Synthesis of different 3,5-diazidofuranoses: A new and general synthesis pathway

Article abstract of DOI:10.1080/07328300701540175

Diamino- and diazidofuranoses represent useful precursors, for example, for the synthesis of substituted nucleosides and metal complexes, respectively. Known procedures for their synthesis lack the availability of cheap starting materials, adequate yields, and the access to all possible diastereomeres. Therefore, 3,5-diazido-3,5-dideoxy- and -2,3,5-trideoxyfuranoses both with ribo- and xylo-configuration were prepared using different approaches.

Full text of DOI:10.1080/07328300701540175

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Synthesis of Different 3,5‐Diazidofuranoses:
A New and General Synthesis Pathway
Daniel Koth a , Andrea Fiedler a , Sandy Scholz a & Michael Gottschaldt a
a Institute for Organic and Macromolecular Chemistry, Jena, Germany
Version of record first published: 31 Aug 2007.
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Different 3,5‐Diazidofuranoses: A New and General Synthesis Pathway, Journal of Carbohydrate Chemistry,
26:5-6, 267-278
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Journal of Carbohydrate Chemistry, 26:267–278, 2007
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300701540175
Synthesis of Different
3,5-Diazidofuranoses:
A New and General
Synthesis Pathway
Daniel Koth, Andrea Fiedler, Sandy Scholz, and
Michael Gottschaldt
Institute for Organic and Macromolecular Chemistry, Jena Germany
Diamino- and diazidofuranoses represent useful precursors, for example, for the syn-
thesis of substituted nucleosides and metal complexes, respectively. Known procedures
for their synthesis lack the availability of cheap starting materials, adequate yields,
and the access to all possible diastereomeres. Therefore, 3,5-diazido-3,5-dideoxy- and
-2,3,5-trideoxyfuranoses both with ribo- and xylo-configuration were prepared using
different approaches.
Keywords Furanoses, Diazides, Nucleophilic substitution
INTRODUCTION
The synthesis of azido-, amino-, and acetamido-substituted sugars and nucleo-
sides received attention since their derivatives often display biological activity.
Amino sugars are structural components of macrolide antibiotics.[1] Azido
nucleosides such as AZT have been used as antiviral agents.[2] The coordi-
nation of biologically and catalytically active metal ions by selectively
modified amino carbohydrates has also gained much attention. For example,
the synthesis of cisplatin analogs,[3] radiotracers,[4] and antifungal agents[5]
has been reported. Metal complexes of functionalized amino carbohydrates
have been synthesized[6] and successfully used as catalysts.[7–9] Nucleosides
Received March 30, 2006; accepted April 18, 2007.
Address correspondence to Michael Gottschaldt, Institute for Organic and Macro-
molecular Chemistry, FSU Jena, Humboldtstrasse 10, 07743 Jena, Germany. E-mail:
michael.gottschaldt@uni-jena.de
267

D. Koth et al.
268
bearing amino groups at the sugar moiety have been applied as ligands for the
coordination of metal ions.[10–12]
Their synthesis starting from naturally occurring nucleosides by insertion
of amino groups often displays major problems due to the influence of the
nucleobase and is strongly limited by the availability of the starting materials.
On the other hand, the creation of artificial nucleosides by coupling of sugar
derivatives to nucleobases and other heterocyclic systems is well explored.[13]
On this background we report an advanced synthesis of 3,5-diazido-3,5-
dideoxy- and -2,3,5-trideoxy-furanose derivatives (1–4, Fig. 1) as useful
building blocks for the design of new 30,50-diazido-nucleosides and chiral
metal complexes thereof.
RESULTS AND DISCUSSION
For both the biological activity and the formation of metal complexes, the
absolute configuration is crucial. It is determined by the most demanding
step, the nucleophilic substitution with azide anions. The synthesis of the differ-
ent 3,5-diazido-derivatives 1, 2, and 4 has been described earlier, but with low
yields or less practical synthetic effort. Derivative 3 has not been prepared
yet. 1 was obtained in 61% yield by Brimacombe et al., but starting from
rather expensive 1,2-O-isopropylidene-a-D-allofuranose.[14] Ozols et al. showed
the synthesis for 3,5-diazido-3,5-dideoxy-1,2-O-isopropylidene-a-D-ribofuranose
2, but the desired compound could be obtained only in low yields. The corre-
sponding elimination compound was formed as a byproduct in the same
amount and the structural characterization was not sufficient.[15] Moravcova
et al. tried to optimize the synthesis of 2 by using Mitsunobu reaction conditions,
but with less success.[16] The 3,5-diazido-2,3,5-trideoxy-D-ribofuranoside 4 was
obtained by Graef et al. in a four-step reaction sequence, but starting from a
rarely available derivative.[17] Other furanoside diazides bearing the substitu-
ents at different positions and configurations have been synthesized by Unger
et al. starting from a 2,3-anhydro-a-D-lyxofuranoside using nucleophilic ring
opening reactions.[18] Obviously, the known procedures for the synthesis of
3,5-diazidofuranoses are less efficient, lengthy, and complicated.
Figure 1: Target structures of 3,5-diazidofuranoses.

3,5-Diazidofuranoses
269
The treatment of readily available D-xylose with acetone in the presence of
sulfuric acid and anhydrous copper(II) sulfate results in the 1,2-O-isopropyli-
dene-furanoside in good yields (Sch. 1).
Mesylation of the free hydroxy groups leads to the methane-
sulfonyl ester 7, which is the precursor for the target compound 2. In
contrast to the known procedure, we used lithium azide as nucleophil
and N-methylpyrrolidone as solvent and obtained the diazide 2 in 68%
yield. Having done so, the formation of the elimination product can be
avoided. This byproduct is formed in all other known pathways in nearly
the same amount as the title compound and is difficult to separate from
it. The synthesis of the diazide 1 was described earlier, but starting from
an uncommon allofuranose derivative.[14] The problems in the synthesis
of 1 occur because of the difficult accessibility of the 1,2-O-isopropylidene-
ribo-furanoside 9. The benzoylation of the primary hydroxy group in 6
followed by oxidation and subsequent reduction at C-3 leads to an inversion
of the absolute configuration. After the saponification, the ribofuranoside 9
could be obtained in an overall yield of 70%.
Standard methods for the conversion of 9 to the corresponding diazide 1
led to a mixture of various products. Therefore, different leaving groups,
nucleophiles, and solvents were tested. Only the use of triflate as the
leaving group and phase transfer conditions led to the desired product 1 in
60% overall yield.
There is only one report for the synthesis of the deoxy derivative 4 from
methyl-5-iodo-2,5-dideoxy-xylofuranoside as starting material.[17] Starting
from 2-deoxy-D-ribose 11 stirred in dry methanol in the presence of catalytical
amounts of acid, the methyl glycoside 12 could be formed. Its conversion to the
5-O-tosyl-intermediate 13 followed by the reaction with lithium azide in DMF
Scheme 1: Synthesis of the 3,5-diazido-3,5-dideoxy-furanoses in ribo- (1) and
xylo-configuration (2): a) 1: (CH3)2CO, CuSO4, H2SO4; 2: 0.1% HCl, 85%; b) MsCl, pyridine, 08C,
88%; c) LiN3, NMP, 68%; d) 1: BzCl, Et3N, CH2Cl2, 08C; 2: Ac2O, CH2Cl2, PDC, reflux, 78%; e) 1:
EtOH, NaBH4, 08C; 2: NaOMe, MeOH, reflux, 90%; f) Tf2O, pyridine, CH2Cl2, –258C, 79%; g)
(CH2Cl)2, H2O, NaN3, 18-crown-6, 15-crown-5, But4NBF4, reflux, 76%.

D. Koth et al.
270
Scheme 2: Synthesis of the 3,5-diazido-2,3,5-trideoxy-furanoses in ribo- (3) and xylo-
configuration (4): a) MeOH, HCl, 08C, 74%; b) TsCl, pyridine, –58C, 70%; c) NaN3, DMF, 908C,
52%; d) 1: TsCl, CH2Cl2, pyridine, –58C; 2: LiN3, DMF, 658C, 62%; e) 1: Tf2O, CH2Cl2, pyridine,
–158C; 2: DMF, H2O, 15-crown-5, NaNO2, 71%; f) 1: Tf2O, CH2Cl2, pyridine, –158C; 2: LiN3, DMF,
408C, 68%.
(Sch. 2) gave the 5-azido-derivative 14. According to the synthesis used, the
2-deoxy-derivatives could only be obtained as an anomeric mixture.
The inversion of the configuration at C-3 could be carried out by pre-
paring the 3-O-triflate-derivative and in situ reaction with sodium nitrite
in DMF in the presence of water and crown ether to yield 71% of 15.
Applying the standard procedure by forming the sulfonester with triflic
anhydride and its subsequent nucleophilic substitution with lithium azide,
the methyl-3,5-diazido-2,3,5-trideoxy-D-ribofuranoside 4 could be formed.
In contrast to this, the novel xylo-diazide 3 could be prepared in a straight-
forward synthesis from 12 by tosylation and reaction with sodium azide in
DMF in 40% overall yield. Compound 4 could be obtained as colorless low
viscous oil.
CONCLUSION
In summary, we prepared four different 3,5-diazido-3,5-dideoxy-and -2,3,5-tri-
deoxyfuranoses, both with ribo- and xylo-configurations.
Although there are a few papers reporting the synthesis of the target com-
pounds, this is the first time a synthesis for all isomers is described. All reac-
tions start from readily available D-xylose and 2-deoxy-D-ribose and can be
performed in relatively high yields.
Though in a few papers synthetic studies have been reported to reach
these compounds, herewith the first report was given for the synthesis of
all isomeres applying new methods. This opens up new possibilities for the
synthesis of still unknown artificial nucleosides and chiral metal complexes.
For their application it is not necessary to separate the anomeres of the
deoxy-derivatives.

3,5-Diazidofuranoses
271
EXPERIMENTAL
General Methods
Electronic spectra were recorded with a Varian Cary 1 or Cary 5E spectro-
photometer at rt. IR spectra were measured on a Perkin-Elmer 2000 spectro-
meter and NMR spectra on a Bruker AC-200; mass spectra were carried out
on a Finnigan MAT SSQ 710 or a Finnigan MAT 95XL TRAP, and elemental
analyses on a Leco CHNS 932.
3,5-Diazido-3,5-dideoxy-1,2-O-isopropylidene-a-D-
xylofuranose (1)
Dissolved was 0.47 g of 10 (1.0 mmol) in 10 mL dichloroethane and after
that 5 mL water, 510 mg sodium azide (7.85 mmol), 50 mg 18-crown-6 as well
as 15-crown-5, and 100 mg tetrabutylammonium tetrafluoroborate were
added and the resulting mixture was heated under reflux with vigorous
stirring. After 10 h the TLC indicated the complete conversion. The layers
were separated, the aqueous layer was extracted twice with chloroform, and
the combined organic layers were evaporated. The obtained crude product
purified by filtration over Celite gave 190 mg of 1 (yield 76%) as a yellow oil.
1H NMR (CDCl3) d 5.85 (d, 1H, H-1), 4.63 (d, 1H, H-2), 4.26 (dt, 1H, H-4),
3.94 (d, 1H, H-3), 3.56, 3.44 (2dd, 2H, H-5, H-50), 1.45, 1.27 (2s, 6H, CH3); 13C
NMR (CDCl3) d 112.5 (C(CH3)2), 104.7 (C1), 83.3 (C2), 77.6 (C4), 66.1 (C3),
49.5 (C5), 26.6, 26.2 (C(CH3)2); MS (EI) m/z 225 [M-15]þ; IR: 2991, 2939,
2096, 1378, 1083, 1019 cm21; Anal. Calcd for C8H12N6O3: C, 40.00; H, 5.04;
N, 34.98; Found: C, 41.43; H, 5.08; N, 33.75; ESI-HRMS m/z 225.07288 [M-
15]þ, C7H9N6O3 calc. 225.07361307.
3,5-Diazido-3,5-dideoxy-1,2-O-isopropylidene-a-D-
ribofuranose (2)
To a solution of 1.24 g of 7 (3.58 mmol) in 20 mL N-methylpyrrolidone, 1 g
lithium azide (20 mmol) was added. The resulting solution was heated for 8 h at
1408C until the TLC indicated the complete conversion of 7. The solvent was
removed under reduced pressure and the dark brown precipitate was extracted
twice with ethyl acetate. The combined organic layers were dried over sodium
sulfate, filtered off, and evaporated. The resulting slight yellow oil was purified
1
by flash column chromatography. Yield 585 mg of 2 (68%). H NMR (CDCl3) d
5.84 (d, 1H, H-1) 4.76 (m, 1H, H-2), 4.20 (m, 1H, H-4), 3.74 (dd, 1H, H-5),
3.49 (m, 1H, H-3), 3.36 (dd, 1H, H-50), 1.57 and 1.37 (2s, 6H, CH3); 13C NMR
(CDCl3) d 113.4 (C(CH3)2), 104.1 (C1), 80.0 (C2), 76.7 (C4), 60.8 (C3), 50.3
(C5), 26.4 (C(CH3)2); MS (EI) m/z 225 [M-15]þ; IR: 2992, 2940, 2102, 1727,

D. Koth et al.
272
1670, 1375, 1155, 1043 cm21; Anal. Calcd for C8H12N6O3: C, 40.00; H, 5.04; N
34.98; Found: C, 40.10; H, 5.05; N, 34.86; ESI-HRMS m/z 225.07206 [M-15],
C7H9N6O3 calc. 225,07361307.
Methyl-3,5-diazido-2,3,5-trideoxy-D-xylofuranoside (3)
Dissolved was 8.3 g of the ditosylate 15 (18 mmol) in 100 mL dried DMF;
8.82 g lithium azide (180 mmol) was added and the reaction mixture was
heated at 908C for 6 h. After evaporation the resulting mixture was extracted
with ethyl acetate, dried with sodium sulfate, filtered off, and evaporated to
give 2.8 g of 3 as light yellow oil (yield 78%). The crude product was purified
by flash column chromatography (yield 52%). 1H NMR (CDCl3) d 5.12 (dd,
1H, H-1), 4.21–4.10 (m, 1H, H-4), 3.71–3.34 (m, 6H, H-3, H-5, H-50, -OCH3),
2.31–2.16 (m, 2H, H-2, H-20); 13C NMR (CDCl3) d 103.9 (C1), 77.9 (C4), 61.6
(C3), 55.4 (C5), 50.4 (-OCH3), 39.2 (C-2); IR (ATR) 2935, 2839, 2095, 1445,
1266, 1106, 1044, 983 cm21; Anal. Calcd for C6H10N6O2: C, 36.36; H, 5.09; N,
42.41; Found: C, 38.48; H, 5.27; N, 39.94; ESI-HRMS m/z 221.07498
[M þ Na], C6H10N6O2Na calc. 221.076293.
Methyl-3,5-diazido-2,3,5-trideoxy-D-ribofuranoside (4)
Dissolved was 200 mg of 15 (1.1 mmol) in dried methylene chloride, which
was then treated with 0.191 mL pyridine. Added was 100 mL triflic acid anhy-
dride (30 mmol) portionwise with vigorous stirring at –158C. After the addition
had been completed, the reaction mixture was stirred for 30 min, washed with
ice water and sodium chloride solution, dried with calcium chloride, filtered off,
and evaporated at 308C. The formed product was quite unstable and had to be
handled with care. All steps had to be done as fast as possible. Otherwise, the
product decomposed by elimination. It had been used immediately for the
next reaction step. Dissolved was 141 mg of the formed methyl-5-azido-2,5-
dideoxy-3-O-trifluormethanesulfonyl-D-xylofuranoside (0.065 mmol) in 10 mL
DMF. After addition of 225 mg lithium azide (4.6 mmol), the reaction mixture
was slightly heated until the TLC indicated the complete conversion. After
the removal of the solvent extraction with ethyl acetate and evaporation,
77 mg of 4 could be obtained (yield 68%). The crude product was purified by
flash column chromatography (yield 41%). 1H NMR (MeOD) 5.15–5.02
(m, 1H, H-1) 4.21–4.11 (m, 1H, H-4), 3.66–3.35 (m, 6H, H-3, H-5, H-50,
-OCH3), 2.31–2.16 (m, 2H, H-2, H-20); 13C NMR (CDCl3) d 105.16, 104.63
(C1), 80.29, 78.36 (C4), 68.56, 68.54 (C3), 55.10, 54.10 (C5), 51.83, 50.06
(-OCH3), 39.20, 38.80 (C-2); MS (EI) m/z 198 [M þ ]. Anal. Calcd for
C6H10N6O2: C, 36.36; H, 5.09; N, 42.41; Found: C, 39.00; H, 5.31; N, 36.76;
ESI-HRMS m/z 221.07568 [M þ Na], C6H10N6O2Na calc. 221.076293.

3,5-Diazidofuranoses
273
1,2-O-Isopropylidene-a-D-xylofuranose (6)
To 42 g D-xylose (280 mmol) and 70 g of anhydrous copper(II) sulfate
(439 mmol) suspended in 800 mL dried acetone, 4 mL concentrated sulfuric
acid was added. The reaction mixture was stirred overnight, neutralized
with sodium hydrogen carbonate, and filtered off, and the filter cake was
washed thoroughly with acetone. The combined organic layers were evapor-
ated and dried in vacuo. The formed 1,2,3,5-di-O-isopropylidene-a-D-xylofura-
nose was dissolved in 250 mL of a 0.2% aqueous hydrochloric acid and stirred at
rt until the TLC (Rf 0.5 in ethyl acetate) indicated the complete conversion to
the desired mono-isopropylidene derivative. After neutralization the reaction
mixture was concentrated to a small volume and extracted with ethyl
acetate. The organic layer was dried with sodium sulfate, filtered off, and evap-
1
orated to yield 45 g of 6 (85%). H NMR (DMSO-D6) d 5.91 (d, 1H, H-1), 5.15
(d, 1H, H-2), 4.65 (dd, 1H, H-4), 4.37 (d, 1H, H-3), 3.95 (s, 2H, -OH), 3.36
(m, 2H, H-5 and H-50), 1.38, 1.23 (2s, 6H, -CH3); 13C NMR (DMSO-D6) d
110.2 (C(CH3)2), 104.2 (C1), 85.0 (C2), 81.7 (C4), 73.4 (C3), 58.0 (C5), 26.6,
26.4 (2s, 6H, CH3). MS (EI) m/z 191 [M þ 1].
1,2-O-Isopropylidene-3,5-di-O-methanesulfonyl-a-D-
xylofuranose (7)
Dissolved was 10 g of 6 (52 mmol) in 50 mL dried pyridine. After dropwise
addition of 13.3 g methanesulfonyl chloride (115 mmol), the reaction mixture
was stirred for 3 h, and then 20 mL methanol was added and the mixture
stirred again for 30 min. After evaporation and extraction with ethyl acetate,
the combined organic layers were dried with sodium sulfate, filtered off, evap-
1
orated, and dried in vacuo to yield 15.8 g of 7 as a white solid (88%). H NMR
(CDCl3) d 5.93 (d, 1H, H-1), 5.00 (d, 1H, H-2), 4.77 (d, 1H, H-3), 4.51 (m, 1H,
H-4), 4.36 (dd, 2H, H-5, H-50), 3.10, 3.00 (s, 6H, –SO2CH3), 1.45, 1.18 (2s,
6H, -CCH3); 13C NMR (DMSO-D6) d 113.0 (C(CH3)2), 104.9 (C1), 85.0 (C2),
80.4 (C4) 76.2 (C3), 65.2 (C5), 38.4, 37.6 (–SO2CH3), 26.6, 26.2 (C(CH3)2).
5-O-Benzoyl-1,2-O-isopropylidene-3-oxo-a-D-xylofuranose (8)
To 20 g of 6 (105 mmol) dissolved in 50 mL dried methylene chloride, 10.6 g
triethylamine (105 mmol) was added. After cooling down to 08C, 16.2 g benzoyl
chloride (116 mmol) dissolved in 50 mL methylene chloride was slowly added.
After 3 h the TLC indicated the complete conversion of 6. The reaction
mixture was washed twice with water, dried with sodium sulfate, filtered off,
and evaporated to yield 30.6 g of 5-O-benzoyl-1,2-O-isopropylidene-a-D-xylo-
1
furanose as a white solid (99%). H NMR (CDCl3) d 7.99, 7.50, 7.39 (3d, 5H,
CHaryl), 5.89 (d, 1H, H-1), 4.52 (d, 1H, H-2), 4.33–4.31 (m, 2H, H-3, H-4),
4.13 (m, 2H, H-5, H-50), 1.44, 1.24 (2s, 6H, C(CH3)2); 13C NMR (CDCl3) d

D. Koth et al.
274
167.4 (C55O), 133.6, 130.1, 129.9, 129.2, 128.6, 128.5 (Caryl), 111.9 (C(CH3)2),
105.2 (C1), 85.0 (C2), 78.5 (C4), 74.4 (C3), 61.3 (C5), 26.8, 26.1 (C(CH3)2); MS
(DEI) m/z 295 [M þ 1]þ; IR(ATR) 3426, 2991, 2949, 1715, 1450, 1379, 1270,
1089, 1070, 1009, 707 cm21; Anal. Calcd for C15H18O6: C, 61.22; H, 6.16;
Found: C, 61.18; H, 6.14.
Dissolved was 1 g of 5-O-benzoyl-1,2-O-isopropylidene-a-D-xylofuranose
(3.4 mmol) in 20 mL methylene chloride. To the stirred solution 1 g acetic
acid anhydride (10.2 mmol) and 0.8 g PDC (2.2 mmol) were added. The
reaction mixture was heated under reflux for 2 h, filtered through Celite,
evaporated, dissolved in chloroform, washed with aqueous sodium hydrogen
carbonate solution, dried with calcium chloride, filtered off, and evaporated.
The crude product was dissolved in boiling heptane, filtered through Celite,
1
and evaporated to yield 0.8 g of 8 as a white solid (79%). H NMR (CDCl3) d
7.89, 7.47, 7.38 (3d, 5H, CHaryl), 6.07 (d, 1H, H-1), 4.62 (m, 2H, H-5, H-50),
4.36 (d, 1H, H-2), 1.44, 1.36 (2s, 6H, C(CH3)2); 13C NMR (CDCl3) d 207.6
(C3), 165.7 (C55O), 133.4, 130.1, 129.9, 129.5, 129.3, 128.5 (Caryl), 114.4
(C(CH3)2), 103.0 (C1), 77.5 (C2), 76.1 (C4), 63.4 (C5), 27.4 and 27.0 (C(CH3)2).
MS (DEI) m/z 293 [M þ 1]þ; IR(ATR) 2996, 2926, 1771, 1724, 1451, 1376,
1089, 1070, 1009, 707 cm21; Anal. Calcd for C15H16O6: C, 61.64; H, 5.52;
Found: C, 61.89; H, 6.09.
1,2-O-Isopropylidene-a-D-ribofuranose (9)
In 30 mL ethanol, 4.5 g of 8 (15.4 mmol) was dissolved and cooled down to
08C. Added dropwise was 0.6 g NaBH4 (15.9 mmol) dissolved in 20 mL water
over 2 h with vigorous stirring. After complete addition the reaction mixture
was allowed to warm up to rt, stirred overnight, and neutralized with acetic
acid. After evaporation the formed 5-O-benzoyl-1,2-O-isopropylidene-a-D-ribo-
furanose was dissolved in methanol and 0.5 mL sodium methanolate solution
was added and the resulting mixture was heated for 1 h. After neutralization
with ammonium chloride, the reaction mixture was evaporated and redissolved
in ethyl acetate and filtered off. The crude product was purified by flash column
chromatography using ethyl acetate/methanol 1:1, yielding 2.64 g of compound
1
9 (90%). H NMR (MeOD) d 5.64 (d, 1H, H-1), 4.46 (m, 1H, H-2), 3.78 (m, 2H,
H-5, H-50), 3.71 (s, 1H, H-4), 3.53 (d, 1H, H-3), 1.44, 1.24 (2s, 6H, C(CH3)2);
13C NMR (MeOD) d 113.7 (C(CH3)2), 105.3 (C1), 81.7 (C2), 80.8 (C4), 72.1
(C3), 61.7 (C5), 27.0, 26.7 (C(CH3)2); MS (EI) m/z 191 [M þ 1]þ; Anal. Calcd
for: C8H14O5: C, 50.52; H, 7.42; Found: C, 51.31; H, 7.04.
1,2-O-Isopropylidene-3,5-di-O-trifluoromethanesulfonyl-a-D-
ribofuranose (10)
To a solution of 0.5 g of 9 (2.6 mmol) in 20 mL methylene chloride, 0.5 g
pyridine (6.3 mmol) was added and the solution was cooled down to –258C.

3,5-Diazidofuranoses
275
After addition of 2.3 g triflic acid anhydride (7.9 mmol) dissolved in 10 mL
methylene chloride, the reaction mixture was stirred for 30 min, allowed to
warm up to rt, and stirred for 30 minutes. The organic layer was washed with
sodium hydrogen carbonate solution and twice with water, evaporated, and
dried in vacuo to yield 0.94 g (79%) of 10. The obtained white powder could be
1
stored under argon atmosphere in the refrigerator. H NMR (CDCl3) d 5.81
(d, 1H, H-1), 4.36 (m, 1H, H-2), 4.09 (m, 1H, H-4), 4.01 (d, 1H, H-3), 3.68
(m, 2H, H-5, H-50), 1.35, 1.19 (2s, 6H, C(CH3)2); 13C NMR (CDCl3) d 112.7
(C(CH3)2), 106.3 (C1), 86.9 (C2), 82.4 (C4), 75.8 (C3); 61.0 (C5), 27.1, 26.4
(C(CH3)2).
Methyl-2-deoxy-D-ribofuranoside (12)
Dissolved was 10 g of 2-deoxy-D-ribose (74.55 mmol) in 80 mL of dried
methanol, which was then cooled down to 08C; 0.5 mL concentrated sulfuric
acid was added and the reaction mixture was stirred for 24 h. After neutraliz-
ation with ion exchange resin Amberlite IRA 420 (OH2 coated), filtration, and
evaporation, the crude product was purified by flash column chromatography
1
to yield 8.13 g (74%) of 12 as anomeric mixture. H NMR (DMSO-D6) d 5.07
(m, 1H, H-1 major anomer), 4.74 (m, 0.2H, H-1 minor anomer), 4.47–3.55
(m, 4H, H-3, H-4, H-5, H-50), 3.36, 3.34 (2s, 3H, -OCH3), 2.28–2.14 (m, 2H,
H-2, H-20); 13C NMR (DMSO-D6) d 105.4, 105.3 (C1), 87.1, 86.9 (C4), 72.4,
71.8 (C3), 63.5, 62.7 (C5), 55.5, 54.8 (-OCH3), 42.0, 41.3 (C2). Anal. Calcd for
C6H12O4: C, 48.64; H, 8.16, Found: C, 48.59; H, 8.37.
Methyl-2-deoxy-3,5-di-O-tosyl-D-ribofuranoside (13)
To 4 g of 12 (27 mmol) dissolved in pyridine, 11.3 g p-toluenesulfonyl chloride
(60 mmol) was added portionwise with vigorous stirring at –58C. After 10 h the
TLC indicated the complete conversion of the starting material. The reaction
mixture was evaporated and extracted with ethyl acetate to give the product
1
in 70% yield as anomeric mixture. H NMR (DMSO-D6) d 7.77 (d, 2H, CHaryl),
7.5 (dd, 4H, CHaryl), 7.1 (d, 2H, CHaryl), 5.04 (m, 1H, H-1), 4.60 (m, 1H, H-3),
4.10–3.80 (m, 3H, H-4, H-5, H-50), 3.26, 3.02 (2s, 3H, -OCH3), 2.40, 2.27 (2s,
6H, (-CH3)tosyl), 2.12–1.97 (m, 2H, H-2, H-20); 13C NMR (DMSO-D6) d 145.4,
138.0, 132.7, 131.8, 127.5, 125.4 (Caryl), 104.7 (C1), 80.3 (C4), 69.3 (C3), 68.8
(C5), 54.5 (-OCH3), 38.1 (C2), 20.0 ((CH3)tosyl). IR (ATR) 1596, 1359, 1171,
1095, 987, 916, 811, 654 cm21; Anal. Calcd for C20H24O8S2: C, 52.62; H, 5.30;
S, 14.05; Found: C, 52.62; H, 5.32; S, 13.70.
Methyl-5-azido-2,5-dideoxy-D-ribofuranoside (14)
To 4 g of 12 (27 mmol) dissolved in 20 mL methylene chloride and 2.37 g
pyridine (30 mmol), 5.7 g p-toluenesulfonyl chloride (30 mmol) was added

D. Koth et al.
276
portionwise with vigorous stirring at –58C. After 7 h the TLC indicated the
complete formation of the methyl-5-O-tosyl-2-deoxy-D-ribofuranoside. The
reaction mixture was evaporated, extracted with ethyl acetate, dried with
sodium sulfate, filtered off, and evaporated to give 6.35 g of the monotosylate
(78% yield) that was used for the next reaction step without further purifi-
cation. Dissolved was 2.5 g (8.26 mmol) of the monotosylate in dried DMF
(40 mL), 4.0 g lithium azide (82 mmol) was added, and the reaction mixture
was heated for 5 h at 658C. After evaporation and extraction, the crude
product was purified by flash column chromatography to yield 1.14 g (80%)
of 14 as anomeric mixture. 1H NMR (CDCl3) d 5.27–5.04 (m, 1H, H-1),
4.40–4.07 (m, 2H, H-3, H-4), 3.99–3.35 (m, 5H, (-CH3), H-5, H-50), 2.28–
2.02 (m, 2H, H-2, H-20); 13C NMR (CDCl3) d 105.6, 105.4 (C1), 85.7, 84.6
(C4), 73.4, 73.0 (C3), 55.4, 54.9 (C5), 53.8, 52.7 (-CH3), 41.6, 41.2 (C2). Anal.
Calcd for C6H11N3O3: C, 41.61; H, 6.40; N, 24.27; Found: C, 41.61; H, 6.23;
N, 24.02.
Methyl-5-azido-2,5-dideoxy-D-xylofuranose (15)
Dissolved was 200 mg of 14 (1.15 mmol) in 2 mL dried methylene chloride,
and 0.2 mL dried pyridine was added. The reaction mixture was cooled down to
–158C and 357 mg (1.265 mmol) triflic acid anhydride was added slowly. After
20 min the reaction mixture was allowed to warm up to rt, washed with ice
water and sodium hydrogen carbonate solution, dried, and evaporated to
yield methyl-5-azido-2,5-dideoxy-3-O-trifluormethanesulfonyl-D-ribofurano-
side. This compound was unstable and was used immediately in the next
reaction step without further purification. It was dissolved in 50 mL DMF,
and three drops of 15-crown-5, 30 mL water, 154 mg sodium nitrite
(12.2 mmol) were added and the reaction mixture was stirred overnight.
After evaporation the crude product was purified by flash column chromato-
1
graphy to give 142 mg (71%) of 15 as anomeric mixture. H NMR (CDCl3) d
5.29–5.06 (m, 1H, H-1), 4.50–4.11 (m, 2H, H-3, H-4), 3.53–3.36 (m, 5H,
(-CH3), H-5, H-50), 2.27–2.06 (m, 2H, H-2, H-20); 13C NMR (CDCl3) d 105.1,
104.1 (C1), 83.1, 78.4 (C4), 71.8, 71.5 (C3), 55.3, 55.0 (C5), 52.0, 50.1 (-CH3),
43.0, 41.4 (C2); Anal. Calcd for C6H11N3O3: C, 41.61; H, 6.40; N, 24.27;
Found: C, 41.60; H, 5.96; N, 24.00.
ACKNOWLEDGEMENT
Financial support by the Deutsche Forschungsgemeinschaft (Collaborative
Research Centre 436, Jena, Germany), the Fonds der Chemischen Industrie
(Germany), and the Thueringer Ministerium fu¨r Wissenschaft, Forschung
und Kultur (Erfurt, Germany) is gratefully acknowledged.

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277
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