Novel synthesis of purine acyclonucleosides possessing a chiral 9-hydroxyalkyl group by sugar modification of 9-D-ribitylpurines

Article abstract of DOI:10.1039/a707193k

A novel approach to the synthesis of purine acyclonucleosides having chiral carbons in the N⁹-hydroxyalkyl chain was achieved by using 9-(2,3-O-isopropylidene-D-ribityl)purines 1, which are readily prepared from commercially available purine nucleosides. 9-[(2S,3.R)-2,3,4-Trihydroxybutyl]purines 4a and 4b, 9-[(2S,3S)-2,3,4-trihydroxybutyl]purines 6a and 6b, L-eritadenine 8, and its analogue 11 are conveniently synthesized via key intermediates, (2S,3S)-2,3-isopropylidenedioxy-4-(purin-9-yl)butanals 2 prepared by NaIO₄ oxidation of diols 1.

Full text of DOI:10.1039/a707193k

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Novel synthesis of purine acyclonucleosides possessing a chiral
9-hydroxyalkyl group by sugar modification of 9-D-ribitylpurines
Kosaku Hirota,*,a Yasunari Monguchi,a Hironao Sajiki,a Magoichi Sakoa
and Yukio Kitadeb
a Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, Mitahora-higashi,
Gifu 502-8585, Japan
b Department of Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido,
Gifu 501-1193, Japan
A novel approach to the synthesis of purine acyclonucleosides having chiral carbons in the N9-hydroxy-
alkyl chain was achieved by using 9-(2,3-O-isopropylidene-D-ribityl)purines 1, which are readily prepared
from commercially available purine nucleosides. 9-[(2S,3R)-2,3,4-Trihydroxybutyl]purines 4a and 4b,
9-[(2S,3S)-2,3,4-trihydroxybutyl]purines 6a and 6b, L-eritadenine 8, and its analogue 11 are conveniently
synthesized via key intermediates, (2S,3S)-2,3-isopropylidenedioxy-4-(purin-9-yl)butanals 2 prepared by
NaIO4 oxidation of diols 1.
Introduction
B
B
HO
During the search for effective, selective and nontoxic antiviral
O
HOH2C
agents, a potent antiviral agent, 9-[(2-hydroxyethoxy)methyl]-
guanine (acyclovir) has been developed for the treatment of
herpes virus type 1 infections.1 The discovery of acyclovir has
stimulated extensive research in the synthesis of new acyclo-
nucleosides in which the carbohydrate moieties are acyclic
chains mimicking the sugar portion of naturally occurring
nucleosides. Several purine acyclonucleosides having chiral car-
bons in the N9-hydroxyalkyl chain, such as -eritadenine2,3 and
buciclovir4 have been shown to possess antiviral activity. Most
H
H
HO
OH
HO
OH
Scheme 1 B = adenin-9-yl or guanin-9-yl
analogues 8 and 11 as potential antiviral agents by taking
advantage of two of the chiral carbons of substrates 1.8
Results and discussion
NH2
O
First, (2S,3S)-4-(adenin-9-yl)-2,3-isopropylidenedioxybutanal
2a was synthesized as a chiral key intermediate for the prepar-
ation of acycloadenosines. Oxidation of diol 1a7 with NaIO4
afforded aldehyde 2a in 92% yield. The structure of compound
2a was determined by 1H NMR spectral analyses. Thus, the 1H
NMR {(CD3)2SO, [2H6]DMSO} spectrum of compound 2a
exhibited complicated signals at room temperature. Upon rais-
ing the probe temperature to 100 ЊC these signals came to merge
into one set of signals for the aldehyde structure. The aldehyde
2a would exist in the form of both a polymer and a hydrate at
ambient temperature; Schmid et al. have reported that -glycer-
aldehyde acetonide tended to polymerize and easily form a
hydrate in the presence of water.9 Reduction of compound 2a
with NaBH4 afforded the primary alcohol 3a in 78% yield. The
stereochemistry of alcohol 3a was confirmed by its conversion
into the corresponding (R)-(ϩ)-α-methoxy-α-(trifluoromethyl)-
phenylacetate (MTPA ester).10 19F NMR analyses of the ester
showed no formation of any detectable epimeric isomer. This
fact evidently indicates that the formation of compounds 2a
and 3a proceeds with complete retention of steric configur-
ation. The alcohol 3a smoothly underwent removal of the
isopropylidene protection with 80% aq. AcOH to afford 9-
[(2S,3R)-2,3,4-trihydroxybutyl]adenine 4a,11,12 quantitatively.
On the other hand, an epimer 5a was synthesized by inversion
at the 2-position of the aldehyde 2a and by the subsequent
reduction. Lee and co-workers have reported that an alcoholic
solvent was favourable for the easy epimerization of 2,3-
erythro-aldose acetonide to 2,3-threo-aldose acetonide.13 There-
fore, treatment of compound 2a with NaOMe in MeOH fol-
lowed by reduction with NaBH4 gave a mixture of alcohols 5a
N
N
N
N
N
NH
N
N
NH2
HO2C
H
HOH2C
H
H
HO
OH
HO
D-eritadenine
buciclovir
synthetic methods for the preparation of such acyclonucleo-
sides involve the condensation of a base moiety with an
appropriate side-chain moiety.5 These methods, however, incur
some difficulties in stereoselective synthesis of the side-chain
moiety and/or regioselective condensation of the base moiety
with the side-chain moiety. Synthetic methods starting from
commercially available nucleosides such as adenosine and
guanosine have been unprecedented except for an example of
oxidative cleavage of the 2Ј,3Ј-cis-diol portion of ribonucleo-
sides with NaIO4.6
A few years ago we reported a convenient formation of
acyclonucleosides, 9--ribitylpurines 1, by the reductive
cleavage of the C-1Ј᎐O-4Ј bond of purine nucleosides with
diisobutylaluminium hydride (DIBAL).7 The 9--ribitylpurines
1 were utilized for the development of a novel methodology to
prepare acyclonucleosides having chiral carbons in the side
chain from commercially available purine nucleosides. Our
strategy involves two disconnections of the C-1Ј᎐O-4Ј and
C-4Ј᎐C-5Ј bonds of purine nucleosides as depicted in Scheme
1. In this paper, we describe the asymmetric construction of
9-(2,3,4-trihydroxybutyl)purines
4 and 6 and eritadenine
J. Chem. Soc., Perkin Trans. 1, 1998
941

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and 3a (5a:3a = 94:6). Both epimers could be separated by
silica gel column chromatography to give isomer 5a in 66%
yield. Enantiomeric purity of product 5a was confirmed by
the conversion to its MTPA ester and its 19F NMR analysis.
Deprotection of compound 5a afforded 9-[(2S,3S)-2,3,4-
trihydroxybutyl]adenine 6a12 in 60% yield (Scheme 2).
any detectable epimer. Deprotection of compound 7 with 10%
aq. AcOH gave -eritadenine 8 quantitatively, whose optical
activity, [α]D26 Ϫ14.3 (c 0.07, 1  HCl),† was identical with that
reported by Holy et al. (Scheme 3).3b
A
A
This methodology was applied to the synthesis of acyclogua-
nosines. When oxidation of 9-(2,3-O-isopropylidene--ribityl)-
guanine 1b and subsequent reduction were conducted under
analogous reaction conditions, a diastereomeric mixture of
compound 3b (erythro) and its (3ЈS)-isomer 5b (threo) was
formed in the ratio 83:17. The NaIO4 oxidation of diol 1b in a
sodium acetate buffer (pH 4) gave the aldehyde 2b as a hydrate
in 87% yield and subsequent reduction of aldehyde 2b led to the
quantitative formation of a chiral alcohol 3b without epimeri-
zation. Deprotection of compound 3b with 80% aq. AcOH
afforded 9-[(2S,3R)-2,3,4-trihydroxybutyl]guanine 4b in 93%
yield (Scheme 2). The preparation of a (3ЈS)-epimer 6b was
HO2C
H
ii
i
HO2C
H
H
H
O
O
HO
OH
8
7
A
A
A
HO
v
iii
iv
N
NC
NC
H
2a
H
H
H
H
H
O
O
O
O
HO
OH
B
B
B
HO
OH
9
10
11
i
ii
OHC
H
HOH2C
A
H
H
O
H
A
O
O
O
O
O
HO
HO
vi
v
HO
HO
H
1a, b
2a, b
3a, b
H
O
O
HO
13
OH
iv
iii
B
A = adenin-9-yl
12
B
B
Scheme 3 Reagents and conditions: i, Pt/C, O2, water; ii, 10% AcOH;
iii, NH2OHؒHCl, NaOMe, MeOH; iv, SOCl2, DMF; v, CF3CO2H; vi,
HCHO, 2  NaOH, water; then NaBH4
HOH2C
HOH2C
H
HOH2C
H
iii
H
O
H
H
H
OH
O
HO
OH
HO
Furthermore, the synthesis of the nitrile 11, which is struc-
turally analogous to -eritadenine 8, was attempted. The reac-
tion of compound 2a with 1.5 mol equiv. of hydroxylamine
afforded the oxime 9 in 71% yield as a mixture of geometrical
isomers (E:Z = 38:62). Dehydration of oxime 9 by using 5 mol
equiv. of thionyl dichloride in dimethylformamide (DMF) gave
the nitrile 10 in 79% yield as a single diastereomer. The steric
configuration of compound 10 (erythro-isomer) was confirmed
6a, b
5a, b
4a, b
a series : B = adenin-9-yl
b series : B = guanin-9-yl
Scheme 2 Reagents and conditions: i, for 2a, aq. NaIO4; for 2b, NaIO4,
AcOH–AcONa buffer (pH 4); ii, aq. NaBH4, pH 7–8; iii, 80% AcOH;
iv, for 5a, NaOMe, MeOH, then aq. NaBH4; for compound 5b, K2CO3,
MeOH; then aq. NaBH4
1
by comparison of its H NMR spectrum with those of com-
pounds 2a, 3 and 5 and by nuclear Overhauser effect (NOE)
experiments on compounds 10 and 5a. Thus, the difference in
chemical shifts of the two methyl singlets of the isopropylidene
group in nitrile 10 (0.23 ppm) is close to those in erythro-
compounds 2a, 3a and 3b (0.22, 0.21, and 0.19 ppm, respect-
ively), but larger than those in threo-compounds 5a and 5b (0.06
and 0.04 ppm, respectively).13b Irradiation of 2-H of compound
10 showed an NOE enhancement (8.6%) at 3-H, whereas in a
similar NOE experiment on threo-compound 5a an enhance-
ment was hardly observed (see Experimental section). These
facts supported the idea that the conversion of 2a into 10 pro-
ceeded with retention of enantiomeric configuration; otherwise,
the inversion at both the 2- and 3-position would occur com-
pletely. Deprotection of compound 10 with CF3CO2H (TFA)
afforded the desired dihydroxy nitrile 11 in 57% yield.
Another synthetic application of compound 2a as a chiral
intermediate was examined for the synthesis of tetraol 13 which
has the sole chiral centre in the alkyl chain. Crossed aldol con-
densation of aldehyde 2a and formaldehyde in basic media fol-
lowed by NaBH4 reduction afforded isopropylidene-protected
tetraol 12 in 89% yield in a one-pot procedure. The optical
rotation of product 12 was [α]D28 Ϫ38.5 (c 0.27, MeOH). The
desired tetraol 13 was obtained by treatment of compound 12
with TFA in 83% yield.
conducted using a modified method of that described for com-
pound 6a. Thus, treatment of compound 2b with K2CO3 in
MeOH gave the (2R)-epimer of aldehyde 2b as a diastereomeric
mixture with 2b (threo:erythro = >95:<5) in 75% yield, and
subsequent NaBH4 reduction gave the corresponding alcohol
5b. Deprotection of compound 5b afforded the desired 9-
[(2S,3S)-2,3,4-trihydroxybutyl]guanine 6b as the sole isomer in
88% yield.
It is noteworthy that the stereochemistry at the 3Ј-position of
acyclonucleosides 4 and 6 could be easily controlled by the use
of the aldehyde 2 as a chiral pool.
The aldehyde 2a was utilized as a novel approach to the syn-
thesis of -eritadenine 8, which is the enantiomer of naturally
occurring -eritadenine.3 Votruba and Holy have reported that
-eritadenine, which is the most effective, next to -eritadenine,
of the four stereoisomeric eritadenines, inhibits S-adenosyl--
homocysteine hydrolase.3a Our first attempted preparation of -
eritadenine 8, oxidation of compound 2a with KMnO4 in aq.
alkaline solution, resulted in the formation of an epimeric mix-
ture of the corresponding carboxylic acid 7 (erythro) and its
(2R)-isomer (threo) in 63% yield (erythro:threo = 32:68). The
epimerization of -eritadenine methyl ester under basic condi-
tions has been described in the literature.14 Therefore, the Pt/
C-catalyzed oxidation of compound 2a with O2 was carried out
under neutral conditions to afford acid 7 in 46% yield without
† [α]D-Values are given in units of 10Ϫ1 deg cm2 gϪ1
.
942
J. Chem. Soc., Perkin Trans. 1, 1998

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Among acyclic analogues of adenosine, compounds 4a, 6a
and 13 were virtually inactive against influenza A, respiratory
syncytial virus, human immunodeficiency virus, herpes simplex
virus type 1, and human cytomegalovirus with EC50 values of
>40 µg mlϪ1. Biological evaluations of adenosine analogues 8
and 11 and guanosine analogues 4b and 6b are in progress.
This methodology using 2Ј,3Ј-O-isopropylidene-protected 9-
-ribitylpurines as chiral starting materials was shown to be
widely applicable to the synthesis of biologically interesting
acyclonucleosides. In particular, the aldehydes 2a and 2b are
useful intermediates for the preparation of purine acyclonucleo-
sides mimicking ribonucleosides.
quenched with ethylene glycol (13.9 µl, 0.25 mmol), further
stirred at 0 ЊC for 1 h and concentrated in vacuo. The residue
was purified by reversed-phase chromatography (water–MeCN,
9:1) to give solid aldehyde 2b as a monohydrate (134.8 mg,
87%), mp 257 ЊC (decomp.) (Found: C, 46.2; H, 5.45; N, 22.4.
C12H17N5O5 requires C, 46.30; H, 5.50; N, 22.50%); λmax(water)/
nm 252; νmax(KBr)/cmϪ1 3346, 3160, 2989, 2942, 2784, 1693,
1657, 1621, 1575, 1542, 1486, 1384, 1222, 1166, 1076, 1044, 889,
847, 780, 726, 637 and 580; δH(400 MHz; [2H6]DMSO) 1.21 and
1.43 (each 3 H, s, isopropylidene), 3.96 (1 H, t, J 6.8, 2-H), 4.00
(1 H, dd, J 14.2 and 10.7, 4-H), 4.26 (1 H, dd, J 14.2 and 2.4,
4-H), 4.40 (1 H, ddd, J 10.7, 6.8 and 2.4, 3-H), 4.88 (1 H, td,
J 6.8 and 5.9, 1-H), 6.16 (1 H, d, J 6.8, 1-OH), 6.23 (1 H, d,
J 5.9, 1-OH), 6.41 (2 H, br s, guanine 2-NH2), 7.59 (1 H, s,
guanine 8-H) and 10.48 (1 H, s, guanine N1-H); δC([2H6]DMSO)
25.36, 27.78, 43.45, 74.25, 79.59, 88.04, 108.21, 116.33, 138.09,
151.13, 153.34 and 156.69; m/z (FAB, NBA) 312 (Mϩ ϩ H,
88%).
Experimental
Mps (uncorrected) were determined with a Yanagimoto melting
point apparatus. Elemental analyses were performed by the
microanalytical laboratory of our university. Optical rotations
were measured on a JASCO DIP-370 polarimeter. UV absorp-
tion spectra were recorded on a Shimadzu 260 spectrophoto-
meter. IR spectra were measured using a Perkin-Elmer 1640
FT-IR spectrometer. 1H NMR spectra were recorded on a
JEOL JNM GX-270 (270 MHz) or a JNM EX-400 (400 MHz)
spectrometer. Chemical shifts (δH) are expressed in ppm relative
to tetramethylsilane in CDCl3 as solvent or internally refer-
enced to the residual protonated solvent resonances (δH 2.49) in
[2H6]DMSO as solvent. J-Values are given in Hz. 13C and 19F
NMR spectra were recorded on a JEOL JNM EX-400 spec-
trometer (100 MHz and 376 MHz, respectively). Solvent peak
(CDCl3 δC 77.0; [2H6]DMSO: δC 39.5) was used as an internal
standard for 13C NMR, and TFA (δF Ϫ76.5) was used as an
external standard for 19F NMR. Mass spectra and high-
resolution mass spectra were taken on JEOL JMS-D 300 or a
JMS-SX 102A machine. Fast-atom bombardment (FAB) mass
spectra were measured with m-nitrobenzyl alcohol (NBA) as
matrix.
9-[(2ЈS,3ЈR)-4Ј-Hydroxy-2Ј,3Ј-isopropylidenedioxybutyl]-
adenine 3a
To aq. aldehyde 2a (27.7 mg, 0.1 mmol in 5 ml) was added
NaBH4 (18.9 mg, 0.5 mmol) at 0 ЊC and then the pH of the
reaction mixture was adjusted to 7–8 with 10% aq. AcOH.
After being stirred at 0 ЊC for 1.5 h, the mixture was concen-
trated in vacuo. The residue was purified by column chroma-
tography on silica gel (CHCl3–MeOH, 18:1) to give compound
3a (21.7 mg, 78%) as a solid, which was recrystallized from
EtOH–Et2O, mp 192–194 ЊC (lit.,12 182–184 ЊC) (Found: C,
51.45; H, 6.2; N, 24.75. C12H17N5O3ؒ1/10H2O requires C, 51.27;
H, 6.17; N, 24.92%); the existence of water in this product
was confirmed by 1H NMR analysis; λmax(MeOH)/nm 260;
νmax(KBr)/cmϪ1 3436, 3298, 3225, 2986, 2943, 2881, 1676, 1605,
1575, 1477, 1418, 1384, 1306, 1242, 1061, 909, 844, 779 and 721;
δH(270 MHz; [2H6]DMSO) 1.20 and 1.41 (each 3 H, s, isopro-
pylidene), 3.62 (2 H, t, J 5.4, 4Ј-H2), 4.19 (1 H, dd, J 13.7 and
10.3, 1Ј-H), 4.24 (1 H, dd, J 6.4 and 5.4, 3Ј-H), 4.36 (1 H, dd,
J 13.7 and 2.4, 1Ј-H), 4.56 (1 H, ddd, J 10.3, 6.4 and 2.4, 2Ј-H),
5.03 (1 H, t, J 5.4, 4Ј-OH), 7.19 (2 H, s, 6-NH2), 8.07 (1 H, s,
2- or 8-H) and 8.12 (1 H, s, 8- or 2-H); δC([2H6]DMSO) 25.35,
27.83, 43.47, 58.96, 74.54, 76.81, 108.12, 118.54, 141.15, 149.52,
152.28 and 155.90; m/z (EI) 279 (Mϩ, 22%), 264 (46), 204 (97)
and 136 (100).
TLC analyses were carried out on precoated Silicagel 60 F254
plates (Merck, Art 5715). The silica gel used for column chro-
matography was Wakogel C-300 or Fujigel BW-200. Reversed-
phase chromatography was accomplished by Sep-Pak (C18)
cartridge (Waters).
(2S,3S)-4-(Adenin-9-yl)-2,3-isopropylidenedioxybutanal 2a
To a stirred aqueous solution of 9-(2,3-O-isopropylidene--
ribityl)adenine 1a (853 mg, 2.76 mmol in 25 ml) was added
NaIO4 (885 mg, 4.14 mmol) at 0 ЊC and the mixture was stirred
at 0 ЊC for 1 h. The mixture was quenched with ethylene glycol
(153.8 µl, 2.76 mmol) and was further stirred at 0 ЊC for 1 h.
After the solvent had been evaporated off in vacuo, anhydrous
MeOH was added to the residue. The precipitate was filtered off
over a Celite pad and then the filtrate was concentrated to dry-
ness. The residue was purified by column chromatography on
silica gel (CHCl3–MeOH, 30:1) to give title aldehyde 2a (700
9-[(2ЈS,3ЈR)-4Ј-Hydroxy-2Ј,3Ј-isopropylidenedioxybutyl]-
guanine 3b
Compound 2b (15.6 mg, 0.05 mmol) was treated in a manner
similar to that described for the preparation of compound 3a.
After being stirred at room temperature for 1 h, the mixture was
concentrated in vacuo. The residue was purified by reversed-
phase chromatography (water–MeCN, 9:1) to give title com-
pound 3b (14.6 mg, 99%) as a solid, λmax(MeOH)/nm 254;
νmax(KBr)/cmϪ1 3397, 3135, 2986, 2939, 2772, 1691, 1655, 1479,
1379, 1219, 1167, 1072, 1050, 842, 781, 694 and 634; δH(400
MHz; [2H6]DMSO) 1.22 and 1.41 (each 3 H, s, isopropylidene),
3.57 (2 H, m, 4Ј-H2), 4.01 (1 H, dd, J 14.2 and 10.3, 1Ј-H), 4.17
(1 H, dd, J 14.2 and 2.9, 1Ј-H), 4.20 (1 H, q, J 6.4, 3Ј-H), 4.48
(1 H, ddd, J 10.3, 6.4 and 2.9, 2Ј-H), 4.98 (1 H, t, J 4.9, 4Ј-OH),
6.43 (2 H, br s, 2-NH2), 7.64 (1 H, s, 8-H) and 10.50 (1 H, s, N1-
H); δC([2H6]DMSO) 25.31, 27.80, 43.08, 59.00, 74.58, 76.75,
108.04, 116.35, 137.76, 151.17, 153.43 and 156.71; m/z (EI) 295
(Mϩ, 87%), 280 (63), 220 (75), 165 (100) and 152 (98) [Found
(EI): Mϩ, 295.1289. C12H17N5O4 requires M, 295.1280].
mg, 92%) as an amorphous substance, λmax(water)/nm 260; νmax
-
(KBr)/cmϪ1 3345, 3213, 2988, 2938, 1615, 1479, 1380, 1331,
1298, 1222, 1162, 1076, 891, 797 and 648; δH(400 MHz;
[2H6]DMSO; 100 ЊC) 1.32 and 1.54 (each 3 H, s, isopropyl-
idene), 4.20 (1 H, dd, J 14.2 and 9.3, 4-H), 4.44 (1 H, dd, J 14.2
and 3.4, 4-H), 4.74 (1 H, dd, J 7.3 and 2.0, 2-H), 4.90 (1 H, ddd,
J 9.3, 7.3 and 3.4, 3-H), 6.78 (2 H, br s, adenine 6-NH2), 8.02
(1 H, s, adenine, 2- or 8-H), 8.16 (1 H, s, adenine 8- or 2-H) and
9.74 (1 H, d, J 2.0, CHO); m/z (EI) 277 (Mϩ, 17%), 190 (100)
and 136 (79) [Found (EI): Mϩ, 277.1185. C12H15N5O3 requires
M, 277.1175].
Preparation of (؉)-MTPA ester of alcohol 3a
(2S,3S)-4-(Guanin-9-yl)-2,3-isopropylidenedioxybutanal 2b
To a stirred suspension of 9-(2,3-O-isopropylidene--ribityl)-
guanine 1b (162.7 mg, 0.5 mmol) in AcOH–AcONa buffer (pH
4) (~100 ml) was added NaIO4 (160.4 mg, 0.75 mmol) at 0 ЊC
and the mixture was stirred at room temp. for 1.5 h before being
To a solution of (R)-(ϩ)-α-(trifluoromethyl)phenylacetic acid
(19.7 mg, 0.084 mmol) and DMF (6.5 µl, 0.084 mmol) in hex-
ane (3.5 ml) was added oxalyl dichloride (36.6 µl, 0.42 mmol) at
room temp. After being stirred for 1 h, the mixture was filtered
and the filtrate was evaporated in vacuo. To the residue was
J. Chem. Soc., Perkin Trans. 1, 1998
943

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added a mixture of alcohol 3a (19.6 mg, 0.07 mmol), Et3N (29.3
µl, 0.21 mmol) and 4-(dimethylamino)pyridine (DMAP) (6.0
mg, 0.049 mmol) in CH2Cl2 (0.7 ml), and further pyridine (0.1
ml) after 23 h. This operation was repeated until the disappear-
ance of starting alcohol 3a was observed by TLC analysis
(CHCl3–MeOH, 5:1). As a result MTPA (78.7 mg, 0.336
mmol), DMF (26.0 µl, 0.377 mmol), hexane (14 ml), oxalyl
dichloride (166.4 µl, 1.907 mmol), Et3N (118.5 µl, 0.85 mmol)
and DMAP (24.0 mg, 0.196 mmol) were used for the esteri-
fication. Several drops of MeOH were added to the mixture,
which was then concentrated in vacuo. The residue was purified
by column chromatography on silica gel (CHCl3–MeOH,
100:1–50:1) to give the (ϩ)-MTPA ester of alcohol 3a (26.1
mg, 75%) as a solid, λmax(MeOH)/nm 260; νmax(KBr)/cmϪ1 3449,
3334, 3316, 3142, 2951, 2856, 1761, 1665, 1605, 1579, 1477,
1380, 1271, 1243, 1168, 1127, 1086, 1022, 989, 920, 724 and
652; δH(400 MHz; CDCl3) 1.27 and 1.50 (each 3 H, s, isopro-
pylidene), 3.60 (3 H, s, OCH3), 3.85 (1 H, dd, J 14.2 and 9.8,
1Ј-H), 4.32 (1 H, dd, J 14.2 and 2.4, 1Ј-H), 4.44–4.52 (3 H, m,
2Ј-, 3Ј- and 4Ј-H), 4.58 (1 H, m, 4Ј-H), 5.89 (2 H, s, 6-NH2),
7.33–7.58 (5 H, m, Ph), 7.71 (1 H, s, 2- or 8-H) and 8.33 (1 H, s,
8- or 2-H); δF(CDCl3) Ϫ72.14; m/z (EI) 495 (Mϩ, 14%), 480
(24), 204 (100) and 189 (40) [Found (EI): Mϩ, 495.1738.
C22H24F3N5O5 requires M, 495.1729].
anhydrous MeOH (2.0 ml) at room temp. was added NaOMe
(30.7 µl of a 4.88  solution in MeOH, 0.15 mmol) dropwise.
After being stirred at room temp. for 11 h, the resulting solution
was quenched with AcOH (1.0 ml of a 5 × 10Ϫ2  solution in
MeOH, 0.05 mmol) and concentrated in vacuo. The residue was
roughly purified by column chromatography on silica gel
(CHCl3–MeOH, 18:1) to give the (2R)-epimer of aldehyde 2a
(18.3 mg, 0.066 mmol).
To an aqueous solution of the (2R)-epimer of aldehyde
2a (18.3 mg, 0.066 mmol in 3 ml) was added NaBH4 (10.1
mg, 0.33 mmol) at 0 ЊC. After being stirred at 0 ЊC for 0.5 h
and then being stirred at room temp. for 1 h, the mixture was
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (CHCl3–MeOH, 17:1) to give title
compound 5a (18.5 mg, 66% for 2 steps from aldehyde 2a) as a
solid, which was recrystallized from EtOH–Et2O, mp 167–
169 ЊC (lit.,12 158–159 ЊC) [Found: C, 51.75; H, 6.2; N, 24.5.
C12H17N5O3ؒ1/10(C2H5)2O requires C, 51.94; H, 6.33; N,
24.43%]; the existence of diethyl ether in this product was con-
firmed by 1H NMR analysis; λmax(MeOH)/nm 259; δH(400
MHz; [2H6]DMSO) 1.21 and 1.27 (each 3 H, s, isopropylidene),
3.42–3.49 (2 H, m, 4Ј-H2), 3.76 (1 H, dt, J 7.8 and 4.9, 3Ј-H),
4.19 (1 H, ddd, J 7.8, 6.4 and 4.4, 2Ј-H), 4.30 (1 H, dd, J 14.7
and 6.4, 1Ј-Ha), 4.39 (1 H, dd, J 14.7 and 4.4, 1Ј-Hb), 4.89 (1 H,
t, J 5.4, 4Ј-OH), 7.20 (2 H, br s, 6-NH2), 8.06 (1 H, s, 2- or 8-H)
and 8.13 (1 H, s, 8- or 2-H); NOE, irradiate 2Ј-H, observe 4Ј-H
(1.7%), 3Ј-H (1.8%) and 1Ј-Hb (2.1%); irradiate 3Ј-H, observe
4Ј-H (1.8%), 2Ј-H (1.4%), 1Ј-Ha (1.5%) and 1Ј-Hb (1.0%);
δC([2H6]DMSO) 26.85, 27.03, 44.62, 61.12, 75.89, 78.87, 108.74,
118.32, 141.31, 149.63, 152.50 and 155.92; m/z (FAB, NBA) 280
(M ϩ H, 84%).
9-[(2ЈS,3ЈR)-2Ј,3Ј,4Ј-Trihydroxybutyl]adenine 4a
A solution of partially protected triol 3a (42 mg, 0.15 mmol) in
80% aq. AcOH was stirred at 60 ЊC for 5 h and then the solvent
was evaporated off in vacuo. The residue was purified by
reversed-phase chromatography (water–MeCN, 19:1) to give
title triol 4a (35 mg, 98%) as a solid, mp 232–233 ЊC (lit.,11
218–219 ЊC; lit.,12 >260 ЊC) (Found: C, 44.5; H, 5.4; N, 29.05.
C9H13N5O3ؒ1/8H2O requires C, 44.76; H, 5.53; N, 29.00%);
9-[(2ЈS,3ЈS)-4Ј-Hydroxy-2Ј,3Ј-isopropylidenedioxybutyl]guanine
5b
1
the existence of water in this product was confirmed by H
NMR analysis; λmax(MeOH)/nm 260; νmax(KBr)/cmϪ1 3396,
3331, 3263, 2925, 1659, 1608, 1577, 1487, 1419, 1334, 1306,
1248, 1209, 1080, 1054, 887, 796, 767, 724, 683, 651 and 598;
δH(400 MHz; [2H6]DMSO) 3.29 (1 H, m, 3Ј-H), 3.38 (1 H, dt,
J 10.8 and 5.4, 4Ј-H), 3.57 (1 H, ddd, J 10.8, 5.4 and 3.9,
4Ј-H), 3.70 (1-H, m, 2Ј-H), 4.04 (1 H, dd, J 14.2 and 8.3,
1Ј-H), 4.40 (1 H, dd, J 14.2 and 2.9, 1Ј-H), 4.45 (1 H, t,
J 5.4, 4Ј-OH), 4.97 (1 H, d, J 5.4, 3Ј-OH), 5.07 (1 H, d, J 6.4,
2Ј-OH), 7.16 (2 H, br s, 6-NH2), 8.00 (1 H, s, 2- or 8-H) and
8.11 (1 H, s, 8- or 2-H); δC([2H6]DMSO) 46.47, 63.00,
69.68, 73.30, 118.58, 141.80, 148.65, 152.10 and 155.90; m/z
(EI) 239 (Mϩ, 11%), 221 (23), 190 (36), 178 (94), 148 (96) and
135 (100).
To a suspension of aldehyde 2b (78 mg, 0.25 mmol) in
anhydrous MeOH (20 ml) at room temp. was added K2CO3 (69
mg, 0.5 mmol). After being stirred at room temp. for 20 h, the
resulting solution was neutralized with 10% aq. AcOH and
concentrated in vacuo. The residue was purified by reversed-
phase chromatography (water–MeCN, 19:1) to give the (2R)-
epimer of aldehyde 2b (58 mg, 75%) as a hydrate; λmax(water)/
nm 252; νmax(KBr)/cmϪ1 3423, 3218, 3137, 2989, 2940, 2758,
1689, 1638, 1604, 1543, 1478, 1377, 1217, 1161, 1076, 904, 852,
782, 690 and 638; δH(400 MHz; [2H6]DMSO) 1.26 and 1.28
(each 3 H, s, isopropylidene), 3.56 (1 H, dd, J 7.3 and 5.9, 2Ј-H),
4.03 (1 H, dd, J 14.2 and 7.3, 4Ј-H), 4.18 (1 H, td, J 7.3 and 3.4,
3Ј-H), 4.26 (1 H, dd, J 14.2 and 3.4, 4Ј-H), 4.74 (1 H, td, J 6.3
and 5.9, 1Ј-H), 6.03 (1 H, d, J 6.3, 1Ј-OH), 6.09 (1 H, d, J 6.3,
1Ј-OH), 6.41 (2 H, br s, guanine 2-NH2), 7.65 (1 H, s, guanine
8-H), 10.28 (1 H, br s, guanine N1-H); m/z (FAB, NBA) 312
(Mϩ ϩ H, 26%) [Found (FAB): (Mϩ ϩ H), 312.1302. C12H18-
N5O5 requires m/z, 312.1308].
To a suspension of the (2R)-epimer of aldehyde 2b (31 mg,
0.1 mmol) in water (10 ml) was added NaBH4 (19 mg, 0.5
mmol) at 0 ЊC. After being stirred at 0 ЊC for 10 min and at
room temp. for 70 min, the mixture was neutralized with 10%
aq. AcOH and concentrated in vacuo. The residue was purified
by reversed-phase chromatography (water–MeCN, 19:1–9:1)
to give title compound 5b (26 mg, 88%) as a solid, λmax(MeOH)/
nm 253; νmax(KBr)/cmϪ1 3422, 3132, 2988, 2937, 2761, 1690,
1655, 1638, 1608, 1543, 1479, 1378, 1216, 1162, 1075, 1063, 845,
782, 690 and 637; δH(400 MHz; [2H6]DMSO) 1.25 and 1.29
(each 3 H, s, isopropylidene CH3), 3.39–3.45 (2 H, m, 4Ј-H2),
3.77 (1 H, dt, J 7.8 and 4.9, 3Ј-H), 4.06–4.20 (3 H, m, 1Ј-H2 and
2Ј-H), 4.83 (1 H, t, J 5.4, 4Ј-OH), 6.41 (2 H, br s, 2-NH2), 7.63
(1 H, s, 8-H) and 10.52 (1 H, s, N1-H); δC([2H6]DMSO) 26.88,
26.99, 44.40, 61.08, 75.66, 79.11, 108.67, 116.16, 137.78, 151.26,
153.54 and 156.75; m/z (EI) 295 (Mϩ, 26%), 280 (33), 219 (86),
164 (55) and 151 (100) [Found (EI): Mϩ, 295.1299. C12H17N5O4
requires M, 295.1280].
9-[(2ЈS,3ЈR)-2Ј,3Ј,4Ј-Trihydroxybutyl]guanine 4b
A solution of partially protected triol 3b (10 mg, 33.9 µmol) in
80% aq. AcOH (~2 ml) was stirred at 70 ЊC for 4.5 h and then
the solvent was evaporated off in vacuo. The residue was puri-
fied by reversed-phase chromatography (water–MeCN, 19:1) to
give title triol 4b (8 mg, 93%) as a solid, λmax(MeOH)/nm 253;
νmax(KBr)/cmϪ1 3455, 3425, 3388, 3194, 2927, 2855, 2649, 1690,
1638, 1611, 1476, 1396, 1359, 1194, 1170, 1111, 1077, 1042, 914,
867, 784, 740 and 699; δH(400 MHz; [2H6]DMSO) 3.27 (1 H, m,
3Ј-H), 3.36 (1 H, dt, J 11.2 and 5.9, 4Ј-H), 3.55–3.62 (2 H, m,
2Ј- and 4Ј-H), 3.83 (1 H, dd, J 14.2 and 8.3, 1Ј-H), 4.22 (1 H, dd,
J 14.2 and 2.4, 1Ј-H), 4.43 (1 H, t, J 5.9, 4Ј-OH), 4.87 (1 H, d,
J 4.9, 3Ј-OH), 5.03 (1 H, d, J 5.9, 2Ј-OH), 6.42 (2 H, br s,
2-NH2), 7.56 (1 H, s, 8-H) and 10.49 (1 H, s, N1-H); δC([2H6]-
DMSO) 46.18, 62.98, 69.73, 73.26, 116.27, 138.44, 151.19,
153.31 and 156.74; m/z (FAB, NBA) 256 (Mϩ ϩ H, 15%)
[Found (FAB): (Mϩ ϩ H), 256.1039. C9H14N5O4 requires m/z
256.1046].
9-[(2ЈS,3ЈS)-4Ј-Hydroxy-2Ј,3Ј-isopropylidenedioxybutyl]adenine
5a
To a stirred solution of aldehyde 2a (27.7 mg, 0.1 mmol) in
944
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
Preparation of (؉)-MTPA ester of alcohol 5a
s, adenine 8- or 2-H); δC([2H6]DMSO) 25.62, 27.76, 44.88,
74.41, 77.89, 108.19, 118.54, 141.58, 149.70, 152.15, 155.85 and
169.29; m/z (FAB, Gly) 294 (Mϩ ϩ H, 11%) [Found (FAB):
(Mϩ ϩ H), 294.189. C12H16N5O4 requires m/z 294.1202].
The (ϩ)-MTPA ester of alcohol 5a was obtained by the pro-
cedure described for the preparation of (ϩ)-MTPA ester of
diastereomer 3a, in 73% yield, λmax(MeOH)/nm 260; νmax(neat)/
cmϪ1 3319, 3152, 2927, 2855, 1752, 1646, 1602, 1471, 1455,
1419, 1378, 1243, 1172, 1109, 1022, 917, 848, 799, 764, 720
and 648; δH(400 MHz; CDCl3) 1.20 and 1.26 (each 3 H, s, iso-
propylidene), 3.56 (3 H, s, OCH3), 3.80 (1 H, ddd, J 8.3, 4.4 and
3.9, 2Ј-H), 4.17 (1 H, dt, J 8.3 and 3.9, 3Ј-H), 4.37 (2 H, t, J 3.9,
4Ј-H), 4.48 (1 H, dd, J 12.2 and 4.4, 1Ј-H), 4.57 (1 H, dd, J 12.2
and 3.9, 1Ј-H), 5.79 (2 H, br s, 6-NH2), 7.39–7.54 (5 H, m, Ph),
7.88 (1 H, s, 2- or 8-H) and 8.29 (1 H, s, 8- or 2-H); δF(CDCl3)
Ϫ72.21; m/z (FAB, NBA) 496 (Mϩ ϩ H, 32%) [Found (FAB):
(Mϩ ϩ H), 496.1790. C22H25F3N5O5 requires m/z, 496.1808].
L-Eritadenine [(2S,3S)-4-(adenin-9-yl)-2,3-dihydroxybutanoic
acid] 8
A solution of compound 7 (49 mg, 0.167 mmol) in 10% aq.
AcOH (6 ml) was stirred at 65 ЊC for 4 h, and then the solvent
was evaporated off in vacuo to give diol 8 (42 mg, 99%) as a
solid, [α]D26 Ϫ14.3 (c 0.07, 1  HCl) {lit.,3b [α]D20 Ϫ14.8 (c 0.5, 1 
HCl)}; λmax(MeOH)/nm 260; δH(400 MHz; [2H6]DMSO) 3.27
(1 H, d, J 8.3, 2-H), 3.63 (1 H, td, J 8.3 and 2.4, 3-H), 4.03 (1 H,
dd, J 13.7 and 8.3, 4-H), 4.38 (1 H, dd, J 13.7 and 2.4, 4-H),
7.12 (2 H, br s, adenine 6-NH2), 8.03 (1 H, s, adenine 2- or 8-H)
and 8.10 (1 H, s, adenine 8- or 2-H); δC(100 MHz; [2H6]DMSO)
46.63, 70.54, 71.25, 118.43, 141.66, 149.69, 152.15, 155.83 and
175.18; m/z (FAB, Gly) 254 (Mϩ ϩ H, 10%) [Found (FAB):
(Mϩ ϩ H), 54.0879. C9H12N5O4 requires m/z 254.0889].
9-[(2ЈS,3ЈS)-2Ј,3Ј,4Ј-Trihydroxybutyl]adenine 6a
A solution of partially protected triol 5a (27.9 mg, 0.1 mmol) in
80% aq. AcOH (2.5 ml) was stirred at 70 ЊC for 19 h and then
the solvent was evaporated off in vacuo. The residue was puri-
fied by reversed-phase chromatography (water–MeCN, 19:1)
and the resulting product was triturated with MeOH–Et2O to
give title triol 6a (14.4 mg, 60%) as a solid, mp 233–236 ЊC
(decomp.) (lit.,12 215 ЊC) (Found: C, 45.0; H, 5.6; N, 27.95.
C9H13N5O5ؒ1/3CH3OH requires C, 44.85; H, 5.78; N, 28.03%);
the existence of methanol in this product was confirmed by 1H
NMR analysis; λmax(MeOH)/nm 260; δH(400 MHz; [2H6]-
DMSO) 3.37–3.42 (2 H, m, 3Ј- and 4Ј-H), 3.47 (1 H, ddd,
J 10.3, 5.4 and 4.4, 4Ј-H), 3.88 (1 H, m, 2Ј-H), 4.10 (1 H, dd,
J 14.2 and 9.3, 1Ј-H), 4.23 (1 H, dd, J 14.2 and 4.4, 1Ј-H), 4.49
(1 H, t, J 4.4, 4Ј-OH), 4.73 (1 H, d, J 4.9, 3Ј-OH), 4.78 (1 H, d,
J 6.8, 2Ј-OH), 7.15 (2 H, br s, 6-NH2), 8.02 (1 H, s, 2- or 8-H)
and 8.12 (1 H, s, 8- or 2-H); δC([2H6]DMSO) 46.29, 62.14, 68.78,
71.85, 118.63, 141.53, 148.58, 152.10 and 155.83; m/z (FAB,
NBA) 240 (Mϩ ϩ H, 12%).
(2R,3S)-4-(Adenin-9-yl)-2,3-isopropylidenedioxybutanal oximes
9 (E/Z)
To a stirred solution of hydroxylamine hydrochloride (125 mg,
1.8 mmol) in anhydrous MeOH (30 ml) was added NaOMe
(369 µl of 4.88  solution in MeOH, 1.8 mmol) at room temp.
The mixture was stirred at room temp. for 3 h and was then
filtered through a Celite pad to remove resulting NaCl. The
mixture of the filtrate and aldehyde 2a (333 mg, 1.2 mmol) was
stirred at room temp. for 6 h and was then concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (CHCl3–MeOH, 30:1–10:1) to give geometrical mix-
ture 9 (249 mg, 71%; E/Z = 38:62) as a solid, which was recrystal-
lized from EtOH, mp 234–237 ЊC (decomp.) (Found: C, 49.1;
H, 5.45; N, 28.55. C12H16N6O3 requires C, 49.31; H, 5.52; N,
28.75%); λmax(MeOH)/nm 260; νmax(KBr)/cmϪ1 3328, 3199,
2989, 2937, 2884, 1690, 1647, 1611, 1579, 1480, 1422, 1382,
1340, 1306, 1248, 1219, 1164, 1072, 981, 953, 911, 876, 797, 727
and 650; δH(400 MHz; [2H6]DMSO); for (Z)-isomer: 1.25 and
1.48 (each 3 H, s, isopropylidene), 4.03 (1 H, dd, J 13.87 and
9.8, 4-H), 4.16 (1 H, dd, J 13.7 and 2.9, 4-H), 4.80 (1 H, ddd,
J 9.8, 6.8 and 2.9, 3-H), 5.27 (1 H, dd, J 6.8 and 4.4, 2-H), 6.97
(1 H, d, J 4.4, 1-H), 7.18 (2 H, br s, adenine 6-NH2), 8.03 (1 H, s,
adenine 2- or 8-H), 8.11 (1 H, s, adenine 8- or 2-H) and 11.65
(1 H, s, N-OH); for (E)-isomer: 1.26 and 1.47 (each 3 H, s,
isopropylidene), 4.21 (2 H, m, 4-H2), 4.72 (1 H, q, J 6.8,
3-H), 4.79 (1 H, m, 2-H), 7.20 (2 H, br s, adenine 6-NH2), 7.46
(1 H, d, J 7.8, 1-H), 8.05 (1 H, s, adenine 2- or 8-H), 8.12 (1 H,
s, adenine 8- or 2-H) and 11.28 (1 H, s, N-OH); m/z (EI)
292 (Mϩ, 51%), 277 (25), 234 (29), 217 (41), 148 (97) and 135
(100).
9-[(2ЈS,3ЈS)-2Ј,3Ј,4Ј-Trihydroxybutyl]guanine 6b
A solution of partially protected triol 5b (17 mg, 57.6 µmol) in
80% aq. AcOH (~5 ml) was stirred at 70 ЊC for 9 h and then
solvent was evaporated off in vacuo. The residue was purified by
reversed-phase chromatography (water–MeCN, 19:1) to give
title triol 6b (13 mg, 88%) as a solid, λmax(MeOH/nm 254;
νmax(KBr)/cmϪ1 3423, 3144, 2961, 2767, 1693, 1657, 1620, 1544,
1478, 1404, 1378, 1314, 1195, 1171, 1117, 1074, 810, 780, 691,
635, 595 and 560; δH(400 MHz; [2H6]DMSO) 3.29–3.40 (2 H, m,
3Ј- and 4Ј-H), 3.45 (1 H, dt, J 10.3 and 5.9, 4Ј-H), 3.79 (1 H,
dddd, J 8.8, 6.8, 4.9 and 2.4, 2Ј-H), 3.92 (1 H, dd, J 14.2 and 8.8,
1Ј-H), 4.00 (1 H, dd, J 14.2 and 4.9, 1Ј-H), 4.47 (1 H, t, J 5.9,
4Ј-OH), 4.67 (1 H, d, J 5.4, 3Ј-OH), 4.71 (1 H, d, J 6.8, 2Ј-OH),
6.40 (2 H, br s, 2-NH2), 7.58 (1 H, s, 8-H) and 10.47 (1 H, s, N1-
H); δC([2H6]DMSO) 45.90, 62.12, 68.72, 71.76, 116.40, 138.18,
151.22, 153.40 and 156.82; m/z (FAB, NBA) 256 (Mϩ ϩ H,
10%) [Found (FAB) (Mϩ ϩ H), 256.1039. C9H14N5O4 requires
m/z, 256.1046].
(2R,3S)-4-(Adenin-9-yl)-2,3-isopropylidenedioxybutanenitrile 10
To a solution of oxime 9 (102 mg, 0.35 mmol) in DMF (0.7 ml)
was added thionyl dichloride (127.7 µl, 1.75 mmol) at 0 ЊC.
After being stirred at 0 ЊC for 2.5 h, the mixture was concen-
trated in vacuo. The residue was purified by column chroma-
tography on silica gel (CHCl3–MeOH, 20:1–10:1) to give
nitrile 10 (76 mg, 79%) as a solid, λmax(MeOH)/nm 260;
νmax(neat)/cmϪ1 3345, 3151, 2991, 2940, 1658, 1602, 1490, 1422,
1379, 1331, 1312, 1236, 1153, 1073, 730 and 646; δH(400 MHz;
[2H6]DMSO) 1.27 and 1.50 (each 3 H, s, isopropylidene), 4.45
(1 H, dd, J 14.2 and 9.3, 4-H), 4.61 (1 H, dd, J 14.2 and 3.4,
4-H), 4.80 (1 H, ddd, J 9.3, 4.9 and 3.4, 3-H), 5.41 (1 H, d, J 4.9,
2-H), 7.24 (2 H, s, adenine 6-NH2), 8.14 (1 H, s, adenine 2- or
8-H) and 8.15 (1 H, s, adenine 8- or 2-H); δH(400 MHz; CDCl3)
1.34 and 1.64 (each 3 H, s, isopropylidene), 4.48 (1 H, dd, J 14.2
and 7.8, 4-H), 4.68 (1 H, ddd, J 7.8, 5.4 and 3.9, 3-H), 4.73 (1 H,
dd, J 14.2 and 3.9, 4-H), 4.94 (1 H, d, J 5.4, 2-H), 5.87 (2 H, br s,
adenine 6-NH2), 7.94 (1 H, s, adenine 2- or 8-H) and 8.36 (1 H,
s, adenine 8- or 2-H); NOE (CDCl3), irradiate 2-H, observe 3-H
(2S,3S)-4-(Adenin-9-yl)-2,3-isopropylidenedioxybutanoic acid 7
A mixture of aldehyde 2a (127 mg, 0.46 mmol) and 3% Pt/C
(149 mg, 0.023 mmol of Pt) in water (5 ml) was stirred under
oxygen (balloon) at 45 ЊC. The pH of the reaction mixture was
adjusted to ~7.5 with aq. NaHCO3 twice during the reaction.
After being stirred at 45 ЊC for 49 h, the mixture was filtered
through a Celite pad and concentrated in vacuo. The residue
was purified by reversed-phase chromatography (water–MeCN,
19:1) to give acid 7 (62 mg, 46%) as a solid, λmax(MeOH)/nm
260; νmax(KBr)/cmϪ1 3424, 3187, 2990, 2937, 1637, 1607, 1479,
1422, 1379, 1331, 1305, 1249, 1217, 1081, 1052, 891, 850,
797, 725 and 650; δH(400 MHz; [2H6]DMSO) 1.17 and 1.40
(each 3 H, s, isopropylidene), 4.02 (1 H, dd, J 14.2 and 9.8,
4-H), 4.33 (1 H, dd, J 14.2 and 2.9, 4-H), 4.41 (1 H, d, J 6.8,
2-H), 4.51 (1 H, ddd, J 9.8, 6.8 and 2.9, 3-H), 7.12 (2 H, br s,
adenine 6-NH2), 8.08 (1 H, s, adenine 2- or 8-H) and 8.09 (1 H,
J. Chem. Soc., Perkin Trans. 1, 1998
945

View Article Online
(8.6%); δC(CDCl3) 25.78, 27.07, 44.23, 66.32, 74.88, 113.47,
115.79 (CN), 119.54, 141.03, 149.93, 153.21 and 155.58; m/z
(EI) 274 (Mϩ, 35%), 259 (25), 216 (76), 149 (100) and 135 (68)
[Found (EI): Mϩ, 274.1169. C12H14N6O2 requires M, 274.1178].
3323, 3193, 2940, 2887, 1683, 1656, 1620, 1580, 1478, 1423,
1340, 1309, 1253, 1054, 723, 652 and 609; δH(400 MHz;
[2H6]DMSO) 3.42–3.55 (4 H, m, 4Ј-H and 3Ј-CH2OH), 3.84
(1 H, m, 2Ј-H), 4.10 (1 H, dd, J 14.2 and 10.3, 1Ј-H), 4.29 (1 H,
br s, 3Ј-OH), 4.45 (1 H, dd, J 14.2 and 2.0, 1Ј-H), 4.48 (2 H, br,
4Ј-OH and 3Ј-CH2OH), 4.84 (1 H, br 2Ј-OH), 7.17 (2 H, br s,
6-NH2), 8.02 (1 H, s, 2- or 8-H) and 8.12 (1 H, s, 8- or 2-H);
δC([2H6]DMSO) 45.28, 62.10, 62.82, 70.90, 74.96, 118.61,
141.79, 149.56, 151.77 and 155.61; m/z (FAB, NBA) 270
(Mϩ ϩ H, 4%) [Found (FAB): (Mϩ ϩ H), 270.1210. C10H16-
N5O4 requires m/z, 270.1202].
(2R,3S)-4-(Adenin-9-yl)-2,3-dihydroxybutanenitrile 11
A solution of compound 10 (43 mg, 0.157 mmol) in TFA (2 ml)
was stirred at room temp. for 45 h, and then solvent was
removed in vacuo. The residue was purified by reversed-phase
chromatography (water–MeCN, 4:1) to give diol 11 (21 mg,
57%) as a solid, λmax(MeOH)/nm 260; νmax(KBr)/cmϪ1 3423,
3178, 2931, 2244 (CN), 1702, 1653, 1609, 1478, 1422, 1303,
1252, 1074, 794, 727, 650 and 591; δH(400 MHz; [2H6]DMSO)
3.99 (1 H, m, 3-H), 4.05 (1 H, dd, J 13.7 and 8.8, 4-H), 4.37
(1 H, dd, J 13.7 and 2.4, 4-H), 4.45 (1 H, t, J 6.4, 2-H), 6.04
(1 H, d, J 6.4, 3-OH), 6.82 (1 H, d, J 6.4, 2-OH), 7.21 (2 H, s,
adenine 6-NH2), 8.03 (1 H, s, adenine 2- or 8-H) and 8.13 (1 H,
s, adenine 8- or 2-H); δC([2H6]DMSO) 45.68, 63.49, 69.82,
118.60, 119.84, 141.58, 149.54, 152.28 and 155.92; m/z (FAB,
NBA) 235 (Mϩ ϩ H, 8%) [Found (FAB) (Mϩ ϩ H), 235.0949.
C9H11N6O2 requires m/z, 234.0943].
References
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12 A. Holy, Collect. Czech. Chem. Commun., 1982, 47, 173.
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9-[(2ЈS)-4Ј-Hydroxy-3Ј-hydroxymethyl-2Ј,3Ј-isopropylidene-
dioxybutyl]adenine 12
To a suspension of aldehyde 2a (27.7 mg, 0.1 mmol) and for-
maldehyde (45.0 µl of 37 wt.% solution in water, 0.6 mmol) was
added 2  NaOH (0.1 ml, 0.2 mmol) at room temp. and the
mixture was stirred at this temp. for 24 h. The mixture was
treated with NaBH4 (15.1 mg, 0.4 mmol) at 0 ЊC and was stirred
at 0 ЊC for 2 h, neutralized by the addition of 10% aq. AcOH,
and then concentrated in vacuo. The residue was purified by
column chromatography on silica gel (CHCl3–MeOH, 15:1) to
give compound 12 (27.6 mg, 89%) as a solid, mp 192–194 ЊC
(decomp.) (Found: C, 48.8; H, 6.05; N, 22.0. C13H19N5O4ؒ
1/2H2O requires C, 49.05; H, 6.33; N, 22.00%); the existence of
water in this product was confirmed by 1H NMR analysis; [α]D28
Ϫ38.5 (c 0.27 in MeOH); λmax(MeOH)/nm 260; νmax(KBr)/cmϪ1
3421, 3338, 3222, 2990, 2937, 2875, 1648, 1604, 1578, 1479,
1421, 1382, 1324, 1246, 1216, 1054, 932, 842, 722 and 646;
δH(400 MHz; [2H6]DMSO) 1.21 and 1.38 (each 3 H, s, isopro-
pylidene), 3.45–3.51 (2 H, m, 4Ј-H and 3Ј-CHHOH), 3.53–3.58
(2 H, m, 4Ј-H and 3Ј-CHHOH), 4.36 (1 H, dd, J 12.7 and 9.8,
1Ј-H), 4.41 (1 H, d, J 9.8, 2Ј-H), 4.50 (1 H, d, J 12.7, 1Ј-H), 4.83
(2 H, m, 4Ј-OH and 3Ј-CH2OH), 7.18 (2 H, s, 6-NH2), 8.07
(1 H, s, 2- or 8-H) and 8.13 (1 H, s, 8- or 2-H); δC([2H6]DMSO)
26.66, 28.44, 42.98, 60.70, 62.31, 77.16, 83.81, 107.75, 118.47,
140.85, 149.47, 152.37 and 155.90; m/z (EI) 309 (Mϩ, 12%), 294
(18), 251 (36), 234 (46), 203 (32) and 136 (100).
14 M. Hashimoto, Y. Saito, H. Seki and T. Kamiya, Tetrahedron Lett.,
1970, 1359.
9-[(2ЈS)-2Ј,3Ј,4Ј-Trihydroxy-3Ј-(hydroxymethyl)butyl]adenine
13
A solution of compound 12 (21.2 mg, 0.069 mmol) in TFA
(1 ml) was stirred at room temp. for 2 h, and then solvent was
removed in vacuo. The residue was purified by reversed-phase
chromatography (water–MeCN, 19:1) to give tetraol 13 (15.3
mg, 83%) as a solid, λmax(MeOH)/nm 261; νmax(KBr)/cmϪ1 3403,
Paper 7/07193K
Received 6th October 1997
Accepted 17th November 1997
946
J. Chem. Soc., Perkin Trans. 1, 1998