Lewis acid mediated reductive ring opening of 2-methoxyethylidene acetals: A new approach to 2-methoxyethyl (MOE) ethers of cis-diols

Article abstract of DOI:10.1055/s-2005-872686

The reductive opening of 2-methoxyethylidene acetals of vicinal diols in uridine and 1,4-anhydro-D-ribitol in the presence of TiCl₄ and Et₃SiH was investigated. The 3′-O-(2-methoxyethyl) ether of uridine and the 2′-O-(2-methoxyethyl)

Full text of DOI:10.1055/s-2005-872686

LETTER
2437
Lewis Acid Mediated Reductive Ring Opening of 2-Methoxyethylidene
Acetals: A New Approach to 2-Methoxyethyl (MOE) Ethers of cis-Diols
R
eductive Rin
t
g-Ope
n
e
ing of 2-M
p
ethoxyethyli
h
dene
A
cetalsen Hanessian,* Roger Machaalani
Department of Chemistry,, Université de Montréal, C. P. 6128, Succ. Centre-Ville, Montréal, PQ, H3C 3J7, Canada
Fax +1(514)3435728; E-mail: stephen.hanessian@umontreal.ca
Received 22 June 2005
and coworkers1b have described a highly efficient, two-
step method to prepare 2¢-O-anhydrouridine intermediate.
Abstract: The reductive opening of 2-methoxyethylidene acetals
of vicinal diols in uridine and 1,4-anhydro-D-ribitol in the presence
of TiCl4 and Et3SiH was investigated. The 3¢-O-(2-methoxyethyl)
ether of uridine and the 2¢-O-(2-methoxyethyl) ether of 1,4-an-
hydro-D-ribitol were isolated and characterized. The results were
rationalized based on coordination effects involving proximal sub-
stituents.
We considered a hitherto unexplored approach for the
synthesis of 2¢-O-(2-methoxyethyl) ether nucleosides
such as 1 (Scheme 1) relying on the reductive opening of
a 2-methoxymethyl-1,3-dioxolane unit in 2. Thus, biden-
tate coordination of the 2- or 3-oxygen atoms in 3 or 5
with a Lewis acid would lead to the oxocarbenium ions 4
and 6, respectively, which can undergo in situ reduction
with triethylsilane to afford 7 or 8 as preponderant prod-
ucts or as a mixture. In the case of a purine or a pyrimidine
analogue corresponding to 2, the preferred product would
be 7 in the context of antisense chemistry.
Key words: acetal, reductive opening, nucleoside, antisense
Selective etherification of vicinal diols has been an area of
extensive study over the years, especially with the emer-
gence of nucleoside 2¢-O-alkyl ethers as modified sub-
units for the development of antisense therapeutic
applications.1,2 In particular, 2¢-O-(2-methoxyethyl) nu-
cleosides have gained considerable importance because
their incorporation into antisense oligonucleotides has
conferred high resistance to various nucleases, in addition
to offering distinct advantages over non-modified coun-
terparts as second-generation clinical candidates.3–5 The
potential of modified oligonucleotides as antiviral and an-
ticancer agents is under intense study.6
OMe
MeO
R
R
O
O
Lewis acid
Et3SiH
O
PG
OMe
PGO
PTSA
OH
HO
O
O
1
2
OMe
O
R
R
O
R
O
O
PGO
O
PG
O
PG
There are several methods for the selective 2¢-O-methyla-
tion of various purine and pyrimidine nucleosides.1 There
are comparatively fewer methods for the formation of the
corresponding 2¢-O-(2-methoxyethyl) ethers. One of the
earliest reports by Martin2a utilized D-ribose as a starting
material. Elaboration of known synthetic steps led to pu-
rine and pyrimidine nucleosides in which the 2¢-OH group
was unprotected. A similar sequence was also developed
from D-glucose.7 Alkylation of the 2¢-OH group afforded
the desired 2¢-O-(2-methoxyethyl) ethers after deprotec-
tion. More recently, other approaches have been devised
using appropriately O-protected nucleosides. Thus, Reese
and coworkers2b developed an efficient ring opening of a
2,2¢-anhydrouridine with aluminum 2-methoxyethoxide
as a ‘soft’ nucleophile. Practical syntheses of 2¢-O-(2-
methoxyethyl) uridine and cytidine were thus developed.
Theodorakis and coworkers8 developed a new bis-silylat-
H
O
OMe
O
LA
O
O
HO
LA
OMe
7
O
3
4
R
R
O
O
R
O
O
PG
O
PG
PGO
OLA
O
O
O
O
OH
MeO
O
H
LA
MeO
8
5
6
R = uracil, cytosine, guanine, adenosine or thymine
Scheme 1
ing reagent [methylene bis(diisopropylsilyl)chloride] In actual practice we chose uridine 9 as a model nucleo-
which engaged the 3¢,5¢-hydroxyls of guanosine, thereby side. Thus, protection of the primary hydroxyl group as a
allowing efficient alkylation of the 2¢-OH group with 2- tert-butyldiphenylsilyl ether9 (10), followed by treatment
methoxyethyl bromide in the presence of NaHMDS. Ross with 2-methoxyacetaldehyde dimethyl acetal in the pres-
ence of PTSA in refluxing toluene gave the corresponding
2¢,3¢-O-(2-methoxyethylidene) acetal 11 as a single dia-
SYNLETT 2005, No. 16, pp 2437–2440
Advanced online publication: 21.09.2005
DOI: 10.1055/s-2005-872686; Art ID: S05905ST
© Georg Thieme Verlag Stuttgart · New York
0
4
.1
0
.2
0
0
5
stereomer in 75% yield (Scheme 2). We tentatively assign
an endo-orientation for the methoxymethyl group based
on NOE studies.10 A smooth reaction took place in the

2438
S. Hanessian, R. Machaalani
LETTER
O
HN
presence of TiCl4 and triethylsilane to afford 5¢-O-TBDPS
uridine 3¢-O-(2-methoxyethyl) ether 12 in 76% yield.10
Treatment with TBAF gave uridine 3¢-O-(2-methoxy-
ethyl) ether 13 in excellent overall yield. A survey of
several Lewis acids and reducing agents revealed TiCl4
and Et3SiH to be the best combination.11 Dichloromethane
was found to be the best solvent since precipitation or
decomposition was observed with more polar solvents or
solvent mixtures.12
O
1) TBDPSCl,
imidazole, DMF,
90%
HN
NH
NH
O
O
O
O
TBDPSO
HO
2) methoxyacet-
aldehyde,
dimethyl acetal,
O
OMe
O
OH
HO
PTSA, toluene, 78%
15
β-pseudouridine (14)
O
HN
NH
O
TiCl4, Et3SiH
O
O
RO
HN
N
OMe
MeO
U
O
O
CH2Cl2
82%
RO
OH
MeO
O
O
TBDPSCl, imid
OMe, PTSA
toluene
HO
OH
HO
16, R = TBDPS
17, R = H
TBAF, THF
DMF
90%
HO
OH
80%
R = TBDPS 10
75%
9
O
O
HN
O
HN
O
U
NH
O
O
NH
O
U
O
RO
TiCl4, Et3SiH
O
U
O
O
TBAF
THF
TiCl4, Et3SiH
RO
BzO
BzO
HO
CH2Cl2
MeO
76%
O
O
CH2Cl2
72%
OH
MeO
O
O
O
OH
11
O
OMe
91%
12
13
19
18
OMe
OMe
Scheme 2
(Cl)4Ti
A study of effect of substituents and protective groups on
the reductive opening was hampered by insolubility.
Thus, various 5¢-esters of uridine (benzoate, acetate,
pivaloate, methyl carbonate) were recovered unchanged
after work up, reflecting on the possible formation of
TiCl4 complexes or aggregates involving the polar carbo-
nyl groups in conjunction with the acetal oxygens.
H
N
O
O
O
(Cl4)Ti
BzO
NH
N
O
BzO
NH
O
O
O
H
O
O
O
OMe
OMe
Suspecting an influence of the nucleobase on the reactiv-
ity of the C-2¢–O atom in the initial coordination, we at-
tempted the same reaction with b-pseudouridine13 (14,
Scheme 3). Once again, treatment of the corresponding
acetal 15 with TiCl4 and Et3SiH gave the 3¢-O-(2-meth-
oxyethyl) ether 16 in 82% yield. Curiously, the corre-
sponding 5¢-benzoate 18 gave the anomerized C-
nucleoside 19 without ring-opening. Evidently, in this
case, activation of the furanosyl ring oxygen by the Lewis
acid triggered ring-opening via an azadienium inter-
mediate, which undergoes face-selective cycloetherifi-
cation to a-pseudouridine (19, Scheme 3).
Scheme 3
O
O
O
TiCl4,
Et3SiH
O
O
O
R
O
O
CH2Cl2
R
OMe
O
HO
R = H, 22 (73%)
R = OMe, 23 (82%)
OMe
R = H, 20
R = OMe, 21
Scheme 4
In an effort to probe the effect of the aglycone further, we
conducted the reductive ring opening with the 5¢-benzoate
and p-bromobenzoate esters of 1,5-anhydro-D-ribitol ace-
tals 20 and 21 (Scheme 4), which were also assigned as
being endo-oriented according to NOE studies similar to
the ones performed on 11. In this case the corresponding
2¢-O-(2-methoxyethyl) ethers 22 and 23 were obtained in
73% and 82% yields, respectively. The corresponding 5-
p-nitrobenzoate, 5-p-methoxybenzyl, 5-TBDPS ethers, as
well as various aliphatic 5-esters led to precipitates from
which starting acetals could be recovered.
on the regioselectivity of the reductive ring-opening reac-
tion of furanosyl acetals. Nevertheless, a plausible expla-
nation for the formation of the 3¢-O-methoxyethyl ethers
of 5¢-O-TBDPS uridine acetals can be given in Figure 1.
The prevalence of Ti-coordinated species such as A and B
can be influenced by steric effects (TBDPS), and in addi-
tion by coordination to the pyrimidine group carbonyl as
in A (or its dimer, etc.). The desired acetal coordination in
B may not be prevalent in the equilibrium due to the steric
effect of the TBDPS group, and more importantly, due to
the lesser basicity of the C-2¢ oxygen on account of its
Clearly, the formation of insoluble complexes with TiCl4
hampered our study of the effect of 1- and 5-substituents
Synlett 2005, No. 16, 2437–2440 © Thieme Stuttgart · New York

LETTER
Reductive Ring-Opening of 2-Methoxyethylidene Acetals
2439
O
O
O
NH
O
NH
O
N
N
O
NH
O
O
RO
RO
N
O
RO
8
O
OTi
O
O
O
O
H
LA
MeO
O
OMe
2
A
A1
O
O
NH
O
NH
O
N
N
O
O
RO
RO
H–
O
O
LA O
O
O
7
LA
OMe
B
B1
O
O
O
O
R
R
H
O
O
22 and 23
O
O
O
O
O
LA
LA
OMe
C
C1
Figure 1
proximity to the anomeric carbon and a lower tendency to opening depends on the presence of a proximal coordina-
participate in oxocarbenium ion formation as in B → B1. tive site such as an ester or a uracil carbonyl.
Evidently, a cooperative effect of the methoxy and
uracilyl carbonyl group with the Lewis acid can sustain a
weaker interaction with the C-2¢ acetal oxygen in the
Acknowledgment
We thank the Natural Sciences and Engineering Research Council
of Canada (NSERC) for financial assistance, Dr. Bruce Ross (Isis
Pharmaceuticals, Carlsbad, California) for stimulating discussions,
and Clément Talbot for technical assistance.
formation of 8 via A → A1.
This hypothesis is substantiated by the regioselective re-
versal of reductive opening in the case of the 1,5-anhydro-
D-ribitol acetals 20 and 21, where coordination can now
occur between the ethylenedioxy moiety in conjuction
with an additional anchoring with the ester carbonyl as in
C en route to formation of the oxocarbenium C1 and the
observed 2¢-O-(2-methoxyethyl) ethers 22 and 23. The
non-reactivity of the corresponding TBDPS ether under
the same conditions demonstrates the importance of the
‘third’ coordination site involving the ester carbonyl. Pre-
sumably, this is compensated in the case of 2 by the urac-
ilyl C-2 carbonyl. Thus, a combination of electronic, and
to some extent steric effects seems to dictate the course of
these TiCl4-mediated reductive openings of 2¢,3¢-O-(2-
methoxyethylidene) acetals.
References
(1) (a) Beigelman, L.; Harberli, P.; Sweedler, D.; Karpeisky, A.
Tetrahedron 2000, 56, 1047. (b) Ross, B. S.; Springer, R.
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Res. Dev. 2000, 4, 170. (e) Von Matt, P.; Lochmann, T.;
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G.; Ross, B. S. US Patent 5,861,493, 1999.
There are a number of reported Lewis acid mediated ring
openings of 1,3-dioxolane acetals,14 but none, to the best
of our knowledge, involving an 2-methoxyethylidene
acetal as reported herein.
(3) (a) Uhlmann, E.; Peyman, A. Chem. Rev. 1990, 90, 544.
(b) Irgolic, K. J. In Houben–Weyl, Vol. E12b; Klamann, D.,
Ed.; Thieme: Stuttgart, 1990, 4th ed., 150.
(4) Zamecnik, P. C.; Stephenson, M. L. Proc. Natl. Acad. Sci.
U.S.A. 1978, 75, 280.
In conclusion, we have reported on the synthesis and re-
ductive ring opening of 2¢,3¢-(2-methoxyethyl) ethylidene
acetals of uridine, pseudouridine and the corresponding
1,4-anhydro-D-ribitol derivatives. The regioselectivity of
(5) Kurreck, J. Eur. J. Biochem. 2003, 270, 1628.
Synlett 2005, No. 16, 2437–2440 © Thieme Stuttgart · New York

2440
S. Hanessian, R. Machaalani
LETTER
min, followed by the addition of Et3SiH (0.6 mL, 3.68
(6) (a) Antisense Drug Technology; Crooke, S. T., Ed.; Dekker:
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mmol). The mixture was then slowly brought to r.t. over a
period of 18 h. Then, H2O (1.5 mL) and CH2Cl2 (1.5 mL)
were added and the mixture and stirred for 10 min. The two
phases were separated, the aqueous phase was extracted with
CH2Cl2 (2 ꢀ 2 mL) and the organic phase was washed with
NaCl (5 mL) and dried over Na2SO4. The organic layer was
then concentrated and purified by flash chromatography
(5:1, EtOAc–hexane) to afford 12 as a colorless oil (38 mg,
0.070 mmol, 76%). Rf = 0.19 (5:1, EtOAc–hexane);
[a]D +0.78 (c 7.00, MeOH).
(7) Martin, P. Helv. Chim. Acta 2003, 86, 204.
(8) Chow, S.; Wen, K.; Sanghvi, S. Y.; Theodorakis, E. A.
Nucleosides, Nucleotides Nucleic Acids 2003, 22, 583.
(9) (a) Sproat, B. S.; Beijer, B.; Groti, M.; Ryder, U.; Morand,
K. L.; Lamond, A. I. J. Chem. Soc., Perkin Trans. 1 1994,
419. (b) Hanessian, S.; Lavallée, P. Can. J. Chem. 1975, 53,
2975.
(10) For examples of endo- and exo-acetals, see:
(a) Venkatesalu, B.; Lin, L. G.; Cherian, X. M.; Czarnik, A.
W. Carbohydr. Res. 1987, 170, 124. (b) See also: Grindley,
T. B.; Szarek, W. A. Carbohydr. Res. 1972, 25, 187.
(c) Typical Procedure 10 → 11 → 12.
(11) We have also used a combination of ZnCl2/L-Selectride,
BF3·OEt2/Et3SiH, however, no opening of the acetal was
observed under these conditions.
(12) Decomposition was observed when MeCN and
nitromethane were used as solvent.
Compound 11: to a mixture of 10 (4.5 g, 9.32 mmol) and
PTSA (90 mg, 0.466 mmol) in toluene (65 mL) was added
methoxyacetaldehyde dimethyl acetal (1.95 mL, 27.35
mmol). The mixture was stirred at 125 °C for 1 h, cooled to
r.t. and concentrated. The crude product was purified by
flash chromatography (5:1, EtOAc–hexane) to afford 11 (3.7
g, 6.87 mmol, 75%) as a white solid. Rf = 0.46 (5:1, EtOAc–
hexane); mp 60–63 °C; [a]D +4.9 (c 0.45, MeOH).
Compound 12: to 11 (50 mg, 0.092 mmol) in CH2Cl2 (1.5
mL) at –78 °C was added TiCl4 (0.92 mL, 0.92 mmol, 1 M
CH2Cl2). The mixture was stirred at this temperature for 10
(13) Hanessian, S.; Machaalani, R. Tetrahedron Lett. 2003, 44,
8321.
(14) For example, see: (a) Guindon, Y.; Ogilvie, W. W.;
Bordeleau, J.; Li, C. W.; Durkin, K.; Gorys, V.; Juteau, H.;
Lemieux, R.; Liotta, D.; Simoneau, B.; Yoakim, C. J. Am.
Chem. Soc. 2003, 125, 428. (b) Corcoran, C. R.
Tetrahedron Lett. 1990, 31, 2101. (c) Mori, A.; Fujiwara, J.;
Maruoka, K.; Yamamoto, H. J. Organomet. Chem. 1985,
285, 83. (d) Liptak, A.; Fügedi, P.; Nanasi, P. Carbohydr.
Res. 1978, 65, 209.
Synlett 2005, No. 16, 2437–2440 © Thieme Stuttgart · New York