An efficient synthesis of methyl 2,3-anhydro-α-D-ribofuranoside

Article abstract of DOI:10.1016/S0008-6215(00)00277-9

An efficient synthesis of methyl 2,3-anhydro-α-D-ribofuranoside is reported. Its preparation is achieved via a four-step sequence from methyl 2,3,5-tri-O-benzoyl-α-D-arabinofuranoside in 74% overall yield.

Full text of DOI:10.1016/S0008-6215(00)00277-9

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Carbohydrate Research 330 (2001) 267–270
Note
An efficient synthesis of methyl
2,3-anhydro-a-D-ribofuranoside
Christopher S. Callam, Rajendrakumar Reddy Gadikota, Todd L. Lowary*
Department of Chemistry, The Ohio State Uni6ersity, 100 West 18th A6enue, Columbus, OH 43210, USA
Received 11 September 2000; accepted 12 October 2000
Abstract
An efficient synthesis of methyl 2,3-anhydro-a-
D
-ribofuranoside is reported. Its preparation is achieved via a
-arabinofuranoside in 74% overall yield. © 2001 Elsevier
four-step sequence from methyl 2,3,5-tri-O-benzoyl-a-
D
Science Ltd. All rights reserved.
Keywords: Anhydro sugars; Furanosides
2,3-Anhydrofuranose derivatives 1 and 2
(Chart 1) have found widespread application
in the synthesis of modified nucleoside
analogs1 and carbohydrate derivatives2 due to
the ease with which the epoxide moiety can be
regioselectively opened by nucleophiles.3 Al-
though an expeditious synthesis of 2 has been
reported,4 a similarly efficient route for the
preparation of 1 is not available. Anhydro
sugar 1 was first synthesized by Baker and
co-workers5 in 1958. Using 1,2-O-isopropyli-
prepared7 in multigram quantities from
binose (Scheme 1).
D-ara-
As illustrated in Scheme 2, our route to 1
began with Zemple´n deacylation of 4. Follow-
ing the reaction, the solution was neutralized,
concentrated to an oil, and the resulting
residue was partitioned between water and
dichloromethane. Evaporation of the aqueous
layer, followed by coevaporation with toluene,
provided the product 5, which was sufficiently
pure for the subsequent reaction. Treatment
of this triol with 1,3-dibromo-1,1,3,3-
dene-a- -xylofuranose as the starting mate-
D
rial, the product was obtained in approxi-
mately 25% overall yield in five steps. A mod-
ification of this procedure, which provides
higher yields, has since been reported;6 how-
ever, this route still involves five steps with
purification of each intermediate. In this Note,
we report an efficient synthesis of 1 from
methyl 2,3,5-tri-O-benzoyl-a- -arabinofura-
D
noside (4), a compound that can be easily
* Corresponding author. Tel.: +1-614-2924926; fax: +1-
614-2921685.
E-mail address: lowary@chemistry.ohio-state.edu (T. L.
Lowary).
Scheme 1. As described in Ref. 7: (a) CH3OH, HCl, rt; (b)
BzCl, pyridine, 0 °C“rt; (c) crystallization.
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(00)00277-9

268
C.S. Callam et al. / Carbohydrate Research 330 (2001) 267–270
methanol with
D-arabinose, could be used as
the starting material. Indeed, we found
(Scheme 3) that 3 could be converted to a
mixture of epoxides, 1 and 8 using the route
outlined in Scheme 2. The overall yield for
this reaction sequence was comparable to that
obtained for the transformation of 4 to 1.
However, it was not possible to separate 1 and
8 either by crystallization or by chromatogra-
phy.† Furthermore, attempts to derivatize the
mixture with benzoyl chloride, triphenyl-
methyl chloride, or t-butylchlorodiphenylsi-
lane produced inseparable mixtures of
glycoside products.‡
Scheme 2. (a) NaOCH3, CH3OH, rt, quantitative; (b) (i-
Pr2SiBr)2O, pyridine, 0 °C“rt, 89%; (c) (CF3SO2)O, pyridine,
0 °C; (d) n-Bu4NF, THF, 83%, two steps.
In summary, we report an efficient synthesis
of methyl 2,3-anhydro-a-
from readily available methyl 2,3,5-tri-O-ben-
zoyl-a- -arabinofuranoside (4). The product
is produced in 74% overall yield via a four-
step sequence that can be carried out in less
than 3 days. Only two chromatographic
purifications are required. We have also
D
-ribofuranoside (1)
D
Scheme 3.
tetraisopropyldisiloxane8 in pyridine provided
the known alcohol 69, which was easily
purified by chromatography. The resulting oil
was dissolved in pyridine, cooled to 0 °C, and
then stirred with triflic anhydride for 5 min.
Conventional workup provided crude triflate
7, which was immediately treated with tetra-n-
butyl ammonium fluoride at room tempera-
ture. After stirring for 1 h, TLC indicated a
clean conversion of 7 to the target, 1. Workup
and chromatography afforded the product in
74% overall yield from 4.
demonstrated that subjecting methyl b-
binofuranoside, present in an anomeric mix-
ture of methyl -arabinofuranosides, to this
reaction sequence affords methyl 2,3-anhydro-
b- -ribofuranoside (8). Therefore, the method
D
-ara-
D
D
described here could also be used for the
preparation of 8, through either fractional
distillation of the a/b epoxide mixture ob-
tained from 3 or by starting with pure methyl
b-
-arabinofuranoside.§ It should also be
D
mentioned that the route described here could
The conversion of 4 to 1 can easily be
carried out in less than 3 days. Nevertheless,
in an effort to further speed access to 1, we
investigated the possibility that triflate 7 could
be synthesized in one pot from 5, thus elimi-
nating a chromatographic purification. We
therefore treated triol 5 with 1,3-dibromo-
1,1,3,3-tetraisopropyldisiloxane and pyridine
and then, upon indication of its complete
conversion to 6 (by TLC), added triflic anhy-
dride. Unfortunately, this resulted in the for-
mation of, in addition to 7, a number of
unidentifiable byproducts. When crude triflate
7 synthesized in this way was treated with
tetra-n-butyl ammonium fluoride, epoxide 1
was isolated in only 50% yield from 4. We also
investigated if the crude reaction product 3,
which resulted from Fisher glycosylation of
be used to prepare the enantiomers of 1 and 8
from
L
-arabinose, which is considerably less
expensive than the
L
-xylose required by the
previously described method.¶,6
† It has been reported (Ref. 5) that 1 and 8 can be separated
by fractional distillation.
‡ The 5-O-p-toluenesulfonyl derivatives of 1 and 8 have
been reported (Ref. 2a) to be separable both by chromatogra-
phy and by crystallization.
§ Pure methyl b-
D-arabinofuranoside is conveniently ob-
tained by chromatography of the mother liquor from the
crystallization of 4 (Scheme 1), followed by Zemple´n deacyla-
tion. C.S. Callam and T.L. Lowary, unpublished results.
¶ 100 g of
L-arabinose can be purchased (from Sigma
Chemical Co.) for US$ 75.00; the same amount of
US$ 380.
L-xylose is

C.S. Callam et al. / Carbohydrate Research 330 (2001) 267–270
269
brought to rt and allowed to stir for 4 h. The
solvent was evaporated and the residue was
co-evaporated with CCl4 (2×20 mL). The
flask was then cooled to 0 °C, and a solution
1. Experimental
General.—Solvents were distilled from the
appropriate drying agents before use. Unless
stated otherwise, all reactions were carried out
at rt under a positive pressure of Ar and were
monitored by TLC on Silica Gel 60 F254 (0.25
mm, E. Merck). Spots were detected under
UV light or by charring with 10% H2SO4 in
EtOH. Solvents were evaporated under re-
duced pressure and below 40 °C (water bath).
Organic solutions of crude products were
dried over anhyd Na2SO4. Column chro-
matography was performed on Silica Gel 60
(40–60 mm). The ratio between silica gel and
crude product ranged from 100 to 50:1 (w/w).
1H NMR spectra were recorded in CDCl3 at
500 MHz, and chemical shifts are referenced
to TMS (0.0). 13C NMR spectra were recorded
of methyl-a- -arabinofuranoside (5) (1.72 g,
D
10.5 mmol) in C5H5N (50 mL) was added
dropwise. The reaction mixture was brought
to rt and then stirred for 1.5 h, before water
(100 mL) was added. Diethyl ether (100 mL)
was added, the phases separated, and the or-
ganic layer was washed with satd aq sodium
bicarbonate (25 mL) before being dried. The
drying agent was then removed by filtration,
and the solvent was evaporated to yield crude
6 (4.86 g). Purification of the product by
chromatography (5:1 hexane–EtOAc) af-
1
forded 6 as a clear oil (3.8 g, 89%). The H
13
and C NMR spectra of this compound were
identical to that previously reported for 6.9
13
in CDCl3 at 125 MHz and C chemical shifts
Methyl
2,3-anhydro-h- -ribofuranoside
D
are referenced to internal CDCl3 (77.00). The
(1).—A solution of 6 (3.8 g, 9.4 mmol) in dry
C5H5N (50 mL) was cooled to 0 °C in an ice
bath. To this solution was added (CF3SO)2O
(3.96 g, 14.1 mmol), and the reaction mixture
was stirred for 5 min before water (25 mL)
and CH2Cl2 (25 mL) were added. The organic
layer was washed with water (25 mL), dried,
filtered, and concentrated to yield crude 7 as a
light orange oil which was co-evaporated
twice with MePh. The residue was dissolved in
THF (50 mL) and then tetra-n-butyl ammo-
nium fluoride trihydrate (8.86 g, 28.2 mmol)
was added. The solution was stirred for 1 h
and then concentrated. The resulting oil was
purified by column chromatography (3:1
EtOAc–hexane) to yield 1 as a clear colorless
oil (1.14 g, 83% over two steps). Rf 0.3 (3:1
EtOAc–hexane); [h]2D3 +19.2° (c 2.3, H2O);
assignment of resonances in the H and 13C
1
NMR spectra of 1 were made by two-dimen-
sional homonuclear and heteronuclear shift
correlation experiments. Elemental analyses
were performed by Atlantic Microlab Inc.,
Norcross, GA.
Methyl h-
D
-arabinofuranoside (5).—To a
solution of methyl 2,3,5-tri-O-benzoyl-a-
D
-
arabinofuranoside (4) (5.00 g, 10.5 mmol) in
7:1 CH3OH–CH2Cl2 (100 mL) was added a 1
M solution of NaOMe (2 mL, 2 mmol). The
solution was stirred at rt until the reaction was
complete by TLC and then neutralized by the
addition of HOAc. The reaction mixture was
concentrated, and the resulting residue was
partitioned between CH2Cl2 and water. The
aq layer was extracted twice with CH2Cl2 and
then concentrated. Residual water was re-
moved by co-evaporation (twice) with MePh,
and the product was then dried under vacuum
overnight to yield 5 as a colorless oil (1.72 g,
lit.,5 [h]2D9 +13.1° (c 2.3, H2O) lit.,6 [a]D20
+
1
21.6° (c 2.3, H2O); H NMR (500 MHz,
CDCl3): lH 5.22 (d, 1 H, J1,2 0.4 Hz, H-1),
4.35 (dd, 1 H, J4,5 3.7, J4,5% 3.9 Hz, H-4), 3.82
(dd, 1 H, J1,2 0.4, J2,3 2.9, Hz, H-2), 3.76 (dd,
1 H, J4,5 3.7, J5,5% 11.8, H-5) 3.74 (d, 1 H, J2,3
2.9 Hz, H-3), 3.69 (dd, 1 H, J4,5% 3.9, J5,5% 11.8,
H-5%), 3.53 (s, 3 H, OCH3); 13C NMR (125
MHz, CDCl3): lC 102.6 (C-1), 78.9 (C-4), 63.0
(C-5), 56.8 (C-3), 56.7 (OCH3), 56.3 (C-2);
Anal. Calcd for C6H10O4: C, 49.31; H, 6.90.
Found: C, 49.28; H, 6.93.
quantitative). The H and 13C NMR spectra
1
of this compound were identical to that previ-
ously reported for 5.10
Methyl
diyl)-h-
3,5-O-(tetraisopropylsiloxane-1,3-
-arabinofuranoside (6).—A solution
D
of 1,1,3,3-tetraisopropylsiloxane (2.71 g, 11
mmol) in dry CCl4 (50 mL) was cooled to
0 °C, and Br2 (3.70 g, 23 mmol) was added
dropwise over 30 min. The solution was

270
C.S. Callam et al. / Carbohydrate Research 330 (2001) 267–270
1994, 50, 1435–1448. (d) Benefice-Malouet, S.; Coe, P.
Acknowledgements
L.; Walker, R. T. Carbohydr. Res. 1992, 229, 293–305.
(e) Yamashita, A.; Rosowsky, A. J. Org. Chem. 1976, 41,
3422–3425. (f) Reist, E. J.; Holton, S. L. Carbohydr. Res.
1969, 9, 71–77.
This work was supported by The National
Institutes of Health (AI44045) and the OSU
Spectroscopy Institute.
3. Williams, N. R. Ad6. Carbohydr. Chem. Biochem. 1970,
25, 109–179.
4. Martin, M. G.; Ganem, B.; Rasmussen, J. R. Carbohydr.
Res. 1983, 123, 332–334.
5. Anderson, C. D.; Goodman, L.; Baker, B. R. J. Am.
Chem. Soc. 1958, 80, 5247–5252.
References
6. Unger, F. M.; Christian, R.; Waldsta¨tten, P. Carbohydr.
Res. 1978, 67, 257–262.
7. Fletcher, H. G. Methods Carbohydr. Chem. 1963, 2,
228–230.
8. Otmar, M.; Rosenberg, I.; Masoj´ıdkova´, M.; Holy, A.
Collect. Czech. Chem. Commun. 1993, 58, 2159–2179.
9. D’Souza, F. W.; Ayers, J. D.; McCarren, P. R.; Lowary,
T. L. J. Am. Chem. Soc. 2000, 122, 1251–1260.
10. Gorin, P. A. J.; Mazurek, M. Can. J. Chem. 1975, 53,
1212–1223.
1. (a) Adiwidjaja, G.; Schulze, O.; Voss, J.; Wirshning, J.
Carbohydr. Res. 2000, 325, 107–119. (b) Mori, S.; Katoh,
A.; Takenaka, H.; Tanaka, H.; Kaji, H.; Samejima, T.;
Mitsunobu, O. Nucleosides Nucleotides 1994, 13, 2081–
2104. (c) Montgomery, J. A.; Thomas, H. J. J. Hetero-
cycl. Chem. 1979, 16, 353–357. (d) Jenkins, S. R.;
Walton, E. Carbohydr. Res. 1973, 26, 71–81.
2. (a) Godskesen, M.; Lundt, I. Tetrahedron Lett. 1998, 39,
5841–5844. (b) Dai, K.; Mitsunobu, O. Chem. Lett. 1997,
517–518. (c) Brandstetter, T.; Maier, M. E. Tetrahedron
.