The synthesis of novel 3', 5'-homocyclic nucleotides as potential anti-HIV agents

Article abstract of DOI:10.1039/a900800d

(5S)-(5-toY-Butyldimethylsiloxymethyl)furan-2(5//)-one has been converted into cytosine 2', 3'-dideoxy-3', 5'homocyclic monophosphate (and its 5-fluoro congener) together with an adenosine homocyclic monophosphate. These were designed as inhibitors of HIV reverse transcriptase although they did not possess such activity.

Full text of DOI:10.1039/a900800d

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The synthesis of novel 3Ј,5Ј-homocyclic nucleotides as potential
anti-HIV agents
Michael G. B. Drew, Stephen Gorsuch, Jayne H. M. Gould and John Mann*
Department of Chemistry, The University of Reading, Whiteknights, Reading, UK RG6 6AD
Received (in Glasgow) 23rd November 1998, Accepted 24th February 1999
(5S)-(5-tert-Butyldimethylsiloxymethyl)furan-2(5H)-one has been converted into cytosine 2Ј,3Ј-dideoxy-3Ј,5Ј-
homocyclic monophosphate (and its 5-fluoro congener) together with an adenosine homocyclic monophosphate.
These were designed as inhibitors of HIV reverse transcriptase although they did not possess such activity.
There is little doubt that of all approaches taken in the search
for new drugs to treat HIV infection, inhibition of the enzyme
reverse transcriptase has been the most successful strategy.
Recent discoveries include biologically potent -series nucleo-
tides1 and variously protected phosphates like 1 which are pro-
by host-specific phosphodiesterases to furnish the pro-active
drug. In this paper we describe the successful synthesis of such
compounds and their biological activity.
Results and discussion
Photoinduced addition of methanol to (5S)-(5-tert-butyl-
dimethylsiloxymethyl)furan-2(5H)-one 5 provided adduct 6 as
previously described,5 and this was converted into the bis-
silylated adduct 7 which was reduced (DIBAL-H). The hemi-
acetal product was acetylated to generate the anomeric acetates
8 (Scheme 1). Since our previous studies had demonstrated the
interesting biological properties of 2a and 2b, and the marked
potency of 2b relative to 2a, it was of interest to prepare their
cyclic phosphate analogues. These pyrimidines were attached
using Vorbruggen-type condensation (TMSI),6 to furnish the
two nucleosides 9 and 10 as a mixture of anomers.
Protection of the free amino group of nucleoside 9 as its
2-(p-nitrophenyl)ethyl carbamate7 (Peoc) yielded the fully pro-
tected nucleoside anomers 11, which to our delight were now
separable by flash chromatography. Indeed this technique has
now been used to separate many substituted cytidines. All
attempts to protect the free amino group of the corresponding
5-fluorocytidine derivatives 10 proved unsuccessful and this was
attributed to the strong electron withdrawing properties of the
α-fluorine atom.
The silyl ether groups of the separated anomers 11á and 11â,
and of the unprotected fluorocytidine 10, were removed (pTSA
in MeOH), and the resultant diols 12á, 12â and 2b were
subjected to phosphorylation. Treatment of 12á and 12â with
bis(benzotriazolyl) phenyl phosphate (from 2 equiv. of 1-
hydroxybenzotriazole and phenyl phosphorodichloridate in the
presence of triethylamine) in pyridine,8 afforded the desired
cyclic phosphates 13á and 13â (35% α and 31% β after chrom-
atography). An X-ray crystallographic study of 13α was fully
consistent with this structure (Fig. 1).† Subsequent carbamate
hydrolysis (MeOH–Et3N–H2O) of the β-anomer was then
achieved in moderate yield (42%), to generate the required
3Ј,5Ј-homocyclic-nucleotide analogue 14â.
All attempts to phosphorylate fluoride 2b under conditions
similar to those previously employed failed to generate the
required product. Only when treated directly with phenyl phos-
phorodichloridate in neat pyridine was the requisite phosphate
15 obtained, albeit in extremely poor yield (7%). Despite
showing poor reactivity towards protection, it now seemed
evident that the free amino group was sufficiently reactive
drugs of 3Ј-azido-3Ј-deoxythymidine (AZT) monophosphate.2
We have already described the synthesis of the novel nucleoside
analogues 2Ј,3Ј-dideoxy-3Ј-(hydroxymethyl)cytidine 2a and the
5-fluorocytidine 2b which possess potent anti-viral activity3 at
the micromolar level against herpes simplex 1 and 2 and against
HIV-1. It is known that cellular kinases activate compounds of
this type to produce their triphosphate forms and there is sig-
nificant evidence that initial mono-phosphorylation is the rate
limiting step.4 While other anti-viral agents such as acyclovir
are activated by virus-specific thymidine kinases (e.g. herpes
simplex), 2Ј,3Ј-dideoxynucleosides have an absolute require-
ment for cellular kinases, for which they usually have poor affin-
ity. This is often the reason for limited potency. With this in
mind, we attempted to synthesise the novel monophosphate
and cyclic phosphate forms of compounds 2a,b. In an effort to
complement this work, the novel 3Ј-hydroxymethyl-purine
nucleoside 3 and its respective cyclic phosphate 4 were also pre-
pared. These compounds, it was hoped, would be cleaved in vivo
† This preliminary work has previously been communicated (ref. 9).
J. Chem. Soc., Perkin Trans. 1, 1999, 969–978
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Scheme 2 Reagents and conditions: i, AllylOP(NPri2)2, tetrazole,
Pri2NH, DCM, 25 ЊC, 20 min; ii, TBAF, THF, 25 ЊC, 1 h; iii, tetrazole,
DCM, 25 ЊC, 18 h; iv, t-BuOOH, Et3N, MeCN, 3 h, 25 ЊC; v, DIBAL-H,
DCM, Ϫ78 ЊC, 2 h; vi, Ac2O, Py, DMAP, 25 ЊC, 18 h.
steps, but also allows greater flexibility in analogue formation
as the choice of base need only be made at the very end of the
synthesis. Treatment of the photoadduct 6 with the PIII reagent
allyl tetraisopropylphosphorodiamidite10 resulted in formation
of the phosphoramidite ester 16 in 85% yield. Deprotection of
the primary hydroxy group (TBAF–THF) then afforded the
cyclisation precursor 17. Treatment of 17 with tetrazole, as a
dilute solution in DCM, furnished the cyclic phosphite, 18
which was then readily oxidised (tert-butyl hydroperoxide),
in high yield (98%), to the phosphate 19. Purification was
problematic due to the acid sensitivity of the intermediate
phosphite and phosphoramidites: the use of silica and silica–
Et3N chromatography systems resulted in considerable de-
composition. Use of alumina and Florisil showed little
improvement. With the exception therefore of the deprotected
adduct, all intermediates were used without purification. As
1
expected, H-NMR spectra of phosphate 19 showed a partial
Scheme 1 Reagents and conditions: i, TBDMSCl, imidazole, DCM,
0 ЊC→rt, 1 h (99%); ii, DIBAL-H, DCM, Ϫ78 ЊC, 3 h; iii, Ac2O, Py,
doubling of signals due to the presence of the phosphorus
atom. Confirmation of our structural assignment and the
stereochemical integrity of 19 was achieved by X-ray analysis
and the ORTEP plot is shown in Fig. 2. Reduction of the
lactone with DIBAL-H under standard conditions provided
the lactol, which was acetylated (Ac2O–pyridine) to afford the
desired glycosidation precursor 20 (65% overall yield).
Formation of the protected nucleotide 21 was now achieved
in good yield (Scheme 3), using the bis(TMS) derivative of
5-fluorocytosine in the presence of SnCl4. Unfortunately, the
resultant anomeric ratio showed no preference for the β-
anomer. All that remained was for Pd0-catalysed removal of the
allyl group to afford the fully deprotected nucleotide analogue
22.
DMAP, 0 ЊC, 18
h
(60%); iv, Bis(TMS)cytosine [bis(TMS)-5-
(98%); v, 2-(p-nitro-
fluorocytosine], TMSI, DCM, 25 ЊC,
2
h
phenyl)ethyl chloroformate, Py, DMAP, 18 h (83%); vi, TsOH, MeOH,
25 ЊC, 2 h (70%); vii, PhOP(O)Cl2, HOBT, Et3N, THF, Py, 4 h (35%
and 31%); viii, Et3N–MeOH–water 1:5:1, CHCl3, 50 ЊC, 8 h (42%);
ix, PhOP(O)Cl2, Py, 25 ЊC, 18 h (10%).
to participate in unwanted phosphorylation side-reactions.
Clearly the decision to phosphorylate in the presence of
unprotected cytosine was an unwise one. While giving access to
small quantities of cyclicphosphate necessary for biological
screening, this reaction offered limited utility for accessing
larger quantities needed for further investigations.
An alternative strategy could involve the installation of the
cyclic phosphate unit prior to addition of the pyrimidine base.
This approach would require the formation of the 5,7-fused
ring phospholactone 19 (Scheme 2). This route benefits not
only from the elimination of laborious protection/deprotection
Despite our success in the pyrimidine series and the relative
ease of preparation of the key bicyclic phosphate unit 19, it was
disappointing to find that this approach could not be extended
into the purine series for the synthesis of homocyclic adenosine
analogues. A range of conditions were employed to effect
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Fig. 1 The structure of 13á with the atomic numbering scheme. Ellipsoids shown at 30% occupancy.
Fig. 2 The structure of 19 with the atomic numbering scheme.
Ellipsoids shown at 30% occupancy. One molecule (of three in the
asymmetric unit) is shown.
Scheme
3
Reagents and conditions: i, Bis(TMS)cytosine, SnCl4,
Scheme 4 Reagents and conditions: i, bis(TMS)adenine or bis(TMS)-
MeCN, 0 ЊC, 2 h; ii, Pd(PPh3)4, Pri2NH, MeCN, 25 ЊC, 5 h.
6-N-benzoyladenine; ii, TESOTf, MeCN, 60 ЊC, 18 h; iii, TBAF,
THF, 25 ЊC, 2 h; iv, PhOP(O)Cl2, Py, 25 ЊC, 18 h (38%); v, ZnBr2,
MeOH, CHCl3, 25 ЊC, 72 h (68%).
sugar/base coupling, including SnCl4 and silyl triflates as Lewis
acids, although these all proved unsatisfactory. SnCl4 merely
induced acetate destruction while triethylsilyl triflate caused
de-allylation.
(CMV), but none of then exhibited any significant activity
(compound 3 showed slight activity against VZV: IC50 = 43
µM). Compounds 3, 25, 26 and 4 were also screened as agonists
of the various adenosine receptors, but none showed any activ-
ity. The lack of activity probably indicates that the compounds
are not gaining access to the viral cells or are not substrates for
endogenous phosphodiesterases.
By returning to our original methodology of sugar/base
coupling prior to phosphorylation, we were able to circumvent
these problems. Formation of bis(trimethylsilyl)adenine using
hexamethyldisilazane (HMDS), LiI and TMSCl, followed by
triethylsilyl triflate catalysed adenylation of 8 afforded the
requisite protected anomeric nucleoside 23 in 74% yield. The
6-N-benzoyladenosine derivative 24 was also shown to be
equally accessible (Scheme 4). Double desilylation of 23 and 24
using TBAF–THF afforded the requisite unprotected nucleo-
side 3 and the phosphorylation precursor 25. The 6-N-benzoyl-
3Ј-hydroxymethyladenosine 25 was treated, as a dilute solution
in dry pyridine, with phenyl phosphorodichloridate to generate
the cyclic phosphate 26 in 38% yield. This was subsequently
deprotected using ZnBr2–MeOH–CHCl3 (ref. 11) to afford the
requisite 3Ј,5Ј-homocyclic nucleoside analogue 27.
Experimental
General experimental details are given in ref. 3.
(4R,5S)-5-(tert-Butyldimethylsiloxymethyl)-4-(hydroxymethyl)-
tetrahydrofuran-2-one (6)
The protected butenolide (5)3 (10 g, 43.8 mmol) and benzophe-
none (8 g, 43.9 mmol) were added to a Pyrex photochemical
reactor containing AR methanol (350 ml). After degassing for 1
hour with a constant stream of argon, the reagents were irradi-
ated for 6 hours with a 500 W medium pressure Hg discharge
lamp. The now yellow solution was evaporated to dryness
Extensive biological evaluation was carried out on com-
pounds 3, 14, 15, 22, 26 and 4. The compounds were screened
for anti-viral activity against HIV-1, HIV-2, Herpes simplex 1
and 2 (HSV-1,2), Varicella zoster (VZV) and cytomegalovirus
J. Chem. Soc., Perkin Trans. 1, 1999, 969–978
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in vacuo to afford a deep yellow solid. Purification by flash-
column chromatography (gradient elution, 50:50 to 75:25
ether–light petroleum as eluant) afforded the title compound
(6) as a light yellow oil (5.1 g, 19.6 mmol, 45%). [α]D25 ϩ4.0 (c 0.9
in CHCl3); νmax (film)/cmϪ1 3430s (OH), 3000–2800s (CH),
1760s (CO), 1473m (C–O); δH(400 MHz; CDCl3; Me4Si) 0.08
(3H, s, Me), 0.09 (3H, s, Me), 0.90 [9H, s, C(CH3)3], 2.32 (1H,
dd, Jgem 16.9, J3a,4 4.8, 3a-H), 2.62–2.69 (2H, m, 4-H and OH),
2.73 (1H, dd, Jgem 16.9, J3b,4 9.3, 3b-H), 3.65 (1H, dd, Jgem 10.6,
J7a,4 7.0, 7a-H), 3.71 (1H, dd, Jgem 10.6, J7b,4 5.1, 7b-H), 3.77
(1H, dd, Jgem 11.2, J6a,5 3.1, 6a-H), 3.86 (1H, dd, Jgem 11.2, J6b,5
3.9, 6b-H), 4.42 (1H, m, 5-H); δC(100 MHz; CDCl3; Me4Si)
Ϫ5.8 (Me), Ϫ5.7 (Me), 18.2 [C(CH3)3], 25.6 [C(CH3)3], 31.7
(C-3), 39.2 (C-4), 63.4 (C-7), 64.5 (C-6), 82.6 (C-5), 176.9 (C-2);
m/z (CI) [Found: MNH4ϩ, 278.1788. C12H24O4Si requires
MNH4ϩ, 278.1788].
6-H), 4.07 (1H, dd, J4,3 8.8, J4,5 4.0, 4-H), 6.29 (1H, d, J1,2 4.4,
1-H); β-anomer: 0.06 (6H, s, 2 × Me), 0.07 (6H, s, 2 × Me), 0.90
[18H, s, 2 × C(CH3)3], 1.85 (1H, dd, Jgem 13.9, J2a,3 3.7, 2a-H),
2.04 (3H, s, COMe), 2.30 (1H, dd, Jgem 13.9, J2b,3 5.5, 2b-H),
2.36–2.46 (1H, m, 3-H), 3.61–3.77 (4H, m, 5-H and 6-H), 3.93
(1H, dt, J4,3 7.7, J4,5 5.5, 4-H), 6.24 (1H, d, J1,2 4.8, 1-H); δC(100
MHz; CDCl3; Me4Si) α-anomer: Ϫ5.4 (MeSi), Ϫ5.3 (MeSi),
18.4 [C(CH3)3], 21.4 (COMe), 25.9 [C(CH3)3], 35.0 (C-2), 41.5
(C-3), 64.8 (C-6), 64.9 (C-5), 83.6 (C-4), 99.5 (C-1), 170.4
(C᎐O); β-anomer: Ϫ5.5 (MeSi), Ϫ5.3 (MeSi), 18.3 [C(CH ) ],
᎐
3
3
21.5 (COMe), 25.8 [C(CH3)3], 35.9 (C-2), 41.6 (C-3), 63.7
(C-6), 66.2 (C-5), 83.7 (C-4), 99.0 (C-1) and 170.4 (C᎐O). m/z
᎐
(CI) [Found: (M Ϫ OAc)ϩ, 359.2438. C20H42O5Si2 requires
(M Ϫ OAc)ϩ, 359.2438].
1-[3Ј-C-(tert-Butyldimethylsiloxymethyl)-5Ј-O-(tert-butyl-
dimethylsilyl)-2Ј,3Ј-dideoxy-á-D- and -â-D-erythro-pento-
furanosyl]cytosine (9)
(4R,5S)-4,5-Bis(tert-butyldimethylsiloxymethyl)tetrahydro-
furan-2-one (7)
To a solution of iodine (0.76 g, 2.54 mmol) in CH2Cl2 (6.2 cm3)
was added hexamethyldisilane (0.68 cm3, 2.8 mmol). The mix-
ture was heated at reflux at 70 ЊC for 1 h, after which time
the purple colour had disappeared leaving a near colourless
To a solution of photoadduct (6) (4.4 g, 17 mmol) and imida-
zole (1.29 g, 18.7 mmol) at 0 ЊC in DCM (40 ml) was added
dropwise, a DCM solution of tert-butyldimethylsilyl chloride
(2.72 g, 17.7 mmol). After stirring the mixture at 0 ЊC for 15
minutes and for a further 30 minutes at room temperature,
water (50 ml) was added and the mixture extracted with DCM
(3 × 30 ml). The combined organic extracts were washed with
brine, dried (MgSO4) and evaporated to dryness in vacuo. Puri-
fication by flash-column chromatography (1.5:8.5 ether–light
petroleum as eluant) afforded the title compound (7) as a light
yellow oil (6.31 g, 16.8 mmol, 99%). [α]D25 ϩ5.1 (c 1.4 in CHCl3);
νmax (film)/cmϪ1 3000–2800s (CH), 1763s (CO), 1471m (C–O),
1389m; δH(400 MHz; CDCl3; Me4Si) 0.01 (6H, s, 2 × Me), 0.02
(3H, s, Me), 0.03 (3H, s, Me), 0.84 [9H, s, C(CH3)3], 0.85 [9H, s,
C(CH3)3], 2.26 (1H, dd, Jgem 16.5, J3a,4 3.7, 3a-H), 2.53–2.59
(1H, m, 4-H), 2.63 (1H, dd, Jgem 16.5, J3b,4 9.5, 3b-H), 3.54 (1H,
dd, Jgem 9.9, J7a,4 6.2, 7a-H), 3.59 (1H, dd, Jgem 9.9, J7b,4 4.6, 7b-
H), 3.64 (1H, dd, Jgem 11.4, J6a,5 2.9, 6a-H), 3.84 (1H, dd, Jgem
11.4, J6b,5 2.9, 6b-H), 4.35 (1H, dt, J5,4 6.2, J5,6 2.9, 5-H); δC(100
MHz; CDCl3; Me4Si) Ϫ5.6 (Me2Si), 18.1 [C(CH3)3], 25.7
[C(CH3)3], 31.6 (C-3), 38.8 (C-4), 63.8 (C-7), 64.6 (C-6), 82.4
(C-5), 176.9 (C-2); m/z (CI) [Found: MHϩ, 375.2374.
C18H38O4Si2 requires MHϩ, 375.2387].
solution. The solution of trimethylsilyl iodide (1 mol dmϪ3
obtained was allowed to cool and was then used immediately.
)
To a solution of the acetate (8) (1.85 g, 4.42 mmol) in dry
CH2Cl2 (35 cm3) under an atmosphere of nitrogen was added
2-O,4-N-bis(trimethylsilyl)cytosine (5.0 mmol), followed by
trimethylsilyl iodide (4.7 cm3, 4.74 mmol), dropwise. The reac-
tion mixture was stirred at room temperature for 2 h, and then
quenched by the addition of water (10 cm3). The organic layer
was washed with saturated aqueous sodium thiosulfate solution
(2 × 100 cm3), dried (MgSO4) and the solvent removed in vacuo.
The residue was purified by flash chromatography (10%
MeOH:90% CH2Cl2) to give the nucleoside (9) as a white
1
amorphous solid (1.76 g, 85%) in a ratio of α:β = 1:1.3 by H
NMR, Rf 0.40 (10% MeOH:90% CH2Cl2); mp 98–99 ЊC (“soft-
ening”); νmax (CHCl3)/cmϪ1 3315 (br, NH2), 3191 (br, NH2),
2955, 2929, 2858, 1720, 1648 (C᎐O), 1485, 1472, 1255 and 1127;
᎐
δH(400 MHz, CD3OD) α-anomer: 0.06 (6 H, s, 2 × Me), 0.10
t
(3 H, s, Me), 0.11 (3 H, s, Me), 0.89 (9 H, s, Bu), 0.93 (9 H, s,
tBu), 1.88 (1 H, ddd, Jgem 13.2, J2Ј,3Ј 8.4, J2Ј,1Ј 6.2, 2Ј-H), 2.47–
2.52 (1 H, m, 3Ј-H), 2.63 (1 H, ddd, Jgem 13.2, J2Ј,3Ј 8.8, J2Ј,1Ј 6.2,
2Ј-H), 3.64–3.75 (3 H, m, 5Ј-H, 2 × 6Ј-H), 3.87 (1 H, dd, Jgem
11.0, J5Ј,4Ј 3.2, 5Ј-H), 4.21–4.25 (1 H, m, 4Ј-H), 6.00 (1 H, d, J5,6
7.7, 5-H), 6.04–6.07 (1 H, m, 1Ј-H) and 7.84 (1 H, d, J6,5 7.7,
6-H), β-anomer: 0.08 (3 H, s, Me), 0.09 (3 H, s, Me), 0.13 (3 H,
1-O-Acetyl-3-C-(tert-butyldimethylsiloxymethyl)-5-O-(tert-
butyldimethylsilyl)-2,3-dideoxy-á-D- and -â-D-erythro-pento-
furanose (8)
t
t
To a solution of lactone (7) (6.31 g, 16.8 mmol) in DCM (60 ml)
at Ϫ78 ЊC (CO2–acetone) was added dropwise DIBAL-H (19
ml, 1 M solution in toluene, 19 mmol). After 1 hour, MeOH (3
ml) was added and the solution stirred for a further 1 hour. The
mixture was then treated with EtOAc (15 ml) and saturated
aqueous NaHCO3 (3 ml) and allowed to warm to room tem-
perature over 2 hours. The solution was dried over MgSO4,
filtered through Celite and evaporated to afford the crude lactol
as a light yellow oil. Without purification, the lactol was dis-
solved in DCM (20 ml) and pyridine (5 ml), and the solution
cooled to 0 ЊC and treated with acetic anhydride (3 ml). After
warming to room temperature and stirring for 3 days, water
(30 ml) was added and the solution extracted with DCM
(2 × 20 ml). The combined organic phases were washed with
brine, dried (MgSO4) and evaporated in vacuo to afford a light
red oil. Purification by flash-column chromatography (9:1 light
petroleum–ether as eluant) afforded the title compound (8) as a
colourless oil (4.1 g, 9.8 mmol, 58%); νmax (film)/cmϪ1 3000–
2800s (CH), 1751s (CO), 1473m (C–O), 1362m, 1256w; δH(400
MHz; CDCl3; Me4Si) α-anomer: 0.04 (6H, s, 2 × Me), 0.05 (6H,
s, 2 × Me), 0.89 [18H, s, 2 × C(CH3)3], 1.98 (1H, dd, Jgem 13.2,
J2a,3 2.6, 2a-H), 2.03 (3H, s, COMe), 2.29 (1H, dd, Jgem 13.2, J2b,3
4.8, 2b-H), 2.36–2.46 (1H, m, 3-H), 3.61–3.77 (4H, m, 5-H and
s, Me), 0.14 (3 H, s, Me), 0.92 (9 H, s, Bu), 0.95 (9 H, s, Bu),
2.11 (1 H, ddd, Jgem 13.6, J2Ј,3Ј 8.1, J2Ј,1Ј 3.3, 2Ј-H), 2.36 (1 H,
ddd, Jgem 13.6, J2Ј,3Ј 8.8, J2Ј,1Ј 7.0, 2Ј-H), 2.47–2.52 (1 H, m,
3Ј-H), 3.64–3.75 (2 H, m, 5Ј-H, 6Ј-H), 3.84 (1 H, dd, Jgem 11.7,
J6Ј,3Ј 2.6, 6Ј-H), 4.01 (1 H, dt, J4Ј,5Ј 7.7, J4Ј,3Ј 5.1, J4Ј,5Ј 2.6, 4Ј-H),
4.07 (1 H, dd, Jgem 11.4, J5Ј,4Ј 2.6, 5Ј-H), 5.93 (1 H, d, J5,6 7.7,
5-H), 6.04–6.07 (1 H, m, 1Ј-H) and 8.29 (1 H, d, J6,5 7.7, 6-H);
δC(100.4 MHz, CD3OD) α-anomer: Ϫ5.2 (2 × Me2Si), 19.2
(CMe3), 26.5 (CMe3), 37.1 (C-2Ј), 43.4 (C-3Ј), 64.6 (C-6Ј), 66.3
(C-5Ј), 85.2 (C-4Ј), 89.1 (C-1Ј), 95.8 (C-5), 142.9 (C-6), 155.7
(C-4) and 165.9 (C᎐O): β-anomer: Ϫ5.3 (2 × Me Si), 19.3
᎐
2
(CMe3), 26.4 (CMe3), 37.7 (C-2Ј), 40.6 (C-3Ј), 64.6 (C-6Ј), 66.3
(C-5Ј), 85.8 (C-4Ј), 87.9 (C-1Ј), 95.2 (C-5), 143.7 (C-6), 156.0
(C-4) and 165.6 (C᎐O) [Found: (M ϩ H)ϩ, 470.2888.
᎐
C22H44N3O4Si2 requires MHϩ, 470.2870].
1-[3Ј-C-(tert-Butyldimethylsiloxymethyl)-5Ј-O-(tert-butyl-
dimethylsilyl)-2Ј,3Ј-dideoxy-á-D- and -â-D-erythro-pento-
furanosyl]-5-fluorocytosine (10)
A 1 M solution of TMSI was freshly prepared by refluxing
hexamethyldisilane (0.3 g, 2.05 mmol) and iodine (0.44 g, 1.73
mmol) in DCM (3.5 ml) until a clear solution was obtained.
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A suspension of 5-fluorocytosine (0.50 g, 3.9 mmol) and
N,O-bis(trimethylsilyl)acetamide (5 ml, excess) was refluxed
for 1 hour. Excess reagents were removed in vacuo and the
residue co-evaporated with toluene (3 × 15 ml) until crystallis-
ation occurred. The bis(trimethylsilyl)-5-fluorocytosine thus
obtained, was re-dissolved in dry DCM (5 ml) and transferred
to an oven-dried vessel under argon, containing acetate (8)
(1.47 g, 3.5 mmol) and dry DCM (20 ml). TMSI solution (3.5
ml, 1 M solution prepared above, 3.5 mmol) was added and
the solution stirred for 2 hours. Water (4 ml) was added and
the mixture washed with NaS2O3 (25 ml) and extracted with
DCM (3 × 30 ml). The combined organic extracts were dried
(MgSO4) and evaporated to afford a gummy foam. Purification
by flash-column chromatography (15:85 MeOH–DCM as
eluant) afforded the title compound (10) as a white micro-
crystalline solid (1.602 g, 3.3 mmol, 94%); νmax (film)/cmϪ1
(C-6), 145.0 (C–NO2), 147.0 (C-quart, Ar), 152.1 (C-4), 154.9
(C᎐O, nPeoc) and 162.0 (C-2).
᎐
β-Anomer: white amorphous solid (0.58 g, 40%), Rf 0.60 (45%
EtOAc–40% light petroleum–15% MeCN); [α]D21 ϩ39.1 (c 0.5,
CHCl3); νmax (CDCl3)/cmϪ1 2952, 2928, 2857, 1747 (C᎐O,
᎐
nPeoc), 1735, 1668, 1662, 1623, 1519 (C–NO2), 1501, 1345
(C–NO2), 1227 and 1197; δH(400 MHz, CDCl3) 0.04 (3 H, s,
Me), 0.05 (3 H, s, Me), 0.11 (3 H, s, Me), 0.13 (3 H, s, Me), 0.88
(9 H, s, tBu), 0.93 (9 H, s, tBu), 2.08–2.16 (1 H, m, 2Ј-H), 2.40–
2.48 (2 H, m, 2Ј-H, 3Ј-H), 3.11 (2 H, t, J 6.6, CH2-nPeoc), 3.61
(1 H, dd, Jgem 10.3, J6Ј,3Ј 5.3, 6Ј-H), 3.65 (1 H, dd, Jgem 10.3, J6Ј,3Ј
4.4, 6Ј-H), 3.77 (1 H, dd, Jgem 11.7, J5Ј,4Ј 2.0, 5Ј-H), 4.03–4.12
(2 H, m, 4Ј-H, 5Ј-H), 4.44 (2 H, t, J 6.6, CH2-nPeoc), 6.05–6.07
(1 H, m, 1Ј-H), 7.09 (1 H, d, J5,6 7.0, 5-H), 7.40 (2 H, d, J 8.6,
p-NO2Ph), 7.50 (1 H, br s, NH), 8.19 (2 H, d, J 8.6, p-NO2Ph)
and 8.60 (1 H, d, J6,5 7.0, 6-H); δC(100.4 MHz, CDCl3) Ϫ5.5
(2 × Me), Ϫ5.4 (2 × Me), 18.3 (CMe3), 18.5 (CMe3), 25.9
(CMe3), 26.0 (CMe3), 35.0 (CH2-nPeoc), 36.7 (C-2Ј), 38.3
(C-3Ј), 62.4 (C-6Ј), 62.8 (C-5Ј), 65.4 (CH2-nPeoc), 84.6 (C-4Ј),
87.1 (C-1Ј), 93.7 (C-5), 123.9 (Ar), 129.8 (Ar), 145.0 (C–NO2),
3319s (NH ), 3080s (NH ), 3000–2800s (CH), 1690s (C᎐O),
᎐
2
2
1684s, 1620m (C᎐C), 1512m; δ (250 MHz; CDCl ; Me Si)
᎐
H
3
4
α-anomer: 0.02 (3H, s, Me), 0.03 (3H, s, Me), 0.12 (3H, s, Me),
0.13 (3H, s, Me), 0.91 [9H, s, C(CH3)3], 0.93 (9H, s, C(CH3)3],
1.75–1.82 (2H, m, 2Јa-H, 3Ј-H), 2.11 (1H, ddd, Jgem 13.9, J2Јb,3Ј
8.1, J2Јb,1Ј 5.9, 2Јb-H), 3.53–3.65 (2H, m, 6Ј-H), 3.68 (1H, dd,
Jgem 11.0, J5Јa,4Ј 4.4, 5Јa-H), 3.8 (1H, dd, Jgem 11.0, J5Јb,4Ј 3.7,
5Ј-H), 4.18 (1H, dt, J4Ј,5Ј 4.4, J4Ј,3Ј 2.2, 4Ј-H), 6.03 (1H, t, J1Ј,2Ј
5.9, 1Ј-H), 7.59 (1H, d, JH,F 6.2, 6-H) β-anomer: 0.04 (3H,
s, Me), 0.05 (3H, s, Me), 0.07 (3H, s, Me), 0.08 (3H, s, Me),
0.87 [9H, s, C(CH3)3], 0.88 [9H, s, C(CH3)3], 2.34–2.44 (2H, m,
145.3 (C-6), 147.0 (C-quart, Ar), 152.1 (C-4), 155.0 (C᎐O,
᎐
nPeoc) and 161.9 (C-2).
1-[2Ј,3Ј-Dideoxy-3Ј-C-(hydroxymethyl)-á-D-erythro-pento-
furanosyl]-4-N-(p-nitrophenylethoxycarbonyl)cytosine (12á)
To a solution of the α-anomer of the fully protected nucleoside
(11) (0.43 g, 0.78 mmol) in dry THF (11 cm3) under an atmos-
phere of argon was added tetrabutylammonium fluoride (1.0
mol dmϪ3 in THF, 1.2 cm3), and the reaction mixture stirred at
room temperature for 2 h. The solvent was removed in vacuo,
and the residue purified by flash chromatography (10–20%
MeOH–OH2Cl2) to give the diol (12á) (0.23 g, 67%) as a white
amorphous solid, Rf 0.36 (10% MeOH–90% CH2Cl2); mp 82–
84 ЊC (“softening”); [α]D25 Ϫ47.1 (c 0.5, MeOH); νmax (CHCl3)/
cmϪ1 3387 (br, OH), 2934, 1748 (C᎐O, nPeoc), 1736, 1649 (C᎐O,
2Јa-H, 3Ј-H), 2.72 (1H, ddd, Jgem 13.6, J2Јb, 8.4, J2Ј,1Ј 6.6,
3Ј
2Јb-H), 3.53–3.65 (2H, m, 6Ј-H), 3.76 (1H, dd, Jgem 11.7, J5Јa,4Ј
2.2, 5Јa-H), 3.98–4.0 (1H, m, 4Ј-H), 4.10 (1H, dd, Jgem 11.7,
J5Јb,4Ј 2.2, 5Јb-H), 6.02 (1H, t, J1Ј,2Ј 5.9, 1Ј-H), 8.32 (1H, d, JH,F
6.2, 6-H); m/z (CI) [Found: MHϩ, 488.2780. C22H42N3Si2O4F
requires MHϩ, 488.2776].
1-[3Ј-C-(tert-Butyldimethylsiloxymethyl)-5Ј-O-(tert-butyl-
dimethylsilyl)-2Ј,3Ј-dideoxy-á-D- and -â-D-erythro-pento-
furanosyl]-4-N-(p-nitrophenylethoxycarbonyl)cytosine (11)
᎐
᎐
cytosine), 1619, 1560, 1501 and 1348 (NO2); δH(400 MHz,
d6–DMSO) 1.71–1.78 (1 H, m, 2Ј-H), 2.26–2.31 (1 H, m, 3Ј-H),
2.52–2.58 (1 H, m, 2Ј-H), 3.08 (2 H, t, J 6.6, CH2-nPeoc), 3.37–
3.40 (2 H, m, 2 × 6Ј-H), 3.41–3.47 (1 H, m, 5Ј-H), 3.55–3.60
(1 H, m, 5Ј-H), 4.12–4.16 (1 H, m, 4Ј-H), 4.36 (2 H, t, J 6.6,
CH2-nPeoc), 5.94 (1 H, J1Ј,2Ј 6.0, 1Ј-H), 7.01 (1 H, d, J5,6 7.5,
5-H), 7.61 (2 H, d, J 8.8, p-NO2Ph), 8.08 (1 H, d, J6,5 7.5, 6-H),
8.17 (2 H, d, J 8.8, p-NO2Ph) and 10.7 (1 H, br s, NH); δC(100.4
MHz, d6-DMSO) 34.2 (CH2-nPeoc), 36.1 (C-2Ј), 42.0 (C-3Ј),
61.6 (C-6Ј), 63.0 (C-5Ј), 64.9 (CH2-nPeoc), 84.1 (C-4Ј), 87.3
(C-1Ј), 94.0 (C-5), 123.3 (Ar), 130.4 (Ar), 144.3 (C-6), 146.3
(C–NO ), 146.4 (C-quart, Ar), 154.8 (C᎐O, nPeoc) and 162.7
To a solution of the nucleoside (9) (1.01 g, 2.15 mmol) in dry
pyridine (14 cm3) under an atmosphere of argon was added
dimethylaminopyridine (68 mg), followed by 2-(p-nitrophenyl)-
ethyl chloroformate (0.64 g, 2.8 mmol), and the reaction mix-
ture was stirred at room temperature overnight. The reaction
was quenched by the addition of water (30 cm3), and the aque-
ous layer extracted with CH2Cl2 (3 × 30 cm3). The combined
organic extracts were washed with aqueous HCl (2 mol dmϪ3
,
3 × 60 cm3), saturated aqueous NaHCO3 solution (3 × 60 cm3)
and brine (2 × 60 cm3). The organic layer was dried (MgSO4),
and the solvent removed under reduced pressure. The residue
was purified by flash chromatography (45% EtOAc–40% pet-
roleum ether–15% MeCN) to give the fully protected nucleoside
(11) as two separable anomers (1.18 g, 83% overall).
᎐
2
(C-2) [Found: (M ϩ H)ϩ, 435.1536. C19H23N4O8 requires MHϩ,
435.1516].
1-[2Ј,3Ј-Dideoxy-3Ј-C-(hydroxymethyl)-â-D-erythro-pento-
furanosyl]-4-N-(p-nitrophenylethoxycarbonyl)cytosine (12â)
α-Anomer: white powder (0.61 g, 43%), Rf 0.63 (45% EtOAc–
40% light petroleum–15% MeCN); mp 172–174 ЊC; [α]D23 Ϫ44.8
(c 1.1, CHCl3); νmax (CDCl3)/cmϪ1 2954, 2931, 2856, 1748 (C᎐O,
To a solution of the β-anomer of the fully protected nucleoside
(11) (0.24 g, 0.43 mmol) in MeOH (AnalaR, 4.0 cm3) and H2O
(0.9 cm3) was added toluene-p-sulfonic acid monohydrate (89
mg, 0.47 mmol), and the reaction mixture stirred at room tem-
perature for 2 h. After neutralisation with basic resins (IRA 93,
3.2 cm3), the mixture was stirred for a further 4 h and then
filtered. The solvent was removed in vacuo, and the residue
purified by flash chromatography (10-20% MeOH–CH2Cl2) to
give the diol (12â) (0.11 g, 59%) as a white amorphous solid, Rf
0.41 (10% MeOH–90% CH2Cl2); mp 82–84 ЊC (‘softening’);
[α]D23 ϩ27.5 (c 0.2, MeOH); νmax (CHCl3)/cmϪ1 3247 (br, OH),
᎐
nPeoc), 1736, 1664, 1655, 1625, 1520 (C–NO2), 1346 (C–NO2)
and 1231; δH(400 MHz, CDCl3) 0.01 (6 H, s, 2 × Me), 0.02 (3 H,
t
t
s, Me), 0.08 (3 H, s, Me), 0.85 (9 H, s, Bu), 0.91 (9 H, s, Bu),
1.77–1.84 (1 H, m, 2Ј-H), 2.46–2.49 (1 H, m, 2Ј-H), 2.97–3.0
(1 H, m, 3Ј-H), 3.12 (2 H, t, J 6.8, CH2-nPeoc), 3.50–3.54 (1 H,
m, 6Ј-H), 3.61 (1 H, dd, Jgem 10.3, J6Ј,3Ј 4.8, 6Ј-H), 3.70 (1 H,
dd, Jgem 11.0, J5Ј,4Ј 4.4, 5Ј-H), 3.83 (1 H, dd, Jgem 11.0, J5Ј,4Ј 3.3,
5Ј-H), 4.21–4.24 (1 H, m, 4Ј-H), 4.44 (2 H, t, J 6.8, CH2-nPeoc),
6.05 (1 H, t, J1Ј,2Ј 6.0, 1Ј-H), 7.16 (1 H, d, J5,6 7.5, 5-H), 7.40
(2 H, d, J 8.6, p-NO2Ph), 7.78 (1 H, br s, NH), 7.93 (1 H, d, J6,5
7.5, 6-H) and 8.18 (2 H, d, J 8.6, p-NO2Ph); δC(100.4 MHz,
CDCl3) Ϫ5.5 (2 × Me), Ϫ5.4 (Me), Ϫ5.3 (Me), 18.2 (CMe3),
18.3 (CMe3), 25.8 (CMe3), 25.9 (CMe3), 34.9 (CH2-nPeoc), 36.6
(C-2Ј), 42.2 (C-3Ј), 63.1 (C-6Ј), 65.0 (C-5Ј), 65.5 (CH2-nPeoc),
84.0 (C-4Ј), 88.6 (C-1Ј), 94.2 (C-5), 123.9 (Ar), 129.8 (Ar), 143.4
2950, 2933, 1738(C᎐O, nPeoc), 1733, 1641, 1564, 1517 (NO ),
᎐
2
1506, 1346 (NO2), 1257 and 1109; δH (400 MHz, d6-DMSO)
1.97–2.05 (1 H, m, 2Ј-H), 2.21–2.30 (2 H, m, 2Ј-H, 3Ј-H), 3.08
(2 H, t, J 6.4, CH2-nPeoc), 3.42–3.47 (2 H, m, 2 × 6Ј-H), 3.60
(1 H, dd, Jgem 12.1, J5Ј,4Ј 3.7, 5Ј-H), 3.76 (1 H, dd, Jgem 12.1, J5Ј,4Ј
J. Chem. Soc., Perkin Trans. 1, 1999, 969–978
973

View Article Online
2.8, 5Ј-H), 3.85–3.87 (1 H, m, 4Ј-H), 4.36 (2 H, t, J 6.4, CH2-
nPeoc), 5.90–5.91 (1 H, m, 1Ј-H), 6.96 (1 H, d, J5,6 7.5, 5-H),
7.61 (2 H, d, J 8.4, p-NO2Ph), 8.17 (2 H, d, J 8.4, p-NO2Ph),
8.48 (1 H, d, J6,5 7.5, 6-H), and 10.7 (1 H, br s, NH); δC(100.4
MHz, d6-DMSO) 34.2 (CH2-nPeoc), 36.2 (C-2Ј), 38.9 (C-3Ј),
60.9 (C-6Ј), 61.2 (C-5Ј), 64.9 (CH2-nPeoc), 84.4 (C-4Ј), 86.2
(C-1Ј), 93.5 (C-5), 123.4 (Ar), 130.5 (Ar), 144.6 (C-6), 146.4
overnight. The reaction was quenched by the addition of
MeOH (1.5 cm3), the solvent removed in vacuo by azeotroping
with toluene (2 × 3 cm3), and the residue was purified by flash
chromatography with gradient elution (0–5% MeOH–EtOAc)
to give the cyclic phosphate ester (13â) (45 mg, 31%) as an off-
white solid, Rf 0.42 and 0.38 (5% MeOH–95% CH2Cl2); δH(400
MHz, CDCl3), integration values for the discrete diastereomers
have not been given but were in the approximate ratio of 5:1
with respect to the signals for the discrete diastereomers: 2.29–
2.43 (m, 4 × 2-HЈ), 2.56–2.64 (m, 2 × 3Ј-H), 3.11 (t, J 6.6,
2 × CH2-nPeoc), 4.09 (dd, Jgem 12.8, J6Ј,3Ј 10.3, 6Ј-H), 4.14–4.24
(m, 3 × 6Ј-H), 4.32 (dd, Jgem 11.7, J5Ј,4Ј 3.7, 5Ј-H), 4.34–4.42
(m, 2 × 4Ј-H, 5Ј-H), 4.45 (t, J 6.6, 2 × CH2-nPeoc), 4.49–4.58
(m, 5Ј-H), 4.67 (ddd, J5Ј,P 18.3, Jgem 10.6, J5Ј,4Ј 4.4, 5Ј-H), 6.05
(dd, J1Ј,2Ј 6.8, J1Ј,2Ј 1.6, 1Ј-H), 6.12 (d, J1Ј,2Ј 7.0, 1Ј-H), 7.22 (d,
J 7.7, 4 × Ar), 7.32–7.38 (m, 2 × 5-H, 6 × Ar), 7.41 (d, J 8.4,
4 × Ar-nPeoc), 7.76 (d, J6,5 7.3, 6-H), 7.89 (d, J6,5 6.6, 6-H)
and 8.17 (d, J 8.4, 4 × Ar nPeoc); δP(81 MHz, CDCl3) Ϫ5.2
and Ϫ5.7 (Found: Mϩ, 572.1294. C25H25N4O10P requires Mϩ,
572.1308).
(C–NO ), 154.2 (C᎐O, nPeoc) and 162.3 (C-2).
᎐
2
1-[2Ј,3Ј-Dideoxy-3Ј-C-(hydroxymethyl)-á-D-erythro-pento-
furanosyl]-4-N-(p-nitrophenylethoxycarbonyl)cytosine phenyl
5Ј,6Ј-cyclic phosphate (13á)
To a solution of 1-hydroxybenzotriazole (98 mg, 0.72 mmol) in
dry THF (2 cm3) under an atmosphere of argon, was added
Et3N (0.10 cm3, 0.72 mmol) followed by phenyl phosphoro-
dichloridate (0.05 cm3, 0.36 mmol) dropwise. A white precipitate
formed immediately on addition of the phosphorylating agent,
and the reaction mixture was stirred at room temperature for
1 h. The reaction mixture containing bis-benzotriazolyl phenyl
phosphate was filtered through a Whatman 1.0 µm syringe filter
and added directly to a solution of the diol (12á) (0.13 g, 0.30
mmol) in dry pyridine (5 cm3), dropwise over a period of 2 h.
The reaction mixture was stirred at room temperature under an
atmosphere of argon overnight. Et3N (0.22 cm3, 1.5 mmol) was
added and the reaction mixture stirred at room temperature for
a further 24 h. The reaction was quenched by the addition of
MeOH (2.0 cm3), the solvent removed in vacuo and the residue
purified by flash chromatography with gradient elution (0–10%
MeOH–OH2Cl2) to give the cyclic phosphate ester (13á) (60
mg, 35%) as an off-white solid, Rf 0.34 (0.5% MeOH–95%
CH2Cl2); δH (400 MHz, CDCl3 and CD3OD), integration values
for the discrete diastereoisomers have not been given but were
in the approximate ratio of 2:1 with respect to the signals for
the discrete diastereomers, 1.75–1.84 (m, 2 × 2Ј-H), 2.45–2.51
(m, 2Ј-H), 2.80–2.87 (m, 2 × 3Ј-H), 2.93–2.99 (m, 2Ј-H), 3.14
(t, J 6.6, CH2-nPeoc), 3.51 (dd, Jgem 11.0, J6Ј,3Ј 6.6, 6Ј-H), 3.59
(dd, Jgem 11.0, J6Ј,3Ј 5.1, 6Ј-H), 3.76 (dd, Jgem 11.0, J6Ј,3Ј 4.4,
6Ј-H), 3.82 (dd, Jgem 11.0, J6Ј,3Ј 4.0, 6Ј-H), 4.12–4.25 (m, 5Ј-H,
2 × 4Ј-H), 4.40 (ddd, J5Ј,P 24.9, Jgem 11.7, J5Ј,3Ј 3.7, 5Ј-H), 4.47 (t,
J 6.6, 2 × CH2-nPeoc), 4.50–4.55 (m, 5Ј-H), 4.59 (ddd, J5Ј,P 19.2,
Jgem 10.3, J5Ј,4Ј 4.2, 5Ј-H), 6.02 (t, J1Ј,2Ј 5.9, 1Ј-H), 6.09 (t, J1Ј,2Ј
6.6, 1Ј-H), 7.20–7.27 (m, 2 × 5-H, 4 × ArH), 7.38 (t, J 7.7,
6 × ArH), 7.46 (d, J 8.8, 4 × Ar nPeoc), 7.95 (d, J6,5 7.7, 6-H),
7.99 (d, J6,5 7.3, 6-H) and 8.19 (d, J 8.8, 4 × Ar nPeoc); δC (100.4
MHz, CDCl3 and CD3OD) 34.8 (CH2-nPeoc), 35.7 (C-2Ј), 36.6
(C-2Ј), 42.7 (C-3Ј), 42.8 (C-3Ј), 62.4 (C-6Ј), 65.0 (C-6Ј), 65.4
(CH2-nPeoc), 67.2 (C-5Ј), 68.4 (C-5Ј), 81.5 (C-4Ј), 84.4 (C-4Ј),
88.3 (C-1Ј), 88.7 (C-1Ј), 119.7 (2 × C-5), 123.6 (Ar), 123.8 (Ar),
125.7 (Ar), 129.8 (Ar), 142.8 (Ar), 142.9 (Ar), 143.3 (C-6), 143.4
(C-6), 145.2 (C–NO2), 146.9 (C-quart), 150.0 (C-quart), 152.8
1-[2Ј,3Ј-Dideoxy-3Ј-C-(hydroxymethyl)-â-D-erythro-pento-
furanosyl]cytosine phenyl 5Ј,6Ј-cyclic phosphate (14â)
To a solution of the protected nucleotide (13â) (36 mg, 0.06
mmol) in CHCl3 (1.0 cm3) was added a solution of Et3N–
MeOH–H2O, 1:5:1 (1.0 cm3). The reaction mixture was stirred
at room temperature for 3 days, and then heated at 50 ЊC for a
further 8 h. The solvent was removed under reduced pressure
and the residue purified by flash chromatography with gradient
elution (10–30% EtOH–CH2Cl2) to give the title compound
(14â) (10 mg, 42%) as a white amorphous solid, Rf 0.28 (20%
EtOH–80% CH2Cl2 and 8 drops AcOH); δH(400 MHz,
CD3OD), integration values for the discrete diastereomers have
not been given but were in the approximate ratio of 2:1 with
respect to the signals for the discrete diastereomers, 2.16–
2.21 (m, 4 × 2-HЈ), 2.71–2.78 (m, 2 × 3Ј-H), 4.0 (dd, J5Ј,P 20.9,
Jgem 11.0, 5Ј-H), 4.05–4.17 (m, 2 × 4Ј-H, 2 × 5Ј-H), 4.23 (ddd,
J6Ј,P 22.3, Jgem 10.3, J6Ј,3Ј 8.2, 6Ј-H), 4.32–4.44 (m, 3 × 6Ј-H),
4.49 (ddd, J5Ј,P 20.0, Jgem 10.3, J5Ј,4Ј 3.9, 5Ј-H), 5.81 (d, J5,6 7.7,
5-H), 5.83 (d, J5,6 7.7, 5-H), 5.99 (dd, J1Ј,2Ј 6.6, J1Ј,2Ј 3.7, 1Ј-H),
6.03 (dd, J1Ј,2Ј 6.9, J1Ј,2Ј 2.9, 1Ј-H), 7.15 (t, J 7.9, 6 × Ar), 7.30
(t, J 7.9, 4 × Ar), 7.57 (d, J 7.7, 6-H) and 7.59 (d, J 7.7,
6-H) [Found: (M ϩ H)ϩ, 380.1011. C16H19N3O6P requires
MHϩ, 380.1011].
1-[2Ј,3Ј-Dideoxy-3Ј-C-(hydroxymethyl)-á-D- and -â-D-erythro-
pentofuranosyl]-5-fluorocytosine (2b)
To a 10% aqueous methanolic solution (60 ml) of bis-silyl
nucleoside (10) (2.4 g, 4.92 mmol) was added toluene-p-sulfonic
acid (1.87 g, 9.84 mmol). After 2 hours IRA-93 ion exchange
resin (100 ml) was added and the mixture stirred for a further
2 hours until pH 7 was achieved. The mixture was filtered and
the filtrate evaporated to dryness. Purification of the residue by
flash column chromatography (20:80 MeOH–DCM as eluant)
afforded the title compound 2b as a white amorphous powder
(0.88 g, 3.4 mmol, 70%); mp 81–87 ЊC; νmax (film)/cmϪ1 3330s
(OH), 2925s (NH ), 1680s (C᎐O), 1611s (C᎐C), 1511m, 1462m,
(2 × C-4), 155.6 (2 × C᎐O, nPeoc) and 163.2 (2 × C-2).
᎐
1-[2Ј,3Ј-Dideoxy-3Ј-C-(hydroxymethyl)-â-D-erythro-pento-
furanosyl]-4-N-(p-nitrophenylethoxycarbonyl)cytosine phenyl
5Ј,6Ј-cyclic phosphate (13â)
To a solution of 1-hydroxybenzotriazole (83 mg, 0.62 mmol) in
dry THF (1.7 cm3) under an atmosphere of argon, cooled to
0 ЊC, was added Et3N (0.09 cm3, 0.62 mmol) followed by phenyl
phosphorodichloridate (0.04 cm3, 0.31 mmol), dropwise. A
white precipitate formed immediately on addition of the phos-
phorylating agent. The reaction mixture was allowed to warm
to room temperature and stirred at this temperature for 1 h. The
reaction mixture containing bis-benzotriazolyl phenyl phos-
phate was filtered through a Whatman 1.0 µm syringe filter and
added directly to a solution of the diol (12â) (0.11 g, 0.25
mmol) in dry pyridine (4.5 cm3), dropwise over a period of 1 h.
The reaction mixture was stirred at room temperature under an
atmosphere of argon for 4 h. Et3N (0.18 cm3, 1.25 mmol) was
added and the reaction mixture stirred at room temperature
᎐
᎐
2
1378m; δH(250 MHz; CDCl3; Me4Si) α-anomer: 1.67 (1H, ddd,
Jgem 13.6, J2Јa,3Ј 9.2, J2Јa,1Ј 6.6, 2Јa-H), 2.09–2.38 (1H, m, 3Ј-H),
2.49 (1H, ddd, Jgem 13.6, J2Јb,3Ј 8.1, J2Јb,1Ј 6.2, 2Јb-H), 3.44 (1H,
dd, Jgem 12.5, J5Јa,4Ј 5.5, 5Јa-H), 3.48–3.59 (2H, m, 6Ј-H), 3.61
(1H, dd, Jgem 12.5, J5Јb,4Ј 2.6, 5Јb-H), 4.05 (1H, ddd, J4Ј,3Ј 8.1,
J4Ј,5Јa 5.5, J4Ј,5Јb 2.6, 4Ј-H), 5.83 (1H, dt, J1Ј,2Ј 6.2, J1Ј,3Ј 1.5, 1Ј-H),
7.70 (1H, d, JH,F 6.6, 6-H) β-anomer: 1.93–2.03 (1H, m, 2Јa-H),
2.09–2.38 (2H, m, 2Јb-H, 3Ј-H), 3.48–3.59 (3H, m, 5Јa-H,
6Ј-H), 3.73 (1H, dd, Jgem 12.8, J5Јb,4Ј 2.9, 5Јb-H), 3.79 (1H, ddd,
J4Ј,3Ј 8.1, J4Ј,5Јa 4.8, J4Ј,5Јb 2.9, 4Ј-H), 5.81–5.82 (1H, m, 1Ј-H), 7.9
(1H, d, JH,F 6.6, 6-H); m/z (CI) [Found: MHϩ, 260.1039.
C10H14N3O4F requires MHϩ, 260.1046].
974
J. Chem. Soc., Perkin Trans. 1, 1999, 969–978

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1-[2Ј,3Ј-Dideoxy-3Ј-C-(hydroxymethyl)-â-D- and -á-D-erythro-
pentofuranosyl]-5-fluorocytosine phenyl 5Ј,6Ј-cyclic phosphate
(15)
was evaporated in vacuo to afford a thick black oil. Purification
by rapid short path flash chromatography (2:8 EtOAc–ether as
eluant) afforded the title compound (17) as a light yellow oil
(0.81 g, 2.4 mmol, 83%); m/z (CI) [Found: MHϩ, 334.1793.
C15H28NPO5 requires MHϩ, 334.1783]. Due to the presence of
tetrabutylammonium fluoride residues and the instability of
this compound, further characterisation or purification was not
possible.
To a stirred solution of diol (2b) (100 mg, 0.38 mmol) in freshly
distilled pyridine (5 ml) under an atmosphere of argon was
added dropwise, in pyridine (1 ml), phenyl phosphorodichlori-
date (100 mg, 0.46 mmol). After 18 hours, DCM (15 ml)
was added and the mixture washed with saturated aqueous
NaHCO3 (3 ml). The organic phase was washed with brine,
dried (MgSO4) and evaporated. Purification of the residue by
flash-column chromatography (gradient elution, 90:10 to
85:15 DCM–MeOH as eluant) afforded the title compound
(15) as an amorphous white solid (12 mg, 0.030 mmol, 7%). mp
103–108 ЊC; due to the complexity of this NMR spectrum, it
was not usually possible to differentiate α/β signals (1:4 ratio);
δH(400 MHz; CDCl3; Me4Si) 1.7–1.85, 2.81–2.9 (1H, m, 2Јa-H),
2.18–2.2 (1H, m, 2Јb-H), 2.55–2.63, 2.7–2.8, 2.9–3.0 (1H, m,
3Ј-H), 3.85–4.02 (1H, m, 6Јa-H), 4.03–4.25, 4.25–4.7 (4H,
m, 6Јb-H, 4Ј-H, 5Ј-H), 5.6–5.9 (1H, br s, NH), 5.95 [0.2H, t,
J1Ј,2Ј 6.6, 1Ј-H (α-anomer)], 5.99–6.05 [0.8H, 2 × d, J1Ј,2Ј 7.0,
1Ј-H (β-anomer)], 7.15–7.38 (5H, m, Ph), 7.39–7.45 [0.8H,
2 × d, J6,F 6.23, 6-H (β-anomer)], 7.45–7.55 [0.2H, 2 × d,
J6,F 7.0, 6-H (α-anomer)], 7.6–7.8 (1H, br s, NH); δC(100 MHz;
CDCl3; Me4Si) 35.0, 35.7, 35.8, 36.0 (2Ј-C), 43.6, 44.6, 46.2,
47.3 (3Ј-C), 65.5, 70.1, 72.3, 72.4 (5Ј-C and 6Ј-C), 81.0, 82.2,
82.3, 82.6 (4Ј-C), 86.3, 86.7, 88.0, 88.3 (1Ј-C), 119.8, 119.9,
120.0, 125.5, 125.6, 129.7, 129.9, 136.0, 138.1 (OPh), 124.0,
124.3, 124.4 (6-C), 150.0 (5-C), 153.2 (4-C), 158.0 (2-C);
m/z (CI) [Found: MHϩ, 398.0936. C16H17N3PO6F requires
MHϩ, 398.0917].
(1R,7S)-4-(Prop-2Ј-enyloxy)-3,5,8-trioxa-4-phosphabicyclo-
[5.3.0]decan-9-one (18)
To a stirred solution of phosphoramidite (17) (130 mg, 0.34
mmol) in dry DCM (10 ml) at 0 ЊC (ice–water) under argon was
added tetrazole (30 mg, 0.37 mmol). The solution was stirred at
0 ЊC for 2 hours and then gradually allowed to warm to room
temperature over 18 hours. Evaporation of the solvent in vacuo
followed by rapid flash-column chromatography of the residue
(100% ether as eluant) afforded the title compound (18) as a
colourless oil (40 mg, 0.17 mmol, 51%); νmax (film)/cmϪ1 3000–
2800s (CH), 1790s (CO), 1468m (C–O), 1190s, 876w; δH(250
MHz; CDCl3; Me4Si) (all multiplicities and coupling constants
are assigned using P-decoupled spectra). Conformer No. 1: 2.25
(1H, dd, Jgem 17.0, J10a,1 2.5, 10-Ha), 2.67 (1H, dd, Jgem 17.0,
J10b,1 8.1, 10-Hb), 3.15–3.35 (1H, m, 1-H), 3.75 (1H, dd,
Jgem 11.7, J2a,1 8.5, 2-Ha), 4.2 (1H, dd, Jgem 10.3, J6a,7 6.23, 6-Ha),
4.2–4.35 (3H, m, 6-Hb, 2-Hb and 7-H), 4.36–4.45 (2H, m, 1Ј-H),
5.24 (1H, dd, Jcis 10.3, Jgem 1.5, 3Ј-H), 5.34 (1H, dd, Jtrans 17.2,
Jgem 1.5, 3Ј-H), 5.87–6.04 (1H, m, 2Ј-H). Conformer No. 2:
2.31 (1H, dd, Jgem 17.0, J10,1 2.5, 10-Ha), 2.62 (1H, dd, Jgem 17.0,
J10b,1 8.0, 10-Hb), 2.72–2.91 (1H, m, 1-H), 3.85 (1H, dd, Jgem
11.0, J6a,7 9.5, 6-Ha), 3.96–4.03 (2H, m, 2-H), 4.2–4.4 (2H, m,
1Ј-H), 4.51 (1H, dd, Jgem 11.0, J6b,7 5.8, 6-Hb), 4.73–4.85 (1H, m,
7-H), 5.22 (1H, dd, Jcis 10.3, Jgem 1.5, 3Ј-H), 5.32 (1H, dd, Jtrans
17.2, Jgem 1.6, 3Ј-H), 5.87–6.04 (1H, m, 2Ј-H); δC(66 MHz;
CDCl3; Me4Si) Conformer No. 1: 33.7 (10-C), 44.5 (1-C), 64.7
(6-C), 64.8 (1Ј-C), 66.7 (2-C), 81.5 (7-C), 117.4 (3Ј-C), 134.0
(2Ј-C), 174.3 (2-C). Conformer No. 2: 33.2 (10-C), 44.5 (1-C),
63.0 (6-C), 64.9 (1Ј-C), 67.9 (2-C), 81.5 (7-C), 117.4 (3Ј-C),
134.2 (2Ј-C), 174.4 (9-C); m/z (CI) [Found: (M ϩ NH4)ϩ,
251.0922. C9H13PO5 requires MNH4ϩ, 251.0922].
(4R,5S)-[Allyloxy(diisopropylamino)phosphinoxymethyl]-5-
(tert-butyldimethylsiloxymethyl)tetrahydrofuran-2-one (16)
To a stirred solution of tetrazole (70 mg, 1.0 mmol) in dry
DCM at 25 ЊC under an atmosphere of argon was added diiso-
propylamine (100 mg, 1.0 mmol). After 1 hour and the form-
ation of a thick suspension, the photoadduct (6) (0.5 g, 1.92
mmol) was added. This mixture was again stirred for 1 hour
and then treated with allyl tetraisopropyl phosphorodiamidite
(0.63 ml, 2.0 mmol). After 2 hours the mixture was washed with
aq. NaHCO3 (5 ml) and extracted with DCM (3 × 10 ml). The
combined organic extracts were dried over MgSO4 and evapor-
ated. Purification of the residue by rapid flash-column chrom-
atography (15:85 ether–light petroleum as eluant) afforded the
title compound (16) as a light yellow oil (0.73 g, 1.60 mmol,
85%); νmax (film)/cmϪ1 3000–2800s (CH), 1783s (CO), 1463m
(C–O), 1364m, 1256m, 1184s, 1125, 1026s, 976s; δH(250 MHz;
CDCl3; Me4Si) 0.06 (3H, s, SiMe), 0.07 (3H, s, SiMe), 0.88 [9H,
s, C(CH3)3], 1.16 (6H, d, JMe,CH 1.58, 2 × isopropyl-Me), 1.18
(6H, d, JMe,CH 1.58, 2 × isopropyl-Me), 2.36 (1H, dd, Jgem 12.6,
J3a,4 9.2, 3a-H), 2.65–2.84 (2H, m, 4-H and 3b-H), 3.52–3.75
(5H, m, 6a-H and 7-H and 2 × isopropyl-CH), 3.88 (1H, dd,
(1R,7S)-4-(Prop-2Ј-enyloxy)-3,5,8-trioxa-4ë5-phosphabicyclo-
[5.3.0]decane-4,9-dione (19)
To a stirred solution of cyclic phosphite (18) (230 mg, 0.99
mmol), distilled Et3N (0.25 ml) and dry MeCN (20 ml) at room
temperature under argon was added tert-butyl hydroperoxide
(0.18 ml, 5.6 M solution in decane, excess). After 1 hour isopro-
panol (5 ml) was added. The solution was stirred for a further
2 hours and then evaporated in vacuo to afford a gummy oil.
Flash-column chromatography of the residue (100% EtOAc as
eluant) afforded the title compound (19) as a white crystalline
solid (240 mg, 0.97 mmol, 98%); νmax (film)/cmϪ1 3000–2800s
(CH), 1791s (CO), 1471w (C–O), 1423w, 1276s (P᎐O), 1203s,
Jgem 11.3, J6b,5 2.9, 6b-H), 4.03–4.2 (2H, m, OCH C᎐C), 4.44
᎐
᎐
2
1118s, 1027s (P–O–Alkyl), 834m; δH(250 MHz; CDCl3; Me4Si)
(all multiplicities and coupling constants are assigned using
P-decoupled spectra). Conformer No. 1: 2.35 (1H, dd, Jgem 17.0,
J10a,1 6.8, 10-Ha), 2.57 (1H, dd, Jgem 17.0, J10b,1 7.9, 10-Hb), 2.83–
3.03 (1H, m, 1-H), 3.92 (1H, m, 6-Ha), 4.14 (1H, dd, Jgem 11.5,
J2a,1 5.8, 2-Ha), 4.28 (1H, dd, Jgem 11.5, J2b,1 3.9, 2-Hb), 4.56–
4.65 (3H, m, 1Ј-H and 6-Hb), 4.83 (1H, dt, J6,7 9.9, J1,7 5.2, 7-H),
5.3 (1H, dd, Jcis 10.4, Jgem 1.6, 3Ј-Ha), 5.39 (1H, dd, Jtrans 18.6,
Jgem 1.6, 3Ј-Hb), 5.87–6.04 (1H, m, 2Ј-H). Conformer No. 2:
2.41 (1H, dd, Jgem 16.9, J10a,1 7.1, 10-Ha), 2.7 (1H, dd, Jgem 16.9,
J10b,1 8.2, 10-Hb), 3.28–3.47 (1H, m, 1-H), 3.87–3.95 (1H, m,
2-Ha), 4.07–4.19 (1H, m, 6-Ha), 4.4–4.51 (3H, m, 7-H, 2-Hb and
6-Hb), 4.57–4.65 (2H, m, 1Ј-H), 5.3 (1H, dd, Jcis 10.4, Jgem 1.6,
3Ј-Ha), 5.4 (1H, dd, Jtrans 18.5, Jgem 1.6, 3Ј-Hb), 5.87–6.04 (1H,
m, 2Ј-H); δC(62.5 MHz; CDCl3; Me4Si) Conformer No. 1:
31.7 (10-C), 43.9 (1-C), 66.4 (2-C), 67.6 (6-C), 69.6 (1Ј-C),
(1H, ddd, J5,4 8.9, J5,6a 2.8, J5,6b 2.8, 5-H), 5.11–5.16 (1H, m, Jcis
10.3, CH᎐CH cis), 5.28 (1H, ddd, Jtrans 17.2, Jgem 3.5, JH,P 1.7,
᎐
2
CH᎐CH
), 5.83–6.05 (1H, m, CH᎐CH ); δ (66 MHz;
᎐
2 C
᎐
2
trans
CDCl3; Me4Si) Ϫ5.5 (2 × MeSi), 18.2 [C(CH3)3], 24.4, 24.5,
24.6, 24.7 (4 × isopropyl CH3), 25.8 [C(CH3)3], 31.9 (3-C), 37.8
(4-C), 42.9, 43.1 (2 × isopropyl CH), 64.2, 64.3, 64.4, 64.5
(2 × CH2-O-P), 82.4 (5-C), 115.7 (C᎐CH ), 135.4, 135.5
᎐
2
(C᎐CH-O), 176.8 (C᎐O); m/z (CI) [Found: MHϩ, 447.2560.
᎐
᎐
C21H42NPO5Si requires MHϩ, 447.2569].
(4R,5S)-[Allyloxy(diisopropylamino)phosphinoxymethyl]-
5-(hydroxmethyl)tetrahydrofuran-2-one (17)
To a THF (20 ml) solution of silyl-phosphoramidite ester (16)
(1.5 g, 2.92 mmol) at 25 ЊC was added TBAF (2.9 ml, 1 M
solution in THF, 2.9 mmol). After one hour the black solution
J. Chem. Soc., Perkin Trans. 1, 1999, 969–978
975

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80.1 (7-C), 119.6 (3Ј-C), 132.0 (2Ј-C), 173.1 (9-C). Conformer
No. 2: 32.4 (10-C), 43.3 (1-C), 66.7 (6-C), 67.5 (2-C), 69.7
(1Ј-C), 80.3 (7-C), 119.5 (3Ј-C), 132.1 (9Ј-C), 173.1 (2-C);
m/z (CI) [Found: MHϩ, 249.0528. C9H13PO6 requires MHϩ,
249.0528].
was added tetrakis(triphenylphosphine)palladium (2 mg, 1.7
µM). After 5 hours the formation of a white precipitate was
observed. The solvent was evaporated in vacuo and the residue
purified by flash-column chromatography (40:60 MeOH–
DCM as eluant) to afford the title compound (22) as a white
glassy solid (30 mg, 0.07 mmol, 65%); mp 135–138 ЊC; νmax
(film)/cmϪ1 3500–3200s (NH ), 3000–2800s (CH), 1682s (C᎐O),
᎐
(1R,7S)-4-Oxo-4-(prop-2Ј-enyloxy)-3,5,8-trioxa-4-phospha-
bicyclo[5.3.0]decan-9-yl acetate (20)
2
1614s (C᎐C), 1510m (C᎐N), 1397w, 1232s (P᎐O), 1077s (P–O–
᎐
᎐
᎐
Alkyl); δH(250 MHz; CDCl3; Me4Si) α-anomer: 1.35 (12H, d,
To a solution of lactone (19) (0.25 g, 1.0 mmol) in DCM (20 ml)
at Ϫ78 ЊC (CO2–acetone) under argon was added dropwise
DIBAL-H (1.3 ml, 1 M solution in toluene, 1.3 mmol). After
2 hours, MeOH (0.5 ml) was added and the solution stirred for
a further 1 hour. The mixture was treated with EtOAc (2 ml) and
saturated aqueous NaHCO3 (1 ml) and then allowed to warm
to room temperature over 2 hours. The solution was then dried
over MgSO4, filtered through Celite and evaporated to afford
the crude lactol as a colourless oil. Without purification this
was dissolved in DCM (20 ml) and pyridine (0.24 ml, 3.0
mmol), cooled to 0 ЊC and treated with acetic anhydride (3 ml)
and DMAP (5 mg, cat.). After warming to room temperature
and stirring for 1 hour, water (5 ml) was added and the solution
extracted with DCM (2 × 10 ml). The combined organic phases
were washed with brine, dried (MgSO4) and evaporated in vacuo
to afford a colourless oil. Purification by flash-column chrom-
atography (100% EtOAc as eluant) afforded the title compound
(20) as a colourless oil (0.19 g, 0.65 mmol, 65%); νmax (film)/
cmϪ1 3000–2800s (CH), 1739s (CO), 1378w (C–O), 1236s
JCH,CH 6.5, 4 × CH3), 2.20 (1H, dd, J2Јa,2Јb 9.9, J2Јa,1Ј 4.6, 2Јa-H),
3
2.21 (1H, dd, J2Јb,2Јa 9.9, J2Јb,3Ј 4.6, 2Јb-H), 2.9–3.0 (1H, m, 3Ј-H),
3.51 (2H, septet, JCH,CH3 6.5, CHCH3), 3.7–3.95 (1H, m, 5Јa-H),
4.0–4.25 (3H, m, 5Јb, 6Ј-H), 4.25–4.4 (1H, m, 4Ј-H), 6.07–6.14
(1H, m, 1Ј-H), 7.78 (1H, d, JH,F 6.5, 6-H); β-anomer: 1.35 (12H,
d, JCH,CH 6.5, 4 × CH3), 1.79 (1H, ddd, Jgem 12.7, J2Јa,3Ј 7.7,
3
2Јa-H), 2.72 (1H, ddd, Jgem 12.7, J2Јb,1Ј 6.3, 2Јb-H), 2.8–3.0 (1H,
m, 3Ј-H), 3.51 (2H, septet, JCH,CH 6.5, CHCH3), 3.7–3.95 (2H,
3
m, 6Јa-H, 5Јa-H), 4.0–4.3 (2H, m, 6Јb-H, 5Јa-H), 4.5 (1H, dt,
J4Ј,5Ј 9.6, J4Ј,3Ј 4.7, 4Ј-H), 6.12 (1H, dd unresolved, J1Ј,2Јb 6.3,
1Ј-H), 7.96 (1H, d, JH,F 6.5, 6-H); δC(62.5 MHz; CDCl3; Me4Si).
α-anomer: 19.7 (4 × CH3), 37.4 (2Ј-C), 45.2 (3Ј-C), 49.2
(CHCH3), 66.9 (6Ј-C), 67.7 (5Ј-C), 85.0 (4Ј-C), 88.0 (1Ј-C),
126.7 (d, 6-C), 138.1 (d, 5-C), 157.2 (4-C) 160.1 (2-C) β-anomer:
19.7 (4 × CH3), 37.6 (2Ј-C), 47.9 (3Ј-C), 49.2 (CHCH3), 67.0
(6Ј-C), 67.8 (5Ј-C), 84.1 (4Ј-C), 89.3 (1Ј-C), 126.5 (d, 6-C), 138.2
(d, 5-C), 157.2 (4-C) 160.1 (2-C) m/z; (CI) [Found: M Ϫ (5FC ϩ
iPr)Hϩ, 194. C16H28N4PO6F requires M Ϫ (5FC ϩ iPr)Hϩ, 194;
Found: (M = 5FC)Hϩ, 130.0410. C4H4FN3O requires (M =
5FC)Hϩ, 130.0416.
(P᎐O), 1020s (P–O–Alkyl), 931w, 834m; δ (250 MHz; CDCl ;
᎐
H
3
Me4Si) 1.6–2.0 (2H, m, 10-H), 2.05 (3H, 2 × s, Me), 2.51–2.7
(1H, m, 1-H), 3.7–4.5 (5H, m, 2-H, 6-H and 7-H), 4.51–4.66
(2H, m, 1Ј-H), 5.26 (1H, dd, Jcis 10.2, Jgem 1.5, 3Ј-Ha), 5.38 (1H,
dd, Jtrans 17.0, Jgem 1.5, 3Ј-Hb), 5.85–6.05 (1H, m, 2Ј-H), 6.30
(1H, dd, J9,10a 6.0, J9,10b 3.8, 9-H); δC(62.5 MHz; CDCl3; Me4Si)
21.1, 21.2, 21.3 (COMe), 34.2, 34.9, 35.0, 35.8 (10-C), 43.3,
43.9, 45.3, 46.2 (1-C), 66.9, 67.0 (2-C), 68.7, 68.8 (6-C), 68.9,
69.0 (1Ј-C), 80.1, 80.8, 81.9, 82.5 (7-C), 97.3, 97.4, 97.5, 97.9
(9-C), 118.7, 118.9 (3Ј-C), 131.9, 132.0, 132.1 (2Ј-C), 170.0,
170.1, 170.2, 170.3 (CO); m/z (CI) [Found: MHϩ, 293.0777.
C11H17PO7 requires MHϩ, 293.0790].
9-[3Ј-C-(tert-Butyldimethylsiloxymethyl)-5Ј-O-(tert-butyl-
dimethylsilyl)-2Ј,3Ј-dideoxy-á-D- and -â-D-erythro-pentofurano-
syl]adenine (23)
To an oven-dried vessel containing bis(TBDMS)-acetate (8)
(250 mg, 0.6 mmol), bis(trimethylsilyl)adenine (200 mg, 0.72
mmol) and HPLC grade MeCN (5 ml) was added triethylsilyl
triflate (14 µL, 0.06 mmol). After 18 hours at 60 ЊC the sol-
vent was evaporated and the residue purified by flash column
chromatography (9:91 MeOH–DCM as eluant). This afforded
the title compound (23) as a colourless oil in 1:1.25 α:β ano-
meric ratio. (220 mg, 0.50 mmol, 74%); νmax (film)/cmϪ1 3322
and 3172br s (NH2), 2954–2860s (CH), 1649m (NH2 bending),
1590m, 1471m, 1254, 1092br, 837s, 777m; δH(400 MHz; CDCl3;
Me4Si) α-anomer: 0.03–0.07 (12H, 4 × s, 4 × MeSi), 0.84–0.88
[18H, 2 × s, C(CH3)3], 2.42–2.7 (3H, m, 2Ј-H, 3Ј-H), 3.67 (2H,
d, J6Ј,3Ј 4.4, 6Ј-H), 3.72 (1H, dd, Jgem 11.0, J5Јa,4Ј 4.0, 5Јa-H), 3.82
(1H, dd, Jgem 11.0, J5Јb,4Ј 4.0, 5Јb-H), 4.25 (1H, ddd, J4Ј,3Ј 7.7,
J4Ј,5Јa 4.0, J4Ј,5Јb 4.0, 4Ј-H), 5.8 (2H, br, NH2), 6.28 (1H, m, 1Ј-H),
8.03 (1H, s, 8-H), 8.31 (1H, s, 2-H); β-anomer: 0.03–0.07 (12H,
4 × s, 4 × MeSi), 0.84–0.88 [18H, 2 × s, C(CH3)3], 2.42–2.7 (3H,
m, 2Ј-H, 3Ј-H), 3.67 (2H, d, J6Ј,3Ј 4.4, 6Ј-H), 3.77 (1H, dd,
Jgem 11.36, J5Јa,4Ј 3.3, 5Јa-H), 3.98 (1H, dd, Jgem 11.36, J5Јb.4Ј 3.3,
5Јb-H), 4.03 (1H, ddd, J4Ј,3Ј 6.6, J4Ј,5Јa 3.3, J4Ј,5Јb 3.3, 4Ј-H), 5.8
(2H, br, NH2), 6.28 (1H, m, 1Ј-H), 8.28–8.3 (2H, 2 × s, 8-H,
2-H); δC(62.5 MHz; CDCl3; Me4Si) α/β anomers: Ϫ5.5, Ϫ5.3
(MeSi), 18.3, 18.4 [C(CH3)3], 25.8, 25.8 [C(CH3)3], 35.6, 36.3
(2Ј-C), 40.2, 42.7 (3Ј-C), 62.8, 63.1 (6Ј-C), 63.9, 64.8 (5Ј-C),
82.8, 83.8 (4Ј-C), 84.7, 85.3 (1Ј-C), 138.5, 139.1 (8-C), 152.7,
152.8 (2-C), 120.5, 120.6, 148.5, 149.5, 155.3, 155.4 (4-C, 5-C,
6-C); m/z (CI) [Found: MHϩ, 494.2990. C23H43N5O3Si2 requires
MHϩ, 494.2983].
Allyl 1-[2Ј,3Ј-dideoxy-3Ј-C-(hydroxymethyl)-â-D- and -á-D-
erythro-pentofuranosyl]-5-fluorocytosine 5Ј,6Ј-cyclic phosphate
(21)
A suspension of 5-fluorocytosine (37 mg, 0.29 mmol) and N,O-
bis(trimethylsilyl)acetamide (1 ml, excess) was refluxed for 1
hour. Excess reagents were removed in vacuo and the residue
co-evaporated with toluene (3 × 2 ml) until crystallisation
occurred. The bis(trimethylsilyl)-5-fluorocytosine thus obtained
was re-dissolved in dry MeCN (5 ml) and transferred to an oven-
dried vessel under argon, containing acetate (20) (75 mg, 0.26
mmol). The flask was cooled to 0 ЊC, and the mixture treated
with SnCl4 (0.28 ml, 1 M solution in DCM, 0.28 mmol),
and stirred for 4 hours. After warming to room temperature,
aqueous sodium potassium tartrate (5 ml) was added, and the
mixture was stirred for a further 1 hour and extracted with
DCM (3 × 5 ml). The combined organic phases were dried over
MgSO4 and evaporated. Purification by flash-column chrom-
atography (10:90 MeOH–DCM as eluant) afforded the title
compound (21) as an impure clear oil (75 mg, 0.20 mmol, 80%,
crude). Repeated purification failed to remove impurities. This
compound was de-allylated without exhaustive characterisation
or further purification.
6-N-Benzoyl-9-[3Ј-C-(tert-butyldimethylsiloxymethyl)-5Ј-O-
(tert-butyldimethylsilyl)-2Ј,3Ј-dideoxy-á-D- and -â-D-erythro-
pentofuranosyl]adenine (24)
1-[2Ј,3Ј-Dideoxy-3Ј-C-(hydroxymethyl)-â-D- and -á-D-erythro-
pentofuranosyl]-5-fluorocytosine diisopropylammonium 5Ј,6Ј-
cyclic phosphate (22)
To an oven-dried flask under argon containing N-benzoyl-
adenine (167 mg, 0.70 mmol), dry pyridine (0.5 ml), TMSCl
(1 drop) and HPLC grade MeCN (5 ml) was added bis(tri-
methylsilyl)trifluoroacetamide (360 mg, 1.4 mmol). After 20
To a stirred solution of allyl phosphate (21) (40 mg, 0.11
mmol), diisopropylamine (100 mg) and MeCN (5 ml) at 25 ЊC
976
J. Chem. Soc., Perkin Trans. 1, 1999, 969–978

View Article Online
minutes, acetate (8) (0.28 g, 0.67 mmol) and triethylsilyl triflate
(10 µL, 0.04 mmol) were added and the solution heated at 60 ЊC
for 18 hours. The solvent was evaporated and the residue puri-
fied by flash column chromatography (4:96 MeOH–DCM as
eluant). This afforded the title compound as a colourless oil in a
1:1.25 α/β anomeric ratio (296 mg, 0.50 mmol, 75%); νmax
2Јa-H, 3Ј-H), 2.77–2.81 (1H, m, 2Ј-b), 3.65–3.7 (4H, m, 6Ј-H,
5Ј-H), 4.33 (1H, m, 4Ј-H), 6.4 (1H, m, 1Ј-H), 7.3–7.6 (3H, m,
Ph), 8.1 (2H, d, JPh 7.7, Ph), 8.39 (1H, s, 8-H), 8.75 (1H, s, 2-H),
10.2–10.5 (1H, br, NH); β-anomer: 2.41 (1H, ddd, Jgem 13.9,
J2Јa,1Ј 6.9, J2Јa,3Ј 6.9, 2Јa-H), 2.62–2.81 (2H, m, 2Јb-H, 3Ј-H),
3.71–3.81 (3H, m, 6Ј-H, 5Јa-H), 3.96 (1H, dd, Jgem 12.1, J5Јb,4Ј
3.3, 5Јb-H), 4.11 (1H, ddd, J4Ј,3Ј 6.6, J4Ј,5Јa 3.3, J4Ј,5Јb 3.3, 4Ј-H),
6.35 (1H, m, 1Ј-H), 7.3–7.6 (3H, m, Ph), 8.1 (2H, d, JPh 7.7, Ph),
8.43 (1H, s, 8-H), 8.77 (1H, s, 2-H), 10.2–10.5 (1H, br, NH);
δC(100 MHz; CDCl3; Me4Si) α/β anomers: 35.1, 36.3 (2Ј-C),
41.3, 43.3 (3Ј-C), 62.0, 63.1 (6Ј-C), 63.4, 63.5 (5Ј-C), 83.9, 85.4
(4Ј-C), 85.2, 86.4 (1Ј-C), 123.4, 123.6, 149.9, 150.0, 151.0, 151.5
(4-C, 5-C, 6-C), 128.3, 128.8, 132.9, 133.7 (Ph), 141.7, 142.3
(film)/cmϪ1 3260br s (NH), 3000–2800s (CH), 1702s (C᎐O),
᎐
1611 and 1580 (NH bending), 1514m, 1255m, 1093s, 837s,
778m; δH(400 MHz; CDCl3; Me4Si) α-anomer: 0.03–0.07 (12H,
4 × s, 4 × MeSi), 0.83–0.9 [18H, 2 × s, C(CH3)3], 2.46–2.8 (3H,
m, 2Ј-H, 3Ј-H), 3.68 (2H, d, J6Ј,3Ј 5.12, 6Ј-H), 3.68–3.73 (1H, m,
5Јa-H), 3.84 (1H, dd, Jgem 11.0, J5Јb,4Ј 3.66, 5Јb-H), 4.29 (1H, m,
4Ј-H), 6.37 (1H, m, 1Ј-H), 7.45–7.6 (3H, m, Ph), 7.98 (2H, m,
Ph), 8.21 (1H, s, 8-H), 8.75 (1H, s, 2-H), 9.0–9.2 (1H, br s, NH);
β-anomer: 0.03–0.07 (12H, 4 × s, 4 × MeSi), 0.83–0.9 [18H,
2 × s, C(CH3)3], 2.46–2.8 (3H, m, 2Ј-H, 3Ј-H), 3.55–3.7 (2H, m,
6Ј-H), 3.77 (1H, dd, Jgem 11.36, J5Јa,4Ј 3.3, 5Јa-H), 3.98 (1H, dd,
Jgem 11.36, J5Јb,4Ј 2.9, 5Јb-H), 4.07 (1H, m, 4Ј-H), 6.37 (1H, m,
1Ј-H), 7.45–7.6 (3H, m, Ph), 7.98 (2H, m, Ph), 8.46 (1H, s, 8-H),
8.74 (1H, s, 2-H), 9.0–9.2 (1H, br s, NH); δC(62.5 MHz; CDCl3;
Me4Si) α/β anomers: Ϫ5.5, Ϫ5.3 (MeSi), 18.3, 18.5 [C(CH3)3],
25.8, 25.9 [C(CH3)3], 35.6, 36.3 (2Ј-C), 40.2, 42.6 (3Ј-C), 62.7,
63.1 (6Ј-C), 63.9, 64.8 (5Ј-C), 83.0, 84.0 (4Ј-C), 85.1, 85.5 (1Ј-C),
127.8, 128.7, 132.6 (Ph), 141.0, 141.6 (8-C), 150.9, 152.4 (2-C),
123.2, 123.3, 132.8, 133.0, 149.3, 150.6 (4-C, 5-C, 6-C), 154.3
(8-C), 152.3, 152.5 (2-C), 165.8 (C᎐O); m/z (CI) [Found: MHϩ,
᎐
370.1522 C18H19N5O4 requires MHϩ, 370.1515].
6-N-Benzoyl-9-[2Ј,3Ј-dideoxy-3Ј-C-(hydroxymethyl)-â-D- and
-á-D-erythro-pentofuranosyl]adenine phenyl 5Ј,6Ј-cyclic
phosphate (26)
To a solution of diol (25) (200 mg, 0.54 mmol) in dry pyridine
(10 ml) at 25 ЊC under argon was added dropwise phenyl phos-
phorodichloridate (150 µL, 0.75 mmol). After 18 hours of
stirring, the solvent was evaporated and the residue purified
by flash-column chromatography (10:90 MeOH–DCM). This
afforded the title compound as a colourless oil (105 mg, 0.21
mmol, 38%); νmax (film)/cmϪ1 3500–3000m (NH amide), 3000–
(C᎐O); m/z (CI) [Found: MHϩ, 598.3246. C H N O Si
᎐
30 47
5
4
2
requires MHϩ, 598.3245].
2800w (CH), 1694s (C᎐O amide), 1613 and 1581s (NH bend-
᎐
ing), 1488s, 1455s, 1286s, 1260s (P᎐O), 1212s (P–O–Aryl), 1050s
᎐
9-[2Ј,3Ј-Dideoxy-3Ј-C-(hydroxymethyl)-á-D- and -â-D-erythro-
pentofuranosyl]adenine (3)
(P–O–Alkyl); δH(400 MHz; CDCl3; Me4Si) α-anomer: 2.75–2.9
(2.5 H, m, 2Ј-H, 0.5 3Ј-H), 3.1–3.25 (0.5H, m, 3Ј-H), 3.96–4.6
(4H, m, 6Ј-H, 5Ј-H), 4.76–4.97 (1H, 2 × m, 4Ј-H), 6.3–6.35 (1H,
m, 1Ј-H), 7.2–7.4 (5H, m, O-Ph), 7.5–7.66 (3H, m, Bz), 8.02
(2H, d, JPh 7.7, Bz), 8.08 (1H, 2 × s, 8-H), 8.8 (1H, 2 × s, 2-H),
9.3 (1H, br, NH); β-anomer: 2.35–2.42 (1H, m, 2Јa-H), 2.75–2.9
(1H, m, 2Јb-H), 3.6 (1H, m, 3Ј-H), 3.96–4.6 (5H, m, 6Ј-H, 5Ј-H,
4Ј-H), 6.35–6.4 (1H, m, 1Ј-H), 7.2–7.4 (5H, m, O-Ph), 7.5–7.66
(3H, m, Bz), 8.02 (2H, d, JPh 7.7, Bz), 8.05 (1H, 2 × s, 8-H), 8.75
(1H, 2 × s, 2-H), 9.3 (1H, br, NH); δC(100 MHz; CDCl3; Me4Si)
α/β anomers: 33.4, 33.5, 34.4, 35.3 (2Ј-C), 44.3, 44.8, 46.6, 47.3
(3Ј-C), 66.8, 66.9, 67.2, 67.4, 67.6, 68.0, 68.1, 68.3 (5Ј-C, 6Ј-C),
81.5, 81.8, 82.5, 82.8 (4Ј-C), 84.8, 85.2, 85.4, 85.8 (1Ј-C), 119.7,
119.9, 125.5, 127.8, 128.7, 129.1, 129.8, 132.8, 133.3 (Ph), 123.5,
123.8, 123.9, 124.0, 149.7, 150.1, 150.3, 151.3, 151.4 (4-C, 5-C,
6-C), 140.9, 141.6, 141.7, 142.3 (8-C), 152.5, 152.6, 152.7 (2-C),
To a THF solution (10 ml) of bis-silyl nucleoside (23) (160 mg,
0.32 mmol) at room temperature was added TBAF (0.64 ml,
1 M solution in THF, 0.64 mmol). After 2 hours the solvent was
removed in vacuo and the residue purified by flash column
chromatography (10:90 MeOH–DCM as eluant). This
afforded the title compound as a white amorphous solid (80
mg, 0.3 mmol, 80%); mp 151–153 ЊC (decomp.); (Found: C,
49.3; H, 5.8; N, 25.3; C11H15N5O3 requires C, 49.8; H, 5.7; N,
26.39%); νmax (film)/cmϪ1 3600–3100br (OH, NH2), 3000–2800m
(CH), 1648 and 1603s, (NH2 bending) 1477w, 1417w, 1246w,
1103w, 1044w; δH(400 MHz; CDCl3; Me4Si) α-anomer: 2.4–2.8
(3H, m, 2Ј-H, 3Ј-H), 3.66–3.78 (3H, m, 6Ј-H, 5Јb-H), 3.83 (1H,
dd, J5Јa,5Јb 12.1, J5Јa,4Ј 3.7, 5Јa-H), 4.31 (1H, ddd, J4Ј,3Ј 8.1, J4Ј,5Јb
4.4, J4Ј,5Јa 3.7, 4Ј-H), 6.30 (1H, dd, J1Ј,2Јa 5.9, J1Ј,2Јb 5.9, 1Ј-H),
8.23 (1H, s, 8-H), 8.4 (1H, s, 2-H); β-anomer: 2.4–2.8 (3H, m,
2Ј-H, 3Ј-H), 3.66–3.78 (3H, m, 6Ј-H, 5Јb-H), 3.95 (1H, dd,
J5Јa,5Јb 12.2, J5Јa,4Ј 2.7, 5Јa-H), 4.1 (1H, ddd, J4Ј,3Ј 6.6, J4Ј,5Јa 2.7,
J4Ј,5Јb 3.3, 4Ј-H), 6.34 (1H, dd, J1Ј,2Ј 6.6, 1Ј-H), 8.28 (1H, s, 8-H),
8.3 (1H, s, 2-H); δC(100 MHz; CDCl3; Me4Si) α-anomer:
35.4 (2Ј-C), 42.1 (3Ј-C), 61.3 (6Ј-C), 61.9 (5Ј-C), 82.9 (4Ј-C),
84.3 (1Ј-C), 119.0, 147.8, 155.2 (2-C, 4-C, 6-C), 138.5 (8-C),
151.7 (5-C); β-anomer: 34.5 (2Ј-C), 40.5 (3Ј-C), 62.5 (6Ј-C),
62.6 (5Ј-C), 84.1 (4Ј-C), 85.4 (1Ј-C), 119.3, 148.4, 155.2 (2-C,
4-C, 6-C), 139.1 (8-C), 151.9 (5-C); m/z (CI) [Found: MHϩ,
266.1260. C11H15N5O3 requires MHϩ, 266.1253].
164.7 (C᎐O); m/z (CI) [Found: MHϩ, 508.1361. C H N PO
᎐
24 22
5
6
requires MHϩ, 508.1386].
9-[2Ј,3Ј-Dideoxy-3Ј-C-(hydroxymethyl)-â-D- and -á-D-erythro-
pentofuranosyl]adenine phenyl 5Ј,6Ј-cyclic phenylphosphate (4)
To a MeOH–CHCl3 (4:1, 10 ml) solution of benzoyl adenine
(26) (100 mg, 0.2 mmol) at room temperature was added zinc
bromide (90 mg, 4 mmol, 20 equiv.). After stirring for 72 hours
the solvent was evaporated and the residue purified by flash
column chromatography (10:90 MeOH–DCM as eluant). This
afforded the title compound as an amorphous white solid
(55 mg, 0.136 mmol, 68%); νmax (film)/cmϪ1 3600–3100s (NH2),
1620s, 1500m, 1252m, 1150m, 1046s, 920s; δH(400 MHz;
CD3OD; Me4Si) 2.42–2.53 (0.5H, m, 2Ј-H), 2.61–2.84 (1.5H, m,
2Ј-H), 2.9 (0.5H, m, 3Ј-H), 3.6–3.7 (0.5H, m, 3Ј-H), 4.0–4.61
(4H, m, 5Ј-H, 6Ј-H), 4.75–4.9 (1H, m, 4Ј-H), 6.4 (1H, m,
1Ј-H), 7.23–7.4 (5H, m, O-Ph), 8.2–8.3 (2H, 8 × s, 8-H, 2-H);
δC(100 MHz; CD3OD; Me4Si) α/β anomers: 34.6, 35.6, 35.8
(2Ј-C), 45.8, 45.9, 48.0 (3Ј-C), 69.2, 69.3, 69.4, 69.5, 69.6,
69.7, 69.9, 70.0, 70.1, 70.2 (5Ј-C, 6Ј-C), 82.5, 83.6 (4Ј-C),
86.1, 86.4, 86.6, 86.8 (1Ј-C), 120.6, 120.7, 120.8, 120.9, 121.0,
126.8, 131.1, 131.2 (Ph), 141.9, 142.2, 142.5, 142.6 (8-C), 149.7,
150.3, 150.4, 151.6, 151.7, 157.1 (4-C, 5-C, 6-C), 153.7 (2-C);
m/z (CI) [Found: MHϩ, 404.1123. C17H18N5PO5 requires MHϩ,
404.1124].
6-N-Benzoyl-9-[2Ј,3Ј-dideoxy-3Ј-C-(hydroxymethyl)-á-D- and
-â-D-erythro-pentofuranosyl]adenine (25)
To a THF solution (30 ml) of bis-silyl nucleoside (24) (630 mg,
1.05 mmol) at room temperature was added TBAF (2.1 ml, 1 M
solution in THF, 2.10 mmol). After 2 hours the solvent was
removed in vacuo and the residue purified by flash column
chromatography (9:91 MeOH–DCM as eluant). This afforded
the title compound as a white amorphous solid (200 mg, 0.54
mmol, 52%) (Found: C, 57.8; H, 5.8; N, 19.5; C18H19N5O4
requires C, 58.5; H, 5.2; N, 18.9%); mp 69–71 ЊC; νmax (film)/
cmϪ1 3600–3100br (OH, NH2), 3000–2800m (CH), 1697s
(C᎐O), 1613 and 1581s (NH bending), 1457s, 1256w, 1094w;
᎐
2
δH(400 MHz; CDCl3; Me4Si) α-anomer: 2.51–2.64 (2H, m,
J. Chem. Soc., Perkin Trans. 1, 1999, 969–978
977

View Article Online
Crystal data‡
AIDS programme for PhD studentships. We also thank Dr
Rob Young of Glaxo-Wellcome for arranging the biological
evaluation studies, and EPSRC and the University of Reading
for funds for the Image Plate System. This paper is dedicated
to Ralph Raphael, a superb chemist and a great human being.
Compound 13á. C9H13PO6, M = 248.16, monoclinic, space
group P21, a = 9.856(12), b = 6.064(6), c = 11.657(14) Å, β =
126.02(1)Њ, V = 563.6 Å3, Z = 2, Dc = 1.462 Mg mϪ3, F(000) 260,
µ = 0.254 mmϪ1. Reflections collected 1481, independent reflec-
tions 891 [R(int) = 0.0230], Final R indices [I > 2σ(I)] R1 =
0.0513, wR2 = 0.1463.
References
1 J. W. Beach, L. S. Jeong, A. J. Alves, D. Pohl, H. O. Kim, C.-N.
Chang, S.-L. Doong, R. F. Schinazi, Y.-C. Cheng and C. K. Chu,
J. Org. Chem., 1992, 57, 2217; T.-S. Lin, M.-Z. Luo, M.-C. Liu,
Y.-L. Zhu, E. Gullen, G. E. Dutschman and Y.-C. Cheng, J. Med.
Chem., 1996, 39, 1757; T.-S. Lin, M.-Z. Luo and M.-C. Liu,
Tetrahedron, 1995, 51, 1055.
2 X. Pannecoucke, G. Parmentier, G. Schmitt, F. Dolle and B. Luu,
Tetrahedron, 1994, 50, 1173; I. Lefebvre, C. Perigaud, A. Pompon,
A.-M. Aubertin, J.-L. Girardet, A. Kirn, G. Gosselin and J.-L.
Imbach, J. Med. Chem., 1995, 38, 3941; C. McGuigan, R. N.
Pathirana, J. Balzarini and E. de Clercq, J. Med. Chem., 1993, 36,
1048; C. McGuigan, R. N. Pathirana, J. Balzarini, E. de Clercq and
M. P. H. Davies, Bioorg. Med. Chem. Lett., 1994, 4, 427.
3 J. Mann and A. C. Weymouth-Wilson, J. Chem. Soc., Perkin Trans.
1, 1994, 3141.
4 M. A. Johnson, G. Ahluwalia, M. C. Connelly, D. A. Cooney,
S. Broder, D. G. John and A. Fridland, J. Biol. Chem., 1988, 263,
15354; M. A. Johnson and A. Fridland, Mol. Pharmacol., 1989, 36,
291.
5 J. Mann and A. C. Weymouth-Wilson, Synlett, 1992, 67.
6 H. Vorbruggen, Acta Biochim. Pol., 1996, 43, 25.
7 F. Himmelsbach, B. S. Schulz, T. Trichtinger, R. Charubala and
W. P fl eiderer, Tetrahedron, 1984, 40, 59.
Compound 19. C25H25N4O10P, M = 572.5, orthorhombic,
space group P212121, a = 11.589(12), b = 24.07(2), c = 28.51(2)
Å, V = 7953(13) Å3, Z = 12, Dc = 1.434 Mg mϪ3, F(000) = 3576,
µ = 0.168 mmϪ1. Reflections collected 14542, independent
reflections 9591 [R(int) = 0.0311], Final R indices [I > 2σ(I)],
R1 = 0.0701, wR2 = 0.1954.
Data for both crystals were collected with Mo-Kα radiation
using the MARresearch Image Plate System. The crystals were
positioned 70 mm from the Image Plate. 95 Frames were meas-
ured at 2Њ intervals with a counting time of 2 min. Data analysis
was carried out with the XDS program.12 Both structures were
solved using direct methods with the Shelxs86 program.13 In
compound 13á there were three molecules in the asymmetric
unit with similar conformations. In both structures the non-
hydrogen atoms were refined with anisotropic thermal param-
eters. The hydrogen atoms were included in geometric positions
and given thermal parameters equivalent to 1.2 times those of
the atom to which they were bonded. Both structures were
refined to convergence on F2 using Shelxl.14
8 C. A. A. Van Boeckel, G. A. Van der Marel, P. Westerduin and
J. H. Van Boom, Synthesis, 1982, 399.
9 J. Mann and J. H. M. Gould, Chem. Commun., 1997, 243.
10 M. D. Chappell and R. L. Halcomb, Tetrahedron, 1997, 53,
11109.
11 R. Kierzek, H. Ito, R. Bhatt and K. Itakura, Tetrahedron Lett.,
1981, 22, 3761.
Acknowledgements
Stephen Gorsuch and Jayne Gould respectively thank the
University of Reading and the Medical Research Council
12 W. Kabsch, J. Appl. Crystallogr., 1988, 21, 916.
13 SHELXS-86, G. M. Sheldrick, Acta Crystallogr., Sect. A, 1990, 46,
467.
14 SHELXL-93, G. M. Sheldrick, 1993, a Program for Crystal
Structure Refinement, University of Göttingen.
‡ Full crystallographic details, excluding structure factor tables, have
been deposited at the Cambridge Crystallographic Data Centre
(CCDC). For details of the deposition scheme, see ‘Instructions for
Authors’, J. Chem. Soc., Perkin Trans. 1, available via the RSC web
page http://www.rsc.org/authors. Any request to the CCDC for this
material should quote the full literature citation and the reference
number 207/307.
Paper 9/00800D
978
J. Chem. Soc., Perkin Trans. 1, 1999, 969–978