A facile and simple entry into isodideoxynucleosides

Article abstract of DOI:10.1039/b109785g

Sharpless asymmetric dihydroxylations of homoallylic alcohol derivative 3 with AD mix-α afforded α addition product 4a predominantly. Compound 4a was produced with very high selectivity when 3 was treated with AD mix-β. The inherent hydroxylic functionali

Full text of DOI:10.1039/b109785g

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A facile and simple entry into isodideoxynucleosides
Angshuman Chattopadhyay* and Avinash Salaskar
Bio-organic Division, Bhabha Atomic Research Centre, Mumbai-400 085, India
1
Received (in Cambridge, UK) 25th October 2001, Accepted 25th January 2002
First published as an Advance Article on the web 18th February 2002
Sharpless asymmetric dihydroxylations of homoallylic alcohol derivative 3 with AD mix-α afforded α addition
product 4a predominantly. Compound 4a was produced with very high selectivity when 3 was treated with AD mix-β.
The inherent hydroxylic functionalities of 4a were judiciously exploited to develop a simple and efficient synthesis of
(3ЈS,5ЈS)-isodideoxynucleosides. I and II are two representative target molecules for our synthesis in this regard.
dideoxyisonucleosides as well. Here, in order to establish the
viability of our strategy, we present the synthesis of a pyrimidine-
isodideoxynucleoside (I) and a purineisodideoxynucleoside
(II), as representative target molecules, both with S,S absolute
Introduction
During the last two decades, there has been ever-increasing
attention paid to the synthesis of different analogs of natural
nucleosides and to understanding their chemistry with regard
to biological perspectives. This has been triggered by the finding
that a number of 2Ј,3Ј-dideoxynucleosides like ddI, ddC, AZT,
etc. are effective therapeutic agents for the treatment of AIDS.1
Subsequently, many modified nucleosides have become useful
agents for the treatment of cancer and viral diseases due to their
good antitumour and antiviral activity.2 Unfortunately, the
therapeutic use of these dideoxynucleosides and other deoxy-
purine nucleosides is often restricted due to the rapid hydrolysis
of their glycosidic linkage under acidic conditions, such as
stereochemistry which is comparable with -dideoxynucleo-
those in the gastric environment, and because of the action of
sides. It is worth mentioning that a variety of -enantiomers of
enzymes.3 In view of this, the molecular design and synthesis of
known antiviral nucleosides have antiviral activity equal to or
bioactive nucleosides that are stable towards acid and enzym-
better than their -enantiomers, besides having lower cyto-
atic deamination has drawn considerable attention in recent
toxicity.6e,f It is believed that these -isomers or their tri-
years. Besides this, the toxicities associated with certain nucleo-
phosphate derivatives interact with viral enzymes and inhibit
side analogs, as well as the emergence of drug-resistant viral
viral DNA production without causing any significant change
strains, warrant the search for additional novel and structurally
to normal human DNA. Thus, the synthesis of modified
diverse compounds with improved biological efficiency and
-nucleosides assumes enormous significance in one’s hopes of
minimal toxic effects.
producing safer drugs. Both I and II comprise a pentofuranose
Among different nucleoside analogs, isonucleosides represent
skeleton with a base and a functionalized as well as chiral
a class in which the nucleobase is linked with 2Ј-deoxyribose at
carbon chain substituent at the 3Ј- and 5Ј-position, respectively,
different positions other than the C-1Ј of the normal 2Ј,3Ј-
maintaining a cis relationship with each other (in isonucleosides
dideoxynucleosides (using normal nucleoside numbering, Chart
the numbering of the furan ring atoms is different from that
1). Consequently, several - and -isonucleosides are reported to
of the normal nucleosides as shown in Chart 1). As will be
evident later on, our route has an inherent flexibility regard-
ing the achievement of various stereo chemical and structural
modifications of the resulting isodideoxynucleosides.
Results and discussion
Chart 1
Our retrosynthetic analysis is outlined in Scheme 1. We envis-
exhibit activity against a broad spectrum of viruses and some
tumour cell lines,4 in addition to a number of branched-chain
sugar isonucleosides that are found to possess interesting bio-
logical activities.5 Quite obviously, the absence of a glycosidic
linkage in their structures makes isodideoxynucleosides con-
siderably stable chemically. In view of their possible therapeutic
Scheme 1
potential, the preparation of isonucleosides with varied struc-
tural and/or stereochemical combinations has drawn enormous
attention from synthetic chemists in recent years.6
In our ongoing programme on the synthesis of bioactive
compounds, we have earlier exploited the easily available (R)-
2,3-O-cyclohexylideneglyceraldehyde (1) for the synthesis of
2Ј,3Ј-dideoxynucleosides.7a–c We herein report its utility in
developing a short and very simple route for the synthesis of
aged the synthesis of the target molecules via an asymmetric
dihydroxylation of an olefin and a ring-closing reaction as the
key steps. We started with silyl derivative 37d (Scheme 2) of the
homoallylic alcohol 2b that is stereoselectively preparable7d
from 1 on a practical scale. The terminal olefin of 3 was sub-
jected to asymmetric dihydroxylation using both types of
Sharpless reagent,8 AD mix-α [K2OsO2(OH)4, (DHQ)2-PHAL
(hydroquinine 1,4-phthalazinediyl diether), K3Fe(CN)6 and
DOI: 10.1039/b109785g
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This journal is © The Royal Society of Chemistry 2002
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Scheme 2 Reagents: i) ref. 7d; ii) AD mix-α or AD mix-β, t-BuOH–H2O; iii) BzCN, TEA, CH2Cl2; iv) TBAF, THF; v) 2,2-dimethoxypropane,
PTSA; vi) p-Tos-Cl, Py, DMAP; vii) thymine, K2CO3, 18-Crown-6, DMF; viii) CF3COOH–H2O, CH2Cl2; ix) adenine, K2CO3, 18-Crown-6, DMF;
x) BzCl, TMSCl, Py; xi) NH3, MeOH.
K2CO3] and AD mix-β [K2OsO2(OH)4, (DHQD)2-PHAL
(hydroquinidine 1,4-phthalazinediyl diether), K3Fe(CN)6 and
K2CO3] to produce diols 4a and 4b in good yield and in both the
cases hydroxylation predominantly took place from the α-face.
However, AD mix-α reaction yielded 4a and 4b as the major
and minor products respectively (4a : 4b 77.5 : 22.5), while use
of AD mix-β produced 4a with very high selectivity (4a : 4b
95.5 : 4.5). The diasteromers 4a and 4b are conveniently separ-
able from each other by normal column chromatography. The
stereochemistry at the site (C-2 position) bearing the freshly
generated secondary hydroxy group of diol 4a was assigned to
be similar to that of the major product in the case of a reported
AD mix-α dihydroxylation of a homoallylic alcohol9a that has
good structural resemblance with 2b. Furthermore, the pattern
of the 1H-NMR spectrum of diol 4a showing four nicely separ-
able multiplets at δ 3.41–3.50 (1H), 3.57–3.65 (1H), 3.76–3.84
(2H) and 4.01–4.10 (3H) is appreciably comparable (in that
spectral region) to that of the major dihydroxylation product.9a
Finally, the C-2 stereochemistry of diol 4a was determined from
the acetonide (4d) that was prepared in three steps, viz selective
monobenzoylation of the primary hydroxy group of 4a, desilyl-
ation of its other hydroxy group, and acid-catalyzed reaction of
the resulting 1,3-diol (4c) with 2,2-dimethoxypropane. In the
13C-NMR spectrum of compound 4d, the signals at δC 19.7 and
31.0 (due to two methyls) and at δC 98.6 (due to ketal carbon) of
the acetonide moiety of the six membered ring confirm the syn
relationship10 of the corresponding 1,3-diol unit of diol 4c. It
1
is worth mentioning that the H-NMR spectrum of the minor
product (4b) shows three nearly overlapping multiplets at
δ 3.42–3.47 (1H), 3.50–3.8 (3H) and 3.84–4.2 (3H). It is inter-
esting to note that both AD mix-α and AD mix-β gave the
same compound 4a as the major product, in contrast with the
usual observations that show a change in selectivity.8b More-
over, for dihydroxylation of their homoallylic alcohol sub-
strate Herdewijn et al. didn’t observe appreciable variation of
selectivity while using AD mix-α9a or AD mix-β.9b However, in
our case the selectivity of the formation of diol 4a improved
drastically in the case of AD mix-β.
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Tosylation of diol 4a using two equivalents of toluene-p-
sulfonyl chloride yielded ditosylderivative 5 in appreciable yield.
Desilylation of 5 with tetrabutylammonium fluoride (TBAF)
took place with concomitant intramolecular substitution of the
primary OTs group to generate compound 6 only. In this case,
the tetrahydrofuran moiety of 6 was produced with absolute
regioselectivity as the other route, involving the formation of a
highly strained oxetane via intramolecular substitution of the
secondary OTs group of 5, is thermodynamically unfavourable.
Moreover, substitution of the more reactive and less hindered
primary OTs group in 5 is kinetically favourable with respect to
substitution of the secondary one. Now, compound 6 has been
separately treated with thymine and adenine to produce iso-
dideoxynucleosides 7a and 7b, respectively, following invertive
SN2 displacement of OTs at C-3Ј with the bases. After usual
work-up, the crude residue containing compound 7a was as
such subjected to deketalization by treatment with aqueous tri-
fluoroacetic acid to yield compound I. Benzoylation of the NH2
group of 7b and deketalization of the product afforded the diol
8. Finally, debenzoylation of compound 8 has been effected
smoothly to afford compound II.
the same solvent mixture (120 mL). The mixture was stirred at
0 ЊC for 6 h and then at room temperature overnight. It was
then cooled to 0 ЊC and treated with solid Na2SO3 (7 g). The
mixture was stirred for 1 h at room temperature and extracted
with chloroform. The combined organic extract was washed
successively with water and brine and then dried. Solvent
removal and column chromatography of the residue (silica gel;
0–5% methanol in chloroform, v/v) afforded diols 4a (1.17 g,
65%) and 4b (340 mg, 18.9%). The Rf (5% methanol in
chloroform)-values of 4a and 4b are 0.60 and 0.51, respectively.
Diol 4a. [α]2D2 ϩ9.03 (c 0.30, CHCl3); νmax/cmϪ1 (film) 3419,
2857, 1364, 1252; 1H-NMR (CDCl3) δ 0.08 (s, 6H), 0. 87 (s, 9H),
1.4–1.6 (m, 10H, overlapped with br s, D2O-exchangeable,
2H), 1.7–1.8 (m, 2H), 3.41–3.50 (m, 1H), 3.57–3.65 (m, 1H),
3.76–3.84 (m, 2H), 4.01–4.10 (m, 3H).
Diol 4b. [α]2D2 ϩ20.72 (c 0.40, CHCl3); νmax/cm (film) 3419,
Ϫ1
1
2857, 1364, 1252; H-NMR (CDCl3) δ 0.078 (s, 6H), 0. 89
(s, 9H), 1.4–1.6 (m, 10H), 1.7–1.8 (m, 2H, overlapped with br s,
D2O exchangeable, 2H), 3.42–3.47 (m, 1H), 3.50–3.80 (m, 3H),
3.84–4.2 (m, 3H).
Using AD mix-ꢁ. Following an identical experimental pro-
cedure as above, olefin 3 (1.64 g, 0.005 mol) was treated with
AD mix-β (14.5 g) in t-BuOH–water (1 : 1, v/v) to produce diols
4a (1.47 g, 81.7%) and 4b (70 mg, 3.9%).
Conclusions
In summary, a short and straightforward route for the synthesis
of isodideoxynucleosides has been developed starting with
easily available aldehyde 1. This has been generalized through
the preparation of both a pyrimidyl (I) and a purinyl (II)
nucleoside. Both nucleoside analogs I and II have, at the C-5Ј
position, rather than a hydroxymethyl functionality as observed
normally, a functionalized chiral substituent comprising both a
primary and a secondary hydroxy group that are amenable to
versatile chemical and stereochemical elaboration independ-
ently of each other. The efficacy of this approach lies in the
easy availability of anti-2b on a reasonably good scale7d and
the highly stereoselective dihydroxylation of olefin 3 under prac-
tically stereospecific conditions. Moreover, the reasonable
stability of the cyclohexylidene ketal functionality proved to be
considerably advantageous as this, by efficiently protecting two
hydroxy groups, affords selective manipulation of the other
(protected) hydroxy group of the intermediates without any
difficulty. In hindsight, this route has the inherent advantage of
attaining stereochemical flexibility through exploitation of the
corresponding syn-alcohol 2a that can be prepared stereo-
selectively.7c Furthermore, starting from readily available alde-
lyde (S)-(1)11 the present protocol is likely to produce another
series of isomers of I and II.
1-O-Benzoyl-2,4-O-isopropylidene-5,6-O-cyclohexylidene-3-
deoxy-D-ribo-hexitol (4d)
To a cooled (0 ЊC) solution of diol 4a (108 mg, 0.3 mmol) in
dichloromethane (20 mL) containing triethylamine (0.02 mL)
was added a solution of benzoyl cyanide (40 mg, 0.31 mmol) in
dichloromethane (10 mL) over a period of 40 min. The mixture
was stirred at that temperature for 30 min more and quenched
with water. The organic layer was washed successively with 5%
aqueous HCl, water, and brine and then dried. Solvent was
removed and the residue was filtered through a short pad of
silica gel with elution with ethyl acetate in hexane (20%, v/v).
The residue after solvent removal from the filtrate was dissolved
in THF (15 mL) and treated with a solution of tetrabutyl-
ammonium fluoride in THF (2.5 mL; 1 M). The mixture was
stirred for 1 h, then treated with water, and extracted with
chloroform. After usual work-up and solvent removal from
the organic layer, the residue was purified by passage
through a short pad of silica gel and elution with MeOH in
CHCl3 (5%, v/v).
The resulting diol 4c was mixed in 2,2-dimethoxypropane
(4 mL) and a catalytic amount of toluene-p-sulfonic acid. The
mixture was stirred for 1 h and treated with water. This mixture
was then extracted with diethyl ether. Usual work-up and solv-
ent removal from the organic extract gave a residue that was
purified by column chromatography (silica gel; 0–10% ethyl
acetate in petroleum ether (60–80 ЊC), v/v) to afford compound
Experimental
Chemicals used as starting materials are commercially available
and were used without further purification. All solvents used
for extraction and chromatography were distilled twice at
atmospheric pressure prior to use. Tetrahydrofuran and ether
were dried by heating over LiAlH4. N,N-Dimethylformamide
was dried by heating over calcium hydride and was then dis-
tilled under reduced pressure. IR spectra were recorded with
1
4d (70 mg, 59.8%); H NMR (CDCl3) δ 1.35 (s, 3H), 1.37
(s, 3H), 1.4–1.6 (m, 10H); 1.8–2.0 (m, 2H), 3.7–4.0 (m, 4H),
4.22–4.32 (m, 3H), 7.30–7.57 (m, 3H), 8.01 (m, 2H); 13C NMR
(CDCl3) δC 166.3 (CO), 132.8 (C, para), 129.9 (C–CO), 129.5
(2C, meta), 128.2 (2C, ortho), 109.9 (O–C–O, cyclohexylidene),
98.6 (O–C(CH3)2–O), 70.3, 67.9, 67.3, 66.8, 64.8 (C-1, C-2, C-4,
C-5, C-6), 36.3 (cyclohexylidene), 34.7 (cyclohexylidene), 31.0
(CH3), 29.7 (C-3), 24.6 (cyclohexylidene), 23.8 (cyclohexyl-
idene), 23.6 (cyclohexylidene), 19.7 (CH3).
a Perkin-Elmer spectrophotometer model 837. H- and 13C-
1
NMR spectra were scanned with a Bruker Ac-200 (200 MHz)
instrument for solutions in CDCl3. Optical rotations were
measured with a JASCO DIP-360 polarimeter; [α]D-values
are given in units of 10Ϫ1 deg cmϪ2 gϪ1. Organic extracts were
desiccated over dry Na2SO4.
5,6-O-Cyclohexylidene-4-O-(tert-butyldimethylsilyl)-3-deoxy-
D-ribo-hexitol (4a) and 5,6-O-cyclohexylidene-4-O-(tert-butyl-
dimethylsilyl)-3-deoxy-D-arabino-hexitol (4b)
5,6-O-Cyclohexylidene-4-O-(tert-butyldimethylsilyl)-1,2-di-
O-tosyl-3-deoxy-D-ribo-hexitol (5)
To a solution of diol 4a (3.6g, 0.01 mol) and 4-(dimethyl-
amino)pyridine (DMAP) (100 mg) in pyridine (30 mL) at 0 ЊC
was added p-tosyl chloride (4.2 g, 0.021 mol). The mixture was
stirred at 0 ЊC for 4 h and then at room temperature overnight.
Using AD mix-ꢀ. A solution of olefin 3 (1.63 g, 0.005 mole) in
a solvent mixture of t-BuOH–water (1 : 1; 25 mL) was added to
a cooled (0 ЊC) and well stirred suspension of AD mix-α (8 g) in
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It was treated with cold water and extracted with ether. The
combined organic extract was washed successively with water,
and brine and then dried. Solvent removal and column chrom-
atography of the residue (silica gel; 0–10% ethyl acetate in
(c 1.09, CHCl3); 1H-NMR (CDCl3) δ 1.3–1.6 (m, 10H), 2.0–2.2
(m, 1H), 2.6–2.8 (m, 1H), 3.65–3.83 (ddd, J = 11.7, 5.7, 4.8 Hz,
1H), 3.9–4.3 (m, 4H), 4.44 (dd, J = 9.8, 5.4 Hz, 1H), 5.33
(m, 1H, H-3), 5.70 (br s, 2H, NH2), 8.23 (s, 1H, adenine), 8.35
(s, 1H, adenine).
hexane, v/v) afforded compound 5 (5.9 g, 88.3%); [α]2D2 ϩ3.17
Ϫ1
(c 0.725, CHCl3); νmax/cm
(film) 2857, 1597, 1371, 1176;
1H-NMR (CDCl3) δ 0.068 (s, 6H), 0.85 (s, 9H), 1.4–1.6
(m, 10H), 1.9–2.0 (m, 2H), 2.44 (s, 6H), 3.5–3.8 (m, 3H), 3.9–4.3
(m, 3H), 4.95 (m, 1H), 7.25–7.35 (m, 4H), 7.68–7.72 (m, 4H).
9-{(3S,5S)-5-[(1R)-1,2-Dihydroxyethyl]tetrahydrofuran-3-yl}-
N 6-benzoyladenine (8)
Following a reported procedure,12 compound 7b (345 mg,
1 mmol) was treated with trimethylsilyl chloride (540 mg,
5 mmol) and benzoyl chloride (700 mg, 5 mmol) in pyridine
(10 mL) to yield the benzoylated product. After usual work-up,
and solvent removal under reduced pressure, the crude residue
was obtained in almost quantitative yield.
2S,4R)-4-( p-Tolylsulfonyloxy)-2-[(1R)-1,2-cyclohexylidene-
dioxyethyl]tetrahydrofuran (6)
A solution of tetrabutylammonium fluoride in THF (25 mL;
1 M) was added to a solution of 5 (3.34 g, 0.005 mol) in THF
(50 mL). The resulting solution was stirred at room temperature
overnight. The reaction was quenched by the addition of satur-
ated aqueous NH4Cl (10 mL). The mixture was diluted with
ether, the phases were separated, and the aqueous phase was
thoroughly extracted with ether. The combined organic extract
was washed successively with water and brine. Solvent was
removed under reduced pressure and the residue was chrom-
atographed (silica gel; 0–15% ethyl acetate in hexane, v/v) to
afford compound 6 (1.51 g, 79.5%) (Found: C, 59.42; H, 7.05.
This, without being purified further, was subjected to deket-
alization by treating its solution in CH2Cl2 (40 mL) with 80%
aqueous trifluoroacetic acid (10 mL) at 0 ЊC. The reaction mix-
ture was concentrated under reduced pressure. The residue was
loaded on a silica gel column and eluted successively with ethyl
acetate, acetone, and methanol in chloroform (7%, v/v) to
afford compound 8 (290 mg, 81.2%); [α]2D2 Ϫ15.19 (c 0.38,
1
MeOH); H-NMR (CD3OD) δ 2.20–2.50 (m, 1H), 2.55–2.75
(m, 1H), 3.50–3.70 (m, 2H), 3.75–4.0 (m, 1H), 4.0–4.50 (m, 3H),
5.43 (m, 1H), 7.52–7.63 (m, 3H, aromatic), 8.0 (d, J = 5.5 Hz,
2H, aromatic), 8.28 (s, 1H, adenine), 8.73 (s, 1H, adenine).
C19H26O6S requires C, 59.66; H, 6.85%); [α]2D2 Ϫ2.01 (c 1.19,
Ϫ1
CHCl3); νmax/cm
(film) 1375, 1180; 1H-NMR (CDCl3)
δ 1.4–1.6 (m, 10H), 1.95–2.34 (m, 2H), 2.44 (s, 3H), 3.66–3.73
(m, 1H), 3.75–3.86 (m, 1H), 3.93–4.13 (m, 4H), 5.11 (m, 1H),
7.34 (d, J = 8 Hz, 2H), 7.78 (d, J = 8 Hz, 2H).
9-{(3S,5S)-5-[(1R)-1,2-Dihydroxyethyl]tetrahydrofuran-3-yl}
adenine (II)
A solution of compound 8 (200 mg, 0.54 mmol) in saturated
methanolic ammonia (30 mL) was stirred for 18 h at room
temperature. The solvent was removed under reduced pressure
and the residue was chromatographed (silica gel; 0–12% meth-
anol in chloroform, v/v) to afford compound II (117 mg, 81.9%)
as white solid (Found: C, 50.05; H, 5.88; N, 26.59. C11H15O3N5
requires C, 49.80; H, 5.69; N, 26.39%); [α]2D2 Ϫ9.84 (c 0.12,
1-{(3S,5S)-5-[(1R)-1,2-Dihydroxyethyl]tetrahydrofuran-3-yl}
thymine (I)
A mixture of thymine (200 mg, 1.6 mmol), potassium carbon-
ate (276 mg, 2 mmol), 18-crown-6 (528 g, 2 mmol) and com-
pound 6 (382 mg, 1 mol) in DMF (25 mL) was stirred at 75–80
ЊC for 15 h. It was cooled to room temperature and chloroform
was added. The organic layer was thoroughly washed with
water to remove DMF, then with brine, and was then dried.
Solvent was removed under reduced pressure. The residue was
partially purified by loading on a short silica gel column and
was eluted successively with ethyl acetate in hexane (15%, v/v)
and methanol in chloroform (5%, v/v) to isolate compound 7a
in the latter fraction which was concentrated under reduced
pressure. The residue was dissolved in CH2Cl2 (40 mL) and
stirred with 80% aqueous trifluoroacetic acid (10 mL) at 0 ЊC
for nearly 1 h until starting material 7a had disappeared (TLC).
The reaction mixture was concentrated under reduced pressure.
The residue was loaded on a silica gel column and eluted suc-
cessively with ethyl acetate, acetone, and methanol in chloro-
form (7%, v/v) to obtain pure compound I in the last fraction
(108 mg, 42.2%) as a white solid (Found: C, 51.36; H, 6.50; N,
11.18. C11H16O5N2 requires C, 51.55; H, 6.29; N, 10.93%); [α]2D2
1
MeOH); H-NMR (CD3OD) δ 2.23 (m, 1H), 2.52 (m, 1H),
3.4–3.6 (m, 2H), 3.7–4.04 (m, 3H), 4.10–4.16 (m, 1H), 5.16 (m,
1H), 8.15 (s, 1H, adenine), 8.18 (s, 1H, adenine); 13C-NMR
(CD3OD) δC 156.3 (C-6), 153.1 (C-2), 146.1 (C-4), 137.4 (C-8),
119.1 (C-5), 82.4 (C-5Ј), 71.8 (C-2Ј), 69.5 (C-6Ј), 63.3 (C-7Ј),
57.1 (C-3Ј), 33.4 (C-4Ј).
References
1 (a) H. Mitsua and S. Broder, Proc. Natl. Acad. Sci. U.S.A., 1986, 83,
1911; (b) H. Mitsua, K. J. Weinhold, P. A. Furman, M. H. St. Clair,
S. N. Lehrman, R. C. Gallo, D. Bolognesi, D. W. Barry and
S. Broder, Proc. Natl. Acad. Sci. U.S.A., 1985, 82, 7096.
2 (a) Nucleosides and Nucleotides as Antitumour and Antiviral Agents,
eds. C. K. Chu and D. C. Baker, Plenum, New York, 1993; (b)
E. De Clercq, in Targets for the Design of Antiviral Agents, eds.
E. De Clercq and R. T. Walker, Plenum, New York, 1994, pp.
203–230; (c) D. M. Huryn and M. Okabe, Chem. Rev., 1992, 92,
1745; (d ) C. Perigaud, G. Gosselin and J. L. Imbach, Nucleosides,
Nucleotides, 1992, 11, 903; (e) H. Mitsua, R. Yarchoan and
S. Broder, Science, 1990, 249, 1533; ( f ) E. De Clerq, Nucleosides
Nucleotides, 1994, 13, 1271.
3 (a) J. L. York, J. Org. Chem., 1981, 46, 2171; (b) V. E. Marquez and
M. I. Lim, Med. Res. Rev., 1986, 6, 1; (c) V. E. Marquez, C. K.
Tseng, J. A. Kelly, H. Mitsua, S. Broder, J. Roth and J. Driscoll,
Biochem. Pharmacol., 1987, 36, 2719; (d ) T. Kawaguchi, S.
Fukushima, M. Ohmura, M. Mishima and M. Nakano, Chem.
Pharm. Bull., 1989, 37, 1944; (e) V. Nair and G. S. Buenger, J. Org.
Chem., 1990, 55, 3695.
4 (a) V. Nair and T. S. Jahnke, Antimicrob. Agents Chemother., 1995,
39, 1017; (b) V. Nair and Z. M. Nuesca, J. Am. Chem. Soc., 1992,
114, 7951; (c) K. F. Soike and V. J. Whiterock, Antiviral Res., 1994,
23, 219; (d ) D. M. Huryn, B. C. Sluboski, S. Y. Tam, M. Weigele,
I. Sim, B. D. Anderson, H. Mitsua and S. Broder, J. Med. Chem.,
1992, 35, 2347; (e) M. F. Jones, S. E. Noble, C. A. Robertson,
R. Storer, R. M. Highcock and R. B. Lamount, J. Chem. Soc.,
Perkin Trans. 1, 1992, 1437.
1
Ϫ5.29 (c 0.378, MeOH); H-NMR (CD3OD) δ 1.86 (s, 3H)
1.87–2.07 (m, 1H), 2.25–2.50 (m, 1H), 3.40–3.65 (m, 3H), 3.75–
4.0 (m, 2H), 4.05–4.10 (m, 1H), 5.1–5.3 (m, 1H, H-3), 7.63 (s,
1H, thymine); 13C-NMR (CD3OD) δC 164.3 (C-4), 151.1 (C-2),
137.6 (C-6), 111.1 (C-5), 79.7 (C-5Ј), 71.7 (C-2Ј), 70.5 (C-6Ј),
63.1 (C-7Ј), 54.6 (C-3Ј), 32.4 (C-4Ј), 11.6 (5-CH3).
9-{(3S,5S)-5-[(1R)-1,2-Cyclohexylidenedioxyethyl]-
tetrahydrofuran-3-yl} adenine (7b)
Following a similar procedure of glycosylation as above,
adenine (404 mg, 3 mmol) was treated with potassium carb-
onate (552 mg, 4 mmol), 18-crown-6 (1.056 g, 4 mmol) and
compound 6 (764 mg, 2 mmol) in DMF (30 mL). After usual
work-up, column chromatography of the residue (silica gel;
0–5% methanol in chloroform, v/v) afforded compound 7b
(432 mg, 62.6%) (Found: C, 59.33; H, 6.60; N, 20.50.
C17H23O3N5 requires C, 59.12; H, 6.71; N, 20.28%); [α]2D2 Ϫ14.10
788
J. Chem. Soc., Perkin Trans. 1, 2002, 785–789

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5 (a) T. Kira, A. Lakefuda, S. Shuto, A. Matsuda, M. Baba and
S. Shigeta, Nucleosides, Nucleotides, 1995, 14, 571; (b) A. Kakefuda,
S. Shuto, T. Nagahada, J. Seki, T. Sasaki and A. Matsuda,
Tetrahedron, 1994, 50, 10167; (c) J. A. Tino, J. M. Clark, A. K. Field,
G. A. Jacobs, K. A. Lis, T. L. Michalik, B. McGreever-Rubin, W. A.
Slarsuchyk, S. H. Spergel, J. E. Sundeen, A. V. Tuomari, E. R.
Weaver, M. G. Young and R. J. Zahler, J. Med. Chem., 1993, 36,
1221.
6 (a) D. M. Huryn, B. C. Sluboski, S. Y. Tam, L. J. Todaro and
M. Weigele, Tetrahedron Lett., 1989, 30, 6259; (b) P. J. Bolon, T. B.
Sells, Z. M. Nuesca, D. F. Pardy and V. Nair, Tetrahedron, 1994, 50,
7747; (c) See ref. 4a; (d ) R. R. Talekar and R. H. Wightman,
Tetrahedron, 1997, 53, 3831; (e) Y. Diaz, F. Bravo and S. J. Castillon,
J. Org. Chem., 1999, 64, 6508 and references cited therein; ( f ) M. E.
Jung and C. J. Nichols, J. Org. Chem., 1998, 63, 347 and references
cited therein.
1999, 64, 6874; (c) B. Dhotare and A. Chattopadhyay, Synthesis,
2001, 1347; (d ) A. Chattopadhyay, J. Org. Chem., 1996, 61,
6104.
8 (a) C. H. Kolb, M. S. VanNieuwenhze and K. B. Sharpless,
Chem. Rev., 1994, 94, 2483; (b) K. B. Sharpless, W. Amberg, Y. L.
Bennani, G. A. Crispino, J. Hartung, K. Jeong, H. Kwong,
K. Morikawa, Z. Wang, D. Xu and X. Zhang, J. Org. Chem., 1992,
57, 2768.
9 (a) N. Hossain, J. Rozenski, E. D. Clercq and P. Herdewijn,
Tetrahedron, 1996, 52, 13655; (b) N. Hossain, Z. Rozenski, E. D.
Clercq and P. Herdewijn, J. Org. Chem., 1997, 62, 2442.
10 (a) D. A. Evans, D. L. Riger and J. R. Gage, Tetrahedron Lett., 1990,
31, 7099; (b) S. D. Rychnovsky and D. J. Skalitzky, Tetrahedron Lett.,
1990, 31, 945.
11 M. Grauert and U. Scholkopf, Justus Leibigs Ann. Chem., 1985,
1817.
7 (a) A. Chattopadhyay, Tetrahedron Asymmetry, 1997, 8, 2727; (b)
A. Chattopadhyay, S. Hassrajani and B. Dhotare, J. Org. Chem.,
12 G. S. Ti, B. L. Gaffney and R. A. Jones, J. Am. Chem. Soc., 1982,
104, 1316.
J. Chem. Soc., Perkin Trans. 1, 2002, 785–789
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