Efficient synthesis of methyl 3,5-di-O-benzyl-α-D-ribofuranoside and application to the synthesis of 2′-C-β-alkoxymethyluridines

Article abstract of DOI:10.1021/ol071075b

Methyl 3,5-di-O-arylmethyl-α-D-ribofuranosides have been used extensively as synthons to construct 2'-C-branched ribonucleosides. Herein, we describe efficient access to methyl 3,5-di-O-arylmethyl-α-D- ribofuranosides (aryl: 2-ClC₆H₄, 3-ClC₆H ₄, 4-ClC₆H₄, 4-BrC₆H₄, 2,4-Cl₂C₆H₃, Ph) in 72-82% yields from methyl D-ribofuranoside. We also demonstrate efficient access to the versatile precursor methyl 3,5-di-O-benzyl-α-D-ribofuranoside (3f) and the synthesis of 2′-C-β-methoxymethyl- and 2′-C-β-ethoxymethyluridine in six steps from 3f with overall yields of 18% and 32%, respectively.

Full text of DOI:10.1021/ol071075b

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3009-3012
Efficient Synthesis of Methyl
3,5-Di-O-benzyl- -ribofuranoside and
Application to the Synthesis of
-C- -Alkoxymethyluridines
r-D
2′
â
Nan-Sheng Li,* Jun Lu, and Joseph A. Piccirilli*
Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biology,
and Department of Chemistry, UniVersity of Chicago, 929 East 57th Street,
Chicago, Illinois 60637
nli@uchicago.edu; jpicciri@uchicago.edu
Received May 8, 2007
ABSTRACT
Methyl 3,5-di-O-arylmethyl-
we describe efficient access to methyl 3,5-di-O-arylmethyl-
in 72 82% yields from methyl -ribofuranoside. We also demonstrate efficient access to the versatile precursor methyl 3,5-di-O-benzyl-r-D-
r
-D
-ribofuranosides have been used extensively as synthons to construct 2
′
-C-branched ribonucleosides. Herein,
r-D-ribofuranosides (aryl: 2-ClC6H4, 3-ClC6H4, 4-ClC6H4, 4-BrC6H4, 2,4-Cl2C6H3, Ph)
−
D
ribofuranoside (3f) and the synthesis of 2
′-C-â-methoxymethyl- and 2′-C-â-ethoxymethyluridine in six steps from 3f with overall yields of 18%
and 32%, respectively.
2′-C-Branched ribonucleosides represent an important and
diverse class of nucleoside analogues with potential both as
therapeutic agents and as probes to define the relationship
between nucleic acid structure and biological function.1 In
this work we sought to prepare 2′-C-â-methoxymethyl- and
2′-C-â-ethoxymethyluridines as members of a series of 2′-
C-branched ribonucleosides for investigating the mechanism
of RNA cleavage.2 Construction of these nucleosides often
begins with a partially protected ribose derivative such as
Ia-d (Scheme 1). Perbenzylation of methyl ribofuranoside
followed by tin(IV) chloride (SnCl4)-mediated selective O-2
debenzylation allows access to Ib and Ic.3 Subsequent
oxidation, branch installation, and glycosylation after suitable
protection has enabled synthesis of a variety of 2′-branched
nucleosides.1a,4 During our efforts to synthesize 2′-C-â-
alkoxymethyluridines,5 we encountered two apparent limita-
tions with the selective debenzylation reaction. First, only
Scheme 1
(1) (a) Harry-O’kuru, R. E.; Smith, J. M.; Wolfe, M. S. J. Org. Chem.
1997, 62, 1754 and references cited therein. (b) Gordon, P. M.; Fong, R.;
Deb, S.; Li, N.-S.; Schwans, J. P.; Ye, J.-D.; Piccirilli, J. A. Chem. Biol.
2004, 11, 237. (c) Schwans, J. P.; Li, N.-S.; Piccirilli, J. A. Angew. Chem.,
Int. Ed. 2004, 43, 3033.
(2) Ye, J.-D.; Li, N.-S.; Dai, Q.; Piccirilli, J. A. Angew. Chem., Int. Ed.
2007, 46, 3714.
10.1021/ol071075b CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/13/2007

the â anomer of methyl ribofuranoside has served as a
substrate, thereby limiting the overall yield from D-ribose.3
Second, SnCl4 catalyzes intramolecular C-arylation when the
benzyl group lacks electron-withdrawing groups,6 apparently
precluding access to the potentially more versatile, non-
halogenated partially protected ribose derivative Id. Herein,
we address these limitations to allow efficient access to
methyl 3,5-di-O-benzyl-R-D-ribofuranoside (3f). We then use
3f to access 2′-C-â-methoxymethyl- and 2′-C-â-ethoxy-
methyluridines.
zylation of methyl ribofuranoside (Table 1). We found that
inclusion of tetrabutylammonium iodide (3% equiv) im-
proved yield significantly, possibly via in situ generation of
4-chlorobenzyl iodide, a more reactive benzylating agent than
4-chlorobenzyl chloride. Proceeding to the debenzylation
step, we first tested whether the R anomer could serve as a
substrate. We found that in the presence of SnCl4 (0-4 °C
for 36 h), R-2 gives 3c in 76% yield, similar to the yield
from â-2 (83%) (Scheme 2). Together with the improved
Beginning with the reaction conditions developed by O.
Martin3a (Table 1; entry 1) and P. Martin3b for the synthesis
Scheme 2
Table 1. Preparation of 2
molar ratio of
1:NaH:4-ClBnCl
time
(h)
yieldc
(%)
no.a
solvent
catalystb
1d
2
3
4
5
1:9.3:9.5
1:6.0:6.0
1:4.5:4.5
1:3.3:3.3
1:4.5:4.5
DMSO
DMF
DMF
DMF
DMF
-
+
+
+
-
15e
3
3
9
3
81
98
93
92
85
a All reactions were carried out under argon at room temperature. b n-
Bu4N+I- (3% equiv) was used as catalyst. c Combined isolated yield of
â-2 plus R-2. d Reference 3a; dimysl sodium was used as a base and prepared
in situ from sodium hydride and dry Me2SO at 60 °C for 45 min; methyl
D-ribofuranoside (â/R ≈ 10:1) was prepared according to Barker and
Fletcher (Barker, R.; Fletcher, H. G., Jr. J. Org. Chem. 1961, 26, 4605),
and only â-2 was isolated. e Overnight reaction.
synthesis of 2 (Table 1, no. 2), the ability to access 3c from
R-2 increases the overall yield of 3c from D-ribose compared
to the previous synthesis3a (70% vs 51%).
We used our optimized conditions7 to synthesize a variety
of methyl 3,5-di-O-arylmethyl-R-D-ribofuranosides (3) (Table
2). We first prepared methyl 2,3,5-tri-O-haloarylmethyl-R/
of methyl 2,3,5-tri-O-(4-chlorobenzyl)-â-D-ribofuranoside (2)
and methyl 2,3,5-tri-O-(2,4-dichlorobenzyl)-â-D-ribofurano-
side, respectively, we optimized conditions for 4-chloroben-
Table 2. Preparation of 3a-f
(3) (a) Martin, O. R.; Kurz, K. G.; Rao, S. P. J. Org. Chem. 1987, 52,
2922. (b) Martin, P. HelV. Chim. Acta 1995, 78, 486.
(4) (a) Eldrup, A. B.; Allerson, C. R.; Bennett, C. F.; Bera, S.; Bhat, B.;
Bhat, N.; Bosserman, M. R.; Brooks, J.; Burlein, C.; Carroll, S. S.; Cook,
P. D.; Getty, K. L.; MacCoss, M.; McMasters, D. R.; Olson, D. B.; Prakash,
T. P.; Prhavc, M.; Song, Q.; Tomassini, J. E.; Xia, J. J. Med. Chem. 2004,
47, 2283. (b) Franchetti, P.; Cappellacci, L.; Marchetti, S.; Trincavelli, L.;
Martin, C.; Mazzoni, M. R.; Lucacchini, A.; Grifantini, M. J. Med. Chem.
1998, 41, 1708. (c) Tang, X.-Q.; Liao, X.; Piccirilli, J. A. J. Org. Chem.
1999, 64, 747. (d) Li, N.-S.; Piccirilli, J. A. J. Org. Chem. 2006, 71, 4018.
(e) Ding, Y.; Girardet, J.-L.; Hong, Z.; Lai, V. C. H.; An, H.; Koh, Y.;
Shaw, S. Z.; Zhong, W. Bioorg. Med. Chem. Lett. 2005, 15, 709. (f) Ye,
J.-D.; Liao, X.; Piccirilli, J. A. J. Org. Chem. 2005, 70, 7902. (g) Li, N.-S.;
Tang, X.-Q.; Piccirilli, J. A. Org. Lett. 2001, 3, 1025. (h) Babu, B. R.;
Keinicke, L.; Petersen, M.; Nielsen, C.; Wengel, J. Org. Biomol. Chem.
2003, 1, 3514. (i) Li, N.-S.; Piccirilli, J. A. J. Org. Chem. 2003, 68, 6799.
(j) Eldrup, A. B.; Prhavc, M.; Brooks, J.; Bhat, B.; Prakash, T. P.; Song,
Q.; Bera, S.; Bhat, N.; Dande, P.; Cook, P. D.; Bennett, C. F.; Carroll, S.
S.; Ball, R. G.; Bosserman, M.; Burlein, C.; Colwell, L. F.; Fay, J. F.; Flores,
O. A.; Getty, K.; LaFemina, R. L.; Leone, J.; MacCoss, M.; McMasters,
D. R.; Tomassini, J. E.; Langen, D. V.; Wolanski, B.; Olson, D. B. J. Med.
Chem. 2004, 47, 5284. (k) Martin, P. HelV. Chim. Acta 1996, 79, 1930. (l)
Kawasaki, A. M.; Casper, M. D.; Prakash, T. P.; Manalili, S.; Sasmor, H.;
Manoharan, M.; Cook, P. D. Tetrahedron Lett. 1999, 40, 661. (m) Peng,
C. G.; Damha, M. J. Nucleic Acids Res. 2005, 33, 7019. (n) Schmit, C.
Synlett 1994, 238. (o) Schmit, C. Synlett 1994, 241. (p) Jeannot, F.; Gosselin,
G.; Mathe, C. Org. Biomol. Chem. 2003, 1, 2096. (q) Li, N.-S.; Piccirilli,
J. A. J. Org. Chem. 2004, 69, 4751. (r) Li, N.-S.; Piccirilli, J. A. Synthesis
2005, 2865.
no.
product
Ar
conditions iia
yield (%)b
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
2,4-Cl2C6H3
Ph
0 °C to rt, 22 h
0 °C to rt, 23 h
0 °C to rt, 28 h
0 °C to rt, 24 h
0 °C to rt, 24 h
0 °C to rt, 18 h
0-4 °C, 48 h
82
75
75
75
75
61
72
3f
Ph
a Reaction conditions ii are for the SnCl4-mediated reaction. b Isolated
yield based on methyl ribofuranoside (1).
â-D-ribofuranosides from 1 and the corresponding arylmethyl
chlorides. After workup, the crude mixtures were treated with
SnCl4 (0 °C to room temperature over 24 h) to give 3a-e in
yields ranging from 75% to 82%.
(5) We focused on Ib-d (protected with benzyl ethers) as synthons for
2′-C-â-alkoxymethyluridines because the benzoate esters of IIa react with
Grignard reagents used to install the alkoxymethyl branch at C-2.
(6) (a) Martin, O. R. Tetrahedron Lett. 1985, 26, 2055. (b) Martin, O.
R. Carbohydr. Res. 1987, 171, 211. (c) Martin, O. R.; Mahnken, R. E. J.
Chem. Soc., Chem. Commun. 1986, 497.
(7) Perbenzylation reactions were carried out with 1:NaH:arylmethyl
chloride:n-Bu4N+I- (1:4.5:3.0:0.03) in DMF at room temperature for 3 h.
Our procedure eliminates the need to separate the anomers of 2,3,5-tri-O-
halobenzyl-R/â-D-ribofuranosides.
3010
Org. Lett., Vol. 9, No. 16, 2007

Among the methyl 3,5-di-O-arylmethyl-R-D-ribofurano-
sides, methyl 3,5-di-O-benzyl-R-D-ribofuranoside (3f) may
provide the most versatile intermediate for the synthesis of
2′-C-branched nucleosides, as benzyl ethers tolerate a greater
variety of conditions than do halobenzyl ethers. Nevertheless,
only one report has appeared in the literature describing the
use of 3f for the synthesis of nucleosides,8 possibly because
access to this compound has required a multistep synthesis
(eight steps from D-xylose with 14% overall yield8,9). We
know of no reported attempts to access 3f via the perben-
zylation/selective debenzylation reaction sequence, possibly
due to anticipated problems with selective debenzylation. In
the presence of SnCl4, benzylated glycofuranosyl acetates
undergo efficient intramolecular Friedel-Crafts alkylation
rather than 2-O-debenzylation.6 These observations led to
the expectation that chemoselective 2-O-debenzylation re-
quires deactivated benzyl substituents.6 However, along with
the C-arylation product (30% yield) methyl 2,3,5-tri-O-(3-
methylbenzyl)-â-D-ribofuranoside gives some debenzylation
product (49% yield)6b suggesting that the methyl glycoside
may favor debenzylation. We examined SnCl4-mediated
debenzylation of methyl 2,3,5-tri-O-benzyl-R/â-D-ribofura-
noside, reasoning that the less activated phenyl ring might
resist C-arylation of the methyl glycoside. We prepared
methyl 2,3,5-tri-O-benzyl-D-ribofuranoside as a mixture of
anomers. Exposure to SnCl4 at 0-25 °C for 18 h converted
the anomeric mixture to 3f in 61% yield with no evidence
of the C-arylation product (Table 2, no. 6). Longer exposure
at low temperature (0-4 °C for 48 h) increased the yield of
3f to 72% (Table 2, no. 7). This synthesis allows more
efficient access to 3f (64% in three steps from D-ribose) than
the previous synthesis (14% in eight steps from D-xylose8,9).
We used 3f to construct alkoxymethyluridines for inves-
tigating the mechanism of RNA cleavage.2 Dess-Martin
periodinane oxidation of 3f gave 3,5-di-O-benzyl-2-keto-1-
R-O-methyl-D-ribofuranose (4) in 97% yield (Scheme 3).
nesium at low temperature (-25 to -30 °C).10 We obtained
di-O-benzyl-2-C-â-methoxymethyl-1-R-O-methyl-D-ribofura-
nose (5a) in 50% yield by treating 4 with in situ prepared
methoxymethylmagnesium chloride11 at -78 °C for 1 h, then
at room temperature for 48 h. Reactions of vinylmagnesium
chloride and allymagnesium chloride with ketone 4 at -78
°C to room temperature for 16 h gave 5b and 5c in 57%
and 71% yield, respectively.
To prepare the sugar for stereoselective glycosylation, we
treated 5a with BzCl in the presence of DMAP and obtained
the corresponding benzoate ester 6a in 64% yield (32%
overall yield from 4). Using crude 5a, we obtained 6a in
37% overall yield from 4 (Scheme 4). Analogously, using
Scheme 4
the crude addition product from reaction of ethoxymethyl-
magnesium chloride and ketone 4, we obtained 6b in 49%
overall yield (Scheme 4).
Glycosylation of persilylated uracil with 6a in the presence
of SnCl4 (at room temperature for 48 h) gave uridine
derivative 7a in 70% yield. With 6b as the glycosyl donor,
reactions required 96 h and gave uridine derivative 7b in
only 58% yield. As a possible strategy to improve the
reaction, we prepared 6c (57% yield), expecting that the
electron-donating tert-butyl substituent might stabilize the
1,2-acyloxonium ion intermediate that putatively forms
during the glycosylation reaction. 6c reacted with persilated
uracil within 24 h and gave 7c in 68% yield. Although we
could protect 5a by reaction with acetic anhydride (6 equiv)
(triethylamine (10 equiv) and DMAP (0.2 equiv) in the
absence of solvent; ∼29% yield), the resulting 2′-O-acetate
derivative reacted very slowly with persilylated uracil.
Continuing with the synthesis of the target nucleosides,
sodium hydroxide treatment converted 7a to 8a in 79% yield,
and 7b and 7c to 8b in 74% and 92% yield, respectively.
Palladium(II) hydroxide-catalyzed hydrogenation removed
Scheme 3
Unstable alkoxymethylmagnesium chlorides such as meth-
oxymethyl- and ethoxymethylmagnesium chlorides require
in situ preparation from alkoxymethyl chlorides and mag-
(8) Ritzmann, G.; Klein, R. S.; Hollenberg, D. H.; Fox, J. J. Carbohydr.
Res. 1975, 39, 227.
(9) (a) Su, T.-L.; Klein, R. S.; Fox, J. J. J. Org. Chem. 1982, 47, 1506.
(b) Anderson, C. D.; Goodman, L.; Baker, B. R. J. Am. Chem. Soc. 1958,
80, 5427. (c) Baker, B. R.; Schaub, R. E. J. Am. Chem. Soc. 1955, 77,
5900.
(10) (a) Castro, B. Bull. Soc. Chim. Fr. 1967, 1533. (b) Kim, M.;
Grzeszczyk, B.; Zamojski, A. Tetrahedron 2000, 56, 9319.
(11) Ketone addition reactions usually give yields ranging from 35% to
82% depending upon the steric environment of the carbonyl group. See:
De Botton, M. Bull. Soc. Chim. Fr. 1973, 2472.
Org. Lett., Vol. 9, No. 16, 2007
3011

the benzyl groups efficiently to give the target nucleosides,
2′-C-â-methoxymethyluridine (9a) and 2′-C-â-ethoxymethyl-
uridine (9b) in 92% and 90% yield, respectively.12
methoxymethyluridine (9a) and 2′-C-â-ethoxymethyluridine
(9b). In constructing these uridine analogues, we generated
a series of glycosyl donors esterified at the C-2 hydroxyl
group as the acetate, benzoate, or tert-butylbenzoate ester.
Glycosylation efficiency followed the order 4-t-BuBz > Bz
> Ac, presumably reflecting the relative stability of the
corresponding 1,2-acyloxonium ion intermediates. This
reactivity trend, which has not been reported previously,
suggests a possible general strategy to improve glycosylation
reactions involving sterically hindered or electron-poor
glycosyl donors.
In summary, we have established an efficient strategy for
acquisition of methyl 3,5-di-O-arylmethyl-R-D-ribofurano-
sides, which serve as valuable precursors for the synthesis
of 2′-C-branched nucleosides. We improved the procedure
for benzylation of methyl ribofuranoside and extended the
scope of the subsequent O-2 selective debenzylation reaction
to include R-anomers. Using this three-step strategy, we
demonstrated efficient access to methyl 3,5-di-O-benzyl-D-
ribofuranoside, a potentially more valuable intermediate for
nucleoside synthesis. Benzyl ethers tolerate a wider range
of reagents and conditions than do the corresponding
chorobenzyl ethers, including organometallic reagents (RLi/
E+,13 ArB(OH)2/Pd(II) complex,14 and ArSnBu3/Cu2O, etc.15).
We used 3f to develop efficient syntheses of 2′-C-â-
Acknowledgment. N.-S.L. is a Research Specialist, J.L.
is a Research Associate, and J.A.P. is an Investigator of the
Howard Hughes Medical Institute. We thank the following
members of the Piccirilli laboratory for helpful discussions
and critical comments on the manuscript: Q. Dai, J.
Frederiksen, S. Koo, R. Sengupta, K. Sundaram, and J. Ye.
(12) The 2′-â-configurations of 9a and 9b were confirmed by NOSEY
experiment. We obsevered strong NOEs between H-6 and 2′-CH2OR (R )
Me, Et), suggesting that the nucleobase and 2′-CH2OR are on the same
side of the ribose ring.
Supporting Information Available: Experimental pro-
cedures, compound characterizations, 1H and 13C NMR
spectra of 9a and 9b, and 13C NMR spectra of all other
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Iwao, M. J. Org. Chem. 1990, 55, 3622.
(14) (a) Herrmann, W. A.; Oefele, K.; Schneider, S. K.; Herdtweck, E.;
Hoffamann, S. D. Angew. Chem., Int. Ed. 2006, 45, 3859. (b) Navarro, O.;
Marion, N.; Oonishi, Y.; Kelly, R. A., III; Nolan, S. P. J. Org. Chem. 2006,
71, 685. (c) Zeng, F.; Yu, Z. J. Org. Chem. 2006, 71, 5274.
(15) Li, J.-H.; Tang, B.-X.; Tao, L.-M.; Xie, Y.-X.; Liang, Y.; Zhang,
M.-B. J. Org. Chem. 2006, 71, 7488.
OL071075B
3012
Org. Lett., Vol. 9, No. 16, 2007