Facile conversion of 4-endo-hydroxy-2-oxabicyclo[3.3.0]oct-7-en-3-one into carbocyclic 2′-deoxyribonucleoside analogues

Article abstract of DOI:10.1039/a906464h

The readily available 3,5-syn-disubstituted cyclopentenes 9-13 react with N-bromosuccinimide (or N-bromoacetamide) and silver acetate in glacial acetic acid in a highly stereoselective manner to furnish the bromoacetates 14-18 in good yields, A plausible

Full text of DOI:10.1039/a906464h

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Facile conversion of 4-endo-hydroxy-2-oxabicyclo[3.3.0]oct-7-en-3-
one into carbocyclic 2Ј-deoxyribonucleoside analogues
Anupma Dhanda,a Lars J. S. Knutsen,b† May-Britt Nielsen,a Stanley M. Robertsa and
David R. Varleyc
a Department of Chemistry, University of Liverpool, Liverpool, UK L69 7ZD
b Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Malov, Denmark
c Department of Chemistry, University of Exeter, Exeter, Devon, UK EX4 4QD
Received (in Cambridge, UK) 9th August 1999, Accepted 11th October 1999
The readily available 3,5-syn-disubstituted cyclopentenes 9–13 react with N-bromosuccinimide (or N-bromo-
acetamide) and silver acetate in glacial acetic acid in a highly stereoselective manner to furnish the bromoacetates
14–18 in good yields. A plausible explanation for the observed selectivity is proposed. Hydrodebromination of
compounds 14, 17, 18 and 19 provided the corresponding 2Ј-deoxyribonucleoside analogues 20–23.
Introduction and background information
The disubstituted cyclopentenes 1, 2 and simple derivatives are
readily available and have been shown to be valuable building
blocks in organic synthesis.1 We have contributed to this field
Fig. 1
previously by demonstrating that both these molecules may be
usedtomakeselected2Ј,3Ј-dideoxydidehydrocarbocyclicnucleo-
transformed into the dichloro compound 13 through diazo-
tization and a modified Sandmeyer reaction.
sides of type 3 (Fig. 1) as well as aristeromycin.2
The ready availability of compounds of type 3 has encour-
aged researchers to investigate regio- and stereo-controlled
functionalisation of the alkene unit. However, the control
of stereochemistry on addition to the olefin bond can be
unexpectedly capricious. For example, dihydroxylation of 3
(R = COCH3, base = adenine) using osmium tetraoxide and
N-methylmorpholine N-oxide gave a mixture of ribo- and lyxo-
nucleoside analogues which proved to be difficult to separate.3
Similarly, conversion of 2Ј,3Ј-dideoxydidehydrocarbocyclic
nucleosides into carbocyclic deoxyribonucleosides by hydro-
boration followed by treatment with basic peroxide gave a
mixture of 2Ј- and 3Ј-deoxycarbocyclic nucleosides.4
In contrast we reported recently that cyclopentene derivatives
of type 3 gave bromoacetates regio- and stereo-selectively on
treatment with N-bromosuccinimide (NBS) or N-bromo-
acetamide (NBA) and silver acetate in acetic acid at room tem-
perature over 18 hours.5 In this paper we detail this method-
ology and show how the strategy may be applied to the syn-
thesis of a wide range of carbocyclic 2Ј-deoxyribonucleoside
derivatives.
The key step in the conversion of the 2Ј,3Ј-dideoxydidehydro-
carbocyclic nucleosides 9–13 into 2Ј-deoxyribonucleosides
involves regio- and stereo-selective bromo-acetoxylation
employing N-bromosuccinimide (or N-bromoacetamide) with
silver acetate in acetic acid. The corresponding bromo-acetates
14–18 were formed as the sole products in 47–69% isolated
yield, except in the case of the conversion of alkene 12 into
bromo-acetate 18 when a small amount (13%) of an unidenti-
fied isomer of 18 was isolated by chromatography. Treatment
of the 5Ј-tritylated compound 16 with aqueous acetic acid
furnished the alcohol 19.
The structure of the bromo-ester 14 was elucidated by X-ray
crystallography5 and the analogues 15–18 were assigned the
same stereochemistry as 14 on account of the similarity of the
spin patterns in the 1H NMR spectra of all these haloesters.
Hydrodehalogenation of the bromo-compounds 14, 17, 18
and 19 was accomplished using tri-n-butyltin hydride in
hot tetrahydrofuran containing azoisobutyronitrile (AIBN)
(Scheme 2). The isolated yields of the carbocyclic nucleosides
20, 21, 22 and 23 were good to excellent (68–92%). Alternatively
the bromoester 14 may be converted into the epoxide 24 in
69% yield using potassium carbonate in methanol at room
temperature.8
Results and discussion
Our preferred pathway to diol 2 and hence esters 4 and 5
involves the preparation and further transformation of the
hydroxy-lactone 6 (Scheme 1) as described previously.6 On
the other hand, lithium aluminium hydride (LAH) reduction of
the lactone 6 provided the triol 7 which was readily converted
into the triacetate 8.
Transformation of the esters 4 and 5 into 2Ј,3Ј-dideoxy-
didehydrocarbocyclic nucleosides 9–11 involved organo-
palladium chemistry, paralleling methodology introduced and
popularised by Trost and co-workers.7 Similarly the triacetate 8
was converted into the diester 12, while the aminopurine 9 was
The protected carbocyclic nucleosides may be reacted further
(Scheme 2), for example by removing the acetate groups directly
under mild conditions (20 → 25) or by modifying the base
unit prior to hydrolysis (e.g. 21 → 26 → 27).
As an indication of the simplicity and efficiency of this new
process, the readily available cyclopentene derivative 9 has been
converted into the carbocyclic 2Ј-deoxyribonucleoside 25 in
three steps and 50% yield overall.
Mechanistic considerations
The stereoselectivity of the addition of BrOAc across the
alkene unit in the 3,5-cis-disubstituted cyclopent-1-ene deriv-
atives 9–13 deserves comment.
† Present address, Cerebrus Ltd., Oakdene Court, 613 Reading Road,
Winnersh, Wokingham, UK RG41 5UA.
J. Chem. Soc., Perkin Trans. 1, 1999, 3469–3475
This journal is © The Royal Society of Chemistry 1999
3469

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Scheme 1 Reagents and conditions: i, LiAlH4, THF, reflux, 4 h; ii, Ac2O, pyridine, DMAP, room temp., 24 h, (81% for 4, 100% for 5 and 79% for 8);
iii, triphenylmethyl chloride, dichloromethane, Et3N, DMAP, room temp., 24 h, (78%); iv, NBS or NBA, AgOAc, AcOH, room temp., 18 h, (35% for
14, 48% for 15, 69% for 16, 56% for 17 and 49% for 18); v, 2-amino-6-chloropurine (for 9, 11 and 12), 6-chloropurine (for 10), NaH, Pd(PPh3)4, DMF,
50 ЊC, 3 h, (48% for 9, 28% for 10, 55% for 11 and 48% for 12); vi, Me3SiCl, isopentyl nitrite, dichloromethane 0 ЊC, 2 h → room temp. 5 h, (61%);
vii, AcOH (80%), 50 ЊC, 6 h, (66%).
Fig. 2
Fig. 3
Based on Kitagiri’s studies9 the compounds 9–13 probably
adopt a conformation with the two substituents in equatorial
axial positions and the Cieplak effect cannot operate. In the
latter case bromonium ion formation takes place on the less-
hindered face and the small nucleophile attacks at the more
electropositive site.
positions (Fig. 2). The formation of the intermediate brom-
onium ion is probably reversible.10 The syn-bromonium ion is
favoured by the Cieplak effect,11 with the axial C–H bonds
donating into a low lying, vacant σ* orbital associated with the
incipient bond(s) in the transition state. The acetate anion then
attacks at the position distant from the C–N bond.
Experimental
General details
The addition of silver acetate to the reaction mixture has a
beneficial effect. For example, reaction of the alkene 9 with
NBA in glacial acetic acid but in the absence of silver acetate
resulted in a less selective reaction; while the bromoester 14 was
still a major product, NMR evidence suggested that other
isomers were formed concurrently.
All moisture-sensitive reactions were performed using freshly
distilled anhydrous solvents under a static nitrogen or argon
atmosphere in dried glassware. Diethyl ether and tetrahydro-
furan (THF) were used freshly distilled, under a stream of
nitrogen, from sodium benzophenone ketyl. Toluene was dis-
tilled over phosphorus pentoxide. Dichloromethane (DCM)
was distilled over calcium hydride and stored over potassium
hydroxide. Other reagents and solvents were obtained com-
mercially and used as received without further purification
unless otherwise specified.
The recent result by Ganem et al.12 (Fig. 3) seems, at first
sight, to be at odds with the results obtained in these labor-
atories. However, according to Katagiri, the presence of two
heteroatoms on the cyclopentene ring forces the five-membered
ring to adopt a different conformation with the substituents in
3470
J. Chem. Soc., Perkin Trans. 1, 1999, 3469–3475

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pounds are racemic; stereodescriptors are used to indicate
relative stereochemistry. The numbering of carbocyclic nucleo-
sides and 5Ј homologues, which is used in the NMR assign-
ments, is as follows:
(1S,5R)-1-Acetoxy-5-(triphenylmethoxymethyl)cyclopent-2-ene
5
The monoprotected cyclopentenediol (1S,5R)-5-(triphenyl-
methoxymethyl)cyclopent-2-en-1-ol (580 mg, 1.63 mmol) was
dissolved in a mixture of pyridine (15 cm3) and acetic anhydride
(15 cm3) and stirred at room temperature for 17 h. The reaction
mixture was quenched with saturated aqueous ammonium
chloride solution (60 cm3). Diethyl ether (60 cm3) was added to
the mixture, the layers were separated and the organic phase
was washed with saturated aqueous sodium hydrogen carbonate
solution (30 cm3) and brine (30 cm3). The solution was dried
(MgSO4), filtered and the filtrate was evaporated in vacuo; the
pyridine was evaporated in vacuo by azeotropic distillation with
toluene, to give the title compound 5 as a clear oil [650 mg,
100%, Rf (dichloromethane–EtOH, 19:1) 0.8] (Found: C, 80.9;
H, 6.6. C13H18O6 requires C, 80.9; H, 6.6%) δH(300 MHz;
CDCl3) 1.79 (3 H, s, CH3 of Ac), 2.17 [1 H, m, C(4)CH2], 2.42
[1 H, m, C(4)CH2], 2.70 [1 H, m, C(5)CH], 3.21 [2 H, m,
C(1Ј)CH2], 5.80 [1 H, dd, J 7.0 and 2.0, C(1)CH], 5.86 [1 H, m,
C(3)CH], 6.09 [1 H, m, C(2)CH], 7.24–7.33 (9 H, m, Ph), 7.43
(6 H, m, Ph); δC(75 MHz; CDCl3) 20.8 (CH3, CH3 of Ac), 34.7
(CH2, C4), 41.3 (CH, C5), 62.4 (CH2, C1Ј), 78.3 (CH, C1), 86.2
(C, Ph3C), 126.9 (CH, Ph), 127.7 (CH, Ph), 128.8 (CH, Ph),
129.6 (CH, C3), 137.3 (CH, C2), 144.3 (C, Ph), 170.5 (C᎐O);
᎐
m/z (EI) 321 ([M Ϫ C6H5]ϩ, 0.6%), 243 (Ph3Cϩ, 100%), 165
(58%).
Scheme 2 Reagents and conditions: i, nBu3SnH, AIBN, THF, reflux,
3–7 h, (68–92%); ii, K2CO3, MeOH, 24 h, (69%); iii, K2CO3, MeOH,
2 h, (96%); iv, NH2OCH3ؒHCl, diisopropylethylamine, dioxane, 60 ЊC,
72 h, (57%); v, K2CO3, MeOH, 2 h, (90%).
(1R,5S,1ЈS)-(1Ј,2Ј-Dihydroxyethyl)cyclopent-2-en-1-ol 7
A suspension of lithium aluminium hydride (1.42 g, 37.5 mmol)
in THF (30 cm3) was heated under reflux for 30 min. A solution
of hydroxy-lactone 6 (2.37 g, 17.0 mmol) in THF (30 cm3) was
added dropwise while maintaining a gentle reflux and the mix-
ture was then heated under reflux for 4 h. TLC analysis [EtOH–
CH2Cl2 (1:9)] indicated the absence of starting material (Rf
0.40) and formation of a single product (Rf 0.02). The reaction
mixture was quenched by dropwise addition of water (1.5 cm3)
at 0 ЊC. NaOH (2 , 4.3 cm3) was added dropwise at 0 ЊC, and
the mixture was stirred for 10 min at 0 ЊC. Water (1.5 cm3) was
added at 0 ЊC. The viscous mixture was filtered; the solid
material was washed with ethyl acetate and the filtrate was
evaporated in vacuo to give the crude triol 7 as a yellow oil. To
recover the triol retained in the LiAlH4 suspension, the suspen-
sion was refluxed at 65 ЊC for 24 h in THF. The mixture was
filtered while warm, and the filtrate evaporated in vacuo to give
an additional amount of the crude triol 7 as a yellow oil (total
weight of yellow oil 2.25 g). The triol 7 was carried on to the
next step without purification.
All reactions were stirred magnetically and monitored by
thin layer chromatography (TLC), performed on glass-backed
plates coated with Merck 60F-254 silica gel. Visualisation was
achieved either via treatment with potassium permanganate,
ceric ammonium molybdate, p-anisaldehyde and/or UV light
(254 nm). Flash column chromatography was performed using
Merck 60 silica gel (40–60 µm). Nuclear magnetic resonance
(1H, 13C) spectra were recorded on Bruker AMX400, AM250,
AC200, AC300 and Varian 300 Gemini 2000 spectrometers. All
chemical shifts (δ) are quoted in parts per million (ppm) and
are reported relative to an internal standard, tetramethylsilane
1
(TMS) (δ 0.00) for H and chloroform (δ 77.0) for 13C. The
following abbreviations are used to define the multiplicities: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s broad
singlet. Coupling constants (J) are measured in Hertz (Hz).
Protons were assigned using the necessary NMR experiments
(1H–1H COSY), whereas DEPT experiments were performed
for the assignment of carbons. Melting points were determined
on an electrothermal instrument and are uncorrected. Infrared
spectra were recorded on a Perkin-Elmer 881 infrared spectro-
(1R,5S,1ЈS)-1-Acetoxy-5-(1Ј,2Ј-diacetoxyethyl)cyclopent-2-ene
8
photometer and are recorded in reciprocal centimetres (cmϪ1
,
Triol 7 (3.62 g, 25 mmol) was dissolved in a mixture of pyridine
(40 cm3) and acetic anhydride (40 cm3). DMAP (100 mg)
was added and the solution was stirred at room temperature
overnight. The reaction mixture was quenched with saturated
aqueous ammonium chloride solution (70 cm3). Diethyl ether
(100 cm3) was added to the mixture, the layers were separated
and the organic phase was washed with saturated aqueous
sodium hydrogen carbonate solution (100 cm3) and brine (100
wavenumbers). Mass spectra were recorded on a TRIO1000
spectrometer at the Chemistry Department, University of
Liverpool, at the EPSRC Mass Spectroscopy Centre, Swansea
using a VG ZAB-E high resolution instrument as well as at the
Chemistry Department, University of Exeter using a Kratos
Profile HV3 high resolution instrument. Microanalyses were
performed using a Carlo Erba elemental analyser. All com-
J. Chem. Soc., Perkin Trans. 1, 1999, 3469–3475
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cm3). The solution was dried (MgSO4), filtered and the filtrate
was evaporated in vacuo to give a yellow oil. Crystallisation of
the crude material from petroleum ether (bp 40–60 ЊC) (petrol)
gave the title compound 8 as a white crystalline solid [3.72 g,
13.75 mmol, 55%, Rf (petrol–EtOAc, 1:4) 0.2]; mp 83–84 ЊC
(petrol) (Found: C, 57.8; H, 6.7. C13H18O6 requires C, 57.8;
H, 6.7%) (HRMS: found: [M ϩ NH4]ϩ 288.14476. C13H22NO6
requires 288.14471); νmax (CH2Cl2)/cmϪ1 2948, 1734, 1371,
1227, 1017, 750; δH(300 MHz; CDCl3) 1.98 (3 H, s, CH3 of Ac),
2.00 (3 H, s, CH3 of Ac), 2.02 (3 H, s, CH3 of Ac), 2.30 [2 H, m,
C(4)CH2], 2.56 [1 H, m, C(5)CH], 3.98 [1 H, dd, J 12.3 and 5.5,
C(2Ј)CH2], 4.37 [1 H, dd, J 12.3 and 2.3, C(2Ј)CH2], 5.22 [1 H,
ddd, J 5.8, 5.5 and 2.3, C(1Ј)CH], 5.63 [1 H, m, C(1)CH], 5.84
[1 H, m, C(3)CH], 6.10 [1 H, m, C(2)CH]; δC(75 MHz; CDCl3)
20.6 (CH3, CH3 of Ac), 20.7 (CH3, CH3 of Ac), 20.8 (CH3, CH3
of Ac), 33.3 (CH2, C4), 41.9 (CH, C5), 64.5 (CH2, C2Ј), 70.3
MHz; CDCl3) 20.8 (CH3, CH3 of Ac), 34.9 (CH2, C6Ј), 44.5
(CH, C4Ј), 60.1 (CH, C1Ј), 66.0 (CH2, C5Ј), 129.3 (CH, C2Ј),
131.8 (C, C5), 138.7 (CH, C3Ј), 148.4 (CH, C8), 150.8 and 151.4
(C, C4 and C, C6), 151.7 (CH, C2), 170.7 (C, C᎐O).
᎐
(1ЈR,4ЈS)-2-Amino-6-chloro-9-[4Ј-(triphenylmethoxymethyl)-
cyclopent-2Ј-en-1Ј-yl]purine 11
Compound 11 was prepared in a similar manner to that
described for compound 9 using 2-amino-6-chloropurine
(119 mg, 0.70 mmol), (1R,2R)-1-acetoxy-2-(triphenylmethoxy-
methyl)cyclopent-4-ene 5 (307 mg, 0.77 mmol) and tetrakis-
(triphenylphosphine)palladium (40 mg, 0.035 mmol) to give
the desired product 11 as a clear oil [194 mg, 55%, Rf (petrol–
EtOAc, 1:4) 0.51] (HRMS: found: Mϩ 507.18292. C30H26-
ClN5O requires 507.18259); δH(300 MHz; CDCl3) 1.59 [1 H, m,
C(6Ј)CH2], 2.77 [1 H, ddd, J 14.0, 7.0 and 7.0, C(6Ј)CH2], 3.16
[3 H, m, C(4Ј)CH and C(5Ј)CH2], 5.03 (2 H, br s, NH2), 5.56
[1 H, m, C(1Ј)CH], 5.84 [1 H, m, C(2Ј)CH], 6.26 [1 H, m,
C(3Ј)CH], 7.26–7.53 (15 H, m, Ph), 7.65 [1 H, s, C(8)CH]; δC(75
MHz; CDCl3) 35.1 (CH2, C6Ј), 45.6 (CH, C4Ј), 59.4 (CH, C1Ј),
65.9 (CH2, C5Ј), 86.3 (C, Ph3C), 125.8 (C, C5), 127.1 (CH, Ph),
127.8 (CH, Ph), 128.6 (CH, Ph), 128.9 (CH, C2Ј), 139.4 (CH,
C3Ј), 140.5 (CH, C8), 143.9 (C, Ph), 151.7 (C, C4), 153.9 (C,
C6), 159.0 (C, C2).
(CH, C1Ј), 77.1 (CH, C1), 129.7 and 137.3 (CH᎐CH), 170.3,
᎐
170.4, 170.7 (C᎐O).
᎐
(1ЈR,4ЈS)-2-Amino-6-chloro-9-[4Ј-(acetoxymethyl)cyclopent-2Ј-
en-1Ј-yl]purine 9
2-Amino-6-chloropurine (1.07 g, 6.3 mmol) and sodium
hydride (60% dispersed in mineral oil, 252 mg, 6.3 mmol) in
DMF (10 cm3) were stirred for 20 min at room temperature and
for 10 min at 50 ЊC. The resultant solution was added to a
suspension of 4 (1.13 g, 5.7 mmol) and tetrakis(triphenylphos-
phine)palladium (728 mg, 0.630 mmol) in DMF (10 cm3) via
cannula, rinsing with DMF (2 × 3 cm3). The reaction mixture
was stirred in the dark for 3 h at 50 ЊC and then cooled to room
temperature whereupon water (40 cm3) was added. The mixture
was extracted with dichloromethane (3 × 50 cm3) and the com-
bined organic layers were dried (MgSO4), filtered and the
filtrate was concentrated in vacuo to give a yellow crude oil.
The oil was purified by column chromatography over silica gel,
eluting first with petrol–EtOAc (4:1) to give recovered starting
material 4 [339 mg, 33% recovered, Rf (petrol–EtOAc, 4:1)
0.30], then with petrol–EtOAc (1:2) which provided the title
compound 9 as a clear oil [843 mg, 48%, Rf (petrol–EtOAc, 1:2)
0.30] (Found: C, 50.7; H, 4.6, N, 22.6; Mϩ 307.08343. C13H14-
ClN5O2 requires C, 50.7; H, 4.6, N, 22.8%; Mϩ 307.08359); νmax
(CH2Cl2)/cmϪ1 3325, 3310, 2950, 2850, 1750, 1625, 1575, 1410,
1230, 775, 730; δH(200 MHz; CDCl3) 1.65–1.80 [1 H, m,
C(6Ј)CH2], 2.10 (3 H, s, CH3 of Ac), 2.87 [1 H, dt, J 14.2, 8.9
and 8.4, C(6Ј)CH2], 3.20 [1 H, m, C(4Ј)CH], 4.15 [1 H, dd,
J 11.1 and 5.6, C(5Ј)CH2], 4.25 [1 H, dd, J 11.1 and 5.6,
C(5Ј)CH2], 5.18 (2 H, br s, NH2), 5.60 [1 H, m, C(1Ј)CH], 5.91
[1 H, ddd, J 5.5, 4.3 and 2.1, C(2Ј)CH], 6.18 [1 H, ddd, J 5.5, 4.1
and 2.1, C(3Ј)CH], 7.82 [1 H, s, C(8) CH]; δC(75 MHz; CDCl3)
20.8 (CH3, CH3 of Ac), 34.6 (CH2, C6Ј), 44.5 (CH, C4Ј), 59.6
(CH, C1Ј), 66.2 (CH2, C5Ј), 125.7 (C, C5), 129.9 (CH, C2Ј),
137.9 (CH, C3Ј), 140.6 (CH, C8), 151.4 and 153.5 (C, C4 and C,
(1ЈR,4ЈS,5ЈS)-2-Amino-6-chloro-9-[4Ј-(1Љ,2Љ-diacetoxyethyl)-
cyclopent-2Ј-en-1Ј-yl]purine 12
Compound 12 was prepared in a similar manner to that
described for compound 9 using 2-amino-6-chloropurine (3.04
g, 17.4 mmol) and triacetate 8 (3.92 g, 14.5 mmol) to give the
desired product 12 as a clear oil [2.62 g, 48%, Rf (petrol–EtOAc,
1:2) 0.30] (HRMS: found: Mϩ 379.10474. C16H18ClN5O4
requires 379.10495); δH(200 MHz; CDCl3) 1.85 [1 H, m,
C(7Ј)CH2], 2.05 (3 H, s, CH3 of Ac), 2.10 (3 H, s, CH3 of Ac),
2.75 [1 H, m, C(7Ј)CH2], 3.20 [1 H, m, C(4Ј)CH], 4.10 [1 H, dd,
J 12.2 and 6.0, C(6Ј)CH2], 4.35 [1 H, dd, J 12.2 and 4.0,
C(6Ј)CH2], 5.45 [4 H, m, C(1Ј)CH, C(5Ј)CH, NH2], 5.83 [1 H,
ddd, J 5.5, 4.4 and 2.1, C(2Ј)CH], 6.05 [1 H, ddd, J 5.5, 4.1 and
2.1, C(3Ј)CH], 7.75 [1 H, s, C(8)CH]; δC(75 MHz; CDCl3) 20.5
(CH3, CH3 of Ac), 20.8 (CH3, CH3 of Ac), 33.0 (CH2, C7Ј), 45.6
(CH, C4Ј), 60.4 (CH, C1Ј), 64.1 (CH, C5Ј), 73.0 (CH2, C6Ј),
125.8 (C, C5), 130.2 (CH, C2Ј), 136.0 (CH, C3Ј), 141.0 (CH,
C8), 151.6 (C, C4), 153.6 (C, C6), 159.1 (C, C2), 170.6 and 170.8
(C, C᎐O).
᎐
(1ЈR,4ЈS)-2,6-Dichloro-9-[4Ј-(acetoxymethyl)cyclopent-2Ј-en-1Ј-
yl]purine 13
2-Amino-6-chloropurine 9 (475 mg, 1.54 mmol) was dissolved
in dichloromethane (8 cm3) and the solution was cooled to 0 ЊC.
Trimethylchlorosilane (0.58 cm3, 4.62 mmol) was added rapidly
followed by slow addition of isopentyl nitrite (0.62 cm3, 4.62
mmol) maintaining the temperature at 0 ЊC. The mixture was
stirred for 2 h at 0 ЊC and then for 5 h at room temperature.
The reaction was quenched with water (6 cm3) and extracted
with dichloromethane (2 × 10 cm3). The combined organic
layers were washed with saturated aqueous sodium hydrogen-
carbonate solution (10 cm3) and brine (10 cm3), dried (MgSO4)
and the solvent evaporated in vacuo to give a yellow oil. The oil
was purified by column chromatography over silica gel eluting
with petrol–EtOAc (1:2) to give the 2,6-dichloropurine 13 as
a yellow oil [309 mg, 0.944 mmol, 61%, Rf (petrol–EtOAc,
1:2) 0.30] (Found: C, 47.6; H, 3.7; N, 17.0. C13H12Cl2N4O2
requires C, 47.7; H, 3.7; N, 17.1%) (HRMS: found: [M ϩ H]ϩ
327.04181. C13H13Cl2N4O2 requires 327.04156); δH(200 MHz;
CDCl3) 1.70 [1 H, m, C(6Ј)CH2], 2.15 (3 H, s, CH3 of Ac), 2.96
[1 H, dd, J 14.3 and 8.9, C(6Ј)CH2], 3.20 [1 H, m, C(4Ј)CH],
4.11 [1 H, dd, J 11.1 and 5.1, C(5Ј)CH2], 4.23 [1 H, dd, J 11.1
and 5.1, C(5Ј)CH2], 5.80 [1 H, m, C(1Ј)CH], 5.95 [1 H, ddd,
C6), 159.1 (C, C2), 171.0 (C, C᎐O).
᎐
(1ЈR,4ЈS)-6-Chloro-9-[4Ј-(acetoxymethyl)cyclopent-2Ј-en-1Ј-
yl]purine 10
Compound 10 was prepared in a similar manner to that
described for compound 9 using 6-chloropurine (154 mg, 1.0
mmol) and (1R,5R)-5-(acetoxymethyl)cyclopent-2-en-1-ol 2
(487 mg, 2.5 mmol) to give the desired product 10 as colourless
solid [82 mg, 28%, Rf (petrol–EtOAc, 1:2) 0.35]; mp 107–
108 ЊC (HRMS: found: Mϩ 293.0805. C13H13ClN4O2 requires
293.0805); νmax (CHCl3)/cmϪ1 3009, 1742, 1487; δH(300 MHz;
CDCl3) 1.66 [1 H, m, C(6Ј)CH2], 2.00 (3 H, s, CH3 of Ac), 2.87
[1 H, m, C(6Ј)CH2], 3.15 [1 H, ddddd, J 8.8, 5.5, 5.5, 2.2 and 2.0
C(4Ј)CH], 4.04 [1 H, dd, J 11.2 and J 5.4, C(5Ј)CH2], 4.12 [1 H,
dd, J 11.2 and J 5.5, C(5Ј)CH2], 5.76 [1 H, dddd, J 8.8, 5.7, 2.0
and 2.0, C(1Ј)CH], 5.92 [1 H, ddd, J 5.5, 2.2 and 2.0, C(2Ј)CH],
6.16 [1 H, ddd, J 5.5, 2.2 and 2.2, C(3Ј)CH], 8.02 [1 H, s,
C(2)CH or C(8)CH], 8.70 [1 H, s, C(2)CH or C(8)CH]; δC(75
3472
J. Chem. Soc., Perkin Trans. 1, 1999, 3469–3475

View Article Online
J 5.5, 4.3 and 2.1, C(2Ј)CH], 6.20 [1 H, ddd, J 5.5, 4.0 and 2.1,
C(3Ј)CH], 8.20 [1 H, s, C(8)CH]; δC(75 MHz; CDCl3) 20.8
(CH3, CH3 of Ac), 35.1 (CH2, C6Ј), 44.7 (CH, C4Ј), 60.3 (CH,
C1Ј), 66.0 (CH, C5Ј), 123.2 (C, C5), 129.2 (CH, C2Ј), 139.1
(CH, C3Ј), 143.9 (CH, C8), 151.9 and 152.8 (C, C4 and C, C6),
2.11 [4 H, m, CH3 of Ac and C(6Ј)CH2], 2.40 [2 H, m, C(6Ј)CH2
and C(4Ј)CH], 3.48 [2 H, m, C(5Ј)CH2], 4.64 [1 H, m, C(2Ј)CH],
4.83 [1 H, m, C(1Ј)CH], 5.13 (2 H, br s, NH2), 5.37 [1 H, m,
C(3Ј)CH], 7.25–7.37 (9H, m Ph), 7.43–7.49 (6H, m, Ph), 7.74
[1 H, s, C(8)CH]; δC(75 MHz; CDCl3) 20.8 (CH3, CH3 of Ac),
30.2 (CH2, C6Ј), 43.4 (CH, C4Ј), 55.4 (CH, C2Ј), 55.7 (CH,
C1Ј), 64.8 (CH2, C5Ј), 80.9 (CH, C3Ј), 87.0 (C, Ph3C), 125.4
(C, C5), 127.2 (CH, Ph), 127.9 (CH, Ph), 128.7 (CH, Ph), 140.6
(CH, C8), 143.9 (C, Ph), 151.5 (C, C4), 153.8 (C, C6), 159.1 (C,
C2), 169.7 (C, C᎐O); m/z (EI) 324 (15%, Mϩ Ϫ Ph C Ϫ Br), 243
153.1 (C, C2), 171.7 (C, C᎐O).
᎐
(1ЈR,2ЈR,3ЈR,4ЈR)-2-Amino-6-chloro-9-[3Ј-acetoxy-4Ј-(acetoxy-
methyl)-2Ј-bromocyclopentan-1Ј-yl]purine 14
᎐
3
(81%, Ph3Cϩ), 170 (100%), 43 (50%, Acϩ).
To a solution of 9 (215 mg, 0.70 mmol) in glacial acetic acid
(8 cm3) was added N-bromoacetamide (112 mg, 0.77 mmol)
and silver acetate (130 mg, 0.77 mmol) and the reaction mixture
was stirred at room temperature overnight. Saturated aqueous
sodium hydrogen carbonate solution and solid sodium hydro-
gen carbonate were added until neutral pH was obtained. The
solid material was removed by filtration and the filtrate was
extracted with dichloromethane (3 × 100 cm3). The combined
organic layers were dried (MgSO4) and the solvent was evapor-
ated in vacuo to give a red oil. Purification of the crude oil by
column chromatography over silica gel using gradient elution
[CH2Cl2 (100%) then EtOH–CH2Cl2 (5:95)] gave the bromo-
acetate 14 as a clear oil. The oil was crystallised from
dichloromethane and petrol to give compound 14 as fine long
white crystals [109 mg, 35%, Rf (EtOH–CH2Cl2, 5:95) 0.26];
mp 136–137 ЊC (Found: C, 40.3; H, 3.8; N, 15.5. C15H17-
BrClN5O4 requires C, 40.3; H, 3.8; N, 15.7%) (HRMS: found:
[M ϩ H]ϩ 446.02259. C15H18BrClN5O4 requires 446.02307);
νmax (CHCl3)/cmϪ1 3523, 3009, 1743, 1608, 1208; δH(300 MHz;
CDCl3) 2.11 (3 H, s, CH3 of Ac), 2.15 (3 H, s, CH3 of Ac), 2.37–
2.58 [3 H, m, C(6Ј)CH2 and C(4Ј)CH], 4.33 [1 H, dd, J 11.4 and
6.0, C(5Ј)CH2], 4.42 [1 H, dd, J 11.4 and 6.0, C(5Ј)CH2], 4.75
[1 H, m, C(2Ј)CH], 4.92 [1 H, m, C(1Ј)CH], 5.17 (2 H, br s,
NH2), 5.44 [1 H, m, C(3Ј)CH], 7.90 [1 H, s, C(8)CH]; δC(75
MHz; CDCl3) 20.7 (CH3, CH3 of Ac), 20.8 (CH3, CH3 of Ac),
30.0 (CH2, C6Ј), 42.5 (CH, C4Ј), 55.1 (CH, C2Ј), 55.7 (CH,
C1Ј), 65.0 (CH2, C5Ј), 80.5 (CH, C3Ј), 125.4 (C, C5), 140.5
(CH, C8), 149.1 and 152.0 (C, C4 and C, C6), 159.2 (C, C2),
(1ЈR,2ЈR,3ЈR,4ЈR)-2,6-Dichloro-9-[3Ј-acetoxy-4Ј-(acetoxy-
methyl)-2Ј-bromocyclopentan-1Ј-yl]purine 17
Compound 17 was prepared in a similar manner to that
described for compound 14 using compound 13 (291 mg, 0.89
mmol) and N-bromosuccinimide (192 mg, 1.07 mmol) to
give the desired product 17 as a clear oil [233 mg, 56%, Rf
(petrol–EtOAc, 1:2) 0.37] (Found: C, 38.9; H, 3.3; N, 11.8; Mϩ
464.97211. C15H15BrCl2N4O4 requires C, 38.7; H, 3.2; N, 12.0%;
464.97320); δH(300 MHz; CDCl3) 2.13 (3 H, s, CH3 of Ac), 2.18
(3 H, s, CH3 of Ac), 2.50–2.68 [3 H, m, C(6Ј)CH2 and
C(4Ј)CH], 4.38 [2 H, dd, J 8.4 and 2.7, C(5Ј)CH2], 4.78 [1 H, m,
C(2Ј)CH], 5.15 [1 H, m, C(1Ј)CH], 5.45 [1 H, m, C(3Ј)CH], 8.25
[1 H, s, C(8)CH]; δC(75 MHz; CDCl3) 20.8 (CH3, CH3 of Ac),
20.9 (CH3, CH3 of Ac), 30.4 (CH2, C6Ј), 42.7 (CH, C4Ј), 54.9
(CH, C2Ј), 56.3 (CH, C1Ј), 64.8 (CH2, C5Ј), 80.4 (CH, C3Ј)
131.5 (C, C5), 143.9 (CH, C8), 149.1 and 152.0 (C, C4 and C,
C6), 159.2 (C, C2), 169.9 and 170.8 (C, C᎐O).
᎐
(1ЈR,2ЈR,3ЈR,4ЈR,5ЈS)-2-Amino-6-chloro-9-[3Ј-acetoxy-2Ј-
bromo-4Ј-(1Љ,2Љ-diacetoxyethyl)cyclopentan-1Ј-yl]purine 18
To a solution of 12 (171 mg, 0.45 mmol) in glacial acetic acid
(10 cm3) was added N-bromoacetamide (79 mg, 0.54 mmol) and
silver acetate (91 mg, 0.54 mmol) and the reaction mixture was
stirred at room temperature for 16 h. Saturated aqueous sodium
hydrogen carbonate solution and solid sodium hydrogen
carbonate were added until neutral pH was attained. The
solid materials were removed by filtration and the filtrate was
extracted with dichloromethane (2 × 40 cm3). The combined
organic layers were dried (MgSO4) and solvent evaporated in
vacuo to give a crude yellow oil. The crude oil was purified by
column chromatography over silica gel eluting with dichloro-
methane–EtOH (19:1), affording a mixture of diastereo-
isomers as a clear oil. Crystallisation from tert-butyl methyl
ether gave the bromoacetate 18 as a colourless solid [115 mg,
49%, Rf (dichloromethane–EtOH, 19:1) 0.37] (HRMS: found:
Mϩ 517.03581. C18H21BrClN5O6 requires 517.03638); δH(300
MHz; CDCl3) 2.09 (3 H, s, CH3 of Ac), 2.12 (3 H, s, CH3 of
Ac), 2.16 (3 H, s, CH3 of Ac), 2.48–2.62 [3 H, m, C(7Ј)CH2 and
C(4Ј)CH], 4.12 [1 H, dd, J 12.0 and 6.0 C(6Ј)CH2], 4.39 [1 H,
dd, J 12.0 and 3.0, C(6Ј)CH2], 4.62 [1 H, m, C(2Ј)CH], 4.85
[1 H, m, C(1Ј)CH], 5.44 (2 H, s, NH2), 5.58 [1 H, m, C(5Ј)CH],
5.79 [1 H, m, C(3Ј)CH], 7.80 [1 H, s, C(8)CH]; δC(75 MHz;
CDCl3) 20.4 (CH3, CH3 of Ac), 20.7 (CH3, CH3 of Ac), 20.7
(CH3, CH3 of Ac), 29.4 (CH2, C7Ј), 42.9 (CH, C4Ј), 54.9 (CH,
C1Ј), 55.4 (CH, C3Ј), 63.5 (CH, C5Ј), 71.5 (CH2, C6Ј), 79.0
(CH, C2Ј), 125.5 (CH, C5), 141.0 (C, C8), 151.6 (C, C4), 153.6
169.7 and 170.9 (C, C᎐O) [Crystal data:5 colourless prism,
᎐
monoclinic, P21/n, 0.15 × 0.20 × 0.25 mm, a = 15.597(5), b =
7.077(2), c = 17.178(2) Å, β = 96.13(2)Њ, U = 1885.4 Å3, T =
Ϫ120 ЊC, Z = 4, µ(Mo-Kα) = 23.29 cmϪ1; 3769 reflections
measured, 3630 unique, R = 0.055, Rw = 0.080. CCDC 182/834].
(1ЈR,2ЈR,3ЈR,4ЈR)-6-Chloro-9-[3Ј-acetoxy-4Ј-(acetoxymethyl)-
2Ј-bromocyclopentan-1Ј-yl]purine 15
Compound 15 was prepared in a similar manner to that
described for compound 14 using compound 10 (73 mg, 0.25
mmol) and N-bromoacetamide (35 mg, 0.25 mmol) to give the
desired product 15 as a colourless glassy solid [52 mg, 48%,
Rf (dichloromethane–MeOH–NH3, 94:5:1) 0.30] (HRMS:
found: Mϩ 430.0034. C15H16BrClN4O4 requires 430.0043);
δH(300 MHz; CDCl3) 2.08 (3 H, s, CH3 of Ac), 2.17 (3 H, s, CH3
of Ac), 2.55 [3 H, m, C(6Ј)CH2 and C(4Ј)CH], 4.35 [2 H, m,
C(5Ј)CH2], 4.79 [1 H, m, C(2Ј)CH], 5.13 [1 H, m, C(1Ј)CH],
5.40 [1 H, m, C(3Ј)CH], 8.26 [1 H, s, C(2)CH], 8.70 [1 H, s,
C(8)CH]; δC(75 MHz; CDCl3) 20.8 (CH3, CH3 of Ac), 20.9
(CH3, CH3 of Ac), 30.1 (CH2, C6Ј), 42.5 (CH, C4Ј), 55.1 (CH,
C2Ј), 56.2 (CH, C1Ј), 64.9 (CH2, C5Ј), 80.5 (CH, C3Ј), 125.4
(C, C5), 143.6 (CH, C8), 150.8 (C, C4), 151.6 (C, C6), 152.0
(C, C6), 159.1 (C, C2), 169.2, 170.5 and 170.6 (C, C᎐O).
᎐
(CH, C2), 169.5 and 170.7 (C, C᎐O).
᎐
(1ЈR,2ЈR,3ЈR,4ЈR)-2-Amino-6-chloro-9-[3Ј-acetoxy-2Ј-bromo-
4Ј-(hydroxymethyl)cyclopentan-1Ј-yl]purine 19
(1ЈR,2ЈR,3ЈR,4ЈR)-2-Amino-6-chloro-9-[3Ј-acetoxy-2Ј-bromo-
4Ј-(triphenylmethoxymethyl)cyclopent-1Ј-yl]purine 16
Compound 16 (98 mg, 0.15 mmol) was dissolved in an aqueous
solution of acetic acid (80%, 3 cm3) and stirred for 6 h at 50 ЊC.
The solvent was evaporated in vacuo and the resulting crude oil
was purified by column chromatography over silica gel eluting
with petrol–EtOAc (1:9). The title compound 19 was obtained
as an oil (40 mg, 66%) (HRMS: found Mϩ 403.00439. C13H15-
Compound 16 was prepared in a similar manner to that
described for compound 14 using compound 11 (141 mg, 0.28
mmol) and N-bromoacetamide (45 mg, 0.31 mmol) to give
the desired product 16 as a yellow oil [125 mg, 69%, Rf
(dichloromethane–EtOH, 19:1) 0.58]; δH (200 MHz; CDCl3)
J. Chem. Soc., Perkin Trans. 1, 1999, 3469–3475
3473

View Article Online
BrClN5O3 requires 403.00467); δH(400 MHz; acetone-d6) 2.11
(3 H, s, CH3 of Ac), 2.43 [3 H, m, C(6Ј)CH2 and C(4Ј)CH], 3.82
[2 H, m, C(5Ј)CH2], 4.14 (1 H, br s, OH), 4.88 [1 H, m,
C(2Ј)CH], 4.99 [1 H, m, C(1Ј)CH], 5.45 [1 H, m, C(3Ј)CH], 6.30
(2 H, br s, NH2), 8.15 [1 H, s, C(8)CH]; δC(100 MHz; acetone-
d6) 21.3 (CH3, CH3 of Ac), 30.2 (CH2, C6Ј), 46.6 (CH, C4Ј),
56.9 (CH, C2Ј), 57.7 (CH, C1Ј), 64.9 (CH2, C5Ј), 81.9 (CH,
C3Ј), 125.4 (C, C5), 142.4 (CH, C8), 151.6 (C, C4), 155.3 (C,
nitrogen through for 15 min The bromoacetate 18 (34 mg, 0.07
mmol), AIBN (21 mg, 0.13 mmol) and tri-n-butyltin hydride
(0.26 cm3, 0.99 mmol) were added to the degassed THF and the
reaction mixture was stirred under reflux for 7 h. The solvent
was evaporated in vacuo and the crude material was purified
by column chromatography over silica gel eluting with hexane
(to remove tin residues) followed by dichloromethane–MeOH
(24:1) to give the product 22 as a colourless oil [26 mg, 90%, Rf
(dichloromethane–MeOH, 24:1) 0.17] (HRMS: found: Mϩ
439.12555. C18H22ClN5O6 requires 439.12585); δH(300 MHz;
CDCl3) 2.08 (6 H, s, 2 × CH3 of Ac), 2.12 (3 H, s, CH3 of Ac),
2.15–2.27 [2 H, m, C(7Ј)CH2], 2.51–2.71 [3 H, m, C(4Ј)CH and
C(2Ј)CH2], 4.12 [1 H, dd, J 12.0 and 7.0, C(6Ј)CH2], 4.39 [1 H,
dd, J 12.0 and 3.0, C(6Ј)CH2], 4.87 [1 H, m, C(1Ј)CH], 5.30
(2 H, s, NH2), 5.40 [1 H, m, C(3Ј)CH], 5.53 [1 H, m, C(5Ј)CH],
7.73 [1 H, s, C(8)CH]; δC(100 MHz; CDCl3) 20.9 (CH3, CH3 of
Ac), 21.0 (CH3, CH3 of Ac), 21.2 (CH3, CH3 of Ac), 32.3 (CH2,
C7Ј), 37.6 (CH2, C2Ј), 45.1 (CH, C4Ј), 54.6 (CH, C1Ј), 63.9
(CH, C5Ј), 71.8 (CH2, C6Ј), 74.7 (CH, C3Ј), 126.0 (CH, C5),
141.3 (C, C8), 151.7 (C, C4), 153.3 (C, C6), 158.8 (C, C2), 170.0,
C6), 161.2 (C, C2), 170.8 (C, C᎐O).
᎐
(1ЈR,3ЈS,4ЈR)-2-Amino-6-chloro-9-[3Ј-acetoxy-4Ј-(acetoxy-
methyl)cyclopentan-1Ј-yl]purine 20
THF (10 cm3) was degassed by cooling it to 0 ЊC and bubbling
nitrogen through for 15 min. The bromoacetate 14 (120 mg,
0.27 mmol), AIBN (9.0 mg, 0.06 mmol) and tri-n-butyltin
hydride (0.72 cm3, 2.69 mmol) were added to the degassed THF
and the reaction mixture was stirred under reflux for 3 h. TLC
analysis did not indicate any conversion and further tri-n-
butyltin hydride (0.36 cm3, 1.35 mmol) was added to the
reaction mixture and stirring under reflux was continued for
another 60 min. After cooling to room temperature, EtOAc (25
cm3), saturated potassium fluoride solution (5 cm3) and solid
potassium fluoride (1 g) were added and the mixture was stirred
for 30 min to precipitate the unreacted tributyltin hydride as the
fluoride salt. The solid material was removed by filtration and
the filtrate was washed with water (3 × 30 cm3) and brine (20
cm3) and dried (MgSO4). The solvent was evaporated in vacuo
and the crude material was purified by column chromatography
over silica gel, eluting with dichloromethane–EtOH (29:1),
followed by dichloromethane–EtOH (19:1) to give the product
20 as a white crystalline solid [88 mg, 92%, Rf (dichloro-
methane–EtOH, 19:1) 0.26]; mp 121–124 ЊC (tert-butyl methyl
ether) (HRMS: found: Mϩ 367.10470. C15H18ClN5O4 requires
367.10473); δH(400 MHz; CDCl3) 1.98 [1 H, m, C(6Ј)CH2],
2.08 (6 H, s, 2 × CH3 of Ac), 2.30 [1 H, dd, J 13.0 and
8.0, C(6Ј)CH2], 2.52–2.62 [3 H, m, C(2Ј)CH2 and C(4Ј)CH],
4.30 [2 H, m, C(5Ј)CH2], 4.90 [1 H, m, C(1Ј)CH], 5.22 [3 H, m,
C(3Ј)CH and NH2], 7.78 [1 H, s, C(8)CH]; δC(100 MHz; CDCl3)
20.8 (CH3, CH3 of Ac), 21.1 (CH3, CH3 of Ac), 33.0 (CH2, C6Ј),
37.3 (CH, C2Ј), 43.6 (CH, C4Ј), 54.1 (CH, C1Ј), 64.8 (CH2,
C5Ј), 75.4 (CH, C3Ј), 126.0 (C, C5), 140.9 (CH, C8), 151.6 (C,
170.7 and 170.8 (C, C᎐O).
᎐
(1ЈR,3ЈS,4ЈR)-2-Amino-6-chloro-9-[3Ј-acetoxy-4Ј-(hydroxy-
methyl)cyclopentan-1Ј-yl]purine 23
THF (2 cm3) was degassed by cooling it to 0 ЊC while nitrogen
was bubbled through the solvent for 15 min. The bromoacetate
19 (20 mg, 0.05 mmol), AIBN (16 mg, 0.10 mmol) and tri-n-
butyltin hydride (0.14 cm3, 0.50 mmol) were added to the
degassed THF and the reaction mixture was stirred under
reflux for 3 h. No products were detectable by TLC analysis and
further tri-n-butyltin hydride (0.07 cm3, 0.25 mmol) was added
to the reaction mixture, which was stirred for another 2 h. The
solvent was evaporated in vacuo and the crude material was
purified by column chromatography on silica gel eluting with
hexane (to remove tin residues) followed by dichloromethane–
MeOH (19:1) to give the product 23 as an oil, still contamin-
ated with traces of tributyltin hydride [13 mg, Rf (dichloro-
methane–EtOH, 19:1) 0.36]; δH(200 MHz; acetone-d6) 2.10
(3 H, s, CH3 of Ac), 2.22–2.43 [2 H, m, C(6Ј)CH2], 2.43–2.65
[2 H, m, C(2Ј)CH2], 3.72 [2 H, dd, J 5.5 and 5.2, C(5Ј)CH2], 4.00
(1 H, t, J 5.0, OH), 5.00 [1 H, m, C(1Ј)CH], 5.19 [1 H, m,
C(3Ј)CH], 6.24 (2 H, br s, NH2), 8.12 [1 H, s, C(8)CH].
C4), 153.4 (C, C6), 158.7 (C, C2), 170.3 and 171.0 (C, C᎐O).
᎐
(1ЈR,3ЈS,4ЈR)-2,6-Dichloro-9-[3Ј-acetoxy-4Ј-(acetoxymethyl)-
cyclopentan-1Ј-yl]purine 21
(1ЈR,2ЈS,3ЈR,4ЈR)-2-Amino-6-chloro-9-[4Ј-(hydroxymethyl)-
2Ј,3Ј-epoxycyclopentan-1Ј-yl]purine 24
THF (10 cm3) was degassed by cooling it to 0 ЊC and bubbling
nitrogen through for 15 min. The degassed THF was added to
the bromoacetate 17 (148 mg, 0.318 mmol), AIBN (83 mg,
0.636 mmol) and tris(trimethylsilyl)silane (0.20 cm3, 0.636
mmol) via a cannula. The reaction mixture was stirred under
reflux for 24 h. The solvent was removed in vacuo and the crude
material purified by column chromatography over silica gel
eluting with petrol–EtOAc (1:2) yielding the title compound
21 as a yellow oil [81 mg, 68%, Rf (petrol–EtOAc, 1:2) 0.40]
(Found: C, 46.8; H, 4.3, N, 14.8; Mϩ 386.05520. C15H16Cl2N4O4
requires C, 46.5; H, 4.2, N, 14.5%; 386.05487); δH(300 MHz;
CDCl3) 1.99 [1 H, m, C(6Ј)CH2], 2.10 (6 H, s, 2 × CH3 of Ac),
2.45 [1 H, m, C(6Ј)CH2], 2.60 [3 H, m, C(2Ј)CH2 and C(4Ј)CH],
4.15–4.30 [2 H, ABX, JAB 18.0, JAX 5.1 and JBX 5.4, C(5Ј)CH2],
5.10 [1 H, m, C(1Ј)CH], 5.25 [1 H, m, C(3Ј)CH], 8.10 [1 H, s,
C(8)CH]; δC(75 MHz; CDCl3) 20.8 (CH3, CH3 of Ac), 21.0
(CH3, CH3 of Ac), 33.7 (CH2, C6Ј), 38.0 (CH, C2Ј), 43.8 (CH,
C4Ј), 54.6 (CH, C1Ј), 64.4 (CH2, C5Ј), 75.0 (CH, C3Ј), 130.1 (C,
C5), 144.1 (CH, C8), 152.1 and 153.1 (C, C4 and C, C6), 159.4
To a stirred, cooled solution (0 ЊC) of the acetoxy bromide 13
(89 mg, 0.20 mmol) in methanol (10 cm3) was added potassium
carbonate (27 mg, 0.20 mmol). The reaction was stirred at room
temperature for 24 h. Methanol (10 cm3) was added and the
solution adsorbed onto silica gel. Column chromatography
over silica (Merck 7729) eluting with dichloromethane–
methanol (9:1) gave the title compound 24 as a colourless
powder (39 mg, 69%) (HRMS: found: Mϩ 281.06824. C11H12-
ClN5O2 requires 281.06795); δH(400 MHz; CDCl3) 1.80 [1 H,
ddd, J 15.0, 7.0 and 7.0, C(6Ј)CH2], 2.11 [1 H, ddd, J 15.0, 7.0
and 7.0, C(6Ј)CH2], 2.40 [1 H, m, C(4Ј)CH], 3.37 [2 H, m,
C(5Ј)CH2], 3.72 [1 H, m, C(3Ј)CH], 3.98 [1 H, d, J 2.0,
C(2Ј)CH], 4.80 (1 H, br s, OH), 4.84 [1 H, m, C(1Ј)CH], 6.93
(2 H, s, NH2), 8.19 [1 H, s, C(8)CH]; δC(100 MHz; CDCl3) 32.4
(CH2, C6Ј), 42.3 (CH, C4Ј), 54.4 (CH, C1Ј), 58.3 (CH, C2Ј),
61.3 (CH, C3Ј), 61.9 (CH2, C5Ј), 123.8 (C, C5), 141.5 (CH, C8),
149.9 (C, C4), 154.5 (C, C6), 160.2 (C, C2).
(1ЈR,3ЈS,4ЈR)-2-Amino-6-chloro-9-[3Ј-hydroxy-4Ј-(hydroxy-
methyl)cyclopentan-1Ј-yl]purine 25
(C, C2), 170.4 and 170.9 (C, C᎐O).
᎐
(1ЈR,3ЈS,4ЈR,5ЈS)-2-Amino-6-chloro-9-[3Ј-acetoxy-4Ј-(1Љ,2Љ-
diacetoxyethyl)cyclopentan-1Ј-yl]purine 22
THF (3 cm3) was degassed by cooling it to 0 ЊC and bubbling
A solution of 20 (43 mg, 0.12 mmol) and potassium carbonate
(9 mg, 0.07 mmol) in methanol (5.0 cm3) was stirred at room
temperature for 2 h. The reaction mixture was neutralised with
3474
J. Chem. Soc., Perkin Trans. 1, 1999, 3469–3475

View Article Online
Guile, J. Am. Chem. Soc., 1992, 114, 8745; F. Burlina, A. Favre,
saturated aqueous ammonium chloride solution and stirred for
a further 15 min. The solvent was evaporated in vacuo and the
crude material was purified by column chromatography over
silica gel, eluting with dichloromethane–MeOH (9:1). The diol
25 was obtained as a clear oil [32.0 mg, 96%, Rf (dichloro-
methane–MeOH, 9:1) 0.17] (HRMS: found: Mϩ 283.08416.
C11H14ClN5O2 requires 283.08359); δH(300 MHz; CD3OD)
1.93 [1 H, m, C(6Ј)CH2], 2.17–2.25 [2 H, m, C(4Ј)CH and
C(2Ј)CH2], 2.36–2.53 [2 H, m, C(2Ј)CH2 and C(6Ј)CH2], 3.72
[2 H, m, C(5Ј)CH2], 4.31 [1 H, m, C(3Ј)CH], 5.06 [1 H, m,
C(1Ј)CH], 8.19 [1 H, s, C(8)CH]; δC(75 MHz; CD3OD) 32.2
(CH2, C6Ј), 38.9 (CH2, C2Ј), 48.4 (CH, C4Ј), 52.8 (CH, C1Ј),
62.1 (CH, C5Ј), 71.5 (CH, C3Ј), 123.3 (CH, C5), 141.1 (C, C8),
149.4 (C, C4), 153.1 (C, C6), 159.2 (C, C2).
J.-L. Fourrey and M. Thomas, Bioorg. Med. Chem. Lett., 1997, 7,
247; H. R. Olivo and J. Yu, J. Chem. Soc., Perkin Trans. 1, 1998, 391;
R. McCague, H. F. Olivo and S. M. Roberts, Tetrahedron Lett.,
1993, 34, 3785; T. Berranger and Y. Langlois, Tetrahedron Lett.,
1995, 36, 5523; M. T. Crimmins and B. W. King, J. Org. Chem., 1996,
61, 4192. cis-4-Hydroxymethylcyclopent-2-enol: H. Paulsen and
U. Maass, Chem. Ber., 1981, 114, 346; A. B. Smith, B. H. Toder,
R. E. Richmond and S. J. Branca, J. Am. Chem. Soc., 1984, 106,
4001; D. M. Hodgson, J. Witherington and B. A. Moloney, J. Chem.
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5, 337; J. Nokami, H. Matsuura, K. Nakasima and S. Shibata,
Chem. Lett., 1994, 1071; H. Kapeller, C. Marschner, M.
Weissenbacher and H. Griengl, Tetrahedron, 1998, 54, 1439;
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2 S. M. Roberts and K. A. Shoberu, J. Chem. Soc., Perkin Trans. 1,
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Sutherland, J. Chem. Soc., Perkin Trans. 1, 1992, 589; S. M. Roberts
and K. A. Shoberu, J. Chem. Soc., Perkin Trans. 1, 1992, 2419; for
a full review of synthetic approaches to cyclopentyl carbocyclic
nucleosides see M. T. Crimmins, Tetrahedron, 1998, 54, 9229.
3 E. A. Saville-Jones, S. D. Lindell, N. S. Jennings, J. C. Head and
M. J. Ford, J. Chem. Soc., Perkin Trans. 1, 1991, 2603.
(1ЈR,3ЈS,4ЈR)-2-Chloro-6-N-methoxyamino-9-[3Ј-acetoxy-4Ј-
(acetoxymethyl)cyclopentan-1Ј-yl]purine 26
Compound 21 (15 mg, 0.04 mmol), diisopropylethylamine (0.04
cm3, 0.25 mmol) and methoxylamine hydrochloride (16 mg,
0.19 mmol) were dissolved in dioxane (5 cm3). The reaction
mixture was stirred at 60 ЊC for 3 days then cooled to room
temperature and the solvent evaporated in vacuo. Purification
of the crude product by column chromatography over silica gel
eluting with petrol–EtOAc (1:2) gave the title compound 26
as a clear oil [9 mg, 0.02 mmol, 57%, Rf (petrol–EtOAc, 1:2)
0.25] (HRMS: found: Mϩ 397.11496. C16H20ClN5O5 requires
397.11530); δH(200 MHz; CDCl3) 1.99 [1 H, m, C(6Ј)CH2], 2.10
(3 H, s, CH3 of Ac), 2.11 (3 H, s, CH3 of Ac), 2.40 [1 H, m,
C(6Ј)CH2], 2.60 [3 H, m, C(2Ј)CH2 and C(4Ј)CH], 4.00 (3 H, s,
OCH3), 4.20 [2 H, m, C(5Ј)CH2], 5.10 [1 H, m, C(1Ј)CH], 5.30
[1 H, m, C(3Ј)CH], 7.98 [1 H, s, C(8)CH], 9.00 (1 H, br s, NH);
δC(75 MHz; CDCl3) 20.7 (CH3, CH3 of Ac), 21.0 (CH3, CH3 of
Ac), 33.9 (CH2, C6Ј), 38.0 (CH, C2Ј), 43.7 (CH, C4Ј), 53.8 (CH,
C1Ј), 64.5 (CH2, C5Ј), 65.0 (CH3, CH3 of HNOCH3), 75.0 (CH,
C3Ј) 129.0 (C, C5), 146.0 (CH, C8), 152.0 and 153.5 (C, C4 and
4 D. R. Deardorff, R. G. Linde, A. M. Martin and M. J. Shulman,
J. Org. Chem., 1989, 54, 2759.
5 J. V. Barkley, A. Dhanda, L. J. S. Knutsen, M.-B. Nielsen, S. M.
Roberts and D. R. Varley, Chem. Commun., 1998, 1117.
6 Racemic materials were used in this study; however the optically
active compounds are readily available, R. McCague, R. A.
MacKeith, H. F. Olivo, S. M. Roberts, S. J. C. Taylor and H. Xiong,
Bioorg. Med. Chem., 1994, 2, 387; for alternative methods of
preparation of optically active hydroxylactone 6 see S. Kudis and
G. Helmchen, Tetrahedron, 1998, 54, 10449; F. Burlina, P. Clivio,
J.-L. Fourrey, C. Riche and M. Thomas, Tetrahedron Lett., 1994, 35,
8151; N. Gathergood and K. A. Jørgensen, Chem. Commun., 1999,
1869.
7 B. M. Trost, R. Madsen, S. G. Guile and A. E. H. Elia, Angew.
Chem., Int. Ed. Engl., 1996, 35, 1569; B. M. Trost, G.-H. Kuo and
T. Benneche, J. Am. Chem. Soc., 1988, 110, 621.
8 B. M. Dominguez and P. M. Cullis, Tetrahedron Lett., 1999, 40,
5783.
C, C2), 161.0 (C, C6), 170.1 and 170.3 (C, C᎐O).
᎐
9 N. Katagiri, Y. Ito, K. Kitano, A. Toyota and C. Kaneko, Chem.
Pharm. Bull., 1994, 42, 2653.
10 G. Bullucci, G. Berti, G. Ingrosso and E. Mastrorilli, Tetrahedron
Lett., 1973, 3911; R. Rodebaugh and B. Fraser-Reid, J. Am. Chem.
Soc., 1994, 116, 3155.
11 A. S. Cieplak, J. Am. Chem. Soc., 1981, 103, 4540; A. S. Cieplak,
B. D. Tait and C. R. Johnson, J. Am. Chem. Soc., 1989, 111, 8447.
12 F. Lang, D. J. Kassab and B. Ganem, Tetrahedron Lett., 1998, 39,
5903.
Acknowledgements
We thank Novo Nordisk A/S for studentships (to A. D., M.-B.
N. and D. R. V.).
References
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