Ring opening of 4′,5′-epoxynucleosides: A novel stereoselective entry to 4′-C-branched nucleosides

Article abstract of DOI:10.1021/ol020259h

(Matrix presented) Stereoselective synthesis of 4′-α -carbon-substituted nucleosides has been accomplished through epoxidation of 4′,5′-unsaturated nucleosides with dimethyldioxirane (DMDO) and successive SnCl₄-promoted ring opening of the resulting 4′,5′-epoxynucleosides with organosilicon reagents.

Full text of DOI:10.1021/ol020259h

ORGANIC
LETTERS
2
003
Vol. 5, No. 9
399-1402
Ring Opening of
′,5′-Epoxynucleosides: A Novel
1
4
Stereoselective Entry to 4′-C-Branched
Nucleosides
Kazuhiro Haraguchi,* Shingo Takeda, and Hiromichi Tanaka
School of Pharmaceutical Sciences, Showa UniVersity, 1-5-8 Hatanodai,
Shinagawa-ku, Tokyo 142-8555, Japan
harakazu@pharm.showa-u.ac.jp
Received December 30, 2002
ABSTRACT
Stereoselective synthesis of 4′-r-carbon-substituted nucleosides has been accomplished through epoxidation of 4′,5′-unsaturated nucleosides
with dimethyldioxirane (DMDO) and successive SnCl -promoted ring opening of the resulting 4′,5′-epoxynucleosides with organosilicon reagents.
4
Nucleoside analogues are recognized as an important class
of biologically active compounds, especially as antiviral and
antitumor agents. Recently, 4′-substituted nucleosides have
radical cyclization of a 3′-O-silicon-tethered nucleoside C4′-
radical and electrophilic substitution of nucleoside 5′-esters.
Although ring opening of epoxides with carbon nucleo-
6
7
1
attracted much attention because of the discovery of the
philes constitutes a powerful synthetic operation for C-C
bond-forming reactions, little attention has been paid for
8
potent anti-HIV agents 4′-azido- (1) and 4′-cyanothymidine
2
(
2). Although incorporation of heteroatoms into the 4′-
its application to the synthesis of branched sugar-nucleo-
9
position of nucleosides can be carried out by the simple
sides. In this paper, we wish to describe a novel method
2,3
electrophilic addition to 4′,5′-unsaturated nucleosides, this
method is not suitable for carbon substituents.
for the stereoselective synthesis of 4′-R-carbon-substituted
nucleosides based on epoxidation of 4′,5′-unsaturated nucleo-
The most commonly utilized method for the preparation
of 4′-branched analogues is manipulation of 4′-hydroxy-
methyl derivatives of nucleosides or sugars prepared via an
aldol-Cannizzaro reaction of the corresponding aldehyde.
Other recently reported methods include intramolecular
sides followed by SnCl
silicon reagents.
One would readily anticipate from their enol ether structure
that 4′,5′-unsaturated nucleosides would be highly susceptible
to nucleophilic attack under acidic conditions. In fact, it has
4
-assisted ring opening with organo-
4
,5
(
1) For a review, see: Nucleosides and Nucleotides as Antitumor and
AntiViral Agents; Chu, C. K., Baker, D. C., Eds.; Plenum Press: New York,
993.
2) Prisbe, E. J.; Maag, H.; Verheyden, J. P. H.; Rydzewski, R. M. In
(4) (a) Nomura, M.; Shuto, S.; Tanaka, M.; Sasaki, T.; Mori, S.; Shigeta,
S.; Matsuda, A. J. Med. Chem. 1999, 42, 2901-2908. (b) Ohrui, H.; Kohgo,
S.; Kitano, K.; Sakata, S.; Kodama, E.; Yoshimura, K.; Matsuoka, M.;
Shigeta, S.; Mitsuya, H. J. Med. Chem. 2000, 43, 4516-4525.
(5) Other synthetic methods: (a) Secrist, J. A, III; Winter, W. J., Jr. J.
Am Chem. Soc. 1978, 100, 2554-2555. (b) Haraguchi, K.; Tanaka, H.;
Itoh, Y.; Yamaguchi, K.; Miyasaka, T. J. Org. Chem. 1996, 61, 851-858.
(6) Sugimoto, I.; Shuto, S.; Matsuda, A. J. Org. Chem. 1999, 64, 7153-
7157.
(7) Jung, M. E.; Toyota, A. J. Org. Chem. 2001, 66, 2624-2635.
(8) For a review, see: Smith, J. G. Synthesis 1984, 629-656.
(9) Ashwell, M.; Jones, A. S.; Walker, R. T. Nucleic Acids Res. 1987,
15, 2157-2166.
1
(
Nucleosides and Nucleotides as Antitumor and AntiViral Agents; Chu, C.
K., Baker, D. C., Eds.; Plenum Press: New York, 1993; pp 101-113.
(3) (a) Jenkins, I. D.; Verheyden, J. P. H.; Moffatt, J. G. J. Am. Chem.
Soc. 1976, 98, 3346-3357. (b) Owen, G. R.; Verheyden, J. P. H.; Moffatt,
J. G. J. Org. Chem. 1976, 41, 3010-3017. (c) Verheyden, J. P. H.; Moffatt,
J. G. J. Am. Chem. Soc. 1975, 97, 4386-4395. (d) Sasaki, T.; Minamoto,
K.; Kuroyanagi, S.; Hattori, K. Tetrahedron Lett. 1973, 14, 2731-2733.
e) Sasaki, T.; Minamoto, K.; Hattori, K. J. Am. Chem. Soc. 1973, 95, 1350-
351.
(
1
1
0.1021/ol020259h CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/03/2003

been reported that m-CPBA-oxidation of 4′,5′-unsaturated
thymidine (4′,5′-didehydro-5′-deoxythymidine) in MeOH
resulted in the formation of 4′-methoxythymidine as a
mixture of 4′-epimers.2 We, therefore, examined dimethyl-
dioxirane (DMDO), which can be used under neutral
conditions in aprotic solvents.11 When 3′-O-TBDMS-4′,5′-
unsaturated thymidine (3) was treated with an acetone
Scheme 3
,10
2 2
solution of DMDO (1.5 equiv) in CH Cl at -30 °C, the
reaction went to completion within 0.5 h and 4′,5′-epoxy-
1
thymidine 4 (a single isomer, evidenced by H NMR) was
obtained simply by removal of the solvents (Scheme 1). The
was determined by nOe experiment: 5 H-1′/Me-4′ (4%), 6
H-3′/Me-4′ (9%), and H-6/Me-4′ (3%). As shown in Scheme
Scheme 1
3, the result can be rationalized by assuming that the oxonium
intermediate is in equilibrium as the conformers A and B,
and that “intramolecular” methyl transfer to the 4′-position
had occurred predominantly from B due to the steric
repulsion associated with A. This assumption led us to
examine Lewis acid-mediated intermolecular ring opening
of 4 with organosilicon reagents.
Reaction of 4 with allyltrimethylsilane (3 equiv) using
1
SnCl
4
(3 equiv) gave two products (Scheme 4). Their H
depicted stereochemistry of 4 came from the observed nOe
correlation between H-5′/Si-t-Bu (0.9%) as well as the
assumption that the R-face of the 4′,5′-double bond would
be shielded by the TBDMS group. Although DMDO has
Scheme 4
12
been known to oxidize the pyrimidine base of nucleosides,
no such side reaction was observed in the epoxidation of 3.
The initial attempt to ring-open 4 was carried out with
Me
3
Al (3 equiv) as shown in Scheme 2. Although exclusive
Scheme 2
NMR spectra showed that the more polar product was the
expected 4′-R-allylthymidine 8 [nOe data: H-5′/H-3′ (5.3%)
and H-1′/CH dCHCH -4′ (0.8%)] while the less polar one
2 2
was its 5′-O-trimethylsilyl derivative (7). Thus, simple
extractive workup of the reaction mixture followed by
treatment with NH
yield. The use of other Lewis acids, such as TiCl
3
/MeOH enabled the isolation of 8 in 80%
2
or EtAlCl ,
4
gave mainly thymine, and 8 was obtained only in very low
yields (5-7%).
The above SnCl -assisted stereoselective allylation also
4
worked with 4′,5′-epoxides derived from 9 and 13 (Figure
cleavage of the oxirane ring at the 4′-position was seen, the
stereochemical outcome of this reaction was discouraging,
forming the 4′-â-methyl isomer 6 (64%) as the major product
together with 5 (5%). The stereochemistry of these products
(
10) Maag, H.; Rydzewski, R. M.; McRoberts, M. J.; Crawford-Ruth,
D.; Verheyden, J. P. H.; Prisbe, E. J. J. Med. Chem. 1992, 35, 1440-1451.
11) (a) Adam, W.; Hadjiarapoglou, L.; Smerz, A. Chem. Ber. 1991,
(
1
24, 227-232. (b) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber.
1
991, 124, 2377.
(
12) Example of oxidative modification of pyrimidine base with
DMDO: Saladino, R.; Bernini, R.; Crestini, C.; Minocione, E.; Bergamini,
A.; Marini, S.; Palamara, A. T. Tetrahedron 1995, 51, 7561-7578.
Figure 1.
1400
Org. Lett., Vol. 5, No. 9, 2003

mixture, 4′-R-allyluridine 11 was isolated in 90% overall
1
yield from 9. In the case of 12, to avoid N -oxidation with
2
DMDO, it was necessary to acylate the 6-NH group. By
6
using the N -pivaloyl derivative 13, 4′-R-allyladenosine 14
was obtained in 52% overall yield.
To elucidate the mechanism of the present allylation, the
above-mentioned reactions of 9 were studied in some detail.
Epoxidation of 9 with DMDO gave a 4′,5′-epoxide 15 as a
single isomer, although its stereochemistry could not be
determined with an nOe experiment. When this epoxide was
4 2 2
reacted solely with SnCl in CH Cl , two 4′-chlorinated
products (17 and 18) were isolated. The stereochemistry was
established on the basis of an nOe experiment. Analysis of
their J1′,2′ and J2′,3′ values suggested that 17 and 18 would
take the conformations as shown in Scheme 5, respectively.
4
Independent treatment of 17 and 18 again with SnCl resulted
in isomerization, forming both compounds. Although no
reaction took place by adding allyltrimethylsilane to a
Figure 2.
CH
SnCl
reaction to give the spiro intermediate 19 (a mixture of two
2
Cl
2
solution of 17, addition of a catalytic amount of
(0.5 equiv) to this mixture caused an instantaneous
2
). Thus, allylation of the epoxide prepared from 9 gave a
4
3
mixture of 10 and 11. After NH /MeOH treatment of the
Scheme 5
Org. Lett., Vol. 5, No. 9, 2003
1401

diastereomers) that was isolated by HPLC and fully char-
acterized. In the reaction medium, 19 was found to be
converted slowly to 10 and 11. Compound 18 behaved
exactly in the same manner as 17. These observations led
us to propose the reaction mechanism in Scheme 5. The
4′-â- (17′) and 4′-R-chloro (18′) derivatives exist in equi-
librium, and are interconvertible through the oxonium ion
4
16. For the SnCl -assisted reaction with allyltrimethylsilane,
1
8′ would be kinetically less favored because of the
1
3
pseudoequatorial orientation of the chlorine atom, and
presumably also due to steric hindrance exerted by the base
moiety. On the other hand, the pseudoaxial chlorine atom
in 17′ as well as the sterically less encumbered R-face permit
Figure 3.
In conclusion, a novel method for the stereoselective
synthesis of 4′-R-carbon-substituted nucleoside analogues has
been disclosed, using the SnCl -assisted ring opening of 4′,5′-
epoxynucleosides with organosilicon reagents. The evidence-
based reaction mechanism of 4′-R-selective allylation has
also been proposed through the present study.
N
its ready S 2 reaction with allyltrimethylsilane to lead to
the intermediate 19. The â-effect of the silicon atom ensures
regioselective opening of the spiro ring to yield 20. Trapping
of 20 with TMSCl gives rise to 10, whereas quenching with
4
2
H O furnishes 11.
Finally, the scope of the present reaction was briefly
examined by reacting 4′,5′-epoxythymidine derivative 4 with
other organosilicon reagents (Figure 3). Compounds 21
Acknowledgment. Financial support from the Ministry
of Education, Culture, Sports, Science and Technology
Grant-in-Aid No. 11771391 to K.H.) is gratefully acknowl-
edged.
(
47%) and 22 (32%) were synthesized as a single isomer by
using (2-bromoallyl)trimethylsilane and (cyclopentenyl)-
trimethylsilane, respectively, in CH Cl in the presence of
SnCl (3 equiv). It would be worthy to mention that the
present method provides an access to a potent anti-HIV agent,
′-R-cyanothymidine, since a cyano group can be introduced
into the 4′-position by using cyanotrimethylsilane to yield
3 (45%).
(
2
2
4
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 3, 5, 6,
4
1
8
-14, 17-19, and 21-23; H NMR and MS spectrum of
compound 4. This material is available free of charge via
the Internet at http://pubs.acs.org.
2
(13) Eliel, E. L.; Ro, R. S. Chem. Ind. 1956, 251-252.
OL020259H
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Org. Lett., Vol. 5, No. 9, 2003