Synthesis of spiroacetal-nucleosides as privileged natural product-like scaffolds

Article abstract of DOI:10.1039/b818314g

The elaboration of a 6,6-spiroacetal scaffold to incorporate a nucleoside unit at the anomeric position is described. The novel spiroacetal-nucleoside hybrids 11 were generated via nucleosidation of acetoxy-spiroacetal 10 with a series of silylated nucleobases under Vorbrueggen conditions.

Full text of DOI:10.1039/b818314g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of spiroacetal-nucleosides as privileged natural
product-like scaffolds†
Ka Wai Choi and Margaret A. Brimble*
Received 16th October 2008, Accepted 19th December 2008
First published as an Advance Article on the web 23rd February 2009
DOI: 10.1039/b818314g
The elaboration of a 6,6-spiroacetal scaffold to incorporate a nucleoside unit at the anomeric position is
described. The novel spiroacetal-nucleoside hybrids 11 were generated via nucleosidation of
acetoxy-spiroacetal 10 with a series of silylated nucleobases under Vorbr u¨ ggen conditions.
Introduction
Nature has always been an important source of lead compounds
for the development of new therapeutic agents. Evolutionary
selection pressures have resulted in chemical biodiversity that
has been exploited extensively by the pharmaceutical industry.
By modifying a biologically active lead compound, libraries
of structurally similar, but non-natural, synthetic analogues are
created such that the molecular complexity is kept to a minimum
whilst improvements are made to the desired pharmacological
1
activity.
The number of biological targets available for screening has
increased substantially in recent years through a better under-
standing of biological pathways and the successful sequencing of
2
the human genome. Hence, it has become increasingly common
to subject natural products and their synthetic analogues to broad
1
1–13
Fig. 1 Privileged 6,6-spiroacetal structures.
phenotypic discovery screens to identify any biological activity not
found in the original natural product. By combining biologically
active motifs within a natural product-inspired scaffold system, a
library of compounds can be generated for screening of potential
14
Porco et al. synthesised a series of 6,6-spiroacetal derivatives
containing three sites for further synthetic elaboration to probe
for biological activity. A structurally diverse 6,6-spiroacetal-based
library constructed by Waldmann et al. resulted in the discovery
of the lead compound 3 as an inhibitor of several important protein
phosphatases (Fig. 1).
Nucleoside analogues are an important class of antiviral agent
that are designed to mimic naturally occurring nucleosides. After
phosphorylation, the activated nucleoside analogue inhibits viral
polymerases and terminates the elongating viral nucleic acid chain,
3,4
bioactivity.
12
Spiroacetals, in particular 1,7-dioxaspiro[5.5]undecanes, are a
common structural element in many natural products isolated
from a variety of sources that display a wide range of bi-
ological activities. For example, many simple spiroacetals are
5
,6
7
insect pheromones; routiennocin is an ionophore antibiotic;
8
okadaic acid and tautomycin are protein phosphatase inhibitors;
integramycin is a HIV-1 intregrase inhibitor; the milbemycins
and avermectins are anthelmintic and insecticidal agents and the
spongistatins are marine antimitotic macrolides.
9
15
thus selectively suppressing viral replication.
5
A naturally occurring nucleoside consists of a hydroxymethyl
group, a glycoside linker and a heterocyclic base (Fig. 2). The
hydroxymethyl group is crucial for intracellular phosphorylation
whereas the glycoside unit is not well recognised by the nucleic
acid processing enzymes and merely acts as a spacer to present
the hydroxymethyl substituent and the heterocyclic base to the
10
More importantly, many truncated synthetic spiroacetals de-
rived from more complex spiroacetal containing natural products,
such as spiroacetals 1–3, provide the basic pharmacophore for the
11,12
observed biological activity.
The 6,6-spiroacetal unit has also
been used to replace the rigid galactose disaccharide core in a sialyl
13
Lewis X mimetic 4 (Fig. 1).
Several research groups have reported the generation of libraries
3
based on a 6,6-spiroacetal scaffold. For example, Ley et al. and
Department of Chemistry, The University of Auckland, 23 Symonds St,
Auckland, New Zealand. E-mail: m.brimble@auckland.ac.nz; Fax: +64 9
3
737422; Tel: +64 9 3737599 ext. 88259
†
Electronic supplementary information (ESI) available: Characterisation
data of acetoxy-spiroacetal 10, nucleosides 15a–h and 11a–k. See DOI:
1
Fig. 2 General structure of naturally occurring nucleosides and nucleo-
side analogues.
16
0.1039/b818314g
1
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target enzymes. Based on these observations, the synthesis of
nucleoside analogues that vary in the nature of spacer and
nucleobase, provides a significant opportunity to develop new
16
antiviral agents.
Our research group has a long standing interest in the synthesis
of spiroacetals present in a wide range of biologically significant
1
7
compounds. This synthetic effort has prompted the investigation
of elaborating the 6,6-spiroacetal unit to provide novel and diverse
functionality. In the present work, we were interested in the
chemical attachment of the spiroacetal scaffold to a biologically
relevant nucleobase. These spiroacetal derivatives allow diversifi-
cation at the biologically relevant anomeric position, providing
novel spiroacetal-based nucleosides. Further incorporation of a
hydroxymethyl group on the spiroacetal ring also provides an
additional site for further derivatisation as well as furnishing
an essential phosphorylation site. The combination of these
important bioactive motifs provides access to a unique hybrid
of functionality and the collection of spiroacetal-nucleosides
reported herein provides novel probes to screen for potential
bioactivity in phenotypic assays.
Scheme 1 Synthesis of spiroacetal-nucleosides 11 generated by the
nucleosidation of acetoxy-spiroacetal 10 with a range of persilylated bases
under Vorbr u¨ ggen conditions.
22
1
3 which is accessible from the previously reported lactone 14
23
(
Scheme 2).
To date, the synthesis of a 6,6-spiroacetal ring system bearing
a heterobase at the anomeric position, has not been reported.
Related examples of spirocyclic nucleosides include the naturally
18
occurring herbicidal (+)-hydantocidin (6) and synthetic anti-
19
HIV TSAO-T (7). Biological evaluation of the 2¢-spirocyclic
20
Scheme 2 Retrosynthesis of spiroacetal-nucleosides 11.
nucleosides 8 prepared by Wengel et al. and the 4¢-spirocyclic
21
nucleosides 9 prepared by Paquette et al. are also currently
underway (Fig. 3).
Preparation of acetoxy-spiroacetal 10
Lactone 14 was prepared from commercially available ethyl 2-
oxocyclopentanecarboxylate in 87% yield over five steps using
23
procedures adapted from the work reported by Taylor et al.
Conversion of lactone 14 to ethoxy-spiroacetal 12 was carried
out in 58% yield over four steps via ketone 13 using procedures
22
recently reported by our research group.
With ethoxy-spiroacetal 12 in hand, attention focused on its
conversion to acetoxy-spiroacetal 10 under a range of reagents and
conditions. The best result was obtained when ethoxy-spiroacetal
1
2 was treated with camphorsulfonic acid (CSA) in aqueous THF
◦
at 40 C to give a lactol intermediate which was immediately
acetylated to afford acetoxy-spiroacetal 10 in 58–66% yield over
two steps (Scheme 3). Many attempts to effect the direct conversion
of ketone 13 to acetoxy-spiroacetal 10 using a variety of reagents
and conditions only afforded the desired acetoxy-spiroacetal 10 in
1
8
19
Fig. 3 (+)-Hydantocidin (6), TSAO-T (7), 2¢-spirocyclic nucleosides
8
20
21
and 4¢-spirocyclic nucleosides 9.
22
We recently reported the synthesis of a series of spiroacetal
hybrids containing a triazole unit at the anomeric position that
provided an isostere to mimic the biological relevant peptide
bond. Using a similar rationale, we herein report the synthesis
of a series of spiroacetal-nucleosides 11 generated by the nucle-
osidation of acetoxy-spiroacetal 10 with several persilylated bases
under Vorbr u¨ ggen conditions (Scheme 1).
3
0–35% yield after acetylation.
NMR analysis of acetoxy-spiroacetal 10 revealed a character-
22
istic anomeric 2-H resonance at d
Hz) establishing that the acetoxy group adopted an equatorial
position. A characteristic quaternary spirocarbon C-6 resonated
at d 99.1 ppm and a NOESY correlation between 2-H and 8-H
H
6.00 ppm (dd, J2ax,3ax 10.1
C
established the bis-anomerically stabilised spiroacetal ring system
Results and discussion
(Fig. 4).
The retrosynthesis adopted for the desired spiroacetal-nucleosides
Preparation of spiroacetal-nucleosides 15
11 hinged on disconnection of the anomeric C–N bond linking
the spiroacetal to the nucleobase. With this idea in mind, it was
With acetoxy-spiroacetal 10 and ethoxy-spiroacetal 12 in hand,
attention next turned to the subsequent nucleosidation with a
range of silylated nucleobases to access the desired spiroacetal-
nucleosides 15. Under Vorbr u¨ ggen conditions, a persilylated
22
proposed that previously prepared ethoxy-spiroacetal 12 can be
converted to acetoxy-spiroacetal 10 which is then elaborated to
nucleosides 11. Ethoxy-spiroacetal 12 is synthesised from ketone
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Given the inability of ethoxy-spiroacetal 12 to effect the desired
reaction, the nucleosidation of acetoxy-spiroacetal 10 using a
persilylated pyrimidine was next investigated using the two-
24,25
pot Vorbr u¨ ggen procedure.
The silylation was effected using
hexamethyldisilazane (HMDS) with catalytic ammonium sulfate
which avoided the use of N,O-bis(trimethylsilyl)acetimide (BSA)
and the subsequent formation of the acetamide by-product.
5
F
Gratifyingly, nucleosidation using 5-fluorocytosine ( C), 4-N-
Ac
acetylcytosine ( C), thymine (T), uracil (U) and 5-fluorouracil
5
F
(
U) carried out in the presence of TMSOTf in CH
2
2
Cl at room
temperature successfully produced spiroacetal-nucleosides 15a–e
in 20–46% yield (Scheme 4 and Table 1).
Although the nucleosidation of acetoxy-spiroacetal 10 with
a range of persilylated pyrimidines was successful, the yields
obtained for the reactions were moderate. Hence, an optimisation
study of the nucleosidation was conducted using the synthesis of
thymidine 15c as a model reaction (Scheme 5).
Scheme 3 Synthesis of acetoxy-spiroacetal 10. Reagents and conditions:
◦
(
a) CSA, aq. THF, 40 C, 18 h; (b) Ac
2
O, DMAP (cat.), NEt
3
, CH
2
Cl
2
,
rt, 2 h, 58–66% over 2 steps; (c) PPTS (pyridinium para-toluenesulfonate),
aq. acetone, reflux, 6–24 h; (d) Ac O, DMAP (cat.), NEt , CH Cl , rt, 2 h,
0–35% over 2 steps.
2
3
2
2
3
Fig. 4 Structures of acetoxy-spiroacetal 10 and nucleoside analogues
5a–h showing the bis-anomerically stabilised spiroacetal ring system and
1
their equatorial substituents. NOESY correlations are denoted by arrows.
heterobase is added to an oxonium ion generated from a spiroac-
etal bearing a leaving group at the anomeric position in the
24,25
presence of a Lewis acid.
TMSOTf was the initial choice of
Lewis acid due to its proven ability to effect successful oxonium
Scheme 5 Nucleosidation of acetoxy-spiroacetal 10 with persilylated
thymine under a range of Vorbr u¨ ggen conditions. See Table 2 for reaction
conditions.
22,26
ion generation in a model study,
and its use by others for
27,28
structurally related spiroacetals.
Nucleosidation of ethoxy-spiroacetal 12 was first attempted
because acetal 12 was obtained in higher yield in one less synthetic
step than acetoxy-spiroacetal 10. Unfortunately, nucleosidation
of ethoxy-spiroacetal 12 with persilylated 5-fluorocytosine using
A variety of reagents and conditions were evaluated as sum-
marised in Table 2. Nucleosidation reactions conducted using
one-pot conditions wherein acetoxy-spiroacetal 10 was treated
with BSA and TMSOTf in MeCN for 3 h were disappointing.
Similarly, the two pot procedure wherein acetoxy-spiroacetal 10
24,25
the two-pot Vorbr u¨ ggen conditions
<1%) of the desired spiroacetal-5-fluorocytidine 15a as identified
by NMR spectroscopy (Scheme 4). The starting ethoxy-spiroacetal
2 was also recovered from the reaction in more than 50% yield
only gave a trace amount
(
1
was treated with SnCl
4
or BF
3
·OEt
2
in MeCN or CH
2
Cl only
2
together with a complex mixture of degraded material. Recovery of
starting material indicated that ethoxy-spiroacetal 12 was a weak
glycosyl donor for nucleosidation in the context of the present
work.
proceeded in low yield. An equivalent yield of 45% was obtained
29
using TIPSOTf in CH
2
2
Cl at room temperature but the reaction
took longer to proceed than the reaction using TMSOTf under
similar conditions.
TIPSOTf is a stronger Lewis acid than TMSOTf but with
29
better air and moisture stability due to its steric bulk. Therefore,
TIPSOTf was suggested to provide a good alternative to the use of
29
TMSOTf. This suggestion was consistent with the above results
for the nucleosidation of acetoxy-spiroacetal 10 with persilylated
thymine under Vorbr u¨ ggen conditions. However, attempts to
extend the use of TIPSOTf to nucleosidations involving other
persilylated pyrimidines, namely uracil and 5-fluorouracil, only
proceeded in lower yield than the analogous reaction using
TMSOTf (Scheme 6 and Table 3). It was therefore established that
the use of TMSOTf in CH
preferred method for the nucleosidation of acetoxy-spiroacetal 10
with persilylated pyrimidines.
2
Cl at room temperature was in fact the
2
Scheme 4 Nucleosidation of acetoxy-spiroacetal 10 with a range of
persilylated pyrimidines under Vorbr u¨ ggen conditions. See Table 1 for
reaction conditions.
1
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Table 1 Summary of reagents and conditions used for the nucleosidation of acetoxy-spiroacetal 10 with a range of persilylated pyrimidines using two-pot
Vorbr u¨ ggen conditions (Scheme 4)
Entry
1
Persilylated pyrimidine
Silylation conditions
a
Nucleosidation conditions
b
Product
Yield (%)
22
2
3
a
a
b
b
46
45
4
a
b
36
5
a
b
20
Reagents and conditions: (a) pyrimidine, HMDS, (NH
4
)
2
SO
4
2 2
(cat.), reflux, 1–4 h; (b) 10, TMSOTf, CH Cl , rt, 2–3 h.
Table 2 Summary of reagents and conditions used for optimising the nucleosidation of acetoxy-spiroacetal 10 with persilylated thymine under a range
of Vorbr u¨ ggen conditions (Scheme 5)
Entry
Silylation reagent
Lewis acid
Reaction conditions
MeCN, rt, 3 h
Yield (%)
1
2
3
4
5
6
BSA (one pot)
HMDS
HMDS
HMDS
HMDS
TMSOTf
TMSOTf
33
45
24
CH
CH
2
Cl
Cl
2
, rt, 3 h
, rt, 3 h
SnCl
SnCl
4
2
2
4
MeCN, rt, 3 h
Complex mixture
45
Complex mixture
TIPSOTf
BF
·OEt
CH
CH
2
Cl
Cl
2
, rt, 18 h
, rt, 3 h
HMDS
3
2
2
2
Having demonstrated the successful nucleosidation of acetoxy-
spiroacetal 10 with pyrimidine bases, the more difficult nucle-
osidations using purine bases were next investigated. Purines
have several nitrogens available for possible alkylation. Unlike
the pyrimidines, the difference in the steric hindrance exerted
by the neighbouring groups near the nitrogens is not significant
enough to allow for selective alkylation. Alkylation of purines,
therefore, may not be regioselective and a mixture of N7 and
N9 regioisomers are commonly isolated for guanosine and some
25,30
adenosine derivatives.
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Table 3 Summary of reagents and conditions used for the nucleosidation of acetoxy-spiroacetal 10 with persilylated uracil or 5-fluorouracil under
two-pot Vorbr u¨ ggen conditions (Scheme 6). The percentages in parentheses represent the yield obtained when TMSOTf was used for the nucleosidation
(
Table 1)
Entry
Persilylated pyrimidine
Silylation conditions
U, BSA, reflux, 1 h
Nucleosidation conditions
Product
Yield
1
2
3
U(TMS)
2
TIPSOTf, CH
TIPSOTf, CH
TIPSOTf, CH
2
2
2
Cl
2
Cl
2
Cl
2
, rt, 18 h
, rt, 18 h
, rt, 18 h
15d
15e
15e
9% (cf. 36%)
Complex mixture (cf. 20%)
Complex mixture (cf. 20%)
5
F
F
5F
U(TMS)
2
U, BSA, reflux, 1 h
5
5F
U(TMS)
2
4 2 4
U, HMDS, (NH ) SO
(
cat.), reflux, 1 h
Nevertheless, the nucleosidation of acetoxy-spiroacetal 10 with
N-acylated adenine or guanine was carried out. The silylation step
was carried out using BSA under reflux after discovering that the
use of HMDS was very slow by comparison. Later, the silylation
step was effected by heating the purine base with a mixture of
BSA, HMDS and toluene under reflux, thus producing cleaner
persilylated purines. In this case, TIPSOTf was used to generate
the oxonium ion intermediate for the nucleosidation due to its
better air and moisture stability.
Gratifyingly using these conditions, the nucleosidation of
acetoxy-spiroacetal 10 with persilylated N-benzoyladenine gave
the desired N9-substituted spiroacetal-adenosine 15f in 35–37%
yield as the only regioisomer. On the other hand, nucleosidation
of persilylated N-acetylguanine gave a mixture of N9-guanosine
1
5g and N7-guanosine 15h in 20% and 11% yield, respectively
Scheme 6 Nucleosidation of acetoxy-spiroacetal 10 with persilylated
uracil or 5-fluorouracil under a range of Vorbr u¨ ggen conditions. See
Table 3 for reaction conditions.
(Scheme 7 and Table 4). Preparative thin layer chromatography
(PLC) was required to separate the N7 and N9 regioisomers.
Table 4 Summary of reagents and conditions used for the nucleosidation of acetoxy-spiroacetal 10 with persilylated purines using the two-pot Vorbr u¨ ggen
procedure (Scheme 7)
Entry Persilylated purine
1
Silylation conditions
Nucleosidation conditions
10, TIPSOTf, CH Cl , rt, 18 h
Product
Yield (%)
35–37%
N-Benzoyladenine,
HMDS–BSA–toluene, reflux, 1 h
2
2
5
N-Acetylguanine,
HMDS–BSA–toluene, reflux, 1 h
10, TIPSOTf, CH
2
Cl
2
, rt, 18 h
15g: 20%,
15h: 11%
1
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position. The alignment of 1,3-dipole moments between the basic
substituent and the C–O bond of the neighbouring ring may
32
also disfavour the formation of axial isomer. The formation of
the equatorial substituted nucleosidation was consistent with the
experimental observations and ab initio calculations carried out
27
by Mead and Zemribo on a closely related 6,6-spiroacetal ring
system. Similar exclusive production of the equatorial isomers
from the nucleosidation of pyranosides or furanosides lacking a
stereodirecting neighbouring group have also been reported in the
Scheme 7 Nucleosidation of acetoxy-spiroacetal 10 with a range of
persilylated purines under Vorbr u¨ ggen conditions. See Table 4 for reaction
conditions.
33
literature.
For all the nucleosidations performed using acetoxy-spiroacetal
Desilylation and deacylation of spiroacetal-nucleosides 15
1
0, only a single diastereomer of the individual nucleosidation
was obtained. NMR analysis of nucleoside analogues 15a–h
revealed the characteristic anomeric H2¢ protons at d 5.85–
.22 ppm. These protons resonated as doublets of doublets with a
The desilylation of TBDPS-protected spiroacetal-nucleosides
H
1
5a–i was carried out primarily using the mild reagent,
6
34
HF·triethylamine after the successful deprotection of struc-
characteristic large 1,2-diaxial coupling constant (J2ax,3ax 10.6–11.1
Hz) establishing that the nucleoside substituent in analogues 15a–h
adopted the equatorial position. Characteristic NOESY correla-
tions between H2¢ and H8¢ were observed for nucleosides 15a–h,
thus confirming the adoption of the bis-anomerically stabilised
spiroacetal conformation in which both the TBDPS-protected
hydroxymethyl and nucleobase adopted equatorial positions on
their associated tetrahydropyran rings (Fig. 4).
22
turally related spiroacetal-triazole series. Removal of the silyl
ether group in spiroacetal-nucleosides 15a–i using HF·triethyl-
amine proceeded smoothly in THF to give nucleosides 11a–i in 65–
9
2% yield. The reactions were very sluggish at room temperature
and required use of prolonged reaction times and excess reagents.
The deprotections were, therefore, carried out at an elevated
◦
temperature of 40 C to increase the rate of reaction (Scheme 8
and Table 5).
Recrystallisation of uridine 15d from dichloromethane–hexane
afforded pale yellow needles that allowed structural determination
31
by X-ray crystallography. The results were consistent with the
above NMR analysis which established that the spiroacetal rings
adopted a bis-anomerically stabilised conformation and both the
uracil and TBDPS-protected hydroxymethyl substituent occupied
the equatorial positions on their respective tetrahydropyran rings
(
Fig. 5).
Scheme 8 Desilylation of TBDPS-protected nucleosides 15a–i. See
Table 5 for reaction conditions.
Attempts to desilylate protected thymidine 15c using a non-
fluoride based reagent, caesium(III) chloride and sodium iodide in
35
MeCN failed to give thymidine 11c with only a complex mixture
resulting (Table 5).
Using the favoured desilylation conditions (HF·triethylamine at
◦
4
0 C), N-deacetylation of protected cytidine 15b also occurred
concomitantly to give the desired cytidine 11b in 69% yield.
However, deacylation was not observed for the reaction of
adenosine 15f and guanosines 15g and 15h with HF·triethylamine
under the same conditions (Table 5). Therefore, use of a separate
N-deacylation step under mild conditions was required to unmask
the purine moiety in protected spiroacetal-nucleosides 11f–h and
15f without effecting cleavage of the sensitive spiroacetal ring and
the pseudo N-glycosidic bond (Scheme 9).
Fig. 5 X-Ray crystal structure of uridine 15d with displacement ellipsoids
31
drawn at the 50% probability level.
Only the equatorial substituted nucleoside analogues 15a–h
were isolated from the nucleosidation step. This may be due to
the destabilising steric interactions exerted by the bulky TBDPS-
protected hydroxymethyl group if the nucleoside occupied an axial
Scheme 9 N-Deacylation of protected purines 11f–h and 15f. See Table 6
for reaction conditions.
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Table 5 Summary of reagents and conditions used for the desilylations of TBDPS-protected nucleosides 15a–i (Scheme 8)
Entry
1
TBDPS ether
Reagents and conditions
a
Product
Yield (%)
77
a
2
3
a
a
69
76–79
4
5
b
a
Complex mixture
73
6
a
65
7
a
85
8
a
92
1
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Table 5 (Contd.)
Entry
9
TBDPS ether
Reagents and conditions
a
Product
Yield (%)
91
1
0
a
82
◦
a
Reagents and conditions: (a) 3HF·NEt
3
, THF, 40 C, 1–2 d; (b) CeCl
3
·H
2
O, NaI, MeCN, reflux, 3 h. One-pot desilylation/N-deacetylation was achieved
b
for this particular reaction. Synthesised via N-debenzoylation of adenosine 15f. See Table 6 for reaction conditions.
3
6
Use of the mild reagent, zinc(II) bromide in MeOH–CHCl
3
nucleosides. The knowledge gleaned in this synthetic study also
provides momentum for future elaboration of 6,6-spiroacetals to
incorporate other biologically active motifs. In addition to the
chemical diversity reflected by this series of spiroacetal hybrids,
compounds prepared in this study can also be used as probes to
screen for potential bioactivity in broad phenotypic assays.
failed to effect N-deacylation of protected purine 11f and only
a complex mixture was recovered. This result was attributed to
the undesired coordination of zinc(II) ion to the spiroacetal ring
oxygens rather than the purine N1, thus initiating undesired ring-
opening side reactions. Given the metal-coordinating ability of
spiroacetals in general, metal based N-deacylation was deemed
unsuitable (Scheme 9 and Table 6).
N-Deacylation using non-metal based reagents was next ex-
amined. Gratifyingly, protected purines 11g, 11h and 15f were
heated at 100–120 C under microwave irradiation in a mixture
22
Experimental
General
◦
37
Experiments requiring anhydrous conditions were performed
under a dry nitrogen atmosphere using flame-dried apparatus
and standard techniques in handling air- and moisture-sensitive
materials unless otherwise stated. Solvents used for reactions, ex-
tractions and chromatographic purifications were distilled (except
for diethyl ether), unless otherwise stated. Commercial reagents
were analytical grade or were purified by standard procedures
of NEt
3
, H O and MeOH successfully affording the desired
spiroacetal-nucleosides 11j, 11k and 15i in 86–93% yield (Scheme 9
and Table 6).
2
No epimerisation of the C6¢ spirocentre or the C2¢/C8¢
anomeric centre was observed during the desilylation and deacyla-
tion reactions. Similar to other spiroacetal analogues synthesised
in this series, the structures of spiroacetal-nucleosides 11a–k were
confirmed by NMR analysis. Spiroacetal-nucleosides 11a–k also
adopted the bis-anomerically stabilised spiroacetal conformation
with both the hydroxymethyl and basic substituents occupy-
ing equatorial positions on their respective tetrahydropyran
rings.
38
prior to use. Microwave reactions were conducted in sealed
ꢀ
R
reaction vessels using a Discover LabMate microwave synthesiser
CEM Corporation) at the temperature stated. Separation of
(
mixtures was performed by flash chromatography using Kieselgel
S 63–100 mm (Riedel-de-Hahn) silica gel with the indicated eluent
or by PLC using Kieselgel 60 F254 (Merck) silica plates with the
indicated eluent.
Conclusion
Synthesis of acetoxy-spiroacetal 10
In conclusion, the elaboration of a 6,6-spiroacetal ring system to
incorporate a nucleoside unit at the anomeric position together
with a synthetically useful hydroxymethyl group has been success-
fully accomplished. Given the importance of a nucleobase unit
as a molecular handle recognised by nucleic acid processing
enzymes, the assembly of a spiroacetal containing a nucleobase as
reported herein, generates a novel series of spiroacetal-containing
(
2
2R*,6S*,8S*)-8-(tert-Butyldiphenylsilyloxymethyl)-
-acetoxy-1,7-dioxaspiro[5.5]undecane (10)
Method A: using ketone 13 as the starting material
22
A solution of ketone 13 (100 mg, 167 mmol) and PPTS (8.39 mg,
33.4 mmol) in a 2 : 1 mixture of acetone–water (3.0 mL) was
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Table 6 Summary of reagents and conditions used for the N-deacylation of protected purines 11f–h and 15f (Scheme 9)
Entry
1
N-Acylated nucleoside
Reagents and conditions
a
Product
—
Yield (%)
Complex mixture
a
2
b
90
3
b
93
4
b
86
◦
a
2 3 3
Reagents and conditions: (a) ZnBr , MeOH–CHCl , rt, 3 d; (b) aq. MeOH–NEt , microwave, 100–120 C, 30 min. Adenosine 15i was then desilylated
using HF·triethylamine. See Table 5 for reaction conditions.
heated to reflux. After 24 h, a saturated solution of NaHCO
3
Method B: using ethoxy-spiroacetal 12 as the starting material
(
3 mL) and toluene (3 mL) were added and the aqueous phase
was extracted with Et
extracts were dried over MgSO
yield the crude lactol as a pale yellow oil. This unstable lactol was
used directly in the acetylation described below without further
purification.
2
O (3 ¥ 3 mL). The combined organic
and concentrated in vacuo to
To a solution of ethoxy-spiroacetal 12 (485 mg, 1.04 mmol) in a
4
4 : 1 mixture of THF–water (18 mL) was added CSA monohydrate
◦
(104 mg, 414 mmol) and the mixture was stirred at 40 C overnight.
A saturated solution of NaHCO (20 mL) and Et O (20 mL)
3
2
were added and the aqueous phase was extracted with Et O (3 ¥
2
To a solution of crude lactol in anhydrous CH
room temperature was added DMAP (4.08 mg, 33.4 mmol), NEt
23.3 mL, 167 mmol) and Ac O (13.3 mL, 134 mmmol). After 2 h,
brine (2 mL) was added and the aqueous phase was extracted
with CH Cl (3 ¥ 3 mL). The combined organic extracts were
dried over MgSO and concentrated in vacuo. Purification by flash
chromatography using hexane–Et O–EtOAc (99 : 1 : 0, 99 : 0 : 1
2
Cl
2
(1.5 mL) at
30 mL). The combined organic extracts were dried over MgSO4
3
and concentrated in vacuo to yield the lactol as a pale yellow oil.
The unstable lactol was used directly in the acetylation described
below without further purification.
(
2
2
2
To a solution of crude lactol in anhydrous CH Cl (9.0 mL) at
2
2
4
room temperature was added DMAP (25.3 mg, 207 mmol), NEt3
2
(216 mL, 1.55 mmol) and Ac O (117 mL, 1.24 mmol). After 3 h,
2
to 97 : 0 : 3) yielded the title compound 10 (27.5 mg, 34% over 2
the mixture was filtered through a pad of silica and the eluent was
steps) as a white powder. Recrystallisation of acetoxy-spiroacetal
concentrated in vacuo. Purification by flash chromatography using
1
0 from hexane–CH
2
Cl
2
afforded white prisms.
hexane–Et O–EtOAc (99 : 1 : 0, 99 : 0 : 1 to 97 : 0 : 3) yielded the
2
1
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title compound 10 (298 mg, 58% over 2 steps) as a white powder.
(method A) described above. Purification was carried out by flash
chromatography using hexane–EtOAc (9 : 1 to 1 : 1) as eluent.
Recrystallisation of acetoxy-spiroacetal 10 from hexane–CH
2
Cl
2
afforded white prisms.
1
-{(2¢S*,6¢S*,8¢S*)-8¢-(tert-Butyldiphenylsilyloxymethyl)-1¢,7¢-
General procedures for nucleosidation under Vorbr u¨ ggen
dioxaspiro[5.5]undecan-2¢-yl}thymidine (15c)
24,25
conditions
Method A. The title compound 15c (10.5 mg, 45%) was
prepared as a pale yellow oil from thymine (8.49 mg, 67.3 mmol),
acetoxy-spiroacetal 10 (20.4 mg, 42.3 mmol) and TMSOTf solution
Method A: nucleosidation with pyrimidine bases
To a suspension of the pyrimidine base (1.2–2.0 equiv.) in
HMDS (0.50–1.0 mL) under an atmosphere of argon was added
ammonium sulfate (2 crystals) and the mixture was heated to
reflux until the white solid dissolved. After 3–4 h, the mixture was
concentrated in vacuo to afford a thick yellow oil. A solution of
(104 mL, 72.5 mmol) using the general procedure (method A)
described above. Purification was carried out by flash chromatog-
raphy using hexane–EtOAc (19 : 1, 9 : 1 to 4 : 1) as eluent.
1
-{(2¢S*,6¢S*,8¢S*)-8¢-(tert-Butyldiphenylsilyloxymethyl)-1¢,7¢-
acetoxy-spiroacetal 10 in CH
2
Cl
2
(1.0–1.1 mL) was transferred to
dioxaspiro[5.5]undecan-2¢-yl}uridine (15d)
the yellow oil via cannula. Freshly prepared TMSOTf solution
-
1
(
1.6–2.2 equiv., 0.70 mol L in CH
After 3 h, a solution of saturated NaHCO
2 mL) were added and the mixture was stirred for 15 min.
The aqueous phase was extracted with CH Cl (3 ¥ 4 mL).
The combined organic extracts were dried over MgSO and
2
Cl
2
) was then added dropwise.
Method A. The title compound 15d (7.50 mg, 36%) was
prepared as a pale yellow powder from uracil (6.95 mg, 61.9
mmol), acetoxy-spiroacetal 10 (18.8 mg, 38.9 mmol) and TMSOTf
solution (95.4 mL, 66.8 mmol) using the general procedure
(method A) described above. Purification was carried out by flash
chromatography using hexane–EtOAc (19 : 1 to 7 : 3) as eluent.
Recrystallisation of uridine 15d from hexane–CH Cl afforded
3
(2 mL) and CH Cl
2
2
(
2
2
4
concentrated in vacuo. Purification by flash chromatography
using hexane–EtOAc as eluent yielded the spiroacetal nucleo-
side 15.
2
2
pale yellow needles.
Method B: nucleosidation with purine bases
1-{(2¢S*,6¢S*,8¢S*)-8¢-(tert-Butyldiphenylsilyloxymethyl)-1¢,7¢-
dioxaspiro[5.5]undecan-2¢-yl}-5-fluorouridine (15e)
A suspension of the purine base (1.3 equiv.) in a 1 : 4 : 5 mixture of
N,O-bis(trimethylsilyl)acetimide–HMDS–toluene (1.0 mL) under
an atmosphere of argon was heated to reflux until the white solid
dissolved. After 2 h, the mixture was concentrated in vacuo to
afford a thick yellow oil. A solution of acetoxy-spiroacetal 10 in
Method A. The title compound 15e (4.00 mg, 19%) was
prepared as a pale yellow oil from 5-fluorouracil (7.75 mg, 59.6
mmol), acetoxy-spiroacetal 10 (18.0 mg, 37.2 mmol) and TMSOTf
solution (92.0 mL, 64.4 mmol) using the general procedure
(method A) described above. Purification was carried out by flash
chromatography using hexane–EtOAc (19 : 1, 4 : 1 to 7 : 3) as
eluent.
CH
Freshly prepared TIPSOTf solution (1.4 equiv., 0.52 mol L in
CH Cl ) was then added dropwise. After 18 h, a saturated solution
of NaHCO (2 mL) and CH Cl (2 mL) were added and the
mixture stirred for 15 min. The aqueous phase was extracted
with CH Cl (3 ¥ 4 mL). The combined organic extracts were
dried over MgSO and concentrated in vacuo. Purification by
2
Cl
2
(1.5 mL) was transferred to the yellow oil via cannula.
-
1
2
2
3
2
2
6
-N-Benzoyl-9-{(2¢S*,6¢S*,8¢S*)-8¢-(tert-butyldiphenylsilyloxy-
2
2
methyl)-1¢,7¢-dioxaspiro[5.5]undecan-2¢-yl}adenosine (15f)
4
Method B. The title compound 15f (14.5 mg, 35%) was
prepared as a pale yellow oil from 6-N-benzoyladenine (19.3 mg,
flash chromatography using hexane–EtOAc as eluent yielded the
spiroacetal nucleoside 15.
8
0.8 mmol), acetoxy-spiroacetal 10 (30.0 mg, 62.2 mmol) and
TIPSOTf (167 mL, 86.9 mmol) using the general procedure
method B) described above. Purification was carried out by flash
1
-{(2¢S*,6¢S*,8¢S*)-8¢-(tert-Butyldiphenylsilyloxymethyl)-1¢,7¢-
(
dioxaspiro[5.5]undecan-2¢-yl}-5-fluorocytidine (15a)
chromatography (twice) using hexane–EtOAc (19 : 1, 9 : 1 to 1 : 1)
as eluent.
Method A. The title compound 15a (6.10 mg, 22%) was
prepared as a pale yellow oil from 5-fluorocytosine (12.4 mg,
9
7.0 mmol), acetoxy-spiroacetal 10 (24.0 mg, 49.7 mmol) and
TMSOTf solution (159 mL, 111 mmol) using the general procedure
method A) described above. Purification was carried out by flash
2
-N-Acetyl-9-{(2¢S*,6¢S*,8¢S*)-8¢-(tert-butyldiphenylsilyloxy-
methyl)-1¢,7¢-dioxaspiro[5.5]undecan-2¢-yl}guanosine (15g) and
(
(
2S*,6S*,8S*)-2-N-acetyl-7-{8¢-(tert-butyldiphenylsilyloxy-
chromatography using hexane–EtOAc (19 : 1, 1 : 1 to 1 : 4) as
eluent.
methyl)-1¢,7¢-dioxaspiro[5.5]undecan-2¢-yl}guanosine (15h)
Method B. The title N9-guanosine 15g (7.72 mg, 20%) and
N7-guanosine 15h (4.00 mg, 11%) were prepared as colourless oils
from 2-N-acetylguanine (15.6 mg, 80.8 mmol), acetoxy-spiroacetal
4
-N-Acetyl-1-{(2¢S*,6¢S*,8¢S*)-8¢-(tert-butyldiphenylsilyloxy-
methyl)-1¢,7¢-dioxaspiro[5.5]undecan-2¢-yl}cytidine (15b)
10 (30.0 mg, 62.2 mmol) and TIPSOTf (167 mL, 87.1 mmol) using
Method A. The title compound 15b (14.3 mg, 46%) was
prepared as a colourless oil from 4-N-acetylcytosine (9.86 mg,
the general procedure (method B) described above. Purification
was carried out by flash chromatography using hexane–EtOAc
(19 : 1, 3 : 2, 1 : 4 to 0 : 1) as eluent followed by PLC using
hexane–EtOAc (1 : 1) as eluent.
64.4 mmol), acetoxy-spiroacetal 10 (25.9 mg, 53.7 mmmol) and
TMSOTf solution (123 mL, 86.4 mmol) using the general procedure
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General procedures for deprotection of spiroacetal nucleosides 15
(1.0 mL) using the general procedure (method A) described above.
Purification was carried out by flash chromatography (twice) using
hexane–EtOAc (4 : 1, 1 : 1 to 0 : 1) as eluent.
34
Method A: desilylation using 3HF·NEt
A solution of TBDPS-protected nucleoside 15 and 3HF·NEt
3
3
(3.0–
.4 mL per 1.0 mmol) in anhydrous THF (300 mL–1.5 mL) under an
1
-{(2¢S*,6¢S*,8¢S*)-8¢-(Hydroxymethyl)-1¢,7¢-
5
◦
dioxaspiro[5.5]undecan-2¢-yl}-5-fluorouridine (11e)
atmosphere of argon was stirred at 40 C for 24–48 h. A solution
of saturated NaHCO (2 mL) was added dropwise. The aqueous
3
Method A. The title compound 11e (1.00 mg, 65%) was
prepared as a pale yellow oil from TBDPS-protected fluorouridine
phase was extracted with EtOAc (6 ¥ 3 mL) and the combined
organic extracts were concentrated in vacuo. Purification by flash
chromatography using the appropriate eluent yielded spiroacetal-
nucleoside 11.
1
5e (2.70 mg, 4.89 mmmol) and 3HF·NEt
3
(25.0 mL) in THF
(500 mL) using the general procedure (method A) described above.
Purification was carried out by flash chromatography (twice) using
hexane–EtOAc–MeOH (4 : 1 : 0, 0 : 1 : 0 to 0 : 19 : 1) as eluent.
Method B: deacylation using NEt
irradiation
3
–H O–MeOH and microwave
2
37
6
-N-Benzoyl-9-{(2¢S*,6¢S*,8¢S*)-8¢-(hydroxymethyl)-1¢,7¢-
dioxaspiro[5.5]undecan-2¢-yl}adenosine (11f)
A solution of acyl-protected purine nucleosides in a mixture
of NEt
3
–H O–MeOH was irradiated in a sealed tube at 100–
2
Method A. The title compound 11f (6.50 mg, 85%) was
prepared as a pale yellow oil from TBDPS-protected adenosine
◦
120 C under microwave irradiation. After 30 min, the reaction
was concentrated in vacuo and a solution of saturated NaHCO
3
1
5f (12.0 mg, 18.1 mmol) and 3HF·NEt
3
(54.0 mL) in THF
(
(
0.5 mL) was added. The aqueous phase was extracted with EtOAc
5 ¥ 3 mL) and the combined organic extracts were concentrated in
(1.5 mL) using the general procedure (method A) described above.
Purification was carried out by flash chromatography (twice) using
hexane–EtOAc–MeOH (4 : 1 : 0, 0 : 1 : 0 to 0 : 19 : 1) as eluent.
vacuo. Purification by flash chromatography using the appropriate
eluent yielded spiroacetal-nucleoside 11.
2
-N-Acetyl-9-{(2¢S*,6¢S*,8¢S*)-8¢-(hydroxymethyl)-1¢,7¢-
1
-{(2¢S*,6¢S*,8¢S*)-8¢-(Hydroxymethyl)-1¢,7¢-
dioxaspiro[5.5]undecan-2¢-yl}guanosine (11g)
dioxaspiro[5.5]undecan-2¢-yl}-5-fluorocytidine (11a)
Method A. The title compound 11g (2.80 mg, 91%) was
Method A. The title compound 11a (2.40 mg, 77%) was pre-
prepared as a colourless oil from TBDPS-protected guanosine
pared as a pale yellow oil from TBDPS-protected fluorocytidine
1
5g (5.00 mg, 8.12 mmol) and 3HF·NEt
3
(24.6 mL) in THF
1
5a (5.50 mg, 9.97 mmol) and 3HF·NEt
3
(30.0 mL) in THF
(750 mL) using the general procedure (method A) described
(
500 mL) using the general procedure (method A) described
above. Purification was carried out by flash chromatography using
hexane–EtOAc–MeOH (4 : 1 : 0, 0 : 1 : 0 to 0 : 9 : 1) as eluent
followed by PLC using EtOAc–MeOH (99 : 1) as eluent.
above. Purification was carried out by flash chromatography using
hexane–EtOAc–MeOH (4 : 1 : 0, 0 : 1 : 0, 0 : 19 : 1 to 0 : 9 : 1) as
eluent.
2
-N-Acetyl-7-{(2¢S*,6¢S*,8¢S*)-8¢-(hydroxymethyl)-1¢,7¢-
1
-{(2¢S*,6¢S*,8¢S*)-8¢-(Hydroxymethyl)-1¢,7¢-
dioxaspiro[5.5]undecan-2¢-yl}guanosine (11h)
dioxaspiro[5.5]undecan-2¢-yl}cytidine (11b)
Method A. The title compound 11h (2.00 mg, 82%) was
prepared as a colourless oil from TBDPS-protected guanosine
Method A. The title compound 11b (3.90 mg, 69%) was
prepared as a pale yellow oil from TBDPS-protected cytidine
1
(
5h (4.00 mg, 6.50 mmol) and 3HF·NEt
3
(20.0 mL) in THF
750 mL) using the general procedure (method A) described
1
(
5b (11.0 mg, 19.1 mmol) and 3HF·NEt
3
(104 mL) in THF
700 mL) using the general procedure (method A) described
above. Purification was carried out by flash chromatography using
hexane–EtOAc–MeOH (1 : 1 : 0, 0 : 1 : 0 to 0 : 19 : 1) as eluent.
above. Purification was carried out by flash chromatography using
hexane–EtOAc–MeOH (4 : 1 : 0, 0 : 1 : 0 to 0 : 9 : 1) as eluent.
1
-{(2¢S*,6¢S*,8¢S*)-8¢-(Hydroxymethyl)-1¢,7¢-
9-{(2¢S*,6¢S*,8¢S*)-8¢-(tert-Butyldiphenylsilyloxymethyl)-1¢,7¢-
dioxaspiro[5.5]undecan-2¢-yl}adenosine (15i)
dioxaspiro[5.5]undecan-2¢-yl}thymidine (11c)
Method A. The title compound 11c (3.30 mg, 79%) was
prepared as a pale yellow oil from TBDPS-protected thymidine
Method B. The title compound 15i (8.50 mg, 90%) was
prepared as a colourless solid from adenosine 15f (11.2 mg, 16.9
1
5c (7.40 mg, 13.5 mmol) and 3HF·NEt
3
(72.0 mL) in THF
mmol) in a 1 : 2 : 10 mixture of NEt
3
–H O–MeOH (2.6 mL) using
2
(
300 mL) using the general procedure (method A) described
the general procedure (method B) described above. Purification
was carried out by flash chromatography (twice) using hexane–
EtOAc (4 : 1, 1 : 1 to 0 : 1) as eluent.
above. Purification was carried out by flash chromatography using
hexane–EtOAc (4 : 1 to 1 : 1) as eluent.
1
-{(2¢S*,6¢S*,8¢S*)-8¢-(Hydroxymethyl)-1¢,7¢-
9-{(2¢S*,6¢S*,8¢S*)-8¢-(Hydroxymethyl)-1¢,7¢-
dioxaspiro[5.5]undecan-2¢-yl}adenosine (11i)
dioxaspiro[5.5]undecan-2¢-yl}uridine (11d)
Method A. The title compound 11d (2.90 mg, 73%) was
Method A. The title compound 11i (4.20 mg, 92%) was pre-
prepared as a pale yellow oil from TBDPS-protected uridine
pared as a colourless powder from TBDPS-protected adenosine
15d (7.20 mg, 13.5 mmol) and 3HF·NEt
3
(40.5 mL) in THF
15i (8.00 mg, 14.3 mmol) and 3HF·NEt
3
(42.9 mL) in THF
1
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(
1.5 mL) using the general procedure (method A) described
above. Purification was carried out by flash chromatography using
CH Cl –MeOH (99 : 1 to 9 : 1) as eluent.
Med. Chem. Lett., 2000, 10, 541–545; H. Huang, C. Mao, S.-T.
Jan and F. M. Uckun, Tetrahedron Lett., 2000, 41, 1699–1702; S.
Mitsuhashi, H. Shima, T. Kawamura, K. Kikuchi, M. Oikawa, A.
Ichihara and H. Oikawa, Bioorg. Med. Chem. Lett., 1999, 9, 2007–
2
2
2
012.
9
-{(2¢S*,6¢S*,8¢S*)-8¢-(Hydroxymethyl)-1¢,7¢-
12 O. Barun, K. Kumar, S. Sommer, A. Langerak, T. U. Mayer,
O. M u¨ ller and H. Waldmann, Eur. J. Org. Chem., 2005, 4773–
dioxaspiro[5.5]undecan-2¢-yl}guanosine (11j)
4
788.
1
1
1
3 A. A. Birkbeck, S. V. Ley and J. C. Prodger, Bioorg. Med. Chem. Lett.,
1
4 B. A. Kulkarni, G. P. Roth, E. Lobkovsky and J. A. Porco, Jr., J. Comb.
Chem., 2002, 4, 56–72.
5 R. G. Finch, D. Greenwood, S. R. Norrby and R. J. Whitney,
Antibiotics and Chemotherapy: Anti-Infective Agents and their Use in
Therapy, Churchill Livingstone, Edinburgh, 8th edn., 2003; H. P. Rang,
M. M. Dale, and J. M. Ritter, Pharmacology, Churchill Livingstone,
Edinburgh, 4th edn., 1999.
Method B. The title compound 11j (2.90 mg, 93%) was
prepared as a colourless oil from guanosine 11g (3.50 mg, 9.27
995, 5, 2637–2642.
mmol) in a 1 : 1 : 10 mixture of NEt
the general procedure (method B) described above. Purification
was carried out by flash chromatography using CH Cl –MeOH
99 : 1, 19 : 1 to 9 : 1) as eluent.
3
–H
2
O–MeOH (3.6 mL) using
2
2
(
1
1
6 R. Challand and R. J. Young, Antiviral Chemotherapy, Oxford Univer-
7
-{(2¢S*,6¢S*,8¢S*)-8¢-(Hydroxymethyl)-1¢,7¢-
sity Press, Oxford, 1997.
dioxaspiro[5.5]undecan-2¢-yl}guanosine (11k)
7 J. E. Robinson and M. A. Brimble, Chem. Commun., 2005, 1560–1562;
K. Meilert and M. A. Brimble, Org. Lett., 2005, 7, 3497–3500; K.
Meilert and M. A. Brimble, Org. Biomol. Chem., 2006, 4, 2184–2192;
R. Halim, M. A. Brimble and J. Merten, Org. Biomol. Chem., 2006, 4,
Method B. The title compound 11k (1.30 mg, 86%) was
prepared as a colourless oil from guanosine 11h (1.70 mg, 4.50
1
387–1399; M. A. Brimble, C. L. Flowers, M. Trzoss and K. Y. Tsang,
mmol) in a 1 : 1 : 10 mixture of NEt
the general procedure (method B) described above. Purification
was carried out by flash chromatography using CH Cl –MeOH
99 : 1, 19 : 1 to 9 : 1) as eluent.
3
–H
2
O–MeOH (3.6 mL) using
Tetrahedron, 2006, 62, 5883–5896; M. A. Brimble and C. J. Bryant,
Chem. Commun., 2006, 4506–4508; M. A. Brimble and C. V. Burgess,
Synthesis, 2007, 754–760; M. A. Brimble and C. J. Bryant, Org. Biomol.
Chem., 2007, 5, 2858–2866; J. E. Robinson and M. A. Brimble, Org.
Biomol. Chem., 2007, 5, 2572–2582; K. Y. Tsang and M. A. Brimble,
Tetrahedron, 2007, 63, 6015–6034.
2
2
(
1
1
8 M. Nakajima, K. Itoi, Y. Takamatsu, T. Kinoshita, T. Okazaki, K.
Kawakubo, M. Shindo, T. Honma, M. Tohjigamori and T. Haneishi,
J. Antibiot., 1991, 44, 293–300; Germany Pat., DE 4129616 A1, 1992;
Japan Pat., JP 04222589 A, 1992.
9 J. Balzarini, M.-J. P e´ rez-P e´ rez, A. San-F e´ lix, D. Schols, C.-F. Perno,
A.-M. Vandamme, M.-J. Camarasa and E. De Clercq, Proc. Natl. Acad.
Sci. U. S. A., 1992, 89, 4392–4396.
Acknowledgements
The authors thank the New Zealand Tertiary Education Com-
mission for the award of a Bright Future Top Achiever Doctoral
Scholarship and the University of Auckland for the award of a
Doctoral Scholarship to KWC.
2
2
0 B. R. Babu, L. Keinicke, M. Petersen, C. Nielsen and J. Wengel, Org.
Biomol. Chem., 2003, 1, 3514–3526.
1 L. A. Paquette, Aust. J. Chem., 2004, 57, 7–17 and references cited
therein; S. Dong and L. A. Paquette, J. Org. Chem., 2005, 70, 1580–
1596 and references cited therein; R. Hartung and L. A. Paquette,
J. Org. Chem., 2005, 70, 1597–1604; R. E. Hartung and L. A. Paquette,
Synthesis, 2005, 3209–3218; L. A. Paquette and S. Dong, J. Org. Chem.,
2005, 70, 5655–5664; R. E. Hartung and L. A. Paquette, Heterocycles,
2006, 67, 75–78; S. Dong and L. A. Paquette, J. Org. Chem., 2006, 71,
1647–1652.
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