Stereoisomeric pyrimidine nucleoside analogues based on the 1,3-dihydrobenzo[c]furan core

Article abstract of DOI:10.1039/b006417n

Stereoisomeric pyrimidine nucleoside analogues based on the 1,3-dihydrobenzo[c]furan core was described. The overall yield of 3-benzoyloxymethyl-1,3-dihydro-1-methoxybenzo[c]furan from aldehyde was 42%. After removal of the protecting group the four stere

Full text of DOI:10.1039/b006417n

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Stereoisomeric pyrimidine nucleoside analogues based on the
1,3-dihydrobenzo[c]furan core
David F. Ewing,* Nour-Eddine Fahmi, Christophe Len, Grahame Mackenzie* and
Alessandra Pranzo
1
Department of Chemistry, University of Hull, Hull, UK HU6 7RX
Received (in Cambridge, UK) 4th August 2000, Accepted 4th September 2000
First published as an Advance Article on the web 16th October 2000
A new efficient route is described to uracil, thymidine and cytosine derivatives of 1,3-dihydrobenzo[c]furan which are
aromatic analogues of the well known antiviral 2Ј,3Ј-dideoxy-2Ј,3Ј-didehydronucleosides. These systems contain two
chiral centres (corresponding to α/β and / centres in a furanose sugar) and a route involving application of the
Sharpless asymmetric oxidation methodology allowed access to each of the four stereoisomers of the uracil derivative
in enantiomerically pure form.
lipophilicity compared to d4T. Furthermore, this system is
Introduction
clearly very rigid. It has been speculated1c that the confor-
One of the many modifications which have been made to the
structure of a regular nucleoside in an attempt to enhance
mational restriction imposed by the double bond in d4T
is an important factor in its interaction with viral enzymes.
chemotherapeutic potential is the introduction of a double
Nucleoside analogues with conformational rigidity imposed by
bond into the 2Ј,3Ј position to give a 2Ј,3Ј-didehydro-2Ј,3Ј-
cyclopropanation of a furanose or carbocyclic ring have been
dideoxyribonucleoside (d4N).1 A study of the anti-HIV activity
reported recently.8
of the d4Ns was reported by Balzarini et al.2 over ten years ago
We now report further studies of a synthetic route which
allows more efficient access to the 1,3-dihydrobenzo[c]furan
glycone and thus to the corresponding uracil, thymine and
and since then there has been increasing interest in this class
of compound. Both the cytosine (d4C) 1 and thymidine (d4T)
2 analogues are potent antiviral agents against the ATH8 cell
cytosine nucleoside analogues. Since two chiral centres are
line. Many substituted variants of d4C, d4T and d4U have been
generated in this system the nucleoside analogues are normally
examined for antiviral activity3 and d4T is now an approved
obtained as a pair of diastereoisomers although the ultimate
objective was the synthesis of stereoisomerically pure nucleo-
side analogues. The nucleoside diastereoisomers could be
separated by chromatography but resolution of the optical
anti-HIV drug (Stavudine).4 It is notable that the carbo-
cyclic analogue of d4G (carbovir) 3 also has potent anti-HIV
activity.5
isomers was not considered feasible. Hence a method has
been developed which allows complete stereoselectivity in the
generation of the C3 chiral centre in the 1,3-dihydrobenzo-
[c]furan system and thus provides access to each of the four
uracil stereoisomers in enantiomerically pure form.
Results and discussion
The starting point is compound 5 which is o-phthalaldehyde
with one aldehyde group protected with propane-1,3-diol7
(Scheme 1). The remaining aldehyde group is easily converted
to the cyanohydrin 6 in high yield. Treatment of crude 6 with
HCl in methanol results in a sequence of reactions. The alde-
hyde protecting group is cleaved and the resulting aldehyde
cyclises spontaneously with the cyanohydrin hydroxy group
to generate the dihydrofuran ring. Subsequently the hydroxy
An important aspect of anti-HIV therapy is the suppression
of viral replication in the brain and many derivatives of
d4T have been synthesised and tested as prodrugs, particularly
targeted at producing a therapeutic brain concentration.6 In
this regard enhanced lipophilicity is likely to be advantageous.
We have recently reported7 the first synthesis of the interesting
analogue of d4T in which the 2,3 double bond is incorporated
into a benzene ring producing a derivative of the benzo[c]furan
system 4. This new class of nucleoside with a modified glycone
is attractive because it retains the phosphorylation site, it is
likely to be more resistant to the hydrolytic process that con-
tributes to the short half-life of d4T in vivo3 and it has enhanced
group generated at C1 is converted to a methoxy group and
the cyano group converted to the methyl ester (possibly via
an imidate). Thus a one-pot set of reactions results in the con-
version of compound 6 to methoxy ester 7 with the hydroxy
ester 8 as a minor product. These two esters are readily
separated by chromatography. Reduction of the ester function
with LiAlH4 and protection of the resulting alcohol 9 as the
benzoyl derivative 10 are both high yield steps. The overall yield
of 3-benzoyloxymethyl-1,3-dihydro-1-methoxybenzo[c]furan
(10) from aldehyde 5 was 42% and hence the procedure shown
in Scheme 1 constitutes an efficient route to the required
glycone.
DOI: 10.1039/b006417n
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This journal is © The Royal Society of Chemistry 2000
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Scheme 1 Reagents and conditions: i, NaHSO3, KCN, aq. THF at 5 ЊC;
ii, HCl in MeOH, 0 ЊC; iii, LiAlH4, ether at 0 ЊC; iv, BzCl in pyridine
at 0 ЊC; v, silylated uracil or thymine, TMSOTf; vi, NH3 in MeOH;
vii, Et3N, 1,2,3-triazole, POCl3, 0 ЊC, then reacted with uracil nucleoside
at 24 ЊC for 24 h; viii, aq. NH3 in dioxane at 20 ЊC for 12 h.
Scheme 2 Reagents and conditions: i, AD-mix-α (or AD-mix-β), aq.
t-BuOH, Ϫ10 ЊC; ii, BzCl, pyridine, CHCl3; iii, PTSA, aq. acetone;
MeOH–HCl; iv, silylated uracil, TMSOTf, MeCN; v, NH3 in MeOH.
corresponding dihydroxy derivatives 24 and 25 using the
commercial Sharpless reagents, AD-mix-α and AD-mix-β,
respectively. This asymmetric dihydroxylation reaction was
quantitative and completely stereoselective (ee >99% as con-
firmed by the use of a chiral shift reagent) and this effectively
leads to a resolution of one of the chiral centres in the
1,3-dihydrobenzo[c]furan system. The configuration at this
chiral centre, as indicated in the structures, was assigned by
the asymmetric dihydroxylation mnemonic rules.10 Selective
benzoylation of the primary hydroxy group in the diols 24 and
25 gave the esters 26 and 27 and these were each cyclised
and methylated to afford the corresponding 1,3-dihydro-
benzo[c]furan derivatives 28 and 29. Both compounds are
obtained as a single stereoisomer. This means that the con-
figuration at the chiral centre generated in the Sharpless
reaction (which becomes C3 in the product) exerts complete
stereocontrol over the cyclisation step and only the trans species
is formed (i.e. 28 and 29 are enantiomers). This is in sharp
contrast to the cyclisation of the analogous benzyl derivative of
the racemic diol which gives a mixture of cis and trans racemic
1,3-dihydrobenzo[c]furans.7 Formation of the uracil derivatives
by standard Vorbrüggen chemistry11 results in anomerisation
and in each case a mixture of diastereoisomers is formed
i.e. species 28 leads to a mixture of uracils 30 (1R,3S) and 31
(1S,3S) and species 29 gives uracils 32 (1R,3R) and 33 (1S,3R).
Fortunately these isomer pairs (equivalent to an anomeric pair
of glycosyl nucleosides) can be readily separated by silica gel
chromatography. The stereochemical purity of compounds
30–33 was confirmed by chiral HPLC.12 After removal of the
protecting group the four stereoisomers of 1-(3-hydroxymethyl-
1,3-dihydrobenzo[c]furan-1-yl)uracil were obtained. Thus there
has been no loss in the chiral integrity of the C3 site throughout
Compound 10 is obtained as a pair of diastereoisomers in the
ratio 1:1.25. The major species was identified as the trans-
isomer by the criteria established previously,7 principally the
value of the four-bond coupling J1,3 which is large in this iso-
mer. Separation of the isomers at this stage was difficult and
only the cis-isomer could be isolated in pure crystalline form.
Coupling of the diastereoisomeric mixture with silylated uracil
in presence of trimethylsilyl triflate gave a corresponding
mixture of nucleoside analogues 11 and 12 which were readily
separated by chromatography. An analogous condensation
of the glycone with silylated thymine gave the corresponding
mixture of cis- and trans-nucleoside analogues 15 and 16.
Crystallisation of this isomeric mixture gave the pure cis-isomer
but the trans-isomer was obtained as a 7:1 mixture with the
cis-isomer. The protected cytosines 19 and 20 were obtained by
standard nucleoside conversion9 from the separated uracils and
were thus obtained as pure diastereoisomers. Debenzoylation
of these six compounds gave the corresponding unprotected
nucleoside analogues 13, 14, 17, 18, 21 and 22. Thus the
1,3-dihydrobenzo[c]furan nucleoside analogues with the range
of standard pyrimidine bases are readily accessible as pure
diastereoisomers.
Each of the nucleoside analogues obtained by the method
shown in Scheme 1 is of course a pair of enantiomers i.e. the
cis compound 13 is a mixture of the (1R,3S) and (1S,3R)
species. Since enantiomerically pure nucleosides were required
for screening purposes a synthetic strategy was sought which
would avoid the need for tedious resolution procedures. This
has been achieved by application of the Sharpless asymmetric
dihydroxylation methodology10 (Scheme 2). The ethene deriv-
ative 23, obtained from phthalaldehyde,7 was converted to the
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the sequence of reactions starting from the diols 24 and 25.
These enantiomerically pure nucleoside analogues are being
screened for antiviral activity and the results will be reported
elsewhere.
temperature for 1 h, then EtOAc (100 mL) was added at 0 ЊC
and the mixture stirred for a further 1 h. Water was added
dropwise and the mixture filtered and extracted with EtOAc.
The extract was worked up and the crude product purified by
chromatography (hexane–EtOAc, 7:3) to afford 1,3-dihydro-3-
hydroxymethyl-1-methoxybenzo[c]furan (9) (Rf 0.18, hexane–
EtOAc, 7:3) as a yellow oil (10.0 g, 86%).
Experimental
General
A solution of benzoyl chloride (7.88 g, 61.9 mmol) in CHCl3
(7 mL) was added to a solution of compound 9 (9.3 g, 51.6
mmol) in pyridine (50 mL) at 0 ЊC. The mixture was stirred
overnight at room temperature and then poured into ice–water
and extracted with CH2Cl2. The organic layer was worked up
and the crude product chromatographed (hexane–EtOAc, 9:1)
to give the 1,3-dihydrobenzo[c]furan 10 as a pair of diastereo-
ismers, cis:trans ratio 1:1.25, obtained as a gum (12.0 g, 82%);
Rf 0.6 (hexane–EtOAc, 7:3) (Found: C, 71.93; H, 5.66. Calc. for
C17H16O4: C, 71.81; H, 5.67%). The major isomer (trans) was
obtained in a stereochemically pure form by crystallization
from hexane–EtOAc; mp 84–86 ЊC; δH (CDCl3) 3.45 (3 H, s,
OMe), 4.52 (1 H, m, J3,8a 6.0, J8a,8b 11.9, H-8a), 4.68 (1 H, m,
J3,8b 3.7, H-8b), 5.69 (1 H, m, H-3), 6.28 (1 H, d, J1,3 2.2, H-1),
7.3–7.60 (7 H, m, aromatic H), 7.95 (2 H, m, benzoyl);
δC (CDCl3) 54.5 (OMe), 66.9 (C-8), 81.0 (C-3), 107.2 (C-1),
166.3 (CO); cis isomer δH (CDCl3) 3.52 (3 H, s, OMe), 4.54 (1 H,
m, J3,8a 6.0, J8a,8b 11.9, H-8a), 4.64 (1 H, m, J3,8b 3.7, H-8b), 5.49
(1 H, m, H-3), 6.15 (1 H, s, H-1), 7.3–7.60 (7 H, m, aromatic H),
8.06 (2 H, m, benzoyl); δC (CDCl3) 54.5 (OMe), 67.9 (C-8), 81.1
(C-3), 107.4 (C-1), 166.4 (CO).
NMR spectra were recorded with a Lambda 400 spectrometer
using standard conditions with a data point resolution of
ca. 0.1 Hz. 1H Chemical shifts were measured relative to
Me4Si and 13C chemical shifts relative to CDCl3 (77.0 ppm) or
(CD3)2SO (39.5 ppm). All coupling constants are given in Hz.
1
Assignments of the H spectra were made by detailed analysis
using decoupling or correlation techniques where appropriate.
Diastereoisomer ratios were determined from the integration
of suitable peaks. Column chromatography was performed on
silica gel (230–400 mesh; Prolabo) and TLC on silica gel 60, F254
(Merck) with detection by UV absorbance or phosphomolybdic
acid. Optical rotation values are given in 10Ϫ1 deg cm2 gϪ1
.
2-[2-(1,3-Dioxan-2-yl)phenyl]-2-hydroxyacetonitrile (6)
A saturated aqueous solution of sodium bisulfite (85 mL) was
added dropwise to a stirred solution of 2-(1,3-dioxan-2-
yl)benzaldehyde7 5 (24.0 g, 125 mmol) and potassium cyanide
(9.7 g, 150 mmol) in aqueous THF (1:1, 100 mL). Crushed
ice was added to maintain the temperature at 5 ЊC during the
addition and the mixture was stirred for 2 h at this temperature
until the aldehyde was totally consumed (TLC). The mixture
was extracted with dichloromethane and the organic layer
worked up to give 6 as a yellow oil (24.8 g, 91%) which was
used directly; δH (CDCl3) 1.55, 2.20, 3.89, 4.10, 4.33 (6 H, m,
dioxanyl), 4.5 (1 H, br s, OH), 5.81 (1 H, s, dioxanyl), 5.99 (1 H,
s, H-2), 7.4–7.65 (4 H, m, aromatic H); δC (CDCl3) 25.5, 67.5,
67.6, 102.0 (dioxanyl), 62.5 (C-2), 118.7 (CN), 128.3, 129.6,
134.1, 135.6 (aromatic C).
cis- and trans-1-(3-Benzoyloxymethyl-1,3-dihydrobenzo[c]furan-
1-yl)uracil (11 and 12)
Chlorotrimethylsilane (1 mL) and a crystal of ammonium sul-
fate were added to a suspension of uracil (1.41 g, 12.66 mmol)
in hexamethyldisilazane (25 mL) and the mixture refluxed with
exclusion of moisture until a clear solution was obtained (3 h).
Volatiles were removed by repeated co-evaporation with toluene
to leave a syrup. This syrup and the 1,3-dihydrobenzo[c]furan
10 (3.0 g, 10.55 mmol) were taken up in dry MeCN (60 mL) and
trimethylsilyl trifluoromethanesulfonate (2.44 mL, 12.66 mmol)
added at Ϫ15 ЊC. After stirring for 2 h at 0 ЊC, sat. NaHCO3
solution (20 mL) was added, the mixture stirred for 30 min
and then extracted with CH2Cl2. This extract was worked up
and the crude product chromatographed (hexane–EtOAc 1:1)
to give a mixture of the uracil nucleoside analogues 11 and 12
as a white foam (2.6 g, 70%), cis:trans ratio 1:2.3 (Found: C,
65.91; H, 4.40; N, 7.78. Calc. for C17H16O4: C, 65.92; H, 4.42;
N, 7.68%).
These diastereoisomers were separated by column chrom-
atography (hexane–EtOAc, 7:3); the compound eluting first
was the cis isomer 11, mp 168–170 ЊC (EtOH); Rf 0.22 (hexane–
EtOAc, 1:1); δH (CDCl3) 4.82 (2 H, tight AB m, J3,8 3.2, 3.9,
H-8), 5.32, 6.98 (2 H, d, J 8.4, uracil), 5.60 (1 H, m, H-3), 7.20–
7.60 (8 H, m, H-1 and aromatic H), 7.85 (2 H, m, benzoyl), 8.12
(1 H, br s, NH); δC (CDCl3) 65.3 (C-8), 81.9 (C-3), 87.5 (C-1),
103.1 (uracil), 150.9, 162.8, 166.1 (CO); trans isomer (12), mp
150–152 ЊC (EtOH), Rf 0.17 (hexane–EtOAc, 1:1); δH (CDCl3)
4.55 (1 H, m, J3,8a 5.7, J8a,8b 11.9, H-8a), 4.68 (1 H, m, J3,8b 3.7,
H-8b), 5.65, 6.81 (2 H, 2 d, J 8.4, uracil), 5.83 (1 H, J1,3 2.9,
H-3), 7.59 (1 H, d, H-1), 7.30–7.60 (8 H, m, aromatic H),
7.95 (2 H, m, benzoyl), 8.95 (1 H, br s, NH); δC (CDCl3)
66.6 (C-8), 82.5 (C-3), 88.5 (C-1), 103.3 (uracil), 150.8, 162.8,
166.2 (CO).
1,3-Dihydro-1-methoxy-3-methoxycarbonylbenzo[c]furan (7)
A solution of the nitrile 6 (24 g, 0.109 mol) in dry methanol was
saturated with dry HCl at 0 ЊC for 1 h. The solution was main-
tained at this temperature for a further 2 h then poured into ice
and slowly neutralised with sat. NaHCO3 solution (500 mL).
The solution was extracted with CH2Cl2, the extract worked up
and the residue either used directly or chromatographed using a
gradient of ethyl acetate in hexane (10–50%) to afford the ester
7 as a yellow oil (14.0 g, 66%). This compound was a diastereo-
ismeric mixture (cis:trans ratio, 1:1.4); Rf 0.69 (hexane–
EtOAc, 1:1); δH (CDCl3) 3.45, 3.50 (2 s, OMe), 3.75, 3.77 (2 s,
CO2Me), 5.59 (1 H, s, H-3, cis), 5.78 (1 H, d, J1,3 1.8, H-3, trans),
6.2 (1 H, s, H-1, cis), 6.37 (1 H, d, H-1, trans), 7.3–7.50 (4 H,
m, aromatic H); δC (CDCl3) 52.4, 52.5, 54.3, 55.0 (OMe),
80.6, 80.8 (C-3), 107.7, 108.2 (C-1), 121.9, 122.5, 122.9, 123.0,
128.9, 129.0, 129.5, 129.7, 137.1, 137.2 (aromatic C), 170.5,
170.6 (CO).
A second component was the hydroxy ester 8, obtained as a
yellow solid (1.36 g, 6%). The diastereomeric mixture had
a cis:trans ratio of 2.7:1 (Found: C, 61.75; H, 5.14. Calc. for
C10H10O4: C, 61.85; H, 5.19%); δH (CDCl3) 3.85, 3.86 (2 s,
CO2Me), 5.62 (1 H, s, H-3, cis), 5.85 (1 H, d, J1,3 2.2, H-3,
trans), 6.48 (1 H, d, J1,OH 11, H-1, cis), 6.48 (1 H, dd, J1,3 2.2,
J1,OH 8.5 Hz, H-1, trans), 3.25 (1 H, d, OH cis), 3.7 (1 H, d, OH
trans), 7.3–7.50 (4 H, m, aromatic H); δC (CDCl3) 52.7, 53.0
(OMe), 81.04, 81.08 (C-3), 102.5, 102.6 (C-1), 172.5 (CO).
cis- and trans-1-(3-Benzoyloxymethyl-1,3-dihydrobenzo[c]furan-
1-yl)thymine (15 and 16)
3-Benzoyloxymethyl-1,3-dihydro-1-methoxybenzo[c]furan (10)
Chlorotrimethylsilane (1 mL) and a crystal of ammonium sul-
fate were added to a suspension of thymine (0.67 g, 5.28 mmol)
in hexamethyldisilazane (10 mL) and the mixture refluxed
with exclusion of moisture until a clear solution was obtained
A solution of ester 7 (13.5 g, 64.9 mmol) in dry Et2O (300 mL)
was added dropwise at 0 ЊC to a suspension of LiAlH4 (3.3 g,
86.5 mmol) in Et2O (300 mL). The mixture was stirred at room
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(2 h). The solvent was evaporated and the residue taken up in
dry MeCN (20 mL). The 1,3-dihydrobenzo[c]furan 10 (1.0 g,
3.52 mmol) was added and then trimethylsilyl trifluoro-
methanesulfonate (0.956 g, 0.78 mL, 4.22 mmol) was added at
Ϫ35 ЊC, under nitrogen. After stirring under nitrogen for 1 h
sat. NaHCO3 (20 mL) was added, the mixture stirred for 30 min
and then extracted with CH2Cl2 (40 mL). The extract was
worked up and the crude product (yellow oil) chromatographed
(hexane–EtOAc 7:3, then 1:1) to give a mixture of the thymine
nucleoside analogues 15 and 16 as white solid (65%), mp 175–
177 ЊC, cis:trans ratio 1:1.6 (Found: C, 66.50; H, 4.97; N,
7.24. Calc. for C21H18O5N2: C, 66.66; H, 4.79; N, 7.40%).
Crystallisation of this mixture of diastereoisomers from
EtOH gave the pure cis isomer 15; δH (CDCl3) 1.6 (3 H, d, Me),
4.75 (1 H, m, J3,8 4.5, J8a,8b 12.5, H-8a), 4.83 (1 H, m, J3,8b 3.2,
H-8b), 5.59 (1 H, m, H-3), 6.72 (1 H, q, thymine), 7.20–7.60
(8 H, m, H-1 and aromatic H), 7.85 (2 H, m, benzoyl), 8.15
(1 H, br s, NH); δC (CDCl3) 12.0 (Me), 65.6 (C-8), 81.5 (C-3),
87.4 (C-1), 112.4 (thymine), 151.5, 163.7, 166.8 (CO); from
the crystallisation liquor the trans isomer 16 was obtained in
70% diastereoisomeric purity; δH (CDCl3) 1.5 (3 H, d, Me), 4.54
(1 H, m, J3,8a 6.6, J8a,8b 11.9, H-8a), 4.66 (1 H, m, J3,8b 3.6,
H-8b), 6.57 (1 H, q, thymine), 5.85 (1 H, J1,3 2.9, H-3), 7.30–
7.60 (8 H, m, aromatic H and H-1), 7.95 (2 H, m, benzoyl), 8.15
(1 H, br s, NH); δC (CDCl3) 12.8 (Me), 66.6 (C-8), 82.5 (C-3),
88.2 (C-1), 151.0, 163.8, 166.8 (CO).
removed under vacuum. The residue was partitioned between
dichloromethane (30 mL) and ice-cold sat. aq. NaHCO3
(30 mL). The aqueous phase was extracted with dichloro-
methane and the combined extracts worked up to give the
1,2,4-triazol-1-yl derivatives 19 or 20 respectively which were
each used directly without further purification. cis-Isomer 19,
Rf 0.59 (CHCl3–MeOH, 9:1); δH (DMSO) 4.80 (1 H, m,
J3,8a 5.4, J8a,8b 12.0, H-8a), 4.84 (1 H, m, J3,8b 3.2, H-8b), 5.74
(1 H, m, H-3), 6.66 (1 H, d, J 7.2, cytosine), 7.45–7.65 (8 H, m,
H-1 and aromatic H), 7.85 (2 H, m, benzoyl), 8.02 (1 H, d,
cytosine), 8.37 (1 H, s, NH), 9.44 (1 H, s, triazolyl); δC (DMSO)
66.1 (C-8), 82.6 (C-3), 89.6 (C-1); trans isomer 20, Rf 0.62
(CHCl3–MeOH 9:1); δH (DMSO) 4.63 (1 H, m, J3,8a 5.1, J8a,8b
12.0, H-8a), 4.76 (1 H, m, J3,8b 3.2, H-8b), 6.10 (1 H, J1,3 2.9,
H-3), 6.90 (1 H, 2 d, J 7.2, cytosine), 7.40–7.66 (8 H, m,
aromatic H and H-1), 7.81 (2 H, m, benzoyl), 8.19 (1 H,
d, cytosine), 8.38 (1 H, br s, NH), 9.44 (triazolyl); δC (DMSO)
66.3 (C-8), 83.0 (C-3), 90.6 (C-1).
30% Aq. NH3 (3 mL) was added to a solution of the 1,2,4-
triazol-1-yl derivative 19 or 20 (0.5 g, 1.05 mmol) in 1,4-dioxane
(9 mL) and the mixture stirred at 20 ЊC for 12 h. The solvent
was evaporated and the residue dissolved in methanol (10 mL)
which was previously saturated with ammonia. The mixture
was stirred for 24 h, the solvent evaporated and the residue
purified by flash chromatography (CHCl3–MeOH, 4:1) to give
the cytosine nucleoside analogue 21 or 22 respectively; cis
isomer 21, 235 mg (75%); mp 164–166 ЊC (aq. EtOH); Rf 0.11
(CHCl3–MeOH 9:1); δH (DMSO) 3.83 (2 H, m, H-8), 5.04
(1 H, t, OH), 5.22 (1 H, m, H-3), 5.62 (1 H, d, J 7.3, uracil),
7.2 (3 H, br m, NH2 and cytosine), 7.2–7.45 (8 H, m, H-1 and
aromatic H); δC (DMSO) 63.1 (C-8), 84.2 (C-3), 87.2 (C-1),
94.5, 137.7, 165.9 (cytosine), 122.1, 122.4, 128.5, 129.2, 140.3,
141.8 (aromatic C), 155.7 (CO); trans isomer 22, 275 mg (88%);
mp 204–206 ЊC (aq. EtOH); Rf 0.11 (CHCl3–MeOH, 9:1)
(Found: C, 59.70; H, 5.11; N, 16.06. Calc. for C13H14N3O3: C,
59.85; H, 5.41; N, 16.11%); δH (DMSO) 3.63 (1 H, m, J3,8a 5.5,
J8a,8b 11.7, H-8a), 3.72 (1 H, m, J3,8b 4.5, H-8b), 4.95 (1 H, t,
OH), 5.48 (1 H, m, J1,3 2.7, H-3), 5.63 (1 H, d, J 7.6, cytosine),
7.05 (1 H. d, cytosine), 7.21 (2 H, br s, NH2), 7.39 (1 H, d,
J1,3 2.7, H-1), 7.25–7.45 (aromatic H); δC (DMSO) 64.0 (C-8),
84.8 (C-3), 88.1 (C-1), 94.7, 137.8, 165.6 (cytosine), 122.1,
122.3, 128.5, 129.2, 140.4, 141.2 (aromatic C), 155.5 (CO).
cis- and trans-1-(1,3-Dihydro-3-hydroxymethylbenzo[c]furan-1-
yl)uracil (13 and 14)
The protected nucleoside 11 (0.5 g, 1.37 mmol) was dissolved in
methanolic ammonia (20 mL) and the mixture stirred for 24 h.
Evaporation of the solvent and column chromatography
(CHCl3–MeOH, 9:1) gave the cis isomer 13 (0.27 g, 75%); mp
115–117 ЊC (EtOH) (Found: C, 59.90; H, 4.75; N, 10.44. Calc.
for C13H12N2O4: C, 59.99; H, 4.65; N, 10.77%); δH (DMSO)
3.83 (2 H, dd, J3,8 3.2, J8,OH 5.0, H-8), 5.05 (1 H, t, OH), 5.24
(1 H, m, H-3), 7.29 (1 H, s, H-1), 5.52, 7.31 (2 H, 2 d, J 8.1,
uracil), 7.30–7.50 (4 H, m, aromatic H), 11.4 (1 H, br s, NH);
δC (DMSO) 62.8 (C-8), 84.4 (C-3), 86.6 (C-1), 102.1, 136.3
(uracil), 122.2, 122.5, 129.5, 131.2, 140.5, 141.0 (aromatic C),
151.1, 163.2 (CO).
Nucleoside 12 was deprotected in the same way as above to
give the trans isomer 14 (88%) as a hygroscopic off-white solid;
δH (DMSO) 3.64 (1 H, ddd, J8a,8b 11.9, J3,8a 4.8, J8,OH 5.5, H-8a),
3.73 (1 H, ddd, J3,8b 4.0, H-8b), 4.94 (1 H, t, OH), 5.49 (1 H,
m, H-3), 5.51, 7.03 (2 H, 2 d, J 8.1, uracil), 7.32 (1 H, d, J1,3 2.68
[in CDCl3], H-1), 7.30–7.50 (4 H, m, aromatic H), 11.4 (1 H,
br s, NH); δC (DMSO) 63.8 (C-8), 85.1 (C-3), 87.6 (C-1), 102.4,
136.2 (uracil), 122.2, 122.4, 128.6, 129.6, 140.7, 140.8 (aromatic
C), 150.9, 163.1 (CO).
(S)- and (R)-1-[2-(1,3-Dioxan-2-yl)phenyl]ethane-1,2-diol
(24 and 25)
AD-mix-α or AD-mix-β (19.98 g) in a mixture of tert-butyl
alcohol (71.35 mL) and water (71.35 mL) was stirred at room
temperature until both phases were clear. The mixture was
cooled to 0 ЊC and [2-(1,3-dioxan-2-yl)phenyl]ethene (2.71 g,
14.27 mmol) was added to the mixture at Ϫ10 ЊC. The resulting
slurry was stirred vigorously at 0 ЊC for 1 h. Sodium sulfite
(21.4 g) was added and the mixture stirred at 20 ЊC for 30 min,
then diluted with water (80 mL) and extracted with dichloro-
methane. This extract was worked up and the crude product
purified by column chromatography (gradient of hexane–
EtOAc, 3:7; then 2:8, then 1:9, then pure EtOAc) to give the
diol as an oil (Found: C, 63.03; H, 7.35. Calc. for C12H16O4ؒ
0.25H2O: C, 63.00; H, 7.27%); AD-mix-α reagent gave the
(S)-enantiomer 24, 2.7 g (85%) (ee >99% by comparison of
NMR spectra with added chiral shift reagent), [α]D22 ϩ32.8
(c 3.86 in CHCl3); AD-mix-β gave the (R)-enantiomer 25,
2.5 g (78%) (ee >99% by comparison of NMR spectra with
added chiral shift reagent), [α]D22 Ϫ33.6 (c 3.42 in CHCl3); both
enantiomers had Rf 0.1 (hexane–ethyl acetate, 3:7); δH (CDCl3)
1.46, 2.25, 3.89, 4.25 (6 H, m, dioxanyl), 2.7, 3.2 (2 H, two br s,
OH), 3.75 (2 H, m, OCH2), 5.24 (1 H, m, OCH), 5.81 (1 H, s,
dioxanyl), 7.4–7.65 (4 H, m, aromatic H); δC (CDCl3) 25.6,
67.2, 67.6, 101.0 (dioxanyl), 67.2, 70.5 (OCH2CHO), 126.7,
126.9, 127.8, 129.3, 135.6, 139.0 (aromatic C).
cis- and trans-1-(1,3-Dihydro-3-hydroxymethylbenzo[c]furan-1-
yl)thymine (17 and 18)
Protected nucleoside 15 or 16 (1.39 g, 3.67 mmol) in meth-
anolic ammonia (70 mL) was stirred at room temperature for
24 h. The solvent was evaporated off and the residue purified by
chromatography (hexane–ethyl acetate, 3:8) to give compound
17 or 18 identical to the products reported previously.7
cis- and trans-1-(1,3-Dihydro-3-hydroxymethylbenzo[c]furan-1-
yl)cytosine (21 and 22)
Et3N (1.91 mL, 13.73 mmol) was added dropwise to a stirred
mixture of 1,2,4-triazole (0.99 g, 14.37 mmol), POCl3 (0.47 g,
0.29 mL, 3.05 mmol) and acetonitrile (10 mL) cooled to 0 ЊC.
A solution of the uracil nucleoside analogue 11 or 12 (1.0 g,
1.37 mmol) in acetonitrile (5 mL) was added and the mixture
stirred at 24 ЊC for 24 h. Et3N (1.4 mL, 9.59 mmol) and water
(0.6 mL) were added, and after 10 min the solvents were
3564
J. Chem. Soc., Perkin Trans. 1, 2000, 3561–3565

View Article Online
(S)- and (R)-1-O-Benzoyl-2-[2-(1,3-dioxan-2-yl)phenyl]ethane-
1,2-diol (26 and 27)
give the (1S,3R) isomer 33, [α]D27 ϩ25 (c 2.4 in CHCl3), and the
(1R,3R) isomer 32 [α]D27 ϩ98 (c 2.4 in CHCl3). Each of these
isomers had NMR data identical to those of the corresponding
racemic compounds 11 and 12.
Benzoyl chloride (12.55 g, 18.15 mmol) in chloroform (6 mL)
was added to the diol 24 or 25 (3.7 g, 16.53 mmol) in pyridine
(39 mL) at Ϫ20 ЊC and the mixture stirred for 2 h at Ϫ10 ЊC,
then overnight at 20 ЊC. Ice–water was added, the mixture
stirred for 30 min and then extracted with dichloromethane.
This extract was worked up and the crude product purified by
column chromatography (hexane–ethyl acetate, 7:3) to afford
the protected diol 26 or 27 as an oil, 4.9 g (89%) (Found: C,
69.02; H, 6.08. Calc. for C19H14O4: C, 69.49; H, 6.14%); (S)-
enantiomer (26) [α]D22 ϩ30.2 (c 4.04 in CHCl3), (R)-enantiomer
27 [α]D22 Ϫ28.9 (c 3.97 in CHCl3); both enantiomers had Rf 0.5
(hexane–ethyl acetate, 7:3); δH (CDCl3) 1.45, 2.23, 4.00, 4.25
(6 H, m, dioxanyl), 3.1 (1 H, d, OH), 4.43, 4.67 (2 H, two dd,
OCH2), 5.55 (1 H, m, OCH), 5.74 (1 H, s, dioxanyl), 7.2–8.2
(4 H, m, aromatic H); δC (CDCl3) 25.6, 67.47, 67.54, 100.8
(dioxanyl), 68.6, 69.1 (OCH2CHO), 171.2 (CO).
(1R,3S)-, (1S,3S)-, (1R,3R)- and (1S,3R)-1-(3-Hydroxymethyl-
1,3-dihydrobenzo[c]furan-1-yl)uracils (34, 35, 36 and 37)
Each of the protected nucleosides was treated as detailed above
for the racemic compounds to give the stereochemically pure
uracil derivatives; (1R,3S) isomer 34, mp 164–166 ЊC, [α]D25 ϩ69
(c 1.5, MeOH); (1S,3S) isomer 35, mp 87 ЊC, [α]D25 Ϫ90 (c 1.0,
MeOH); (1R,3R) isomer 36, [α]D25 ϩ89 (c 1.2, MeOH); (1S,3R)
isomer 37, [α]D25 Ϫ67 (c 0.9, MeOH). In all cases the NMR data
were identical to those of the racemic compounds 13 and 14.
References
1 For recent reviews of antiviral research see: (a) Design of
Anti-AIDS Drugs, ed. E. De Clercq, Vol. 14 Pharmacochemistry
Library, Elsevier, Amsterdam, 1990; (b) D. M. Huryn and
M. Okabe, Chem. Rev., 1992, 98, 1745; (c) A. A. Krayevsky and
K. A. Watanabe, Modified Nucleosides as Anti-AIDS Drugs: Current
Status and Perspectives, Bioinform, Moscow, 1993; (d) Nucleosides
and Nucleotides as Antitumor and Antiviral Agents, ed. C. K. Chu
and D. C. Baker, Plenum Press, New York, London, 1993;
(e) R. J. Young and R. Challand, Antiviral Chemotherapy, Bio-
chemical and Medicinal Chemistry Series, ed. J. Mann, Spectrum
Academic Publishers, Oxford, 1996.
2 J. Balzarini, G.-J. Kang, M. Dalal, P. Herdewijn, E. De Clercq,
S. Broder and D. G. Johns, Mol. Pharmacol., 1987, 32, 162.
3 T.-S. Lin and M.-C. Lui, in Nucleosides and Nucleotides as
Antitumor and Antiviral Agents, eds. C. K. Chu and D. C. Baker,
Plenum Press, New York, London, 1993, pp. 177–201; see also
M. Nasr and S. R. Turk, pp. 203–217.
(1S,3S)- and (1R,3R)-3-Benzoyloxymethyl-1,3-dihydro-1-
methoxybenzo[c]furan (28 and 29)
Compound 26 or 27 (4.74 g, 14.43 mmol) and toluene-p-
sulfonic acid (0.18 g, 0.9 mmol) in a mixture of acetone (47 mL)
and water (54 mL) was refluxed for 2.5 h. The solution was
neutralised (sat. aq. Na2CO3) and extracted with ethyl acetate,
dried (MgSO4) and concentrated in vacuo to give the 1-
hydroxy-1,3-dihydrobenzo[c]furan derivative as a white solid,
3.5 g (90%), mp 94–96 ЊC, Rf 0.2 (hexane–ethyl acetate, 7:3)
(Found: C, 70.92; H, 5.27. Calc. for C16H14O4: C, 71.10; H,
5.22%). This material (3.21 g, 11.88 mmol) was methylated
directly by stirring with methanolic HCl (1%, 60 mL) at 20 ЊC
for 1 h. The solution was concentrated to about 10 mL and
the precipitate collected to give the 1,3-dihydro-1-methoxy-
benzo[c]furan 28 or 29 as a white solid, 3.1 g (92%); Rf 0.5
(hexane–ethyl acetate, 7:3); mp 102–104 ЊC (Found: C, 72.00;
H, 5.60. Calc. for C17H16O4: C, 71.81; H, 5.67%); (1S,3S)-
enantiomer [α]D22 ϩ53.5 (c 2.5 in CHCl3) (1R,3R)-enantiomer
[α]D22 Ϫ54.2 (c 2.5 in CHCl3); both enantiomers had NMR data
identical to those for the racemic compound trans-10.
4 A. P. Lea and D. Faulds, Drugs, 1996, 51, 846.
5 M. T. Crimmins and B. W. King, J. Org. Chem., 1996, 61, 1236.
6 E. Palomino, D. Kessel and J. P. Horowitz, J. Med. Chem., 1989,
32, 622; J. M. Gallo, Adv. Drug Delivery Rev., 1994, 14, 199.
7 D. F. Ewing, N.-E. Fahmi, C. Len, G. Mackenzie, G. Ronco, P. Villa
and G. Shaw, Nucleosides Nucleotides, 1999, 18, 2613.
8 M. Okabe and R.-C. Sun, Tetrahedron Lett., 1989, 17, 2203;
V. E. Marquez, M. A. Siddiqui, A. Ezzitouni, P. Russ, J. Wang,
R. W. Wagner and M. D. Matteucci, J. Med. Chem., 1996, 39, 3739;
A. Ezzitouni, P. Russ and V. E. Marquez, J. Org. Chem., 1997,
62, 4870; B. K. Chun, S. Olgen, J. H. Hong, M. G. Newton and
C. K. Chu, J. Org. Chem., 2000, 65, 685.
(1R,3S)-, (1S,3S)-, (1R,3R)- and (1S,3R)-1-(3-Benzoyloxy-
methyl-1,3-dihydrobenzo[c]furan-1-yl)uracils (30, 31, 32 and 33)
9 K. J. Divakar and C. B. Reese, J. Chem. Soc., Perkin Trans. 1, 1982,
1171.
Compound 28 was converted to the uracil nucleoside analogue
by the procedure employed above for the racemate. The mixture
of stereoisomers (cis:trans ratio 1:2) was separated by chrom-
atography as above to give the minor (1R,3S) isomer 30 [α]D27 Ϫ26
(c 2.4 in CHCl3), and the major (1S,3S) isomer 31, [α]D27 Ϫ97
(c 2.4 in CHCl3). Similarly compound 29 was converted to a
cis–trans mixture of uracil derivatives which was separated to
10 K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino,
J. Hartung, K.-S. Jeong, H.-L. Kwong, K. Moikawa, Z.-M. Wang,
D. Xu and X.-L. Zhang, J. Org. Chem., 1992, 57, 2768; H. C. Kolb,
M. S. VanNieuwenhze and K. B. Sharpless, Chem. Rev., 1994, 94,
2483.
11 H. Vorbrüggen, K. Krolikiewicz and B. Bennua, Chem. Ber., 1981,
114, 1234.
12 C. Len and C. Vaccher, unpublished work.
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