Intramolecular cyclization of some acyclic nucleoside analogs

Article abstract of DOI:10.1135/cccc19960442

Reaction of stereoisomeric 8-bromo-9-(2,3-O-isopropylidene-2,3,4-trihydroxybutyl)adenines (8) with concentrated aqueous ammonia, sodium hydride, potassium tert-butoxide, or 1,8-diazabicyclo-[5,4,0]undec-7-ene afforded 4′-O,8-anhydro-9-(2,3-O-isopropyliden

Full text of DOI:10.1135/cccc19960442

442
Janeba, Holy, Votavova, Masojidkova:
INTRAMOLECULAR CYCLIZATION OF SOME ACYCLIC NUCLEOSIDE
ANALOGS*
Zlatko JANEBA, Antonin HOLY, Hana VOTAVOVA and Milena MASOJIDKOVA
Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic
Received August 21, 1995
Accepted November 26, 1995
Reaction of stereoisomeric 8-bromo-9-(2,3-O-isopropylidene-2,3,4-trihydroxybutyl)adenines (8) with
concentrated aqueous ammonia, sodium hydride, potassium tert-butoxide, or 1,8-diazabicyclo-
[5,4,0]undec-7-ene afforded 4′-O,8-anhydro-9-(2,3-O-isopropylidene-2,3,4-trihydroxybutyl)adenines 9
(derivatives of 1,3-oxazepino[2,3-e]adenine). The CD spectra of optically active stereoisomers of 9
have been studied and it was found that for threo isomers 9a and 9b their character corresponds to
5′-O,8-cycloadenosine. The compounds 9 were also prepared by oxidative cyclization of 9-(2,3-O-
isopropylidene-2,3,4-trihydroxybutyl)adenines (7) with lead(IV) acetate in benzene. Reaction of 9-(4-
hydroxybutyl)adenine (14) with lead(IV) acetate smoothly afforded the seven-membered ring
derivative, 4′-O,8-anhydro-9-(4-hydroxybutyl)adenine (15); no anhydro products with five-, six-, and
eight-membered ring were found. 2′,3′-O-Isopropylideneinosine (16) reacted with lead(IV) acetate to
give 5′-O,8-cyclo-2′,3′-O-isopropylideneinosine (17) whereas 9-(4-hydroxybutyl)hypoxanthine (18)
afforded no cyclic products.
Key words: Nucleosides; Acyclic analogs; Purine derivatives.
In the nucleoside chemistry, purine derivatives modified in the position 8 are of par-
ticular importance. Some of them (e.g. compounds derived from 8-amino- or 8-
hydroxyguanine) exhibit significant biological (e.g. immunomodulatory) effects1,2.
These derivatives are usually prepared by reaction of 8-halogenopurines with the
corresponding nucleophile such as ammonia, amines, hydrazine, azides, alkoxides, etc.
When the sugar moiety participates in such reactions, we can postulate (or even directly
prove) a participation of the so-called cyclonucleosides3.
Some time ago we investigated such reactions with acyclic nucleoside analogs in
which the sugar (aldopentofuranose) residue is replaced by a chain bearing hydroxyl
functionalities. We focused on adenine derivatives, particularly SAH hydrolase inhibi-
tors such as 9-(S)-(2,3-dihydroxypropyl)adenine (DHPA)4, which exhibit antiviral ac-
* A part of this work constitutes the Thesis of one of the authors (Z. J.) and has been preliminarily published:
Janeba Z., Dvorakova H., Holy A.: Collect. Czech. Chem. Commun. 58 (Special Issue), 247 (1993).
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Intramolecular Cyclization
443
tivity and show further effects on proliferating systems. Most nucleophilic reactions of
adenine bases, containing a bromine atom at C-8 and protected hydroxy groups, pro-
ceed analogously as those of nucleosides, i.e. under formation of products substituted in
position 8 with the corresponding nucleophile5.
However, compounds containing free hydroxy groups in the side chain react anoma-
lously6,7: their reaction with ammonia or primary amines affords 8-hydroxyadenine
derivatives with amino group in the side chain. In the reaction of 2,3-dihydroxypropyl
derivative 1 two isomeric amino derivatives 2 and 3 were isolated (Scheme 1). One can
assume that the reaction involves a cyclonucleoside analog which is opened by nucleo-
philic attack under formation of 8-hydroxyadenine derivative containing the nucleo-
philic group in the side chain. The existence of such cyclic form has been proven7.
The original study on this subject has shown7 that also 8-bromo-9-(2,3,4-trihydroxy-
butyl)adenine (4) on reaction with aqueous ammonia afforded the 3-amino-2,4-dihydroxy-
butyl derivative 5 whose formation requires a cyclic intermediate 6 (Scheme 2).
We set out to investigate the mentioned reaction under conditions allowing formation
of a seven-membered ring derivative as the only possible intermediate, to prepare such
cyclic structures independently and to assess their reactivity with nucleophiles. As a
model we have chosen the mentioned group of 8-bromo-9-(2,3,4-trihydroxy-
butyl)adenines, protected in positions 2 and 3 of the side chain by a 1,3-dioxolane ring
(“isopropylidene derivatives”).
For the starting adenine derivatives of threo configuration both enantiomeric forms
2S,3S and 2R,3R have already been described (compounds 7a and 7b, respectively),
whereas the erythro isomer 7c is hitherto known only in the racemic form6. In this
study we prepared the (2S,3R)-erythro isomer 7e from 2′,3′-O-isopropylideneadenosine
by reductive cleavage with excess of diisobutylaluminium hydride in dry tetrahydro-
furan8 and subsequent shortening of the aliphatic chain in the obtained 1-(adenin-9-yl)-
1-deoxy-2,3-O-isopropylidene-D-ribitol.
NH2
N
NH2
N
NH2
N
N
N
N
N
N
N
N
N
N
Br
OH
OH
+
OH
NH2
OH
OH
OH
NH2
1
2
3
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

444
Janeba, Holy, Votavova, Masojidkova:
The (2R,3S)-erythro isomer 7d was obtained by reduction of methyl ester of 2′,3′-O-
isopropylidene-D-eritadenine9 with Dowex 1 X 2 (BH4− form) in aqueous methanol10.
The compounds 7 were converted into the bromo derivatives 8 by bromination with
2.5 equivalents of bromine in a mixture of dioxane and 10% aqueous solution of so-
dium dihydrogen phosphate. Intramolecular cyclization of the bromo compounds 8 was
performed by treatment with 2 equivalents of sodium hydride in dioxane and gave
4′-O,8-anhydro-9-(2,3-O-isopropylidene-2,3,4-trihydroxybutyl)adenines 9 (1,3-oxa-
zepino[2,3-e]adenine derivatives* (Scheme 3). The reaction with both the threo (8a,
8b) and erythro (8c) isomers was complete on standing for 2–3 days at room tempera-
ture. After neutralization of the reaction mixture, the cyclic products 9 were obtained
by crystallization from ethanol. The erythro derivative 9c was only sparingly soluble in
common organic solvents as well as in water and crystallized directly from the reaction
mixture.
Compound 8b was also cyclized by action of 2 equivalents of potassium tert-butoxide.
Reaction of the threo derivatives 8a and 8b with DBU in acetonitrile, dimethylform-
amide or diethylene glycol dimethyl ether proceeded slowly and gave low yields
NH
N
NH
N
2
2
N
N
N
N
N
N
NH OH
4
Br
OH
OH
NH
2
OH
OH
OH
OH
4
5
NH
N
2
N
N
O
N
OH
OH
6
SCHEME 2
* Instead of the IUPAC-compatible name 1,3-oxazepino[2, 3-e]adenines we commonly use the name anhydro
derivatives.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Intramolecular Cyclization
445
whereas the racemic erythro derivative 8c on treatment with DBU in dimethylform-
amide gave the cyclic product 9c in high yield.
When treated with aqueous ammonia7 at 100 °C in an autoclave, bromo derivatives 8
afforded the cyclic anhydro compounds 9 (9a: 14%, 9b: 10%, and 9c: 79%). In addi-
tion, we observed the formation of the corresponding 8-hydroxy and 8-amino deriva-
tives as products of nucleophilic substitution in the position 8. In the reaction of
derivative 8b, small amounts of hydroxy derivative 10 and 8-amino derivative 11 were
isolated and characterized (Scheme 4). In no case, however, “anomalous” products with
amino group in the side chain have been detected. As shown by direct experiments, the
anhydro derivatives 9 did not react with ammonia under the given conditions.
The acyclic analogs of cyclonucleosides are also stable toward alkaline hydrolysis.
Neither 4′-O,8-anhydro-9-(2S,3S)-(2,3-O-isopropylidene-2,3,4-trihydroxybutyl)adenine
(9a) nor 4′-O,8-anhydro-9-(4-hydroxybutyl)adenine (15) reacted with 1 M sodium hy-
droxide even at 50 °C.
According to a recent paper of Japanese authors11, a 5′-O,8-cycloadenosine deriva-
tive was prepared by oxidative cyclization of 2′,3′-O-isopropylideneadenosine with
lead(IV) acetate. In our case, an analogous reaction of 9-(2,3-O-isopropylidene-2,3,4-
trihydroxybutyl)adenines 7 with lead(IV) acetate also afforded cyclic anhydro deriva-
tives 9, identical with those prepared from the 8-bromo derivatives 8.
NH2
NH2
N
N
N
N
N
Br2
N
Br
OH
O
OH
dioxane
N
N
O
O
O
8
7
7-9 configuration
Pb(OAc)4
benzene
NaOH
dioxane
NH2
N
a (2S, 3S)
N
b (2R, 3R)
N
O
c racemic erythro
d (2R, 3S)
N
O
e (2S, 3R)
O
9
SCHEME 3
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

446
Janeba, Holy, Votavova, Masojidkova:
Compared with 2′,3′-O-isopropylideneadenosine, the reaction of the acyclic nucleo-
side analogs required a larger excess of lead(IV) acetate (1.7–1.8 equivalents) and a
longer reaction time (in some cases longer than 20 h). Even then the yields of the
products 9 were much lower (17–46%). As side products in the cyclization of com-
pound 7b and 7d we isolated 9-(2R,3R)-(4-O-acetyl-2,3-O-isopropylidene-2,3,4-tri-
hydroxybutyl)adenine and 9-(2R,3S)-(4-O-acetyl-2,3-O-isopropylidene-2,3,4-trihydroxy-
butyl)adenine, respectively.
In order to find out whether this reaction with lead(IV) acetate could afford anhydro
derivatives with rings other than seven-membered, we selected monohydroxyalkyl-
adenines as simple models. The six-membered ring structures, mentioned in the lite-
NH2
N
N
O
N
N
O
O
9b
NH2
N
NH2
N
N
N
N
N
NH4OH
N
N
Br
OH
OH
O
OH
O
O
O
8b
10
NH2
N
N
N
N
NH2
OH
O
O
11
SCHEME 4
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Intramolecular Cyclization
447
rature7, could not be prepared by this method: even upon reflux for 24 h, 9-(3-hydroxy-
propyl)adenine (12a) did not react in the desired way and the reaction mixture con-
tained only the O-acetyl derivative of the starting compound. On the other hand,
reaction of 9-(4-hydroxybutyl)adenine (14) with 2 equivalents of lead(IV) acetate in
refluxing toluene after 9 h gave 4′-O,8-anhydro-9-(4-hydroxybutyl)adenine (15) in a
good yield (Scheme 5); this confirms that this oxidative cyclization easily affords anhy-
dro derivatives with seven-membered ring. Treatment of 9-(5-hydroxypentyl)adenine
(12b) with 2 equivalents of lead(IV) acetate in benzene, however, did not afford any
eight-membered ring derivative.
NH
2
N
N
N
N
CH (CH ) CH OH
2
2 n
2
12
n
a
b
1
3
When working with dioxane, tert-butyl alcohol or acetic acid instead of benzene or
toluene, the reaction with lead(IV) acetate did not take place at all, even with racemic
erythro-9-(2,3-O-isopropylidene-2,3,4-trihydroxybutyl)adenine (7c) which otherwise is
a good substrate.
Since the original paper11 mentioned a positive effect of N6-benzoylation on the
course of this reaction in the adenosine series, we prepared N6-benzoyl-9-(2-hydroxy-
ethyl)adenine, N6-benzoyl-9-(2-hydroxybutyl)adenine and N6-benzoyl-9-(3-hydroxy-
butyl)adenine by benzoylation with benzoyl chloride and chlorotrimethylsilane in
NH2
N
NH2
N
N
N
N
N
Pb(OAc)4
toluene
N
N
O
CH2 (CH2)3
CH2(CH2)2CH2OH
14
15
SCHEME 5
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

448
Janeba, Holy, Votavova, Masojidkova:
pyridine12. None of these compounds reacted with lead(IV) acetate in benzene or toluene.
On prolonged treatment under otherwise the same conditions, (2R,3R)-N6-benzoyl-9-
(2,3-O-isopropylidene-2,3,4-trihydroxybutyl)adenine (13) underwent complete deben-
zoylation to give (2R,3R)-4′-O,8-anhydro-9-(2,3-O-isopropylidene-2,3,4-trihydroxy-
butyl)adenine (9b).
NHCOPh
N
N
O
N
N
OH
N
HN
N
N
O
CH CH CH CH OH
O
2
2
2
2
18
13
In this context, we also investigated the behaviour of guanine and hypoxanthine deri-
vatives toward lead(IV) acetate. Whereas 2′,3′-O-isopropylideneinosine (16) on treat-
ment with 2.5 equivalents of lead(IV) acetate in refluxing toluene for 7 h afforded the
cyclic product 17 in 40% yield (Scheme 6), attempted cyclization of the analogous
inosine derivative failed. The corresponding hypoxanthine derivative 18, prepared by
deamination of 9-(4-hydroxybutyl)adenine (14) with isoamyl nitrite in 80% acetic acid,
did not react in benzene. No reaction was also observed with 2′,3′-O-isopropylidene-
guanosine13 in refluxing benzene (6 h).
Detailed study of CD spectra of adenine cyclonucleosides14 shows a considerable
dependence on the conformation of the molecule, particularly on the angle between the
O
O
N
N
N
N
NH
HN
O
N
N
HO
O
O
Pb(OAc)4
toluene
O
O
O
O
16
17
SCHEME 6
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Intramolecular Cyclization
449
plane of the heterocyclic chromophore and the chiral part of the molecule (sugar).
Therefore the CD spectra of 5′-O,8-cyclonucleosides differ markedly from those of
2′-O,8-cyclonucleosides and their 3′-O,8-isomers. The character of CD spectra of com-
pounds 9a and 9b agrees qualitatively with that of adenine 5′-O,8-cyclonucleoside14,
the absolute molar elipticity value of the maximum being even by 30% higher than for
5′-O,8-cycloadenosine. The CD spectra of all the cyclic anhydro derivatives 9 consist
of two bands of opposite sign (Fig. 1). One of them has a maximum at 260 nm, the
other at about 206 nm for the threo and 212 nm for the erythro derivatives. The spectra
of enantiomeric compounds 9a and 9b are mirror images of each other, confirming thus
their optical purity. The same is true for the CD spectra of enantiomers 9d and 9e.
Spectra of the erythro and threo compounds differ mainly in intensity of both bands.
EXPERIMENTAL
The compounds were dried over phosphorus pentoxide at 13 Pa. Melting points were determined on
a Kofler block and are uncorrected. Thin-layer chromatography was performed on Silufol UV 254
foils (Kavalier, Votice, Czech Republic) in the systems chloroform–methanol (9 : 1) (S1), chloro-
form–methanol (85 : 15) (S2) and chloroform–methanol (4 : 1) (S3). Preparative thin-layer chromato-
graphy on silica gel was carried out on 40 × 17 × 0.4 cm plates (UV indicator, Kavalier, Votice,
Czech Republic). Column chromatography was done on silica gel (30 µm) of the same provenience.
Spots were detected by UV light at 254 nm.
CD spectra were measured in water on a Jobin Yvon Mark V instrument. The concentration of the
measured solutions was determined from the absorbancies at the absorption maxima; the εmax values
for threo enantiomers 11a and 11b (ε260 = 15 800) and erythro enantiomers 11d and 11e (ε263 = 14 100)
were determined experimentally.
UV spectra (λmax, ε) were taken in aqueous solutions on a Beckmann DU-65 instrument. Mass
spectra (m/z, rel.%) were measured on a ZAB-EQ (VG Analytical, Manchester, U.K.) mass spec-
trometer using FAB technique (Xe, accelerating voltage 8 kV). The samples were dissolved in methanol
and a mixture of thioglycerol and glycerol (3 : 1) was used as a matrix.
50 000
2
1
Θ
3
4
0
4
3
2
1
FIG. 1
CD spectra in aqueous solution:
1 9b, 2 9a, 3 9e, 4 9d
–50 000
200
250
300
λ, nm
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

450
Janeba, Holy, Votavova, Masojidkova:
Proton NMR spectra (δ, ppm; J, Hz) were measured on Varian UNITY 200 (200 MHz) or Varian
UNITY 500 (500 MHz) spectrometers in hexadeuteriodimethyl sulfoxide with tetramethylsilane as
internal standard. 13C NMR spectra were taken on a Varian UNITY-500 instrument (125.7 MHz) and
the chemical shifts were referenced to the solvent signal (δ(CD3SOCD3) = 39.7 ppm) or, for solu-
tions in D2O, to dioxane as external standard (δ(dioxane) = 66.86 ppm). The carbon signals of the
types C, CH, CH2 and CH3 were distinguished on the basis of J-modulated spectra (“Attached Proton
Test Pulse Sequence”)15.
9-(4-Hydroxybutyl)adenine (14)
A mixture of adenine (18 g, 0.13 mol) and potassium carbonate (38.6 g, 0.28 mol) in dimethylform-
amide (230 ml) was stirred at 140 °C. After stirring for 0.5 h, 4-bromobutyl acetate (45 g, 0.23 mol)
was added dropwise during 50 min and the reaction mixture was heated at 140 °C for 9 h. The inso-
luble portion was removed by filtration of the hot mixture and the filtrate was evaporated. The
residue was codistilled with toluene and then chromatographed on a column. Crystallization from
ethanol afforded 17.4 g (52%) of crystalline 9-(4-acetoxybutyl)adenine16
.
The obtained N9-isomer (15 g, 60 mmol) was deacetylated by treatment with 0.1 M methanolic
sodium methoxide (400 ml) for 0.5 h. The mixture deposited crystals which were collected, washed
with ethanol and ether and dried in vacuo. The filtrate was neutralized with Dowex 50 (H+ form),
made slightly alkaline with triethylamine, and filtered. The solvent was evaporated and the residue
was crystallized from ethanol. Total yield of 9-(4-hydroxybutyl)adenine (14) was 13.4 g (95%), m.p.
198–200 °C, RF 0.37 (S4). For C9H13N5O (207.2) calculated: 52.12% C, 6.27% H, 33.78% N; found:
51.94% C, 6.29% H, 33.63% N. 1H NMR spectrum: 8.145 s, 1 H and 8.14 s, 1 H (H-2 and H-8);
7.23 brs, 2 H (NH2); 4.46 t, 1 H, J(OH,4′) = 4.9 (OH); 4.14 t, 2 H, J(1′,2′) = 7.1 (H-1′); 3.39 dt, 2 H,
J(4′,3′) = 6.6 (H-4′); 1.82 m, 2 H (H-2′); 1.37 m, 2 H (H-3′). 13C NMR spectrum: 156.16 (C-6);
152.56 (C-2); 149.76 (C-4); 141.06 (C-8); 118.96 (C-5); 60.34 (C-4′); 43.06 (C-1′); 29.69 (C-3′);
25.50 (C-2′). Mass spectrum: 208 (100, M + H).
The above chromatography also afforded 1.25 g (4%) of 3-(4-acetoxybutyl)adenine, m.p. 178–180 °C.
For C11H15N5O2 (249.2) calculated: 52.97% C, 6.02% H, 28.09% N; found: 53.11% C, 6.14% H,
1
27.62% N. H NMR spectrum: 8.36 s, 1 H and 7.78 s, 1 H (H-2 and H-8); 8.15 brs, 1 H and 7.90 brs,
1 H (NH2); 4.33 t, 2 H, J(1′,2′) = 7.1 (H-1′); 4.00 t, 2 H, J(4′,3′) = 6.6 (H-4′); 1.97 s, 3 H (OAc);
1.94 m, 2 H (H-2′); 1.56 m, 2 H (H-3′). 13C NMR spectrum: 170.58 (CO); 155.19 (C-6); 152.68
(C-8); 149.89 (C-4); 143.56 (C-2); 120.66 (C-5); 63.45 (C-4′); 49.11 (C-1′); 25.57 and 25.36 (C-2′
and C-3′); 20.87 (CH3). Mass spectrum: 250 (100, M + H).
9-(4-Hydroxybutyl)hypoxanthine (18)
Isoamyl nitrite (5 ml) was added to a solution of 9-(4-hydroxybutyl)adenine (14; 1.0 g, 4.8 mmol) in
80% acetic acid (50 ml) and the reaction mixture was set aside for 2 days at room temperature. The
solvent was evaporated, the residue was codistilled with water, deionized on Dowex 50 X 8 (H+
form) and purified by column chromatography on silica gel. Crystallization from methanol afforded
1
compound 18 (0.3 g, 30%), m.p. 165–168 °C, RF 0.29 (S3). H NMR spectrum: 12.27 brs, 1 H (NH);
8.09 s, 1 H and 8.03 s, 1 H (H-2 and H-8); 4.46 t, 1 H, J(OH,4′) = 5.1 (OH); 4.14 t, 2 H, J(1′,2′) = 7.3
(H-1′); 3.38 m, 2 H (H-4′); 1.81 m, 2 H and 1.36 m, 2 H (H-2′ and H-3′). 13C NMR spectrum:
156.92 (C-6); 148.63 (C-4); 145.64 (C-2); 140.58 (C-8); 124.13 (C-5); 60.29 (C-4′); 43.47 (C-1′);
29.60 (C-3′); 26.66 (C-2′). Mass spectrum: 209 (100, M + H).
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Intramolecular Cyclization
451
9-(2S,3R)-(2,3-O-Isopropylidene-2,3,4-trihydroxybutyl)adenine (7e)
1
Compound 7e was prepared by a described procedure8. M.p. >250 °C, RF 0.46 (S3). H NMR spec-
trum: 8.13 s, 1 H and 8.08 s, 1 H (H-2 and H-8); 7.20 brs, 2 H (NH2); 5.05 brs, 1 H (OH); 4.57 ddd,
1 H, J(2′,3′) = 6.4 (H-2′); 4.37 dd, 1 H, J(1a′,2′) = 2.9, J(gem) = 14.2 (Ha-1′); 4.26 q, 1 H, J = 6.2
(H-3′); 4.21 dd, 1 H, J(1b′,2′) = 10.3, J(gem) = 14.2 (Hb-1′); 3.63 d, 2 H, J(4′,3′) = 6.1 (H-4′); 1.43 s,
3 H and 1.21 s, 3 H (2 × CH3). Mass spectrum: 280 (100, M + H).
9-(2R,3S)-(2,3-O-Isopropylidene-2,3,4-trihydroxybutyl)adenine (7d)
1
Compound 7d was prepared by a described procedure10. Its m.p., RF, and H NMR and mass spectra
were identical with those of compound 7e.
N6-Benzoyl-9-(2R,3R)-(2,3-O-isopropylidene-2,3,4-trihydroxybutyl)adenine (13)
A solution of 9-(2R,3R)-(2,3-O-isopropylidene-2,3,4-trihydroxybutyl)adenine (7b; 1.7 g, 6 mmol) and
benzoyl chloride (3.6 ml) in pyridine (30 ml) was stirred in a stoppered flask for 1 h in the dark17
.
The reaction mixture was poured on ice, and the precipitate was taken up in chloroform. The chloroform
phase was washed successively with water, a solution of sodium hydrogen carbonate and water, and
dried over magnesium sulfate. The chloroform was evaporated, the residue was dissolved in pyridine
(80 ml) and cooled with ice. Sodium hydroxide (1 M solution, 80 ml) was added and the reaction
mixture was stirred for 10 min with cooling. After neutralization with acetic acid, the solvent was
evaporated and the residue was partitioned between water and chloroform. The chloroform layer was
washed with a solution of sodium hydrogen carbonate and with water, and dried. The solvent was
evaporated and the crude residue was column chromatographed (chloroform–methanol (99 : 1)).
Crystallization from ethanol afforded 0.75 g (32%) of compound 13, m.p. 138–140 °C, RF 0.43 (S2).
For C19H21N5O4 (383.4) calculated: 59.52% C, 5.52% H, 18.27% N; found: 59.52% C, 5.45% H,
1
18.04% N. H NMR spectrum: 11.17 s, 1 H (NH); 8.76 s, 1 H and 8.43 s, 1 H (H-2 and H-8); 8.06 d,
2 H and 7.64 t, 1 H and 7.55 t, 2 H (arom); 4.97 t, 1 H, J(OH,4′) = 5.5 (OH); 4.56 dd, 1 H, J(1a′,2′) = 3.9,
J(gem) = 14.4 (Ha-1′); 4.47 dd, 1 H, J(1b′,2′) = 6.8, J(gem) = 14.4 (Hb-1′); 4.27 td, 1 H, J(2′,1a′) = 3.9,
J(2′,1b′) = 6.8, J(2′,3′) = 7.8 (H-2′); 3.82 dt, 1 H, J(3′,4a′) = J(3′,4b′) = 4.9, J(3′,2′) = 7.8 (H-3′);
3.55 dt, 1 H, J(4a′,3′) = J(4a′,OH) = 5.2, J(gem) = 11.5 (Ha-4′); 3.52 dt, 1 H, J(4b′,3′) = J(4b′,OH) = 5.4,
J(gem) = 11.5 (Hb-4′); 1.29 s, 3 H and 1.26 s, 3 H (2 × CH3). 13C NMR spectrum: 165.53 (C=O);
152.82 (C-6); 151.80 (C-2); 150.34 (C-4); 145.38 (C-8); 133.64, 132.62, 128.68 4C (C-arom), 125.30
(C-5); 109.16 (O–C–O); 79.11 (C-3′); 76.19 (C-2′); 61.40 (C-4′); 45.32 (C-1′); 27.22 and 27.11 (2 × CH3).
Mass spectrum: 384 (53%, M + H).
Benzoylation of Acyclic Adenine Nucleosides (Ref.12
)
A mixture of the corresponding adenine derivative (15 mmol), pyridine (80 ml) and chlorotrimethyl-
silane (13 ml) was stirred at room temperature (calcium chloride protecting tube) for 1 h. Benzoyl
chloride (10 ml) was added and stirring was continued for further 2 h. The reaction mixture was
cooled to 0 °C, water (15 ml) and concentrated ammonia (35 ml) were added dropwise during 5 min
and the mixture was stirred at 0 °C for 30 min. The solvent was evaporated and the residue was
codistilled with water and extracted with acetone. The product was crystallized from water and then
from ethanol or ethyl acetate with ether added to turbidity, or purified by chromatography on a column
of silica gel.
N6-Benzoyl-9-(2-hydroxyethyl)adenine: yield 2.3 g (54%), m.p. 185–188 °C, RF 0.58 (S2). For
C14H13N5O2 (283.3) calculated: 59.36% C, 4.63% H, 24.72% N; found: 59.17% C, 4.56% H, 24.32% N.
1H NMR spectrum: 11.15 brs, 1 H (NH); 8.74 s, 1 H and 8.43 s, 1 H (H-2 and H-8); 8.10–8.02 m,
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2 H and 7.70–7.50 m, 3 H (arom); 5.08 t, 1 H, J(OH,2′) = 5.2 (OH); 4.34 t, 2 H, J(1′,2′) = 5.2
(H-1′); 3.82 q, 2 H, J(2′,1′) = J(2′,OH) = 5.2 (H-2′). 13C NMR spectrum: 165.91 (CO); 152.86 (C-6);
151.56 (C-2); 150.23 (C-4); 145.48 (C-8); 133.77, 132.61, 128.69 4C (C arom); 125.70 (C-5); 59.36
(C-2′); 46.30 (C-1′). Mass spectrum: 284 (100, M + H).
N6-Benzoyl-9-(3-hydroxybutyl)adenine: yield 1.54 g (50%), m.p. 155–157 °C, RF 0.31 (S2). For
C16H17N5O2 (311.3) calculated: 61.72% C, 5.46% H, 22.50% N; found: 61.65% C, 5.49% H, 22.33% N.
1H NMR spectrum: 11.14 s, 1 H (NH); 8.74 s, 1 H and 8.49 s, 1 H (H-2 and H-8); 8.06 d, 2 H and
7.60 t, 1 H and 7.53 t, 2 H (arom); 4.75 d, 1 H, J(OH,3′) = 4.6 (OH); 4.38 ddd, 1 H, J(1′a,2′) = 5.9
and 7.8, J(gem) = 13.7 (Ha-1′); 4.32 brpent, 1 H, J(1′b,2′) = 7.3 and 7.3, J(gem) = 13.7 (Hb-1′); 3.61 m,
1 H (H-3′); 1.97 m, 1 H and 1.86 m, 1 H (H-2′); 1.10 d, 3 H, J(4′,3′) = 6.3 (H-4′). Mass spectrum:
312 (100, M + H).
Bromination of 9-(2,3-O-Isopropylidene-2,3,4-trihydroxybutyl)adenines (7)
Bromine (0.5 ml, 19.4 mmol) was added to a suspension of compound 7a, 7b or 7c (2.0 g, 7 mmol)
in a mixture of dioxane (90 ml) and 10% aqueous solution of sodium hydrogen phosphate (90 ml)
and the mixture was stirred at room temperature for 24 h. Concentrated solution of sodium hydrogen
sulfite was added until the mixture became colourless and the product was taken up in chloroform (6 × 30 ml).
The chloroform extract was dried over magnesium sulfate, filtered, the solvent was evaporated and
the product was crystallized from ethyl acetate.
A. Compound 8a: yield 1.6 g (65%), m.p. 166–168 °C (ethyl acetate), RF 0.74 (S3). For
C12H16BrN5O3 (358.2) calculated: 40.24% C, 4.50% H, 19.55% N, 22.31% Br; found: 40.15% C,
1
4.53% H, 20.03% N, 22.21% Br. H NMR spectrum: identical with that of 13b (see B). UV (pH 7):
267.0 (14 700). Mass spectrum: 358 (100, M + H).
B. Compound 8b: yield 1.8 g (71%), m.p. 166–168 °C (ethyl acetate), RF 0.75 (S3). For
C12H16BrN5O3 (358.2) calculated: 40.24% C, 4.50% H, 19.55% N, 22.31% Br; found: 40.17% C,
1
4.48% H, 19.87% N, 22.35% Br. H NMR spectrum: 8.14 s, 1 H (H-2); 7.42 brs, 2 H (NH2); 4.92 t,
1 H, J(OH,4′) = 5.4 (OH); 4.35 dd, 1 H, J(1a′,2′) = 5.4, J(gem) = 14.4 (Ha-1′); 4.31 dd, 1 H,
J(1b′,2′) = 6.1, J(gem) = 14.4 (Hb-1′); 4.25 brdt, 1 H, J(2′,1a′) = J(2′,1b′) = 5.6, J(2′,3′) = 7.6 (H-2′);
3.95 dt, 1 H, J(3′,4a′) = J(3′,4b′) = 4.9, J(3′,2′) = 7.6 (H-3′); 3.47 t, 2 H, ΣJ = 10.5 (H-4′); 1.27 s, 3 H
and 1.26 s, 3 H (2 × CH3). 13C NMR spectrum: 154.95 (C-6); 153.08 (C-2); 151.02 (C-4); 127.25
(C-8); 119.05 (C-5); 109.18 (O–C–O); 79.48 (C-3′); 75.78 (C-2′); 61.31 (C-4′); 46.42 (C-1′); 27.25
and 27.01 (2 × CH3). UV spectrum (pH 7): 267.0 (14 000). Mass spectrum: 358 (29, M + H).
C. Compound 8c: yield 1.0 g (41%), m.p. 208–210 °C (ethanol), RF 0.71 (S3). For C12H16BrN5O3
(358.2) calculated: 40.24% C, 4.50% H, 19.55% N, 22.31% Br; found: 39.88% C, 4.57% H, 19.80% N,
22.26% Br. 1H NMR spectrum: 8.13 s, 1 H (H-2); 7.40 brs, 2 H (NH2); 5.09 t, 1 H, J(OH,4′) = 5.4
(OH); 4.69 ddd, 1 H, J = 4.9, 6.3 and 8.6 (H-2′); 4.33–4.27 m, 3 H (H-1′and H-3′); 3.70 dt, 1 H,
J(4a′,3′) = 5.1, J(4a′,OH) = 5.4, J(gem) = 11.2 (Ha-4′); 3.67 brdt, 1 H, J(4b′,3′) = 6.3, J(4b′,OH) = 5.4,
J(gem) = 11.2 (Hb-4′); 1.42 s, 3 H and 1.18 s, 3 H (2 × CH3). 13C NMR spectrum: 154.97 (C-6);
152.87 (C-2); 151.08 (C-4); 127.14 (C-8); 119.19 (C-5); 108.56 (O–C–O); 76.74 (C-3′); 73.96 (C-2′);
59.10 (C-4′); 45.13 (C-1′); 27.79 and 25.34 (2 × CH3). UV spectrum (pH 7): 267.0 (10 900). Mass
spectrum: 358 (57, M + H).
4′-O,8-Anhydro-9-(2,3-O-isopropylidene-2,3,4-trihydroxybutyl)adenines (9a–9d)
A. By reaction of compound 8a with NaH. To a solution of compound 8a (0.5 g, 1.4 mmol) in
dioxane (25 ml) was added 60% dispersion of sodium hydride in mineral oil (110 mg, 2.8 mmol).
The mixture was stirred at room temperature for 2 days and then neutralized with acetic acid. After
evaporation, the residue was crystallized from ethanol to give 0.24 g (61%) of compound 9a, m.p.
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274–276 °C, RF 0.65 (S3). For C12H15N5O3 (277.3) calculated: 51.98% C, 5.45% H, 25.26% N;
1
found: 51.51% C, 5.28% H, 24.78% N. H NMR and 13C NMR spectra were identical with those of
compound 9b (see procedure B). UV (pH 7): 260.0 (13 400). Mass spectrum: 278 (100, M + H).
B. By reaction of compound 8b with potassium tert-butoxide. To a solution of compound 8b (0.1 g,
0.3 mmol) in dioxane (5 ml) was added potassium tert-butoxide (68 mg, 0.6 mmol) and the mixture
was stirred at room temperature under exclusion of moisture. After neutralization with acetic acid
and filtration, the filtrate was evaporated and the residue crystallized from ethanol to give 85 mg
(51%) of compound 9b, m.p. 278–280 °C, RF 0.61 (S3). For C12H15N5O3 (277.3) calculated: 51.98% C,
1
5.45% H, 25.26% N; found: 51.42% C, 5.38% H, 24.81% N. H NMR spectrum: 8.13 s, 1 H (H-2);
7.07 s, 2 H (NH2); 4.77–4.66 m, 2 H, 4.08 m, 2 H, 3.87–3.83 m, 2 H (NCH2, OCH2, H-2′ and H-3′);
1.45 s, 3 H and 1.37 s, 3 H (2 × CH3). 13C NMR spectrum: 154.96 (C-6); 153.86 (C-8); 152.10
(C-2); 148.82 (C-4); 114.22 (C-5); 110.67 (O–C–O); 79.24 (C-3′); 76.75 (C-2′); 70.93 (C-4′); 40.88 (C-
1′); 26.68 and 26.62 (2 × CH3). UV spectrum (pH 7): 260.0 (15 800). Mass spectrum: 278 (100, M + H).
C. By reaction of compound 8c with NaH. To a solution of compound 8c (0.5 g, 1.4 mmol) in
dioxane (25 ml) was added 60% disperion of sodium hydride in mineral oil (110 mg, 2.8 mmol).
After stirring at room temperature for 3 days, the mixture was neutralized with acetic acid, the crystals
were collected and washed with water and acetone. Yield 0.31 g (66%) of compound 9c, m.p. >250 °C,
RF 0.33 (S2). For C12H15N5O3 (277.3) calculated: 51.98% C, 5.45% H, 25.26% N; found: 51.50% C,
1
5.58% H, 25.63% N. For the H NMR and 13C NMR spectra see method D. MS: 278 (100, M + H).
D. By reaction of compound 8c with DBU. A mixture of compound 8c (0.7 g, 2 mmol), DBU (0.7 ml)
and dimethylformamide (21 ml) was heated at 110 °C for 6 h. The deposited crystals were collected,
washed with water and acetone, and dried. Yield 0.48 g (88%) of compound 9c, m.p. >250 °C, RF 0.35
(S2). For C12H15N5O3 (277.3) calculated: 51.98% C, 5.45% H, 25.26% N; found: 51.82% C, 5.32% H,
1
25.41% N. H NMR spectrum: 8.06 s, 1 H (H-2); 6.49 brs, 2 H (NH2); 4.75 dd, 1 H, J(1a′,2′) = 1.5,
J(gem) = 13.7 (Ha-1′); 4.72 ddd, 1 H, J(3′,2′) = 7.3, J(3′,4a′) = 5.4, J(3′,4b′) = 1.7 (H-3′); 4.59 dd,
1 H, J(4a′,3′) = 5.4, J(gem) = 14.9 (Ha-4′); 4.58 ddd, 1 H, J(2′,1a′) = 1.5, J(2′,1b′) = 3.9, J(2′,3′) = 7.3
(H-2′); 4.43 dd, 1 H, J(1b′,2′) = 3.9, J(gem) = 13.7 (Hb-1′); 4.37 dd, 1 H, J(4b′,3′) = 1.7, J(gem) = 14.9;
1.32 s, 3 H and 1.23 s, 3 H (2 × CH3). 13C NMR spectrum: 153.65 and 153.59 (C-8 and C-6); 150.39
(C-2); 149.45 (C-4); 115.06 (C-5); 108.30 (O–C–O); 75.18 (C-3′); 73.04 (C-2′); 68.79 (C-4′); 41.41
(C-1′); 26.10 and 24.74 (2 × CH3). Mass spectrum: 278 (52, M + H).
E. By reaction of compound 7c with lead(IV) acetate. Compound 7c (0.6 g, 2.1 mmol) was added
to a solution of lead(IV) acetate (1.15 g, 2.6 mmol) in benzene (300 ml). After reflux for 11 h,
another portion (0.5 g, 1.1 mmol) of lead(IV) acetate was added and the mixture was stirred and
refluxed for another 12 h. The hot mixture was filtered and the filtrate was concentrated. Crystal-
1
lization from methanol afforded 0.27 g (46%) of compound 9c. For the H NMR, 13C NMR and mass
spectra and m.p. see method D. UV spectrum (pH 7): 263.0 (11 573).
F. By reaction of compound 7b with lead(IV) acetate. Compound 7b (2 g, 7 mmol) was added to
a solution of lead(IV) acetate (3.7 g, 8.4 mmol) in benzene (1 l) and the mixture was refluxed for 11 h.
Another portion (1.9 g, 4.2 mmol) of lead(IV) acetate was then added and the refluxing was conti-
nued for another 11 h. The hot mixture was filtered and the filtrate was taken down. Column
chromatography and crystallization from methanol gave 0.72 g (37%) of compound 9b. For
C12H15N5O3 (277.3) calculated: 51.98% C, 5.45% H, 25.26% N; found: 51.65% C, 5.34% H, 25.37% N.
1
For H NMR, 13C NMR and mass spectra and m.p. see procedure D.
The procedure also gave 0.4 g (17%) of 9-(2R,3R)-(4-O-acetyl-2,3-O-isopropylidene-2,3,4-
trihydroxybutyl)adenine; 1H NMR spectrum: 8.14 s, 1 H and 8.09 s, 1 H (H-2 and H-8); 7.30 brs, 2 H
(NH2); 4.43 dd, 1 H, J(1a′,2′) = 4.2, J(gem) = 14.6 (Ha-1′); 4.38 dd, 1 H, J(1b′,2′) = 5.6, J(gem) = 14.6
(Hb-1′); 4.27 dt, 1 H, J(2′,3′) = 7.8 (H-2′); 4.12 dd, 2 H, J(4a′,3′) = 3.9, J(gem) = 11.7 (Ha-4′); 4.06 dd,
J(4b′,3′) = 5.8, J(gem) = 11.7 (Hb-4′); 3.94 ddd, 1 H, J(3′,2′) = 7.8 (H-3′); 2.01 s, 3 H (OAc); 1.30 s,
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3 H and 1.22 s, 3 H (2 × CH3). 13C NMR spectrum: 170.23 (CO); 156.16 (C-6); 152.76 (C-2);
149.86 (C-4); 141.50 (C-8); 118.53 (C-5); 109.55 (O–C–O); 75.89 and 75.87 (C-3′ and C-2′); 63.50
(C-4′); 44.20 (C-1′); 26.99 and 26.96 (2 × CH3). Mass spectrum: 322 (100, M + H).
G. By reaction of compound 7e with lead(IV) acetate. Lead(IV) acetate (1.58 g, 3.6 mmol) was
added to a solution of compound 7e (0.5 g, 1.8 mmol) in dry benzene (400 ml). After reflux for 10 h,
the hot mixture was filtered, the filtrate was evaporated and the crude product was crystallized from
methanol to give 0.15 g (30%) of compound 9e, m.p. >250 °C. Its 1H NMR and 13C NMR spectra
were identical with those of compound 9d (see procedure H). UV spectrum (pH 7): 263.0 (14 100).
Mass spectrum: 278 (100, M + H).
H. By reaction of compound 7d with lead(IV) acetate. Compound 7d (0.43 g, 1.5 mmol) was
added to lead(IV) acetate (1.43 g, 3.2 mmol) in dry toluene (300 ml). After reflux for 15 h, the hot
mixture was filtered and the filtrate was evaporated. Crystallization from methanol afforded 0.1 g
1
(23%) of compound 9d, m.p. >250 °C. H NMR spectrum: 8.05 s, 1 H (H-2); 6.59 brs, 2 H (NH2);
4.76 dd, 1 H, J(1a′,2′) = 1.3, J(gem) = 13.4 (Ha-1′); 4.73 ddd, 1 H, J(3′,4a′) = 5.1, J(3′,4b′) = 1.6,
J(3′,2′) = 7.5 (H-3′); 4.59 dd, 1 H, J(4a′,3′) = 5.1, J(gem) = 14.9 (Ha-4′); 4.57 ddd, 1 H, J(2′,1a′) = 1.3,
J(2′,1b′) = 3.8, J(2′,3′) = 7.5 (H-2′); 4.42 dd, 1 H, J(1b′,2′) = 3.8, J(gem) = 13.4 (Hb-1′); 4.37 dd, 1 H,
J(4b′,3′) = 1.6, J(gem) = 14.9 (Hb-4′); 1.32 s, 3 H and 1.22 s, 3 H (2 × CH3). 13C NMR spectrum:
153.79 and 153.77 (C-8 and C-6); 150.63 (C-2); 149.50 (C-4); 115.00 (C-5); 108.44 (O–C–O); 75.37
(C-3′); 73.14 (C-2′); 69.18 (C-4′); 41.53 (C-1′); 26.27 and 24.93 (2 × CH3). UV spectrum (pH 7):
263.0 (13 900). Mass spectrum: 278 (100, M + H).
The reaction mixture also contained 9-(2R,3S)-(4-O-acetyl-2,3-O-isopropylidene-2,3,4-trihydroxy-
1
butyl)adenine. H NMR spectrum: 8.14 s, 1 H and 8.02 s, 1 H (H-2 and H-8); 7.24 brs, 2 H (NH2);
4.67 ddd, 1 H, J(2′,1a′) = 3.4, J(2′,1b′) = 9.7, J(2′,3′) = 6.2 (H-2′); 4.45 td, 1 H, J(3′,4a′) = 4.6,
J(3′,2′) = J(3′,4b′) = 6.6 (H-3′); 4.35 dd, 1 H, J(1a′,2′) = 3.4, J(gem) = 13.9 (Ha-1′); 4.27 dd, 1 H,
J(4a′,3′) = 4.6, J(gem) = 11.7 (Ha-4′); 4.24 dd, 1 H, J(1b′,2′) = 9.7, J(gem) = 13.9 (Hb-1′); 4.16 dd,
1 H, J(4b′,3′) = 6.6, J(gem) = 11.7 (Hb-4′); 2.05 s, 3 H (OAc); 1.43 s, 3 H and 1.22 s, 3 H (2 × CH3).
Mass spectrum: 322 (100, M + H).
Reaction of 8-Bromo-9-(2,3-O-isopropylidene-2,3,4-trihydroxybutyl)adenines 8a–8c with Ammonia
A. Compound 8a (0.36 g, 1 mmol) in concentrated aqueous ammonia (45 ml) was heated at 100 °C
in an autoclave for 16 h. After evaporation, the residue was subjected to preparative thin-layer chro-
matography (silica gel, S3). Yield 40 mg (14%) of compound 9a and 80 mg (22%) of the starting 8a.
B. Compound 8b (1 g, 3 mmol) in concentrated aqueous ammonia (40 ml) was heated for 8 h at
100 °C in an autoclave. The solvent was evaporated and the residue was separated by preparative
thin-layer chromatography on silica gel (S2). Yield 80 mg (10%) of compound 9b (RF 0.58 (S3)), 20 mg
(2%) of the 8-hydroxy derivative 10 (RF 0.39 (S3)) and 15 mg (2%) of the 8-amino derivative 11 (RF 0.30
(S3)). A part of the starting compound 8b (0.6 g, 60%) was recovered.
1
Compound 10: H NMR spectrum: 10.22 brs, 1 H (OH); 8.02 s, 1 H (H-2); 6.45 brs, 2 H (NH2);
4.84 t, J(OH,4′) = 5.3 (OH); 4.21 brq, 1 H (H-2′); 3.97 dd, 1 H, J(1a′,2′) = 6.3, J(gem) = 13.9 (Ha-1′);
3.92 m, 1 H (H-3′); 3.86 dd, 1 H, J(1b′,2′) = 6.1, J(gem) = 13.9 (Hb-1′); 3.38 brt, 2 H, J = 5.1
(H-4′); 1.28 s, 3 H and 1.26 s, 3 H (2 × CH3). 13C NMR spectrum: 152.76 (C-6); 151.56 (C-2);
148.29 (C-8); 147.11 (C-4); 109.35 (O–C–O); 103.77 (C-5); 80.60 (C-3′); 75.53 (C-2′); 62.02 (C-4′);
42.67 (C-1′); 27.58 and 27.57 (2 × CH3).
Compound 11: 1H NMR spectrum: 7.93 s, 1 H (H-2); 6.52 br, 2 H and 6.39 br, 2 H (2 × NH2);
4.18 m, 3 H (NCH2 and OCH); 3.90 m, 1 H (OCH); 3.42 m, 2 H (OCH2); 1.28 s, 6 H (2 × CH3).
13C NMR spectrum: 152.43 (C-4); 152.18 (C-6); 150.11 (C-8); 148.97 (C-2); 116.80 (C-5); 108.89
(O–C–O); 79.45 (C-3′); 75.78 (C-2′); 61.22 (C-4′); 42.88 (C-1′); 27.23 and 26.98 (2 × CH3).
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C. Reaction of compound 8c: A solution of compound 8c (0.35 g, 1 mmol) in concentrated
aqueous ammonia (46 ml) was heated at 100 °C for 20 h in an autoclave. The reaction mixture de-
posited crystals of compound 9c which were collected, washed with methanol and ether, and dried.
Yield 0.2 g (79%) of compound 9c. The filtrate was subjected to preparative thin-layer chromato-
graphy on silica gel (S3). 1H NMR spectrum identified 8-amino-9-(2,3-O-isopropylidene-2,3,4-trihy-
1
droxybutyl)adenine as a side product: H NMR spectrum: 7.89 s, 1 H (H-2); 6.32 s, 2 H and 6.30 s,
2 H (2 × NH2); 4.90 br, 1 H (OH); 4.58 ddd, 1 H, J(2′,3′) = 6.6 (H-2′); 4.23 brq, 1 H, J = 6.1 (H-3′);
4.15 dd, 1 H, J(1a′,2′) = 9.8, J(gem) = 14.7 (Ha-1′); 4.08 dd, 1 H, J(1b′,2′) = 3.2, J(gem) = 14.7
(Hb-1′); 3.74 dd, 1 H, J(4a′,3′) = 5.8, J(gem) = 11.5 (Ha-4′); 3.59 dd, 1 H, J(4b′,3′) = 5.8, J(gem) = 11.5
(Hb-4′); 1.39 s, 3 H and 1.18 s, 3 H (2 × CH3). 13C NMR spectrum: 152.25 (C-4); 151.51 (C-6);
149.92 (C-8); 148.64 (C-2); 115.84 (C-5); 108.22 (O–C–O); 77.15 (C-3′); 73.99 (C-2′); 62.80 (C-4′);
41.67 (C-1′); 27.65 and 25.30 (2 × CH3).
Reaction of N6-Benzoyl-9-(2R,3R)-(2,3-O-isopropylidene-2,3,4-trihydroxybutyl)adenine (13) with
Lead(IV) Acetate
Compound 13 (0.4 g, 1.04 mmol) was dried by codistillation with toluene (3 × 25 ml), then dissolved
in toluene (300 ml) and lead(IV) acetate (0.7 g, 1.57 mmol) was added. After reflux for 8.5 h, the
hot mixture was filtered and the filtrate was evaporated. The residue was separated by preparative
thin-layer chromatography on silica gel (S3). Crystallization of the crude product from ethanol af-
forded 0.06 g (20%) of compound 9b.
Reaction of 9-(3-Hydroxypropyl)adenine (12a) with Lead(IV) Acetate
A mixture of 9-(3-hydroxypropyl)adenine (12a; 0.35 g, 1.8 mmol), lead(IV) acetate (1.6 g, 3.6 mmol)
and benzene (200 ml) was refluxed for 15 h. The usual workup afforded 0.12 g (34%) of the starting
1
compound 12a and 9-(3-acetoxypropyl)adenine (0.05 g, 11%) as the only product. H NMR spectrum:
8.14 s, 1 H and 8.135 s, 1 H (H-2 and H-8); 7.23 brs, 2 H (NH2); 4.22 t, 2 H, J(1′,2′) = 7.1 (H-1′);
3.97 t, 2 H, J(3′,2′) = 6.3 (H-3′); 2.13 pent, 2 H, ΣJ = 26.5 (H-2′); 1.93 s, 3 H (OAc). Mass spectrum:
236 (100, M + H).
Reaction of 9-(4-Hydroxybutyl)adenine (14) with Lead(IV) Acetate in Acetic Acid
A suspension of 9-(4-hydroxybutyl)adenine (14; 0.1 g, 0.48 mmol) and lead(IV) acetate (0.33 g, 0.75 mmol)
in acetic acid (25 ml) was stirred at room temperature overnight and then was heated at 100 °C for
5 h. Another portion of lead(IV) acetate (0.22 g, 0.50 mmol) was added and the heating at 100 °C
was continued for another 3.5 h. The hot reaction mixture was filtered, the residue was codistilled
with dioxane and extracted with chloroform. After evaporation of the solvent, the residue was separated
1
by preparative thin-layer chromatography on silica gel (S1). H NMR spectrum detected the O-acetyl
derivative and the N6,O-diacetyl derivative of the starting compound 14 as the only products.
1
N6-Acetyl-9-(4-acetoxybutyl)adenine. H NMR spectrum: 10.40 br, 1 H (NH); 8.61 s, 1 H and 8.47 s,
1 H (H-2 and H-8); 4.27 t, 2 H, J(1′,2′) = 7.1 (H-1′); 4.00 t, 2 H, J(4′,3′) = 6.4 (H-4′); 1.99 s, 3 H
and 1.97 s, 3 H (NAc, OAc); 1.92–1.86 m, 2 H and 1.63–1.52 m, 2 H (H-2′ and H-3′).
1
9-(4-Acetoxybutyl)adenine. H NMR spectrum: 8.15 s, 1 H and 8.14 s, 1 H (H-2 and H-8); 7.21 brs,
2 H (NH2); 4.16 t, 2 H, J(1′,2′) = 7.0 (H-1′); 4.00 t, 2 H, J(4′,3′) = 6.6 (H-4′); 1.97 s, 3 H (OAc);
1.85 m, 2 H and 1.52 m, 2 H (H-2′ and H-3′).
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Janeba, Holy, Votavova, Masojidkova:
4′,8-Anhydro-9-(4-hydroxybutyl)adenine (15)
A suspension of 9-(4-hydroxybutyl)adenine (14; 0.5 g, 2.4 mmol, pre-dried by codistillation with toluene
(3 × 25 ml)) in dry toluene (300 ml) was stirred and refluxed. Lead(IV) acetate (2.15 g, 4.8 mmol)
was added and the mixture was refluxed for 9 h. The mixture was filtered while hot and the filtrate
was taken down. Crystallization from ethanol–ethyl acetate afforded compound 15 (0.1 g, 20%).
Thin-layer chromatography (silica gel, S2) of the mother liquors afforded further 0.15 g of compound 15
and 0.1 g (20%) of the starting compound 14. Total yield of the compound 15 was 0.25 g (51%).
M.p. 245–247 °C, RF 0.71 (S2). For C9H11N5O (205.2) calculated: 52.67% C, 5.40% H, 34.13% N;
found: 52.80% C, 5.22% H, 33.90% N. 1H NMR spectrum: 8.08 s, 1 H (H-2); 6.93 brs, 2 H (NH2);
4.21 m, 2 H (H-1′); 4.08 m, 2 H (H-4′); 2.03 m, 2 H and 1.86 m, 2 H (H-2′ and H-3′). 13C NMR
spectrum: 156.43 (C-8); 154.73 (C-6); 151.56 (C-2); 148.89 (C-4); 114.83 (C-5); 73.70 (C-4′); 42.15
(C-1′); 30.68 (C-3′); 26.09 (C-2′). Mass spectrum: 206 (100, M + H).
5′-O,8-Cyclo-2′,3′-O-isopropylideneinosine (17)
Lead(IV) acetate (1.80 g, 4 mmol) was added to a solution of 2′,3′-O-isopropylideneinosine (16; 0.5 g,
1.62 mmol) in dry benzene (500 ml). After reflux for 7 h, the hot mixture was filtered and the filtrate
was evaporated. Crystallization from ethanol afforded 0.2 g (40%) of compound 17, m.p. >250 °C,
RF 0.63 (S3). For C13H14N4O5 (306.3) calculated: 50.98% C, 4.61% H, 18.29% N, found: 51.43% C,
5.10% H, 17.86% N. 1H NMR spectrum: 12.40 brs, 1 H (NH); 8.06 s, 1 H (H-2); 6.00 brs, 1 H,
J(1′,2′) = 0.5 (H-1′); 5.09 brd, 1 H, J(2′,1′) = 0.5, J(2′,3′) = 5.6 (H-2′); 4.93 brd, 1 H, J(3′,4′) = 0.5,
J(3′,2′) = 5.6 (H-3′); 4.76 brs, 1 H (H-4′); 4.62 dd, 1 H, J(5a′,4′) = 2.2, J(gem) = 12.9 (Ha-5′); 4.11 brd,
1 H, J(5b′,4′) = 1.0, J(gem) = 12.9 (Hb-5′); 1.45 s, 3 H and 1.30 s, 3 H (2 × CH3). 13C NMR spectrum:
156.03 (C-6); 152.61 (C-8); 146.15 (C-2); 146.02 (C-4); 119.72 (C-5); 112.13 (O–C–O); 86.44 (C-1′);
85.62 (C-4′); 84.94 (C-2′); 81.07 (C-3′); 74.40 (C-5′); 26.04 and 24.43 (2 × CH3). Mass spectrum:
307 (100, M + H).
The authors are indebted to Dr H. Dvorakova of this Institute for valuable help and discussion, to Dr
K. Ubik and Dr J. Kohoutova for the mass spectral measurements and to the staff of the Analytical
Laboratory (Dr V. Pechanec, Head) for the elemental analyses.
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