Solid-phase synthesis of 7-substituted 3H-imidazo[2,1-i]purines

Article abstract of DOI:10.1039/b612655c

A method for solid-supported synthesis of N,N-disubstituted (3H-imidazo[2,1-i]purin-7-yl)methyl amines has been developed. The key features of this library synthesis are: (i) immobilization of commercially available N⁶-benzoyl-5′-O-(4,4′-dimethoxytrityl)-2′- deoxyadenosine 3′-(2-cyanoethyl N,N-diisopropylphosphoramidite) by phosphitylation to a hydroxyl-functionalized support, (ii) quantitative conversion of the deprotected adenine base to 3H-imidazo[2,1-i]purine-7- carbaldehyde with bromomalonaldehyde in DMF in the presence of formic acid and 2,6-lutidine, (iii) reductive amination of the formyl group followed by N-alkylation or N-acylation, and (iv) release from the support by acidolytic cleavage of the N-glycosidic bond. Steps (ii) and (iii) have been optimized in some detail by using (adenin-9-yl)acetic acid anchored to a Phe-Wang resin as a model compound. The Royal Society of Chemistry.

Full text of DOI:10.1039/b612655c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Solid-phase synthesis of 7-substituted 3H-imidazo[2,1-i]purines
Tuomas Karskela* and Harri Lo¨nnberg
Received 1st September 2006, Accepted 30th October 2006
First published as an Advance Article on the web 10th November 2006
DOI: 10.1039/b612655c
A method for solid-supported synthesis of N,N-disubstituted (3H-imidazo[2,1-i]purin-7-yl)methyl
amines has been developed. The key features of this library synthesis are: (i) immobilization of
commercially available N6-benzoyl-5ꢀ-O-(4,4ꢀ-dimethoxytrityl)-2ꢀ-deoxyadenosine 3ꢀ-(2-cyanoethyl
N,N-diisopropylphosphoramidite) by phosphitylation to a hydroxyl-functionalized support, (ii)
quantitative conversion of the deprotected adenine base to 3H-imidazo[2,1-i]purine-7-carbaldehyde
with bromomalonaldehyde in DMF in the presence of formic acid and 2,6-lutidine, (iii) reductive
amination of the formyl group followed by N-alkylation or N-acylation, and (iv) release from the
support by acidolytic cleavage of the N-glycosidic bond. Steps (ii) and (iii) have been optimized in some
detail by using (adenin-9-yl)acetic acid anchored to a Phe–Wang resin as a model compound.
Introduction
Results and discussion
Purine-based compounds display an exceptionally wide spec-
trum of biological activities. As summarized by Legraverend
and Grierson1 in their recent review, numerous purine-based
compounds are currently in medical use against viral infections,
cancer, systemic mastocytosis and organ rejection, and an in-
creasing number of purine derivatives have been reported to show
potential as inhibitors of kinases,2 phosphodiesterases,3 chaperone
Hsp904 and sulfotransferases,5 as inducers of interferon6 and
effectors of cell dedifferentiation,7 as agonists8 and antagonists9
of adenosine receptors, as antagonists of corticotropin-releasing
factor,10 and as anti-mycobacterium agents.11 Numerous targeted
combinatorial libraries of substituted purines have been prepared
to improve the efficiency and reduce the toxicity of the drug
candidates. However, in surprisingly few cases has solid-phase
chemistry been utilized, but the libraries have been obtained
by conventional solution phase transformations. Only libraries
of 2,6-disubstituted,12 2,6,9-trisubstituted13 purines and 2,6,8-
trisubstituted purine nucleosides14 have been prepared by solid-
phase parallel synthesis. The present study is aimed at adding
a solid-supported synthesis of 7-substituted 3H-imidazo[2,1-
i]purines to this repertoire. The idea of using 3H-imidazo[2,1-
i]purine as a scaffold of a combinatorial library is based on the
observations of others,15 according to which pyrrolo-, imidazo-
and triazolo-purinones, i.e. tricyclic extensions of xanthine nu-
cleus, exhibit high affinity to adenosine receptors. 3H-imidazo[2,1-
i]purines have previously been obtained in solution by a reac-
tion of 9-substituted adenine with a-halocarbonyl compounds,16
epoxycarbonyl compounds,17 2-chloroketene diethyl acetal18 and
1-acetoxy-4-(acetoxyimino)-1,4-dihydroquinoline.19 In the present
study, the reaction of adenine with bromomalonaldehyde was
successfully optimized to result in a quantitative conversion of
a support-bound adenine to 7-formyl-3H-imidazo[2,1-i]purine
that served as a starting material for the subsequent transfor-
mations.
The solid-supported synthesis applied to the preparation of 7-
substituted 3H-imidazo[2,1-i]purines is outlined in Scheme 1. The
key steps of this library synthesis are quantitative conversion
of adenine base to 3H-imidazo[2,1-i]purine-7-carbaldehyde and
reductive amination of this product. These steps were first studied
in some detail by using (adenin-9-yl)acetic acid anchored to a
Phe–Wang resin as a model compound.
Scheme 1
The preparation of [N6-(4-methoxytrityl)adenin-9-yl]acetic acid
(5) has been recently described.20 This compound was cou-
pled to deprotected commercially available N-Fmoc–Phe–Wang
Department of Chemistry, University of Turku, Turku, FIN-20014, Finland
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Scheme 2
resin using O-(benzotriazol-1-yl)-N,N,Nꢀ,Nꢀ-tetramethyluronium
tetrafluoroborate (TBTU) in the presence of N,N-diisopro-
pylethylamine (DIEA) as an activator (Scheme 2). Two equivalents
of the acid component and three hours reaction time gave 6 in a
70% yield, according to the 4-monomethoxytrityl cation assay. A
separate capping step was not introduced to protect the unreacted
amino groups, since they reacted with bromomalonaldehyde21
in the next step and were most likely converted to (2-bromo-3-
oxopropenyl)amino groups.
Bromomalonaldehyde is known to react with pyrimidine and
purine bases, yielding a variety of products16d,22,23 in aqueous so-
lutions. Adenosine and 9-methyladenine, for example, give the re-
spective 3H-imidazo[2,1-i]purine and 3H-imidazo[2,1-i]purine-7-
carbaldehyde derivatives.22 Both have been suggested to be formed
through a common intermediate, viz. an acyclic carbinolamine
that still contains the halogen substituent. This intermediate may
undergo cyclization by displacement of the halogen substituent
by the adenine N1 atom, or hydrolytic deformylation may take
place prior to the cyclization and, hence, a 7-unsubstituted ring-
system is obtained. In both cases, elimination of water from the
cyclic carbinolamine intermediate obtained then leads to the 3H-
imidazo[2,1-i]purine ring system, bearing either a formyl group
or a hydrogen atom at C7. These two derivatives are obtained in
an approximately equimolar ratio when the pH is below 3.5. At
higher pH, the unsubstituted derivative predominates.
with 2ꢀ-deoxyadenosine gives the 7-formyl derivative in DMF
at room temperature in modest 19% yield. Under similar con-
ditions, an even lower yield may be expected on polystyrene.
Elevated temperature and an appropriate buffer system, how-
ever, dramatically alter the situation. As seen from Table 1, a
somewhat acidic buffer system is needed to drive the forma-
tion of 3H-imidazo[2,1-i]purine-7-carbaldehyde to completion.
Triethylammonium acetate buffer25 gave only a 14% conver-
sion of 6 to solid-supported N-[(7-formylimidazo[2,1-i]purin-3-
yl)acetyl]phenylalanine (7) with five equivalents of bromomalon-
aldehyde in 330 min (entry 1). Triethylammonium formate buffer
(entries 2 and 3) was more efficient, but the yield was still lower
than that obtained in the absence of any buffer constituents (entries
4–6). When triethylamine was replaced with a weaker base, viz. 2,6-
lutidine, a good yield was obtained (entries 7–10). The reaction rate
Table 1 Effect of buffer on the solid-supported synthesis of N-[(7-
formylimidazo[2,1-i]purin-3-yl)acetyl]phenylalanine (7) on Wang resin in
DMF (see Scheme 1)
Entry
Buffer
Equiv.a
t/min
Yield
1
2
Acetic acid–triethylamine
Formic acid–triethylamine
Formic acid–triethylamine
—
—
—
Formic acid–2,6-lutidine
Formic acid–2,6-lutidine
Formic acid–2,6-lutidine
Formic acid–2,6-lutidine
10/10
10/10
28/10
—
—
—
50/10
30/10
10/10
30/10
330
330
270
65
180
360
65
180
270
360
14%
35%
39%
51%
55%
62%
54%
87%
92%
93%
3
4
5
On the basis of the preceding results, water was considered to
be a suboptimal solvent for the fabrication of 3H-imidazo[2,1-
i]purine-7-carbaldehydes. Fortunately, anhydrous DMF turned
out to allow almost quantitative conversion of adenine to this
product, when the reaction was carried out on a polystyrene solid
support at somewhat elevated temperature (60 ◦C). According
to a previous report,24 the reaction of bromomalonaldehyde
6
7
8
6
10
a Compared to the amount of 6. 5 equiv. of bromomalonaldehyde was
used. T = 60 ◦C.
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was rather insensitive to the ratio of the concentrations of formic
acid and 2,6-lutidine. For the synthesis of 7, indicated in Scheme 2,
a 1 : 1 ratio was used.
The conditions described above were then applied to the
synthesis of a library of substituted (imidazo[2,1-i]purin-7-
yl)methylamines, as outlined in Scheme 1. This approach makes
use of the facile acid-catalyzed depurination of purine 2ꢀ-
deoxyribonucleosides as a release method from the solid-support.
The method is mild; the products can be cleaved from the support
with 5% trifluoroacetic acid in dichloromethane in one hour, i.e.
under conditions that t-butyl ester protections largely tolerate.
The N-glycosidic bond nevertheless withstands the formic acid
treatments involved in generation of the additional imidazole ring
and subsequent reductive amination of the formyl group.
Aminomethylpolystyrene was first acylated with (4-methoxy-
trityloxy)butyric acid in DMF using diisopropylcarbodiimide
(DIC) and 1-hydroxybenzotriazole (HOBt) as activators. The
trityl protection was then removed and a N6-benzoyl-5ꢀ-O-
(4,4ꢀ-dimethoxytrityl)-2ꢀ-deoxyadenosine 3ꢀ-(2-cyanoethyl-N,N-
diisopropylphosphoramidite) building block was coupled to the
exposed hydroxy functions by 4,5-dicyanoimidazole activation
and oxidized to a phosphate triester (1) with aqueous iodine
(Scheme 1). All the protecting groups were then removed, the 4,4ꢀ-
dimethoxytrityl group acidolytically and the N-benzoyl and O-
(2-cyanoethyl) protections by treatment with aqueous alkali. The
exposed 5ꢀ-hydroxy and phosphodiester groups did not hamper
the subsequent reactions. Treatment of the deprotected support-
bound 2ꢀ-deoxyadenosine with bromomalonaldehyde under the
conditions described in the foregoing gave the desired support-
bound 3-(2ꢀ-deoxy-b-D-erythro-pentofuranosyl)-3H-imidazo[2,1-
i]purine-7-carbaldeyde (2) in an almost quantitative yield, as seen
from the HPLC traces of the acidolytically released crude product
(Fig. 2).
Reductive amination of the support-bound 3H-imidazo[2,1-
i]purine-7-carbaldehyde (7) was sluggish when acetic acid was used
as a catalyst. With ten equivalents of benzylamine and sodium
cyanoborohydride in DMF acidified with 4% acetic acid, 30%
of the starting material remained unreacted after 24 hours. On
using formic acid, the amination was complete in 5 hours. No
reduction of the formyl group26,27 to a hydroxymethyl function
was detected under these conditions. This was the case even
when amination with a sterically hindered amine was attempted:
all the aldehyde remained unchanged after 4 hours treatment.
The source of the hydride ion markedly influenced the reaction
rate. Under similar reaction conditions, 6.7 equiv. of sodium
cyanoborohydride (20 equiv. of hydride ions) gave 2.4 times as
high yield as 8 equiv. of sodium triacetoxyborohydride (8 equiv. of
hydride ions). Sodium cyanoborohydride in a mixture of MeOH
and DMF was, hence, used for the syntheses. Although 10 equiv.
of benzylamine and a short 30 minutes reaction time for imine
formation prior to sodium cyanoborohydride addition was used,
about 6% of dialkylated product was formed.
Acetylation of the solid-supported N-benzyl(imidazo[2,1-
i]purin-7-yl)methylamine group was performed with acetic an-
hydride in dichloromethane. Acidolytic release from the support
yielded N-{[7-(N-benzylacetamidomethyl)imidazo[2,1-i]purin-3-
yl]acetyl}phenylalanine (8). Fig. 1 shows the HPLC trace of the
crude product.
Fig. 2 HPLC trace of crude 3H-imidazo[2,1-i]purine-7-carbaldehyde
cleaved from the resin (RP HPLC, 0–100% MeCN, 0.1% TFA, k = 220 nm).
Reductive amination of 2 was attempted with a set of ten
amines under the conditions optimized with 7 (Scheme 3). It was
observed that after the one hour imine formation and subsequent
four hours reduction step, aniline (entry 4a) had reacted quantita-
tively, unhindered primary amines (entries 4b–d) had produced
84–92% product, while sterically hindered primary amines, t-
butylamine and tris(hydroxymethyl)aminomethane (entries 4e,f),
gave only a 35% yield. Among secondary amines, diethylamine
and diisopropylamine (entries 4g,h) did not react. By contrast,
Fig. 1 HPLC trace of crude N-{[7-(N-benzylacetamidomethyl)imidazo-
[2,1-i]purin-3-yl]acetyl}phenylalanine (8) (RP HPLC, 0–100% MeCN,
0.1% TFA, k = 220 nm).
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Scheme 3
piperidine (entry 4i) reacted smoothly, giving a 73% yield. It
was, hence, concluded that the method is suitable for unhindered
amines but sterically more demanding amines give lower or non-
existent yields. Benzylamine (entry 4b) and t-butyl glycine acetate
(entry 4d) both gave, additionally, 4% of dialkylated products.
Support 2 was finally subjected to consecutive reductive ami-
nation and alkylation to obtain 4-aminobutyric acid derivatives
4l–n and to reductive amination followed by acylation to ob-
tain derivatives 4o–q and N-benzyl-N-[(3H-imidazo[2,1-i]purin-7-
yl)methyl]acetamide (4r). The synthesis of 4r was performed as de-
scribed for 8, except that the reductive amination was repeated be-
fore the acylation. Reductive amination of 2 with 4-aminobutyric
acid t-butyl ester and 4-aminobutyric acid gave, besides the
expected 4j and 4k, 4–6% of dialkylated side products. In addition,
the reaction with 4-aminobutyric acid yielded 7% of a lac-
tamized product, obtained in all likelihood by cyanoborohydride
activation.28–30 The lactam formation was verified by HPLC by
spiking with 1-[(3H-imidazo[2,1-i]purin-7-yl)methyl]pyrrolidin-
2-one (4q), synthesized by 2-(1H-benzotriazol-1-yl)-1,1,3,3,-
tetramethyluronium hexafluorophosphate (HBTU)/DIEA medi-
ated cyclization of 4j, and by identical mass spectra of the side
product and 4q. Lactamization of 4j was also achieved by acetic
anhydride treatment. The latter method is of minor practical value,
owing to concomitant formation of 21% of acetylated product 4o.
Reductive alkylations leading to compounds 4l–n were per-
formed under similar conditions as the reductive aminations
discussed above. For all the alkylations, three hours reaction
time was sufficient when ten equivalents of aldehyde were used.
Acylation of 4k was tested with acetic anhydride (4o) and Fmoc
protected glycine by TBTU/DIEA activation (4p). As expected, 4k
was fully acetylated in one hour under the conditions employed.
Coupling of Fmoc glycine by using an active ester method was
also completed in 1 hour. By contrast, 65% of the starting
material remained unchanged after the same reaction time when a
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symmetrical anhydride preformed in a 1 : 9 mixture of DMF and
CH2Cl2 was used for the coupling in the same solvent (data not
presented).
Optimization of the formation of N-[(7-formylimidazo[2,1-i]-
purin-3-yl)acetyl]phenylalanine on Wang resin. Resin 6 (5 mg)
was preswollen in DMF (20 lL). Bromomalonaldehyde, formic
or acetic acid, triethylamine or 2,6-lutidine from freshly prepared
stock solutions were added in quantities indicated in Table 1 and
the volume of the reaction mixture was filled up to 50 lL with
DMF. The mixture was agitated at 60 ◦C for a chosen time, after
which the resin was washed with DMF, CH2Cl2, MeOH, CH2Cl2,
and MeOH, and dried in a vacuum desiccator. Reaction products
were cleaved from the solid support and assayed by RP HPLC as
described in general remarks.
In summary, a solid-supported synthesis for N,N-disubstituted
(3H-imidazo[2,1-i]purin-7-yl)methylamines has been developed.
Commercially available 2ꢀ-deoxyadenosine phosphoramidite
reagent immobilized by conventional phosphitylation to a
hydroxy-functionalized support may be used as a traceless
acid-labile linker. Alternatively, [N6-(4-methoxytrityl)adenin-9-
yl]acetic acid may be immobilized by acylation to commercially
available amino acid derivatized Wang resins to obtain the N,N-
disubstituted (3H-imidazo[2,1-i]purin-7-yl)methylamines as N3-
linked amino acid (or peptide) derivatives.
Solid supported N-[(7-formylimidazo[2,1-i]purin-3-yl)acetyl]-
phenylalanine (7). Formic acid (57 lL, 1.5 mmol), 2,6-
lutidine (175 lL, 1.5 mmol) and bromomalonaldehyde (113 mg,
0.75 mmol) were dissolved in 1.27 mL DMF. The solution was
added onto 6 (150 mg, 0.105 mmol). The mixture was stirred at
Experimental
◦
General Remarks
60 C for 4 h. The resin was washed with DMF, MeOH, DMF,
CH2Cl2, 10% MeOH in CH2Cl2 and MeOH. 1H NMR (500 MHz,
The chemical shifts are given in ppm downfield from internal
(CH3)4Si. Appropriate 2D NMR methods, e.g. HMBC, HSQC
and COSY, were used for peak assignment. RP HPLC analyses
and separations were performed on a Hypersil HyPurity Elite
C18 (150 × 4.6 mm, 5 lm) and Hypersil ODS column (250 ×
10 mm, 5 lm), respectively, applying a linear gradient from 0.1%
aq. TFA to MeCN in 30 min at a flow rate of 1.0 mL min−1
(Hypurity column) or 3.0 mL min−1 (ODS column). The detection
wavelength was 220 nm.
Solvents and reagents were dried or tested for dryness before
use. Unless otherwise indicated, analytical samples and products
were cleaved from the resin by shaking in 1 : 1 TFA–DCM mixture
for 1 hour. Resin was filtered by suction, rinsed successively with
CH2Cl2 (1 mL) and MeOH (1 mL), and the solvents were removed
under reduced pressure (rotary evaporation). Yields for products
4a–r were calculated from HPLC chromatograms of filtrates.
HPLC fractions containing purified products were evaporated
to dryness on a centrifugal concentrator. Trityl protections were
removed by washing the resin with 3% dichloroacetic acid and
3% MeOH in CH2Cl2 until no colour evolved when rinsed with
3% dichloroacetic acid in CH2Cl2. The deprotected resin was
subjected to successive washings with CH2Cl2, CH2Cl2/MeOH,
10% pyridine in CH2Cl2, CH2Cl2, CH2Cl2–MeOH and MeOH
and dried in a vacuum desiccator.
(CD3)2SO) for the product cleaved from the resin: d = 2.92 (dd,
3
2
2J = 13.8 Hz, JHa,HbA = 5.1 Hz, 1 H, Hb,PheA), 3.08 (dd, J =
3
3
13.8 Hz, JHa,HbB = 8.8 Hz, 1 H, Hb,PheB), 4.47 (ddd, JHa,HbA
=
3
3
5.1 Hz, JHa,HbB = 8.8 Hz, JHa,NH = 8.0 Hz, 1 H, Ha,Phe), 5.01
2
2
(d, J = 16.7 Hz, 1 H, CH2,ACO), 5.14 (d, J = 16.7 Hz, 1 H,
CH2,BCO), 7.19–7.29 (m, 5 H, ArPhe), 8.43 (s, 1 H, H 2ꢀ), 8.60 (s,
1 H, H 8ꢀ), 8.78 (d, JHa,NH = 8.0 Hz, 1 H, NH), 9.88 (s, 1 H, H
3
5ꢀ), 10.01 (s, 1 H, CHO) ppm; 13C NMR (125 MHz, (CD3)2SO):
d = 36.75 (CH2Phe), 45.73 (CH2Ac), 53.80 (CHPhe), 122.08 (C9b),
124.68 (C7), 126.51 (C4Phe), 128.24 (C3Phe), 129.20 (C2Phe), 136.47
(C5), 137.23 (C1Phe), 142.01 (C3a), 144.79 (C2), 144.96 (C9a),
147.99 (C8), 165.92 (CONH), 172.49 (CO2H), 179.12 (CHO) ppm.
HRMS (EI+) calcd for C19H16N6O4 392.1233; found 392.1233.
N -{[7-(N -benzylacetamidomethyl)imidazo[2,1-i]purin-3-yl]-
acetyl}phenylalanine (8). Benzylamine (35.2 lL, 323 lmol) and
formic acid (20 ll) dissolved in DMF (215 lL) were added on
resin 7 (46 mg, 32.3 lmol). After 30 min shaking, 85% NaCNBH3
(19.1 mg, 258 lmol) in a mixture of DMF (200 lL) and MeOH
(30 lL) was added and the reaction mixture was shaken for
additional 5 h. The support was washed with DMF, 10% MeOH in
DMF, H2O, MeOH, CH2Cl2, 10% MeOH in CH2Cl2 and MeOH
and dried in vacuum desiccator. The resin was shaken in 20% acetic
anhydride in CH2Cl2 (1 mL) for 1 h and washed with CH2Cl2, 10%
Py in CH2Cl2, CH2Cl2, 10% MeOH in CH2Cl2 and MeOH. Release
from the resin and HPLC purification of the product, as described
above, gave 8 (7.2 mg, 42%, overall yield 29%). The product
exhibited NMR signals as two conformers in 4 : 1 ratio. Only the
major conformer is assigned here. 1H NMR (500 MHz, (CD3)2SO):
d = 2.12 (s, 3 H, CH3CO), 2.94 (dd, 2J = 13.8 Hz, 3JHa,HbA = 8.8 Hz,
1H, Hb,PheA), 3.08(dd, 2J =13.8Hz, 3JHa,HbB =4.9Hz, 1H, Hb,PheB),
4.48 (ddd, 3JHa,HbB = 4.9 Hz, 3JHa,HbA = 8.8 Hz, 3JHa,NH = 7.9 Hz, 1 H,
N-[(Adenin-9-yl)acetyl]phenylalanine–Wang resin (6). Com-
mercial Na-Fmoc-Phe–Wang polystyrene resin (0.15 g,
1.0 mmol g−1) was deprotected by 20 min treatment with 20%
piperidine in DMF. The resin was washed successively with DMF,
CH2Cl2, 10% MeOH in CH2Cl2 and MeOH, and dried in vacuum.
The pyridine salt of [N6-(4-methoxytrityl)adenin-9-yl]acetic acid
(163 mg, 0.30 mmol), TBTU (96.3 mg, 0.30 mmol) and DIEA
(0.10 mL, 0.60 mmol) were dissolved in DMF (1.40 mL). The
solution was added onto Phe–Wang resin and the reaction mixture
was shaken for 3 h. The resin was subsequently washed with
DMF, CH2Cl2, 10% MeOH in CH2Cl2 and MeOH. According
to the 4-methoxytrityl cation assay, the loading of the resin was
70% of the theoretical value. Removal of the 4-methoxytrityl
protection yielded 6. HRMS (FAB+) for the product cleaved
from the resin: calcd for [MH+] C16H17N6O3 341.1362; found
341.1363.
H
a,Phe), 4.59 (s, 2 H, CH2,Bn), 4.99 (d, 2J = 15.8 Hz, 1 H, CH2,AIm),
5.03 (d, 2J = 15.8 Hz, 1 H, CH2,BIm), 5.10 (d, 2J = 16.8 Hz, 1 H,
2
CH2,ACO), 5.16 (d, J = 16.8 Hz, 1 H, CH2,BCO), 7.12–7.33 (m,
10 H, ArPhe, ArBn), 7.92 (s, 1 H, H8), 8.50 (s, 1 H, H2), 8.87 (d,
3JHa,NH = 7.9 Hz, 1 H, NH), 9.40 (s, 1 H, H5), 12.88 (s, 1 H, CO2H)
ppm; 13C NMR (125 MHz, (CD3)2SO): d = 22.52 (CH3,Ac), 36.79
(CH2Phe), 37.70 (CH2Im), 45.78 (CH2Pur), 50.49 (CH2,Bn), 53.83
(CHPhe), 119.07 (C9b), 122.12 (C7), 125.37 (C8), 126.42 (C2Bn),
126.58 (C4Phe), 127.33 (C4Bn), 128.31 (C3Phe), 128.74 (C3Bn), 129.23
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(C2Phe), 135.95 (C5), 136.93 (C1Bn), 137.21 (C1Phe), 138.50 (C9a),
142.00 (C3a), 145.23 (C2), 165.92 (CONHPhe), 171.47 (CONHBn),
172.48 (CO2H) ppm. HRMS (FAB+) calcd for [MH+] C28H28N7O4
526.2203; found 526.2201.
N -Benzyl-(3H-imidazo[2,1-i]purin-7-yl)methylamine
(4b).
Yield 84%. HRMS (EI+) calcd for C15H14N6 278.1278; found
278.1278.
N -Propyl-(3H-imidazo[2,1-i]purin-7-yl)methylamine
(4c).
Yield 92%. HRMS (EI+) calcd for C11H14N6 230.1280; found
230.1280.
4-(4-Methoxytrityloxy)butyramidomethyl polystyrene. Sodium
(4-methoxytrityloxy)butyrate (0.941 g, 2.5 mmol), diisopropyl-
carbodiimide (0.392 mL, 2.5 mmol) and 1-hydroxybenzotriazole
hydrate (0.384 g, 2.5 mmol) were dissolved in DMF (21 mL)
and added on a preswollen aminomethyl polystyrene resin (2.5 g,
0.5 mmol g−1). After 5 h of shaking, the resin was washed
successively with DMF, CH2Cl2, 10% MeOH in CH2Cl2 and
MeOH. According to the monomethoxytrityl cation assay, the
loading of the resin was 0.40 mmol g−1.
tert-Butyl {[(3H-imidazo[2,1-i]purin-7-yl)methyl]amino}acetate
(4d). 91% of tert-butyl protections were removed under the
cleavage conditions employed. The combined yield of the tert-
butyl ester and free acid was 90%. HRMS (ESI+) calcd for
[MH+] C14H19N6O2 303.1564; found 303.1560 and for C10H11N6O2
247.0938; found 247.0938.
N-tert-Butyl-(3H-imidazo[2,1-i]purin-7-yl)methylamine
(4e).
Solid-supported 3-(3ꢀ-O-phosphono-2ꢀ-deoxy-b-D-erythro-pento-
furanosyl)imidazo[2,1-i]purine-7-carbaldehyde (2). 4,5-Dicyano-
imidazole (0.738 g, 6.25 mmol) and N6-benzoyl-5ꢀ-O-(4,4ꢀ-
dimethoxytrityl)-2ꢀ-deoxyadenosine 3ꢀ-(2-cyanoethyl-N,N-diiso-
propylphosphoramidite (5.36 g, 6.25 mmol) were dissolved in
THF (25 mL). The solution was added onto detritylated and
preswollen 4-(4-methoxytrityloxy)butyramidomethyl polystyrene.
The mixture was shaken for 1 h, washed with THF and subjected
to 20 min oxidation with 0.1 mol L−1 iodine in pyridine containing
2% water. The resin was rinsed with pyridine, 5% water in
pyridine, pyridine, CH2Cl2, CH2Cl2–MeOH and MeOH and dried.
According to the dimethoxytrityl cation assay, the loading of the
resin was 0.360 mmol g−1. The DMTr protection was removed
as described earlier. The base labile N6-benzoyl and OP-(2-
cyanoethyl) protections were removed by refluxing the resin for
4 h in THF (36 mL) containing 1 mol L−1 aqueous NaOH (4 mL).
The resin was rinsed with THF, water, THF–water, THF, CH2Cl2
and MeOH, after which it was dried, giving solid-supported 2ꢀ-
deoxyadenosine 3ꢀ-phosphate (1).
Yield 36%. HRMS (EI+) calcd for C11H14N6 244.1436; found
244.1439.
2-(Hydroxymethyl)-2-{[(3H-imidazo[2,1-i]purin-7-yl)methyl]-
amino}propane-1,3-diol (4f). Yield 35%. HRMS (ESI+) calcd for
[MH+] C12H17N6O3 293.1357; found 293.1352.
7-[(Piperidin-1-yl)methyl]-3H-imidazo[2,1-i]purine (4i). Yield
73%. HRMS (FAB+) calcd for [MH+] C13H17N6 257.1515; found
230.1524.
N-[(3H-Imidazo[2,1-i]purin-7-yl)methyl]-4-aminobutanoic acid
(4j). 4-Aminobutyric acid (41.2 mg, 0.40 mmol) was suspended
in a mixture of formic acid (60 ll), MeOH (90 ll), and DMF
(1.35 mL). The suspension was added onto resin 2 (150 mg,
50 lmol) and the mixture was shaken 30 min before adding 85%
NaCNBH3 (25.1 mg, 0.34 mmol). After 5 h 30 min shaking, the
resin was washed with DMF, MeOH, 10% MeOH in DMF, DCM,
10% MeOH in DCM and MeOH. Yield 88%. HRMS (ESI+) calcd
for [MH+] C12H15N6O2 275.1251; found 275.1257.
Formic acid (2.83 mL, 75 mmol), 2,6-lutidine (2.91 mL,
25 mmol) and bromomalonaldehyde (1.89 g, 12.5 mmol) were dis-
solved in 19.3 mL DMF. The solution was added onto preswollen
1. The mixture was stirred at 60 ◦C for 3.5 h. The resin was
washed with DMF, CH2Cl2, pyridine, 10% MeOH in CH2Cl2 and
MeOH. According HPLC analysis of a cleaved sample, conversion
of the starting material to the solid-supported 3H-imidazo[2,1-
i]purine-7-carbaldehyde had not taken place quantitatively and,
hence, the reaction was repeated using halved amounts of reagents.
1H NMR (500 MHz, D2O) for 7-formyl-3H-imidazo[2,1-i]purine
released from the support: d = 8.45 (s, 1 H, H2), 8.52 (s, 1 H, H8),
9.93 (s, 1 H, CHO), 10.01 (s, 1 H, H5). HRMS (EI+) calcd for
C8H5N5O 187.0494; found 187.0499.
tert-Butyl N-[(3H-imidazo[2,1-i]purin-7-yl)methyl]-4-amino-
butanoate (4k). The synthesis was performed as described for
4j, except that tert-butyl 4-aminobutanoate (79.6 mg, 0.50 mmol)
was used instead of 4-aminobutyric acid. Analytical sample was
cleaved from the resin by shaking in 5% TFA in DCM for
1 hour. The resin was filtered by suction and rinsed successively
with CH2Cl2 (1 mL) and MeOH (1 mL). The filtrate was
neutralized with pyridine and solvents were evaporated under
reduced pressure. Yield 91%. HRMS (EI+) calcd for C16H22N6O2
330.1804; found 330.1801.
N-Ethyl-N-[(3H-imidazo[2,1-i]purin-7-yl)methyl]-4-aminobuta-
noic acid (4l). Acetaldehyde (4.0 mg, 91 lmol), 85% NaCNBH3
(6.7 mg, 91 lmol), formic acid (12 ll), MeOH (30 ll) and DMF
(260 ll) were mixed and added onto solid-supported 4j (30 mg,
9 lmol). The reaction mixture was shaken for 3 h and then washed
with CH2Cl2, 10% MeOH in DMF, MeOH, CH2Cl2, 10% MeOH
in CH2Cl2 and MeOH. Yield 74%. 1H NMR (500 MHz, D2O): d =
Synthesis of N-alkyl-(3H-imidazo[2,1-i]purin-7-yl)methylamines
(4a–i). An appropriate primary or secondary amine (16.7 lmol)
and formic acid (2.0 lL, 52 lmol) dissolved in DMF (25 lL) were
added on support 2. After 1 h imine formation, 85% NaCNBH3
(0.84 mg, 11 lmol) dissolved in DMF (20 lL) and MeOH (3 lL)
were added and the reaction mixture was shaken for additional
4 h. Solid support was washed with DMF, 10% MeOH in DMF,
H2O, MeOH, DCM, 10% MeOH in DCM and MeOH.
1.40 (t, 3JH1
= 7.3 Hz, 3 H, CH3,Et), 2.07 (m, 2 H, H3), 2.50 (t,
ꢀꢀ
ꢀꢀ
,H2
JH2,H3 = 6.9 Hz, 2 H, H2), 3.34 (m, 2 H, H4), 3.40 (q, 3JH1
=
3
ꢀꢀ
ꢀꢀ
,H2
7.3 Hz, 2 H, CH2,Et), 4.99 (s, 2 H, CH2Im), 8.04 (s, 1 H, H8ꢀ), 8.48
(s, 1 H, H2ꢀ), 9.31 (s, 1 H, H5ꢀ). HRMS (FAB+) calcd for [MH+]
C14H19N6O2 303.1569; found 303.1564.
N -Phenyl-(3H-imidazo[2,1-i]purin-7-yl)methylamine
(4a).
Yield 100%. HRMS (EI+) calcd for C14H12N6 264.1123; found
264.1121.
N-(2-Hydroxyethyl)-N-[(3H-imidazo[2,1-i]purin-7-yl)methyl]-
4-aminobutanoic acid (4m). The synthesis was performed as
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Org. Biomol. Chem., 2006, 4, 4506–4513 | 4511
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described for 4l, except that glycolaldehyde dimer (10.8 mg,
90 lmol) was used instead of acetaldehyde. Yield 80%. 1H NMR
(500 MHz, D2O): d = 2.11 (m, 2 H, H3), 2.51 (t, 3JH2,H3 = 6.8 Hz,
0.32 mmol) dissolved in DMF (275 lL) were added onto 2
(30 mg, 10 lmol). After 30 min shaking, 85% NaCNBH3 (6.3 mg,
85 lmol) was added to the reaction mixture and the shaking was
continued for 4 h 30 min. The resin was washed with DMF, 10%
MeOH in DMF, MeOH, CH2Cl2, 10% MeOH in CH2Cl2 and
MeOH. The reaction was repeated and the resin was dried in a
vacuum desiccator. The resin was shaken in 20% acetic anhydride
in CH2Cl2 (1 mL) for 1 h and washed with CH2Cl2, 10% Py in
CH2Cl2, DCM, 10% MeOH in CH2Cl2 and MeOH. Yield 79%.
1H NMR (500 MHz, 10% CD3OD, CDCl3): d = 2.28 (s, 3 H,
CH3CO), 4.54 (s, 2 H, CH2,Bn), 5.05 (s, 2 H, CH2Im), 7.16 (m, 2 H,
HBn2), 7.35–7.38 (m, 3 H, HBn3, HBn4), 7.51 (s, 1 H, H8), 8.33 (s,
1 H, H2), 9.40 (s, 1 H, H5). HRMS (EI+) calcd for C17H16N6O1
320.1386; found 320.1389.
3
3
ꢀꢀ
ꢀꢀ
2 H, H2), 3.40 (t, JH3,H4 = 8.1 Hz, 2 H, H4), 3.53 (t, JH1
=
,H2
3
ꢀꢀ
ꢀꢀ
5.1 Hz, 2 H, CH2NEt), 4.04 (t, JH1
= 5.1 Hz, 2 H, CH2OEt),
,H2
5.09 (s, 2 H, CH2Im), 8.10 (s, 1 H, H8ꢀ), 8.51 (s, 1 H, H2ꢀ), 9.37 (s,
1 H, H5ꢀ). HRMS (FAB+) calcd for [MH+] C14H19N6O3 319.1519;
found 319.1507.
N-(Carboxymethyl)-N-[(3H-imidazo[2,1-i]purin-7-yl)methyl]-
4-aminobutanoic acid (4n). The synthesis was performed as
described for 4l, except that glyoxylic acid monohydrate (8.3 mg,
90 lmol) was used instead of acetaldehyde. Yield 80%. 1H NMR
(500 MHz, D2O): d = 2.23 (m, 2 H, H3), 2.67 (t, 3JH2,H3 = 6.8 Hz,
2 H, H2), 3.52 (t, 3JH3,H4 = 7.9 Hz, 2 H, H4), 4.08 (s, 2 H, CH2CO),
5.15 (s, 2 H, CH2Im), 8.26 (s, 1 H, H8ꢀ), 8.71 (s, 1 H, H2ꢀ), 9.78 (s,
1 H, H5ꢀ). HRMS (FAB+) calcd for [MH+] C14H17N6O4 333.1311;
found 333.1322.
Acknowledgements
This project was financed by TEKES (The National Technology
Agency).
N -Acetyl-N -[(3H-imidazo[2,1-i]purin-7-yl)methyl]-4-amino-
butanoic acid (4o). Solid-supported 4k (30 mg, 9 lmol) was
flushed 1 h with freshly prepared solution of acetic anhydride
(100 ll), 2,6-lutidine (100 ll), and N-methylimidazole (160 ll)
in THF (1.64 mL). The resin was washed with THF, CH2Cl2, 5%
AcOH in CH2Cl2, 10% MeOH in CH2Cl2 and MeOH. The product
was cleaved from the solid support and purified as 4l. Yield 91%.
1H NMR (500 MHz, D2O): d = 1.91 (m, 2 H, H3), 2.23 (s, 3 H,
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CH3CO), 2.41 (t, JH2,H3 = 7.1 Hz, 2 H, H2), 3.45 (t, JH3,H4
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1
from the solid support and purified as 4l. Yield 60%. H NMR
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3
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This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 4506–4513 | 4513
©