Diastereoselective synthesis of β-aryl-C-nucleosides from 1,2-anhydrosugars

Article abstract of DOI:10.1021/ol061701p

(Chemical Equation Presented) The cis opening of glycal epoxides with arylaluminum reagents provides strict stereocontrol in C-glycosylation. β-Aryl-C-2-deoxynucleosides are obtained from known glycals by an epoxidation-glycosylation-deoxygenation sequenc

Full text of DOI:10.1021/ol061701p

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4319-4322
Diastereoselective Synthesis of
-Aryl-C-nucleosides from
1,2-Anhydrosugars
â
Ishwar Singh and Oliver Seitz*
Humboldt-UniVersita¨t zu Berlin, Institut fu¨r Chemie, Brook-Taylor-Strasse 2,
D-12489 Berlin, Germany
oliVer.seitz@chemie.hu-berlin.de
Received July 11, 2006
ABSTRACT
The cis opening of glycal epoxides with arylaluminum reagents provides strict stereocontrol in C-glycosylation.
â
-Aryl-C-2-deoxynucleosides
are obtained from known glycals by an epoxidation−glycosylation−deoxygenation sequence.
The replacement of nucleobases in oligodesoxynucleotides
by designed surrogates is a frequently applied approach to
confer new functions to DNA.1-4 Aromatic base surrogates
have been introduced with an aim to explore molecular
interactions in DNA-DNA and DNA-protein recognition
processes. For example, C-glycosidically linked aryl groups
have allowed the role of hydrogen bonding and stacking to
be discerned in DNA duplex formation.5-12 Aromatic base
surrogates can be accepted by DNA-polymerases and have
thus been used to extend the genetic code.5,6,13-15 We,16 and
others,17-20 have incorporated polycyclic aromatic hydro-
carbons as a means of studying the mechanism of DNA
methylation and DNA repair. Interesting opportunities also
are provided by fluorescent base surrogates which have utility
as spectroscopic probes.21
Most studies have relied on the use of â-configured 1-C-
aryl-2-deoxynucleotides, which mimic the anomeric stereo-
chemistry of natural nucleosides. A crucial step in the
synthesis of these building blocks is the â-selective incor-
poration of the aryl moiety.22 The commonly used coupling
of O-toluoyl-protected 1-chloro-2-deoxyriboside (Hoffer’s
chlorosugar)23 with arylcadmium, arylmagnesium, arylzinc,
or arylcopper reagents yields mixtures of anomers, with the
less desired R-anomer as the major compound.16,24,25 Sub-
(1) Kool, E. T. Acc. Chem. Res. 2002, 35, 936-943.
(2) Rist, M. J.; Marino, J. P. Curr. Org. Chem. 2002, 6, 775-793.
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727-733.
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(6) Matray, T. J.; Kool, E. T. Nature 1999, 399, 704-708.
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(16) Beuck, C.; Singh, I.; Bhattacharya, A.; Heckler, W.; Parmar, V. S.;
Seitz, O.; Weinhold, E. Angew. Chem., Int. Ed. 2003, 42, 3958-3960.
(17) Sun, L. P.; Wang, M.; Kool, E. T.; Taylor, J. S. Biochemistry 2000,
39, 14603-14610.
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Commun. 2002, 500-501.
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(19) Kwon, K.; Jiang, Y. L.; Stivers, J. T. Chem. Biol. 2003, 10, 351-
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5949-5959.
(21) Gao, J. M.; Watanabe, S.; Kool, E. T. J. Am. Chem. Soc. 2004,
126, 12748-12749.
(22) Wu, Q. P.; Simons, C. Synthesis 2004, 1533-1553.
(23) Hoffer, M. Chem. Ber.-Recl. 1960, 93, 2777-2781.
(24) Ren, R. X. F.; Chaudhuri, N. C.; Paris, P. L.; Rumney, S.; Kool, E.
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G.; Romesberg, F. E. J. Am. Chem. Soc. 2000, 122, 3274-3287.
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10.1021/ol061701p CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/19/2006

sequent acid-catalyzed anomerization reactions allow a shift
in the anomeric ratio to provide the â-product in excess.24,26
Friedel-Crafts alkylation of activated aromatic hydrocarbons
using Lewis acids and methoxysugars as glycosyl donors
provides direct access to predominantly â-C-aryl nucleo-
sides.27 In all of these syntheses, laborious separation from
the R-anomers is still a necessity and, at times, a most
challenging step. High â-selectivity has been reported for
methods that draw upon the coupling of aryllithium reagents
to benzyl- or disiloxane-protected 2-deoxyribonolactones.7,12,28
Two subsequent stereodifferentiating reactions are combined
in a reaction sequence that comprises palladium-catalyzed
coupling of aryl iodides with glycals and reduction of the
3′-keto group.29 We envisioned that the stereoselective
opening of epoxides with arylmetal reagents should provide
a more facile means of exerting strict stereocontrol in
C-glycosylation reactions. The trans opening of 1,2-anhy-
droribose has been used for the preparation of nucleosides.30
To our surprise, C-glycosylation with 1,2-anhydro furanoid
sugars has not been described. In this paper, we present our
study on the diastereoselective C-glycosylation with 1,2-
anhydro sugars. It is shown that the coupling of arylalumi-
num reagents with 1,2-anhydroarabinose enables rapid and
â-selective syntheses of 1′-C-aryl-2′-deoxynucleosides con-
taining interesting aryl aglycons such as methylnaphthalenes
and phenylnaphthalenes. It has been noted previously that
glycosylation of heterocycles via glycal epoxide intermedi-
ates proceeds with high diastereoselectivity.30 We reckoned
that the trans-selective opening of 1,2-anhydroribose A with
organocuprates followed by deoxygenation would provide
the desired 1-C-aryl-2-deoxynucleoside in pure â-anomeric
form (Scheme 1). As an alternative entry we considered the
suitably protected 1,2-anhydroribose such as A (R ) TBDPS,
R′ ) TMS) was required. The known 5-O-protected glycal
4 was synthesized from thymidine as described (Scheme 2).31
Scheme 2. Synthesis of Protected 1,2-Anhydroribose
The free 3-hydroxy group in 4 was necessary to achieve the
desired selectivity in the epoxidation of the 1,2-double bond
from the R-side to furnish 1,2-anhydroribose 5. Next, the
3-hydroxyl group was protected in the presence of the
epoxide 5; this was required to render the 2′-hydroxy group,
after epoxide opening, amenable to Barton deoxygenation.
However, attempts to reinstall the 3-O-TMS ether in 5 were
plagued by concomitant opening of the epoxide. After
noticing the high reactivity of the glycal epoxide 5, it was
deemed important to avoid protecting group manipulations
at this stage of the synthesis.
It was anticipated that a cis opening of the 1,2-anhydroara-
binose 8 would allow the synthesis of aryl-â-C-arabino-
nucleosides 9 featuring an unprotected hydroxyl group at
carbon-2 (Scheme 3).31 The required epoxide 8 was obtained
from the known glycal 731 (prepared by a two-step synthesis
from thymidine in 86%) by treatment with dimethyldioxirane
(DMDO) in dichloromethane at 0 °C. Epoxidation of the
fully protected glycal 7 occurred selectively from the â-side.
The subsequent C-glycosylation reactions were explored
using the naphthyl group as aglycon. Treatment of 8 with
1-naphthyllithium in the presence of aluminum trichloride
conferred the desired cis opening. However, TLC analysis
revealed the formation of various byproducts. Attempts to
minimize decomposition by using BF3‚Et2O for cis opening
did not furnish the desired product 9. The reaction of glycal
epoxide 8 with trinaphthylaluminum, itself obtained from
naphthyl Grignard reagent and aluminum trichloride, pro-
ceeded smoothly. The characteristic cross-peaks for H1′ and
H4′ in the NOESY spectrum confirmed the â-configuration
of 1-aryl-C-arabinonucleoside 9. Best results were obtained
by omitting the workup of 8 and by using thioanisole to
quench excess DMDO. Under these conditions, 1-naphthyl-
Scheme 1. Diastereoselective C-Glycosylation via
1,2-Anhydro Furanoid Sugars
cis-selective opening of the glycal epoxide B having the
arabino configuration.
We first attempted the trans-selective opening of glycal
epoxide A having the ribo configuration. The synthesis of a
(26) Jiang, Y. L.; Stivers, J. T. Tetrahedron Lett. 2003, 44, 85-88.
(27) Hainke, S.; Arndt, S.; Seitz, O. Org. Biomol. Chem. 2005, 3, 4233-
4238.
(28) Wichai, U.; Woski, S. A. Org. Lett. 1999, 1, 1173-1175.
(29) Farr, R. N.; Outten, R. A.; Cheng, J. C. Y.; Daves, G. D.
Organometallics 1990, 9, 3151-3156.
(31) Cameron, M. A.; Cush, S. B.; Hammer, R. P. J. Org. Chem. 1997,
62, 9065-9069.
(30) Chow, K.; Danishefsky, S. J. Org. Chem. 1990, 55, 4211-4214.
4320
Org. Lett., Vol. 8, No. 19, 2006

Scheme 3. Cis-Selective Opening of 1,2-Anhydroarabinose
Scheme 4. Synthesis of â-Aryl-C-nucleosides 17a-d
â-C-arabinonucleoside 9 was afforded in 70% combined
yield. The next step was the deoxygenation of the 2′-hydroxy
group of the arabinonucleoside 9. The phenylthionocarbonate
10a, thiocarbonylimidazole 10b, and methyl xanthate 10c
were synthesized. However, attempts to achieve the deoxy-
genation of 10a-c by using tributyltinhydride or tris-
(trimethylsilyl)silane32 as the reducing agent, and AIBN failed
to deliver significant yields of desired product 11.
We presumed that the deoxygenation was not successful
due to the bulkiness of the two TBDPS groups and we
reasoned that the use of tert-butyldimethylsilyl (TBDMS)
protecting groups would provide less steric hindrance. To
investigate this assumption, the TBDMS-protected glycal
1231 was prepared from thymidine. Epoxidation of 12 and
cis opening of epoxide 13 with trinaphthylaluminum was
performed as described for TBDPS-protected glycal 7. The
1-naphthyl-â-C-arabinonucleoside 14a was obtained in 50%
yield from 12. Importantly, the 3′,5′-O-TBDMS-protected
arabinose derivative was amenable to deoxygenation. In the
event, the 2′-hydroxyl group was allowed to react with
thiocarbonyldiimidazole followed by treatment with tris-
(trimethylsilyl)silane and AIBN (Scheme 4). The two-step
Barton deoxygenation33 furnished the 2′-deoxynucleoside 16a
in 82% yield. Final desilylation was performed by treatment
with tetrabutylammonium fluoride in tetrahydrofuran to
afford fully deprotected 2′-deoxy-1′-â-naphthylnucleoside
17a8,24 in 98% yield.
After having secured synthetic access to the â-naphthyl-
2′-deoxynucleoside 17a, we explored the generality of the
route. Within an ongoing project toward the use of bulky
base surrogates as probes of enzymatic DNA methylation,
we were in need of methyl- and phenylnaphthalene-based
arylnucleosides 17b-d. The required bromonaphthalenes
20b-d were synthesized starting from 5- and 7-bromote-
tralones 18b,c (Scheme 5).34 The reaction with methylmag-
nesium chloride at 0 °C furnished alcohols 19b and 19c in
(33) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574-1585.
(34) Cornelius, L. A. M.; Combs, D. W. Synth. Commun. 1994, 24,
2777-2788.
(32) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188-194.
Org. Lett., Vol. 8, No. 19, 2006
4321

A survey of the important methods for synthesis of â-aryl-
C-nucleoside synthesis reveals that the shortest routes are
provided by methods that lack diastereoselectivity in the
C-glycosylation step. For example, the use of arylcadmium
reagents24 and Hoffer’s chlorosugar23 requires six steps in
total to furnish â-aryl-C-nucleosides in up to 14% overall
yield. The use of arylcopper reagents has allowed for
improvements of the C-glycosylation step; however, the
desired â-anomer still is formed as minor compound.16
Predominant formation of â-products has been observed in
Friedel-Crafts glycosylation chemistry, in which a Lewis
acid induced the reaction of methoxy sugars with arenes to
allow most rapid access, four steps in total, to aryl-C-
nucleosides.27 This route is restricted to electron-rich arenes
(Hammett-Brown σ+arene < -0,4). In addition, the â-product
still has to be separated from minor amounts of the R-anomer,
which can be difficult. Diastereoselective C-glycosylation
can be achieved by Heck-type couplings of arylpalladium
species to glycals.29 The yields that have been reported for
the seven-step synthesis vary between 12 and 33%.35,36 The
reaction of O-benzyl-protected ribonolactone with aryllithium
reagents and subsequent silane reduction also provides
â-selectivity in aryl-2′-deoxynucleoside synthesis.12 Aryl-
C-nucleosides were obtained in 3% overall yield after 10
steps starting from commercially available ribose. The use
of disiloxane-protected 2-ribonolactone allowed short syn-
theses of C-nucleosides in high yield with up to 83%
diastereomeric excess.28 The cis-opening of 1,2-anhydroara-
binose by arylaluminum reagents described by us proceeds
with exclusive â-selectivity and requires 7 steps, two of
which (epoxidation-glycosylation and two-step Barton deoxy-
genation) can be performed consecutively without purifica-
tion. Interestingly, aryl-C-nucleosides such as the 2′-deoxy-
1′-C-phenylnaphthylnucleoside 17d are obtained in up to
26% overall yield. The convenient protocol compares well
to existing methods of aryl-C-nucleoside synthesis and avoids
cumbersome steps such as iodoarene synthesis or separation
of anomeric mixtures.
Scheme 5. Synthesis of Naphthalenes 20b-d
80% and 75% yield, respectively. Subsequent treatment with
TFA and triphenylmethanol delivered the corresponding
bromonaphthalenes 20b and 20c in 78% and 70% yield. The
preparation of 5-bromo-1-phenylnaphthalene 20d was ac-
complished in 41% overall yield by exposing 5-bromote-
tralone 18c to phenylmagnesium bromide followed by acid-
mediated aromatization.
For the synthesis of the 2′-deoxy-1′-â-naphthylnucleosides
14b-d, the bromonaphthalenes 20b-d were converted to
the corresponding trinaphthylaluminum reagents via Grignard
intermediates. Sequential epoxidation of glycal 12 and cis-
selective opening of glycal epoxide 13 proceeded with 40-
65% combined yield. To reduce the amount of aryl equiva-
lents in the organoaluminum reagent the use of dimethyl-
naphthylaluminum was investigated. In this case (method
2), the combined yield of the epoxidation-C-glycosylation
sequence amounted to 41% for the naphthyl- and the
phenylnaphthylnucleoside 14a and 14d and 44% and 22%
for the methylnaphthylnucleosides 14c and 14b, respectively.
Remarkably, the reaction still proceeded with exclusive cis
selectivity, products from trans opening reactions were not
detected. It was noticed that the use of dimethyl-1-(5-phenyl)-
naphthenylaluminum led to the formation of minor amounts
of two new easily separable products, arabinose dimer and
trimer (see the Supporting Information). In progressing to
the desired 2′-deoxynucleosides, the 2′-hydroxyl groups in
arabinose derivatives 14b-d were removed by means of the
described two-step procedure. The deoxygenation at the
TBDMS-protected arabinose again proceeded smoothly.
Deprotection of the â-anomeric 2′-deoxyribose-C-nucleosides
16b-d was performed by fluoride-mediated O-desilylation.
Column chromatography furnished the unprotected aryl-C-
nucleosides 17b-d in excellent 98-99% yields.
Acknowledgment. I.S. is grateful for a fellowship of the
Alexander von Humboldt Foundation. We acknowledge
support from DFG, Fonds der Chemischen Industrie, and
Schering AG.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL061701P
(35) Zhang, H. C.; Daves, G. D. J. Org. Chem. 1992, 57, 4690-4696.
(36) Li, J. S.; Shikiya, R.; Marky, L. A.; Gold, B. Biochemistry 2004,
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4322
Org. Lett., Vol. 8, No. 19, 2006