Synthesis of bicyclic nucleosides by ring-closing metathesis

Article abstract of DOI:10.1039/b101364p

The ring-closing metathesis method is applied in the construction of conformationally restricted bicyclic nucleosides. From diacetone-D-glucose, the unsaturated bicyclic carbohydrate derivative 11 is efficiently obtained through two vinyl group Grignard a

Full text of DOI:10.1039/b101364p

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Synthesis of bicyclic nucleosides by ring-closing metathesis
Jacob Ravn and Poul Nielsen*
Department of Chemistry, University of Southern Denmark, Odense University,
5230 Odense M, Denmark
1
Received (in Cambridge, UK) 12th February 2001, Accepted 15th March 2001
First published as an Advance Article on the web 6th April 2001
The ring-closing metathesis method is applied in the construction of conformationally restricted bicyclic nucleosides.
From diacetone--glucose, the unsaturated bicyclic carbohydrate derivative 11 is efficiently obtained through two
vinyl group Grignard additions, subsequent metathesis of the double bonds, and resolution of the stereochemistry by
an oxidation/reduction reaction sequence. Two separate routes differing in the 3-O-protecting group are compared.
Thus, an additional protecting step improves the yields significantly. Standard conversions of 11 give the bicyclic
nucleoside 22 containing an olefinic moiety with a high potential for further functionalisation. As examples, two
simple bicyclic ribo-nucleoside analogues 4 and 5, which are restricted to the unusual South-type conformations,
are synthesised.
siderable attention during the last few years.3–5 In particular,
Introduction
nucleoside analogues with bicyclic carbohydrate moieties have
The natural nucleosides of DNA and RNA are known to exist
been designed as potential antiviral agents3 and as the
in an equilibrium between two major conformers, the North
monomers in conformationally restricted oligonucleotide
(N) and the South (S) types (Fig. 1).1 This conformational
behaviour forms the basis of the two major double-helical struc-
tures, the A- and B-forms. The N-type (3Ј-endo) conformations
are preferred by the ribo-nucleosides found in RNA and result
in A-form duplexes, whereas the S-type (2Ј-endo) conform-
ations give B-form duplexes as adopted by the 2Ј-deoxy-
sequences.4,5 Due to the decrease in conformational freedom
introduced by the bicyclic nucleosides, these oligonucleotides
have displayed very promising results as compounds with
improved recognition of complementary RNA and DNA
sequences.4,5 As a pioneer example, the bicyclic nucleosides 1
(Fig. 1) were synthesised by Leumann and co-workers and
nucleosides found in most DNA sequences.1 Furthermore, this
incorporated into oligonucleotides.6–9 The nucleoside structure
conformational equilibrium of nucleosides is considered as
1 is known to prefer an S-type conformation,6 but the torsion
essential for many other biological functions including the
angle γ describing the C-4Ј–C-5Ј bond1 is found to prefer the
binding to nucleoside/nucleotide-converting enzymes.1,2
ϩac/ϩap range,6 which is not the preferred range in A- and
Conformational restriction of nucleosides has received con-
B-type duplex structures.1 Thus, oligomers containing
exclusively 1 are found to prefer Hoogsteen base-pairing over
the normal Watson–Crick base-pairing.8 In general, the binding
affinities towards complementary nucleic acid sequences were
slightly improved compared to unmodified oligodeoxynucleo-
tides but very dependent on the nucleotide sequences.7,8
Improved binding affinities have been introduced with a tri-
cyclic analogue of 1 in which γ is restricted into the less
unfavourable ϩac range.10
After the introduction of 1, several bicyclic nucleoside
analogues have been synthesised and investigated as building
blocks in oligonucleotide sequences.5 The best results concern-
ing the hybridisation with complementary RNA have been
obtained with nucleoside analogues restricted to N-type con-
formations.4,5 As a prime example, oligonucleotides containing
the nucleosides 3 (Fig. 1) are known as LNA (Locked Nucleic
Acids) and display very strong recognition of both RNA and
DNA.11 As other examples, two different bicyclic carbocyclic
nucleosides, the so-called methanocarba nucleosides, restricted
to either S- or N-type conformations have been presented and
used in several studies on oligonucleotides12 as well as on the
conformational preferences of the substrates in nucleoside/
nucleotide-converting enzymes and nucleoside-recognising
receptors.13
Also, bi- and tricyclic nucleosides with conformations in
between N- and S-type conformations have been presented.14–16
As an example, nucleoside 2 (Fig. 1) has been incorporated into
oligonucleotides displaying enhanced affinity towards RNA in
a fully modified sequence.14 This nucleoside has been suggested
Fig. 1 (a) Conformational equilibrium of nucleosides. (b) Examples
of bicyclic nucleosides.
to prefer an O-4Ј-endo, East (E) type1 conformation,16 which
DOI: 10.1039/b101364p
J. Chem. Soc., Perkin Trans. 1, 2001, 985–993
This journal is © The Royal Society of Chemistry 2001
985

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has been further confirmed by X-ray17 as well as NMR studies
on duplex structures containing 2.18
Here we present a simple synthesis of new bicyclic nucleo-
sides taking advantage of a ring-closing metathesis (RCM)
reaction. This technology has recently achieved considerable
attention for its convenient and widespread synthetic appli-
cations.19 In particular, the introduction of Grubbs’ catalyst
A as a very stable, efficient and functional group-tolerant
catalyst19 prompted us to investigate the use of the RCM reac-
tion in the construction of bicyclic nucleosides containing
olefinic moieties. Thus, we hereby introduce a conformational
restriction into the natural nucleoside structure by incorpor-
ating an unsaturated bridge between C-3Ј and C-5Ј. A protected
bicyclic nucleoside intermediate 22 is synthesised and con-
sidered as a key compound in the construction of other func-
tionalised bi- or tricyclic nucleosides for potential applications
in oligonucleotide sequences or as antiviral compounds. As the
first examples, the simple bicyclic nucleosides 4 and 5, which are
conformationally restricted ribo-nucleoside analogues and close
derivatives of the first bicyclic 2Ј-deoxynucleosides 1, are hereby
presented.
Scheme 1 Reagents and conditions: i, NaIO4, aq. MeOH; ii, vinyl-
MgBr, THF; iii, Grubbs’ catalyst A, CH2Cl2; iv, PCC, CH2Cl2; v,
NaBH4, CeCl3ؒ7H2O, MeOH; vi, BnBr, NaH, DMF; vii, Ac2O,
pyridine.
Results
Chemical synthesis
field and the signal overlap was decreased. From the NOE-
difference spectra of 12 a weak mutual contact between H-5
and H-1 was observed, confirming the C-5 configuration. From
the NOE-difference spectra of 9, the lack of any contacts
between H-5 and H-1/H-2 indicates the opposite C-5 configur-
ation. In combination, the coupling constants and NOE
experiments confirm the stereochemical determinations of
compounds 8–12.
The 3Ј-C-vinylallose derivative 6 was obtained from diacetone-
-glucose using oxidation, a stereoselective Grignard reaction
and a selective deprotection following a known procedure
(Scheme 1).20 This vicinal diol was cleaved to give an aldehyde
which was used without purification as a substrate in a second
Grignard addition using vinylmagnesium bromide. This
afforded the product 7 as an epimeric mixture in a 1 : 3 ratio
and in 57% yield. The aldehyde was also obtained by in situ
deprotection of the primary acetonide and diol oxidation using
periodic acid following a protocol by Robins et al.21 However, in
the present example this method did not improve the overall
yield of 7. The diastereomers of 7 were not separated but used
directly in an RCM reaction using Grubbs’ catalyst A. This
reaction afforded smoothly the two tricyclic compounds 8 and
9 in 24 and 67% yield, respectively, after chromatographic
separation. The reaction products were not analytically pure
at this stage due to remains of the ruthenium catalyst, but after
a subsequent benzylation the protected analogues 10 and 11
were obtained as pure compounds and in acceptable yields (70
and 80%, respectively). Attempts to obtain analytically pure
RCM products using a lead additive22 or tris(hydroxymethyl)-
phosphine23 failed in this case.
Even though the major isomer 9 has the preferred C-5 con-
figuration we converted the other isomer 8 to give 9 in two steps
using a mild oxidation followed by a selective reduction using
Luche conditions24 in order to avoid any 1,4-hydride addition
on the intermediate α,β-unsaturated ketone. Due to the struc-
ture of the tricyclic system the boron hydride could only
approach the ketone from the convex site thereby affording 9 as
the only product in 73% yield over the two steps. This further
confirmed our determination of the configurations of 8 and 9.
In the present synthesis of the key compound 11 (Scheme 1),
the second Grignard addition could be considered as the yield-
limiting step. Therefore, we decided to improve this by protec-
ting the tertiary alcohol moiety of the starting material before
the second Grignard reaction. Thus, compound 1320 was con-
verted to the benzyl ether 1425 in 97% yield (Scheme 2). In this
case, the combined selective cleavage/oxidation method using
periodic acid21 was superior and the subsequent Grignard
addition gave the epimers 15 and 16 in a 4 : 1 ratio and a signifi-
cantly higher (88%) yield over the two steps. The epimers were
separated, and an RCM reaction using Grubbs’ catalyst A and
the major product 15 as the substrate afforded smoothly the
product 17 in 79% yield. However, double the amount of
catalyst (10 mol%) was necessary in order to finish the reac-
tion. Benzylation of 17 afforded a product which was found to
be 10, determined beforehand to have the wrong C-5 configur-
ation (vide supra). Thus, the ratio of the Grignard addition has
in fact been inverted from a 1 : 3 ratio to a 4 : 1 ratio in favour
of the opposite isomer by using the 3-O-protected starting
material. Nevertheless, 17 was very efficiently converted to the
The stereochemistry of the two epimeric compounds 10 and
1
3
11 was solved via H NMR using JHH coupling constants as
well as NOE experiments. Thus, in the constrained ring systems
the small 3JH4H5 coupling constants (<1 Hz and 2.5 Hz for 8 and
10, respectively) indicate the trans-position of the hydrogens
in accordance with torsion angles near 90Њ, whereas the larger
3JH4H5 coupling constants (4.6 Hz for 9, not determined for 11)
indicate the corresponding cis-position of the hydrogens in
accordance with smaller torsion angles. For further confirm-
ation of the configurations, NOE experiments were performed.
Due to significant overlap of signals in both 8 and 10, however,
no useful NOE-difference spectra were obtained and, instead,
the hydroxy groups of 8 were esterified to give the diacetylated
compound 12. As expected, the H-5 signal was shifted down-
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J. Chem. Soc., Perkin Trans. 1, 2001, 985–993

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Fig. 2 Different chelations explaining the stereoselectivity in the
Grignard reactions.
result, 1,2-dichloroethane was used as solvent and the reaction
temperature was elevated. However, in that case only 19 was
obtained, in 67% yield. Nevertheless, the recent introduction of
the improved catalyst B,29 vide supra, prompted us to use this in
an improvement of the reaction. Fortunately, the reaction gave
smoothly the expected product 18 in a very high (88%) yield.
These results remain unexplained but confirm the reported effi-
ciency of the improved Grubbs’ catalyst B.29,30 Problematic
RCM reactions with terminal allylic benzyl ethers using catalyst
A have been reported before19 and B has in general been
recognised as a much more reactive metathesis catalyst.19,30
The key intermediate 11 was hydrolysed and acetylated
to give in 85% yield the anomeric mixture of 20 in a ≈1 : 1
ratio (Scheme 3). This mixture was coupled to thymine in a
Scheme 2 Reagents and conditions: i, BnBr, NaH, DMF; ii, H5IO6,
EtOAc; iii, vinylMgBr, THF; iv, Grubbs’ catalyst A, CH2Cl2; v, PCC,
CH2Cl2; vi, NaBH4, CeCl3ؒ7H2O, MeOH; vii, Grubbs’ catalyst A,
ClCH2CH2Cl; viii, Grubbs’ catalyst B, CH2Cl2.
other and preferred epimer 18 in 93% yield using the same
oxidation and selective reduction sequence as in the conversion
of 8 to 9. Subsequently, 18 was as expected easily benzylated to
give the key compound 11 in 97% yield.
The observed change in the stereoselectivity between the
different Grignard reactions might find some preliminary
explanation from the ability of the divalent magnesium ion
from the coexisting magnesium bromide to co-ordinate with
two different oxygens. Thus, the magnesium ion can co-ordinate
with the carbonyl oxygen as well as with either the 3-oxygen in a
β-chelation or the ring oxygen in an α-chelation (Fig. 2).26
In the former case, the carbonyl group would be orientated
towards nucleophilic attack from the re-face, giving predomin-
ately the 5(R)-product as in 16, whereas the latter chelation type
would orientate the carbonyl group towards attack from
the si-face, giving predominantly the 5(S)-product as in 15.
Thus, when the Grignard reaction is performed without a
3-O-protecting group, a 3-oxyanion is formed and a strong
β-chelation involving this anion and magnesium explains the
favouring of the 5(R)-product in 7. With the alternative 3-benzyl
ether, an α-chelation with magnesium is preferred and the
5(S)-product 15 is favoured.
The minor product of the last Grignard reaction, 16, was
also used in an RCM reaction using Grubbs’ catalyst A in
refluxing dichloromethane but, surprisingly, afforded a mix-
ture of products from which only 10% of the expected product
18 was isolated. The major product was isolated in 33% yield
and from NMR determined to be 19. Thus, an ABX3 system
was identified, and chemical shifts further verified an ethyl
ketone group. This isomerisation of allylic alcohols has been
reported before using other ruthenium catalysts27 and as a side
reaction in metathesis reactions.28 In an attempt to improve this
Scheme 3 Reagents and conditions: i, 80% AcOH; ii, Ac2O, pyridine;
iii, thymine, N,O-bis(trimethylsilyl)acetamide, TMS triflate, CH3CN;
iv, MeONa, MeOH; v, BCl3, hexane, CH2Cl2; vi, H2, Pd(OH)2–C,
MeOH; vii, C6F5OC(᎐S)Cl, DMAP, CH2Cl2; viii, AIBN, Bu3SnH,
᎐
benzene; ix, H2, Pd(OH)2–C, cyclohexa-1,4-diene, MeOH.
modified Vorbrüggen-type nucleobase coupling reaction. Due
to anchimeric assistance the β-nucleoside 21 was, as expected,
obtained as the only product. This was easily deacetylated to
give the bicyclic key nucleoside 22 in 88% yield from 20.
The nucleoside 22 has wide further potential for diverse and
selective chemical treatments of the 2Ј-hydroxylic and/or the
olefinic functionalities. However, the structure of 22 had to be
exclusively confirmed and, therefore, we decided first to explore
the obvious conversion of 22 into the original bicyclic nucleo-
side 1 (Base = thymine). Thus, the secondary alcohol moiety
was converted to a thionocarbonate ester 23 as a precursor for a
deoxygenation reaction. However, this reaction afforded only a
20% yield of the product in combination with uncharacterised
side products. Nevertheless, 23 was treated with tributyltin
hydride and a radical initiator to give the 2Ј-deoxynucleoside
derivative 24 in a medium (50%) yield. As double bonds have
J. Chem. Soc., Perkin Trans. 1, 2001, 985–993
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been reduced before with cyclohexa-1,4-diene as the hydrogen
donor,31 we treated 24 with both cyclohexadiene and hydrogen
simultaneously, and the deprotected as well as saturated target
compound 1 (Base = thymine) was obtained in 61% yield. The
structure was confirmed by comparison of all NMR data with
the corresponding literature data.6 The present synthesis of 1
from 22 was performed in a low overall yield. However, the
structure of 22 including the C-5Ј configuration has been
exclusively confirmed.
geometry optimisations at the 3-21G* level found that the
E-type conformation is not a low-energy conformation. Thus,
the only low-energy conformation found that complies with the
experimental data is a perfect S-type conformation with P =
180Њ, Φmax1 = 33Њ and θH4ЈH5Ј = Ϫ31Њ corresponding to a γ ≈ 89Њ.
Another low-energy conformation, with P = 1Њ, Φmax = 32Њ and
θH4ЈH5Ј = 25Њ, was found. However, this N-type conformation
3
can be entirely excluded from the large JH1ЈH2Ј coupling
constant (vide supra).
In order to obtain the two deprotected derivatives 4 and 5,
the bicyclic nucleoside 22 was treated with hydrogen and a
palladium catalyst. This afforded smoothly the deprotected as
well as saturated nucleoside 5 in 98% yield. The unsaturated
deprotected bicyclic nucleoside 4 was obtained in 82% yield by
the use of a strong Lewis acid for cleavage of the benzylic
ethers.
Discussion
In the present synthetic work, the RCM methodology has been
successfully applied to the construction of bicyclic nucleosides.
As expected, the RCM method has been very efficient in the
construction of the cyclopentene ring. With the more efficient
catalyst B, the problem with an unexpected isomerisation of the
substrate 16 was also solved. Thus, an unsaturated tricyclic
carbohydrate derivative 11 has been efficiently obtained and
converted through 20 to a bicyclic unsaturated key nucleoside
22. Overall, 22 was obtained in high yields using either of
the two synthetic routes. Thus, 22 was obtained in 11 steps and
17% yield from diacetone--glucose following the first route
(Schemes 1 and 3) and 22% including the use of the isomer 8.
However, following the other route (Schemes 2 and 3), which
includes an additional protecting step, 22 was obtained in 13
steps and 36% yield when all of the material of 18 obtained
through 17 as well as through the efficient RCM reaction
performed on 16 was included. The reaction sequence might, in
theory, be even further improved, if the separation of 15 and 16
were avoided and the RCM reaction performed on the mixture
of these using the improved catalyst B. Subsequently, an
oxidation/reduction procedure on the mixture of 17 and 18
would give exclusively 18. Hereby, this synthetic strategy would
present a highly stereoselective route with no need for tedious
separations of isomers. Of course, other nucleobases are
expected to react stereoselectively with 20. Thus, the strategy
opens an obvious potential for similar bicyclic derivatives of
other nucleosides.
Conformational behaviour
In order to study the conformational behaviour of the bicyclic
3
nucleosides 4 and 5, the experimental JHH coupling constants
contain a fair amount of information. Thus, 3JH1ЈH2Ј was found
to be 7.3 and 8.5 Hz for 4 and 5, respectively. These large coup-
ling constants prove both nucleosides to adopt (at least broadly
defined) S-type conformations according to the Karplus
relationship between 3JH1ЈH2Ј and the pseudorotation angle P.1,32
Thus, for 4 the coupling constant correlates with a pseudo-
rotation angle in either of two possible ranges 90–110Њ or 180–
200Њ. For 5, the pseudorotation angle is in the range 110–180Њ.32
This is in agreement with the nucleoside 1 (Base = thymine)
which, likewise, has been found to adopt an S-type conform-
ation with P = 128Њ as found by X-ray crystallography.6 As
found for 1 and other bi- and tricyclic nucleosides6,16 we believe
both 4 and 5 to exist in only one conformation each and not as
dynamic equilibria between two or more conformers.
3
Also the JH4ЈH5Ј coupling constants contain useful inform-
ation and were found to be 5.8 and 5.1 Hz for 4 and 5, respec-
3
tively. From a Karplus relationship between JH4ЈH5Ј and the
torsion angle θH4ЈH5Ј,
16,32 both these coupling constants comply
with four different ranges of θH4ЈH5Ј of which two can be
excluded due to the covalent geometry. Thus, θH4ЈH5Ј could for
both nucleosides be found in the range around 30Њ as well as
around Ϫ30Њ corresponding to γ of around 150Њ or 90Њ, respec-
tively. For 1 (Base = thymine) this torsion angle γ was found
from X-ray crystallography to be 149Њ and the coupling con-
The present synthetic strategy was not meant as an improved
synthetic route towards the known and intensively investi-
gated6–8 bicyclic nucleosides 1. Therefore, we did not put any
effort into improving the disappointing yields of 23 and 24.
However, this might after all present an improved synthetic
strategy compared to the completely different synthesis of 1
published by Leumann and co-workers6 if the deoxygenation
procedure could be significantly optimised. It might also be
preferable to perform the hydrogenation of the double bond
before the deoxygenation process.
In our synthetic strategy, it was a main purpose to obtain a
key bicyclic nucleoside compound 22 with the potential of
treating the double bond and the 2Ј-hydroxy group independ-
ently and without affecting the 5Ј- and 3Ј-hydroxy groups.
Therefore, we did not optimise the protecting-group strategy for
the specific syntheses of 4 and 5 as this, obviously, suggests
the general use of, e.g., acetic esters instead of benzyl ethers.
The nucleoside 22 can be considered as a key compound in the
development of other bi- and tricyclic nucleoside analogues.
Thus, the olefinic moiety is new in the construction of bicyclic
nucleosides and opens a wide potential of derivatisation, reveal-
ing, e.g., alcohols and amines as well as additional ring systems.
Thus, as an example the introduction of amino groups into
bicyclic nucleosides and oligonucleotides as presented recently
by Leumann and co-workers9 gives the possibility of studying
the hybridisation behaviour of zwitterionic oligonucleotides.
The two deprotected nucleosides 4 and 5 represent new
conformationally restricted ribo-nucleoside analogues. Even
though the conformational analysis has not been very com-
prehensive, our experimental data suggest the nucleoside 5 to
adopt a conformation closely resembling the conformation of 1
3
stant JH4ЈH5Ј was 5.3 Hz.6 As it seems probable that the
cyclopentane ring should behave similarly in both 1 and 5, we
expect γ of the ribo-nucleoside 5 to be in the same ϩac/
ϩap range (γ ≈ 150Њ) as for its 2Ј-deoxy analogue 1. With the
furanose in the same S-type (1Ј-exo)1 conformation as for 1,6
both five-membered rings adopt envelope conformations as
found for other bicyclic [3.3.0] nucleoside systems, e.g. 2.16
Due to the greater constraint in the cyclopentene ring of 4
compared to the cyclopentane ring of 5, the unsaturated
nucleoside 4 is expected to be more conformationally restricted
than 5. The cyclopentene ring must take an envelope form with
C-4Ј flipping out of the plane. Hence, one of these flips would
drive the furanose ring towards the S-type conformation,
whereas the other could twist the furanose ring into an E-type
or N-type conformation. The E-type is an unusual high-energy
conformation in unmodified nucleosides1 but has been found to
be the preferred furanose conformation in other bicyclic, e.g. 2,
3
and tricyclic nucleoside analogues.16 The JH1ЈH2Ј coupling con-
stant of 4 complies with both an E-type conformation with P in
the 90–110Њ range and a high S-type with P in the 180–200Њ
range (vide supra). The former corresponds to a θH4ЈH5Ј ≈ 30Њ
and a γ ≈ 150Њ, whereas the latter corresponds to a θH4ЈH5Ј ≈ Ϫ30Њ
and a γ ≈ 90Њ. Thus, both of the two different conformations
comply with the experimental coupling constants. However,
from ab initio calculations using the Gaussian94 program,33
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J. Chem. Soc., Perkin Trans. 1, 2001, 985–993

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with γ in the ϩac/ϩap range and the furanose ring in an S-type
(1Ј-exo) conformation. On the other hand, the nucleoside 4
adopts a ‘higher’ S-type (2Ј-endo) conformation and with γ in
the ϩsc/ϩac range. However, neither 4 nor 5 has the same
degree of conformational restriction as, e.g., the nucleoside 3,
which is perfectly locked in an N-type (3Ј-endo) conformation.11
Nevertheless, both 4 and 5 can be considered as ribo-nucleoside
analogues which are conformationally restricted towards the
S-type conformations. For unmodified ribo-nucleosides this
conformation is the less favoured in the equilibrium with the
N-type conformations.1 Therefore, 5 and perhaps to a higher
degree 4 and/or analogues of these with other nucleobases
might have interesting biological properties and might, e.g., find
useful applications as tools in the studies of conformational
preferences and structure–activity relations in nucleoside/
nucleotide-converting enzymes. On the other hand, we do not
expect these ribo-nucleosides to improve the affinity of
their corresponding oligonucleotides towards complementary
nucleic acid sequences. Thus, the restriction in an S-type con-
formation demands the formation of a B-type helix but also
brings the 2Ј-OH group towards a pseudoequatorial position
which might give rise to steric interference in B-type duplex
formation. However, at least for 4 the torsion angle γ prefers the
ϩsc/ϩac range which is much more typically found in duplex
structures compared to the ϩac/ϩap range of 1 and 5.1
Thus, oligodeoxynucleotides containing the 2Ј-deoxy analogue
of 4 might reveal significant improvements in hybridisation
properties compared to the original oligomers of 1.
at The Microanalytical Laboratory, Department of Chemistry,
University of Copenhagen.
(5R/S)-6,7-Dideoxy-1,2-di-O-isopropylidene-C-vinyl-ꢀ-D-
ribohept-6-enofuranose 7
To a solution of triol 620 (3.18 g, 12.7 mmol) in MeOH (25 cm3)
and water (25 cm3) was added NaIO4 (3.0 g, 14.0 mmol) and the
reaction mixture was stirred at room temperature for 30 min.
The white precipitate was filtered off and the solvent was partly
removed in vacuo. The residue was continuously extracted with
CH2Cl2 (150 cm3) overnight and the organic extract was dried
(MgSO4), and then concentrated in vacuo. The residue was
re-dissolved in anhydrous tetrahydrofuran (THF) (100 cm3)
and the solution was cooled to 0 ЊC. A 1 M solution of vinyl-
magnesium bromide in THF (30 cm3, 30 mmol) was added
dropwise over a period of 30 min and the mixture was stirred at
room temperature for 16 h. Water (250 cm3) was added and the
solution was neutralised with 4 M acetic acid. The solvent was
partly removed in vacuo and the residue was extracted with
CH2Cl2 (3 × 100 cm3). The combined organic extracts were
washed with saturated aq. NaHCO3 (2 × 100 cm3) and then
dried (MgSO4). The solvent was removed by distillation under
reduced pressure, and the residue was purified by silica gel
column chromatography (CH2Cl2–MeOH 96 : 4, v/v) to give
the mixture of diastereomers 7 (1.74 g, 57%, R/S 3 : 1) as a
white solid (Found: C, 59.74; H, 7.62. C12H18O5 requires C,
59.49; H, 7.49%); δH (CDCl3) 1.38 (s, CH3), 1.61 (s, CH3), 2.32
(m, 5-OH), 2.77 [s, 3-OH(S)], 3.09 [s, 3-OH(R)], 3.73 (m, 4-H),
4.20 (m, 5-H), 4.26 (m, 2-H), 5.20–5.46 (m, CH᎐CH ), 5.51–5.68
᎐
2
Conclusions
(m, CH᎐CH ), 5.80–6.04 (m, CH᎐CH ); δ (CDCl ) 26.5, 71.0,
᎐
᎐
2
2
C
3
71.2, 81.0, 82.2, 83.4, 84.1, 84.8, 103.1, 103.5, 113.0, 116.2, 116.3,
We have developed a novel and very convenient synthetic
strategy towards new bicyclic nucleosides taking advantage of
stereoselective methods as well as the RCM methodology and
starting from a very cheap starting material. Hereby, two
bicyclic ribo-nucleosides 4 and 5 have been obtained. These
nucleosides are expected to be useful tools as restricted
analogues of the natural ribo-nucleosides and to display
interesting biological properties. The use of the protected
bicyclic nucleoside derivative 22 in the construction of other
derivatised, bicyclic and/or tricyclic nucleosides as well as
further applications of the RCM method in the construction
of nucleoside and nucleotide derivatives are in progress in our
laboratory.
116.6, 116.8, 134.0, 134.0, 135.2, 137.3; EI-MS m/z 242 [Mϩ].
(9S)- and (9R)-(1R,2R,6R,8R)-1,9-Dihydroxy-4,4-dimethyl-
3,5,7-trioxatricyclo[6.3.0.02,6]undec-10-ene 8 and 9
To a solution of 7 (1.37 g, 5.66 mmol) in anhydrous CH2Cl2
(60 cm3) was added A (286 mg, 0.33 mmol) and the mixture was
stirred at room temperature for 16 h and then at 40 ЊC for 3 h.
The solvent was removed by distillation under reduced pressure,
and the residue was purified by silica gel column chromato-
graphy (CH2Cl2–MeOH 96 : 4, v/v) to give the two products 8
(294 mg, 24%) and 9 (801 mg, 67%) as darkly coloured solids
which were used without further purification.
(1R,2R,6R,8R,9S)-1,9-Dihydroxy-4,4-dimethyl-3,5,7-trioxa-
tricyclo[6.3.0.02,6]undec-10-ene 8. δH (CDCl3) 1.40 (3H, s, CH3),
1.62 (3H, s, CH3), 3.76 (1H, s, OH), 3.88 (1H, s, OH), 4.29 (1H,
app. s, 4-H), 4.46 (1H, app. s, 5-H), 4.46 (1H, d, J 3.6, 2-H), 5.71
(1H, d, J 3.6, 1-H), 5.81 (1H, d, J 5.7, 7-H), 6.08 (1H, dd, J 5.7
and 1.1, 6-H); δC (CDCl3) 27.2, 27.4, 79.4, 81.4, 89.1, 90.8,
105.6, 113.0, 134.8, 137.3; EI-MS m/z 214 [Mϩ].
Experimental
All commercial reagents were used as supplied. Light petroleum
refers to the fraction with distillation range 60–80 ЊC. All
reactions were performed under an atmosphere of nitrogen.
Column chromatography was carried out on glass columns
using silica gel 60 (0.040–0.063 mm). NMR spectra were
obtained on a Bruker AC250, a Varian Gemini 2000 or a Varian
Unity 500 spectrometer. 1H NMR spectra were recorded at 250
MHz, 300 MHz or 500 MHz and 13C NMR spectra were
recorded at 62.5 MHz or 75 MHz. Values for δ are in ppm
relative to tetramethylsilane as internal standard. J-Values are
in Hz. 1H1H-COSY spectra were recorded for compounds 4, 5,
8, 11, 12, 15, 16 and 19. 1H NOE-difference spectra were
(1R,2R,6R,8R,9R)-1,9-Dihydroxy-4,4-dimethyl-3,5,7-trioxa-
tricyclo[6.3.0.02,6]undec-10-ene 9. δH (CDCl3) 1.42 (3H, s, CH3),
1.62 (3H, s, CH3), 2.60 (1H, d, J 10.2, 5-OH), 3.12 (1H, s,
3-OH), 4.36 (1H, d, J 4.6, 4-H), 4.45 (1H, d, J 3.8, 2-H), 4.95
(1H, dd, J 10.2 and 4.6, 5-H), 5.68 (1H, dd, J 5.7 and 1.4, 6-H),
5.84 (1H, d, J 3.8, 1-H), 6.03 (1H, d, J 5.7, 7-H); δC (CDCl3)
27.2, 27.2, 76.1, 83.2, 83.6, 89.5, 106.3, 113.5, 130.3, 141.0;
EI-MS m/z 214 [Mϩ].
recorded for compounds 9 and 12 and H13C-COSY spectra
1
were recorded for compounds 4, 5, 12, 15, 16 and 19. Assign-
ments of NMR signals follow standard carbohydrate and
nucleoside style. However, compound names for bi- and
tricyclic compounds are given according to von Baeyer nomen-
clature. Fast-atom bombardment (FAB) mass spectra were
recorded in positive-ion mode on a Kratos MS50TC spec-
trometer, and EI mass spectra were recorded on an SSQ710
Finnigan MAT spectrometer. High-resolution MALDI mass
determinations were performed on an Ionspec Ultima Fourier
Transform mass spectrometer. Microanalyses were performed
Alternative method for the preparation of 9
To a solution of 8 (1.75 g, 8.18 mmol) in CH2Cl2 (50 cm3) was
added pyridinium chlorochromate (PCC) (3.5 g, 16.2 mmol).
The mixture was stirred at room temperature for 14 h and the
mixture was filtered through a layer of silica. The filter was
rinsed with ethyl acetate (150 cm3), and the filtrate was concen-
trated by distillation under reduced pressure. The residue was
J. Chem. Soc., Perkin Trans. 1, 2001, 985–993
989

View Article Online
re-dissolved in MeOH (50 cm3) and treated with CeCl3ؒ7H2O
(2.98 g, 8.0 mmol). This solution was cooled to 0 ЊC, NaBH4
(405 mg, 10.7 mmol) was added in small portions, and the
mixture was stirred at 0 ЊC for 1 h. Water (50 cm3) was added
and the solution was neutralised with 4 M acetic acid and con-
tinuously extracted with CH2Cl2 (150 cm3) overnight. The
organic extracts were dried (MgSO4) and the solvent was
removed by distillation under reduced pressure. The residue was
purified by silica gel column chromatography (CH2Cl2–MeOH
96 : 4, v/v) to give the product 9 (1.28 g, 73%) as a white solid.
THF (50 cm3, 50 mmol) was added dropwise over a period of
30 min and the mixture was stirred at room temperature for 48
h. Water (350 cm3) was added and the solution was neutralised
with 4 M acetic acid. The solvent was partly removed by distil-
lation under reduced pressure and the residue was extracted
with CH2Cl2 (3 × 250 cm3). The combined organic extracts were
washed with saturated aq. NaHCO3 (2 × 300 cm3) and then
dried (MgSO4). The solvent was removed by distillation under
reduced pressure, and the residue was purified by silica gel
column chromatography (light petroleum–ethyl acetate 7 : 3,
v/v) to give the two products 15 (6.38 g, 69%) and 16 (1.70 g,
19%) as clear oils.
(1R,2R,6R,8R,9S)-1,9-Diacetoxy-4,4-dimethyl-3,5,7-trioxa-
tricyclo[6.3.0.02,6]undec-10-ene 12
(5S)-3-O-Benzyl-6,7-dideoxy-1,2-di-O-isopropylidene-3-C-
vinyl-ꢀ-D-ribo-hept-6-enofuranose 15. δH (CDCl3) 1.39 (3H, s,
CH3), 1.60 (3H, s, CH3), 2.27 (1H, br s, OH), 4.12 (1H, d, J 6.7,
4-H), 4.23 (1H, dd, J 6.7 and 5.8, 5-H), 4.59 (1H, d, J 11.3,
CH2Ph), 4.65 (1H, d, J 3.6, 2-H), 4.67 (1H, d, J 11.3, CH2Ph),
5.22 (1H, d, J 10.4, 7-Hb), 5.28 (1H, d, J 18.1, CH᎐CH ), 5.39
To a solution of 8 (149 mg, 0.696 mmol) in anhydrous pyridine
(4 cm3) was added acetic anhydride (1 cm3), and the solution
was stirred at room temperature for 16 h. The reaction mixture
was quenched with water (4 cm3) and extracted with CH2Cl2
(3 × 10 cm3). The combined extracts were washed with satur-
ated aq. NaHCO3 (2 × 10 cm3) and then dried (MgSO4). The
solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography
(CH2Cl2–MeOH 99 : 1, v/v) to give the product 12 (152 mg,
73%) as a clear oil; δH (CDCl3) 1.37 (3H, s, CH3), 1.53 (3H, s,
CH3), 2.08 (3H, s, COCH3), 2.09 (3H, s, COCH3), 4.60 (1H, s,
4-H), 4.89 (1H, d, J 4.0, 2-H), 5.38 (1H, d, J 2.5, 5-H), 5.83 (1H,
d, J 4.0, 1-H), 6.12 (1H, ddd, J 5.6, 2.5 and 1.1, 6-H), 6.48 (1H,
d, J 5.6, 7-H); δC (CDCl3) 20.9, 20.9 (COCH3), 26.9, 27.6
[C(CH3)2], 79.9 (5-C), 80.0 (2-C), 88.1 (4-C), 93.8 (3-C), 106.4
(1-C), 112.7 [C(CH3)2], 135.3 (6-C), 136.0 (7-C), 169.7, 169.9
(COCH3).
᎐
2
(1H, d, J 17.1, 7-Ha), 5.45 (1H, d, J 11.2, CH᎐CH ), 5.86 (1H,
᎐
2
d, J 3.6, 1-H), 5.89 (1H, dd, J 18.1 and 11.2, CH᎐CH ), 5.98
᎐
2
(1H, ddd, J 17.1, 10.4 and 5.8, 6-H), 7.25–7.38 (5H, m, Ph);
δC (CDCl3) 26.6, 26.9 (2 × CH3), 66.9 (CH2Ph), 71.0 (5-C), 81.7
(2-C), 84.2 (4-C), 84.5 (3-C), 103.9 (1-C), 113.1 [C(CH3)2], 116.4
(7-C), 118.1 (CH᎐CH ), 126.9, 127.3, 128.2 (Ph), 135.0
᎐
2
(CH᎐CH ), 135.8 (6-C), 138.5 (Ph); EI-MS m/z 332 [Mϩ].
᎐
2
(5R)-3-O-Benzyl-6,7-dideoxy-1,2-di-O-isopropylidene-3-C-
vinyl-ꢀ-D-ribo-hept-6-enofuranose 16. δH (CDCl3) 1.38 (3H, s,
CH3), 1.61 (3H, s, CH3), 2.65 (1H, br s, OH), 3.98 (1H, d, J 9.0,
4-H), 4.16 (1H, dd, J 9.0 and 5.7, 5-H), 4.62 (1H, d, J 10.9,
CH2Ph), 4.66 (1H, d, J 3.6, 2-H), 4.70 (1H, d, J 10.9, CH2Ph),
5.20 (1H, d, J 10.5, 7-Hb), 5.38 (1H, d, J 18.0, CH᎐CH ), 5.38
3-O-Benzyl-1,2;5,6-di-O-isopropylidene-3-C-vinyl-ꢀ-D-allo-
᎐
2
furanose25 14
(1H, d, J 17.0, 7-Ha), 5.56 (1H, d, J 11.5, CH᎐CH ), 5.83 (1H,
᎐
2
d, J 3.6, 1-H), 5.95 (1H, dd, J 18.0 and 11.5, CH᎐CH ), 5.96
᎐
2
A 60% oily dispersion of sodium hydride (1.08 g, 27 mmol)
was suspended in anhydrous N,N-dimethylformamide (DMF)
(50 cm3) and the mixture was cooled to 0 ЊC. A solution of
compound 1320 (4.03 g, 14.08 mmol) in anhydrous DMF (10
cm3) was added dropwise over a period of 30 min. The mixture
was stirred at 50 ЊC for 1 h and then cooled to 0 ЊC. Benzyl
bromide (4.7 g, 27.5 mmol) was added dropwise and the reac-
tion mixture was stirred at room temperature for 16 h. The
solvent was removed by distillation under reduced pressure and
the residue was re-dissolved in CH2Cl2 (300 cm3). The solution
was washed with saturated aq. NaHCO3 (2 × 100 cm3) and then
dried (MgSO4). The solvent was removed by distillation under
reduced pressure, and the residue was purified by silica gel
column chromatography (light petroleum–ethyl acetate 9 : 1,
v/v) to give the product 14 (5.14 g, 97%) as a clear oil;
δH (CDCl3) 1.33 (3H, s, CH3), 1.38 (3H, s, CH3), 1.42 (3H, s,
CH3), 1.61 (3H, s, CH3), 3.95 (2H, d, J 5.9, 6-H2), 4.16 (1H, q,
J 5.9, 5-H), 4.31 (1H, d, J 5.9, 4-H), 4.60 (1H, d, J 11.4,
CH2Ph), 4.62 (1H, d, J 3.7, 2-H), 4.68 (1H, d, J 11.4, CH2Ph),
(1H, ddd, J 17.0, 10.5 and 5.7, 6-H), 7.28–7.39 (5H, m, Ph);
δC (CDCl3) 26.6, 26.7 (2 × CH3), 67.7 (CH2Ph), 70.8 (5-C), 80.9
(2-C), 82.2 (4-C), 86.1 (3-C), 104.3 (1-C), 113.1 [C(CH3)2], 116.4
(7-C), 119.0 (CH᎐CH ), 127.4, 127.6, 128.3 (Ph), 134.2, 137.5
᎐
2
(CH᎐CH , 6-C), 137.8 (Ph); EI-MS m/z 332 [Mϩ].
᎐
2
(1R,2R,6R,8R,9S)-1-Benzyloxy-9-hydroxy-4,4-dimethyl-3,5,7-
trioxatricyclo[6.3.0.02,6]undec-10-ene 17
To a solution of 15 (5.8 g, 17.4 mmol) in anhydrous CH2Cl2
(200 cm3) was added the catalyst A (750 mg, 0.89 mmol) and the
mixture was stirred at room temperature for 48 h. At this time
another portion of A (750 mg, 0.89 mmol) was added and the
mixture was stirred for an additional 72 h. The solvent was
removed by distillation under reduced pressure, and the residue
was purified by silica gel column chromatography (light
petroleum–ethyl acetate 7 : 3, v/v) to give the product 17 (4.18 g,
79%) as a darkly coloured solid which was used without further
purification in the next step; δH (CDCl3) 1.41 (3H, s, CH3), 1.61
(3H, s, CH3), 1.94 (1H, br s, OH), 4.49 (1H, s, 4-H), 4.50 (1H, d,
J 2.5, 5-H), 4.58 (1H, d, J 11.3, CH2Ph), 4.61 (1H, d, J 3.6,
2-H), 4.69 (1H, d, J 11.3, CH2Ph), 5.71 (1H, d, J 3.6, 1-H), 6.04
(1H, dd, J 5.8 and 0.5, 7-H), 6.17 (1H, ddd, J 5.8, 2.5 and 1.4,
6-H), 7.21–7.39 (5H, m, Ph); δC (CDCl3) 27.5, 27.5, 67.1, 79.4,
81.3, 90.0, 94.6, 106.1, 113.5, 127.5, 127.7, 128.2, 138.5, 134.4,
138.6; FAB-MS m/z 305 [M ϩ Hϩ].
5.29 (1H, d, J 18.2, CH᎐CH ), 5.46 (1H, d, J 11.3, CH᎐CH ),
᎐
᎐
2
2
5.82 (1H, d, J 3.7, 1-H), 5.86 (1H, dd, J 18.2 and 11.3,
CH᎐CH ), 7.21–7.41 (5H, m, Ph); δ (CDCl3) 138.8, 135.5,
᎐
2
C
128.0, 127.1, 126.9, 118.6, 112.9, 108.8, 104.4, 84.9, 82.1, 81.4,
74.0, 66.8, 66.3, 26.9, 26.7, 26.6, 25.3; FAB-MS m/z 377
[M ϩ Hϩ].
(5S)- and (5R)-3-O-Benzyl-6,7-dideoxy-1,2-di-O-isopropylidene-
3-C-vinyl-ꢀ-D-ribo-hept-6-enofuranose 15 and 16
(1R,2R,6R,8R,9R)-1-Benzyloxy-9-hydroxy-4,4-dimethyl-3,5,7-
trioxatricyclo[6.3.0.02,6]undec-10-ene 18
To a solution of 14 (10.4 g, 27.6 mmol) in ethyl acetate
(300 cm3) was added periodic acid (6.5 g, 28.5 mmol) and the
reaction mixture was stirred at room temperature for 1 h. The
white precipitate was filtered off and the solvent was removed
by distillation under reduced pressure. The residue was re-
dissolved in anhydrous THF (250 cm3) and the solution was
cooled to 0 ЊC. A 1 M solution of vinylmagnesium bromide in
Method A, from 17. To a solution of 17 (3.65 g, 12.0 mmol) in
CH2Cl2 (100 cm3) was added PCC (3.1 g, 14.4 mmol) and the
mixture was stirred at room temperature for 14 h. Ethyl acetate
(200 cm3) was added and the mixture was filtered through a
layer of silica. The filter was rinsed with ethyl acetate (400 cm3),
and the filtrate was concentrated in vacuo. The residue was re-
990
J. Chem. Soc., Perkin Trans. 1, 2001, 985–993

View Article Online
dissolved in MeOH (100 cm3) and treated with CeCl3ؒ7H2O (4.5
g, 12.1 mmol). This solution was cooled to 0 ЊC and added to
NaBH4 (750 mg, 19.8 mmol) in small portions and the mixture
was stirred at 0 ЊC for 30 min. Water (100 cm3) was added and
the solution was neutralised with 4 M acetic acid and extracted
with CH2Cl2 (3 × 100 cm3). The combined organic extracts were
dried (Na2SO4) and the solvent was removed by distillation
under reduced pressure and the residue was purified by silica gel
column chromatography (CH2Cl2–MeOH 96 : 4, v/v) to give
the product 18 (3.40 g, 93%) as a white solid (Found: C, 66.92;
H, 6.61. C17H20O5 requires C, 67.09; H, 6.62%); δH (CDCl3) 1.42
(3H, s, CH3), 1.64 (3H, s, CH3), 2.70 (1H, d, J 10.5, OH), 4.41
(1H, d, J 11.3, CH2Ph), 4.60 (1H, d, J 4.5, 4-H), 4.61 (1H, d,
J 3.6, 2-H), 4.63 (1H, d, J 11.3, CH2Ph), 4.80 (1H, ddt, J 10.5,
4.5 and 1.4, 5-H), 5.78 (1H, d, J 3.6, 1-H), 5.88 (1H, ddd, J 5.8,
1.8 and 0.8, 7-H), 6.13 (1H, dt, J 5.8 and 1.4, 6-H), 7.26–7.36
(5H, m, Ph); δC (CDCl3) 27.3, 27.5, 67.8, 76.4, 83.2, 83.2, 94.6,
106.6, 114.2, 127.6, 127.7, 128.3, 129.4, 138.1, 142.4; FAB-MS
m/z 327 [M ϩ Naϩ].
27.3, 27.5, 67.9, 71.8, 82.0, 82.5, 82.9, 94.9, 107.4, 113.4, 127.7,
127.8, 127.8, 128.1, 128.3, 128.4, 130.2, 137.8, 138.2, 140.7;
FAB-MS m/z 395 [M ϩ Hϩ].
(1R,2R,6R,8R,9S)-1,9-Bis(benzyloxy)-4,4-dimethyl-3,5,7-tri-
oxatricyclo[6.3.0.02,6]undec-10-ene 10
Method A, from 8. Same procedure as for the preparation of
14 was used with NaH (25 mg, 0.63 mmol), 8 (21 mg, 0.098
mmol), benzyl bromide (106 mg, 0.62 mmol) and DMF (4 cm3).
Purification by silica gel column chromatography (light
petroleum–ethyl acetate 4 : 1, v/v) gave the product 10 (27 mg,
70%) as a clear oil.
Method B, from 17. Same procedure as for the preparation
of 14 was used with NaH (60 mg, 1.5 mmol), 17 (188 mg,
0.62 mmol), benzyl bromide (265 mg, 1.55 mmol) and DMF
(10 cm3). Purification by silica gel column chromatography
(light petroleum–ethyl acetate 4 : 1, v/v) gave the product 10
(133 mg, 55%) as a clear oil; δH (CDCl3) 1.41 (3H, s, CH3), 1.62
(3H, s, CH3), 4.28 (1H, d, J 2.5, 5-H), 4.55 (1H, d, J 12.0,
CH2Ph), 4.57 (1H, d, J 2.5, 4-H), 4.62 (2H, s, CH2Ph), 4.65 (1H,
d, J 3.6, 2-H), 4.68 (1H, d, J 12.0, CH2Ph), 5.69 (1H, d, J 3.6,
1-H), 5.94 (1H, d, J 5.8, 7-H), 6.12 (1H, ddd, J 5.8, 2.4 and 1.3,
6-H), 7.20–7.42 (10H, m, Ph); δC (CDCl3) 27.4, 27.6, 67.3, 71.7,
82.2, 86.5, 87.4, 94.8, 105.8, 113.6, 127.2, 127.4, 127.7, 127.7,
128.1, 128.4, 134.9, 136.5, 137.8, 138.9; FAB-MS m/z 395
[M ϩ Hϩ].
Method B, from 16. To a solution of 16 (168 mg, 0.51 mmol)
in anhydrous CH2Cl2 (10 cm3) was added the catalyst B (21 mg,
0.025 mmol) and the mixture was stirred at 40 ЊC for 1 h. The
solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography
(light petroleum–ethyl acetate 7 : 3, v/v) to give the product 18
(135 mg, 88%) as a grey solid.
3-O-Benzyl-6,7-dideoxy-1,2-di-O-isopropylidene-3-C-vinyl-ꢀ-D-
ribo-heptofuran-5-ulose 19
(3R/S,1R,4R,5R,8R)-3,4-Diacetoxy-5,8-bis(benzyloxy)-2-oxa-
bicyclo[3.3.0]oct-6-ene 20
To a solution of 16 (72 mg, 0.217 mmol) in anhydrous 1,2-
dichloroethane (4 cm3) was added A (18 mg, 0.022 mmol) and
the mixture was stirred under reflux at 83 ЊC for 24 h. The
solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography
(light petroleum–ethyl acetate 4 : 1, v/v) to give the product 19
(48 mg, 67%) as a darkly colored oil; δH (CDCl3) 1.01 (3H, t,
J 7.3, CH2CH3), 1.39 (3H, s, CH3), 1.62 (3H, s, CH3), 2.45 (1H,
dq, J 18.0 and 7.3, CH2CH3), 2.60 (1H, dq, J 18.0 and 7.3,
CH2CH3), 4.62 (1H, d, J 11.1, CH2Ph), 4.67 (1H, d, J 3.6, 2-H),
4.73 (1H, d, J 11.1, CH2Ph), 4.81 (1H, s, 4-H), 5.33 (1H, d,
A solution of 11 (3.21 g, 8.14 mmol) in 80% aq. acetic acid
(50 cm3) was stirred at 90 ЊC for 16 h. The solvents were
removed by distillation under reduced pressure and the residue
was coevaporated with anhydrous EtOH (3 × 30 cm3), toluene
(3 × 30 cm3), and anhydrous pyridine (30 cm3) and re-dissolved
in anhydrous pyridine (30 cm3). Acetic anhydride (20 cm3) was
added dropwise and the solution was stirred at room temper-
ature for 16 h. The reaction mixture was quenched with ice-cold
water (50 cm3) and extracted with CH2Cl2 (3 × 100 cm3). The
combined extracts were washed with saturated aq. NaHCO3
(2 × 100 cm3) and then dried (MgSO4). The solvent was
removed by distillation under reduced pressure, and the residue
was purified by silica gel column chromatography (light
petroleum–ethyl acetate 4 : 1, v/v) to give the anomeric mixture
20 (3.03 g, 85%) as a clear oil (Found: C, 67.53; H, 5.92.
C25H26O7ؒ1/5H2O requires C, 67.79; H, 6.03%); δC (CDCl3)
170.0, 169.9, 169.5, 169.4, 138.5, 138.4, 137.9, 137.7, 136.9,
133.2, 131.2, 128.4, 128.3, 128.3, 128.2, 128.1, 127.8, 127.7,
127.6, 127.5, 126.9, 126.8, 101.1, 96.6, 95.5, 92.5, 84.5, 82.9,
81.6, 80.6, 77.8, 75.7, 72.3, 72.0, 67.6, 67.3, 21.1, 21.0, 20.7,
20.5; FAB-MS m/z 379 [M Ϫ OAc].
J 17.6, CH᎐CH ), 5.42 (1H, d, J 11.3, CH᎐CH ), 5.67 (1H, dd,
᎐
᎐
2
2
J 17.6 and 11.3, CH᎐CH ), 5.97 (1H, d, J 3.6, 1-H), 7.25–7.34
᎐
2
(5H, m, Ph); δC (CDCl3) 6.9 (CH2CH3), 26.6, 26.9 [C(CH3)2],
33.4 (CH2CH3), 67.3, 81.2 (2-C, CH2Ph), 85.8, 85.9 (3-C, 4-C),
104.2 (1-C), 113.2 [C(CH3)2], 119.1 (2Ј-C), 127.1 , 127.4, 128.2
(Ph), 133.4 (1Ј-C), 138.0 (Ph), 206.2 (CO).
(1R,2R,6R,8R,9R)-1,9-Bis(benzyloxy)-4,4-dimethyl-3,5,7-tri-
oxatricyclo[6.3.0.02,6]undec-10-ene 11
Method A, from 9. Same procedure as for the preparation of
14 was used with NaH (1.1 g, 27.5 mmol), 9 (1.17 g, 5.47
mmol), benzyl bromide (4.68 g, 27.4 mmol) and DMF
(45 cm3). Purification by silica gel column chromatography
(light petroleum–ethyl acetate 4 : 1, v/v) gave the product 11
(1.73 g, 80%) as a white solid.
(1R,3R,4R,5R,8R)-4-Acetoxy-5,8-bis(benzyloxy)-3-(thymin-1-
yl)-2-oxabicyclo[3.3.0]oct-6-ene 21
A mixture of 20 (3.03 g, 6.91 mmol) and thymine (1.81 g, 14.4
mmol) was dried and dissolved in anhydrous CH3CN (100 cm3).
The mixture was treated with N,O-bis(trimethylsilyl)acetamide
(9.0 cm3, 36.4 mmol) and stirred under reflux for 15 min. After
cooling of the mixture to 0 ЊC, TMS triflate (2.5 cm3, 13.8
mmol) was added dropwise and the solution was stirred at
50 ЊC for 16 h. The reaction mixture was quenched with ice-
cold saturated aq. NaHCO3 (100 cm3) and extracted with
CH2Cl2 (3 × 75 cm3). The combined extracts were dried
(MgSO4) and the solvent was removed by distillation under
reduced pressure. The residue was purified by silica gel column
chromatography (CH2Cl2–MeOH 97 : 3, v/v) to give the
product 21 (3.18 g, 91%) as a white solid material (Found: C,
66.23; H, 5.60; N, 5.39. C28H28N2O7 ؒ1/5H2O requires C, 66.18;
Method B, from 18. Same procedure as for the preparation of
14 was used with NaH (915 mg, 22.9 mmol), 18 (2.23 g, 7.33
mmol), benzyl bromide (4.03 g, 23.6 mmol) and DMF (60
cm3). Purification by silica gel column chromatography (light
petroleum–ethyl acetate 4 : 1, v/v) gave the product 11 (2.80 g,
97%) as a white solid (Found: C, 72.97; H, 6.71. C24H26O5
requires C, 73.08; H, 6.71%); δH (CDCl3) 1.42 (3H, s, CH3), 1.65
(3H, s, CH3), 4.39 (1H, d, J 10.8, CH2Ph), 4.51 (1H, d, J 11.6,
CH2Ph), 4.59 (1H, d, J 3.9, 2-H), 4.65 (1H, d, J 10.8, CH2Ph),
4.67–4.69 (2H, m, 4-H and 5-H), 4.76 (1H, d, J 11.6, CH2Ph),
5.94 (1H, d, J 3.9, 1-H), 5.97 (1H, dd, J 6.0 and 1.4, 7-H), 6.11
(1H, dt, J 6.0 and 1.4, 6-H), 7.25–7.40 (10H, m, Ph); δC (CDCl3)
J. Chem. Soc., Perkin Trans. 1, 2001, 985–993
991

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H, 5.63; N, 5.51%); δH (CDCl3) 1.60 (3H, d, J 1.1, 5-CH3), 2.09
(3H, s, COCH3), 4.36 (1H, d, J 11.4, CH2Ph), 4.45 (1H, d,
J 11.4, CH2Ph), 4.57 (1H, d, J 11.3, CH2Ph), 4.64 (1H, m,
5Ј-H), 4.70 (1H, d, J 5.4, 4Ј-H), 4.75 (1H, d, J 11.3, CH2Ph),
5.04 (1H, d, J 6.1, 2Ј-H), 6.11–6.18 (2H, m, 6Ј-H and 7Ј-H),
6.16 (1H, d, J 6.1, 1Ј-H), 7.25–7.36 (10H, m, Ph), 7.54 (1H, d,
J 1.1, 6-H), 8.44 (1H, br s, NH); δC (CDCl3) 12.1, 20.6, 67.0,
72.6, 170.2, 78.6, 80.7, 83.4, 89.2, 93.3, 111.4, 127.0, 127.7,
127.8, 128.1, 128.4, 128.6, 133.8, 135.6, 136.8, 137.4, 137.8,
150.3, 163.4; FAB-MS m/z 505 [M ϩ Hϩ].
m/z 284 [Mϩ]; HR MALDI FT-MS m/z 307.0906. Calc.
307.0901 [M ϩ Naϩ].
(1R,3R,4R,5R,8R)-5,8-Bis(benzyloxy)-4-pentafluorophenoxy-
thiocarbonyloxy-3-(thymin-1-yl)-2-oxabicyclo[3.3.0]oct-6-ene 23
To a solution of 22 (154 mg, 0.33 mmol) in CH2Cl2 (3 cm3) was
added 4-(dimethylamino)pyridine (DMAP) (80 mg, 0.66 mmol)
and the mixture was cooled to Ϫ20 ЊC. Pentafluorophenyl
chlorothionoformate (0.10 cm3, 0.62 mmol) was added drop-
wise and the solution was stirred at room temperature for 16 h.
The reaction mixture was diluted with CH2Cl2 (7 cm3) and
washed with saturated aq. NaHCO3 (2 × 10 cm3) and then dried
(MgSO4). The solvent was removed by distillation under
reduced pressure and the residue was purified by silica gel
column chromatography [0–2% (v/v) MeOH in CH2Cl2] to give
the product 23 contaminated with a pentafluorophenyl com-
pound as well as unidentified by-products. The product was
purified by additional chromatography to give the title com-
pound 23 (46 mg, 20%) as a clear oil, δH (CDCl3) 1.54 (3H, d,
J 1.1, CH3), 4.38 (1H, d, J 11.5, CH2Ph), 4.54 (1H, d, J 11.5,
CH2Ph), 4.58 (1H, d, J 11.5, CH2Ph), 4.64 (1H, m, J 5.1, 5Ј-H),
4.75 (1H, d, J 11.5, CH2Ph), 4.77 (1H, d, J 5.1, 4Ј-H), 5.69 (1H,
d, J 5.2, 2Ј-H), 6.13–6.21 (2H, m, 6Ј-H, 7Ј-H), 6.49 (1H, d, J 5.2,
1Ј-H), 7.27–7.39 (10H, m, Ph), 7.60 (1H, d, J 1.1, 6-H), 8.90
(1H, br s, NH); δC (CDCl3) 12.1, 67.6, 72.5, 80.8, 83.9, 87.4,
89.3, 93.4, 111.5, 127.1, 127.9, 127.9, 128.2, 128.4, 128.6, 132.5,
135.8, 137.0, 137.2, 138.2, 150.3, 164.0, 191.3; δF (CDCl3)
Ϫ152.3 (2F, m), Ϫ157.1 (2F, m), Ϫ162.5 (1F, m); FAB-MS
m/z 689 (M ϩ Hϩ).
(1R,3R,4R,5R,8R)-5,8-Bis(benzyloxy)-4-hydroxy-3-(thymin-1-
yl)-2-oxabicyclo[3.3.0]oct-6-ene 22
To a solution of 21 (3.18 g, 6.30 mmol) in anhydrous methanol
(40 cm3) was added sodium methoxide (704 mg, 13.0 mmol)
and the mixture was stirred at room temperature for 16 h. The
reaction mixture was neutralised with aq. HCl and extracted
with CH2Cl2 (2 × 150 cm3). The combined extracts were
washed with saturated aq. NaHCO3 (2 × 100 cm3) and then
dried (MgSO4). The solvent was removed by distillation under
reduced pressure to give the product 22 (2.84 g, 97%) as a white
solid material (Found: C, 67.88; H, 5.72; N, 6.04. C26H26N2O6
requires C, 67.52; H, 5.67; N, 6.06%); δH (CDCl3) 1.54 (3H, d,
J 1.1, CH3), 3.20 (1H, d, J 8.2, 2Ј-OH), 4.10 (1H, dd, J 8.2 and
6.1, 2Ј-H), 4.44 (1H, d, J 11.1, CH2Ph), 4.50 (1H, d, J 11.1,
CH2Ph), 4.58 (1H, d, J 11.3, CH2Ph), 4.63 (1H, m, 5Ј-H), 4.71
(1H, d, J 5.7, 4Ј-H), 4.76 (1H, d, J 11.3, CH2Ph), 6.07 (1H, d,
J 6.1, 7Ј-H), 6.15 (1H, m, 6Ј-H), 6.16 (1H, d, J 6.1, 1Ј-H), 7.26–
7.38 (10H, m, Ph), 7.58 (1H, d, J 1.1, 6-H), 8.18 (1H, br s, NH);
δC (CDCl3) 12.0, 67.1, 72.7, 78.8, 80.4, 81.9, 91.8, 93.6, 111.0,
127.7, 127.8, 128.2, 128.2, 128.6, 128.6, 133.3, 135.9, 136.7,
137.0, 137.4, 150.7, 163.5; FAB-MS m/z 463 [M ϩ Hϩ].
(1R,3R,5R,8R)-5,8-Bis(benzyloxy)-3-(thymin-1-yl)-2-oxabi-
cyclo[3.3.0]octane 24
The thionocarbonate 23 (46 mg, 0.067 mmol) was dissolved in
anhydrous benzene (1.0 cm3) and azaisobutyronitrile (AIBN)
(5 mg, 0.03 mmol) was added. The mixture was flushed with
argon for 20 min, Bu3SnH (0.03 cm3, 0.11 mmol) was added,
and the reaction mixture stirred at 90 ЊC for 16 h. The mixture
was allowed to cool to room temperature and the solvent was
removed under reduced pressure. Purification by silica gel
chromatography [0–3% (v/v) MeOH in CH2Cl2] gave the
product 24 (15 mg, 50%) which was used without further purifi-
cation in the next step, δH (CDCl3) 1.57 (3H, d, J 1.3, CH3), 2.17
(1H, dd, J 13.8, 6.9, 2Ј-Hb), 2.80 (1H, dd, J 13.8, 6.2, 2Ј-Ha),
4.37 (1H, d, J 11.3, CH2Ph), 4.45 (1H, d, J 11.3, CH2Ph), 4.57
(1H, d, J 11.3, CH2Ph), 4.65 (2H, br s, 4Ј-H, 5Ј-H), 4.77 (1H, d,
J 11.3, CH2Ph), 6.02–6.08 (2H, m, 6Ј-H, 7Ј-H), 6.47 (1H, dd,
J 6.2, 6.9, 1Ј-H), 7.26–7.37 (10H, m, Ph), 7.76 (1H, d, J 1.3,
6-H), 8.52 (1H, br s, NH); δC (CDCl3) 12.1, 44.1, 67.1, 72.6,
81.0, 84.1, 88.1, 96.8, 110.5, 127.3, 127.8, 127.9, 128.0, 128.5,
128.5, 134.5, 135.0, 136.3, 137.7, 137.8, 150.2, 163.7; FAB-MS
m/z 447 (M ϩ Hϩ).
(1R,3R,4R,5S,8R)-4,5,8-Trihydroxy-3-(thymin-1-yl)-2-oxa-
bicyclo[3.3.0]oct-6-ene 4
A solution of 22 (80 mg, 0.17 mmol) in anhydrous CH2Cl2 (2.5
cm3) was stirred at Ϫ78 ЊC and a 1 M solution of BCl3 in hexane
(0.4 cm3, 0.4 mmol) was added dropwise. After stirring
for 5 h at Ϫ78 ЊC the mixture was treated with methanol
(2 cm3) and water (0.1 cm3) and stirred at room temperature
for 1 h. The solvents were removed by distillation under
reduced pressure and the residue was purified by silica gel
column chromatography (CH2Cl2–MeOH 93 : 7, v/v) to give
the product 4 (40 mg, 82%) as a white solid; δH (DMSO-d6) 1.82
(3H, s, CH3), 3.85 (1H, d, J 7.3, 2Ј-H), 4.07 (1H, d, J 5.8, 4Ј-H),
4.59 (1H, d, J 5.8, 5Ј-H), 5.75–5.85 (2H, m, 6Ј-H and 7Ј-H),
5.96 (1H, d, J 7.3, 1Ј-H), 7.86 (1H, s, 6-H), 11.35 (1H, s, NH);
δC (DMSO-d6) 12.2 (CH3), 72.5 (5Ј-C), 77.3 (2Ј-C), 86.1
(4Ј-C), 87.0 (3Ј-C), 90.1 (1Ј-C), 109.2 (5-C), 134.5, 135.8 (6Ј-C
and 7Ј-C), 136.9 (6-C), 150.9 (2-C), 163.7 (4-C); HR MALDI
FT-MS m/z 305.0744. Calc. 305.0744 [M ϩ Naϩ].
(1R,3R,5S,8R)-5,8-Dihydroxy-3-(thymin-1-yl)-2-oxabicyclo-
[3.3.0]octane 1 (Base ؍ thymine)
(1R,3R,4R,5S,8R)-4,5,8-Trihydroxy-3-(thymin-1-yl)-2-oxa-
bicyclo[3.3.0]octane 5
A solution of 24 (15 mg, 0.034 mmol) in methanol (1.0 cm3) was
treated with 20% Pd(OH)2–C (10 mg) and cyclohexa-1,4-diene
(0.05 cm3, 0.53 mmol) and the mixture was degassed with argon
and flushed with H2 for 5 min. After stirring under an atmos-
phere of H2 for 16 h the mixture was filtered through a pad of
Celite and the solvent was removed by distillation under
reduced pressure to give the product 1 (5.5 mg, 61%) as a white
A solution of 22 (65 mg, 0.14 mmol) in methanol (3 cm3) was
added to 20% Pd(OH)2–C (25 mg) and the mixture was degassed
with argon and flushed with H2 for 5 min. After stirring under
an atmosphere of H2 for 2 h the mixture was filtered through a
pad of Celite and the solvent was removed by distillation under
reduced pressure to give the product 5 (39 mg, 98%) as a white
solid; δH (DMSO-d6) 1.47 (1H, m, 7Ј-H), 1.72 (1H, m, 6Ј-H),
1.81 (3H, s, CH3), 1.86–1.94 (2H, m, 6Ј-H and 7Ј-H), 3.81 (1H,
dd, J 8.5 and 6.2, 2Ј-H), 4.92 (1H, d, J 5.1, 4Ј-H), 4.96 (1H, m,
5Ј-H), 4.93 (1H, d, J 5.3, 5Ј-OH), 5.04 (1H, s, 3Ј-OH), 5.31 (1H,
d, J 6.2, 2Ј-OH), 5.81 (1H, d, J 8.5, 1Ј-H), 7.74 (1H, s, 6-H),
11.32 (1H, s, NH); δC (DMSO-d6) 12.2 (CH3), 32.0 (6Ј-C), 33.9
(7Ј-C), 70.7 (5Ј-C), 77.2 (2Ј-C), 81.9 (3Ј-C), 87.0 (1Ј-C), 88.6
(4Ј-C), 109.5 (5-C), 136.6 (6-C), 150.9 (2-C), 163.7 (4-C); EI-MS
1
solid; H and 13C NMR were in accordance with published
data.6
Acknowledgements
The Danish Natural Science Research Council is thanked for
financial support. Dr M. Petersen and Dr J. P. Jacobsen are
992
J. Chem. Soc., Perkin Trans. 1, 2001, 985–993

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15 (a) N. K. Christensen, M. Petersen, P. Nielsen, J. P. Jacobsen,
thanked for assistance with molecular modelling and ab initio
calculations.
C. E. Olsen and J. Wengel, J. Am. Chem. Soc., 1998, 120, 5458;
(b) M. Raunkjær, C. E. Olsen and J. Wengel, J. Chem. Soc., Perkin
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16 P. Nielsen, M. Petersen and J. P. Jacobsen, J. Chem. Soc., Perkin
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17 G. Minasov, M. Teplova, P. Nielsen, J. Wengel and M. Egli,
Biochemistry, 2000, 39, 3525.
18 L. B. Jørgensen, P. Nielsen, J. Wengel and J. P. Jacobsen, J. Biomol.
Struct. Dyn., 2000, 18, 45.
19 For recent reviews see (a) R. H. Grubbs and S. Chang, Tetrahedron,
1998, 54, 4413; (b) M. Jørgensen, P. Hadwiger, R. Madsen, A. E.
Stütz and T. M. Wrodnigg, Curr. Org. Chem., 2000, 4, 565; (c) A.
Fürstner, Angew. Chem., Int. Ed., 2000, 39, 3012; (d) T. M. Trnka
and R. H. Grubbs, Acc. Chem. Res., 2001, 34, 18.
20 The syntheses of 6 and 13 have been described in detail in ref. 16.
Moreover, see (a) D. C. Baker, D. K. Brown, D. Horton and R. G.
Nickol, Carbohydr. Res., 1974, 32, 299; (b) J. Marco-Contelles,
P. Ruiz, L. Martínez and A. Martínez-Grau, Tetrahedron, 1993, 49,
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and M. Geoffroy, Carbohydr. Lett., 1995, 1, 343.
21 M. J. Robins, S. F. Wnuk, X. Yang, C.-S. Yuan, R. T. Borchardt,
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22 L. A. Paquette, J. D. Schloss, I. Efremov, F. Fabris, F. Gallou,
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23 H. D. Maynard and R. H. Grubbs, Tetrahedron Lett., 1999, 40,
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References and notes
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J. Chem. Soc., Perkin Trans. 1, 2001, 985–993
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