-diols 1. In particular, both chloro- and bromobenzene were
used as substrates for the biotransformation using P. putida
F39/D,40–42 Scheme 1. The selective reduction of the disubstituted
double bond using diimide prepared in situ afforded the diols 2 in
a clean reaction. The reduction was insensitive to the nature of
the halogen atom on the unreacted olefin, and both starting mate-
rials gave the product with the same excellent isolated yield.
Furthermore, 20,30-dideoxyadenosine (ddA), in addition to its
antiviral and antibacterial activities,10–12 may retard tumor cell
proliferation.13
These nucleosides have been synthesized by the structural
modification of other nucleosides using chemical or enzymatic
(transglycosylation) methods, or else, through the coupling of a car-
bohydrate intermediate with an activated nucleobase.14–16 The car-
bohydrate intermediate is prepared from either a carbohydrate or a
non-carbohydrate precursor. Thus, 2,3-dideoxyfuranosides have
been prepared from sugars and derivatives such as levoglucosenone,
X
X
X
Pseudomonas
putida F39/D
OH
OH
OH
OH
PAD, AcOH
MeOH, 0 °C
90 %
> 99 % ee
2-deoxyribose,
D
-xylose,
D
-lyxofuranosides, and mannitol.17–27
-glutamic acid,21,30–33 and
X = a, Cl
b, Br
1
2
Pentenoic acid,28 crotonaldehyde,29
L
O3, NaHCO3,
CH2Cl2:MeOH (1:1);
then (CH3)2S
some unsaturated ethers34,35 have been used as precursors.
All these preparations of 2,3-dideoxyfuranosides involve be-
tween four and nine steps, and the reported yields fall in the range
of 10–50%.
72 %
OMe
COOMe
HO
O
In connection with our work on the biotransformation of aro-
matic substrates,36–39 we herein report a short chemoenzymatic
3
route to methyl D-2,3-dideoxyriboside, starting from monohalo-
Scheme 1. Synthesis of intermediate 3.
genated aromatic compounds such as bromo- or chloro-benzene.
These simple aromatics are converted to chiral cyclohexadienedi-
ols 1 (Scheme 1), through a whole-cell oxidation using Pseudomo-
nas putida F/39D.40–42 Enantiopure diols of type 1, derived from the
Subsequent ozone-mediated cleavage of the cyclohexene ring in
methanol afforded a dihydroxyformyl-ester, which existed as a
mixture of five- and six-membered hemiacetalic forms in that
medium. Acetylization with an ionic exchange resin in methanol
gave a 7:3 mixture of the corresponding methyl acetals (70% for
the two steps), the major isomer being the more stable tetrahydro-
furan methyl acetal 3. We were intrigued by the possibility of
* Corresponding author. Tel.: +598 2 924 7881; fax: +598 2 924 1906.
E-mail address: gseoane@fq.edu.uy (G.A. Seoane).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.039

970
J. C. Ramos et al. / Tetrahedron: Asymmetry 21 (2010) 969–972
forming the methyl acetal directly in the methanolic solution used
for the oxidative cleavage and, to that end, several conditions were
tested. The ozonolysis was performed in methanol in both basic
(adding solid NaHCO3, from 1 to 8 equiv) and acidic conditions (gi-
ven by the HX generated in the cleavage). In all cases, no methyl
acetal was seen by 1H NMR. Fortunately, when mixtures of dichlo-
romethane and methanol were used as a solvent, the methyl ace-
tals were formed predominantly. Using a 1:1 dichloromethane/
MeOH mixture and 2 equiv of NaHCO3 afforded the methyl acetal
3 as the only isolable product, with no traces of the six-membered
acetal. The tetrahydrofuran derivative 3 was obtained as a 1.2:1
anomeric mixture in 72% yield (Scheme 1). Once again, there was
no difference in the ozonolysis when using the chloro- or bromo-
olefin 2a or 2b. Due to availability reasons, the most used starting
material for the preparation of 3 was the bromocycloalkene 2b.
mized with respect to temperature, solvent, and reducing agent.
The metaperiodate-mediated cleavage was best performed at low
temperature in a biphasic THF/H2O system (6:1). The use of sodium
borohydride or LAH in the last step gave consistently lower yields,
even though the medium used for these reactions is not acidic
and therefore, seems to be more suitable for the stability of the
acetal 5.
It is interesting to note that the starting 1.2:1 anomeric ratio in
diol 4 changed to a 2:1 ratio in riboside 5. This could be attributed
to the selectivity in the reaction sequence or, more likely, to a dif-
ferential stability of the anomers resulting in a selective decompo-
sition of the minor isomer. All attempts to separate this mixture
and that of the corresponding acyl derivatives on C-5 (benzoate
and 3,5-dinitrobenzoates) were unsuccessful. In order to obtain a
pure sample and also to clarify the reasons for the observed varia-
tion in the anomeric ratio, we attempted to separate the anomeric
mixture in 4 through derivatization. Thus, the diols 4 were diacet-
ylated, separated by column chromatography, and hydrolyzed
The major isomer was tentatively assigned as the
a-anomer
using 1H NMR and by comparison with the known 1H NMR data
of 2,3-dideoxysugar derivatives.19,26 The NOE data were not con-
clusive, showing low enhancements for the signals of both ano-
mers, which is not unexpected for this type of furanosic systems.
Finally, the stereochemical assignment was confirmed at the end
of the sequence by comparison of the specific rotation values with
again to obtain pure a- and b-anomers of 4 (Scheme 3).
The difference in the outcome of the C–C cleavage of the side
chain of both anomers of 4 is remarkable, suggesting a selective
decomposition of the b-anomer, in agreement with our hypothesis
on the differential stability of each anomer in the conditions used.
Riboside 5 is a versatile intermediate in the preparation of dide-
oxynucleosides, via coupling with a suitable protected nucleo-
base.14 It is noteworthy that, whatever the configuration of the
anomeric carbon, a mixture of anomers will be produced in the
coupling, because the same carbocation results from elimination
those reported for the a- and b-anomers of 5 (see below).
Next, the side chain on C-4 was converted into the desired
hydroxymethyl group via a reduction–oxidation–reduction se-
quence. Thus, the reduction of ester 3 with sodium borohydride in
THF at room temperature afforded diol 4 in 90% yield (with the same
1.2:1 anomeric ratio). The oxidative cleavage of the diol proved
difficult, due to the unstability of the resulting aldehyde, which
was detected by TLC but could not be isolated in pure form. Conse-
quently, the diol was submitted to a ‘one-pot-two-steps’ reaction,
consisting of oxidative C–C cleavage with sodium metaperiodate
followed by sodium cyanoborohydride reduction in acid medium
of the b- or
3. Conclusion
The preparation of the methyl
a
-methoxy group.45
D
-2,3-dideoxyriboside, precursor
to give methyl D-2,3-dideoxyriboside 5 in 68% isolated yield (for
the two steps), Scheme 2. The last sequence was thoroughly opti-
in the synthesis of dideoxynucleosides, was accomplished in five
steps from cyclohexadienediols of microbial origin with an overall
yield of 40%. It is worth mentioning that the whole sequence does
not involve specific protection steps and requires only two purifi-
cation steps using column chromatography. In conclusion, we have
reported a short, rapid, and efficient procedure that compares well
with the reported syntheses of this sugar derivative and allows for
HO
a) NaIO4, THF:H2O
-40 to 0 °C
CH2OH
NaBH4,
HO
O
3
O
OMe
5, (α:β, 2:1)
OMe
THF, r. t.
90%
b) NaBH3CN, AcOH
(pH = 5)
its preparation in multigram quantities. In addition, the a- and b-
anomers can be obtained separately in 19% and 8%, respectively,
4, (α:β, 1.2:1)
68%
Scheme 2. Synthesis of methyl
D-2,3-dideoxyriboside 5.
using the procedure outlined in Scheme 3.
HO
HO
O
OMe
4
Ac2O, Et3N, DMAP
CH2Cl2, r.t.
90%
AcO
AcO
HO
HO
a) NaIO4, THF:H2O
CH2OH
K2CO3,
MeOH
-40 to 0 °C
O
O
O
b) NaBH3CN, AcOH
OMe
OMe
OMe
OMe
OMe
α-6
80%
α-4
α-5
(pH = 5)
85%
+
AcO
AcO
HO
HO
a) NaIO4, THF:H2O
-40 to 0 °C
K2CO3,
MeOH
CH2OH
O
OMe
O
O
b) NaBH3CN, AcOH
(pH = 5)
80%
β-6
β-4
β-5
40%
Scheme 3. Separation of anomeric mixtures of 4 and 5.

J. C. Ramos et al. / Tetrahedron: Asymmetry 21 (2010) 969–972
971
(40 mg, 90%), which was used in the next step without further
purification. IR (liquid film)/cmꢁ1: 3421, 2925, 2853, 1734, 1697,
1636, 1561, 1509, 1457, 1410, 1208, 1102, 1039, 1010, 831, 703,
663. HRMS (ESI): calcd for C7H14NaO4 185.0790, found 185.0782.
4. Experimental
4.1. General
All non-hydrolytic reactions were carried out in a nitrogen atmo-
sphere with standard techniques for the exclusion of air. All solvents
were distilled prior to use. Melting points were determined on a
Gallenkamp capillary melting point apparatus and are uncorrected.
GC–MS analyses were performed using a QP-Shimadzu GC–MS
4.2.3. Methyl
A mixture of
MeOH (10 mL) was stirred for 4 h. After filtration of the K2CO3,
the solvent was evaporated to give -4 as a clear oil (21 mg,
a
-
D
-2,3-dideoxyglucofuranoside
a-4
a
-6 (40 mg, 0.16 mmol) and K2CO3 (3 mg) in
a
equipped with a DB5 column (Alltech, 30 m ꢀ 0.25 mm ꢀ 0.25
lm)
80%): Rf = 0.20 (3:7, hexanes/EtOAc, detection: p-anisaldehyde,
black); ½a 2D3
ꢂ
¼ þ45 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3):
operated under constant carrier flow of 1 mL/min (He). The initial
temperature was 70 °C (0 min), then raised to 320 °C at 10 °C/min;
the injector temperature 220 °C and the interphase temperature
d = 1.83 (m, 1H, CH2), 1.98 (m, 3H, CH2), 3.34 (s, 3H, CH3), 3.61
(m, 1H, CH2), 3.76 (m, 2H, CH), 4.05 (m, 1H, CH), 5.03 (dd, J = 4.6,
1.5 Hz, CH). 13C NMR (100 MHz, CDCl3): d = 24.4, 32.0, 54.8, 63.8,
73.8, 78.6, 105.2.
250 °C. Injection (1 lL) was in the split mode, and Total Ion Current
detection was used. Infrared spectra were recorded either on neat
samples (KBr disks) or in solution on a Shimadzu DR-8100 FT-IR
spectrometer. NMR spectra were obtained in CDCl3 on a Bruker
Avance DPX-400 instrument. Proton chemical shifts (d) are reported
in parts per million (ppm) downfield from TMS as an internal refer-
ence, and carbon chemical shifts are reported in ppm relative to the
center line of the CDCl3 triplet (77.0 ppm). Optical rotations were
4.2.4. Methyl a-D-2,3-dideoxyglucofuranoside b-4
Treatment 31 mg of b-6 as indicated above afforded b-4 as a
clear oil (16 mg, 79%): Rf = 0.20 (3:7, hexanes/EtOAc, detection:
p-anisaldehyde, black);
½
a 2D3
ꢂ
¼ ꢁ37 (c 0.9, CHCl3); 1H NMR
(400 MHz, CDCl3): d = 1.83 (m, 1H, CH2), 1.98 (m, 3H, CH2), 3.38
(s, 3H, CH3), 3.61 (m, 1H, CH2), 3.76 (m, 2H, CH), 4.18 (m, 1H,
CH), 4.98 (d, J = 4.3 Hz, CH). 13C NMR (100 MHz, CDCl3): d = 23.8,
32.8, 55.0, 63.8, 73.1, 81.3, 105.3.
measured on a Zuzi 412 polarimeter using a 1 dm cell. [a]D values
are given in units of 10ꢁ1 deg cm2 gꢁ1. Diols 1a and 1b were obtained
by fermentation of the corresponding arenes. Analytical TLC was
performed on Silica Gel 60F-254 plates and visualized with UV light
(254 nm) and/or p-anisaldehyde in acidic ethanolic solution. Flash
column chromatography was performed using silica gel (Kieselgel
60, EM reagent, 230–400 mesh).
4.2.5. Methyl D-5,6-O-diacetyl-2,3-dideoxyglucofuranoside a-6
and b-6
A mixture of 4 (50 mg, 0.31 mmol), Ac2O (0.12 mL, 1.24 mmol),
Et3N (0.35 mL, 2.5 mmol), and catalytic amounts of DMAP in CH2Cl2
(15 mL) was stirred for 3 h, then H2O was added (20 mL) and the
reaction mixture was extracted with CH2Cl2 (3 ꢀ 15 mL). The com-
bined organic layer was washed with saturated CuSO4 (15 mL),
brine (15 mL), dried over Na2SO4, and the solvent was removed at
a reduced pressure. The residue was purified by column chromatog-
raphy (10% deactivated silica gel, hexanes/EtOAc, 7:3) to obtain the
corresponding anomers with a combined yield of 90% (68 mg). IR
(liquid film)/cmꢁ1: 2955, 2834, 1746, 1441, 1371, 1225, 1042,
995, 864. HRMS (ESI): calcd for C11H18NaO6 269.1001, found
269.0998.
4.2. Synthetic procedures
(1S,2S)-3-Chlorocyclohex-3-ene-1,2-diol 2a and (1S,2S)-3-bromo-
cyclohex-3-ene-1,2-diol 2b were synthesized according to previ-
ously reported procedures.46
4.2.1. Hydroxy-(5-methoxytetrahydrofuran-2-yl)acetic acid
methyl ester 3
A mixture of O2/O3 (60% O3 in O2) was bubbled through a solu-
tion of compound 2a (80 mg, 0.54 mmol) and NaHCO3 (97 mg,
1.09 mmol) in a mixture of CH2Cl2/MeOH (14 mL, 1:1) at ꢁ78 °C,
until a blue color persisted. After the removal of the excess of O3
at ꢁ78 °C with N2, dimethyl sulfide (0.32 mL, 4.36 mmol) was
added, and the temperature was allowed to rise overnight until
room temperature, whereupon the solvent was removed at re-
duced pressure. The residue was purified by column chromatogra-
phy (10% deactivated silica gel, hexanes/EtOAc, 7:3) to afford
compound 3 as a clear oil (73 mg, 70%). Rf = 0.30 (7:3, hexanes/
EtOAc, detection: p-anisaldehyde, black); 1H NMR (400 MHz,
CDCl3): d = 1.95 (m, 7H, CH2), 2.09 (m, 1H, CH2), 3.06 (s (br), 1H,
OH), 3.33 (d, J = 1.7 Hz, 3H, CH3), 3.35 (d, J = 1.8 Hz, 3H, CH3),
3.55 (s (br), 1H, OH), 3.78 (d, J = 1.6 Hz, 3H, CH3), 3.79 (d,
J = 1.8 Hz, 3H, CH3), 4.39 (m, 3H, CH), 4.47 (m, 1H, CH), 4.98 (d,
J = 4.4 Hz, CH), 5.08 (dd, J = 4.4, 1.2 Hz, CH); 13C NMR (100 MHz,
CDCl3): d = 23.0, 23.3, 32.2, 32.8, 52.4, 52.7, 54.7, 55.2, 72.1, 72.8,
4.2.6. Methyl
-6
a-D-5,6-O-diacetyl-2,3-dideoxyglucofuranoside
a
Rf = 0.30 (7:3, hexanes/EtOAc, detection: p-anisaldehyde, black);
½ ꢂ
a 2D3
¼ þ50 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3): d = 1.72 (m,
1H, CH2), 1.90 (m, 3H, CH2), 2.05 (s, 3H, CH3), 2.08 (s, 3H, CH3),
3.31 (s, 3H, CH3), 4.10 (dd, J = 6.7, 12.1 Hz, 1H, CH2), 4.18 (dt,
J = 5.8, 7.7 Hz, 1H, CH), 4.37 (dd, J = 3.0, 12.0 Hz, 1H, CH2), 5.01
(dd, J = 1.12, 4.9 Hz, 1H, CH), 5.06 (dt, J = 3.0, 6.4 Hz, 1H, CH). 13C
NMR (100 MHz, CDCl3): d = 20.6, 21.1, 25.3, 33.6, 54.6, 63.1, 73.0,
81.4, 105.3, 170.1, 170.7.
4.2.7. Methyl b-D-5,6-O-diacetyl-2,3-dideoxyglucofuranoside b-6
Rf = 0.25 (7:3, hexanes/EtOAc, detection: p-anisaldehyde, black);
½
a 2D3
ꢂ
¼ ꢁ21 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3): d = 1.97 (m,
76.7, 78.8, 81.8, 105.6, 105.7, 172.1, 172.8; IR liquid film/cmꢁ1
:
4H, CH2), 2.09 (s, 3H, CH3), 2.11 (s, 3H, CH3), 3.35 (s, 3H, CH3),
4.19 (m, 2H, CH), 4.51 (dd, J = 2.7, 12.2 Hz, 1H, CH2), 4.99 (d,
J = 3.6 Hz, 1H, CH), 5.12 (dt, J = 2.7, 6.3 Hz, 1H, CH). 13C NMR
(100 MHz, CDCl3): d = 20.8, 21.0, 26.0, 32.7, 54.9, 63.2, 73.5, 78.2,
105.5, 170.3, 170.8.
3449, 2956, 1744, 1508, 1441, 1364, 1265, 1210, 1102, 1044,
977, 948, 911, 851, 548; HRMS (ESI): calcd for C8H14NaO5
213.0739, found 213.0742.
4.2.2. Methyl
D
-2,3-dideoxyglucofuranoside 4
(50 mg, 0.25 mmol) and NaBH4 (50 mg,
A
mixture of
3
4.2.8. Methyl D-ribofuranoside a-5 and b-5
1.26 mmol) in THF (15 mL) was stirred for 12 h, and then the reac-
tion was quenched with H2O (20 mL), extracted with AcOEt
(6 ꢀ 15 mL), dried over Na2SO4, and the solvent was evaporated
A mixture of 4 (55 mg, 0.33 mmol), and NaIO4 (71 mg, 0.33 mg)
in THF (12 mL) was stirred at -40 °C for 0.5 hours, then H2O (2 mL)
was added, and the mixture was let to reach 0 °C, whereupon
NaBH3CN (7 mg, 0.11 mmol) was added, and the pH was adjusted
to give 447 (1.2:1 mixture of
a- and b-anomers) as a yellow oil

972
J. C. Ramos et al. / Tetrahedron: Asymmetry 21 (2010) 969–972
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to 5 with AcOH. After 4 h of additional stirring, the reaction
mixture was quenched with H2O (20 mL), extracted with AcOEt
(15 mL ꢀ 6), and the combined organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The residue
was purified by column chromatography (10% deactivated silica
gel, hexanes/EtOAc, 4:6) to afford compound 5 (2:1 mixture of
and b-anomers) as a clear oil (31 mg, 68%). Rf 0.40 (3:7, hexanes/
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a-
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´
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4.2.9. Methyl
a-
D-ribofuranoside
a-5
Using the same procedure on
a
-4, pure a-5 was obtained in 85%
yield: ½a 2D3
ꢂ
¼ þ142 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 1,68 (m, 1H, CH2), 1.95 (m, 3H, CH2), 3.37 (s, 3H, CH3), 3.54
(dd, J = 5.5, 11.6 Hz 1H, CH2), 3.77 (dd, J = 3.4, 11.6 Hz, 1H, CH2),
4.24 (dtd, J = 9.4, 6.1, 3.1 Hz, 1H, CH), 5.08 (dd, J = 4.6, 1.3 Hz, 1H,
CH). 13C NMR (100 MHz, CDCl3): d = 24.9, 32.4, 54.7, 64.9, 78.2,
105.5.
4.2.10. Methyl b-D-ribofuranoside b-5
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ꢂ
¼ ꢁ115 (c 0.1, CHCl3); 1H NMR (400 MHz, CDCl3):
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Acknowledgments
Support for this work from DINACYT (SECYT-MEC-PDT FPR/F/BI/
49/20), PEDECIBA (Programa de Desarrollo de Ciencias Básicas,
Project URU/97/016) and ANII (Agencia Nacional de Investigación
e Innovación) is gratefully acknowledged. The authors also thank
Dr. A. Rodríguez for HRMS ESI TOF-MS analyses (Polo Tecnológi-
co-FQ; Proyecto Enlaces-UE URY-2003-5906), and Professor T.
Hudlicky for providing the cultures of P. putida F39/D.
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