Aza-C-nucleosides as a new class of nucleosides

Article abstract of DOI:10.1055/s-1999-3609

The synthesis of a new type of nucleoside analogue, aza-C-nucleosides, has been accomplished by the reaction of a number of hydroxylated piperidine and pyrrolidine derivatives with 5-bromouracil in pyridine. The conversion of the aza sugar (+)-cis-N-benzyl-4-hydroxymethylpiperidin-3-ol ((±)-5a) into (±)-5b with trans-configuration was accomplished in five steps by successive tritylation, mesylation, S(N)2 reaction with sodium acetate, deacetylation by treatment with sodium methoxide to give (±)-9 and finally detritylation with 80% acetic acid to give (±)-5b.

Full text of DOI:10.1055/s-1999-3609

PAPER
1937
Aza-C-nucleosides as a New Class of Nucleosides
Mads D. Sørensen, Nagy M. Khalifa, Erik B. Pedersen*
Department of Chemistry, University of Southern Denmark, Odense University, DK-5230 Odense M, Denmark
Fax +45 66158780; E-mail: EBP@Chem.sdu.dk
Received 7 May 1999; revised 2 July 1999
Abstract: The synthesis of a new type of nucleoside analogue, aza-
C-nucleosides, has been accomplished by the reaction of a number
of hydroxylated piperidine and pyrrolidine derivatives with 5-bro-
mouracil in pyridine. The conversion of the aza sugar (±)-cis-N-
benzyl-4-hydroxymethylpiperidin-3-ol ((±)-5a) into (±)-5b with
trans-configuration was accomplished in five steps by successive
tritylation, mesylation, S 2 reaction with sodium acetate, deacety-
N
lation by treatment with sodium methoxide to give (±)-9 and finally
detritylation with 80% acetic acid to give (±)-5b.
Key words: aza-C-nucleosides, aza sugars, nucleoside synthesis,
piperidine sugar analogues, pyrollidine sugar analogues
Figure 1
The conversion of ethyl 1-benzyl-3-oxopiperidine-4-car-
The synthesis of sugar modified nucleoside analogues has boxylate hydrochloride (4) to the diastereomeric mixture
been an active research area for many years. An interest- of
(±)-cis-1-benzyl-4-(hydroxymethyl)piperidin-3-ol
ing class of nucleosides is C-nucleosides in which the sug- ((±)-5a) and (±)-trans-1-benzyl-4-(hydroxymethyl)pipe-
ar part is linked to a heterocyclic base through a carbon- ridin-3-ol ((±)-5b) has been accomplished according to a
7
to-carbon bond instead of a carbon-to-nitrogen bond as in slightly modified literature procedure. The commercially
the most common nucleosides. Several C-nucleosides available 4 was treated with sodium hydroxide in metha-
have been found in nature, and the first example was nol to liberate it from the hydrogen chloride. Subsequent-
1
pseudouridine 1 (Y-uridine) which was isolated in 1957.
ly the mixture was treated with 12 equivalents of sodium
Many of the naturally occurring C-nucleosides are antibi- borohydride to obtain a diastereomeric mixture of (±)-5a
2
otics and exhibit anticancer and/or antiviral activity. In and (±)-5b (Scheme 1). All attempts to achieve a satisfy-
another class of nucleosides, one has replaced the natural ing separation of (±)-5a and (±)-5b by silica gel chroma-
glycons with aza sugars, which are polyhydroxylated cy- tography failed, and it turned out that laborious column
clic amines. Due to their structural relationship to sugars chromatography on alumina or preparative high-pressure
3
polyhydroxylated piperidines, e.g. isofagomine (3,4-di- liquid chromatography (HPLC) were the only useful
hydroxy-5-hydroxymethylpiperidine analogue of glu- methods for separation. The reduction products (±)-5a
cose), are interesting candidates for the inhibition of and (±)-5b were formed in the ratio of 3.7:1.
various glycosidases. Carbocyclic nucleoside analogues
have been synthesized where one of the carbon atoms in a
carbocyclic ring is replaced by a nitrogen atom (e.g. the
4
3
´-aza-3´-deoxythymidine carboanalogue or the pyrro-
5
lidinyl analogues of 2´,3´-dideoxycytidine 2 ).
This paper represents a new type of nucleoside analogue
which is a hybrid of some of the characteristic elements
outlined above. The nucleoside consists of an aza sugar
linked from the nitrogen atom to the nucleobase at a car-
bon atom (e.g. 3). This new type of nucleoside is called an
aza-C-nucleoside.
6
Scheme 1
Phillips discovered in 1951 that 5-bromouracil reacts
with amines to give 5-substituted aminouracils. When two
to five equivalents of the amine were refluxed for a brief
interval with 5-bromouracil, it gave the respective 5-sub-
stituted aminouracil in excellent yield. The fact that 5-
substituted aminouracils can be synthesized in this man-
ner led to the idea that different aza sugars could react
with 5-bromouracil to produce the new aza-C-nucleo-
sides.
It was possible to convert the cis-isomer ((±)-5a) into the
trans-isomer ((±)-5b) in five steps. Compound (±)-5a was
tritylated with an excess of trityl chloride in pyridine in
the presence of 4-dimethylaminopyridine (DMAP) and
(
±)-cis-1-benzyl-4-[(trityloxy)methyl]piperidin-3-ol ((±)-
6
) was obtained in a crystalline form in 73% yield after 6
Synthesis 1999, No. 11, 1937–1943 ISSN 0039-7881 © Thieme Stuttgart · New York

1
938
M. D. Sørensen et al.
PAPER
days of reaction. Mesylation of (±)-6 with methanesulfo- thyl)piperidin-3-ol ((±)-10b), respectively, in excellent
nyl chloride in pyridine gave the 3-O-mesyl derivative yields (Scheme 3).
(
(±)-7) as a crystalline compound in 86% yield. NMR
6
The amines used by Phillips in the synthesis of 5-substi-
spectroscopy verified the mesylation of the 3-OH group.
The H NMR spectrum showed the appearance of a singlet
at d 2.64 (CH SO ) and a downfield shift for H-3 at d 5.02
(
trum showed a strong downfield shift for C-3 at 77.31
ppm (compared to 64.87 ppm for (±)-6) and the appear-
ance of the methylsulfonyl group at 38.49 ppm. Inversion
of configuration at C-3 caused by a S 2 reaction was ac-
complished by heating a solution of (±)-7 in DMF at
1
for 3 days. The C NMR data for a sample of the crude
product confirmed the synthesis of the acetylated com-
pound (±)-8. The significant shift of the methylsulfonyl
tuted aminouracils were not only reagents but acted also
as solvents. Some of the aza sugars that were used in the
present work are solids. Therefore a suitable solvent had
to be found for the reaction between 5-bromouracil and
the aza sugars used. DMF was tested for this purpose, but
it turned out that a small amount of 5-(dimethylami-
no)uracil was formed as a byproduct due to the presence
of dimethylamine as an impurity in DMF. Pyridine on the
other hand was a suitable solvent, and in addition this sol-
vent also acts as an acid acceptor. (±)-5-[cis-3-Hydroxy-
1
3
2
1
3
compared to d 3.96 for H-3 in (±)-6). The C NMR spec-
N
00 °C in the presence of a large excess of sodium acetate
1
3
4
(
-(hydroxymethyl)piperidin-1-yl]uracil ((±)-11a) and
±)-5-[trans-3-hydroxy-4-(hydroxymethyl)piperidin-1-
yl]uracil ((±)-11b) were synthesized by refluxing a mix-
ture of 5-bromouracil and three equivalents of the appro-
priate aza sugar, (±)-10a and (±)-10b respectively, in
pyridine for 24 h (Scheme 3). Using less than three equiv-
alents of the aza sugar made it very difficult to get rid of
unreacted 5-bromouracil.
13
group at 38.49 ppm had disappeared. Furthermore the C
NMR spectrum showed an upfield shift for C-3 at 64.34
ppm (compared to 77.31 ppm for (±)-7). Without purifica-
tion, (±)-8 was deacetylated by treatment with a catalytic
amount of sodium methoxide in methanol to give (±)-
trans-1-benzyl-4-[(trityloxy)methyl]piperidin-3-ol ((±)-
9
) in 70% overall yield after column chromatography
from (±)-7. After detritylation of (±)-9 with 80% acetic ac-
id, (±)-5b was obtained in 89% yield after column chro-
matography (Scheme 2).
Scheme 3
NMR evidence for the assignment of the structures is
Reaction conditions: a) TrCl, pyridine, DMAP, r.t., 6 d, 73%; b)
MsCl, pyridine, 0 °C for 10 min then 4 h at r.t., 86%; c) NaOAc, DMF,
based on 2D NMR experiments, the position of 3´-H and
its coupling with the protons in the 2´-position. In the H
1
100 °C, 3 d; d) NaOMe, MeOH, r.t., 2 d, 70%; e) 80% AcOH, reflux,
10 min, 89%.
NMR spectrum for the cis-isomer ((±)-11a) the signal for
Scheme 2
the equatorial proton in the 3´-position (3´-H ) appeared at
e
3
.80 ppm. The axial proton (3´-H ) for the trans-isomer
a
(
3
(±)-11b) showed an upfield absorption at 3.29-
.45 ppm. The coupling pattern of 2´-H for (±)-11a ap-
Debenzylation of (±)-5a and (±)-5b by catalytic hydro-
genolysis was attempted with palladium-on-carbon as the
catalyst. It turned out to be a poor choice of catalyst, and
therefore Pearlman catalyst (20% palladium hydroxide-
on-carbon) was used instead. Treatment of (±)-5a and (±)-
a
peared as a doublet-doublet originating from a large gem-
inal coupling to 2´-H and a small vicinal coupling to 3´-
e
H . For (±)-11b the coupling pattern of 2´-H appeared as
e
a
a triplet originating from a large geminal coupling to 2´-
H and a large vicinal coupling to 3´-H .
5
b with this catalyst in the presence of hydrogen under
e
a
pressure gave the free amines (±)-cis-4-(hydroxymeth-
yl)piperidin-3-ol ((±)-10a) and (±)-trans-4-(hydroxyme-
A similar synthetic pathway as the one described for (±)-
1a and (±)-11b has been performed in the synthesis of a
mixture of the structural isomers (±)-5-[cis-4-hydroxy-3-
1
Synthesis 1999, No. 11, 1937–1943 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Aza-C-nucleosides as a New Class of Nucleosides
1939
(
5
hydroxymethyl)piperidin-1-yl]uracil ((±)-15a) and (±)-
-[trans-4-hydroxy-3-(hydroxymethyl)piperidin-1-yl]-
uracil((±)-15b) (Scheme 4). The commercially available
starting material ethyl 1-benzyl-4-oxopiperidine-3-car-
boxylate hydrochloride (12) was reduced with sodium
borohydride under almost the same conditions as de-
8
scribed earlier and as described for the reduction of 4, to
yield a mixture of (±)-cis-, and (±)-trans-1-benzyl-3-(hy-
droxymethyl)piperidin-4-ol ((±)-13a/(±)-13b). Refluxing
of the reaction mixture for 3 h before it was left standing
overnight gave an improved yield. No problems with the
purification of the product was stated in the literature, but
in the present work, it was discovered that some rather sta-
ble boron complexes were formed, according to mass
spectrometry experiments. In order to liberate (±)-13a/
(
±)-13b from these boron complexes it was found neces-
sary to repeat refluxing of the reaction mixture with meth-
anol and evaporating the methanol several times. A
diastereomeric mixture of (±)-13a/(±)-13b (1.5:1) in 75%
yield was obtained after silica gel chromatography. De-
benzylation of (±)-13a/(±)-13b with 10% palladium-on-
carbon in the presence of hydrogen under pressure gave a
mixture of (±) cis-, and (±) trans-3-(hydroxymethyl)pipe-
ridin-4-ol ((±)-14a/(±)-14b) in 94% yield. Refluxing a
mixture of 5-bromouracil and three equivalents of (±)-
Scheme 4
1
4a/(±)-14b in pyridine for 24 h gave a mixture of (±)-5-
[
(
cis-4-hydroxy-3-(hydroxymethyl)piperidin-1-yl]uracil
(±)-15a) and (±)-5-[trans-4-hydroxy-3-(hydroxymeth-
yl)piperidin-1-yl]uracil ((±)-15b) in 65% yield. A satisfy-
ing separation of the diastereomeric mixture was not
possible by silica gel chromatography. Also an attempt to
separate the corresponding acetylated diastereomers of 13
failed. The separations of the intermediate stereoisomers
were rather difficult. Small samples of (±)-13a and (±)-
1
3b were separated and used for spectroscopy. The trans
configuration of (±)-13b was deduced from 2D COSY
1
and H NMR coupling constants. Large H-H axial-axial
couplings to 2-H and 5-H proved the hydroxymethyl
a
a
group and hydroxy group, respectively, to be equatorial.
Only compound (±)-13b was available in a sufficient
amount for debenzylation to (±)-14b which again was
used for the spectral assignment. In this case the trans
Scheme 5
1
configuration was proved by two large H NMR axial-ax-
ial couplings to 4-Ha.
A five molar excess of sodium borohydride was capable
of reducing the ß-oxo ester in methanol to the diol 23.
Reduction of commercially available ethyl isonipecotate
8
(
(
16) with LiAlH in THF gave piperidin-4-ylmethanol
17) in 83% yield. Three equivalents of 17 was reacted
4
9
-11
Debenzylation was done using 20% palladium hydroxide-
on-carbon in the presence of hydrogen under pressure to
give 4-(hydroxymethyl)pyrrolidin-3-ol 24 as a diastereo-
meric mixture in 96% yield. The target compound 5-[3-
hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl]uracil 25 was
obtained as a 4:1 cis/trans diastereomeric mixture in 61%
yield by refluxing a mixture of 5-bromouracil and three
equivalents of the aza sugar in pyridine for 24 h. All at-
tempts to separate the diastereomeric mixture 25 by chro-
matography on alumina oxide or silica gel were
unsuccessful (Scheme 6).
with 5-bromouracil in pyridine to give 5-[4-(hydroxyme-
thyl)piperidin-1-yl]uracil (18) in 61% yield (Scheme 5).
The structural isomer (±)-5-[3-(hydroxymethyl)piperidin-
1
-yl]uracil ((±)-21) was synthesized in a similar manner
starting from commercially available ethyl nipecotate
19) (Scheme 5).
(
For the synthesis of the pyrrolidino aza-C-nucleoside 25
we started from ethyl N-benzyl-N-(2-carbethoxyeth-
1
2
yl)glycinate 22 which in a Dieckmann condensation was
cyclized to 1-benzyl-4-(hydroxymethyl)pyrrolidin-3-ol.
Synthesis 1999, No. 11, 1937–1943 ISSN 0039-7881 © Thieme Stuttgart · New York

1
940
M. D. Sørensen et al.
PAPER
3
7
.94 (d, 1H, J = 6.9 Hz, 3-OH), 4.30 (t, 1H, J = 5.1 Hz, CH OH),
.32 (m, 5H, Harom).
2
1
3
C NMR (DMSO-d ): d = 23.15 (C-5), 42.16 (C-4), 52.25 (C-6),
6
5
1
9.25 (C-2), 62.05, 62.13 (CH OH, CH Ph), 64.93 (C-3), 126.80,
28.12, 128.84, 138.66 (Carom.).
2
2
EI-MS: m/z = 221 (M+).
(
±) trans-1-Benzyl-4-(hydroxymethyl)piperidin-3-ol ((±)-5b)
7
13
Yield 0.79 g (17%); mp 102-105 ∞C (Lit. 104-104.5 ∞C, Lit.
1
04 ∞C).
1
H NMR (DMSO-d ): d = 1.17-1.28 (m, 2H, 4-H , 5-H ), 1.65 (t,
6
a
a
1
1
H, J = 10.3 Hz, 2-H ), 1.67 (m, 1H, 5-H ), 1.83 (td, 1H, J = 11.2,
a
e
.8 Hz, 6-H ), 2.73 (dt, 1H, J = 10.4, 3.5 Hz, 6-H ), 2.85 (dd, 1H,
a
e
J = 10.4, 4.5 Hz, 2-H ), 3.21-3.34 (m, 2H, 3-H , CH OH), 3.36 (d,
e
a
2
1
3
H, J = 13.4 Hz, CH Ph), 3.47 (d, 1H, J = 13.2 Hz, CH Ph),
2
2
.63 (dt, 1H, J = 10.3, 3.8 Hz, CH OH), 4.35 (t, 1H, J = 5.1 Hz,
2
CH OH), 4.58 (d, 1H, J = 5.3 Hz, 3-OH), 7.29 (m, 5H, Harom).
2
1
3
C NMR (DMSO-d ): d = 26.93 (C-5), 45.54 (C-4), 52.90 (C-6),
6
6
1
0.60 (C-2), 62.04 (CH Ph), 62.72 (CH OH), 67.72 (C-3), 126.89,
28.18, 128.83, 138.69 (Carom).
2
2
Scheme 6
EI-MS: m/z = 221 (M+).
NMR spectra were recorded on a Bruker AC-300 FT NMR spec-
1
13
trometer at 300 MHz for H NMR and at 62.9 MHz for C NMR
with TMS as an internal standard. EI mass spectra were recorded on
a Finnigan MAT SSQ 710. FAB mass spectra were recorded on a
Kratos MS 50 RF. Thin layer chromatography (TLC) analyses were
carried out with use of TLC plates 60 F254 purchased from Merck
and were visualized in an iodine chamber and/or with a ninhydrin
spray reagent (0.3 g ninhydrin in 100 ml butan-1-ol and 3 ml
HOAc). The silica gel (0.040-0.063 mm) and aluminium oxide
(±) cis-1-Benzyl-4-[(trityloxy)methyl]piperidin-3-ol ((±)-6)
Compound (±)-5a (3.20 g, 14.46 mmol) was coevaporated with an-
hyd pyridine (2 ¥ 15 mL) to remove traces of H O, and was then
2
dissolved in anhyd pyridine (50 mL) under Ar. Triphenylmethyl
chloride (TrCl) (6.05 g, 21.69 mmol) and a catalytic amount of N,N-
dimethylaminopyridine (DMAP) was added. The reaction was
monitored by TLC and after 3 d at r.t. the mixture was heated for 3
h at 50 ∞C. The heating had no effect and an additional amount of
TrCl (1.20 g) was added after 4 and 5 days of reaction, respectively.
After a total of 6 days of reaction, the mixture was poured into ice-
water (100 mL) and stirred for 1 h. The mixture was extracted with
CH Cl (2 ¥ 150 mL) and the combined organic fractions were
(
0.063-0.200 mm) used for column chromatography were pur-
chased from Merck. Microanalysis were carried out at the H. C.
Ørsted Institute, Universitetparken 5, DK-2100 Copenhagen. Pre-
parative HPLC was performed on a Waters Delta Pak 300 A, 15m,
RP 18, 57 ¥ 300 mm column. Ethyl 1-benzyl-3-oxopiperidine-4-
carboxylate hydrochloride, ethyl isonipecotate, ethyl nipecotate,
and ethyl N-benzyl-N-(2-carbetoxyethyl)glycinate were purchased
from Aldrich. Ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hy-
drochloride was purchased from Acros. 5-Bromouracil was pur-
chased from Sigma.
2
2
washed with sat. aq NaHCO (2 ¥ 50 mL). The organic phase was
3
dried (MgSO ), filtered and coevaporated with anhyd toluene in
4
vacuo. The residue was purified by silica gel column chromatogra-
phy (CH Cl ) to give the title compound (±)-6 as white crystals;
2
2
yield 4.89 g (73%); mp 178-179 ∞C.
1
H NMR (CDCl ): d = 1.37-1.55 (m, 2H, 5-H , 5-H ), 1.65 (m, 1H,
3
e
a
4
-H ), 1.97 (td, 1H, J = 11.8, 4.0 Hz, 6-H ), 2.14 (d, 1H, J = 11.4
a
a
(
(
±)cis-, and(±)trans-1-Benzyl-4-(hydroxymethyl)piperidin-3-ol
(±)-5a, (±)-5b)
NaBH (9.53 g, 252 mmol) was added in small portions to a stirred
mixture of NaOH (0.84 g, 21 mmol) and 4 (6.25 g, 21 mmol) in an-
hyd MeOH (100 mL) at r.t. The addition was continued over 2 h to
avoid vigorous reflux and foaming of the mixture. After stirring for
4 h, H O (125 mL) was added dropwise over 30 min and stirring
was continued for 24 h. The MeOH was distilled off in vacuo and
the remaining aqueous residue was extracted with CHCl (3 ¥
50 mL), dried (MgSO ), filtered and evaporated in vacuo. The
Hz, 2-H ), 2.67 (m, 1H, 6-H ), 2.81 (m, 1H, 2-H ), 2.91-3.03 (m,
a
e
e
2
H, CH OTr, 3-OH), 3.22 (dd, 1H, J = 7.7, 8.8 Hz, CH OTr),
2
2
4
3.49 (s, 2H, CH Ph), 3.96 (m, 1H, 3-H ), 7.16-7.33 (m, 15H,
2
e
Harom), 7.41-7.48 (m, 5H, Harom).
1
3
C NMR (CDCl ): d = 23.76 (C-5), 40.74 (C-4), 52.89 (C-6),
3
5
8
1
9.62 (C-2), 62.57 (CH Ph), 64.87 (CH OTr), 65.84 (C-3),
6.29 (C(Ph)3), 127.15, 128.31, 128.99, 138.26 (Carom-benzyl),
26.89, 127.74, 128.80, 144.40 (Carom-trityl).
2
2
2
2
3
2
C H NO ◊ 0.2 H O calc.
C
C
82.26
82.12
H
H
7.21
7.11
N
N
3.00
3.03
4
32 33
2
2
highly viscous oil was chromatographed on a 35 ¥ 6 cm column of
alumina (Merck II) (1% MeOH in CHCl ). The cis-isomer (±)-5a
(
463.6)
found
3
+
FAB-MS (3-nitrobenzylalcohol): m/z = 464 (M +1).
was the first compound eluated from the column and was isolated
as white crystals. The trans-isomer (±)-5b was isolated from the
second fraction as a white powder. The diastereomeric mixture
could also be separated by preparative HPLC on a RP 18 column
with 96% EtOH/H O (20:80) at 50 ml/min to give (±)-5b t (HPLC)
(±) cis-1-Benzyl-3-(methylsulfonyl)-4-[(trityloxy)methyl]piperi-
dine ((±)-7)
Compound (±)-6 (2.20 g, 4.75 mmol) was coevaporated with anhyd
2
R
5
5 min, and (±)-5a t (HPLC) 78 min.
pyridine (2 ¥ 15 mL) to remove traces of H O and dissolved in an-
2
R
hyd pyridine (40 mL) under Ar. To this stirred solution at 0 ∞C
methanesulfonyl chloride (1.10 mL, 14.25 mmol) was added via a
syringe and the mixture was then stirred first at 0 ∞C for 10 min and
then at r.t. for 4 h. The mixture was again cooled to 0 ∞C and 50%
aq pyridine (30 mL) was added. The mixture was diluted with
CHCl (200 mL), washed successively with H O (100 mL), sat. aq
(
±) cis-1-Benzyl-4-(hydroxymethyl)piperidin-3-ol ((±)-5a)
7 13
Yield 2.91 g (63%); mp 76-77 ∞C (Lit. 77–78 ∞C, Lit. 78 ∞C).
1
H NMR (DMSO-d ): d = 1.33-1.59 (m, 3H, 4-H , 5-H , 5-H ),
6
a
e
a
1
2
3
.94 (td, 1H, J = 10.2, 2.5 Hz, 6-H ), 2.04 (dd, 1H, J = 11.6, 1.8 Hz,
a
-H ), 2.65-2.76 (m, 2H, 2-H , 6-H ), 3.27 (m, 1H, CH OH),
a
e
e
2
3
2
.42 (s, 2H, CH Ph), 3.47 (m, 1H, CH OH), 3.72 (m, 1H, 3-H ),
2
2
e
NaHCO (100 mL), and H O (100 mL). The organic phase was
3
2
Synthesis 1999, No. 11, 1937–1943 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Aza-C-nucleosides as a New Class of Nucleosides
1941
dried (MgSO ), filtered and coevaporated with anhyd toluene in
residue was purified by recrystallization from EtOAc (70 mL) to
4
vacuo. The residue was purified by silica gel column chromatogra-
give the title compound (±)-10a as a white powder; yield 1.64 g
1
4
15
phy (1% MeOH in CH Cl ) to give the title compound (±)-7 as
(89%); mp 122-126 (Lit. 129-130 ∞C, Lit. 126-127 ∞C).
14
2
2
white fluffy crystals; yield 2.22 g (86%); mp 54 ∞C.
NMR was in agreement with previously reported results.
1
H NMR (CDCl ): d = 1.43 (m, 1H, 5-H ), 1.57 (qd, 1H, J = 12.3,
3
e
(
±)-5-[cis-3-Hydroxy-4-(hydroxymethyl)piperidin-1-
yl]uracil((±)-11a)
A mixture of (±)-10a (1.37 g, 10.42 mmol) and 5-bromouracil
0.66 g, 3.47 mmol) in anhyd pyridine (10 mL) was refluxed for
4 h, cooled to r.t. and evaporated in vacuo. Traces of pyridine were
coevaporated with toluene. The residue was dissolved in MeOH
50 mL) under heating, and the hot solution was filtered. After cool-
4
.0 Hz, 5-H ), 1.83 (m, 1H, 4-H ), 2.06 (td, 1H, J = 11.5, 3.0 Hz, 6-
a
a
H ), 2.20 (d, 1H, J = 13.0 Hz, 2-H ), 2.64 (s, 3H, Ms), 2.89 (m, 1H,
a
a
6
1
5
-H ), 3.05-3.17 (m, 2H, CH OTr), 3.30 (m, 1H, 2-H ), 3.49 (d,
e
2
e
(
2
H, J = 13.4 Hz, CH Ph), 3.57 (d, 1H, J = 13.4 Hz, CH Ph),
2
2
.02 (m, 1H, 3-H ), 7.19-7.34 (m, 15H, Harom), 7.38-7.44 (m, 5H,
e
Harom).
(
1
3
C NMR (CDCl ): d = 23.62 (C-5), 38.49 (CH SO ), 40.14 (C-4),
3
3
2
ing to 0 ∞C the precipitate was isolated by filtration and purified by
recrystallization from MeOH (40 mL) to give the title compound
5
7
2.28 (C-6), 56.53 (C-2), 62,40 (CH Ph), 63.51 (CH OTr),
7.31 (C-3), 86.79 (C(Ph) ), 127.23, 128.26, 129.13, 137.67 (C
2
2
3
arom-
(
±)-11a as a white powder; yield 556 mg (66%); mp 260-264 ∞C.
benzyl), 127.17, 127.90, 128.69, 143.87 (Carom-trityl).
1
H NMR (DMSO-d ): d = 1.37-1.45 (m, 1H, 5´-H ), 1.45-1.67 (m,
6
e
C H NO S
calc.
C
C
73.17
73.11
H
H
6.51
N
N
2.59
2.60
3
3
35
4
2
H, 4´-H , 5´-H ), 2.39 (td, 1H, J = 10.6, 2.5 Hz, 6´-H ), 2.58 (dd,
a a a
(541.7)
found
6.48
1H, J = 11.9, 1.8 Hz, 2´-H ), 3.07 (dd, 1H, J = 11.7, 3.3 Hz, 2´-H ),
a
e
+
3.21 (m, 1H, 6´-H
e
), 3.30 (dd, 1H, J = 10.4, 6.4 Hz, CH
2
OH),
FAB-MS (3-nitrobenzyl alcohol): m/z = 542 (M +1).
3
4
1
.49 (dd, 1H, J = 10.4, 6.5 Hz, CH OH), 3.80 (m, 1H, 3´-H ),
.12 (br s, 1H, 3´-OH), 4.34 (br s, 1H, CH OH), 6.78 (s, 1H, 6-H),
0.42 (br s, 1H, NH), 11.02 (br s, 1H, NH).
2
e
2
(
±) trans-1-Benzyl-4-[(trityloxy)methyl]piperidin-3-ol ((±)-9)
A mixture of (±)-7 (500 mg, 0.92 mmol) and NaOAc (0.76 g,
.2 mmol) in anhyd DMF (10 mL) was stirred at 100 ∞C until TLC
5% MeOH in CH Cl ) showed the absence of starting material (3
1
3
C NMR (DMSO-d ): d = 23.01 (C-5´), 41.89 (C-4´), 49.46 (C-6´),
9
6
5
6.19 (C-2´), 62.04 (CH OH), 64.65 (C-3´), 126.90, 126.94 (C-5,
(
2
2
2
C-6), 150.46 (C-2), 161.91 (C-4).
days). The mixture was cooled to r.t. and evaporated in vacuo. The
residue was dissolved in CHCl (50 mL) and washed successively
3
C H N O
4
calc.
C
C
49.79
49.82
H
H
6.27
6.22
N
N
17.42
17.22
1
0
15
3
with sat. aq NaHCO (20 mL) and H O (2 ¥ 20 mL). The organic
3
2
(
241.3)
found
phase was dried (MgSO ), filtered and evaporated in vacuo. This
4
gave crude (±)-8 as a brown viscous oil. The product was dissolved
in MeOH (10 mL) and a mixture of NaOMe (17 mg, 0.31 mmol) in
MeOH (3 mL) was added. The mixture was stirred at r.t. for 48 h.
EI-MS: m/z = 241 (M+).
(±) trans-4-(Hydroxymethyl)piperidin-3-ol ((±)-10b)
The MeOH was distilled off in vacuo and H O (25 mL) was added.
2
20% Pd(OH) -C (116 mg) was mixed with a solution of (±)-5b
2
The mixture was extracted with CHCl (3 ¥ 50 mL) and the com-
(777 mg, 3.51 mmol) in EtOH-H O 1:1 (15 mL). The mixture was
3
2
bined organic fractions were dried (MgSO ), filtered and evaporat-
4
hydrogenated at r.t. under pressure (60 psi). After 24 h the mixture
was filtered through Celite and the solvent evaporated in vacuo. The
title compound (±)-10b was isolated as a brown oil, and the bulk of
the product was carried on to the next step without further purifica-
tion; yield 444 mg (96%). A small portion was triturated in EtOAc
to give a light brown oil used for characterization.
ed in vacuo. The residue was purified by silica gel column
chromatography (1% MeOH in CH Cl ) to give the title compound
2
2
(
±)-9 as a very viscous oil; yield 298 mg (70% overall yield calcu-
lated from (±)-7).
1
H NMR (CDCl ): d = 1.27-1.43 (m, 1H), 1.81-1.93 (m, 1H),
3
1
2
1
.27-2.38 (m, 1H), 2.57-2.73 (m, 1H), 2.87-3.01 (m, 2H), 3.18 (t,
H NMR (DMSO-d ): d = 1.32-1.50 (m, 2H, 4-H , 5-H ), 1.80 (m,
6
a
a
H, J = 9.1 Hz, 3-H ), 3.34 (dd, 1H, J = 5.7, 9.5 Hz), 3.41 (d, 2H,
a
1H, 5-H ), 2.46 (t, 1H, J = 11.2 Hz, 2-H ), 2.66 (m, 1H, 6-H ),
e
a
a
J = 4.6 Hz), 3.50 (d, 1H, J = 13.2, CH Ph), 3.96 (d, 1H, J = 13.2,
3.04-3.12 (m, 2H, 6-H , 2-H ), 3.34 (dd, 1H, J = 10.8, 5.5 Hz,
2
e
e
CH Ph), 7.21-7.37 (m, 15H, Harom), 7.44-7.49 (m, 5H, Harom).
2
CH
2
OH), 3.50 (m, 1H, 3-H
a
), 3.56 (dd, 1H, J = 11.0, 2.4 Hz,
1
3
CH OH).
C NMR (CDCl ): d = 28.56 (C-5), 40.93 (C-4), 52.62 (C-6),
2
3
1
3
5
8
1
9.34 (C-2), 59.92 (CH Ph), 64.22 (CH OTr), 65.63 (C-3),
7.04 (C(Ph) ), 127.74, 128.34, 128.78 (Carom-benzyl), 127.09,
27.92, 128.58, 144.02 (Carom-trityl).
2
2
C NMR (DMSO-d ): d = 24.01 (C-5), 42.70 (C-4), 43.80 (C-6),
6
3
48.28 (C-2), 61.34 (CH OH), 64.36 (C-3).
2
EI-MS: m/z = 131 (M+).
Deprotection of (±)-9 to give (±)-5b
(
(
±)-5-[trans-3-Hydroxy-4-(hydroxymethyl)piperidin-1-yl]uracil
(±)-11b)
Compound (±)-9 (200 mg, 0.43 mmol) was refluxed with 80%
HOAc (10 mL) for 10 min. After cooling to r.t. the mixture was
evaporated in vacuo and the residue was made alkaline with slow
The title compound was synthesized from (±)-10b (400 mg,
.05 mmol) and 5-bromouracil (194 mg, 1.02 mmol) in anhyd pyri-
dine (5 mL) in the same way as compound (±)-11a. Yield 132 mg
54%) as a brown powder; mp 277-280 ∞C.
3
addition of sat. aq NaHCO at r.t. After stirring for 30 min, the mix-
3
ture was extracted with CHCl (3 ¥ 50 mL), and the combined or-
3
(
ganic fractions were dried (MgSO ), filtered and evaporated in
4
1H NMR (DMSO-d
): d = 1.19-1.39 (m, 2H, 4´-H
1.74 (m, 1H, 5´-H ), 2.05 (t, 1H, J = 11.4 Hz, 2´-H ), 2.26 (m, 1H,
6´-H ), 3.16 (m, 1H, 6´-H ), 3.29-3.45 (m, 4H, CH OH, 2´-H , 3´-
, H O), 3.66 (dd, 1H, J = 10.3, 2.4 Hz, CH OH), 4.39 (br s, 1H,
, 5´-H ),
a a
vacuo. The residue was purified by silica gel column chromatogra-
6
phy (0-10% MeOH in CH Cl ) to give (±)-5b; yield 85 mg (89%).
e
a
2
2
The spectroscopical data were identical with those earlier stated for
a
e
2
e
(
±)-5b in this work.
H
a
2
2
CH OH), 4.73 (br s, 1H, 3´-OH), 6.72 (s, 1H, 6-H), 10.42 (br s, 1H,
2
NH), 11.00 (br s, 1H, NH).
(
2
(
±) cis-4-(Hydroxymethyl)piperidin-3-ol ((±)-10a)
0% Pd(OH) -C (462 mg) was mixed with a solution of (±)-5a
13
2
C NMR (DMSO-d ): d = 26.82 (C-5´), 45.30 (C-4´), 49.77 (C-6´),
6
3.10 g, 14.00 mmol) in EtOH-H O 1:1 (50 mL). The mixture was
2
57.26 (C-2´), 62.56 (CH OH), 67.31 (C-3´), 126.37, 126.53 (C-5,
2
hydrogenated at r.t. under pressure (100 psi). After 60 h the mixture
was filtered through Celite and the solvent evaporated in vacuo. The
C-6), 150.43 (C-2), 161.73 (C-4).
Synthesis 1999, No. 11, 1937–1943 ISSN 0039-7881 © Thieme Stuttgart · New York

1
942
M. D. Sørensen et al.
PAPER
C H N O ◊ 0.4 H O calc.
C
48.34
found C 48.60
EI-MS: m/z = 241 (M+).
H
H
6.41
6.43
N
N
16.91
16.85
(±) cis-3-(Hydroxymethyl)piperidin-4-ol ((±)-14a)
1
1
0
15
3
4
2
H NMR (DMSO-d ): d = 1.48 (m, 2H, 5-H , 5-H ), 1.57 (m, 1H,
6
a
e
(241.3)
3
3
3
-H ), 2.53-2.68+2.79 (m+m, 3H+1H, 2-H , 2-H , 6-H , 6-H ),
a a e a e
.35 (m, 1H, CH OH), 3.44 (dd, 1H, J = 6.0, 10.4 Hz, CH OH),
2
2
.82 (m, 1H, 4-H).
(
(
±)cis-, and(±)trans-1-Benzyl-3-(hydroxymethyl)piperidin-4-ol
(±)-13a/(±)-13b)
1
3
C NMR (DMSO-d ): d = 33.36 (C-5), 41.31 (C-3), 43.69 (C-6),
6
4
3.94 (C-2), 60.71 (CH OH), 65.37 (C-4).
2
NaBH (4.54 g, 120 mmol) was added in small portions to a stirred
4
EI-MS: m/z = 131 (M+).
mixture of NaOH (0.40 g, 10 mmol) and 12 (2.98 g, 10 mmol) in
anhyd MeOH (30 mL) at r.t. Addition was continued over 30 min to
avoid vigorous reflux and foaming of the mixture. After stirring for
an additional 30 min at r.t. the mixture was refluxed for 3 h and then
left standing for 20 h at r.t. H O (50 mL) was added dropwise over
3
in vacuo and the remaining residue was added a new portion of
MeOH (20 mL). The mixture was refluxed for 10 min, cooled to r.t.
and again the MeOH was distilled in vacuo. This process was re-
(
±) trans-3-(Hydroxymethyl)piperidin-4-ol ((±)-14b)
1
H NMR (DMSO-d ): d = 1.25 (dq, 1H, J = 4.0, 11.4 Hz, 5-H ),
6
a
1
.34 (m, 1H, 3-H ), 1.71 (m, 1H, 5-H ), 2.16 (t, 1H, J = 11.4 Hz, 2-
a
e
2
H ), 2.40 (m, 1H, 6-H ), 2.88 (m, 1H, 2-H ), 3.00 (m, 1H, 6-H ),
3
CH OH), 3.62 (dd, 1H, J = 7.3, 10.4 Hz, CH OH).
1
a a e e
0 min and stirring was continued for 24 h. The MeOH was distilled
.21 (dt, 1H, J = 4.4, 10.1 Hz, 4-H ), 3.28 (dd, 1H, J = 7.5, 10.6 Hz,
a
2
2
3
C NMR (DMSO-d ): d = 35.35 (C-5), 44.46 (C-3), 46.99 (C-6),
6
4
7.55 (C-2), 61.31 (CH OH), 68.93 (C-4).
2
peated five times, and the remaining H O solution was extracted
with CHCl (4 ¥ 50 mL), dried (MgSO ), filtered and evaporated
in vacuo. The higly viscous yellow oil was passed through a short
2
EI-MS: m/z = 131 (M+).
3
4
column of silica gel, eluting with 0-50% MeOH in CH Cl . When
2
2
(±) 5-[cis/trans-4-Hydroxy-3-(hydroxymethyl)piperidin-1-
yl]uracil ((±)-15a/(±)-15b)
the less polar starting material was eluted the polarity of the eluent
was increased and the more polar diastereomeric mixture of (±)-13a
and (±)-13b was obtained as a viscous oil; yield 1.66 g (75%). Ac-
cording to NMR integrals (±)-13a and (±)-13b were formed in the
ratio of 1.5:1.
The title compound was synthesized in the same way as (±)-11a
from (±)-14a/(±)-14b (2.75 g, 21 mmol) and 5-bromouracil (1.34 g,
7
mmol) in anhyd pyridine (25 mL). Yield 1.09 g (65%) as a light
brown powder; mp 261—264 ∞C. According to NMR integrals (±)-
1
5a and (±)-15b were formed in the ratio of 1.2:1.
Tedious column chromatography on silica gel (50% MeOH in
CH Cl ) gave first a small sample of the pure diastereomer 13b and
1
2
2
H NMR (DMSO-d ): d = 1.48 (dq, 1H, J = 4.0, 11.5 Hz, 5´-Ha, 15b),
6
then 13a which were used for characterization.
1
2
.55-1.69 (m, 3H, 3´-H
, 5´-H
, 5´-H
), 1.73-1.84 (m,
e, 15a
a, 15b
a, 15a
H, 3´-H
, 5´-He, 15b), 2.16 (t, 1H, J = 11.0 Hz, 2´-H
),
(
±) cis-1-Benzyl-3-(hydroxymethyl)piperidin-4-ol ((±)-13a)
a, 15a
a, 15b
1
2.34 (m, 1H, 6´-Ha, 15b), 2.56 (t, 1H, J = 11.4 Hz, 2´-Ha, 15a),
H NMR (DMSO-d ): d = 1.57 (m, 2H, H-5 , 5-H ), 1.69 (m, 1H, 3-
H ), 2.16 (t, 1H, J = 10.4 Hz, 2-H ), 2.36 (m, 2H, 6-H , 6-H ),
6
a
e
2
3
3
.75 (m, 1H, 6´-Ha, 15a), 2.82-2.93 (m, 2H, 2´-He, 15a, 6´-He, 15a),
a
a
a
e
.14-3.36 (m, 4H, 2´-He, 15b, 6´-He, 15b, 4´-H , CH OH15b), 3.35-
2
3
.45 (dd, 1H, J = 3.5, 10.4 Hz, 2-H ), 3.28-3.52 (m, 2H, CH OH),
a, 15b
2
e
2
.54 (m, 2H, CH OH ), 3.67 (m, 1H, CH OH15b), 3.85 (m, 1H, 4´-
.40 (d, 1H, J = 13.4 Hz, CH Ph), 3.46 (d, 1H, J = 13.4 Hz,
2
15a
2
2
He, 15a), 4.31-4.47 (m, 3H, OH), 4.62 (d, 1H, J = 4.2 Hz, 4´-OH),
CH Ph), 3.79 (m, 1H, 4-H ), 4.28 (s, 1H, CH OH), 4.33 (d, 1H,
2
e
2
6
1
.71 (s, 1H, 6-H15b), 6.73 (s, 1H, 6-H15a), 10.41 (br s, 2H, 2 ¥ NH),
1.02 (br s, 2H, 2 ¥ NH).
J = 3.3 Hz, 4-OH), 7.18-7.35 (m, 5H, Harom).
1
3
C NMR (DMSO-d ): d = 32.68 (C-5), 43.33 (C-3), 48.26 (C-6),
6
13C
NMR (DMSO-d6): d = 32.40 (C-5´15a), 34.11 (C-5´15b),
5
1
1.12 (C-2), 61.16 (CH OH), 62.56 (CH Ph), 64.24 (C-4), 126.79,
28.16, 128.80, 138.93 (Carom).
2
2
4
4
6
3.17 (C-3´15a), 45.44 (C-6´15a), 45.88 (C-3´15b), 48.14 (C-2´15a),
8.63 (C-6´15b), 51.88 (C-2´15b),
60.75 (CH OH15a),
EI-MS: m/z = 221 (M+).
2
1.13 (CH OH15b), 64.06 (C-4´15a), 68.06 (C-4´15b), 125.98 (C-
2
(
±) trans-1-Benzyl-3-(hydroxymethyl)piperidin-4-ol ((±)-13b)
515a), 126.20 (C-515b), 126.87 (C-615b), 127.29 (C-615a), 150.44 (C-
215b), 150.47 (C-215a), 161.78 (C-415b), 161.90 (C-415a).
1
H NMR (DMSO-d ): d = 1.40 (qd, 1H, J = 11.5, 4.0 Hz, 5-H ),
1
H ), 1.86 (td, 1H, J = 11.9, 2.4 Hz, 6-H ), 2.70 (m, 1H, 2-H ),
2
3
4
7
6
a
.49 (m, 1H, 3-H ), 1.68 (t, 1H, J = 11.0 Hz, 2-H ), 1.73 (m, 1H, 5-
a a
C H N O
4
calc.
C
C
49.79
49.65
H
H
6.27
6.21
N
N
17.42
17.30
1
0
15
3
e
a
e
(
241.3)
found
.87 (m, 1H, 6-H ), 3.11 (m, 1H, CH OH), 3.22 (m, 1H, 4-H ),
e
2
a
.41 (m, 2H, CH Ph), 3.61 (dd, 1H, J = 10.6, 4.0 Hz, CH OH),
EI-MS: m/z = 241(M+).
2
2
.32 (br s, 1H, CH OH), 4.54 (d, 1H, J = 5.1 Hz, 4-OH), 7.18-
2
.33 (m, 5H, Harom).
5-[4-(Hydroxymethyl)piperidin-1-yl]uracil (18)
1
3
9
C NMR (DMSO-d ): d = 34.32 (C-5), 45.95 (C-3), 51.74 (C-6),
The title compound was synthesized from 17 (1.20 g, 10.42 mmol)
and 5-bromouracil (0.50 g, 2.62 mmol) in dry pyridine (10 mL) in
the same way as compound (±)-11a. Yield 359 mg (61%) as an off-
white powder; mp 278-280 ∞C.
6
5
1
5.03 (C-2), 61.35 (CH OH), 62.19 (CH Ph), 68.53 (C-4), 126.91,
2
2
28.23, 128.48, 138.76 (Carom).
EI-MS: m/z = 221 (M+).
1
H NMR (DMSO-d ): d = 1.20 (m, 2H, 3´-H , 5´-H ), 1.41 (m, 1H,
6
a
a
4
3
2
´-H), 1.66 (m, 2H, 3´-H , 5´-H ), 2.29 (m, 2H, 2´-H , 6´-H ), 3.16-
(
(
1
±) cis-, and (±) trans-3-(Hydroxymethyl)piperidin-4-ol ((±)-14a/
±)-14b)
e
e
a
a
.33 (m, 4H, 2´-H , 6´-H , CH OH), 6.71 (s, 1H, 6-H), 10.62 (br s,
e
e
2
H, 2 ¥ NH).
0% Pd-C (864 mg) was mixed with a solution of (±)-13a/(±)-13b
(
5.80 g, 26.2 mmol) in EtOH-H O 1:1 (110 mL). The mixture was
13C NMR (DMSO-d6): d = 28.56 (C-3´, C-5´), 38.01 (C-4´),
2
hydrogenated at r.t. under pressure (100 psi). After 35 h the mixture
was filtered through Celite and the solvent evaporated in vacuo. The
mixture of (±)-14a/(±)-14b was isolated as a very viscous oil; yield
5
1
0.00 (C-2´, C-6´), 65.89 (CH OH), 126.07, 127.19 (C-6, C-5),
50.44 (C-2), 161.75 (C-4).
2
C H N O ◊ 0.3 H O calc.
C
C
52.07
52.07
H
H
6.82
6.84
N
N
18.22
17.82
1
0
15
3
3
2
3
.23 g (94%). A small sample of the pure diastereomer (±)-13b was
debenzylated in a similar manner and used for spectral assignment.
(225.3)
found
EI-MS: m/z = 225 (M+).
Synthesis 1999, No. 11, 1937–1943 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Aza-C-nucleosides as a New Class of Nucleosides
1943
(
±) 3-(Hydroxymethyl)piperidine ((±)-20)
with toluene. The residue was recrystallized from MeOH to give
830 mg (61%) yield in a 4:1 cis/trans diastereomeric mixture of the
title compound 25 as a brownish powder; mp 273–275 °C.
1
A solution of 19 (10.0 mL, 10.12 g, 64.37 mmol) in anhyd THF
(
(
100 mL) was slowly added to a ice-cooled suspension of LiAlH4
3.40 g, 90 mmol) in anhyd THF (300 mL). After the visibel gas
H NMR (DMSO-d ): d = 2.0-2.3 (m, 1H, 4´-H), 2.75 (dd, 1H,
6
evolution ceased, the mixture was left standing at r.t. for 20 h. The
reaction was quenched with MgSO ◊7H O until all evolution of gas
ceased, and the slurry was filtered and washed with anhyd THF. The
THF fraction was evaporated in vacuo and the viscous product was
purified by vacuum destillation to give the title compound (±)-20 as
a viscous oil; yield 5.79 g (78%); bp 90 ∞C/0.03 mbar.
J = 9.8, 5.9 Hz, 5´-H), 2.85 (dd, 1H, J = 9.8, 4.1 Hz, 5´-H), 3.13.7
4
2
(
m, 4H, 2´-H, CH OH), 3.90 (q, 1H, J = 4.8 Hz, 3´-H), 4.7 (br s, 2H,
2
2
x OH), 6.35 (s, 1H, 6-H (trans isomer)), 6.41 (s, 1H, 6-H (cis iso-
mer)), 10.3 (br s, 1H, NH), 10.9 (br s, 1H, NH).
1
3
)
C NMR (DMSO-d ) cis isomer: d = 48.96 (C-4´), 51.65 (C-5´ ,
6
)
5
7.73 (C-2´), 61.80 (CH OH), 71.06 (C-3´ , 120.25 (C-5), 125.34
1
2
H NMR (DMSO-d ): d = 0.96 (qd, 1H, J = 11.7, 4.0 Hz, 4-H ),
6
a
(
C-6), 150.22 (C-2), 161.62 (C-4).
1
.30 (qt, 1H, J = 12.1, 3.8 Hz, 5-H ), 1.39-1.57 (m, 2H, 5-H , 3-
a e
C H N O ◊ 0.4 H O calc.
C
C
45.76
45.70
H
H
5.97
5.96
N
N
17.79
17.55
H ), 1.67 (m, 1H, 4-H ), 2.12 (t, 1H, J = 11.5 Hz, 2-H ), 2.36 (td,
1
2
9
13
3
4
2
a
e
a
H, J = 11.5, 2.7 Hz, 6-H ), 2.81 (dt, 1H, J = 11.7, 3.5 Hz, 6-H ),
a
e
(236.23)
found
.94 (dd, 1H, J = 11.7, 3.5 Hz, 2-H ), 3.19 (m, 2H, CH OH).
e
2
EI-MS: m/z = 227 (M+).
1
3
C NMR (DMSO-d ): d = 25.71 (C-5), 27.80 (C-4), 39.41 (C-3),
6
4
6.64 (C-6), 49.89 (C-2), 64.50 (CH OH).
2
EI-MS: m/z = 115 (M+).
References
(
1) Davis, F. F.; Allen, F. W. J. Biol. Chem. 1957, 227, 907.
(
±)-5-[3-(Hydroxymethyl)piperidin-1-yl]uracil ((±)-21)
The title compound was synthesized from (±)-20 (1.20 g,
0.42 mmol) and 5-bromouracil (0.50 g, 2.62 mmol) in dry pyri-
(2) Watanabe, K. A. The Chemistry of C-Nucleosides. In
Chemistry of Nucleosides and Nucleotides; Townsend, L. B.
Ed., Plenum Press: New York, Vol. 3. 1994; p. 421.
(3) Jespersen, T. M.; Dong, W.; Sierks, M. R.; Skrydstrup, T.;
Lundt, I.; Bols, M. Angew. Chem. Int. Ed. Engl. 1994, 33,
1778.
1
dine (10 mL) in the same way as compound (±)-11a. Yield 280 mg
(48%) as a white powder; mp 244-246 ∞C.
1
H NMR (DMSO-d ): d = 0.97 (m, 1H, 4´-H ), 1.50 (m, 1H, 5´-H ),
6
a
a
(
(
4) Ng; K. E.; Orgel, L. E. J. Med. Chem. 1989, 32, 1754.
5) Harnden, M. R.; Jarvest, R. L. Tetrahedron Lett. 1991, 32,
1
.59-1.73 (m, 3H, 5´-H , 4´-H , 3´-H ), 2.08 (t, 1H, J = 10.4 Hz, 2´-
e e a
H ), 2.29 (td, 1H, J = 11.0, 2.5 Hz, 6´-H ), 3.11-3.32 (m, 4H, 6´-H ,
2
1
a
a
e
3863.
´-H , CH OH), 4.44 (t, 1H, J = 5.1 Hz, CH OH), 6.68 (s, 1H, 6-H),
e
2
2
(
(
6) Phillips, A. P. J. Am. Chem. Soc. 1951, 73, 1061.
7) Lewis, N. J.; Barker, K. K.; Fox, R. M.; Mertes, M. P. J. Med.
Chem. 1973, 16, 156.
0.40 (br s, 1H, NH), 11.00 (br s, 1H, NH).
1
3
C NMR (DMSO-d ): d = 24.37 (C-5´), 26.64 (C-4´), 38.52 (C-3´),
6
5
1
0.76 (C-6´), 53.89 (C-2´), 64.08 (CH OH), 126.17 (C-6),
2
(8) Jaeger, E.; Biel, J. H. J. Org. Chem. 1965, 30, 740.
(
27.30 (C-5), 150.37 (C-2), 161.75 (C-4).
9) Bradbury, B. J.; Baumgold, J.; Paek, R.; Kammula, U.;
C H N O
3
calc.
C
C
53.32
52.93
H
H
6.71
6.68
N
N
18.65
18.35
Zimmet, J.; Jacobson, K. A. J. Med. Chem. 1991, 34, 1073.
10) Clemo, G. R.; Metcalfe, T. P. J. Chem. Soc. 1937, 1523.
11) Wawzonek, S.; Wilkinson, T. C. J. Org. Chem. 1966, 31,
1
0
15
3
(
(
(225.3)
found
EI-MS: m/z = 225 (M+).
1732.
(
12) King, J. A.; McMillan, F. H. J. Am. Chem. Soc. 1950, 72,
4
2
-(Hydroxymethyl)pyrrolidin-3-ol (24)
1236.
8
0% Pd(OH) /C (1.1 g) was mixed with a solution of 23 (5.0 g, 24
(13) Valckx, L.; Anteunis, M. J. O.; Van Bever, W. F. M.: Van
Nueten, J. M. Eur. J. Med. Chem. - Chimica Therapeutica
1975, 10, 364.
(14) Barrett, S. D.; Jaen, J. C.; Caprathe, A. J. T.; Tecle, H. Org.
Prep. Proc. Int. 1997, 29, 330.
2
mmol) in EtOH/H O 1:1 (100 mL). The mixture was hydrogenated
at r.t. under pressure (150 psi). After 48 h the mixture was filtered
through Celite and the solvent evaporated in vacuo to give 2.7 g
2
(96%) yield of the product as a colorless viscous oil which can be
used without further purification.
(15) Spry, D. O.; Aaron, H. S. J. Org. Chem. 1969, 34, 3674.
5
-[3-Hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl]uracil (25)
Article Identifier:
A mixture of 24 (2.1 g, 18 mmol) and 5-bromouracil (1.15 g, 6
mmol) in anhyd pyridine (20 mL) was refluxed for 24 h, cooled to
r.t. and evaporated in vacuo. Traces of pyridine were coevaporated
1
437-210X,E;1999,0,11,1937,1943,ftx,en;P02699SS.pdf
Synthesis 1999, No. 11, 1937–1943 ISSN 0039-7881 © Thieme Stuttgart · New York