Synthesis of two precursors of heterocarbocyclic nucleoside analogues

Article abstract of DOI:10.1002/ejoc.200500515

The racemic heterobicyclic amino alcohols 6 and 7, which are of interest as intermediates in the synthesis of nucleoside analogues with heterobicyclic pseudosugars, were efficiently prepared from 2-thienylsuccinic acid via methyl 4-hydroxyimino-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylate [(±)-14]. The target compounds were obtained together by direct reduction of (±)-14 with AlH₃ in refluxing THF, and were separated by flash chromatography of their N-acetylated derivatives. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500515

FULL PAPER
DOI: 10.1002/ejoc.200500515
Synthesis of Two Precursors of Heterocarbocyclic Nucleoside Analogues
[a]
[a]
[a]
[a]
Paula Abeijón, José M. Blanco,* Franco Fernández, Marcos D. García, and
Carmen López[
a]
Keywords: Heterocarbocyclic nucleoside / Heterobicyclic amino alcohol / AlH reduction
3
The racemic heterobicyclic amino alcohols 6 and 7, which
are of interest as intermediates in the synthesis of nucleoside
analogues with heterobicyclic pseudosugars, were efficiently
prepared from 2-thienylsuccinic acid via methyl 4-hy-
droxyimino-5,6-dihydro-4H-cyclopenta[b]thiophene-6-car-
boxylate [(± ±-14]. The target compounds were obtained
3
together by direct reduction of (± ±-14 with AlH in refluxing
THF, and were separated by flash chromatography of their
N-acetylated derivatives.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006±
1. Introduction
Over the past two decades, several types of nucleoside
and nucleoside analogues have been identified as potent,
selective inhibitors of the replication of HIV-1, HSV-2,
HBV and/or HCMV in vitro and in vivo, and some of these
substances now constitute the basis of clinically important
[
1]
therapies. One major class of modified nucleosides com-
prises the carbocyclic nucleosides, or carbanucleosides, in
which the sugar ring oxygen has been replaced by a methyl-
[
2]
ene group.
The first member of this class was the carbocyclic ana-
logue of adenosine described by Shealy in 1966,[ and inter-
est was spurred by the discovery of the antibiotic and anti-
tumoural activities of the natural carbocyclic nucleosides
3]
[
4]
[5]
aristeromycin (1) and neplanocin A (2). Since then,
many synthetic carbanucleosides have been prepared, in-
eroaromatic nucleosides can be obtained by constructing a
purine or pyrimidine base on the amino group, following
conventional methods.
cluding the HIV-inhibitors carbovir (3)[ and abacavir (4),
6]
[7]
the latter of which is used therapeutically.
[
11]
More recently, Mackenzie and co-workers[ have modi-
fied the nucleoside analogue stavudine (5) by fusing a ben-
zene ring to the carbasugar, which increases lipophilicity
8]
(
and hence access to the central nervous system, a major
[
9]
reservoir of HIV ) while maintaining the rigidity imposed
by the C2Ј–C3’ double bond, and analogous carbanucleos-
ides have been prepared in which an aromatic heterocycle
[
10]
is fused to the carbasugar of carbovir or abacavir.
Here
we describe the efficient preparation of the heterobicyclic
amino alcohols 6 and 7, from which the corresponding het-
2. Results and Discussion
Amino alcohols 6 and 7 were prepared as racemic mix-
tures awaiting determination of the biological activity of
the corresponding nucleoside analogues prior to pursueing
enantiomeric separation. As a common intermediate for the
two, we first prepared hydroxyimino ester 14, starting from
commercial thiophene-2-carbaldehyde. Knoevenagel con-
densation of the latter with ethyl malonate afforded the un-
[
a] Departamento de Química Orgánica, Facultade de Farmacia,
Universidade de Santiago de Compostela,
1
5782 Santiago de Compostela, Spain
Fax: +34-981-594-912
E-mail: qojb@usc.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2006, 759–764
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
759

P. Abeijón, J. M. Blanco, F. Fernández, M. D. García, C. López
FULL PAPER
Scheme 1. (a) Diethyl malonate, piperidine, toluene, reflux; (b) KCN/H
2
O, EtOH, reflux (c) (1) 1.5 n NaOH, reflux; (2) 6 m HCl, reflux;
3 2 2
(d) AcCl, reflux; (e) AlCl , 1,2-dichloroethane, room temp.; (f) MeOH, TsOH, reflux; (g) NH OH·HCl, NaAc/H O, EtOH, reflux.
saturated diester 8, which was converted into thien-2-ylsuc-
Compound 19 was also the only product when l-se-
cinic acid (10) by addition of KCN and hydrolysis/decar- lectride was used to investigate the stereoselectivity of the
[
19]
boxylation of the intermediate 9 (Scheme 1). Attempted di- reduction reaction (Entry 3). However, heating 14 for 5 h
[
20]
rect synthesis of 4-oxo-5,6-dihydro-4H-cyclopenta[b]thio- with AlH in refluxing THF
(Entry 4) gave the desired
3
phene-6-carboxylic acid (12) by heating of 10 with poly-
phosphoric acid (PPA) at 70 °C achieved a yield of only 4%,
and heating with PPA in xylene at 100 °C[ only increased
this value to 12%; in both cases, most of the starting diacid
failed to react, and nor was there any reaction when 10
was treated with trimethylsilyl polyphosphate (PPSE, easily
12]
[13]
prepared from P O and hexamethyldisiloxane)
in a re-
2
5
fluxing mixture of dichloromethane and P O (although
2
5
PPSE has successfully been used for other intramolecular
Friedel–Crafts cyclizations in aprotic media for example, to
obtain substituted 9H-selenoxanthen-9-ones.)[
14]
Finally,
acid 12 was obtained in 57% yield by heating 10 in re-
fluxing acetyl chloride and treating the resulting anhydride
1
1 with AlCl in 1,2-dichloroethane. Esterification of 12
3
and reaction of the ester 13 with hydroxylamine–hydrochlo-
ride then afforded 14 as a mixture of the (E)- and (Z)-hy-
droxyimino esters in 46% yield from 12.
Expecting a simultaneous reduction of the oxime and es-
[
15]
ter groups,
14 was treated with LiAlH for 6 h in re-
4
[16]
fluxing THF, but the product (19;
yield 23%) was the
result of a selective ester reduction (see Supporting Infor-
mation, Table S1, Entry 1). Increasing the reaction time to
3
1
3 h afforded a lower yield of 19 (11%) together with an
1% yield of amino alcohol 20,[ presumably the result of
17]
Beckmann rearrangement of 19 and subsequent reduction
[
18]
(Entry 2).
Scheme 2. (a) AlH
1) K CO , MeOH, room temp.; (2) flash chromatography; (d) (1)
m HCl, MeOH, reflux; (2) Amberlite IRA-400 (OH).
3 2 3
, THF, reflux; (b) Ac O, Et N, room temp.; (c)
(
2
3
2
760
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 759–764

Synthesis of Two Precursors of Heterocarbocyclic Nucleoside Analogues
FULL PAPER
cis and trans amino alcohols 6 and 7 in 55% combined yield (CH=C), 62.27 and 61.94 (2 CH
2
), 14.55 and 14.33 (2 CH
EIMS: m/z (%) = 255 (6) [M + 1] , 254 (38) [M ], 209 (51) [M
3
) ppm.
+
+
+
1
–
],
and 1:1 ratio as deduced from the H NMR spectrum.
OEt], 182 (9), 164 (46) [M – 2 OEt], 136 (41) [M+ – C
+
5
10 3
H O
After the failure of attempts to separate 6 and 7 chro-
matographically, they were diacetylated by treatment with
Ac O in Et N at room temperature (Scheme 2). However,
+
1
5
08 (100) [C
6
H
4
S] , 82 (11), 69 (29). C12
H
14
O
4
S (254.30): calcd. C
6.68, H 5.55, S 12.61; found C 56.80, H 5.57, S 12.45.
2
3
the diacetylated derivatives 15 and 16 were also inseparable, 3.1.2 (±)-(Thien-2-yl)succinic Acid (10): A solution of KCN (1.5 g,
except for analytical samples that were obtained by frac- 23.1 mmol) in water (10 mL) was added to a solution of 8 (3 g,
1
3
1.8 mmol) in EtOH (50 mL), and the mixture was refluxed for
h, treated with a solution of NaOH (0.56 g, 14.0 mmol) in water
tional crystallization from 1:1 hexane/EtOAc and were
identified by X ray crystallography of a crystal of 16 (Fig-
ure S1; see Supporting Information).[21]
(10 mL), and refluxed for a further 1 h, after which the ethanol was
removed under reduced pressure while water was simultaneously
added to maintain a constant volume. After cooling to 40 °C, the
reaction mixture was brought to pH 1 by addition of 6 n HCl
Partial saponification of the mixture of 15 and 16 with
K CO in MeOH at room temperature then afforded the
2
3
acetamides 17 and 18 in 20% and 17% yield (from 14) after
efficient separation by flash chromatography. Finally, acid
(
8 mL) and refluxed for 1 h, after which it was cooled to room
temperature and then left overnight in a refrigerator. It was then
hydrolysis of these acetamides with 2 m HCl in MeOH gave extracted with EtOAc (3×80 mL), the organic extracts were washed
the corresponding hydrochlorides, which were converted with aqueous Na CO (3×50 mL), and the combined aqueous
into the racemic amino alcohols 6 and 7 by ion exchange phases were brought to pH 1 with 1 n H SO and extracted with
EtOAc (3×80 mL). The organic extract was dried with anhydrous
Na SO , and concentration under reduced pressure then afforded
a solid that was recrystallized from toluene as pure (±)-10 (2.19 g,
2
3
2
4
chromatography on a basic resin. Configurational assign-
ment of 7 as the trans isomer (and hence that of 6 as the
cis isomer) was confirmed by converting 7 into its diacetyl
derivative, 16.
2
4
9
1
=
3%). M.p. 159–161 °C. IR (KBr): ν˜ = 3028, 2925, 2642, 1693,
–
1 1
412, 1306, 1282, 1181 cm . H NMR (300 MHz, [D
6
]DMSO): δ
H), 12.42 (br. s, 1 H, D O exch.,
H), 7.40 (dd, J = 4.9, 1.3 Hz, 1 H, 5-Harom), 6.99–6.94 (m, 2
H),
.95 and 2.66 (the AB part of an ABX system, JAB = 16.9, JAX
12.46 (br. s, 1 H, D
2
O exch., CO
2
2
CO
2
3. Experimental Section
H, 3-Harom, 4-Harom), 4.15 (dd, J = 9.9, 5.2 Hz, 1 H, CHCO
2
2
9
=
3.1 General: Melting points are uncorrected and were determined
13
2 3
.9, JBX = 5.2 Hz, 2 H, CH ) ppm. C NMR (75 MHz, CDCl ):
with a Reichert Kofler Thermopan or in capillary tubes in a Büchi
δ = 173.45 and 172.55 (2 CO), 140.93 (C-2arom), 127.19, 125.89
and 125.37 (C-3,-4-5)arom, 42.57 (CHCH ), 38.33 (CHCH ) ppm.
EIMS: m/z (%) = 201 (0.02) [M + 1] , 200 (0.75) [M ], 182 (62)
5
1
10 apparatus. Infrared spectra were recorded with a Perkin–Elmer
2
2
1
640 FTIR spectrophotometer. H NMR spectra (300 MHz) and
+
+
1
3
C NMR spectra (75 MHz) were recorded with a Bruker AMX
00 spectrometer using TMS as internal reference (chemical shifts
+
O], 154 (100) [M+ – CO
+
[M
– H H], 113 (67), 110 (38) [M – 2
8 8 4
H], 97 (53), 85 (24), 58 (16). C H O S (200.21): calcd. C 47.99,
2
2
3
CO
2
in δ values, J in Hz). Mass spectra were recorded with a Kratos
MS-59 spectrometer. HRMS were obtained using MICROMASS
AUTOSPEC mass spectrometer. Microanalyses were performed
with a Perkin–Elmer 240B elemental analyser by the Microanalysis
Service of the University of Santiago. X-ray diffraction data were
collected with an Enraf–Nonius CAD4 automatic diffractometer
using the program CAD4-EXPRESS. Most of reactions were mon-
itored by TLC on pre-coated silica gel plates (Merck 60 F254,
H 4.03, S 16.02; found C 47.89, H 3.91, S 16.22.
3.1.3 (±)-(Thien-2-yl)succinic Anhydride (11): Acetyl chloride
(12.33 mL, 0.17 mol) was added to 10 (2.6 g, 12.99 mmol) under
argon, and the mixture was refluxed for 3 h. Concentration under
reduced pressure by azeotropic codistillation with toluene then af-
forded 11 (2.32 g, 98%) as a brownish viscous liquid that crys-
tallized upon cooling. M.p. 50–52 °C (toluene). IR (KBr): ν˜ = 3099,
–
1
1
0.25 mm). Synthesized products were purified by flash column
3002, 2949, 2879, 1858, 1780, 1408, 1237, 1178 cm . H NMR
(300 MHz, CDCl ): δ = 7.33 (dd, J = 5.0, 1.2 Hz, 1 H, 5-Harom),
7.07–7.02 (m, 2 H, 3-Harom,4-H)arom), 4.63–4.58 (m, 1 H, CHCO),
chromatography on silica gel (Merck 60, 230–240 mesh) and crys-
tallized if necessary. Solvents were dried by distillation prior use.
3
3
1
.53 and 3.23 (the AB part of an ABX system, JAB = 18.7, JAX =
0.1, JBX = 7.0 Hz, 2 H, CH ) ppm. C NMR (75 MHz, CDCl ):
2 3
3
.1.1 Diethyl (Thien-2-ylmethylene)malonate (8): Diethyl malonate
13
(36.7 g, 0.23 mol) was added dropwise to a mixture of thiophene-2-
δ = 170.31 and 168.22 (2 CO), 135.89 (C-2arom), 127.90, 126.72
and 126.57 (C-3,-4,-5)arom, 42.23 (CHCH ), 37.32 (CHCH ) ppm.
EIMS: m/z (%) = 183 (0.91) [M + 1] , 182 (11) [M ], 168 (2), 154
carbaldehyde (20 g, 0.18 mol), AcOH (5.5 mL), piperidine (5.5 mL)
and toluene (150 mL). The mixture was refluxed for 6.5 h in an
apparatus with a Dean–Stark trap for removal of water, and was
then concentrated under reduced pressure. The residue was taken
into dichloromethane (170 mL), and this solution was washed suc-
cessively with satd. NaHCO
and water (3×150 mL), and then dried with anhydrous Na
Removal of the solvent under reduced pressure afforded 8 as a
viscous whitish liquid (44.8 g, 99%). IR (film): ν˜ = 3105, 2982,
1
2
2
+
+
4) [M+ – CO], 110 (100) [C
S (182.20): calcd. C 52.74, H 3.32, S 17.60; found C 52.68,
H 3.42, S 17.48.
+
(
6 6
H S] , 95 (3), 69 (10), 66 (12).
8 6 3
C H O
3
(3×150 mL), 3 n HCl (3×150 mL)
SO
2
4
.
3.1.4 (±)-4-ꢀxo-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carbox-
ylic Acid (12): A solution of 11 (1.88 g, 10.32 mmol) in 1,2-dichlor-
oethane (6 mL) was added dropwise under argon, over 40 min, to
–1
1
724, 1617, 1465, 1420, 1254, 1203 cm . H NMR (300 MHz, a solution of AlCl
CDCl ): δ = 7.82 (s, 1 H, CH=C), 7.51 (d, J = 4.9 Hz, 1 H, 5- The mixture was stirred at room temperature for 5 h, poured into
arom), 7.35 (d, J = 3.1 Hz, 1 H, 3-Harom), 7.06 (t, J = 4.3 Hz, 1 a mixture of ice and hydrochloric acid, and extracted with EtOAc
H, 4-Harom), 4.39 (c, J = 7.1 Hz, 2 H, CH CH ), 4.28 (c, J = 7.1 Hz, (4×50 mL). The organic phase was extracted with aqueous
), 1.36 (t, J = 7.1 Hz, 3 H, CH CH ), 1.31 (t, J = Na CO (3×50 mL), and the aqueous extract was acidified with 1 n
.1 Hz, 3 H, CH CH ): δ = HCl and extracted with EtOAc (4×50 mL). The combined organic
) ppm. 13C NMR (75 MHz, CDCl
66.69 and 164.72 (2 CO), 136.51 (C-2arom), 135.04 (CH=C), phases were washed with water (3×60 mL) and dried with anhy-
34.73 (C-5arom), 132.03 and 128.17 (C-3, C-4)arom 122.88 drous Na SO , and concentration under reduced pressure then
3
(3.8 g, 28.5 mmol) in 9 mL of the same solvent.
3
H
2
3
2
7
1
1
H, CH
2
CH
3
2
3
2
3
2
3
3
,
2
4
Eur. J. Org. Chem. 2006, 759–764
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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761

P. Abeijón, J. M. Blanco, F. Fernández, M. D. García, C. López
FULL PAPER
yielded 2.1 g of a viscous orange liquid that was chromatographed
on silica gel (60 g) using 1:1 hexane/EtOAc (23×60 mL) as eluent.
Recrystallization from EtOAc afforded 12 (1.09 g, 58%) as a white
solid. M.p. 174.5–176 °C. IR (KBr): ν˜ = 3114, 3093, 2973, 2599,
adding concentrated H
at 0 °C to a 1 m solution of LiAlH
mixture vigorously for 1 h at room temperature.[ Once prepared,
11.5 mL (22.7 mmol) of AlH was added dropwise at 0 °C under
2
SO
4
(99.99%, 0.8 mL, 15 mmol) dropwise
4
in THF (30 mL) and stirring the
20]
3
–1
1
1
731, 1639, 1507, 1465, 1391, 1306, 1241, 1216 cm . H NMR argon to a solution of 14 (0.5 g, 2.37 mmol) in dry THF (20 mL),
300 MHz, [D ]DMSO): δ = 9.57 (br. s, 1 H, D O exch., CO H), and the mixture was stirred under reflux for 5 h. After addition of
.70 (d, J = 5.0 Hz, 1 H, 2-H), 7.12 (d, J = 5.1 Hz, 1 H, 3-H), 4.50 THF/H O (1:1, 15 mL) and water (20 mL) at 0 °C, stirring was
continued while the mixture reached room temperature. The or-
H), ganic solvent was removed under reduced pressure, and the solid
(
6
2
2
7
2
1
3
(t, J = 5.0 Hz, 1 H, 6-H), 3.12 (d, J = 5.1 Hz, 2 H, CH
2
) ppm.
C
NMR (75 MHz, [D
6
]DMSO): δ = 195.91 (CO), 171.97 (CO
2
1
5
67.11 (C-6a), 145.62 (C-3a), 133.94 (C-2), 119.04 (C-3), 44.69 (C- formed was filtered off and washed with EtOAc (3×40 mL). The
+
), 42.66 (C-6) ppm. EIMS: m/z (%) = 183 (6) [M + 1] , 182 (54)
aqueous filtrate was extracted with EtOAc (3×40 mL), and the
combined organic phases were dried with anhydrous Na SO . Re-
moval of the solvent under reduced pressure left 0.27 g of an oily
residue that when chromatographed on silica gel (10 g) with 2:5
+
+
O], 153 (11) [M – CO]], 137 (100) [M+
+
[M ], 164 (42) [M – H
2
–
2
4
+
CO
C
2
H], 109 (34) [C
6
H
5
S] , 84 (7), 82 (9), 69 (11), 65 (37), 63 (12).
8
H
6
O
3
S (182.20): calcd. C 52.74, H 3.32, S 17.60; found C 52.91,
H 3.39, S 17.38.
CH
and 7 (0.22 g, 55%). This mixture (0.22 g, 1.3 mmol) was stirred
with Ac O (3 mL) and dry Et N (3 mL) for 6 h under argon at
room temperature, the resulting mixture was concentrated to dry-
ness, and the solid residue was washed successively with saturated
2 2
Cl /iPrOH as eluent afforded a 1:1 yellowish pasty mixture of
6
3.1.5 (±)-Methyl 4-ꢀxo-5,6-dihydro-4H-cyclopenta[b]thiophene-6-
2
3
carboxylate (13): A solution of 12 (1.38 g, 7.58 mmol) in dry
MeOH (40 mL) containing pTsOH (0.1 g, 0.53 mmol) was refluxed
for 5 h under argon. Concentration to dryness then afforded 1.5 g
of a viscous liquid residue that when chromatographed on silica gel
NaHCO
3
(3×20 mL) and water (3×40 mL), dried with anhydrous
Na SO , and concentrated under reduced pressure. The resulting
2
4
(50 g) with hexane/EtOAc, 6:1 (33×40 mL) as eluent yielded a
pasty residue was chromatographed on silica gel (20 g) with hexane/
EtOAc (1:2) as eluent, affording a mixture of the acetates 15 and
whitish liquid that crystallized in the refrigerator. Recrystallization
from hexane/EtOAc afforded 13 (1.37 g, 92%) as a white solid.
M.p. 58.5–61 °C. IR (KBr): ν˜ = 3566, 3085, 2953, 1750, 1706, 1517,
16 as a yellow oil that crystallized upon standing at 5 °C (0.27 g,
83%). A sample subjected to fractional crystallization from hexane/
–
1
1
1
458, 1436, 1394, 1321, 1252, 1206 cm . H NMR (300 MHz,
CDCl ): δ = 7.39 (d, J = 5.1 Hz, 1 H, 2-H), 7.13 (d, J = 5.1 Hz, 1
H, 3-H), 4.38–4.35 (m, 1 H, 6-H), 3.80 (s, 3 H, OCH ), 3.39 and 15: Reddish white solid, m.p. 123–125 °C. IR (KBr): ν˜ = 3282,
.17 (the AB part of an ABX system, JAB = 18.5, JAX = 7.4, JBX
3.0 Hz, 2 H, CH ): δ = 195.89 (300 MHz, CDCl
) ppm. 13C NMR (75 MHz, CDCl
CO), 170.92 (CO CH ), 166.14 (C-6a), 137.83 (C-3a), 132.94 (C- = 5.0 Hz, 1 H, 3-H), 6.01 (d, J = 7.3 Hz, D
), 119.82 (C-3), 53.36 (CH ), 44.77 (C-5), 42.67 (C-6) ppm. EIMS: 5.33–5.26 (m, 1 H, 4-H), 4.21 and 4.04 (AB part of an ABM sys-
], tem, JAB = 10.6, JAM = 8.13, JBM = 6.25 Hz, 2 H, OCH ), 3.50–
], 136 (56), 119 (16), 109 (30) 3.46 (m, 1 H, 6-H), 3.10 (dt, J = 13.8, J = 8.0 Hz, 1 H, 5-H), 2.08
S (196.22): calcd. C 55.09, (s, 3 H, CH ), 1.96 (s, 3 H, CH ), 1.87 (dt, J = 13.8, J = 5.2 Hz, 1
H 4.11, S 16.34; found C 55.00, H 3.99, S 16.52. H, 5-H) ppm. C NMR (75 MHz, CDCl ): δ = 171.27 and 169.98
2 CO), 146.72 and 144.99 (C-3a,-6a), 130.43 (C-2), 121.80 (C-3),
EtOAc (1:1) afforded pure 15 and pure 16 for analysis.
3
3
–
1
1
3
=
(
2
3072, 2961, 1743, 1638, 1557, 1371, 1234 cm .
): δ = 7.21 (d, J = 5.0 Hz, 1 H, 2-H), 6.85 (d, J
O exch., 1 H, NH),
H NMR
2
3
3
2
3
2
3
+
+
+
m/z (%) = 197 (4) [M + 1] , 196 (37) [M ], 164 (20) [M – OCH
3
2
+
1
53 (18), 137 (100) [M – CO
2
CH
3
+
[C
6
H
5
S] , 97 (7), 69 (10), 65 (23). C
9
H
8
O
3
3
3
1
3
3
(
3.1.6 (±)-Methyl 4-Hydroxyimino-5,6-dihydro-4H-cyclopenta[b]thio-
6
2
8.12 (CH
2
O), 50.44 (C-4), 42.08 (C-5), 40.19 (C-6), 23.68 and
phene-6-carboxylate (14): A solution of hydroxylamine hydrochlo-
ride (0.55 g, 7.91 mmol) and sodium acetate (1.2 g, 8.82 mmol) in
water (3 mL) was added to the keto ester 13 (0.87 g, 4.43 mmol),
and EtOH was added until dissolution was complete (20 mL). This
solution was refluxed for 5 h and cooled to room temperature, and
after removal of EtOH under reduced pressure the solution was
+
1.30 (2×CH
3
) ppm. EIMS: m/z (%) = 254 (7) [M + 1] , 253 (6)
+
+
+
[M ], 210 (9) [M – Ac], 193 (89), 167 (31) [M – 2 Ac], 150 (99),
+
+
1
37 (16) [M – C
5 8 3 5 9 3
H O ], 133 (100), 122 (15) [M – C H NO ] ppm.
12 3
C H15NO
S (253.32): calcd. C 56.90, H 5.79, N 5.53, S 12.66;
found C 56.78, H 6.04, N 5.68, S 12.57.
extracted with Et
were dried with anhydrous Na
duced pressure then afforded 14 (a mixture of E and Z isomers) as
a white solid (0.90 g, 96%). M.p. 148–151 °C. IR (KBr): ν˜ = 3200,
2
O (3×30 mL). The combined organic extracts
SO , and concentration under re-
16: Yellowish white solid, m.p. 100–102 °C. IR (KBr): ν˜ = 3306,
–
1
1
2
4
3050, 2943, 2889, 1731, 1638, 1538, 1385, 1252 cm . H NMR
(300 MHz, CDCl ): δ = 7.24 (d, J = 5.0 Hz, 1 H, 2-H), 6.86 (d, J
= 5.0 Hz, 1 H, 3-H), 5.85 (d, J = 7.3 Hz, D O exch., 1 H, NH),
5.38–5.31 (m, 1 H, 4-H), 4.18 and 3.99 (AB part of an ABM sys-
tem, JAB = 10.5, JAM = 8.3, JBM = 6.3 Hz, 2 H, OCH ), 3.68–3.63
3
2
3
1
=
078, 2940, 2865, 1742, 1654, 1508, 1435, 1401, 1329, 1271,
–1 1
207 cm . H NMR (300 MHz, CDCl
8.12 (br. s, 1 H, D O exch., NOH), 7.36 (d, J = 4.9 Hz, 1 H, 2-
H), 7.10 (d, J = 5.1 Hz, 1 H, 3-H), 4.27 (dd, J = 8.0, 3.6 Hz, 1 H,
-H) 3.79 (s, 3 H, OCH ), 3.69 and 3.54 (the AB part of an ABX
system, JAB = 18.5, JAX = 8.1, JBX = 3.6 Hz, 2 H, CH
NMR (75 MHz, CDCl ): δ = 172.14 (CO Me), 157.83 (C=N),
50.97 (C-6a), 142.83 (C-3a), 132.37 (C-2), 119.05 (C-3), 53.13
3
) (two isomers apparent): δ
2
2
(m, 1 H, 6-H), 2.63 (ddd, Jgem = 13.9, Jvic = 8.1, Jvic = 5.5 Hz, 1
H, 5-H), 2.39 (ddd, Jgem = 13.9, Jvic = 7.9, Jvic = 3.9 Hz, 1 H, 5-
1
3
6
3
H), 2.07 (s, 3 H, CH
CDCl ): δ = 171.24 and 170.02 (2 CO), 146.58 and 145.62 (C-3a,
-6a), 130.53 (C-2), 121.85 (C-3), 67.81 (CH O), 50.58 (C-4), 42.45
(C-5), 40.14 (C-6), 23.67 and 21.27 (2 CH ) ppm. EIMS: m/z (%)
3 3
), 1.95 (s, 3 H, CH ) ppm. C NMR (75 MHz,
1
3
2
) ppm.
C
3
3
2
2
1
3
+
+
+
(
+
CH
3
+
), 44.57 (C-6), 35.27 (C-5) ppm. EIMS: m/z (%) = 212 (15) [M
= 254 (2) [M + 1] , 253 (1) [M ], 210 (3) [M – Ac], 193 (53), 167
+
+
], (4) [M+ – 2 Ac], 151 (30) [M – C
+
], 137 (17) [M+ – C
]. C12 S (253.32): calcd.
1] , 212 (73) [M ], 195 (8), 162 (13), 152 (100) [M – CO
2
CH
3
4
H
6
O
3
5 8 3
H O ],
35 (75) [M+ – C
H
O
3
], 121 (14) [M – C
NO S (211.24): calcd. C 51.17, H 4.29,
N 6.63, S 15.18; found C 51.06, H 4.35, N 6.76, S 15.03.
+
H
4
NO
], 108 (20), 97 134 (100), 122 (25) [M – C
+
H
NO
H15NO
3
1
2
4
2
3
5
9
3
(8), 69 (10), 63 (15). C
9
H
9
3
C 56.90, H 5.97, N 5.53, S 12.66; found C 57.07, H 6.06, N 5.42,
S 12.50.
3
.1.7 (±)-cis-[4-Acetylamino-5,6-dihydro-4H-cyclopenta[b]thien-6-yl]- 3.1.8 (±)-cis-N-[(6-Hydroxymethyl)-5,6-dihydro-4H-cyclopenta[b]-
methyl Acetate (15) and (±)-trans-[4-Acetylamino-5,6-dihydro-4H- thien-4-yl]acetamide (17) and (±)-trans-N-[(6-Hydroxymethyl)-5,6-
cyclopenta[b]thien-6-yl]methyl Acetate (16): AlH was prepared by dihydro-4H-cyclopenta[b]thien-4-yl]acetamide (18): Potassium car-
3
762
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 759–764

Synthesis of Two Precursors of Heterocarbocyclic Nucleoside Analogues
FULL PAPER
–
1 1
bonate (1.88 g, 13.60 mmol) was added to a 1:1 solution of 15/16
(film): ν˜ = 3344, 2925, 1654, 1560, 1504, 1458, 1040 cm . H NMR
]MeOH): δ = 7.36 (d, J = 5.02 Hz, 1 H, 2-H), 7.01
(d, J = 5.02 Hz, 1 H, 3-H), 4.49–4.41 (m, 1 H, 4-H), 3.68–3.49 (m,
3 H, OCH +6-H), 2.61–2.49 (m, 1 H, 5-H), 2.42–2.31 (m, 1 H, 5-
(
0.92 g, 3.64 mmol) in MeOH (12 mL), and the mixture was stirred (300 MHz, [D
for 2.5 h at room temperature and brought to pH 7 by addition of
saturated NH Cl solution (40 mL). The organic solvent was re-
4
4
2
3
1
moved under reduced pressure, and the solid formed was redis-
solved in water (60 mL). This solution was extracted with EtOAc
H) ppm. C NMR (75 MHz, [D
(C-3a,-6a), 129.48 (C-2), 121.09 (C-3), 65.86 (CH
43.55 (C-6), 42.23 (C-5) ppm. EIMS: m/z (%) = 169 (12) [M ], 168
(3) [M – 1] , 152 (7) [M – OH], 138 (100) [C
(24). HMRS m/z calcd. for [C 11NOS] 169.0561, found 169.0571.
4
]MeOH): δ = 147.05 and 146.11
2
O), 51.79 (C-4),
+
(
3×60 mL), and the combined organic extracts were dried with an-
hydrous Na SO and concentrated under reduced pressure. The so-
lid residue so obtained was chromatographed on silica gel (22 g)
with CH Cl /iPrOH (15:1) as eluent, it afforded first 17 (0.33 g,
3%) and then 18 (0.29 g, 38%).
+
+
2
4
7 8
H SN], 123 (6), 122
8
H
2
2
Supporting Information (see footnote on the first page of this arti-
cle): The ORTEP plot of the structure of (±)-16 and the details of
the reduction of hydroxyimino ester 14 is available.
4
1
1
1
7: M.p. 155–157 °C. IR (KBr): ν˜ = 3276, 2964, 1635, 1553, 1372,
–1 1
041 cm . H NMR (300 MHz, CDCl
3
): δ = 7.23 (d, J = 4.9 Hz,
H, 2-H), 6.87 (d, J = 4.9 Hz, 1 H, 3-H), 6.35 (d, J = 7.6 Hz, 1
H, NH), 5.31 (dt, J = 8.4, J = 3.1 Hz, 1 H, 4-H), 3.86 and 3.69
AB part of an ABM system, JAB = 10.4, JAM = 4.3, JBM = 3.5 Hz,
Acknowledgments
(
2
8
H, OCH
.4 Hz, 5-H), 2.21 (br. s, D
2
), 3.42–3.36 (m, 1 H, 6-H), 3.11 (dt, 1 H, J = 13.8, J =
O exch., 1 H, OH), 1.99 (dt, J = 13.8,
) ppm. 13C NMR (75 MHz,
): δ = 169.72 (CO), 147.98 and 145.14 (C-3a,-6a), 130.26 (C-
), 122.21 (C-3), 66.16 (CH O), 49.79 (C-4), 43.50 (C-6), 42.09 (C-
), 23.82 (CH ) ppm. EIMS: m/z (%) = 152 (0.23) [C 10SN], 138
SN], 122 (16), 58 (100). C10 S (211.28): calcd. C
The authors thank the Xunta de Galicia for financial support un-
der projects PGIDT01 PXI20302PR and PGIDT02BTF20305PR.
2
J = 3.3 Hz, 1 H, 5-H), 1.92 (s, 3 H, CH
CDCl
2
5
3
3
2
[1] a) J. M. Colacino, K. A. Staschke, Prog. Drug. Res. 1998, 50,
259–322; b) M. V. Kolb, Prog. Drug. Res. 1997, 48, 195–232; c)
E. De Clercq, Curr. Med. Chem. 2001, 8, 1543–1572; d) H. Tan,
C. K. Chu, F. D. Boudinot, Adv. Drug Delivery Rev. 1999, 39,
3
8
H
(11) [C
7
H
8
H13NO
2
5
1
6.85, H 6.20, N 6.63, S 15.18; found C 57.11, H 6.11, N 6.68, S
5.07.
117–151; e) T. S. Mansour, R. Storer, Curr. Pharmaceutical De-
sign 1997, 3, 227–264.
1
1
5
6
8: M.p. 94–96 °C. IR (KBr): ν˜ = 3531, 3254, 2925, 1612, 1562,
261, 1057 cm . H NMR (300 MHz, CDCl ): δ = 7.24 (d, J =
3
.0 Hz, 1 H, 2-H), 6.88 (d, J = 5.0 Hz, 1 H, 3-H), 5.77 (d, J =
.4 Hz, 1 H, NH), 5.39–5.33 (m, 1 H, 4-H), 3.79–3.52 (m, 3 H,
[2] a) E. Ichicawa, K. Kato, Curr. Med. Chem. 2001, 8, 385–423;
b) X.-F. Zhu, Nucleosides, Nucleotides Nucleic Acids 2000, 19,
–1 1
651–690; c) M. T. Crimmins, Tetrahedron 1998, 54, 9229–9272;
d) L. Agrofoglio, E. Suhas, A. Farese, R. Condom, S. R. Chal-
land, R. A. Earl, R. Guedj, Tetrahedron 1994, 50, 10611–10670.
3] a) Y. F. Shealy, J. D. Clayton, J. Am. Chem. Soc. 1966, 88,
OCH
2
, 6-H), 2.67 (ddd, Jgem = 13.8, Jvic = 7.8, Jvic = 4.7 Hz, 1 H,
[
5
2
-H), 2.35 (ddd, Jgem = 13.8, Jvic = 7.8, Jvic = 4.1 Hz, 1 H, 5-H),
.02 (br. s, D
3885–3887; b) Y. F. Shealy, J. D. Clayton, J. Am. Chem. Soc.
1
3
2
O exch., 1 H, OH), 1.97 (s, 3 H, CH
): δ = 169.98 (CO), 147.87 and 146.98 (C-
a,-6a), 130.26 (C-2), 121.98 (C-3), 66.83 (CH O), 50.80 (C-4),
3.61 (C-6), 42.30 (C-5), 23.76 (CH ) ppm. EIMS: m/z (%) = 193
O], 168 (3) [M – Ac], 152 (46) [C 10SN], 138 (100)
SN], 122 (66) ppm. C10 S (211.28): calcd. C 56.85, H
3
) ppm.
C
1
969, 91, 3075–3083; c) Y. F. Shealy, J. D. Clayton, J. Pharm.
NMR (75 MHz, CDCl
3
4
3
Sci. 1973, 62, 1432.
2
[4] T. Kusaka, H. Yamamoto, M. Shibata, M. Muroi, T. Kishi,
K. T. Mizuno, J. Antibiot. 1968, 21, 255–261.
[5] S. Yaginuma, N. Muto, M. Tsujino, Y. Sudate, M. Hayashi, M.
Otani, J. Antibiot. 1981, 34, 359–366.
3
+
+
(33) [M – H
2
8
H
[C
7
H
8
H13NO
2
[
[
6] R. Vince, M. Hua, J. Med. Chem. 1990, 33, 17–21.
6
.20, N 6.63, S 15.18; found C 56.94, H 6.26, N 6.59, S 15.09.
7] a) M. B. Faletto, W. H. Miller, E. P. Garvey, M. H. St. Clair,
S. M. Daluge, S. S. Good, Antimicrob. Agents Chemother. 1997,
41, 1099–1107; b) R. H. Foster, D. Faulds, Drugs 1998, 729–
3
.1.9 (±)-cis-(4-Amino-5,6-dihydro-4H-cyclopenta[b]thien-6-yl)meth-
anol (6): A solution of 17 (0.132 g, 0.78 mmol) in a mixture of
MeOH (3 mL) and 2 n HCl (3 mL) was refluxed for 8 h and then
reduced to dryness by evaporation under reduced pressure followed
by azeotropic distillation with EtOH (2×20 mL). The solid residue
was dissolved in MeOH (4 mL), loaded on a 10 mL Amberlite
IRA-400(OH) column, and eluted with MeOH (100 mL). Concen-
tration of the eluate under reduced pressure left an oily residue that
afforded 6 (0.042 g, 40%) as an orange oil after chromatography
on silica gel (8 g) with dichloromethane/methanol (1:1) as eluent .
736; c) S. M. Daluge, M. T. Martín, B. R. Sickles, D. A. Living-
ston, Nucleosides, Nucleotides Nucleic Acids 2000, 19, 297–327.
8] a) D. F. Ewing, N.-E. Fahmi, C. Len, G. Mackenzie, A. Prauzo,
J. Chem. Soc., Perkin 1 2000, 3561–3565; b) D. F. Ewing, N.-
E. Fahmi, C. Len, G. Mackenzie, G. Ronco, P. Villa, G. Shaw,
Nucleosides Nucleotides Nucleic Acids 1999, 18, 2613–2630.
9] L. Belmonte, P. Baré, M. M. E. De Bracco, B. H. Ruibal-Ares,
Curr. Med. Chem. 2003, 10, 303–312.
[
[
[10] a) M. J. Figueira, O. Caamaño, F. Fernández, J. M. Blanco,
Tetrahedron 2002, 58, 7233–7240; b) M. I. Nieto, O. Caamaño,
F. Fernández, G. Gómez, J. Balzarini, E. De Clercq, Nucleo-
sides, Nucleotides Nucleic Acids 2002, 21, 243–255; c) F.
Fernández, X. García-Mera, M. Morales, J.-E. Rodríguez-
Borges, Synthesis 2001, 239–242; d) M. I. Nieto, J. M. Blanco,
O. Caamaño, F. Fernández, C. López, X. García-Mera, J. Balz-
arini, E. De Clercq, Nucleosides, Nucleotides Nucleic Acids
–
1 1
IR (film): ν˜ = 3346, 2923, 1841, 1587, 1503, 1438, 1037 cm . H
NMR (300 MHz, [D ]MeOH): δ = 7.30 (d, J = 4.9 Hz, 1 H, 2-H),
.97 (d, J = 4.9 Hz, 1 H, 3-H), 4.34–4.29 (m, 1 H, 4-H), 3.78–3.52
m, 3 H, OCH , 6-H), 3.16–2.88 (m, 1 H, 5-H), 1.98–1.81 (m, 1 H,
-H) ppm. 13C NMR (75 MHz, [D
]MeOH): δ = 149.05 and 145.08
O), 52.09
C-4), 43.59 (C-6), 43.14 (C-5) ppm. EIMS: m/z (%) = 168 (0.62)
4
6
(
5
2
4
(C-3a,-6a), 129.05 (C-2), 121.04 (C-3), 65.72 (CH
2
(
1
999, 18, 2253–2263.
+
+
[M – 1] , 152 (6) [M – OH], 138 (100) [C
7 8
H SN], 123 (19), 122
[
11] a) J. M. Blanco, O. Caamaño, F. Fernández, J. E. Rodríguez-
(95). HMRS m/z calcd. for [C 11NOS] 169.0561, found 169.0569.
8
H
Borges, J. Balzarini, E. De Clercq, Chem. Pharm. Bull. 2003,
5
1, 1060–1063; b) J. M. Blanco, O. Caamaño, F. Fernández,
3
.1.10 (±)-trans-(4-Amino-5,6-dihydro-4H-cyclopenta[b]thien-6-yl)-
X. García-Mera, A. R.-Hergueta, C. López, J. E. Rodríguez-
methanol (7): A solution of 18 (0.104 g, 0.49 mmol) in a mixture
of EtOH (2.5 mL) and 2 n HCl (2.5 mL) was refluxed for 24 h.
Compound 7 (0.034 g, 41%) was obtained as a brown oil by a
procedure analogous to that by which 6 was obtained from 17. IR
Borges, J. Balzarini, E. De Clercq, Chem. Pharm. Bull. 1999,
47, 1314–1317.
[12] G. Ferrand, J. Barbanton, 1986. Depin, J. C. Fr. Demande FR
2567125, Chem. Abstr. 105: 172281.
Eur. J. Org. Chem. 2006, 759–764
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
763

P. Abeijón, J. M. Blanco, F. Fernández, M. D. García, C. López
FULL PAPER
[
[
[
13] T. Imamoto, T. Matsumoto, H. Yokoyama, M. Yokoyama, K.-
5.2 Hz, 1 H, 2-H), 6.41 (d, J = 5.2 Hz, 1 H, 3-H), 5.08 (br. s,
I. Yamaguchi, J. Org. Chem. 1984, 49, 1105–1110.
D
2
O exch., 1 H, OH), 4.72 (t, J = 5.3 Hz, D
NH), 3.49–3.34 (m, 2 H, CH O), 3.09–3.03 (m, 2 H, 2×5-H),
2.88–2.81 (m, 1 H, 7-H), 1.88–1.79 (m, 1 H, 6-H), 1.72–1.63
2
O exch., 1 H,
14] E. M. Berman, H. D. H. Showalter, J. Org. Chem. 1989, 54,
2
5642–5644.
1
3
15] a) E. Lee-Ruff, W.-Q. Wan, J.-L. Jiang, J. Org. Chem. 1994,
(m, 1 H, 6-H) ppm. C NMR (75 MHz, [D
144.88 (C-3a), 122.67 (C-2), 118.97 (C-3), 111.65 (C-7a), 66.88
(CH O), 39.11 (C-5), 36.79 (C-7), 26.07 (C-6). EIMS: m/z (%)
= 170 (12) [M + 1] , 169 (31) [M ], 151 (21) [M – H
(2) [M – CH
m/z calcd. for [C
6
]DMSO): δ =
5
9, 2114–2118; b) H. Boumchita, M. Legraverend, E. Bisagni,
Heterocycles 1991, 32, 1785–1792; c) K. Soai, A. J. Ookawa, J.
Org. Chem. 1986, 51, 4000–4005.
2
+
+
+
2
O], 138
NO], 108 (100). HMRS
H11NOS] 169.0561, found 169.0552.
+
+
[16] (±)-(4-Hydroxyimino-5,6-dihydro-4H-cyclopenta[b]thien-6-yl)-
2 4
OH], 123 (48) [M – CH
methanol (19). Viscous liquid. IR (film): ν˜ = 3383, 2937, 2810,
8
–1
1
1
654, 1559, 1399, 1269 cm . H NMR (300 MHz, [D
DMSO): δ = 10.45 (s, D O exch., 1 H, NOH), 7.50 (d, J =
.9 Hz, 1 H, 2-H), 7.00 (d, J = 4.9 Hz, 1 H, 3-H), 5.04 (t, J =
.9 Hz, D O exch., 1 H, OH), 3.57–3.52 (m, 1 H, 6-H), 3.43–
.27 (m, 2 H, CH3
H, 5-H) ppm. 1 C NMR (75 MHz, [D
6
]- [18] M. N. Rerick, C. H. Trottier, R. A. Daignault, J. D. De Foe,
2
Tetrahedron Lett. 1963, 4, 629–634.
[19] A. R. Hergueta, C. López, F. Fernández, O. Caamaño, J. M.
Blanco, Tetrahedron: Asymmetry 2003, 14, 3773–3778.
4
4
3
1
2
2
O), 3.21–3.13 (m, 1 H, 5-H), 2.74–2.67 (m, [20] a) N. M. Yoon, H. C. Brown, J. Am. Chem. Soc. 1968, 90,
6
]DMSO): δ = 156.20
2927–2938; b) H. C. Brown, N. M. Yoon, J. Am. Chem. Soc.
1966, 88, 1464–1472.
[21] CCDC-268240 (16) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(
3
=
1
1
C=N), 155.21 (C-6a), 141.93 (C-3a), 131.55 (C-2), 118.33 (C-
), 65.01 (CH O), 42.24 (C-6), 34.94 (C-5) ppm. EIMS: m/z (%)
184 (4) [M + 1] , 183 (33) [M ], 152 (100) [M – NOH],
35 (70) [M+ – H
NO ]. HMRS m/z calcd. for [C NO S]
83.0354, found 183.0346.
2
+
+
+
2
2
8
H
9
2
[
17] (±)-(4,5,6,7-Tetrahydrothieno[3,2-b]pyridin-7-yl)methanol (20).
Received: July 11, 2005
Published Online: November 21, 2005
M.p. 145–147 °C. IR (KBr): ν˜ = 3238, 2920, 1569, 1490, 1331,
–1 1
1
6
027 cm . H NMR (300 MHz, [D ]DMSO): δ = 6.98 (d, J =
764
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 759–764