A stereocontrolled method for the synthesis of d- and l-2-deoxy-C- nucleosides using an intramolecular Sakurai-type cyclisation reaction

Article abstract of DOI:10.1039/c0cc00467g

A novel synthetic procedure has been developed that provides access to d/l-2-deoxy-C-nucleosides from 3,4-epoxytetrahydrofuran in seven steps and in moderate to good yields. The key chemical transformation was the Lewis acid catalysed intramolecular cyclisation reaction of an acetal for which the stereochemical outcome was dependent of the reagents' ratio.

Full text of DOI:10.1039/c0cc00467g

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A stereocontrolled method for the synthesis of D- and L-2-deoxy-C-
nucleosides using an intramolecular Sakurai-type cyclisation reactionw
Rebecca R. Midtkandal,a Simon J. F. Macdonaldb and Marie E. Migaud*a
Received 18th March 2010, Accepted 26th April 2010
First published as an Advance Article on the web 20th May 2010
DOI: 10.1039/c0cc00467g
A novel synthetic procedure has been developed that provides
access to D/L-2-deoxy-C-nucleosides from 3,4-epoxytetra-
hydrofuran in seven steps and in moderate to good yields. The
key chemical transformation was the Lewis acid catalysed
intramolecular cyclisation reaction of an acetal for which the
stereochemical outcome was dependent of the reagents’ ratio.
for the biological screening of the D- and the L-2-deoxy-C-
nucleoside series.
Specifically, we report methodology towards the synthesis
of furanosyl 2-deoxy-C-nucleosides, which is
a major
extension of our research into new routes to modified nucleo-
sides.12 This novel synthetic route (Scheme 1) includes the
Lewis acid assisted formation of an oxonium ion that cyclises
to yield an exo-alkene furanose (6), used as a synthetic
intermediate. The stereochemical outcome of the cyclisation
of 5 to give 6 proves to be dependent on the Lewis acid to
substrate ratio, which makes this route a flexible tool in the
pursuit of novel C-nucleosides. The only precedent for
accessing furanose compounds via exo-alkene intermediates
is the work of Oriyama et al.13 Unfortunately, their procedure
was unsuccessful when applied to our more elaborate targets.
Instead we approached the intermediate 6 via an acetal
formation reaction that provided the necessary precursor 5.14
We began by preparing the alcohol 3 (Scheme 1), which was
achieved by treating the commercially available 3,4-epoxytetra-
hydrofuran, 1, with two equivalents of [(trimethylsilyl)methyl]-
lithium to afford the diol, 2.15 This diol could then be
selectively protected to give 3 in 89% yield (over two steps).
Rapid purification of 3 was required to prevent alkene
isomerisation. However, once isolated this species was stable
when stored at ꢀ5 1C or lower. The next step consisted of
reacting the alcohol 3 with the chloroether 4 in the presence
of a base to form the acetal 5 in 73% yield and as a mixture of
A short, versatile route to C-nucleosides which offers stereo-
control at the anomeric centre would represent a major new
addition to the syntheses of novel antiviral and/or antiproli-
ferative agents, as the discovery of such agents is critically
dependent on their synthetic accessibility. Many D-C-nucleosides
are known to have antiviral and/or antiproliferative activity,
with two well known examples being tiazofurin and benzamide
riboside.1 In addition, there has been increasing interest in
L-nucleosides, as some examples display antiviral and
antitumor activities.2,3 The current synthetic routes to D- or
L-C-nucleosides, while elegant, often require lengthy prepara-
tion of synthetic intermediates from reagents of pre-defined
chirality, which limits the versatility and range of possible
synthetic targets.4–8 The syntheses of 2-deoxy-C-nucleosides
have proven to be even more challenging with regards to
controlling the stereochemistry at the ‘‘anomeric’’ centre,
with little flexibility with regards to the overall molecular
chirality.9–11 We describe here a route which provides access
to such C-nucleosides and which has the advantage of starting
from non-carbohydrate-based reagents. This route gives access
to both enantiomeric series simultaneously and availability
diastereomers.14 The chloroether
4 was prepared from
the corresponding dimethylacetal in a reaction with acetyl
chloride and thionyl chloride.16 It was expected that the
acetal 5, when exposed to Lewis acid conditions, would cyclise
to form the exo-alkene C-nucleoside intermediate 6.14
a Queen’s University Belfast, School of Chemistry and Chemical
Engineering, Belfast, BT9 5AG, UK. E-mail: m.migaud@qub.ac.uk
b GlaxoSmithKline, Stevenage Pharmaceuticals R&D facility, Gunnels
Wood Road, Stevenage, Herts, SG1 2NY, UK
w Electronic supplementary information (ESI) available: Additional
information on experimental details and exemplar NMR spectra. See
DOI: 10.1039/c0cc00467g
Of the Lewis acids screened, only TMSNTf2 yielded the
cyclised product 6. Lewis acids that did not yield any of the
desired product included SnCl2 and AcCl (the preferred
Scheme 1 A novel synthetic route to D/L-C-nucleosides.
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catalyst in Oriyama’s reaction),13 AlCl3, BF3ꢂOEt2, Sn(NTf2)2,
Sn(OTf)2, TMSOTf, nBu3SnNTf2 and HNTf2.
Table 1, entry 1, gives the result of the initial cyclisation
reaction that was carried out with 0.1 molar equivalents of
TMSNTf2 relative to the acetal 5. This resulted in the
formation of 6 in 29% yield after 1 hour, with a diastereomeric
ratio of 1 : 2 6a (cis) : 6b (trans). The stereochemistry was
confirmed by NOE experiments (Fig. 1).
Table 1 Optimisation of the cyclisation reaction of the acetal 5
Entry Equiv. LA Temp./1C Yield 6 (%) dr 6a : 6bc Reaction time
1
2
3
4
5
6
7
0.1
1.0
2.0
5.0
2.0
0.25
2.0
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
0
29a
40a
43a
0a
1 : 2
1 : 2
2 : 1
—
2 : 1
1 : 2
—
1 h
1 h
5 min
5 min
5 min
1 h
72b
70b
0b
0
5 min
a
b
Aqueous workup. Workup by filtration. Ratio measured in the
c
Scheme 2 Proposed cyclisation transition states.
1H-NMR spectrum of the mixture of diastereomers after purification.
D- and L-2-deoxy-C-nucleosides isolated. Using this method
mixtures of biologically relevant D- and L-deoxy-C-nucleosides
can be separated as the final step of this synthetic sequence,
making it possible to access multiple target molecules for
biological screening simultaneously.
We hypothesise that this cyclisation proceeds via an
oxonium ion 10 (Scheme 2) and we rationalise the relationship
between the stereoselectivity of the cyclisation and the
stoichiometry of the Lewis acid as follows: the oxonium ion
10 was generated by the Lewis acid assisted removal of the
methoxy group from 5, and an intramolecular Sakurai-type
cyclisation17 of this intermediate yielded 6. One equivalent or
less of Lewis acid in the reaction required regeneration of the
Lewis acid. If the cyclisation occurred at a faster rate than the
Lewis acid regeneration, it was unlikely that the Lewis acid
could participate in the cyclisation itself. The outcome of the
reaction would then depend on the activation energy for the
transition states leading to the two diastereomers 6a and 6b.
As the trans configuration between the phenyl substituent and
the silyl protected O-methylene (shown with red colour in
Scheme 2) allowed for the furthest distance between the two
relatively large substituents, it was anticipated that the
activation energy for this configuration was lower, leading to
6b as the major product. In addition, as shown in Fig. 2,
hydrogen bonding could occur between the silyl protected
oxygen and the hydrogen shown in red.18,19 This would favour
the trans configuration.
Fig. 1 NOE effects.
In an attempt to improve the yield of the cyclisation, in
entry 2 the amount of Lewis acid was increased from 0.1 to
1.0 molar equivalents, with only an 11% increase in yield. In
entry 3 the amount of Lewis acid was again increased, now to
2.0 molar equivalents, which resulted in reduction of the
reaction time to 5 minutes, inversion of the diastereoisomeric
ratio and 43% yield. Attempting in entry 4 to increase the
amount of Lewis acid further, to 5 molar equivalents, did not
give any product formation. However, once the optimised
workup conditions were identified, reaction yields were
improved significantly. In entry 5 the aqueous extraction used
previously was abandoned and replaced with direct filtration
of the reaction mixture through a short pad of silica gel. This
increased the yield of 6 to 72%, retaining the diastereomeric
ratio of 2 : 1, cis : trans. In entries 6 and 7 the temperature
was raised to 0 1C. Using 0.25 molar equivalents of Lewis acid
in entry 6 gave a 70% yield of 6. In entry 7, 2.0 molar
equivalents Lewis acid gave no product, showing that to
obtain a 2 : 1 ratio cis : trans a temperature of ꢀ78 1C is
required.
For reactions employing two equivalents of Lewis acid, one
equivalent could remove the methoxy group from 5 to form
10, and the other could then complex the initial transition state
and break the previously formed hydrogen bond. As a
consequence, it could be anticipated that the energy required
to form the cis diastereomer was lowered, and this resulted in
Once the exo-alkene furanose intermediate was accessed, the
cis diastereomer, 6a, was converted to 7 by ozonolysis. The
silyl ether was then deprotected to give the free alcohol 8 in
order to facilitate stereoselective reduction of the ketone. This
deprotection was conducted under acidic conditions, as the
standard fluoride-based methods resulted in epimerisation of
the stereocenter adjacent to the ketone. Selective reduction of
the ketone yielded the D/L-2-deoxy-C-nucleoside 9. The race-
mate mixture has been separated using chiral HPLC and the
Fig. 2 Possible hydrogen bonding within a proposed transition state.
Chem. Commun., 2010, 46, 4538–4540 | 4539
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an increased formation of 6a versus 6b under these conditions.
The acetal 5 was formed from 3 with a diastereomeric ratio of
1 : 1. As the acetal stereocenter was destroyed in the forma-
tion of the intermediate 10, no attempt was made to adjust the
ratio of diastereomers as the outcome of the cyclisation step
did not depend on this ratio. This was confirmed by carrying
out the cyclisation reaction on the separated diastereomers of
5 as well as the 1 : 1 mixture. No difference in outcome of the
cyclisation reaction was observed.
In conclusion,
a
new synthetic procedure has been
developed that provides access to D/L-2-deoxy-C-nucleosides
in moderate to good yields. This powerful route provides
separable diastereomeric mixtures of C-nucleoside inter-
mediates, which can be produced with either diastereomer in
excess by simply varying the amount of Lewis acid used in the
key cyclisation step. This, combined with the option of
separating enantiomers after completing the synthesis, makes
this a divergent route suitable for accessing a wide range of
synthetic biologically relevant targets. As such, this method is
a valuable addition to the existing pool of synthetic procedures
to access D/L-2-deoxy-C-nucleosides.
To establish the scope of this method, a selection of
analogues of the cyclised compound 6 were prepared, where
the aromatic moiety has been varied (Table 2).
This work was supported by an FP6 EST-Marie Curie
Scholarship and GlaxoSmithKline (Stevenage, UK). We
would like to thank Eric Hortense and Jolanta Haluszczak
for help separating the racemate at GSK.
Table 2 The exo-alkene furanosides prepared
Notes and references
z Details of this conversion and experimental data to be found in
ESI.w
Yield
12 (%)
Yield
13 (%)
dr 13
cis : transa
Analogue
a
R
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a
Ratio measured in the 1H-NMR spectrum of the mixture of
b
diastereomers after purification. Based on H-NMR only.
1
It is thought that the difference in yield between 13a and 13b
is due to difference in electronic properties of a halogen being
in meta versus para positions on a phenyl ring. 13a was
converted to the 2-deoxy-C-nucleoside using the route
presented for 9 and in similar yields indicating that the
sequence can be applied to functionalised aromatics.z This
demonstrates the scope of this method which provides a route
to a variety of C-nucleoside intermediates not accessed
previously and that is amiable to divergent library syntheses.
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This journal is The Royal Society of Chemistry 2010
4540 | Chem. Commun., 2010, 46, 4538–4540