Synthesis of 5′-functionalized adenosine: Suppression of cyclonucleoside formation

Article abstract of DOI:10.1016/S0040-4039(01)00395-1

A new method of preparation for 5′-amino-2′,3′-isopropylidene adenosine 1, an important precursor to many adenosine derivatives, is described. This procedure suppresses the undesired intramolecular cyclization and does not require chemical protection of the exocyclic amino group of the adenine ring. The use of a 5′-phophate triester activating group is representative of natural biological substitution at this position, which likely contributes to its greater stability and selective reactivity. This sequence is efficient and should allow easy access to compounds of type 1 in high yield.

Full text of DOI:10.1016/S0040-4039(01)00395-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3153–3154
Synthesis of 5%-functionalized adenosine: suppression of
cyclonucleoside formation
Fei Liu and David J. Austin*
Department of Chemistry, Yale University, New Haven, CT 06520, USA
Received 4 February 2001; revised 28 February 2001; accepted 8 March 2001
Abstract—A new method of preparation for 5%-amino-2%,3%-isopropylidene adenosine 1, an important precursor to many adenosine
derivatives, is described. This procedure suppresses the undesired intramolecular cyclization and does not require chemical
protection of the exocyclic amino group of the adenine ring. The use of a 5%-phophate triester activating group is representative
of natural biological substitution at this position, which likely contributes to its greater stability and selective reactivity. This
sequence is efficient and should allow easy access to compounds of type 1 in high yield. © 2001 Elsevier Science Ltd. All rights
reserved.
Functional group transformation at the 5%-carbon of
nucleosides is an important aspect of nucleoside deriva-
tizations for the study of biological systems. The need
for efficient functionalization at this position is height-
ened by growing recognition that binding specificity for
nucleotide binding pockets can be ascribed to binding
interactions in the phosphate recognition site.1
yield of 1.5 In fact, intramolecular displacement of
sulfonate is so rapid that it interferes with product
isolation and purification. Numerous reports have pro-
vided solutions to the problem of undesired cyclo-
nucleoside formation, all of which involve electron-den-
sity reduction on the base by protecting either the N6
(5)6 or the N1 (6)7 with electron withdrawing groups.
This unfortunately increases the synthesis of 1 to a
five-step sequence. In the course of our investigation of
the synthesis of 5%-functionalized adenosine derivatives
we have found an alternative biomimetic approach that
does not lead to intramolecular cyclization or require
additional protection steps. Herein, we report a new
and efficient preparation of 1, via a phosphate triester
intermediate, in a three-step sequence with 75% overall
isolated yield.
Amine-nucleoside 1, a 5%-transformed analogue of 2%,3%-
isopropylidene adenosine 3, is a useful precursor for
many adenosine derivatives. Several syntheses of 1 have
been described, most of which utilize a sulfonate or
halide group to activate the 5%-position.2–4 Subsequent
substitution is usually conducted with an azide as the
nucleophile, which is then reduced to give amine
nucleoside 1. The yields reported for this sequence are
variable, ranging from 14%2 to 50%,4 mainly due to the
formation of cycloadenosine 4, which results from the
intramolecular nucleophilic substitution by N3 (Scheme
1). It was reported that, upon rotation of the adenine
ring of 5%-activated adenosine, the N3 of the base can
readily displace the 5%-activation to give the ionic
cycloadenosine, causing a steep decrease of the overall
N
In order to facilitate a more efficient strategy for the
synthesis of amino-nucleoside 1, we investigated 5%-
modified nucleosides with various leaving groups. Phos-
phate triester modified 5%-diphenylphosphate-5%-
deoxy-2%,3%-isopropylidene adenosine 7 has been previ-
ously reported.8 Based on the described synthesis, using
N
N
NH2
NH2
NH2
O
O
O
N
N
N
H2N
X
HO
N
N
N
N
N
N
O
O
O
O
O
O
1
2
3
X = OTs, OMs, Cl, I
X = N3
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00395-1

3154
F. Liu, D. J. Austin / Tetrahedron Letters 42 (2001) 3153–3154
NH2
N
NH2
N
N
H
N
N
N
N
NH2
O
O
O
N
N
N
N
X
Bz
X
X
O
N
N
N
N
O
N
N
X
O
O
O
O
4
2
5
6
O
O
O
O
Scheme 1. Mechanism of cyclonucleoside formation and suppression strategies.
N
N
O
PhO
PhO
NH2
NH2
O
O
N
N
P
c
O
N3
b
a
1
3
N
N
N
N
O
O
O
O
7
8
Scheme 2. Reagents and conditions: (a) DPPA, DBU, p-dioxane, rt, quantitative; (b) NaN3, cat. tetrabutylammonium iodide, cat.
15-crown-5, refluxing p-dioxane, 90%; (c) triphenylphosphine, pyridine/NH4OH, 1:1, rt, 84%.
phosphonic acid under Mitsunobu-like conditions, we
found that 3 was sufficiently reactive toward diphenyl
phosphoryl azide (DPPA) in the presence of DBU,9 to
give 8 in excellent yield (Scheme 2).6 Surprisingly, the
phosphate triester 7 was not sufficiently reactive, even
in refluxing THF, to facilitate any intramolecular sub-
stitution at the 5%-position. After investigating a variety
of reaction conditions, it was found that using p-diox-
ane under refluxing conditions (110°C), with the addi-
tion of excess sodium azide, 15-crown-5 and a catalytic
amount (10 mol%) of tetrabutylammonium chloride, 8
could be formed in nearly quantitative yield.
from the Yale Corporation and the National Cancer
Institute of the National Institutes of Health (PO1
CA49639).
References
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To further simplify the synthetic sequence, formation of
phosphate triester 7 was examined in p-dioxane and
found to be a suitable solvent for the Mitsunobu-like
reaction. This modification allows the synthesis of 8 in
a two-step, one-pot procedure without the need to
isolate intermediate 7.10 Staudinger reduction11 of azide
8 proceeds efficiently to give 1, which can be readily
purified by flash chromatography on a silica gel
column.
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10. In a typical experiment, 3 (307 mg, 1 mmol) was sus-
pended, with magnetic agitation, in dry p-dioxane (0.2
M) at room temperature under a nitrogen atmosphere.
DPPA (0.43 mL, 2 mmol) and DBU (0.45 mL, 3 mmol)
were then added in a dropwise fashion and stirring was
continued for 3 h. After addition of sodium azide (325
mg, 5 mmol), tetrabutylammonium iodide (37 mg, 0.1
mmol) and 15-crown-5 (20 mL, 0.1 mmol), the reaction
mixture was refluxed for 3–5 h. Purification by flash
chromatography gave 8 as a white solid (300 mg, 90%
yield).
The enhanced selectivity of 7 for intermolecular azide
displacement over intramolecular cyclonucleoside for-
mation is intriguing and may be due to the relative
leaving group abilities of sulfonates and phosphates.
While the phosphate triester does exhibit a lower reac-
tivity toward nucleophilic substitution than the sulfo-
nate, presumably due to electronic differences, the
resistance toward intramolecular reactivity could also
be due to a steric or stereoelectronic conformational
restriction. We are currently investigating the generality
of this approach for the synthesis of additional 5%-
modified nucleosides of both natural and unnatural
origin.
Acknowledgements
11. Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2,
635–646.
The authors wish to acknowledge financial support
.