A stereoselective approach to nucleosides and 4′-thioanalogues from acyclic precursors

Article abstract of DOI:10.1021/ja905452f

D- and L-nucleosides and analogues thereof, including the 4′-thionucleoside series, are one of the most important biological and pharmaceutically active classes of compounds. A novel approach to their synthesis from chiral acyclic thioaminal, bearing the nucleobase, is described.

Full text of DOI:10.1021/ja905452f

Published on Web 11/10/2009
A Stereoselective Approach to Nucleosides and
4′-Thioanalogues from Acyclic Precursors
Daniel Chapdelaine, Benoit Cardinal-David, Michel Pre´vost, Marc Gagnon,
Isabelle Thumin, and Yvan Guindon*
Institut de recherches cliniques de Montre´al (IRCM), Bio-organic Chemistry Laboratory, 110 aVenue
des Pins Ouest, Montre´al, Que´bec, Canada H2W 1R7, Department of Chemistry, UniVersite´ de
Montre´al, C.P. 6128, succursale Centre-Ville, Montre´al, Que´bec, Canada, H3C 3J7 and Department
of Chemistry, McGill UniVersity, 801 Sherbrooke Street West, Montre´al, Que´bec, Canada, H3A 2K6
Received July 9, 2009; E-mail: yvan.guindon@ircm.qc.ca
Abstract: D- and L-nucleosides and analogues thereof, including the 4′-thionucleoside series, are one of
the most important biological and pharmaceutically active classes of compounds. A novel approach to
their synthesis from chiral acyclic thioaminal, bearing the nucleobase, is described.
Introduction
Since endogenous nucleosides are key components of the
molecular building blocks of life, one should not be surprised
of the critical role that analogues of these compounds play in
the treatment of various diseases. For example, three drugs in
this compound class decitarabine,1 clofarabine,2 and 5-azacy-
tidine3 (AZT) have been recently approved for the treatment of
leukemic and myelodysplastic syndromes. Analogues, such as
the 4′-thio-ꢀ-D-arabinofuranosyl (4′-thio-Ara-C), have shown
improved activity against solid tumors relative to their “oxa”
counterparts due to an increase in stability toward enzyme-
mediated hydrolysis,4 that results in improved pharmacokinetic
properties. Similarly 4′-thio-oligonucleosides form duplexes with
similar affinity as that of their “oxa” counterparts with the
additional benefit of possessing nuclease-promoted strand scis-
sion resistance.5 While most of these analogues exert their
effects through termination of DNA elongation, alternate
mechanisms also include inhibition of ribonucleotide reductase
and DNA methylation.
Figure 1. Nucleoside and 4′-thionucleoside analogues in the xylose, ribose,
arabinose, and the lyxose series.
oxa and 4′-thio molecules in D- and L-series. Highlighted in
Figure 1 are the 1,2-cis isomers which, for steric reasons, are
difficult to prepare using the present approaches.
We have synthesized 16 of the possible 32 isomers depicted
in Figure 1. Two stereoselective cyclizations of acyclic chiral
thioaminals bearing a nucleobase at C-1′ are used, a novel
approach that is reported herein.
Nucleoside analogues are also used as antiviral agents6 (e.g.,
zidovudine [AZT]).7 Of particular importance, from a structural
standpoint, is the discovery that analogues in the L-series could
also be inhibitors of crucial enzymes such as the reverse
transcriptase of HIV (e.g., lamivudine [L-3TC]).7
Results and Discussion
A novel approach to the synthesis of nucleoside analogues
should therefore take into account the need to access both 4′-
The existing paradigm that widely governs the synthesis of
nucleosides dictates that a nucleobase (purine or pyrimidine,
modified or not) be attached to an activated cyclic glycosyl or
thioglycosyl donor in a bimolecular reaction.8 The stereoselec-
tivities observed in the coupling steps depends either on steric
effect, anchimeric participation from a neighboring acyloxy
group,9 1,3-induction (ribose series),10 or a concerted stereospe-
cific displacement of an anomeric halide.11
(1) Gore, S. D.; Jones, C.; Kirkpatrick, P. Nat. ReV. Drug DiscoVery 2006,
5, 891.
(2) Bonate, P. L.; Arthaud, L.; Cantrell, W. R.; Stephenson, K., Jr.; Secrist,
J. A., III; Weitman, S. Nat. ReV. Drug DiscoV. 2006, 5, 855.
(3) Issa, J.-P. J.; Kantarjian, H. M.; Kirkpatrick, P. Nat. ReV. Drug
DiscoVery 2005, 4, 275.
(4) Dyson, M. R.; Coe, P. L.; Walker, R. T. J. Med. Chem. 1991, 34,
2782.
Specifically the limits of this approach lie first in the syntheses
of the thioglycosyl donors which often are poorly yielded.
Second, the synthesis of sterically encumbered analogue mol-
(5) (a) Hancox, E. L.; Connolly, B. A.; Walker, R. T. Nucleic Acids Res.
1993, 21, 3485. (b) Dande, P.; Prakash, T. P.; Sioufi, N.; Gaus, H.;
Jarres, R.; Berdeja, A.; Swayze, E. E.; Griffey, R. H.; Bhat, B. J. Med.
Chem. 2006, 49, 1624.
(6) De Clerq, E. J. Clin. Virol. 2004, 30, 115.
(7) Mitsuya, H., Ed. Anti-HIV Nucleosides: Past, Present and Future;
Landes R. G. Co.: Georgetown, TX, 1997.
(8) Vorbru¨ggen, H.; Ruh-Pohlenz, C. Handbook of Nucleoside Synthesis;
Wiley: New York, 2001.
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17242 J. AM. CHEM. SOC. 2009, 131, 17242–17245
10.1021/ja905452f CCC: $40.75  2009 American Chemical Society

4′-Thioanalogues from Acyclic Precursors
A R T I C L E S
Scheme 1. C4′-C1′ (red arrow) and C1′-C4′ (blue arrow)
Cyclization Pathways
Scheme 2. C4′-C1′ Cyclization*
ecules is also difficult as in D- or L- ꢀ-arabinosides or lyxosides
(see cis series, Figure 1). Obviously, the collision of the silylated
thymine nucleobase to the more hindered face of the glycosyl or
thioglycosyl donor is not favored because of steric factors, thus,
the higher energy of the transition states leading to these products.
From a conceptual standpoint, a kinetically controlled cy-
clization of an acyclic precursor already containing the nucleo-
base (i.e., formation of the furanose ring downstream from the
addition of the nucleobase) may be better suited to create these
sterically encumbered molecules than the bimolecular processes
currently used. We hypothesized that such cyclizations may
involve a stereogenic center (at C1′) bearing the nucleobase and
a thioether, which may serve as a leaving group or alternatively
as a nucleophile as illustrated in Scheme 1. In order to take
advantage of the stereochemistry of the thioaminal at C1′, both
types of cyclizations should involve “SN2-like” nucleophilic
displacements. Avoiding the formation of iminium ion12 (i.e.,
SN1-competing mechanism) will therefore be crucial to the
success of this strategy. The presence of an alkoxy at C2′ and
the chemoselective and soft activation of the thioethers at C1′
by thiophilic Lewis acids such as dimethyl(methylthio)sulfonium
tetrafluoroborate13 should disfavor such intermediates.
The first cyclization protocol will involve the intramolecular
displacement of the activated thioalkyl group of the thioaminal
at C1′ by the secondary hydroxyl group at C4′ (C4′-C1′
cyclization). This process would lead to the desired nucleosides
and analogues thereof with inversion of configuration at C1′,
as illustrated in Scheme 1. The acyclic 1,2-syn isomer would
give the C1′-C2′ trans nucleoside series, not withstanding the
stereochemistry of the substituent at C3′ and C4′. Similarly, the
anti thioaminals should lead to the C1′-C2′ cis nucleoside
series.
* Reagents and conditions: 1.2 equiv Me2S(SMe)BF4, THF, RT, (1-3 h).
of configuration at C1′ (C1′-C4′ cyclization); the 1,2-syn
isomers leading to the C1′-C2′ cis geometry and the 1,2-anti
isomers to the C1′-C2′ trans geometry. Both types of cycliza-
tions should be stereocontrolled and stereospecific, an exciting
strategy not previously exploited.
Our first cyclization strategy was tested on acyclic syn- or
anti-ethylthio- and benzylthio-N-thymidine thioaminals. A che-
moselective activation of the thioether moiety was achieved by
adding 1.1 equiv of dimethyl(methylthio)sulfonium tetrafluo-
roborate (Me2S(SMe)BF4) to a tetrahydrofuran (THF) solution
of the thioaminal at room temperature.16 As illustrated in
Scheme 2, in all cases the cyclization was diastereospecific, and
the final products were obtained in good to excellent yields.
An inversion of configuration had occurred at C1′ (products
9-16), suggesting that an “SN2-like” mechanism was operative.
Even highly sterically congested molecules (such as 12 and 14)
were efficiently synthesized, attesting to the potential of this
approach. The dependency of the C1′-C2′ relative stereochem-
istry of the final product to the C1′-C2′ relative stereochemistry
of the thioaminal is in sharp contrast to the pioneering work of
Liotta12 who used acyclic hemiaminals in his synthesis of AZT,
where strong Brønsted acids were employed and iminium ion
intermediates suggested since both C1′ epimers gave the same
product.
Alternatively, the sulfur of the thioaminal can serve as a
nucleophile when the C4′ hydroxyl is converted into a leaving
group,14 as illustrated in Scheme 1. The potential concomitant
loss of a benzyl halide15 from benzyl sulfonium would promote
such reactions. This would result in the transformation of the
thioaminals into 4′-thionucleosides in the L-series with retention
(9) (a) Li, N.-S.; Piccirilli, J. A. J. Org. Chem. 2006, 71, 4018. (b)
Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981, 114,
1234.
(10) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.; Woerpel,
K. A. J. Am. Chem. Soc. 2005, 127, 10879.
(11) Howell, H. G.; Brodfuehrer, P. R.; Brundidge, S. P.; Benigni, D. A.;
Sapino, C. J. Org. Chem. 1988, 53, 85.
Our second cyclization strategy was tested on mesyloxy
derivatives at C4′ as illustrated in Scheme 3. A solution of a
given diastereomerically pure thioaminal in presence of an
(12) Hager, M. W.; Liotta, D. C. J. Am. Chem. Soc. 1991, 113, 5117.
(13) Trost, B. M.; Murayama, E. J. Am. Chem. Soc. 1981, 63, 6529.
(14) Yokoyama, M. Synthesis 2000, 1637.
(15) (a) Le´pine, C.; Roy, C.; Delorme, D. Tetrahedron Lett. 1994, 35, 1843.
(b) Dyson, M. R.; Coe, P. L.; Walker, R. T. Carbohydr. Res. 1991,
216, 237.
(16) Guindon, Y.; Gagnon, M.; Thumin, I.; Chapdelaine, D.; Jung, G.;
Gue´rin, B. Org. Lett. 2002, 4, 241.
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A R T I C L E S
Chapdelaine et al.
Scheme 4. Synthesis of Acyclic Thioaminals in D-Xylose Series
Scheme 3. C1′-C4′ Cyclization*
Scheme 5. One-Pot Sequence (D-Ribose)
was used for the synthesis of the syn-thioaminals illustrated
in Scheme 4. The dithioacetal 33 was first obtained as
described in the literature from D-xylose in three steps.18 After
silylation (34) or mesylation (35) of the C4′-OH, a solution
of the appropriate dithioacetal was exposed to persilylated
thymine (2 equiv) and I2 (2 equiv). Respective ratios of 7:1
and 12:1 (syn:anti) were obtained for C4′-OTBS (36, 37)
and C4′-OMs thioaminals (17, 18) at ambient temperature.
D-Lyxoside, riboside, and arabinoside dithioacethals were
treated similarly with ratios ranging from 4:1 to 15:1 in favor
of the syn compounds as described in the Supporting
Information. A study aimed at defining the reasons at the
origin of this diastereoselectivity and at maximizing the ratios
through a protecting group strategy is presently underway.
The stereoselective synthesis of anti-thioaminals awaits
further displacement.
* Reagents and conditions a: NaI, pinacolone, 106°C; b: NaI, 2,6-lutidine,
145°C.
excess of NaI (to debenzylate the putative benzylthio sulfonium
intermediate) in pinacolone or in 2,6-lutidine was heated at
reflux for 2-5 h. This second cyclization strategy was also
successful. This reaction provided direct access to L-4′-thio-
nucleosides in good to excellent yields. The 1,2-trans thioami-
nals gave the respective 1,2-trans cyclized products (entries 2,
4, 6, and 8, Scheme 3) while the 1,2-syn products gave the 1,2-
cis thionucleosides (entries 1, 3, 5, and 7). Again, the synthesis
of highly sterically congested molecules (25, 27, 29, and 31)
using this approach with the level of diastereoselectivity was
achieved. No displacement of the mesylate by our nucleobase
(N-silylated nucleobases) was noted.
Other pyrimidines (e.g., cytosine) or purine (e.g., adenine)
derivatives have been tested successfully in the two cyclization
protocols; adjustments in the reaction conditions are at times
needed and will be reported in separate studies.
In the beginning of our studies both syn- and anti-
thioaminals (1-8) were prepared as a mixture from the
corresponding thioacetals. The exciting results obtained in
the cyclization steps now justify that diastereoselective or
enantioselective syntheses of acyclic thioaminals bearing
nucleobases can be developed. Our first studies aimed at these
objectives dealt with simpler models.16 We reported that good
to excellent syn diastereoselectivity was obtained when a
bulky substituent was present at C2′ of thioacetals activated
by the sulfonium salt Me2S(SMe)BF4 in acetonitrile, or by a
combination of Hg(OAc)2/TMSOTf17 in dichloromethane, in
the presence of persilylated nucleobases (thymine, cytosine).
We then hypothesized that iodine (this study) could be a more
practical and less toxic activating agent. Such an approach
The sequence of reactions also has the potential to be
combined and realized in the same reaction vessel (Scheme 5).
Such an approach has to be considered to minimize the use of
solvents, a benefit from an environmental standpoint. We
planned to combine four reactions: protection of the hydroxyl
at C4 of the thioacetals; the coupling reaction to give the syn-
thioacetals, the removal of the protecting group at C4, and the
cyclization C4′-C1′. We decided first to optimize the coupling
step. The diethyl thioacetal 38 was selected as starting material,
the yields and reaction time being slightly increased, regardless
of the nature of the protecting group at C2′. To achieve our
(17) Brånalt, J.; Kvarnstro¨m, I.; Niklasson, G.; Svensson, S. C. T.; Classon,
B.; Samuelsson, B. J. Org. Chem. 1994, 59, 1783.
(18) Wirsching, J.; Voss, J. Eur. J. Org. Chem. 1999, 691.
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4′-Thioanalogues from Acyclic Precursors
A R T I C L E S
Scheme 6. One-Pot Sequence Case of Conditions of D-Xylose and
D-Arabinose
the one-pot sequence are similar to the ones obtained in
stepwise sequence.
Conclusion
We have shown that the stereocenter at C1′ of acyclic
thioaminals bearing a nucleoside can be used to create C4′
thionucleoside analogues in the L-series. The stereochemistry
at C1′ was maintained in the final product. Alternatively 4-oxa
analogues could be constructed using acyclic thioaminal. The
stereochemistry at C1 was inverted in the latter cases. The
cyclization reactions used are remarkably insensitive to steric
effects, as affirmed by some of the final products which are
highly sterically stranded. Accessing the L-thioanalogues
represents as well an opportunity for drug discovery. The
“SN2-like” displacements (C4′-C1′ and C1′-C4′ cyclization
modes) may well represent a novel paradigm particularly
useful for the synthesis of sterically encumbered molecules
in the 2-oxy series. The construction of novel acyclic
thioaminal, not derived from the natural pentoses, could also
lead to novel scaffolds of medicinal interest. We have already
embarked on this project. These new findings will expand
our capacity to explore the chemical space of various enzymes
or receptors of biological significance.
one-pot sequence, we selected to replace the TBS protecting
group by a more labile TES. The corresponding thioacetal 38,
with a free hydroxyl group at C4′, was reacted in THF with
TESOTf in presence of 2,6-lutidine at -40 °C for a period of
30 min. The silylated thymine and iodine were added to the
THF solution stirred at 0 °C until the disappearance of the
starting material.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council (NSERC) for its financial support
as well as Dr. Mohammed Bencheqroun for assistance in the
preparation of this manuscript. Fellowship support from NSERC
PSGD and FQRNT B2 (B.C.-D.) is also gratefully acknowledged.
Addition of the HF · pyridine to cleave the TES protecting
group for a period of 45 min at room temperature, followed
by the addition of the Me2S(SMe)BF4, led unfortunately to
poor yields. Replacing the HF · pyridine by trifluoroacetic acid
in the protecting group cleavage step led to impressive results:
a ratio (D-arabinose) of 5:1 of the C1′-C2′ anti isomer in
90% yield was observed as illustrated in Scheme 6. Similar
conditions were used for the thioacetals derived from D-xylose
and D-ribose, and the C1′-C2′ anti products were obtained
in ratio of 14:1 and 20:1 in excellent yields. The yields of
Supporting Information Available: Experimental details. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA905452F
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