Synthesis of 7-substituted 3-β-d-ribofuranosyl-3h-imidazo[2,1-i] purines

Article abstract of DOI:10.1135/cccc2011069

A method for the synthesis of 7-substituted 3-β-D-ribofuranosyl-3H- imidazo[2,1-i]purines has been devised whereby compounds were prepared in a few steps from a common intermediate, 3-(2′,3′-O-isopropylidene-β- D-ribofuranosyl)-3H-imidazo[2,1-i]purine-7-c

Full text of DOI:10.1135/cccc2011069

Derivatives of Ethenoadenosine
1043
SYNTHESIS OF 7-SUBSTITUTED
3-β-D-RIBOFURANOSYL-3H-IMIDAZO[2,1-i]PURINES
1,
2
3
Tuomas KARSKELA *, Karel D. KLIKA and Harri LÖNNBERG
Department of Chemistry, University of Turku, Vatselankatu 2, FIN-20014 Turku, Finland;
1
2
3
e-mail: tuokarsk@utu.fi, klikakd@yahoo.co.uk, harlon@utu.fi
Received April 8, 2011
Accepted May 2, 2011
Published online July 21, 2011
Dedicated to Professor Antonín Holý on the occasion of his 75th birthday in recognition of his
outstanding contributions to the area of nucleic acid chemistry.
A method for the synthesis of 7-substituted 3-β-D-ribofuranosyl-3H-imidazo[2,1-i]purines has
been devised whereby compounds were prepared in a few steps from a common intermedi-
ate, 3-(2′,3′-O-isopropylidene-β-D-ribofuranosyl)-3H-imidazo[2,1-i]purine-7-carbaldehyde, ob-
tained from the reaction of 2′,3′-O-isopropylideneadenosine with bromomalonaldehyde. The
formyl group of the carbaldehyde was subsequently reductively aminated and the resulting
secondary amines were then further derivatized either by acylation, lactamization or re-
ductive alkylation.
Keywords: Nucleosides; Heterocycles; Purine bases; NMR spectroscopy.
Purine nucleosides and their congeners have found applications in medici-
nal research as antivirals1,2, antiprotozoal agents3, adenosine receptor
agonists4–6, adenosine kinase inhibitors7,8 and in the treatment of lym-
phoid malignancies9–12 and systemic mastocytosis13, just to name a few ex-
amples. Although the structural analogs of purine nucleosides have for this
reason been the subject of extensive synthetic studies, there is still room for
further modifications. We now report on the preparation of 7-substituted
3-(β-D-ribofuranosyl)-3H-imidazo[2,1-i]purines to expand the structural di-
versity of purine-derived compounds. The rationale for the preparation of
these compounds is that whilst the structures closely resemble adenosine,
the nitrogen atoms analogous to the N6 and N-1 atoms in adenosine are
blocked. These moieties of adenosine are usually engaged in H-bonding
with the target protein. It is hoped that this blocking will lead to improved
selectivity, since it is expected that only a limited number of potential tar-
gets are able to bind these compounds efficiently as ligands.
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 1043–1054
© 2011 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2011069

1044
Karskela, Klika, Lönnberg:
As an extension of our previous studies on solid-supported derivatization
of 3-substituted 3H-imidazo[2,1-i]purine-7-carbaldehydes14,15, a solution-
phase synthesis for related nucleoside analogs, 7-substituted 3-β-D-ribo-
furanosyl-3H-imidazo[2,1-i]purines, was developed. The compounds were
prepared in a few steps from a common intermediate, 3-(2′,3′-O-isopropyl-
idene-β-D-ribofuranosyl)-3H-imidazo[2,1-i]purine-7-carbaldehyde (2), ob-
tained by reacting 2′,3′-O-isopropylideneadenosine (1) with bromomalon-
aldehyde (Scheme 1). In this sequence, the formyl group was first re-
ductively aminated with piperidine (3a), morpholine (4a), benzylamine (5)
or tert-butyl 4-aminobutanoate (7). The resulting secondary amines (5 and
7) were then derivatized either by acetylation (6), lactamization (8) or re-
ductive alkylation (9) after which the isopropylidene protecting group was
removed.
H2N
N
N
N
O
N
N
HO
HO
N
N
i
N
N
O
O
O
O
1
O
O
2
6'
7'
ii
iv
N
N
iii
NR1
N
N
N
N
N
HO
HO
N
N
N
N
X
O
O
RO
RO
OR
OR
5: R = isopropylidene, R1 = H
6: R = H, R1 = Ac
3a: X = CH2, R = isopropylidene
3b: X = CH2, R = H
4a: X = O, R = isopropylidene
4b: X = O, R = H
v
v
vi,v
N
9"
O
N
HN
O
N
O
O
HO
N
N
8
O
5"
N
7
1"
9a
N
viii
N
3"
3"'
O
N
O
7
9b
5
1"'
2
HO
N
N
3a
O
4'
1'
vii,v
N
5"'
O
RO
OR
N
N
N
HO
N
9: R = isopropylidene
10: R = H
N
O
v
HO
OH
8
SCHEME 1
Conditions: i) BrCH(CHO)2, HCO2H, 2,6-lutidine, DMF; ii) piperidine (for 3a), morpholine (for
4a), NaBH(OAc)3, AcOH, DCE; iii) Cl– +H3N(CH2)3COOt-Bu, NaBH(OAc)3, DCE; iv) BnNH2,
NaCNBH3, AcOH, THF; v) FeCl3·6H2O, MeOH, DCM (for 3b), 0.1 M HCl (aq.)/ THF (for 4b, 6, 8
and 10); vi) 1. Ac2O, Pyridine 2. NaOMe, MeOH; vii) 1. 50% TFA/DCM, 2. HBTU, DIEA, DMF;
viii) PhCHO, ZnCl2, NaCNBH3, MeOH
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 1043–1054

Derivatives of Ethenoadenosine
1045
RESULTS AND DISCUSSION
Formylethenoadenosine
(3-β-D-ribofuranosyl-3H-imidazo[2,1-i]purine-
7-carbaldehyde)16 and its 2′-deoxy analog17 have been previously synthe-
sized by the reaction of bromomalonaldehyde with adenosine in aqueous
solution and 2′-deoxyadenosine in DMF, respectively. Both methods, how-
ever, only provided low yields of their respective product carbaldehydes. By
contrast, ethyl and tert-butyl 2-(7-formyl-3H-imidazo[2,1-i]purin-3-yl)ace-
tates have been obtained by solution-phase synthesis in good yields15 by
applying the anhydrous conditions previously14 optimized for solid-support
chemistry. However, the reaction of unprotected adenosine under similar
conditions produced only a thick dark product mixture that was difficult to
fractionate into pure products. Protection of the 2′ and 3′ hydroxyl groups
of the ribose moiety with an isopropylidene group to yield 2′,3′-O-iso-
propylideneadenosine (1) markedly improved the situation. This approach
thereby facilitated the production of the desired target compound, 3-(2′,3′-
O-isopropylidene-β-D-ribofuranosyl)-3H-imidazo[2,1-i]purine-7-carbaldehyde
(2), in 81% yield after analogous reaction followed by purification using
silica gel chromatography.
The conditions applied previously14 for the reductive amination of a
formyl group on a solid support were found to be too harsh to be used in
solution-phase synthesis. For example, treatment with sodium cyanoboro-
hydride in THF containing 1% formic acid was found to give a product
mixture where the reduced starting material was the main component (data
not presented). The replacement of formic acid with acetic acid reduced the
amount of this side product but still did not lead to a generally satisfactory
result. Only when using benzylamine as the nucleophile was the obtained
yield of the amination product 5 sufficiently acceptable. Sodium tri-
acetoxyborohydride in DCE was found to produce less byproducts and thus
it was used for the amination of 2 with piperidine, morpholine and tert-
butyl 4-aminobutanoate to obtain, respectively, compounds 3a, 4a and 7.
Of the secondary amines, 5 was subjected to acetylation and 7 to lac-
tamization and alkylation. Although the treatment of 5 with acetic anhy-
dride esterified the 5′-hydroxyl group in addition to the secondary nitrogen
atom, the 5′-O-acetyl group could be selectively removed by the application
of sodium hydride in methanol. Finally, acidolytic removal of the iso-
propylidene protection then yielded the desired nucleoside 6.
NMR spectroscopic examination of 6 revealed that it existed as two
interconverting conformations in solution as evidenced by the cross-signals
present in an EXSY spectrum between corresponding protons in the major
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 1043–1054

1046
Karskela, Klika, Lönnberg:
and minor species. Compound 6 contains an acetamide moiety and thus it
is expected to have restricted rotation about the amide bond. The structural
assignment of these conformers was based on quantum mechanical (QM)-
calculated energies and QM-predicted 13C NMR chemical shifts, both of
which indicated that the conformer having the carbonyl oxygen trans to
the benzyl group (conformer A, the major species) was preferred (∆G =
12 kJ mol–1) over the conformer with cis orientation (conformer B), see
Fig. 1.
Compound 7 was first converted to a carboxylic acid by TFA promoted
removal of the tert-butyl group under anhydrous conditions and the ex-
posed γ-aminobutyric acid moiety was then lactamized in dilute solution
using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-
phosphate (HBTU) as an activator and N,N-diisopropylethylamine as the
base. Finally, the isopropylidene protecting group was also removed to ob-
tain 8. Alternatively, compound 7 was also subjected to reductive
18
benzylation with benzaldehyde in DCE using zinc-modified NaCNBH3 as
the reducing agent. Of note, the reaction was found to be very slow using
either NaBH(OAc)3 or NaCNBH3 without zinc chloride addition and, fur-
thermore, the addition of acetic or formic acid instead brought about the
formation of acylated and lactamized side products19. The product (9) was
acidolytically deprotected to yield compound 10.
All the synthetic processes described above involved the removal of the
2′,3′-O-isopropylidene protection as the last step. Of note, this step, some-
what unexpectedly, was found to be a rather difficult one. Of the numerous
methods attempted, including 80% aqueous AcOH at 25 °C 20, I2/MeOH 21
,
FIG. 1
The trans (conformer A, left) and cis (conformer B, right) structures of compound 6 calculated
at the B3LYP/6-31G(d,p) level of theory. N.b. the ribose moiety was substituted by methyl to
expedite the modeling calculations
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 1043–1054

Derivatives of Ethenoadenosine
1047
PdCl2(CH3CN)2 22, CAN 23, CAN-SiO2 24, and hydrolysis at pH 2, many were
found to be too inefficient whilst harsher treatments such as 80% aqueous
AcOH at reflux20 or a 1:1 mixture of 1 M HCl (aq.) and THF 25, resulted in
side reactions such as depurination or even pyrimidine ring opening. The
best results were obtained using a 1:1 mixture of 0.1 M HCl (aq.) and THF at
55 °C or FeCl3·6H2O in a 1:19 mixture of MeOH and DCM at elevated tem-
perature26. The Brønsted acid-catalyzed reaction, however, was still accom-
panied by some depurination whilst the Lewis acid-catalyzed reaction,
though cleaner, was hampered by a more laborious work up that resulted
ultimately in reduced yields. The former method was therefore mainly used
since it was more convenient, faster and approximately equally yielding as
the latter.
In conclusion, a method to produce 7-substituted 3H-imidazo[2,1-i]-
purines on solid support was successfully adapted to solution chemistry
to produce 7-substituted 3-β-D-ribofuranosyl-3H-imidazo[2,1-i]purines. Be-
cause of the different nature of the reaction media, several modifications to
the reaction conditions were necessitated. In addition, the use of a protect-
ing group for the ribose ring of the starting material was required. Unfortu-
nately, the isopropylidene protection was more stable than expected which
reduced the yields of the acid labile end products. For further develop-
ments, it could be worthwhile to thus evaluate other protection strategies.
EXPERIMENTAL
Solvents and reagents were dried or tested for dryness before use when appropriate. The
purified products existed as transparent glassy solids after rotary evaporation except com-
pound 2 which was a white solid.
NMR spectra (δ, ppm; J, Hz), at 298.1 K (uncorrected) unless otherwise indicated, were
recorded on Bruker Avance spectrometers with field strengths of 14.1, 10.75 and 9.4 T. Gen-
eral NMR experimental details (e.g. standard gradient-selected COSY, HMBC and HSQC)
have been described elsewhere27. NMR samples in solvents as indicated consisted of dilute
samples (~5 mg in ca. 0.6 ml) up to concentrated samples (~50 mg in ca. 0.6 ml). 1H and
13C chemical shifts were referenced internally to the solvent peaks28 (DMSO: δH 2.50,
δC 39.52; MeOH: δH 3.31, δC 49.00 and HOD: δH 4.79) or to TMS in the case of CDCl3 solu-
tions (δ 0 for both 1H and 13C). 15N chemical shifts were referenced externally to 90%
nitromethane in CD3NO2 (δ 0). Assignment of the H-5′s 29 (proR and proS) and iso-
propylidene methyl 1H and 13C nuclei30 (endo and exo) were derived from literature. Direct
observations of the 15N nuclei were facilitated by the QDEPT pulse sequence adapted31 from
methodology32,33 developed for one-bond 1H–13C interactions. The method of cycling the
1H-selection pulse and the J-dependent interpulse delays, scaled accordingly to span the
range 24.1–4.7 Hz, was taken from Jiang33. In the case of dilute samples, indirect 15N obser-
vations were taken from HMBC spectra (appropriately only reported to one decimal place).
15N chemical shifts were in accordance with previous examinations27a,27b,34 with shielded
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 1043–1054

1048
Karskela, Klika, Lönnberg:
resonances for sp3-type nitrogens (N-3, N-6) and deshielded resonances for sp2-type nitro-
gens (N-1, N-4, N-9).
Geometry optimizations, frequency calculations and chemical shielding calculations using
GIAO were performed using the Gaussian09W program35 at the restricted B3LYP/6-31G(d,p)
level of theory for all calculations with inclusion of methanol as the solvent using the
IEF-PCM model.
A Bruker ESI-QTOF mass spectrometer was used for the measurement of high resolution
mass spectra.
3-(2,3-O-Isopropylidene-β-D-ribofuranosyl)-3H-imidazo[2,1-i]purine-7-carbaldehyde (2)
2′,3′-O-Isopropylideneadenosine (1; 0.50 g, 1.63 mmol) and bromomalonaldehyde (0.37 g,
2.44 mmol) were dissolved in a mixture of formic acid (0.19 ml, 5.01 mmol), 2,6-lutidine
(0.53 ml, 4.57 mmol) and dry DMF (9.3 ml). The reaction mixture was agitated in a
stoppered bottle at 60 °C for 6 h during which time the color of the mixture turned a dark
orange. The reaction was monitored by TLC (10% MeOH/CH2Cl2) and upon completion, the
volatiles were removed by a rotary evaporator and the residue taken up in DCM followed by
extraction with saturated NaHCO3. The organic phase was dried over Na2SO4 and then evap-
orated to dryness after filtration. The crude material was purified by silica gel column chro-
matography (5% MeOH in DCM) yielding 0.47 g (81%) of 2. Some batches contained minor
amounts of a fluorescent intensely orange-colored byproduct. The impurity was not charac-
terized. 1H NMR (500 MHz, DMSO-d6): 10.00 s, 1 H (H-1′′); 9.91 s, 1 H (H-5); 8.74 s, 1 H
(H-2); 8.58 s, 1 H (H-8); 6.33 d, 1 H, J = 2.6 (H-1′); 5.40 dd, 1 H, J = 6.2, 2.6 (H-2′); 5.12 br,
1 H (OH); 5.03 dd, 1 H, J = 6.2, 2.6 (H-3′); 4.29 dt, 1 H, J = 4.9, 2.6 (H-4′); 3.59 dd, 1 H, J =
–11.8, 4.9 (H-5′proS); 3.55 dd, 1 H, J = –11.8, 4.9 (H-5′proR); 1.56 s, 3 H (H-7′endo); 1.34 s, 3 H
(H-7′exo). 13C NMR (126 MHz, DMSO-d6): 179.17 (C-1′′), 147.83 (C-8), 144.71 (C-9a), 142.22
(C-2), 140.96 (C-3a), 136.76 (C-5), 124.72 (C-7), 122.99 (C-9b), 113.13 (C-6′), 90.12 (C-1′),
87.23 (C-4′), 84.07 (C-2′), 81.36 (C-3′), 61.44 (C-5′), 26.99 (C-7′endo), 25.15 (C-7′exo).
15N NMR (50 MHz, DMSO-d6): –204.00 (N-3), –184.15 (N-6), –145.62 (N-4), –142.61 (N-9),
+
–137.16 (N-1). HRMS: calculated for [M + H+] C16H18N5O5 360.1302 amu; found 360.1303 amu.
3-(2,3-O-Isopropylidene-β-D-ribofuranosyl)-7-(piperidin-1-ylmethyl)-
3H-imidazo[2,1-i]purine (3a)
Compound 2 (0.100 g, 0.278 mmol) was suspended in DCE (1 ml) to which piperidine
(30.2 µl, 0.306 mmol) and acetic acid (31.8 µl, 0.556 mmol) were added under magnetic stir-
ring. NaBH(OAc)3 (0.295 g, 1.39 mmol) in DCE (1 ml) was added to the reaction mixture in
three aliquots with reaction monitoring by TLC (10% H2O/MeCN). After ca. 24 h, the reac-
tion mixture was taken to dryness and the residue taken up twice with water and once with
MeOH with solvent removal effecting the co-evaporation of any residual acetic acid. The
crude material was purified by silica gel column chromatography (10% H2O in MeCN) yield-
ing 0.083 g (61%) of 3a as an acetate salt. 1H NMR (500 MHz, CDCl3): 9.25 s, 1 H (H-5);
8.48 s, 1 H (H-2); 7.47 s, 1 H (H-8); 6.33 d, 1 H, J = 2.9 (H-1′); 5.37 dd, 1 H, J = 6.2, 2.9
(H-2′); 5.08 dd, 1 H, J = 6.2, 2.8 (H-3′); 4.41–4.35 m, 1 H (H-4′); 3.99 s, 2 H (H-1′′); 3.79 dd,
1 H, J = –11.9, 4.1 (H-5′proS); 3.73 dd, 1 H, J = –11.9, 4.7 (H-5′proR); 2.55 s, 4 H (H-3′′); 1.94 s,
3 H (AcO–); 1.63 s, 3 H (H-7′endo); 1.62–1.54 m, 4 H (H-4′′); 1.54–1.42 m, 2 H (H-5′′); 1.40 s,
3 H (H-7′exo). 13C NMR (126 MHz, CDCl3): 178.96 (AcO–), 143.06 (C-9a), 141.93 (C-2),
139.83 (C-3a), 137.51 (C-5), 133.71 (C-8), 124.21 (C-9b), 122.18 (C-7), 115.33 (C-6′), 92.58
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 1043–1054

Derivatives of Ethenoadenosine
1049
(C-1′), 88.62 (C-4′), 86.03 (C-2′), 82.95 (C-3′), 63.34 (C-5′), 55.13 (C-3′′), 52.63 (C-1′′), 27.58
(C-7′endo), 26.66 (C-4′′), 25.55 (C-7′exo), 25.07 (C-5′′), 22.79 (AcO–). HRMS: calculated for [M +
+
H+] C21H29N6O4 429.2245 amu; found 429.2248 amu.
7-(Piperidin-1-ylmethyl)-3-β-D-ribofuranosyl-3H-imidazo[2,1-i]purine (3b)
Compound 3a (34.2 mg, 70.0 µmol), FeCl3·6H2O (37.8 mg, 0.140 mmol) and MeOH (50 µl)
in DCM (950 µl) were refluxed first for 7 h and then allowed to stand at room temperature
overnight. One eq. of FeCl3·6H2O was then added and refluxing was continued for a few
hours until the reaction was complete as indicated by TLC (10% MeOH in DCM). Aqueous
NaHCO3 (1 ml, half-saturated solution) was then added under stirring followed by evapora-
tion to dryness. The residue containing the deprotected product 3b and ferric hydroxide was
suspended in aqueous MeOH and mixed with silica gel followed by evaporation of the sol-
vent. The product 3b was eluted from the silica gel with 20% H2O in MeCN by suction-
filtration and then further purified by HPLC (0–50% MeOH/H2O, 0.1 TFA, 250 × 21.2 mm,
5 µm Hypersil ODS2, UV detection at λ = 220 nm). Yield 23 mg (65%) of 3b as a TFA salt.
1H NMR (500 MHz, DMSO-d6): 9.21 s, 1 H (H-5); 8.57 s, 1 H (H-2); 7.44 s, 1 H (H-8); 6.05 d,
1 H, J = 5.7 (H-1′); 5.60 br, 1 H (OH); 5.33 br, 1 H (OH); 5.12 br, 1 H (OH); 4.60–4.62 m, 1 H
(H-2′); 4.18–4.22 m, 1 H (H-3′); 3.98–4.00 m, 1 H (H-4′); 3.87 s, 2 H (H-1′′); 3.69–3.72 m, 1 H
(H-5′proS); 3.57–3.60 m, 1 H (H-5′proR); 2.37 br, 4 H (H-3′′); 1.43–1.49 m, 4 H (H-4′′);
1.33–1.41 m, 2 H (H-5′′). 13C NMR (126 MHz, DMSO-d6): 141.23 (C-9a), 140.10 (C-2), 138.32
(C-3a), 136.22 (C-5), 132.52 (C-8), 123.09 (C-9b), 121.00 (C-7), 87.95 (C-1′), 85.63 (C-4′),
74.14 (C-2′), 70.33 (C-3′), 61.34 (C-5′), 53.55 (C-3′′), 51.45 (C-1′′), 25.56 (C-4′′), 23.98 (C-5′′).
15N NMR (50 MHz, DMSO-d6): –206.90 (N-3), –179.15 (N-6), –152.42 (N-4), –150.82 (N-9),
+
–137.77 (N-1), N-1′′ not observed. HRMS: calculated for [M + H+] C18H25N6O4 389.1932 amu;
found 389.1924 amu.
3-(2,3-O-Isopropylidene-β-D-ribofuranosyl)-7-(morpholinomethyl)-
3H-imidazo[2,1-i]purine (4a)
The synthesis was performed as described for 3a except that morpholine (48.4 µl, 0.556 mmol)
was substituted for piperidine. The reaction was monitored by TLC (10% MeOH in DCM)
and upon completion, the reaction mixture was stirred with aqueous NaHCO3 prior to evap-
oration. The crude material was purified by silica gel column chromatography (10% MeOH/
CH2Cl2) yielding 0.116 g (97%) of 4a. 1H NMR (600 MHz, CDCl3): 9.16 s, 1 H (H-5); 8.18 s,
1 H (H-2); 7.50 s, 1 H (H-8); 6.07 d, 1 H, J = 4.5 (H-1′); 5.24 dd, 1 H, J = 5.9, 4.5 (H-2′);
5.16 dd, 1 H, J = 6.0, 1.6 (H-3′); 4.60–4.56 m, 1 H, J = 1.9 (H-4′); 4.05 dd, J = –12.4, 2.1
(H-5′proS); 3.89 dd, 1 H, J = –12.4, 2.0 (H-5′proR); 3.88 d, 1 H, J = 14.1 (H-1′′); 3.84 d, 1 H, J =
14.1 (H-1′′); 3.68 t, 4 H, J = 4.3 (H-4′′); 2.49–2.42 m, 4 H (H-3′′); 1.68 s, 3 H (H-7′endo); 1.40 s,
3 H (H-7′exo). 13C NMR (151 MHz, CDCl3): 142.23 (C-9a), 140.45 (C-2), 137.62 (C-3a),
135.71 (C-5), 133.99 (C-8), 125.31 (C-9b), 119.88 (C-7), 114.35 (C-6′), 93.71 (C-1′), 86.15
(C-4′), 83.95 (C-2′), 81.66 (C-3′), 66.84 (C-4′′), 63.20 (C-5′), 53.40 (C-3′′), 52.60 (C-1′′), 27.60
(C-7′endo), 25.34 (C-7′exo). 15N NMR (50 MHz, DMSO-d6): –206.05 (N-3), –179.18 (N-6),
–152.39 (N-4), –150.7 (N-9), –137.86 (N-1), N-1′′ not observed. HRMS: calculated for [M +
+
H+] C20H27N6O5 431.2037 amu; found 431.2033 amu.
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Karskela, Klika, Lönnberg:
7-(Morpholinomethyl)-3-β-D-ribofuranosyl-3H-imidazo[2,1-i]purine (4b)
Compound 4a (23.8 mg, 55.2 µmol) was dissolved in 0.1 M HCl in aqueous (53%) THF
(2 ml) and the reaction mixture was stirred on an oil bath at 50 °C for 4.5 h and monitored
by TLC (20% H2O in MeCN). Upon completion, the solution was cooled to room tempera-
ture, the pH adjusted to 8 with saturated NaHCO3 followed by evaporation to dryness. The
crude material was purified by silica gel column chromatography (10–12.5% H2O in MeCN)
yielding 17 mg (80%) of 4b. 1H NMR (400 MHz, D2O): 9.03 s, 1 H (H-5); 8.41 s, 1 H (H-2);
7.45 s, 1 H (H-8); 6.15 d, 1 H, J = 5.6 (H-1′); 4.84 t, 1 H, J = 5.4 (H-2′); 4.49 dd, 1 H, J = 5.2,
4.0 (H-3′); 4.30 q, 1 H, J = 3.8 (H-4′); 3.96 dd, 1 H, J = –12.8, 3.2 (H-5′proS); 3.94 s, 2 H
(H-1′′); 3.89 dd, 1 H, J = –12.8, 4.2 (H-5′proR); 3.73 t, 4 H, J = 4.6 (H-4′′); 2.69–2.52 m, 4 H
(H-3′′). 13C NMR (101 MHz, D2O): 142.40 (C-9a), 142.08 (C-2), 139.61 (C-3a), 137.45 (C-5),
134.33 (C-8), 123.65 (C-9b), 121.55 (C-7), 90.14 (C-1′), 86.96 (C-4′), 75.50 (C-2′), 71.90
(C-3′), 67.56 (C-4′′), 62.88 (C-5′), 53.81 (C-3′′), 51.49 (C-1′′). 15N NMR (50 MHz, DMSO-d6):
–206.90 (N-3), –179.31 (N-6), –152.27 (N-4), –150.88 (N-9), –137.77 (N-1), N-1′′ not ob-
+
served. HRMS: calculated for [M + H+] C17H23N6O5 391.1724 amu; found 391.1728 amu.
7-[(Benzylamino)methyl]-3-(2,3-O-isopropylidene-β-D-ribofuranosyl)-
3H-imidazo[2,1-i]purine (5)
Compound 2 (0.108 g, 0.300 mmol), benzylamine (32.8 µl, 0.300 mmol), NaCNBH3 (85%,
23.0 mg, 0.311 mmol) and acetic acid (34.4 µl, 0.601 mmol) were stirred in dry THF (2.0 ml)
for 24 h. The reaction mixture was evaporated to dryness and the residue taken up in DCM
and extracted with saturated NaHCO3. The organic phase was dried over Na2SO4 and again
evaporated to dryness after filtration. The crude material was purified by silica gel column
chromatography (10% MeOH/CH2Cl2) yielding 0.11 g (81%) of 5. 1H NMR (500 MHz,
CDCl3): 9.18 s, 1 H (H-5); 8.16 s, 1 H (H-2); 7.44 s, 1 H (H-8); 7.34–7.22 m, 5 H (Ph); 6.07 d,
1 H, J = 4.3 (H-1′); 5.43 br, 1 H (OH); 5.24 dd, 1 H, J = 6.0, 4.3 (H-2′); 5.16 dd, 1 H, J = 6.0,
1.7 (H-3′); 4.56–5.54 m, 1 H (H-4′); 4.15 s, 2 H (H-1′′); 4.03 dd, 1 H, J = –12.4, 2.1 (H-5′proS);
3.88 dd, 1 H, J = –12.4, 1.6 (H-5′proR); 3.80 s, 2 H (H-1′′′); 1.67 s, 3 H (H-7′endo); 1.40 s, 3 H
(H-7′exo). 13C NMR (101 MHz, CDCl3): 141.99 (C-9a), 140.35 (C-2), 139.47 (C-2′′′), 137.61
(C-3a), 135.99 (C-5), 132.84 (C-8), 128.66 (C-4′′′), 128.32 (C-3′′′), 127.38 (C-5′′′), 125.17
(C-9b), 122.13 (C-7), 114.32 (C-6′), 93.57 (C-1′), 86.30 (C-4′), 84.03 (C-2′), 81.69 (C-3′),
63.20 (C-5′), 53.17 (C-1′′′), 42.60 (C-1′′), 27.64 (C-7′endo), 25.40 (C-7′exo). HRMS: calculated
+
for [M + H+] C23H27N6O4 451.2088 amu; found 451.2087 amu.
7-[(N-Acetyl-N-benzyl)aminomethyl]-3-β-D-ribofuranosyl-3H-imidazo[2,1-i]purine (6)
Compound 5 (20.5 mg, 45.5 µmol), acetic anhydride (0.500 ml, 5.29 mmol) and pyridine
(0.200 ml, 2.48 mmol) were stirred in DCM (4.5 ml) until all of the starting material had
been consumed according to TLC monitoring (10% MeOH in DCM). The reaction mixture
was then evaporated to dryness and the residue taken up in DCM and extracted with satu-
rated NaHCO3. The organic phase was dried over Na2SO4 and again evaporated to dryness
after filtration. The remaining mixture of acetylated products was dissolved in dry MeOH
(1.0 ml) containing sodium hydride (60% dispersion in mineral oil, 3.0 mg, 75 µmol). When
deacetylation of the hydroxyl groups was complete, the mixture was diluted with DCM and
extracted with 3% aq. KH2PO4. The organic phase was dried over Na2SO4 and the solvent
was removed after filtration. The product was purified by silica gel column chromatography
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 1043–1054

Derivatives of Ethenoadenosine
1051
(5% MeOH in DCM) yielding 16.5 mg (74%) of 6. The isopropylidene protection was re-
moved as described for 4b and the deprotected material was purified by silica gel column
chromatography (10% H2O/MeCN) yielding 11 mg (53% from 5) of 6. Conformers A and B
denoted by demarkations A and B, respectively. 1H NMR (500 MHz, CD3OD): 9.48 s, 0.9 H
(H-5A); 8.98 s, 0.1 H (H-5B); 8.85 s, 0.9 H (H-2A); 8.81 s, 0.1 H (H-2B); 7.84 s, 0.1 H (H-8B);
7.81 s, 0.9 H (H-8A); 7.32–7.24 m, 1.8 H (H-4′′′A); 7.23–7.16 m, 2.7 H (H-3′′A, H-5′′′A);
7.11–7.03 m, 1.8 H (H-4′′′B); 7.01–6.94 m, 2.7 H (H-3′′′B, H-5′′′B); 6.26 d, 0.9 H, J = 5.1
(H-1′A); 6.23 d, 0.1 H, J = 5.0 (H-1′B); 5.15 s, 2 H (1′′); 4.72 s, 2 H (H-1′′′); 4.70–4.68 m, 1 H
(H-2′); 4.40–4.38 m, 1 H (H-3′); 4.20–4.18 m, 1 H (H-4′); 3.92 dd, 1 H, J = –12.2, 3.2
(H-5′proS); 3.82 dd, 1 H, J = –12.2, 3.5 (H-5′proR); 2.40 s, 0.3 H (H-4′′B); 2.28 s, 2.7 H (H-4′′A).
13C NMR (126 MHz, CD3OD): 174.44 (C-3′′A), 174.08 (C-3′′B), 143.20 (C-9a), 142.03 (C-2A),
141.81 (C-2B), 140.20 (C-3a), 137.49 (C-2′′′), 137.30 (C-5A), 135.96 (C-5B), 134.41 (C-8A),
133.38 (C-8B), 129.92 (C-4′′′A), 129.24 (C-4′′′B), 128.66 (C-5′′′A), 128.37 (C-3′′′B), 127.91
(C-5′′B), 127.47 (C-3′′′A), 124.25 (C-9b), 121.94 (C-7), 90.78 (C-1′A), 90.87 (C-1′B), 87.30
(C-4′), 76.20 (C-2′), 72.03 (C-3′), 62.94 (C-5′), 52.15 (C-1′′′A), 49.73 (C-1′′′B), 43.86 (C-1′′B),
+
39.00 (C-1′′A), 21.88 (C-4′′B), 21.81 (C-4′′A). HRMS: calculated for [M + H+] C22H25N6O5
453.2881 amu; found 453.2883 amu.
3-(2,3-O-Isopropylidene-β-D-ribofuranosyl)-7-[N-(4-tert-butoxy-4-oxobutyl)aminomethyl]-
3H-imidazo[2,1-i]purine (7)
Compound 2 (0.300 g, 0.835 mmol) and tert-butyl 4-aminobutanoate hydrochloride (0.196 g,
1.00 mmol) were suspended in DCE (6 ml) to which NaBH(OAc)3 (0.505 g, 2.38 mmol) was
added in three batches. The reaction mixture was stirred at room temperature for 24 h fol-
lowed by refrigeration over a weekend and then evaporation to dryness. To remove any re-
sidual acetic acid, the residue was taken up twice with water (2 × 10 ml) to effect co-removal
via solvent evaporation. The crude material was purified by silica gel column chromatogra-
phy (10–15% H2O/MeCN) yielding 0.224 g (53%) of 7. 1H NMR (500 MHz, CD3OD): 9.18 s,
1 H (H-5); 8.44 s, 1 H (H-2); 7.53 s, 1 H (H-8); 6.25 d, 1 H, J = 2.9 (H-1′); 5.29 dd, 1 H, J =
6.1, 2.9 (H-2′); 5.01 dd, H 1, J = 6.1, 2.7 (H-3′); 4.46 s, 2 H (H-1′′); 4.37–4.30 m, 1 H (H-4′);
3.74 dd, 1 H, J = –11.9, 4.0 (H-5′proS); 3.69 dd, 1 H, J = –12.0, 4.7 (H-5′proR); 2.96–2.88 m, 2 H
(H-3′′); 2.31 t, 2 H, J = 7.2 (H-5′′); 1.85 p, 2 H, J = 7.2 (H-4′′); 1.58 s, 3 H (H-7′endo); 1.35 s,
12 H (H-7′exo, H-9′′). 13C NMR (126 MHz, CD3OD): 173.21 (C-6′′), 142.20 (C-9a), 141.26
(C-2), 139.04 (C-3a), 136.17 (C-5), 133.68 (C-8), 123.06 (C-9b), 119.99 (C-7), 114.45 (C-6′),
91.66 (C-1′), 87.76 (C-4′), 85.15 (C-2′), 82.07 (C-3′), 80.90 (C-8′′), 62.48 (C-5′), 47.67 (C-3′′),
41.11 (C-1′′), 32.68 (C-5′′), 27.43 (C-9′′), 26.73 (C-7′endo), 24.72 (C-7′exo), 23.56 (C-4′′). HRMS:
+
calculated for [M + H+] C24H35N6O6 503.2613 amu; found 503.2611 amu.
7-[(2-Oxopyrrolidin-1-yl)methyl]-3-β-D-ribofuranosyl-3H-imidazo[2,1-i]purine (8)
Compound 7 (23.0 mg, 45.8 µmol) was stirred for 1 h in a 1:1 mixture of TFA and DCM
after which the volatiles were removed under vacuum. To the residue, HBTU (19.1 mg,
50.3 µmol) and DIEA (8.9 µl, 50.3 µmol) dissolved in dry DMF (3.0 ml) were added. After
two days, an additional one-half equivalent of HBTU was added to the incomplete reaction
and stirring was continued for an additional day. After completion of the reaction, the DMF
was evaporated off and the isopropylidene protection removed as described for 4b. The
deprotected material was purified by silica gel column chromatography (10–12.5%
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 1043–1054

1052
Karskela, Klika, Lönnberg:
H2O/MeCN) yielding 7.7 mg (43% from 7) of 8. 1H NMR (500 MHz, CD3OD): 9.15 s, 1 H
(H-5); 8.53 s, 1 H (H-2); 7.58 s, 1 H (H-8); 6.16 d, 1 H, J = 5.3 (H-1′); 4.93 s, 1 H (H-1′′);
4.71 t, 1 H, J = 5.2 (H-2′); 4.38 t, 1 H, J = 4.6 (H-3′); 4.16 q, 1 H, J = 3.5 (H-4′); 3.90 dd, 1 H,
J = –12.2, 3.1 (H-5′proS); 3.79 dd, 1 H, J = –12.2, 3.6 (H-5′proR); 3.39 t, 2 H, J = 7.1 (H-5′′);
2.43 t, 2 H, J = 8.1 (H-3′′); 2.05–1.95 m, 2 H, J = 8.1, 7.1 (H-4′′). 13C NMR (126 MHz,
CD3OD): 178.03 (C-3′′), 143.19 (C-9a), 142.01 (C-2), 140.27 (C-3a), 136.88 (C-5), 133.98
(C-8), 124.32 (C-9b), 121.28 (C-7), 90.75 (C-1′), 87.23 (C-4′), 76.19 (C-2′), 71.97 (C-3′), 62.87
(C-5′), 47.90 (C-4′′), 36.56 (C-1′′), 31.77 (C-6′′), 18.49 (C-5′′). 15N NMR (50 MHz, DMSO-d6):
–206.70 (N-3), –180.00 (N-6), –151.62 (N-4), –150.36 (N-9), –137.7 (N-1), N-1′′ not observed.
+
HRMS: calculated for [M + H+] C17H21N6O5 389.1568 amu; found 389.1564 amu.
3-(2,3-O-Isopropylidene-β-D-ribofuranosyl)-7-{[N-(4-tert-butoxy-4-oxobutyl)-
N-benzyl]aminomethyl}-3H-imidazo[2,1-i]purine (9)
Compound 7 (35.2 mg, 70.0 µmol) and benzaldehyde (14.3 µl, 0.140 mmol) were dissolved
in dry MeOH (0.40 ml) to which ZnCl2 (9.5 mg, 70.0 µmol) and NaCNBH3 (85%, 10.4 mg,
0.140 mmol) in dry MeOH (0.20 ml) were added followed by stirring for 28 h. The reaction
was monitored by TLC (10% H2O/MeCN) and by ESI-MS analysis. Upon completion of the
reaction, saturated aq. NaHCO3 (0.20 ml) and water (0.3 ml) were added and the mixture
was extracted with DCM, after which the water phase was concentrated to near dryness and
some MeCN was added. The volatiles were removed and the product was purified by silica
gel column chromatography (2.5% H2O/MeCN) yielding 37.4 mg (90%) of 9. 1H NMR
(400 MHz, CDCl3): 8.87 s, 1 H (H-5); 8.26 s, 1 H (H-2); 7.48 s, 1 H (H-8); 7.36–7.29 m, 2 H
(H-4′′′); 7.29–7.19 m, 3 H (H-2′′′, H-3′′′); 6.12 d, 1 H, J = 4.1 (H-1′); 5.24 dd, 1 H, J = 6.0, 4.1
(H-2′); 5.17 dd, 1 H, J = 6.0, 1.5 (H-3′); 4.58–4.55 m, 1 H, J = 2.1 (H-4′); 4.05 dd, 1 H, J =
–12.3, 2.2 (H-5′proS); 3.91 dd, 1 H, J = –12.3, 2.5 (H-5′proR); 3.90 d, 1 H, J = 14.3 (H-1′′);
3.86 d, 1 H, J = 14.3 (H-1′′); 3.63 d, 1 H, J = 13.3 (H-1′′′); 3.58 d, 1 H, J = 13.3 (H-1′′′);
2.54–2.42 m, 2 H (H-3′′); 2.16–2.06 m, 2 H (H-5′′); 1.87–1.75 m, 2 H (H-4′′); 1.68 s, 3 H
(H-7′endo); 1.41 s, 3 H (H-7′exo); 1.36 s, 9 H (H-9′′). 13C NMR (101 MHz, CDCl3): 172.61
(C-6′′), 141.95 (C-9a), 140.36 (C-2), 138.25 (C-2′′′), 137.78 (C-3a), 135.71 (C-5), 133.66 (C-8),
129.23 (C-3′′′), 128.60 (C-4′′′), 127.49 (C-5′′′), 124.76 (C-9b), 121.18 (C-7), 114.21 (C-6′),
93.27 (C-1′), 86.48 (C-4′), 84.27 (C-2′), 81.79 (C-3′), 80.42 (C-8′′), 63.09 (C-5′), 58.43 (C-1′′′),
53.01 (C-3′′), 48.06 (C-1′′), 33.17 (C-5′′), 28.10 (C-9′′), 27.60 (C-7′endo), 25.40 (C-7′exo), 22.13
+
(C-4′′). HRMS: calculated for [M + H+] C31H41N6O6 593.3082 amu; found 593.3071 amu.
3-(β-D-Ribofuranosyl)-7-{[N-(4-tert-butoxy-4-oxobutyl)-N-benzyl]aminomethyl}-
3H-imidazo[2,1-i]purine (10)
Compound 9 (26.5 mg, 44.7 µmol) was deprotected as described for 4b and the product was
purified by silica gel column chromatography (10% MeOH/CH2Cl2) yielding 12.6 mg (51%)
of 10. 1H NMR (500 MHz, 2:5 CD3OD/CDCl3): 8.87 s, 1 H (H-5); 8.33 s, 1 H (H-2); 7.44 s,
1 H (H-8); 7.36–7.30 m, 2 H (H-4′′′); 7.30–7.26 m, 2 H (H-3′′′); 7.26–7.21 m, 1 H (H-5′′′);
6.10 d, 1 H, J = 6.1 (H-1′); 4.73 dd, 1 H, J = 6.1, 5.1 (H-2′); 4.44 dd, 1 H, J = 5.1, 2.9 (H-3′);
4.29 ddd, 1 H, J = 2.9, 2.4 (H-4′); 3.99 dd, 1 H, J = –12.6, 2.4 (H-5′proS); 3.92 s, 2 H (H-1′′);
3.84 dd, 1 H, J = –12.6, 2.4 (H-5′proS); 3.63 s, 2 H (H-1′′′); 2.57–2.46 m, 2 H (H-3′′); 2.15 t,
2 H, J = 7.3 (H-5′′); 1.83 p, 2 H, J = 7.3 (H-4′′); 1.36 s, 9 H (C-9′′). 13C NMR (126 MHz, 2:5
CD3OD/CDCl3): 173.41 (C-6′′), 141.91 (C-9a), 140.90 (C-2), 138.48 (C-2′′′), 138.43 (C-3a),
135.90 (C-5), 132.93 (C-8), 129.40 (C-3′′′), 128.77 (C-4′′′), 127.70 (C-5′′′), 124.12 (C-9b),
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 1043–1054

Derivatives of Ethenoadenosine
1053
121.84 (C-7), 90.45 (C-1′), 86.76 (C-4′), 81.01 (C-8′′), 75.05 (C-2′), 71.33 (C-3′), 62.51 (C-5′),
58.64 (C-1′′′), 53.22 (C-3′′), 48.09 (C-1′′), 33.35 (C-5′′), 28.04 (C-9′′), 22.34 (C-4′′). 15N NMR
(50 MHz, DMSO-d6): –206.79 (N-3), –179.50 (N-6), –152.49 (N-4), –150.64 (N-9), –137.58
+
(N-1), N-1′′ not observed. HRMS: calculated for [M + H+] C28H37N6O6 553.2769 amu; found
553.2762 amu.
The National Graduate School of Organic Chemistry and Chemical Biology and Turun
Yliopistosäätiö are thanked for financial support. J. Sinkkonen is thanked for assistance with the
molecular modeling.
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